XIIa factor inhibitor

Abstract

The compounds of the present invention are modulators of factor XII (e.g., factor XIIa). In particular, the compounds are inhibitors of factor XIIa and may be useful as anticoagulants.

Description

[Technical Field]

[0001] The present invention relates to a compound and a therapeutic (or preventive) method using the compound. The present invention also relates to a process and method for producing the compound of the present invention. The compound of the present invention is a modulator of factor XII (e.g., factor XIIa). In particular, the compound is a factor XIIa inhibitor and may be useful as an anticoagulant. [Background technology]

[0002] Cardiovascular disease is a leading cause of death in developed countries, affecting millions of people worldwide every year. This disease is generally caused by atherosclerosis of the arterial walls, which develops over many years and is characterized by endothelial inflammation, subendothelial lipid deposition, macrophage infiltration, and plaque formation. In the acute phase of the disease, atherosclerotic plaques become unstable and prone to rupture, inducing thrombosis. The formation of thrombi (blood clots) that block blood vessels and consequently deprive tissue of oxygen constitutes a major triggering event that leads to morbidity and mortality. Blood clot formation is caused by the activation and aggregation of platelets. Platelet thrombi solidify through the activation of coagulation and the formation of fibrin networks. Arterial occlusion by thrombosis leads to tissue death downstream, and depending on where this occurs, is associated with the development of myocardial infarction, stroke, or claudication.

[0003] Venous thrombosis is independent of atherosclerosis but has a different etiology, as it is induced by circulatory arrest due to fixation and is often associated with spontaneous anticoagulant deficiencies (e.g., antithrombin, protein C and S) and surgical procedures. Venous thrombosis usually occurs in the legs or arms (deep vein thrombosis, DVT) and can result in embolus (thrombus fragments) that block smaller downstream vessels, particularly in the lungs (pulmonary embolism, PE). Other triggers for DVT include cancer, nephrotic syndrome, antiphospholipid syndrome, and heart failure.

[0004] Thrombosis is a very serious condition, with up to 25,000 deaths annually from venous thrombosis and 200,000 deaths from arterial thrombosis in the UK alone. In January 2010, the UK National Institute for Health and Clinical Excellence (NICE) published new guidelines to increase screening for early signs of thrombosis in hospitalized patients.

[0005] Current medications for treating or preventing thrombosis target either platelets or coagulation. Generally, antiplatelet agents are used to prevent arterial disease, while anticoagulants are used to prevent stroke in patients with atrial fibrillation, deep vein thrombosis (DVT), and pulmonary embolism (PE). The greatest clinical problem associated with the use of current anticoagulants is the risk of bleeding. During anticoagulation therapy, depending on the patient group and the choice of anticoagulation therapy, 1–3% of patients experience major bleeding, and 15–18% experience minor bleeding.

[0006] Warfarin and heparin (including all its derivatives) are the most commonly used anticoagulants. Warfarin, the oldest approved long-term oral anticoagulant, requires regular monitoring via prothrombin time (PT) coagulation assays to determine the optimal dosage, which places a significant burden on healthcare systems and patients' quality of life. Warfarin is nonspecific and targets several coagulation enzymes, while heparin, administered subcutaneously or intravenously, targets activator X (FXa) and / or thrombin depending on its molecular weight. Furthermore, commercially available or developmental non-vitamin K oral anticoagulants (NOACs) targeting thrombin or FXa also carry a significant bleeding risk comparable to heparin and warfarin, except for intracranial hemorrhage, where NOACs yield better results than warfarin. However, NOACs have been associated with increased gastrointestinal bleeding compared to low molecular weight heparin and vitamin K antagonists, including warfarin (Non-Patent Literature 1).

[0007] Therefore, the clinical need for novel anticoagulants that do not cause bleeding remains unmet. This goal has been a desire in this field for over 60 years. However, because the mechanisms involved in thrombosis were thought to be the same as those involved in hemostasis, anticoagulant therapy has always been considered to carry an unavoidable risk of bleeding.

[0008] Because patients with FXII deficiency exhibited a significant prolongation of in vitro surface-activated clotting time, factor XII (FXII) was identified 50 years ago as a clotting protein in the endogenous pathway of blood coagulation. However, a series of studies have convincingly shown that FXII does not play a role in normal hemostasis. Evidence from within the last 10 years has confirmed that FXII is essential for thrombus formation in vivo (Non-Patent Literature 2-6). A unique characteristic of FXII is that, unlike deficiencies of all other clotting factors, FXII deficiency does not result in bleeding. Therefore, FXIIa is a very attractive target for the discovery of anticoagulants that could potentially have a significantly improved safety profile.

[0009] The research challenged dogma in the fields of hemostasis and thrombosis by demonstrating a novel mechanism in thrombosis involving FXII. These studies provide clear evidence that FXII is essential for thrombus formation but not for hemostasis. FXII-deficient mice were significantly protected against thrombosis when administered collagen and epinephrine infusions, but did not exhibit prolonged bleeding time during surgery or tail decapitation. Similar protection against thrombosis was observed in mesenteric arterioles exposed to FeCl3 and in the aorta after mechanical injury. Infusion of human FXII in these models restored thrombus formation. The groundbreaking nature of these findings is demonstrated by the discussion regarding the function of FXII and the role of the contact coagulation pathway activated by FXIIa, which had dominated the field for several years. The debate intensified because FXII deficiency does not cause bleeding, while deficiencies in all other coagulation proteases do. This debate led to the idea that FXII is not necessary for physiological coagulation and that FXII activation is an in vitro phenomenon.

[0010] However, studies have shown that FXII is activated by negatively charged surfaces and activated platelet surfaces (Non-Patent Literature 7). The aforementioned in vivo and in vitro studies demonstrate that FXII plays a previously unrecognized role in thrombosis. The production of FXIIa stabilizes thrombi through enhanced thrombinogenesis, fibrin deposition, and a direct pro-thrombus-forming effect on fibrin structure. Although this mechanism does not appear to play a role in normal hemostasis, FXII deficiency is phenotypically silent in humans and mice, making FXII an ideal target for the development of novel anticoagulants to treat thrombosis.

[0011] The efficacy of FXII deficiency in reducing thrombosis has been demonstrated in several different in vivo thrombosis models. In addition to the aforementioned models, the role of FXII in thrombosis has been demonstrated in a mouse model of carotid artery ligation-induced thrombosis and a mouse model of cerebral microvascular thrombosis secondary to transient occlusion of the middle cerebral artery. Infarct size in the brain was significantly reduced in FXII-deficient mice and recovered to large infarcts upon injection of human FXII. FXII inhibition has also been shown to reduce the risk of venous thrombosis. One study demonstrated that a contact-activated Kunitz inhibitor (Ir-CPI) isolated from tick salivary glands effectively reduced thrombosis in mouse and rat models of vascular ligation-induced venous thrombosis. This inhibitory protein was also effective in reducing PE in a mouse model induced by collagen and epinephrine injection and a mouse model of dorsal cutaneous arteriolar thrombosis. Again, there was no effect on bleeding time in animals treated with Ir-CPI. Inhibition of FXIIa with HD-Pro-Phe-Arg-chloromethyl ketone (PCK) has also been shown to prevent thrombosis. These studies provide preclinical evidence for the concept that FXIIa inhibition is effective in treating thrombosis.

[0012] Non-patent document 8 demonstrated that the recombinant full-human antibody 3F7 binds to the FXIIa enzyme pocket. In mice and rabbits, 3F7 interfered with FXIIa-mediated coagulation, eliminating thrombus formation in blood flow and blocking experimental thrombosis. In rabbits, 3F7 provided thromboprotection as efficiently as heparin, but unlike heparin, 3F7 treatment did not impair hemostatic ability or increase bleeding from wounds. Larsson et al. concluded that FXIIa targeting is a safe model of thromboprotection in bypass systems and provides a clinically relevant anticoagulation strategy that is not complicated by excessive bleeding.

[0013] Dabigatran, apixaban, rivaroxaban, edoxaban, and betrixaban are all approved for short-term use as oral FXa / thrombin inhibitors. Dabigatran is 3-({2-[(4-carbamimidyl-phenylamino)-methyl]-1-methyl-1H-benzimidazole-5-carbonyl}pyridine-2-yl-amino)-propionic acid.

[0014] [ka] Dabigatran is also approved for use in the long-term prevention of stroke in patients with atrial fibrillation (AF), as described in U.S. Patent No. 6,087,380 (Patent Document 1).

[0015] Rivaroxaban is (S)-5-chloro-N-{[2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]oxazolidine-5-yl]methyl}thiophene-2-carboxamide. [ka]

[0016] Rivaroxaban is also approved for use to reduce the risk of attacks in nonvalular atrial fibrillation (nonvalular AF). It has demonstrated superiority over warfarin in protecting atrial fibrillation from stroke and non-CNS systemic embolism when administered once daily. Rivaroxaban has also shown a significant reduction in clinically significant major and non-major bleeding rates, as well as intracranial hemorrhage rates, compared to warfarin. Rivaroxaban is described in U.S. Patent No. 7,157,456 (Patent Document 2).

[0017] Apixaban is also a factor Xa inhibitor approved for use in the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation.

[0018] Apixaban is 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidine-1-yl)phenyl]-4,5-dihydropyrazolo[5,4-c]pyridine-3-carboxamide. [ka]

[0019] Apixaban is described in U.S. Patent No. 6,413,980 (Patent Document 3).

[0020] Edoxaban is N'-(5-chloropyridine-2-yl)-N 2 It is -((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-yl)carbonyl]amino}cyclohexyl)ethanediamide. [ka]

[0021] Edoxaban is another factor Xa inhibitor approved for use in the prevention of stroke and systemic embolism, as well as in the treatment of deep vein thrombosis, in patients with non-valvular atrial fibrillation. Edoxaban is described in U.S. Patent No. 7,365,205 (Patent Document 4).

[0022] Betrixaban is N-(5-chloropyridine-2-yl)-2-[4-(N,N-dimethylcarbamidoyl)benzamide]-5-methoxybenzamide. [ka]

[0023] Betrixaban is a factor Xa inhibitor approved for use in the prevention of venous thromboembolism in patients with moderate to severe exercise limitations. Betrixaban is described in U.S. Patent No. 6,376,515 (Patent Document 5). [Prior art documents] [Patent Documents]

[0024] [Patent Document 1] U.S. Patent No. 6,087,380 [Patent Document 2] U.S. Patent No. 7,157,456 [Patent Document 3] U.S. Patent No. 6,413,980 [Patent Document 4] U.S. Patent No. 7,365,205 [Patent Document 5] U.S. Patent No. 6,376,515 [Patent Document 6] European Patent Application EP0672658 [Patent Document 7] International patent application WO2002 / 064559 [Patent Document 8] International patent application WO02 / 50056 [Patent Document 9] International patent application WO2019 / 186164 [Non-patent literature]

[0025] [Non-Patent Document 1] Valkhoff VE, Kuipers EJ, Tjwa ET, "New Oral Anticoagulants Increase Risk for Gastrointestinal Bleeding: A Systematic Review and Meta-analysis Holster IL," Gastroenterology, July 2013; 145(1):105-112. [Non-Patent Document 2] Renne T, Pozgajova M, Gruner S, Schuh K, Pauer HU, Burfeind P, Gailani D, Nieswandt B, "Defective thrombus formation in mice lacking coagulation factor XII," Journal of Experimental Medicine (J. Exp. Med.), 2005;202:271-281. [Non-Patent Document 3] Kleinschnitz C, Stoll G, Bendszus M, Schuch K, Pauer HU, Burfeind P, Renne C, Gailani D, Nieswandt B, Renne T, "Targeting coagulation factor XII provides protection from pathological thrombosis in cerebral ischemia without interfering with hemostasis," Journal of Experimental Medicine (J. Exp. Med.), 2006;203:513-518; [Non-Patent Document 4] Renne T, Nieswandt B, and Gailani D, "The intrinsic pathway of coagulation is essential for thrombus stability in mice," Blood Cells Mol. Dis., 2006; 36:148-151. [Non-Patent Document 5] Hagedorn I, Schmidbauer S, Pleines I, Kleinschnitz C, Kronthaler U, Stoll G, Dickneite G, Nieswandt B, "Factor XIIa inhibitor recombinant human albumin infestin-4 abolishes occlusive arterial thrombus formation without affecting bleeding," Circulation, 2010;121:1510-1517. [Non-Patent Document 6] Matafonov A, Leung PY, Gailani AE, Grach SL, Puy C, Cheng Q, Sun MF, McCarty OJ, Tucker EI, Kataoka H, ​​Renne T, Morrissey JH, Gruber A, Gailani D, Factor XII inhibition reduces thrombus formation in a primate thrombosis model. Blood, 2014;13;123(11):1739-46) [Non-Patent Document 7] Zakharova et al., PLoS One, February 17, 2015; 10(2):e0116665 [Non-Patent Document 8] Magnus Larsson et al., "A Factor XIIa Inhibitory Antibody Provides Thromboprotection in Extracorporeal Circulation Without Increasing Bleeding Risk," Science Translational Medicine (Sci. Transl. Med.) 6, 2014; 222ra17 [Overview of the project]

[0026] Recent investigations into major pharmaceutical companies' cardiovascular pipelines have not identified any oral inhibitors of FXIIa. Infestin-4 is a biologic produced by CSL Behring that targets FXIIa and has shown efficacy in FeCl3-inducible thrombosis models in mice and rabbits. Other antibody approaches targeting FXII(a) have also shown efficacy in vivo. However, if infestin-4 or the antibody approaches are successful, they require intravenous administration, which makes them less suitable for long-term anticoagulation.

[0027] FXII deficiency in humans is asymptomatic, and unlike other coagulation factor deficiencies that cause bleeding, deficiency or inhibition of FXII activity exhibits anticoagulant effects, meaning that selective FXII inhibitors may reduce the bleeding risk associated with currently available anticoagulant therapies.

[0028] Eli Lilly's European patent application EP0672658 (Patent Document 6) describes a phenylalanine proline derivative useful as a thrombin inhibitor.

[0029] Merck's international patent application WO2002 / 064559 (Patent Document 7) also describes a phenylalanine proline derivative useful as a thrombin inhibitor. The compound is an inhibitor that selectively inhibits cyclooxygenase-2 rather than selectively inhibits cyclooxygenase-1.

[0030] Merck's international patent application WO02 / 50056 (Patent Document 8) describes benzylamine and cyclohexylamine derivatives useful as thrombin inhibitors.

[0031] International patent application WO2019 / 186164 (Patent Document 9) from the University of Leeds describes a compound that is a modulator of factor XII.

[0032] Some aspects of the present invention are aimed at at least partially mitigating the problems associated with the prior art.

[0033] An object of one embodiment of the present invention is to provide a compound that inhibits FXII activity, particularly FXIIa activity, for example, a compound that inhibits the serine protease activity of FXIIa.

[0034] An object of one embodiment of the present invention is to provide a compound having physicochemical and pharmacokinetic properties consistent with the potential for oral bioavailability.

[0035] An object of one embodiment of the present invention is to provide a compound that exhibits reduced cytotoxicity or increased solubility compared to prior art compounds and existing treatments.

[0036] Another object of one embodiment of the present invention is to provide a compound having a simple pharmacokinetic profile and an appropriate duration of action after administration. A further object of a particular embodiment of the present invention is to provide a compound in which the metabolized fragments or fragments of the drug after absorption are generally considered safe (GRAS).

[0037] An object of certain embodiments of the present invention is to provide a target modulator, where this embodiment selectively modulates a target over other targets. An object of certain embodiments of the present invention is to provide a compound that is a selective FXIIa inhibitor. In particular, an object of certain embodiments of the present invention is to provide a compound that selectively inhibits FXIIa over thrombin and FXa.

[0038] Certain embodiments of the present invention satisfy some or all of the above objects.

[0039] According to the present invention, there are provided compounds of formula (I) and their pharmaceutically acceptable salts: Formula (I) TIFF0007888622000006.tif42170 wherein -X is selected from a bond, -C(O)-, C 1-3 alkylenyl, and C2 alkenylenyl; R 1 is selected from -NR <000​​​​​​​​​​​​​​​​Alkyl - Heterocyclic group having 1, 2, or 3 heteroatoms selected from 3- to 7-membered O, N, or S, and substituted or unsubstituted - C 1-6 Independently selected from heterocyclic aromatic compounds having 1, 2, or 3 heteroatoms selected from alkyl-5~6 memberned N or S; If substitution is performed here, R 1 The substituents are: halo, =O, -CN, -OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl,-OC 3-6 Cycloalkyl, -OC 1-6 Haloalkyl,-C 1-6 Alkyl-OC 1-6 Alkyl,-C 1-6 Alkyl-OC 3-6 Cycloalkyl,-C 1-6 Alkyl-OC 1-6 Haloalkyl, -NR 1c R 1d ,-NR 1c (SO2)R 1d ,-NR 1c (C(O))R 1d ,-C(O)NR 1c R 1d ,-SO2NR 1c R 1d A 5-10 member heteroaryl group having 1, 2, or 3 heteroatoms selected from O, N, or S, and a 6-10 member alkyl group; where R 1c and R 1d Each time, independently, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 A cyclohaloalkyl group, a 5-10 membered heteroaryl group having 1, 2, or 3 heteroatoms selected from O, N, or S, and a 6-10 membered aryl group are selected; If substitution is performed here, R 1a and R 1b The substituents are halo,-CN,-OH,C 1-6 Alkyl, C 3-7Cycloalkyl, C 1-6 Haloalkyl, C 3-7 Cyclohaloalkyl,-OC 1-6 Alkyl,-OC 3-7 Cycloalkyl,-C 1-6 Alkyl-OC 1-6 Alkyl,-C 1-6 Alkyl-OC 3-7 Cycloalkyl, -C 1-6 Alkyl-OC 1-6 Haloalkyl,-C 1-6 Alkyl-OC 3-7 Cyclohaloalkyl,-C 1-6 Haloalkyl-OC 1-6 Alkyl,-C 1-6 Haloalkyl-OC 3-7 Cycloalkyl,-C 1-6 Haloalkyl-OC 1-6 Haloalkyl,-C 1-6 Haloalkyl-OC 3-7 Cyclohaloalkyl, -NR 1e R 1f ,NH(=NH)NR 1e R 1f ,-NR 1e (SO2)R 1f ,-NR 1e (C(O))R 1f ,-C(O)NR 1e R 1f , and -SO2NR 1e R 1f ;R 1e and R 1f Each time, independently, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 A cyclohaloalkyl group, a heteroaryl group having 1, 2, or 3 heteroatoms selected from 5-10 membered O, N, or S, and a 6-10 membered aryl group are selected; R 2 H,C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Selected from cycloalkyl and 3- to 6-membered heterocycloalkyl groups; R3 is halo, -CN, -OH, C 1-6 alkyl, C 1-6 haloalkyl, -O-C 1-6 alkyl, -O-C 1-6 haloalkyl, -NR 3a R 3b , -NR 3a (C(O))R 3b , and -C(O)NR 3a R 3b is selected from; where R 3a and R 3b each time are each independently H, C 1-6 alkyl, C 3-6 [[ID=二十九]]cycloalkyl, a heteroaryl group having 1, 2 or 3 heteroatoms selected from O, N or S in a 5- to 10-membered ring, and a 6- to 10-membered aryl group are selected; m is selected from 0, 1, 2, 3, or 4; In the formula, the residue TIFF ‌000788862200000‌7.tif18170 is TIFF ‌000788862200000‌8.tif18170 (where L is a bond, -O-, -NR 4b -, and -NR 4c C(O)-) and TIFF ‌000788862200000‌9.tif20170 is selected from; [[ID=四十七]]H, -OH, halo, C 1-4 alkyl, or C[[ID=五十]] 1-4 is selected from haloalkyl; [[ID=五十三]]R 4b [[ID=五十五]]is H, C 1-6 alkyl, or -C(O)C 1-6 is alkyl; [[ID=六十一]]R 4c is H or C 1-6 is alkyl; [[ID=六十七]]R 4d [[ID=六十九]]is H or C 1-6 is alkyl; R 4e and R 4f each time are each independently H, -CN, halo, C 1-4 alkyl, C 1-4 It should be noted that there may be some inaccuracies in the translation due to the complexity and possible ambiguity of the original text, especially in the chemical formula and technical term parts. It is recommended to check with relevant chemical experts for more accurate understanding.​Haloalkyl, -OR 4g , -NR 4g R 4h ,C 3-8 Selected from cycloalkyl, 3-6 membered heterocyclic, 6-10 membered aryl, and 5-10 membered heteroaryl, where C 3-8 Cycloalkyl, 3-6 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl groups are classified as 1, 2, or 3R. 4i Independently selected to be substituted or not substituted by; where R 4g and R 4h Each of these will be called Haro and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 Cyclohaloalkyl, -OR 4j ,-NR 4k R 4l ,-NR 4k (C(O))R 4l ,-C(O)NR 4k R 4l ,-CN,-C(O)R 4g ,=O,-SO2R 4g Selected from benzyl, phenyl, unsubstituted 5 or 6-membered heteroaryl, or methyl-substituted 5 or 6-membered heteroaryl; R 4j H,C 1-4 Alkyl, C 1-4 Haloalkyl, phenyl, or benzyl is selected; R 4k and R 4l Each of these will be H, C 1-6 Alkyl, C 3-6 A cycloalkyl group, a heteroaryl group having 1, 2, or 3 heteroatoms selected from 5-10 membered O, N, or S, and a 6-10 membered heteroaryl group are independently selected; n is selected from 0, 1, 2, 3, or 4; R 4 H, Halo, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 4g ,-NR 4g R 4h , single-ring or double-ring 6-10 member aryl, C 3-8Selected from cycloalkyl, heterocyclic rings containing 1, 2, or 3 heteroatoms selected from 3-6 member O, N, or S, bicyclic (condensed, bridged, or spiro) 6-10 member cycloalkyl ring systems, bicyclic (condensed, bridged, or spiro) 6-10 member cycloalkenyl ring systems, and bicyclic (condensed, bridged, or spiro) heterocyclic systems containing 1, 2, or 3 heteroatoms selected from 6-10 member O, N, or S, where C 3-8 Cycloalkyl, C 4-8 Cycloalkenyls, 3-6 membered heterocycles, 6-10 membered aryl groups, 5-10 membered heteroaryl groups, bicyclic (condensed, bridged, or spiro) 6-10 membered cycloalkyl ring systems, bicyclic (condensed, bridged, or spiro) 6-10 membered cycloalkenyl ring systems, or bicyclic (condensed, bridged, or spiro) 6-10 membered heterocycle systems are unsubstituted or have 1, 2, or 3 R groups. 4i It is replaced by; R 5 is H or C1-6 alkyl; o is selected from 1, 2, or 3; R 5a and R 5b These are H, substituted or unsubstituted C, respectively. 1-6 Alkyl, substituted, or unsubstituted C 3-6 Cycloalkyl and substituted or unsubstituted C 1-6 A substituent is independently selected from haloalkyl groups, where each substituent is independently selected from halo, -OH, and -CN groups; Ring A is a 6-10 member heterocyclic ring system containing a heteroaryl group having 1, 2, or 3 heteroatoms selected from substituted or unsubstituted 5-10 member monocyclic or bicyclic O, N, or S; a substituted or unsubstituted 6-10 member monocyclic or bicyclic aryl group; and a substituted or unsubstituted monocyclic or bicyclic (condensed, bridging, or spiro) O, N, or S, wherein if substituted, the heteroaryl group, aryl group, or heterocyclic ring system is halo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, deuterated C 1-6Alkyl, -OR 5c , -NR 5c R 5d or -NR 5c R 5d Selected from C1-4 alkyl groups substituted with one, two, or three substituents; R 5c and R 5d These are H, substituted or unsubstituted C, respectively. 1-6 Alkyl, substituted, or unsubstituted C 3-6 Cycloalkyl and substituted or unsubstituted C 1-6 The substituents are independently selected from haloalkyl groups, where each substituent is independently selected from halo, -OH, and -CN groups.

[0040] In some embodiments, -X is selected from bond and -C(O)-.

[0041] In some embodiments, -X is -C(O)-.

[0042] In some embodiments, R 1 -NR 1a R 1b , selected from heteroaryl groups having 1, 2, or 3 heteroatoms selected from substituted or unsubstituted 5 or 6-membered monocyclic O, N, or S; substituted or unsubstituted 6-membered monocyclic aryl groups; substituted or unsubstituted 3- to 8-membered monocyclic or bicyclic (condensed, bridged, or spiro) cycloalkyl groups; and heterocyclic groups having 1, 2, or 3 heteroatoms selected from substituted or unsubstituted 3- to 8-membered monocyclic or bicyclic (condensed, bridged, or spiro) O, N, or S.

[0043] In some embodiments, R 1 -NR 1a R 1b, selected from heteroaryl groups having 1, 2, or 3 heteroatoms selected from substituted or unsubstituted 5 or 6-membered monocyclic O, N, or S, and heterocyclic groups having 1, 2, or 3 heteroatoms selected from substituted or unsubstituted 3 to 8-membered monocyclic or bicyclic (condensed, bridging, or spiro) O, N, or S.

[0044] In some embodiments, R 1 -NR 1a R 1b , and selected from substituted or unsubstituted 3- to 8-membered monocyclic or bicyclic (condensed, bridged, or spiro) heterocyclic groups.

[0045] In some embodiments, R 1 is a substituted or unsubstituted 3- to 8-membered monocyclic or bicyclic (condensed, bridging, or spiro) heterocyclic group having 1, 2, or 3 heteroatoms selected from O, N, or S. In some cases, R 1 This is a heterocyclic ring system containing a substituted or unsubstituted 3- to 8-membered monocyclic or bicyclic (condensed, bridging, or spiro) nitrogen atom and 0, 1, or 2 additional heteroatoms selected from O, N, or S, and further optionally R 1 A heterocyclic ring system is a substituted or unsubstituted 3- to 8-membered monocyclic or bicyclic (condensed, bridging, or spiro) nitrogen atom and 0, 1, or 2 additional heteroatoms selected from O, N, or S, where the heterocyclic ring system is bonded to the nitrogen atom via -X-. The additional heteroatoms are sometimes selected from O and N.

[0046] In some embodiments, -XR 1 The structure is The filename is TIFF0007888622000010.tif28170. In the formula, Ring B is a 3- to 8-membered heterocyclic system containing 0, 1, or 2 additional heteroatoms selected from substituted or unsubstituted monocyclic or bicyclic (condensed, bridging, or spiro) O, N, or S. The additional heteroatoms may be selected from O and N.

[0047] In some embodiments, R 1 A heterocyclic ring system is a substituted or unsubstituted 3- to 8-membered monocyclic or bicyclic (condensed, bridging, or spiro) nitrogen atom and zero or one additional heteroatom selected from O, N, or S, wherein the heterocyclic ring system is bonded to the nitrogen atom via -X-. The additional heteroatom may be selected from O and N.

[0048] In some embodiments, R 1 It is a substituted or unsubstituted 4- to 7-membered monocyclic group, or a heterocyclic group having 1, 2, or 3 heteroatoms selected from O, N, or S. In some cases, R 1 This is a heterocyclic ring system consisting of a substituted or unsubstituted 4- to 7-membered monocyclic ring, a nitrogen atom, and 0, 1, or 2 additional heteroatoms selected from O, N, or S. Furthermore, it is a heterocyclic ring system consisting of a substituted or unsubstituted 4- to 7-membered monocyclic ring, 0, 1, or 2 additional heteroatoms selected from O, N, or S, where the heterocyclic ring system is bonded to the nitrogen atom via -X-. The additional heteroatoms are optionally selected from O and N.

[0049] In some embodiments, -XR 1 The structure is TIFF0007888622000011.tif28170 That is the case. In the formula, Ring B is a substituted or unsubstituted monocyclic or bicyclic (condensed, bridging, or spiro) 4- to 7-membered heterocyclic system containing 0, 1, or 2 additional heteroatoms selected from O, N, or S. The additional heteroatoms are selected from O and N as needed.

[0050] In some embodiments, R 1A is a substituted or unsubstituted 4- to 7-membered monocyclic or bicyclic (condensed, bridging, or spiro) heterocyclic ring system containing a nitrogen atom and zero or one additional heteroatoms selected from O, N, or S, where the heterocyclic ring system is bonded to the nitrogen atom via -X-. The additional heteroatoms are sometimes selected from O and N.

[0051] In some embodiments, R 1 It is a substituted or unsubstituted 5 or 6-membered monocyclic group, or a heterocyclic group having 1, 2 or 3 heteroatoms selected from O, N, or S. In some cases, R 1 It is a substituted or unsubstituted 5 or 6-membered monocyclic ring, a heterocyclic ring system containing a nitrogen atom and 0, 1, or 2 additional heteroatoms selected from O, N, or S. Furthermore, R may be included. 1 A is a substituted or unsubstituted 5 or 6-membered monocyclic ring system, a heterocyclic ring system containing a nitrogen atom and 0, 1, or 2 additional heteroatoms selected from O, N, or S, where the heterocyclic system is bonded to the nitrogen atom via -X-. The additional heteroatoms are sometimes selected from O and N.

[0052] In some embodiments, -XR 1 The structure is The filename is TIFF0007888622000012.tif28170. In the formula, Ring B is a substituted or unsubstituted monocyclic heterocyclic system containing zero, one, or two additional heteroatoms selected from five-membered or six-membered oxygen, nitrogen, or sulfur. The additional heteroatoms are selected from oxygen and nitrogen as needed.

[0053] In some embodiments, R 1 A is a substituted or unsubstituted five- or six-membered monocyclic, heterocyclic ring system containing a nitrogen atom and zero or one additional heteroatoms selected from O, N, or S, where the heterocyclic system is bonded to the nitrogen atom via -X-. The additional heteroatoms are sometimes selected from O and N.

[0054] The embodiment includes R 1 The substitutions or non-substituents listed below can be selected: TIFF0007888622000013.tif172170

[0055] In some embodiments, when R is substituted, 1 The substituents are halo,C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl,-OC 1-6 Haloalkyl,-C 1-6 Alkyl-OC 1-6 Alkyl,-C 1-6 -OC 1-6 Haloalkyl and -NR 1c R 1d Selected from.

[0056] In some embodiments, when R is substituted, 1 The substituents are halo,C 1-3 Alkyl, C 1-3 Haloalkyl, -OC 1-3 Alkyl,-OC 1-3 Haloalkyl,-C 1-3 Alkyl-OC 1-3 Alkyl,-C 1-3 -OC 1-3 Haloalkyl and -NR 1c R 1d Selected from.

[0057] In some embodiments, when R is substituted, 1 The substituents are halo,C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, and -OC 1-6 Selected from haloalkyl groups.

[0058] In some embodiments, when R is substituted, 1 The substituents are halo,C 1-3 Alkyl, C 1-3 Haloalkyl, -OC 1-3Alkyl, and -OC 1-3 Selected from haloalkyl groups.

[0059] In some embodiments, when R is substituted, 1 The substituents are halo,C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl,-OC 1-6 Haloalkyl and -NR 1c R 1d Selected from.

[0060] In some embodiments, when R is substituted, 1 The substituents are halo,C 1-3 Alkyl, C 1-3 Haloalkyl, -OC 1-3 Alkyl,-OC 1-3 Haloalkyl and -NR 1c R 1d Selected from.

[0061] In some embodiments, when R is substituted, 1 The substituents are halo,C 1-6 Alkyl, C 1-6 Haloalkyl and -OC 1-6 Selected from alkyl groups.

[0062] In some embodiments, when R is substituted, 1 The substituents are halo,C 1-3 Alkyl, C 1-3 Haloalkyl and -OC 1-3 Selected from alkyl groups.

[0063] In some embodiments, when R is substituted, 1 The substituents are selected from F, Me, Et, CF3, -OMe, -OEt, and -NMe2.

[0064] In some embodiments, if R is substituted, 1The substituents are selected from F, Me, Et, CF3, -OMe, and -OEt.

[0065] In some embodiments, R 1 Each of these may independently have one or two substituents as defined above.

[0066] In some embodiments, R 1c and R 1d These are H and C, which are independent of each other. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and C 3-6 Selected from cyclohaloalkyl groups.

[0067] In some embodiments, R 1c and R 1d These are H and C, which are independent of each other. 1-3 Alkyl, C 1-3 Selected from haloalkyl, C3 cycloalkyl, and C3 cyclohalalkyl.

[0068] In some embodiments, R 1c and R 1d These are H and C, which are independent of each other. 1-6 Alkyl, and C 3-6 Selected from cycloalkyl groups.

[0069] In some embodiments, R 1c and R 1d These are H and C, which are independent of each other. 1-3 Selected from alkyl and C3 cycloalkyl groups.

[0070] In some embodiments, R 1c and R 1d Each of these is independently selected from H, Me, and C3 cycloalkyl groups.

[0071] In some embodiments, R 1 -NR 1a R 1bThat is the case.

[0072] In some embodiments, -XR 1 The structure is The filename is TIFF0007888622000014.tif20170.

[0073] In some embodiments, R 1a and R 1b These are, independently, substitutional or non-substitutional C. 1-6 Alkyl, substituted, or unsubstituted C 3-7 Cycloalkyl, substituted or unsubstituted 3-7 member, heterocyclic group having 1, 2 or 3 heteroatoms selected from O, N or S, substituted or unsubstituted -C 1-6 Alkyl-C 3-7 Cycloalkyl, substituted or unsubstituted - C 1-6 The alkyl group is selected from a 3- to 7-membered heterocyclic group (the 3- to 7-membered heterocyclic group has 1, 2, or 3 heteroatoms selected from O, N, or S).

[0074] In some embodiments, R 1a and R 1b These are, independently, substitutional or non-substitutional C. 1-3 Alkyl, substituted, or unsubstituted C 3-7 Cycloalkyl, 3- to 7-membered heterocyclic group having 1, 2, or 3 heteroatoms selected from substituted or unsubstituted O, N, or S, substituted or unsubstituted -C 1-3 Alkyl-C 3-7 Cycloalkyl, substituted or unsubstituted - C 1-3 The alkyl-3- to 7-membered heterocyclic group is selected (the 3- to 7-membered heterocyclic group has 1, 2, or 3 heteroatoms selected from O, N, or S).

[0075] In some embodiments, R 1a and R 1b These are, independently, substitutional or non-substitutional C. 1-3 Alkyl, substituted, or unsubstituted C 3-6Cycloalkyl, heterocyclic group having 1, 2, or 3 heteroatoms selected from 3-6 member O, N, or S, substituted or unsubstituted -C 1-3 Alkyl-C 3-6 Cycloalkyl, substituted or unsubstituted - C 1-3 The alkyl group is selected from an alkyl-3-6 membered heterocyclic group (the 3-6 membered heterocyclic group has 1, 2, or 3 heteroatoms selected from O, N, or S).

[0076] In some embodiments, R 1a and R 1b These are, independently, substitutional or non-substitutional C. 1-3 Alkyl, substituted or unsubstituted C3 cycloalkyl, 3- to 6-membered heterocyclic group having 1, 2 or 3 heteroatoms selected from substituted or unsubstituted O, N or S, substituted or unsubstituted -C 1-3 The alkyl group is selected from an alkyl-3-6 membered heterocyclic group (the 3-6 membered heterocyclic group has 1, 2, or 3 heteroatoms selected from O, N, or S).

[0077] In some embodiments, R 1a and R 1b These are, independently, substitutional or non-substitutional C. 1-3 Alkyl, substituted or unsubstituted C3 cycloalkyl, heterocyclic group having 1, 2 or 3 heteroatoms selected from substituted or unsubstituted 4, 5 or 6-membered O, N or S, substituted or unsubstituted -C 1-3 The alkyl group is selected from an alkyl-4, 5, or 6-membered heterocyclic group (the 4, 5, or 6-membered heterocyclic group has 1, 2, or 3 heteroatoms selected from O, N, or S).

[0078] In some embodiments, R 1a and R 1b Each of these can be substituted or not substituted on a case-by-case basis. 1-3 Alkyl, and substituted or unsubstituted C 3-6 Selected from cycloalkyl groups.

[0079] In some embodiments, R1a and R 1b Each of these can be substituted or not substituted on a case-by-case basis. 1-3 Selected from alkyl and substituted or unsubstituted C3 cycloalkyl groups.

[0080] In some embodiments, R 1a and R 1b Each of these can be substituted or not substituted on a case-by-case basis. 1-3 Selected from alkyl groups.

[0081] In some embodiments, R 1a and R 1b Each of these is independently selected from substituted or unsubstituted Me and substituted or unsubstituted C3 cycloalkyl groups on a case-by-case basis.

[0082] In some embodiments, R 1a and R 1b In all of these, it is Me. In some embodiments, R 1a is Me, and R 1b It is a C3 cycloalkyl group.

[0083] In some embodiments, R 1a and R 1b These are each independent and may be changed to -NR depending on the circumstances. 1e R 1f C replaced by 1-3 Selected from alkyl and substituted or unsubstituted C3 cycloalkyl groups.

[0084] In some embodiments, R 1a and R 1b This involves substitution or non-substitution of C each time. 1-3 Alkyl, and substituted or unsubstituted-C 1-3 The alkyl group is selected from an alkyl-3-6 membered heterocyclic group (the 3-6 membered heterocyclic group has 1, 2, or 3 heteroatoms selected from O, N, or S).

[0085] In some embodiments, R 1a and R 1bThis involves substitution or non-substitution of C each time. 1-3 Alkyl, and substituted or unsubstituted-C 1-3 The alkyl group is selected from an alkyl-4, 5, or 6-membered heterocyclic group (the 4, 5, or 6-membered heterocyclic group has 1, 2, or 3 heteroatoms selected from O, N, or S).

[0086] In some embodiments, R 1a and R 1b This involves substitution or non-substitution of C each time. 1-3 The group is selected from alkyl groups and substituted or unsubstituted C2 alkyl-4, 5, or 6-membered heterocyclic groups (the 4, 5, or 6-membered heterocyclic groups having 1, 2, or 3 heteroatoms selected from O, N, or S).

[0087] In some embodiments, R 1a and R 1b This includes substitution or non-substitution Me, and substitution or non-substitution C. 1-3 The alkyl group is selected from an alkyl-4, 5, or 6-membered heterocyclic group (the 4, 5, or 6-membered heterocyclic group has 1, 2, or 3 heteroatoms selected from O, N, or S).

[0088] In some embodiments, R 1a and R 1b Each time, the following are selected from substituted or unsubstituted Me and substituted or unsubstituted C2 alkyl-4, 5, or 6-membered heterocyclic groups (the 4, 5, or 6-membered heterocyclic groups having 1, 2, or 3 heteroatoms selected from O, N, or S).

[0089] In some embodiments, R 1a and R 1b Each of these can be substituted or not substituted on a case-by-case basis. 1-3 Alkyl and Selected from TIFF0007888622000015.tif26170, the formula Ring C is a heterocyclic system containing 0, 1, or 2 additional heteroatoms selected from substituted or unsubstituted monocyclic 3-6 member O, N, or S atoms.

