Pyrrolidinone urea FPR2 agonist

Abstract

This disclosure relates to compounds of formula I that are formylpeptide 2 (FPR2) receptor agonists and / or formylpeptide 1 (FPR1) receptor agonists. This disclosure also provides compositions and methods using the compounds for, for example, the treatment of atherosclerosis, heart failure, and related diseases. JPEG2026516737000190.jpg5755I

Description

[Technical Field]

[0001] Cross-references to related applications This application claims the benefits of U.S. Provisional Application No. 63 / 496,756, filed on 18 April 2023, the disclosures of which are incorporated herein by reference in their entirety. [Background technology]

[0002] The present invention relates to novel pyrrolidinone urea compounds that are formylpeptide 2 (FPR2) receptor agonists, compositions comprising the same, and methods of using them for the treatment of, for example, atherosclerosis, heart failure, chronic obstructive pulmonary disease (COPD), and related diseases.

[0003] Formylpeptide receptor 2 (FPR2) belongs to a small group of G protein-coupled receptors with seven transmembrane domains, primarily expressed on mammalian phagocytic leukocytes, and known to play a crucial role in host defense and inflammation. FPR2 exhibits high sequence homology with FPR1 and FPR3. These receptors bind to a wide variety of structurally diverse agonists, including N-formylpeptides and non-formylpeptides, which act as chemoattractants and activate phagocytic cells. Annexin A1, an endogenous anti-inflammatory peptide, and its N-terminal fragment also bind to human FPR1 and FPR2. Importantly, lipoxin A4, an anti-inflammatory eicosanoid belonging to a newly discovered class of small-molecule anti-inflammatory mediators (SPMs), has been identified as a specific agonist of FPR2 (Ye RD., et al., Pharmacol. Rev., 2009, 61, 119-61).

[0004] Endogenous FPR2 anti-inflammatory ligands such as lipoxin A4 and annexin A1 bind to receptors, undergoing Gi coupling and Ca 2+Lipoxins induce diverse cytoplasmic cascades, including mobilization and β-arrestin recruitment. Activation of FPR2 by lipoxin A4 alters the action of peptide agonists such as serum amyloid A (SAA), affecting phosphorylation pathways differently depending on the cell type. Lipoxins regulate components of both the innate and adaptive immune systems, including neutrophils, macrophages, T cells, and B cells. In neutrophils, lipoxins regulate their motility, cytotoxicity, and lifespan. In macrophages, lipoxins inhibit macrophage apoptosis and promote efferocytosis. In most inflammatory cells, lipoxins suppress the expression of pro-inflammatory cytokines such as IL-6, IL-1β, and IL-8, and enhance the expression of the anti-inflammatory cytokine IL-10 (Chandrasekharan JA, Sharma-Walia N,. J. Inflamm. Res., 2015, 8, 181-92). The primary effects of lipoxins on neutrophils and macrophages are the termination of inflammation and the initiation of inflammatory healing. The latter is mainly involved in promoting anti-fibrotic wound healing and restoring homeostasis to damaged tissue (Romano M., et al., Eur. J. Pharmacol., 2015, 5, 49-63).

[0005] Chronic inflammation is part of the pathogenesis of many human diseases, and stimulation of the deinflammatory pathway by FPR2 agonists may have both protective and reparative effects. Ischemia-reperfusion (I / R) injury is a common feature of several diseases with high morbidity and mortality rates, such as myocardial infarction and stroke. Unproductive wound healing associated with cardiomyocyte death and pathological remodeling due to ischemia-reperfusion injury leads to scarring, fibrosis, and progressive loss of cardiac function. Modulation of FPR2 has been proposed to promote post-injury myocardial wound healing and mitigate harmful myocardial remodeling (Kain V., et al., J. Mol. Cell. Cardiol., 2015, 84, 24-35). Furthermore, FPR2 anti-inflammatory agents in the central nervous system may be useful therapeutic agents for various clinical I / R conditions, such as stroke (Gavins FN., Trends Pharmacol. Sci., 2010, 31, 266-76) and I / R-induced spinal cord injury (Liu ZQ ., et al., Int. J. Clin. Exp. Med., 2015, 8, 12826-33).

[0006] Novel anti-inflammatory agonists targeting FPR2 have shown beneficial effects in treating I / R-induced injury, and the usefulness of these ligands can be applied to other diseases. In the cardiovascular system, both the FPR2 receptor and its anti-inflammatory agonist have been found to be involved in the stabilization and healing of atherosclerotic plaques (Petri MH., et al., Cardiovasc. Res., 2015, 105, 65-74; and Fredman G., et al., Sci. Trans. Med., 2015, 7(275);275ra20). FPR2 agonists have also been shown to be beneficial in preclinical models of chronic inflammatory human diseases such as infections, psoriasis, dermatitis, ocular inflammation, sepsis, pain, metabolic / diabetic diseases, cancer, COPD, asthma and allergic diseases, cystic fibrosis, acute lung injury and fibrosis, rheumatoid arthritis and other joint diseases, Alzheimer's disease, renal fibrosis, and organ transplantation (Romano M., et al., Eur. J. Pharmacol., 2015, 5, 49-63, Perrett, M., et al., Trends in Pharm. Sci., 2015, 36, 737-755). [Overview of the project]

[0007] The present invention provides novel pyrrolidinone ureas and their analogues (including stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates) that are useful as FPR2 agonists.

[0008] The present invention also provides methods and intermediates for producing the compound of the present invention or its stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates.

[0009] The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one of the compound of the present invention or its stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates.

[0010] The compound of the present invention can be used in therapeutic applications.

[0011] The compounds of the present invention can be used to treat and / or prevent a number of FPR2-related diseases or disorders, including inflammatory diseases, heart disease, chronic respiratory diseases, cancer, sepsis, allergic symptoms, HIV retroviral infection, cardiovascular diseases, neuroinflammation, neuropathy, pain, prion diseases, amyloidosis, and immune disorders. Heart diseases include angina pectoris, unstable angina, myocardial infarction, acute coronary artery disease, iatrogenic disorders of the heart, and heart failure (acute heart failure, chronic heart failure of ischemic and non-ischemic origin, systolic heart failure, diastolic heart failure, and reduced ejection fraction heart failure (HF). R EF, and heart failure with preserved ejection fraction (HF) P The group is selected from the group consisting of (but not limited to) EF).

[0012] The compounds of the present invention can be used alone, in combination with other compounds of the present invention, or in combination with one or more other agents.

[0013] Other features and advantages of the present invention will become apparent from the following detailed description and claims. [Modes for carrying out the invention]

[0014] Description of the Invention The present invention encompasses compounds represented by formula I that are formylpeptide 2 (FPR2) receptor agonists, compositions comprising them, and methods of using them in the treatment of, for example, atherosclerosis, heart failure, chronic obstructive pulmonary disease (COPD), and related diseases.

[0015] In the first aspect, the present invention relates to formula I: [ka] I [In the formula, * is an asymmetric carbon atom; Ring A is a C6 aryl or a 6-membered heteroaryl; Ring B is a C6 aryl or a 6-membered heteroaryl; Ring C is a 4- to 9-membered saturated heterocyclic ring containing 0 to 3 additional heteroatoms selected from O and N; R 1 is halo, alkyl, or haloalkyl; R 2 is halo, alkyl, haloalkyl, or C 3-6 cycloalkyl; R 3 is hydrogen, fluoro, hydroxy, hydroxyalkyl, or alkoxy; R 4 is hydrogen, halo, haloalkyl, hydroxy, oxo, hydroxyalkyl, cyano, alkyl, alkoxy, alkoxyalkyl, cycloalkyl, (R 5 )(R 6 )N, (alkyl)2(O)P, (alkyl)2(O)PO, (alkoxy)2(O)P, (alkoxy)(alkyl)(O)P, (alkyl)2(O)Palkyl, (alkoxy)2(O)Palkyl, (alkoxy)(alkyl)(O)Palkyl, alkylSO2, cycloalkylSO2, or (R 5 )(R 6 )NCO; R 5 is hydrogen, alkyl, hydroxyalkyl, alkylCO, cycloalkylCO, halocycloalkylCO, cycloalkyl, alkylSO2, alkylSO2alkyl or heterocyclic ring; R 6 is hydrogen or alkyl; or NR 5 R 6 together form a 4- to 6-membered heterocycle substituted with 0 to 3 substituents selected from oxo, hydroxy, fluoro, alkyl, haloalkyl, alkoxy, and haloalkoxy; provided that the formula:

Chemical formula

[0016] In a second aspect within the scope of the first aspect, the present invention provides a compound represented by formula I, or a pharmaceutically acceptable salt thereof. Here, Ring A is, [ka] and; Ring B is, [ka] is; and Ring C is, [ka] and; The other variable groups are defined as shown in formula I.

[0017] In a third aspect within the scope of the first and second aspects, the present invention relates to formula II: [ka] II [In the formula, Q is CH, CR 2 , or N; R 1 is a halo or haloalkyl; R 2 is a halo, alkyl, or cycloalkyl; R 3 is hydrogen or hydroxyalkyl; R 4 (R) 5 )(R6 )N, (alkyl)2(O)P, (alkyl)2(O)PO, (alkyl)2(O)Palkyl, alkylSO2, cycloalkylSO2; R 5 These are hydrogen, alkyl, hydroxyalkyl, alkylCO, cycloalkylCO, halocycloalkylCO, cycloalkyl, alkylSO2, alkylSO2alkyl, or heterocycle; R 6 is hydrogen or alkyl; or NR 5 R 6 [These are combined and substituted with 0-2 substituents selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, and selected from oxo and alkyl groups.] The present invention provides the compound shown, or a pharmaceutically acceptable salt thereof.

