Condensed azines as dynamin-1-like protein inhibitors and their use

Abstract

Compounds of formula (I) or pharmaceutically acceptable salts thereof are provided, which are useful for inhibiting Drp1 and treating various Drp11-mediated conditions or diseases. JPEG2026510505000203.jpg3055

Description

Related applications

[0001] This application claims priority to U.S. Provisional Application No. 63 / 419,132, filed on 25 October 2022. The entire contents of the aforementioned application are expressly incorporated herein by reference. [Technical Field]

[0002] This disclosure relates to inhibitors of dynamin-1-like protein (Drp1) and pharmaceutically acceptable salts thereof, compositions of these compounds, processes for their production, and their use in the treatment of diseases. [Background technology]

[0003] Dynamin-1-like proteins are GTPases that regulate mitochondrial fission. In humans, dynamin-1-like proteins, typically called dynamin-associated protein 1 (Drp1), are encoded by the DNM1L gene. Inhibitors of Drp1 block cell death, suggesting that mitochondrial fission is a crucial step in apoptosis. The Drp1 sequence (OMIM 603850) is publicly available, for example, from the GenBank® sequence database (e.g., BAA22193 (human, protein, AB006965 (human, nucleic acid))).

[0004] In healthy cells, fusion and fission events are involved in regulating mitochondrial morphology. The dynamin-related protein Drp1 mediates the fission of the outer mitochondrial membrane and is typically activated during cell division. In particular, during M phase, Drp1 is activated, and this activation induces mitochondrial fission to ensure the even distribution of mitochondria to each daughter cell. Mitochondrial fission produces smaller mitochondria that are more capable of generating reactive oxygen species, promoting mitophagy, or accelerating cell proliferation compared to larger mitochondria (Archer SL. Mitochondrial dynamics--mitochondrial fission and fusion in human diseases. N Engl J Med. 2013 369(23):2236-51). When apoptosis is induced, Drp1 migrates from the cytosol to the mitochondria, where it preferentially localizes to potential sites of organelle division. Drp1 is regulated by phosphorylation, with phosphorylation at serine 616 increasing its activity and phosphorylation at serine 637 decreasing its activity. Inhibition of Drp1 prevents loss of mitochondrial membrane potential and release of cytochrome c, revealing reproducible organelle swelling. Notably, inhibition of Drp1 blocks cell death, suggesting mitochondrial fission as a crucial step in cellular apoptosis. Furthermore, inhibition of Drp1 has been shown to reduce reactive oxygen species by decreasing mitochondrial fission. Therefore, modulation of Drp1 activity is effective in treating various conditions, such as cardiovascular disease, kidney disease, eye disease, cancer, ischemia-reperfusion injury, and neurodegenerative and cognitive diseases. In fact, Drp1 is an important biological target for compounds used to aid in the treatment and prevention of diseases such as cardiovascular disease, kidney disease, eye disease, cancer, cognitive disease, and other related diseases.

[0005] Therefore, there is a need for Drp1 inhibitors as potential therapeutic agents for treating diseases or disorders that respond to Drp1 inhibition. [Overview of the Initiative]

[0006] The present disclosure provides compounds that are Drp1 inhibitors. In a first aspect, the present disclosure relates to a compound having formula I or a pharmaceutically acceptable salt thereof.

Chemical formula

[0007] Another aspect of this disclosure relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutical carrier.

[0008] In yet another embodiment, the Disclosure provides a method for treating a Drp1-mediated disease or disorder in a subject, the method comprising administering to the subject in an effective amount a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier. In some embodiments, the method is for the treatment of cancer.

[0009] Another aspect of this disclosure relates to the use of effective amounts of the compounds described herein or pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment of a Drp1-mediated disease or disorder. Also provided are compounds described herein or pharmaceutically acceptable salts thereof for use in the treatment of a Drp1-mediated disease or disorder.

[0010] Another aspect of this disclosure relates to a pharmaceutical composition comprising the compounds described herein or pharmaceutically acceptable salts thereof, and a pharmaceutical carrier, for treating a Drp1-mediated disease or disorder, particularly cancer. [Modes for carrying out the invention]

[0011] In this specification, the term "Drp1 inhibitor" refers to a substance that effectively reduces the activity of Drp1. The Drp1 activity of a substance can be tested by contacting the substance with cells expressing Drp1, detecting its binding to Drp1, and then detecting a signal that serves as an indicator of Drp1 inactivation (see Biological Example 1).

[0012] This disclosure provides compounds and pharmaceutically acceptable compositions thereof that may be useful in treating diseases or disorders mediated by Drp1 function / activity. In some embodiments, the compounds of this disclosure are Drp1 inhibitors.

[0013] Compounds and compositions In the first embodiment, the present disclosure relates to a compound of formula (I), [ka] Or provide a pharmaceutically acceptable salt thereof, wherein the variables in formula (I) are as defined in the first embodiment above.

[0014] In a second embodiment, the compound of the present disclosure is represented by formula (IA), [ka] or a pharmaceutically acceptable salt thereof (wherein the formula is the variable R shown in formula (IA)). 1 , R 2 , R 3 , and R 4 (This is as described in the first embodiment.)

[0015] In the third embodiment, with respect to a compound of formula (I) or (IA) or a pharmaceutically acceptable salt thereof, R 4is H or C 1-3 It is alkyl, and the remaining variables are as described in the first or second embodiment.

[0016] In the fourth embodiment, with respect to a compound of formula (I) or (IA) or a pharmaceutically acceptable salt thereof, R 4 is H or -CH3, and the remaining variables are as described in the third embodiment. In certain embodiments, for a compound of formula (I) or (IA) or a pharmaceutically acceptable salt thereof, R 4 H is the remaining variable, as described in the third embodiment.

[0017] In the fifth embodiment, with respect to a compound of formula (I) or (IA) or a pharmaceutically acceptable salt thereof, R 1 is a 5-membered or 6-membered monocyclic heteroaryl, and the 5-membered or 6-membered monocyclic heteroaryl can optionally have one or two R 1a Replaced by each R 1a is Halo, Cyano, C 1-4 Alkyl, C 3-4 Cycloalkyl, and C 1-3 The alkoxy is selected independently, and the remaining variables are as described in the first, second, third, or fourth embodiment. In a particular embodiment, R 1 This is an optional choice of one or two R 1a It is a 5-membered monocyclic heteroaryl substituted with, and each R 1a is Halo, Cyano, C 1-4 Alkyl, C 3-4 Cycloalkyl, and C 1-3 The variables are independently selected from the group consisting of alkoxys, and the remaining variables are as described in the first, second, third, or fourth embodiment.

[0018] In the sixth embodiment, with respect to a compound of formula (I) or (IA) or a pharmaceutically acceptable salt thereof, R 1 The group consists of imidazoyl, pyrazoyl, triazoyl, and thiazoyl, and each of them is optionally selected from one or two R 1aThis is replaced, and the remaining variables are as described in the fifth embodiment.

[0019] In the seventh embodiment, with respect to a compound of formula (I) or (IA) or a pharmaceutically acceptable salt thereof, R 1 The following structural formula [ka] They are represented by, and each of them can optionally be one or two R 1a Replaced by each R 1a The group is independently selected from the group consisting of -CH3, -CH2CH3, -CH2CH2CH3, -C(CH3)3, cyclopropyl, -OCH3, -Cl, and cyano, and the remaining variables are as described in the sixth embodiment.

[0020] In the eighth embodiment, with respect to a compound of formula (I) or (IA) or a pharmaceutically acceptable salt thereof, R 1 The group is selected from imidazoyl and thiazoyl, and each of them is optionally selected from one or two R 1a Replaced by each R 1a The group consisting of -CH3, cyclopropyl, and -OCH3 was independently selected, and the remaining variables were as described in the fifth embodiment.

[0021] In the ninth embodiment, with respect to a compound of formula (I) or (IA) or a pharmaceutically acceptable salt thereof, R 2 C 1-3 Alkyl, C 3-6 Cycloalkyl, crosslinked C 5-8 Cycloalkyls, 3-6 membered monocyclic heterocyclines, or 5- or 6 membered monocyclic heteroaryls, each of which optionally contains 1-3 R groups. 2a Replaced by each R 2a is Halo, Cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, and C 1-3Independently selected from the group consisting of alkoxy, and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, or eighth embodiments.

[0022] In the tenth embodiment, for the compound of formula (I) or (IA) or a pharmaceutically acceptable salt thereof, R 2 is C 1-3 alkyl, cyclopropyl, cyclobutyl, bicyclo[1.1.1]pentanyl, oxetanyl, tetrahydropyranyl, or isoxazolyl, each of which is optionally substituted with one to three R 2a and the remaining variables are as described in the ninth embodiment.

[0023] In the eleventh embodiment, for the compound of formula (I) or (IA) or a pharmaceutically acceptable salt thereof, R 2 is optionally C substituted with one to three R 2a alkyl, or R 1-3 is represented by the structural formula 2 or

Chemical formula

Chemical formula

[0024] In the twelfth embodiment, for the compound of formula (I) or (IA) or a pharmaceutically acceptable salt thereof, R 2is -CF3, -CH2CH2OCH3, -CH2OCH3, -CH2OH, -CH(OH)CH3, -CH(CH3)CH2OCH3, -CH(CH3)CN, -CH(CH3)OCH3, -CH(CH3)OCH2CH3, -CH(CH3)OCH2CH2CH3, -CF2CH2OH, or R 2 is represented by the following structural formula [Chemical formula] or [Chemical formula] and the remaining variables are as described in the 11th embodiment.

[0025] In the 13th embodiment, for the compound of formula (I) or (IA) or a pharmaceutically acceptable salt thereof, R 2 is C 1-3 alkyl, cyclopropyl, cyclobutyl, oxetanyl, or tetrahydropyranyl, and C 1-3 alkyl, cyclopropyl, and cyclobutyl are each optionally substituted with 1 to 3 R 2a and the remaining variables are as described in the 9th embodiment.

[0026] In the 14th embodiment, for the compound of formula (I) or (IA) or a pharmaceutically acceptable salt thereof, R 2 is -CH(CH3)CN, -CH(CH3)OCH3, -CH(CH3)OCH2CH3, -CH(CH3)OCH2CH2CH3, or R 2 is represented by the following structural formula [Chemical formula] or [Chemical formula] and the remaining variables are as described in the 13th embodiment.

[0027] In the 15th embodiment, with respect to a compound of formula (I) or (IA) or a pharmaceutically acceptable salt thereof, R 3 C 1-4 Alkyl or C 3-4 They are cycloalkyl groups, each of which optionally contains 1 to 3 R groups. 3a Replaced by each R 3a C 1-3 Alkyl, -OH, and C 1-3 The variables are independently selected from the group consisting of alkoxys, and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth embodiment.

[0028] In the sixteenth embodiment, with respect to a compound of formula (I) or (IA) or a pharmaceutically acceptable salt thereof, R 3 C 1-4 Alkyl or cyclopropyl, C 1-3 Alkyl groups can optionally have 1 to 3 R groups. 3a Replaced by each R 3a The elements are selected independently from -CH3, OH, and -OCH3, and the remaining variables are as described in the 15th embodiment.

[0029] In the 17th embodiment, with respect to a compound of formula (I) or (IA) or a pharmaceutically acceptable salt thereof, R 3 is -CH3, -CH2CH3, -CH2CH2OH, -CH2CH2OCH3, -CH(CH3)CH2OCH3, -C(CH3)2CH2OCH3, or cyclopropyl, and the remaining variables are as described in the 16th embodiment. In certain embodiments, for a compound of formula (I) or (IA) or a pharmaceutically acceptable salt thereof, R 3 is -CH2CH3, -CH2CH2OH, -CH2CH2OCH3, or -CH(CH3)CH2OCH3, and the remaining variables are as described in the 16th embodiment.

[0030] In the eighteenth embodiment, the disclosure provides a compound described herein (for example, any one of the compounds from Examples 1 to 54) or a pharmaceutically acceptable salt thereof.

[0031] In the 19th embodiment, the disclosure provides a compound selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9]

[0032] The compounds and intermediates described herein may be isolated and used in neutral forms. Alternatively, if a moiety capable of forming a salt exists, the compound or intermediate may be isolated and used as the corresponding salt. As used herein, the terms “salt” or “salts” refer to acid-added or base-added salts of the compounds described herein. “Salt” includes, in particular, “pharmaceutically acceptable salts.” The term “pharmaceutically acceptable salt” refers to a salt that retains the biological efficacy and properties of the compounds described herein and is typically not biologically or otherwise inappropriate. In many cases, the compounds of this disclosure can form acid and / or base salts due to the presence of an amino group and / or a carboxyl group, or a similar group.

[0033] Pharmacokinetically acceptable acid addition salts can be formed using inorganic or organic acids, such as acetate, aspartic acid, benzoate, besilate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphor sulfate, chloride / hydrochloride, chlortheophyllonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactate. These include bionates, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methyl sulfate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, sulfate, sulfosalicylate, tartrate, tolsilate, and trifluoroacetate.

[0034] Examples of inorganic acids from which salts can be derived include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.

[0035] Examples of organic acids that can be derived from salts include acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, and sulfosalicylic acid.

[0036] Pharmacopoecially acceptable base addition salts can be formed using inorganic and organic bases.

[0037] Examples of inorganic bases from which salts can be derived include ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper, with salts of ammonium, potassium, sodium, calcium, and magnesium being particularly suitable.

[0038] Organic bases from which salts may be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins. Specific organic amines include isopropylamine, benzathine, choline, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0039] Salts can be synthesized from compounds containing basic or acidic moieties by conventional chemical methods. Generally, such salts can be produced by reacting the free acid form of these compounds with a stoichiometric amount of an appropriate base (such as Na, Ca, Mg, or K hydroxides, carbonates, bicarbonates, etc.) or by reacting the free base form of these compounds with a stoichiometric amount of an appropriate acid. Such reactions are typically carried out in water, an organic solvent, or a mixture of the two. Generally, when feasible, the use of a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable. A list of additional suitable salts can be found, for example, in “Remington’s Pharmaceutical Sciences”, 20th Edition, Mack Publishing Company, Easton, Pennsylvania (1985), and “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0040] The deuterium compounds of formula (I) or (IA) can generally be produced by conventional techniques known to those skilled in the art or by using appropriate deuterium reagents instead of the non-labeled reagents previously used, by processes similar to those described in the accompanying examples and products. In one embodiment, the present disclosure provides a deuterated compound described herein or a pharmaceutically acceptable salt thereof.

[0041] Another embodiment of the present disclosure is a compound disclosed herein, comprising a compound of formula (I) or (IA) or a compound in the examples, or a pharmaceutically acceptable salt of any of the foregoing, wherein one or more hydrogen atoms are replaced by deuterium. The degree of deuterium enrichment at any of the sites where hydrogen is replaced by deuterium is at least 50%, 75%, 85%, 90%, 95%, 98% or 99%. The degree of deuterium enrichment is in mole percent and is obtained by dividing the number of compounds in which deuterium is enriched at the site of enrichment by the number of compounds having hydrogen or deuterium at the site of enrichment.

[0042] The pharmaceutically acceptable solvates according to the present disclosure may be those in which the solvate of crystallization may be isotopically substituted, for example, including D2O, d6-acetone, d6-DMSO.

[0043] It will be recognized by those skilled in the art that the compounds of the present disclosure may contain chiral centers and thus may exist in different stereoisomeric forms. As used herein, the terms "optical isomer" or "stereoisomer" refer to any of the various stereoisomeric arrangements that may exist for a given compound of the present disclosure. It should be understood that substituents may be attached to the chiral centers of carbon atoms. Thus, the present disclosure includes enantiomers, diastereomers or racemates of the compounds.

[0044] "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The term "racemic" or "rac" is used, where appropriate, to indicate a racemic mixture. When specifying the stereochemistry of a compound of the present disclosure, a single stereoisomer having the known relative and absolute configuration of two chiral centers is specified using the conventional RS system (e.g., (1S,2S)). "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S. Resolved compounds of unknown absolute configuration can be designated as (+) or (-) according to the direction (right or left rotation) in which they rotate plane-polarized light at the wavelength of the sodium D line. Alternatively, resolved compounds can be defined by the respective retention times of the corresponding enantiomers / diastereomers via chiral HPLC.

[0045] Certain compounds described herein contain one or more chiral centers or axes and may therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined from the standpoint of absolute stereochemistry as (R)- or (S)-.

[0046] Unless otherwise specified, the compounds of this disclosure include all such possible stereoisomers, including racemic mixtures, optically pure forms, and intermediate mixtures. Optically active (R)- and (S)-stereoisomers are produced using chiral synthones or chiral reagents, or by conventional techniques (e.g., using a suitable solvent or mixture of solvents to achieve good separation, such as CHIRALPAK available from Daicel Corporation). RTM and CHIRALCEL RTM Separation can be performed using chiral SFC or HPLC chromatography columns. If the compound contains a double bond, the substituent may be in an E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis or trans configuration. All tautomer forms are also intended to be included.

[0047] This disclosure also provides a pharmaceutical composition comprising a compound described herein (for example, a compound described in any one of the embodiments described above), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0048] How to use The compounds described herein have Drp1 inhibitory activity. As used herein, “Drp1 inhibitory activity” refers to the ability of a compound or composition to induce a detectable decrease in Drp1 activity in vivo or in vitro.

[0049] In certain embodiments, the Disclosure provides a method for treating a disease or disorder (referred to herein as “Drp1-mediated disease or disorder”) that responds to inhibition of Drp1 activity in a subject requiring treatment. The method comprises administering to the subject a compound described herein (for example, a compound described in any one of Embodiments 1 to 19), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof.

[0050] In certain embodiments, the Disclosure provides the use of a compound described herein (e.g., a compound described in any one of the first to nineteenth embodiments) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutically acceptable compound for the treatment of a Drp1-mediated disease or disorder in a subject requiring treatment.

[0051] In certain embodiments, the Disclosure provides a compound described herein (for example, a compound described in any one of Embodiments 1 to 19) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, for use in the treatment of a Drp1-mediated disorder or disease in a subject requiring treatment.

[0052] In certain embodiments, the Disclosure provides a pharmaceutical composition comprising one of the compounds described herein (e.g., one of the compounds described in any one of the first to nineteenth embodiments) or a pharmaceutically acceptable salt thereof for treating a Drp1-mediated disorder.

[0053] In certain embodiments, the Disclosure provides the use of a compound described herein (e.g., a compound described in any one of the first to nineteenth embodiments) or a pharmaceutically acceptable salt thereof for the treatment of a Drp1-mediated disease or disorder in a subject requiring treatment.

[0054] In certain embodiments, Drp1-mediated diseases or disorders include muscle structure disorders, nerve activation disorders, muscle fatigue disorders, muscle mass disorders, beta-oxidation disorders, metabolic disorders, cancer, vascular diseases, ophthalmic vascular diseases, muscular eye diseases, or kidney diseases.

[0055] In a particular embodiment, Muscle structure disorders are selected from the following group: Bethlem myopathy, central nervous system disorders, congenital fibrous disequilibrium, distal muscular dystrophy (MD), Duchenne & Becker MD, Emery-Dreyfus MD, facioscapulohumeral MD, vitreous myopathy, limb girdle muscle MD, myosodium channel disorders, myotonic chondrodysplasia, myotonic dystrophy, myotubular myopathy, nemaline body disease, oculopharyngeal MD, and stress urinary incontinence. Neuronal activation disorders are selected from the group consisting of amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease, Guillain-Barré syndrome, Lambert-Eaton syndrome, multiple sclerosis, myasthenia gravis, nerve injury, peripheral neuropathy, spinal muscular atrophy, delayed ulnar nerve palsy, and toxic myoneuropathy. Muscle fatigue disorders are selected from the group consisting of chronic fatigue syndrome, diabetes mellitus (type 1 or type 2), glycogen storage disorders, fibromyalgia, ataxia of Friedreich, intermittent claudication, lipid storage myopathy, MELAS, mucopolysaccharidosis, Pompe disease, and thyroid-toxic myopathy. Muscle mass disorders are selected from a group consisting of cachexia, cartilage degeneration, cerebral palsy, compartment syndrome, severe myopathy, inclusion body myositis, muscle atrophy (disuse), sarcopenia, steroid myopathy, and systemic lupus erythematosus. Beta-oxidation disorders are selected from the group consisting of systemic carnitine transporter deficiency, carnitine palmitoyltransferase (CPT) II deficiency, very long-chain acyl-CoA dehydrogenase (LCHAD or VLCAD) deficiency, trifunctional enzyme deficiency, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, short-chain acyl-CoA dehydrogenase (SCAD) deficiency, and riboflavin-responsive β-oxidation disorder (RR-MADD). Metabolic diseases include hyperlipidemia, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, HDL hypocholesterolemia, LDL hypercholesterolemia and / or HDL noncholesterolemia, VLDL hyperproteinemia, abnormal lipoproteinemia, apolipoprotein AI hypoproteinemia, atherosclerosis, arteriosclerotic diseases, cardiovascular diseases, cerebrovascular diseases, peripheral circulatory diseases, metabolic syndrome, syndrome X, obesity, diabetes (type I or type II), hyperglycemia, insulin The group consists of diabetes resistance, impaired glucose tolerance, hyperinsulinemia, diabetic complications, heart failure, myocardial infarction, cardiomyopathy, hypertension, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), thrombosis, Alzheimer's disease, neurodegenerative diseases including Parkinson's disease, demyelinating diseases, multiple sclerosis, adrenoleukodystrophy, dermatitis, psoriasis, acne, skin aging, demodicosis, inflammation, arthritis, asthma, irritable bowel syndrome, ulcerative colitis, Crohn's disease, and pancreatitis. Vascular diseases are selected from the group consisting of peripheral vascular insufficiency, peripheral vascular disease, intermittent claudication, peripheral vascular disease (PVD), peripheral artery disease (PAD), peripheral artery occlusive disease (PAOD), and peripheral artery occlusive disease. Ocular vascular diseases are selected from the group consisting of age-related macular degeneration (AMD), Stargardt disease, hypertensive retinopathy, diabetic retinopathy, retinopathy, macular degeneration, retinal hemorrhage, and glaucoma. Muscle-related eye diseases are selected from the group consisting of strabismus, progressive extraocular muscle palsy, esotropia, exotropia, refractive and accommodation disorders, hyperopia, myopia, astigmatism, anisometropia, presbyopia, accommodation disorders, and internal ocular muscle palsy. Kidney diseases are selected from the group consisting of glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, acute nephritis, recurrent hematuria, persistent hematuria, chronic nephritis, rapidly progressive glomerulonephritis, acute renal failure, chronic renal failure, diabetic nephropathy, and Bartter syndrome.

[0056] In other embodiments, Drp1-mediated diseases or disorders are selected from the group consisting of hereditary lipodystrophy, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), renal ischemia / reperfusion injury (IRI), Duchenne & Becker muscular dystrophy, diabetes mellitus (type I or type II), obesity, and sarcopenia.

[0057] In other embodiments, the Drp1-mediated disease or disorder is selected from the group consisting of inflammatory diseases of the bone, T cell immunosuppression, neuropathic pain, cancer, Alpers disease, CPEO - chronic progressive external ophthalmoplegia, Kearns - Sayre syndrome (KSS), Leber hereditary optic neuropathy (LHON), MELAS - mitochondrial myopathy, encephalomyopathy, lactic acidosis, and stroke - like episodes, MERRF - myoclonic epilepsy and ragged - red fiber disease, NARP - neurogenic muscle weakness, ataxia, retinitis pigmentosa, Pearson syndrome, platinum - based chemotherapy - induced ototoxicity, cocaine syndrome, xeroderma pigmentosum A, Wallerian degeneration, and HIV - induced lipodystrophy.

[0058] In other embodiments, the Drp1-mediated disease or disorder is selected from the group consisting of acute kidney injury, myocardial ischemia, pulmonary arterial hypertension, polycystic kidney disease, Huntington's disease, neurodegenerative diseases, or Charcot - Marie - Tooth disease.

[0059] In other embodiments, the Drp1-mediated disease or disorder is a neurodegenerative disease. In other embodiments, the neurodegenerative disease is Parkinson's disease.

[0060] The compounds described herein or their pharmaceutically acceptable salts may be used to reduce the expression or activity of Drp1, or alternatively, may affect the properties and / or behavior of Drp1 in cells.