[0090] In some embodiments, R 1a and R 1b Each of these can be substituted or not substituted on a case-by-case basis. 1-3 Alkyl and Selected from TIFF0007888622000016.tif26170, where Ring C is a substituted or unsubstituted monocyclic, 4, 5, or 6-membered heterocyclic system containing 0, 1, or 2 additional heteroatoms selected from O, N, or S.

[0091] In some embodiments, R 1a and R 1b Each of these independently substitutes or does not substitute Me and Selected from TIFF0007888622000017.tif26170, the formula Ring C is a heterocyclic system containing 0, 1, or 2 additional heteroatoms selected from substituted or unsubstituted monocyclic 3-6 member O, N, or S atoms.

[0092] In some embodiments, R 1a and R 1b Each of these independently substitutes or does not substitute Me and Selected from TIFF0007888622000018.tif26170, the formula Ring C is a heterocyclic system containing 0, 1, or 2 additional heteroatoms selected from substituted or unsubstituted monocyclic 4, 5, or 6-membered O, N, or S.

[0093] In some embodiments, R 1a and R 1b Each of these can be substituted or not substituted on a case-by-case basis. 1-3 Alkyl and Selected from TIFF0007888622000019.tif21170, the rings in the formula are either substituted or non-substituted.

[0094] In some embodiments, R 1a and R 1bEach of these independently substitutes or does not substitute Me and Selected from TIFF0007888622000020.tif21170, the rings in the formula are either substituted or non-substituted.

[0095] In some embodiments, R 1a and R 1b Each of these can be substituted or not substituted on a case-by-case basis. 1-3 Alkyl and Selected from TIFF0007888622000021.tif23170, the rings in the formula are either substituted or non-substituted.

[0096] In some embodiments, R 1a and R 1b Each of these independently substitutes or does not substitute Me and Selected from TIFF0007888622000022.tif23170, the rings in the formula are either substituted or non-substituted.

[0097] In some embodiments, R 1a and R 1b One of them is selected from the following group: TIFF0007888622000023.tif123170

[0098] In some embodiments, R 1a and R 1b Each of these can be substituted or not substituted on a case-by-case basis. 1-3 The group is selected from alkyl and heterocyclic groups having 1, 2, or 3 heteroatoms selected from substituted or unsubstituted 3-6 member O, N, or S atoms.

[0099] In some embodiments, R 1a and R 1b Each of these can be substituted or not substituted on a case-by-case basis. 1-3 The group is selected from alkyl and heterocyclic groups having 1, 2, or 3 heteroatoms selected from substituted or unsubstituted 4, 5, or 6-membered O, N, or S atoms.

[0100] In some embodiments, R 1a and R 1b Each of these can be substituted or not substituted on a case-by-case basis. 1-3 The group is selected from alkyl groups and heterocyclic groups having 1, 2, or 3 heteroatoms selected from substituted or unsubstituted 5 or 6-membered O, N, or S atoms.

[0101] In some embodiments, R 1a and R 1b Each is independently selected from a heterocyclic group having substituted or unsubstituted Me and 1, 2, or 3 heteroatoms selected from substituted or unsubstituted 3-6 member O, N, or S atoms.

[0102] In some embodiments, R 1a and R 1b Each is independently selected from a heterocyclic group having substituted or unsubstituted Me and 1, 2, or 3 heteroatoms selected from substituted or unsubstituted 4, 5, or 6-membered O, N, or S atoms.

[0103] In some embodiments, R 1a and R 1b Each is independently selected from a heterocyclic group having substituted or unsubstituted Me and 1, 2, or 3 heteroatoms selected from substituted or unsubstituted 5 or 6-membered O, N, or S.

[0104] In some embodiments, R 1a and R 1b Each of these can be substituted or not substituted on a case-by-case basis. 1-3 Alkyl and The ring in formula TIFF0007888622000024.tif23170 is non-substitutable, or As shown in TIFF0007888622000025.tif34170, it can be replaced at any position within the ring.

[0105] In some embodiments, R1a and R 1b Each of these independently substitutes or does not substitute Me and The ring in formula TIFF0007888622000026.tif22170 is non-substitutable, or As shown in TIFF0007888622000027.tif33170, it can be replaced at any position within the ring.

[0106] In some embodiments, R 1a and R 1b Each of these can be substituted or not substituted on a case-by-case basis. 1-3 Alkyl and The ring in formula TIFF0007888622000028.tif25170 is non-substitutable, or As shown in TIFF0007888622000029.tif26170, it can be replaced at any position within the ring.

[0107] In some embodiments, R 1a and R 1b Each of these independently substitutes or does not substitute Me and The ring in formula TIFF0007888622000030.tif26170 is non-substitutable, or As shown in TIFF0007888622000031.tif26170, it can be replaced at any position within the ring.

[0108] In some embodiments, R 1a and R 1b One of them is selected from the following group: TIFF0007888622000032.tif88170

[0109] In some embodiments, when R is substituted, 1a and R 1b The substituents are halo,-CN,-OH,C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Haloalkyl, -OC1-6 Alkyl,-OC 3-7 Cycloalkyl, -OC 1-6 Haloalkyl,-C 1-6 Alkyl-OC 1-6 Alkyl,-C 1-6 Alkyl-OC 3-7 Cycloalkyl,-C 1-6 Alkyl-OC 1-6 Haloalkyl, -NR 1e R 1f , -NR 1e (SO2)R 1f , -NR 1e (C(O))R 1f -C(O)NR 1e R 1f , and -SO2NR 1e R 1f Selected from.

[0110] In some embodiments, when R is substituted, 1a and R 1b The substituents are halo,-CN,-OH,C 1-3 Alkyl, C 3-7 Cycloalkyl, C 1-3 Haloalkyl,-O-C3alkyl,-OC 3-7 Cycloalkyl, -OC 1-3 Haloalkyl,-C 1-3 Alkyl-OC 1-3 Alkyl,-C 1-3 Alkyl-OC 3-7 Cycloalkyl,-C 1-3 Alkyl-OC 1-3 Haloalkyl, -NR 1e R 1f , -NR 1e (SO2)R 1f , -NR 1e (C(O))R 1f -C(O)NR 1e R 1f , and -SO2NR 1e R 1f Selected from.

[0111] In some embodiments, R 1a and R 1bIf substitution occurs, each substituent independently becomes a halo,C 1-3 Alkyl, C 1-3 Haloalkyl,-O-C3alkyl,-OC 1-3 Haloalkyl,-C 1-3 Alkyl-OC 1-3 Alkyl,-C 1-3 Alkyl-C 1-3 Haloalkyl, C 3-6 Cycloalkyl and -NR 1e R 1f Selected from.

[0112] In some embodiments, R 1a and R 1b If substitution occurs, each substituent independently becomes a halo,C 1-3 Alkyl, C 1-3 Haloalkyl,-O-C3alkyl,-C 1-3 Alkyl-OC 1-3 Alkyl, C3 cycloalkyl, and -NR 1e R 1f Selected from.

[0113] In some embodiments, R 1a and R 1b If substitution occurs, each substituent independently becomes a halo,C 1-3 Alkyl, C 1-3 Haloalkyl,-O-C3alkyl,-OC 1-3 Haloalkyl, C 3-6 Cycloalkyl and -NR 1e R 1f Selected from.

[0114] In some embodiments, R 1a and R 1b If substitution occurs, each substituent independently becomes a halo,C 1-3 Alkyl, C 1-3 Selected from haloalkyl, -O-C3alkyl, and C3 cycloalkyl.

[0115] In some embodiments, R 1a and R 1bIf substitution occurs, each substituent is independently selected from F, Me, Et, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3, -OMe, -OEt, CH2OMe, CH2CH2OMe, and cyclopropyl.

[0116] In some embodiments, R 1a and R 1b If substitution occurs, each substituent is independently selected from F, Me, Et, CF3, -OMe, and -OEt.

[0117] In some embodiments, R 1a and R 1b If substituted, each substituent is -NR 1e R 1f That's fine.

[0118] In some embodiments, R 1e and R 1f These are H, C, and C, respectively, and each is independent. 1-6 Alkyl, and C 3-6 Selected from cycloalkyl groups.

[0119] In some embodiments, R 1e and R 1f These are H, C, and C, respectively, and each is independent. 1-3 Selected from alkyl and C3 cycloalkyl groups.

[0120] In some embodiments, R 1e and R 1f Each of these is independently selected from H, Me, and C3 cycloalkyl groups each time.

[0121] In some embodiments, R 1e and R 1f Each of these is independently selected from Me, Et, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, and CH2CF3 each time.

[0122] In some embodiments, R1 This is a monocyclic heteroaryl group having one, two, or three heteroatoms selected from substituted or unsubstituted 5 or 6-membered O, N, or S atoms.

[0123] In some embodiments, R 1 X is a monocyclic heteroaryl group having 1, 2, or 3 heteroatoms selected from substituted or unsubstituted 5 or 6-membered O, N, or S, where X is a bond.

[0124] In some embodiments, R 1 is either a substitution or a non-substitution. Selected from TIFF0007888622000033.tif74170.

[0125] In some embodiments, R 2 H,C 1-6 Alkyl, and C 1-6 Selected from haloalkyl groups.

[0126] In some embodiments, R 2 H,C 1-3 Alkyl, and C 1-3 Selected from haloalkyl groups.

[0127] In some embodiments, R 2 H and C 1-6 Selected from alkyl groups.

[0128] In some embodiments, R 2 H and C 1-3 Selected from alkyl groups.

[0129] In some embodiments, R 2 It is selected from H, Me, and Et.

[0130] In some embodiments, R 2 H is H.

[0131] In some embodiments, R 3 Ha, Halo, -CN, -OH, C 1-3 Alkyl, C 1-3 Haloalkyl, -OC 1-3 Alkyl,-OC 1-3 Haloalkyl, -NR 3a R 3b ,-NR 3a (C(O))R 3b , and -C(O)NR 3a R 3b Selected from.

[0132] In some embodiments, R 3 Ha, Halo, -CN, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl,-OC 1-6 Haloalkyl and -NR 3a R 3b Selected from.

[0133] In some embodiments, R 3 Ha, Halo, -CN, -OH, C 1-3 Alkyl, C 1-3 Haloalkyl, -OC 1-3 Alkyl,-OC 1-3 Haloalkyl and -NR 3a R 3b Selected from.

[0134] In some embodiments, R 3 Ha, Haro, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, and -OC 1-6 Selected from haloalkyl groups.

[0135] In some embodiments, R 3 Ha, Haro, C 1-3 Alkyl, C 1-3 Haloalkyl, -OC 1-3 Alkyl, and -OC 1-3 Selected from haloalkyl groups.

[0136] In some embodiments, R 3 The following are selected from Halo, Me, CF3, -O-Me, and -O-CF3.

[0137] In some embodiments, R 3a and R 3b These are H, C, and C, respectively, and each is independent. 1-6 Alkyl and C 3-6 Selected from cycloalkyl groups.

[0138] In some embodiments, R 3a and R 3b These are H, C, and C, respectively, and each is independent. 1-3 Selected from alkyl and C3 cycloalkyl groups.

[0139] In some embodiments, R 3a and R 3b Each of these is independently selected from H, Me, and C3 cycloalkyl groups on a case-by-case basis.

[0140] In some embodiments, m is selected from 0 or 1.

[0141] In some embodiments, m is 0.

[0142] In some embodiments, -XR 1 teeth The structure is TIFF0007888622000034.tif28170. In the formula, Ring B is a heterocyclic ring system containing 0, 1, or 2 additional heteroatoms selected from substituted or unsubstituted monocyclic or bicyclic (condensed, bridging, or spiro) 4-7 member O, N, or S, where, if substituted, R 1 The substituents are selected from F, Me, Et, CF3, -OMe, -OEt, and -NMe2, R 2 The substituents are selected from H, Me, and Et, and m is 0.

[0143] In some embodiments, -XR 1 teeth The structure is TIFF0007888622000035.tif28170. In the formula, Ring B is a heterocyclic ring system containing 0, 1, or 2 additional heteroatoms selected from substituted or unsubstituted monocyclic or bicyclic (condensed, bridging, or spiro) 4-7 member, O, N, or S, where R is substituted. 1 The substituents are selected from F, Me, Et, CF3, -OMe, and -OEt, R 2 The substituents are selected from H, Me, and Et, and m is 0.

[0144] In some embodiments, -XR 1 teeth It has the structure of TIFF0007888622000036.tif20170. 1a and R 1b Each of these can be substituted or not substituted on a case-by-case basis. 1-3 Alkyl, substituted or unsubstituted C3 cycloalkyl, heterocyclic group having 1, 2 or 3 heteroatoms selected from substituted or unsubstituted 4, 5 or 6-membered O, N or S, substituted or unsubstituted -C 1-3 Selected from alkyl-4, 5, or 6-membered heterocyclic groups (the said 4, 5, or 6-membered heterocyclic groups have 1, 2, or 3 heteroatoms selected from O, N, or S); R 2 m is selected from H, Me, and Et, and m is 0.

[0145] In some embodiments, -XR 1 teeth It has the structure of TIFF0007888622000037.tif20170. 1a and R 1b Each of these can be substituted or not substituted on a case-by-case basis. 1-3 Selected from alkyl and substituted or unsubstituted C3 cycloalkyl groups; R 2 m is selected from H, Me, and Et, and m is 0.

[0146] In some embodiments, TIFF0007888622000038.tif18170 is The file is TIFF0007888622000039.tif18170, where L is a combination, -NR 4b -, and -NR 4c Selected from C(O)-

[0147] In some embodiments, TIFF0007888622000040.tif18170 is The formula is TIFF0007888622000041.tif18170, where L is selected from the combinations and -O).

[0148] In some embodiments, TIFF0007888622000042.tif18170 is The filename is TIFF0007888622000043.tif18170, where L represents a bond.

[0149] In some embodiments, TIFF0007888622000044.tif18170 is The filename is TIFF0007888622000045.tif18170, where L is a join and R is a join. 4a H is H.

[0150] In some embodiments, TIFF0007888622000046.tif18170 is The filename is TIFF0007888622000047.tif22170.

[0151] In some embodiments, TIFF0007888622000048.tif18170 is TIFF0007888622000049.tif22170, and in the formula R 4d H is H.

[0152] In some embodiments, R 4a The element is selected from H, OH, or F.

[0153] In some embodiments, R 4a H,C 1-4 Alkyl, or C 1-4 Selected from haloalkyl groups.

[0154] In some embodiments, R 4a H,C 1-3 Alkyl, or C 1-3 Selected from haloalkyl groups.

[0155] In some embodiments, R 4a H,C 1-2 Alkyl, or C 1-2 Selected from haloalkyl groups.

[0156] In some embodiments, R 4a This is selected from H, C1 alkyl, or C1 haloalkyl (e.g., CF3).

[0157] In some embodiments, R 4a This is CF3.

[0158] In some embodiments, R 4a H is H.

[0159] In some embodiments, R 4b H,C 1-3 Alkyl or -C(O)C 1-3 It is alkyl.

[0160] In some embodiments, R 4b This is H, Me, or -C(O)Me.

[0161] In some embodiments, R 4b H is H.

[0162] In some embodiments, R 4c is H or C 1-3 It is alkyl.

[0163] In some embodiments, R 4c H is H.

[0164] In some embodiments, R 4d is H or C 1-3 It is alkyl.

[0165] In some embodiments, R 4d H is H.

[0166] In some embodiments, R 4e and R 4f H and C are independent of each other. 1-4 Selected from alkyl groups.

[0167] In some embodiments, R 4e and R 4f H is H.

[0168] In some embodiments, R 4g and R 4h These are H and C, each independently, each time. 1-3 Selected from alkyl groups.

[0169] In some embodiments, R 4g and R 4h Each of these is independently selected from H and C1 alkyl groups each time.

[0170] In some embodiments, R 4g and R 4h H is H.

[0171] In some embodiments, R 4i Each of these is independent and each time, Haro,C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 3-6Cyclohaloalkyl,-OR 4j ,-NR 4k (C(O))R 4l ,-CN,-C(O)R 4g ,-CN,-C(O)R 4g Selected from ,=O, unsubstituted 5- or 6-membered heteroaryls, or methyl-substituted 5- or 6-membered heteroaryls.

[0172] In some embodiments, R 4i Each of these is independent and each time, Haro,C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl,-OR 4j ,-C(O)R 4g , and are selected from = O.

[0173] In some embodiments, R 4i Each of these is independently and each time halo, C1 alkyl, C1 haloalkyl, C3 cycloalkyl, -OR 4j ,-C(O)R 4g , and are selected from = O.

[0174] In some embodiments, R 4i Each of these is independent and each time, Haro,C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 4j ,-NR 4k (C(O))R 4l ,-CN,-C(O)R 4g Selected from ,=O, and unsubstituted 5- or 6-membered heteroaryls or methyl-substituted 5- or 6-membered heteroaryls.

[0175] In some embodiments, R 4i Each of these is independent and each time, Haro,C 1-3 Alkyl, C 1-4 Haloalkyl, -OR 4j ,-C(O)R 4g , and are selected from = O.

[0176] In some embodiments, R 4i Each of these is independently, and each time, halo, C1 alkyl, C1 haloalkyl, -OR 4j ,-C(O)R 4g , and are selected from = O.

[0177] In some embodiments, R 4i These are each independently, and each time they are halo, C1 alkyl, C1 haloalkyl, and -OR 4j Selected from.

[0178] In some embodiments, R 4i H,C 1-4 Alkyl, and C 1-4 Selected from haloalkyl groups.

[0179] In some embodiments, R 4i The C1 alkyl group is selected from H, C1 alkyl, and C1 haloalkyl groups.

[0180] In some embodiments, n is selected from 0, 1, or 2.

[0181] In some embodiments, n is 1.

[0182] In some embodiments, n is 0.

[0183] In some embodiments, R 4 The selected group consists of monocyclic or bicyclic 6-10 membered aryl rings, monocyclic or bicyclic 5-10 membered heteroaryl rings, bicyclic (condensed, bridged, or spiro) 6-10 membered cycloalkyl ring systems, bicyclic (condensed, bridged, or spiro) 6-10 membered cycloalkenyl rings, and bicyclic (condensed, bridged, or spiro) cycloalkyl ring systems containing one, two, or three heteroatoms selected from O, N, or S, where the monocyclic or bicyclic (condensed, bridged, or spiro) 6-10 membered cycloalkenyl ring system or the monocyclic or bicyclic (condensed, bridged, or spiro) 6-10 membered heterocycle is unsubstituted or contains one, two, or three R4i It has been replaced with.

[0184] In some embodiments, R 4 The monocyclic 6-membered aryl ring, monocyclic 5 or 6-membered heteroaryl ring, bicyclic (condensed, bridged, or spiro) 8-10 membered cycloalkyl ring system, bicyclic (condensed, bridged, or spiro) 8-10 membered cycloalkenyl ring, and monocyclic or bicyclic (condensed, bridged, or spiro) cycloalkyl ring system containing 1, 2, or 3 heteroatoms selected from O, N, or S, where the monocyclic (condensed, bridged, or spiro) 6-membered aryl ring, monocyclic 5 or 6-membered heteroaryl ring, bicyclic (condensed, bridged, or spiro) 8-10 membered cycloalkenyl ring system, or monocyclic or bicyclic (condensed, bridged, or spiro) 8-10 membered heterocycle is unsubstituted or contains 1, 2, or 3 R 4i It has been replaced with.

[0185] In some embodiments, R 4 The monocyclic 6-membered aryl ring, monocyclic 5 or 6-membered heteroaryl ring, bicyclic (condensed, bridged, or spiro) 8-10 membered cycloalkyl ring system, bicyclic (condensed, bridged, or spiro) 8-10 membered cycloalkenyl ring, and monocyclic or bicyclic (condensed, bridged, or spiro) cycloalkyl ring system containing 1, 2, or 3 heteroatoms selected from 9-10 membered O, N, or S, where the monocyclic (condensed, bridged, or spiro) 6-membered aryl ring, monocyclic 5 or 6-membered heteroaryl ring, bicyclic (condensed, bridged, or spiro) 8-10 membered cycloalkenyl ring system, or monocyclic or bicyclic (condensed, bridged, or spiro) 8-10 membered heterocycle is unsubstituted or contains 1, 2, or 3 R 4i It has been replaced with.

[0186] In some embodiments, R 4The heterocyclic systems are selected from monocyclic or bicyclic 6-10 membered aryls, monocyclic or bicyclic 5-10 membered heteroaryls, and monocyclic or bicyclic (condensed, bridged, or spiro) 6-10 membered heteroatoms selected from O, N, or S, where the monocyclic or bicyclic 6-10 membered aryls, monocyclic or bicyclic 5-10 membered heteroaryls, or monocyclic or bicyclic (condensed, bridged, or spiro) 6-10 membered heterocyclic systems are unsubstituted or contain 1, 2, or 3 R 4i It has been replaced with.

[0187] In some embodiments, R 4 The heterocyclic systems are selected from monocyclic 6-membered aryls, monocyclic 5- or 6-membered heteroaryls, and monocyclic or bicyclic (condensed, bridged, or spiro) 8- to 10-membered O, N, or S atoms, where the monocyclic 6-membered aryl, monocyclic 5- or 6-membered heteroaryl, or monocyclic or bicyclic (condensed, bridged, or spiro) 6- to 10-membered heterocyclic systems are either unsubstituted or contain 1, 2, or 3 R atoms. 4i It has been replaced with.

[0188] In some embodiments, R 4 The heterocyclic system is selected from monocyclic 6-membered aryls, monocyclic 5- or 6-membered heteroaryls, and bicyclic (condensed, bridging, or spiro) 9- or 10-membered O, N, or S, where the monocyclic 6-membered aryl, monocyclic 5- or 6-membered heteroaryl, or bicyclic 9- or 10-membered heterocyclic system is unsubstituted or contains 1, 2, or 3 R 4i It has been replaced with.

[0189] In some embodiments, R 4 is C 1-4 It is a haloalkyl group.

[0190] In some embodiments, R 4 H is H.

[0191] In some embodiments, TIFF0007888622000050.tif17170 is The filename is TIFF0007888622000051.tif20170.

[0192] In some embodiments, TIFF0007888622000052.tif17170 is TIFF0007888622000053.tif27170, and in the formula, R 4m is Me, Et, Pr, F, Cl, CF3, OMe, OCH2F, OCHF2, OCF3, Selected from TIFF0007888622000054.tif17170.

[0193] In some embodiments, TIFF0007888622000055.tif17170 is TIFF0007888622000056.tif28170, and in the formula, R 4m The element is selected from Me, F, Cl, CF3, and OMe.

[0194] In some embodiments, TIFF0007888622000057.tif17170 is TIFF0007888622000058.tif34170, and in the formula, R 4m is Me, Et, Pr, F, Cl, CF3, OMe, OCH2F, OCHF2, OCF3, Selected from TIFF0007888622000059.tif17170.

[0195] In some embodiments, TIFF0007888622000060.tif17170 is TIFF0007888622000061.tif35170, and in the formula, R 4m This is selected from Me, F, Cl, CF3, and OMe.

[0196] In some embodiments, TIFF0007888622000062.tif17170 is TIFF0007888622000063.tif27170, and in the formula, R 4m is Me, Et, Pr, F, Cl, CF3, OMe, OCH2F, OCHF2, OCF3, Selected from TIFF0007888622000064.tif17170.

[0197] In some embodiments, TIFF0007888622000065.tif17170 is TIFF0007888622000066.tif27170, and in the formula, R 4m This is selected from Me, F, Cl, CF3, and OMe.

[0198] In some embodiments, TIFF0007888622000067.tif16170 is TIFF0007888622000068.tif34170, and in the formula, R 4m is Me, Et, Pr, F, Cl, CF3, OMe, OCH2F, OCHF2, OCF3, Selected from TIFF0007888622000069.tif16170.

[0199] In some embodiments, TIFF0007888622000070.tif17170 is TIFF0007888622000071.tif34170, and in the formula, R 4m This is selected from Me, F, Cl, CF3, and OMe.

[0200] In some embodiments, TIFF0007888622000072.tif17170 is The file is TIFF0007888622000073.tif30170, and in the formula, R 4mis Me, Et, Pr, F, Cl, CF3, OMe, OCH2F, OCHF2, OCF3, Selected from TIFF0007888622000074.tif17170.

[0201] In some embodiments, TIFF0007888622000075.tif17170 is TIFF0007888622000076.tif23170, and in the formula, R 4m is Me, Et, Pr, F, Cl, CF3, OMe, OCH2F, OCHF2, OCF3, Selected from TIFF0007888622000077.tif18170.

[0202] In some embodiments, TIFF0007888622000078.tif16170 is The file is TIFF0007888622000079.tif30170, and in the formula, R 4m is Me, Et, Pr, F, Cl, CF3, OMe, OCH2F, OCHF2, OCF3, Selected from TIFF0007888622000080.tif17170.

[0203] In some embodiments, TIFF0007888622000081.tif17170 is TIFF0007888622000082.tif34170, and in the formula, R 4m is Me, Et, Pr, F, Cl, CF3, OMe, OCH2F, OCHF2, OCF3, Selected from TIFF0007888622000083.tif16170.

[0204] In some embodiments, TIFF0007888622000084.tif16170 is The file is TIFF0007888622000085.tif30170, and in the formula, R 4mis Me, Et, Pr, F, Cl, CF3, OMe, OCH2F, OCHF2, OCF3, Selected from TIFF0007888622000086.tif17170.

[0205] In some embodiments, TIFF0007888622000087.tif16170 is TIFF0007888622000088.tif127170 Selected from.

[0206] In some embodiments, TIFF0007888622000089.tif17170 is TIFF0007888622000090.tif140170 Selected from.

[0207] In some embodiments, TIFF0007888622000091.tif18170 is Selected from TIFF0007888622000092.tif206170.

[0208] In some embodiments, R 5 is H or C 1-3 It is alkyl.

[0209] In some embodiments, R 5 H is H.

[0210] In some embodiments, o is 1.

[0211] In some embodiments, o is 2.

[0212] In some embodiments, o is 3.

[0213] In some embodiments, R 5a and R 5b H and C are independent of each other.1-4 Selected from alkyl groups.

[0214] In some embodiments, R 5a and R 5b H is H.

[0215] In some embodiments, Ring A is selected from a bicyclic heteroaryl group having 1, 2, or 3 heteroatoms selected from substituted or unsubstituted 9- to 10-membered O, N, or S, and a 9- to 10-membered heterocyclic ring system containing 1, 2, or 3 heteroatoms selected from substituted or unsubstituted bicyclic (condensed, bridging, or spiro) O, N, or S, where, if substituted, the bicyclic heteroaryl group or bicyclic heterocyclic ring system is halo,-CN,C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, deuterated C 1-6 Alkyl,-OR 5c ,-NR 5c R 5d or -NR 5c R 5d C replaced by 1-4 It is substituted with one, two, or three independent substituents selected from alkyl groups. In some cases, the heteroatom is selected from O or N.

[0216] In some embodiments, Ring A is selected from a bicyclic heteroaryl group having 1, 2, or 3 heteroatoms selected from substituted or unsubstituted 9-membered O, N, or S, and a heterocyclic ring system containing 1, 2, or 3 heteroatoms selected from substituted or unsubstituted bicyclic (condensed, bridging, or spiro) 9-membered O, N, or S, where, if substituted, the bicyclic heteroaryl group or bicyclic heterocyclic ring system is halo,-CN,C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, deuterated C 1-6 Alkyl,-OR 5c ,-NR 5c R 5d or -NR 5c R5d C replaced by 1-4 It is substituted with one, two, or three independent substituents selected from alkyl groups. In some cases, the heteroatom is selected from O or N.

[0217] In some embodiments, Ring A is selected from a monocyclic heteroaryl group having 1, 2, or 3 heteroatoms selected from substituted or unsubstituted 5 or 6-membered, O, N, or S, and a substituted or unsubstituted monocyclic aryl group, where, if substituted, the monocyclic heteroaryl group or monocyclic aryl group is halo,-CN,C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, deuterated C 1-6 Alkyl,-OR 5c ,-NR 5c R 5d or -NR 5c R 5d C replaced by 1-4 It is substituted with one, two, or three independent substituents selected from alkyl groups. In some cases, the heteroatom is selected from O or N.

[0218] In some embodiments, TIFF0007888622000093.tif30170 is The filename is TIFF0007888622000094.tif29170.

[0219] In some embodiments, TIFF0007888622000095.tif30170 is The filename is TIFF0007888622000096.tif30170.

[0220] If Ring A is substituted, the bicyclic heteroaryl group or bicyclic heterocyclic system is independently a halo,C 1-6 Alkyl, C 1-6 Haloalkyl, deuterated C 1-6 alkyl, or -OR 5cIt may be substituted with one, two, or three substituents selected from the following.

[0221] If Ring A is substituted, the bicyclic heteroaryl group or bicyclic heterocyclic system is independently a halo,C 1-3 Alkyl, C 1-3 Haloalkyl, deuterated C 1-3 alkyl, or -OR 5c It may be substituted with one, two, or three substituents selected from the following.

[0222] If Ring A is substituted, the bicyclic heteroaryl group or bicyclic heterocyclic system is independently a halo (e.g., F), C1 alkyl, C1 haloalkyl (e.g., CFH2, CF2H, or CF3), deuterated C1 alkyl (e.g., -CD3), or -OR 5c It may be substituted with one, two, or three substituents selected from the following.

[0223] If Ring A is substituted, the bicyclic heteroaryl group or bicyclic heterocyclic system is independently a halo,C 1-6 Alkyl, C 1-6 Haloalkyl, deuterated C 1-6 alkyl, or -OR 5c It may be substituted with one or two substituents selected from the following.

[0224] If Ring A is substituted, the bicyclic heteroaryl group or bicyclic heterocyclic system is independently a halo,C 1-3 Alkyl, C 1-3 Haloalkyl, deuterated C 1-3 alkyl, or -OR 5c It may be substituted with one or two substituents selected from the following.

[0225] If Ring A is substituted, the bicyclic heteroaryl group or bicyclic heterocyclic system is independently a halo (e.g., F), C1 alkyl, C1 haloalkyl (e.g., CFH2, CF2H, or CF3), deuterated C1 alkyl (e.g., -CD3), or -OR 5c It may be substituted with one or two substituents selected from the following.

[0226] If Ring A is substituted, a heteroaryl group having 1, 2, or 3 heteroatoms selected from 5-6 member monocyclic O, N, or S, or a 6-member monocyclic aryl group, is independently a halo,C 1-6 Alkyl, C 1-6 Haloalkyl, deuterated C 1-6 Alkyl or -OR 5c It may be substituted with one, two, or three substituents selected from the following.

[0227] If Ring A is substituted, a heteroaryl group having 1, 2, or 3 heteroatoms selected from 5-6 member monocyclic O, N, or S, or a 6-member monocyclic aryl group, is independently a halo,C 1-3 Alkyl, C 1-3 Haloalkyl, deuterated C 1-3 Alkyl or -OR 5c It may be substituted with one, two, or three substituents selected from the following.

[0228] If Ring A is substituted, the heteroaryl group having 1, 2, or 3 heteroatoms selected from 5-6 membered monocyclic O, N, or S, or the 6-membered monocyclic aryl group, can independently be halo (e.g., F), C1 alkyl, C1 haloalkyl (e.g., CFH2, CF2H, or CF3), deuterated C1 alkyl (e.g., -CD3), or -OR 5c It may be substituted with one, two, or three substituents selected from the following.

[0229] If Ring A is substituted, a heteroaryl group having 1, 2, or 3 heteroatoms selected from 5-6 member monocyclic O, N, or S, or a 6-member monocyclic aryl group, is independently a halo,C 1-6 Alkyl, C 1-6 Haloalkyl, deuterated C 1-6 alkyl, or -OR 5c It may be substituted with one or two substituents selected from the following.

[0230] If Ring A is substituted, a heteroaryl group having 1, 2, or 3 heteroatoms selected from 5-6 member monocyclic O, N, or S, or a 6-member monocyclic aryl group, is independently a halo,C 1-3 Alkyl, C 1-3 Haloalkyl, deuterated C 1-3 alkyl, or -OR 5c It may be substituted with one or two substituents selected from the following.

[0231] If Ring A is substituted, the heteroaryl group having 1, 2, or 3 heteroatoms selected from 5-6 member monocyclic O, N, or S, or the 6-member monocyclic alkyl group, can independently be halo (e.g., F), C1 alkyl, C1 haloalkyl (e.g., CFH2, CF2H, or CF3), deuterated C1 alkyl (e.g., -CD3), or -OR 5c It may be substituted with one or two substituents selected from the following.

[0232] In some embodiments, R 5c and R 5d These are H, C, and C, respectively, and each is independent. 1-3 Alkyl, C 3-6 Cycloalkyl, and C 1-3 Selected from haloalkyl groups.

[0233] In some embodiments, R 5c and R 5d Each of these is independently selected from H, Me, cyclopropyl, and CF3 each time.

[0234] In this embodiment, Ring A is either substituted or non-substituted. Selected from TIFF0007888622000097.tif213170 and TIFF0007888622000098.tif79170.

[0235] In some embodiments, Ring A is either substituted or non-substituted. Selected from TIFF0007888622000099.tif96170.

[0236] In some embodiments, Ring A is either substituted or non-substituted. Selected from TIFF0007888622000100.tif39170.

[0237] In some embodiments, Ring A is either substituted or non-substituted. Selected from TIFF0007888622000101.tif42170.

[0238] In some embodiments, Ring A is either substituted or non-substituted. Selected from TIFF0007888622000102.tif77170.

[0239] In some embodiments, Ring A is either substituted or non-substituted. Selected from TIFF0007888622000103.tif44170.

[0240] As will be apparent to those skilled in the art, the compounds of the present invention contain a number of stereocenters. The present invention encompasses all possible stereoisomers, whether in the form of a single stereoisomer or a mixture thereof.

[0241] The preferred stereochemistry of the piperidine group is as follows: (Equation Ia) TIFF0007888622000104.tif43170

[0242] Regarding pyrrolidine -L-(CR 4e R 4f ) n -R 4 The preferred stereochemistry of the base is: (Formula Ib) TIFF0007888622000105.tif42170

[0243] The preferred stereochemistry of the 2-position of the pyrrolidine ring is: (Formula Ic) TIFF0007888622000106.tif42170

[0244] Regarding pyrrolidine -L-(CR 4e R 4f ) n -R 4 The preferred stereochemistry of the group is that it has a trans relationship with the group at position 2, as shown below. (Formula Id) TIFF0007888622000107.tif42170

[0245] The preferred stereochemistry of the structure of formula (I) is as follows: TIFF0007888622000108.tif43170

[0246] In some embodiments, -XR 1 teeth The structure is TIFF0007888622000109.tif28170. In the formula, Ring B is a heterocyclic system containing 0 or 1 additional heteroatoms selected from substituted or unsubstituted monocyclic or bicyclic (condensed, bridging, or spiro) 4-7 member O, N, or S; where substituted, R 1 The substituents are selected from F, Me, Et, CF3, -OMe, -OEt, and -NMe2, R 2 The substituent is selected from H, Me, and Et, and m is 0, and TIFF0007888622000110.tif17170 is The filename is TIFF0007888622000111.tif20170. If necessary, TIFF0007888622000112.tif155170, where R 4m are Me, Et, Pr, F, Cl, CF3, OMe, OCH2F, OCHF2, CF3, Selected from TIFF0007888622000113.tif16170.

[0247] In some embodiments, -XR 1 teeth The structure is TIFF0007888622000114.tif28170. In the formula, Ring B is a heterocyclic system containing 0 or 1 additional heteroatoms selected from substituted or unsubstituted monocyclic or bicyclic (condensed, bridging, or spiro) 4-7 member O, N, or S; where substituted, R 1 The substituents are selected from F, Me, Et, CF3, -OMe, -OEt, and -NMe2, R 2 The substituent is selected from H, Me, and Et, and m is 0, and TIFF0007888622000115.tif17170 is The filename is TIFF0007888622000116.tif20170. If necessary, TIFF0007888622000117.tif17170 is The filename is TIFF0007888622000118.tif27170, Here, R 4m are Me, Et, Pr, F, Cl, CF3, OMe, OCH2F, OCHF2, CF3, Selected from TIFF0007888622000119.tif17170.

[0248] In some embodiments, -XR 1 teeth The structure is TIFF0007888622000120.tif28170. In the formula, Ring B is a heterocyclic system containing 0 or 1 additional heteroatoms selected from substituted or unsubstituted monocyclic or bicyclic (condensed, bridging, or spiro) 4-7 member O, N, or S; where substituted, R 1 The substituents are selected from F, Me, Et, CF3, -OMe, -OEt, and -NMe2, R 2 The substituent is selected from H, Me, and Et, and m is 0, and TIFF0007888622000121.tif17170 is TIFF0007888622000122.tif21170, where R 4d The substituent is H. If necessary, TIFF0007888622000123.tif17170 is TIFF0007888622000124.tif38170, where R 4m are Me, Et, Pr, F, Cl, CF3, OMe, OCH2F, OCHF2, CF3, Selected from TIFF0007888622000125.tif17170.

[0249] In some embodiments, -XR 1 teeth The structure is TIFF0007888622000126.tif28170. In the formula, Ring B is a heterocyclic system containing 0 or 1 additional heteroatoms selected from substituted or unsubstituted monocyclic or bicyclic (condensed, bridging, or spiro) 4-7 member O, N, or S; where substituted, R 1 The substituents are selected from F, Me, Et, CF3, -OMe, -OEt, and -NMe2, R 2 The substituent is selected from H, Me, and Et, and m is 0, and TIFF0007888622000127.tif17170 is The filename is TIFF0007888622000128.tif20170. If necessary, TIFF0007888622000129.tif17170 is TIFF0007888622000130.tif29170, where R 4m This is selected from Me, Et, F, Cl, CF3, and OMe. Furthermore, if necessary, TIFF0007888622000131.tif17170 is TIFF0007888622000132.tif63170, where R 4m It is selected from Me, Et, F, Cl, CF3, and OMe.

[0250] In some embodiments, -XR 1 teeth It has the structure of TIFF0007888622000133.tif20170, R 1a and R 1b These are replaced independently each time (using -NR as needed). 1e R 1f (May be substituted with) or unsubstituted C 1-3 Selected from alkyl and substituted or unsubstituted C3 cycloalkyl groups, R 2 m is selected from H, Me and Et, and m is 0, and TIFF0007888622000134.tif17170 is The filename is TIFF0007888622000135.tif20170. If necessary, here TIFF0007888622000136.tif17170 is TIFF0007888622000137.tif127170, where R 4m is Me, Et, Pr, F, CI, CF3, OMe, OCH2F, OCHF2, OCF3 Selected from TIFF0007888622000138.tif17170.