[0018] In a fourth aspect within the scope of the third aspect, the present invention relates to formula III: [ka] III [In the formula, R 1 is a halo or haloalkyl; R 2 is a halo, alkyl, or cycloalkyl; R 3 is hydrogen or hydroxymethyl; R 5 These are hydrogen, alkyl, hydroxyalkyl, alkylCO, cycloalkylCO, halocycloalkylCO, cycloalkyl, alkylSO2, alkylSO2alkyl, or heterocycle; R 6 is hydrogen or alkyl; or NR 5 R 6 [These are combined and substituted with 0-2 substituents selected from azetidinyl, piperazinyl, and morpholinyl, and selected from oxo and alkyl groups.] The present invention provides the compound shown, or a pharmaceutically acceptable salt thereof.

[0019] In a fifth aspect within the scope of the first aspect, the present invention relates to formula IV: [ka] IV [In the formula, R 1 is a halo or haloalkyl; R 2 is a halo, alkyl, or cycloalkyl; R 4 (R) 5 )(R 6 )N is; R 5 is hydrogen, alkyl, or hydroxyalkyl; and R 6 [It is hydrogen or alkyl.] The present invention provides the compound shown, or a pharmaceutically acceptable salt thereof.

[0020] In a sixth aspect within the scope of the first aspect, the present invention relates to formula V: [ka] V [In the formula, R 1 is a halo or haloalkyl; R 2 is a halo, alkyl, or cycloalkyl; R 4 (R) 5 )(R 6 )N is; R 5 is hydrogen, alkyl, or hydroxyalkyl; and R 6 [It is hydrogen or alkyl.] The present invention provides the compound shown, or a pharmaceutically acceptable salt thereof.

[0021] In a seventh aspect within the scope of the first aspect, the present invention relates to formula VI: [ka] VI [In the formula, R 1 is a halo or haloalkyl; R 2 is a halo, alkyl, or cycloalkyl; and R 4 [These are hydrogen, haloalkyl, hydroxyalkyl, alkyl, or alkoxyalkyl] The present invention provides the compound shown, or a pharmaceutically acceptable salt thereof.

[0022] In the eighth aspect within the scope of the first aspect, the present invention provides a compound represented by formula I, or a pharmaceutically acceptable salt thereof. Here, Ring A is, [ka] and; Ring B is, [ka] is; and Ring C is, [ka] and; R 1 is Cl or CF3; R 2 is F; and R 4 It is hydrogen or alkyl.

[0023] Another aspect of the present invention, within the scope of the first aspect, is formula IIa: [ka] IIa [In the formula, * is an asymmetric carbon atom; Q is CH, CR 2 , or N; R 1 is a halo or haloalkyl; R 2 is a halo, alkyl, or cycloalkyl; R 3 is hydrogen or hydroxyalkyl; R 4 (R) 5 )(R 6 )N, (alkyl)2(O)P, (alkyl)2(O)PO, (alkyl)2(O)Palkyl, alkylSO2, cycloalkylSO2; R 5 These are hydrogen, alkyl, hydroxyalkyl, alkylCO, cycloalkylCO, halocycloalkylCO, cycloalkyl, alkylSO2, alkylSO2alkyl, or heterocycle; R 6 is hydrogen or alkyl; or NR 5 R 6 [These are combined and substituted with 0-2 substituents selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, and selected from oxo and alkyl groups.] The compound represented by [formula], or a pharmaceutically acceptable salt thereof.

[0024] Another aspect of the present invention, within the scope of the first aspect, is formula IIIa: [ka] IIIa [In the formula, * is an asymmetric carbon atom; R 1 is a halo or haloalkyl; R 2 is a halo, alkyl, or cycloalkyl; R 3 is hydrogen or hydroxymethyl; R 5 These are hydrogen, alkyl, hydroxyalkyl, alkylCO, cycloalkylCO, halocycloalkylCO, cycloalkyl, alkylSO2, alkylSO2alkyl, or heterocycle; R 6 is hydrogen or alkyl; or NR 5 R 6 [These are combined and substituted with 0-2 substituents selected from azetidinyl, piperazinyl, and morpholinyl, and selected from oxo and alkyl groups.] The compound represented by [formula], or a pharmaceutically acceptable salt thereof.

[0025] Another aspect of the present invention is formula IVa: [ka] IVa [In the formula, * is an asymmetric carbon atom; R 1 is a halo or haloalkyl; R 2 is a halo, alkyl, or cycloalkyl; R 4 (R) 5 )(R 6 )N is; R 5 is hydrogen, alkyl, or hydroxyalkyl; and R 6 [It is hydrogen or alkyl.] The compound represented by [formula], or a pharmaceutically acceptable salt thereof.

[0026] Another aspect of the present invention is formula Va: [ka] Va [wherein R 1 is halo or haloalkyl; R 2 is halo, alkyl, or cycloalkyl; R 4 is hydrogen, haloalkyl, hydroxyalkyl, alkyl, or (R 5 )(R 6 )N; R 5 is hydrogen, alkyl, or hydroxyalkyl; and R 6 is hydrogen or alkyl] is a compound represented by the formula, or a pharmaceutically acceptable salt thereof.

[0027] Another aspect of the present invention is a compound of formula VIa: [Chemical formula] VIa [wherein * is an asymmetric carbon atom; R 1 is halo or haloalkyl; R 2 is halo, alkyl, or cycloalkyl; and R 4 is hydrogen, haloalkyl, hydroxyalkyl, alkyl, or alkoxyalkyl] is a compound represented by the formula, or a pharmaceutically acceptable salt thereof.

[0028] For the compounds of formulas I to VI, the range of any example of the variable substituents including R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 can be applied independently of the range of any other example of the variable substituents. Accordingly, the present invention includes combinations of different aspects.

[0029] In one non-limiting embodiment, for a compound of formula I, ring A is [ka] And; R 1 is a halo or haloalkyl; ring B is [ka] And; R 2 is a halo; ring C is [ka] And; R 3 is hydrogen or hydroxyalkyl; R 4 These are halo, hydroxy, hydroxyalkyl, alkyl, alkoxy, alkoxyalkyl, (alkyl)2(O)P, (alkyl)2(O)PO, (alkyl)2(O)Palkyl, or alkylSO2.

[0030] In another non-limiting embodiment, for the compound of formula I, ring A is [ka] And; R 1 is a halo or haloalkyl; ring B is [ka] And; R 2 is isopropyl or cyclopropyl; ring C is [ka] And; R 3 is hydrogen or hydroxyalkyl; R 4 These are halo, hydroxyalkyl, alkyl, alkoxy, alkoxyalkyl, (alkyl)2(O)P, (alkyl)2(O)PO, (alkyl)2(O)Palkyl, or alkylSO2.

[0031] In another non-limiting embodiment, for the compound of formula I, ring A is [ka] And; R 1 is a halo or haloalkyl; ring B is [ka] And; R 2 is a halo; ring C is [ka] And; R 3 is hydrogen or hydroxyalkyl; R 4 is, (R 5 )(R 6 )N is; R 5 R is a cycloalkyl CO, a halocycloalkyl CO, or a 4-6 member heterocyclyl; 6 is hydrogen or alkyl; or NR 5 R 6 They came together, [ka] It forms.

[0032] In another non-limiting embodiment, for the compound of formula I, ring A is [ka] And; R 1 is a halo or haloalkyl; ring B is [ka] And; R 2 is a halo; ring C is [ka] And; R 3 is hydrogen or hydroxyalkyl; and R4 It is a halo.

[0033] In one non-limiting embodiment, for a compound of formula I, ring A is [ka] And; R 1 is a halo or haloalkyl; ring B is [ka] And; R 2 is a halo; ring C is [ka] And; R 3 is hydrogen or hydroxyalkyl; and R 4 These are hydrogen, halo, hydroxy, oxo, hydroxyalkyl, alkoxy, (alkyl)2(O)P, (alkyl)2(O)PO, (alkyl)2(O)Palkyl, or alkylSO2.

[0034] In another non-limiting embodiment, for the compound of formula I, ring A is [ka] And; R 1 is a halo or haloalkyl; ring B is [ka] And; R 2 is isopropyl or cyclopropyl; ring C is [ka] And; R 3 is hydrogen or hydroxyalkyl; R 4R is hydrogen, halo, hydroxy, oxo, hydroxyalkyl, alkoxy, (alkyl)2(O)P, (alkyl)2(O)PO, (alkyl)2(O)Palkyl, or alkylSO2; R 5 is hydrogen, alkyl, hydroxyalkyl, or cycloalkyl CO; and R 6 It is hydrogen or alkyl.

[0035] In another non-limiting embodiment, for the compound of formula I, ring A is [ka] And; R 1 is a halo or haloalkyl; ring B is [ka] And; R 2 is a halo; ring C is [ka] And; R 3 is hydrogen or hydroxyalkyl; R 4 is, (R 5 )(R 6 )N is; R 5 R is hydrogen, alkyl, hydroxyalkyl cycloalkyl CO, halocycloalkyl CO, or a 4-6 member heterocycline; 6 is hydrogen or alkyl; or NR 5 R 6 They came together, [ka] It forms.

[0036] In another non-limiting embodiment, for the compound of formula I, ring A is [ka] And; R 1 is a halo or haloalkyl; ring B is [ka] And; R 2 is a halo; ring C is [ka] And; R 3 is hydrogen or hydroxyalkyl; R 4 is hydroxyalkyl or (R 5 )(R 6 )N is; R 5 is hydrogen or alkyl; and R 6 It is hydrogen or alkyl.

[0037] In another non-limiting embodiment, for the compound of formula I, ring A is [ka] And; R 1 is a halo or haloalkyl; ring B is [ka] And; R 2 is a halo; ring C is [ka] And; R 3 is hydrogen or hydroxyalkyl; and R 4 It is a halo.

[0038] In one non-limiting embodiment, for a compound of formula I, ring A is [ka] And; R 1 is a halo or haloalkyl; ring B is [ka] And; R 2is a halo; ring C is [ka] And; R 3 is hydrogen or hydroxyalkyl; R 4 These are halo, hydroxy, hydroxyalkyl, alkyl, alkoxy, alkoxyalkyl, (alkyl)2(O)P, (alkyl)2(O)PO, (alkyl)2(O)Palkyl, or alkylSO2.