[0061] One embodiment of the present disclosure is a method of reducing the expression or activity of Drp1 in a subject, or alternatively, affecting the properties and / or behavior of Drp1 in a subject, the method comprising administering to the subject an effective amount of at least one compound described herein, or a pharmaceutically acceptable salt thereof.

[0062] In certain embodiments, the present disclosure relates to the aforementioned method where the subject is a mammal.

[0063] In certain embodiments, the present disclosure relates to the aforementioned method, wherein the subject is a primate.

[0064] In certain embodiments, the present disclosure relates to the aforementioned method, wherein the subject is a human being.

[0065] As used herein, “effective dose” and “therapeutic dose” can be used interchangeably. This means an amount effective in treating or alleviating one or more of the severity of any disease, disorder, or condition cited herein. In some embodiments, the effective dose may be between 10 μg and 500 mg.

[0066] Compounds and compositions obtained by the methods disclosed herein may be administered in any amount and via any route of administration that is effective in treating or alleviating the severity of one or more of the diseases, disorders, or conditions cited above.

[0067] In certain embodiments, the present disclosure relates to the aforementioned method by which the compound is administered orally.

[0068] In certain embodiments, the present disclosure relates to the aforementioned method by which the compound is administered parenterally.

[0069] In certain embodiments, the disclosure relates to the aforementioned methods by which the compound is administered intramuscularly, intravenously, subcutaneously, pulmonaryly, rectally, subarachnoidally, topically, or intranasally.

[0070] In certain embodiments, the present disclosure relates to the aforementioned method by which the compound is administered systemically.

[0071] The compounds of this disclosure are typically used as part of a pharmaceutical composition (e.g., the compounds of this disclosure and at least one pharmaceutically acceptable carrier). As used herein, the term “pharmaceutically acceptable carrier” includes, as known to those skilled in the art, generally recognized safe (GRAS) solvents, dispersion media, surfactants, antioxidants, preservatives (e.g., antimicrobial agents, antifungal agents), isotonic agents, salts, antiseptics, drug stabilizers, buffers (e.g., maleic acid, tartaric acid, lactic acid, citric acid, acetic acid, sodium bicarbonate, sodium phosphate, etc.), and analogues and combinations thereof (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289–1329). Unless any conventional carrier is incompatible with the active ingredient, its use in a therapeutic or pharmaceutical composition is intended. For the purposes of this disclosure, solvates and hydrates are considered pharmaceutical compositions comprising the compounds of this disclosure with a solvent (i.e., a solvate) or water (i.e., a hydrate).

[0072] The formulations may be produced using conventional dissolution and mixing procedures. For example, a bulk active pharmaceutical ingredient (i.e., the compound of the Disclosure or a stabilized form of the compound (e.g., a complex with a cyclodextrin derivative or other known compounding agent)) is dissolved in a suitable solvent in the presence of one or more of the excipients described above. The compounds of the Disclosure are typically formulated into drug dosage forms to provide a controllable dose of the drug and to provide a product that is appropriate and easy for patients to handle.

[0073] Pharmaceutical compositions (or formulations) for application may be packaged in various ways depending on the method used to administer the drug. Generally, distribution articles include a container in which the pharmaceutical formulation is placed in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), pouches, ampoules, plastic bags, and metal cylinders. Containers may also include tamper-evident assemblies to prevent accidental access to the contents of the package. Furthermore, containers have labels attached to them that describe the contents of the container. Appropriate warnings are also included on the labels.

[0074] Pharmaceutical compositions containing the compounds of this disclosure are generally formulated for parenteral or oral administration, or alternatively for use as suppositories.

[0075] For example, the pharmaceutical oral compositions of this disclosure can be prepared in solid form (including, but not limited to, capsules, tablets, pills, granules, powders, or suppositories) or in liquid form (including, but not limited to, solutions, suspensions, or emulsions). The pharmaceutical compositions can be subjected to conventional pharmaceutical operations such as sterilization, and / or may contain conventional inert diluents, lubricants, or buffers, as well as adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, and buffers.

[0076] Typically, the pharmaceutical composition is a tablet or gelatin capsule containing the active ingredient along with the following: a) Diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, b) Lubricants, such as silica, talcam, stearic acid, its magnesium or calcium salts, and / or polyethylene glycol, in tablet form. c) Binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, as needed d) Disintegrants, such as starch, agar, alginic acid or its sodium salt, or effervescent mixtures, and / or e) Absorbents, colorants, flavors, and sweeteners.

[0077] The tablets may be film-coated or enterically coated according to methods known in the art.

[0078] Compositions suitable for oral administration include compounds of the present disclosure in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use are produced according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives to provide a pharmaceutically accurate and palatable product. Tablets may contain the active ingredient in a mixture with non-toxic, pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin, or acacia; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period. For example, time-delaying materials such as glyceryl monostearate or glyceryl distearate may be used. Formulations for oral use may be presented as hard gelatin capsules, in which case the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules, in which case the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0079] Parenteral compositions (e.g., intravenous (IV) formulations) are isotonic aqueous solutions or suspensions. Parenteral compositions may be sterilized and / or may contain adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, solution enhancers, salts and / or buffers for adjusting osmotic pressure. In addition, they may also contain other therapeutically useful substances. The compositions are generally produced according to conventional mixing, granulation, or coating methods and contain about 0.1–75% or about 1–50% of the active ingredient.

[0080] The compounds or pharmaceutically active ingredients of the present disclosure for use in subjects (e.g., humans) are typically administered orally or parenterally in therapeutic doses. When administered intravenously via infusion, the dose may depend on the infusion rate at which the IV formulation is administered. Generally, the therapeutically effective dose of a compound, pharmaceutically active ingredient, or combination thereof depends on the species, weight, age, and individual condition, disorder, or disease, or the severity thereof being treated. A physician, pharmacist, clinician, or veterinarian skilled in the art can readily determine the effective amount of each active ingredient necessary to prevent, treat, or inhibit the progression of a disorder or disease.

[0081] The above dose characteristics can be advantageously demonstrated in in vitro and in vivo studies using mammals, e.g., mice, rats, dogs, monkeys, or isolated organs, tissues, and products thereof. The compounds of this disclosure can be applied in vitro in the form of a solution, e.g., an aqueous solution, and in vivo enterally, parenterally, advantageously intravenously, e.g., as a suspension, or in an aqueous solution. The in vitro dose is approximately 10 -3 Molar concentration and 10 -9 It may also be within the range of molar concentration.

[0082] definition As used herein, “patient,” “subject,” or “individual” are used interchangeably and refer to either a human or a non-human animal. The term includes mammals such as humans. Typically, an animal is a mammal. A subject also refers to, for example, primates (e.g., humans, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In some embodiments, the subject is a human.

[0083] As used herein, the terms “inhibit,” “inhibit,” or “to inhibit” refer to a reduction or suppression of a given condition, symptom, or disorder or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0084] As used herein, the terms “treat,” “treating,” or “treatment” any disease, condition, or disorder refer to therapeutic treatment or prophylactic treatment. Treatment includes the management and care of a patient aimed at combating a disease, condition, or disorder, and includes the administration of the compounds of this disclosure to achieve a desired pharmacological and / or physiological effect. Therapeutic treatment includes partially or substantially achieving one or more of the following: partially or entirely reducing the degree of the disease, condition, or disorder; improving or enhancing clinical symptoms, complications, or indicators associated with the disease, condition, or disorder; slowing, inhibiting, or reducing the likelihood of progression of the disease, condition, or disorder; or eliminating the disease, condition, or disorder. Prophylactic treatment refers to reducing the likelihood of the development of symptoms or complications of a disease, condition, or disorder.

[0085] As used herein, a subject is "in need of" treatment (in some embodiments, a human) if such subject derives a biological, medical, or quality of life benefit from such treatment.

[0086] As used herein, the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted.” Generally, the term “optionally substituted” refers to the replacement of a hydrogen radical in a given structure with a radical of a specified substituent. Specific substituents are described in the definitions and descriptions of the compounds and their examples. Unless otherwise indicated, an optionally substituted group may have substituents at each substitutable position of the group, and if two or more positions in any given structure can be substituted with two or more substituents selected from a specified group, the substituents may be the same or different at each position. In some embodiments, “one or more” substituents can be 1, 2, 3, 4, 5, 6, etc., and each of them may be the same or different. In some embodiments, “one or more” substituents can be 1 to 6, 1 to 4, 1 to 3, or 1 to 2 substituents, and each of them may be the same or different.

[0087] As used herein, the term “alkyl” refers to a fully saturated branched or unbranched hydrocarbon moiety. 1-6 The term "alkyl" refers to alkyl groups that have 1 to 6 carbon atoms. 1-4 The term "alkyl" refers to alkyl groups that have 1 to 4 carbon atoms. 1-3 "Alkyl" and "C 1-2 The term "alkyl" should be interpreted accordingly. 1-4 Typical examples of "alkyl" include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl. Similarly, the alkyl portion of an alkoxy (i.e., the alkyl portion) has the same definition as above. Where indicated as "optionally substituted," the alkane radical or alkyl portion may be unsubstituted or substituted with one or more substituents (generally 1 to 3 substituents, except in the case of halogen substituents such as perchloro or perfluoroalkyl).

[0088] As used herein, the term "alkoxy" refers to a fully saturated branched or unbranched alkyl moiety (i.e., C) bonded via oxygen crosslinking. 1-4 Alkyl is as defined herein --O--C 1-4 This refers to an alkyl group. Typical examples of alkoxys include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, and tert-butoxy. In some embodiments, the alkoxy group has 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 3 carbon atoms, and in some embodiments, it has about 1 to 2 carbon atoms. 1-6 The term "alkoxy" refers to an alkoxy molecule that has 1 to 6 carbon atoms. 1-3 The term "alkoxy" refers to an alkoxy having 1 to 3 carbon atoms. 1-2 The term "alkoxy" should be interpreted accordingly.

[0089] The number of carbon atoms in the group is referred to in this specification by the prefix "C" x-xx Specified by ", where x and xx are integers. For example, "C 1-3 "Alkyl" refers to an alkyl group that has 1 to 3 carbon atoms.

[0090] "Halogen" or "halo" may be fluorine, chlorine, bromine, or iodine.

[0091] As used herein, the term “haloalkyl” refers to an alkyl group as defined herein, in which at least one of the hydrogen atoms is substituted by a halo atom. 1-6 The term "haloalkyl" refers to a haloalkyl group having 1 to 6 carbon atoms. 1-4 "Haloalkyl" and "C 1-3The term "haloalkyl" should be interpreted accordingly. A haloalkyl group can be a monohaloalkyl, dihaloalkyl, or polyhaloalkyl group containing a perhaloalkyl group. A monohaloalkyl group may have one iodine, bromo, chloro, or fluoro group within the alkyl group. Dihaloalkyl groups and polyhaloalkyl groups may have two or more combinations of the same halo atom or different halo groups within the alkyl group. Typically, a polyhaloalkyl group contains up to 13, or 12, or 11, or 10, or 9, or 8, or 7, or 6, or 5, or 4, or 3, or 2 halo groups. 1-6 Non-limiting examples of haloalkyls include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. A perhaloalkyl group refers to an alkyl group in which all hydrogen atoms are replaced by halo atoms.

[0092] As used herein, the term “haloalkoxy” refers to an alkoxy group as defined herein, in which at least one of the hydrogen atoms on the alkyl moiety is substituted with a halo atom. 1-6 The term "haloalkoxy" refers to a haloalkoxy group having 1 to 6 carbon atoms. 1-4 "Haloalkoxy" and "C 1-3The term "haloalkoxy" should be interpreted accordingly. A haloalkoxy group can be a monohaloalkoxy, dihaloalkoxy, or polyhaloalkoxy containing a perhaloalkyl group. A monohaloalkyl group may have one iodo, bromo, chloro, or fluoro atom within the alkyl portion of the alkoxy group. Dihaloalkoxy and polyhaloalkoxy groups may have two or more combinations of the same halo atom or different halo groups within the alkyl portion of the alkoxy group. Typically, a polyhaloalkoxy group contains up to 13, or 12, or 11, or 10, or 9, or 8, or 7, or 6, or 5, or 4, or 3, or 2 halo groups. 1-6 Examples of haloalkoxys include fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, pentafluoroethoxy, heptafluoropropoxy, difluorochloromethoxy, dichlorofluoromethoxy, difluoroethoxy, difluoropropoxy, dichloroethoxy, and dichloropropoxy.

[0093] The term "aryl" refers to an aromatic carbocyclic monocyclic radical or a fused ring radical containing 6 to 10 carbon atoms. Examples include phenyl and naphthyl.

[0094] The term "heteroaryl" refers to a 5- to 10-membered aromatic radical containing 1-4 heteroatoms selected from N, O, and S. In some cases, the nitrogen atom in the heteroaryl may be quaternized. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic." The heteroaryl group may be monocyclic or bicyclic. In some embodiments, the monocyclic heteroaryl is a 5- or 6-membered monocyclic heteroaryl ring. Five- or six-membered monocyclic heteroaryls include, for example, pyrrolyl, furanil, thiophenyl (or thienyl), imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, flazanil, oxadiazolyl, thiadiazolyl, dithiazolyl, triazolyl, tetrazolyl, pyridinyl, pyranil, thiopyranil, pyrazinyl, pyrimidinyl, pyridadinyl, oxazinyl, thiadinyl, dioxynyl, dithinyl, oxathianyl, triazinyl, and tetradinyl. Bicyclic heteroaryls include groups in which a monocyclic heteroaryl ring is condensed with one or more aryl or heteroaryl rings. Non-limiting examples include indolyl, indazoyl, benzofuranil, benzimidazolyl, and imidazo[1,2-a]pyridine.

[0095] The term "carbocyclic ring" refers to a saturated or partially unsaturated hydrocarbon ring with 4 to 12 members, which may exist as a monocyclic ring, a bicyclic ring (including fused rings, spirocyclic rings, or bridging rings), or a spirocyclic ring.

[0096] The term "carbocyclyl" refers to a 4- to 12-membered saturated or partially unsaturated hydrocarbon ring radical, which may exist as a monocycle, bicyclic ring (including fused rings, spirocycles, or bridging rings), or spirocycle.

[0097] Bicyclic carbocyclyl groups include, for example, cyclohexyl, cyclohexenyl, 2,3-dihydroindenyl, indanyl, decahydronaphthalenyl, and other unsaturated carbocyclic radicals condensed with cycloalkyl or aryl groups, such as 1,2,3,4-tetrahydronaphthalenyl. Unless otherwise specified, carbocyclic rings generally contain 4 to 10 ring members.

[0098] "C 3-6 The term "cycloalkyl" refers to a fully saturated carbon ring radical (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl). 3-4 The term "cycloalkyl" refers to a fully saturated carbon ring radical (e.g., cyclopropyl, cyclobutyl).

[0099] The term "heterocyclic" refers to a 4- to 12-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S. The heterocyclic group may be monocyclic or bicyclic (e.g., bridged, fused, or spiro-dicyclic).

[0100] The term "heterocyclyl" refers to a 4- to 12-membered saturated or partially unsaturated heterocyclic radical containing 1 to 4 heteroatoms independently selected from N, O, and S. The heterocyclyl group may be monocyclic or bicyclic (e.g., bridged, condensed, or spirodicyclic).

[0101] Examples of monocyclic saturated or partially unsaturated heterocyclic radicals include, but are not limited to, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, and pyrrolidinyl. The bicyclic heterocyclyl group includes, for example, saturated or partially unsaturated heterocyclic radicals condensed to another saturated or partially unsaturated heterocyclic radical, cycloalkyl, aryl, or heteroaryl ring, such as indolinyl, indolin-2-onyl, 2,3-dihydro-1H-pyrrolopyridinyl, 6,7-dihydro-5H-pyrrolopyridinyl, 2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl, 1,4,5,6-tetrahydrocyclopenta[c]pyrazolyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, 5,6-dihydro-4H-cyclopenta[b]thiophenyl, and 4,7-dihydro-5H-thieno[2,3-c]pyranyl. In some embodiments, the heterocyclyl group is a 3- to 6-membered monocyclic heterocyclyl group. In some embodiments, the 3-6 membered monocyclic heterocyclyl group is oxetanyl and tetrahydropyranyl. In some embodiments, the heterocyclyl group is a 4-6 membered monocyclic heterocyclyl group. In some embodiments, the heterocyclyl group is an 8-10 membered bicyclic heterocyclyl group.

[0102] As used herein, the term “spiro” ring means a system of two rings in which both rings share one common atom. Examples of spiro rings include 5-oxaspiro[2.3]hexanyl, oxaspiro[2.4]heptanyl, 5-oxaspiro[2.4]heptanyl, 4-oxaspiro[2.4]heptanyl, 4-oxaspiro[2.5]octanyl, 6-oxaspiro[2.5]octanyl, oxaspiro[2.5]octanyl, oxaspiro[3.4]octanyl, oxaspiro[bicyclo[2.1.1]hexane-2,3'-oxetane]-1-yl, oxaspiro[bicyclo[3.2.0]heptane-6,1'-cyclobutane]-7-yl, 2,6-diazaspiro[3.3]heptanyl, -oxa-6-azaspiro[3.3]heptanyl Examples include nyl, 2,2,6-diazaspiro[3.3]heptanyl, 3-azaspiro[5.5]undecanyl, 3,9-diazaspiro[5.5]undecanyl, 7-azaspiro[3.5]nonanyl, 2,6-diazaspiro[3.4]octanyl, 8-azaspiro[4.5]decanyl, 1,6-diazaspiro[3.3]heptanyl, 5-azaspiro[2.5]octanyl, 4,7-diazaspiro[2.5]octanyl, 5-oxa-2-azaspiro[3.4]octanyl, 6-oxa-1-azaspiro[3.3]heptanyl, 3-azaspiro[5.5]undecanyl, and 3,9-diazaspiro[5.5]undecanyl.

[0103] The term "condensed" ring refers to a system of two rings that share two adjacent ring atoms. A condensed heterocycle contains at least one ring system in which a ring atom is a heteroatom selected from O, N, and S (e.g., 3-oxabicyclo[3.1.0]hexane). 5-12 The term "cycloalkyl" refers to a 5- to 12-membered crosslinked carbon ring radical. 5-12 Examples of cycloalkyls include, but are not limited to, bicyclo[1.1.1]pentanyl.

[0104] As used herein, the term “bridged” refers to a 5- to 12-membered cyclic portion linked by two non-adjacent ring atoms (e.g., bicyclo[1.1.1]pentane, bicyclo[2.2.1]heptane, and bicyclo[3.2.1]octane). 5-12 The term "cycloalkyl" refers to a 5- to 12-membered crosslinked carbon ring radical. 5-12 Examples of cycloalkyls include, but are not limited to, bicyclo[1.1.1]pentanyl.

[0105] The phrase "pharmaceutically acceptable" indicates that a substance, composition, or dosage form must be chemically and / or toxicologically compatible with the other components of the formulation and / or the mammal being treated with it.

[0106] Unless otherwise specified, the term “compounds of this disclosure” means compounds of formula (I) or (IA), as well as all stereoisomers (including diastereoisomers and enantiomers), rotamers, and tautomers. If a moiety capable of forming salts exists, salts, in particular pharmaceutically acceptable salts, are also included.

[0107] As used herein, the terms “a,” “an,” and “the,” and similar terms as used in the context of this disclosure (particularly in the context of the claims), should be construed to cover both singular and plural forms unless otherwise indicated herein or unless clearly inconsistent with the context. Any and all examples or exemplary terms (e.g., “etc.”) used herein are intended merely to better illustrate the invention and, unless otherwise stated, do not limit the claims.

[0108] The intermediates and compounds of this disclosure may exist in different tautomerized forms, and all such forms may be encompassed within the scope of this disclosure. The terms “tautomer” or “tautomerized form” refer to structural isomers of different energies that are interconvertible across low-energy barriers. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton transfer, such as ketoenols and imine-enamine isomerization. A specific example of a proton tautomer is an imidazole moiety in which a proton can move between two ring nitrogen atoms. Valence tautomers include interconversions via several rearrangements of bonding electrons.

[0109] In one embodiment, the disclosure relates to a compound of formula (I) or (IA) as defined herein in its free form. In another embodiment, the disclosure relates to a compound of formula (I) or (IA) as defined herein in the form of a salt. In yet another embodiment, the disclosure relates to a compound of formula (I) or (IA) as defined herein in the form of an acid-added salt. In a further embodiment, the disclosure relates to a compound of formula (I) or (IA) as defined herein in the form of a pharmaceutically acceptable salt. In yet another embodiment, the disclosure relates to a compound of formula (I) or (IA) as defined herein in the form of a pharmaceutically acceptable acid-added salt. In yet yet another embodiment, the disclosure relates to any one of the compounds of the embodiment in its free form. In yet yet another embodiment, the disclosure relates to any one of the compounds of the embodiment in its salt form. In yet another embodiment, the disclosure relates to any one of the compounds of the embodiment in its acid-added salt form. In yet yet another embodiment, the disclosure relates to any one of the compounds of the embodiment in its pharmaceutically acceptable salt form. In yet another embodiment, the disclosure relates to any one of the compounds of the examples in the form of a pharmaceutically acceptable acid addition salt.

[0110] The compounds of this disclosure can be synthesized by synthetic routes involving processes similar to those well known in the chemical field, particularly in light of the description contained herein. Starting materials are generally available from commercially available sources such as Sigma-Aldrich, or can be quickly produced using methods well known to those skilled in the art (e.g., Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v.1-19, Wiley, New York (1967-1999 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. Springer-Verlag, Berlin (including augmented edition) (also available from the Beilstein online database)).

[0111] For illustrative purposes, the reaction scheme shown below provides a potential route for synthesizing the compounds and key intermediates of this disclosure. For a more detailed description of each reaction step, please refer to the Examples section below. Specific starting materials and reagents are shown in the scheme and described below, but other starting materials and reagents can be readily substituted to provide a variety of derivatives and / or reaction conditions.

[0112] Example (abbreviation) Cs2CO3 = Cesium Carbonate DCM = CH2Cl2 = Dichloromethane DIPEA = DIEA = Diisopropylethylamine DMF = Dimethylformamide DMSO = Dimethyl sulfoxide Et2O = Diethyl ether HCl=EA=ethyl acetate EtOH = Ethanol h=time H2O = Water H2SO4 = sulfuric acid HATU = Hexafluorophosphate azabenzotriazole tetramethyluronium HCl = hydrochloric acid HNO3 = Nitric Acid HPLC = High-Pressure Liquid Chromatography K2CO3 = potassium carbonate KI = potassium iodide LCMS = Liquid Chromatography Mass Spectrometry LDA = Lithium diisopropylamide LiAlH4 = LAH = Lithium Aluminum Hydrogenate LiBH4 = Lithium boron hydride LiCl = Lithium Chloride MeCN=ACN=CH3CN=acetonitrile MeOH = methanol N2 = Nitrogen Na2SO4 = sodium sulfate NaH = Sodium hydride NaOEt = Sodium Ethoxide NaOH = sodium hydroxide NaOMe = Sodium Methoxide n-BuLi=n-butyllithium NH4Cl = Ammonium chloride NH4OH = Ammonium hydroxide NMR=Nuclear Magnetic Resonance Spectroscopy NOESY = Nuclear Overhauser Effect Spectroscopy Pd(PPh3)4 = Tetrakis(triphenylphosphine)palladium(0) Pd / C = Palladium on carbon Pd2(dba)3 = Tris(dibenzylideneacetone)dipalladium(0) POBr3 = phosphoryl bromide POCl3 = phosphoryl chloride PPA = Polyphosphate RT=room temperature t-BuOH = tert-butanol t-BuOK = potassium tert-butoxide TEA = Et3N = Triethylamine TFA = Trifluoroacetic acid THF = Tetrahydrofuran TLC = Thin-Layer Calculation Xanthophos=4,5-bis(diphenylphosphin)-9,9-dimethylxanthene

[0113] Example 1: N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)oxetan-3-carboxamide [ka] [ka] Synthesis of 1,6-nitroquinoline-2,4-diol [ka] To a stirred solution of quinoline-2,4-diol (5 g, 31.03 mmol) in H2SO4 (45 mL), HNO3 (1.2 mL) was added dropwise under RT. The mixture was stirred under RT for 30 minutes. Next, the reaction mixture was poured into ice-cold water (200 mL). The formed precipitate was filtered, washed with water (50 mL), and dried under vacuum to obtain 6-nitroquinoline-2,4-diol (4.5 g, yield: 70%) as a yellow solid. 1 1H NMR (400 MHz, DMSO-d 6, δ):11.48-12.14(m,2H),8.56(d,J=2.57 Hz,1H),8.32(dd,J=9.05,2.57Hz,1H),7.39(d,J=9.05 Hz,1H),5.83(s,1H).