[0251] In some embodiments, -XR 1 teeth It has the structure of TIFF0007888622000139.tif20170, R 1a and R 1b These are replaced independently each time (using -NR as needed). 1e R 1f (May be substituted with) or unsubstituted C 1-3 Selected from alkyl and substituted or unsubstituted C3 cycloalkyl groups, R 2 m is selected from H, Me and Et, and m is 0, and TIFF0007888622000140.tif17170 is The filename is TIFF0007888622000141.tif20170. If necessary, here TIFF0007888622000142.tif17170 is TIFF0007888622000143.tif26170, where R 4m is Me, Et, Pr, F, CI, CF3, OMe, OCH2F, OCHF2, OCF3 Selected from TIFF0007888622000144.tif16170.

[0252] In some embodiments, -XR 1 teeth It has the structure of TIFF0007888622000145.tif20170, R 1a and R 1b These are replaced independently each time (using -NR as needed). 1e R 1f (May be substituted with) or unsubstituted C 1-3 Selected from alkyl and substituted or unsubstituted C3 cycloalkyl groups, R 2 m is selected from H, Me and Et, and m is 0, and TIFF0007888622000146.tif17170 is TIFF0007888622000147.tif21170, where R 4dH is H. If necessary, here TIFF0007888622000148.tif17170 is The filename is TIFF0007888622000149.tif39170. Here, R 4m is Me, Et, Pr, F, CI, CF3, OMe, OCH2F, OCHF2, OCF3 Selected from TIFF0007888622000150.tif17170.

[0253] In some embodiments, -XR 1 teeth It has the structure of TIFF0007888622000151.tif20170, R 1a and R 1b Each of these can be independently substituted or not substituted in each case. 1-3 Selected from alkyl and substituted or unsubstituted C3 cycloalkyl groups, R 2 m is selected from H, Me and Et, and m is 0, and TIFF0007888622000152.tif17170 is The filename is TIFF0007888622000153.tif21170. If necessary, here TIFF0007888622000154.tif17170 is TIFF0007888622000155.tif28170, where R 4m The following are selected from Me, F, CI, CF3, and OM. Furthermore, if necessary, TIFF0007888622000156.tif16170 is TIFF0007888622000157.tif62170, where R 4m The following are selected from Me, F, CI, CF3, and OM.

[0254] In some embodiments, -XR 1 teeth It has the structure of TIFF0007888622000158.tif20170, R 1a and R 1b Each of these can be substituted or not substituted on a case-by-case basis. 1-3 Alkyl and Selected from TIFF0007888622000159.tif26170, where Ring C is a heterocyclic system containing 0, 1, or 2 additional heteroatoms selected from substituted or unsubstituted monocyclic 4, 5, or 6-membered O, N, or S, R 2 m is selected from H, Me, and Et, and m is 0, and TIFF0007888622000160.tif17170 is The filename is TIFF0007888622000161.tif20170. If necessary, here TIFF0007888622000162.tif16170 is TIFF0007888622000163.tif127170, where R 4m is Me, Et, Pr, F, CI, CF3, OMe, OCH2F, OCHF2, OCF3 Selected from TIFF0007888622000164.tif16170.

[0255] In some embodiments, -XR 1 teeth It has the structure TIFF0007888622000165.tif20170, R 1a and R 1b Each of these can be substituted or not substituted on a case-by-case basis. 1-3 Alkyl and Selected from TIFF0007888622000166.tif25170, where Ring C is a heterocyclic system containing 0, 1, or 2 additional heteroatoms selected from substituted or unsubstituted monocyclic 4, 5, or 6-membered O, N, or S, R 2 m is selected from H, Me, and Et, and m is 0, and TIFF0007888622000167.tif17170 is The filename is TIFF0007888622000168.tif20170. If necessary, here TIFF0007888622000169.tif17170 is TIFF0007888622000170.tif27170, where R 4m is Me, Et, Pr, F, CI, CF3, OMe, OCH2F, OCHF2, OCF3 Selected from TIFF0007888622000171.tif16170.

[0256] In some embodiments, -XR 1 teeth It has the structure of TIFF0007888622000172.tif21170, R 1a and R 1b Each of these can be substituted or not substituted on a case-by-case basis. 1-3 Alkyl and Selected from TIFF0007888622000173.tif26170, where Ring C is a heterocyclic system containing 0, 1, or 2 additional heteroatoms selected from substituted or unsubstituted monocyclic 4, 5, or 6-membered O, N, or S, R 2 m is selected from H, Me, and Et, and m is 0, and TIFF0007888622000174.tif17170 is TIFF0007888622000175.tif21170, where R 4d H is H. If necessary, here TIFF0007888622000176.tif16170 is TIFF0007888622000177.tif38170, where R 4m is Me, Et, Pr, F, CI, CF3, OMe, OCH2F, OCHF2, OCF3 Selected from TIFF0007888622000178.tif16170.

[0257] In some embodiments, -XR 1 teeth It has the structure TIFF0007888622000179.tif20170, R 1a and R 1b Each of these can be substituted or not substituted on a case-by-case basis. 1-3 Alkyl and Selected from TIFF0007888622000180.tif25170, where Ring C is a heterocyclic system containing 0, 1, or 2 additional heteroatoms selected from substituted or unsubstituted monocyclic 4, 5, or 6-membered O, N, or S, R 2 m is selected from H, Me, and Et, and m is 0, and TIFF0007888622000181.tif18170 is The filename is TIFF0007888622000182.tif20170. If necessary, here, TIFF0007888622000183.tif17170 is TIFF0007888622000184.tif159170, where R 4m is Me,Et,Pr,F,CI,CF3,OMe,OCH2F,OCHF2,OCF3, Selected from TIFF0007888622000185.tif16170.

[0258] In some embodiments, -XR 1 teeth It has the structure of TIFF0007888622000186.tif20170, R 1a and R 1b Each of these can be substituted or not substituted on a case-by-case basis. 1-3 A heterocyclic system containing an alkyl group and zero, one, or two additional heteroatoms selected from substituted or unsubstituted monocyclic 4, 5, or 6-membered O, N, or S groups, R 2 m is selected from H, Me, and Et, and m is 0, and TIFF0007888622000187.tif17170 is The filename is TIFF0007888622000188.tif20170. If necessary, here, TIFF0007888622000189.tif17170 is TIFF0007888622000190.tif27170, where R 4m is Me,Et,Pr,F,CI,CF3,OMe,OCH2F,OCHF2,OCF3, Selected from TIFF0007888622000191.tif16170.

[0259] In some embodiments, -XR 1 teeth It has the structure of TIFF0007888622000192.tif20170, R 1a and R 1b Each of these can be substituted or not substituted on a case-by-case basis. 1-3 A heterocyclic system containing an alkyl group and zero, one, or two additional heteroatoms selected from substituted or unsubstituted monocyclic 4, 5, or 6-membered O, N, or S groups, R 2 m is selected from H, Me, and Et, and m is 0, and TIFF0007888622000193.tif17170 is TIFF0007888622000194.tif21170, where R 4d H is H. If necessary, here, TIFF0007888622000195.tif17170 is TIFF0007888622000196.tif39170, where R 4m is Me,Et,Pr,F,CI,CF3,OMe,OCH2F,OCHF2,OCF3, Selected from TIFF0007888622000197.tif16170.

[0260] In some embodiments, -XR 1 teeth The structure TIFF0007888622000198.tif28170 is present, where Ring B is a heterocyclic system containing 0 or 1 additional heteroatoms selected from substituted or unsubstituted monocyclic or bicyclic (condensed, bridging, or spiro) 4-7 member O, N, or S atoms, where R is substituted. 1 The substituents are selected from F, Me, Et, CF3, -OMe, -OEt, and -NMe2, R 2 m is selected from H, Me and Et, and m is 0, and TIFF0007888622000199.tif30170 is The code is TIFF0007888622000200.tif37170. Depending on the case, Ring A is selected from heteroaryl groups having 1, 2, or 3 heteroatoms selected from substituted or unsubstituted bicyclic 9-10 member O, N, or S, and 9-10 member heterocyclic ring systems containing 1, 2, or 3 heteroatoms selected from substituted or unsubstituted bicyclic (condensed, bridging, or spiro) O, N, or S, where, if substituted, the bicyclic heteroaryl group or bicyclic heterocyclic ring system is halo,-CN,C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, deuterated C 1-6 Alkyl,-OR 5c ,-NR 5c R 5d or -NR 5c R 5d C replaced by 1-4 It is substituted with one, two, or three independent substituents selected from alkyl groups. In some cases, ring A is selected from a heteroaryl group having one, two, or three heteroatoms selected from substituted or unsubstituted monocyclic 5-6 member O, N, or S groups, or a substituted or unsubstituted monocyclic 6-membered aryl group, where, if substituted, the monocyclic heteroaryl group or monocyclic aryl group is halo,-CN,C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, deuterated C 1-6 Alkyl,-OR 5c , -NR 5cR 5d or -NR 5c R 5d C replaced by 1-4 It is substituted with one, two, or three independent substituents selected from alkyl groups.

[0261] In some embodiments, -XR 1 teeth The structure TIFF0007888622000201.tif28170 is formed, where Ring B is a heterocyclic system containing 0 or 1 additional heteroatoms selected from substituted or unsubstituted monocyclic or bicyclic (condensed, bridging, or spiro) 4-7 member O, N, or S atoms, where R is substituted. 1 The substituents are selected from F, Me, Et, CF3, -OMe, and -OEt, R 2 m is selected from H, Me and Et, and m is 0, and TIFF0007888622000202.tif30170 is The code is TIFF0007888622000203.tif30170. Depending on the case, Ring A is selected from heteroaryl groups having 1, 2, or 3 heteroatoms selected from substituted or unsubstituted bicyclic 9-10 member O, N, or S, and heterocyclic ring systems containing 1, 2, or 3 heteroatoms selected from substituted or unsubstituted bicyclic (condensed, bridging, or spiro) 9-10 member O, N, or S, where, if substituted, the bicyclic heteroaryl group or bicyclic heterocyclic ring system is halo,-CN,C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, deuterated C 1-6 Alkyl,-OR 5c ,-NR 5c R 5d or -NR 5c R 5d C replaced by 1-4 It is substituted with one, two, or three independent substituents selected from alkyl groups.

[0262] In some embodiments, -XR 1 teeth TIFF0007888622000204.tif has the structure of 20170, and R 1a and R 1b are each independently, each time substituted (optionally substituted with -NR 1e R 1f ), or unsubstituted C 1-3 alkyl and substituted or unsubstituted C3 cycloalkyl, R 2 is selected from H, Me and Et, and m is 0, and TIFF0007888622000205.tif30170 is TIFF0007888622000206.tif37170. Optionally, Ring A is a substituted or unsubstituted bicyclic heteroaryl group having 1, 2 or 3 heteroatoms selected from O, N or S in a 9- to 10-membered ring, and a substituted or unsubstituted bicyclic (fused, bridged or spiro) heterocyclic ring system containing 1, 2 or 3 heteroatoms selected from O, N or S in a 9- to 10-membered ring. Here, when substituted, the bicyclic heteroaryl group or the bicyclic heterocyclic ring system is halo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, deuterated C 1-6 alkyl, -OR 5c , -NR 5c R 5d or -NR 5c R 5d substituted C 1-4 alkyl selected from 1, 2 or 3 independent substituents. Also optionally Ring A is selected from a substituted or unsubstituted monocyclic heteroaryl group having 1, 2 or 3 heteroatoms selected from O, N or S in a 5- to 6-membered ring, a substituted or unsubstituted monocyclic 6-membered aryl group. Here, when substituted, the monocyclic heteroaryl group or the monocyclic aryl group is halo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, deuterated C 1-6 alkyl, -OR 5c , -NR 5c R5d or -NR 5c R 5d C replaced by 1-4 It is substituted with one, two, or three independent substituents selected from alkyl groups.

[0263] In some embodiments, -XR 1 teeth It has the structure of TIFF0007888622000207.tif21170, R 1a and R 1b Each of these can be substituted or not substituted on a case-by-case basis. 1-3 Selected from alkyl and substituted or unsubstituted C3 cycloalkyl groups, R 2 m is selected from H, Me, and Et, and m is 0, and TIFF0007888622000208.tif30170 is The code is TIFF0007888622000209.tif30170. Depending on the case, ring A is selected from heteroaryl groups having 1, 2, or 3 heteroatoms selected from substituted or unsubstituted bicyclic 9-10 member O, N, or S, and heterocyclic ring systems containing 1, 2, or 3 heteroatoms selected from substituted or unsubstituted bicyclic (condensed, bridging, or spiro) 9-10 member O, N, or S, where, if substituted, the bicyclic heteroaryl group or bicyclic heterocyclic ring system is halo,-CN,C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, deuterated C 1-6 Alkyl,-OR 5c ,-NR 5c R 5d or NR 5c R 5d C replaced by 1-4 It is substituted with one, two, or three independent substituents selected from alkyl groups.

[0264] In some embodiments, -XR 1 teeth It has the structure TIFF0007888622000210.tif20170, R 1a and R1b Each of these can be substituted or not substituted on a case-by-case basis. 1-3 Selected from alkyl and substituted or unsubstituted C3 cycloalkyl groups, R 2 m is selected from H, Me, and Et, and m is 0, and TIFF0007888622000211.tif30170 is The code is TIFF0007888622000212.tif37170. Depending on the case, ring A is selected from heteroaryl groups having 1, 2, or 3 heteroatoms selected from substituted or unsubstituted bicyclic 9-10 member O, N, or S, and heterocyclic ring systems containing 1, 2, or 3 heteroatoms selected from substituted or unsubstituted bicyclic (condensed, bridging, or spiro) 9-10 member O, N, or S, where, if substituted, the bicyclic heteroaryl group or bicyclic heterocyclic ring system is halo,-CN,C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, deuterated C 1-6 Alkyl,-OR 5c ,-NR 5c R 5d or NR 5c R 5d C replaced by 1-4 It is substituted with one, two, or three independent substituents selected from alkyl groups. In some cases, ring A is selected from a heteroaryl group having one, two, or three heteroatoms selected from substituted or unsubstituted monocyclic 5-6 member O, N, or S groups, or a substituted or unsubstituted monocyclic 6-membered aryl group, where, if substituted, the monocyclic heteroaryl group or monocyclic aryl group is halo,-CN,C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, deuterated C 1-6 Alkyl,-OR 5c , -NR 5c R 5d or -NR 5c R 5d C replaced by 1-4 It is substituted with one, two, or three independent substituents selected from alkyl groups.

[0265] In some embodiments, TIFF0007888622000213.tif16170 is TIFF0007888622000214.tif20170, and TIFF0007888622000215.tif30170 is TIFF0007888622000216.tif29170. In some cases, TIFF0007888622000217.tif17170 is TIFF0007888622000218.tif29170, where R 4m is selected from Me, F, CI, CF3, and OMe. Further, in some cases, where TIFF0007888622000219.tif16170 is TIFF0007888622000220.tif69170, in the formula, R 4m is selected from Me, F, Cl, CF3, and OMe. In some cases, ring A is selected from a heteroaryl group having 1, 2, or 3 heteroatoms selected from O, N, or S in a bicyclic 9- to 10-membered ring, which may be substituted or unsubstituted, and a heterocyclic ring system containing 1, 2, or 3 heteroatoms selected from O, N, or S in a bicyclic (fused, bridged, or spiro) 9- to 10-membered ring, where, when substituted, the bicyclic heteroaryl group or the bicyclic heterocyclic ring system is halo, -CN, C 1-6 alkyl, C1-6 haloalkyl,, C 3-6 cycloalkyl, deuterated C 1-6 alkyl, -OR 5c , -NR 5c R 5d or -NR 5c R 5d substituted C 1-4 alkyl selected from 1, 2, or 3 independent substituents.

[0266] In some embodiments, TIFF0007888622000221.tif17170 is The filename is TIFF0007888622000222.tif20170. TIFF0007888622000223.tif30170 is The filename is TIFF0007888622000224.tif37170. Depending on the circumstances, here, TIFF0007888622000225.tif17170 is TIFF0007888622000226.tif158170, where R 4m is Me,Et,Pr,F,CI,CF3,OMe,OCH2F,OCHF2,OCF3, Selected from TIFF0007888622000227.tif17170. Depending on the case, ring A is selected from heteroaryl groups having 1, 2, or 3 heteroatoms selected from substituted or unsubstituted bicyclic 9-10 member O, N, or S, and heterocyclic ring systems containing 1, 2, or 3 heteroatoms selected from substituted or unsubstituted bicyclic (condensed, bridging, or spiro) 9-10 member O, N, or S, where, if substituted, the bicyclic heteroaryl group or bicyclic heterocyclic ring system is halo,-CN,C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, deuterated C 1-6 Alkyl,-OR 5c ,-NR 5c R 5d or NR 5c R 5d C replaced by 1-4 It is substituted with one, two, or three independent substituents selected from alkyl groups. In some cases, ring A is selected from a heteroaryl group having one, two, or three heteroatoms selected from substituted or unsubstituted monocyclic 5-6 member O, N, or S groups, or a substituted or unsubstituted monocyclic 6-membered aryl group, where, if substituted, the monocyclic heteroaryl group or monocyclic aryl group is halo,-CN,C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, deuterated C 1-6 Alkyl,-OR 5c, -NR 5c R 5d or -NR 5c R 5d C replaced by 1-4 It is substituted with one, two, or three independent substituents selected from alkyl groups.

[0267] In some embodiments, TIFF0007888622000228.tif16170 is It is TIFF0007888622000229.tif20170, and also, TIFF0007888622000230.tif30170 is It is TIFF0007888622000231.tif37170. Depending on the case, in the formula, TIFF0007888622000232.tif17170 is TIFF0007888622000233.tif27170, where R 4m is Me,Et,Pr,F,CI,CF3,OMe,OCH2F,OCHF2,OCF3, Selected from TIFF0007888622000234.tif17170. Depending on the case, ring A is selected from heteroaryl groups having 1, 2, or 3 heteroatoms selected from substituted or unsubstituted bicyclic 9-10 member O, N, or S, and heterocyclic ring systems containing 1, 2, or 3 heteroatoms selected from substituted or unsubstituted bicyclic (condensed, bridging, or spiro) 9-10 member O, N, or S, where, if substituted, the bicyclic heteroaryl group or bicyclic heterocyclic ring system is halo,-CN,C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, deuterated C 1-6 Alkyl,-OR 5c ,-NR 5c R 5d or NR 5c R 5d C replaced by 1-4It is substituted with one, two, or three independent substituents selected from alkyl groups. In some cases, ring A is selected from a heteroaryl group having one, two, or three heteroatoms selected from substituted or unsubstituted monocyclic 5-6 member O, N, or S groups, or a substituted or unsubstituted monocyclic 6-membered aryl group, where, if substituted, the monocyclic heteroaryl group or monocyclic aryl group is halo,-CN,C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, deuterated C 1-6 Alkyl,-OR 5c , -NR 5c R 5d or -NR 5c R 5d C replaced by 1-4 It is substituted with one, two, or three independent substituents selected from alkyl groups.

[0268] In some embodiments, TIFF0007888622000235.tif17170 is The file is TIFF0007888622000236.tif20170, and in the formula, R 4d is H, and, TIFF0007888622000237.tif30170 is It is TIFF0007888622000238.tif37170. Depending on the case, in the formula, TIFF0007888622000239.tif17170 is TIFF0007888622000240.tif39170, and in the formula, R 4m is Me,Et,Pr,F,CI,CF3,OMe,OCH2F,OCHF2,OCF3, Selected from TIFF0007888622000241.tif17170. Depending on the case, ring A is selected from heteroaryl groups having 1, 2, or 3 heteroatoms selected from substituted or unsubstituted bicyclic 9-10 member O, N, or S, and heterocyclic ring systems containing 1, 2, or 3 heteroatoms selected from substituted or unsubstituted bicyclic (condensed, bridging, or spiro) 9-10 member O, N, or S, where, if substituted, the bicyclic heteroaryl group or bicyclic heterocyclic ring system is halo,-CN,C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, deuterated C 1-6 Alkyl,-OR 5c ,-NR 5c R 5d or NR 5c R 5d C replaced by 1-4 It is substituted with one, two, or three independent substituents selected from alkyl groups. In some cases, ring A is selected from a heteroaryl group having one, two, or three heteroatoms selected from substituted or unsubstituted monocyclic 5-6 member O, N, or S groups, or a substituted or unsubstituted monocyclic 6-membered aryl group, where, if substituted, the monocyclic heteroaryl group or monocyclic aryl group is halo,-CN,C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, deuterated C 1-6 Alkyl,-OR 5c , -NR 5c R 5d or -NR 5c R 5d C replaced by 1-4 It is substituted with one, two, or three independent substituents selected from alkyl groups.

[0269] In some embodiments, -XR 1 teeth The structure TIFF0007888622000242.tif28170 is present in the formula, where ring B is a heterocyclic system containing 0 or 1 additional heteroatom selected from substituted or unsubstituted monocyclic or bicyclic (condensed, bridging, or spiro) 4-7 member O, N, or S, where R is substituted. 1 The substituents are selected from F, Me, Et, CF3, -OMe and -OEt, R 2 m is selected from H, Me, and Et, and m is 0. TIFF0007888622000243.tif17170 is It is TIFF0007888622000244.tif20170, and also, TIFF0007888622000245.tif30170 is The filename is TIFF0007888622000246.tif30170.

[0270] In some embodiments, -XR 1 teeth The structure TIFF0007888622000247.tif28170 is present in the formula, where ring B is a heterocyclic system containing 0 or 1 additional heteroatom selected from substituted or unsubstituted monocyclic or bicyclic (condensed, bridging, or spiro) 4-7 member O, N, or S, where R is substituted. 1 The substituents are selected from F, Me, Et, CF3, -OMe, -OEt, and -NMe2, R 2 m is selected from H, Me, and Et, and m is 0. TIFF0007888622000248.tif17170 is It is TIFF0007888622000249.tif20170, and also, TIFF0007888622000250.tif30170 is The filename is TIFF0007888622000251.tif30170.

[0271] In some embodiments, -XR 1 teeth It has the structure of TIFF0007888622000252.tif20170, R 1a and R 1b C is either substituted or non-substituted. 1-3 Selected from alkyl and substituted or unsubstituted C3 cycloalkyl groups, R 2 m is selected from H, Me, and Et, and m is 0. TIFF0007888622000253.tif17170 is It is TIFF0007888622000254.tif20170, and also, TIFF0007888622000255.tif30170 is The filename is TIFF0007888622000256.tif30170.

[0272] In some embodiments, -XR 1 teeth It has the structure of TIFF0007888622000257.tif20170, R 1a and R 1b This is a substitution (sometimes -NR) 1e R 1f (Substituted with) or unsubstituted C 1-3 Selected from alkyl and substituted or unsubstituted C3 cycloalkyl groups, R 2 m is selected from H, Me, and Et, and m is 0. TIFF0007888622000258.tif17170 is It is TIFF0007888622000259.tif20170, and also, TIFF0007888622000260.tif30170 is The filename is TIFF0007888622000261.tif30170.

[0273] In some embodiments, -XR 1 teeth It has the structure of TIFF0007888622000262.tif20170, R 1a and R 1b C is either substituted or non-substituted. 1-3Selected from alkyl and heterocyclic groups having 1, 2, or 3 heteroatoms selected from substituted or unsubstituted 4, 5, or 6-membered O, N, or S, R 2 m is selected from H, Me, and Et, and m is 0. TIFF0007888622000263.tif17170 is It is TIFF0007888622000264.tif20170, and also, TIFF0007888622000265.tif30170 is The filename is TIFF0007888622000266.tif30170.

[0274] In some embodiments, -XR 1 teeth It has the structure of TIFF0007888622000267.tif20170, R 1a and R 1b Each of these can be substituted or not substituted C independently. 1-3 Alkyl and Selected from TIFF0007888622000268.tif26170, Ring C is a heterocyclic system containing 0, 1, or 2 additional heteroatoms selected from substituted or unsubstituted monocyclic 4, 5, or 6-membered O, N, or S, R 2 m is selected from H, Me, and Et, and m is 0. TIFF0007888622000269.tif17170 is It is TIFF0007888622000270.tif20170, and also, TIFF0007888622000271.tif30170 is The filename is TIFF0007888622000272.tif30170.

[0275] In some embodiments, compounds of formula (I) are selected from the table below: TIFF0007888622000273.tif223170TIFF0007888622000274.tif245170TIFF00078886220 00275.tif210170TIFF0007888622000276.tif213170TIFF0007888622000277.tif213170 TIFF0007888622000278.tif248170TIFF0007888622000279.tif223170TIFF00078886220 00280.tif239170TIFF0007888622000281.tif216170TIFF0007888622000282.tif213170 TIFF0007888622000283.tif213170TIFF0007888622000284.tif216170TIFF00078886220 00285.tif216170TIFF0007888622000286.tif210170TIFF0007888622000287.tif229170 TIFF0007888622000288.tif226170TIFF0007888622000289.tif204170TIFF00078886220 00290.tif248170TIFF0007888622000291.tif204170TIFF0007888622000292.tif110170

[0276] In one embodiment of the present invention, a compound of the present invention for use as a pharmaceutical is provided.

[0277] In another embodiment, the present invention provides a pharmaceutical formulation comprising the compound of the present invention and a pharmaceutically acceptable excipient.

[0278] In one embodiment, the pharmaceutical composition may be a composite product containing separate pharmaceutically active agents.

[0279] In a preferred embodiment of the present invention, the compound is a selective FXIIa inhibitor. The term "selective FXIIa inhibitor" means a compound that selectively inhibits FXIIa more than thrombin and FXa. Generally, the compounds of the present invention may have a selectivity for FXIIa over thrombin of at least 10 times, preferably at least 100 times.

[0280] According to another aspect of the present invention, compounds of the present invention are provided for use in the prevention or treatment of conditions regulated by factor XIIa. Conditions preventable or treatable by the regulation of factor XIIa are typically conditions preventable or treatable by the inhibition of factor XIIa. Therefore, compounds of the present invention can be used for the prevention or treatment of conditions preventable or treatable by the inhibition of factor XIIa.

[0281] In another embodiment, the compounds provided by the present invention may be used in the prevention or treatment of the following diseases, or as a co-therapy in the treatment or prevention of the following diseases: Other diseases in which inhibition of FXIIa may be beneficial, such as thrombosis, deep vein thrombosis, pregnancy-related thrombosis, congenital prothrombogenic disorders, thrombosis due to autoimmune conditions, transient ischemic attack, myocardial infarction, peripheral artery occlusion, pulmonary embolism, deep vein microvascular disease, stroke (including patients with atrial fibrillation with or without chronic kidney disease), disseminated intravascular coagulation (DIC), arthritis, neuroinflammatory disorders, Alzheimer's disease, vascular dementia, macular degeneration, diabetic retinopathy, diabetic macular edema, cerebral edema in stroke, edema of other causes, hereditary angioedema, or acquired angioedema; Alternatively, it may be used to reduce the risk of venous and / or arterial thrombosis in patients with the following indications: Viral or bacterial infection, reperfusion injury (also known as ischemia-reperfusion injury), renal failure, liver disease, myocardial infarction, angina pectoris (including unstable angina), atherosclerosis, stroke, cancer, asymptomatic cerebral ischemia, and neurotraumatic injury; Alternatively, it can be used to reduce the risk of venous and / or arterial thrombosis occurring during medical procedures selected from the following: Complex left-sided resection (pulmonary vein resection, VT ablation), transcatheter aortic valve implantation (TAVR) (also known as transcatheter aortic valve implantation (TAVI)), spinal or epidural anesthesia, lumbar diagnostic puncture, thoracic surgery, abdominal surgery, major orthopedic surgery, liver biopsy, transurethral resection of the prostate, endoscopy with biopsy, prostate or bladder biopsy, supraventricular tachycardia (including left-sided ablation by single transseptal puncture), angiography, implantation of pacemakers or implantable cardioverter-defibrillators (ICDs) (except in complex anatomical situations such as congenital heart disease), mechanical valve implantation, prosthetic valve implantation, left ventricular assist devices (LVADs), reocclusion and restenosis after angioplasty or coronary artery bypass grafting, extracorporeal circulation such as extracorporeal membrane oxygenation (ECMO), coronary artery bypass grafting (CABG), and medical procedures involving contact with artificial surfaces, including renal dialysis; Alternatively, it is used to reduce the risk of venous and / or arterial thrombosis occurring in patients undergoing medical procedures selected from the following: Transcatheter aortic valve replacement (TAVR) (also known as transcatheter aortic valve implantation (TAVI)), major orthopedic surgery, pacemaker or implantable cardioverter-defibrillator (ICD) implantation (excluding complex anatomical situations such as congenital heart disease), mechanical valve implantation, prosthetic valve implantation, left ventricular assist devices (LVAD), reocclusion and restenosis after angioplasty or coronary artery bypass grafting, extracorporeal circulation such as extracorporeal membrane oxygenation (ECMO) and coronary artery bypass grafting (CABG).

[0282] The compounds provided by the present invention may be used in the prevention or treatment of the following diseases, or as a co-therapy in the treatment or prevention of the following diseases: thrombosis, deep vein thrombosis, pregnancy-related thrombosis, thrombosis due to autoimmune conditions, venous and arterial thrombosis as a result of viral or bacterial infection, sepsis, complex left-sided resection (pulmonary vein isolation, VT ablation), reperfusion injury (also known as ischemia-reperfusion injury), transcatheter aortic valve replacement (TAVR) (also known as transcatheter aortic valve implantation (TAVI)), spinal or epidural anesthesia, lumbar diagnostic puncture, thoracic surgery, abdominal surgery, major orthopedic surgery, liver biopsy, transurethral resection of the prostate, renal failure, liver disease, endoscopy with biopsy, prostate or bladder biopsy, electrophysiological studies or radiofrequency catheter ablation for supraventricular tachycardia (including left-sided ablation by unilateral transseptal puncture), angiography, pacemaker Patients with atrial fibrillation, including mechanical valve implantation, prosthetic valve implantation, myocardial infarction, angina pectoris (including unstable angina), reocclusion and restenosis after stroke, patients with atrial fibrillation to reduce the risk of stroke, patients with atrial fibrillation and chronic kidney disease, transient ischemic attack, pulmonary embolism, peripheral artery embolism, deep vein microvascular disease, and patients requiring extracorporeal membrane oxygenation (ECMO). Other conditions in which inhibition of FXIIa may be beneficial include patients requiring extracorporeal membrane oxygenation such as coronary artery bypass grafting (CABG), disseminated intravascular coagulation (DIC), atherosclerosis, asymptomatic cerebral ischemia, stroke, neurotraumatic injury, medical procedures including contact with artificial surfaces including renal dialysis, Alzheimer's disease, vascular dementia, macular degeneration, diabetic macular edema, cerebral edema in stroke, edema of other causes, hereditary angioedema, or acquired angioedema.

[0283] The conditions that can be prevented or treated by inhibiting factor XIIa may be conditions related to blood viscosity, blood coagulation, or thrombus formation, for example, the condition may be thrombosis.

[0284] Embodiments of the present invention provide compounds for use in the prevention or treatment of, or in combination with, symptoms associated with high bleeding risk, low bleeding risk, or thromboembolic disorders.

[0285] Embodiments of the present invention provide compounds for use in the prevention or treatment of symptoms associated with a high risk of bleeding, or in co-therapy thereof.

[0286] Embodiments of the present invention provide compounds for use in the prevention or treatment of symptoms associated with low bleeding risk, or in co-therapy thereof.

[0287] Embodiments of the present invention provide compounds for use in the prevention or treatment of symptoms associated with thromboembolic disorders, or in co-therapy thereof.

[0288] Embodiments of the present invention provide compounds for use as part of the prevention or treatment of symptoms associated with high bleeding risk, wherein the treatment is selected from complex left-sided resection (pulmonary vein isolation, VT ablation), spinal or epidural anesthesia, lumbar diagnostic puncture, thoracic surgery, abdominal surgery, major orthopedic surgery, liver biopsy, transurethral resection of the prostate, kidney biopsy, treatment of liver disease or renal failure.

[0289] Embodiments of the present invention provide compounds for use as part of the prevention or treatment of symptoms associated with low bleeding risk, wherein the treatment is selected from therapies including biopsy, endoscopic examination by prostate or bladder biopsy, electrophysiological study or radiofrequency catheter ablation for supraventricular tachycardia (including left-sided ablation by single transseptal puncture), angiography, implantation of a pacemaker or implantable cardioverter-defibrillator (ICD) (excluding complex anatomical situations such as congenital heart disease), mechanical valve implantation, or prosthetic valve implantation.

[0290] In one embodiment, the compounds of the present invention are used to avoid or mitigate contraindications of existing anticoagulant therapies such as dabigatran, rivaroxaban, apixaban, warfarin, edoxaban, and betrixaban.

[0291] One aspect of the present invention provides the use of the compounds of the present invention to avoid or mitigate contraindications of existing anticoagulant therapies such as dabigatran, rivaroxaban, apixaban, warfarin, edoxaban, and betrixaban.

[0292] In one embodiment, the compound of the present invention is used to mitigate the contraindications of treatment using rivaroxaban, where the contraindications are 15 mL / min / 1.73 m 2 This may include patients with an estimated glomerular filtration rate (eGFR) of less than 50%, active bleeding, current or recent gastrointestinal ulcers, esophageal varices, recent brain or spinal cord injury, recent brain, spinal cord, or ophthalmic surgery, recent intracranial hemorrhage, malignant neoplasms, vascular aneurysms, artificial heart valves, coagulation disorders due to liver disease, and clinically relevant bleeding risks, as well as patients with Child-Pugh level B and C cirrhosis, or patients taking any other anticoagulant except when switching to or from warfarin treatment, and patients taking potent inhibitors of cytochrome P3A4 enzyme and P-glycoprotein such as ketoconazole, or HIV protease inhibitors such as ritonavir.

[0293] In one embodiment, the compound of the present invention is used to mitigate contraindications to treatment using apixaban, where the contraindications are a creatinine clearance (CrCl) of less than 15 mL / min or 15 mL / min / 1.73 m 2This may include patients with an eGFR of less than 50%, active bleeding, current or recent gastrointestinal ulcers, esophageal varices, recent brain or spinal cord injury, recent brain, spine, or ophthalmic surgery, recent intracranial hemorrhage, malignant neoplasms, vascular aneurysms, coagulation disorders due to liver disease and clinically relevant bleeding risks, artificial heart valves, patients taking any other anticoagulant except when switching to or switching from warfarin treatment, or patients taking potent inhibitors of cytochrome P3A4 enzyme and P-glycoprotein such as ketoconazole, e.g., ketoconazole, or HIV protease inhibitors such as ritonavir, e.g., ritonavir.

[0294] In one embodiment, the compound of the present invention is used to mitigate contraindications to treatment with edoxaban, the contraindications including the avoidance of edoxaban in NVAF patients with CrCl levels exceeding 95 mL / min due to a higher risk of ischemic stroke compared to warfarin.

[0295] In one embodiment, the compounds of the present invention are used to mitigate contraindications to treatment with dabigatran, where contraindications include the prevention of stroke with atrial fibrillation (prevention of systemic embolism associated with stroke and non-valvular atrial fibrillation), patients with renal impairment or undergoing dialysis with CrCl less than 15 mL / min, treatment of DVT or PE (indicated for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients treated with parenteral anticoagulants for 5-10 days), patients with CrCl less than 30 mL / min or undergoing dialysis, and prevention of DVT or PE (indicated for the prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE) after total hip arthroplasty). Dabigatran is contraindicated in combination with defibrotide, mifepristone, and dried concentrated human prothrombin complex. Dabigatran should not be used in combination with the following: antithrombin alpha, antithrombin iii, apixaban, carbamazepine, dalteparin, dexamethasone, doxorubicin, doxorubicin liposome, doronedarone, edoxaban, enoxaparin, fondaparinux, fosphenytoin, heparin, ketoconazole, repiridine, nefazodone, phenobarbital, phenytoin, primidone, rifampicin, St. John's wort, tenofovir DF, tipranavir, vinblastine, and warfarin.

[0296] In one embodiment, the compounds of the present invention are used to mitigate contraindications to treatment using dabigatran, where contraindications include renal impairment (CrCl < 15 mL / min), hemodialysis, hypersensitivity, active pathological bleeding, impaired hemostasis, mechanical or artificial heart valves, thromboembolic events (e.g., valve thrombosis, stroke, TIA, MI), excessive major bleeding (mainly postoperative pericardial effusion requiring intervention for hemodynamic degradation), increased risk of bleeding during childbirth, anticoagulants for active bleeding, elective surgery or invasive procedures, increased risk of stroke, antiplatelet agents, warfarin, heparin Use in patients undergoing fibrinolytic therapy, and in combination with long-term NSAIDs or aspirin, with congenital or acquired coagulation disorders, conditions such as ulcerative gastrointestinal disease and other gastritis, recent bleeding, recent brain, spine, or ophthalmic surgery, patients undergoing neuroaxial anesthesia (spinal / epidural anesthesia), patients undergoing spinal puncture at risk of developing epidural or spinal hematoma that may cause long-term or permanent paralysis, including co-administration with P-gp inducers and inhibitors, P-gp inducers (e.g., rifampicin) or any combination thereof.

[0297] In one embodiment, the compound of the present invention is used to mitigate contraindications to treatment using betrixaban, which include patients taking P-gp inhibitors, patients with severe renal impairment, patients with hepatic impairment, patients with intrinsic coagulation disorders, or patients with artificial heart valves, concomitant administration with drugs that affect hemostasis (thus increasing the risk of bleeding), concomitant administration with aspirin, concomitant administration with other antiplatelet agents, concomitant administration with other anticoagulants, concomitant administration with heparin, concomitant administration with thrombolytic agents, concomitant administration with selective serotonin reuptake inhibitors (SSRIs), concomitant administration with serotonin-norepinephrine reuptake inhibitors (SNRIs), and concomitant administration with nonsteroidal anti-inflammatory drugs (NSAIDs).

[0298] In one embodiment, the compounds of the present invention can be used as anticoagulants for the prevention and / or treatment of thromboembolic disorders, where the disorder is one of the following: myocardial infarction, angina pectoris (including unstable angina), reocclusion and restenosis after angioplasty or coronary artery bypass surgery, stroke, patients with atrial fibrillation to reduce the risk of stroke, patients with atrial fibrillation and chronic kidney disease, transient ischemic attack, peripheral artery occlusion, reperfusion injury also known as ischemia-reperfusion injury, transcatheter aortic valve replacement (TAVR) also known as transcatheter aortic valve implantation (TAVI), pulmonary embolism, deep vein microvascular disease, or patients requiring extracorporeal membrane oxygenation (ECMO).

[0299] In one embodiment, the compounds according to the present invention may be applied to prevent and / or treat disseminated intravascular coagulation (DIC).

[0300] In one embodiment, the compounds of the present invention can also be applied to the prevention and / or treatment of atherosclerosis and arthritis, and further, to the prevention and / or treatment of thrombosis in patients with cancer.