[0039] In another non-limiting embodiment, for the compound of formula I, ring A is [ka] And; R 1 is a halo or haloalkyl; ring B is [ka] And; R 2 is a halo; ring C is [ka] And; R 3 is hydrogen or hydroxyalkyl; R 4 is, (R 5 )(R 6 )N is; R 5 R is hydrogen, alkyl, hydroxyalkyl cycloalkyl CO, halocycloalkyl CO, or a 4-6 member heterocycline; 6 is hydrogen or alkyl; or NR 5 R 6 They came together, [ka] It forms.

[0040] In another non-limiting embodiment, for the compound of formula I, ring A is [ka] And; R 1 is a halo or haloalkyl; ring B is [ka] And; R 2 is a halo; ring C is [ka] And; R 3 is hydrogen or hydroxyalkyl; and R 4 It is a halo.

[0041] In one non-limiting embodiment, for a compound of formula I, ring A is [ka] And; R 1 is a halo or haloalkyl; ring B is [ka] And; R 2 is a halo; ring C is [ka] And; R 3 is hydrogen or hydroxyalkyl; R 4 These are halo, hydroxy, hydroxyalkyl, alkyl, alkoxy, alkoxyalkyl, (alkyl)2(O)P, (alkyl)2(O)PO, (alkyl)2(O)Palkyl, or alkylSO2.

[0042] In another non-limiting embodiment, for the compound of formula I, ring A is [ka] And; R 1 is a halo or haloalkyl; ring B is [ka] And; R 2 is isopropyl or cyclopropyl; ring C is [ka] And; R 3 is hydrogen or hydroxyalkyl; R 4 R is a halo, hydroxyalkyl, alkyl, alkoxy, alkoxyalkyl, (alkyl)2(O)P, (alkyl)2(O)PO, (alkyl)2(O)Palkyl, or alkylSO2; 5 This includes hydrogen, alkyl, hydroxyalkyl, or cycloalkyl CO; and R 6 It is hydrogen or alkyl.

[0043] In another non-limiting embodiment, for the compound of formula I, ring A is [ka] And; R 1 is a halo or haloalkyl; ring B is [ka] And; R 2 is a halo; ring C is [ka] And; R 3 is hydrogen or hydroxyalkyl; R 4 is, (R 5 )(R 6 )N is; R 5 R is hydrogen, alkyl, hydroxyalkylcycloalkylCO, halocycloalkylCO, or a 4-6 member heterocyclyl; 6 is hydrogen or alkyl; or NR 5 R 6 They came together, [ka] It forms.

[0044] In another non-limiting embodiment, for the compound of formula I, ring A is [ka] And; R 1 is a halo or haloalkyl; ring B is [ka] And; R 2 is a halo; ring C is [ka] And; R 3 is hydrogen or hydroxyalkyl; R 4 is hydroxyalkyl or (R 5 )(R 6 )N is; R 5 is hydrogen or alkyl; and R 6 It is hydrogen or alkyl.

[0045] In another non-limiting embodiment, for the compound of formula I, ring A is [ka] And; R 1 is a halo or haloalkyl; ring B is [ka] And; R 2 is a halo; ring C is [ka] And; R 3 is hydrogen or hydroxyalkyl; and R 4 It is a halo.

[0046] In another non-limiting embodiment, for the compound of formula I, ring A is [Chemical formula] where; R 1 is halo or haloalkyl; Ring B is [Chemical formula] where; R 2 is halo; Ring C is [Chemical formula] where; R 3 is hydrogen or hydroxyalkyl; and R 4 is hydrogen or alkoxyalkyl.

[0047] In another non-limiting embodiment, for the compound of formula I, Ring A is [Chemical formula] where; R 1 is halo or haloalkyl; Ring B is [Chemical formula] where; R 2 is halo; Ring C is [Chemical formula] where; R 3 is hydrogen or hydroxyalkyl; and R 4 [[ID=6l]]is hydrogen or hydroxyalkyl.

[0048] In another non-limiting embodiment, for the compound of formula I, Ring A is [Chemical formula] where; R 1 is halo or haloalkyl; Ring B is [Chemical formula] and; R 2 is a halo; ring C is [Chemical formula] and; R 3 is hydrogen or hydroxyalkyl; and R 4 is hydrogen or alkyl.

[0049] In another non-limiting embodiment, for the compound of formula I, ring A is [Chemical formula] and; R 1 is halo or haloalkyl; ring B is [Chemical formula] and; R 2 is halo; ring C is [Chemical formula] and; and R 3 is hydrogen or hydroxyalkyl.

[0050] In another non-limiting embodiment, for the compound of formula I, ring A is [Chemical formula] and; R 1 is halo or haloalkyl; ring B is [Chemical formula] and; R 2 is halo; ring C is [Chemical formula] and; and R 3 is hydrogen or hydroxyalkyl.

[0051] In another non-limiting embodiment, for the compound of formula I, ring A is [ka] And; R 1 is a halo or haloalkyl; ring B is [ka] And; R 2 is a halo; ring C is [ka] And; R 3 is hydrogen or hydroxyalkyl; and R 4 It is hydrogen or alkyl.

[0052] In another non-limiting embodiment, for the compound of formula I, ring A is [ka] And; R 1 is a halo or haloalkyl; ring B is [ka] And; R 2 is a halo; ring C is [ka] And; R 3 is hydrogen or hydroxyalkyl; and R 4 It is hydrogen or alkyl.

[0053] In another non-limiting embodiment, for the compound of formula I, ring A is [ka] And; R 1 is a halo or haloalkyl; ring B is [ka] And; R 2 Halo; ring C is, [ka] And; R 3 is hydrogen or hydroxyalkyl; and R 4 is hydrogen or alkyl.

[0054] In another non-limiting embodiment, for the compound of formula I, ring A is [ka] And; R 1 is a halo or haloalkyl; ring B is [ka] And; R 2 is a halo; ring C is [ka] And; R 3 is hydrogen or hydroxyalkyl; and R 4 It is hydrogen or alkyl.

[0055] In one embodiment, the compound of the present invention is FPR2 EC 50 Compounds with a concentration of ≥0.01 μM and <0.1 μM are selected.

[0056] In another embodiment, the compound of the present invention is FPR2 EC 50 Compounds with a concentration of ≥0.006 μM and <0.01 μM are selected.

[0057] In another embodiment, the compound of the present invention is FPR2 EC 50 Compounds with a concentration of ≥0.001 μM and <0.006 μM are selected.

[0058] In another embodiment, the compound of the present invention is FPR2 EC 50The compounds are selected from those with a concentration of <0.001 μM.

[0059] A dash "-" without a space between two letters or symbols is used to indicate a substituent bond point. For example, -CONH2 is bonded via a carbon atom.

[0060] The structural formulas used in this specification are: [ka] Bonds indicated by wavy lines, such as those shown above, represent bonds where the part or substituent is attached to the core or backbone structure. "Cyano" means -CN. "Hydroxy" refers to the -OH group. "Oxo" means =O. "Alkyl" refers to a linear or branched alkyl group having 1 to 6 carbon atoms. "Lower alkyl" refers to linear or branched alkyl groups with 1 to 3 carbon atoms. "Cycloalkyl" refers to a monocyclic ring system consisting of 3 to 7 carbon atoms. "Halo" refers to fluoro, chloro, bromo, and iodine. "Haloalkyl" refers to a halo-substituted alkyl group. Haloalkyl includes all halide isomers, from monohalo to perhalo.

[0061] "Haloalkoxy" refers to a halosubstituted alkyl group bonded via an oxygen atom. Haloalkoxy includes not only monosubstituted alkoxy groups, but also multiple halosubstituted alkoxy groups, and even hyperhalosubstituted alkoxy groups. Examples include trifluoromethoxy, chloromethoxy, and bromomethoxy. "Alkoxycarbonyl" refers to an alkoxysubstituted carbonyl group (e.g., -C(O)OR), where R represents an optionally substituted alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, or similar group.

[0062] "Alkoxy" refers to an alkyl group that is bonded to the rest of the molecule via an oxygen bond. Typical examples of such groups are -OCH3 and -OC2H5. Unless otherwise specified, all alkoxy groups described or claimed herein are linear or branched. "Alkoxyalkyl" refers to an alkyl group in which at least one hydrogen atom is substituted with an alkoxy group. "Hydroxyalkyl" refers to an alkyl group in which at least one hydrogen atom is replaced by a hydroxyl group.

[0063] "Aryl" refers to a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 12 carbon atoms, or a bicyclic fused ring system in which one or both rings are aromatic. A bicyclic fused ring system consists of a phenyl group fused with a 4 to 7-membered aromatic or non-aromatic carbon ring. Typical examples of aryl groups include, but are not limited to, phenyl, indanyl, indenyl, naphthyl, and tetrahydronaphthyl.

[0064] "Heteroaryl" refers to a monocyclic or bicyclic aromatic ring system of 5-7 members or 8-11 members, having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. If no bond position is specified, the bond may be at any appropriate position as understood by those skilled in the art. Only combinations of substituents and bond patterns that result in stable compounds as understood by those skilled in the art are permitted. Terms in parentheses and multiple parentheses are intended to clarify the bond relationships for those skilled in the art. For example, the term ((R)alkyl) means an alkyl substituent further substituted with substituent R.

[0065] A “heterocyclyl” or “heterocycle” refers to a 5- to 7-membered monocyclic or 8- to 11-membered polycyclic heterocycle that is saturated, partially unsaturated, or fully unsaturated and contains a carbon atom and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S, and also includes polycyclic groups in which any of the heterocycles defined above is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N → O and S(O)p, where p is 0, 1, or 2). The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or other substituent (if defined)). The heterocycle may be bonded to its pendant group at any heteroatom or carbon atom that forms a stable structure. The heterocycles described herein may be substituted at the carbon or nitrogen atom, insofar as the resulting compound is stable. The nitrogen in the heterocycle may optionally be quaternized. If the total number of S and O atoms in a heterocycle exceeds 1, it is preferable that these heteroatoms are not adjacent to each other. It is preferable that the total number of S and O atoms in a heterocycle is 1 or less. When the term "heterocycle" is used, it is intended to include heteroaryl groups.

