Fusion azines as actin-1-like inhibitors and uses thereof

Abstract

The present invention provides compounds of Formula (I): # imgabs0 # or a pharmaceutically acceptable salt thereof, which are useful for inhibiting Drp1 and treating a variety of Drp11 mediated conditions or diseases.

Description

[0001] Related Applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 419,132, filed Oct. 25, 2022. The entire content of the foregoing application is hereby expressly incorporated by reference. Field of the Invention

[0003] The present disclosure relates to inhibitors of dynamin-1-like protein (Drp1) and pharmaceutically acceptable salts thereof, compositions of these compounds, processes for their preparation, and their use in the treatment of diseases. Background of the Invention

[0004] Dynamin-1-like protein is a GTPase that regulates mitochondrial fission. In humans, dynamin-1-like protein is commonly referred to as dynamin-related protein 1 (Drp1), which is encoded by the DNM1L gene. Drp1 inhibitors can prevent cell death, suggesting that mitochondrial fission is an important step in apoptosis. The Drp1 sequence (OMIM 603850) is publicly available, for example, from sequence databases such as BAA22193 (human, protein), AB006965 (human, nucleic acid).

[0005] In healthy cells, fusion and fission events are involved in regulating mitochondrial morphology. Drp1 is a dynamin-related protein that mediates the fission of the outer mitochondrial membrane and is typically activated during cell division. Specifically, during the M phase, Drp1 is activated, inducing mitochondrial fission to ensure the uniform distribution of mitochondria to each daughter cell. Mitochondrial fission generates smaller mitochondria, which are more capable of producing 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). After induction of apoptosis, Drp1 translocates from the cytosol to the mitochondria and preferentially localizes to potential sites of organelle fission in the mitochondrion. Drp1 is regulated by phosphorylation, with phosphorylation at serine 616 increasing activity and phosphorylation at serine 637 decreasing activity. Inhibition of Drp1 prevents the loss of mitochondrial membrane potential and the release of cytochrome c and reveals reproducible swelling of the organelle. Unexpectedly, Drp1 inhibition blocks cell death, implying that mitochondrial fission is an important step in apoptosis. In addition, due to reduced mitochondrial fission, Drp1 inhibition has been shown to reduce reactive oxygen species. Thus, modulating Drp1 activity can be effective in treating a variety of disorders, such as cardiovascular diseases, kidney diseases, ophthalmic disorders, cancer, ischemia-reperfusion injury, and neurodegenerative and cognitive diseases. In fact, Drp1 is an important biomarker for compounds used to help treat and prevent diseases such as cardiovascular diseases, kidney diseases, ophthalmic diseases, cancer, cognitive diseases, and other related diseases.

[0006] Accordingly, there is a need for Drp1 inhibitors as potential therapeutic agents for treating diseases or disorders responsive to Drp1 inhibition. SUMMARY OF THE INVENTION

[0007] The present disclosure provides compounds that are inhibitors of Drp1. In a first aspect, the present disclosure relates to compounds having Formula I:

[0008]

[0009] or a pharmaceutically acceptable salt thereof, wherein:

[0010] X 1 is CH or N;

[0011] R 1 is an optionally substituted 5- to 10-membered monocyclic or bicyclic heteroaryl group with one or more R 1a substituents;

[0012] Each R 1aIndependently 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;

[0013] R 2 is C 1-6 alkyl, C 3-6 cycloalkyl, bridged C 5-12 cycloalkyl, phenyl, 3- to 10-membered monocyclic or bicyclic heterocyclic group or 5- to 10-membered monocyclic or bicyclic heteroaryl, each optionally substituted with one or more R 2a substituents;

[0014] Each R 2a is independently selected from 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 ;

[0015] R 2b , R N2a and R N2b are each independently H, C 1-6 alkyl or C 1-6 haloalkyl;

[0016] R 3 is C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, 3- to 10-membered monocyclic or bicyclic heterocyclic group or 5- to 10-membered monocyclic or bicyclic heteroaryl, each optionally substituted with one or more R 3a substituents;

[0017] Each R 3a is independently selected from the group consisting of halo, C 1-6 alkyl, OH, C 1-6 alkoxy and C 1-6 haloalkoxy;

[0018] R 4 is H, C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl; and

[0019] R 5is H, C 1-6 alkyl or C 1-6 haloalkyl.

[0020] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier.

[0021] In another aspect, the present disclosure provides a method of treating a Drp1-mediated disease or disorder in a subject, which comprises administering to the subject an effective amount of 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 treating cancer.

[0022] Another aspect of the present disclosure relates to the use of an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating a Drp1-mediated disease or disorder. Also provided is a compound described herein or a pharmaceutically acceptable salt thereof for treating a Drp1-mediated disease or disorder.

[0023] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier, the pharmaceutical composition for treating a Drp1-mediated disease or disorder, particularly cancer. Detailed Description

[0024] As used herein, the phrase "Drp1 inhibitor" refers to a substance that effectively reduces Drp1 activity. 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 indicative of Drp1 inactivation (see Biological Example 1).

[0025] The present disclosure provides compounds and pharmaceutical compositions thereof that can be used to treat diseases or disorders via mediating Drp1 function / activity. In some embodiments, the compounds of the present disclosure are Drp1 inhibitors.

[0026] Compounds and Compositions

[0027] In a first embodiment, the present disclosure provides a compound of formula (I):

[0028]

[0029] or a pharmaceutically acceptable salt thereof, wherein the variables in formula (I) are as defined in the first aspect above.

[0030] In a second embodiment, the compound of the present disclosure is represented by formula (IA):

[0031]

[0032] or a pharmaceutically acceptable salt thereof; wherein the variable R depicted in formula (IA) 1 , R 2 , R 3 and R 4 are as described in the first embodiment.

[0033] In the third embodiment, for the compound of formula (I) or (IA) or a pharmaceutically acceptable salt thereof, R 4 is H or C 1-3 alkyl; and the remaining variables are as described in the first or second embodiment.

[0034] In the fourth embodiment, for the compound of formula (I) or (IA) or a pharmaceutically acceptable salt thereof, R 4 is H or -CH 3 ; and the remaining variables are as described in the third embodiment. In a specific embodiment, for the compound of formula (I) or (IA) or a pharmaceutically acceptable salt thereof, R 4 is H; and the remaining variables are as described in the third embodiment.

[0035] In the fifth embodiment, for the compound of formula (I) or (IA) or a pharmaceutically acceptable salt thereof, R 1 is a 5- or 6-membered monocyclic heteroaryl, wherein the 5- or 6-membered monocyclic heteroaryl is optionally substituted with 1 or 2 R 1a ; each R 1a is independently selected from the group consisting of halo, cyano, C 1-4 alkyl, C 3-4 cycloalkyl, and C 1-3 alkoxy; and the remaining variables are as described in the first, second, third, or fourth embodiment. In a specific embodiment, R 1 is a 5-membered monocyclic heteroaryl optionally substituted with 1 or 2 R 1a ; each R 1a is independently selected from the group consisting of halo, cyano, C 1-4 alkyl, C 3-4 cycloalkyl, and C 1-3 alkoxy; and the remaining variables are as described in the first, second, third, or fourth embodiment.

[0036] In the sixth embodiment, for the compound of formula (I) or (IA) or a pharmaceutically acceptable salt thereof, R 1 is selected from the group consisting of imidazolyl, pyrazolyl, triazolyl, and thiazolyl, each optionally substituted with 1 or 2 R 1a ; and the remaining variables are as described in the fifth embodiment.

[0037] In the seventh embodiment, for the compound of formula (I) or (IA) or a pharmaceutically acceptable salt thereof, R1 is represented by the following structural formula: each optionally substituted by 1 or 2 Rs 1a where each R 1a is independently selected from the group consisting of: -CH 3 -, -CH 2 CH 3 -, -CH 2 CH 2 CH 3 -, -C(CH 3 ) 3 -, cyclopropyl, -OCH 3 -, -Cl, and cyano; and the remaining variables are as described in the sixth embodiment.

[0038] In the eighth embodiment, for the compound of formula (I) or (IA) or a pharmaceutically acceptable salt thereof, R 1 is selected from the group consisting of imidazolyl and thiazolyl, each optionally substituted by 1 or 2 Rs 1a where each R 1a is independently selected from the group consisting of: -CH 3 -, cyclopropyl, and -OCH 3 -; and the remaining variables are as described in the fifth embodiment.

[0039] In the ninth embodiment, for the compound of formula (I) or (IA) or a pharmaceutically acceptable salt thereof, R 2 is C 1-3 alkyl, C 3-6 cycloalkyl, bridged C 5-8 cycloalkyl, a 3- to 6-membered monocyclic heterocyclic group, or a 5- or 6-membered monocyclic heteroaryl group, each optionally substituted by 1 to 3 Rs 2a where each R 2a is independently selected from the group consisting of halo, cyano, C 1-3 alkyl, C 1-3 haloalkyl, -OH, and C 1-3 alkoxy; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, or eighth embodiment.

[0040] 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]pentyl, oxetanyl, tetrahydropyranyl, or isoxazolyl, each optionally substituted by 1 to 3 Rs 2a ; and the remaining variables are as described in the ninth embodiment.

[0041] In the eleventh embodiment, for the compound of formula (I) or (IA) or a pharmaceutically acceptable salt thereof, R 2 is optionally C 2a alkyl substituted with 1 to 3 R 1-3 groups, or R 2 is represented by the following structural formula: each optionally substituted with 1 or 2 R 2a groups, each R 2a being 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 ; and the remaining variables are as described in the tenth embodiment.

[0042] In the twelfth embodiment, for the compound of formula (I) or (IA) or a pharmaceutically acceptable salt thereof, 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 represented by the following structural formula: and the remaining variables are as described in the eleventh embodiment.

[0043] In the thirteenth embodiment, for the compound of formula (I) or (IA) or a pharmaceutically acceptable salt thereof, R 2 is C 1-3an alkyl group, a cyclopropyl group, a cyclobutyl group, an oxetanyl group or a tetrahydropyranyl group, wherein C 1-3 the alkyl group, the cyclopropyl group and the cyclobutyl group are each optionally substituted with 1 to 3 R 2a substituents; and the remaining variables are as described in the ninth embodiment.

[0044] In the fourteenth embodiment, for a compound of formula (I) or (IA) or a pharmaceutically acceptable salt thereof, 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 , or R 2 is represented by the following structural formula: and the remaining variables are as described in the third embodiment.

[0045] In the fifteenth embodiment, for a compound of formula (I) or (IA) or a pharmaceutically acceptable salt thereof, R 3 is C 1-4 alkyl or C 3-4 cycloalkyl, each optionally substituted with 1 to 3 R 3a substituents; each R 3a is independently selected from the group consisting of C 1-3 alkyl, -OH and C 1-3 alkoxy; 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.

[0046] In the sixteenth embodiment, for a compound of formula (I) or (IA) or a pharmaceutically acceptable salt thereof, R 3 is C 1-4 alkyl or a cyclopropyl group, wherein the C 1-3 alkyl is optionally substituted with 1 to 3 R 3a substituents; each R 3a is independently selected from -CH 3 , OH and -OCH 3 ; and the remaining variables are as described in the fifteenth embodiment.

[0047] In the seventeenth embodiment, for a compound of formula (I) or (IA) or a pharmaceutically acceptable salt thereof, R 3 is -CH 3 , -CH 2 CH 3, -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 or cyclopropyl; and the remaining variables are as described in the sixteenth embodiment. In a particular embodiment, for a compound of formula (I) or (IA) or a pharmaceutically acceptable salt thereof, R 3 is -CH 2 CH 3 , -CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 or -CH(CH 3 )CH 2 OCH 3 ; and the remaining variables are as described in the sixteenth embodiment.

[0048] In the eighteenth embodiment, the present disclosure provides a compound of any one of the compounds described herein (e.g., Examples 1-54) or a pharmaceutically acceptable salt thereof.

[0049] In the nineteenth embodiment, the present disclosure provides a compound selected from the group consisting of:

[0050]

[0051]

[0052]

[0053]

[0054]

[0055]

[0056]

[0057]

[0058]

[0059] or a pharmaceutically acceptable salt thereof.

[0060] The compounds and intermediates described herein can be isolated and used in neutral form. Alternatively, when moieties capable of forming salts are present, the compounds or intermediates can be isolated and used in their corresponding salt forms. As used herein, the term "salt" refers to acid addition salts or base addition salts of the compounds described herein. "Salt" specifically includes "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds described herein and are generally biologically or otherwise desirable. In many cases, the compounds of the present disclosure are capable of forming acid and / or base salts through the presence of amino and / or carboxyl groups or groups similar thereto.

[0061] Pharmaceutically acceptable acid addition salts can be formed with inorganic acids or organic acids, such as acetates, aspartates, benzoates, benzenesulfonates, bromides / hydrobromides, bicarbonates / carbonates, bisulfates / sulfates, camphorsulfonates, chlorides / hydrochlorides, alginates, citrates, ethanedisulfonates, fumarates, glucoheptonates, gluconates, glucuronates, hippurates, hydroiodides / iodides, hydroxyethylsulfonates, lactates, lactobionates, lauryl sulfates, malates, maleates, malonates, mandelates, methanesulfonates, methyl sulfates, naphthoates, naphthalenesulfonates, nicotinates, nitrates, octadecanoates, oleates, oxalates, palmitates, pamoates, phosphates / hydrogen phosphates / dihydrogen phosphates, polygalacturonates, propionates, stearates, succinates, sulfates, sulfosalicyclates, tartrates, toluenesulfonates, and trifluoroacetates.

[0062] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and acids similar thereto.

[0063] Organic acids from which salts can be derived include, for example, 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, sulfosalicylic acid, and acids similar thereto.

[0064] Pharmaceutically acceptable base addition salts can be formed with inorganic bases and organic bases.

[0065] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals in rows I to XII of the periodic table. In certain embodiments, the salts are derived from sodium salts, potassium salts, ammonium salts, calcium salts, magnesium salts, iron salts, silver salts, zinc salts, and copper salts; particularly suitable salts include ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

[0066] Organic bases capable of forming salts include, for example, primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, choline salts, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0067] Salts can be synthesized from compounds containing basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of an appropriate base (such as hydroxides, carbonates, bicarbonates, etc. of Na, Ca, Mg, or K), 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 or an organic solvent or a mixture of both. Generally, a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is used when feasible. Lists of other suitable salts can be found, for example, in “Remington's Pharmaceutical Sciences”, 20th Edition, Mack Publishing Company, Easton, Pa., (1985); and “Handbook of Pharmaceutical Salts: Properties, Selection, and Use”, Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0068] The deuterated compounds of formula (I) or (IA) can generally be prepared by conventional techniques known to those skilled in the art or by processes similar to those described in the attached examples and preparations using appropriate deuterated reagents to replace the previously employed non-labeled reagents. In one embodiment, the present disclosure provides the deuterated compounds described herein or pharmaceutically acceptable salts thereof.

[0069] Another embodiment of the present disclosure is a compound disclosed herein, including 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 site where hydrogen has been replaced by deuterium is at least 50%, 75%, 85%, 90%, 95%, 98%, or 99%. The degree of deuterium enrichment is a mole percentage and is obtained by dividing the number of compounds having deuterium enrichment at the enrichment site by the number of compounds having hydrogen or deuterium at the enrichment site.

[0070] Pharmaceutically acceptable solvates according to the present disclosure include those solvates in which the crystallization solvent can be isotopically substituted, such as D 2 O, d 6 -acetone, d 6-DMSO.

[0071] Those skilled in the art will recognize 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 isomers" or "stereoisomers" refer to any of the various stereoisomeric configurations that may exist for a given compound disclosed in the present invention. It should be understood that substituents may be attached to the chiral centers of carbon atoms. Accordingly, the present disclosure includes the enantiomers, diastereomers or racemates of said compounds.

[0072] "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. In appropriate cases, the term "racemic" or "rac" is used to refer to a racemic mixture. When specifying the stereochemistry of a compound of the present disclosure, the conventional RS system (e.g., (1S,2S)) is used to specify the relative and absolute configurations of a single stereoisomer having two known chiral centers. "Diastereomers" 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 RS system. When the compound is a pure enantiomer, the stereochemistry of each chiral carbon can be specified by R or S. A resolved compound of unknown absolute configuration can be designated as (+) or (-) according to the direction (right or left) in which it rotates plane-polarized light at the wavelength of the sodium D line. Alternatively, a resolved compound can be defined by the corresponding retention time of the enantiomer / diastereomer via chiral HPLC.

[0073] Certain compounds described herein contain one or more asymmetric centers or axes and thus can give rise to enantiomers, diastereomers and other stereoisomeric forms that can be defined as (R)- or (S)- according to absolute stereochemistry.

[0074] Unless otherwise stated, the compounds of the present disclosure are intended to include all such possible stereoisomers, including racemic mixtures, optically pure forms and intermediate mixtures. The optically active (R)- and (S)- stereoisomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques (e.g., on chiral SFC or HPLC columns, such as CHIRALPAK RTM and CHIRALCEL RTM using a solvent or solvent mixture suitable for achieving good separation). If the compound contains a double bond, the substituents can be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituents can have a cis or trans configuration. All tautomeric forms are also intended to be included.

[0075] The present disclosure also provides a pharmaceutical composition comprising a compound described herein (e.g., a compound according to any one of the foregoing embodiments) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0076] Method of Use

[0077] 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.

[0078] In certain embodiments, the present disclosure provides a method of treating a disease or disorder responsive to inhibition of Drp1 activity (referred to herein as a "Drp1-mediated disease or disorder") in a subject in need thereof. The method comprises administering to the subject 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 pharmaceutical composition thereof.

[0079] In certain embodiments, the present 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 pharmaceutical composition comprising the compound or pharmaceutically acceptable salt described herein for the manufacture of a medicament for treating a Drp1-mediated disease or disorder in a subject in need thereof.

[0080] In certain embodiments, the present disclosure provides 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 pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof for treating a Drp1-mediated disorder or disease in a subject in need thereof.

[0081] In certain embodiments, the present disclosure provides a pharmaceutical composition comprising a compound described herein (e.g., a compound described in any one of the first to nineteenth embodiments) or a pharmaceutically acceptable salt thereof, the pharmaceutical composition being for treating a Drp1-mediated disorder.

[0082] In certain embodiments, the present 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 treating a Drp1-mediated disease or disorder in a subject in need thereof.

[0083] In certain embodiments, the Drp1-mediated disease or disorder is a muscle structure disorder, a neuronal activation disorder, a muscle fatigue disorder, a muscle mass disorder, a β-oxidation disease, a metabolic disease, cancer, a vascular disease, an ocular vascular disease, a muscle eye disease, or a kidney disease.