[0301] In one embodiment, the compound of the present invention is used in a method for preventing and / or treating thrombosis.

[0302] In one embodiment of the present invention, the compounds disclosed herein may be used as anticoagulants.

[0303] In another embodiment, the present invention provides a method for preventing or treating a symptom selected from the following: Other diseases in which inhibition of FXIIa may be beneficial, such as thrombosis, deep vein thrombosis, pregnancy-related thrombosis, congenital thromboprotoxic disorders, thrombosis due to autoimmune conditions, transient ischemic attack, myocardial infarction, peripheral artery occlusion, pulmonary embolism, deep vein microvascular disease, stroke (including patients with atrial fibrillation with or without chronic renal disease), disseminated intravascular coagulation (DIC), Alzheimer's disease, vascular dementia, macular degeneration, diabetic macular edema, cerebral edema in stroke, edema of other causes, hereditary angioedema, or acquired angioedema; Alternatively, the following methods are provided to reduce the risk of venous thrombosis and / or arterial thrombosis in patients with indications selected from the following: Viral or bacterial infection, reperfusion injury (also known as ischemia-reperfusion injury), renal failure, liver disease, myocardial infarction, angina pectoris (including unstable angina), atherosclerosis, stroke, cancer, asymptomatic cerebral ischemia, and neurotraumatic injury; Alternatively, the following methods are provided to reduce the risk of venous and / or arterial thrombosis occurring during medical procedures selected from the following: Complex left-sided resection (pulmonary vein isolation, VT ablation), reperfusion injury (also known as ischemia-reperfusion injury), transcatheter aortic valve replacement (TAVR) (also known as transcatheter aortic valve implantation (TAVI)), spinal or epidural anesthesia, lumbar diagnostic puncture, thoracic surgery, abdominal surgery, major orthopedic surgery, liver biopsy, transurethral resection of the prostate, renal failure, liver disease, endoscopy with biopsy, prostate or bladder biopsy, electrophysiological studies or radiofrequency catheterization for supraventricular tachycardia Medical procedures involving contact with artificial surfaces, including luablation (including left-sided ablation via unilateral transseptal puncture), angiography, pacemaker or implantable cardioverter-defibrillator (ICD) implantation (excluding complex anatomical conditions such as congenital heart disease), mechanical valve implantation, prosthetic valve implantation, left ventricular assist devices (LVADs), reocclusion and restenosis after angioplasty or coronary artery bypass grafting, extracorporeal circulation such as extracorporeal membrane oxygenation (ECMO), coronary artery bypass grafting (CABG), and renal dialysis; Alternatively, the following methods are provided to reduce the risk of venous and / or arterial thrombosis occurring in patients who have undergone a medical procedure selected from the following: Transcatheter aortic valve replacement (TAVR) (also known as transcatheter aortic valve implantation (TAVI)), major orthopedic surgery, pacemaker or implantable cardioverter-defibrillator (ICD) implantation (excluding complex anatomical situations such as congenital heart disease), mechanical valve implantation, prosthetic valve implantation, left ventricular assist devices (LVAD), reocclusion and restenosis after angioplasty or coronary artery bypass grafting, extracorporeal circulation such as extracorporeal membrane oxygenation (ECMO) and coronary artery bypass grafting (CABG); Herein, the above method includes administering a therapeutically effective amount of the compound of the present invention, or administering a therapeutically effective amount of the compound of the present invention as co-therapy to a patient in need.

[0304] In one embodiment, the present invention provides a method for the prevention and / or treatment of thrombosis or deep vein thrombosis, the symptoms of which the prevention and / or treatment are thrombosis, pregnancy-related thrombosis, congenital thromboprotoxic disorders, thrombosis resulting from autoimmune conditions, venous and arterial thrombosis as a result of viral or bacterial infection, sepsis, complex left-sided resection (pulmonary vein isolation, VT ablation), spinal or epidural anesthesia, lumbar diagnostic puncture, thoracic surgery, abdominal surgery, major orthopedic surgery, liver biopsy, Transurethral resection of the prostate, kidney biopsy, renal failure, liver disease, endoscopy with biopsy, prostate or bladder biopsy, electrophysiological studies or radiofrequency catheter ablation for supraventricular tachycardia (including left-sided ablation via unilateral transseptal puncture), angiography, pacemaker or implantable cardioverter-defibrillator (ICD) implantation (except in complex anatomical situations such as congenital heart disease), mechanical valve implantation, artificial valve implantation, myocardial infarction, angina pectoris (including unstable angina), angioplasty or aortic artery Thrombosis in patients with reocclusion after coronary artery bypass grafting, stroke, atrial fibrillation to reduce the risk of stroke, atrial fibrillation and chronic kidney disease, transient ischemic attack, peripheral artery embolism, pulmonary embolism, deep vein microvascular disease, extracorporeal membrane oxygenation (ECMO), extracorporeal membrane oxygenation such as coronary artery bypass grafting (CABG), disseminated intravascular coagulation (DIC), atherosclerosis, arthritis, cancer, asymptomatic ischemic stroke, and neuropathy. Other diseases in which inhibition of FXIIa may be beneficial, such as transtraumatic injuries, neuroinflammatory disorders, medical procedures including contact with artificial surfaces including renal dialysis, Alzheimer's disease, vascular dementia, macular degeneration, diabetic retinopathy, diabetic macular edema, cerebral edema in stroke, other causes of edema, hereditary angioedema or acquired angioedema, wherein the above method comprises administering a therapeutically effective amount of the compound of the present invention or administering a therapeutically effective amount of the compound of the present invention as co-therapy.

[0305] In one embodiment of the present invention, a method for preventing coagulation is provided, comprising administering a therapeutically effective amount of the compound of the present invention.

[0306] In one embodiment of the present invention, a method for preventing and / or treating thrombosis is provided, comprising administering a therapeutically effective amount of the compound of the present invention.

[0307] In one embodiment of the present invention, the use of the compound of the present invention in the manufacture of a pharmaceutical product for use in the prevention and / or treatment of a condition (which may be thrombosis) that can be prevented and / or treated by inhibition of factor XII (or optionally factor XIIa).

[0308] In another embodiment of the present invention, a pharmaceutical composition comprising the compound of the present invention and a pharmaceutically acceptable excipient is provided.

[0309] In one embodiment, the pharmaceutical composition may be a combination product containing an additional pharmaceutically active agent. The additional pharmaceutically active agent may be one of those disclosed elsewhere in this specification.

[0310] The compounds of the present invention may be used for the prevention and / or treatment of any of the conditions disclosed above. Alternatively, the compounds of the present invention may be used as co-therapy in the prevention and / or treatment of the conditions disclosed above. When the compounds of the present invention are used as co-therapy for a particular condition, it means that the compounds of the present invention may be used in combination with other therapies known in the art for that condition. For example, FXII(a) inhibitors may be used in combination with antiplatelet therapy to provide an enhanced antithrombotic effect without increasing the risk of bleeding compared to antiplatelet therapy alone. Furthermore, FXII(a) inhibitors may be used in combination with other therapies.

[0311] The following are definitions of terms used in this application. Any term not defined herein shall have the usual meaning as one would understand it to those skilled in the art.

[0312] The term "halo" or "halogen" refers to one of the halogens in Group 17 of the periodic table. In particular, the term refers to fluorine, chlorine, bromine, and iodine. Preferably, the term refers to fluorine or chlorine.

[0313] The term "alkyl" refers to a linear or branched hydrocarbon chain. For example, "C 1-6 "alkylene" refers to a linear or branched hydrocarbon chain containing 1, 2, 3, 4, 5, or 6 carbon atoms, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl. "Alkylene group" may similarly be linear or branched and may have two bonding positions to the remainder of the molecule. Furthermore, an alkylene group may correspond, for example, to one of the alkyl groups listed in this paragraph. Alkyl and alkylene groups may be unsubstituted or substituted with one or more substituents. Possible substituents are listed below. Substituents for alkyl groups may be halogens such as fluorine, chlorine, bromine, and iodine, OH, C 1-6 It can be an alkoxy.

[0314] The term "alkoxy" refers to an alkyl group that is bonded to a molecule via oxygen. For example, "C 1-6 "Alkoxy" means a group containing 1, 2, 3, 4, 5, or 6 carbon atoms, where the alkyl portion can be linear or branched, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl. Therefore, alkoxy groups may also be methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, and n-hexoxy. The alkyl portion of the alkoxy group may be unsubstituted or substituted with one or more substituents. Possible substituents are listed below. Substituents of the alkyl group may also be halogens such as fluorine, chlorine, bromine, and iodine, and OH, C 1-6 It can be an alkoxy.

[0315] The term "haloalkyl" refers to a hydrocarbon chain substituted with at least one halogen atom, such as fluorine, chlorine, bromine, and iodine, each independently selected. For example, "C 1-6 "Haloalkyl" refers to a linear or branched hydrocarbon containing 1, 2, 3, 4, 5, or 6 carbon atoms substituted with at least one halogen. The halogen atom can be located at any position on the hydrocarbon chain. For example, C 1-6 Haloralkyls include chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl (e.g., 1-chloromethyl and 2-chloroethyl), trichloroethyl (e.g., 1,2,2-trichloroethyl, 2,2,2-trichloroethyl), fluoroethyl (e.g., 1-fluoromethyl and 2-fluoromethyl), trifluoroethyl (e.g., 1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl), chloropropyl, trichloropropyl, fluoropropyl, and trifluoropropyl.

[0316] The term "alkenyl" refers to a branched or straight hydrocarbon chain containing at least one double bond. For example, "C 2-6 The term "alkynyl" refers to a branched or straight hydrocarbon chain having 2, 3, 4, 5, or 6 carbon atoms and containing at least one double bond. The double bond may exist as an E or Z isomer. The double bond may be at any possible position in the hydrocarbon chain. For example, "C 2-6 The "alkenyl" may be etenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, and hexadienyl.

[0317] The term "alkynyl" refers to a branched or straight hydrocarbon chain containing at least one triple bond. For example, "C 2-6The term "alkynyl" refers to a branched or straight hydrocarbon chain having 2, 3, 4, 5, or 6 carbon atoms and containing at least one triple bond. The triple bond may be at any possible position in the hydrocarbon chain. For example, "C2-6 alkynyl" may be ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0318] The term "carbocyclic" refers to a cyclic system containing saturated or unsaturated carbon atoms. A "carbocyclic" system may be a monocyclic, bicyclic, or tricyclic fused polycyclic system. A "carbocyclic" moiety may contain 3 to 14 carbon atoms, for example, 3 to 8 carbon atoms in a monocyclic system and 7 to 14 carbon atoms in a polycyclic system. "Carbocyclic" encompasses fused cyclic systems including cycloalkyl moies, cycloalkenyl moies, aryl ring systems, and aromatic moies.

[0319] The term "heterocyclic" refers to a saturated or unsaturated cyclic system containing at least one heteroatom selected from N, O, or S. A "heterocyclic" system may contain one, two, three, or four heteroatoms, for example, one or two. A "heterocyclic" system may be a monocyclic or fused polycyclic system, for example, a bicyclic or tricyclic system. A "heterocyclic" portion may contain 3 to 14 carbon atoms, for example, 3 to 8 carbon atoms in a monocyclic system and 7 to 14 carbon atoms in a polycyclic system. A "heterocyclic" system includes heterocycloalkyl moieties, heterocycloalkenyl moieties, and heteroaromatic moieties. For example, the heterocyclic group may be oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, and tetrahydropyran.

[0320] The term "cycloalkyl" refers to a saturated hydrocarbon ring system. For example, "C 3-8 A "cycloalkyl" refers to a ring system containing 3, 4, 5, 6, 7, or 8 carbon atoms. For example, "C 3-8"Cycloalkyl" may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

[0321] "C 3-8 The term "cycloalkenyl" refers to an unsaturated hydrocarbon ring system containing 3, 4, 5, 6, 7, or 8 non-aromatic carbon atoms. As long as the ring system is not aromatic, the ring may contain multiple double bonds. For example, "C 3-8 "Cycloalkyl" may be cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadiene, cyclooctenyl, and cycloatadienyl.

[0322] The term "heterocycloalkyl" refers to a saturated hydrocarbon ring system containing a carbon atom and at least one heteroatom within a ring selected from N, O, and S. For example, there may be one, two, or three heteroatoms, and possibly one or two. A "heterocycloalkyl" may be bonded to the rest of the molecule via any carbon atom or heteroatom. One or more "heterocycloalkyls" may be bonded to the rest of the molecule, for example, one or two, and these bonds can be via any atom in the ring. For example, a "heterocycloalkyl" may be "C 3-8 "heterocycloalkyl" or "C 3-8 It may also be "complex algebra". 3-8 "heterocycloalkyl" or "C 3-8 The term "heterocyclic ring" refers to a saturated hydrocarbon ring system in which at least one of the heteroatoms in the ring, selected from N, O, and S, contains 3, 4, 5, 6, 7, or 8 atoms. "Heterocycloalkyl" may also be oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, and tetrahydropyran.

[0323] The term "heterocycloalkenyl" refers to a non-aromatic unsaturated hydrocarbon ring system containing a carbon atom and at least one heteroatom in the ring selected from N, O, and S. For example, there may be one, two, or three heteroatoms, and possibly one or two. A "heterocycloalkenyl" may be bonded to the rest of the molecule via any carbon atom or heteroatom. One or more "heterocycloalkenyls" may be bonded to the rest of the molecule, for example, one or two remaining, and these bonds may be via any atom in the ring. For example, a "heterocycloalkenyl" may be "C 3-8 It may also be "heterocycloalkenyl". 3-8 The term "heterocycloalkenyl" refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7, or 8 atoms, where at least one of the atoms is a heteroatom in the ring selected from N, O, and S. "Heterocycloalkenyl" may also be tetrahydropyridine, dihydropyran, dihydrofuran, or pyrroline.

[0324] When the term "aromatic" is applied to substituents as a whole, it refers to a monocyclic or polycyclic ring system in which all atoms contributing to the conjugated π system are coplanar, or a conjugated π system within a ring system has 4n+2 electrons.

[0325] The term "aryl" refers to an aromatic hydrocarbon ring system. The ring system has 4n+2 electrons in the conjugated π system within the ring, where all atoms contributing to the conjugated π system are in the same plane. For example, "aryl" may be phenyl and naphthyl. The aryl system itself may be substituted with other groups. The term "aryl" also includes bicyclic or tricyclic ring systems that are not entirely aromatic but contain an aromatic ring within the ring system, such as indanes or tetralines.

[0326] The term "heteroaryl" refers to an aromatic hydrocarbon ring system having at least one heteroatom in a single ring or fused ring system, selected from O, N, and S. The ring or ring system has 4n+2 electrons in the conjugated π system, where all atoms contributing to the conjugated π system are in the same plane. For example, "heteroaryl" may be imidazole, thien, furan, thiantrene, pyrrole, benzimidazole, pyrazole, pyrazine, pyridine, pyrimidine, and indole. The term "heteroaryl" also includes bicyclic or tricyclic ring systems that are not entirely aromatic but contain an aromatic ring. The heteroatom may be present in a ring system of aromatic or non-aromatic rings. For example, heteroaryl also includes chromene, chroman, indoline, and tetrahydroquinoline.

[0327] A bond ending in TIFF0007888622000293.tif6170 indicates that the bond is attached to another atom not shown in the structure. A bond that terminates inside the cyclic structure and not on an atom in the cyclic structure indicates that the bond could attach to any atom in the cyclic structure if permitted by valence.

[0328] Solid and dotted lines represent bonds that can be either single or double bonds, where chemically possible. For example, the bonds shown below can be either single or double bonds. TIFF0007888622000294.tif13170

[0329] If a portion is substituted, it is chemically possible and can be substituted at any point on the portion that matches the valence requirement. This portion may be substituted with one or more substituents, e.g., 1, 2, 3, or 4 substituents; there may be one or two substituents on one group. If there are two or more substituents, the substituents may be the same or different. Substituents include OH, NHR, amidino, guanidino, hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, C(O)H, acyl, acyloxy, carboxy, sulfo, sulfamoyl, carbamoyl, cyano, azo, nitro, halo, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 2-6 Alkenil, C 2-6 Alkynyl, aryl, heteroaryl, or alkaryl may be selected. If substituted with an alkyl group, the substituent may be =O. R is H, C 1-6 Alkyl, C 3-8 The group may be selected from cycloalkyl, phenyl, benzyl, or phenethyl groups, where R is H or C 1-3 It is alkyl. If a portion is substituted with two or more substituents and two substituents are adjacent, then C 4-8 The ring is a saturated or unsaturated hydrocarbon ring having 4, 5, 6, 7, or 8 carbon atoms, along with the atoms of the substituted portion, or a saturated or unsaturated hydrocarbon ring having 4, 5, 6, 7, or 8 carbon atoms and 1, 2, or 3 heteroatoms.

[0330] Substituents exist only at chemically possible positions, and those skilled in the art can determine (experimentally or theoretically) which substitutions are chemically possible and which are not without undue effort.

[0331] Ortho, meta, and para substitutions are well understood terms in the art. Without a doubt, an "ortho" substitution is a substitution pattern in which an adjacent carbon atom has a substituent, such as a simple group (e.g., the fluoro group in the example below), or TIFF0007888622000295.tif6170 is the other part of the molecule indicated by the binding end. TIFF0007888622000296.tif23170

[0332] A "meta" substitution is a substitution pattern in which two substituents are located on a single carbon atom that has been removed from each other; that is, there is a single carbon atom between the substituted carbons. In other words, the substituent is on a second atom that is far from the atom with the other substituent. For example, the following groups are meta-substituted. TIFF0007888622000297.tif23170

[0333] A "para" substitution is a substitution pattern in which two substituents are located on two carbon atoms that have been removed from each other; that is, there are two carbon atoms between the substituted carbons. In other words, there is a substituent on a third atom that is separated from the atom with another substituent. For example, the following groups are para-substituted. TIFF0007888622000298.tif14170

[0334] "Acyl" refers to an organic radical derived from an organic acid by, for example, the removal of a hydroxyl group (e.g., a radical having the formula RC(O)-). In the formula, R is H, C 1-6 Alkyl, C 3-8 The group may be selected from cycloalkyl, phenyl, benzyl, or phenethyl groups, for example, R is H or C 1-3 It is alkyl. In one embodiment, the acyl is alkyl-carbonyl. Examples of acyl groups include, but are not limited to, formyl, acetyl, propionyl, and butyryl. A specific acyl group is acetyl.

[0335] Throughout this specification, the disclosure of compounds also includes their pharmaceutically acceptable salts, solvates, and stereoisomers. Where a compound has a stereocenter, both (R) and (S) stereoisomers are intended by the present invention, and equally, mixtures of stereoisomers or racemic mixtures are completed by this application. Where a compound of the present invention has two or more stereocenters, any combination of (R) and (S) stereoisomers is intended. Combinations of (R) and (S) stereoisomers may result in a mixture of diastereomers or a single diastereoisomer. The compounds of the present invention may exist as a single stereoisomer, or as a mixture of stereoisomers such as a racemic mixture and a mixture of other enantiomers, and a mixture of diastereomers. Where the mixture is a mixture of enantiomers, the enantiomer excess may be any of those disclosed above. Where the compound is a single stereoisomer, the compound may further contain other diastereoisomers or enantiomers as impurities. Therefore, the enantiomeric excess (ee) or diastereomer excess (de) of a single stereoisomer does not necessarily have to be 100%, but the ee or de may be at least about 85% and at least 60% or less. For example, the ee or de may be 90% or more, 90% or more, 80% or more, 70% or more, 60% or more, 50% or more, 40% or more, 30% or more, 20% or more, or 10% or more.

[0336] The present invention aims to provide pharmaceutically acceptable salts of the compounds of the present invention. These may include acid addition salts and base salts of the compounds. These may also be acid addition salts and base salts of the compounds. Furthermore, the present invention aims to provide solvates of the compounds. These may also be hydrates or other solvated forms of the compounds.

[0337] A suitable acid addition salt is formed from an acid that forms a non-toxic salt. Examples include acetate, aspartate, benzoate, besilate, bicarbonate / carbonate, bisulfate / sulfate, borate, camusylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 1,5-naphthalenedisulfonate, 2-naphthylate, nicotinate, nitrate, orotinate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, sugarate, stearate, succinate, tartrate, tosylate, and trifluoroacetate.

[0338] Suitable base salts are formed from bases that form non-toxic salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, and zinc salts. Acids and bases may also form hemisalts, such as hemisulfates and hemicalcium salts. For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0339] A pharmaceutically acceptable salt of the compound of formula (I) can be prepared by one or more of the following three methods: (i) by reacting the compound of the present invention with a desired acid or base; (ii) by using a desired acid or base to remove an acid or base-unstable protecting group from a suitable precursor of the compound of the present invention, or by opening the ring of a suitable cyclic precursor such as a lactone or lactam; or (iii) Converting one salt of the compound of the present invention to another salt by reaction with a suitable acid or base, or by means of a suitable ion exchange column.

[0340] All three reactions are typically carried out in solution. The resulting salt may precipitate and be collected by filtration or recovered by evaporation of the solvent. The degree of ionization in the resulting salt can vary from fully ionized to almost unionized.

[0341] The compounds of the present invention may exist in both non-solvated and solvated forms. The term “solvate” is used herein to describe a molecular complex comprising the compounds of the present invention and one or more pharmaceutically acceptable solvent molecules, such as ethanol, in stoichiometric amounts. The term “hydrate” is used when the solvent is water.

[0342] Complex compounds such as clathrates and drug-host inclusion complexes are included within the scope of the present invention, where, in contrast to the solvates described above, the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are drug complexes containing two or more organic and / or inorganic components, which may be present in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionized, partially ionized, or non-ionized. For a review of such complexes, see the article by Haleblian in the Journal of Pharmaceutical Science (J Pharm Sci), 64(8), 1269-1288 (August 1975).

[0343] Hereafter, all references to any compound of any given formula include references to its salts, solvates, and complexes, as well as references to the solvates and complexes of its salts.

[0344] The compounds of the present invention include compounds of several formulas defined herein (including all of their polymorphs and their crystal habits), their prodrugs and isomers (including optical isomers, geometric isomers and tautomers) as defined herein, and isotopically labeled compounds of the present invention.

[0345] The present invention also includes all pharmaceutically acceptable isotope-labeled compounds of the present invention, in which one or more atoms are replaced by atoms having the same atomic number but having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.

[0346] Suitable isotopes to include in the compound of the present invention include, for example, 2 H and 3 Hydrogen isotopes like H, 11 C, 13 C and 14 carbon isotopes like C, 36 Chlorine isotopes such as Cl, 32 Fluorine isotopes such as F, 123 I and 125 Iodine isotopes like I, 13 N and 15 Nitrogen isotopes such as N, 15 O, 17 O and 18 Oxygen isotopes like O, 125 Phosphorus isotopes such as P, and 18 Examples include sulfur isotopes such as S.

[0347] Specific isotope-labeled compounds, such as those incorporating radioactive isotopes, are useful in drug and / or substrate tissue distribution studies. Radioactive isotope tritium, i.e. 3 H, and carbon-14, i.e. 14 C is particularly beneficial for this purpose in terms of their ease of implementation and easy detection means.

[0348] Substitution with heavier isotopes such as deuterium, i.e., 2H, can provide certain therapeutic advantages, such as increased in vivo half-life or reduced dose requirements, and may be recommended in some situations.

[0349] Before purification, the compounds of the present invention may exist as a mixture of enantiomers, depending on the synthetic procedure used. These enantiomers can be separated by conventional techniques known in the art. Therefore, the present invention encompasses individual enantiomers and mixtures thereof.

[0350] In some steps of the manufacturing process for the compounds of the present invention, it may be necessary to protect potentially reactive functional groups that are not to be reacted, and consequently, to cleave such protecting groups. In such cases, any compatible protecting group can be used. In particular, methods of protection and deprotection such as those described in "Protective Groups in Organic Synthesis A." by T. WGREENE, Willey Interscience Publication 1981, or "Protecting groups." by PJ Kocienski, Georg Thieme Verlag 1994, can be used. All of the reactions and preparations of novel starting materials used in the aforementioned methods, as well as conventional suitable reagents and reaction conditions for their performance or preparation, and procedures for isolating the desired product, are well known to those skilled in the art by prior art and by referring to the prior art and the examples and preparations herein.

[0351] Furthermore, the compounds of the present invention and the intermediates for their preparation can be purified according to various well-known methods, such as crystallization or chromatography.

[0352] One or more compounds of the present invention can be combined with one or more pharmaceutical agents, such as anti-inflammatory agents, anti-fibrotic agents, chemotherapeutic agents, anticancer agents, immunosuppressants, antitumor vaccines, cytokine therapies, or tyrosine kinase inhibitors, for the treatment of ROCK-modulated conditions such as fibrous diseases, autoimmune, inflammatory fibrous conditions, inflammatory conditions, central nervous system disorders, or cancer.

[0353] Such combination therapy can be achieved by simultaneous, sequential, or separate administration of the individual components of the treatment. Such combination products utilize the compounds of the present invention within the therapeutically effective dosage range described above, and other pharmaceutically active agents within their approved dosage ranges.

[0354] The compounds of the present invention can be administered in vivo, either alone or in combination with other pharmaceutically active agents, such as those particularly effective in treating and / or preventing the aforementioned diseases. Suitable combinations include, for example, the compounds of the present invention and preferably one or more of the following active substances: lipid-lowering agents, particularly HMG-CoA-(3-hydroxy-3-methylglutaryl-coenzyme A)-reductase inhibitors; coronary artery treatment agents / vasodilators, particularly ACE (angiotensin-converting enzyme) inhibitors; AII (angiotensin II) receptor antagonists; β-adrenergic receptor antagonists; alpha-1-adrenergic receptor antagonists; diuretics; Calcium channel blockers; substances that increase cyclic guanosine monophosphate (cOMP), e.g., soluble guanylate cyclase stimulants; plasminogen activators (thrombolytic / fibrinolytic agents) and thrombolytic / fibrinolytic compounds, e.g., inhibitors of plasminogen activator inhibitors (PAI inhibitors) or thrombin-activated fibrinolysis inhibitors (TAFIs); substances with anticoagulant activity (anticoagulants); substances that inhibit platelet aggregation (platelet aggregation inhibitors, slambocyte aggregation inhibitors); and fibrinogen receptor antagonists (glycoprotein IIb / IIIa antagonists).

[0355] The compounds of the present invention may be advantageous in the treatment of cancer because cancer patients may have a thrombus-promoting state and require anticoagulants. This must usually be balanced by the risk of bleeding, and therefore, the compounds described herein provide safer anticoagulants in cancer patients because they reduce the risk of bleeding. For the treatment of cancer, the compounds of the present invention may be administered in combination with known cancer treatments.

[0356] The compounds of the present invention may exist in single-crystal form, as a mixture of crystalline forms, or in amorphous form. Therefore, compounds of the present invention intended for pharmaceutically active use may be administered as crystalline or amorphous products. They can be obtained as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze-drying, spray-drying, or evaporative drying. Microwave or high-frequency drying may be used for this purpose.

[0357] The dosage of the above-mentioned compounds of the present invention will, of course, vary depending on the compound used, the mode of administration, the desired treatment, and the disorder being addressed. Those skilled in the art of drug administration will readily identify the appropriate dosage, for example, the dosage may be a standard dosage.

[0358] The compounds of the present invention or their pharmaceutically acceptable salts may be used alone, but generally, they are administered in the form of pharmaceutical compositions in which the compounds of the present invention or their pharmaceutically acceptable salts are associated with a pharmaceutically acceptable adjuvant, diluent, or carrier. Conventional procedures for the selection and preparation of appropriate pharmaceutical formulations are described, for example, in "Pharmaceuticals Science of Dosage Form Designs" by MEAulton, Churchill Livingston, 1988.

[0359] Depending on the method of administration of the compound of the present invention, the pharmaceutical composition used to administer the compound of the present invention comprises, by weight percentage, all of which are based on the whole composition, preferably 0.05 to 99% by weight (weight percent) of the compound of the present invention, more preferably 0.05 to 80% by weight of the compound of the present invention, even more preferably 0.10 to 70% by weight of the compound of the present invention, and even more preferably 0.10 to 50% by weight of the compound of the present invention.

[0360] Pharmaceutical compositions may be administered topically (e.g., onto the skin) in the form of, for example, creams, gels, lotions, solutions, or suspensions; or systemically orally in the form of, for example, tablets, capsules, syrups, powders, or granules; or parenterally in the form of sterile solutions, suspensions, or emulsions for injection (including intravenous, subcutaneous, intramuscular, intravascular, or injectable); or rectally in the form of suppositories; or by aero.

[0361] For oral administration, the compounds of the present invention may be mixed with an adjuvant or carrier (e.g., lactose, saccharose, sorbitol, mannitol), starch (e.g., potato starch, corn starch, or amylopectin), a cellulose derivative, a binder (e.g., gelatin or polyvinylpyrrolidone), and / or a lubricant (e.g., magnesium stearate, calcium stearate, polyethylene glycol, wax, paraffin), and then compressed into tablets. If coated tablets are required, the cores prepared as described above may be coated with a concentrated sugar solution that may contain, for example, gum arabic, gelatin, talcum, and titanium dioxide. Alternatively, the tablets may be coated with a suitable polymer dissolved in an organic solvent that readily volatilizes.

[0362] For the preparation of soft gelatin capsules, the compounds of the present invention may be mixed with, for example, vegetable oil or polyethylene glycol. Hard gelatin capsules may contain granules of the compounds using any of the above-mentioned tablet excipients. Alternatively, liquid or semi-solid formulations of the compounds of the present invention may be filled into hard gelatin capsules. Liquid preparations for oral administration may be syrups or suspensions (for example, in the form of a solution containing the compounds of the present invention), with the remainder being a mixture of sugar and ethanol, water, glycerol, and propylene glycol. Optionally, such liquid preparations may contain carboxymethylcellulose as a coloring agent, flavoring agent, sweetener (such as saccharin), preservative, and / or thickener, or other excipients known to those skilled in the art.

[0363] For intravenous (parenteral) administration, the compounds of the present invention may be administered as sterile aqueous or oily solutions.

[0364] The therapeutic dose of the compounds of the present invention will naturally vary according to well-known principles of medicine, depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration.

[0365] The dose level, dose frequency, and duration of treatment of the compounds of the present invention are expected to vary depending on the patient's formulation and clinical indication, age, and comorbidity status. The standard duration of treatment with the compounds of the present invention may be any duration. For example, the duration of treatment may be several days, several weeks, several months, or several years. Treatment may be indefinite. Treatment may be 1 to 7 months for most clinical indications. In cases of recurrent infections or infections associated with tissues or graft materials with insufficient blood supply, such as bones, joints, airways, endocardium, and dental tissue, it may be necessary to extend the duration of treatment beyond 7 days.

[0366] The present invention can also be defined according to the following sections: 1. Compounds of formula (I) and their pharmaceutically acceptable salts: TIFF0007888622000299.tif42170 expression -X is a bond, -C(O)-, C 1-3 Selected from alkylenyl and C2 alkenyl; R 1 -NR 1a R 1b , selected from substituted or unsubstituted 5-10 member monocyclic or bicyclic heteroaryl groups having 1, 2 or 3 heteroatoms selected from O, N or S, substituted or unsubstituted 6-10 member monocyclic or bicyclic aryl groups, substituted or unsubstituted 3-10 member monocyclic or bicyclic (condensed, bridged or spiro) cycloalkyl groups, and substituted or unsubstituted 3-10 member monocyclic or bicyclic (condensed, bridged or spiro) heterocyclic groups having 1, 2 or 3 heteroatoms selected from O, N or S, where R 1a and R 1b C is either substituted or non-substituted. 1-6 Alkyl and substituted or unsubstituted C 3-6 Each is independently selected from the cycloalkyl groups. If substitution is performed here, R 1 The substituents are halo, =O,-CN,-OH,C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl,-OC 3-6 Cycloalkyl, -OC 1-6 Haloalkyl, -NR 1c R 1d ,-NR 1c (SO2)R 1d ,-NR 1c (C(O))R 1d ,-C(O)NR 1c R 1d , and -SO2NR 1c R 1d , a heteroaryl group having 1, 2, or 3 heteroatoms selected from 5-10 membered O, N, or S, and a 6-10 membered aryl group selected from; where R 1c and R 1d Each of them is independent, and H and C are used each time. 1-6 Alkyl, C 3-6Selected from cycloalkyl groups, heteroaryl groups having 1, 2, or 3 heteroatoms selected from 5-10 membered O, N, or S, and 6-10 membered aryl groups. If substitution is performed here, R 1a and R 1b The substituents are halo,-CN,-OH,C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, -OC 1-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -OO-C 1-6 Haloalkyl, -NR 1e R 1f ,-NR 1e (SO2)R 1f ,-NR 1e (C(O))R 1f ,-C(O)NR 1e R 1f , and -SO2NR 1e R 1f ;R 1e and R 1f Each of them is independent, and H, C each time 1-6 Alkyl, C 3-6 Selected from cycloalkyl groups, heteroaryl groups having 1, 2, or 3 heteroatoms selected from 5-10 membered O, N, or S, and 6-10 membered aryl groups. R 2 H,C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Selected from cycloalkyl and 3- to 6-membered heterocycloalkyl groups; R 3 is Haro,-CN,-OH,C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -NR 3a R 3b ,-NR 3a (C(O))R 3b , and -C(O)NR 3a R 3b Selected from, where R 3a and R3b Each of them is independent, and H, C each time 1-6 Alkyl, C 3-6 Selected from cycloalkyl groups, heteroaryl groups having 1, 2, or 3 heteroatoms selected from 5-10 membered O, N, or S, and 6-10 membered aryl groups. m is selected from 0, 1, 2, or 3; In the formula, the residue TIFF0007888622000300.tif18170 is, The filename is TIFF0007888622000301.tif18170, where L is a bond, -O-, -NR 4b -, and -NR 4c Selected from C(O)-; and TIFF0007888622000302.tif20170R 4a H, -OH, halo, C 1-4 Alkyl, or C 1-4 Selected from haloalkyl groups; R 4b H,C 1-6 Alkyl or -C(O)C 1-6 It is alkyl; R 4c is H or C1-6 alkyl; R 4d is H or C 1-6 It is alkyl; R4 e and R4 f Each of these is independent and is used as H, -CN, Haro, C each time. 1-4 Alkyl, C 1-4 Haloalkyl, -OR 4g ,-NR 4g R 4h ,C 3-8 Selected from cycloalkyl, 3-6 membered heterocyclic, 6-10 membered aryl, and 5-10 membered heteroaryl, where C 3-8 The cycloalkyl, 3-6 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl groups are unsubstituted or 1, 2, or 3R. 4i It is substituted with the base; here, R 4g and R 4hEach of them is independent, and each time, Haro,C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 4j ,-NR 4k R 4l ,-NR 4k (C(O))R 4l ,-C(O)NR 4k R 4l ,-CN,-C(O)R 4g ,=O,-SO2R 4g Selected from benzyl, phenyl, unsubstituted 5 or 6-membered heteroaryl, or methyl-substituted 5 or 6-membered heteroaryl; R 4j H,C 1-4 Alkyl, C 1-4 Selected from haloalkyl, benzyl, and phenyl; R 4k and R 4l Each of them is independent, and H, C each time 1-6 Alkyl, C 3-6 Selected from cycloalkyl groups, heteroaryl groups having 1, 2, or 3 heteroatoms selected from 5-10 membered O, N, or S, and 6-10 membered aryl groups. n is selected from 0, 1, 2, 3, or 4. R 4 H, Halo, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 4g ,-NR 4g R 4h , single-ring or bi-ring 6-10 membered aryl, C 3-8 Selected from cycloalkyl, 3-6 member heterocyclic rings, monocyclic or bicyclic 5-10 member heteroaryl, bicyclic (condensed, bridged, or spiro) 6-10 member cycloalkyl ring systems, and monocyclic or bicyclic (condensed, bridged, or spiro) 6-10 member heterocyclic systems containing 1, 2, or 3 heteroatoms selected from O, N, or S, C 3-8 Cycloalkyl groups, 3-6 membered heterocyclic rings, 6-10 membered aryl groups, 5-10 membered heteroaryl groups, or 6-10 membered heterocyclic systems are either unsubstituted or have 1, 2, or 3 R groups. 4i It is replaced by; R 5 is H or C1-6 It is alkyl, selected from 1 or 2; R 5a and R 5b Each of these is independent, and each time H, substitution, or non-substitution C is used. 1-6 Alkyl, substituted, or unsubstituted C 3-6 Cycloalkyl, and substituted or unsubstituted C 1-6 A haloalkyl group is selected, where each substituent is independently selected from halo, -OH, and -CN; Ring A is a heterocyclic ring system comprising a heteroaryl group having 1, 2, or 3 heteroatoms selected from substituted or unsubstituted 5-10 member monocyclic or bicyclic O, N, or S groups, a substituted or unsubstituted 6-10 member monocyclic or bicyclic aryl group, and a heterocyclic ring system comprising 1, 2, or 3 heteroatoms selected from substituted or unsubstituted monocyclic or bicyclic (condensed, bridging, or spiro) 6-10 member O, N, or S groups, wherein, if substituted, the heteroaryl group, aryl group, or heterocyclic ring system is halo,-CN,C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, deuterated C 1-6 Alkyl,-OR 5c ,-NR 5c R 5d or -NR 5c R 5d C is replaced by 1-4 Selected from alkyl groups substituted with one, two, or three substituents; R 5c and R 5d Each of these is independent, and each time H, substitution, or non-substitution C is used. 1-6 Alkyl, substituted, or unsubstituted C 3-6 Cycloalkyl, and substituted or unsubstituted C 1-6 A haloalkyl group is selected, where each substituent is independently selected from halo, -OH, and -CN.

[0367] 2. Compounds described in Section 1, wherein -X is -C(O)-.

[0368] 3.R 1However, -NR 1a R 1b The compounds according to Section 1 or 2, which are selected from a monocyclic heteroaryl group having 1, 2, or 3 heteroatoms selected from substituted or unsubstituted 5 or 6-membered O, N, or S, and a heterocyclic group having 1, 2, or 3 heteroatoms selected from substituted or unsubstituted 3 to 8-membered monocyclic or bicyclic (condensed, bridged, or spiro) O, N, or S.

[0369] 4.R 1 The compound according to Section 3, wherein is a heterocyclic ring system comprising a nitrogen atom and 0 or 1 additional heteroatoms selected from substituted or unsubstituted 4- to 7-membered monocyclic or bicyclic (condensed, bridging, or spiro) O, N, or S, wherein the heterocyclic ring system is bonded to -X via the nitrogen atom.