[0066] This invention encompasses all pharmaceutically acceptable salt forms of the compound. A pharmaceutically acceptable salt is one in which the counterion does not significantly contribute to the physiological activity or toxicity of the compound and functions as a pharmacological equivalent in itself. These salts can be prepared using commercially available reagents according to general organic synthesis techniques. Examples of anionic salts include acetates, acistrates, besilates, bromides, chlorides, citrates, fumarates, glucuronides, hydrobroms, hydrochlorides, hydroiodides, iodides, lactates, maleates, mesilates, nitrates, pamoates, phosphates, succinates, sulfates, tartrates, tosylates, and xinofoates. Examples of cationic salts include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc.

[0067] Some of the compounds of the present invention have stereoisomers. The present invention includes all stereoisomers of the compounds, including enantiomers and diastereomers. Methods for producing and separating stereoisomers are known in the art. The present invention includes all tautomers of the compounds. The present invention includes atropisomers and rotational isomers.

[0068] This invention is intended to encompass all isotopes of atoms present in a compound. Isotopes include atoms with the same atomic number but different mass numbers. As a general example, but not limited to, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include, 13 C and 14It contains C. The isotope-labeled compounds of the present invention can usually be prepared by means of the prior art known to those skilled in the art, or by methods similar to those described herein, using a suitable isotope-labeled reagent instead of an unlabeled reagent. Such compounds can be used in a variety of applications, such as standards and reagents in the measurement of biological activity. In the case of stable isotopes, such compounds may modify their biological, pharmacological, or pharmacokinetic properties in a desirable manner.

[0069] biological methods N-formyl peptide receptors (FPRs) are a family of chemoattractant receptors that promote leukocyte responses during inflammation. FPRs belong to the seven-transmembrane G protein-coupled receptor superfamily and bind to inhibitory G proteins (Gi). Three family members (FPR1, FPR2, and FPR3) have been identified in humans, primarily present in bone marrow cells, with diverse distributions and reported expression in multiple organs and tissues. Following agonist binding, FPRs activate numerous physiological pathways, including intracellular signaling, Ca2+ recruitment, and transcription. This family interacts with a variety of ligands, including proteins, polypeptides, and fatty acid metabolites, activating both pro-inflammatory and pro-inflammatory downstream responses.

[0070] The FPR2 receptor binds to multiple ligands and triggers both inflammatory and anti-inflammatory responses. The release of inflammatory mediators by FPR2 is promoted by endogenous protein ligands such as serum amyloid A (SAA) and amyloid β (1-42), while the resolution of inflammation is induced by ligands such as the arachidonic acid metabolites lipoxin A4 (LXA4) and epilipoxin (ATL), and the docosahexenoic acid metabolite resolvin D1 (RvD1). Fatty acid metabolites that promote inflammation resolution mediate the suppression and resolution of inflammation via the FPR2 receptor by stimulating phagocytosis of apoptotic neutrophils by macrophages. The removal of apoptotic neutrophils induces the release of cytokines that activate the inflammation resolution pathway.

[0071] The FPR1 receptor was isolated as a high-affinity receptor for N-formylmethionine-containing peptides (e.g., N-formylmethionine-leucyl-phenylalanine (FMLP)). This protein guides mammalian phagocytic and leukocytes to invading pathogens or inflammatory tissue, activating these cells to kill pathogens or remove cellular debris.

[0072] Cyclic adenosine monophosphate (cAMP) assays for FPR2 and FPR1 384-well Proxiplates (Perkin-Elmer) pre-added with the test compound in DMSO (1% final concentration) were mixed with a mixture of forskolin (5 μM final concentration for FPR2, 10 μM final concentration for FPR1) and IBMX (200 μM final concentration) at a final concentration of 1.7 nM to 100 μM. Chinese hamster ovary cells (CHO cells) overexpressing human FPR1 or human FPR2 receptors were cultured in F-12 (Ham's) medium supplemented with 10% qualified FBS, 250 μg / ml zeosin, and 300 μg / ml hygromycin (Life Technologies). The reaction was initiated by adding 2,000 human FPR1 cells or 4,000 human FPR2 cells per well to Dulbecco's PBS (containing calcium and magnesium) (Life Technologies) supplemented with 0.1% BSA (Perkin-Elmer). The reaction mixture was incubated at room temperature for 30 minutes. Intracellular cAMP concentration was measured using the HTRF HiRange cAMP assay reagent kit (Cisbio) according to the manufacturer's instructions. Solutions of cryptotate-labeled anti-cAMP antibody and d2-fluorescent-labeled cAMP antibody were prepared separately in the provided lysis buffer. After the reaction was complete, cells were lysed with equal volumes of d2-cAMP solution and anti-cAMP solution. After incubation at room temperature for 1 hour, time-resolved fluorescence intensity was measured using Envision (Perkin-Elmer) at excitation wavelengths of 400 nm and emission wavelengths of 590 nm and 665 nm. Calibration curves were created by plotting the ratio of emission intensity at 665 nm to 590 nm against cAMP concentration using external cAMP standards in the concentration range of 1 μM to 0.1 pM. Next, the potency of the compounds and their inhibitory effect on active cAMP production were determined by fitting a four-parameter logistic equation from the cAMP level versus compound concentration plots.

[0073] The examples disclosed below were tested in the FPR2 and FPR1 cAMP assays described above and were confirmed to possess FPR2 and / or FPR1 agonist activity. Table 1 below shows the EC2 values ​​measured in the FPR2 and FPR1 cAMP assays for the following examples.50 Show the value.

[0074] Table 1 [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6]

[0075] Animal models To evaluate myocardial fibrosis in non-ischemic heart disease with hypertension, mice were administered angiotensin II to stimulate cardiac hypertrophy and left ventricular fibrosis. Mice received angiotensin II via a subcutaneously implanted osmotic minipump. Another group of mice received a subcutaneous pump containing saline (surgical "sham surgery" group). These mice were used as a control group for pump implantation surgery. After pump implantation, mice were treated with either a compound (QD) or a compound-free administration solution (QD, hereafter referred to as "vehicle"). In this model, when myocardial fibrosis reached its peak progression and was left untreated, this high level of fibrosis persisted until angiotensin II was depleted (approximately 4 weeks after implantation). Mice were treated with an intervention therapy using a compound that induces regression of myocardial fibrosis for 2–4 weeks. At the end of the treatment period, the hearts were removed from the animals, and collagen levels / fibrosis were evaluated by cross-sectional histological examination of the heart.

[0076] Pharmaceutical composition and method of use The compounds of the present invention can be administered to patients for the treatment of various conditions and disorders, including atherosclerosis, heart failure, asthma, COPD, lung diseases including cystic fibrosis, neuroinflammatory diseases including multiple sclerosis, Alzheimer's disease, and stroke, as well as chronic inflammatory diseases such as inflammatory bowel disease, rheumatoid arthritis, psoriasis, sepsis, lupus, and renal fibrosis.

[0077] Another aspect of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I in combination with a pharmaceutical carrier.

[0078] Another aspect of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I in combination with at least one other therapeutic agent and a pharmaceutical carrier.

[0079] Unless otherwise specified, the following terms have the meanings set forth below. "Patient" means a person deemed suitable for treatment by a practitioner in the field, and to the best of the practitioner's understanding, includes all appropriate mammalian species, including humans, that may potentially benefit from treatment with FPR2 and / or FPR1 agonists. Common risk factors include, but are not limited to, age, sex, weight, family history, sleep apnea, alcohol or smoking, arrhythmias due to physical inactivity, or signs of insulin resistance such as acanthosis nigricans, hypertension, dyslipidemia, or polycystic ovary syndrome (PCOS). "To treat" or "treatment" includes treatment of a patient as understood by a practitioner in the field, and includes suppression of the disease (i.e., halting disease progression), alleviation of the disease (i.e., causing disease regression), and / or prevention of disease onset in the patient. "Therapeutic dose" is intended to include the amount of an effective or beneficial compound as understood by a practitioner in the field.

[0080] "Pharmaceutical composition" means a composition comprising the compound of the present invention in combination with at least one additional pharmaceutically acceptable carrier. "Pharmaceutically acceptable carrier" refers to a medium for delivering a biologically active agent as understood by those skilled in the art, such as diluents, preservatives, fillers, flow modifiers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, and compounding agents. Pharmaceutically acceptable carriers are formulated according to several factors known to those skilled in the art. These include, but are not limited to, the type and nature of the active agent being formulated, the target recipient of the drug-containing composition, the intended route of administration of the composition, and the target therapeutic indication. A description of a suitable pharmaceutically acceptable carrier and the factors involved in its selection is publicly known in the art in reference to Allen, LV, Jr. et al., Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition, Pharmaceutical Press (2012).

[0081] The solid composition is usually formulated in dose units, and compositions that provide approximately 1 to 1000 mg of the active ingredient per single dose are preferred. Examples of doses include 1 mg, 10 mg, 100 mg, 250 mg, 500 mg, and 1000 mg.

[0082] Liquid compositions are typically specified in terms of dosage unit ranges. Generally, the dosage unit range for liquid compositions is 1 to 100 mg / mL. Examples of dosages include 1 mg / mL, 10 mg / mL, 25 mg / mL, 50 mg / mL, and 100 mg / mL.

[0083] Another aspect of the present invention is a method for treating a heart disease, comprising administering a therapeutically effective amount of a compound of formula I to a patient.

[0084] Another aspect of the present invention is a method for treating a heart disease, wherein the heart disease is selected from the group consisting of angina pectoris, unstable angina, myocardial infarction, heart failure, acute coronary artery disease, acute heart failure, chronic heart failure, and iatrogenic injury of the heart.

[0085] Another aspect of the present invention is a method for treating cardiac disease following myocardial infarction.