[0084] In some embodiments:

[0085] Muscular structure disorders are selected from the group consisting of: Bethlem myopathy, central core disease, congenital fiber type disproportion, distal muscular dystrophy (MD), Duchenne and Becker MD, Emery-Dreifuss MD, facioscapulohumeral MD, hyaline body myopathy, limb-girdle MD, muscle sodium channel disorders, myotonic chondrodystrophy, myotonic dystrophy, myotubular myopathy, nemaline myopathy, external ophthalmoplegia-pharyngeal MD, and stress urinary incontinence;

[0086] Neuronal activation disorders are selected from the group consisting of: amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease, Guillain-Barre syndrome, Lambert-Eaton syndrome, multiple sclerosis, myasthenia gravis, nerve injury, peripheral neuropathy, spinal muscular atrophy, tardy ulnar palsy, and toxic myoneural disorders;

[0087] Muscular fatigue disorders are selected from the group consisting of: chronic fatigue syndrome, diabetes (type I or II), glycogen storage disease, fibromyalgia, Friedreich's ataxia, intermittent claudication, lipid storage myopathy, MELAS, mucopolysaccharidosis, Pompe disease, and thyrotoxic myopathy;

[0088] Muscle mass disorders are selected from the group consisting of: cachexia, cartilage degeneration, cerebral palsy, compartment syndrome, polymyositis, inclusion body myositis, muscle atrophy (disuse), sarcopenia, steroid myopathy, and systemic lupus erythematosus;

[0089] β-oxidation diseases are selected from the group consisting of: systemic carnitine transporter, carnitine palmitoyl transferase (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);

[0090] Metabolic diseases are selected from the group consisting of: hyperlipidemia, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, low HDL cholesterol, high LDL cholesterol and / or non-cholesterol HLD, high VLDL protein, dyslipoproteinemia, low apolipoprotein A-I, atherosclerosis, arteriosclerosis disease, cardiovascular system disease, cerebrovascular disease, peripheral circulatory disease, metabolic syndrome, syndrome X, obesity, diabetes (type I or type II), hyperglycemia, insulin resistance, impaired glucose tolerance, hyperinsulinemia, diabetic complications, cardiac insufficiency, 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, hair diseases, inflammation, arthritis, asthma, intestinal allergy syndrome, ulcerative colitis, Crohn's disease, and pancreatitis;

[0091] Vascular diseases are selected from the group consisting of: peripheral vascular insufficiency, peripheral vascular disease, intermittent claudication, peripheral vascular disease (PVD), peripheral arterial disease (PAD), peripheral arterial obstructive disease (PAOD), and peripheral occlusive arterial disease;

[0092] 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;

[0093] Muscular eye diseases are selected from the group consisting of: strabismus, progressive external ophthalmoplegia, esotropia, exotropia, refractive and accommodative disorders, hyperopia, myopia, astigmatism, anisometropia, presbyopia, accommodative disorders, and internal ophthalmoplegia; and

[0094] Renal diseases are 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's syndrome.

[0095] 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 and Becker muscular dystrophy, diabetes (type I or II), obesity, and sarcopenia.

[0096] In other embodiments, Drp1-mediated diseases or disorders are selected from the group consisting of: bone inflammatory diseases, T cell immunomodulation, neuropathic pain, cancer, Alpers's Disease, CPEO - chronic progressive external ophthalmoplegia, Kearns-Sayra 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 weakness, ataxia, retinitis pigmentosa, Pearson Syndrome, platinum-based chemotherapy-induced ototoxicity, Cockayne syndrome, xeroderma pigmentosum type A, Wallerian degeneration, and HIV-induced lipodystrophy.

[0097] In other embodiments, Drp1-mediated diseases or disorders are 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.

[0098] In other embodiments, the Drp1-mediated disease or disorder is a neurodegenerative disease. In other embodiments, the neurodegenerative disease is Parkinson's disease.

[0099] The compounds described herein or their pharmaceutically acceptable salts can be used to reduce the expression or activity of Drp1 in cells or otherwise affect the properties and / or behavior of Drp1.

[0100] One embodiment of the present disclosure includes a method of reducing the expression or activity of Drp1 in a subject or otherwise affecting the properties and / or behavior of Drp1, the method comprising administering to the subject an effective amount of at least one compound described herein or a pharmaceutically acceptable salt thereof.

[0101] In certain embodiments, the present disclosure relates to the foregoing method, wherein the subject is a mammal.

[0102] In certain embodiments, the present disclosure relates to the foregoing method, wherein the subject is a primate.

[0103] In certain embodiments, the present disclosure relates to the foregoing method, wherein the subject is a human.

[0104] As used herein, "effective amount" and "therapeutically effective amount" are used interchangeably. It means an amount effective to treat one or more of the diseases, disorders or afflictions described herein or to reduce their severity. In some embodiments, the effective dose can range from 10 μg to 500 mg.

[0105] In accordance with the methods of the present disclosure, the compounds and compositions can be administered in any amount and by any route of administration effective to treat one or more of the above diseases, disorders or afflictions or to reduce their severity.

[0106] In certain embodiments, the present disclosure relates to the foregoing method, wherein the compound is administered orally.

[0107] In certain embodiments, the present disclosure relates to the foregoing method, wherein the compound is administered parenterally.

[0108] In certain embodiments, the present disclosure relates to the foregoing method, wherein the compound is administered intramuscularly, intravenously, subcutaneously, pulmonary, rectally, intrathecally, topically or intranasally.

[0109] In certain embodiments, the present disclosure relates to the foregoing method, wherein the compound is administered systemically.

[0110] The compounds of the present disclosure are generally used as pharmaceutical compositions (e.g., the compounds of the present disclosure and at least one pharmaceutically acceptable carrier). As used herein, the term "pharmaceutically acceptable carrier" includes solvents, dispersion media, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, salts, preservatives, pharmaceutical stabilizers, buffers (e.g., maleic acid, tartaric acid, lactic acid, citric acid, acetic acid, sodium bicarbonate, sodium phosphate and the like) and the like and combinations thereof that are generally regarded as safe (GRAS) as known to those skilled in the art (see, e.g., Remington's Pharmaceutical Sciences, 18th Edition 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 contemplated. For the purposes of the present disclosure, solvates and hydrates are considered to be pharmaceutical compositions comprising the compounds of the present disclosure and a solvent (i.e., solvate) or water (i.e., hydrate).

[0111] Conventional dissolution and mixing procedures can be used to prepare the formulation. For example, in the presence of one or more of the above excipients, the active pharmaceutical ingredient (i.e., the compound of the present disclosure or a stable form of the compound (e.g., a complex with a cyclodextrin derivative or other known complexing agents)) is dissolved in a suitable solvent. The compounds of the present disclosure are generally formulated into pharmaceutical dosage forms to provide an easily controllable drug dose and to provide an elegant and easy-to-handle product for the patient.

[0112] The pharmaceutical composition (or formulation) for administration can be packaged in a variety of ways depending on the method used to administer the drug. Generally, the article for dispensing includes a container in which the pharmaceutical formulation is stored in a suitable form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include tamper-proof components to prevent inadvertent access to the contents of the package. In addition, a label describing the contents of the container is placed on the container. The label may also include appropriate warnings.

[0113] The pharmaceutical composition comprising the compound of the present disclosure is generally formulated for parenteral or oral administration or for use as a suppository.

[0114] For example, the oral pharmaceutical compositions of the present disclosure can be made 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 composition can be subjected to conventional pharmaceutical operations such as sterilization and / or may contain conventional inert diluents, lubricants, or buffering agents, as well as adjuvants such as preservatives, stabilizers, wetting agents, emulsifying agents, and buffering agents, etc.

[0115] Typically, the pharmaceutical composition is a tablet or gelatin capsule comprising the active ingredient and

[0116] a) diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine;

[0117] b) lubricants such as silica, talc, stearic acid, its magnesium or calcium salts, and / or polyethylene glycol; also applicable to tablets

[0118] c) binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone; if required

[0119] d) disintegrants such as starch, agar, alginic acid or its sodium salt, or effervescent mixtures; and / or

[0120] e) absorbents, coloring agents, flavoring agents, and sweetening agents.

[0121] Tablets can be film-coated or enteric-coated according to methods known in the art.

[0122] Suitable compositions for oral administration include tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs of the compounds of the present disclosure. Compositions intended for oral use are prepared by any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from sweetening agents, flavoring agents, coloring agents, and preservatives in order to provide a pharmaceutically elegant and palatable preparation. Tablets may contain the active ingredient admixed with non-toxic pharmaceutically acceptable excipients suitable for tablet manufacture. These excipients are, 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; binding agents such as starch, gelatin, or acacia; and lubricating agents 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 and thereby provide a sustained action over a longer period. For example, time-delay materials such as glyceryl monostearate or glyceryl distearate may be employed. Formulations for oral use may be presented as hard gelatin capsules in which 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 the active ingredient is mixed with water or an oily medium such as peanut oil, liquid paraffin, or olive oil.

[0123] Parenteral compositions (e.g., intravenous (IV) formulations) are isotonic aqueous solutions or suspensions. Parenteral compositions may be sterilized and / or contain adjuvants such as preservatives, stabilizers, wetting agents or emulsifying agents, solubilizing agents, salts for regulating osmotic pressure, and / or buffering agents. In addition, they may contain other substances of therapeutic value. The compositions are generally prepared according to conventional mixing, granulating, or coating methods and contain from about 0.1 - 75% or contain from about 1 - 50% of the active ingredient.

[0124] The compounds or pharmaceutical compositions of the present disclosure for a subject (e.g., a human) are generally administered orally or enterally in a therapeutic dose. When injected intravenously via infusion, the dose may depend on the infusion rate of the IV formulation administered. Generally, the therapeutically effective dose of the compound, pharmaceutical composition, or combination thereof depends on the species, body weight, age, and condition of the subject, the disorder or disease being treated, or the severity thereof. A physician, pharmacist, clinician, or veterinarian of ordinary skill in the art can readily determine the effective amount of each active ingredient required to prevent, treat, or inhibit the progression of a disorder or disease.

[0125] The above dose characteristics can be demonstrated by the in vitro and in vivo testing of mammals, such as mice, rats, dogs, monkeys, or their isolated organs, tissues, and specimens, used advantageously. The compounds of the present 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 an aqueous solution). The in vitro dose can vary in the range between about 10 -3 molar concentration and 10 -9 molar concentration.

[0126] Definitions

[0127] As used herein, the terms "patient", "subject", or "individual" are used interchangeably and refer to a human or non-human animal. The terms include mammals, such as humans. Generally, the animal is a mammal. The subject also refers to, for example, a primate (e.g., a human, male or female), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird, and the like. In certain embodiments, the subject is a primate. In some embodiments, the subject is a human.

[0128] As used herein, the terms "inhibit", "inhibition", or "inhibiting" refer to a reduction or inhibition of a given disorder, symptom, or condition or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0129] As used herein, the terms "treat", "treating", or "treatment" of any disease, disorder, or condition refer to a therapeutic treatment or a prophylactic treatment. Treatment includes the management and care of a patient for the purpose of combating a disease, disorder, or condition, and includes the administration of the compounds of the present disclosure to obtain the desired pharmacological and / or physiological effects. Therapeutic treatment includes partially or substantially achieving one or more of the following results: partially or completely reducing the extent of the disease, disorder, or condition; improving or ameliorating the clinical symptoms, complications, or metrics associated with the disease, disorder, or condition; or delaying, inhibiting, or reducing the likelihood of progression of the disease, disorder, or condition; or eliminating the disease, disorder, or condition. Prophylactic treatment refers to reducing the likelihood of manifesting the symptoms or complications of a disease, disorder, or condition.

[0130] As used herein, a subject "needs" such treatment if the subject (in some embodiments, a human) will benefit biologically, medically, or in terms of quality of life from the treatment.

[0131] As used herein, the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted". Generally, the term "optionally substituted" means that a hydrogen group in a given structure is replaced by a group 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 a substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted by more than one substituent selected from the specified groups, the substituents at each position may be the same or different. In some embodiments, the "one or more" substituents may be 1, 2, 3, 4, 5, 6, etc. substituents, and each substituent may be the same or different. In some embodiments, the "one or more" substituents may be 1 to 6, 1 to 4, 1 to 3, or 1 to 2 substituents, and each substituent may be the same or different.

[0132] As used herein, the term "alkyl" refers to a fully saturated branched or unbranched hydrocarbon moiety. The term "C 1-6 alkyl" refers to an alkyl having 1 to 6 carbon atoms. The term "C 1-4 alkyl" refers to an alkyl having 1 to 4 carbon atoms. The terms "C 1-3 alkyl" and "C 1-2 alkyl" shall be construed accordingly. Representative examples of "C 1-4 alkyl" include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl. Similarly, the alkyl moiety of an alkoxy group (i.e., the alkyl portion) has the same definition as described above. When indicated as "optionally substituted", the alkane group or alkyl moiety may be unsubstituted or substituted with one or more substituents (generally 1 to 3 substituents, except in the case of halogen substituents of perchloro or perfluoroalkyl).

[0133] As used herein, the term "alkoxy" refers to a fully saturated branched or unbranched alkyl moiety attached via an oxygen bridge (i.e., --O--C 1-4 alkyl, where C 1-4 alkyl is as defined herein). Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, and similar groups. In some embodiments, the alkoxy has 1-6 carbons, 1-4 carbons, or 1-3 carbons, and in some embodiments has about 1-2 carbons. The term "C 1-6 alkoxy" refers to an alkoxy having 1 to 6 carbon atoms, and the term "C 1-3 alkoxy" refers to an alkoxy having 1 to 3 carbon atoms. The term "C 1-2 alkoxy" shall be construed accordingly.

[0134] The number of carbon atoms in a group is herein denoted by the prefix "C x-xx” is specified, where x and xx are integers. For example, “C 1-3 alkyl” is an alkyl group having 1 to 3 carbon atoms.

[0135] “Halogen” or “halo group” can be fluorine, chlorine, bromine, or iodine.

[0136] As used herein, the term “haloalkyl” refers to an alkyl group as defined herein, wherein at least one hydrogen atom is replaced by a halogen atom. The term “C 1-6 haloalkyl” refers to a haloalkyl group having 1 to 6 carbon atoms. The terms “C 1-4 haloalkyl” and “C 1-3 haloalkyl” shall be construed accordingly. A haloalkyl group can be a mono-haloalkyl group, a di-haloalkyl group, or a poly-haloalkyl group, including a per-haloalkyl group. A mono-haloalkyl group can have one iodine, bromine, chlorine, or fluorine within the alkyl group. A di-haloalkyl group and a poly-haloalkyl group can have two or more identical halogen atoms or a combination of different halo groups within the alkyl group. Generally, a poly-haloalkyl 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. C 1-6 Non-limiting examples of C haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. A per-haloalkyl group refers to an alkyl group in which all hydrogen atoms are replaced by halogen atoms.

[0137] As used herein, the term “haloalkoxy” refers to an alkoxy group as defined herein, wherein at least one hydrogen atom on the alkyl moiety is replaced by a halogen atom. The term “C 1-6 haloalkoxy” refers to a haloalkoxy group having 1 to 6 carbon atoms. The terms “C 1-4 haloalkoxy” and “C 1-3 haloalkoxy” shall be construed accordingly. A haloalkoxy group can be a mono-haloalkoxy group, a di-haloalkoxy group, or a poly-haloalkoxy group, including a per-haloalkoxy group. A mono-haloalkoxy group can have one iodine, bromine, chlorine, or fluorine within the alkyl moiety of the alkoxy group. A di-haloalkoxy group and a poly-haloalkoxy group can have two or more identical halogen atoms or a combination of different halo groups within the alkyl moiety of the alkoxy group. Generally, a poly-haloalkoxy 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. C 1-6 Non-limiting examples of C haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, pentafluoroethoxy, heptafluoropropoxy, difluorochloromethoxy, dichlorofluoromethoxy, difluoroethoxy, difluoropropoxy, dichloroethoxy, and dichloropropoxy.

[0138] The term "aryl" refers to an aromatic carbocyclic monocyclic group having 6 to 10 carbon atoms or a group of two fused ring systems. Examples include phenyl and naphthyl.

[0139] The term "heteroaryl" refers to a 5- to 10-membered aromatic group containing 1-4 heteroatoms independently selected from N, O, and S. In some cases, the nitrogen atom in the heteroaryl can be quaternized. The term "heteroaryl" can be used interchangeably with the terms "heteroaromatic ring", "heteroaryl group", or "heteroaromatic". The heteroaryl can be monocyclic or bicyclic. In some embodiments, the monocyclic heteroaryl is a 5- or 6-membered monocyclic heteroaryl. 5- or 6-membered monocyclic heteroaryls include, for example, pyrrolyl, furyl, thiophenyl / thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, triazolyl, tetrazolyl, pyridyl, pyranyl, thiopyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazinyl, thiazinyl, dioxolenyl, dithioleneyl, oxathiolanyl, triazinyl, tetrazinyl, and similar groups. Bicyclic heteroaryls include groups in which a monocyclic heteroaromatic ring is fused to one or more aromatic or heteroaromatic rings. Non-limiting examples include indolyl, indazolyl, benzofuryl, benzimidazolyl, and imidazo[1,2-a]pyridine.

[0140] The term "carbocycle" refers to a 4- to 12-membered saturated or partially unsaturated hydrocarbon ring and can exist as a monocyclic, bicyclic (including fused, spiro, or bridged carbocycles), or spiro ring.

[0141] The term "carbocyclic group" refers to a 4- to 12-membered saturated or partially unsaturated hydrocarbon ring group and can exist as a monocyclic, bicyclic (including fused, spiro, or bridged carbocycles), or spiro ring.

[0142] Bicyclic carbocyclic groups include, for example, unsaturated carbocyclic groups fused to another unsaturated carbocyclic group, cycloalkyl, or aryl, such as cyclohexyl, cyclohexenyl, 2,3-dihydroindenyl, indanyl, decahydronaphthyl, and 1,2,3,4-tetrahydronaphthyl. Unless otherwise specified, carbocycles generally contain 4 to 10 ring members.

[0143] The term "C 3-6 cycloalkyl" refers to a completely saturated carbocyclic group (such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl). The term "C 3-4 cycloalkyl" refers to a completely saturated carbocyclic group (such as cyclopropyl, cyclobutyl).

[0144] The term "heterocycle" refers to a 4- to 12-membered saturated or partially unsaturated heterocycle containing 1 to 4 heteroatoms independently selected from N, O, and S. The heterocyclic group can be monocyclic or bicyclic (e.g., bridged, fused, or spiro bicyclic).

[0145] The term "heterocyclic group" refers to a 4- to 12-membered saturated or partially unsaturated heterocyclic group containing 1 to 4 heteroatoms independently selected from N, O, and S. The heterocyclic group can be monocyclic or bicyclic (e.g., bridged, fused, or spirobicyclic).