[0370] 5.R 1 Compounds described in Section 3, in which the compound is selected from substituted or unsubstituted: TIFF0007888622000303.tif172170

[0371] 6. If R is to be substituted, 1 The substituents are halo,C 1-3 Alkyl, C 1-3 Haloalkyl and -OC 1-3 A compound selected from alkyl groups, as described in any one of sections 3 to 5.

[0372] 7.R 1 ga-NR 1a R 1b The compound described in Section 3.

[0373] 8.R 1a and R 1b However, each can be substituted or not substituted C independently. 1-3 and compounds selected from substituted or unsubstituted C3 cycloalkyl groups, as described in Section 7.

[0374] 9.R 1a and R 1b If substituted, each substituent is a halo,C1-3 Alkyl, C 1-3 Haloalkyl, -OC 1-3 Alkyl, -OC 1-3 Haloalkyl, C 3-6 Cycloalkyl and -NR 1e R 1f A compound selected independently from any one of sections 7-8.

[0375] 10.R 2 However, H and C 1-3 A compound selected from alkyl groups, as described in any of the preceding sections.

[0376] 11. A compound described in any of the preceding sections, where m is 0.

[0377] 12. Residue TIFF0007888622000304.tif19170 is, The compound is TIFF0007888622000305.tif18170, where L is a bond, as described in any of the preceding sections.

[0378] 13. Residue TIFF0007888622000306.tif18170 is, TIFF0007888622000307.tif21170, where R 4d A compound described in any one of sections 1 to 11 above, wherein H is present.

[0379] 14.R 4e and R 4f A compound as described in any of the preceding sections, wherein H is present.

[0380] 15. A compound described in any of the preceding sections in which n is 1.

[0381] 16. A compound listed in any one of sections 1 to 13 where n is 0.

[0382] 17.R 4However, selected from monocyclic or bicyclic 6-10 membered aryls, monocyclic or bicyclic 5-10 membered heteroaryls, and heterocyclic systems containing 1, 2, or 3 heteroatoms selected from monocyclic or bicyclic (condensed, bridged, or spiro) 6-10 membered O, N, or S, where the monocyclic or bicyclic 6-10 membered aryl, monocyclic or bicyclic 5-10 membered heteroaryl, or monocyclic or bicyclic (condensed, bridged, or spiro) 6-10 membered heterocyclic system is unsubstituted, or contains 1, 2, or 3 R 4i A compound described in any of the preceding sections, which is substituted with the above.

[0383] 18.R 4i However, each is independent, and each time it is treated as halo, C1 alkyl, C1 haloalkyl, and -OR 4j A compound selected from any of the above sections.

[0384] 19.R 4 A compound described in any one of sections 1 to 16, wherein the compound is H.

[0385] 20. A compound described in any of the preceding sections, wherein R5 is H.

[0386] 21. A compound described in any of the preceding sections, wherein o is 1.

[0387] 22.R 5a and R 5b A compound as described in any of the preceding sections, wherein H is present.

[0388] 23. Ring A comprises a bicyclic heteroaryl group having 1, 2, or 3 heteroatoms selected from substituted or unsubstituted 9-10 member O, N, or S, and a heterocyclic system containing 1, 2, or 3 heteroatoms selected from substituted or unsubstituted bicyclic (condensed, bridging, or spiro) 9-10 member O, N, or S, where, if substituted, the bicyclic heteroaryl group or heterocyclic system is halo,-CN,C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, deuterium C 1-6 Alkyl,-OR5c ,-NR 5c R 5d , or -NR 5c R 5d C replaced by 1-4 Any of the compounds in the preceding section, substituted with one, two, or three independent groups selected from alkyl groups.

[0389] 24. A bicyclic heteroaryl group or bicyclic heterocyclic system is a halo, C 1-3 Alkyl, C 1-3 Haloalkyl, deuterated C 1-3 Alkyl, or -OR 5c The compounds described in any of the above sections, which may be substituted with one, two, or three substituents independently selected from the above.

[0390] 25. Ring A is a compound selected from any one of the sections 1 to 22 below: TIFF0007888622000308.tif46170

[0391] 26. A pharmaceutical preparation comprising any of the compounds described in Sections 1 to 25 and a pharmaceutically acceptable excipient.

[0392] 27. Use as a medicine of any compound described in any one of Sections 1 to 25.

[0393] 28. Thrombosis, deep vein thrombosis, pregnancy-related thrombosis, thrombosis due to autoimmune conditions, venous and arterial thrombosis resulting from viral or bacterial infection, complex left-sided resection (pulmonary vein resection, VT ablation), reperfusion injury (also known as ischemia-reperfusion injury), transcatheter aortic valve replacement (TAVR) (also known as transcatheter aortic valve implantation (TAVI)), spinal or epidural anesthesia, thoracic surgery, abdominal surgery, major orthopedic surgery, liver biopsy, transurethral resection of the prostate, kidney biopsy, renal failure, liver disease, endoscopy with biopsy, prostate or bladder biopsy, electrophysiological studies or radiofrequency catheter ablation for supraventricular tachycardia (including left-sided ablation by unilateral transseptal puncture), angiography, pacemaker or implantable cardioverter-defibrillator (ICD) implantation (except in complex anatomical situations such as congenital heart disease), Mechanical valve implantation, including prosthetic valve implantation, myocardial infarction, angina pectoris (including unstable angina), reocclusion after angioplasty or coronary artery bypass surgery, stroke, patients with atrial fibrillation to reduce the risk of stroke, patients with atrial fibrillation and chronic kidney disease, transient ischemic attack, peripheral artery occlusion, pulmonary embolism, deep vein microvascular disease, patients requiring extracorporeal membrane oxygenation (ECMO), patients requiring extracorporeal membrane oxygenation such as coronary artery bypass grafting (CABG), Use for the prevention or treatment of symptoms selected from other diseases in which inhibition of FXIIa may be beneficial, including disseminated intravascular coagulation (DIC), atherosclerosis, arthritis, thrombosis in cancer patients, asymptomatic cerebral ischemia, stroke, neurotraumatic injury, medical procedures including contact with artificial surfaces including renal dialysis, Alzheimer's disease, vascular dementia, macular degeneration, diabetic macular edema, cerebral edema in stroke, edema of other causes, hereditary angioedema, or acquired angioedema.

[0394] (Examples and Synthesis) 1¹H-NMR: Spectra are obtained using a Bruker DRX 400 MHz or Jeol ECS 400 MHz spectrometer. Spectra are measured at 294 K (unless otherwise specified), and chemical shifts (δ values) are reported in parts per million (ppm) relative to one of the following: TMS (0.0 ppm), DMSO-d6 (2.50 ppm), CDCl3 (7.26 ppm), acetonitrile-d3 (1.94 ppm), or CD2Cl2 (5.32 ppm). Coupling constants (J) are reported in Hertz (Hz), and spectral splitting patterns are shown as singlet (s), doublet (d), triplet (t), quadruplet (q), multiplet or higher overlapping signals (m), and broad signal (br), with the solvent given in parentheses. 1 ¹H-NMR integrals are quantified when visible. If the integral is missing, it is assumed that some proton signals are (partially) obscured by residual DMSO and / or water peaks. Rotational isomers were observed for many compounds. Studies have shown that such compounds... 1 The H-NMR signals were observed to fuse at high temperatures.

[0395] AbbreviationsThe following abbreviations are used in the examples and other parts of this specification: Ac: Acetate; Boc: tert-butyloxycarbonyl; Cbz: Carbobenzyloxy; CV: Column volume; DCM: Dichloromethane; Dioxane: 1,4-Dioxane; DIPEA: Diisopropylethylamine; DMAP: 4-(dimethylamino)pyridine; DMF: N,N-dimethylformamide; DMSO: Dimethyl sulfoxide; Â: Ethyl acetate; h: 1 hour; HATU: 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; HPLC: High-performance liquid chromatography. min: minute; LCMS: liquid chromatography-mass spectrometry; LiHMDS: lithium hexamethyldisilazide; M: per mole; MS: mass spectrometry; MW: microwave; Prep: preparative; quant.: quantitative (converted); Rt: retention time; rt or RT: room temperature; SCX: strong cation exchange; TEA: triethylamine; TFA: trifluoroacetic acid; THF: tetrahydrofuran; SPhos: 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl; ULC: ultra-high performance liquid chromatography.

[0396] Analytical methods The products and intermediates were analyzed using reversed-phase HPLC-MS with the following parameters.

[0397] HPLC analysis method (performed using an Agilent 1100 LC instrument with Waters ZQ mass spectrometry):

[0398] AnalpH2_MeOH_4min :Phenomenex Luna C18(2) 3μm, 50×4.6mm; A = water + 0.1% formic acid; B = MeOH + 0.1% formic acid; 45℃; %B: 0.0min 5%, 1.0min 37.5%, 3.0min 95%, 3.5min 95%, 3.5min 5%, 4.0min 5%; 2.25mL / min.

[0399] AnalpH9_MeOH_4minPhenomenex Luna C18(2) 3μm, 50×4.6mm; A = Water pH 9 (Ammonium bicarbonate 10mM); B = MeOH + 0.1% Formic Acid; 45℃; %B: 0.0min 5%, 1.0min 37.5%, 3.0min 95%, 3.5min 95%, 3.51min 5%, 4.0min 5%; 2.25mL / min. PDA 210-400nm and MS detection 120-950Da, ESi+ / - (Waters ZQ LCMS).

[0400] AnalpH2_MeCN_4min Waters Xbridge C18 3.5μm, 50×4.6mm; A = Water pH 9 (Ammonium bicarbonate 10mM); B = MeCN; 45℃; %B: 0.0min 5%, 1.0min 37.5%, 3.0min 95%, 3.5min 95%, 3.51min 5%, 4.0min 5%; 2.25mL / min. PDA 210-40nm and MS detection 120-950Da, ESi+ / -.

[0401] AnalpH9_MeCN_4min Waters Xbridge C18 3.5μm, 50×4.6mm; A = Water pH 9 (Ammonium bicarbonate 10mM); B = MeCN; 45℃; %B: 0.0min 5%, 1.0min 37.5%, 3.0min 95%, 3.5min 95%, 3.51min 5%, 4.0min 5%; 2.25mL / min. PDA 210-40nm and MS detection 120-950Da, ESi+ / -.

[0402] AnalpH2_MeOH_QC_V1 Phenomenex Gemini NX C18 5μm, 150×4.6mm; A = Water + 0.1% Formic Acid; B = MeOH + 0.1% Formic Acid; 40℃; %B: 0.0min 5%, 0.5min 5%, 7.5min 95%, 10.0min 95%, 10.1min 5%, 13.0min 5%; 1.5mL / min. PDA 210-400nm and MS detection 120-950Da, ESi+ / - (Waters ZQ LCMS).

[0403] AnalpH9_MeOH_QC_V1Phenomenex Gemini NX C18 5μm, 150×4.6mm; A=Water + pH9 (Ammonium Bicarbonate 10mM); B=MeOH; 40℃; %B: 0.0min5%, 0.50min5%, 7.5min95%, 10.0min95%, 10.1min5%, 13.0min5%; 1.5mL / min. PDA 210-400nm and MS detection 120-950Da, ESi+ / - (Waters ZQ LCMS).

[0404] AnalpH2_MeCN_QC_V2 Phenomenex Gemini NX C18 5μm, 150×4.6mm; A=Water + 0.1% Formic Acid; B=MeCN + 0.1% Formic Acid; 40℃; %B: 0.0min5%, 0.5min5%, 7.5min95%, 10.0min95%, 10.1min5%, 13.0min5%; 1.5mL / min. PDA 210-400nm and MS detection 120-950Da, ESi+ / -. (Waters ZQ LCMS).

[0405] AnalpH9_MeCN_QC_V2 Phenomenex Gemini NX C18 5μm, 150×4.6mm; A=pH9 10mM ammonium bicarbonate aqueous solution; B=MeCN; 40℃; %B: 0.0min 5%, 0.50min 5%, 7.5min 95%, 10.0min 95%, 10.1min 5%, 13.0min 5%; 1.5mL / min. PDA210-400nm and MS detection 120-950Da, ESi+ / - (Waters ZQ LCMS).

[0406] HPLC analysis method (performed on a Waters Acuity UPLC equipped with a Waters QDA mass spectrometer):

[0407] UPLC_pH2_MeCN_QC_V1Waters BEH C18 1.7μm, 100×2.1mm; A = Water + 0.1% Formic Acid; B = MeCN + 0.1% Formic Acid; 40℃; %B: 0.05min 5%, 5.00min 95%, 6.60min 5% 0.35mL / min. PDA 210-400nm and MS detection 120-1000Da, ESi+ / - (Waters QDA LCMS).

[0408] UPLC_pH10_MeCN_QC_V1 Waters BEH C18 1.7μm, 100×2.1mm; A=pH10 water + 0.1% ammonia water; B=MeCN; 40℃; %B: 0.05min 5%, 5min 95%, 6.6min 5%, 0.35mL / min. PDA 210-400nm and MS detection 120-1000 Da, ESi+ / - (Waters QDA LCMS).

[0409] Thermo_MeOH_UHPLC_1.2 min Phenomenex Kinetex, 2.6 μM, 50 × 2.1 mm, A = water + 0.1% formic acid; B = MeOH + 0.1% formic acid; 2 - 95% B0 - 1.0 min; 1.3 mL / min.

[0410] Common method: General method 1 (GM1): Amide coupling A mixture of carboxylic acid (1.0 equivalent), amine (1.0–1.5 equivalents), N,N-diisopropylethylamine or triethylamine (3.0–6.0 equivalents), and HATU (1.0–1.2 equivalents) was stirred in an anhydrous solvent such as DMF and / or DCM at room temperature or 0°C for 1–72 hours.

[0411] The solvent was removed under reduced pressure, and the residue was dissolved in RINKAN or DCM (or, if necessary, the reaction mixture was directly diluted). A mixture of water and / or brine and / or saturated NaHCO3 aqueous solution was added, and the product was extracted with RINKAN or DCM. The organic phase was washed with brine (up to three times) and / or 10% citric acid aqueous solution, if necessary. The organic phase was dried over Na2SO4 or MgSO4, or passed through a hydrophobic frit (phase separator, Biotage) and concentrated under vacuum. The crude was used without further purification, filtered through a silica plug, and purified by flash column chromatography or preparative HPLC.

[0412] If necessary, the reaction mixture was purified directly by preparative HPLC without aqueous post-treatment.

[0413] If necessary, the starting amine reaction product may be used as a TFA or HCl salt.

[0414] General method 2 (GM2): Boc deprotection Boc deprotection method 2A: Boc deprotection method 2A: The Boc-protecting amine was stirred for 1 to 18 hours in a mixture of DCM:TFA (in a ratio of 10:1 to 1:1).

[0415] Boc Deprotection Method 2B Boc-protected amines were dissolved in ethyl acetate or dioxane, and either 4M HCl in dioxane or 1M HCl in Et2O was added. The reaction mixture was stirred at room temperature for 1 to 18 hours.

[0416] The reaction mixture was concentrated in a vacuum to obtain the crude product, which was then used directly in the next reaction or purified by one of the following methods: a) SCX-2 If necessary, continue with preparative HPLC b) Dissolve in water and add NH3 aqueous solution (35%) until pH = 10. The resulting suspension was extracted with ethyl acetate, then with DCM. The two organic fractions were combined and evaporated to dryness. c) The reaction mixture was diluted with DCM and washed with saturated ammonium bicarbonate or sodium bicarbonate and optionally brine. The organic layer was dried over MgSO4 and filtered. If necessary, preparative HPLC was then performed. d) Grind the coarse powder with Et2O or DCM. e) The crude product was directly purified by preparative HPLC.

[0417] General method 3 (GM3): Hydrogenation One equivalent of Cbz-protecting amine was dissolved in either EtOH, MeOH, or MeOH:DCM (1:1), placed under an N2 atmosphere, and Pd / C (10 wt%) was added. An H2 atmosphere was introduced, and the mixture was stirred at room temperature for 1 to 72 hours. The mixture was filtered through Celite, and the filtrate was concentrated to obtain the crude product, which was used without further purification or purified by SCX-2 or preparative HPLC.

[0418] If necessary, additional aliquots of Pd / C may be added during the reaction process.

[0419] synthesis S1 reagent: Synthesis of (7-fluoro-1H-pyrrolo[3,2-c]pyridine-2-yl)methanamine (M05712-int) TIFF0007888622000309.tif30170

[0420] Step 1: 3-bromo-5-fluoropyridine-4-amine (2 g, 9.95 mmol), 4-(dimethylamino)pyridine (DMAP) (608 mg, 4.97 mmol), and triethylamine (4.2 mL, 29.8 mmol) were dissolved in DCM (30 mL). Di-tert-butyl dicarbonate (4.6 g, 20.9 mmol) dissolved in DCM (10 mL) was added to the reaction mixture and stirred overnight at room temperature. The mixture was washed with water (2 × 100 mL) and 10% citric acid aqueous solution (100 mL) to remove DMAP. The organic fraction was passed through a phase separation cartridge (Biotage), evaporated to dryness, and redissolved in methyl alcohol (50 mL). Potassium carbonate (4.1 g, 29.8 mmol) was added and heated under reflux for 4 hours (ambient temperature 90°C). The reaction mixture was filtered, the filtrate was evaporated to dryness, and purified by flash column chromatography (SiO2, Biotage Isolera type, 25g Sfar column, elution with 100% isohexane to 25% ethyl acetate in isohexane; target substance was eluted with 15% ethyl acetate in isohexane). The fractions containing the target substance were combined and evaporated to obtain tert-butyl N-(3-bromo-5-fluoro-4-pyridyl)carbamate (2.2g, 77%) as a yellow oil. AnalpH9_MeCN_4min, Rt:2.20 min, m / z 291.0 and 293.0 [M+H] + Bromide fission Step 2: A solution of N-Boc-prop-2-inylamine (1.2 g, 7.56 mmol), tert-butyl N-(3-bromo-5-fluoro-4-pyridyl)carbamate (1.1 g, 3.78 mmol), bis(triphenylphosphine)palladium(II) dichloride (133 mg, 0.189 mmol), copper(I) iodide (22 mg, 0.113 mmol), and triethylamine (2.1 mL, 15.1 mmol) was dissolved in DMF (25 mL) and degassed by passing N2 through for several minutes. The mixture was then heated in a microwave reactor at 100 °C for 1.5 hours. The reaction mixture was evaporated to dryness, redissolved in DCM (100 mL), and washed with water (50 mL) and brine (50 mL). The organic fraction was passed through a phase separation cartridge (Biotage) and evaporated to dryness. The crude product was redissolved in DMF (40 mL), and the solution was heated overnight at 100°C. The mixture was evaporated to dryness, and the crude product was purified by flash column chromatography (SiO2, Biotage Isolella type, 100 g shale column, eluted with 25% siRNA to 100% isohexane; the target substance was eluted with 65-80% siRNA in isohexane). The fraction containing the product was purified again by flash column chromatography (SiO2, Biotage Isolella, 100 g shale column, eluted with 50% siRNA to 100% isohexane), and tert-butyl N-[(7-fluoro-1H-pyrrolo[3,2-c]pyridine-2-yl)methyl]carbamate (701 mg, 70%) was obtained as a yellow solid. AnalpH9_MeCN_4min, Rt:1.94 min, m / z 266.2 [M+H] + Step 3: N-[(7-fluoro-1H-pyrrolo[3,2-c]pyridine-2-yl)methyl]carbamate tert-butyl (320 mg, 1.21 mmol) was dissolved in DCM (20 mL), and trifluoroacetic acid (5.0 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The mixture was evaporated to dryness, redissolved in MeOH, and loaded into an SCX-2 cartridge (Biotage, 5 g). The column was washed several times with MeOH, and then the bound target substance was eluted with 3.5 M NH3 in MeOH. The solvent was evaporated to obtain (7-fluoro-1H-pyrrolo[3,2-c]pyridine-2-yl)methaneamine (178 mg, 89%) as a brown gum-like substance. AnalpH9_MeCN_4min, Rt:0.98min, m / z166.2[M+H]+

[0421] Synthesis of (3-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-yl)methanamine (M05855-int) Step 1: A solution of 7-bromo-3-methyl-[1,2,4]triazolo[4.3-a]pyridine (250 mg, 1.18 mmol) in 1,4-dioxane (10 mL) was stirred, and potassium N-boc-aminomethyltrifluoroborate (559 mg, 2.36 mmol), palladium(II) acetate (53 mg, 0.24 mmol), and SPhos (194 mg, 0.47 mmol) were added. Cesium carbonate (1.15 g, 3.54 mmol) in water (2.5 mL) was added to this. N2 was blown into the reaction mixture for 5 minutes. The solution was then heated in a microwave reactor at 120 °C for 2 hours. The reaction mixture was passed through a Celite cartridge (2.5 g, Biotage), flushed with methanol, and the combined filtrate was concentrated under reduced pressure. Water (10 mL) was added, and the product was extracted into DCM (3 × 20 mL). The combined organic layers were washed with saturated NH4 water (10 mL), followed by brine (10 mL), then passed through a phase separator cartridge (Biotage), and concentrated under vacuum to obtain tert-butyl((3-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-yl)methyl)carbamate (387 mg crude, quantitative). The crude product was used directly in the next step without further purification, assuming a 100% yield (307 mg). AnalpH9_MeCN_4min, Rt:1.63min, m / z263.2[M+H] + Step 2: Dissolve N-[(3-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-yl)methyl]carbamate tert-butyl (307 mg, 1.18 mmol) in DCM (12 mL). Cool the reaction mixture to 0°C and add trifluoroacetic acid (4 mL) dropwise over 5 minutes while stirring. Allow the solution to reach room temperature and stir for 2 hours. Concentrate the reaction mixture under vacuum, redissolve the crude residue in MeOH (2 mL), and load it into an SCX-2 cartridge (2 g, Biotage). Elute with MeOH (3 CV), then elute the bound amine with 3.5 M NH3 in MeOH. Remove the solvent under reduced pressure, and grind the solid with DCM to obtain (3-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-yl)methaneamine (102 mg, 53%) as a white solid. AnalpH9_MeCN_4min, Rt:0.54min, m / z 163.2[M+H] +

[0422] Synthesis of (3-methoxy-1-methyl-1H-indazole-5-yl)methanamine (M05810-int) Step 1: To a solution of 5-bromo-3-methoxy-1H-indazole (250 mg, 1.10 mmol) in N,N-dimethylformamide (10 mL), sodium hydride (60% dispersion in oil) (53 mg, 1.32 mmol) was added at 0°C. The solution was warmed to room temperature and stirred for 30 minutes. Iodomethane (0.14 mL, 2.20 mmol) was added, and the solution was stirred at room temperature for 3 hours. LC-MS showed the formation of two positional isomers in a ratio of 5:95. The reaction mixture was diluted with water (50 mL) and extracted with  (3 × 30 mL). The combined organic fraction was washed with brine (3 × 30 mL), passed through a phase separation cartridge (Biotage), and evaporated to dryness. The crude material was then purified by preparative HPLC to obtain two isomer target substances. The desired isomer, 5-bromo-3-methoxy-1-methylindazole (197 mg, 74%, white solid), was preferentially formed. AnalpH9_MeCN_4min, Rt:2.58min, m / z 241.0 and 243.0[M+H]+ 1 H-NMR (400MHz, DMSO-D6) δ7.76(s,1H); 7.50(s,1H), 7.49(s,1H), 3.99(s,3H), 3.86(s,3H) Step 2: To a solution of 5-bromo-3-methoxy-1-methyl-indazole (197 mg, 0.82 mmol) in N,N-dimethylformamide (4.0 mL), tetrakis(triphenylphosphine)palladium (0) (94 mg, 0.082 mmol), followed by zinc cyanide (115 mg, 0.981 mmol), was added. After degassing by bubbling with N2 for 5 minutes, the mixture was heated in a microwave reactor at 100°C for 1.5 hours. The mixture was diluted with ethyl acetate (50 mL) and washed with saturated aqueous solution of NaHCO3 (3 × 30 mL). The organic extract was passed through a phase separation cartridge (Biotage) and concentrated under vacuum. The crude material was then purified by flash column chromatography (SiO2, Biotage Isolella, 25 g SNAP column, eluted from 100% isohexane to 50% ethyl in isohexane; target substance eluted to 30% ethyl in isohexane). The fractions containing the target substance were combined and evaporated to obtain 3-methoxy-1-methyl-indazole-5-carbonitrile (81 mg, 53%) as a white solid. AnalpH9_MeCN_4min, Rt:2.11min, m / z188.2[M+H] + Step 3: To a methanol (10 mL) solution of 3-methoxy-1-methyl-indazole-5-carbonitrile (81 mg, 0.43 mmol), di-tert-butyl dicarbonate (189 mg, 0.865 mmol), followed by nickel(II) chloride (5.7 mg, 0.043 mmol), was added. The solution was cooled to 0°C, and sodium borohydride (115 mg, 3.03 mmol) was added gradually over 10 minutes. The solution turned black upon addition, and foaming was observed. After all of the sodium borohydride had been added, the solution was warmed to room temperature and stirred for 3 hours. The reaction was quenched with water (3 mL), and then the solvent was removed under vacuum. The crude residue was redissolved in  (20 mL). The organic solution was washed with a saturated aqueous solution of NaHCO3 (20 mL), followed by a 1% aqueous solution of diethylenetriamine (20 mL), NaHCO3 (20 mL), saturated brine (10 mL), and finally water (10 mL). The organic phase was passed through a phase separation cartridge (Biotage), and the solvent was removed under vacuum to obtain tert-butyl N-[(3-methoxy-1-methyl-indazole-5-yl)methyl]carbamate (113 mg, 90%) as a colorless oil. AnalpH9_MeCN_4min, Rt:2.36min, m / z292.2[M+H] + Step 4: N-[(3-methoxy-1-methyl-indazole-5-yl)methyl]carbamate tert-butyl (113 mg, 0.39 mmol) was dissolved in DCM (15 mL). Trifluoroacetic acid (5.0 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated to dryness, redissolved in MeOH, and packed into an SCX-2 column (Biotage, 2 g). The column was washed several times with MeOH, and then the bound target substance was eluted with 3,5NH3 in MeOH. The solvent was evaporated to obtain (3-methoxy-1-methyl-indazole-5-yl)methanamine (37 mg, 50%) as a colorless gum. AnalpH9_MeCN_4min, Rt:1.31min, m / z 193.2[M+H] + Alternative method for N-alkylation: Step 1 - Method B

[0423] Synthesis of 1-(difluoromethyl)indazole-5-carbonitrili (M05778-int) TIFF0007888622000312.tif341701H-indazole-5-carbonitrile (100 mg, 0.70 mmol) was dissolved in dry N,N-dimethylformamide (5 mL). Cs2CO3 (228 mg, 0.70 mmol) was added, and the mixture was heated to 120°C and vigorously stirred for 5 minutes. Sodium chlorodifluoroacetate (213 mg, 1.4 mmol) was added to the reaction mixture and stirred at 120°C for 1 hour. Sodium chlorodifluoroacetate (106 mg, 0.70 mmol) was added, and the reaction mixture was stirred for another hour. The solvent was removed under vacuum, and the residue was dissolved in DCM (10 mL). The organic solution was washed with water (10 mL), followed by saturated NH4 chlorine aqueous solution (10 mL) and brine (10 mL), and then passed through a phase separator (biotage) to remove the solvent under reduced pressure. The crude product was purified by flash column chromatography (SiO2, Biotage Isolella, 10 g, spher column; eluted with 5-50% siRNA in isohexane) to obtain 1-(difluoromethyl)indazole-5-carbonitrile (73 mg, 54%) as an off-white solid. AnalpH9_MeCN_4min, Rt:1.88, m / z192.1[M+H] + 1 H-NMR (400MHz, CDCl3) δ8.18-8.20(2H,m), 7.88-7.90(1H,m), 7.74(1H,dd, J=8.1,1.4Hz), 7.50 (1H,t, J=59.2Hz)

[0424] The following compounds were prepared by a similar method: TIFF0007888622000313.tif216170

[0425] Synthesis of (7-methoxy-1-methylindazole-5-yl)methanamine (M05799-int) Step 1: A solution of ethyl 7-methoxy-1-methyl-1H-indazole-5-carboxylate (500 mg, 2.13 mmol) in tetrahydrofuran (10 mL) was stirred, lithium borohydride (139 mg, 6.40 mmol) was added, and the mixture was stirred at 65°C for 16 hours. After completion, the mixture was cooled to room temperature and then carefully quenched with 10% aqueous citric acid (20 mL). The solution was then concentrated under vacuum to remove the organic solvent, and the resulting mixture was extracted with DCM (3 × 30 mL). The combined organic layers were then dried over MgSO4, filtered, concentrated to dryness, and (7-methoxy-1-methyl-indazole-5-yl)methanol (400 mg, 98%) was obtained as a yellow oil. AnalpH2_MeOH_4min, Rt:1.93mins, m / z193.2[M+H] + Step 2: A solution of (7-methoxy-1-methyl-indazole-5-yl)methanol (400 mg, 2.08 mmol) in anhydrous DCM (12 mL) was stirred, and Dess Martin periodinane (1.3 g, 3.12 mmol) was added at 0°C. The mixture was stirred for 3 hours, during which time it was warmed to room temperature. The reaction was stopped by adding 20 mL of 20% sodium thiosulfate aqueous solution, and then 10 mL of saturated NaHCO3 aqueous solution was added. The mixture was then stirred for a further 30 minutes. The mixture was extracted with DCM (3 × 20 mL), the combined organic layer was dried over MgSO4, filtered, and concentrated to dryness under reduced pressure to obtain 7-methoxy-1-methyl-indazole-5-carbaldehyde (330 mg, 83%) as a pale yellow solid. AnalpH2_MeOH_4min, Rt:2.55min, m / z191.2[M+H] + Step 3: A methanol (10 mL) solution of 7-methoxy-1-methyl-indazole-5-carbaldehyde (330 mg, 1.74 mmol) was stirred, and at room temperature, a aqueous (10 mL) solution of hydroxylamine hydrochloride (265 mg, 3.82 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was then concentrated under vacuum to remove the organic solvent. The resulting aqueous suspension was extracted with DCM (3 × 30 mL), dried over MgSO4, filtered, and concentrated under vacuum to obtain (5E)-7-methoxy-1-methyl-indazole-5-carbaldehyde oxime (340 mg, 96%) as an orange solid. AnalpH2_MeOH_4min, Rt:2.49min, m / z206.2[M+H] + Step 4: A solution of (5E)-7-methoxy-1-methyl-indazole-5-carbaldehyde oxime (340 mg, 1.66 mmol) in acetic acid (17 mL) was stirred, and zinc powder (1.00 g, 15.3 mmol) was carefully added. The mixture was stirred at 75°C for 16 hours. The mixture was cooled to room temperature and filtered through a Celite pad. The filtrate was concentrated to dryness under vacuum, and the residue was redissolved in MeOH (5 mL). The solution was washed with MeOH (5 CV) and purified by SCX-2 (5 g, Biotage) eluted with 1 M NH3-MeOH (5 CV). The fractions containing the desired product were combined, and the solvent was evaporated under reduced pressure. The residue was lyophilized to obtain (7-methoxy-1-methyl-indazole-5-yl)methaneamine (210 mg, 66%) as an orange-brown gum. AnalpH2_MeOH_4min, Rt:2.01min, m / z192.2[M+H] +

[0426] Synthesis of (3-chloro-1H-pyrrolo[2,3-b]pyridine-5-yl)methanamine (M05899-int) Step 1: 1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (1 g, 6.64 mmol) was dissolved in N,N-dimethylformamide (10 mL). N-chlorosuccinimide (886 mg, 6.64 mmol) was added, and the reaction mixture was heated at 55°C for 6 hours. Further aliquots of N-chlorosuccinimide (300 mg, 2.25 mmol) were added, and the reaction mixture was heated at 55°C for a further 2 hours, then cooled to room temperature and stirred overnight. A white precipitate was observed during the reaction. The reaction mixture was filtered, and the solid was washed with MeOH (1 mL). The precipitate was dried under reduced pressure (6 mbar, 50°C) to obtain 3-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (931 mg, 5.24 mmol, 79%) as a white solid. AnalpH9_MeCN_4MIN;Rt=1.94min;m / z=176.0;178.0;[M+H] + ;98% purity. ステップ2 To a methanol (150 mL) solution of 3-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (931 mg, 5.24 mmol) (the material was not completely submerged in the solution), di-tert-butyl dicarbonate (2288 mg, 10.5 mmol) was added, followed by nickel(II) chloride (69 mg, 0.52 mmol). The solution was cooled to 0°C, and sodium borohydride (1388 mg, 36.7 mmol) was added gradually over 10 minutes. Upon addition of sodium borohydride, the solution turned black, and foaming was observed. After the addition of sodium borohydride was complete, the solution was warmed to room temperature and stirred overnight. The reaction mixture was filtered, and the residue was washed with MeOH. The combined filtrate and washings were evaporated under reduced pressure, and the residue was redissolved in Â. The crude product was washed with a saturated solution of NaHCO3, followed by a 1% solution of diethylenetriamine (20 mL), a saturated solution of NaHCO3, saline solution, and finally water. The organic phase was passed through a phase separation cartridge (Biotage) to remove the solvent. The crude product was purified by flash column chromatography (Biotage Isolera Four) 25 g spher column, DCM -> 5% MeOH / DCM). The target material co-eluted with the nitrile starting material. The product-containing fractions were combined and evaporated under reduced pressure to obtain a mixture of the nitrile starting material and tert-butyl((3-chloro-1H-pyrrolo[2,3-b]pyridine-5-yl)methyl)carbamate as a yellow solid (419 mg). The crude product was used directly in the next step. Step 3: The crude product containing N-[(3-chloro-1H-pyrrolo[2,3-b]pyridine-5-yl)methyl]carbamate tert-butyl (419 mg, 1.49 mmol) was dissolved in trifluoroacetic acid (6.0 mL), and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated, resuspended in 50 mL of MeOH, and filtered. The filtrate was packed into an SCX-2 column (Biotage, 5 g), the column was washed several times with MeOH, and then the bound target substance was eluted with NH3 / MeOH. The solvent was evaporated to obtain (3-chloro-1H-pyrrolo[2,3-b]pyridine-5-yl)methaneamine (201 mg, 1.11 mmol, 74.4%) as a yellow solid. AnalpH9_MeCN_4MINRt=1.37min;m / z+=182.1;85% purity.