[0086] Another aspect of the present invention is a method by which heart disease is associated with chronic heart failure.

[0087] Another aspect of the present invention is a method in which the treatment improves the healing of myocardial wounds.

[0088] Another aspect of the present invention is a method that is a treatment for alleviating myocardial fibrosis.

[0089] The present invention encompasses all conventional methods of administration, but oral and parenteral administration are preferred. Generally, the administration regimen is similar to that of other clinically used cardiovascular drugs. The administration regimen and method of administration of the compounds of the present invention depend on factors known to practitioners of the art, including the age, sex, health status, medical condition, and weight of the recipient; the nature and severity of symptoms; the type of concomitant therapy; the frequency of treatment; the route of administration; and the desired effect. Typically, the daily dose is 0.1 to 100 mg per kg of body weight. Generally, more of the compound is required for oral administration, and less for parenteral administration. However, the specific administration regimen is determined by the physician based on appropriate medical judgment.

[0090] Another aspect of the present invention is a method for treating a heart disease, comprising administering a therapeutically effective amount of a compound of formula I together with at least one other therapeutic agent to a patient in need.

[0091] The compounds of the present invention can be used in combination with other suitable therapeutic agents useful for treating the aforementioned diseases or disorders, such as anti-atherosclerotic agents, anti-dyslipidemia agents, antidiabetic agents, antihyperglycemic agents, anti-hyperinsulinic agents, antithrombotic agents, anti-retinopathy agents, antineuropathy agents, antinephropathy agents, anti-ischemic agents, antihypertensive agents, anti-obesity agents, anti-hyperlipidemia agents, anti-hypertriglyceridemia agents, anti-hypercholesterolemia agents, anti-restenosis agents, anti-pancreatic cancer agents, lipid-lowering inhibitors, appetite suppressants, memory enhancers, anti-dementia agents, cognitive function enhancers, appetite suppressants, heart failure agents, peripheral artery disease treatment agents, malignant tumor treatment agents, and anti-inflammatory agents.

[0092] The compounds of the present invention can be used in combination with one or more, preferably one to three, of the following heart failure treatments selected from loop diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), angiotensin receptor neprilysin inhibitors (ARNIs), beta-blockers, mineralocorticoid receptor antagonists, nitroxyl donors, RXFP1 agonists, APJ agonists, and inotropic agents. These drugs include, but are not limited to, furosemide, bumetanide, torsemide, sacubitril, valsartan, thiazide diuretics, captopril, enalapril, lisinopril, carvedilol, metopolol, bisoprolol, celeracin, spironolactone, eplerenone, ivabradine, candesartan, eprosartan, irvestaline, losartan, olmesartan, telmisartan, and valsartan.

[0093] The compounds of the present invention are useful as standard or reference compounds, for example, as quality standards or controls, in tests or assays targeting FPR2. Such compounds can be provided, for example, as commercially available kits for use in pharmaceutical research targeting FPR2 activity. For example, the compounds of the present invention can be used as reference compounds in assays to compare their known activity with that of compounds having unknown activity. This allows the experimenter to be confident that the assay is being performed correctly and to have a basis for comparison, especially when the test compound is a derivative of the reference compound. When developing new assays or protocols, their effectiveness can be tested using the compounds of the present invention. The compounds of the present invention can also be used in diagnostic assays that include FPR2.

[0094] Methods of Chemistry The abbreviations used in this book are defined as follows: "1x" means once, "2x" means twice, "3x" means three times, "℃" means Celsius, "aq" means aqueous solution, "Col" means column, "eq" means equivalent, "g" means gram, "mg" means milligram, "L" means liter, "mL" means milliliter, "μL" means microliter, "N" means standard, "M" means mole, "nM" means nanomoles, "mol" means mole, "mmol" means millimoles, "min" means minute, "h" means hour, "rt" means room temperature, "RT" means retention time, "ON" means overnight, "atm" means atmospheric pressure, "psi" means pounds per square inch, "conc." means concentrate, "aq" means aqueous solution, "sat" or "sat'd" means saturated, "MW" means molecular weight, "mw" or "μwave" means microwave, "mp" means melting point, "Wt" means weight, "MS" or "Mass" "Spec" is mass spectrometry, "ESI" is electrospray ionization mass spectrometry, "HR" is high resolution, "HRMS" is high resolution mass spectrometry, "LCMS" is liquid chromatography-mass spectrometry, "HPLC" is high-pressure liquid chromatography, "RP HPLC" is reversed-phase HPLC, "TLC" or "tlc" is thin-layer chromatography, "NMR" is nuclear magnetic resonance spectroscopy, "nOe" is nuclear Overhauser effect spectroscopy, "1H" is proton, "δ" is delta, "s" is singlet, "d" is doublet, "t" is triplet, "q" is quadrant, "m" is multiplet, "br" is broadband, "Hz" is Hertz, and "α", "β", "R", "S", "E", and "Z" are stereochemical names well known to those skilled in the art.

[0095] [Table 7] [Table 8]

[0096] The compounds of the present invention can be produced by various methods known in the art, including the methods described in the following schemes and sections on specific embodiments. The structural and variable numbers shown in the synthesis schemes should not be confused with the structural or variable numbers described in the claims or other parts of this specification. The variables in the schemes are for illustrative purposes only to illustrate some methods of producing the compounds of the present invention.

[0097] When planning any synthetic route in this field, it will be recognized that another important consideration is the careful selection of protecting groups to be used to protect the reactive functional groups present in the compounds described in this invention. For experienced professionals, a well-established and authoritative publication describing many alternatives is Greene, TW et al., Protecting Groups in Organic Synthesis, 4th Edition, Wiley (2007).

[0098] Compounds having general formula I (wherein rings A, B, and C are as defined above) can be prepared by one or more of the following synthetic schemes. [ka] (I)

[0099] The present invention comprises a 1-arylpyrrolidinone compound (ring A and ring B are, A substituted phenyl ring or heteroaryl ring, where ring C is The substituted saturated heterocycle can be prepared using a well-protected 3-aminopyrrolidine-2-one 1a (where PG is a protecting group such as Boc or Cbz) as a starting material via the general route shown in Scheme 1. 1-arylpyrrolidinone 1c can be obtained by copper-catalyzed coupling reaction of 1a with substituted iodobenzene 1b or other suitable haloaryl or heteroaryl compounds in a suitable solvent such as butanol or dioxane, in the presence of a base such as potassium carbonate and a suitable ligand such as N,N'-dimethylethylenediamine. Additional methods for this conversion include other variations of Ullmann, Goldberg, and Buchwald copper-catalyzed amidation or Buchwald palladium-catalyzed amidation, using methods known to those skilled in the art for these types of coupling, depending on the properties of ring B (e.g., Yin & Buchwald Organic Lett. 2000, 2 , 1101;Klapers et al.JACS, 2001, 123 , 7727;Klapars et al. JACS, 2002, 124, 7421; 40 , 2657, Surry and Buchwald Angew. Chem. Int. Ed., 2008, 47(See 6338). Subsequently, compound 1e is obtained by aminating 1c using a palladium catalyst to obtain a appropriately substituted amine 1d. Other methods for forming this bond are described in the literature and can be used by those skilled in the art (Surry & Buchwald Chem Sci. 2011;2(1):27-50; Shaughnessy, Ciganek & DeVasher, Organic Reactions. 2014,85:1:1-668). Urea compound 1f can be obtained by removing the Boc or Cbz protecting group from 1e and condensing the resulting free amine with a appropriately substituted phenyl isocyanate 1g or 4-nitrophenyl phenylcarbamate 1h. Suitable isocyanates or 4-nitrophenylcarbamates are commercially available or can be readily obtained from the corresponding aniline by methods known to those skilled in the art. Alternatively, urea compound 1f can also be obtained by treating a deprotected 3-aminopyrrolidinone intermediate with 4-nitrophenyl chloroformate to produce a carbamate, which is then condensed with appropriately substituted aniline 1j. Those skilled in the art will understand that additional compounds of the present invention, in which rings A and B are heteroaryl rings such as pyridine, pyrimidine, and thiazole, can also be prepared using the method outlined in Scheme 1, by using a suitable heteroaryl iodide or bromide instead of 1b, and a heteroarylamine, isocyanate, or p-nitrophenyl carbamate instead of 1g, 1h, or 1i. The chemical reaction for introducing ring C can also be applied to other saturated amine-containing heterocycles. The racemic compounds were separated using either chiral HPLC or SFC to obtain a single enantiomer.

[0100] Scheme 1 [ka]

[0101] Alternatively, as shown in Scheme 2, the compound of the present invention can be prepared by first deprotecting the amine from intermediate 1c, and then forming a urea bond on ring A using the conditions described above for the conversion from 1e to 1f to obtain compound 2a. Next, compound 2a can be coupled with the amine under Pd or Cu catalyzed conditions, as shown in Scheme 1, to convert from 1c to 1e. The racemic compound can be separated using either chiral HPLC or SFC to obtain a single enantiomer.

[0102] Scheme 2 [ka]

[0103] Furthermore, according to the method of Suzuki and Miyaura, the compounds of the present invention can be converted from intermediate 2a to boronate 3b using a palladium-catalyzed borylation reaction, and compound 1f can be obtained by coupling the resulting pinacolatoborone species in an amine-copper-catalyzed Chan-Lam coupling reaction (J. Org. Chem., 2016, 81 (9), pp 3942-3950). The racemic compounds can be separated using chiral HPLC or SFC to obtain a single enantiomer.

[0104] Scheme 3 [ka]

[0105] Alternatively, the compounds of the present invention can also be prepared by nucleophilically substituting the aryl fluoride with the cyclic amine 1d from intermediate 4b to form intermediate 4c. As shown in the scheme above, the compounds described in the present invention are synthesized by deprotection and introduction of the urea. The racemic compounds can be separated using either chiral HPLC or SFC to obtain a single enantiomer.