[0146] Examples of monocyclic saturated or partially unsaturated heterocyclic groups include, but are not limited to, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, and pyrrolidinyl. Bicyclic heterocyclic groups include, for example, saturated or partially unsaturated heterocyclic groups fused to another saturated or partially unsaturated heterocyclic group, cycloalkyl, aryl, or heteroaryl ring, such as dihydroindolyl, indolin-2-one, 2,3-dihydro-1H-pyrrolopyridinyl, 6,7-dihydro-5H-pyrrolopyrazinyl, 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]thienyl, and 4,7-dihydro-5H-thieno[2,3-c]pyranyl. In some embodiments, the heterocyclic group is a 3- to 6-membered monocyclic heterocyclic group. In some embodiments, the 3- to 6-membered monocyclic heterocyclic group is oxetanyl and tetrahydropyranyl. In some embodiments, the heterocyclic group is a 4- to 6-membered monocyclic heterocyclic group. In some embodiments, the heterocyclic group is an 8- to 10-membered bicyclic heterocyclic group.

[0147] As used herein, the term "spiro" ring means a bicyclic system in which the two rings share a common atom. Examples of spiro rings include 5-oxaspiro[2.3]hexyl, oxaspiro[2.4]heptyl, 5-oxaspiro[2.4]heptyl, 4-oxaspiro[2.4]heptyl, 4-oxaspiro[2.5]octyl, 6-oxaspiro[2.5]octyl, oxaspiro[2.5]octyl, oxaspiro[3.4]octyl, 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]heptyl, -oxa-6-azaspiro[3.3]heptyl, 2,2,6-diazaspiro[3.3]heptyl, 3-azaspiro[5.5]undecyl, 3,9-diazaspiro[5.5]undecyl, 7-azaspiro[3.5]nonyl, 2,6-diazaspiro[3.4]octyl, 8-azaspiro[4.5]decyl, 1,6-diazaspiro[3.3]heptyl, 5-azaspiro[2.5]octyl, 4,7-diazaspiro[2.5]octyl, 5-oxa-2-azaspiro[3.4]octyl, 6-oxa-1-azaspiro[3.3]heptyl, 3-azaspiro[5.5]undecyl, 3,9-diazaspiro[5.5]undecyl, and similar groups.

[0148] The term "fused" rings means that two ring systems share two adjacent ring atoms. At least one of the ring systems of the fused heterocycle contains ring atoms that are heteroatoms selected from O, N, and S (e.g., 3-oxabicyclo[3.1.0]hexane). The term "bridged C 5-12 cycloalkyl" means a 5- to 12-membered bridged carbocyclic group. Examples of bridged C 5-12 cycloalkyl include, but are not limited to, bicyclo[1.1.1]pentyl.

[0149] As used herein, the term "bridged" means a 5- to 12-membered cyclic moiety that is connected at two non-adjacent ring atoms (e.g., bicyclo[1.1.1]pentane, bicyclo[2.2.1]heptane, and bicyclo[3.2.1]octane). The term "bridged C 5-12 cycloalkyl" means a 5- to 12-membered bridged carbocyclic group. Examples of bridged C 5-12 cycloalkyl include, but are not limited to, bicyclo[1.1.1]pentyl.

[0150] The phrase "pharmaceutically acceptable" indicates that a substance, composition, or dosage form must be chemically and / or toxicologically compatible with the other ingredients of the formulation and / or the mammal being treated therewith.

[0151] Unless otherwise indicated, the term "compounds of the present disclosure" refers to compounds of formula (I) or (IA), as well as all stereoisomers (including diastereoisomers and enantiomers), rotamers, and tautomers. When moieties capable of forming salts are present, then salts are also included, particularly pharmaceutically acceptable salts.

[0152] Unless otherwise indicated or clearly contradicted by the context, as used herein, the terms "a / an", "the", and similar terms used in the context of the present disclosure (particularly in the context of the claims) shall be construed to cover the singular and the plural. The use of any and all examples or exemplary language (such as "for example") provided herein is merely intended to better illustrate the present disclosure and does not limit the scope of the present disclosure as otherwise claimed.

[0153] The intermediates and compounds of the present disclosure may also exist in different tautomeric forms, and all such forms are encompassed within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can be interconverted via a low energy barrier. For example, proton tautomers (also known as proton transfer tautomers) include interconversions that occur via proton migration, such as keto-enol and imine-enamine isomerization. Specific examples of proton tautomers are imidazole moieties, where the proton can migrate between two ring nitrogens. Valence tautomers include interconversions that occur through some reorganization of bonding electrons.

[0154] In one embodiment, the present disclosure relates to compounds of formula (I) or (IA) as defined herein in free form. In another embodiment, the present disclosure relates to compounds of formula (I) or (IA) as defined herein in salt form. In another embodiment, the present disclosure relates to compounds of formula (I) or (IA) as defined herein in acid addition salt form. In another embodiment, the present disclosure relates to compounds of formula (I) or (IA) as defined herein in pharmaceutically acceptable salt form. In another embodiment, the present disclosure relates to compounds of formula (I) or (IA) as defined herein in pharmaceutically acceptable acid addition salt form. In another embodiment, the present disclosure relates to any one of the exemplified compounds in free form. In another embodiment, the present disclosure relates to any one of the exemplified compounds in salt form. In another embodiment, the present disclosure relates to any one of the exemplified compounds in acid addition salt form. In another embodiment, the present disclosure relates to any one of the exemplified compounds in pharmaceutically acceptable salt form. In another embodiment, the present disclosure relates to any one of the exemplified compounds in pharmaceutically acceptable acid addition salt form.

[0155] The compounds of the present disclosure can be synthesized by synthetic routes that include methods similar to those well-known in the art of chemistry, particularly in accordance with the descriptions contained herein. The starting materials are generally commercially available, for example from Sigma-Aldrich, or can be readily prepared using methods well-known to those skilled in the art (e.g., prepared by methods generally described in: Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, Volumes 1-19, Wiley, New York (1967 - 1999); or Beilsteins Handbuch der organischen Chemie, 4th Aufl., Springer-Verlag, Berlin, including supplementary data (also available via the Beilstein online database)).

[0156] For illustrative purposes, the reaction schemes depicted below provide potential routes for synthesizing the compounds of the present disclosure and key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Although specific starting materials and reagents are described in the schemes and discussed below, other starting materials and reagents can be readily substituted to provide a variety of derivatives and / or reaction conditions.

[0157] Examples

[0158] Abbreviations:

[0159] Cs 2 CO 3 = Cesium carbonate

[0160] DCM = CH 2 Cl 2 = Dichloromethane

[0161] DIPEA = DIEA = Diisopropylethylamine

[0162] DMF = Dimethylformamide

[0163] DMSO = Dimethyl sulfoxide

[0164] Et 2 O = Diethyl ether

[0165] EtOAc = EA = Ethyl acetate

[0166] EtOH = Ethanol

[0167] h = Hour

[0168] H 2 O = Water

[0169] H 2 SO 4 = Sulfuric acid

[0170] HATU = O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0171] HCl = Hydrochloric acid

[0172] HNO 3 = Nitric acid

[0173] HPLC = High performance liquid chromatography

[0174] K 2 CO 3 = Potassium carbonate

[0175] KI = Potassium iodide

[0176] LCMS = Liquid chromatography - mass spectrometry

[0177] LDA = Lithium diisopropylamide

[0178] LiAlH 4 = LAH = Lithium aluminum hydride

[0179] LiBH 4 = Lithium borohydride

[0180] LiCl = Lithium chloride

[0181] MeCN = ACN = CH 3 CN = Acetonitrile

[0182] MeOH = Methanol

[0183] N 2 = nitrogen

[0184] Na 2 SO 4 = sodium sulfate

[0185] NaH = sodium hydride

[0186] NaOEt = sodium ethoxide

[0187] NaOH = sodium hydroxide

[0188] NaOMe = sodium methoxide

[0189] n-BuLi = n-butyllithium

[0190] NH 4 Cl = ammonium chloride

[0191] NH 4 OH = ammonium hydroxide

[0192] NMR = nuclear magnetic resonance spectroscopy

[0193] NOESY = nuclear Overhauser effect spectroscopy

[0194] Pd(PPh 3 ) 4 = tetrakis(triphenylphosphine)palladium(0)

[0195] Pd / C = palladium on carbon

[0196] Pd 2 (dba) 3 = tris(dibenzylideneacetone)dipalladium(0)

[0197] POBr 3 = phosphoryl bromide

[0198] POCl 3 = phosphoryl chloride

[0199] PPA = polyphosphoric acid

[0200] RT = room temperature

[0201] t-BuOH = tert-butanol

[0202] t-BuOK = potassium tert-butoxide

[0203] TEA = Et 3 N = triethylamine

[0204] TFA = trifluoroacetic acid

[0205] THF = tetrahydrofuran

[0206] TLC = thin layer chromatography

[0207] Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethyldibenzopyran

[0208] Example 1: N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)oxetan-3-carboxamide

[0209]

[0210] Scheme:

[0211]

[0212] 1. Synthesis of 6-nitroquinoline-2,4-diol

[0213]

[0214] To a stirred solution of quinoline-2,4-diol (5 g, 31.03 mmol) in H 2 SO 4 (45 mL) was added dropwise HNO 3 (1.2 mL) at room temperature. The mixture was stirred at room temperature for 30 minutes. Then, the reaction mixture was poured into ice-cold water (200 mL). The formed precipitate was filtered and washed with water (50 mL), and dried in vacuo to give 6-nitroquinoline-2,4-diol as a yellow solid (4.5 g, yield: 70%). 1 H 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, 2.57 Hz, 1H), 7.39 (d, J = 9.05 Hz, 1H), 5.83 (s, 1H).

[0215] 2. Synthesis of 2,4-dichloro-6-nitroquinoline

[0216]

[0217] A stirred solution of 6-nitroquinoline-2,4-diol (10 g, 48.51 mmol) in POCl 3 (100 mL) was heated at 100 °C for 24 hours. Then, the reaction mixture was cooled to room temperature and quenched slowly with ice-cold water (100 mL). The formed precipitate was filtered and dried in vacuo to give 2,4-dichloro-6-nitroquinoline as a yellow solid (8.6 g, yield: 73%). 1 HNMR (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).

[0218] 3. Synthesis of 2-chloro-4-(2-methoxyethoxy)-6-nitroquinoline

[0219]

[0220] At room temperature, K 2 CO 3 (1.8 g, 12.43 mmol) was added to a stirred solution of 2,4-dichloro-6-nitroquinoline (2 g, 8.29 mmol) and 2-methoxyethan-1-ol (0.76 g, 9.95 mmol) in DMF (20 mL), and the mixture was heated at 110 °C for 16 h. Then, the reaction mixture was cooled to room temperature and poured into water (200 mL). The aqueous layer was extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo to give a mixture of 2-chloro-4-(2-methoxyethoxy)-6-nitroquinoline and 4-chloro-2-(2-methoxyethoxy)-6-nitroquinoline. The crude product thus obtained was purified by combi flash chromatography (dichloromethane) to give 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: The isomers were confirmed by 2D NOESY. 2-Chloro-4-(2-methoxyethoxy)-6-nitroquinoline: LCMS (ESI+): m / z C 12 H 12 ClN 2 O 4 [M + H] + calculated, 283; found, 283. 1 HNMR (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+): m / z C 12 H 12 ClN 2 O4 [M+H] + Calculated value, 283; experimental 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, 1H), 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).

[0221] 4: Synthesis of 5-(4-(2-methoxyethoxy)-6-nitroquinolin-2-yl)thiazole

[0222]

[0223] 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 N 2 for 30 minutes. 5-(Tributylstannyl)thiazole (0.50 g, 1.32 mmol) and Pd(PPh 3 ) 4 (0.2 g, 0.17 mmol) were added and the mixture was purged with N 2 for 5 minutes. The reaction was heated in a sealed tube at 110 °C for 16 hours. Then, the reaction mixture was cooled to room temperature and diluted with water (50 mL). The aqueous layer was extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The resulting crude material was triturated with CH 3 CN (5 mL) and dried in vacuo to give 5-(4-(2-methoxyethoxy)-6-nitroquinolin-2-yl)thiazole as a white solid (0.24 g, yield: 82%). The resulting compound was used in the next step without purification. LCMS (ESI+): m / z C 15 H 14 N 3 O 4 S [M+H] + Calculated value, 332; experimental value, 332. 1 H 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).

[0224] 5. Synthesis of 4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-amine

[0225]

[0226] To a stirred solution of 5-(4-(2-methoxyethoxy)-6-nitroquinolin-2-yl)thiazole (0.22 g, 0.4 mmol) in MeOH (5 mL) was added 10% Pd / C (50% wet, 30 mg) and the reaction was stirred in a steel pressure vessel under a hydrogen atmosphere at 50 psi at room temperature for 16 h. Subsequently, the reaction mixture was filtered through a pad of diatomaceous earth and washed with DCM (100 mL) containing 10% MeOH. The filtrate was concentrated in vacuo to afford 4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-amine (0.2 g, crude) as a viscous black solid. The crude compound thus obtained was used in the next step without purification. LCMS (ESI+): m / z C 15 H 16 N 3 O 2 S [M + H] + calculated, 302; found, 302. 1 H 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).

[0227] 6. Synthesis of N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)oxetane-3-carboxamide

[0228]

[0229] To a stirred solution of oxetanecarboxylic acid (0.07 g, 0.72 mmol) in DMF (3 mL) was added HATU (0.44 g, 1.17 mmol) and the mixture was stirred for 10 minutes. 4-(2-Methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-amine (0.18 g, 0.60 mmol) was added to the reaction mixture at room temperature and then DIPEA (0.28 mL, 1.56 mmol) was added. The reaction was stirred at room temperature for 16 hours. Then, the reaction mixture was diluted with water (50 mL) and extracted with DCM containing 10% MeOH (2 × 100 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4 dried, filtered and concentrated in vacuo. The resulting crude material was purified by reverse phase preparative HPLC to give N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)oxetanecarboxamide (0.07 g, yield: 30%) as a white solid. HPLC purity: 95.11%. LCMS (ESI+): m / z C 19 H 20 N 3 O 4 S [M + H] + calculated, 386; found, 386. 1 H 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 (quintet, J = 7.54 Hz, 1H), 3.83 - 3.90 (m, 2H), 3.41 (s, 3H).

[0230] Example 2: N-(4-Ethoxy-2-(4-methyl-1H-imidazol-1-yl)quinolin-6-yl)oxetanecarboxamide

[0231]

[0232] Scheme:

[0233]

[0234] 1. Synthesis of 4-ethoxy-6-nitroquinolin-2-ol

[0235]

[0236] To a stirred solution of 6-nitroquinoline-2,4-diol (5 g, 24.26 mmol × 2 batches) in DMF (100 mL) was added K 2 CO 3 (6.7 g, 48.5 mmol) and the mixture was heated to 60 °C for 1 hour. The reaction was cooled to room temperature and iodoethane (3.7 g, 24.26 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. Then, the reaction mixture was poured into ice-cold water (500 mL), the solid was filtered, washed with water (100 mL) and dried in vacuo. The resulting crude material was wet-milled with heptane containing 80% EtOAc to give 4-ethoxy-6-nitroquinolin-2-ol (5 g, crude) as a light brown solid. 1 H 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, 1H), 5.02 (q, J = 7.17 Hz, 2H), 2.26 (t, J = 6.85 Hz, 3H).

[0237] 2. Synthesis of 2-bromo-4-ethoxy-6-nitroquinoline

[0238]

[0239] To a stirred solution of 4-ethoxy-6-nitroquinolin-2-ol (5 g, 21.36 mmol) in toluene (50 mL) at room temperature was added POBr 3 (18 g, 64.10 mmol) and the mixture was heated to 110 °C for 16 hours. Then, the reaction mixture was quenched with ice-cold water (200 mL), the solid was filtered, washed with water (50 mL) and dried in vacuo. The resulting crude material was purified by combiflash chromatography (70 to 80% EtOAc in heptane) to give 2-bromo-4-ethoxy-6-nitroquinoline (3 g, yield: 47%) as a light yellow solid. LCMS (ESI+): m / z C 11 H 10 BrN 2 O 3 [M + H] + Calculated for, 298; found, 298. 1 H 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).

[0240] 3. Synthesis of 4-ethoxy-2-(4-methyl-1H-imidazol-1-yl)-6-nitroquinoline

[0241]

[0242] To a stirred solution of 4-methyl-1H-imidazole (0.1 g, 1.26 mmol) in DMF (10 mL) at room temperature was added Cs 2 CO 3 (0.82 g, 2.52 mmol) and KI (0.013 g, 0.08 mmol) and the mixture was stirred for 10 minutes and 2-bromo-4-ethoxy-6-nitroquinoline (0.25 g, 0.84 mmol) was added at room temperature and the mixture was heated to 100 °C for 16 h. Then, the reaction mixture was cooled to room temperature and poured into ice water (100 mL), the solid was filtered, washed with washing water (20 mL), and dried in vacuo. The obtained crude material was wet-milled with n-pentane (10 mL) and Et 2 O (10 mL) and dried in vacuo to give 4-ethoxy-2-(4-methyl-1H-imidazol-1-yl)-6-nitroquinoline as a pale yellow solid (0.2 g, yield: 80%). LCMS (ESI+): m / z C 15 H 15 N 4 O 3 [M + H] + calculated value, 299; experimental value, 299. 1 H 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).

[0243] 4. Synthesis of 4-ethoxy-2-(4-methyl-1H-imidazol-1-yl)quinolin-6-amine

[0244]

[0245] To a stirred solution of 4-ethoxy-2-(4-methyl-1H-imidazol-1-yl)-6-nitroquinoline (0.2 g, 0.67 mmol) in MeOH (10 mL) was added 10% Pd / C (50% wet, 0.07 g) and the reaction was stirred in a steel pressure vessel under a hydrogen atmosphere at 50 psi at room temperature for 16 h. Subsequently, the reaction mixture was filtered through a Celite pad and washed with MeOH (50 mL). The filtrate was concentrated in vacuo to give 4-ethoxy-2-(4-methyl-1H-imidazol-1-yl)quinolin-6-amine (0.15 g, crude) as a pale yellow solid. The crude compound thus obtained was used in the next step without purification. LCMS (ESI+): m / z C 15 H 17 N 4 O [M+H] + calculated, 269; found, 269. 1 H 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).