[0114] 2. Synthesis of 2,4-dichloro-6-nitroquinoline [ka] A stirred solution of 6-nitroquinoline-2,4-diol (10 g, 48.51 mmol) in POCl3 (100 mL) was heated at 100°C for 24 hours. The reaction mixture was then cooled to RT and slowly quenched with ice-cold water (100 mL). The formed precipitate was filtered and dried under vacuum to obtain 2,4-dichloro-6-nitroquinoline (8.6 g, yield: 73%) as a yellow solid. 1 1H NMR (400 MHz, DMSO-d 6,δ):8.96(d,J=1.47 Hz,1H),8.58-8.66(m,1H),8.16-8.34(m,2H).

[0115] 3. Synthesis of 2-chloro-4-(2-methoxyethoxy)-6-nitroquinoline [ka] A stirred solution of 2,4-dichloro-6-nitroquinoline (2 g, 8.29 mmol) and 2-methoxyethane-1-ol (0.76 g, 9.95 mmol) in DMF (20 mL) was mixed with K2CO3 (1.8 g, 12.43 mmol) via RT and heated at 110 °C for 16 hours. The reaction mixture was then cooled to RT and poured into water (200 mL). The aqueous layer was extracted with siRNA (2 x 200 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain a mixture of 2-chloro-4-(2-methoxyethoxy)-6-nitroquinoline and 4-chloro-2-(2-methoxyethoxy)-6-nitroquinoline. The crude product was purified by combiflash chromatography (dichloromethane) to obtain 2-chloro-4-(2-methoxyethoxy)-6-nitroquinoline (0.4 g, yield: 17%) as an off-white solid and 4-chloro-2-(2-methoxyethoxy)-6-nitroquinoline (0.8 g, yield: 35%) as an off-white solid. Note: Isomers were confirmed by 2D NOESY. 2-chloro-4-(2-methoxyethoxy)-6-nitroquinoline:LCMS(ESI+):C 12 H 12 ClN2O4[M+H] + m / z calculated value, 283; measured value, 283. 1¹H NMR (400 MHz, CHLOROFORM-d,δ): 9.12 (d, J=2.45 Hz, 1H), 8.48 (dd, J=9.29, 2.45 Hz, 1H), 8.05 (d, J=9.29 Hz, 1H), 6.90 (s, 1H), 4.42 (t, J=4.89 Hz, 2H), 3.93 (t, J=4.89 Hz, 2H), 3.51 (s, 3H). 4-Chloro-2-(2-methoxyethoxy)-6-nitroquinoline: LCMS (ESI+): C 12 H 12 ClN2O4[M+H] + m / z calculated value, 283; measured value, 283. 1 H NMR(400 MHz,CHLOROFORM-d,δ):9.05(s,1H),8.44(d,J=9.29 Hz,1H),7.92(d,J=9.29 Hz,1 H),7.24(d,J=14.67 Hz,1H),4.69(t,J=4.40 Hz,2H),3.81(t,J=4.40 Hz,2H),3.48(s,3H).

[0116] Synthesis of 4:5-(4-(2-methoxyethoxy)-6-nitroquinoline-2-yl)thiazole [ka] A stirred solution of 2-chloro-4-(2-methoxyethoxy)-6-nitroquinoline (0.25 g, 0.88 mmol) and LiCl (0.11 g, 2.65 mmol) in 1,4-dioxane (3 mL) was purged with N2 for 30 minutes. 5-(tributylstannyl)thiazole (0.50 g, 1.32 mmol) and Pd(PPh3)4 (0.2 g, 0.17 mmol) were added, and the mixture was further purged with N2 for 5 minutes. The reaction mixture was heated in a sealed tube at 110°C for 16 hours. The reaction mixture was then cooled to RT and diluted with water (50 mL). The aqueous layer was extracted with ELISA (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product obtained was ground with CH3CN (5 mL) and vacuum-dried to obtain 5-(4-(2-methoxyethoxy)-6-nitroquinoline-2-yl)thiazole (0.24 g, yield: 82%) as a white solid. The obtained compound was used in the next step without further purification. LCMS(ESI+):C 15 H 14 N3O4S [M+H] + m / z calculated value, 332; measured value, 332. 1 1H NMR (400 MHz, DMSO-d 6, δ):9.30(s,1H),8.97(s,1H),8.87(d,J=2.45 Hz,1H),8.43(dd,J=9.29,2.93 Hz,1H),8.08(d,J=9.29 Hz,1H),7.85(s,1H),4.60(t,J=3.42 Hz,2H),3.90(t,J=3.91 Hz,2H),3.41(s,3H).

[0117] 5. Synthesis of 4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-amine [ka] To a stirred solution of 5-(4-(2-methoxyethoxy)-6-nitroquinoline-2-yl)thiazole (0.22 g, 0.4 mmol) in MeOH (5 mL), 10% Pd / C (50% wet, 30 mg) was added, and the reaction mixture was stirred at RT in a steel pressure vessel under a hydrogen atmosphere of 50 psi for 16 hours. Next, the reaction mixture was filtered through a Celite pad and washed with 10% MeOH in DCM (100 mL). The filtrate was concentrated under vacuum to obtain 4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-amine (0.2 g, crude product) as a sticky black solid. The obtained crude compound was used in the next step without further purification. LCMS(ESI+):C 15 H 16 N3O2S [M+H] + m / z calculated value, 302; measured value, 302. 1 1H NMR (400 MHz, DMSO-d 6, δ):9.09(s,1H)8.66(s,1H)7.61(d,J=8.80 Hz,1H)7.44(s,1H)7.11(dd,J=9.29,2.45 Hz,1H)7.06(d,J=2.45 Hz,1H)5.71(br s,2H)4.43(d,J=3.91 Hz,2H)3.83(t,J=3.91 Hz,2H)3.39(s,3H).

[0118] 6. Synthesis of N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)oxetane-3-carboxamide [ka] To a stirred solution of oxetane-3-carboxylic acid (0.07 g, 0.72 mmol) in DMF (3 mL), HATU (0.44 g, 1.17 mmol) was added and the mixture was stirred for 10 minutes. 4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-amine (0.18 g, 0.60 mmol) was added to the reaction mixture, followed by the addition of DIPEA (0.28 mL, 1.56 mmol) at RT. The reaction mixture was stirred at RT for 16 hours. Next, the reaction mixture was diluted with water (50 mL) and extracted with 10% MeOH in DCM (2 x 100 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by reverse-phase preparative HPLC to obtain N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)oxetane-3-carboxamide (0.07 g, yield: 30%) as a white solid. HPLC purity: 95.11%. LCMS(ESI+):C 19 H 20 N3O4S [M+H] + m / z calculated value, 386; measured value, 386. 1 1H NMR (400 MHz, DMSO-d 6, δ):10.30(s,1H),9.18(s,1H),8.80(s,1H),8.45(d,J=2.25 Hz,1H),7.97(dd,J=9.13,2.38 Hz,1H),7.87(d,J=9.13 Hz,1H),7.63(s,1H),4.74(d,J=7.50 Hz,4H),4.53(dd,J=5.32,3.69 Hz,2H),4.02(quin,J=7.54 Hz,1H),3.83-3.90(m,2H),3.41(s,3H).

[0119] Example 2: N-(4-ethoxy-2-(4-methyl-1H-imidazole-1-yl)quinoline-6-yl)oxetane-3-carboxamide [ka] [ka] 1. Synthesis of 1,4-ethoxy-6-nitroquinoline-2-ol [ka] A stirred solution of 6-nitroquinoline-2,4-diol (5g, 24.26 mmol x 2 batches) in DMF (100 mL) was mixed with K2CO3 (6.7 g, 48.5 mmol) and heated at 60°C for 1 hour. The reaction mixture was cooled to RT and ethyl iodide (3.7 g, 24.26 mmol) was added. The reaction mixture was stirred at RT for 16 hours. Next, the reaction mixture was poured into ice-cold water (500 mL), the solid was filtered, washed with water (100 mL), and dried under vacuum. The resulting crude product was ground with 80% siRNA in heptane to obtain 4-ethoxy-6-nitroquinoline-2-ol (5 g, crude product) as a light brown solid. 1 ¹H NMR (400 MHz, methanol-d) 4, δ):12.71(s,1H),9.32(d,J=2.45 Hz,1H),9.13(dd,J=9.29,2.45 Hz,1H),8.20(d,J=9.29 Hz,1H),6.82(s,1 H),5.02(q,J=7.17 Hz,2H),2.26(t,J=6.85 Hz,3H).

[0120] 2. Synthesis of 2-bromo-4-ethoxy-6-nitroquinoline [ka] To a stirred solution of 4-ethoxy-6-nitroquinoline-2-ol (5 g, 21.36 mmol) in toluene (50 mL), POBr3 (18 g, 64.10 mmol) was added by RT, and the mixture was heated at 110 °C for 16 hours. Next, the reaction mixture was quenched with ice-cold water (200 mL), the solid was filtered, washed with water (50 mL), and dried under vacuum. The resulting crude product was purified by combiflash chromatography (70-80% ethyl acetate in heptane) to obtain 2-bromo-4-ethoxy-6-nitroquinoline (3 g, yield: 47%) as a pale yellow solid. LCMS(ESI+):C 11 H 10 BrN2O3[M+H] + m / z calculated value, 298; measured value, 298. 1 1H NMR (400 MHz, DMSO-d 6,δ):8.88(d,J=1.96 Hz,1H),8.49(dd,J=9.29,2.45 Hz,1H),8.08(d,J=9.29 Hz,1H),7.43(s,1H),4.44(q,J=7.01 Hz,2H),1.51(t,J=7.09 Hz,3H).

[0121] 3. Synthesis of 4-ethoxy-2-(4-methyl-1H-imidazole-1-yl)-6-nitroquinoline [ka] To a stirred solution of 4-methyl-1H-imidazole (0.1 g, 1.26 mmol) in DMF (10 mL), Cs2CO3 (0.82 g, 2.52 mmol) and KI (0.013 g, 0.08 mmol) were added at RT, and the mixture was stirred for 10 minutes. Then, 2-bromo-4-ethoxy-6-nitroquinoline (0.25 g, 0.84 mmol) was added at RT, and the mixture was heated at 100 °C for 16 hours. Next, the reaction mixture was cooled to RT, poured into ice water (100 mL), filtered, washed with water (20 mL), and vacuum dried. The crude product obtained was pulverized with n-pentane (10 mL) and Et2O (10 mL), and dried in vacuum to obtain 4-ethoxy-2-(4-methyl-1H-imidazole-1-yl)-6-nitroquinoline (0.2 g, yield: 80%) as a pale yellow solid. LCMS(ESI+):C 15 H 15 N4O3[M+H] + m / z calculated value, 299; measured value, 299. 1 1H NMR (400 MHz, DMSO-d 6, δ):8.84(d,J=2.45 Hz,1H),8.70(s,1H),8.45(dd,J=9.29,2.45 Hz,1H),7.99(d,J=9.29 Hz,1H),7.89(s,1H),7.49(s,1H),4.50(q,J=6.85 Hz,2H),2.21(s,3H),1.55(t,J=7.09 Hz,3H).

[0122] 4. Synthesis of 4-ethoxy-2-(4-methyl-1H-imidazole-1-yl)quinoline-6-amine [ka] To a stirred solution of 4-ethoxy-2-(4-methyl-1H-imidazole-1-yl)-6-nitroquinoline (0.2 g, 0.67 mmol) in MeOH (10 mL), 10% Pd / C (50% wet, 0.07 g) was added, and the reaction mixture was stirred at RT in a steel pressure vessel under a hydrogen atmosphere of 50 psi for 16 hours. Next, the reaction mixture was filtered through a Celite pad and washed with MeOH (50 mL). The filtrate was concentrated under vacuum to obtain 4-ethoxy-2-(4-methyl-1H-imidazole-1-yl)quinoline-6-amine (0.15 g, crude product) as a pale yellow solid. The obtained crude compound was used in the next step without further purification. LCMS(ESI+):C 15 H 17 N4O [M+H] + m / z calculated value, 269; measured value, 269. 1 1H NMR (400 MHz, DMSO-d 6, δ):8.47(s,1H),7.74(s,1H),7.56(d,J=8.80 Hz,1H),7.10-7.17(m,2H),7.07(s,1H),5.59(s,2H),4.36(q,J=6.85 Hz,2H),2.18(s,3H),1.48(t,J=6.85 Hz,3H).

[0123] 5. Synthesis of N-(4-ethoxy-2-(4-methyl-1H-imidazole-1-yl)quinoline-6-yl)oxetane-3-carboxamide [ka] To a stirred solution of oxetane-3-carboxylic acid (0.085 g, 0.83 mmol) in DMF (10 mL), HATU (0.53 g, 1.39 mmol) was added and stirred for 10 minutes. 4-ethoxy-2-(4-methyl-1H-imidazole-1-yl)quinoline-6-amine (0.15 g, 0.55 mmol) was added to the reaction mixture, followed by the addition of DIPEA (0.3 mL, 1.67 mmol) via RT. The reaction mixture was stirred via RT for 16 hours. Next, the reaction mixture was diluted with ice-cold water (50 mL) and extracted with 5% MeOH in DCM (2 x 100 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by combiflash chromatography (0-5% MeOH in DCM) to obtain N-(4-ethoxy-2-(4-methyl-1H-imidazole-1-yl)quinoline-6-yl)oxetane-3-carboxamide (0.071 g, yield: 36%) as an off-white solid. HPLC purity: 95.19%. LCMS (ESI+): C 19 H 21 N4O3[M+H] + m / z calculated value, 353; measured value, 353. 1 1H NMR (400 MHz, DMSO-d 6, δ):10.26(s,1H),8.58(d,J=1.00 Hz,1H),8.49(d,J=2.25 Hz,1H),7.93(dd,J=9.13,2.38 Hz,1H),7.77-7.85(m,2H),7.32(s,1H),4.73(d,J=7.50 Hz,4H),4.44(q,J=7.00 Hz,2H),4.01(quin,J=7.47 Hz,1H),2.20(s,3H),1.52(t,J=6.94 Hz,3H).

[0124] Example 3: N-(4-ethoxy-2-(thiazole-5-yl)quinoline-6-yl)oxetan-3-carboxamide [ka] [ka] Synthesis of 1,5-(4-ethoxy-6-nitroquinoline-2-yl)thiazole [ka] 5-(4-(2-methoxyethoxy)-6-nitroquinoline-2-yl)thiazole was prepared using the same procedure as for the production of 5-(4-(2-methoxyethoxy)-6-nitroquinoline-2-yl)thiazole. The resulting compound was purified by combiflash chromatography (5-10% ethyl acetate in heptane) to obtain a yellow solid (0.4 g, yield: 65%). LCMS(ESI+):C 14 H 12 N3O3S [M+H] + m / z calculated value, 302; measured value, 302. 1 1H NMR (400 MHz, DMSO-d 6, δ):9.29(s,1H),8.98(s,1H),8.89(d,J=2.45 Hz,1H),8.43(dd,J=9.29,2.45 Hz,1H),8.08(d,J=9.29 Hz,1H),7.81(s,1H),4.52(q,J=7.01 Hz,2H),1.56(s,3H).

[0125] 2. Synthesis of 4-ethoxy-2-(thiazole-5-yl)quinoline-6-amine [ka] Using the same procedure as for the production of 4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-amine, 4-ethoxy-2-(thiazole-5-yl)quinoline-6-amine was produced as a black solid (0.21 g, crude product) and used in the next step without purification. LCMS(ESI+):C 14 H 14 N3OS [M+H] + m / z calculated value, 272; measured value, 272. 1 1H NMR (400 MHz, DMSO-d 6,δ):9.08(s,1H),8.65(s,1H),7.58-7.62(m,1H),7.40(s,1H),7.08-7.12(m,1H),7.04-7.07(m,1H),5.67(s,2H),4.35(q,J=7.15 Hz,2H),1.49(t,J=7.15 Hz,3H).

[0126] 3. Synthesis of N-(4-ethoxy-2-(thiazole-5-yl)quinoline-6-yl)oxetane-3-carboxamide [ka] N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)oxetane-3-carboxamide was prepared by replacing 4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-amine in N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)oxetane-3-carboxamide with 4-ethoxy-2-(thiazole-5-yl)quinoline-6-yl)oxetane-3-carboxamide to obtain an off-white solid (0.04 g, yield: 31%). HPLC purity: 98.93%. LCMS(ESI+): C 18 H 18 N3O3S [M+H] + m / z calculated value, 356; measured value, 356. 1 1H NMR (400 MHz, DMSO-d 6, δ):10.27(s,1H),9.17(s,1H),8.80(s,1H),8.49(d,J=2.00 Hz,1H),7.82-7.96(m,2H),7.60(s,1H),4.74(d,J=7.38 Hz,4H),4.44(d,J=7.00 Hz,2H),4.01(t,J=7.50 Hz,1H),1.53(t,J=6.94 Hz,3H).

[0127] Example 4: N-(4-ethoxy-2-(thiazole-5-yl)quinoline-6-yl)bicyclo[1.1.1]pentan-1-carboxamide [ka] N-(4-ethoxy-2-(thiazole-5-yl)quinoline-6-yl)bicyclo[1.1.1]pentan-1-carboxamide was prepared by replacing the oxetane-3-carboxylic acid in N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)oxetane-3-carboxamide with bicyclo[1.1.1]pentan-1-carboxamide to obtain an off-white solid (0.05 g, yield: 46%). HPLC purity: 95.22%. LCMS(ESI+): C 20 H 20 N3O2S [M+H] + m / z calculated value, 366; measured value, 366. 1 1H NMR (400 MHz, DMSO-d 6, δ):9.86(s,1H),9.17(s,1H),8.80(s,1H),8.43(d,J=2.25 Hz,1H),8.06(dd,J=9.13,2.38 Hz,1H),7.84(d,J=9.13 Hz,1H),7.58(s,1H),4.44(q,J=6.96 Hz,2H),2.51-2.49(m,1H),2.12(s,6H),1.52(t,J=7.00 Hz,3H).

[0128] Example 5: N-(4-Methoxy-2-(thiazole-5-yl)quinoline-6-yl)oxetane-3-carboxamide [ka] [ka] 1. Synthesis of 1,2-chloro-4-methoxy-6-nitroquinoline [ka] To a stirred solution of 2,4-dichloro-6-nitroquinoline (2 g, 10.64 mmol) in MeOH (20 mL), NaOMe (0.42 g, 31.02 mmol) was added under RT. The reaction mixture was stirred under RT for 16 hours. Next, volatile substances were removed under vacuum. The crude product was diluted with water (50 mL). The aqueous layer was extracted with ELISA (2 x 75 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain a mixture of 2-chloro-4-methoxy-6-nitroquinoline and 4-chloro-2-methoxy-6-nitroquinoline. The crude product was purified by combiflash chromatography (40-50% siRNA in heptane) to obtain 2-chloro-4-methoxy-6-nitroquinoline (0.32 g, yield: 31%) as an off-white solid and 4-chloro-2-methoxy-6-nitroquinoline (0.6 g, yield: 35%) as an off-white solid. Note: Isomers were confirmed by 2D NOESY. 2-chloro-4-methoxy-6-nitroquinoline:LCMS(ESI+):C 10 H8ClN2O3[M+H] + m / z calculated value, 239; measured value, 239. 1 1H NMR (400 MHz, DMSO-d 6, δ): 8.87 (d, J=2.45 Hz, 1H), 8.49 (dd, J=9.29, 2.45 Hz, 1H), 8.07 (d, J=8.80 Hz, 1H), 7.34 (s, 1H), 4.16 (s, 3H). 4-Chloro-2-methoxy-6-nitroquinoline: LCMS(ESI+): C 10 H8ClN2O3[M+H] + m / z calculated value, 239; measured value, 239. 1 1H NMR (400 MHz, DMSO-d 6, δ):8.87(d,J=2.45 Hz,1H),8.50(dd,J=8.80,2.45 Hz,1H),8.03(d,J=9.29 Hz,1H),7.59(s,1H),4.07(s,3H).

[0129] Synthesis of 2.5-(4-methoxy-6-nitroquinoline-2-yl)thiazole [ka] In the synthesis procedure for 5-(4-(2-methoxyethoxy)-6-nitroquinoline-2-yl)thiazole, 5-(4-methoxy-6-nitroquinoline-2-yl)thiazole was produced by substituting 2-chloro-4-methoxy-6-nitroquinoline with 2-chloro-4-(2-methoxyethoxy)-6-nitroquinoline. The resulting compound was purified by combiflash chromatography (40-50% Â in heptane) to obtain the product as a pale yellow solid (0.22 g, yield: 57%). LCMS(ESI+):C 13 H 10 N3O3S [M+H] + m / z calculated value, 288; measured value, 288. 1 1H NMR (400 MHz, DMSO-d 6, δ):9.30(s,1H),9.00(s,1H),8.90(d,J=2.45 Hz,1H),8.44(dd,J=9.05,2.69 Hz,1H),8.09(d,J=9.29 Hz,1H),7.85(s,1H),4.24(s,3H).

[0130] 3. Synthesis of 4-Methoxy-2-(thiazole-5-yl)quinoline-6-amine [ka] 4-Methoxy-2-(thiazole-5-yl)quinoline-6-amine was prepared in the same manner as described for 4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-amine. The resulting compound was pulverized with diethyl ether and n-pentane to obtain the product as a pale yellow solid (0.15 g, yield: 76%). LCMS(ESI+):C 13 H 12 N3OS [M+H] + ,258; Measured value, 258. 1 1H NMR (400 MHz, DMSO-d 6,δ):9.09(s,1H),8.67(s,1H),7.61(d,J=9.29 Hz,1H),7.42(s,1H),7.10(dd,J=8.80,2.45 Hz,1H),7.04(d,J=2.45 Hz,1H),5.67(s,2 H),4.07(s,3 H).

[0131] 4. Synthesis of N-(4-methoxy-2-(thiazole-5-yl)quinoline-6-yl)oxetane-3-carboxamide [ka] N-(4-methoxy-2-(thiazole-5-yl)quinoline-6-yl)oxetane-3-carboxamide was prepared using the same procedure as for N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)oxetane-3-carboxamide. The crude product was purified by combiflash column chromatography (5% MeOH / CH2Cl2) to obtain the product as an off-white solid (0.09 g, yield: 45%). HPLC purity: 97.95%. LCMS (ESI+): C 17 H 16 N3O3S [M+H] + m / z calculated value, 342; measured value, 342. 1 1H NMR (400 MHz, DMSO-d 6, δ)10.27(s,1H),9.18(s,1H),8.82(s,1H),8.59(d,J=2.13 Hz,1H),7.87(d,J=9.01 Hz,1H),7.82(t,J=2.25 Hz,1H),7.62(s,1H),4.75-4.72(m,4H),4.16(s,3H),4.06-3.97(m,1H).

[0132] Example 6: N-(4-ethoxy-2-(2-methylthiazole-5-yl)quinoline-6-yl)oxetane-3-carboxamide [ka] N-(4-ethoxy-2-(2-methylthiazole-5-yl)quinoline-6-yl)oxetane-3-carboxamide was prepared as an off-white solid (0.05 g, yield: 50%) using the same procedure as in Example 3. HPLC purity: 98.23%. LCMS(ESI+): C 19 H 20 N3O3S [M+H] + Calculated m / z value, 370; measured value, 370. 1 1H NMR (400 MHz, DMSO-d 6, δ):10.27(s,1H),8.53(s,1H),8.48(d,J=2.25 Hz,1H),7.88-7.93(m,1H),7.83(d,J=9.13 Hz,1H),7.53(s,1H),4.74(d,J=7.50 Hz,4H),4.43(q,J=7.00 Hz,2H),4.02(quin,J=7.50 Hz,1H),2.70(s,3H),1.53(t,J=7.00 Hz,3H).

