Glycogen synthase kinase 3 inhibitors for therapeutic use

Abstract

A novel compound of formula I and its composition are provided, which is an inhibitor of glycogen synthase kinase 3-beta (GSK3β). Some aspects of the present invention relate to novel compounds and compositions having a superior pharmacokinetic profile compared to conventional GSK3β inhibitors and a pharmacokinetic profile more suitable for therapeutic applications. [Formula 1] TIFF2026529053000089.tif17159

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority under U.S.C. Title 35, Section 119(e) to U.S. Provisional Patent Application No. 63 / 512825, filed on 10 July 2023. The said application is incorporated herein by reference in its entirety.

[0002] Aspects of the present invention relate to novel compositions for treating neurological or psychiatric disorders, including Alzheimer's disease, bipolar disorder, depression, neuroinflammation, or other conditions for which modulation of GSK-3 signaling is clinically beneficial. [Background technology]

[0003] GSK-3 inhibitors have been proposed as therapeutic agents for subjects with neurological and / or psychiatric disorders such as Alzheimer's disease, bipolar disorder, depression, schizophrenia, Parkinson's disease, traumatic brain injury, or neuroinflammation. Because GSK-3 inhibitors are known to increase WNT protein expression, they enhance the regenerative medicine pathways widely proposed for the treatment of neurological and psychiatric disorders. GSK-3 inhibition and / or enhancement of WNT signaling are associated with the potential treatment of type 2 diabetes, diabetic nephropathy, chronic kidney disease, atherosclerosis, alopecia, osteoarthritis, osteoporosis, alcoholic hepatitis, inflammatory bowel disease, exudative age-related macular degeneration, atrophic age-related macular degeneration, diabetic macular edema, Fuchs corneal endothelial dystrophy, corneal epithelial cell defects, dry eye, glaucoma, familial exudative vitreoretinopathy (FEVR), Nolier's disease, Coats' disease, retinopathy of prematurity, macular telangiectasia, retinal vein occlusion, Sjögren's syndrome, sensorineural hearing loss, conductive hearing loss, polycystic kidney disease, focal segmental glomerulosclerosis, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, short bowel syndrome, melanoma, pancreatic cancer, prostate cancer, colon cancer, leukemia, septic shock, and atherosclerosis. GSK-3 inhibitors have been proposed as monotherapy, in combination with lithium, and in combination with other medications for the treatment of bipolar disorder.

[0004] A highly potent and selective radioinhibitor of GSK3β has been developed for use in positron emission tomography (PET) as a diagnostic tool for Alzheimer's disease. PET imaging of GSK3β is also of interest as a diagnostic tool for identifying cancers that express GSK3. PET imaging of GSK3β is also useful in the development of therapeutic agents. PET imaging of GSK3β in the brain can ensure appropriate dosages of GSK3β inhibitors for the treatment of neurological or psychiatric disorders. PET imaging of GSK3β in the brain or other sites can ensure appropriate dosages of GSK3 inhibitors for the treatment of cancer. This imaging can be used in animal studies as part of new drug discovery, clinical trials to establish therapeutic dose ranges, or clinical practice to ensure optimal dosages of therapeutic agents.

[0005] However, the development of a highly potent and selective inhibitor of GSK3β as a therapeutic agent has not yet been successful. One of the challenges is safety, and the development of some GSK3β inhibitors has been discontinued for safety reasons. The obstacles to the development of a safe GSK3β inhibitor are said to be "insurmountable." Because PET scans are performed only once or twice, safety issues are less of a concern in PET imaging applications than in therapeutic applications. Short-term safety data is sufficient for the development of PET ligands, and the short half-life of compounds is attractive for PET imaging because safety issues are reduced if the contrast agent is rapidly metabolized and removed.

[0006] PF-04802367 (also known as PF-367), an oxazole-4-carboxamide, has been reported to be ideal for the discovery of a GSK-3 radiopharmaceutical in the central nervous system, although its rapid binding rate in brain tissue makes it insufficient as an effective therapeutic agent. Subsequent efforts will further investigate the optimization of oxazole carboxamides (OCMs) beyond PF-367, thereby maximizing the potency and selectivity of the compound referred to herein as OCM-51 or Compound 1. [ka]

[0007] However, due to its rapid clearance, compound 1 is not suitable for use as a GSK-3β inhibitor for therapeutic applications. SUMMARY OF THE INVENTION

[0008] The compounds and compositions of the present invention have surprisingly and unexpectedly been found to have excellent potency and selectivity against GSK-3β while providing an improvement in in vivo stability (delayed clearance) necessary for therapeutic applications. In some embodiments, the present invention relates to GSK-3β inhibitors for therapeutic use having the structure of formula I.