[0246] 5. Synthesis of N-(4-ethoxy-2-(4-methyl-1H-imidazol-1-yl)quinolin-6-yl)oxetane-3-carboxamide

[0247]

[0248] To a stirred solution of oxetane-3-carboxylic acid (0.085 g, 0.83 mmol) in DMF (10 mL) was added HATU (0.53 g, 1.39 mmol) and the mixture was stirred for 10 min. At room temperature, 4-ethoxy-2-(4-methyl-1H-imidazol-1-yl)quinolin-6-amine (0.15 g, 0.55 mmol) was added to the reaction mixture and then DIPEA (0.3 mL, 1.67 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. Subsequently, the reaction mixture was diluted with ice-cold water (50 mL) and extracted with DCM containing 5% MeOH (2 × 100 mL). The organic layer was washed with brine (50 mL) and dried over anhydrous Na 2 SO 4Dry, filter and concentrate in vacuo. The resulting crude material was purified by combi flash chromatography (0 to 5% MeOH in DCM) to afford N-(4-ethoxy-2-(4-methyl-1H-imidazol-1-yl)quinolin-6-yl)oxetane-3-carboxamide as an off-white solid (0.071 g, yield: 36%). HPLC purity: 95.19%. LCMS (ESI+): m / z C 19 H 21 N 4 O 3 [M+H] + Calcd for, 353; found, 353. 1 HNMR (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 (quintet, J = 7.47 Hz, 1H), 2.20 (s, 3H), 1.52 (t, J = 6.94 Hz, 3H).

[0249] Example 3: N-(4-Ethoxy-2-(thiazol-5-yl)quinolin-6-yl)oxetane-3-carboxamide

[0250]

[0251] Protocol:

[0252]

[0253] 1. Synthesis of 5-(4-Ethoxy-6-nitroquinolin-2-yl)thiazole

[0254]

[0255] 5-(4-Ethoxy-6-nitroquinolin-2-yl)thiazole was prepared following the procedure for the preparation of 5-(4-(2-methoxyethoxy)-6-nitroquinolin-2-yl)thiazole. The resulting compound was purified by combi flash chromatography (5 to 10% EtOAc in heptane) to afford a yellow solid (0.4 g, yield: 65%). LCMS (ESI+): m / z C 14 H 12 N 3 O 3 S[M+H] +Calculated value, 302; experimental value, 302. 1 H 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).

[0256] 2. Synthesis of 4-ethoxy-2-(thiazol-5-yl)quinolin-6-amine

[0257]

[0258] 4-Ethoxy-2-(thiazol-5-yl)quinolin-6-amine was prepared using the procedure followed for the preparation of 4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-amine, obtained as a black solid (0.21 g, crude), and was used in the next step without purification. LCMS (ESI+): m / z C 14 H 14 N 3 OS [M+H] + Calculated value, 272; experimental value, 272. 1 H 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).

[0259] 3. Synthesis of N-(4-ethoxy-2-(thiazol-5-yl)quinolin-6-yl)oxetane-3-carboxamide

[0260]

[0261] N-(4-Ethoxy-2-(thiazol-5-yl)quinolin-6-yl)oxetan-3-carboxamide was prepared by replacing 4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-amine in N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)oxetan-3-carboxamide with 4-ethoxy-2-(thiazol-5-yl)quinolin-6-amine, giving a pale grey solid (0.04 g, yield: 31%). HPLC purity: 98.93%. LCMS (ESI+): m / z C 18 H 18 N 3 O 3 S[M+H] + Calculated value for, 356; experimental value, 356. 1 H 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).

[0262] Example 4: N-(4-Ethoxy-2-(thiazol-5-yl)quinolin-6-yl)bicyclo[1.1.1]pentane-1-carboxamide

[0263]

[0264] N-(4-Ethoxy-2-(thiazol-5-yl)quinolin-6-yl)bicyclo[1.1.1]pentane-1-carboxamide was prepared by replacing oxetan-3-carboxylic acid in N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)oxetan-3-carboxamide with bicyclo[1.1.1]pentane-1-carboxylic acid, giving a pale grey solid (0.05 g, yield: 46%). HPLC purity: 95.22%. LCMS (ESI+): m / z C 20 H 20 N 3 O 2 S[M+H] + Calculated value for, 366; experimental value, 366. 1 H 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).

[0265] Example 5: N-(4-Methoxy-2-(thiazol-5-yl)quinolin-6-yl)oxetan-3-carboxamide

[0266]

[0267] Scheme:

[0268]

[0269] 1. Synthesis of 2-chloro-4-methoxy-6-nitroquinoline

[0270]

[0271] To a stirred solution of 2,4-dichloro-6-nitroquinoline (2 g, 10.64 mmol) in MeOH (20 mL) at room temperature was added NaOMe (0.42 g, 31.02 mmol). The reaction mixture was stirred at room temperature for 16 h. Then, the volatiles were removed in vacuo. The crude material was diluted with water (50 mL). The aqueous layer was extracted with EtOAc (2 × 75 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 dried, filtered and concentrated in vacuo to give a mixture of 2-chloro-4-methoxy-6-nitroquinoline and 4-chloro-2-methoxy-6-nitroquinoline. The resulting crude material was purified by combi flash chromatography (40 to 50% EtOAc in heptane) to give 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: The isomers were confirmed by 2D NOESY. 2-Chloro-4-methoxy-6-nitroquinoline: LCMS (ESI+): m / z C 10 H 8 ClN 2 O 3 [M + H] + calculated, 239; found, 239. 11H 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+): m / z C 10 H 8 ClN 2 O 3 [M + H] + calculated, 239; found, 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).

[0272] 2. Synthesis of 5-(4-methoxy-6-nitroquinolin-2-yl)thiazole

[0273]

[0274] 5-(4-Methoxy-6-nitroquinolin-2-yl)thiazole was prepared by replacing 2-chloro-4-(2-methoxyethoxy)-6-nitroquinoline with 2-chloro-4-methoxy-6-nitroquinoline in the procedure for synthesizing 5-(4-(2-methoxyethoxy)-6-nitroquinolin-2-yl)thiazole. The resulting compound was purified by combi flash chromatography (40 to 50% EtOAc in heptane) to give the product as a pale yellow solid (0.22 g, yield: 57%). LCMS (ESI+): m / z C 13 H 10 N 3 O 3 S [M + H] + calculated, 288; found, 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).

[0275] 3. Synthesis of 4-methoxy-2-(thiazol-5-yl)quinolin-6-amine

[0276]

[0277] 4-Methoxy-2-(thiazol-5-yl)quinolin-6-amine was prepared analogously to that described for 4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-amine. The resulting compound was wet milled with diethyl ether and n-pentane to give the product as a pale yellow solid (0.15 g, yield: 76%). LCMS (ESI+): m / z C 13 H 12 N 3 OS [M+H] + calculated, 258; found, 258. 1 HNMR (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, 2H), 4.07 (s, 3H).

[0278] 4. Synthesis of N-(4-methoxy-2-(thiazol-5-yl)quinolin-6-yl)oxetane-3-carboxamide

[0279]

[0280] N-(4-Methoxy-2-(thiazol-5-yl)quinolin-6-yl)oxetane-3-carboxamide was prepared using a procedure similar to that for N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)oxetane-3-carboxamide. The crude material was purified by combi flash column chromatography (5% MeOH / CH 2 Cl 2 ) to give the product as an off-white solid (0.09 g, yield: 45%). HPLC purity: 97.95%. LCMS (ESI+): m / z C 17 H 16 N 3 O 3 S [M+H] + calculated, 342; found, 342. 1 H 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).

[0281] Example 6: N-(4-Ethoxy-2-(2-methylthiazol-5-yl)quinolin-6-yl)oxetan-3-carboxamide

[0282]

[0283] N-(4-Ethoxy-2-(2-methylthiazol-5-yl)quinolin-6-yl)oxetan-3-carboxamide was prepared using a procedure similar to that of Example 3 and was obtained as an off-white solid (0.05 g, yield: 50%). HPLC purity: 98.23%. LCMS (ESI+): m / z C 19 H 20 N 3 O 3 S [M + H] + calculated value, 370; experimental value, 370. 1 H 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 (quintet, J = 7.50 Hz, 1H), 2.70 (s, 3H), 1.53 (t, J = 7.00 Hz, 3H).

[0284] Example 7: N-(4-Ethoxy-2-(2-methoxythiazol-5-yl)quinolin-6-yl)oxetan-3-carboxamide

[0285]

[0286] Scheme:

[0287]

[0288] 1. Synthesize 5-(4-Ethoxy-6-nitroquinolin-2-yl)-2-methoxythiazole

[0289]

[0290] 5-(4-Ethoxy-6-nitroquinolin-2-yl)-2-methoxythiazole was prepared using the procedure for 5-(4-(2-methoxyethoxy)-6-nitroquinolin-2-yl)thiazole. The crude material was purified by wet grinding with diethyl ether (25 mL) and n-pentane (25 mL) to give the product as a pale yellow solid (0.16 g, yield: 76%). LCMS (ESI+): m / z C 15 H 14 N 3 O 4 S[M+H] + Calculated for, 332; found, 332. 1 H 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).

[0291] 2. Synthesis of 4-ethoxy-2-(2-methoxythiazol-5-yl)quinolin-6-amine

[0292]

[0293] 4-Ethoxy-2-(2-methoxythiazol-5-yl)quinolin-6-amine was prepared using the procedure followed for the preparation of 4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-amine and was obtained as a pale yellow viscous solid (0.11 g, 85%). LCMS (ESI+): m / z C 15 H 16 N 3 O 2 S[M+H] + Calculated for, 302; found, 302. 1 H 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).

[0294] 3. Synthesis of N-(4-Ethoxy-2-(2-methoxythiazol-5-yl)quinolin-6-yl)oxetane-3-carboxamide

[0295]

[0296] N-(4-Ethoxy-2-(2-methoxythiazol-5-yl)quinolin-6-yl)oxetane-3-carboxamide was prepared using a procedure similar to that of N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)oxetane-3-carboxamide). The crude material was purified by combi flash chromatography (1% MeOH / CH 2 Cl 2 ) to give the product as an off-white solid (0.04 g, yield: 26%). HPLC purity: 97.09%. LCMS (ESI+): m / z C 19 H 20 N 3 O 4 S [M+H] + calculated, 386; found, 386. 1 H 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).

[0297] Example 8: N-(2-(2-Cyclopropylthiazol-5-yl)-4-ethoxyquinolin-6-yl)oxetane-3-carboxamide

[0298]

[0299] Protocol:

[0300]

[0301] 1. Synthesis of 2-Cyclopropyl-5-(tributylstannyl)thiazole

[0302]

[0303] At -78 °C under an argon atmosphere, n-BuLi (1.5 mL, 3.84 mmol, solution in hexane at 2.5 M) was added dropwise to a stirred solution of DIPEA (0.7 mL, 4.80 mmol) in THF (5 mL), and the mixture was kept for 5 minutes and stirred for 40 minutes. At -78 °C, the freshly generated LDA solution was added dropwise to a stirred solution of 2-cyclopropylthiazole (0.4 g, 3.20 mmol) in anhydrous THF (5 mL) over 5 minutes and stirred at the same temperature for 40 minutes. It was added thereto at -78 °C for 1 hour. At -78 °C, tributyltin chloride (0.9 mL, 3.2 mmol) was added dropwise thereto over 5 minutes and stirred at the same temperature for 2 hours. The reaction mixture was quenched with saturated ammonium chloride solution (10 mL) and extracted with EtOAc (2 × 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give a crude material. The obtained crude material was purified by combi flash chromatography (100% heptane) to give 2-cyclopropyl-5-(tributylstannyl)thiazole as a colorless oil (0.2 g, yield: 18%).

[0304] 2. Synthesis of 2-cyclopropyl-5-(4-ethoxy-6-nitroquinolin-2-yl)thiazole

[0305]

[0306] 2-cyclopropyl-5-(4-ethoxy-6-nitroquinolin-2-yl)thiazole was prepared using the procedure for 5-(4-(2-methoxyethoxy)-6-nitroquinolin-2-yl)thiazole. The obtained compound was purified by combi flash chromatography (20% EtOAc / heptane) to give the product as an off-white solid (0.1 g, yield: 48%). HPLC: 98.1%. 1 H 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).

[0307] 3. Synthesis of 2-(2-cyclopropylthiazol-5-yl)-4-ethoxyquinolin-6-amine

[0308]

[0309] 2-(2-Cyclopropylthiazol-5-yl)-4-ethoxyquinolin-6-amine was prepared following the procedure used for the preparation of 4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-amine and was obtained as a pale yellow viscous solid (0.11 g, crude). LCMS (ESI+): m / z C 17 H 18 N 3 OS [M+H] + calculated, 312; found, 312.

[0310] 4. Synthesis of N-(2-(2-Cyclopropylthiazol-5-yl)-4-ethoxyquinolin-6-yl)oxetane-3-carboxamide

[0311]

[0312] N-(2-(2-Cyclopropylthiazol-5-yl)-4-ethoxyquinolin-6-yl)oxetane-3-carboxamide was prepared using a procedure similar to that for N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)oxetane-3-carboxamide and was obtained as an off-white solid (0.008 g, yield: 7%). HPLC purity: 96.44%. LCMS (ESI+): m / z C 21 H 22 N 3 O 3 S [M+H] + calculated, 396; found, 396. 1 H 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).

[0313] Example 9: N-(4-(2-Hydroxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)oxetane-3-carboxamide

[0314]

[0315] Scheme:

[0316]

[0317] 1. Synthesis of 4-(2-(Benzyloxy)ethoxy)-2-chloro-6-nitroquinoline

[0318]

[0319] 4-(2-(Benzyloxy)ethoxy)-2-chloro-6-nitroquinoline was prepared using the procedure followed for the preparation of 2-chloro-4-(2-methoxyethoxy)-6-nitroquinoline. The mixture was purified by combi flash chromatography (50 to 80% EtOAc in heptane) to afford 4-(2-(benzyloxy)ethoxy)-2-chloro-6-nitroquinoline as an off-white solid (0.9 g, yield: 20%) and 2-(2-(benzyloxy)ethoxy)-4-chloro-6-nitroquinoline as an off-white solid (0.9 g, yield: 20%). Note: The isomers were confirmed by 2D NOESY. 4-(2-(Benzyloxy)ethoxy)-2-chloro-6-nitroquinoline: LCMS (ESI+): m / z C 18 H 16 ClN 2 O 4 [M+H] + calculated, 359; found, 359. 1 H 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).

[0320] 2. Synthesis of 5-(4-(2-(Benzyloxy)ethoxy)-6-nitroquinolin-2-yl)thiazole

[0321]

[0322] 5-(4-(2-(Benzyloxy)ethoxy)-6-nitroquinolin-2-yl)thiazole was prepared using the procedure for the preparation of 5-(4-(2-methoxyethoxy)-6-nitroquinolin-2-yl)thiazole. The resulting compound was purified by combi flash chromatography (1% MeOH in CH 2 Cl 2 to afford the product as a light brown solid (0.38 g, yield: 74%). LCMS (ESI+): m / z C 21 H 18 N 3 O4 Calculated value of S[M+H], 408; experimental value, 408. + The calculated value of, 408; the experimental value, 408. 1 H 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).

[0323] 3. Synthesis of 2 - ((6 - nitro - 2 - (thiazol - 5 - yl) quinolin - 4 - yl) oxy) ethanol - 1 - ol

[0324]

[0325] At 0 °C, trifluoroacetic acid (1 mL) was added to 5 - (4 - (2 - (benzyloxy) ethoxy) - 6 - nitroquinolin - 2 - yl) thiazole (0.38 g, 0.13 mmol). The reaction mixture was heated to 80 °C and stirred for 16 hours. Then, volatiles were removed in vacuo to obtain the crude material. The crude product 2 - ((6 - nitro - 2 - (thiazol - 5 - yl) quinolin - 4 - yl) oxy) ethanol - 1 - ol (light brown semi - solid, 0.3 g) was used in the next step without further purification. LCMS (ESI+): m / z C 14 H 12 N 3 O 4 Calculated value of S[M+H], 318; experimental value, 318. + The calculated value of, 318; the experimental value, 318.

[0326] 4. Synthesis of 2 - ((6 - amino - 2 - (thiazol - 5 - yl) quinolin - 4 - yl) oxy) ethanol - 1 - ol

[0327]

[0328] 2 - ((6 - amino - 2 - (thiazol - 5 - yl) quinolin - 4 - yl) oxy) ethanol - 1 - ol was prepared using the procedure for the preparation of 4 - (2 - methoxyethoxy) - 2 - (thiazol - 5 - yl) quinolin - 6 - amine and was obtained as a brown solid (0.22 g, crude). LCMS (ESI+): m / z C 14 H 14 N 3 O 2 Calculated value of S[M+H], 288; experimental value, 288. + The calculated value of, 288; the experimental value, 288.

[0329] 5. Synthesis of N-(4-(2-Hydroxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)oxetan-3-carboxamide

[0330]

[0331] N-(4-(2-Hydroxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)oxetan-3-carboxamide was prepared using a similar procedure to that for the preparation of N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)oxetan-3-carboxamide and was obtained as an off-white solid (0.018 g, yield: 12%) after purification by preparative HPLC. HPLC purity: 98.61%. LCMS (ESI+): m / z C 18 H 18 N 3 O 4 S[M+H] + , calculated value for 372; experimental value, 372. 1 H 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).

[0332] Example 10: 2,2,2-Trifluoro-N-(4-(2-hydroxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)acetamide

[0333]

[0334] 1. Synthesis of 2,2,2-Trifluoro-N-(4-(2-hydroxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)acetamide

[0335] At 0 °C, trifluoroacetic acid (1 mL) was added to 2-((6-amino-2-(thiazol-5-yl)quinolin-4-yl)oxy)ethan-1-ol (50 mg, 0.13 mmol). The reaction was heated to 80 °C and stirred for 16 hours. Subsequently, the volatiles of the reaction mixture were removed under vacuum, wet-milled with acetonitrile (5 mL) and diethyl ether (5 mL), and dried under vacuum to obtain 2,2,2-trifluoro-N-(4-(2-hydroxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)acetamide (0.02 g, yield: 40%) as a light brown solid. HPLC purity: 95.36%. LCMS (ESI+): m / z C 16 H 13 F 3 N 3 O 3 S[M+H] + Calculated value, 384; experimental value, 384. 1 H 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).

[0336] Example 11: N-(4-(2-Methoxyethoxy)-2-(2-methylthiazol-5-yl)quinolin-6-yl)oxetane-3-carboxamide

[0337]

[0338] 1. Synthesis of N-(4-(2-Methoxyethoxy)-2-(2-methylthiazol-5-yl)quinolin-6-yl)oxetane-3-carboxamide

[0339] N-(4-(2-Methoxyethoxy)-2-(2-methylthiazol-5-yl)quinolin-6-yl)oxetane-3-carboxamide was prepared in a similar manner to Example 1. HPLC purity: 98.56%. LCMS (ESI+): m / z C 20 H 22 N 3 O 4 S[M+H] + Calculated value, 400; experimental value, 400. 1H NMR (400 MHz, DMSO-d 6,δ):10.29(s,1H),8.53(s,1H),8.43(s,1H),7.96(d,J = 7.2Hz,1H),7.83(d,J = 9.1Hz,1H),7.57(s,1H),4.73(d,J = 7.5Hz,4H),4.50(d,J = 4.0Hz,2H),4.10–3.92(m,1H),3.85(s,2H),3.41(s,3H),2.70(s,3H).