[0133] Example 7: N-(4-ethoxy-2-(2-methoxythiazole-5-yl)quinoline-6-yl)oxetan-3-carboxamide [ka] [ka] Synthesis of 1.5-(4-ethoxy-6-nitroquinoline-2-yl)-2-methoxythiazole [ka] 5-(4-(2-methoxyethoxy)-6-nitroquinoline-2-yl)thiazole was prepared using the procedure for 5-(4-(2-methoxyethoxy)-6-nitroquinoline-2-yl)thiazole. The crude product was purified by grinding with diethyl ether (25 mL) and n-pentane (25 mL) to obtain the product as a pale yellow solid (0.16 g, yield: 76%). LCMS(ESI+):C 15 H 14 N3O4S [M+H] + m / z calculated value, 332; measured value, 332. 11H NMR (400 MHz, DMSO-d 6, δ):8.88(d,J=2.45 Hz,1H),8.42(dd,J=9.29,2.93 Hz,1H),8.39(s,1H),8.01(d,J=9.29 Hz,1H),7.72(s,1H),4.50(q,J=7.01 Hz,2H),4.12(s,3H),1.55(t,J=6.85 Hz,3H).

[0134] 2. Synthesis of 4-ethoxy-2-(2-methoxythiazole-5-yl)quinoline-6-amine [ka] Using the same procedure as for the production of 4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-amine, 4-ethoxy-2-(2-methoxythiazole-5-yl)quinoline-6-amine was produced as a viscous, pale yellow solid (0.11 g, 85%). LCMS(ESI+):C 15 H 16 N3O2S [M+H] + m / z calculated value, 302; measured value, 302. 1 1H NMR (400 MHz, DMSO-d 6, δ):7.98(s,1H),7.53(d,J=8.80 Hz,1H),7.28(s,1H),7.08(t,J=3.2 Hz,2H),5.56(br s,2H),4.32(q,J=7.2 Hz,2H),4.05(s,3H),1.47(t,J=7.2 Hz,3H).

[0135] 3. Synthesis of N-(4-ethoxy-2-(2-methoxythiazole-5-yl)quinoline-6-yl)oxetane-3-carboxamide [ka] N-(4-ethoxy-2-(2-methoxythiazole-5-yl)quinoline-6-yl)oxetane-3-carboxamide was prepared using the same procedure as for N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)oxetane-3-carboxamide). The crude product was purified by combiflash chromatography (1% MeOH / CH2Cl2) to obtain the product as an off-white solid (0.04 g, yield: 26%). HPLC purity: 97.09%. LCMS (ESI+): C 19 H 20 N3O4S [M+H] + The m / z calculated value is 386; found, 386. 1 1H NMR (400 MHz, DMSO-d 6, δ):10.24(s,1H),8.45(s,1H),8.14(s,1H),7.88(d,J=7.6 Hz,1H),7.78(d,J=9.2 Hz,1H),7.47(s,1H),4.71-4.74(m,4H),4.40(q,J=6.92 Hz,2H),4.08(s 3H),4.05-3.98(m,1H),1.51(t,J=6.94 Hz,3H).

[0136] Example 8: N-(2-(2-cyclopropylthiazole-5-yl)-4-ethoxyquinoline-6-yl)oxetane-3-carboxamide [ka] [ka] Synthesis of 1,2-Cyclopropyl-5-(tributylstannyl)thiazole [ka] To a stirred solution of DIPEA (0.7 mL, 4.80 mmol) in THF (5 mL), n-BuLi (2.5 M solution in hexane, 1.5 mL, 3.84 mmol) was added dropwise at -78°C for 5 minutes under an argon atmosphere, and the mixture was stirred for 40 minutes. To a stirred solution of 2-cyclopropylthiazole (0.4 g, 3.20 mmol) in anhydrous THF (5 mL), the freshly generated LDA solution was added dropwise at -78°C for 5 minutes, and the mixture was stirred at the same temperature for 40 minutes. This was then added at -78°C for 1 hour. Tributyltin chloride (0.9 mL, 3.2 mmol) was added dropwise at -78°C for 5 minutes, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was quenched with saturated ammonium chloride solution (10 mL) and extracted with ÃO (2 x 50 mL). The combined organic extract was dried over sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. The crude product obtained was purified by combiflash chromatography (100% heptane) to obtain 2-cyclopropyl-5-(tributylstannyl)thiazole (0.2 g, yield: 18%) as a colorless oil.

[0137] 2. Synthesis of 2-cyclopropyl-5-(4-ethoxy-6-nitroquinoline-2-yl)thiazole [ka] 2-Cyclopropyl-5-(4-ethoxy-6-nitroquinoline-2-yl)thiazole was prepared using the procedure for 5-(4-(2-methoxyethoxy)-6-nitroquinoline-2-yl)thiazole. The resulting compound was purified by combiflash chromatography (20% siRNA / heptane) to obtain the product as an off-white solid (0.1 g, yield: 48%). HPLC: 98.1%. 1 1H NMR (400 MHz, DMSO-d 6, δ):8.88(d,J=2.93 Hz,1H),8.67(s,1H),8.42(dd,J=9.29,2.45 Hz,1H),8.03(d,J=9.29 Hz,1H),7.74(s,1H),4.50(q,J=6.85 Hz,2H),1.55(t,J=7.09 Hz,3H),1.16-1.27(m,3H),1.02-1.11(m,2H).

[0138] 3. Synthesis of 2-(2-cyclopropylthiazole-5-yl)-4-ethoxyquinoline-6-amine [ka] 2-(2-cyclopropylthiazole-5-yl)-4-ethoxyquinoline-6-amine was prepared as a viscous, pale yellow solid (0.11 g, crude product) using the same procedure as for the production of 4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-amine. LCMS(ESI+):C 17 H 18 N3OS [M+H] + m / z calculated value, 312; measured value, 312.

[0139] 4. Synthesis of N-(2-(2-cyclopropylthiazole-5-yl)-4-ethoxyquinoline-6-yl)oxetane-3-carboxamide [ka] N-(2-(2-cyclopropylthiazole-5-yl)-4-ethoxyquinoline-6-yl)oxetane-3-carboxamide was prepared as an off-white solid (0.008 g, yield: 7%) using the same procedure as for N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)oxetane-3-carboxamide. HPLC purity: 96.44%. LCMS(ESI+):C 21 H 22 N3O3S [M+H] + m / z calculated value, 396; measured value, 396. 1 1H NMR (400 MHz, DMSO-d 6,δ):10.25(s,1H),8.44-8.50(m,2H),7.88-7.92(m,1H),7.77-7.84(m,1H),7.50(s,1H),4.75-4.71(m,4H),4.41(q,J=6.92 Hz,2H),4.06-3.96(m,1H),2.38-2.48(m,1H),1.51(t,J=6.94 Hz,3H),1.13-1.22(m,2H),0.99-1.07(m,2H).

[0140] Example 9: N-(4-(2-hydroxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)oxetane-3-carboxamide [ka] [ka] 1. Synthesis of 4-(2-(benzyloxy)ethoxy)-2-chloro-6-nitroquinoline [ka] 4-(2-(benzyloxy)ethoxy)-2-chloro-6-nitroquinoline was produced using the same procedure as for the production of 2-chloro-4-(2-methoxyethoxy)-6-nitroquinoline. The mixture was purified by combiflash chromatography (50-80% Â in heptane) to obtain 4-(2-(benzyloxy)ethoxy)-2-chloro-6-nitroquinoline (0.9 g, yield: 20%) as an off-white solid and 2-(2-(benzyloxy)ethoxy)-4-chloro-6-nitroquinoline (0.9 g, yield: 20%) as an off-white solid. Note: Isomers were confirmed by 2D NOESY. 4-(2-(benzyloxy)ethoxy)-2-chloro-6-nitroquinoline:LCMS(ESI+):C 18 H 16 ClN2O4[M+H] + m / z calculated value, 359; measured value, 359. 1 1H NMR (400 MHz, DMSO-d 6,δ):8.92(d,J=2.63 Hz,1H),8.51(dd,J=9.26,2.63 Hz,1H),8.09(d,J=9.26 Hz,1H),7.32-7.42(m,5H),7.24-7.31(m,1H),4.64(s,2H),4.55-4.61(m,2H),3.92-3.98(m,2H).

[0141] Synthesis of 2.5-(4-(2-(benzyloxy)ethoxy)-6-nitroquinoline-2-yl)thiazole [ka] 5-(4-(2-(benzyloxy)ethoxy)-6-nitroquinoline-2-yl)thiazole was prepared using the preparation procedure for 5-(4-(2-methoxyethoxy)-6-nitroquinoline-2-yl)thiazole. The resulting compound was purified by combiflash chromatography (1% MeOH in CH2Cl2) to obtain the product as a light brown solid (0.38 g, yield: 74%). LCMS(ESI+):C 21 H 18 N3O4S [M+H] + m / z calculated value, 408; measured value, 408. 1 1H NMR (400 MHz, DMSO-d 6, δ):9.29(s,1H),8.96(s,1H),8.92(d,J=2.45 Hz,1H),8.45(dd,J=9.29,2.93 Hz,1H),8.09(d,J=9.29 Hz,1H),7.32-7.42(m,5H),7.25-7.32(m,1H),4.67(s,4H),3.95-4.02(m,2H).

[0142] 3. Synthesis of 2-((6-nitro-2-(thiazole-5-yl)quinoline-4-yl)oxy)ethane-1-ol [ka] 5-(4-(2-(benzyloxy)ethoxy)-6-nitroquinoline-2-yl)thiazole (0.38 g, 0.13 mmol) was mixed with trifluoroacetic acid (1 mL) at 0°C. The reaction mixture was heated to 80°C and stirred for 16 hours. Next, volatile substances were removed under vacuum to obtain the crude product. The crude product 2-((6-nitro-2-(thiazole-5-yl)quinoline-4-yl)oxy)ethane-1-ol (pale brown semi-solid, 0.3 g) was proceeded to the next step without further purification. LCMS(ESI+):C 14 H 12 N3O4S [M+H] + m / z calculated value, 318; measured value, 318.

[0143] 4. Synthesis of 4.2-((6-amino-2-(thiazole-5-yl)quinoline-4-yl)oxy)ethane-1-ol [ka] 2-((6-amino-2-(thiazole-5-yl)quinoline-4-yl)oxy)ethane-1-ol was produced as a brown solid (0.22 g, crude product) using the procedure for producing 4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-amine. LCMS(ESI+):C 14 H 14 N3O2S [M+H] + m / z calculated value, 288; measured value, 288.

[0144] 5. Synthesis of N-(4-(2-hydroxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)oxetane-3-carboxamide [ka] After preparative HPLC purification, N-(4-(2-hydroxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)oxetane-3-carboxamide was prepared as an off-white solid (0.018 g, yield: 12%) using the same procedure as for the preparation of N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)oxetane-3-carboxamide. HPLC purity: 98.61%. LCMS(ESI+):C 18 H 18 N3O4S [M+H] + m / z calculated value, 372; measured value, 372. 1 1H NMR (400 MHz, DMSO-d 6, δ):10.31(s,1H),9.18(s,1H),8.82(s,1H),8.48(s,1H),7.83-8.02(m,2H),7.63(s,1H),5.04(t,J=5.14 Hz,1H),4.75-4.72(m,4H),4.41(br t,J=4.40 Hz,2H),4.01(p,J=7.34 Hz,1H),3.92(q,J=4.40 Hz,2H).

[0145] Example 10: 2,2,2-trifluoro-N-(4-(2-hydroxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)acetamide [ka] 1. Synthesis of 2,2,2-trifluoro-N-(4-(2-hydroxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)acetamide 2-((6-amino-2-(thiazole-5-yl)quinoline-4-yl)oxy)ethane-1-ol (50 mg, 0.13 mmol) was mixed with TFA (1 mL) at 0°C. The reaction mixture was heated to 80°C and stirred for 16 hours. Next, volatile substances were removed from the reaction mixture under vacuum, and the mixture was pulverized with acetonitrile (5 mL) and diethyl ether (5 mL). The mixture was dried under vacuum to obtain 2,2,2-trifluoro-N-(4-(2-hydroxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)acetamide as a light brown solid (0.02 g, yield: 40%). HPLC purity: 95.36%. LCMS(ESI+): C 16 H 13F3N3O3S [M+H] + m / z calculated value, 384; measured value, 384. 1 1H NMR (400 MHz, DMSO-d 6, δ):11.60(br s,1H),9.20(s,1H),8.85(s,1H),8.49(d,J=1.75 Hz,1H),7.97-8.05(m,1H),7.90-7.94(m,1H),7.66(s,1H),5.04(t,J=5.38 Hz,1H),4.43(t,J=4.75 Hz,2H),3.92(q,J=5.00 Hz,2H).

[0146] Example 11: N-(4-(2-methoxyethoxy)-2-(2-methylthiazole-5-yl)quinoline-6-yl)oxetane-3-carboxamide [ka] 1. Synthesis of N-(4-(2-methoxyethoxy)-2-(2-methylthiazole-5-yl)quinoline-6-yl)oxetane-3-carboxamide N-(4-(2-methoxyethoxy)-2-(2-methylthiazole-5-yl)quinoline-6-yl)oxetane-3-carboxamide was prepared in the same manner as in Example 1. HPLC purity: 98.56%. LCMS(ESI+): C 20 H 22 N3O4S [M+H] + m / z calculated value, 400; measured value, 400. 1HNMR(400 MHz,DMSO-d6,δ):10.29(s,1H),8.53(s,1H),8.43(s,1H),7.96(d,J=7.2 Hz,1H),7.83(d,J=9.1 Hz,1H),7.57(s,1H),4.73(d,J=7.5 Hz,4H),4.50(d,J=4.0 Hz,2H),4.10-3.92(m,1H),3.85(s,2H),3.41(s,3H),2.70(s,3H).

[0147] Example 12: N-(2-(2-chlorothiazol-5-yl)-4-ethoxyquinoline-6-yl)oxetane-3-carboxamide [ka] [ka] 1. Synthesis of 1,2-chloro-5-(4-ethoxy-6-nitroquinoline-2-yl)thiazole [ka] 2-Chloro-5-(4-ethoxy-6-nitroquinoline-2-yl)thiazole was produced as an off-white solid (0.21 g, yield: 37%) using the procedure for producing 5-(4-(2-methoxyethoxy)-6-nitroquinoline-2-yl)thiazole. 1 1H NMR (400 MHz, DMSO-d 6, δ):8.90(d,J=1.96 Hz,1H),8.80(s,1H),8.45(dd,J=9.29,2.45 Hz,1H),8.07(d,J=9.29 Hz,1H),7.83(s,1H),4.52(q,J=6.85 Hz,2H),0.87(br t,J=7.09 Hz,3H).

[0148] 2. Synthesis of 2-(2-chlorothiazol-5-yl)-4-ethoxyquinoline-6-amine [ka] To a stirred solution of 2-chloro-5-(4-ethoxy-6-nitroquinoline-2-yl)thiazole (0.26 g, 0.77 mmol) in EtOH:H2O (5:1, 12 mL), NH4Cl (0.41 g, 7.73 mmol) and Fe powder (0.34 g, 6.19 mmol) were added by RT. The reaction mixture was heated to 100 °C and stirred for 5 hours. Next, the reaction mixture was filtered through Celite, and the filtrate was concentrated under vacuum to obtain 2-(2-chlorothiazole-5-yl)-4-ethoxyquinoline-6-amine as a light brown solid (0.6 g, crude product). LCMS(ESI+):C 14 H 13 ClN3OS [M+H] + m / z calculated value, 306; measured value, 306.

[0149] 3. Synthesis of N-(2-(2-chlorothiazol-5-yl)-4-ethoxyquinoline-6-yl)oxetane-3-carboxamide [ka] N-(2-(2-chlorothiazole-5-yl)-4-ethoxyquinoline-6-yl)oxetane-3-carboxamide was prepared as an off-white solid (0.015 g, yield: 20%) using the same procedure as for the preparation of N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)oxetane-3-carboxamide. HPLC purity: 98.67%. LCMS(ESI+): C 18 H 17 ClN3O3S [M+H] + m / z calculated value, 390; measured value, 390. 1 1H NMR (400 MHz, DMSO-d 6, δ):10.30(s,1H),8.61(s,1H),8.51(d,J=2.25 Hz,1H),7.90-7.97(m,1H),7.85(d,J=9.76 Hz,1H),7.60(s,1H),4.76-4.72(m,4H),4.43(q,J=7.00 Hz,2H),4.05-4.01(m,1H),1.53(t,J=6.94 Hz,3H).

[0150] Example 13: 2-Hydroxy-N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)acetamide [ka] 1. Synthesis of 1,2-hydroxy-N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)acetamide [ka] To a stirred solution of 2-hydroxyacetic acid (0.05 g, 0.72 mmol, 1 equivalent), HATU (0.41 g, 1.17 mmol, 1.5 equivalents) was added and the mixture was stirred at RT for 10 minutes. 4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-amine (0.196 g, 0.65 mmol, 1 equivalent) was added, followed by DIPEA (0.25 mL, 1.84 mmol, 2 equivalents) at RT. The reaction mixture was stirred at RT for 16 hours. Next, the reaction mixture was diluted with water (50 mL) and extracted with 10% MeOH in DCM (2 x 50 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The resulting crude product was purified by preparative HPLC to obtain the title compound as an off-white solid (0.023 g, yield: 9%). HPLC purity: 98.74%. LCMS(ESI+):C 17 H 18 N3O4S [M+H] + m / z calculated value, 360; measured value, 360. 1 1H NMR (400 MHz, DMSO-d 6, δ):10.07(s,1H),9.18(s,1H),8.81(s,1H),8.58(d,J=2.25 Hz,1H),8.04(dd,J=9.13,2.38 Hz,1H),7.86(d,J=9.13 Hz,1H),7.63(s,1H),5.65(t,J=6.00 Hz,1H),4.53(dd,J=5.25,3.63 Hz,2H),4.06(d,J=6.13 Hz,2H),3.84-3.90(m,2H),3.42(s,3H).

[0151] Example 14: (S)-2-hydroxy-N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)propanamide [ka] 1. Synthesis of (S)-2-hydroxy-N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)propanamide (S)-2-hydroxy-N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)propanamide was prepared as a white solid (0.047 g, yield: 16%) using the same procedure as in Example 13. HPLC purity: 97.46%. LCMS(ESI+):C 18 H 20 N3O4S [M+H] + m / z calculated value, 374; measured value, 374. 1 1H NMR (400 MHz, DMSO-d 6, δ):10.03(s,1H),9.18(s,1H),8.80(s,1H),8.60(d,J=2.38 Hz,1H),8.03(dd,J=9.07,2.44 Hz,1H),7.85(d,J=9.13 Hz,1H),7.63(s,1H),5.73(d,J=5.25 Hz,1H),4.52(dd,J=5.25,3.63 Hz,2H),4.15-4.25(m,1H),3.78-3.92(m,2H),3.41(s,3H),1.35(d,J=6.75 Hz,3H).

[0152] Example 15: (R)-2-hydroxy-N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)propanamide [ka] 1. Synthesis of (R)-2-hydroxy-N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)propanamide Using the same procedure as in Example 13, (R)-2-hydroxy-N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)propanamide was prepared as a white solid (0.03 g, yield: 24%). HPLC purity: 97.62%. LCMS(ESI+): C 18 H 20 N3O4S [M+H] + m / z calculated value, 374; measured value, 374. 1 1H NMR (400 MHz, DMSO-d 6,δ):10.06(s,1H),9.18(s,1H),8.80(s,1H),8.60(d,J=1.47 Hz,1H),8.03(dd,J=9.29,1.96 Hz,1H),7.85(d,J=8.80 Hz,1H),7.63(s,1H),5.76(br s,1H),4.52(t,J=4.40 Hz,3H),4.21(br s,1H),3.87(br t,J=3.91 Hz,2H),3.41(s,2H),1.34(d,J=6.36 Hz,3H).

[0153] Example 16: cis-3-hydroxy-N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)cyclobutan-1-carboxamide [ka] 1. Synthesis of cis-3-hydroxy-N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)cyclobutan-1-carboxamide Using the same procedure as in Example 13, cis-3-hydroxy-N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)cyclobutan-1-carboxamide was prepared as an off-white solid (0.03 g, yield: 23%). HPLC purity: 97.23%. LCMS(ESI+): C 20 H 22 N3O4S [M+H] + Calculated m / z value, 400; measured value, 400. 1 1H NMR (400 MHz, DMSO-d 6, δ):10.17(s,1H),9.17(s,1H),8.79(s,1H),8.44(d,J=2.13 Hz,1H),7.95(dd,J=9.07,2.31 Hz,1H),7.84(d,J=9.13 Hz,1H),7.62(s,1H),5.16(d,J=7.00 Hz,1H),4.42-4.58(m,2H),3.96-4.07(m,1H),3.86(dd,J=5.13,3.63 Hz,2H),3.41(s,3H),2.59-2.73(m,1H),2.31-2.44(m,2H),2.01-2.14(m,2H).

[0154] Example 17: Trans-3-hydroxy-N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)cyclobutan-1-carboxamide [ka] 1. Synthesis of trans-3-hydroxy-N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)cyclobutan-1-carboxamide Using the same procedure as in Example 13, trans-3-hydroxy-N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)cyclobutan-1-carboxamide was prepared as an off-white solid (0.03 g, yield: 25%). HPLC purity: 99.20%. LCMS(ESI+): C 20 H 22 N3O4S [M+H] + Calculated m / z value, 400; measured value, 400. 1 1H NMR (400 MHz, DMSO-d 6, δ):10.17(s,1H),9.17(s,1H),8.79(s,1H),8.45(d,J=2.25 Hz,1H),7.94-7.92(m,1H),7.85-7.82(m,1H),7.62(s,1H),5.10(d,J=6.4 Hz,1H),4.54-4.51(m,2H),4.39-4.29(m,1H),3.88-3.85(m,2H),3.41(s,3H),3.13-3.10(m,1H),2.47-2.41(m,2H),2.14-2.06(m,2H).

[0155] Example 18: N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)-2-methylcyclopropane-1-carboxamide [ka] 1. Synthesis of N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)-2-methylcyclopropane-1-carboxamide Using the same procedure as in Example 13, N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)-2-methylcyclopropane-1-carboxamide was prepared as an off-white solid (0.03 g, yield: 24%). HPLC purity: 99.20%. LCMS(ESI+): C 20 H22 N3O3S [M+H] + m / z calculated value, 384; measured value, 384. 1 1H NMR (400 MHz, DMSO-d 6, δ):10.49(s,1H),9.17(s,1H),8.79(s,1H),8.42(d,J=2.13 Hz,1H),7.94(dd,J=9.13,2.38 Hz,1H),7.79-7.88(m,1H),7.61(s,1H),4.48-4.55(m,2H),3.83-3.97(m ,2H),3.40(s,3H),1.56-1.60(m,1H),1.21-1.36(m,1H),1.12(d,J=6.00 Hz,3H),1.04-1.09(m,1H),0.64-0.74(m,1H).

[0156] Example 19: Trans-2-cyano-N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)cyclopropane-1-carboxamide [ka] 1. Synthesis of trans-2-cyano-N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)cyclopropane-1-carboxamide Trans-2-cyano-N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)cyclopropane-1-carboxamide was produced as an off-white solid (0.095 g, yield: 50%) using the same procedure as in Example 13 and trans-2-cyanocyclopropane-1-carboxylic acid as a starting material. HPLC purity: 99.20%. LCMS(ESI+): C 20 H 19 N4O3S [M+H] + m / z calculated value, 395; measured value, 395. 1 1H NMR (400 MHz, DMSO-d 6,δ):10.88(s,1H),9.18(s,1H),8.80(s,1H),8.42(d,J=2.13 Hz,1H),7.93(t,J=2.25 Hz,1H),7.86-7.90(m,1H),7.64(s,1H),4.54-4.50(m,2H),3.78-3.91(m,2H),3.39(s,3H),2.53-2.56(m,1H),2.15- 2.18(m,1H),1.64-1.50(m,1H),1.38-1.51(m,1H).