[0106] Scheme 4 [ka]

[0107] Other features of the present invention will become apparent from the following description of exemplary embodiments for illustrating the invention, but these embodiments are not intended to limit the invention.

[0108] In the exemplary examples, unless otherwise specified, the following methods were used. The intermediates and final products were purified by normal-phase chromatography or reverse-phase chromatography. Unless otherwise specified, normal-phase chromatography was performed using a pre-packed SiO2 cartridge with gradient elution of hexane and ethyl acetate, or DCM and MeOH. Reverse-phase preparative HPLC is performed using a C18 column (UV 220 nm) or a preparative LC-MS detector to obtain gradients between solvent A (90% water, 10% MeOH, 0.1% TFA) and solvent B (10% water, 90% MeOH, 0.1% TFA), or between solvent A (95% water, 5% Acn, 0.1% TFA) and solvent B (5% water, 95% Acn, 0.1% TFA), or between solvent A (95% water, 2% Acn, 0.1% HCOOH) and solvent B (98% Acn, 2% water, 0.1% HCOOH), or between solvent A (95% water, 5% Acn, 10 mM NH4Oac) and solvent B (98% Acn, 2% water, 10 mM NH4Oac), or between solvent A (98% water, 2% Acn, 0.1% NH4OH) and solvent B (98% Elution was performed using a gradient of Acn, 2% water, and 0.1% NH4OH.

[0109] LC / MS method used for characterization of the examples Reverse-phase HPLC / MS analysis was performed using a Waters Acquity system and a Waters MICROMASS® ZQ mass spectrometer.

[0110] Method A: A straight gradient from 0 to 100% B over 3 minutes, with a holding time of 0.75 minutes at 100% B. Ultraviolet visualization at 220 nm Column: Waters BEH C18 2.1 x 50 mm Flow rate: 1.0 mL / min Solvent A: 0.1% TFA, 95% water, 5% Acn Solvent B: 0.1% TFA, 5% water, 95% Acn Method B: A straight gradient from 0 to 100% B over 3 minutes, with a holding time of 0.75 minutes at 100% B. Ultraviolet visualization at 220 nm Column: Waters BEH C18 2.1 x 50 mm Flow rate: 1.0 mL / min Solvent A: 10 mM ammonium acetate, 95% water, 5% Acn Solvent B: 10 mM ammonium acetate, 5% water, 95% Acn

[0111] Analytical HPLC: Method used for characterizing the examples. The products were analyzed using reversed-phase HPLC (analytical HPLC system with Shimadzu Discovery VP software). RT = retention time. Method C: Ascentis Express C18, 2.1 x 50 mm, 2.7 μm particles; Solvent A: 95% water, 5% Acn, 0.05% TFA; Solvent B: 95% Acn, 5% water, 0.1% TFA; Temperature: 50°C; Gradient: 0-100% B over 3 minutes, then held at 100% B for 1 minute; Flow rate: 1.1 mL / min. Method D: Ascentis Express C18, 2.1 x 50 mm, 2.7 μm particles; Solvent A: 95% water, 5% acetonitrile and 10 mM ammonium acetate; Solvent B: 95% Acn, 5% water and 10 mM ammonium acetate; Temperature: 50°C; Gradient: 0-100% B over 3 minutes, then held at 100% B for 1 minute; Flow rate: 1.1 mL / min. Method E: Kinetex BIPHENYL (4.6 x 100 mm), 2.6 μm particles; Solvent A: 95% buffer (0.05% TFA aqueous solution), 5% Acn; Solvent B: 95% Acn, 5% buffer (0.05% TFA aqueous solution); Temperature: 50°C; Gradient: 0-100% B over 3 minutes, then held at 100% B for 1 minute; Flow rate: 1.1 mL / min. Method F: Ascentis Express C18, 2.1 x 50 mm, 2.7 μm particles; Solvent A: 95% water, 5% Acn and 10 mM ammonium formate; Solvent B: 95% Acn, 5% water and 10 mM ammonium formate; Temperature: 50°C; Gradient: 0-100% B over 3 minutes, then held at 100% B for 1 minute; Flow rate: 1.1 mL / min.

[0112] SFC and Chiral Purification Method Method A: DAD-1: CHIRALPAK IA (250*4.6)mm, 5μm; DAD-2: CHIRALPAK IB (250*4.6)mm, 5μm. Solvent system: 0.2% ammonia / Acn:MeOH (1:1) Method B: DAD-1: CHIRALPAK IC (250*4.6)mm, 5μm; DAD-2: CHIRALPAK ID (250*4.6)mm, 5μm. Solvent system: 0.2% ammonia / Acn:MeOH (1:1) Method C:DAD-1:CHIRALPAK IE (250*4.6)mm, 5μm;DAD-2:CHIRALPAK IF (250*4.6)mm, 5μm. Solvent system: 0.2% ammonia / Acn:MeOH (1:1)

[0113] NMR used for characterization of the examples 1 ¹H NMR spectra were acquired using a Bruker or JEOL® Fourier transform spectrometer operating at the following frequencies: ¹H NMR: 300 MHz (Bruker or JEOL®), 400 MHz (Bruker or JEOL®), or 500 MHz (Bruker or JEOL®). 13 ¹³C NMR: 100 MHz (Bruker or JEOL®). Spectral data are reported in the form of chemical shifts (multiplicity, bond constants, number of hydrogen atoms). Chemical shifts are identified in ppm on the low-field side of the tetramethylsilane internal standard (δ units, tetramethylsilane = 0 ppm) and / or relative to the solvent peak. The solvent peak is,1 In the 1H NMR spectrum, CD2HSOCD3 was observed at 2.49 ppm, CD2HOD at 3.30 ppm, CD3CN at 1.94 ppm, and CHCl3 at 7.24 ppm. 13 In the 13C NMR spectrum, it appears at 39.7 ppm for CD3SOCD3, 49.0 ppm for CD3OD, and 77.0 ppm for CDCl3. 13 The 13C NMR spectrum was proton-separated.

[0114] Intermediate 1: 3-aminopyrrolidine-2-one [ka] To a solution of hexamethyldisilazane (11 mL, 152 mmol) in CH3CN (100 mL) stirred at room temperature, a solution of DL-2,4-diaminobutyric acid dihydrochloride (10 g, 152 mmol) in Acn (100 mL) was added. The resulting reaction mixture was heated under reflux for 40 hours. The crude reaction mixture was poured into ice-cooled MeOH (400 mL), stirred at room temperature for 30 minutes, and then distilled off under reduced pressure. The resulting solid was dissolved in CH2Cl2 (700 mL), and the insoluble residue was removed by vacuum filtration. The filtrate was concentrated under reduced pressure to obtain 3-aminopyrrolidine-2-one (4.1 g, 141 mmol, 1 yield 78%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6): δ 7.59 (br. s., 2H), 3.23-3.10 (m, 1H), 3.09 - 3.03 (m, 2H), 2.23-2.22 (m, 1H), 1.70 - 1.57 (m, 1H).

[0115] Intermediate 2: tert-butyl(2-oxopyrrolidine-3-yl)carbamate [ka] Under an argon atmosphere, the mixture was stirred at room temperature and B3-aminopyrrolidine-2-one (4.0 g, 40 mmol) was added to a methanol-triethylamine (130 mL, 9:1) solution to which Boc-anhydrous (9.6 mL, 41 mmol) was added. The reaction mixture was stirred overnight at room temperature, then heated under reflux for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Ether (50 mL) was added to the crude residue and filtered through a Buchner funnel to obtain intermediate 2 (4.0 g, 20 mmol, 50% yield) as a brown solid. 1 H NMR (400MHz, DMSO-d6):δ 7.69 (br. s., 1H), 6.99 (d, J=8.0 Hz, 1H), 4.06 - 3.96 (m, 1H), 3.19 - 3.10 (m, 2H), 2.29 - 2.19 (m, 1H), 1.89 - 1.76 (m, 1H), 1.35 (s, 9H).

[0116] Intermediate 3: tert-butyl(1-(4-bromo-2,3-difluorophenyl)-2-oxopyrrolidine-3-yl)carbamate [ka] To a solution of intermediate 2 (1.0 g, 5.0 mmol) in 1,4-dioxane (10 mL), 1,4-dibromo-2,3-difluorobenzene (1.6 g, 6.0 mmol) and Cs2CO3 (3.3 g, 10 mmol) were added. The reaction mixture was purged with nitrogen for 5 minutes, and xanthophos (0.29 g, 0.50 mmol) and Pd2(dba)3 (0.23 g, 0.25 mmol) were added. The reaction mixture was again purged with nitrogen for 3 minutes and heated at 120°C for 16 hours. The reaction mixture was cooled, filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether-SiO) to obtain intermediate 3 (1.1 g, 2.8 mmol, 47% yield) as a brown solid. MS(ESI) m / z: 391.2 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ 7.61-7.59 (m, 1H), 7.35 - 7.28 (m, 2H), 4.39 - 4.28 (m, 1H), 3.82 - 3.64 (m, 2H), 2.42 - 2.31 (m, 1H), 2.10 - 1.97 (m, 1H), 1.40 (s, 9H).

[0117] Intermediate 4: tert-butyl(1-(2,3-difluoro-4-iodophenyl)-2-oxopyrrolidine-3-yl)carbamate [ka] Intermediate 2 (2.0 g, 10 mmol), 2,3-difluoro-1,4-diiodobenzene (3.7 g, 10 mmol), cesium carbonate (6.5 g, 20 mmol), and xanthophos (0.58 g, 1.0 mmol) were mixed in a 30 mL dioxane solution and purged with nitrogen for 10 minutes. Pd2(dba)3 (0.46 g, 0.50 mmol) was added, and the reaction mixture was heated in a pressure tube at 110°C for 15 hours. The reaction mixture was diluted with SiO2, filtered by Celite, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2-hexane) to obtain intermediate 4 (1.4 g, 3.2 mmol, yield 32%) as a brown solid. MS(ESI) m / z: 439.2 (M+H) + . 1 H NMR (300 MHz, CDCl3δ = 7.49 - 7.42 (m, 1H), 7.05 - 6.98 (m, 1H), 5.13 (br, s., 1H), 4.36 - 4.18 (m, 1H), 3.85 - 3.62 (m, 2H), 2.78 - 2.62 (m, 1H), 2.12 - 1.95 (m, 1H), 1.47 - 1.33 (s, 9H).