[0340] Example 12: N-(2-(2-chlorothiazol-5-yl)-4-ethoxyquinolin-6-yl)oxetane-3-carboxamide

[0341]

[0342] Scheme:

[0343]

[0344] 1. Synthesis of 2-chloro-5-(4-ethoxy-6-nitroquinolin-2-yl)thiazole

[0345]

[0346] 2-Chloro-5-(4-ethoxy-6-nitroquinolin-2-yl)thiazole was prepared using the procedure for preparing 5-(4-(2-methoxyethoxy)-6-nitroquinolin-2-yl)thiazole and was obtained as an off-white solid (0.21 g, yield: 37%). 1 H NMR(400MHz,DMSO-d 6, δ):8.90(d,J = 1.96Hz,1H),8.80(s,1H),8.45(dd,J = 9.29,2.45Hz,1H),8.07(d,J = 9.29Hz,1H),7.83(s,1H),4.52(q,J = 6.85Hz,2H),0.87(br t,J = 7.09Hz,3H).

[0347] 2. Synthesis of 2-(2-chlorothiazol-5-yl)-4-ethoxyquinolin-6-amine

[0348]

[0349] At room temperature, NH 2 was added to a stirred solution of 2-chloro-5-(4-ethoxy-6-nitroquinolin-2-yl)thiazole (0.26 g, 0.77 mmol) in EtOH:H 4Cl (0.41 g, 7.73 mmol) and Fe powder (0.34 g, 6.19 mmol), and the reaction mixture was heated to 100 °C and stirred for 5 h. Then, the reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated in vacuo to give 2-(2-chlorothiazol-5-yl)-4-ethoxyquinolin-6-amine as a light brown solid (0.6 g, crude). LCMS (ESI+): m / z C 14 H 13 ClN 3 OS [M+H] + Calculated for, 306; found, 306.

[0350] 3. Synthesis of N-(2-(2-chlorothiazol-5-yl)-4-ethoxyquinolin-6-yl)oxetane-3-carboxamide

[0351]

[0352] N-(2-(2-chlorothiazol-5-yl)-4-ethoxyquinolin-6-yl)oxetane-3-carboxamide was prepared using a similar procedure to that for the preparation of N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)oxetane-3-carboxamide as an off-white solid (0.015 g, yield: 20%). HPLC purity: 98.67%. LCMS (ESI+): m / z C 18 H 17 ClN 3 O 3 S [M+H] + , calculated for 390; found, 390. 1 H 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).

[0353] Example 13: 2-Hydroxy-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)acetamide

[0354]

[0355] 1. Synthesis of 2-Hydroxy-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)acetamide

[0356]

[0357] To a stirred solution of 2-hydroxyacetic acid (0.05 g, 0.72 mmol, 1 equiv.) was added HATU (0.41 g, 1.17 mmol, 1.5 equiv.) and the mixture was stirred for 10 min at room temperature. To this was added 4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-amine (0.196 g, 0.65 mmol, 1 equiv.) at room temperature, followed by DIPEA (0.25 mL, 1.84 mmol, 2 equiv.). The reaction was stirred at room temperature for 16 h. Then, the reaction mixture was diluted with water (50 mL) and extracted with DCM containing 10% MeOH (2 × 50 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4 2SO4, filtered and concentrated in vacuo. The resulting crude material was purified by preparative HPLC to give the title compound as an off-white solid (0.023 g, yield: 9%). HPLC purity: 98.74%. LCMS (ESI+): m / z C 17 H 18 N 3 O 4 S [M+H] + calculated, 360; found, 360. 1 HNMR (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).

[0358] Example 14: (S)-2-Hydroxy-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)propanamide

[0359]

[0360] 1. Synthesis of (S)-2-Hydroxy-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)propanamide

[0361] Using a procedure similar to that of Example 13, (S)-2-hydroxy-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)propanamide was prepared as a white solid (0.047 g, yield: 16%). HPLC purity: 97.46%. LCMS (ESI+): m / z C 18 H 20 N 3 O 4 S[M+H] + calculated value, 374; experimental value, 374. 1 H 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).

[0362] Example 15: (R)-2-hydroxy-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)propanamide

[0363]

[0364] 1. Synthesis of (R)-2-hydroxy-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)propanamide

[0365] Using a procedure similar to that of Example 13, (R)-2-hydroxy-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)propanamide was prepared as a white solid (0.03 g, yield: 24%). HPLC purity: 97.62%. LCMS (ESI+): m / z C 18 H 20 N 3 O 4 S[M+H] + calculated value, 374; experimental value, 374. 1 H 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).

[0366] Example 16: cis-3-Hydroxy-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)cyclobutane-1-carboxamide

[0367]

[0368] 1. Synthesis of cis-3-Hydroxy-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)cyclobutane-1-carboxamide

[0369] Using a procedure similar to that of Example 13, cis-3-Hydroxy-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)cyclobutane-1-carboxamide was prepared as an off-white solid (0.03 g, yield: 23%). HPLC purity: 97.23%. LCMS (ESI+): m / z C 20 H 22 N 3 O 4 S [M+H] + Calculated value, 400; Experimental value, 400. 1 H 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).

[0370] Example 17: trans-3-Hydroxy-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)cyclobutane-1-carboxamide

[0371]

[0372] 1. Synthesis of trans-3-Hydroxy-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)cyclobutane-1-carboxamide

[0373] Using a procedure similar to that of Example 13, trans-3-Hydroxy-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)cyclobutane-1-carboxamide was prepared as an off-white solid (0.03 g, yield: 25%). HPLC purity: 99.20%. LCMS (ESI+): m / z C 20 H 22 N 3 O 4 S[M+H] + Calculated value, 400; Experimental value, 400. 1 H 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).

[0374] Example 18: N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)-2-methylcyclopropane-1-carboxamide

[0375]

[0376] 1. Synthesis of N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)-2-methylcyclopropane-1-carboxamide

[0377] Using a procedure similar to Example 13, N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)-2-methylcyclopropane-1-carboxamide was prepared as an off-white solid (0.03 g, yield: 24%). HPLC purity: 99.20%. LCMS (ESI+): m / z C 20 H 22 N 3 O 3 S[M+H] + Calculated value for, 384; experimental value, 384. 1 H 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).

[0378] Example 19: trans-2-Cyano-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)cyclopropane-1-carboxamide

[0379]

[0380] 1. Synthesis of trans-2-Cyano-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)cyclopropane-1-carboxamide

[0381] Using a procedure similar to Example 13 and trans-2-cyanocyclopropane-1-carboxylic acid as the starting material, trans-2-cyano-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)cyclopropane-1-carboxamide was prepared as an off-white solid (0.095 g, yield: 50%). HPLC purity: 99.20%. LCMS (ESI+): m / z C 20 H 19 N 4 O 3 S[M+H] + Calculated value for, 395; experimental value, 395. 1 H 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).

[0382] Example 20: N-(4-(2-Methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)-2-(trifluoromethyl)cyclopropane-1-carboxamide

[0383]

[0384] 1. Synthesis of N-(4-(2-Methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)-2-(trifluoromethyl)cyclopropane-1-carboxamide

[0385] Using a procedure similar to that of Example 13, N-(4-(2-Methoxyethoxy)-2-(thiazol-5-yl)quinolin-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+): m / z C 20 H 19 F 3 N 3 O 3 S [M+H] + Calculated value, 438; Experimental value, 438. 1 H 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).

[0386] Example 21: 2-Methoxy-N-(4-(2-Methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)acetamide

[0387]

[0388] 1. Synthesis of 2-methoxy-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)acetamide

[0389] Using a procedure similar to Example 13, 2-methoxy-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)acetamide was prepared as a light brown solid (0.03 g, yield: 25%). HPLC purity: 99.78%. LCMS (ESI+): m / z C 18 H 20 N 3 O 4 S[M+H] + Calculated value for, 374; experimental value, 374. 1 H 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).

[0390] Example 22: 2-methoxy-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)propanamide

[0391]

[0392] 1. Synthesis of 2-methoxy-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)propanamide

[0393] Using a procedure similar to Example 13, 2-methoxy-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)propanamide was prepared as an off-white solid (0.028 g, yield: 22%). HPLC purity: 98.44%. LCMS (ESI+): m / z C 19 H 22 N 3 O 4 Calculated value for S[M+H]+, 388; experimental value, 388. 1 H 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).

[0394] Example 23: N-(4-(2-Methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)tetrahydro-2H-pyran-3-carboxamide

[0395]

[0396] 1. Synthesis of N-(4-(2-Methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)tetrahydro-2H-pyran-3-carboxamide

[0397] Using a procedure similar to Example 13, N-(4-(2-Methoxyethoxy)-2-(thiazol-5-yl)quinolin-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+): m / z C 21 H 24 N 3 O 4 Calculated value of [M + H]+ for S, 414; experimental 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).

[0398] Example 24: 3-Methoxy-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)propanamide

[0399]

[0400] 1. Synthesis of 3-Methoxy-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)propanamide

[0401] Using a procedure similar to that of Example 13, 3-Methoxy-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)propanamide was prepared as an off-white solid (0.04 g, yield: 31%). HPLC purity: 97.11%. LCMS (ESI+): m / z C 19 H 22 N 3 O 4 Calculated value of [M+H]+ for C, H, N, O, S is 388; experimental value is 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).

[0402] Example 25: N-(4-(2-Methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)-2-propoxypropanamide

[0403]

[0404] 1. Synthesis of N-(4-(2-Methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)-2-propoxypropanamide

[0405] Using a procedure similar to that of Example 13, N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)-2-propoxypropanamide was prepared as an off-white solid (0.025 g, yield: 12%). HPLC purity: 97.46%. LCMS (ESI+): m / z C 21 H 26 N 3 O4 Calculated value of S[M+H]+, 416; experimental value, 416. 1 H NMR(400MHz, DMSO-d 6, δ): 9.18(s, 1H) 10.13(s, 1H), 8.80(s, 1H), 8.53(d, J = 2.13Hz, 1H), 8.02(dd, J = 9.13, 2.25Hz, 1H), 7.86(d, J = 9.13Hz, 1H), 7.63(s, 1H), 4.53(t, J = 4.25Hz, 2H), 4.01(q, J = 6.59Hz, 1H), 3.86(t, J = 4.25Hz, 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 = 6.63Hz, 3H), 0.90(t, J = 7.38Hz, 3H).

[0406] Example 26: 2-Ethoxy-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)propanamide

[0407]

[0408] 1. Synthesis of 2-Ethoxy-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)propanamide

[0409] Using a procedure similar to that of Example 13, 2-Ethoxy-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)propanamide was prepared as a light brown solid (0.03 g, yield: 22%). HPLC purity: 97.46%. LCMS(ESI+): m / z C 20 H 24 N 3 O 4 Calculated value of S[M+H]+, 402; experimental value, 402. 1 H NMR(400MHz, DMSO-d 6,δ): 10.17 (s, 1H), 9.18 (s, 1H), 8.81 (s, 1H), 8.54 (d, J = 1.96 Hz, 1H), 8.03 (dd, J = 9.05, 1.96 Hz, 1H), 7.86 (d, J = 9.05 Hz, 1H), 7.64 (s, 1H), 4.52 (t, J = 3.91 Hz, 2H), 4.02 (q, J = 6.60 Hz, 1H), 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).

[0410] Example 27: 2,2 - Difluoro - 3 - hydroxy - N-(4-(2 - methoxyethoxy)-2-(thiazol - 5 - yl)quinolin - 6 - yl)propanamide

[0411]

[0412] 1. Synthesis of 2,2 - Difluoro - 3 - hydroxy - N-(4-(2 - methoxyethoxy)-2-(thiazol - 5 - yl)quinolin - 6 - yl)propanamide

[0413] Using a procedure similar to Example 13, 2,2 - Difluoro - 3 - hydroxy - N-(4-(2 - methoxyethoxy)-2-(thiazol - 5 - yl)quinolin - 6 - yl)propanamide was prepared as an off - white solid (0.025 g, yield: 15%). HPLC purity: 99.20%. LCMS (ESI+): m / z calculated for C 18 H 18 F 2 N 3 O 4 S [M + H]+, 410; found, 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).

[0414] Example 28: 2 - Cyano - N-(4-(2 - methoxyethoxy)-2-(thiazol - 5 - yl)quinolin - 6 - yl)propanamide

[0415]

[0416] 1. Synthesis of 2-cyano-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)propanamide

[0417] Using a procedure similar to that of Example 13, 2-cyano-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)propanamide was prepared as a light yellow solid (0.16 g, yield: 44%). HPLC purity: 99.51%. LCMS (ESI+): m / z C 19 H 19 N 4 O 3 Calculated for S[M+H]+, 383; found, 383. 1 H 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).

[0418] Example 29: 1-methoxy-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)cyclopropane-1-carboxamide

[0419]

[0420] 1. Synthesis of 1-methoxy-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)cyclopropane-1-carboxamide

[0421] Using a procedure similar to that of Example 13, 1-methoxy-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)cyclopropane-1-carboxamide was prepared as an off-white solid (0.035 g, yield: 26%). HPLC purity: 99.56%. LCMS (ESI+): m / z C 20 H 22 N 3 O 4 Calculated for S[M+H]+, 400; found, 400. 1 H 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).

[0422] Example 30: 3,3 - Difluoro - N-(4-(2 - methoxyethoxy)-2-(thiazol - 5 - yl)quinolin - 6 - yl)cyclobutane - 1 - carboxamide

[0423]

[0424] 1. Synthesis of 3,3 - Difluoro - N-(4-(2 - methoxyethoxy)-2-(thiazol - 5 - yl)quinolin - 6 - yl)cyclobutane - 1 - carboxamide

[0425] Using a procedure similar to that of Example 13, 3,3 - Difluoro - N-(4-(2 - methoxyethoxy)-2-(thiazol - 5 - yl)quinolin - 6 - yl)cyclobutane - 1 - carboxamide was prepared as a white solid (0.03 g, yield: 21%). HPLC purity: 99.81%. LCMS(ESI+): m / z C 20 H 20 F 2 N 3 O 3 Calculated value of [M + H]+ for C 1 H 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).

[0426] Example 31: N-(4-(2 - methoxyethoxy)-2-(thiazol - 5 - yl)quinolin - 6 - yl)bicyclo[1.1.1]pentane - 1 - carboxamide

[0427]

[0428] 1. Synthesis of N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)bicyclo[1.1.1]pentane-1-carboxamide

[0429] Using a procedure similar to that of Example 13, N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)bicyclo[1.1.1]pentane-1-carboxamide was prepared as an off-white solid (0.03 g, yield: 23%). HPLC purity: 99.82%. LCMS (ESI+): m / z C 21 H 22 N 3 O 3 Calculated for S[M+H]+, 396; found, 396. 1 H NMR (400 MHz, DMSO-d 6, 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).

[0430] Example 32: 3-Methoxy-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)-2-methylpropanamide

[0431]

[0432] 1. Synthesis of 3-Methoxy-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)-2-methylpropanamide

[0433] Using a procedure similar to that of Example 13, 3-Methoxy-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)-2-methylpropanamide was prepared as an off-white solid (0.032 g, yield: 24%). HPLC purity: 98.94%. LCMS (ESI+): m / z C 20 H 24 N 3 O 4 Calculated for S[M+H]+, 402; found, 402. 1 H 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).

[0434] Example 33: cis-3-Methoxy-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)cyclobutane-1-carboxamide

[0435]

[0436] 1. Synthesis of cis-3-Methoxy-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)cyclobutane-1-carboxamide

[0437] Using a procedure similar to Example 13, cis-3-Methoxy-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)cyclobutane-1-carboxamide was prepared as an off-white solid (0.04 g, yield: 29%). HPLC purity: 96.09%. LCMS (ESI+): m / z C 21 H 24 N 3 O 4 S[M + H] + Calculated value, 414; experimental value, 414. 1 H 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).

[0438] Example 34: trans-3-Methoxy-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)cyclobutane-1-carboxamide

[0439]

[0440] 1. Synthesis of trans-3-methoxy-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)cyclobutane-1-carboxamide

[0441] Using a procedure similar to that of Example 13, trans-3-methoxy-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)cyclobutane-1-carboxamide was prepared as a pale yellow solid (0.04 g, yield: 29%). HPLC purity: 98.63%. LCMS (ESI+): m / z C 21 H 24 N 3 O 4 S[M+H] + Calculated value, 414; experimental value, 414. 1 H NMR (400 MHz, DMSO-d 6, 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).

[0442] Example 35: N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)isoxazole-4-carboxamide

[0443]

[0444] 1. Synthesis of N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)isoxazole-4-carboxamide

[0445] Using a procedure similar to that of Example 13, N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)isoxazole-4-carboxamide was prepared as an off-white solid (0.01 g, yield: 8%). HPLC purity: 97.10%. LCMS (ESI+): m / z C 19 H 17 N 4 O 4 S[M+H] +Calculated value, 397; experimental value, 397. 1 H 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 (m 2H), 3.84 - 3.93 (m, 2H), 3.41 (s, 3H).

[0446] Example 36: (S)-2-Methoxy-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)propanamide

[0447]

[0448] 1. Synthesis of (S)-2-Methoxy-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)propanamide

[0449] Using a procedure similar to that of Example 13, (S)-2-Methoxy-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)propanamide was prepared as a yellow solid (0.07 g, yield: 57%). HPLC purity: 99.82%. LCMS (ESI+): m / z C 19 H 22 N 3 O 4 S [M + H] + Calculated value, 388; experimental value, 388. 1 H 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).

[0450] Example 37: (R)-2-Methoxy-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)propanamide

[0451]

[0452] 1. Synthesis of (R)-2-methoxy-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)propanamide

[0453] Using a procedure similar to Example 13, (R)-2-methoxy-N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)propanamide was prepared as a light yellow solid (0.07 g, yield: 55%). HPLC purity: 99.82%. LCMS (ESI+): m / z C 19 H 22 N 3 O 4 S[M+H] + Calculated value, 388; Experimental value, 388. 1 H 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).

[0454] Example 38: N-(4-((1-methoxypropan-2-yl)oxy)-2-(thiazol-5-yl)quinolin-6-yl)oxetane-3-carboxamide

[0455]

[0456] Scheme:

[0457]

[0458] 1. Synthesis of 1-(2-amino-5-nitrophenyl)ethan-1-one

[0459]

[0460] 1-(2-Fluoro-5-nitrophenyl)ethan-1-one (28 g, 152.88 mmol) was reacted with NH 4A mixture of OH (25%, 230 mL) was heated and stirred in an autoclave at 100 °C for 8 hours. Then, the reaction mixture was filtered, washed with ice-cold water (100 mL), and dried under vacuum. The crude material was wet-milled with acetonitrile (100 mL) and dried under vacuum to give 1-(2-amino-5-nitrophenyl)ethan-1-one (17 g, yield: 75%) as a yellow solid. 1 H 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).