[0157] Example 20: N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)-2-(trifluoromethyl)cyclopropane-1-carboxamide [ka] 1. Synthesis of N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)-2-(trifluoromethyl)cyclopropane-1-carboxamide Using the same procedure as in Example 13, N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)-2-(trifluoromethyl)cyclopropane-1-carboxamide was prepared as an off-white solid (0.04 g, yield: 27%). HPLC purity: 97.49%. LCMS(ESI+): C 20 H 19 F3N3O3S [M+H] + m / z calculated value, 438; measured value, 438. 1 1H NMR (400 MHz, DMSO-d 6, δ):10.83(s,1H),9.19(s,1H),8.81(s,1H),8.44(d,J=2.13 Hz,1H),7.91-7.96(m,1H),7.86-7.91(m,1H),7.65(s,1H),4.50-4.56(m, 2H),3.84-3.90(m,2H),3.40(s,3H),2.31-2.39(m,2H),1.29-1.42(m,2H).

[0158] Example 21: 2-Methoxy-N-(4-(2-Methoxyethoxy)-2-(Thiazol-5-yl)Quinoline-6-yl)Acetamide [ka] 1. Synthesis of 1,2-Methoxy-N-(4-(2-Methoxyethoxy)-2-(Thiazol-5-yl)quinoline-6-yl)acetamide Using the same procedure as in Example 13, 2-methoxy-N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)acetamide was prepared as a light brown solid (0.03 g, yield: 25%). HPLC purity: 99.78%. LCMS(ESI+): C 18 H 20 N3O4S [M+H] + m / z calculated value, 374; measured value, 374. 1 1H NMR (400 MHz, DMSO-d 6, δ):10.17(s,1H),9.18(s,1H),8.81(s,1H),8.52(d,J=2.45 Hz,1H),8.02(dd,J=9.05,2.20 Hz,1H),7.86(d,J=9.29 Hz,1H),7.63(s,1H),4.47-4.56(m,2H),4.06(s,2H),3.84-3.88(m,2H),3.41(s,3H),3.40(s,3H).

[0159] Example 22: 2-Methoxy-N-(4-(2-Methoxyethoxy)-2-(Thiazol-5-yl)Quinoline-6-yl)Propanamide [ka] 1. Synthesis of 1,2-Methoxy-N-(4-(2-Methoxyethoxy)-2-(Thiazol-5-yl)quinoline-6-yl)propanamide Using the same procedure as in Example 13, 2-methoxy-N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)propanamide was prepared as an off-white solid (0.028 g, yield: 22%). HPLC purity: 98.44%. LCMS(ESI+): C 19 H 22 Calculated m / z value of N3O4S [M+H]+, 388; measured value, 388. 1 1H NMR (400 MHz, DMSO-d 6,δ):10.20(s,1H),9.18(s,1H),8.80(s,1H),8.55(d,J=2.25 Hz,1H),8.05(dd,J=9.13,2.38 Hz,1H),7.86(d,J=9.01 Hz,1H),7.63(s,1H),4.49-4.55(m,2H),3.93(q,J=6.71 Hz,1H),3.84-3.88(m,2H),3.41(s,3H),3.34(s,3H),1.36(d,J=6.75 Hz,3H).

[0160] Example 23: N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)tetrahydro-2H-pyran-3-carboxamide [ka] 1. Synthesis of N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)tetrahydro-2H-pyran-3-carboxamide Using the same procedure as in Example 13, N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)tetrahydro-2H-pyran-3-carboxamide was prepared as an off-white solid (0.036 g, yield: 26%). HPLC purity: 99.54%. LCMS(ESI+): C 21 H 24 m / z calculated value of N3O4S [M+H]+, 414; measured value, 414. 1 1H NMR (400 MHz, DMSO-d 6, δ):10.31(s,1H),9.18(s,1H),8.80(s,1H),8.45(d,J=2.25 Hz,1H),7.90-7.96(m,1H),7.83-7.88(m,1H),7.63(s,1H),4.52(dd,J=5.38,3.63 Hz,2H),3.98-4.05(m,1H),3.75-3.92(m,3H),3.42-3.44(m,1H),3.41(s,3H),3.32-3. 38(m,1H),2.65-2.74(m,1H),1.95-2.04(m,1H),1.70-1.82(m,1H),1.50-1.70(m,2H).

[0161] Example 24: 3-Methoxy-N-(4-(2-Methoxyethoxy)-2-(Thiazol-5-yl)Quinoline-6-yl)Propanamide [ka] 1. Synthesis of 3-Methoxy-N-(4-(2-Methoxyethoxy)-2-(Thiazol-5-yl)quinoline-6-yl)propanamide Using the same procedure as in Example 13, 3-methoxy-N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)propanamide was prepared as an off-white solid (0.04 g, yield: 31%). HPLC purity: 97.11%. LCMS(ESI+): C 19 H 22 Calculated m / z value of N3O4S [M+H]+, 388; measured value, 388. 1 1H NMR (400 MHz, DMSO-d 6, δ):10.31(s,1H),9.17(s,1H),8.79(s,1H),8.44(d,J=1.96 Hz,1H),7.94(dd,J=9.29,2.45 Hz,1H),7.85(d,J=8.31 Hz,1H),7.62(s,1H),4.49-4.54(m,2H),3.84-3.88(m,2H),3.66(t,J=6.11 Hz,2H),3.41(s,3H),3.26(s,3H),2.61(br t,J=6.11 Hz,2H).

[0162] Example 25: N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)-2-propoxypropanamide [ka] 1. Synthesis of N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)-2-propoxypropanamide Using the same procedure as in Example 13, N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)-2-propoxypropanamide was prepared as an off-white solid (0.025 g, yield: 12%). HPLC purity: 97.46%. LCMS(ESI+): C 21 H 26 Calculated m / z values ​​of N3O4S [M+H]+, 416; measured values, 416. 1 1H NMR (400 MHz, DMSO-d6, δ):9.18(s,1H)10.13(s,1H),8.80(s,1H),8.53(d,J=2.13 Hz,1H),8.02(dd,J=9.13,2.25 Hz,1H),7.86(d,J=9.13 Hz,1H),7.63(s,1H),4.53(t,J=4.25 Hz,2H),4.01(q,J=6.59 Hz,1H),3.86(t,J=4.25 Hz,2H),3.43-3.51(m,1H),3.41(s,3H),3.34-3.40(m,1H),1.52-1.66(m,2H),1.36(d,J=6.63 Hz, 3H), 0.90(t, J=7.38 Hz, 3H).

[0163] Example 26: 2-Ethoxy-N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)propanamide [ka] 1. Synthesis of 1,2-Ethoxy-N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)propanamide Using the same procedure as in Example 13, 2-ethoxy-N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)propanamide was produced as a light brown solid (0.03 g, yield: 22%). HPLC purity: 97.46%. LCMS(ESI+): C 20 H 24 Calculated m / z values ​​of N3O4S [M+H]+, 402; measured values, 402. 1 1H NMR (400 MHz, DMSO-d 6, δ):10.17(s,1 H),9.18(s,1 H),8.81(s,1 H),8.54(d,J=1.96 Hz,1 H),8.03(dd,J=9.05,1.96 Hz,1 H),7.86(d,J=9.05 Hz,1 H),7.64(s,1 H),4.52(t,J=3.91 Hz 2H),4.02(q,J=6.60 Hz,1 H),3.86(t,J=3.91 Hz 2H),3.43-3.62(m,2H),3.40(s,3H),1.35(d,J=6.60 Hz,3H),1.19(t,J=6.97 Hz,3H).

[0164] Example 27: 2,2-difluoro-3-hydroxy-N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)propanamide [ka] 1. Synthesis of 2,2-difluoro-3-hydroxy-N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)propanamide Using the same procedure as in Example 13, 2,2-difluoro-3-hydroxy-N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)propanamide was prepared as an off-white solid (0.025 g, yield: 15%). HPLC purity: 99.20%. LCMS(ESI+): C 18 H 18 Calculated m / z value of F2N3O4S [M+H]+, 410; measured value, 410. 1 1H NMR (400 MHz, DMSO-d 6, δ):10.88(br s,1H),9.20(s,1H),8.83(s,1H),8.59(d,J=1.47 Hz,1H),8.08(dd,J=9.05,1.71 Hz,1H),7.91(d,J=9.29 Hz,1H),7.67(s,1H),5.82(br s,1H),4.39-4.65(m,2H),3.94(br t,J=13.45 Hz,2H),3.84-3.88(m,2H),3.41(s,3H).

[0165] Example 28: 2-Cyano-N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)propanamide [ka] 1. Synthesis of 2-cyano-N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)propanamide Using the same procedure as in Example 13, 2-cyano-N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)propanamide was prepared as a pale yellow solid (0.16 g, yield: 44%). HPLC purity: 99.51%. LCMS(ESI+): C 19 H 19m / z calculated value of N4O3S [M+H]+, 383; measured value, 383. 1 1H NMR (400 MHz, DMSO-d 6, δ):10.73(s,1H),9.19(s,1H),8.82(s,1H),8.41(d,J=1.2 Hz,1H),7.96-7.88(m,2H),7.66(s,1H),4.53(t,J=3.6 Hz,2H),4.01(q,J=7.2 Hz,1H),3.87(t,J=4.4 Hz,2H),3.41(s,3H),1.56(d,J=7.6 Hz,3H).

[0166] Example 29: 1-Methoxy-N-(4-(2-Methoxyethoxy)-2-(Thiazol-5-yl)Quinoline-6-yl)Cyclopropane-1-Carboxamide [ka] 1. Synthesis of 1-Methoxy-N-(4-(2-Methoxyethoxy)-2-(Thiazol-5-yl)quinoline-6-yl)cyclopropane-1-carboxamide Using the same procedure as in Example 13, 1-methoxy-N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)cyclopropane-1-carboxamide was prepared as an off-white solid (0.035 g, yield: 26%). HPLC purity: 99.56%. LCMS(ESI+): C 20 H 22 Calculated m / z value of N3O4S [M+H]+, 400; measured value, 400. 1 1H NMR (400 MHz, DMSO-d 6, δ):10.31(s,1H),9.18(s,1H),8.81(s,1H),8.61(d,J=1.47 Hz,1H),8.09(dd,J=9.05,1.71 Hz,1H),7.85(d,J=9.29 Hz,1H),7.63(s,1H),4.52(t,J=4.40 Hz,2H),3.86(t,J=3.42 Hz,2H),3.40(s,3H),3.37(s,3H),1.25-1.20(m,2H),1.12-1.19(m,2H).

[0167] Example 30: 3,3-difluoro-N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)cyclobutan-1-carboxamide [ka] 1. Synthesis of 3,3-difluoro-N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)cyclobutan-1-carboxamide Using the same procedure as in Example 13, 3,3-difluoro-N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)cyclobutan-1-carboxamide was prepared as a white solid (0.03 g, yield: 21%). HPLC purity: 99.81%. LCMS(ESI+): C 20 H 20 Calculated m / z value of F2N3O3S [M+H]+, 420; measured value, 420. 1 1H NMR (400 MHz, DMSO-d 6, δ):10.44(s,1H),9.18(s,1H),8.80(s,1H),8.44(d,J=2.25 Hz,1H),7.92-7.99(m,1H),7.86-7.89(m,1H),7.63(s,1H),4.53(dd,J=5.32,3.69 Hz,2H),3.84-3.90(m,2H),3.41(s,3H),3.12-3.20(m,1H),2.75-2.92(m,4H).

[0168] Example 31: N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)bicyclo[1.1.1]pentan-1-carboxamide [ka] 1. Synthesis of N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)bicyclo[1.1.1]pentan-1-carboxamide Using the same procedure as in Example 13, N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)bicyclo[1.1.1]pentan-1-carboxamide was prepared as an off-white solid (0.03 g, yield: 23%). HPLC purity: 99.82%. LCMS(ESI+): C 21 H 22 m / z calculated value of N3O3S [M+H]+, 396; measured value, 396. 1 1H NMR (400 MHz, DMSO-d6, δ):9.88(s,1H),9.17(s,1H),8.80(s,1H),8.42(d,J=2.25 Hz,1H),8.07(dd,J=9.13,2.38 Hz,1H),7.85(d,J=9.13 Hz,1H),7.62(s,1H),4.49-4.56(m,2H),3.82-3.92(m,2H),3.40(s,3H),2.07-2.15(m,7H).

[0169] Example 32: 3-Methoxy-N-(4-(2-Methoxyethoxy)-2-(Thiazol-5-yl)Quinoline-6-yl)-2-methylpropanamide [ka] 1. Synthesis of 3-Methoxy-N-(4-(2-Methoxyethoxy)-2-(Thiazol-5-yl)quinoline-6-yl)-2-methylpropanamide Using the same procedure as in Example 13, 3-methoxy-N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)-2-methylpropanamide was prepared as an off-white solid (0.032 g, yield: 24%). HPLC purity: 98.94%. LCMS(ESI+): C 20 H 24 Calculated m / z values ​​of N3O4S [M+H]+, 402; measured values, 402. 1 1H NMR (400 MHz, CDCl) 3, δ)8.86(s,1H),8.50(s,1H),8.42(d,J=2.38 Hz,1H),8.39(s,1H),7.95(d,J=9.01 Hz,1H),7.79(dd,J=9.01,2.38 Hz,1H),7.13(s,1H),4.44(t,J=4.63 Hz,2H),3.93-3.97(m,2H),3.60(d,J=6.25 Hz,2H),3.53(s,3H),3.48(s,3H),2.69-2.80(m,1H),1.27(d,J=7.25 Hz,3H).

[0170] Example 33: cis-3-methoxy-N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)cyclobutan-1-carboxamide [ka] 1. Synthesis of cis-3-methoxy-N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)cyclobutan-1-carboxamide Using the same procedure as in Example 13, cis-3-methoxy-N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)cyclobutan-1-carboxamide was prepared as an off-white solid (0.04 g, yield: 29%). HPLC purity: 96.09%. LCMS(ESI+): C 21 H 24 N3O4S [M+H] + m / z calculated value, 414; measured value, 414. 1 1H NMR (400 MHz, DMSO-d 6, δ):10.20(s,1H),9.15(s,1H),8.77(s,1H),8.42(s,1H),7.93-7.93(m,1H),7.85(d,J=8.80 Hz,1H),7.60(s,1H),4.46-4.56(m,2H),3.77-3.86(m,3H),3.39(s,3H) ,3.13(s,3H),2.72-2.79(m,1H),2.39-2.49(m,2H),2.08-2.03(m,2H).

[0171] Example 34: Trans-3-methoxy-N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)cyclobutan-1-carboxamide [ka] 1. Synthesis of trans-3-methoxy-N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)cyclobutan-1-carboxamide Using the same procedure as in Example 13, trans-3-methoxy-N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)cyclobutan-1-carboxamide was prepared as a pale yellow solid (0.04 g, yield: 29%). HPLC purity: 98.63%. LCMS(ESI+): C 21 H 24 N3O4S [M+H] + m / z calculated value, 414; measured value, 414. 1 1H NMR (400 MHz, DMSO-d6, δ):10.23(s,1H),9.17(s,1H),8.80(s,1H),8.46(s,1H),7.93-7.98(m,1H),7.85(d,J=8.80 Hz,1H),7.62(s,1H),4.46-4.56(m,2H),3.99-4.10(m,1H),3.82-3.90(m,2H),3. 41(s,3H),3.16(s,3H),3.18-3.23(m,1H),2.39-2.48(m,2H),2.09-2.22(m,2H).

[0172] Example 35: N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)isoxazole-4-carboxamide [ka] 1. Synthesis of N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)isoxazole-4-carboxamide Using the same procedure as in Example 13, N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)isoxazole-4-carboxamide was prepared as an off-white solid (0.01 g, yield: 8%). HPLC purity: 97.10%. LCMS(ESI+): C 19 H 17 N4O4S [M+H] + m / z calculated value, 397; measured value, 397. 1 1H NMR (400 MHz, DMSO-d 6, δ):10.59(s,1H),9.64(s,1H),9.19(s,1H),9.14(s,1H),8.82(s,1H),8.47(d,J=2.38 Hz,1H),8.12(dd,J=9.19,2.44 Hz,1H),7.93(d,J=9.01 Hz,1H),7.66(s,1H),4.53-4.57(m2H),3.84-3.93(m,2H),3.41(s,3H).

[0173] Example 36: (S)-2-Methoxy-N-(4-(2-Methoxyethoxy)-2-(Thiazol-5-yl)Quinoline-6-yl)Propanamide [ka] 1. Synthesis of (S)-2-methoxy-N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)propanamide Using the same procedure as in Example 13, (S)-2-methoxy-N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)propanamide was prepared as a yellow solid (0.07 g, yield: 57%). HPLC purity: 99.82%. LCMS(ESI+): C 19 H 22 N3O4S [M+H] + m / z calculated value, 388; measured value, 388. 1 1H NMR (400 MHz, DMSO-d 6, δ):10.20(s,1H),9.18(s,1H),8.80(s,1H),8.55(d,J=1.96 Hz,1H),8.05(dd,J=9.29,2.45 Hz,1H),7.86(d,J=8.80 Hz,1H),7.63(s,1H),4.50-4.56(m,2H),3.93(q,J=6.68 Hz,1H),3.85-3.89(m,2H),3.41(s,3H),3.34(s,3H),1.36(d,J=6.85 Hz,3H).

[0174] Example 37: (R)-2-Methoxy-N-(4-(2-Methoxyethoxy)-2-(Thiazol-5-yl)Quinoline-6-yl)Propanamide [ka] 1. Synthesis of (R)-2-methoxy-N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)propanamide Using the same procedure as in Example 13, (R)-2-methoxy-N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)propanamide was prepared as a pale yellow solid (0.07 g, yield: 55%). HPLC purity: 99.82%. LCMS(ESI+): C 19 H 22 N3O4S [M+H] + m / z calculated value, 388; measured value, 388. 1 1H NMR (400 MHz, DMSO-d 6,δ):10.20(s,1H),9.18(s,1H),8.80(s,1H),8.55(d,J=2.45 Hz,1H),8.05(dd,J=9.05,2.20 Hz,1H),7.86(d,J=8.80 Hz,1H),7.63(s,1H),4.50-4.56(m,2H),3.93(q,J=6.68 Hz,1H),3.85-3.89(m,2H),3.41(s,3H),3.34(s,3H),1.36(d,J=6.85 Hz,3H).

[0175] Example 38: N-(4-((1-methoxypropan-2-yl)oxy)-2-(thiazole-5-yl)quinoline-6-yl)oxetane-3-carboxamide [ka] [ka] 1. Synthesis of 1-(2-amino-5-nitrophenyl)ethane-1-one [ka] A mixture of 1-(2-fluoro-5-nitrophenyl)ethane-1-one (28 g, 152.88 mmol) and NH4OH (25%, 230 mL) was heated in an autoclave at 100°C and stirred for 8 hours. The reaction mixture was then filtered, washed with ice-cold water (100 mL), and dried under vacuum. The crude product was pulverized with acetonitrile (100 mL) and dried under vacuum to obtain 1-(2-amino-5-nitrophenyl)ethane-1-one (17 g, yield: 75%) as a yellow solid. 1 1H NMR (400 MHz, DMSO-d 6, δ):8.63(d,J=2.45 Hz,1H),8.45(brs,2H),8.09(dd,J=9.29,2.45 Hz,1H),6.88(d,J=9.29 Hz,1H),2.62(s,3H).

[0176] 2. Synthesis of N-(2-acetyl-4-nitrophenyl)thiazole-5-carboxamide [ka] A mixture of 1-(2-amino-5-nitrophenyl)ethane-1-one (19.53 g, 108.40 mmol) and thiazole-5-carboxylic acid (14 g, 108.40 mmol) was mixed with POCl3 (200 mL) and heated at 100°C for 1 hour. The reaction mixture was then cooled to RT and quenched with ice water (200 mL). The resulting solid was filtered and dried under vacuum. The crude product was pulverized with diethyl ether (200 mL) and dried under vacuum to obtain N-(2-acetyl-4-nitrophenyl)thiazole-5-carboxamide (22 g, yield: 70%) as a yellow solid. LCMS(ESI+):C 12 H 10 N3O4S [M+H] + m / z calculated value, 292; measured value, 292. 1 1H NMR (400 MHz, DMSO-d 6, δ):12.39(s,1H),9.43(s,1H),8.79(br d,J=1.96 Hz,1H),8.48-8.65(m,3H),2.78(s,3H).

[0177] 3. Synthesis of 6-nitro-2-(thiazole-5-yl)quinoline-4-ol [ka] To a stirred solution of N-(2-acetyl-4-nitrophenyl)thiazole-5-carboxamide (11 g, 37.80 mmol) in t-butanol (110 mL), t-BuOK (8.48 g, 75.60 mmol) was added by RT, and the reaction mixture was heated at 100 °C for 4 hours. Next, the reaction mixture was filtered, and the resulting solid was mixed with 1N HCl (200 mL) and stirred for 10 minutes. The resulting solid was filtered and dried under vacuum. The crude product was pulverized with acetonitrile (50 mL) and dried under vacuum to obtain 6-nitro-2-(thiazole-5-yl)quinoline-4-ol as a yellow solid (7.5 g, yield: 73%). LCMS(ESI+):C 12 H8N3O3S [M+H] + m / z calculated value, 274; measured value, 274. 1 1H NMR (400 MHz, DMSO-d 6,δ):12.74(br s,1H),9.35(s,1H),8.86(br s,1H),8.69(s,1H),8.39-8.54(m,1H),7.97(br d,J=9.29 Hz,1H),6.67(br s,1H).

[0178] 4. Synthesis of methyl 2-((6-nitro-2-(thiazole-5-yl)quinoline-4-yl)oxy)propanoate [ka] To a stirred solution of 6-nitro-2-(thiazole-5-yl)quinoline-4-ol (2.5 g, 9.15 mmol) in DMF (15 mL), K2CO3 (3.15 g, 22.89 mmol), KI (0.15 g, 0.91 mmol), and methyl 2-bromopropanoate (2.29 g, 13.71 mmol) were added RT. The reaction mixture was heated to 90°C and stirred for 16 hours. The reaction mixture was stirred RT for 16 hours. Next, the reaction mixture was poured into ice-cold water (100 mL), the resulting solid was filtered, washed with water (100 mL), and dried under vacuum. The crude product was pulverized with diethyl ether (25 mL) to obtain methyl 2-((6-nitro-2-(thiazole-5-yl)quinoline-4-yl)oxy)propanoate as a light brown solid (2.2 g, yield: 67%). LCMS(ESI+):C 16 H 14 N3O5S [M+H] + m / z calculated value, 360; measured value, 360. 1 1H NMR (400 MHz, DMSO-d 6, δ):9.30(s,1H),8.94(br d,J=4.89 Hz,2H),8.47(dd,J=9.29,1.96 Hz,1H),8.11(br d,J=9.29 Hz,1H),7.85(s,1H),5.78(q,J=6.85 Hz,1H),3.75(s,3H),1.77(br d,J=6.85 Hz,3H).

[0179] 5. Synthesis of 2-((6-nitro-2-(thiazole-5-yl)quinoline-4-yl)oxy)propan-1-ol [ka] To a stirred solution of methyl 2-((6-nitro-2-(thiazole-5-yl)quinoline-4-yl)oxy)propanoate (1.1 g, 30.06 mmol) in a MeOH:THF (1:1, 24 mL) solution, LiBH4 (2.0 M solution in THF, 9.1 mL, 18.36 mmol) was added dropwise at 0°C for 20 minutes. The reaction mixture was stirred at the same temperature for 6 hours. Next, the reaction mixture was quenched with saturated NH4Cl (50 mL). The aqueous layer was extracted with Âx (2 x 75 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain 2-((6-nitro-2-(thiazole-5-yl)quinoline-4-yl)oxy)propan-1-ol (0.38 g, yield: 30%) as a light brown solid. LCMS(ESI+):C 15 H 14 N3O4S [M+H] + m / z calculated value, 332; measured value, 332. 1 1H NMR (400 MHz, DMSO-d 6, δ):9.29(s,1H),8.97-9.08(m,2H),8.44(dd,J=9.29,2.45 Hz,1H),8.08(d,J=9.29 Hz,1H),7.88(s,1H),5.09-5.22(m,2H),3.75(br t,J=5.14 Hz,2H),1.41(d,J=5.87 Hz,3H).