[0118] Intermediate 5: tert-butyl(R)-(2-oxopyrrolidine-3-yl)carbamate [ka] 1-Propanephosphonic anhydride (50%  solution, 210 mL, 340 mmol) was added at 0°C to a solution of Boc-D-2,4-diaminobutyric acid (50 g, 230 mmol) and TEA (96 mL, 690 mmol) in DCM (1500 mL). The reaction mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction mixture was concentrated under vacuum, and the crude product was purified by column chromatography (MeOH / DCM). The product was recrystallized with  / petroleum ether to obtain intermediate 5 (32 g, 70 mmol, 70% yield) as a white solid. MS(ESI) m / z:201.2 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ = 7.69 (s, 1H), 6.99 (br, d., J = 9.0 Hz, 1H), 4.01 (q, J = 9.0 Hz, 1H), 3.17 - 3.09 (m, 2H), 2.28 - 2.19 (m, 1H), 1.90 - 1.75 (m, 1H), 1.39 (s, 9H).

[0119] Intermediate 6: tert-butyl (R)-(1-(2,3-difluoro-4-bromophenyl)-2-oxopyrrolidine-3-yl)carbamate [ka] Intermediate 5 (20 g, 100 mmol), 2,3-difluoro-1,4-dibromobenzene (14 g, 110 mmol), tripotassium phosphate (32 g, 150 mmol), and cuprous iodide (7.6 g, 40 mmol) were dissolved in 1,4-dioxane (250 mL). The reaction mixture was purged with nitrogen for 5 minutes. N,N'-dimethylethylenediamine (5.5 mL, 50 mmol) was added, and the reaction mixture was heated in a pressure tube at 65°C for 12 hours. The reaction mixture was diluted with ethyl acetate, filtered through Celite, and then concentrated under reduced pressure. The crude product was purified by column chromatography (35% ethyl acetate in petroleum ether) and recrystallized (ethyl acetate / petroleum ether) to obtain intermediate 6 (18 g, 39 mmol, yield 39%) as a white solid. MS(ESI) m / z: 439.0 (M+H) + . 1H NMR (400 MHz, CDCl3) δ = 7.54 (ddd, J = 8.5, 6.3, 2.3 Hz, 1H), 7.09 (ddd, J = 8.5, 6.3, 2.3 Hz, 1H), 5.16 (br, s., 1H), 4.41 - 4.30 (m, 1H), 3.87 (m, 1H), 3.79 - 3.69 (m, 1H), 2.85 - 2.73 (m, 1H), 2.17 - 2.05 (m, 1H), 1.48 (m, 9H).

[0120] Intermediate 7: 3-bromo-1-(4-bromo-2,6-difluorophenyl)pyrrolidine-2-one [ka] Under an argon atmosphere, at 0°C, a stirring solution of 4-bromo-2,6-difluoroaniline (5.0 g, 24 mmol) in acetonitrile (20 mL) was mixed with tripotassium phosphate (2.55 g, 12.0 mmol) and 2,4-dibromobutanoyl chloride (3.18 mL, 24.0 mmol). The resulting reaction mixture was gradually heated to room temperature over 30 minutes and stirred for a further 1 hour. 6N NaOH aqueous solution (1 mL, 6.00 mmol) was added to the reaction mixture, and the mixture was stirred for a further 16 hours. After the reaction was complete, the reaction mixture was filtered through a Celite pad and washed with acetonitrile (10 mL). The filtrate was concentrated under reduced pressure to obtain the crude product. 3-bromo-1-(4-bromo-2,6-difluorophenyl)pyrrolidine-2-one (8.0 g, 23 mmol, 94% yield) was obtained as a pale yellow liquid, which was proceeded to the next step without further purification. MS(ESI) m / z:354.0 [M+H] + .

[0121] Intermediate 8: 3-amino-1-(4-bromo-2,6-difluorophenyl)pyrrolidine-2-one [ka] 3-bromo-1-(4-bromo-2,6-difluorophenyl)pyrrolidine-2-one (8.0 g, 23 mmol) was dissolved in acetonitrile (50 mL) and stirred at room temperature under an argon atmosphere. Ammonium hydroxide (29.3 mL, 225 mmol) was then added. The resulting reaction mixture was gradually heated to 40°C and stirred for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with DCM, washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain crude 3-amino-1-(4-bromo-2,6-difluorophenyl)pyrrolidine-2-one (5.0 g, 17 mmol, yield 76%) as a pale yellow liquid, which was used in the next step without purification. MS(ESI) m / z:291.2 [M+H] + .

[0122] Intermediate 9: tert-butyl(1-(4-bromo-2,6-difluorophenyl)-2-oxopyrrolidine-3-yl)carbamate [ka] A solution of 3-amino-1-(4-bromo-2,6-difluorophenyl)pyrrolidine-2-one (6.0 g, 21 mmol) in THF (100 mL) was stirred at room temperature under an argon atmosphere. DIPEA (10.8 mL, 61.8 mmol) and Boc-anhydrous (5.74 mL, 24.7 mmol) were added, and the mixture was stirred for 16 hours. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. Purification by silica gel column chromatography (60% siRNA-petroleum ether) yielded tert-butyl (1-(4-bromo-2,6-difluorophenyl)-2-oxopyrrolidine-3-yl)carbamate (5.0 g, 12 mmol, 62% yield) as an off-white solid. MS(ESI) m / z: 391.1 [M+H] + . 1H NMR (300 MHz, DMSO-d6) δ = 7.64 (br d, J = 9.0 Hz, 2H), 7.32 (br d, J = 9.0 Hz, 1H), 4.43 - 4.25 (m, 1H), 3.69 - 3.52 (m, 2H), 2.42 - 2.31 (m, 1H), 2.18 - 1.98 (m, 1H), 1.40 (s, 9H).

[0123] Intermediate 10: tert-butyl((R)-1-(4-((R)-3-(dimethylamino)pyrrolidine-1-yl)-2,3-difluorophenyl)-2-oxopyrrolidine-3-yl)carbamate [ka] To a solution of tert-butyl (R)-(1-(4-bromo-2,3-difluorophenyl)-2-oxopyrrolidine-3-yl)carbamate (intermediate 6) (2.0 g, 5.1 mmol) in toluene (20 mL), (3R)-(+)-3-(dimethylamino)pyrrolidine (0.58 g, 5.1 mmol) and cesium carbonate (3.33 g, 10.2 mmol) were added while stirring at room temperature. The reaction mixture was purged with nitrogen for 5 minutes, and xanthophos (0.59 g, 1.0 mmol) and Pd2(dba)3 (0.47 g, 0.51 mmol) were added. The reaction mixture was again purged with nitrogen for 3 minutes, and then heated at 100°C for 16 hours. The reaction mixture was cooled and filtered through a Celite pad. The filtrate was concentrated under reduced pressure to obtain the crude compound. This was purified by column chromatography (eluate: petroleum ether-ethyl acetate, 1% TEA) to obtain tert-butyl ((R)-1-(4-((R)-3-(dimethylamino)pyrrolidine-1-yl)-2,3-difluorophenyl)-2-oxopyrrolidine-3-yl)carbamate (850 mg, 2.00 mmol, yield 39.2%) as a brown solid. MS(ESI) m / z: 425.3 [M+H] + .

[0124] Intermediate 11: (R)-3-amino-1-(4-((R)-3-(dimethylamino)pyrrolidine-1-yl)-2,3-difluorophenyl)pyrrolidine-2-one hydrochloride [ka] Under an argon atmosphere at room temperature, a stirred solution of tert-butyl((R)-1-(4-((R)-3-(dimethylamino)pyrrolidine-1-yl)-2,3-difluorophenyl)-2-oxopyrrolidine-3-yl)carbamate (intermediate 10) (0.85 g, 2.0 mmol) in 1,4-dioxane (10 mL) was mixed with 4M HCl (10.0 mL, 40.0 mmol) in 1,4-dioxane and stirred for 2 hours. The solvent was evaporated under reduced pressure to obtain a rubbery solid, which was further pulverized with diethyl ether (10 ml x 2) and dried to obtain (R)-3-amino-1-(4-((R)-3-(dimethylamino)pyrrolidine-1-yl)-2,3-difluorophenyl)pyrrolidine-2-one hydrochloride (0.65 g, 1.8 mmol, yield 90%) as a brown solid. MS(ESI) m / z: 325.3 [M+H] + . [Examples]

[0125] 1-(4-chloro-2-fluorophenyl)-3-((R)-1-(4-((R)-3-(dimethylamino)pyrrolidine-1-yl)-2,3-difluorophenyl)-2-oxopyrrolidine-3-yl)urea [ka] Under an argon atmosphere, at room temperature, a suspension of (R)-3-amino-1-(4-((R)-3-(dimethylamino)pyrrolidine-1-yl)-2,3-difluorophenyl)pyrrolidine-2-one hydrochloride (intermediate 11) (180 mg, 0.49 mmol) in DMF (2 mL) was stirred, to which DIPEA (0.26 mL, 1.5 mmol) and phenyl(4-chloro-2-fluorophenyl)carbamate (130 mg, 0.49 mmol) were added. The resulting solution was heated at 50°C for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was purified by reverse-phase chromatography followed by chiral HPLC to obtain 1-(4-chloro-2-fluorophenyl)-3-((R)-1-(4-((R)-3-(dimethylamino)pyrrolidine-1-yl)-2,3-difluorophenyl)-2-oxopyrrolidine-3-yl)urea (50 mg, 0.10 mmol, yield 21%) as an off-white solid. MS(ESI) m / z: 496.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ = 8.61 (d, J = 2.5 Hz, 1H), 8.15 (t, J = 8.8 Hz, 1H), 7.42 (dd, J = 11.0, 2.2 Hz, 1H), 7.20 (d, J = 9.1 Hz, 1H), 7.14 (d, J = 7.0 Hz, 1H), 7.05 (t, J = 8.3 Hz, 1H), 6.57 (t, J = 9.1 Hz, 1H), 4.52 - 4.44 (m, 1H), 3.74 - 3.62 (m, 1H), 3.62 - 3.59 (m, 1H), 3.51 - 3.42 (m, 3H), 3.29 - 3.15 (m, 1H), 2.75-2.67 (m, 1H), 2.58 - 2.53 (m, 1H), 2.20 (s, 6H), 2.15 - 1.94 (m, 2H), 1.82 - 1.72 (m, 1H). [Examples]