[0461] 2. Synthesis of N-(2-acetyl-4-nitrophenyl)thiazole-5-carboxamide

[0462]

[0463] POCl was added to a mixture of 1-(2-amino-5-nitrophenyl)ethan-1-one (19.53 g, 108.40 mmol) and thiazole-5-carboxylic acid (14 g, 108.40 mmol) 3 (200 mL), and the mixture was heated to 100 °C for 1 hour. Then, the reaction mixture was cooled to room temperature and quenched with ice-cold water (200 mL). The resulting solid was filtered and dried under vacuum. The crude material was wet-milled with ether (200 mL) and dried under vacuum to give N-(2-acetyl-4-nitrophenyl)thiazole-5-carboxamide (22 g, yield: 70%) as a yellow solid. LCMS (ESI+): m / z C 12 H 10 N 3 O 4 S [M + H] + Calculated value, 292; experimental value, 292. 1 HNMR (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).

[0464] 3. Synthesis of 6-nitro-2-(thiazol-5-yl)quinolin-4-ol

[0465]

[0466] At room temperature, t-BuOK (8.48 g, 75.60 mmol) was added to a stirred solution of N-(2-acetyl-4-nitrophenyl)thiazole-5-carboxamide (11 g, 37.80 mmol) in tert-butanol (110 mL), and the reaction mixture was heated to 100 °C for 4 h. Subsequently, the reaction mixture was filtered, and the resulting solid was mixed with 1 N HCl (200 mL) and stirred for 10 min. The resulting solid was filtered and dried under vacuum. The crude material was wet milled with acetonitrile (50 mL) and dried under vacuum to give 6-nitro-2-(thiazol-5-yl)quinolin-4-ol (7.5 g, yield: 73%) as a yellow solid. LCMS (ESI+): m / z C 12 H 8 N 3 O 3 S[M+H] + calculated for, 274; found, 274. 1 H 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).

[0467] 4. Synthesis of methyl 2-((6-nitro-2-(thiazol-5-yl)quinolin-4-yl)oxy)propionate

[0468]

[0469] At room temperature, K 2 CO 3 (3.15 g, 22.89 mmol), KI (0.15 g, 0.91 mmol) and methyl 2-bromopropionate (2.29 g, 13.71 mmol) were added to a stirred solution of 6-nitro-2-(thiazol-5-yl)quinolin-4-ol (2.5 g, 9.15 mmol) in DMF (15 mL), and the reaction mixture was heated to 90 °C and stirred for 16 h. The reaction mixture was stirred at room temperature for 16 h. Subsequently, 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 material was wet milled with diethyl ether (25 mL) to give methyl 2-((6-nitro-2-(thiazol-5-yl)quinolin-4-yl)oxy)propionate (2.2 g, yield: 67%) as a light brown solid. LCMS (ESI+): m / z C 16 H 14 N 3 O 5S[M+H] + Calculated value, 360; experimental value, 360. 1 H 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).

[0470] 5. Synthesis of 2-((6-nitro-2-(thiazol-5-yl)quinolin-4-yl)oxy)propan-1-ol

[0471]

[0472] To a stirred solution of methyl 2-((6-nitro-2-(thiazol-5-yl)quinolin-4-yl)oxy)propionate (1.1 g, 30.06 mmol) in MeOH:THF (1:1, 24 mL) at 0 °C was added dropwise LiBH 4 (solution in THF, 2.0 M, 9.1 mL, 18.36 mmol) over 20 minutes. The reaction mixture was stirred at the same temperature for 6 hours. Then, the reaction mixture was quenched with saturated NH 4 Cl (50 mL). The aqueous layer was extracted with EtOAc (2 × 75 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo to give 2-((6-nitro-2-(thiazol-5-yl)quinolin-4-yl)oxy)propan-1-ol as a light brown solid (0.38 g, yield: 30%). LCMS (ESI+): m / z C 15 H 14 N 3 O 4 S[M+H] + Calculated value, 332; experimental value, 332. 1 H 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).

[0473] 6. Synthesis of 5-(4-((1-methoxypropan-2-yl)oxy)-6-nitroquinolin-2-yl)thiazole

[0474]

[0475] To a stirred solution of 2-((6-nitro-2-(thiazol-5-yl)quinolin-4-yl)oxy)propan-1-ol (0.38 g, 1.14 mmol) in THF (18 mL) at 0 °C was added NaH (a 60% suspension in mineral oil, 0.03 g, 1.25 mmol). To this was added methyl iodide (0.08 mL, 1.25 mmol) at 0 °C and the reaction mixture was stirred at room temperature for 16 h. Then, the reaction mixture was quenched with saturated NH 4 Cl (50 mL). The aqueous layer was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo to give 5-(4-((1-methoxypropan-2-yl)oxy)-6-nitroquinolin-2-yl)thiazole as a brown solid (0.25 g, yield: 63%). LCMS (ESI+): m / z C 16 H 16 N 3 O 4 S [M+H] + calculated, 346; found, 346. 1 H 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).

[0476] 7. Synthesis of 4-((1-methoxypropan-2-yl)oxy)-2-(thiazol-5-yl)quinolin-6-amine

[0477]

[0478] 4-((1-Methoxypropan-2-yl)oxy)-2-(thiazol-5-yl)quinolin-6-amine was prepared using the procedure followed for the preparation of 4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-amine. The crude material was purified by wet grinding with diethyl ether (25 mL) and n-pentane (25 mL) to give the title product as a brown solid (0.18 g, yield: 78%). LCMS (ESI+): m / z C 16 H 18 N 3 O 2 S[M+H] + calculated for, 316; found, 316. 1 H 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, 1.6H), 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).

[0479] 8. Synthesis of N-(4-((1-methoxypropan-2-yl)oxy)-2-(thiazol-5-yl)quinolin-6-yl)oxetane-3-carboxamide

[0480]

[0481] Using the same procedure as for N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)oxetane-3-carboxamide, N-(4-((1-methoxypropan-2-yl)oxy)-2-(thiazol-5-yl)quinolin-6-yl)oxetane-3-carboxamide was prepared as an off-white solid (0.18 g, yield: 81%). HPLC purity: 99.16%. LCMS (ESI+): m / z C 20 H 22 N 3 O 4 S[M+H] + calculated for, 400; found, 400. 1 H 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).

[0482] Example 39: N-(4-((1-methoxy-2-methylpropan-2-yl)oxy)-2-(thiazol-5-yl)quinolin-6-yl)oxetane-3-carboxamide

[0483]

[0484] Scheme:

[0485]

[0486] 1. Synthesis of methyl 2-methyl-2-((6-nitro-2-(thiazol-5-yl)quinolin-4-yl)oxy)propionate

[0487]

[0488] Methyl 2-methyl-2-((6-nitro-2-(thiazol-5-yl)quinolin-4-yl)oxy)propionate was prepared using the procedure followed for the preparation of methyl 2-((6-nitro-2-(thiazol-5-yl)quinolin-4-yl)oxy)propionate. The resulting compound was purified by combi flash chromatography (1% MeOH in CH 2 Cl 2 to give the title product as a pale yellow solid (0.8 g, yield: 23%). LCMS (ESI+): m / z C 17 H 16 N 3 O 5 S [M + H] + calculated, 374; found, 374. 1 H 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).

[0489] 2. Synthesis of 2-methyl-2-((6-nitro-2-(thiazol-5-yl)quinolin-4-yl)oxy)propan-1-ol

[0490]

[0491] To a stirred solution of methyl 2-methyl-2-((6-nitro-2-(thiazol-5-yl)quinolin-4-yl)oxy)propionate (0.5 g, 1.33 mmol) in THF (1,15 mL) at 0 °C was added dropwise LAH (1.0 M solution in THF, 2.0 mL, 2.00 mmol) over 15 minutes and the reaction mixture was warmed to room temperature and stirred for 2 hours. Then, the reaction mixture was quenched with saturated NH 4 Cl (50 mL). The aqueous layer was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 and filtered and concentrated in vacuo to afford the crude material. The crude material was purified by combiflash chromatography (80% EtOAc in heptane) to give 2-methyl-2-((6-nitro-2-(thiazol-5-yl)quinolin-4-yl)oxy)propan-1-ol as a light brown solid (0.14 g, yield: 30%). LCMS (ESI+): m / z C 16 H 16 N 3 O 4 S [M + H] + calculated, 346; found, 346. 1 H NMR (400 MHz, DMSO-d 6, δ): 9.29 (s, 1H), 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).

[0492] 3. Synthesis of 5-(4-((1-methoxy-2-methylpropan-2-yl)oxy)-6-nitroquinolin-2-yl)thiazole

[0493]

[0494] 5-(4-((1-Methoxy-2-methylpropan-2-yl)oxy)-6-nitroquinolin-2-yl)thiazole was prepared using the procedure followed for the preparation of 5-(4-((1-methoxypropan-2-yl)oxy)-6-nitroquinolin-2-yl)thiazole. The resulting compound was purified by combi flash chromatography (in CH 2 Cl 2 with 1% MeOH) to afford the title product as a brown solid (0.17 g, yield: 54%). LCMS (ESI+): m / z C 17 H 18 N 3 O 4 S [M+H] + calculated, 360; found, 360. 1 H 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).

[0495] 4. Synthesis of 4-((1-Methoxy-2-methylpropan-2-yl)oxy)-2-(thiazol-5-yl)quinolin-6-amine

[0496]

[0497] 4-((1-Methoxy-2-methylpropan-2-yl)oxy)-2-(thiazol-5-yl)quinolin-6-amine was prepared using the procedure followed for the preparation of 4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-amine. The crude compound was triturated with diethyl ether to afford the title compound as a brown solid (0.15 g, yield: 95%). LCMS (ESI+): m / z C 17 H 20 N 3 O 2 S [M+H] + calculated, 330; found, 330. 1 H 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).

[0498] 5. Synthesis of N-(4-((1-methoxy-2-methylpropan-2-yl)oxy)-2-(thiazol-5-yl)quinolin-6-yl)oxetane-3-carboxamide

[0499]

[0500] Using the same procedure as for N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)oxetane-3-carboxamide, N-(4-((1-methoxy-2-methylpropan-2-yl)oxy)-2-(thiazol-5-yl)quinolin-6-yl)oxetane-3-carboxamide was prepared as an off-white solid (0.18 g, yield: 82%). LCMS (ESI+): m / z C 21 H 24 N 3 O 4 S [M + H] + calculated value, 414; experimental value, 414. HPLC purity: 99.70%. 1 H 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).

[0501] Example 40: N-(2-(4-Cyclopropyl-1H-imidazol-1-yl)-4-(2-methoxyethoxy)quinolin-6-yl)oxetane-3-carboxamide

[0502]

[0503] Scheme:

[0504]

[0505] 1. Synthesis of 2-(4-cyclopropyl-1H-imidazol-1-yl)-4-(2-methoxyethoxy)-6-nitroquinoline

[0506]

[0507] 2-(4-Cyclopropyl-1H-imidazol-1-yl)-4-(2-methoxyethoxy)-6-nitroquinoline was prepared using the procedure followed for the preparation of 4-ethoxy-2-(4-methyl-1H-imidazol-1-yl)-6-nitroquinoline. The title product was obtained as a brown solid (0.22 g, yield: 58%). LCMS (ESI+): m / z C 18 H 19 N 4 O 4 [M+H] + calculated, 355; found, 355. 1 H 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).

[0508] 2. Synthesis of 2-(4-cyclopropyl-1H-imidazol-1-yl)-4-(2-methoxyethoxy)quinolin-6-amine

[0509]

[0510] 2-(4-Cyclopropyl-1H-imidazol-1-yl)-4-(2-methoxyethoxy)quinolin-6-amine was prepared using the procedure followed for the preparation of 4-ethoxy-2-(4-methyl-1H-imidazol-1-yl)quinolin-6-amine and was obtained as a brown solid (5 g, yield: 78%). LCMS (ESI+): m / z C 18 H 21 N 4 O 2 [M+H] + calculated, 325; found, 325. 1 H 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).

[0511] 3. Synthesis of N-(2-(4-Cyclopropyl-1H-imidazol-1-yl)-4-(2-methoxyethoxy)quinolin-6-yl)oxetan-3-carboxamide

[0512]

[0513] Using the same procedure as for N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)oxetan-3-carboxamide, N-(2-(4-cyclopropyl-1H-imidazol-1-yl)-4-(2-methoxyethoxy)quinolin-6-yl)oxetan-3-carboxamide was prepared as a white solid (0.05 g, yield: 24%). HPLC purity: 99.82%. LCMS (ESI+): m / z C 22 H 25 N 4 O 4 [M + H] + calculated value, 409; experimental value, 409. 1 H 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).

[0514] Example 41: N-(4-(2-Methoxyethoxy)-2-(4-methyl-1H-imidazol-1-yl)quinolin-6-yl)oxetan-3-carboxamide

[0515]

[0516] Following the procedure of Example 40, N-(4-(2-methoxyethoxy)-2-(4-methyl-1H-imidazol-1-yl)quinolin-6-yl)oxetane-3-carboxamide was prepared as an off-white solid (0.06 g, yield: 26%). HPLC purity: 97.16%. LCMS (ESI+): m / z C 20 H 23 N 4 O 4 [M+H] + calculated, 383; found, 383. 1 H 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).

[0517] Example 42: N-(4-(2-hydroxyethoxy)-2-(1H-imidazol-1-yl)quinolin-6-yl)oxetane-3-carboxamide

[0518]

[0519] Scheme:

[0520]

[0521] 1. Synthesis of 4-(2-(benzyloxy)ethoxy)-2-(1H-imidazol-1-yl)-6-nitroquinoline

[0522]

[0523] 4-(2-(benzyloxy)ethoxy)-2-(1H-imidazol-1-yl)-6-nitroquinoline was prepared using the procedure followed for the preparation of 4-ethoxy-2-(4-methyl-1H-imidazol-1-yl)-6-nitroquinoline. The crude material was purified by flash column chromatography on silica gel (100 - 200 mesh) (CH 2 Cl 2Purified with 2% MeOH in CH₂Cl₂ to obtain the title product as an off-white solid (0.3 g, yield: 61%). LCMS (ESI+): m / z C 21 H 19 N 4 O 4 [M+H] + calculated, 391; found, 391.

[0524] 2. Synthesis of 2-((2-(1H-imidazol-1-yl)-6-nitroquinolin-4-yl)oxy)ethan-1-ol

[0525]

[0526] 2-((2-(1H-imidazol-1-yl)-6-nitroquinolin-4-yl)oxy)ethan-1-ol was prepared following the procedure used for the preparation of 2-((6-nitro-2-(thiazol-5-yl)quinolin-4-yl)oxy)ethan-1-ol. The product was obtained as a yellow solid (0.2 g, yield: 80%). LCMS (ESI+): m / z C 14 H 13 N 4 O 4 [M+H] + calculated, 301; found, 301.

[0527] 3. Synthesis of 2-((6-amino-2-(1H-imidazol-1-yl)quinolin-4-yl)oxy)ethan-1-ol

[0528]

[0529] 2-((6-amino-2-(1H-imidazol-1-yl)quinolin-4-yl)oxy)ethan-1-ol was prepared following the procedure used for the preparation of 4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-amine. The resulting product was obtained as a brown solid (0.22 g, crude). LCMS (ESI+): m / z C 14 H 15 N 4 O 2 [M+H] + calculated, 271; found, 271.

[0530] 4. Synthesis of N-(4-(2-hydroxyethoxy)-2-(1H-imidazol-1-yl)quinolin-6-yl)oxetane-3-carboxamide

[0531]

[0532] N-(4-(2-Hydroxyethoxy)-2-(1H-imidazol-1-yl)quinolin-6-yl)oxetane-3-carboxamide was prepared following the procedure of N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)oxetane-3-carboxamide, as a pale grey solid (0.08 g, yield: 5%). HPLC purity: 97.71%. LCMS (ESI+): m / z C 18 H 19 N 4 O 4 [M+H] + calculated, 355; found, 355. 1 H 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, 2H), 4.03 - 4.00 (m, 1H), 3.92 (q, J = 4.40 Hz, 2H).

[0533] Example 43: N-(4-Cyclopropyloxy-2-(4-methyl-1H-imidazol-1-yl)quinolin-6-yl)oxetane-3-carboxamide

[0534]

[0535] N-(4-Cyclopropyloxy-2-(4-methyl-1H-imidazol-1-yl)quinolin-6-yl)oxetane-3-carboxamide was prepared following the procedure of Example 2. HPLC purity: 99.74%. LCMS (ESI+): m / z C 20 H 21 N 4 O 3 [M+H] + calculated, 365; found, 365. 1 H 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).

[0536] Example 44: N-(2-(4-chloro-1H-imidazol-1-yl)-4-ethoxyquinolin-6-yl)oxetan-3-carboxamide

[0537]

[0538] Scheme:

[0539]

[0540] 1. Synthesis of 2-(4-chloro-1H-imidazol-1-yl)-4-ethoxy-6-nitroquinoline

[0541]

[0542] 2-(4-chloro-1H-imidazol-1-yl)-4-ethoxy-6-nitroquinoline was prepared using the procedure followed for the preparation of 4-ethoxy-2-(4-methyl-1H-imidazol-1-yl)-6-nitroquinoline. The crude compound was wet milled with diethyl ether and n-pentane to afford the title compound as an off-white solid (0.21 g, yield: 65%). LCMS (ESI+): m / z C 14 H 12 ClN 4 O 3 [M + H] + calculated, 319; found, 319. 1 H 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).

[0543] 2. Synthesis of 2-(4-chloro-1H-imidazol-1-yl)-4-ethoxyquinolin-6-amine

[0544]

[0545] 2-(4-Chloro-1H-imidazol-1-yl)-4-ethoxyquinolin-6-amine was prepared following the procedure used for the preparation of 4-ethoxy-2-(4-methyl-1H-imidazol-1-yl)quinolin-6-amine, as a brown solid (0.15 g, yield: 79%). LCMS (ESI+): m / z C 14 H 14 ClN 4 O[M+H] + calculated, 289; found, 289. 1 H NMR (400 MHz, DMSO-d 6, δ): 8.58 (brs, 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).

[0546] 3. Synthesis of N-(2-(4-chloro-1H-imidazol-1-yl)-4-ethoxyquinolin-6-yl)oxetane-3-carboxamide

[0547]

[0548] N-(2-(4-chloro-1H-imidazol-1-yl)-4-ethoxyquinolin-6-yl)oxetane-3-carboxamide was prepared following the procedure for N-(4-ethoxy-2-(4-methyl-1H-imidazol-1-yl)quinolin-6-yl)oxetane-3-carboxamide, as a white solid (0.08 g, yield: 41%). HPLC purity: 96.86%. LCMS (ESI+): m / z C 18 H 18 ClN 4 O 3 [M+H] + calculated, 373; found, 373. 1 H 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).