[0180] Synthesis of 6.5-(4-((1-methoxypropan-2-yl)oxy)-6-nitroquinoline-2-yl)thiazole [ka] To a stirred solution of 2-((6-nitro-2-(thiazole-5-yl)quinoline-4-yl)oxy)propan-1-ol (0.38 g, 1.14 mmol) in THF (18 mL), NaH (60% suspension in mineral oil, 0.03 g, 1.25 mmol) was added at 0°C, and methyl iodide (0.08 mL, 1.25 mmol) was added at 0°C. The reaction mixture was stirred at RT for 16 hours. Next, the reaction mixture was quenched with saturated NH4Cl (50 mL). The aqueous layer was extracted with Âx (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain 5-(4-((1-methoxypropan-2-yl)oxy)-6-nitroquinoline-2-yl)thiazole (0.25 g, yield: 63%) as a brown solid. LCMS(ESI+):C 16 H 16 N3O4S [M+H] + m / z calculated value, 346; measured value, 346. 1 1H NMR (400 MHz, DMSO-d 6, δ):9.29(d,J=1.96 Hz,1H),8.99(d,J=3.91 Hz,1H),8.89(s,1H),8.40-8.49(m,1H),8.09(dd,J=9.29,5.87 Hz,1H),7.89 -7.86(m,1H),5.27-5.42(m,0.5H),4.35-4.56(m,1H),3.87-3.98(m,0.5H),3.66-3.79(m,1H),3.42-3.36(m,3H),1.30-1.46(m,3H).

[0181] 7. Synthesis of 4-((1-methoxypropan-2-yl)oxy)-2-(thiazole-5-yl)quinoline-6-amine [ka] 4-((1-methoxypropan-2-yl)oxy)-2-(thiazole-5-yl)quinoline-6-amine was prepared using the same procedure as for the preparation of 4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-amine. The crude product was purified by grinding with diethyl ether (25 mL) and n-pentane (25 mL) to obtain the title product as a brown solid (0.18 g, yield: 78%). LCMS(ESI+):C 16 H 18 N3O2S [M+H] + m / z calculated value, 316; measured value, 316. 1 1H NMR (400 MHz, DMSO-d 6, δ):9.08(s,1H),8.67(br s,1H),7.60(br dd,J=8.80,4.89 Hz,1H),7.45(br d,J=16.63 Hz,1H),7.11(br d,J=8.31 ​​Hz,1H),7.05(br d,J=11.25 Hz,1H),5.67(br d,J=12.72 Hz,1.6 H),5.16-5.14(m,0.4H),4.27(br d,J=3.91 Hz,1H),3.85-3.82(m,1H),3.62-3.66(m,1H),3.41- 3.35(m,3H),1.22-1.51(m,3H).

[0182] 8. Synthesis of N-(4-((1-methoxypropane-2-yl)oxy)-2-(thiazole-5-yl)quinoline-6-yl)oxetane-3-carboxamide [ka] N-(4-((1-methoxypropane-2-yl)oxy)-2-(thiazole-5-yl)quinoline-6-yl)oxetane-3-carboxamide was prepared as an off-white solid (0.18 g, yield: 81%) using the same procedure as for N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)oxetane-3-carboxamide. HPLC purity: 99.16%. LCMS(ESI+): C 20 H 22 N3O4S [M+H] +Calculated m / z value, 400; measured value, 400. 1 1H NMR (400 MHz, DMSO-d 6, δ):10.28(d,J=3.50 Hz,1H),9.17(d,J=1.25 Hz,1H),8.82(d,J=2.75 Hz,1H),8.51(d,J=2.25 Hz,0.5H),8.42(d,J=2.25 Hz,0.5H),7.91-7.99(m,1H),7.86(dd,J=8.75,5.13 Hz,1H),7.65(d,J=16.01 Hz,1H),5.17-5.30(m,1H),4.76-4.734(m,4H),4.29-4.41(m,1H),3.97-4.07(m,0.5H ),3.82-3.92(m,0.5H),3.63-3.74(m,1H),3.43(s,1.5H),3.36(s,1.5H),1.39(d,6.25 Hz,1.5H),1.33(d,6.25 Hz,1.5H).

[0183] Example 39: N-(4-((1-Methoxy-2-methylpropane-2-yl)oxy)-2-(thiazole-5-yl)quinoline-6-yl)oxetane-3-carboxamide [ka] [ka]

[0184] 1. Synthesis of methyl 2-methyl-2-((6-nitro-2-(thiazole-5-yl)quinoline-4-yl)oxy)propanoate [ka] Methyl 2-methyl-2-((6-nitro-2-(thiazole-5-yl)quinoline-4-yl)oxy)propanoate was prepared using the same procedure as for the preparation of methyl 2-((6-nitro-2-(thiazole-5-yl)quinoline-4-yl)oxy)propanoate. The resulting compound was purified by combiflash chromatography (1% MeOH in CH2Cl2) to obtain the title product as a pale yellow solid (0.8 g, yield: 23%). LCMS(ESI+):C 17 H 16N3O5S [M+H] + m / z calculated value, 374; measured value, 374. 1 1H NMR (400 MHz, DMSO-d 6, δ):9.30(s,1H),8.95(d,J=2.45 Hz,1H),8.76(s,1H),8.48(dd,J=9.05,2.69 Hz,1H),8.12(d,J=9.29 Hz,1H),7.21(s,1H),3.77(s,3H),1.88(s,6H).

[0185] 2. Synthesis of 2-methyl-2-((6-nitro-2-(thiazole-5-yl)quinoline-4-yl)oxy)propan-1-ol [ka] To a stirred solution of methyl 2-methyl-2-((6-nitro-2-(thiazole-5-yl)quinoline-4-yl)oxy)propanoate (0.5 g, 1.33 mmol) in THF (1, 15 mL), LAH (1.0 M solution in THF, 2.0 mL, 2.00 mmol) was added dropwise at 0°C for 15 minutes, and the reaction mixture was heated to RT for 2 hours. Next, the reaction mixture was quenched with saturated NH4Cl (50 mL). The aqueous layer was extracted with ELISA (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the crude product. The crude product was purified by combiflash chromatography (80% siRNA in heptane) to obtain 2-methyl-2-((6-nitro-2-(thiazole-5-yl)quinoline-4-yl)oxy)propan-1-ol (0.14 g, yield: 30%) as a light brown solid. LCMS(ESI+):C 16 H 16 N3O4S [M+H] + m / z calculated value, 346; measured value, 346. 1 1H NMR (400 MHz, DMSO-d 6,δ):9.29(s,1 H),9.09(d,J=2.45 Hz,1H),9.01(s,1H),8.45(dd,J=9.05,2.20 Hz,1H),8.09(d,J=9.29 Hz,1H),7.85(s,1H),5.07(s,1H),4.23(s,2H),1.36(s,6H).

[0186] 3. Synthesis of 3.5-(4-((1-methoxy-2-methylpropane-2-yl)oxy)-6-nitroquinoline-2-yl)thiazole [ka] 5-(4-((1-methoxy-2-methylpropane-2-yl)oxy)-6-nitroquinoline-2-yl)thiazole was prepared using the same procedure as for the preparation of 5-(4-((1-methoxypropane-2-yl)oxy)-6-nitroquinoline-2-yl)thiazole. The resulting compound was purified by combiflash chromatography (1% MeOH in CH2Cl2) to obtain the title product as a brown solid (0.17 g, yield: 54%). LCMS(ESI+):C 17 H 18 N3O4S [M+H] + m / z calculated value, 360; measured value, 360. 1 1H NMR (400 MHz, DMSO-d 6, δ):9.30(s,1H),9.00(s,1H),8.90(d,J=2.45 Hz,1H),8.46(dd,J=9.05,2.69 Hz,1H),8.10(d,J=9.29 Hz,1H),7.90(s,1H),4.37(s,2H),3.26(s,3H),1.37(s,6H).

[0187] 4. Synthesis of 4-((1-Methoxy-2-methylpropane-2-yl)oxy)-2-(thiazole-5-yl)quinoline-6-amine [ka] 4-((1-methoxy-2-methylpropane-2-yl)oxy)-2-(thiazole-5-yl)quinoline-6-amine was prepared using the same procedure as for the preparation of 4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-amine. The crude compound was pulverized with diethyl ether to obtain the title compound as a brown solid (0.15 g, yield: 95%). LCMS(ESI+):C 17 H 20 N3O2S [M+H] + Calculated m / z value, 330; measured value, 330. 1 1H NMR (400 MHz, DMSO-d 6, δ):9.09(br s,1H),8.45-8.30(br s,1H),8.36(br s,2H),7.60(br d,J=8.80 Hz,1H),7.39-7.54(m,1H),7.06-7.15(m,2H),4.17(s,2H),3.24(s,3H),1.35(s,6H).

[0188] 5. Synthesis of N-(4-((1-methoxy-2-methylpropane-2-yl)oxy)-2-(thiazole-5-yl)quinoline-6-yl)oxetane-3-carboxamide [ka] N-(4-((1-methoxy-2-methylpropane-2-yl)oxy)-2-(thiazole-5-yl)quinoline-6-yl)oxetane-3-carboxamide was prepared as an off-white solid (0.18 g, yield: 82%) using the same procedure as for N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)oxetane-3-carboxamide. LCMS(ESI+):C 21 H 24 N3O4S [M+H] + m / z calculated value: 414; measured value: 414. HPLC purity: 99.70%. 1 1H NMR (400 MHz, DMSO-d 6,δ):10.29(s,1H),9.17(s,1H),8.82(s,1H),8.51(d,J=1.96 Hz,1H),7.99(dd,J=9.29,1.96 Hz,1H),7.87(d,J=9.29 Hz,1H),7.65(s,1H),4.76-4.72(m,4H),4.26(s,2H),3.07-4.07(m,1H),3.26(s,3H),2.50(s,6H).

[0189] Example 40: N-(2-(4-cyclopropyl-1H-imidazole-1-yl)-4-(2-methoxyethoxy)quinoline-6-yl)oxetane-3-carboxamide [ka] [ka] 1. Synthesis of 2-(4-cyclopropyl-1H-imidazole-1-yl)-4-(2-methoxyethoxy)-6-nitroquinoline [ka] 2-(4-cyclopropyl-1H-imidazole-1-yl)-4-(2-methoxyethoxy)-6-nitroquinoline was produced using the same procedure as for the production of 4-ethoxy-2-(4-methyl-1H-imidazole-1-yl)-6-nitroquinoline. The title product was obtained as a brown solid (0.22 g, yield: 58%). LCMS(ESI+):C 18 H 19 N4O4[M+H] + m / z calculated value, 355; measured value, 355. 1 1H NMR (400 MHz, DMSO-d 6, δ):8.87(br s,1H),8.65(s,1H),8.47(br d,J=9.39 Hz,1H),8.03(br d,J=9.00 Hz,1H),7.93(s,1H),7.55(s,1H),4.60(br s,2H),3.90(br s,2H),3.40(s,3H),1.84-1.99(m,1H),0.83-0.91(m,2H),0.76-0.74(m,2H).

[0190] 2. Synthesis of 2-(4-cyclopropyl-1H-imidazole-1-yl)-4-(2-methoxyethoxy)quinoline-6-amine [ka] 2-(4-cyclopropyl-1H-imidazole-1-yl)-4-(2-methoxyethoxy)quinoline-6-amine was produced as a brown solid (5g, yield: 78%) using the same procedure as for the production of 4-ethoxy-2-(4-methyl-1H-imidazole-1-yl)quinoline-6-amine. LCMS(ESI+):C 18 H 21 N4O2[M+H] + m / z calculated value, 325; measured value, 325. 1 1H NMR (400 MHz, DMSO-d 6, δ):8.42(s,1H),7.76(s,1H),7.57(d,J=8.80 Hz,1H),7.16(s,1H),7.12(br dd,J=9.05,2.20 Hz,1H),7.06(br d,J=1.96 Hz,1H),5.61(s,2H),4.44(t,J=4.89 Hz,2H),3.83(br t,J=4.40 Hz,2H),3.38(s,3H),1.83-1.92(m,1H),0.78-0.87(m,2H),0.69-0.73(m,2H).

[0191] 3. Synthesis of N-(2-(4-cyclopropyl-1H-imidazole-1-yl)-4-(2-methoxyethoxy)quinoline-6-yl)oxetane-3-carboxamide [ka] N-(2-(4-cyclopropyl-1H-imidazole-1-yl)-4-(2-methoxyethoxy)quinoline-6-yl)oxetane-3-carboxamide was prepared as a white solid (0.05 g, yield: 24%) using the same procedure as for N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)oxetane-3-carboxamide. HPLC purity: 99.82%. LCMS(ESI+):C 22 H25 N4O4[M+H] + m / z calculated value, 409; measured value, 409. 1 1H NMR (400 MHz, DMSO-d 6, δ):10.28(s,1H),8.53(d,J=1.25 Hz,1H),8.44(d,J=2.25 Hz,1H),7.98(dd,J=9.01,2.38 Hz,1H),7.79-7.88(m,2H),7.34(s,1H),4.75-4.71(m,4H),4.49-4.56(m,2H),3.96-4.07(m, 1H),3.87-3.84(m,2H),3.41(s,3H),1.85-1.95(m,1H),0.80-0.88(m,2H),0.69-0.77(m,2H).

[0192] Example 41: N-(4-(2-methoxyethoxy)-2-(4-methyl-1H-imidazole-1-yl)quinoline-6-yl)oxetane-3-carboxamide [ka] N-(4-(2-methoxyethoxy)-2-(4-methyl-1H-imidazole-1-yl)quinoline-6-yl)oxetane-3-carboxamide was prepared as an off-white solid (0.06 g, yield: 26%) according to the procedure of Example 40. HPLC purity: 97.16%. LCMS(ESI+): C 20 H 23 N4O4[M+H] + m / z calculated value, 383; measured value, 383. 1 1H NMR (400 MHz, DMSO-d 6, δ):10.29(s,1H),8.59(s,1H),8.45(d,J=2.38 Hz,1H),7.99(dd,J=9.07,2.44 Hz,1H),7.80-7.87(m,2H),7.37(s,1H),4.74(d,J=7.50 Hz,4H),4.50-4.58(m,2H),3.98-4.05(m,1H),3.86(dd,J=5.13,3.63 Hz,2H),3.41(s,3H),2.21(s,3H).

[0193] Example 42: N-(4-(2-hydroxyethoxy)-2-(1H-imidazole-1-yl)quinoline-6-yl)oxetane-3-carboxamide [ka] [ka] 1. Synthesis of 4-(2-(benzyloxy)ethoxy)-2-(1H-imidazole-1-yl)-6-nitroquinoline [ka] 4-(2-(benzyloxy)ethoxy)-2-(1H-imidazole-1-yl)-6-nitroquinoline was produced using the same procedure as for the production of 4-ethoxy-2-(4-methyl-1H-imidazole-1-yl)-6-nitroquinoline. The crude product was purified by silica gel (100-200 mesh) flash column chromatography (2% MeOH in CH2Cl2) to obtain the title product as an off-white solid (0.3 g, yield: 61%). LCMS(ESI+):C 21 H 19 N4O4[M+H] + m / z calculated value, 391; measured value, 391.

[0194] 2. Synthesis of 2-((2-(1H-imidazole-1-yl)-6-nitroquinoline-4-yl)oxy)ethane-1-ol [ka] 2-((2-(1H-imidazole-1-yl)-6-nitroquinoline-4-yl)oxy)ethane-1-ol was produced using the same procedure as for the production of 2-((6-nitro-2-(thiazole-5-yl)quinoline-4-yl)oxy)ethane-1-ol. The product was obtained as a yellow solid (0.2 g, yield: 80%). LCMS(ESI+):C 14 H 13 N4O4[M+H] + m / z calculated value, 301; measured value, 301.

[0195] 3. Synthesis of 2-((6-amino-2-(1H-imidazole-1-yl)quinoline-4-yl)oxy)ethane-1-ol [ka] 2-((6-amino-2-(1H-imidazole-1-yl)quinoline-4-yl)oxy)ethane-1-ol was synthesized using the same procedure as for the production of 4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-amine. The desired product was obtained as a brown solid (0.22 g, crude product). LCMS(ESI+):C 14 H 15 N4O2[M+H] + m / z calculated value, 271; measured value, 271.

[0196] 4. Synthesis of N-(4-(2-hydroxyethoxy)-2-(1H-imidazole-1-yl)quinoline-6-yl)oxetane-3-carboxamide [ka] N-(4-(2-hydroxyethoxy)-2-(1H-imidazole-1-yl)quinoline-6-yl)oxetane-3-carboxamide was prepared as an off-white solid (0.08 g, yield: 5%) according to the procedure for N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)oxetane-3-carboxamide. HPLC purity: 97.71%. LCMS(ESI+): C 18 H 19 N4O4[M+H] + m / z calculated value, 355; measured value, 355. 1 1H NMR (400 MHz, DMSO-d 6, δ):10.30(s,1H),8.71(s,1H),8.49(d,J=1.47 Hz,1H),8.13(s,1H),7.98(dd,J=9.05,1.71 Hz,1H),7.85(d,J=8.80 Hz,1H),7.41(s,1H),7.15(s,1H),5.06(br t,J=4.89 Hz,1H),4.74-4.71(m,4H),4.44(br t,J=4.40 Hz,2 H),4.03-4.00(m,1H),3.92(q,J=4.40 Hz,2H).

[0197] Example 43: N-(4-cyclopropoxy-2-(4-methyl-1H-imidazole-1-yl)quinoline-6-yl)oxetane-3-carboxamide [ka] N-(4-cyclopropoxy-2-(4-methyl-1H-imidazole-1-yl)quinoline-6-yl)oxetane-3-carboxamide was prepared according to the procedure of Example 2. HPLC purity: 99.74%. LCMS(ESI+): C 20 H 21 N4O3[M+H] + m / z calculated value, 365; measured value, 365. 1 1H NMR (400 MHz, DMSO-d 6, δ):10.35(s,1H),8.65(s,1H),8.49(s,1H),7.95(s,1H),7.89(d,J=8.4 Hz,2H),7.63(s,1H),4.79(d,J=7.4 Hz,4H),4.39(s,1H),4.11-4.03(m,1H),2.28(s,3H),1.09(d,J=7.1 Hz,2H),0.94(brs,2H).

[0198] Example 44: N-(2-(4-chloro-1H-imidazole-1-yl)-4-ethoxyquinoline-6-yl)oxetane-3-carboxamide [ka] [ka] 1. Synthesis of 2-(4-chloro-1H-imidazole-1-yl)-4-ethoxy-6-nitroquinoline [ka] 2-(4-chloro-1H-imidazole-1-yl)-4-ethoxy-6-nitroquinoline was prepared using the same procedure as for the preparation of 4-ethoxy-2-(4-methyl-1H-imidazole-1-yl)-6-nitroquinoline. The crude compound was pulverized with diethyl ether and n-pentane to obtain the title compound as an off-white solid (0.21 g, yield: 65%). LCMS(ESI+):C 14 H 12 ClN4O3[M+H] +m / z calculated value, 319; measured value, 319. 1 1H NMR (400 MHz, DMSO-d 6, δ):8.89(d,J=2.45 Hz,1H),8.81(s,1H),8.50(dd,J=9.05,2.69 Hz,1H),8.34(s,1H),8.06(d,J=9.29 Hz,1H),7.59(s,1H),4.53(q,J=7.01 Hz,2H),1.56(t,J=6.85 Hz,3H).

[0199] 2. Synthesis of 2-(4-chloro-1H-imidazole-1-yl)-4-ethoxyquinoline-6-amine [ka] 2-(4-chloro-1H-imidazole-1-yl)-4-ethoxyquinoline-6-amine was prepared as a brown solid (0.15 g, yield: 79%) using the same procedure as for the production of 4-ethoxy-2-(4-methyl-1H-imidazole-1-yl)quinoline-6-amine. LCMS(ESI+):C 14 H 14 ClN4O [M+H] + m / z calculated value, 289; measured value, 289. 1 1H NMR (400 MHz, DMSO-d 6, δ):8.58(br s,1H),8.15(br s,1H),7.61(br d,J=7.83 Hz,1H),7.00-7.28(m,3H),5.84(br s,2H),4.37(q,J=7.83,Hz,2H),1.49(t,J=8.31 Hz,3H).

[0200] 3. Synthesis of N-(2-(4-chloro-1H-imidazole-1-yl)-4-ethoxyquinoline-6-yl)oxetane-3-carboxamide [ka] N-(2-(4-chloro-1H-imidazole-1-yl)-4-ethoxyquinoline-6-yl)oxetane-3-carboxamide was prepared as a white solid (0.08 g, yield: 41%) according to the procedure for N-(4-ethoxy-2-(4-methyl-1H-imidazole-1-yl)quinoline-6-yl)oxetane-3-carboxamide. HPLC purity: 96.86%. LCMS(ESI+): C 18 H 18 ClNN4O3[M+H] + m / z calculated value, 373; measured value, 373. 1 1H NMR (400 MHz, DMSO-d 6, δ):10.29(br s,1H),8.67(br s,1H),8.52(br s,1H),8.23(br s,1H),7.77-7.99(m,2H),7.38(br s,1H),4.73(d,J=5.38 Hz,4H),4.45(d,J=5.00 Hz,2H),4.03-3.99(m,1H),1.52(t,J=6.63 Hz,3H).

[0201] Example 45: N-(4-ethoxy-2-(4H-1,2,4-triazol-4-yl)quinoline-6-yl)oxetan-3-carboxamide [ka] [ka] Synthesis of 1,4-ethoxy-6-nitro-2-(4H-1,2,4-triazol-4-yl)quinoline [ka] 4-Ethoxy-6-nitro-2-(4H-1,2,4-triazole-4-yl)quinoline was prepared using the same procedure as for the preparation of 4-ethoxy-2-(4-methyl-1H-imidazole-1-yl)-6-nitroquinoline. The crude product was pulverized with diethyl ether and n-pentane to obtain the title compound as a white solid (0.2 g, yield: 69%). LCMS(ESI+):C 13 H 12 N5O3[M+H] + m / z calculated value, 286; measured value, 286.1 1H NMR (400 MHz, DMSO-d 6, δ):9.61(s,1H),8.96(br s,1H),8.55(br d,J=7.83 Hz,1H),8.43(s,1H),8.13(br d,J=9.29 Hz,1H),7.62(s,1H),4.57(t,J=6.36 Hz,2H),1.57(br t,J=6.85 Hz,3H).

[0202] 2. Synthesis of 2,4-ethoxy-2-(4H-1,2,4-triazol-4-yl)quinoline-6-amine [ka] 4-Ethoxy-2-(4H-1,2,4-triazole-4-yl)quinoline-6-amine was prepared using the same procedure as for the preparation of 4-ethoxy-2-(4-methyl-1H-imidazole-1-yl)quinoline-6-amine. The crude compound was pulverized with diethyl ether and n-pentane to obtain the title compound as a white solid (0.14 g, yield: 78%). LCMS(ESI+):C 13 H 14 N5O [M+H] + m / z calculated value, 256; measured value, 256. 1 1H NMR (400 MHz, DMSO-d 6, δ):9.35(s,1H),8.28(s,1H),7.64(d,J=8.80 Hz,1H),7.27(s,1H),7.18(dd,J=8.80,2.45 Hz,1H),7.11(d,J=2.45 Hz,1H),5.72(s,2H),4.36(q,J=6.85 Hz,2H),1.50(t,J=6.85 Hz,3H).

[0203] 3. Synthesis of N-(4-ethoxy-2-(4H-1,2,4-triazol-4-yl)quinoline-6-yl)oxetane-3-carboxamide [ka] N-(4-ethoxy-2-(4H-1,2,4-triazole-4-yl)quinoline-6-yl)oxetane-3-carboxamide was prepared as a white solid (0.058 g, yield: 26%) according to the procedure for N-(4-ethoxy-2-(4-methyl-1H-imidazole-1-yl)quinoline-6-yl)oxetane-3-carboxamide). HPLC purity: 97.70%. LCMS(ESI+): C 17 H 18 N5O3[M+H] + Calculated m / z value, 340; measured value, 340. 1 1H NMR (400 MHz, DMSO-d 6, δ):10.33(s,1H),9.46(s,1H),8.55(d,J=2.25 Hz,1H),8.34(s,1H),7.96-8.04(m,1H),7.88-7.93(m,1H),7.43(s,1H),4.76-4.72(m,4H),4.45(q,J=6.96 Hz,2H),4.04-4.01(m,1H),1.53(t,J=6.94 Hz,3H).