[0427] Synthesis of (3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-7-yl)methanamine (M05913-int) TIFF0007888622000316.tif46170 Step 1: Synthesis of benzyl N-[(2-oxo-4-piperidyl)methyl]carbamate TIFF0007888622000317.tif171704-(aminomethyl)piperidine-2-one (500 mg, 3.90 mmol) was added to a tetrahydrofuran (10 mL) solution, to which a sodium carbonate (827 mg, 7.80 mmol) solution in water (5.0 mL) was added. The solution was cooled to 0°C, and benzyl chloroformate (0.82 mL, 5.85 mmol) was added dropwise while stirring at this temperature. The reaction mixture was stirred at 0°C for 15 minutes, then heated to room temperature and stirred for 4 hours. The reaction was quenched by adding 10 mL of saturated NH4 aqueous solution. THF was removed under vacuum, and the product was extracted into DCM (3 × 30 mL). The combined organic extracts were passed through a phase separator (Biotage), and the product was purified by flash column chromatography (SiO2 Biotage isolella type, 25g spher column; eluted with 10% MeOH in 100% DCM to 10% DCM) to obtain benzyl N-[(2-oxo-4-piperidyl)methyl]carbamate (905 mg, 3.45 mmol, 88%) as a colorless oil. AnalpH9_MeCN_4min, RT:1.70, m / z 263.2[M+H] + Step 2: Synthesis of benzyl (6-methoxy-2,3,4,5-tetrahydropyridine-4-yl)methyl)carbamate A solution of benzyl N-[(2-oxo-4-piperidyl)methyl]carbamate (905 mg, 3.45 mmol) in dichloromethane (20 mL) was stirred, and trimethyloxonium tetrafluoroborate (914 mg, 5.87 mmol) was added gradually at 0°C. The reaction mixture was stirred at 0°C for 30 minutes, then warmed to room temperature and stirred for a further 3 hours. The reaction was quenched by adding saturated aqueous solution of NaHCO3 (15 mL), and the organic layer was separated. The aqueous layer was extracted with DCM (2 × 15 mL), the combined organic extract was washed with saline solution (15 mL), passed through a phase separator (Biotage), and the product was purified by flash column chromatography (SiO2, Biotage isolella, 25 g spher column; eluted with 15% MeOH in 100% DCM) to obtain benzyl ((6-methoxy-2,3,4,5-tetrahydropyridine-4-yl)methyl)carbamate (185 mg, 19%) as a white solid. AnalpH9_MeCN_4min, RT:2.08, m / z277.2[M+H] + Step 3: Synthesis of benzyl N-[(3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-7-yl)methyl]carbamate TIFF0007888622000319.tif23170N-[(6-methoxy-2,3,4,5-tetrahydropyridine-4-yl)methyl]carbamate benzyl (185 mg, 0.67 mmol) was dissolved in methanol (5.0 mL) and acetohydrazide (52 mg, 0.67 mmol) was added. The reaction mixture was heated to 65°C and stirred overnight. The reaction mixture was cooled and the solvent was removed under reduced pressure. Acetic acid (3.0 mL) was added, and the reaction mixture was heated under reflux and stirred for 2 hours. The solvent was removed under reduced pressure, the residue was redissolved in water (5 mL), basicized with saturated aqueous solution of NaHCO3, and the product was extracted into DCM (3 × 10 mL). The combined organic extracts were passed through a phase separator (Biotage) and purified by flash column chromatography (SiO2, Biotage Isolera, 10g spher column; eluted with 10% MeOH in 100% DCM to 10% DCM) to obtain benzyl N-[(3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-7-yl)methyl]carbamate (87 mg, 43%) as a colorless gum. AnalpH9_MeCN_4min, room temperature: 1.73, m / z301.2[M+H] + Step 4: Synthesis of (3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-7-yl)methanamine A methanol (3.0 mL) solution of benzyl N-[(3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-7-yl)methyl]carbamate (87 mg, 0.29 mmol) was stirred, and Pd / C (10 wt%) (3.0 mg, 0.03 mmol) was added under an N2 atmosphere. A hydrogen atmosphere was introduced, and the reaction mixture was stirred for 3 hours. The reaction mixture was filtered through Celite (Isolute model, 2.5 g) and loaded into an SCX cartridge (2 g, Biotage). Next, the cartridge was eluted with MeOH (3CV), and then the amine was eluted with NH3 (3.5 M in MeOH) to obtain (3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-7-yl)methaneamine (43 mg, 89%) as a colorless, rubbery substance. AnalpH9_MeCN_2min, RT:0.39, m / z167.2[M+H]+

[0428] Synthesis of [3-(difluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl]methanamine TIFF0007888622000321.tif21170 Step 1: Synthesis of N-[[3-(difluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl]methyl]methyl]carbamate tert-butyl. To a solution of 7-bromo-3-(difluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine (500 mg, 2.02 mmol) in 1,4-dioxane (10 mL), potassium N-Boc-aminomethyltrifluoroborate (956 mg, 4.03 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (SPhos) (331 mg, 0.806 mmol), and palladium(II) acetate (91 mg, 0.403 mmol) were added. To this, an aqueous solution of cesium carbonate (1970 mg, 6.05 mmol) (2.5 mL) was added. The mixture was stirred and degassed with N2 for 10 minutes. Then the solution was heated to 95°C and stirred overnight. Dioxane was removed under vacuum, and the reaction mixture was diluted with water (10 mL) and DCM (10 mL). The layers were partitioned, and the aqueous solution was further extracted with DCM (2 × 10 mL). The combined organic matter was washed with 1 M HCl (10 mL), saturated NaHCO3 (10 mL), followed by saline solution (10 mL), then passed through a phase separator (Biotage), and concentrated under vacuum to obtain tert-butyl N-[[3-(difluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl]methyl]carbamate (601 mg, 2.01 mmol, 100%) as a yellow oil, which was used as the crude product in the next step. AnalpH9_MeCN_4min:Rt:1.84min, m / z299.2[M+H]+ Step 2: Synthesis of [3-(difluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl]methaneamine. To a solution of tert-butyl N-[[3-(difluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl]methyl]carbamate (601 mg, 2.01 mmol) in dichloromethane (16 mL), trifluoroacetic acid (4.0 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed under vacuum, and the crude product was redissolved in MeOH (3 mL) and packed into an SCX cartridge (5 g, Biotage). The cartridge was then eluted with MeOH, and the amine was then eluted with a 3.5 M NH3 solution in MeOH to obtain [3-(difluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl]methaneamine (346 mg, 1.75 mmol, 87%) as an orange solid. AnalpH9_MeCN_4min:Rt:0.87min, m / z199.1[M+H] +

[0429] S2 reagent Synthesis of (2S)-1-tert-butoxycarbonyl-4-(5-methylindoline-1-yl)pyrrolidine-2-carboxylic acid (M05838-int and M05839-int) Step 1: 5-methylindoline (0.80 mL, 6.17 mmol) was dissolved in methanol (10 mL), and (2S)-1-boc-4-oxo-proline methyl ester (500 mg, 2.06 mmol) was added. The reaction mixture was stirred for 15 minutes, and sodium borohydride cyanohydride (258.33 mg, 4.11 mmol) was added. The reaction mixture was stirred overnight at room temperature. 20 mg of NaBH4 was added, and the mixture was stirred at room temperature for 2 hours. Water (20 mL) and brine (20 mL) were added to the reaction mixture, and the crude product was extracted with RINKAN (2 × 30 mL). The combined organic matter was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was partially purified by flash column chromatography (SiO2, Biotage, 25g sofa column, eluted with 0-80% siRNA / isohexane) to obtain a brown oily mixture of O1-tert-butylO2-methyl(2S)-4-(5-methylindoline-1-yl)pyrrolidine-1,2-dicarboxylate (1.40g, quantitative), which was the source of excess material and contained 5-methylindoline as the main impurity. The crude product was used directly in the next reaction. AnalpH9_MeCN_4min, Rt:2.92min, m / z361.3[M+H] + The main impurity is amine (46%, Rt, 1.98 min). Step 2: O1-tert-butylO2-methyl(2S)-4-(5-methylindolin-1-yl)pyrrolidine-1,2-dicarboxylate (assuming 741 mg, 2.06 mmol from the previous step) was dissolved in methanol (10 mL), and 2 M LiOH (10 mL, 20.0 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed, and the residue was partitioned between ELISA (50 mL) and water (50 mL). The organic layer was discarded, and the aqueous layer was acidified to pH 4 with 2 M HCl. The aqueous phase was then extracted with 2 × 50 mL of ELISA, and the combined organic layers were dried over (MgSO4), filtered, and the solvent removed to obtain (2S)-1-tert-butoxycarbonyl-4-(5-methylindolin-1-yl)pyrrolidine-2-carboxylic acid (706 mg, 99%) as a brown oil, which was used as the starting material for the next step. AnalpH9_MeCN_4min, Rt:1.71min, m / z347.3[M+H] +

[0430] Synthesis of O1-tert-butylO2-methyl(2S)-4-[(6-methoxy-3-pyridyl)methyl]-5-oxo-pyrrolidine-1,2-dicarboxylate (M05875-int) Step 1: Dissolve methyl Boc-L-pyroglutamate (160 mg, 0.66 mmol) in dry THF (10 mL) and cool the solution to -78°C. Add LiHMDS (THF 1 M, 0.72 mL, 0.72 mmol) dropwise over 10 minutes at -78°C. Stir the solution at -78°C for 1 hour, then add a solution of 5-(bromomethyl)-2-methoxypyridine (146 mg, 0.72 mmol) in dry THF (2 mL) dropwise over 10 minutes. Stir the solution at -78°C for 2 hours. Add saturated aqueous NaHCO3 and warm the reaction mixture to room temperature. Dilute the reaction mixture with siRNA (20 mL) and separate the layers. The aqueous layer was further extracted with ELISA (2 × 20 mL), and the combined organic layers were washed with saline solution (20 mL), passed through a phase separator, and concentrated under vacuum. The product was purified by flash column chromatography (SiO2, Biotage, 10 g, spher column, eluted with 0-60% ELISA in isohexane) to obtain O1-tert-butylO2-methyl(2S)-4-[(6-methoxy-3-pyridyl)methyl]-5-oxo-pyrrolidine-1,2-dicarboxylate (138 mg, 58%) as a colorless oil. AnalpH9_MeCN_4min, Rt:2.54min, m / z351.2[M+H] + . 1 H-NMR(400MHz,CDCl3)δ7.88-7.96(1H,m), 7.37-7.43(1H,m), 6.64-6.71(1H,m), 4.56-4.65(1H,m ), 3.89(3H,s), 3.77(3H,s), 3.11-3.16(1H,m), 2.57-2.66(2H,m), 2.25-2.52(2H,m), 1.48(9H,s). Step 2: O1-tert-butylO2-methyl(2S)-4-[(6-methoxy-3-pyridyl)methyl]-5-oxo-pyrrolidine-1,2-dicarboxylate (230 mg, 0.63 mmol) was dissolved in dry THF (5 mL). The mixture was cooled to 0°C, and 1 M BH3-THF (6.32 mL, 6.32 mmol) was added dropwise over 5 minutes under an N2 atmosphere, followed by the dropwise addition of BF3-Et2O (234 μL, 1.9 mmol) over 5 minutes. The reaction mixture was stirred at 0°C for 2 hours, then warmed to room temperature and stirred for another 2 hours. Saturated NaHCO3 (5 mL) aqueous solution was added dropwise at 0°C and stirred for 15 minutes. The solution was diluted with water (10 mL) and ethyl acetate (20 mL). The layers were partitioned, and the aqueous layer was further extracted with ethyl acetate (2 × 20 ml). The combined organic matter was washed with brine (20 mL), passed through a phase separator (Biotage), and concentrated under vacuum. The crude residue was purified by flash column chromatography (SiO2, Biotage isolella, 10 g, spher column, eluted with 0-60% ethyl ethyl in isohexane) to obtain O1-tert-butylO2-methyl(2S,4R)-4-[(6-methoxy-3-pyridyl)methyl]pyrrolidine-1,2-dicarboxylate (185 mg, 83%) as a colorless oil. AnalpH9_MeCN_4min, Rt:2.54min, m / z351.2[M+H] + . Step 3: Dissolve O1-tert-butylO2-methyl(2S,4R)-4-[(6-methoxy-3-pyridyl)methyl]pyrrolidine-1,2-dicarboxylate (185 mg, 0.53 mmol) in methanol (5 mL), and add NaOH (10 mmol, containing 2 M in 5 mL of H2O) dropwise at 0°C. Stir the reaction mixture for 2 hours. Remove the methanol under vacuum, and acidify the resulting aqueous solution to pH 4 with 2 M HCl. Extract the product with ELISA (3 × 10 mL), and pass the combined organic layers through a phase separator (Biotage) and concentrate under vacuum to obtain (2S,4R)-1-tert-butoxycarbonyl-4-[[6-(trifluoromethyl)-3-pyridyl]methyl]pyrrolidine-2-carboxylic acid (172 mg, 97%) as a colorless oil. AnalpH9_MeCN_4min, Rt:1.68min, m / z337.2[M+H] + .

[0431] The following compounds were prepared by a similar method: TIFF0007888622000324.tif192170TIFF0007888622000325.tif124170

[0432] Synthesis of (S)-1-(tert-butoxycarbonyl)-4-(4-methylbenzylidene)pyrrolidine-2-carboxylic acid (M05843-int) Step 1: A solution of (4-methylbenzyl)(triphenyl)phosphonium bromide (2.5 g, 5.6 mmol) in DCM (25 mL) was stirred, and a THF solution of KOtBu (1 M, 5.3 mL, 5.35 mmol) was added at 0°C. The solution was stirred for 30 minutes and allowed to reach room temperature. Then, N-boc-4-oxo-L-proline methyl ester (700 mg, 2.55 mmol) was added, and the reaction mixture was stirred overnight at room temperature. The solvent was removed under vacuum, and the residue was dissolved in ethyl acetate (50 mL) and washed with 10% citric acid aqueous solution (50 mL), saturated NaHCO3 aqueous solution (50 mL), and brine (3 × 50 mL). The combined organic extracts were dried (MgSO4), the solvent was removed, and the residue was purified by flash column chromatography (SiO2, Biotage, 25g spher column, eluted with 0-40% ethyl ethyl in isohexane) to obtain 1-(tert-butyl)2-methyl(S)-4-(4-methylbenzylidene)pyrrolidine-1,2-dicarboxylate (705 mg, 74%) as a pale yellow oil (as a mixture of E and Z stereoisomers). AnalpH2_MeCN_4min, Rt:3.18min, m / z354.2[M+Na] + Step 2: 1-(tert-butyl)2-methyl(S)-4-(4-methylbenzylidene)pyrrolidine-1,2-dicarboxylate (900 mg, 2.72 mmol) in THF at room temperature was added to a solution of lithium hydroxide monohydrate (250 mg, 5.96 mmol) in water (6 mL), and the mixture was stirred for 3 hours. The solvent was evaporated under reduced pressure. The residue was suspended in 10 mol% aqueous citric acid (20 mL) and extracted with ethyl acetate (2 × 25 mL). The combined organic extracts were dried over magnesium sulfate and filtered. The solvent was removed under vacuum, and (S)-1-(tert-butoxycarbonyl)-4-(4-methylbenzylidene)pyrrolidine-2-carboxylic acid (710 mg, 82%) was obtained as a white solid (as a mixture of E and Z stereoisomers). AnalpH9_MeCN_4min, Rt:1.86min, M / z316.1[MH] - 1 H-NMR(400MHz,CD2Cl2)δ7.30-6.92(m,4H), 6.37(d,J=17.9Hz,1H), 4.65-4 .35(1H), 4.36-4.01(m,2H), 3.33-2.73(m,2H), 2.31(s,3H), 1.62-1.27(9H)

[0433] Synthesis of (2S,4R)-1-tert-butoxycarbonyl-4-(spiro[2.5]octa-6-en-6-ylmethyl)pyrrolidine-2-carboxylic acid (M05992-int, M05991-int) TIFF0007888622000327.tif54170 Step 1: Synthesis of tert-butyl-(S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)pyrrolidine-1-carbonexylate 2,2,6,6-tetramethylpiperidine (8.62 mL, 51.05 mmol) and tetrahydrofuran (60 mL) were added to a flask under a nitrogen atmosphere and cooled to -40°C. Then, n-butyllithium (2.5 M solution in hexane) (20 mL, 51.1 mmol) was added dropwise. The reaction mixture was held at -40°C for 1 hour, and then the bath was replaced with an acetone / dry ice bath (-78°C). Next, a THF solution of bis[(pinacolato)boryl]methane (11.4 g, 42.54 mmol) was added at -78°C, and the reaction mixture was stirred at the same temperature for 1 hour. A tetrahydrofuran (60 mL) solution of tert-butyl(2S)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-oxo-pyrrolidine-1-carbonxylate (18.22 g, 55.3 mmol) was added at -78°C. o Add drop by drop with C, -78 o The mixture was stirred in 1C for 2 hours, then stirred overnight at room temperature. The reaction was quenched with ammonium chloride solution (50 mL) and the solvent was removed. The residue was dissolved in DCM (300 mL), washed with brine (2 × 100 mL), dried over magnesium sulfate, filtered, and the solvent was removed under vacuum. The residue was purified by flash column chromatography (SiO2, Biotage, 330 g SFAR) with 0-80% Et2O / i hexane to remove the solvent, and tert-butyl-(S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)pyrrolidine-1-carbonexylate (14.3 g, 29.6 mmol, 70%) was obtained as a pale yellow oil. 1 ¹H-NMR (400MHz, chloroform-D): δ 5.29 (s, 1H), 4.27-3.90 (m, 3H), 3.66-3.45 (m, 2H), 2.80-2.59 (m, 2H), 1.45 (s, 9H), 1.21 (s, 12H), 0.83 (s, 9H), -0.00 (s, 6H) Step 2: Synthesis of tert-butyl-(S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(spiro[2.5]octa-5-en-6-ylmethylene)pyrrolidine-1-carbonoxylate A Teflon screw-top flask was loaded with spiro[2,5]octo-6-en-6-yl trifluoromethanesulfonate (1.56 g, 6.09 mmol) [Reference: AMBYS DICINES -WO2021 / 76938, 2021, A1], potassium carbonate (3.99 g, 12.18 mmol), tert-butyl-(2S,4Z)-2-[tert-butyl]ethyl]-4-[(4,4,5,5-tetramethylene-1,2-dioxaborolan-2-yl)methylene]pyrrolidine-1-carbonexylate (5 g, 11.03 mmol), and a complex of [1,1′-bis(diphenylphosphino)ferropazine]-dichloropadium(II) with dichloromethane (499.6 mg, 0.61 mmol). The flask was sealed and placed under vacuum, then refilled with nitrogen. Next, 1,4-dioxane (50 mL) and water (15 mL) were added, and the suspension was degassed with a nitrogen balloon for 30 minutes. The flask was then sealed under nitrogen, and the reaction mixture was stirred at 90°C for 16 hours. The reaction mixture was cooled and the solvent was removed. The residue was purified by column chromatography (SiO2, Biotage, 100 g SFAR) 0-50% Et2O / Ihexane, and the solvent was removed to obtain tert-butyl-(S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(spiro[2.5]octa-5-en-6-ylmethylene)pyrrolidine-1-carbonexylate as a pale yellow oil. 1 H-NMR (400MHz, chloroform-D) δ5.80(s,1H), 5.54(s,1H), 4.23-3.79(m,4H), 3.59(s,2H), 3.35(d,J=17.4Hz,1H), 2.65(d ,J=61.4Hz,2H), 2.31-2.17(m,2H), 2.00(d,J=23.4Hz,2H), 1.46-1.33(m,9H), 0.86(s,9H), 0.27(s,4H), 0.05(s,6H). Step 3: Synthesis of tert-butyl-(S)-2-(hydroxymethyl)-4-(spiro[2.5]octa-5-en-6-ylmethylene)pyrrolidine-1-carbonoxylate To a solution of tert-butyl-(2S,4Z)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-(spiro[2,5]octa-6-en-6-ylmethylene)pyrrolidine-1-carbonexylate (2.44 g, 5.63 mmol) in methanol (20 mL), iodine (71.4 mg, 0.28 mmol) was added, and the reaction mixture was stirred overnight. Then, saturated sodium thiosulfate was added until the solution was finally colorless and contained acetonitrile. The solvent was removed, and then dichloromethane and magnesium sulfate were added. The suspension was filtered, the solvent evaporated, and the residue was purified by column chromatography (SiO2, Biotage, 50g SFAR) using 0-100% Et2O / i hexane. After removing the solvent, tert-butyl-(2S,4Z)-2-(hydroxymethyl)-4-(spiro[2.5]octa-6-en-6-ylmethylene)pyrrolidine-1-carbonexylate (1.69g, 5.29 mmol, 94%) acid was obtained as a colorless oil. 1 ¹H-NMR (400MHz, chloroform-D): δ 5.79 (d, J=18.8Hz, 1H), 5.56 (s, 1H), 4.19-3.89 (m, 4H), 3.58 (s, 2H), 2.78 (s, 1H), 2.38-1.99 (m, 5H), 1.47 (s, 11H), 0.29 (s, 4H). Step 4: Synthesis of tert-butyl-(2S,4R)-2-(hydroxymethyl)-4-(spiro[2.5]octa-6-en-6-ylmethyl)pyrrolidine-1-carbonoxylate A 50 mL flask was loaded with tert-butyl-(2S,4Z)-2-(hydroxymethyl)-4-(spiro[2.5]octa-6-ene-6-ylmethylene)pyrrolidine-1-carbonxylate (1690 mg, 5.29 mmol) and (1Z;5Z)-cycloocta-1,5-diene;dimethyl-pyridine-1-ium-1-yl-(tricyclohexyl-λ5-phosphanyl)iridium;hexafluorophosphate (133 mg, 0.159 mmol). The flask was evacuated and then refilled with nitrogen. Dichloromethane (20 mL) was then added by syringe, and the resulting orange solution was cooled to 0°C. A hydrogen balloon was bubbling into the solution three times for 15 minutes each, and then the reaction mixture was stirred in the presence of the hydrogen balloon for 2 hours. The solvent was removed, and the residue was purified by column chromatography (SiO2, Biotage 50g SFAR) using 0-100% Et2O / i hexane. After removing the solvent, tert-butyl-(2S,4R)-2-(hydroxymethyl)-4-(spiro[2.5]octa-6-en-6-ylmethyl)pyrrolidine-1-carbonexylate and tert-butyl-(S,E)-2-(hydroxymethyl)-4-(spiro[2.5]octa-5-en-6-ylmethylene)pyrrolidine-1-carbonexylate (1280 mg, 3.98 mmol, 75%) were obtained as a pale yellow oily substance. 1 H-NMR (400MHz, chloroform-D) δ5.40(s,1H), 4.50(s,1H), 3.96(d,J=48.1Hz,1H), 3.61-3.36(m,3H), 3.06(d,J=17.9Hz) ,1H), 2.33(t,J=19.9Hz,1H), 1.91(d,J=46.7Hz,7H), 1.69-1.61(m,2H), 1.45(s,9H), 0.77-0.95(1H), 0.27(s,4H) The presence of diene impurities was not confirmed until the final compound was synthesized. (General formula 1) Step 5: Synthesis of (2S,4R)-1-tert-butoxycarbonyl-4-(spiro[2.5]octa-6-en-6-ylmethyl)pyrrolidine-2-carboxylic acid (M05992-int) tert-butyl-(2S,4Z)-2-(hydroxymethyl)-4-(spiro[2,5]octa-6-en-6-ylmethylene)pyrrolidine-1-carbonexylate (562 mg, 1.76 mmol) was dissolved in acetonitrile (5.0 mL) and water (5.0 mL). Then, iodobenzene diacetate (1247 mg, 3.87 mmol) and 2,2,6,6-tetramethylpiperidinoxy free radical (TEMPO) (55 mg, 0.352 mmol) were added. The mixture was then stirred at room temperature for 4 hours. Dichloromethane (20 ml) and brine (20 ml) were added, the mixture was extracted, the aqueous layer was washed with DCM (20 ml), the organic layer was dried over magnesium sulfate and filtered. The solvent was removed to obtain a crude mixture (450 mg, 1.34 mmol, 76%) of (2S,4R)-1-tert-butoxycarbonyl-4-(spiro[2.5]octa-6-en-6-ylmethyl)pyrrolidine-2-carboxylic acid and (S,E)-1-(tert-butoxycarbonyl)-4-(spiro[2.5]octa-5-en-6-ylmethylene)pyrrolidine-2-carboxylic acid. UPLC_pH9_MeCN_2min, Rt:1.90min, m / z236.3[M+H-Boc] + (Monoalkene), 234.2[M+H-Boc] + (Jien)

[0434] The following compounds were prepared by a similar method: TIFF0007888622000328.tif82170

[0435] Synthesis of (2S,4R)-1-tert-butoxycarbonyl-4-(4-methylphenoxy)pyrrolidine-2-carboxylic acid (M05798-int) TIFF0007888622000329.tif34170 Step 1: Synthesis of O1-tert-butyl O2-methyl(2S,4R)-4-(4-methylphenoxy)pyrrolidine-1,2-dicarboxylate. Boc-cis-hydroxyproline methyl ester (500 mg, 2.04 mmol) was dissolved in tetrahydrofuran (10 mL), and p-cresol (441 mg, 4.08 mmol), followed by triphenylphosphine (1069 mg, 4.08 mmol), was added. The reaction mixture was stirred for 15 minutes, and diisopropyl azodicarboxylate (0.75 mL, 4.08 mmol) was added. The reaction mixture was stirred overnight at room temperature. The solvent was evaporated, and the residue was purified by column chromatography (SiO2, Biotage 25 g SFAR) using 0-20% siRNA / ihexane at 10 CV. The solvent was evaporated to obtain O1-tert-butylO2-methyl(2S,4R)-4-(4-methylphenoxy)pyrrolidine-1,2-dicarboxylate (587 mg, 1.75 mmol, 86%) as a colorless oil. AnalpH9_MeCN_4min, Rt:2.87min, m / z236.3[M+H] + Step 2: Synthesis of (2S,4R)-1-tert-butoxycarbonyl-4-(4-methylphenoxy)pyrrolidine-2-carboxylic acid O1-tert-butylO2-methyl(2S,4R)-4-(4-methylphenoxy)pyrrolidine-1,2-dicarboxylate (587 mg, 1.75 mmol) was dissolved in methanol (10 mL), and 2 M NaOH (8.8 mL, 17.5 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and the residue was partitioned between ELISA (20 mL) and water (20 mL), and the organic matter was discarded. The aqueous solution was acidified to pH 4 (using 2 M HCl) and extracted with 2 × 20 mL of ELISA. The combined organic matter was dried (MgSO4), filtered, and the solvent was evaporated to obtain (2S,4R)-1-tert-butoxycarbonyl-4-(4-methylphenoxy)pyrrolidine-2-carboxylic acid (519 mg, 1.61 mmol, 92%) as a colorless oil. AnalpH9_MeCN_4min, Rt:1.67min, m / z490.3[M+H] +

[0436] Synthesis of S4 reagent: Synthesis of (2R,3S)-1-tert-butoxycarbonyl-3-(pyrrolidine-1-carbonyl)piperidine-2-carboxylic acid Step 1: A solution of (2R,3S)-1-tert-butoxycarbonyl-2-methoxycarbonyl-piperidine-3-carboxylic acid (1.00 g, 3.48 mmol) in DCM (23 mL) was stirred, and pyrrolidine (0.30 mL, 3.65 mmol) and N,N-diisopropylethylamine (1.8 mL, 10.4 mmol) were added. The reaction mixture was stirred at room temperature for 15 minutes, then HATU (1323 mg, 3.48 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. A saturated aqueous solution of NaHCO3 (20 mL) was added. The phases were separated, and the aqueous phase was extracted with DCM (3 × 30 mL). The organic phases were combined and passed through a phase separator. The organic phases were concentrated under vacuum to obtain 2.6 g of crude product. The residue was redissolved in the minimum amount of ELISA and filtered through a silica plug that elutes with ELISA. The fractions containing the product were combined to obtain 2.1 g of O1-tert-butylO2-methyl(2R,3S)-3-(pyrrolidine-1-carbonyl)piperidine-1,2-dicarboxylate (estimated yield 100%, 1.2 g) as a yellow gum-like substance. AnalpH9_MeCN_4min, Rt:2.23min, m / z341.2[M+H] + In some cases, the amine may be used as an HCl salt. Depending on the circumstances, the crude product may be used without silica filtration, or it may be purified by flash column chromatography or preparative HPLC. Step 2: A solution of O1-tert-butyl O2-methyl(2R,3S)-3-(pyrrolidine-1-carbonyl)piperidine-1,2-dicarboxylate (1.18 g, 3.48 mmol) in methyl alcohol (58 mL) was stirred, and 17 mL of 1 M LiOH (17.4 mL, 17.4 mmol) was added at 0°C. The reaction mixture was carefully neutralized to pH 6 by adding 1 M HCl. The MeOH was concentrated under vacuum, and the aqueous phase was carefully adjusted to pH 9 with 1 M KOH (aqueous solution). The aqueous phase was discarded using DCM (20 mL biotage), and the aqueous phase was acidified to pH 4. The aqueous phase was extracted using DCM (3 × 20 mL). The organic phase was combined and passed through a phase separator (biotage), then concentrated under vacuum to obtain (2R,3S)-1-tert-butoxycarbonyl-3-(pyrrolidine-1-carbonyl)piperidine-2-carboxylic acid (545 mg, 48%) as a pale yellow gum-like substance. AnalpH9_MeCN_4min, Rt:1.47min, M / z325.2[MH] - 1 ¹H-NMR (400MHz, CDCl3) δ 5.22 (br s, 0.5H), 4.95 (br s, 0.5H), 4.04 (dd, J=14.0, 3.3Hz, 0.5H), 3.94 (dd, J=13.5, 4.8Hz, 0.5H), 3.41-3.64 (m, 4H), 3.20 (td, J=13.5, 3.3Hz, 0.5H), 3.06 (td, J=13.1, 3.3Hz, 0.5H), 2.85-2.93 (m, 1H), 1.45-2.10 (m, 8H), 1.48 and 1.45 (2S, H) (observed as a mixture of rotational isomers). In some cases, the crude substance may be purified by preparative HPLC (pH 9 MeCN).

[0437] The following compounds were prepared by a similar method: TIFF0007888622000331.tif208170TIFF0007888622000332.tif232170TIFF0007888622000333.tif239170TIFF0007888622000334.tif79170

[0438] Synthesis of (2R,3S)-1-benzyloxycarbonyl-3-(pyrrolidine-1-carbonyl)piperidine-2-carboxylic acid Step 1: A solution of pyrrolidine (0.4 mL, 4.91 mmol) and (2R,3S)-1-((benzyloxy)carbonyl)-2(tert-butoxycarbonyl)piperidine-3-carboxylic acid (1.7 g, 4.68 mmol) in DCM (47 mL) was stirred, and N,N-diisopropylethylamine (2.4 mL, 14.0 mmol) was added at 0°C. The reaction mixture was stirred for 10 minutes, then HATU (2.13 g, 5.61 mmol) was added. After stirring at 0°C for 1 hour, 20 mL of saturated NaHCO3 aqueous solution was added. The phases were separated, and the aqueous phase was extracted with DCM (2 × 30 mL). The organic phases were combined and passed through a phase separator (Biotage). The organic phase was concentrated under reduced pressure, and the residue was purified by flash column chromatography (SiO2, Biotage, 50 g, spher column, elution from 100% isohexane to 100% siRNA) to obtain O1-benzyl O2-tert-butyl(2R,3S)-3-(pyrrolidine-1-carbonyl)piperidine-1,2-dicarboxylate (1.90 g, 98%) as a white solid. AnalpH9_MeCN_4min, Rt:2.64min, m / z417.3[M+H]+ 1 ¹H-NMR (400 MHz, CDCl3) δ 7.33–7.37 (m, 5H), 5.11–5.22 (m, 2.7H), 4.93 (d, J=5.5 Hz, 0.3H), 3.98–4.16 (m, 1H), 3.33–3.70 (m, 5H), 2.60–2.70 (m, 1H), 1.71–2.05 (m, 8H), 1.42 and 1.39 (2s, 9H) (observed as a mixture of rotational isomers) In some cases, the amine may be used as an HCl salt. Step 2: A solution of O1-benzyl O2-tert-butyl(2R,3S)-3-(pyrrolidine-1-carbonyl)piperidine-1,2-dicarboxylate (1.90 g, 4.56 mmol) in DCM (44 mL) was stirred, and Amberlist 15, hydrogen form (2.9 g) was added. The reaction mixture was stirred at room temperature for 6 hours, and then the solid resin was removed by filtration. The filtrate was concentrated under vacuum, the residue was dissolved in a 1:1 MeCN:water mixture, and freeze-dried to obtain (2R,3S)-1-benzyloxycarbonyl-3-(pyrrolidine-1-carbonyl)piperidine-2-carboxylic acid (1.00 g, 61%) as a white solid. AnalpH9_MeCN_4min, Rt:1.62min, m / z 361.2[M+H] + 1 ¹H-NMR (400MHz, CDCl3) δ 7.29-7.40 (m, 5H), 5.26 (br s, 0.6H), 5.10-5.22 (m, 2H), 5.06 (br s, 0.4H), 4.04-4.16 (m, 1H), 3.41-3.63 (m, 4H), 3.28 (td, J=13.5, 3.7Hz, 0.6H), 3.17 (td, J=13.5, 3.7Hz, 0.4H), 2.88-2.92 (m, 1H), 1.38-2.10 (m, 8H) (Observed as a mixture of rotational isomers) In some cases, the crude substance may be purified by preparative HPLC (pH 9 MeCN).

[0439] The following compounds were prepared by a similar method: TIFF0007888622000336.tif208170TIFF0007888622000337.tif202170TIFF0007888622000338.tif220170TIFF0007888622000339.tif62170

[0440] Synthesis of (2R,3S)-1-((benzyloxy)carbonyl)-2-(tert-butoxycarbonyl)piperidine-3-carboxylic acid TIFF0007888622000340.tif71170 A solution of (2R,3S)-2-(tert-butoxycarbonyl)piperidine-3-carboxylic acid and (2S,3R)-2-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (cis-threshold) (12 g, 0.052 mol) in THF (72 mL) and water (72 mL) was stirred, and NaHCO3 (13.2 g, 0.157 mol) was added and the mixture was stirred for 15 minutes. The reaction mixture was cooled and Cbz-OSu (13.05 g, 0.052 mol) was added little by little. The reaction mixture was warmed to room temperature and stirred for 3 hours. Water (100 mL) was added and the organic phase was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with water (100 mL) and concentrated under vacuum to obtain the crude compound, which was purified by column chromatography (230-400 silica gel) using 0-40% ethyl acetate in pet ether. The fraction containing the desired product was concentrated, and the residue was further purified by SFC to obtain (2R,3S)-1-((benzyloxy)carbonyl)-2-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (1.3 g, 6.8%) as a white solid. AnalpH9_MeCN_4min, Rt:1.77min, M / z362.2[MH] - 1 H-NMR(400MHz,DMSO-D6)δ7.30-7.39(m,5H), 5.02-5.21(m,3H), 3.91(d,J=11.9Hz,1H), 2.79-2.84 (m,0.5H), 2.56-2.70(m,1.5H), 1.89(d,J=9.2Hz,1H), 1.64-1.70(m,1H), 1.36(s) and 1.34(s,9H).

[0441] Synthesis of (2R,3S)-1-tert-butoxycarbonyl-3-[2-[(3S)-3-fluoropyrrolidine-1-yl]ethyl-methyl-carbamoyl]piperidine-2-carboxylic acid (M06109-S4) TIFF0007888622000341.tif24170 Step 1: Synthesis of O1-tert-butyl O2-methyl(2R,3S)-3-[2-hydroxyethyl(methyl)carbamoyl]piperidine-1,2-dicarboxylate (2R,3S)-1-(tert-butoxycarbonyl)-2-(methoxycarbonyl)piperidine-3-carboxylic acid (750 mg, 2.61 mmol) was dissolved in anhydrous DCM (20.9 mL), and 2-(methylamino)ethanol (0.25 mL, 3.13 mmol), followed by N,N-diisopropylethylamine (1.4 mL, 7.83 mmol), and finally HATU (1191 mg, 3.13 mmol) were added. The reaction mixture was stirred overnight at room temperature. The reaction was quenched to saturation. The aqueous phase was extracted with NaHCO3 and DCM (×3). All DCM layers were passed through a phase separator, combined, and concentrated under vacuum. The crude product was purified by flash column chromatography (25g Sfar, 0-25% DCM / DCM w / 20% MeOH), and the solvent was removed to obtain O1-tert-butylO2-methyl(2R,3S)-3-[2-hydroxyethyl(methyl)carbamoyl]piperidine-1,2-dicarboxylate (899 mg, 2.61 mmol, 100%) as a colorless oil. UPLC_pH9_MeCN_2min, Rt:1.43min, m / z345.1[M+H] + Step 2: Synthesis of O1-tert-butylO2-methyl(2R,3S)-3-[methyl(2-oxoethyl)carbamoyl]piperidine-1,2-dicarboxylate O1-tert-butyl O2-methyl(2R,3S)-3-[2-hydroxyethyl(methyl)carbamoyl]piperidine-1,2-dicarboxylate (899 mg, 2.61 mmol) was dissolved in DCM (26 mL), cooled to 0°C, and then Dess-Martin periodinane (1.66 g, 3.92 mmol) was added little by little. The reaction mixture was stirred at 0°C for 2.5 hours, and the ice was removed after 1 hour. The reaction was quenched with saturated sodium thiosulfate solution and stirred for 10 minutes. The aqueous phase was then extracted with DCM (×3), all DCM layers were passed through a phase separator, combined, and concentrated under vacuum to obtain O1-tert-butyl O2-methyl(2R,3S)-3-[methyl(2-oxoethyl)carbamoyl]piperidine-1,2-dicarboxylate (894 mg, 2.61 mmol, quantified) as a yellow oil. UPLC_pH9_MeCN_2min, Rt:1.43~1.57min, m / z243.2[M+H-boc] + Step 3: Synthesis of O1-tert-butylO2-methyl(2R,3S)-3-[2-[(3S)-3-fluoropyrrolidine-1-yl]ethyl-methyl-carbamoyl]piperidine-1,2-dicarboxylate

[0442] O1-tert-butylO2-methyl(2R,3S)-3-[methyl(2-oxoethyl)carbamoyl]piperidine-1,2-dicarboxylate (149 mg, 0.435 mmol) was dissolved in MeOH (5.9 mL). (S)-(+)-3-fluoropyrrolidine hydrochloride (67 mg, 0.522 mmol) was added, followed by AcOH (0.3 mL). The reaction mixture was stirred for 1.5 hours, after which sodium borohydride cyanohydride (55 mg, 0.87 mmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched to saturation. The NaHCO3 and aqueous phases were extracted with DCM (×3). All DCM layers were passed through a phase separator, combined, and concentrated under vacuum. The crude product was purified with SCX (2 g) to obtain O1-tert-butylO2-methyl(2R,3S)-3-[2-[(3S)-3-fluoropyrrolidine-1-yl]ethyl-methyl-carbamoyl]piperidine-1,2-dicarboxylate (130 mg, 0.275 mmol, 63%) as a brown oily substance. UPLC_pH9_MeCN_2min, Rt:1.63min, m / z416.2[M+H] + Step 4: Synthesis of (2R,3S)-1-tert-butoxycarbonyl-3-[2-[(3S)-3-fluoropyrrolidine-1-yl]ethyl-methyl-carbamoyl]piperidine-2-carboxylic acid O1-tert-butylO2-methyl(2R,3S)-3-[2-[(3S)-3-fluoropyrrolidine-1-yl]ethyl-methyl-carbamoyl]piperidine-1,2-dicarboxylate (130 mg, 0.313 mmol) was dissolved in MeOH (5.2 mL), and 1 M hydroxylithium (aq) (1.6 mL, 1.56 mmol) was added dropwise. The reaction mixture was stirred at room temperature overnight. 1 M hydroxylithium (aq) (1.6 mL, 1.56 mmol) was added, and the reaction mixture was stirred for 3 hours. 1 M HCl was added, the reaction mixture was concentrated under vacuum, redissolved in DCM, and filtered through a phase separator. The crude product was purified by reverse-phase flushing (diastereomers eluted at approximately 10 CV between 0-30% MeCN and 10-15% MeCN on a 30 g Redisep Gold RF cartridge, pH 9 / MeCN, 30 CV). The fractions containing the product were combined and concentrated to obtain (2R,3S)-1-tert-butoxycarbonyl-3-[2-[(3S)-3-fluoropyrrolidine-1-yl]ethyl-methyl-carbamoyl]piperidine-2-carboxylic acid (80.5 mg, 0.185 mmol, 59%) as a clear film. UPLC_pH9_MeCN_2min, Rt:1.22min, m / z402.3[M+H] +

[0443] The following compounds were prepared by a similar method: TIFF0007888622000342.tif157170

[0444] Synthesis of (2R,3S)-1-tert-butoxycarbonyl-3-[2-(3-fluoroazetidine-1-yl)ethyl-methyl-carbamoyl]piperidine-2-carboxylic acid (M06099-int) TIFF0007888622000343.tif31170 Step 1: Synthesis of tert-butyl N-[2-(3-fluoroazetidine-1-yl)ethyl]-N-methyl-carbamate N-Boc-(methylamino)acetaldehyde (200 mg, 1.15 mmol) was dissolved in methanol (5.0 mL), and 3-fluoroazetidine hydrochloride (129 mg, 1.15 mmol) was added. After 20 minutes, sodium triacetoxyborohydride (245 mg, 1.15 mmol) was added, and the reaction mixture was stirred at room temperature overnight. Sodium bicarbonate aqueous solution (5 mL) was added to the mixture, and it was extracted with DCM (2 x 20 mL). The combined organic matter was passed through a phase separator to remove the solvent. The residue was purified with SCX-2 (5 g), washed with MeOH, and eluted with 0.5 M NH3 / MeOH. After removing the solvent, N-[2-(3-fluoroazetidine-1-yl)ethyl]-N-methylcarbamate tert-butyl (100 mg, 0.430 mmol, 37%) was obtained as a pale yellow oil. AnalpH9_MeCN_4min, Rt: 2.02min, m / z 233.4[M+H] + NMR (CDCl3): 1 H-NMR(400MHz,CHLOROFORM-D)δ5.20-5.01(m,1H), 3.72-3.64(m,2H), 3.19-3.07(m,4H), 2.94-2.86(m,3H), 2.68-2.55(m,2H), 1.53-1.37(m,9H) Step 2: Synthesis of O1-tert-butylO2-methylrac-(2R,3S)-3-[2-(3-fluoroazetidine-1-yl)ethyl-methyl-carbamoyl]piperidine-1,2-dicarboxylate 100 mg, 0.43 mmol of tert-butyl N-[2-(3-fluoroazetidine-1-yl)ethyl]-N-methyl-carbamate was dissolved in 2.0 mL of dichloromethane, and trifluoroacetic acid (0.20 mL) was added. The reaction mixture was stirred overnight at room temperature. The solvent was removed, and the residue was dissolved in 2.0 mL of dichloromethane and (2R,3S)-1-(tert-butoxycarbonyl)-2-(methoxycarbonyl)piperidine-3-carboxylic acid (124 mg, 0.43 mmol). N,N-diisopropylethylamine (0.45 mL, 2.58 mmol) and HATU (164 mg, 0.430 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 4 hours. 20 mL of water was added, and the layers were separated. The water was extracted with 2 × 10 mL of DCM, and the combined organic matter was passed through a phase separator to remove the solvent. The residue was purified with SCX-2 (5g), washed with MeOH, and eluted with 0.5M NH3 / MeOH to obtain O1-tert-butylO2-methylrac-(2R,3S)-3-[2-(3-fluoroazetidine-1-yl)ethyl-methyl-carbamoyl]piperidine-1,2-dicarboxylate (133mg, 0.331 mmol, 77%) as a brown oily substance. AnalpH9_MeCN_4min, Rt:2.13min, m / z402.3[M+H]+ Step 3: Synthesis of (2R,3S)-1-tert-butoxycarbonyl-3-[2-(3-fluoroazetidine-1-yl)ethyl-methyl-carbamoyl]piperidine-2-carboxylic acid O1-tert-butylO2-methylrac-(2R,3S)-3-[2-(3-fluoroazetidine-1-yl)ethyl-methyl-carbamoyl]piperidine-1,2-dicarboxylate (133 mg, 0.331 mmol) was dissolved in methanol (2.0 mL), and 1 M hydroxylithium (aq) (1.66 mL, 1.66 mmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was neutralized with 2 M HCl, and the solvent was removed. The residue was ground using DCM, filtered, and the solvent was removed to obtain the crude compound as an orange oily substance. The product was purified by preparative HPLC to obtain (2R,3S)-1-tert-butoxycarbonyl-3-[2-(3-fluoroazetidine-1-yl)ethyl-methyl-carbamoyl]piperidine-2-carboxylic acid (88 mg, 0.227 mmol, 69%) as a pale yellow oil. AnalpH9_MeCN_4min, Rt:1.49min, m / z388.3[M+H] + General formula 1: TIFF0007888622000344.tif74170