[0549] Example 45: N-(4-Ethoxy-2-(4H-1,2,4-triazol-4-yl)quinolin-6-yl)oxetane-3-carboxamide

[0550]

[0551] Scheme:

[0552]

[0553] 1. Synthesis of 4-Ethoxy-6-nitro-2-(4H-1,2,4-triazol-4-yl)quinoline

[0554]

[0555] 4-Ethoxy-6-nitro-2-(4H-1,2,4-triazol-4-yl)quinoline was prepared using the procedure followed for the preparation of 4-ethoxy-2-(4-methyl-1H-imidazol-1-yl)-6-nitroquinoline. The crude material was wet milled with ether and n-pentane to afford the title compound as a white solid (0.2 g, yield: 69%). LCMS (ESI+): m / z C 13 H 12 N 5 O 3 [M + H] + calculated, 286; found, 286. 1 H 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).

[0556] 2. Synthesis of 4-Ethoxy-2-(4H-1,2,4-triazol-4-yl)quinolin-6-amine

[0557]

[0558] 4-Ethoxy-2-(4H-1,2,4-triazol-4-yl)quinolin-6-amine was prepared using the procedure followed for the preparation of 4-ethoxy-2-(4-methyl-1H-imidazol-1-yl)quinolin-6-amine. The crude compound was wet milled with ether and n-pentane to afford the title compound as a white solid (0.14 g, yield: 78%). LCMS (ESI+): m / z C 13 H 14 N 5O[M+H] + Calculated value, 256; experimental value, 256. 1 H 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).

[0559] 3. Synthesis of N-(4-ethoxy-2-(4H-1,2,4-triazol-4-yl)quinolin-6-yl)oxetane-3-carboxamide

[0560]

[0561] N-(4-ethoxy-2-(4H-1,2,4-triazol-4-yl)quinolin-6-yl)oxetane-3-carboxamide was prepared following the procedure of N-(4-ethoxy-2-(4-methyl-1H-imidazol-1-yl)quinolin-6-yl)oxetane-3-carboxamide, as a white solid (0.058 g, yield: 26%). HPLC purity: 97.70%. LCMS (ESI+): m / z C 17 H 18 N 5 O 3 [M+H] + Calculated value, 340; experimental value, 340. 1 H 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).

[0562] Example 46: N-(2-(4-cyano-1H-imidazol-1-yl)-4-ethoxyquinolin-6-yl)oxetane-3-carboxamide

[0563]

[0564] Scheme:

[0565]

[0566] 1. Synthesis of 1-(4-ethoxy-6-nitroquinolin-2-yl)-1H-imidazole-4-carbonitrile

[0567]

[0568] 1-(4-Ethoxy-6-nitroquinolin-2-yl)-1H-imidazole-4-carbonitrile was prepared using the procedure followed for the preparation of 4-ethoxy-2-(4-methyl-1H-imidazol-1-yl)-6-nitroquinoline. The crude material was wet milled with acetonitrile (25 mL) to afford the title product as a yellow solid (0.19 g, yield: 61%). 1 H 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).

[0569] 2. Synthesis of 1-(6-amino-4-ethoxyquinolin-2-yl)-1H-imidazole-4-carbonitrile

[0570]

[0571] 1-(6-Amino-4-ethoxyquinolin-2-yl)-1H-imidazole-4-carbonitrile was prepared using the procedure followed for the preparation of 4-ethoxy-2-(4-methyl-1H-imidazol-1-yl)quinolin-6-amine. The title product was obtained as a yellow solid (0.1 g, yield: 58%). LCMS (ESI+): m / z C 15 H 14 N 5 O [M+H] + Calculated value, 280; experimental value, 280. 1 H 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 (brt, J = 6.85 Hz, 3H).

[0572] 3. Synthesis of N-(2-(4-cyano-1H-imidazol-1-yl)-4-ethoxyquinolin-6-yl)oxetane-3-carboxamide

[0573]

[0574] N-(2-(4-cyano-1H-imidazol-1-yl)-4-ethoxyquinolin-6-yl)oxetane-3-carboxamide was prepared following the procedure of N-(4-ethoxy-2-(4-methyl-1H-imidazol-1-yl)quinolin-6-yl)oxetane-3-carboxamide and obtained as a white solid (0.012 g, yield: 10%). HPLC purity: 98.02%. LCMS (ESI+): m / z C 19 H 18 N 5 O 3 [M+H] + calculated, 364; found, 364. 1 H 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).

[0575] Example 47: N-(2-(4-(tert-butyl)-1H-imidazol-1-yl)-4-ethoxyquinolin-6-yl)oxetane-3-carboxamide

[0576]

[0577] Scheme:

[0578]

[0579] 1. Synthesis of 2-(4-(tert-butyl)-1H-imidazol-1-yl)-4-ethoxy-6-nitroquinoline

[0580]

[0581] 2-(4-(tert-Butyl)-1H-imidazol-1-yl)-4-ethoxy-6-nitroquinoline was prepared using the procedure followed for the preparation of 4-ethoxy-2-(4-methyl-1H-imidazol-1-yl)-6-nitroquinoline. The title product was obtained as a pale green solid (0.2 g, yield: 86%). LCMS (ESI+): m / z C 18 H 21 N 4 O 3 [M+H] + calculated, 341; found, 341.

[0582] 2. Synthesis of 2-(4-(tert-Butyl)-1H-imidazol-1-yl)-4-ethoxyquinolin-6-amine

[0583]

[0584] 2-(4-(tert-Butyl)-1H-imidazol-1-yl)-4-ethoxyquinolin-6-amine was prepared using the procedure followed for the preparation of 4-ethoxy-2-(4-methyl-1H-imidazol-1-yl)quinolin-6-amine. The title product was obtained as a pale green solid (0.15 g, yield: 82%). LCMS (ESI+): m / z C 18 H 23 N 4 O[M+H] + calculated, 311; found, 311. 1 H 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).

[0585] 3. Synthesis of N-(2-(4-(tert-Butyl)-1H-imidazol-1-yl)-4-ethoxyquinolin-6-yl)oxetane-3-carboxamide

[0586]

[0587] N-(2-(4-(tert-Butyl)-1H-imidazol-1-yl)-4-ethoxyquinolin-6-yl)oxetane-3-carboxamide was prepared following the procedure of N-(4-ethoxy-2-(4-methyl-1H-imidazol-1-yl)quinolin-6-yl)oxetane-3-carboxamide as a pale grey solid (0.06 g, yield: 31%). HPLC purity: 97.48%. LCMS (ESI+): m / z C 22 H 27 N 4 O 3 [M+H] + Calculated for, 395; found, 395. 1 H 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).

[0588] Example 48: 2-Cyano-N-(4-(((S)-1-methoxypropan-2-yl)oxy)-2-(thiazol-5-yl)quinolin-6-yl)propanamide

[0589]

[0590] Scheme:

[0591]

[0592] 1. Synthesis of 5-(4-chloro-6-nitroquinolin-2-yl)thiazole

[0593]

[0594] 5-(4-Chloro-6-nitroquinolin-2-yl)thiazole was prepared following the procedure used for the preparation of 2,4-dichloro-6-nitroquinoline. The crude material was wet milled with Et 2 O to give the desired product as a brown solid (1 g, crude material used in the next step without purification). LCMS (ESI+): m / z C 12 H 7 ClN 3 O 2 S[M+H] +Calculated value, 292; experimental value, 292. 1 H 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).

[0595] 2. Synthesis of (S)-5-(4-((1-methoxypropan-2-yl)oxy)-6-nitroquinolin-2-yl)thiazole

[0596]

[0597] To a stirred solution of 5-(4-chloro-6-nitroquinolin-2-yl)thiazole (0.65 g, 2.22 mmol) in DMF (18 mL) at room temperature was added Cs 2 CO 3 (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). The reaction was stirred at 80 °C for 16 h in a sealed tube. Subsequently, the reaction mixture was diluted with ice-cold water (100 mL) and extracted with EtOAc (2 × 50 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title product as a yellow solid (0.38 g, 49%). LCMS (ESI+): m / z C 16 H 16 N 3 O 4 S [M + H] + Calculated value, 346; experimental value, 346.

[0598] 3. Synthesis of (S)-4-((1-methoxypropan-2-yl)oxy)-2-(thiazol-5-yl)quinolin-6-amine

[0599]

[0600] (S)-4-((1-methoxypropan-2-yl)oxy)-2-(thiazol-5-yl)quinolin-6-amine was prepared following the procedure used for the preparation of 4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-amine, as a brown solid (0.32 g, yield: 92%). 1 H 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).

[0601] 4. Synthesis of 2-cyano-N-(4-(((S)-1-methoxypropan-2-yl)oxy)-2-(thiazol-5-yl)quinolin-6-yl)propanamide

[0602]

[0603] 2-Cyano-N-(4-(((S)-1-methoxypropan-2-yl)oxy)-2-(thiazol-5-yl)quinolin-6-yl)propanamide was prepared following the procedure of N-(4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-yl)oxetane-3-carboxamide as an off-white solid (0.08 g, yield: 42%). HPLC purity: 96.91%. LCMS (ESI+): m / z C 20 H 21 N 4 O 3 S [M + H] + calculated for, 397; found, 397. 1 H 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).

[0604] Example 49: 2-Cyano-N-(4-(((R)-1-methoxypropan-2-yl)oxy)-2-(thiazol-5-yl)quinolin-6-yl)propanamide

[0605]

[0606] Scheme:

[0607]

[0608] 1. Synthesis of (R)-5-(4-((1-methoxypropan-2-yl)oxy)-6-nitroquinolin-2-yl)thiazole

[0609]

[0610] (R)-5-(4-((1-methoxypropan-2-yl)oxy)-6-nitroquinolin-2-yl)thiazole was prepared using the procedure followed for the preparation of (S)-5-(4-((1-methoxypropan-2-yl)oxy)-6-nitroquinolin-2-yl)thiazole. The crude material was purified by silica gel column chromatography (20 - 30% EtOAc / heptane) to give the desired product as a yellow solid (0.4 g, yield: 45%). LCMS (ESI+): m / z C 16 H 16 N 3 O 4 S[M + H] + calculated for, 346; found, 346. 1 H 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).

[0611] 2. Synthesis of (R)-4-((1-methoxypropan-2-yl)oxy)-2-(thiazol-5-yl)quinolin-6-amine

[0612]

[0613] (R)-4-((1-methoxypropan-2-yl)oxy)-2-(thiazol-5-yl)quinolin-6-amine was prepared using the procedure followed for the preparation of 4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-amine and was obtained as a yellow solid (0.45 g, crude material was used for the next step without purification). LCMS (ESI+): m / z C 16 H 18 N 3 O 2 S[M + H] + calculated for, 316; found, 316.

[0614] 3. Synthesis of 2-cyano-N-(4-(((R)-1-methoxypropan-2-yl)oxy)-2-(thiazol-5-yl)quinolin-6-yl)propanamide

[0615]

[0616] 2-cyano-N-(4-(((R)-1-methoxypropan-2-yl)oxy)-2-(thiazol-5-yl)quinolin-6-yl)propanamide was prepared following the procedure of Example 1 as a light yellow solid (0.02 g, yield: 10%). HPLC purity: 95.60%. LCMS (ESI+): m / z C 20 H 21 N 4 O 3 S[M+H] + calculated, 397; found, 397. 1 H 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).

[0617] Example 50: (S)-2-methoxy-N-(4-(((S)-1-methoxypropan-2-yl)oxy)-2-(thiazol-5-yl)quinolin-6-yl)propanamide

[0618]

[0619] (S)-2-methoxy-N-(4-(((S)-1-methoxypropan-2-yl)oxy)-2-(thiazol-5-yl)quinolin-6-yl)propanamide was prepared following the procedure of Example 1 as an off-white solid (0.03 g, yield: 14%). HPLC purity: 99.91%. LCMS (ESI+): m / z C 20 H 24 N 3 O 4 S[M+H] + calculated, 402; found, 402. 1 H 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).

[0620] Example 51: (S)-2-Methoxy-N-(4-(((R)-1-methoxypropan-2-yl)oxy)-2-(thiazol-5-yl)quinolin-6-yl)propanamide

[0621]

[0622] (S)-2-Methoxy-N-(4-(((R)-1-methoxypropan-2-yl)oxy)-2-(thiazol-5-yl)quinolin-6-yl)propanamide was prepared following the procedure of Example 1 and obtained as a yellow solid (0.1 g, yield: 40%). HPLC purity: 98.45%. LCMS (ESI+): m / z C 20 H 24 N 3 O 4 S [M + H] + calculated value, 402; experimental value, 402. 1 H NMR (400 MHz, DMSO-d 6 ) δ 1 HNMR (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).

[0623] Example 52: (R)-N-(4-((1-Methoxypropan-2-yl)oxy)-2-(thiazol-5-yl)quinolin-6-yl)oxetane-3-carboxamide

[0624]

[0625] (R)-N-(4-((1-Methoxypropan-2-yl)oxy)-2-(thiazol-5-yl)quinolin-6-yl)oxetane-3-carboxamide was prepared following the procedure of Example 1 and was obtained as a white solid (0.065 g, yield: 25%). HPLC purity: 98.81%. LCMS (ESI+): m / z C 20 H 22 N 3 O 4 S[M+H] + Calculated for, 400; found, 400. 1 H 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).

[0626] Example 53: N-(4-(2-Methoxyethoxy)-2-(1-methyl-1H-pyrazol-4-yl)quinolin-6-yl)oxetane-3-carboxamide

[0627]

[0628] Scheme:

[0629]

[0630] 1. Synthesis of 1-(2-amino-5-nitrophenyl)ethan-1-one

[0631]

[0632] A mixture of 1-(2-fluoro-5-nitrophenyl)ethan-1-one (28 g, 152.88 mmol) and NH 4 OH (25%, 230 mL) was heated and stirred in an autoclave at 100 °C for 8 h. Subsequently, the reaction mixture was filtered, washed with ice-cold water (100 mL) and dried under vacuum. The crude material was wet-milled with acetonitrile (100 mL) and vacuum-dried to give 1-(2-amino-5-nitrophenyl)ethan-1-one as a yellow solid (17 g, 75%).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).

[0633] 2. Synthesis of N-(2-acetyl-4-nitrophenyl)-1-methyl-1H-pyrazole-4-carboxamide

[0634]

[0635] A mixture of 1-methyl-1H-pyrazole-4-carboxylic acid (2.0 g, 15.87 mmol) in POCl 3 (20 mL) was heated to 40 °C. To this mixture was added 1-(2-amino-5-nitrophenyl)ethan-1-one (2.5 g, 13.88 mmol) at the same temperature. The reaction mixture was heated to 80 °C and stirred for 6 h. Then, 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 in vacuo to give N-(2-acetyl-4-nitrophenyl)-1-methyl-1H-pyrazole-4-carboxamide (2.5 g, yield: 62%) as a brown solid. LCMS (ESI+): m / z C 13 H 13 N 4 O 4 [M + H] + calculated value, 289; experimental 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).

[0636] 3. Synthesis of 2-(1-methyl-1H-pyrazol-4-yl)-6-nitroquinolin-4-ol

[0637]

[0638] To 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) at room temperature was added tBuOK (1.5 g, 6.9 mmol) was added and the reaction mixture was heated to 80 °C and stirred for 6 h. Then, the reaction mixture was filtered and the resulting solid was diluted with 1 N aqueous HCl (10 mL). The precipitated solid was filtered, washed with water (10 mL) and acetonitrile (20 mL), and dried in vacuo to give 2-(1-methyl-1H-pyrazol-4-yl)-6-nitroquinolin-4-ol as a brown solid (0.8 g, yield: 86%). LCMS (ESI+): m / z C 13 H 11 N 4 O 3 [M+H] + calculated, 271; found, 271. 1 H 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).

[0639] 4. Synthesis of 4-(2-methoxyethoxy)-2-(1-methyl-1H-pyrazol-4-yl)-6-nitroquinoline

[0640]

[0641] 4-(2-Methoxyethoxy)-2-(1-methyl-1H-pyrazol-4-yl)-6-nitroquinoline was prepared following the procedure used for the preparation of 4-ethoxy-6-nitroquinolin-2-ol. The title compound was obtained as a brown solid (0.8 g, crude material was used for the next step without purification). LCMS (ESI+): m / z C 16 H 17 N 4 O 4 [M+H] + calculated, 329; found, 329. 1 H 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).

[0642] 5. Synthesis of 4-(2-methoxyethoxy)-2-(1-methyl-1H-pyrazol-4-yl)quinolin-6-amine

[0643]

[0644] 4-(2-Methoxyethoxy)-2-(1-methyl-1H-pyrazol-4-yl)quinolin-6-amine was prepared using the procedure followed for the preparation of 4-(2-methoxyethoxy)-2-(thiazol-5-yl)quinolin-6-amine and was obtained as a brown solid (0.6 g, crude material used in the next step without purification). LCMS (ESI+): m / z C 16 H 19 N 4 O 2 [M+H] + calculated, 299; found, 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).

[0645] 6. Synthesis of N-(4-(2-methoxyethoxy)-2-(1-methyl-1H-pyrazol-4-yl)quinolin-6-yl)oxetane-3-carboxamide

[0646]

[0647] N-(4-(2-Methoxyethoxy)-2-(1-methyl-1H-pyrazol-4-yl)quinolin-6-yl)oxetane-3-carboxamide was prepared following the procedure for N-(4-ethoxy-2-(4-methyl-1H-imidazol-1-yl)quinolin-6-yl)oxetane-3-carboxamide and was obtained as an off-white solid (0.02 g, yield: 85%). HPLC purity: 93.43%. LCMS (ESI+): m / z C 20 H 23 N 4 O 4 [M+H] + calculated, 383; found, 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).

[0648] Example 54: N-(4-Ethoxy-8-methyl-2-(4-methyl-1H-imidazol-1-yl)quinolin-6-yl)oxetan-3-carboxamide

[0649]

[0650] Scheme:

[0651]

[0652] 1. Synthesis of Ethyl 3-((4-bromo-2-methylphenyl)amino)-3-oxopropionate

[0653]

[0654] To a stirred solution of 4-bromo-2-methylaniline (6 g, 32.25 mmol) in CH 2 Cl 2 (60 mL) at room temperature was added Et 3 N (6.5 mL, 38.00 mmol). To this was added ethyl 3-chloro-3-oxopropionate (3 mL, 96.00 mmol) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 5 h. Then, the reaction mixture was diluted with ice-cold water (200 mL) and extracted with CH 2 Cl 2 (2 × 100 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo to give ethyl 3-((4-bromo-2-methylphenyl)amino)-3-oxopropionate (4.3 g, crude) as an off-white solid. This reaction was carried out on a 2 × 3 g scale. The crude material was used in the next step without further purification.