[0204] Example 46: N-(2-(4-cyano-1H-imidazole-1-yl)-4-ethoxyquinoline-6-yl)oxetane-3-carboxamide [ka] [ka] 1. Synthesis of 1-(4-ethoxy-6-nitroquinoline-2-yl)-1H-imidazole-4-carbonitrile [ka] 1-(4-ethoxy-6-nitroquinoline-2-yl)-1H-imidazole-4-carbonitrile was prepared using the same procedure as for the preparation of 4-ethoxy-2-(4-methyl-1H-imidazole-1-yl)-6-nitroquinoline. The crude product was pulverized with acetonitrile (25 mL) to obtain the title product as a yellow solid (0.19 g, yield: 61%). 1 1H NMR (400 MHz, DMSO-d 6,δ):8.89(d,J=2.45 Hz,1H),8.80(s,1H),8.49(dd,J=9.29,2.45 Hz,1H),8.39(s,1H),8.05(d,J=9.29 Hz,1H),7.58(s,1H),4.52(q,J=7.17 Hz,2H),1.56(t,J=6.85 Hz,3H).

[0205] 2. Synthesis of 1-(6-amino-4-ethoxyquinoline-2-yl)-1H-imidazole-4-carbonitrile [ka] 1-(6-amino-4-ethoxyquinoline-2-yl)-1H-imidazole-4-carbonitrile was prepared using the same procedure as for the preparation of 4-ethoxy-2-(4-methyl-1H-imidazole-1-yl)quinoline-6-amine. The title product was obtained as a yellow solid (0.1 g, yield: 58%). LC-MS(ESI+):C 15 H 14 N5O [M+H] + m / z calculated value, 280; measured value, 280. 1 1H NMR (400 MHz, DMSO-d 6, δ):8.97(s,1H),8.80(s,1H),7.62(br d,J=8.80 Hz,1H),7.29(s,1H),7.17(t,J=1.47 Hz,1H),7.09(d,J=1.47 Hz,1H),5.64-5.82(m,2H),4.38(q,J=7.01 Hz,2H),1.50(br t,J=6.85 Hz,3H).

[0206] 3. Synthesis of N-(2-(4-cyano-1H-imidazole-1-yl)-4-ethoxyquinoline-6-yl)oxetane-3-carboxamide [ka] N-(2-(4-cyano-1H-imidazole-1-yl)-4-ethoxyquinoline-6-yl)oxetane-3-carboxamide was prepared as a white solid (0.012 g, yield: 10%) according to the procedure for N-(4-ethoxy-2-(4-methyl-1H-imidazole-1-yl)quinoline-6-yl)oxetane-3-carboxamide. HPLC purity: 98.02%. LCMS(ESI+): C 19 H 18 N5O3[M+H] + m / z calculated value, 364; measured value, 364. 1 1H NMR (400 MHz, DMSO-d 6, δ):10.33(s,1H),9.06(d,J=1.25 Hz,1H),8.90(d,J=1.25 Hz,1H),8.56(d,J=2.25 Hz,1H),7.94-8.01(m,1H),7.89(d,J=9.01 Hz,1H),7.48(s,1H),4.76-4.72(m,4H),4.47(q,J=7.00 Hz,2H),4.04-4.01(m,1H),1.54(t,J=6.94 Hz,3H).

[0207] Example 47: N-(2-(4-(tert-butyl)-1H-imidazole-1-yl)-4-ethoxyquinoline-6-yl)oxetane-3-carboxamide [ka] [ka] 1. Synthesis of 2-(4-(tert-butyl)-1H-imidazole-1-yl)-4-ethoxy-6-nitroquinoline [ka] 2-(4-(tert-butyl)-1H-imidazole-1-yl)-4-ethoxy-6-nitroquinoline was synthesized using the same procedure as for the synthesis of 4-ethoxy-2-(4-methyl-1H-imidazole-1-yl)-6-nitroquinoline. The title product was obtained as a pale green solid (0.2 g, yield: 86%). LC-MS(ESI+):C 18 H 21 N4O3[M+H] +m / z calculated value, 341; measured value, 341.

[0208] 2. Synthesis of 2-(4-(tert-butyl)-1H-imidazole-1-yl)-4-ethoxyquinoline-6-amine [ka] 2-(4-(tert-butyl)-1H-imidazole-1-yl)-4-ethoxyquinoline-6-amine was synthesized using the same procedure as for the synthesis of 4-ethoxy-2-(4-methyl-1H-imidazole-1-yl)quinoline-6-amine. The title product was obtained as a pale green solid (0.15 g, yield: 82%). LC-MS(ESI+):C 18 H 23 N4O [M+H] + m / z calculated value, 311; measured value, 311. 1 1H NMR (400 MHz, DMSO-d 6, δ):8.47(s,1H),7.70(s,1H),7.58(d,J=8.80 Hz,1H),7.04-7.18(m,3H),5.58(s,2H),4.37(q,J=6.36 Hz,2H),1.49(br t,J=6.85 Hz,3H),1.28(s,9H).

[0209] 3. Synthesis of N-(2-(4-(tert-butyl)-1H-imidazole-1-yl)-4-ethoxyquinoline-6-yl)oxetane-3-carboxamide [ka] N-(2-(4-(tert-butyl)-1H-imidazole-1-yl)-4-ethoxyquinoline-6-yl)oxetane-3-carboxamide was prepared as an off-white solid (0.06 g, yield: 31%) following the procedure for N-(4-ethoxy-2-(4-methyl-1H-imidazole-1-yl)quinoline-6-yl)oxetane-3-carboxamide. HPLC purity: 97.48%. LCMS(ESI+): C 22 H 27 N4O3[M+H] +m / z calculated value, 395; measured value, 395. 1 1H NMR (400 MHz, DMSO-d 6, δ):10.26(s,1H),8.58(d,J=1.25 Hz,1H),8.48(d,J=2.25 Hz,1H),7.91-7.96(m,1H),7.83(d,J=9.01 Hz,1H),7.78(d,J=1.25 Hz,1H),7.34(s,1H),4.74-4.72(m,4H),4.46(q,J=6.92 Hz,2H),4.02-4.00(m,1H),1.53(t,J=7.00 Hz,3H),1.29(s,9H).

[0210] Example 48: 2-Cyano-N-(4-(((S)-1-methoxypropan-2-yl)oxy)-2-(thiazole-5-yl)quinoline-6-yl)propanamide [ka] [ka] Synthesis of 1,5-(4-chloro-6-nitroquinoline-2-yl)thiazole [ka] 5-(4-chloro-6-nitroquinoline-2-yl)thiazole was produced using the same procedure as for the production of 2,4-dichloro-6-nitroquinoline. The crude product was ground over Et2O to obtain the desired product as a brown solid (1 g; the crude product was used in the next step without purification). LCMS(ESI+):C 12 H7ClN3O2S [M+H] + m / z calculated value, 292; measured value, 292. 1 1H NMR (400 MHz, DMSO-d 6, δ):9.34(s,1H),9.00(s,1H),8.92(d,J=2.0 Hz,1H),8.71(s,1H),8.53(dd,J=9.0,2.2 Hz,1H),8.22(d,J=9.3 Hz,1H).

[0211] 2. Synthesis of (S)-5-(4-((1-methoxypropan-2-yl)oxy)-6-nitroquinoline-2-yl)thiazole [ka] To a stirred solution of 5-(4-chloro-6-nitroquinoline-2-yl)thiazole (0.65 g, 2.22 mmol) in DMF (18 mL), Cs2CO3 (1.81 g, 5.55 mmol), KI (0.36 g, 0.21 mmol), and (S)-1-methoxypropan-2-ol (0.5 g, 5.57 mmol) were added by RT. The reaction mixture was stirred in a sealed tube at 80°C for 16 hours. Next, the reaction mixture was diluted with ice-cold water (100 mL) and extracted with Â(2 x 50 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the title product (0.38 g, 49%) as a yellow solid. LCMS(ESI+):C 16 H 16 N3O4S [M+H] + m / z calculated value, 346; measured value, 346.

[0212] 3. Synthesis of (S)-4-((1-methoxypropan-2-yl)oxy)-2-(thiazole-5-yl)quinoline-6-amine [ka] (S)-4-((1-methoxypropan-2-yl)oxy)-2-(thiazole-5-yl)quinoline-6-amine was produced as a brown solid (0.32 g, yield: 92%) using the same procedure as for the production of 4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-amine. 1 1H NMR (400 MHz, DMSO-d 6, δ):9.07(br s,1H),8.66(s,1H),7.58(br d,J=8.3 Hz,1H),7.46(s,1H),7.16-6.98(m,3H),5.65(br s,1.6H),5.14-5.11(m,0.4H),3.62(br s,2H),3.33(br s,3H),1.34(br d,J=5.9 Hz,3H).

[0213] 4. Synthesis of 4.2-Cyano-N-(4-(((S)-1-methoxypropane-2-yl)oxy)-2-(thiazole-5-yl)quinoline-6-yl)propanamide [ka] 2-Cyano-N-(4-(((S)-1-methoxypropane-2-yl)oxy)-2-(thiazole-5-yl)quinoline-6-yl)propanamide was prepared as an off-white solid (0.08 g, yield: 42%) following the procedure for N-(4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-yl)oxetane-3-carboxamide. HPLC purity: 96.91%. LCMS(ESI+): C 20 H 21 N4O3S [M+H] + m / z calculated value, 397; measured value, 397. 1 1H NMR (400 MHz, DMSO-d 6, δ):10.72(s,1H),9.18(s,1H),8.84(s,1H),8.38(s,1H),7.99-7.83(m,3H),7.70(s,1H),5.31-5.21(m,1H),4.00(q,J=6.8 Hz,1H),3.75-3.62(m,1H),3.36(s,3H),1.55(br d,J=6.8 Hz,3H),1.39(br d,J=5.9 Hz,3H).

[0214] Example 49: 2-Cyano-N-(4-(((R)-1-methoxypropan-2-yl)oxy)-2-(thiazole-5-yl)quinoline-6-yl)propanamide [ka] [ka] 1. Synthesis of (R)-5-(4-((1-methoxypropan-2-yl)oxy)-6-nitroquinoline-2-yl)thiazole [ka] (R)-5-(4-((1-methoxypropan-2-yl)oxy)-6-nitroquinoline-2-yl)thiazole was produced using the same procedure as for the production of (S)-5-(4-((1-methoxypropan-2-yl)oxy)-6-nitroquinoline-2-yl)thiazole. The crude product was purified by silica gel column chromatography (20-30% Âxy / heptane) to obtain the desired product as a yellow solid (0.4 g, yield: 45%). LCMS(ESI+):C 16 H 16 N3O4S [M+H] + m / z calculated value, 346; measured value, 346. 1 1H NMR (400 MHz, DMSO-d 6, δ):9.30(s,1H),9.01(s,1H),8.90(br s,1H),8.45(br d,J=6.8 Hz,1H),8.09(br d,J=9.3 Hz,1H),7.93(s,1H),5.42-5.29(m,1H),3.83-3.64(m,2H),3.36(s,3H),1.43(br d,J=6.4 Hz,3H).

[0215] 2. Synthesis of (R)-4-((1-methoxypropan-2-yl)oxy)-2-(thiazole-5-yl)quinoline-6-amine [ka] (R)-4-((1-methoxypropan-2-yl)oxy)-2-(thiazole-5-yl)quinoline-6-amine was prepared as a yellow solid (0.45 g, the crude product was used in the next step without purification) using the procedure for the production of 4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-amine. LCMS(ESI+):C 16 H 18 N3O2S [M+H] + m / z calculated value, 316; measured value, 316.

[0216] 3. Synthesis of 2-cyano-N-(4-(((R)-1-methoxypropan-2-yl)oxy)-2-(thiazole-5-yl)quinoline-6-yl)propanamide [ka] 2-Cyano-N-(4-(((R)-1-methoxypropan-2-yl)oxy)-2-(thiazole-5-yl)quinoline-6-yl)propanamide was prepared as a pale yellow solid (0.02 g, yield: 10%) according to the procedure of Example 1. HPLC purity: 95.60%. LCMS(ESI+): C 20 H 21 N4O3S [M+H] + m / z calculated value, 397; measured value, 397. 1 1H NMR (400 MHz, DMSO-d 6, δ):10.71(br s,1H),9.19(s,1H),8.84(s,1H),8.41-8.37(m,1H),7.96-7.87(m,2H),7.70(s,1H),5.33-5.17(m,1H),4.01(q,J=7.2 Hz,1H),3.74-3.64(m,2H),3.37(s,3H),1.56(d,J=7.3 Hz,3H),1.40(d,J=6.3 Hz,3H).

[0217] Example 50: (S)-2-Methoxy-N-(4-(((S)-1-Methoxypropan-2-yl)oxy)-2-(thiazole-5-yl)quinoline-6-yl)propanamide [ka] (S)-2-methoxy-N-(4-(((S)-1-methoxypropan-2-yl)oxy)-2-(thiazole-5-yl)quinoline-6-yl)propanamide was prepared as an off-white solid (0.03 g, yield: 14%) according to the procedure of Example 1. HPLC purity: 99.91%. LCMS(ESI+): C 20 H 24 N3O4S [M+H] + m / z calculated value, 402; measured value, 402. 1 1H NMR (400 MHz, DMSO-d 6,δ):10.18(s,1H),9.17(s,1H),8.82(s,1H),8.52(d,J=2.3 Hz,1H),8.04(dd,J=9.1,2.4 Hz,1H),7.85(d,J=9.0 Hz,1H),7.67(s,1H),5.32-5.15(m,1H),3.93(q,J=6.7 Hz,1H),3.72-3.65(m,2H),3.36(s,3H),3.34(s,3H),1.39(d,J=6.1 Hz,3H),1.36(d,J=6.6 Hz,3H).

[0218] Example 51: (S)-2-Methoxy-N-(4-(((R)-1-Methoxypropan-2-yl)oxy)-2-(Thiazol-5-yl)Quinoline-6-yl)Propanamide [ka] (S)-2-methoxy-N-(4-(((R)-1-methoxypropan-2-yl)oxy)-2-(thiazole-5-yl)quinoline-6-yl)propanamide was prepared as a yellow solid (0.1 g, yield: 40%) according to the procedure of Example 1. HPLC purity: 98.45%. LCMS(ESI+): C 20 H 24 N3O4S [M+H] + m / z calculated value, 402; measured value, 402. 1 1H NMR (400 MHz, DMSO-d6)δ 1 1H NMR (400 MHz, DMSO-d 6, δ):10.19(s,1H),9.19(s,1H),8.83(s,1H),8.53(d,J=2.3 Hz,1H),8.06(dd,J=2.4,9.1 Hz,1H),7.86(d,J=9.1 Hz,1H),7.67(s,1H),5.33-5.19(m,1H),3.93(q,J=6.7 Hz,1H),3.76-3.61(m,2H),3.36(s,3H),3.34(s,3H),1.40(d,J=6.1 Hz,3H),1.36(d,J=6.6 Hz,3H).

[0219] Example 52: (R)-N-(4-((1-methoxypropan-2-yl)oxy)-2-(thiazole-5-yl)quinoline-6-yl)oxetane-3-carboxamide [ka] (R)-N-(4-((1-methoxypropan-2-yl)oxy)-2-(thiazole-5-yl)quinoline-6-yl)oxetane-3-carboxamide was prepared as a white solid (0.065 g, yield: 25%) according to the procedure of Example 1. HPLC purity: 98.81%. LCMS(ESI+): C 20 H 22 N3O4S [M+H] + Calculated m / z value, 400; measured value, 400. 1 1H NMR (400 MHz, DMSO-d 6, δ):10.27(s,1H),9.17(s,1H),8.82(s,1H),8.42(d,J=2.3 Hz,1H),7.96(dd,J=9.1,2.4 Hz,1H),7.86(d,J=9.1 Hz,1H),7.67(s,1H),5.32-5.17(m,1H),4.75-4.72(m,4H),4.04-4.00(m,1H),3.75-3.62(m,2H),3.36(s,3H),1.39(d,J=6.3 Hz,3H).

[0220] Example 53: N-(4-(2-methoxyethoxy)-2-(1-methyl-1H-pyrazole-4-yl)quinoline-6-yl)oxetane-3-carboxamide [ka] [ka] 1. Synthesis of 1-(2-amino-5-nitrophenyl)ethane-1-one [ka] A mixture of 1-(2-fluoro-5-nitrophenyl)ethane-1-one (28 g, 152.88 mmol) and NH4OH (25%, 230 mL) was heated in an autoclave at 100°C and stirred for 8 hours. The reaction mixture was then filtered, washed with ice-cold water (100 mL), and dried under vacuum. The crude product was pulverized with acetonitrile (100 mL) and dried under vacuum to obtain 1-(2-amino-5-nitrophenyl)ethane-1-one (17 g, 75%) as a yellow solid. 1 1H NMR (400 MHz, DMSO-d 6,δ):8.63(d,J=2.45 Hz,1H),8.45(br s,2H),8.09(dd,J=9.29,2.45 Hz,1H),6.88(d,J=9.29 Hz,1H),2.62(s,3H). 2. Synthesis of N-(2-acetyl-4-nitrophenyl)-1-methyl-1H-pyrazole-4-carboxamide [ka] A mixture of 1-methyl-1H-pyrazole-4-carboxylic acid (2.0 g, 15.87 mmol) in POCl3 (20 mL) was heated to 40°C. 1-(2-amino-5-nitrophenyl)ethane-1-one (2.5 g, 13.88 mmol) was added to this mixture at the same temperature. The reaction mixture was heated to 80°C and stirred for 6 hours. Next, the reaction mixture was poured into ice-cold water (100 mL). The precipitated solid was filtered, washed with water (50 mL) and acetonitrile (20 mL), and dried under vacuum to obtain N-(2-acetyl-4-nitrophenyl)-1-methyl-1H-pyrazole-4-carboxamide (2.5 g, yield: 62%) as a brown solid. LCMS(ESI+):C 13 H 13 N4O4[M+H] + m / z calculated value, 289; measured value, 289. 1 1H NMR (400 MHz, DMSO-d 6, δ):12.17(s,1H),8.79(d,J=2.4 Hz,1H),8.72(d,J=9.3 Hz,1H),8.50(dd,J=2.4,9.3 Hz,1H),8.40(s,1H),7.96(s,1H),3.94(s,3H),2.79(s,3H).

[0221] 3. Synthesis of 2-(1-methyl-1H-pyrazole-4-yl)-6-nitroquinoline-4-ol [ka] In a stirred solution of N-(2-acetyl-4-nitrophenyl)-1-methyl-1H-pyrazole-4-carboxamide (1.0 g, 3.46 mmol) in t-BuOH (10 mL), add RT.t BuOK (1.5 g, 6.9 mmol) was added, and the reaction mixture was heated to 80°C and stirred for 6 hours. Next, the reaction mixture was filtered, and the resulting solid was diluted with 10 mL of 1 N HCl aqueous solution. The precipitated solid was filtered, washed with water (10 mL) and acetonitrile (20 mL), and dried under vacuum to obtain 2-(1-methyl-1H-pyrazole-4-yl)-6-nitroquinoline-4-ol (0.8 g, yield: 86%) as a brown solid. LCMS(ESI+):C 13 H 11 N4O3[M+H] + m / z calculated value, 271; measured value, 271. 1 1H NMR (400 MHz, DMSO-d 6, δ):12.04(br s,1H),8.81(br d,J=2.4 Hz,1H),8.54(s,1H),8.44(br dd,J=9.3 Hz,2.4,1H),8.22(s,1H),7.93(br d,J=9.3 Hz,1H),6.55(s,1H),3.94(s,3H).

[0222] 4. Synthesis of 4-(2-methoxyethoxy)-2-(1-methyl-1H-pyrazole-4-yl)-6-nitroquinoline [ka] 4-(2-methoxyethoxy)-2-(1-methyl-1H-pyrazole-4-yl)-6-nitroquinoline was synthesized using the same procedure as for the production of 4-ethoxy-6-nitroquinoline-2-ol. The title compound was obtained as a brown solid (0.8 g, the crude product was used in the next step without purification). LCMS(ESI+):C 16 H 17 N4O4[M+H] + m / z calculated value, 329; measured value, 329. 1 1H NMR (400 MHz, DMSO-d 6,δ):8.87(br s,1H),8.58(br s,1H),8.40(br d,J=9.3 Hz,1H),8.26(br s,1H),8.00(br d,J=8.8 Hz,1H),7.95(br s,1H),4.55(br s,2H),3.99-3.91(m,2H),3.89(br s,3H),3.41(s,3H).

[0223] 5. Synthesis of 4-(2-methoxyethoxy)-2-(1-methyl-1H-pyrazole-4-yl)quinoline-6-amine [ka] 4-(2-methoxyethoxy)-2-(1-methyl-1H-pyrazole-4-yl)quinoline-6-amine was prepared as a brown solid (0.6 g, the crude product was used in the next step without purification) using the same procedure as for the production of 4-(2-methoxyethoxy)-2-(thiazole-5-yl)quinoline-6-amine. LCMS(ESI+):C 16 H 19 N4O2[M+H] + m / z calculated value, 299; measured value, 299. 1 1H NMR (400 MHz, DMSO-d 6, δ):8.87(br s,1H),8.58(br s,1H),8.40(br d,J=9.3 Hz,1H),8.26(br s,0.5H),8.00(br d,J=8.8 Hz,1H),7.95(br s,0.5H),7.51(br s,1H),4.55(br s,2H),4.00-3.92(m,2H),3.89(br s,2H),3.41(s,6H).

[0224] 6. Synthesis of N-(4-(2-methoxyethoxy)-2-(1-methyl-1H-pyrazole-4-yl)quinoline-6-yl)oxetane-3-carboxamide [ka] N-(4-(2-methoxyethoxy)-2-(1-methyl-1H-pyrazole-4-yl)quinoline-6-yl)oxetane-3-carboxamide was prepared as an off-white solid (0.02 g, yield: 85%) following the procedure for N-(4-ethoxy-2-(4-methyl-1H-imidazole-1-yl)quinoline-6-yl)oxetane-3-carboxamide). HPLC purity: 93.43%. LCMS(ESI+): C 20 H 23 N4O4[M+H] + m / z calculated value, 383; measured value, 383. 1 1H NMR (400 MHz, DMSO-d 6, δ):10.21(s,1H),8.43(s,1H),8.38(d,J=2.3 Hz,1H),8.13(s,1H),7.92(dd,J=9.1,2.4 Hz,1H),7.80(d,J=9.1 Hz,1H),7.28(s,1H),4.75-4.71(m,4H),4.46-4.44(m,2H),4.05-3.96(m,1H),3.91(s,3H),3.87-3.82(m,2H),3.40(s,3H).

[0225] Example 54: N-(4-ethoxy-8-methyl-2-(4-methyl-1H-imidazole-1-yl)quinoline-6-yl)oxetane-3-carboxamide [ka] [ka] 1. Synthesis of ethyl 3-((4-bromo-2-methylphenyl)amino)-3-oxopropanoate [ka] Et3N (6.5 mL, 38.00 mmol) was added under RT to a stirred solution of 4-bromo-2-methylaniline (6 g, 32.25 mmol) in CH2Cl2 (60 mL). Ethyl 3-chloro-3-oxopropanoate (3 mL, 96.00 mmol) was added at 0°C. The reaction mixture was heated under RT and stirred for 5 hours. Next, the reaction mixture was diluted with ice-cold water (200 mL) and extracted with CH2Cl2 (2 x 100 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain ethyl 3-((4-bromo-2-methylphenyl)amino)-3-oxopropanoate (4.3 g, crude product) as an off-white solid. This reaction was carried out on a 2 x 3 g scale. The crude product was proceeded to the next step without further purification.