[0445] Synthesis of (2S,4R)-N-((1-methyl-1H-indazole-5-yl)methyl)-4-(4-methylbenzyl)-1-((2R,3S)-3-(morpholine-4-carbonyl)piperidine-2-carbonyl)pyrrolidine-2-carboxamide (M05753) Step 1: A solution of (1-methylindazole-5-yl)methaneamine (950 mg, 5.89 mmol) and Boc-(R)-4-(4-methylbenzyl)-L-proline (1.8 g, 5.6 mmol) in dichloromethane (28 mL) was stirred at room temperature, and N,N-diisopropylethylamine (2.90 mL, 16.8 mmol) was added. The reaction mixture was stirred for 10 minutes, and then HATU (2.6 g, 6.74 mmol) was added all at once. The reaction mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of NaHCO3 (30 mL) was added. The phases were separated, and the aqueous phase was extracted with DCM (2 × 50 mL). The organic phases were combined, passed through a phase separator (Biotage), and then concentrated under vacuum. The residue was purified by flash column chromatography (SiO2, Biotage Isolella type, 100g spher column, elution from 100% DCM to 10% MeOH in DCM) to obtain tert-butyl-(2S,4R)-2-[(1-methylindazole-5-yl)methylcarbamoyl]-4-(p-tolylmethyl)pyrrolidine-1-carboxylate (2.0g, 77%) as a white solid. AnalpH9_MeCN_4min, Rt:2.46min, m / z363.3[M+H-Boc] + Step 2: Dissolve tert-butyl(2S,4R)-2-[(1-methylindazole-5-yl)methylcarbamoyl]-4-(p-tolylmethyl)pyrrolidine-1-carboxylate (2 g) in DCM (50 mL) and add TFA (22 mL) slowly over 2 minutes. Stir the reaction mixture at room temperature for 2.5 hours. Then concentrate the reaction mixture under vacuum. Dissolve the residue in MeOH and purify it via an SCX-2 cartridge (50 g, Biotage). Wash the cartridge with 3 CV of MeOH. Elute the bound compound with 3 CV of 3.5 M NH3 / methanol. Concentrate the solution under vacuum to obtain (2S,4R)-N-((1-methyl-1H-indazole-5-yl)methyl)-4-(4-methylbenzyl)pyrrolidine-2-carboxamide (1.16 g, 74%) as an off-white solid. AnalpH9_MeCN_4min, Rt:2.30min, m / z363.3[M+H] + Step 3: A solution of (2R,3S)-1-tert-butoxycarbonyl-3-(morpholine-4-carbonyl)piperidine-2-carboxylic acid (70 mg, 0.206 mmol) and (2S,4R)-N-[(1-methylindazole-5-yl)methyl]-4-(p-tolylmethyl)pyrrolidine-2-carboxamide (75 mg, 0.206 mmol) in dichloromethane (2.0 mL) was stirred at 0°C, and N,N-diisopropylethylamine (0.072 mL, 0.411 mmol) was added. The reaction mixture was stirred at room temperature for 10 minutes, and then HATU (94 mg, 0.247 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. Saturated NaHCO3 aqueous solution (2 mL) was added. The phases were separated, and the aqueous phase was extracted with DCM (2 × 5 mL). The organic phases were combined, passed through a phase separator, and then concentrated under vacuum. The residue was purified by preparative HPLC. The fraction containing the desired product was concentrated to obtain tert-butyl(2R,3S)-2-[(2S,4R)-2-[(1-methylindazole-5-yl)methylcarbamoyl]-4-(p-tolylmethyl)pyrrolidine-1-carbonyl]-3-(morpholine-4-carbonyl)piperidine-1-carboxylate (70 mg, 0.102 mmol, 50%) as a white solid. AnalpH9_MeCN_4min, Rt:2.64min, m / z687.5[M+H] + Step 4: A solution of tert-butyl(2R,3S)-2-[(2S,4R)-2-[(1-methylindazole-5-yl)methylcarbamoyl]-4-(p-tolylmethyl)pyrrolidine-1-carbonyl]-3-(morpholine-4-carbonyl)piperidine-1-carboxylate (70 mg, 0.102 mmol) in dichloromethane (5.3 mL) was stirred, and trifluoroacetic acid (1.1 mL) was added dropwise at room temperature. The reaction mixture was stirred at room temperature until the starting material was consumed (6 hours). The reaction mixture was concentrated under vacuum. The residue was redissolved in MeOH (1 mL) and loaded into an SCX-2 cartridge (Biotage, 1 g) for elution with MeOH (3 CV). The bound substance was released by elution with a 3.5 M NH3 / methanol solution (3 CV). The product-containing fraction was concentrated under vacuum, and the residue was purified by preparative HPLC. The fraction containing the desired product was concentrated to obtain (2S,4R)-N-[(1-methylindazole-5-yl)methyl]-1-[(2R,3S)-3-(morpholine-4-carbonyl)piperidine-2-carbonyl]-4-(p-tolylmethyl)pyrrolidine-2-carboxamide (41 mg, 69%) as a white solid. AnalpH9_MeOH_QC_v1, Rt:7.85min, m / z587.6[M+H] + AnalpH2_MeOH_QC_v1, Rt:5.87min, m / z587.6[M+H] + 1H-NMR (400MHz, DMSO-D6) δ8.59(t,J=6.2Hz,0.5H), 8.08(t,J=6.0Hz,0.4H), 7.95(d,J=11Hz,1H), 7. 58-7.51(m,2H),7.28(dd,J=8.9,1.1Hz,0.5H),7.24(dd,J=8.7,1.4Hz,0.4H),7.11-7.04(m,4H),5.2 4-5.23(m,0.6H), 4.44-4.24(m,2.5H), 4.02-3.96(m,3.5H), 3.52-3.40(m,8H), 3.16(t,J=8.9Hz,0.5 H), 3.00-2.76(m,3H), 2.70-2.53(m,2H), 2.38-2.08(m,5H), 2.02-1.23(m,5H), 1.13-1.10(m,0.6H).

[0446] The following compounds can be produced in similar ways: TIFF0007888622000346.tif211170TIFF0007888622000347.tif206170TIFF0007888622000348.tif154170TIFF0007888622000349.tif190170TIFF0007888622000350.tif199170TIFF0007888622000351.tif190170TIFF0007888622000352.tif195170TIFF0007888622000353.tif195170TIFF0007888622000354.tif180170TIFF0007888622000355.tif180170TIFF0007888622000356.tif194170TIFF0007888622000357.tif185170TIFF0007888622000358.tif200170TIFF0007888622000359.tif190170TIFF0007888622000360.tif198170TIFF0007888622000361.tif197170TIFF0007888622000362.tif202170TIFF0007888622000363.tif183170TIFF0007888622000364.tif190170TIFF0007888622000365.tif193170TIFF0007888622000366.tif198170TIFF0007888622000367.tif197170TIFF0007888622000368.tif178170TIFF0007888622000369.tif183170TIFF0007888622000370.tif178170TIFF0007888622000371.tif190170TIFF0007888622000372.tif183170TIFF0007888622000373.tif180170TIFF0007888622000374.tif180170TIFF0007888622000375.tif181170TIFF0007888622000376.tif188170TIFF0007888622000377.tif188170TIFF0007888622000378.tif201170TIFF0007888622000379.tif194170TIFF0007888622000380.tif18517 0TIFF0007888622000381.tif194170TIFF0007888622000382.tif200170TIFF0007 888622000383.tif194170TIFF0007888622000384.tif204170TIFF0007888622000 385.tif194170TIFF0007888622000386.tif188170TIFF0007888622000387.tif18 5170TIFF0007888622000388.tif199170TIFF0007888622000389.tif192170TIFF 0007888622000390.tif202170TIFF0007888622000391.tif206170TIFF000788862 2000392.tif202170TIFF0007888622000393.tif202170TIFF0007888622000394.t if190170TIFF0007888622000395.tif174170TIFF0007888622000396.tif205170.

[0447] Synthesis of (2S,4R)-1-((2R,3S)-3-(5-azaspiro[2,4]heptan-5-carbonyl)piperidine-2-carbonyl)-N-((1-methyl-1H-indazole-5-yl)methyl)-4-(4-methylbenzyl)pyrrolidine-2-carboxamide (M05766) Step 1: A solution of (1-methylindazole-5-yl)methaneamine (950 mg, 5.89 mmol) and Boc-(R)-4-(4-methylbenzyl)-L-proline (1.8 g, 5.61 mmol) in dichloromethane (28 mL) was stirred, and N,N-diisopropylethylamine (2.9 mL, 16.8 mmol) was added at room temperature. The reaction mixture was stirred for 10 minutes, and then HATU (2.6 g, 6.74 mmol) was added all at once. The reaction mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of NaHCO3 (30 mL) was added. The phases were separated, and the aqueous phase was extracted with DCM (2 × 50 mL). The organic phases were combined, passed through a phase separator (Biotage), and then concentrated under vacuum. The residue was purified by flash column chromatography (SiO2, Biotage Isolella, 100 g, spher column, elution with 0-10% MeOH in DCM) to obtain tert-butylrac-(2S,4R)-2-[(1-methylindazole-5-yl)methylcarbamoyl]-4-(p-tolylmethyl)pyrrolidine-1-carboxylate (2.0 g, 77%) as a white solid. AnalpH9_MeCN_4min, Rt:2.46min, m / z363.3 [M+H-Boc] + Step 2: Dissolve tert-butyl-(2S,4R)-2-[(1-methylindazole-5-yl)methylcarbamoyl]-4-(p-tolylmethyl)pyrrolidine-1-carbonxylate (2 g) in DCM (50 mL) to form a clear yellow solution. Add TFA (22 mL) dropwise over 2 minutes. Stir the reaction mixture at room temperature for 2.5 hours. Concentrate the reaction mixture under reduced pressure. Dissolve the residue in MeOH and purify it through an SCX-2 cartridge (50 g, Biotage). Wash the cartridge with 3 CV of MeOH. Elute the bound compound with 3 CV of 3.5 M NH3 / methanol. The basic MeOH solution was concentrated under vacuum to obtain (2S,4R)-N-((1-methyl-1H-indazole-5-yl)methyl)-4-(4-methylbenzyl)pyrrolidine-2-carboxamide (1.16 g, yield 74%) as an off-white solid. AnalpH9_MeCN_4min, Rt:2.30min, m / z363.3[M+H] + Step 3: Stir the DCM (2 mL) solution of (2R,3S)-3-(5-azaspiro[2,4]heptan-5-carbonyl)-1-benzyloxycarbonylpiperidine-2-carboxylic acid (52 mg, 0.14 mmol) and (2S,4R)-N-[(1-methylindazole-5-yl)methyl]-4-(p-tolylmethyl)pyrrolidine-2-carboxamide (51 mg, 0.14 mmol), and add N,N-diisopropylethylamine (0.047 mL, 0.27 mmol). o After stirring in C for 10 minutes, HATU (61 mg, 0.16 mmol) was added. o The mixture was stirred in 1°C for 1 hour. The reaction solution was diluted with DCM (10 mL) and a saturated aqueous solution of NaHCO3 (10 mL) was added. The aqueous phase was extracted with DCM (3 × 10 mL). The organic phase was combined, passed through a phase separator, and concentrated under vacuum. The residue was purified by preparative HPLC. The fraction containing the desired product was concentrated, redissolved in 1:1 MeCN:water, and freeze-dried to obtain (2R,3S)-3-(5-azaspiro[2,4]heptan-5-carbonyl)-2-[(2S,4R)-2-[(1-methylindazole-5-yl)methylcarbamoyl]-4-(p-tolylmethyl)pyrrolidine-1-carbonyl]piperidine-1-carboxylate (91 mg, 93%) as a white solid. AnalpH9_MeCN_4min, Rt:2.93 min, m / z731.6[M+H] + Step 4: A solution of benzyl(2R,3S)-3-(5-azaspiro[2,4]heptan-5-carbonyl)-2-[(2S,4R)-2-[(1-methylindazole-5-yl)methylcarbamoyl]-4-(p-tolylmethyl)pyrrolidine-1-carbonyl]piperidine-1-carboxylate (91 mg, 0.12 mmol) in ethanol (2.5 mL) was stirred, placed under reduced pressure at room temperature, filled with nitrogen, and this process was repeated two more times. Palladium 5 wt% carbon (13 mg, 0.13 mmol) was added, the reaction mixture was placed under reduced pressure, filled with hydrogen, and this process was repeated two more times. The reaction mixture was stirred at room temperature until the starting materials were consumed (6 hours). The reaction mixture was filtered through a Celite pad and eluted with DCM. The combined filtrate and washings were concentrated under reduced pressure to obtain 70 mg of crude product as a colorless gum. The residue was purified by preparative HPLC. The fraction containing the desired product was concentrated under vacuum. The residue was redissolved in 1:1 MeCN:water and freeze-dried to obtain (2S,4R)-1-[(2R,3S)-3-(5-azaspiro[2,4]heptan-5-carbonyl)piperidine-2-carbonyl]-N-[(1-methylindazole-5-yl)methyl]-4-(p-tolylmethyl)pyrrolidine-2-carboxamide (50 mg, 67%) as a white solid. AnalpH9_MeOH_QC_v1, Rt: 8.30min, m / z 597.6[M+H] + AnalpH2_MeOH_QC_v1, Rt: 6.26min, m / z 597.6[M+H] + 1H-NMR (400MHz, DMSO-D6) δ8.58(q, J=6.1Hz, 0.6H), 8.08-8.13(m, 0.4H), 7.94-7.96(m, 1H), 7.51-7.58(m, 2H), 7.22-7.29( m, 1H), 7.04-7.10 (m, 4H), 5.19-5.21 (m, 0.6H), 4.25-4.42 (m, 2.3H), 3.98-4.05 (m, 0.5H), 4.01 (s, 3H), 3.36-3.59 (m, 2H), 3.25-3.30(m, 1H), 3.05-3.17(m, 2H), 2.75-2.99(m, 2H), 2.54-2.68(m, 1H), 2.13-2.37(m, 1.5H), 2.26(s, 3H), 1. 88-2.03 (m, 1.3H), 1.64-1.85 (m, 4H), 1.50-1.61 (m, 0.4H), 1.23-1.40 (m, 1H), 1.08-1.15 (m, 0.5H), 0.47-0.60 (m, 4H)

[0448] The following compounds can be produced in similar ways: TIFF0007888622000398.tif184170TIFF0007888622000399.tif172170TIFF0007888622000400.tif172170TIFF0007888622000401.t if176170TIFF0007888622000402.tif172170TIFF0007888622000403.tif172170TIFF0007888622000404.tif174170TIFF00078886220 00405.tif177170TIFF0007888622000406.tif172170TIFF0007888622000407.tif176170TIFF0007888622000408.tif159170TIFF000 7888622000409.tif171170TIFF0007888622000410.tif164170TIFF0007888622000411.tif176170TIFF0007888622000412.tif168170 TIFF0007888622000413.tif172170TIFF0007888622000414.tif177170TIFF0007888622000415.tif177170TIFF0007888622000416.t if177170TIFF0007888622000417.tif173170TIFF0007888622000418.tif199170TIFF0007888622000419.tif181170TIFF00078886220 00420.tif178170TIFF0007888622000421.tif169170TIFF0007888622000422.tif163170TIFF0007888622000423.tif175170TIFF000 7888622000424.tif178170TIFF0007888622000425.tif155170TIFF0007888622000426.tif143170TIFF0007888622000427.tif215170

[0449] Synthesis of alkylated piperidine (reductive alkylation of M05675): Synthesis of (2S,4R)-N-[(1-methylindazole-5-yl)methyl]-1-[(2R,3S)-1-methyl-3-(pyrrolidine-1-carbonyl)piperidine-2-carbonyl]-4-(p-tolylmethyl)pyrrolidine-2-carboxamide (M05757) TIFF0007888622000428.tif42170 (2S,4R)-N-[(1-methylindazole-5-yl)methyl]-4-(p-tolylmethyl)-1-[(2R,3S)-3-(pyrrolidine-1-carbonyl)piperidine-2-carbonyl]pyrrolidine-2-carboxamide (40 mg, 0.07 mmol), 37% formaldehyde solution (formalin) (0.057 g, 0.70 mmol), and acetic acid (0.10 mL) were dissolved in methanol (3.0 mL) and stirred at room temperature for 30 minutes. Sodium borocyanohydride (8.81 mg, 0.140 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The solvent was removed, the residue was dissolved in ELISA, and washed with brine. The organic matter was dried (MgSO4), filtered, and the solvent was removed. The residue was purified by preparative HPLC. After removing the solvent, the residue was freeze-dried in 1:1 MeCN / H2O to obtain (2S,4R)-N-[(1-methylindazole-5-yl)methyl]-1-[(2R,3S)-1-methyl-3-(pyrrolidine-1-carbonyl)piperidine-2-carbonyl]-4-(p-tolylmethyl)pyrrolidine-2-carboxamide (28 mg, 0.048 mmol, 68%) as a white solid. AnalpH2_MeOH_QC_v1, Rt: 6.07min, m / z 585.6[M+H]+ AnalpH9_MeOH_QC_v1, Rt: 8.15min, m / z 585.6[M+H]+ 1H-NMR (400 MHz, DMSO-D6) δ8.26(t, J=6.2Hz, 1H), 7.97-7.89(m, 1H), 7.63(s, 1H), 7.53(t, J=8.5 Hz, 1H), 7.28-7.21(m, 1H), 7.10-7.05(m, 4H), 4.40-4.29(m, 3H), 4.05-4.01(m, 3H), 3 .77-3.68(m, 2H), 3.57-3.47(m, 2H), 3.30-3.18(m, 2H), 2.86-2.82(m, 2H), 2.67-2.5 5(m, 3H), 2.33-2.26(m, 4H), 2.22-2.11(m, 4H), 1.94-1.77(m, 5H), 1.68-1.38(m, 3H).

[0450] The following compounds were prepared by a similar method: Synthesis of (2R,3S)-N-(1-(2-fluoroethyl)piperidine-4-yl)-N-methyl-2-((2S,4R)-2-(((1-methyl-1H-indazole-5-yl)methyl)carbamoyl)-4-(4-methylbenzyl)pyrrolidine-1-carbonyl)piperidine-3-carboxamide (M06083) TIFF0007888622000430.tif73170 Step 1: Synthesis of O1-tert-butyl O2-methyl(2R,3S)-3-[(1-benzyloxycarbonyl-4-piperidyl)-methyl-carbamoyl]piperidine-1,2-dicarboxylate 1-Cbz-4-methylaminopyridine (259 mg, 1.04 mmol) and (2R,3S)-1-(tert-butoxycarbonyl)-2-(methoxycarbonyl)piperidine-3-carboxylic acid (300 mg, 1.04 mmol) were dissolved in dichloromethane (5.0 mL), and N,N-diisopropylethylamine (0.55 mL, 3.13 mmol) was added, followed by HATU (397 mg, 1.04 mmol). The reaction mixture was stirred overnight at room temperature. Water (20 mL) was added and the layers were separated. The water was extracted with DCM (20 mL), and the combined organic matter was passed through a phase separator to remove the solvent. The residue was purified by column chromatography (SiO2, Biotage 25 g SFAR) with 0-100% siRNA / hexane. After removing the solvent, O1-tert-butylO2-methyl(2R,3S)-3-[(1-benzyloxycarbonyl-4-piperidyl)-methyl-carbamoyl]piperidine-1,2-dicarboxylate (510 mg, 0.99 mmol, 94%) was obtained as a colorless gum. AnalpH9_MeCN_4min, Rt: 2.73min, m / z 518.4[M+H]+ Step 2: Synthesis of (2R,3S)-3-[(1-benzyloxycarbonyl-4-piperidyl)-methylcarbamoyl]-1-tert-butoxycarbonylpiperidine-2-carboxylic acid O1-tert-butylO2-methyl(2R,3S)-3-[(1-benzyloxycarbonyl-4-piperidyl)-methyl-carbamoyl]piperidine-1,2-dicarboxylate (510 mg, 0.99 mmol) was dissolved in methanol (5.0 mL), and lithium hydroxide (1 M) (4.9 mL, 4.9 mmol) was added. The reaction mixture was stirred overnight at room temperature. Additional lithium hydroxide (1 M) (4.9 mL, 4.93 mmol) was added, and the reaction mixture was stirred at room temperature for 4 hours. The solvent was removed, and the residue was partitioned between butyl and water. The aqueous solution was acidified to pH 4 and extracted with 2 × 20 mL of butyl. The combined organic matter was dried (MgSO4), filtered, and the solvent was removed. The crude product was purified by reverse-phase chromatography (Teledyne 240 C18 column). After removing the solvent, (2R,3S)-3-[(1-benzyloxycarbonyl-4-piperidyl)-methyl-carbamoyl]-1-tert-butoxycarbonyl-piperidine-2-carboxylic acid (197 mg, 0.391 mmol, 40%) was obtained as a white solid. AnalpH9_MeCN_4min, Rt:1.93min, m / z 504.3[M+H]+ Step 3: Synthesis of tert-butyl(2R,3S)-3-[(1-benzyloxycarbonyl-4-piperidyl)-methyl-carbamoyl]-2-[(2S,4R)-2-[(1-methylindazole-5-yl)methylcarbamoyl]-4-(p-tolylmethyl)pyrrolidine-1-carbonyl]piperidine-1-carboxylate. (2R,3S)-3-[(1-benzyloxycarbonyl-4-piperidyl)-methyl-carbamoyl]-1-tert-butoxycarbonyl-piperidine-2-carboxylic acid (195 mg, 0.39 mmol) and (2S,4R)-N-[(1-methylindazole-5-yl)methyl]-4-(p-tolylmethyl)pyrrolidine-2-carboxamide (140 mg, 0.39 mmol) were dissolved in N,N-dimethylformamide (3.0 mL). The reaction mixture was cooled to 0°C, and then N,N-diisopropylethylamine (0.2 mL, 1.16 mmol) was added dropwise. After 5 minutes, HATU (176 mg, 0.46 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed, and the residue was partitioned between ELISA (20 mL) and brine (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL), the combined organic layers were dried (MgSO4), filtered, and the solvent was removed. The residue was purified by column chromatography (SiO2, Biotage 25 g SFAR) with 0-100% ethyl acetate followed by 0-10% MeOH / DCM. The fraction containing the desired product was also passed through an SCX-2 cartridge (2 g), washed with MeOH, and then the solvent was removed to obtain tert-butyl(2R,3S)-3-[(1-benzyloxycarbonyl-4-piperidyl)-methyl-carbamoyl]-2-[(2S,4R)-2-[(1-methylindazole-5-yl)methylcarbamoyl]-4-(p-tolylmethyl)pyrrolidine-1-carbonyl]piperidine-1-carboxylate (253 mg, 0.298 mmol, 77%) as a colorless oil. AnalpH9_MeCN_4min, Rt: 3.05min, m / z 848.6[M+H]+ Step 4: Synthesis of tert-butyl-(2R,3S)-2-[(2S,4R)-2-[(1-methylindazole-5-yl)methylcarbamoyl]-4-(p-tolylmethyl)pyrrolidine-1-carbonyl]-3-[methyl(4-piperidyl)carbamoyl]piperidine-1-carbonoxylate. 253 mg, 0.3 mmol of tert-butyl(2R,3S)-3-[(1-benzyloxycarbonyl-4-piperidyl)-methyl-carbamoyl]-2-[(2S,4R)-2-[(1-methylindazole-5-yl)methylcarbamoyl]-4-(p-tolylmethyl)pyrrolidine-1-carbonyl]piperidine-1-carboxylate (253 mg, 0.3 mmol) was dissolved in methanol (5.0 mL), and 5 wt% of palladium per 5 carbon atoms (32 mg, 0.298 mmol) was added while consuming N2. The atmosphere was evacuated, replaced with H2 (×3), and then stirred overnight while consuming H2 at room temperature. The reaction mixture was placed directly on an SCX-2 cartridge (2 g), washed with MeOH, and eluted with 1 M NH3 / MeOH. After removing the solvent, tert-butyl(2R,3S)-2-[(2S,4R)-2-[(1-methylindazole-5-yl)methylcarbamoyl]-4-(p-tolylmethyl)pyrrolidine-1-carbonyl]-3-[methyl(4-piperidyl)carbamoyl]piperidine-1-carboxylate (160 mg, 0.224 mmol, 75%) was obtained as a colorless gum. AnalpH9_MeCN_4min, Rt: 2.34min, m / z 714.6[M+H]+ Step 5: Synthesis of tert-butyl(2R,3S)-2-[[1-(2-fluoroethyl)-4-piperidyl]-methyl-carbamoyl]-2-[(2S,4R)-2-[(1-methylindazole-5-yl)methylcarbamoyl]-4-(p-tolylmethyl)pyrrolidine-1-carbonyl]piperidine-1-carboxylate tert-butyl(2R,3S)-2-[(2S,4R)-2-[(1-methylindazole-5-yl)methylcarbamoyl]-4-(p-tolylmethyl)pyrrolidine-1-carbonyl]-3-[methyl(4-piperidyl)carbamoyl]piperidine-1-carbonxylate (75 mg, 0.11 mmol) was dissolved in N,N-dimethylformamide (1.0 mL), and N,N-diisopropylethylamine (0.02 mL, 0.12 mmol) was added. The reaction mixture was stirred overnight at 45°C. Additional 1-fluoro-2-iodoethane (0.01 mL, 0.12 mmol) and N,N-diisopropylethylamine (0.02 mL, 0.12 mmol) were added, and the reaction mixture was stirred at 60°C for 2 hours. Salt water (10 mL) and water (10 mL) were added, and the product was extracted with 2 × 20 mL of butyl. The combined organic matter was dried (MgSO4), filtered, and the solvent was removed. The residue was purified by preparative HPLC. After removing the solvent, tert-butyl(2R,3S)-3-[[1-(2-fluoroethyl)-4-piperidyl]-methyl-carbamoyl]-2-[(2S,4R)-2-[(1-methylindazole-5-yl)methylcarbamoyl]-4-(p-tolylmethyl)pyrrolidine-1-carbonyl]piperidine-1-carboxylate (25 mg, 0.033 mmol, 31%) was obtained as a white solid. AnalpH9_MeCN_4min, Rt: 2.69min, m / z 760.7[M+H]+ Step 6: Synthesis of (2R,3S)-N-[1-(2-fluoroethyl)-4-piperidyl]-N-methyl-2-[(2S,4R)-2-[(1-methylindazole-5-yl)methylcarbamoyl]-4-(p-tolylmethyl)pyrrolidine-1-carbonyl]piperidine-3-carboxamide

[0451] tert-butyl(2R,3S)-3-[[1-(2-fluoroethyl)-4-piperidyl]-methyl-carbamoyl]-2-[(2S,4R)-2-[(1-methylindazole-5-yl)methylcarbamoyl]-4-(p-tolylmethyl)pyrrolidine-1-carbonyl]piperidine-1-carboxylate (25 mg, 0.03 mmol) was dissolved in dichloromethane (1.0 mL), and trifluoroacetic acid (0.30 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed, the residue was purified with SCX-2 (1 g), washed with MeOH, and eluted with 1 M NH3 / MeOH. The solvent was removed, and the residue was freeze-dried to obtain (2R,3S)-N-[1-(2-fluoroethyl)-4-piperidyl]-N-methyl-2-[(2S,4R)-2-[(1-methylindazole-5-yl)methylcarbamoyl]-4-(p-tolylmethyl)pyrrolidine-1-carbonyl]piperidine-3-carboxamide (21 mg, 0.0318 mmol, 97%) as a white solid. UPLC_pH2_MeCN_QC_V1, Rt:2.61, m / z 660.5[M+H]+ UPLC_pH9_MeCN_QC_V1, Rt:4.75, m / z 660.6[M+H]+ 1 H-NMR (400MHz, DMSO-D6) δ8.56 (d, J=5.0Hz, 0.5H), 8.05 (d, J=18.3Hz, 0.5H), 7.95 (d, J=3.2Hz, 1H), 7.57 (d, J=7.8Hz, 1H), 7.52(d, J=5.0Hz, 1H), 7.29(dd, J=8.7, 2.7Hz, 0.5H), 7.22(d, J=8.7Hz, 0.5H), 7.10-7.04(m, 4H), 5.29-5.23(m, 0) .5H), 4.56(t, J=5.0Hz, 1H), 4.45-4.17(m, 4.5H), 3.99(d, J=18.3Hz, 4H), 3.51-3.43(m, 1H), 3.18-3.13(m, 1H), 3.03- 2.83(m, 4H), 2.79(s, 1H), 2.73(s, 1H), 2.68-2.54(m, 6H), 2.26(d, J=2.3Hz, 3H), 2.19-1.23(m, 12H), 1.15-1.08(m, 1H)

[0452] The following compounds were prepared by a similar method: TIFF0007888622000431.tif121170

[0453] Synthesis of (2R,3S)-N-(2-(dimethylamino)ethyl)-N-methyl-2-((2S,4R)-2-(((1-methyl-1H-indazole-5-yl)methyl)carbamoyl)-4-(4-methylbenzyl)pyrrolidine-1-carbonyl)piperidine-3-carboxamide (M05902) Step 1: Dissolve (2R,3S)-1-((benzyloxy)carbonyl)-3-(methoxycarbonyl)piperidine-2-carboxylic acid (123 mg, 0.384 mmol) in anhydrous DCM (3 mL) and place under nitrogen. Add (2S,4R)-N-[(1-methylindazole-5-yl)methyl]-4-(p-tolylmethyl)pyrrolidine-2-carboxamide (143 mg, 0.394 mmol) to the reaction mixture, and then cool the reaction mixture to 0°C. Add DIPEA (0.2 mL) dropwise and stir the reaction mixture for 5 minutes. Add HATU (177 mg, 0.466 mmol) and stir the reaction mixture at 0°C for 3 hours. The reaction was quenched with saturated sodium bicarbonate aqueous solution (10 mL) and extracted with DCM (3 × 20 mL). The combined organic layer was passed through hydrophobic frit and concentrated under reduced pressure to obtain O1-benzyl O3-methyl(2R,3S)-2-[(2S,4R)-2-[(1-methylindazole-5-yl)methylcarbamoyl]-4-(p-tolylmethyl)pyrrolidine-1-carbonyl]piperidine-1,3-dicarboxylate as a pale yellow oil (461 mg crude product, estimated quantitative yield: 249 mg, 0.374 mmol). The crude product was used directly in the next reaction without further purification. AnalpH9_MeCN_4min, Rt: 2.84 min, m / z 666.4 [M+H]+ Step 2: O1-benzyl O3-methyl(2R,3S)-2-[(2S,4R)-2-[(1-methylindazole-5-yl)methylcarbamoyl]-4-(p-tolylmethyl)pyrrolidine-1-carbonyl]piperidine-1,3-dicarboxylate (249 mg, 0.374 mmol) was dissolved in MeOH (6.3 mL). LiOH (1 M, 1.9 mL) was added dropwise to the solution. The reaction mixture was stirred at room temperature for 22.5 hours. The reaction mixture was acidified to pH 6 with 1 M aqueous HCl and partially concentrated under vacuum to remove MeOH. The aqueous solution was basicized to pH 9 with saturated aqueous sodium bicarbonate and then extracted with ELISA (3 × 20 mL). The combined organic extracts were passed through a hydrophobic frit and concentrated under reduced pressure to obtain (2R,3S)-1-benzyloxycarbonyl-2-[(2S,4R)-2-[(1-methylindazole-5-yl)methylcarbamoyl]-4-(p-tolylmethyl)pyrrolidine-1-carbonyl]piperidine-3-carboxylic acid as an off-white solid containing the desired product, or as a mixture of diastereomers (232 mg, batch A). AnalpH9_MeCN_4min, Rt: 2.03min, m / z 652.4[M+H]+(28.2%) and Rt: 2.07min, m / z 652.4[M+H]+(45.5%) The aqueous layer was further acidified to pH 4 and extracted with DCM (3 × 20 mL). The combined DCM layers were passed through hydrophobic frit and concentrated under reduced pressure to obtain (2R,3S)-1-benzyloxycarbonyl-2-[(2S,4R)-2-[(1-methylindazole-5-yl)methylcarbamoyl]-4-(p-tolylmethyl)pyrrolidine-1-carbonyl]piperidine-3-carboxylic acid as a white foam containing the product as a mixture of diastereomers (106 mg, batch B). AnalpH9_MeCN_4min, Rt: 2.04min, m / z 652.4[M+H]+(61.6%) and Rt: 2.08min, m / z 652.4[M+H]+(27.6%) Step 3: (2R,3S)-1-benzyloxycarbonyl-2-[(2S,4R)-2-[(1-methylindazole-5-yl)methylcarbamoyl]-4-(p-tolylmethyl)pyrrolidine-1-carbonyl]piperidine-3-carboxylic acid (Batch B, 106 mg, 0.163 mmol) was dissolved in anhydrous DMF (1.3 mL). N,N,N′-trimethylenediamine (0.11 mL) was added dropwise, followed by DIPEA (0.17 mL). After stirring for 5 minutes, HATU (157 mg, 0.413 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain a yellow oily substance, which was partitioned between DCM (20 mL) and saturated sodium bicarbonate solution (10 mL). The aqueous phase was extracted two more times with DCM (3 × 20 mL). The combined DCM extract was passed through a hydrophobic frit and concentrated under reduced pressure. AnalpH2_MeCN_4min, Rt = 2.03 min, m / z 736.4[M+H]+ The two separated diastereomers were obtained by preparative HPLC purification using the unassigned diastereomer A (37.4 mg) as a colorless solid and the unassigned diastereomer B (25.8 mg) as a colorless solid. Step 4: Benzyl(2R,3S)-3-[2-(dimethylamino)ethyl-methyl-carbamoyl]-2-[(2S,4R)-2-[(1-methylindazole-5-yl)methylcarbamoyl]-4-(p-tolylmethyl)pyrrolidine-1-carbonyl]piperidine-1-carboxylate (unassigned diastereomer B, 25.8 mg, 0.0351 mmol) was dissolved in MeOH (1.2 mL). The reaction vessel was purged and refilled with nitrogen (x3) to make the Pd / C ratio 10% by weight. (5.4 mg) was added. The reaction mixture was purged and refilled with nitrogen three more times, then purged and refilled with hydrogen (x3). The reaction mixture was stirred at room temperature under hydrogen for 2.75 hours. The reaction mixture was filtered through a Celite cartridge (2.5 g), the product was eluted with methanol, and the product-containing fractions were combined and concentrated under reduced pressure. The crude product was purified by preparative HPLC, the product-containing fractions were combined and concentrated under reduced pressure, redissolved in 1:1 MeCN:H2O, and lyophilized to obtain (2R,3S)-N-(2-(dimethylamino)ethyl)-N-methyl-2-((2S,4R)-2-(((1-methyl-1H-indazole-5-yl)methyl)carbamoyl)-4-(4-methylbenzyl)pyrrolidine-1-carbonyl)piperidine-3-carboxamide as a white solid (12.1 mg, 0.0201 mmol, 57%). UPLC_PH9_MECN_QC_V1, Rt: 4.69 min, m / z 602.4 [M+H]+ UPLC_PH2_MECN_QC_V1, Rt: 2.65 min, m / z 602.4 [M+H]+ 1H-NMR(400 MHz, DMSO-d6)δ8.58(s, 0.5H), 8.32(s, 3H), 8.14(s, 0.5H), 7.96(s, 1H), 7.54(d, J=16.9Hz, 2H), 7.26(dd, J=20.1, 8.2Hz, 1H), 7.07(s, 4H), 5. 26(s, 0.5H), 4.41-4.31(m, 2H), 4.01(s, 3H), 3.62-2.89(m, 7H), 2.78- 2.75(m, 1H), 2.67-2.62(m, 1H), 2.40-2.07(m, 11H), 1.90-1.11(m, 7H).