[0655] 2. Synthesis of 3-((4-bromo-2-methylphenyl)amino)-3-oxopropanoic acid

[0656]

[0657] At room temperature, NaOH (2.29 g, 57.30 mmol) dissolved in H 2 O (10 mL) was added to a stirred solution of ethyl 3-((4-bromo-2-methylphenyl)amino)-3-oxopropionate (4.3 g, crude) in MeOH (20 mL), and the mixture was stirred for 16 h. Then, the reaction mixture was diluted with ice-cold water (100 mL) and washed with EtOAc (2 × 50 mL). The pH of the aqueous layer was acidified to pH 5 - 6 with aqueous citric acid and extracted with EtOAc (2 × 50). The organic extracts were dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo to give 3-((4-bromo-2-methylphenyl)amino)-3-oxopropanoic acid as an off-white solid (1.5 g, yield: 17% over 2 steps). 1 H 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).

[0658] 3. Synthesis of 6-bromo-8-methylquinoline-2,4-diol

[0659]

[0660] 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 h. Then, the reaction mixture was quenched with ice-cold water, and the resulting solid was filtered and dried in vacuo to give 6-bromo-8-methylquinoline-2,4-diol as an off-white solid (2.3 g, yield: 82%). This reaction was carried out on a 2 × 1.5 g scale. LCMS (ESI+): m / z C 10 H 9 BrNO 2 [M + H] + calculated, 254; found, 254. 1 H 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).

[0661] 4. Synthesis of 6-bromo-2,4-dichloro-8-methylquinoline

[0662]

[0663] 6-Bromo-2,4-dichloro-8-methylquinoline was prepared using the procedure followed for the preparation of 2,4-dichloro-6-nitroquinoline and was obtained as a brown solid (1.3 g, yield: 49%). 1 H NMR (400 MHz, DMSO-d 6, δ) 8.19 (s, 1H), 8.04 (s, 1H), 8.00 (s, 1H), 2.67 (s, 3H).

[0664] 5. Synthesis of 6-bromo-2-chloro-4-ethoxy-8-methylquinoline

[0665]

[0666] To a stirred solution of 6-bromo-2,4-dichloro-8-methylquinoline (2.3 g, 7.90 mmol) in EtOH (10 mL) at room temperature was added NaOEt (1.6 g, 23.52 mmol). The reaction mixture was stirred at room temperature for 16 h. Then, the volatiles were removed in vacuo. The crude material was diluted with NH 4 Cl (50 mL). The resulting solid was filtered and dried under vacuum to give 6-bromo-2-chloro-4-ethoxy-8-methylquinoline as an off-white solid (1.3 g, yield: 61%). LCMS (ESI+): m / z C 12 H 12 BrClNO [M + H] + calculated, 300; found, 300. 1 H 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).

[0667] 6. Synthesis of 6-bromo-4-ethoxy-8-methyl-2-(4-methyl-1H-imidazol-1-yl)quinoline

[0668]

[0669] 6-Bromo-4-ethoxy-8-methyl-2-(4-methyl-1H-imidazol-1-yl)quinoline was prepared using the procedure followed for the preparation of 4-ethoxy-2-(4-methyl-1H-imidazol-1-yl)-6-nitroquinoline and was obtained as an off-white solid (0.6 g, crude). LCMS (ESI+): m / z C 16 H 17BrN 3 O[M+H] + Calculated value, 346; experimental value, 346.

[0670] 6. Synthesis of N-(4-ethoxy-8-methyl-2-(4-methyl-1H-imidazol-1-yl)quinolin-6-yl)-1,1-diphenylmethanimine

[0671]

[0672] At room temperature, diphenylmethanimine, Cs 2 CO 3 (1.17 g, 1.58 mmol) was added to a stirred solution of 6-bromo-4-ethoxy-8-methyl-2-(4-methyl-1H-imidazol-1-yl)quinoline (0.50 g, 1.44 mmol) in 1,4-dioxane (3 mL), and purged with N 2 for 20 minutes. Xantphos (0.167 g, 0.28 mmol) and Pd 2 (dba) 3 (0.13 g, 0.14 mmol) were added thereto, and purged with N 2 for another 5 minutes. The reaction was heated at 110 °C for 16 hours. Then, the reaction mixture was cooled to room temperature and diluted with ice-cold water (50 mL). The resulting solid was filtered and dried under vacuum. The aqueous layer was extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel (100 - 200 mesh) in 50% EtOAc in heptane to give N-(4-ethoxy-8-methyl-2-(4-methyl-1H-imidazol-1-yl)quinolin-6-yl)-1,1-diphenylmethanimine as a yellow solid (0.4 g, yield: 62%). LCMS (ESI+): m / z C 29 H 27 N 4 O[M+H] + Calculated value, 447; experimental value, 447.

[0673] 7. Synthesis of 4-ethoxy-8-methyl-2-(4-methyl-1H-imidazol-1-yl)quinolin-6-amine hydrochloride

[0674]

[0675] At 0 °C, HCl:H 2 O (1:1, 2 mL) was added to a stirred solution of N-(4-ethoxy-8-methyl-2-(4-methyl-1H-imidazol-1-yl)quinolin-6-yl)-1,1-diphenylmethanimine (0.10 g, 0.22 mmol) in THF (5 mL). The reaction mixture was warmed to room temperature and stirred for 2 h. Then, volatiles were removed in vacuo to afford 4-ethoxy-8-methyl-2-(4-methyl-1H-imidazol-1-yl)quinolin-6-amine hydrochloride (0.09 g, crude) as a light brown solid.

[0676] 8. Synthesis of N-(4-ethoxy-8-methyl-2-(4-methyl-1H-imidazol-1-yl)quinolin-6-yl)oxetane-3-carboxamide

[0677]

[0678] N-(4-ethoxy-8-methyl-2-(4-methyl-1H-imidazol-1-yl)quinolin-6-yl)oxetane-3-carboxamide was prepared following the procedure of N-(4-ethoxy-2-(4-methyl-1H-imidazol-1-yl)quinolin-6-yl)oxetane-3-carboxamide and obtained as an off-white solid (0.012 g, yield: 5%). HPLC purity: 95.87%. LCMS (ESI+): m / z C 20 H 23 N 4 O 3 [M+H] + calculated, 367; found, 367. 1 H 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).

[0679] AlphaLISA assay

[0680] Human DRP1 (UniProtID: O00429.4, residues 1 - 699) and human MiD49 (UnitProtIS: Q96C03.1, residues 126 - 454) were cloned as N-terminal His-tag fusions into the pET15b vector. All constructs were transformed into the E. coli host strain BL21 CodonPlus DE3. Bacteria were grown at 37 °C on an orbital shaker in LB medium containing 100 μg / ml ampicillin and 34 μg / ml chloramphenicol until the OD 600 reached 0.4, at which point the temperature was lowered to 16 °C. Recombinant protein expression was induced for 18 h by the addition of IPTG when the OD 600 was approximately 0.8. All cultures were centrifuged and the bacterial pellet was used for protein purification.

[0681] For His-DRP1, the pellet was resuspended in DRP buffer A (20 mM Tris, 500 mM KCl, 1.8 mM β-ME, pH 8.0) and protease inhibitor mixture (Roche), and then the cells were lysed by sonication (400 W, 3 s on, 3 s off, for a total of 20 min). The lysate was centrifuged at 20,000 g, and then the supernatant was applied to a pre-equilibrated Ni-NTA column with DRP buffer A. The column was washed thoroughly with buffer A containing 50 mM imidazole. The purified His-DRP1 was eluted with DRP buffer A containing 250 mM imidazole and dialyzed overnight against DRP buffer A (cutoff 18 kDa) at 4 °C to remove imidazole. For AlphaLISA, the His-tag was retained on the full-length DRP1.

[0682] For MiD49-GST, the bacterial pellet was resuspended and sonicated in MID lysis buffer (25 mM Tris-HCl pH 7.5, 500 mM NaCl, 5% glycerol, 1 mM TCEP, and 0.5% CHAPS). The lysate was pre-cleared at 20,300 g and then applied to a 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 protein was 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 molecular weight cut-off of 30 kDa and further purified by size-exclusion chromatography on a Superdex-200 column (GE Healthcare) in buffer A. The eluates containing MiD49-GST (126-454) were pooled, concentrated, flash-frozen in aliquots in liquid nitrogen, and stored at -80 °C.

[0683] A total of 100 nl of compounds at concentrations from 100 μM to 991 pM in DMSO were spotted onto a 384-well AlphaPlate (PerkinElmer, Waltham, MA) (diluted 3.165-fold, 11 concentration levels). Recombinant His-DRP1 (200 nM), MiD49-GST (20 nM), and GMP-PNP (100 μM) were mixed in assay buffer (PBS with 1.5% BSA, 1 mM DTT). Five microliters of the protein mixture were 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. Five microliters of the mixed beads were added to each well on the microplate such that the final bead concentration per well was 20 μg / ml. The sealed plate was incubated at room temperature for 60 minutes and protected from light. AlphaLISA signals were detected using an EnVision multimode reader (excitation wavelength 680 nm and emission wavelength 615 nm). GraphPad Prism was used to calculate the IC 50 .

[0684] Example data

[0685]

[0686]

[0687] "++++" means < 0.5 μM; "+++" means 0.5 - 1 μM; "++" means > 1 - 10 μM; "+" means > 10 μM; "NT" means "not tested".

Claims

1. A compound represented by formula (I): or a pharmaceutically acceptable salt thereof, wherein: X 1 is CH or N; R 1 optionally substituted by one or more R 1a 5- to 10-membered monocyclic or bicyclic heteroaryl; Each R 1a is independently selected from the group consisting of: a halogen group, a cyano group, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 3-6 cycloalkyl group, OH, a C 1-6 alkoxy group and a C 1-6 haloalkoxy group; R 2 is C 1-6 alkyl, C 3-6 cycloalkyl, bridged C 5-12 cycloalkyl, phenyl, 3- to 10-membered monocyclic or bicyclic heterocyclic group or 5- to 10-membered monocyclic or bicyclic heteroaryl, each optionally substituted by one or more R 2a substituted; Each R 2a is independently selected from a halogen group, a cyano group, a C 1-6 alkyl group, a C 1-6 haloalkyl group, OH, a C 1-6 alkoxy group, a C 1-6 haloalkoxy group, -C(O)R 2b , -C(O)OR 2b , -C(O)NR N2a R N2b and -NR N2a R N2b ; R 2b 、R N2a and R N2b each independently is H, C 1-6 alkyl or C 1-6 haloalkyl; R 3 is C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, a 3- to 10-membered monocyclic or bicyclic heterocyclic group, or a 5- to 10-membered monocyclic or bicyclic heteroaryl group, each optionally substituted with one or more R 3a substituents; Each R 3a is independently selected from the group consisting of: a halogen group, C 1-6 alkyl, OH, C 1-6 alkoxy, and C 1-6 haloalkoxy; R 4 is H, C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl; and R 5 is H, C 1-6 alkyl or C 1-6 haloalkyl.

2. The compound according to claim 1, wherein the compound is represented by formula (IA): or a pharmaceutically acceptable salt thereof.

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

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

5. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein: R 1 is a 5- or 6-membered monocyclic heteroaryl, wherein the 5- or 6-membered monocyclic heteroaryl is optionally substituted with 1 or 2 R 1a substituents; Each R 1a is independently selected from the group consisting of: a halogen group, a cyano group, a C 1-4 alkyl group, a C 3-4 cycloalkyl group, and a C 1-3 alkoxy group.

6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of imidazolyl, pyrazolyl, triazolyl and thiazolyl, each optionally being substituted with 1 or 2 R 1a substituents.

7. The compound or a pharmaceutically acceptable salt thereof according to claim 6, wherein R 1 is represented by the following structural formula: each is optionally substituted with 1 or 2 R 1a substituents, and each R 1a is independently selected from the group consisting of: -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -C(CH 3 ) 3 , cyclopropyl, -OCH 3 , -Cl, and cyano.

8. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of: imidazolyl and thiazolyl, each optionally substituted with 1 or 2 R 1a substituents, and wherein each R 1a is independently selected from the group consisting of: -CH 3 , cyclopropyl, and -OCH 3 .

9. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein: R 2 is C 1-3 alkyl, C 3-6 cycloalkyl, bridged C 5-8 cycloalkyl, 3- to 6-membered monocyclic heterocyclic group or 5- or 6-membered monocyclic heteroaryl group, each optionally substituted by 1 to 3 R 2a substituents; Each R 2a is independently selected from the group consisting of: a halogen group, a cyano group, C 1-3 alkyl, C 1-3 haloalkyl, -OH and C 1-3 alkoxy.

10. The compound or a pharmaceutically acceptable salt thereof according to claim 9, wherein R 2 is C 1-3 alkyl, cyclopropyl, cyclobutyl, bicyclo[1.1.1]pentyl, oxetanyl, tetrahydropyranyl or isoxazolyl, each optionally substituted with 1 to 3 R 2a substituents.

11. The compound according to claim 10 or a pharmaceutically acceptable salt thereof, wherein R 2 is optionally C 2a alkyl substituted with 1 to 3 R 1-3 groups, or R 2 is represented by the following structural formula: each optionally substituted with 1 or 2 R 2a groups, and wherein 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 .

12. The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein 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 represented by the following structural formula:

13. The compound or a pharmaceutically acceptable salt thereof according to claim 9, wherein R 2 is C 1-3 alkyl, cyclopropyl, cyclobutyl, oxetanyl or tetrahydropyranyl, wherein the C 1-3 alkyl, the cyclopropyl and the cyclobutyl are each optionally substituted with 1 to 3 R 2a substituents.

14. The compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein 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 , or R 2 is represented by the following structural formula:

15. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein: R 3 is C 1-4 alkyl or C 3-4 cycloalkyl, each optionally substituted with 1 to 3 R 3a substituents; Each R 3a is independently selected from the group consisting of: C 1-3 alkyl, -OH, and C 1-3 alkoxy.

16. The compound or a pharmaceutically acceptable salt thereof according to claim 15, wherein: R 3 is C 1-4 alkyl or cyclopropyl, and wherein said C 1-3 alkyl is optionally substituted with 1 to 3 R 3a substituents; Each R 3a is independently selected from -CH 3 , OH and -OCH 3 .

17. The compound or a pharmaceutically acceptable salt thereof according to claim 16, wherein R 3 is -CH 3 -, -CH 2 CH 3 -, -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 or cyclopropyl.

18. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from: or a pharmaceutically acceptable salt thereof.

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

20. A method of treating a dynamin-1-like protein (Drp1)-mediated disease or disorder in a subject, comprising administering to the subject an effective amount of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18 or the 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, a neuronal activation disorder, a muscle fatigue disorder, a muscle mass disorder, a β-oxidation disease, a metabolic disease, cancer, a vascular disease, an ocular vascular disease, a muscle eye disease or a kidney disease.

22. The method according to claim 21, wherein: The muscle structure disorders are selected from the group consisting of Bethlem myopathy, central core disease, congenital fiber type disproportion, distal muscular dystrophy (MD), Duchenne and Becker MD, Emery-Dreifuss MD, facioscapulohumeral MD, hyaline body myopathy, limb-girdle MD, muscle sodium channelopathy, myotonic chondrodystrophy, myotonic dystrophy, myotubular myopathy, nemaline myopathy, oculopharyngeal MD and stress urinary incontinence; The 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, tardy ulnar palsy and toxic myoneural disorders; The muscle fatigue disorders are selected from the group consisting of chronic fatigue syndrome, diabetes (type I or II), glycogen storage disease, fibromyalgia, Friedreich's ataxia, intermittent claudication, lipid storage myopathy, MELAS, mucopolysaccharidosis, Pompe disease and thyrotoxic myopathy; The muscle mass disorders are selected from the group consisting of cachexia, cartilage degeneration, cerebral palsy, compartment syndrome, critical illness myopathy, inclusion body myositis, muscle atrophy (disuse), sarcopenia, steroid myopathy and systemic lupus erythematosus; The β-oxidation diseases are selected from the group consisting of: systemic carnitine transporter, 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); The metabolic diseases are selected from the group consisting of: hyperlipidemia, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, low HDL cholesterol, high LDL cholesterol, and / or HLD non-cholesterolemia, VLDL hyperproteinemia, dyslipoproteinemia, apolipoprotein A-I hypoproteinemia, atherosclerosis, arteriosclerosis diseases, cardiovascular system diseases, cerebrovascular diseases, peripheral circulatory diseases, metabolic syndrome, syndrome X, obesity, diabetes (type I or II), hyperglycemia, insulin resistance, impaired glucose tolerance, hyperinsulinemia, diabetic complications, cardiac insufficiency, 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, hair diseases, inflammation, arthritis, asthma, gut allergy syndrome, ulcerative colitis, Crohn's disease, and pancreatitis; The vascular diseases are selected from the group consisting of: peripheral vascular insufficiency, peripheral vascular diseases, intermittent claudication, peripheral vascular disease (PVD), peripheral arterial disease (PAD), peripheral arterial obstructive disease (PAOD), and peripheral occlusive arterial disease; The ocular vascular diseases are selected from the group consisting of: age-related macular degeneration (AMD), Stargardt's disease, hypertensive retinopathy, diabetic retinopathy, retinopathy, macular degeneration, retinal hemorrhage, and glaucoma; The muscle eye diseases are selected from the group consisting of: strabismus, progressive external ophthalmoplegia, esotropia, exotropia, refractive and accommodative disorders, hyperopia, myopia, astigmatism, anisometropia, presbyopia, accommodative disorders, and internal ophthalmoplegia; and The 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 nephritis, acute renal failure, chronic renal failure, diabetic nephropathy, and Bartter's 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 and Becker muscular dystrophy, diabetes (type I or 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: bone inflammatory diseases, T cell immunomodulation, neuropathic pain, cancer, Alpers' disease, CPEO - chronic progressive external ophthalmoplegia, Kearns - Sayre syndrome (KSS), Leber's hereditary optic neuropathy (LHON), MELAS - mitochondrial myopathy, encephalomyopathy, lactic acidosis and stroke-like episodes, MERRF - myoclonic epilepsy and ragged-red fiber disease, NARP - neurogenic weakness, ataxia, retinitis pigmentosa, Pearson syndrome, platinum-based chemotherapy-induced ototoxicity, Cockayne syndrome, xeroderma pigmentosum type A, Wallerian 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 kidney injury, myocardial ischemia, pulmonary arterial hypertension, polycystic kidney disease, Huntington's disease, neurodegenerative diseases or Charcot - Marie - Tooth disease.

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

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