[0126] 1-((R)-1-(4-((R)-3-(dimethylamino)pyrrolidine-1-yl)-2,3-difluorophenyl)-2-oxopyrrolidine-3-yl)-3-(2-fluoro-4-(trifluoromethyl)phenyl)urea [ka] Under an argon atmosphere, at room temperature, a suspension of (R)-3-amino-1-(4-((R)-3-(dimethylamino)pyrrolidine-1-yl)-2,3-difluorophenyl)pyrrolidine-2-one hydrochloride (intermediate 11) (180 mg, 0.49 mmol) in DMF (3 mL) was stirred, to which DIPEA (0.26 mL, 1.5 mmol) and phenyl(2-fluoro-4-(trifluoromethyl)phenyl) carbamate (150 mg, 0.49 mmol) were added. The resulting solution was heated at 50 °C for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was purified by reverse-phase chromatography followed by chiral HPLC to obtain 1-((R)-1-(4-((R)-3-(dimethylamino)pyrrolidine-1-yl)-2,3-difluorophenyl)-2-oxopyrrolidine-3-yl)-3-(2-fluoro-4-(trifluoromethyl)phenyl)urea (51 mg, 0.10 mmol, yield 20%) as an off-white solid. MS(ESI) m / z: 530.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ = 8.92 (br s, 1H), 8.40 (t, J = 8.3 Hz, 1H), 7.66 (dd, J = 11.8, 2.2 Hz, 1H), 7.51 (br d, J = 9.0 Hz, 1H), 7.32 (d, J = 7.0 Hz, 1H), 7.06 (t, J = 8.6 Hz, 1H), 6.58 (t, J = 9.0 Hz, 1H), 4.54 - 4.47 (m, 1H), 3.74 - 3.62 (m, 1H), 3.66 - 3.56 (m, 1H), 3.54 - 3.36 (m, 3H), 3.30 - 3.18 (m, 1H), 2.75 - 2.67 (m, 1H), 2.58 - 2.53 (m, 1H), 2.20 (s, 6H), 2.15 - 1.97 (m, 2H), 1.82 - 1.69 (m, 1H).

[0127] The following examples listed in Table 2 were prepared using the same procedure as described above for intermediates 1-11 and examples 1 and 2. Table 2 [Table 9] [Table 10] [Table 11] [Table 12] [Table 13] [Table 14] [Table 15] Table 16 Table 17 Table 18 Table 19 Table 20 Table 21 Table 22 Table 23 Table 24 Table 25 Table 26 Table 27 Table 28 Table 29 Table 30 Table 31 Table 32 Table 33 Table 34 Table 35 Table 36 Table 37 Table 38 Table 39 Table 40 Table 41 Table 42 Table 43 Table 44 Table 45 Table 46 Table 47 Table 48 Table 49 Table 50 Table 51 Table 52 Table 53 Table 54 Table 55 Table 56

[0128] Those skilled in the art will see that this disclosure is not limited to the exemplary embodiments described above and can be implemented in other specific forms without departing from its essential features. Therefore, these embodiments should be considered in all respects to be exemplary and not restrictive, and refer to the appended claims rather than the embodiments described above. Accordingly, all modifications within the meaning and equivalents of the claims are intended to be incorporated within the claims.

Claims

1. Formula I: 【Chemistry 1】 I [In the formula, * is an asymmetric carbon atom; Ring A is C 6 It is an aryl or six-membered heteroaryl; Ring B is C 6 It is an aryl or six-membered heteroaryl; The ring C is a 4- to 9-membered saturated heterocycle containing 0 to 3 additional heteroatoms selected from O and N; R 1 is a halo, alkyl, or haloalkyl; R 2 This includes halo, alkyl, haloalkyl, or C 3-6 It is cycloalkyl; R 3 is hydrogen, fluoro, hydroxy, hydroxyalkyl, or alkoxy; Ring C is a 4- to 9-membered saturated heterocycle containing 0 to 3 additional heteroatoms selected from O, S, and N; R 4 is hydrogen, halo, haloalkyl, hydroxy, oxo, hydroxyalkyl, cyano, alkyl, alkoxy, alkoxyalkyl, cycloalkyl, (R 5 )(R 6 )N, (alkyl) 2 (O)P, (alkyl) 2 (O)PO, (alkoxy) 2 (O)P, (alkoxy)(alkyl)(O)P, (alkyl) 2 (O)Palkyl, (alkoxy) 2 (O)Palkyl, (alkoxy)(alkyl)(O)Palkyl, alkylSO 2 , cycloalkylSO 2 , or (R 5 )(R 6 )NCO; R 5 These include hydrogen, alkyl, hydroxyalkyl, alkylCO, cycloalkylCO, halocycloalkylCO, cycloalkyl, and alkylSO 2 , alkylSO 2 It is alkyl or heterocyclic; R 6 is hydrogen or alkyl; or NR 5 R 6 These are combined and substituted with 0 to 3 substituents selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, and selected from oxo, hydroxy, fluoro, alkyl, haloalkyl, alkoxy, and haloalkoxy; However, the formula: 【Chemistry 2】 (Here, R 1 is a halo or haloalkyl; R 2 is a halo; R 5 is a lower alkyl or hydroxyalkyl; and R 6 (It is a lower alkyl group.) [Compounds indicated by are excluded.] The compound indicated by, or a pharmaceutically acceptable salt thereof.

2. Ring A is 【Transformation 3】 And; Ring B is 【Chemistry 4】 and Ring C is 【Transformation 5】 The compound represented by formula I, or a pharmaceutically acceptable salt thereof.

3. Formula II: 【Transformation 6】 II [In the formula, Q is CH, CR 2 , or N; R 1 is a halo or haloalkyl; R 2 is a halo, alkyl, or cycloalkyl; R 3 is hydrogen or hydroxyalkyl; R 4 (R) 5 )(R 6 )N, (alkyl) 2 (O)P, (alkyl) 2 (O)PO, (alkyl) 2 (O)P alkyl, alkyl SO 2 cycloalkylSO 2 And; R 5 These include hydrogen, alkyl, hydroxyalkyl, alkylCO, cycloalkylCO, halocycloalkylCO, cycloalkyl, and alkylSO 2 , alkylSO 2 Being alkyl or heterocyclic; and R 6 is hydrogen or alkyl; or NR 5 R 6 [These are combined and substituted with 0 to 1 substituent selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, and selected from oxo and alkyl groups.] The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

4. Formula III: 【Transformation 7】 III [In the formula, R 1 is Cl or CF 3 And; R 2 is F, Me, or cyclopropyl; R 3 is hydrogen or hydroxymethyl; R 5 These are hydrogen, alkyl CO, cycloalkyl CO, halocycloalkyl CO, and chlorohydrate SO2. 2 , alkylSO 2 It is alkyl or heterocyclic; R 6 is hydrogen or alkyl; or NR 5 R 6 [These are combined and substituted with 0 to 1 substituent selected from azetidinyl, piperazinyl, and morpholinyl, and selected from oxo and alkyl groups.] The compound according to claim 3, as shown in [the provided text], or a pharmaceutically acceptable salt thereof.

5. Formula IV: 【Transformation 8】 IV [In the formula, R 1 is a halo or haloalkyl; R 2 is a halo, alkyl, or cycloalkyl; R 4 (R) 5 )(R 6 )N is; R 5 is hydrogen, alkyl, or hydroxyalkyl; and R 6 [It is hydrogen or alkyl.] The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

6. Formula V: 【Chemistry 9】 V [In the formula, R 1 is a halo or haloalkyl; R 2 is a halo, alkyl, or cycloalkyl; R 4 is hydrogen, haloalkyl, hydroxyalkyl, or alkyl; R 5 is hydrogen, alkyl, or hydroxyalkyl; and R 6 [It is hydrogen or alkyl.] The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

7. Formula VI: 【Chemistry 10】 VI [In the formula, R 1 is a halo or haloalkyl; R 2 is a halo, alkyl, or cycloalkyl; and R 4 These are hydrogen, haloalkyl, hydroxyalkyl, alkyl, and alkoxyalkyl. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

8. Ring A is 【Chemistry 11】 And; Ring B is 【Chemistry 12】 and Ring C is 【Chemistry 13】 And; R 1 However, Cl or CF 3 And; R 2 However, F is; and R 4 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is hydrogen or alkyl.

9. A pharmaceutical composition comprising the compound described in claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

10. A compound according to any one of claims 1 to 8 or a pharmaceutical composition according to claim 9, for use in treatment.

11. A method for treating heart disease, comprising administering a therapeutically effective amount of the pharmaceutical composition according to claim 9 to a patient in need thereof.

12. The method according to claim 11, wherein the cardiac disease is selected from the group consisting of angina pectoris, unstable angina pectoris, myocardial infarction, heart failure, acute coronary artery disease, acute heart failure, chronic heart failure, and iatrogenic injury of the heart.

13. Heart failure can be classified into congestive heart failure, systolic heart failure, diastolic heart failure, and heart failure with reduced ejection fraction (HF). R EF), preserved ejection fraction heart failure (HF) P The method according to claim 12, selected from the group consisting of EF, acute heart failure, ischemic and non-ischemic chronic heart failure.

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