[0454] Synthesis of (2R,3S)-2-((2S,4R)-4-(4-cyclopropylbenzyl)-2-(((1-methyl-1H-indazole-5-yl)methyl)carbamoyl)pyrrolidine-1-carbonyl)-N-(2-(dimethylamino)ethyl)-N-methylpiperidine-3-carboxamide (M06060) TIFF0007888622000433.tif79170 Step 1: Synthesis of (2S,4R)-4-[(4-bromophenyl)methyl]-2-[(1-methylindazole-5-yl)methylcarbamoyl]pyrrolidine-1-carboxylate tert-butyl A solution of Boc-(R)-γ-(4-bromobenzyl)-L-proline (500 mg, 1.3 mmol) and HATU (495 mg, 1.3 mmol) was pre-mixed in N,N-dimethylformamide (2.0 mL) for 5 minutes, then 5-(aminomethyl)-1-methyl-1H-indazole (210 mg, 1.30 mmol) and N,N-diisopropylethylamine (0.68 mL, 3.90 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The solution was diluted with ethyl acetate (15 mL), water (15 mL), and brine (15 mL), and the phases were separated. The aqueous layer was extracted with ethyl acetate (3 × 15 mL), the combined organic matter was washed with brine (30 mL), dried in a phase separator, and the solvent was removed under vacuum. The crude product was purified by flash column chromatography (10 g spher column, 0-100 siRNA in iHex, 5 CV, followed by 0-20% MeOH in DCM) to obtain tert-butyl(2S,4R)-4-[(4-bromophenyl)methyl]-2-[(1-methylindazole-5-yl)methylcarbamoyl]pyrrolidine-1-carboxylate (680 mg, 1.29 mmol, 99%) as a yellow oily substance. AnalpH9_MeCN_4min, Rt: 2.69min, m / z 527.3 / 529.3[M+H]+ Step 2: Synthesis of tert-butyl(2S,4R)-4-[(4-cyclopropylphenyl)methyl]-2-[(1-methylindazole-5-yl)methylcarbamoyl]pyrrolidine-1-carbonoxylate In a microwave vial, tert-butyl(2S,4R)-4-[(4-bromophenyl)methyline]-2-[(1-methylindazole-5-yl)pyrrolidine]pyrrolidine-1-carboxylate (213 mg, 0.36 mmol), di(1-adamantyl)-n-butylphosphine (171 mg, 0.45 mmol), palladium(II) acetate (21 mg, 0.09 mmol), potassium tribaceum phosphate (313 mg, 1.45 mmol), and cyclopropylboronic acid (62 mg, 0.73 mmol) were added, followed by toluene (3.0 ml) and water (0.50 ml). The mixture was degassed under nitrogen for 5 minutes and then capped. The reaction mixture was heated in a microwave at 120°C for 1 hour. The reaction mixture was passed through a Celite plug and washed with ethyl acetate. The filtrate was concentrated under vacuum to obtain an orange oily substance. The crude substance was purified by flash column chromatography (gradient: 0-100% ethyl acetate in isohexane). The desired product, tert-butyl(2S,4R)-4-[(4-cyclopropylphenyl)methyl]-2-[(1-methylindazole-5-yl)methylcarbamoyl]pyrrolidine-1-carboxylate (141 mg, 0.289 mmol, 79%), was isolated as an orange solid. UPLC_pH9_MeCN_2min, Rt:1.95min, m / z 389.2[M+H-boc]+ Step 3: Synthesis of (2S,4R)-4-[(4-cyclopropylphenyl)methyl]-N-[(1-methylindazole-5-yl)methyl]pyrrolidine-2-carboxamide

[0455] 139 mg, 0.28 mmol of tert-butyl(2S,4R)-4-[(4-cyclopropylphenyl)methyl]-2-[(1-methylindazole-5-yl)methylcarbamoyl]pyrrolidine-1-carboxylate was stirred in a solution of dichloromethane (3.0 mL), and TFA (1 mL, 13.07 mmol) was added. The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under vacuum, then dissolved in MeOH, and purified on an SCX-2. The cartridge was washed with MeOH, and the product was then eluted with 1.4 M NH3 in MeOH. The solution was evaporated under vacuum to obtain the desired (2S,4R)-4-[(4-cyclopropylphenyl)methyl]-N-[(1-methylindazole-5-yl)methyl]pyrrolidine-2-carboxamide (88 mg, 0.23 mmol, 80%) as a yellow gum. UPLC_pH9_MeCN_2min, Rt:1.79min, m / z 389.2[M+H-boc]+ Step 4: Synthesis of tert-butyl 2-[(2S,4R)-4-[(4-cyclopropylphenyl)methyl]-2-[(1-methylindazole-5-yl)methylcarbamoyl]pyrrolidine-1-carbonyl]-3-[2-(dimethylamino)ethyl-methylcarbamoyl]piperidine-1-carboxylate] A solution of (2S,4R)-4-[(4-cyclopropylphenyl)methyl]-N-[(1-methylindazole-5-yl)methyl]pyrrolidine-2-carboxamide (88 mg, 0.23 mmol) and (2R,3S)-1-tert-butoxycarbonyl-3-[2-(dimethylamino)ethyl-methyl-carbamoyl]piperidine-2-carboxylic acid (81 mg, 0.23 mmol) in N,N-dimethylformamide (3.0 mL) was stirred, and N,N-diisopropylethylamine (0.059 mL, 0.34 mmol) and HATU (103 mg, 0.272 mmol) were added. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was directly purified by preparative HPLC to obtain two diastereomers. The fraction containing the desired diastereomer was evaporated under vacuum to obtain tert-butyl-2-[(2S,4R)-4-[(4-cyclopropylphenyl)methyl]-2-[(1-methylindazole-5-yl)methylcarbamoyl]pyrrolidine-1-carbonyl]-3-[2-(dimethylamino)ethyl-methyl-carbamoyl]piperidine-1-carbonxylate (36 mg, 0.050 mmol, 22%) as a white solid. AnalpH9_MeCN_4min, Rt:2.78min, m / z 728.7[M+H]+ Step 5: Synthesis of (2R,3S)-2-((2S,4R)-4-(4-cyclopropylbenzyl)-2-(((1-methyl-1H-indazole-5-yl)methyl)carbamoyl)pyrrolidine-1-carbonyl)-N-(2-(dimethylamino)ethyl)-N-methylpiperidine-3-carboxamide (M06060) A solution of tert-butyl(2R,3S)-2-[(2S,4R)-4-[(4-cyclopropylphenyl)methyl]-2-[(1-methylindazole-5-yl)methylcarbamoyl]pyrrolidine-1-carbonyl]-3-[2-(dimethylamino)ethyl-methyl-carbamoyl]piperidine-1-carboxylate (35 mg, 0.05 mmol) in dichloromethane (3.0 mL) was stirred, and TFA (1.0 mL, 13 mmol) was added. The reaction mixture was stirred at room temperature for 8 hours. The reaction mixture was concentrated under vacuum, then dissolved in MeOH, and purified on an SCX-2. The cartridge was washed with MeOH, and the product was eluted with 1.4 M NH3 in MeOH. The solution was evaporated under vacuum, and the crude product was purified by preparative HPLC. The fractions were combined, evaporated under vacuum, and then freeze-dried to obtain the desired product (2R,3S)-2-[(2S,4R)-4-[(4-cyclopropylphenyl)methyl]-2-[(1-methylindazole-5-yl)methylcarbamoyl]pyrrolidine-1-carbonyl]-N-[2-(dimethylamino)ethyl]-N-methyl-piperidine-3-carboxamide (11 mg, 0.0175 mmol, 36%) as a white solid. UPLC_pH9_MECN_QC_V1, Rt:5.74, m / z 628.4 [M+H]+ UPLC_pH2_MECN_QC_V1, Rt:2.7, m / z 628.4 [M+H]+ 1H-NMR (400 MHz, DMSO-D6)δ8.55 (t, J=6.0Hz, 0.5H), 8.05-8.03(m, 0.3H), 7.96(d, J=2.7Hz, 0.9H), 7.57-7.51(m, 2H), 7.26(dd, J=20.6, 9.2Hz, 1H), 7.06-7.03(m, 2H), 6.99-6.95(m, 2H), 5.26-5.26(m, 0.6H), 4.43-4.25(m, 2.3H), 4.02(s, 3.5H), 3.50-3.40(m, 1.7H) ), 3.17-3.04(m, 1.7H), 2.98-2.87(m, 4.4H), 2.76(d, J=7.8Hz, 1.3H), 2.67-2.54(m, 3.7H), 2 solution m, 2.5H), 2.17-2.11 (m, 6.5H), 1.97-1.61(m, 4.5H), 1.48-1.27(m, 1.4H), 1.08(d, J=13.3Hz, 0.6H), 0.93-0.88(m, 2H), 0.64-0.60(m, 2H)

[0456] The following compounds were prepared by a similar method: TIFF0007888622000434.tif190170

[0457] Synthesis of M06003: TIFF0007888622000435.tif100170 Step 1: Synthesis of (2S,4R)-N-[(1-methylbenzotriazol-5-yl)methyl]-4-(spiro[2,5]octa-6-en-6-ylmethyl)pyrrolidine-2-carboxamide (1-methylbenzotriazol-5-yl)methaneamine; dihydrochloride (315.41 mg, 1.34 mmol) and (2S,4R)-1-tert-butoxycarbonyl-4-(spiro[2.5]octa-6-en-6-ylmethyl)pyrrolidine-2-carboxylic acid (450 mg, 1.34 mmol) were combined and dissolved in a mixture of N,N-dimethylformamide (5.0 mL) and N,N-diisopropylethylamine (0.93 mL, 5.37 mmol). HATU (765.13 mg, 2.01 mmol) was added to this solution, and the solution was stirred overnight at room temperature. The crude product was purified by C18 reverse-phase column chromatography (0-80% acetonitrile in water: 0.1% ammonium bicarbonate). After removing the solvent, the Boc-protected intermediate was obtained as a pale yellow oily substance. UPLC_pH9_MeCN_2min, Rt:2.00min, m / z 480.3[M+H]+ Step 2: Synthesis of tert-butyl-(2S,4R)-2-[(1-methylbenzotriazol-5-yl)methylcarbamoyl]-4-(spiro[2.5]octan-6-ylmethyl)pyrrolidine-1-carbonoxylate Tert-butyl-(2S,4R)-2-[(1-methylbenzotriazol-5-yl)methylcarbamoyl]-4-(spiro[2.5]octo-6-en-6-ylmethyl)pyrrolidine-1-carbonxylate (125 mg, 0.26 mmol) was transferred to a 10 mL vial equipped with a stirring bar and ethyl acetate (5.0 mL). Platinum(IV) oxide and Adam catalyst (30 mg, 0.13 mmol) were added, and hydrogen gas was bubbled into the reaction mixture using a hydrogen balloon. The reaction mixture was stirred at room temperature for 4 hours, then an additional PtO2 (20 mg, 0.09 mmol) was added, and the reaction mixture was stirred for a further 1 hour. The crude product was filtered through a Celite plug (1 cm) and washed with additional ELISA (5 mL). The solvent was removed under vacuum to obtain tert-butyl(2S,4R)-2-[(1-methylbenzotriazol-5-yl)methylcarbamoyl]-4-(spiro[2,5]octan-6-ylmethyl)pyrrolidine-1-carboxylate (35 mg, 0.0727 mmol, 27.88%, eDMX266-215-1) as a colorless oil. AnalpH9_MeCN_2min, Rt: = 2.05min, m / z 504.2[M+Na] + Step 3: Synthesis of (2S,4R)-N-[(1-methylbenzotriazol-5-yl)methyl]-4-(spiro[2,5]octan-6-ylmethyl)pyrrolidine-2-carboxamide tert-butyl(2S,4R)-2-[(1-methylbenzotriazole-5-yl)methylcarbamoyl]-4-(spiro[2.5]octane-6-ylmethyl)pyrrolidine-1-carboxylate (35 mg, 0.0727 mmol) was treated with dichloromethane (2 mL) and trifluoroacetic acid (1 mL). The mixture was stirred for 2 hours, and then the solvent was removed. The crude product was purified by preparative HPLC to obtain (2S,4R)-N-[(1-methylbenzotriazole-5-yl)methyl]-4-(spiro[2.5]octane-6-ylmethyl)pyrrolidine-2-carboxamide (23 mg, 0.0603 mmol, 82.96%) as a pale yellow oil. AnalpH9_MeCN_2min, Rt:=1.86min, m / z 382.3 [M+H] + Step 4: Synthesis of [(2S,4R)-2-[(1-methylbenzotriazol-5-yl)methylcarbamoyl]-4-(spiro[2,5]octan-6-ylmethyl)pyrrolidine-1-carbonyl]-3-(pyrrolidine-1-carbonyl)piperidine-1-carboxylate (2S,4R)-N-[(1-methylbenzotriazol-5-yl)methyl]-4-(spiro[2.5]octan-6-ylmethyl)pyrrolidine-2-carboxamide (23 mg, 0.06 mmol) and (2R,3S)-1-tert-butoxycarbonyl-3-(pyrrolidine-1-carbonyl)piperidine-2-carboxylic acid (19.7 mg, 0.06 mmol) were combined in a 0 ml microwave CEM vial and dissolved in a mixture of N,N-dimethylformamide (1.0 mL) and N,N-diisopropylethylamine (0.026 mL, 0.151 mmol). HATU (27.51 mg, 0.07 mmol) was added to this solution, and the solution was stirred overnight at room temperature. The crude product was purified by preparative HPLC to obtain tert-butyl(2R,3S)-2-[(2S,4R)-2-[(1-methylbenzotriazol-5-yl)methylcarbamoyl]-4-(spiro[2.5]octan-6-ylmethyl)pyrrolidine-1-carbonyl]-3-(pyrrolidine-1-carbonyl)piperidine-1-carboxylate (21 mg, 0.0304 mmol, 50.5%) as a white solid. AnalpH9_MeCN_2min, Rt:=2.06min, m / z 690.4 [M+H] + Step 5: Synthesis of (2S,4R)-N-[(1-methylbenzotriazol-5-yl)methyl]-1-[(2R,3S)-3-(pyrrolidine-1-carbonyl)piperidine-2-carbonyl]-4-(spiro[2,5]octan-6-ylmethyl)pyrrolidine-2-carboxamide tert-butyl(2R,3S)-2-[(2S,4R)-2-[(1-methylbenzotriazol-5-yl)methylcarbamoyl]-4-(spiro[2,5]octan-6-ylmethyl)pyrrolidine-1-carbonyl]-3-(pyrrolidine-1-carbonyl)piperidine-1-carboxylate (21 mg, 0.03 mmol) was dissolved in dichloromethane (1.0 mL). The solution was stirred for 1 hour, and then the solvent was removed under reduced pressure. The crude product was separated by preparative HPLC to obtain (2S,4R)-N-[(1-methylbenzotriazol-5-yl)methyl]-1-[(2R,3S)-3-(pyrrolidine-1-carbonyl)piperidine-2-carbonyl]-4-(spiro[2.5]octan-6-ylmethyl)pyrrolidine-2-carboxamide (2.5 mg, 0.0042 mmol, 13.7%) as a white solid. UPLC_pH9_MeCN_QC_V1, Rt:6.95min, m / z 590.5 [M+H] + UPLC_pH2_MeCN_QC_V1, Rt:4.96min, m / z 590.5 [M+H] + 1H-NMR (400MHz, ACETONITRILE-D3) δ7.82(s, 1H), 7.59(d, J=12.8Hz, 1H), 7.40(d, J=22.9Hz, 2H), 5.2 9(s, 0.5H), 5.13(d, J=11.9Hz, 0.5H), 4.48-4.39(m, 3H), 4.19(d, J=15.1Hz, 4H), 3.63(d, J=22.4Hz, 1 H), 3.34(d, J=15.6Hz, 2H), 3.11(dd, J=39.2, 18.5Hz, 4H), 2.92(d, J=12.4Hz, 2H), 2.66-2.53(m, 1H), 2.34(d, J=14.2Hz, 1H), 1.85-1.41(m, 11H), 1.28-1.11(m, 5H), 1.06-0.82(m, 3H), 0.23-0.12(m, 3H). Number of missing protons: 1

[0458] General Test Methods The activity of the compounds of the present invention was determined in vitro using the following assay protocols for screening the activity of FXIIa and other proteases. Each of these assays was performed in a purified system using a chromogenic assay in a microplate plate well. A chromogenic peptide substrate mimicking a native protein substrate is bound to the chromogenic group via an amide bond. Para-nitroaniline (pNA) is released from the peptide after catalysis by a protease, and the absorbance increases, which can be monitored at 405 nm.

[0459] All compounds were dissolved in 100% (v / v) DMSO up to a stock solution of 10 mM, with a maximum concentration of 500 μM for each assay. The final concentration of DMSO was 5% (v / v) in 50 mM Tris and 137 mM NaCl, pH 7.4. When no test compound was added, a final concentration of 5% DMSO was used.

[0460] Determination of factor XIIa inhibition Factor XIIa activity was measured using the chromogenic substrate S-2302 (Chromogenix). The experimentally obtained K M Before adding the chromogenic substrate S-2302 at the same concentration, compounds of various concentrations were co-cultured with 10 nM FXIIa and incubated for 10 minutes at 37°C in 50 mM Tris, 137 mM NaCl, pH 7.4. Dynamic measurements at 405 nm were monitored every 12 seconds for the entire 3-hour period at 37°C. The initial velocity gradient was determined, and IC was calculated. 50 It was used to calculate the value.

[0461] K obtained as described above i The data is shown in Table 1 below. i The classification is based on the value, and the categories are "†", "*", "**", and "***". The category "†" is K with a concentration of 5 μM or higher. i Value (for example, K between 5 μM and 10 μM) i This refers to compounds that have a K value greater than 0.8 μM and less than 5 μM. The category marked with "*" is for compounds with a K value greater than 0.8 μM and less than 5 μM.i This refers to compounds that have a value. The category "**" includes 0.2 μM to 0.8 μM K i This refers to compounds that have a value. The category "***" is K i This refers to compounds with a concentration of less than 0.2 μM.

[0462] Determining Selectivity To determine the selectivity of the test compounds, these compounds were assayed for their inhibitory activity against FXa and other serine proteases, including thrombin. Essentially, the compounds were cultured at gradually increasing concentrations with their respective enzymes, FXa (5 nM) and thrombin (5 nM), at 37°C for 10 minutes, followed by culture with appropriate chromogenic substrates, S2765 (Chromogenix) and GPR (Bakem), in 50 mM Tris 137 mM NaCl, pH 7.4. The substrates were appropriate experimentally obtained K M It was used at concentrations equal to . The reaction rate readings at 405 nm were monitored every 12 seconds for 3 hours at 37°C. The initial velocity gradient was determined, and IC 50 Used to calculate the value. IC 50 The value is K based on the following formula. i Converted to a value: K i =IC 50 / (1+[substrate] / Km)

[0463] Here, [substrate] indicates the concentration of the substrate used in the assay, and Km is the determined value for each enzyme that has its own substrate. The compounds exhibit competitive inhibition.

[0464] The magnification selectivity for thrombin and FXa is also shown in Table 1 below. The magnification selectivity demonstrates the preferential inhibition of FXIIa over FXa and thrombin. The magnification selectivity of the compounds of the present invention for FXIIa relative to thrombin is classified based on the magnification selectivity value, and the categories are "+", "++", and "+++". The "+" category refers to magnification selectivity values ​​less than 10 (e.g., magnification selectivity values ​​less than 10 and greater than 1). The "++" category refers to magnification selectivity values ​​from 10 to 100. The "+++" category refers to magnification selectivity values ​​greater than 100.

[0465] The magnification selectivity of the compounds of the present invention for FXIa is classified based on the magnification selectivity value, and the categories are "o", "oo", and "ooo". The category "o" refers to magnification selectivity values ​​less than 10 (e.g., magnification selectivity values ​​less than 10 and greater than 1). The category "oo" refers to magnification selectivity values ​​between 10 and 100. The category "ooo" refers to magnification selectivity values ​​greater than 100.

[0466] [Table 1] TIFF0007888622000437.tif226170

[0467] Throughout this specification and claims, the terms “comprise” and “contain” and their variations mean “including, but not limited to,” and are not intended to exclude (or exclude) other parts, additives, components, wholes, or steps. Throughout this specification and claims, singular nouns include plural nouns unless the context requires otherwise. In particular, where the indefinite article is used, it should be understood that both singular and plural nouns are considered unless the context requires otherwise.

[0468] Features, wholes, properties, compounds, chemical parts, or chemical groups described in conjunction with a particular aspect, embodiment, or example of the present invention should be understood to be applicable to any other aspect, embodiment, or example described herein, provided that they do not contradict each other. All features disclosed herein (including any appended claims, abstract, and drawings) and / or all steps of any method or process disclosed herein may be combined in any combination, except for any combination in which at least some of such features and / or steps are mutually exclusive. The present invention is not limited to the details of the embodiments described herein. The present invention extends to any novel one or any novel combination of features disclosed herein (including any appended claims, abstract, and drawings), or any novel one or any novel combination of any steps of any method or process disclosed herein.

[0469] The reader's attention is directed to all papers and documents filed concurrently with or prior to this specification in connection with this application and made available to the public together with this specification, the contents of all such papers and documents are incorporated herein by reference.

Claims

1. Equation (I): 【Chemistry 1】 "During the ceremony -X is -C(O)-; R １ -NR １ａ R １ｂ , and comprising 0, 1, or 2 heteroatoms selected from substituted or unsubstituted 3- to 8-membered monocyclic or bicyclic (condensed, bridging, or spiro) O, N, or S groups, where selected from heterocyclic groups linked to -X- via a nitrogen atom; Here, R １ａ and R １ｂ are each independently selected from substituted or unsubstituted C １－６ alkyl, substituted or unsubstituted C ３－７ cycloalkyl, a heterocyclic group having 1, 2 or 3 heteroatoms selected from substituted or unsubstituted 3- to 7-membered O, N or S, substituted or unsubstituted -C １－６ alkyl-C ３－７ cycloalkyl, substituted or unsubstituted -C １－６ alkyl-a heterocyclic group having 1, 2 or 3 heteroatoms selected from substituted or unsubstituted 3- to 7-membered O, N or S, and substituted or unsubstituted -C １－６ alkyl-a heteroaromatic group having 1, 2 or 3 heteroatoms selected from substituted or unsubstituted 5- to 6-membered O, N or S; If R is substituted in the formula, １ The substituents are halo, =O, -CN, -OH, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, -O-C １－６ Alkyl, -O-C ３－６ Cycloalkyl, -O-C １－６ Haloalkyl, -C １－６ Alkyl-O-C １－６ Alkyl, -C １－６ Alkyl-O-C ３－６ Cycloalkyl, -C １－６ Alkyl-O-C １－６ Haloalkyl, -NR １ｃ R １ｄ , -NR １ｃ (SO ２ ) R １ｄ , -NR １ｃ (C(O))R １ｄ , -C(O)NR １ｃ R １ｄ , -SO ２ NR １ｃ R １ｄ , a heteroaryl group having 1, 2, or 3 heteroatoms selected from 5-10 membered O, N, or S, and a 6-10 membered aryl group selected from; Here, R １ｃ and R １ｄ Each of these is H, C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, C ３－６ Independently selected from cyclohaloalkyl groups, heteroaryl groups having 1, 2, or 3 heteroatoms selected from 5-10 membered O, N, or S, and 6-10 membered aryl groups; If substituted, R １ａ and R １ｂ The substituents are halo, -CN, -OH, C １－６ Alkyl, C ３－７ Cycloalkyl, C １－６ Haloalkyl, C ３－７ Cyclohaloalkyl, -O-C １－６ Alkyl, -O-C ３－７ Cycloalkyl, -O-C １－６ Haloalkyl, -O-C ３－７ Cyclohaloalkyl, -C １－６ Alkyl-O-C １－６ Alkyl, -C １－６ Alkyl-O-C ３－７ Cycloalkyl, -C １－６ Alkyl-O-C １－６ Haloalkyl, -C １－６ Alkyl-O-C ３－７ Cyclohaloalkyl, -C １－６ Haloalkyl-OC １－６ Alkyl, -C １－６ Haloalkyl-OC ３－７ Cycloalkyl, -C １－６ Haloalkyl-OC １－６ Haloalkyl, -C １－６ Haloalkyl-OC ３－７ Cyclohaloalkyl, -NR １ｅ R １ｆ ,NH(=NH)NR １ｅ R １ｆ , -NR １ｅ (SO ２ ) R １ｆ , -NR １ｅ (C(O))R １ｆ , -C(O)NR １ｅ R １ｆ , and -SO ２ NR １ｅ R １ｆ Selected from; R １ｅ and R １ｆは Each time, H and C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, C ３－６ Independently selected from cyclohaloalkyl groups, heteroaryl groups having 1, 2, or 3 heteroatoms selected from 5-10 membered O, N, or S, and 6-10 membered aryl groups; R ２ is selected from H, C １－６ alkyl, C １－６ haloalkyl, C ３－６ cycloalkyl, and 3- to 6-membered heterocycloalkyl; R ３ is selected from halo, -CN, -OH, C １－６ alkyl, C １－６ haloalkyl, -O-C １－６ alkyl, -O-C １－６ haloalkyl, -NR ３ａ R ３ｂ , -NR ３ａ (C(O))R ３ｂ and -C(O)NR ３ａ R ３ｂ ; and is selected from Here, R ３ａ and R ３ｂ H, C each time １－６ Alkyl, C ３－６ Selected from cycloalkyl groups, heteroaryl groups having 1, 2, or 3 heteroatoms selected from 5-10 membered O, N, or S, and 6-10 membered aryl groups; m is selected from 0, 1, 2, or 3; In the formula, the residue 【change】 but, 【change】 (Here, L is bond, -O-, -NR) ４ｂ -, and -NR ４ｃ C(O)- (selected from), and 【change】 Selected from; R ４ａ H, -OH, halo, C １－４ Alkyl or C １－４ Selected from haloalkyls; R ４ｂ H, C １－６ Alkyl or -C(O)C １－６ It is a haloalkyl; R ４ｃ is H or C １－６ It is alkyl; R ４ｄ is H or C １－６ It is alkyl; R ４ｅ and R ４ｆ Each of these is H, -CN, Halo, and C. １－４ Alkyl, C １－４ Haloalkyl, -OR ４ｇ , -NR ４ｇ R ４ｈ , C ３－８ Selected from cycloalkyl, 3-6 membered heterocyclic, 6-10 membered aryl, and 5-10 membered heteroaryl; Here, C ３－８ Cycloalkyl groups, 3-6 membered heterocyclic groups, 6-10 membered aryl groups, or 5-10 membered heteroaryl groups are either unsubstituted or have 1, 2, or 3 R groups. ４ｉ Replaced by; Here, R ４ｇ and R ４ｈ H and C each time １－４ Selected from alkyl groups, R ４ｉ Each of these will be called Haro and C. １－４ Alkyl, C １－４ Haloalkyl, C ３－６ Cycloalkyl, C ３－６ Cyclohaloalkyl, -OR ４ｊ , -NR ４ｋ R ４ｌ , -NR ４ｋ (C(O))R ４ｌ , -C(O)NR ４ｋ R ４ｌ , -CN, -C(O)R ４ｇ , = O, -SO ２ R ４ｇ Independently selected from benzyl, phenyl, unsubstituted five- or six-membered heteroaryls, or methyl-substituted five- or six-membered heteroaryls; R ４ｊ H, C １－４ Alkyl, C １－４ Selected from haloalkyl, phenyl, or benzyl; R ４ｋ and R ４ｌ Each of these is H, C １－６ Alkyl, C ３－６ Selected from cycloalkyl groups, heteroaryl groups having 1, 2, or 3 heteroatoms selected from 5-10 membered O, N, or S, and 6-10 membered heteroaryl groups; n is selected from 0, 1, 2, 3, or 4; R ４ H, Halo, -CN, C １－４ Alkyl, C １－４ Haloalkyl, -OR ４ｇ ,-NR ４ｇ R ４ｈ , single-ring or double-ring 6-10 membered aryl, C ３－８ Cycloalkyl, C ４－８ Independently selected from cycloalkenyls, heterocyclic groups containing one, two, or three heteroatoms selected from 3-6 membered O, N, or S, monocyclic or bicyclic heteroaryls containing one, two, or three heteroatoms selected from 5-10 membered O, N, or S, bicyclic (condensed, bridged, or spiro) 6-10 membered cycloalkyl ring systems, bicyclic (condensed, bridged, or spiro) 6-10 membered cycloalkenyl ring systems, and bicyclic (condensed, bridged, or spiro) heterocyclic groups containing one, two, or three heteroatoms selected from 6-10 membered O, N, or S; Here, C ３－８ Cycloalkyl, C ４－８ Cycloalkenyls, 3-6 membered heterocyclic groups, 6-10 membered aryl groups, 5-10 membered heteroaryl groups, bicyclic (condensed, bridged, or spiro) 6-10 membered cycloalkyl ring systems, bicyclic (condensed, bridged, or spiro) 6-10 membered cycloalkenyl ring systems, or bicyclic (condensed, bridged, or spiro) 6-10 membered heterocyclic systems are either unsubstituted or have 1, 2, or 3 R groups. ４ｉ Replaced by; R ５ is H or C １－６ It is alkyl; o is selected from 1, 2, or 3; R ５ａ and R ５ｂ Each of these is H, substituted or unsubstituted C, respectively. １－６ Alkyl, substituted, or unsubstituted C ３－６ Cycloalkyl and substituted or unsubstituted C １－６ Selected independently from haloalkyl groups; Here, each substituent is independently selected from halo, -OH, and -CN; Ring A is selected from monocyclic or bicyclic heteroaryl groups having one, two, or three heteroatoms selected from substituted or unsubstituted 5- to 10-membered O, N, or S; substituted or unsubstituted 6- to 10-membered monocyclic or bicyclic aryl groups; and heterocyclic ring systems containing one, two, or three heteroatoms selected from substituted or unsubstituted monocyclic or bicyclic (condensed, bridging, or spiro) 6- to 10-membered O, N, or S; Here, if substituted, the heteroaryl group, aryl group, or heterocyclic system is a halo, -CN, C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, deuterated C １－６ Alkyl, -OR ５ｃ , -NR ５ｃ R ５ｄ or -NR ５ｃ R ５ｄ C is replaced by １－４ Substituted with one, two, or three substituents selected from alkyl groups; R ５ｃ and R ５ｄ Each of these is H, substituted or unsubstituted C, respectively. １－６ Alkyl, substituted, or unsubstituted C ３－６ Cycloalkyl and substituted or unsubstituted C １－６ Selected independently from haloalkyl groups; Here, each substituent is independently selected from halo, -OH, and -CN, and the compounds of formula (I) and their pharmaceutically acceptable salts.

2. R １ The compound according to claim 1, wherein the compound comprises a monocyclic or bicyclic (condensed, bridging, or spiro) heterocyclic system comprising a substituted or unsubstituted 4- to 7-membered nitrogen atom and 0 or 1 additional heteroatom selected from O, N, or S, wherein the heterocyclic system is -X-bonded via a nitrogen atom, and a pharmaceutically acceptable salt thereof.

3. R １ However, substitution or non-substitution A compound according to claim 1, selected from the above, and a pharmaceutically acceptable salt thereof.

4. If replaced, R １ The substituents are halo, C １－３ Alkyl, C １－３ Haloalkyl and -O-C １－３ A compound according to claim 1, selected from alkyl groups, and a pharmaceutically acceptable salt thereof.

5. R １ However, -NR １ａ R １ｂ The compound according to claim 1, and a pharmaceutically acceptable salt thereof.

6. R １ａ and R １ｂ Each of these can be substituted or not substituted. １－３ Alkyl, substituted, or unsubstituted C ３－７ Cycloalkyl, heterocyclic group having 1, 2, or 3 heteroatoms selected from 3-7 member O, N, or S, substituted or unsubstituted -C １－３ Alkyl-C ３－７ Cycloalkyl, substituted or unsubstituted - C １－３ A compound according to claim 5, independently selected from a heterocyclic group having one, two, or three heteroatoms selected from alkyl-3 to 7-membered O, N, or S, and a pharmaceutically acceptable salt thereof.

7. R １ａ and R １ｂ Each of these can be substituted or not substituted. １－３ Alkyl, substituted, or unsubstituted C ３ Cycloalkyl, heterocyclic group having 1, 2, or 3 heteroatoms selected from 3-6 member O, N, or S, substituted or unsubstituted -C １－３ Alkyl-C ３－７ Cycloalkyl, substituted or unsubstituted - C １－３ A compound according to claim 5, independently selected from a heterocyclic group having one, two, or three heteroatoms selected from alkyl-3 to 7-membered O, N, or S, and a pharmaceutically acceptable salt thereof.

8. R １ａ and R １ｂ If substituted, each substituent is a halo, -CN, -OH, C １－３ Alkyl, C ３－７ Cycloalkyl, C １－３ Haloalkyl, -O-C １－３ Alkyl, -O-C ３－７ Cycloalkyl, -O-C １－３ Haloalkyl, -C １－３ Alkyl-O-C １－３ Alkyl, -C １－３ Alkyl-O-C ３－７ Cycloalkyl, -C １－３ Alkyl-O-C １－３ Haloalkyl, -C １－３ Alkyl-O-C １－３ Haloalkyl, -NR １ｅ R １ｆ , -NR １ｅ (SO ２ ) R １ｆ , -NR １ｅ (C(O))R １ｆ , -C(O)NR １ｅ R １ｆ , and -SO ２ NR １ｅ R １ｆ A compound according to claim 5, selected from the above, and a pharmaceutically acceptable salt thereof.

9. R ２ However, H and C １－３ A compound according to claim 1, selected from alkyl groups, and a pharmaceutically acceptable salt thereof.

10. A compound according to claim 1, wherein m is 0, and a pharmaceutically acceptable salt thereof.

11. residue but, The compound according to claim 1 (where L is a bond), and a pharmaceutically acceptable salt thereof.

12. residue but, (Here, R ４ｄ A compound according to claim 1, wherein (is H), and a pharmaceutically acceptable salt thereof.

13. R ４ｅ and R ４ｆ A compound according to claim 1, wherein is H, and a pharmaceutically acceptable salt thereof.

14. A compound according to claim 1, wherein n is 1, and a pharmaceutically acceptable salt thereof.

15. A compound according to claim 1, wherein n is 0, and a pharmaceutically acceptable salt thereof.

16. R ４ However, selected from monocyclic or bicyclic 5-10 member heteroaryls, bicyclic (condensed, bridged, or spiro) 6-10 member cycloalkyl ring systems, bicyclic (condensed, bridged, or spiro) 6-10 member cycloalkenyl ring systems, and monocyclic or bicyclic 6-10 member heterocyclic systems, the heteroaryl, bicyclic (condensed, bridged, or spiro) 6-10 member cycloalkenyl ring systems containing 1, 2, or 3 heteroatoms selected from monocyclic or bicyclic 5-10 member O, N, or S, or unsubstituted, or containing 1, 2, or 3 R ４ｉ A compound according to claim 1, selected from monocyclic or bicyclic (condensed, cross-linked, or spiro) 6-10 membered heterocyclic systems substituted with , and a pharmaceutically acceptable salt thereof.

17. R ４ｉ However, each time, Hello, C １ Alkyl, C １ Haloalkyl, C ３ Cycloalkyl, C ３ Cyclohaloalkyl and -OR ４ｊ A compound according to claim 1, selected from the above, and a pharmaceutically acceptable salt thereof.

18. R ４ A compound according to claim 1, wherein is H, and a pharmaceutically acceptable salt thereof.

19. R ５ A compound according to claim 1, wherein is H, and a pharmaceutically acceptable salt thereof.

20. A compound according to claim 1, wherein o is 1, and a pharmaceutically acceptable salt thereof.

21. The compound according to claim 1, wherein R 5a and R 5b are H, and a pharmaceutically acceptable salt thereof.

22. Ring A is selected from a 9-10 membered bicyclic heteroaryl group having 1, 2, or 3 heteroatoms selected from substituted or unsubstituted O, N, or S, and a heterocyclic system containing 1, 2, or 3 heteroatoms selected from substituted or unsubstituted bicyclic (condensed, bridging, or spiro) 9-10 membered O, N, or S; Here, if substituted, the bicyclic heteroaryl group or bicyclic heterocyclic system is a halo, -CN, C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, deuterated C １－６ Alkyl, -OR ５ｃ , -NR ５ｃ R ５ｄ or -NR ５ｃ R ５ｄ C is replaced by １－４ The compound according to claim 1, substituted with one, two, or three substituents selected from alkyl groups, and a pharmaceutically acceptable salt thereof.

23. Bicyclic heteroaryl groups or bicyclic heterocyclic systems are halos, C １－３ Alkyl, C １－３ Haloalkyl, deuterated C １－３ Alkyl, -OR ５ｃ The compound according to claim 1, substituted with one, two, or three substituents independently selected from the compound, and a pharmaceutically acceptable salt thereof.

24. Ring A, A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the above.

25. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 24 and a pharmaceutically acceptable excipient.

26. A compound according to any one of claims 1 to 24, for use as a pharmaceutical.

27. To be used for the prevention or treatment, or as co-therapy in the treatment or prevention, of symptoms selected from other diseases for which inhibition of FXIIa may be beneficial, such as thrombosis, deep vein thrombosis, pregnancy-related thrombosis, congenital thromboprogressive disorders, thrombosis due to autoimmune conditions, transient ischemic attack, myocardial infarction, peripheral artery occlusion, pulmonary embolism, deep vein microvascular disease, stroke (including patients with atrial fibrillation with or without chronic renal disease), disseminated intravascular coagulation (DIC), arthritis, neuroinflammatory disorders, Alzheimer's disease, vascular dementia, macular degeneration, diabetic retinopathy, diabetic macular edema, cerebral edema in stroke, edema of other causes, hereditary angioedema, or acquired angioedema. Alternatively, it may be used to reduce the risk of venous and / or arterial thrombosis in patients with indications selected from viral or bacterial infection, reperfusion injury (also known as ischemia-reperfusion injury), renal failure, liver disease, myocardial infarction, angina pectoris (including unstable angina), atherosclerosis, stroke, cancer, asymptomatic cerebral ischemia, and neurotraumatic injury. Alternatively, complex left-sided resection (pulmonary vein resection, VT ablation), transcatheter aortic valve implantation (TAVR) (also known as transcatheter aortic valve implantation (TAVI)), spinal or epidural anesthesia, lumbar diagnostic puncture, thoracic surgery, abdominal surgery, major orthopedic surgery, liver biopsy, transurethral resection of the prostate, kidney biopsy, endoscopy with biopsy, prostate or bladder biopsy, electrophysiological studies or radiofrequency catheter ablation for supraventricular tachycardia (including left-sided ablation by single transseptal puncture), angiography, palpebrae To reduce the risk of venous and / or arterial thrombosis occurring during medical procedures selected from the following: implantation of a smother or implantable cardioverter-defibrillator (ICD) (excluding complex anatomical situations such as congenital heart disease), implantation of mechanical valves, implantation of prosthetic valves, left ventricular assist devices (LVADs), reocclusion and restenosis after angioplasty or coronary artery bypass surgery, extracorporeal circulation such as extracorporeal membrane oxygenation (ECMO), coronary artery bypass grafting (CABG), and medical procedures involving contact with artificial surfaces, including renal dialysis. Alternatively, the compound according to any one of claims 1 to 24, for use in reducing the risk of venous and / or arterial thrombosis occurring in patients undergoing medical procedures selected from transcatheter aortic valve replacement (TAVR) (also known as transcatheter aortic valve implantation (TAVI)), major orthopedic surgery, pacemaker or implantable cardioverter-defibrillator (ICD) implantation (excluding complex anatomical situations such as congenital heart disease), mechanical valve implantation, prosthetic valve implantation, left ventricular assist device (LVAD), angioplasty or reocclusion and restenosis after coronary artery bypass grafting, extracorporeal membrane oxygenation (ECMO), and coronary artery bypass grafting (CABG).

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