[0226] 2. Synthesis of 3-((4-bromo-2-methylphenyl)amino)-3-oxopropanoic acid [ka] To a stirred solution of methyl 3-((4-bromo-2-methylphenyl)amino)-3-oxopropanoate (4.3 g, crude product) in MeOH (20 mL), NaOH (2.29 g, 57.30 mmol) dissolved in H2O (10 mL) was added by RT and stirred for 16 hours. Next, the reaction mixture was diluted with ice-cold water (100 mL) and washed with ELISA (2 x 50 mL). The pH of the aqueous layer was acidified to pH 5-6 with citric acid aqueous solution and extracted with ELISA (2 x 50 mL). The organic extract was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain 3-((4-bromo-2-methylphenyl)amino)-3-oxopropanoic acid (1.5 g, yield: 17% after two steps) as an off-white solid. 1 1H NMR (400 MHz, DMSO-d 6, δ):12.64(br d,J=7.34 Hz,1H),9.55(s,1H),7.42-7.46(m,2H),7.31-7.38(m,1H),3.40(s,2H),2.21(s,3H).

[0227] 3. Synthesis of 6-bromo-8-methylquinoline-2,4-diol [ka] A mixture of 3-((4-bromo-2-methylphenyl)amino)-3-oxopropanoic acid (3 g, 11.02 mmol) and PPA (7.4 g, 21.89 mmol) was heated to 130°C and stirred for 5 hours. The reaction mixture was then quenched with ice-cold water, the resulting solid was filtered, and dried under vacuum to obtain 6-bromo-8-methylquinoline-2,4-diol (2.3 g, yield: 82%) as an off-white solid. This reaction was carried out on a 2 x 1.5 g scale. LCMS(ESI+):C 10 H9BrNO2[M+H] + m / z calculated value, 254; measured value, 254. 1 1H NMR (400 MHz, DMSO-d 6, δ):11.51(br s,1H),10.50(br s,1H),7.74(s,1H),7.53(s,1H),5.78(s,1H),2.39(s,3H).

[0228] 4. Synthesis of 6-bromo-2,4-dichloro-8-methylquinoline [ka] 6-Bromo-2,4-dichloro-8-methylquinoline was produced as a brown solid (1.3 g, yield: 49%) using the same procedure as for the production of 2,4-dichloro-6-nitroquinoline. 1 1H NMR (400 MHz, DMSO-d 6, δ)8.19(s,1H),8.04(s,1H),8.00(s,1H),2.67(s,3H).

[0229] 5. Synthesis of 6-bromo-2-chloro-4-ethoxy-8-methylquinoline [ka] To a stirred solution of 6-bromo-2,4-dichloro-8-methylquinoline (2.3 g, 7.90 mmol) in EtOH (10 mL), NaOEt (1.6 g, 23.52 mmol) was added under RT. The reaction mixture was stirred under RT for 16 hours. Next, volatile substances were removed under vacuum. The crude product was diluted with NH4Cl (50 mL). The resulting solid was filtered and dried under vacuum to obtain 6-bromo-2-chloro-4-ethoxy-8-methylquinoline (1.3 g, yield: 61%) as an off-white solid. LCMS(ESI+):C 12 H 12 BrClNO [M+H] + Calculated m / z value, 300; measured value, 300. 1 1H NMR (400 MHz, DMSO-d 6, δ):8.08(d,J=1.96 Hz,1H),7.83(s,1H),7.15(s,1H),4.35(q,J=6.85 Hz,2H),2.61(s,3H),1.47(t,J=6.85 Hz,3H).

[0230] 6. Synthesis of 6-bromo-4-ethoxy-8-methyl-2-(4-methyl-1H-imidazole-1-yl)quinoline [ka] 6-bromo-4-ethoxy-8-methyl-2-(4-methyl-1H-imidazole-1-yl)quinoline was prepared as an off-white solid (0.6 g, crude product) using the same procedure as for the production of 4-ethoxy-2-(4-methyl-1H-imidazole-1-yl)-6-nitroquinoline. LCMS(ESI+):C 16 H 17 BrN3O [M+H] + m / z calculated value, 346; measured value, 346.

[0231] 6. Synthesis of N-(4-ethoxy-8-methyl-2-(4-methyl-1H-imidazole-1-yl)quinoline-6-yl)-1,1-diphenylmethanymine [ka] To a stirred solution of 6-bromo-4-ethoxy-8-methyl-2-(4-methyl-1H-imidazole-1-yl)quinoline (0.50 g, 1.44 mmol) in 1,4-dioxane (3 mL), diphenylmethaneimine and Cs2CO3 (1.17 g, 1.58 mmol) were added at RT, and the mixture was purged with N2 for 20 minutes. Xantphos (0.167 g, 0.28 mmol) was added, followed by Pd2(dba)3 (0.13 g, 0.14 mmol), and the mixture was further purged with N2 for 5 minutes. The reaction mixture was heated at 110 °C for 16 hours. The reaction mixture was then cooled to RT and diluted with ice-cold water (50 mL). The resulting solid was filtered and dried under vacuum. The aqueous layer was extracted with ELISA (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The crude product was purified by silica gel (100-200 mesh) flash column chromatography (50% ethyl phosphate in heptane) to obtain N-(4-ethoxy-8-methyl-2-(4-methyl-1H-imidazole-1-yl)quinoline-6-yl)-1,1-diphenylmethaneimine (0.4 g, yield: 62%) as a yellow solid. LCMS(ESI+):C 29 H 27 N4O [M+H] + m / z calculated value, 447; measured value, 447.

[0232] 7. Synthesis of 4-ethoxy-8-methyl-2-(4-methyl-1H-imidazole-1-yl)quinoline-6-amine hydrochloride [ka] A stirred solution of N-(4-ethoxy-8-methyl-2-(4-methyl-1H-imidazole-1-yl)quinoline-6-yl)-1,1-diphenylmethaneimine (0.10 g, 0.22 mmol) in THF (5 mL) was mixed with HCl:H2O (1:1, 2 mL) at 0°C. The reaction mixture was heated in RT and stirred for 2 hours. Next, volatile substances were removed under vacuum to obtain 4-ethoxy-8-methyl-2-(4-methyl-1H-imidazole-1-yl)quinoline-6-amine hydrochloride (0.09 g, crude product) as a light brown solid.

[0233] 8. Synthesis of N-(4-ethoxy-8-methyl-2-(4-methyl-1H-imidazole-1-yl)quinoline-6-yl)oxetane-3-carboxamide [ka] N-(4-ethoxy-8-methyl-2-(4-methyl-1H-imidazole-1-yl)quinoline-6-yl)oxetane-3-carboxamide was prepared as an off-white solid (0.012 g, yield: 5%) following the procedure for N-(4-ethoxy-2-(4-methyl-1H-imidazole-1-yl)quinoline-6-yl)oxetane-3-carboxamide). HPLC purity: 95.87%. LCMS(ESI+): C 20 H 23 N4O3[M+H] + m / z calculated value, 367; measured value, 367. 1 1H NMR (400 MHz, DMSO-d 6, δ):10.16(s,1H),8.61(d,J=1.13 Hz,1H),8.33(d,J=2.00 Hz,1H),7.85(d,J=1.13 Hz,1H),7.80(d,J=1.63 Hz,1H),7.32(s,1H),4.74-4.72(m,4H),4.43(q,J=7.00 Hz,2H),4.02-4.39(m,1H),2.65(s,3H),2.21(s,3H),1.51(t,J=7.00 Hz,3H).

[0234] AlphaLISA assay Human DRP1 (UniProtID: O00429.4, residues 1-699) and human MiD49 (UnitProtIS: Q96C03.1, residues 126-454) were cloned into the pET15b vector as N-terminal His-tagged fusions. All constructs were transformed into the E. coli host strain BL21 CodonPlus DE3. The bacteria were incubated in an orbital shaker in LB medium containing 100 μg / ml ampicillin and 34 μg / ml chloramphenicol at 37°C. 600The proteins were grown until the OD reached 0.4, and then the temperature was lowered to 16°C. The recombinant protein had an OD of approximately 0.8 upon addition of IPTG. 600 Expression was observed for 18 hours. All culture rotation was stopped, and the bacterial pellet was used for protein purification.

[0235] For His-DRP1, the pellet was resuspended in DRP buffer A (20 mM Tris, 500 KCl, 1.89 β-ME, pH 8.0) and a protease inhibitor cocktail (Roche), followed by cell disruption by sonication (400 W, pulse 3 seconds on, 3 seconds off, total 20 minutes). The lysate was centrifuged at 20,000 g, and the supernatant was placed in a Ni-NTA column pre-equalized with DRP buffer A. The column was thoroughly washed with buffer A containing 50 mM imidazole. The purified His-DRP1 was eluted with DRP buffer A containing 250 mM imidazole, and imidazole was removed by dialyzing overnight at 4°C (18 kDa cutoff) against DRP buffer A. For AlphaLISA, the His tag was retained throughout the entire length of DRP1.

[0236] For MiD49-GST, the bacterial pellet was resuspended in MID lysis buffer (25 mM Tris-HCl, pH 7.5, 500 mM NaCl, 5% glycerol, 1 mM TCEP, and 0.5% CHAPS) and sonicated. The lysate was pre-clarified with 20,300 g before being placed in the glutathione column. Unbound proteins were washed with MID buffer A (25 mM Tris-HCl, pH 7.5, 300 mM NaCl, 5% glycerol, 1 mM TCEP) and MID buffer B (25 mM Tris-HCl, pH 7.5, 300 mM NaCl, 5% glycerol, 1 mM TCEP, 1 mM GSH). The proteins were eluted with MID buffer C (25 mM Tris-HCl, pH 7.5, 300 mM NaCl, 5% glycerol, 1 mM TCEP, 10 mM GSH). The target protein was concentrated in an ultrafiltration tube with a MW cutoff of 30 kDa and further purified by size exclusion chromatography on a Superdex-200 column (GE Healthcare) in buffer A. The fraction containing MiD49-GST(126-454) was pooled, concentrated, rapidly frozen as disposable aliquots in liquid nitrogen, and stored at -80°C.

[0237] A total of 100 nl of compounds were seeded into a 384-well AlphaPlate (PerkinElmer, Waltham, Massachusetts) at concentrations ranging from 100 μM to 991 pM in DMSO (11 concentrations at 3.165-fold dilutions). Recombinant His-DRP1 (200 nM), MiD49-GST (20 nM), and GMP-PNP (100 μM) were mixed in assay buffer (PBS containing 1.5% BSA and 1 mM DTT). 5 microliters of the protein mixture was added to the plate and incubated at room temperature for 30 minutes. Glutathione donor beads and nickel chelate acceptor beads were diluted and mixed in assay buffer to obtain 40 μg / ml of each bead. 5 microliters of the mixed beads were added to each well on the microplate to achieve a final bead concentration of 20 μg / ml per well. The sealed plate was incubated at room temperature for 60 minutes and protected from light. The AlphaLISA signal was detected using an EnVision Multilabel Reader (excitation 680nm, emission 615nm). An IC was obtained by applying a sigmoid dose-response fit (variable gradient) using GraphPad Prism. 50 I calculated it. [Table 2-1] [Table 2-2]

Claims

1. The compound represented by formula (I), 【Chemistry 1】 or its pharmaceutically acceptable salt (In the formula, X １ is CH or N, R １ This is an optional choice for another R １ａ A 5-10 member monocyclic or bicyclic heteroaryl substituted with, Each R １ａ is independently selected from the group consisting of halo, cyano, C １－６ alkyl, C １－６ haloalkyl, C ３－６ cycloalkyl, OH, C １－６ alkoxy, and C １－６ haloalkoxy, R ２ C １－６ Alkyl, C ３－６ Cycloalkyl, crosslinked C ５－１２ Cycloalkyl, phenyl, 3-10 membered monocyclic or bicyclic heterocyclil, or 5-10 membered monocyclic or bicyclic heteroaryl, each of which optionally contains one or more R ２ａ Replaced by, Each R ２ａ Halo, Cyano, C １－６ Alkyl, C １－６ Haloalkyl, OH, C １－６ Alkoxy, C １－６ Haloalkoxy, -C(O)R ２ｂ , -C(O)OR ２ｂ , -C(O)NR Ｎ２ａ R Ｎ２ｂ , and -NR Ｎ２ａ R Ｎ２ｂ Selected independently from, R ２ｂ , R Ｎ２ａ , and R Ｎ２ｂ These are H and C, respectively, independently. １－６ Alkyl, or C １－６ It is a haloalkyl, R ３ C １－６ Alkyl, C ３－６ Cycloalkyl, phenyl, 3-10 membered monocyclic or bicyclic heterocyclil, or 5-10 membered monocyclic or bicyclic heteroaryl, each of which optionally contains one or more R ３ａ Replaced by, Each R ３ａ Hello, C １－６ Alkyl, OH, C １－６ Alkoxy and C １－６ Independently selected from the group consisting of haloalkoxys, R ４ H, C １－６ Alkyl, C １－６ Haloalkyl, or C ３－６ It is a cycloalkyl, R ５ H, C １－６ Alkyl, or C １－６ (It is a haloalkyl group.)

2. Formula (IA) 【Chemistry 2】 The compound according to claim 1, represented by [formula], or a pharmaceutically acceptable salt thereof.

3. R ４ is H or C １－３ A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, which is alkyl.

4. R ４ is H or -CH ３ The compound according to claim 3 or a pharmaceutically acceptable salt thereof.

5. R １ is a 5-membered or 6-membered monocyclic heteroaryl, wherein the 5-membered or 6-membered monocyclic heteroaryl optionally has one or two R １ａ Replaced by, Each R １ａ Halo, Cyano, C １－４ Alkyl, C ３－４ Cycloalkyl, and C １－３ A compound according to any one of claims 1 to 4, independently selected from the group consisting of alkoxys, or a pharmaceutically acceptable salt thereof.

6. R １ The group is selected from imidazoyl, pyrazoyl, triazoyl, and thiazoyl, and each of them is optionally selected from one or two R １ａ A compound according to claim 5 or a pharmaceutically acceptable salt thereof, which is substituted with.

7. R １ is a structural formula 【Transformation 3】 They are represented by, and each of them optionally has one or two R １ａ Replaced by each R １ａ is, -CH ３ ien-CH ２ CH ３ ien-CH ２ CH ２ CH ３ , -C(CH ３ ) ３ , cyclopropyl, -OCH ３ A compound according to claim 6, or a pharmaceutically acceptable salt thereof, independently selected from the group consisting of , -Cl, and cyano.

8. R １ The group consists of imidazoyl and thiazoyl, and each of them is optionally selected from the group consisting of one or two R １ａ Replaced by each R １ａ is, -CH ３ , cyclopropyl, and -OCH ３ A compound according to claim 5 or a pharmaceutically acceptable salt thereof, independently selected from the group consisting of the above.

9. R ２ C １－３ Alkyl, C ３－６ Cycloalkyl, crosslinked C ５－８ Cycloalkyls, 3-6 membered monocyclic heterocyclines, or 5- or 6 membered monocyclic heteroaryls, each of which optionally comprises 1-3 R groups. ２ａ Replaced by, Each R ２ａ Halo, Cyano, C １－３ Alkyl, C １－３ Haloalkyl, -OH, and C １－３ A compound according to any one of claims 1 to 8, independently selected from the group consisting of alkoxys, or a pharmaceutically acceptable salt thereof.

10. R ２ C １－３ Alkyl, cyclopropyl, cyclobutyl, bicyclo[1.1.1]pentanyl, oxetanyl, tetrahydropyranil, or isoxazoyl, each of which optionally contains 1 to 3 R groups. ２ａ A compound according to claim 9 or a pharmaceutically acceptable salt thereof, which is substituted with.

11. R ２ is optionally C ２ａ alkyl substituted with 1 to 3 R １－３ groups, or R ２ has the structural formula 【Chemistry 4】 or 【Transformation 5】 represented by, each of which is optionally substituted with one or two R ２ａ and each R ２ａ is selected from the group consisting of -F, cyano, -CH ３ , -CF ３ , -OH, -OCH ３ , -OCH ２ CH ３ , and -OCH ２ CH ２ CH ３ The compound according to claim 10 or a pharmaceutically acceptable salt thereof.

12. R ２ is —CF ３ , —CH ２ CH ２ OCH ３ , —CH ２ OCH ３ , —CH ２ OH, —CH(OH)CH ３ , —CH(CH ３ )CH ２ OCH ３ , —CH(CH ３ )CN, —CH(CH ３ )OCH ３ , —CH(CH ３ )OCH ２ CH ３ , —CH(CH ３ )OCH ２ CH ２ CH ３ , —CF ２ CH ２ OH, or R ２ is a structural formula 【Transformation 6】 or 【Transformation 7】 The compound according to claim 11 or a pharmaceutically acceptable salt thereof, as represented by [the specified formula].

13. R ２ C １－３ The C is alkyl, cyclopropyl, cyclobutyl, oxetanyl, or tetrahydropyranyl. １－３ Alkyl, cyclopropyl, and cyclobutyl each optionally contain 1 to 3 R groups. ２ａ A compound according to claim 9 or a pharmaceutically acceptable salt thereof, which is substituted with.

14. R ２ is -CH(CH ３ )CN, -CH(CH ３ ) OCH ３ , -CH(CH ３ ) OCH ２ CH ３ , -CH(CH ３ ) OCH ２ CH ２ CH ３ is or R ２ is a structural formula 【Transformation 8】 or 【Chemistry 9】 The compound according to claim 13 or a pharmaceutically acceptable salt thereof, as represented by [the specified formula].

15. R ３ C １－４ Alkyl or C ３－４ They are cycloalkyl groups, each of which optionally contains 1 to 3 R groups. ３ａ Replaced by, Each R ３ａ C １－３ Alkyl, -OH, and C １－３ A compound according to any one of claims 1 to 14, independently selected from the group consisting of alkoxys, or a pharmaceutically acceptable salt thereof.

16. R ３ C １－４ Alkyl or cyclopropyl, and the C １－３ Alkyl groups optionally have 1 to 3 R groups. ３ａ Replaced by, Each R ３ａ is, -CH ３ OH, and -OCH ３ A compound according to claim 15 or a pharmaceutically acceptable salt thereof, independently selected from the above.

17. R ３ is, -CH ３ ien-CH ２ CH ３ ien-CH ２ CH ２ OH, -CH ２ CH ２ OCH ３ , -CH(CH ３ )CH ２ OCH ３ , -C(CH ３ ) ２ CH ２ OCH ３ The compound according to claim 16 or a pharmaceutically acceptable salt thereof, wherein the compound is cyclopropyl or cyclopropyl.

18. The compound is selected from the following or a pharmaceutically acceptable salt thereof, according to claim 1, or a pharmaceutically acceptable salt thereof. Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

20. A method for treating a dynamin-1-like protein (Drp1)-mediated disease or disorder in a subject, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 19.

21. The method according to claim 20, wherein the Drp1-mediated disease or disorder is a muscle structure disorder, nerve activation disorder, muscle fatigue disorder, muscle mass disorder, beta-oxidation disorder, metabolic disorder, cancer, vascular disease, ophthalmic vascular disease, muscular eye disease, or kidney disease.

22. The aforementioned muscular structural disorders are selected from the group consisting of Vethlem myopathy, central nervous system disorders, congenital fibrous disequilibrium, distal muscular dystrophy (MD), Duchenne & Becker MD, Emery-Dreyfus MD, facioscapulohumeral MD, vitreous myopathy, limb girdle muscle MD, myosodium channel dysfunction, myotonic chondrodysplasia, myotonic dystrophy, myotubular myopathy, nemaline body disease, oculopharyngeal MD, and stress urinary incontinence. The aforementioned neuronal activation disorders are selected from the group consisting of amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease, Guillain-Barré syndrome, Lambert-Eaton syndrome, multiple sclerosis, myasthenia gravis, nerve injury, peripheral neuropathy, spinal muscular atrophy, delayed ulnar nerve palsy, and toxic myoneuropathy. The aforementioned muscle fatigue disorders are selected from the group consisting of chronic fatigue syndrome, diabetes mellitus (type I or type II), glycogen storage disorders, fibromyalgia, Friedreich's ataxia, intermittent claudication, lipid storage myopathy, MELAS, mucopolysaccharidosis, Pompe disease, and thyroid-toxic myopathy. The aforementioned muscle mass impairment is selected from the group consisting of cachexia, cartilage degeneration, cerebral palsy, compartment syndrome, severe myopathy, inclusion body myositis, muscle atrophy (disuse), sarcopenia, steroid myopathy, and systemic lupus erythematosus. The aforementioned beta-oxidation disorders are selected from the group consisting of systemic carnitine transporter deficiency, carnitine palmitoyltransferase (CPT) II deficiency, very long-chain acyl-CoA dehydrogenase (LCHAD or VLCAD) deficiency, trifunctional enzyme deficiency, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, short-chain acyl-CoA dehydrogenase (SCAD) deficiency, and riboflavin-responsive beta-oxidation disorder (RR-MADD). The aforementioned metabolic diseases include hyperlipidemia, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, HDL hypocholesterolemia, LDL hypercholesterolemia and / or HDL noncholesterolemia, VLDL hyperproteinemia, abnormal lipoproteinemia, apolipoprotein A-I hypoproteinemia, atherosclerosis, arteriosclerotic diseases, cardiovascular diseases, cerebrovascular diseases, peripheral circulatory diseases, metabolic syndrome, syndrome X, obesity, diabetes (type I or type II), hyperglycemia, and The group consists of insulin resistance, impaired glucose tolerance, hyperinsulinemia, diabetic complications, heart failure, myocardial infarction, cardiomyopathy, hypertension, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), thrombosis, Alzheimer's disease, neurodegenerative diseases including Parkinson's disease, demyelinating diseases, multiple sclerosis, adrenoleukodystrophy, dermatitis, psoriasis, acne, skin aging, demodicosis, inflammation, arthritis, asthma, irritable bowel syndrome, ulcerative colitis, Crohn's disease, and pancreatitis. The aforementioned vascular diseases are selected from the group consisting of peripheral vascular insufficiency, peripheral vascular disease, intermittent claudication, peripheral vascular disease (PVD), peripheral artery disease (PAD), peripheral artery occlusive disease (PAOD), and peripheral artery occlusive disease. The aforementioned ophthalmic vascular diseases are selected from the group consisting of age-related macular degeneration (AMD), Stargardt disease, hypertensive retinopathy, diabetic retinopathy, retinopathy, macular degeneration, retinal hemorrhage, and glaucoma. The aforementioned muscular eye diseases are selected from the group consisting of strabismus, progressive extraocular muscle paralysis, esotropia, exotropia, refractive and accommodation disorders, hyperopia, myopia, astigmatism, anisometropia, presbyopia, accommodation disorders, and internal ocular muscle paralysis. The method according to claim 21, wherein the kidney disease is selected from the group consisting of glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, acute nephritis, recurrent hematuria, persistent hematuria, chronic nephritis, rapidly progressive nephritis, acute renal failure, chronic renal failure, diabetic nephropathy, and Bartter syndrome.

23. The method according to claim 20, wherein the disease or disorder is selected from hereditary lipodystrophy, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), renal ischemia / reperfusion injury (IRI), Duchenne & Becker muscular dystrophy, diabetes mellitus (type I or type II), obesity, and sarcopenia.

24. The method according to claim 20, wherein the Drp1-mediated disease or disorder is selected from the group consisting of inflammatory bone disease, T-cell immunosuppression, neuropathic pain, cancer, Alpers disease, CPEO-chronic progressive extraocular palsy, Kearns-Sayler syndrome (KSS), Leber's hereditary optic neuropathy (LHON), MELAS-mitochondrial myopathy, encephalomyopathy, lactic acidosis, and stroke-like episodes, MERRF-myoclonic epilepsy and ragged red fibrosis, NARP-neurogenic muscle weakness, ataxia, retinitis pigmentosa, Pearson syndrome, platinum-based chemotherapy-induced ototoxicity, Cockayne syndrome, xeroderma pigmentosum A, Waller's degeneration, and HIV-induced lipodystrophy.

25. The method according to claim 20, wherein the Drp1-mediated disease or disorder is selected from the group consisting of acute renal injury, myocardial ischemia, pulmonary arterial hypertension, polycystic kidney disease, Huntington's disease, neurodegenerative disease, or Charcot-Marie-Tooth disease.

26. The method according to claim 25, wherein the neurodegenerative disease is Parkinson's disease.

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