Chemical formula

[0009] The compounds of this disclosure can also be administered in combination with lithium. This disclosure also provides a method for establishing a diagnosis of bipolar disorder or other conditions for which GSK-3 inhibition is clinically useful, and a method for establishing an appropriate therapeutic dose of the compound of formula I in a subject.

[0010] This disclosure also provides a method for treating subjects with Alzheimer's disease, bipolar disorder, or depression, demonstrating evidence of elevated GSK-3. In some embodiments, this disclosure provides a method for establishing a diagnosis of bipolar disorder or other conditions for which GSK-3 inhibition is clinically useful. In some embodiments, this disclosure provides a method for establishing an appropriate therapeutic dose of a compound of formula I in a subject. [Brief explanation of the drawing]

[0011] [Figure 1] The graph shows the therapeutic concentration range of a drug on a graph representing the percentage of maximum efficacy versus drug concentration.

[0012] [Figure 2] The radioactivity time curves of the relevant C11 compounds in rhesus monkeys are shown.

[0013] [Figure 3] The concentrations in plasma, brain, and CSF of mice at one-hour intervals after injection of 50 mg / kg of the relevant compound are shown.

[0014] [Figure 4] The levels are plotted as residual pCRMP2 levels, normalized to β-III-tubulin, and show relative intensity to DMSO. N=4 per concentration. Cortical glutamatergic neurons were induced from induced pluripotent stem cells and treated with DMSO or different molar concentrations of the test compound for 24 hours. Immunocytochemistry was used to measure CRMP2 and phosphorylated CRMP2 (phosphorylated at the T514 site) and the neuronal marker β-III-tubulin.

[0015] [Figure 5]Rats exhibit positive, appetite-stimulating ultrasonic vocalizations in the 50-60 kHz range when food is available, when they see a friendly rat, or when they are tickled by a familiar human. These vocalizations are thought to reflect a positive emotional state. Five rats were used per group. Adult male Wistar rats were administered either saline, dextroamphetamine (AMP), and lithium at 100 mg / kg, followed by AMP (Li-AMP), or compound 56, followed by AMP (compound 56-AMP). Compound 56 was administered intraperitoneally at 10 mg / kg, and AMP was administered 1 hour later. The time range of 0-120 minutes reflects the timing of AMP administration. [Modes for carrying out the invention]

[0016] Unless otherwise defined, all terms used in the disclosure of this invention, including technical and scientific terms, have the meanings generally understood by those skilled in the art to which this invention belongs.

[0017] As disclosed herein, several ranges of values ​​are provided. Unless otherwise indicated in the context, each intermediate value between the upper and lower limits of that range is also specifically disclosed to the tenth of a unit of the lower limit. Smaller ranges between any stated value or intermediate value within the stated range and any other stated value or intermediate value within that stated range are included in the invention. The upper and lower limits of these smaller ranges may be included in or excluded from the range independently, and each range that includes either the limitation or does not include either the limitation or both limitations is included in the invention, subject to the specifically excluded limitations within the stated range. If the stated range includes one or both limits, ranges that exclude either or both of those included limitations are also included in the invention. The term “about” generally includes ±10% of the stated value. For example, “about 10%” may refer to a range of 9% to 11%, and “about 20” may mean 18 to 22. Preferably, “about” includes ±6% of the stated value. Alternatively, "approximately" can include ±5% of the stated value. Other meanings of "approximately" may become clear from contexts such as rounding; for example, "approximately 1" could mean between 0.5 and 1.4.

[0018] The term "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. Pharmaceutically acceptable salts are understood to be non-toxic. Such salts are acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, or formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, and 2-hydroxyethane. This includes acid addition salts formed with organic acids such as sulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. Additional information regarding appropriate pharmaceutically acceptable salts is found in "Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, PA, 1985," which is incorporated herein by reference.

[0019] One problem with therapeutic agents having a short half-life is that they may need to be administered several times a day. If compounds with a short half-life are administered only once or twice a day, the peak concentration at the end of the dosing interval can be several times higher than the trough concentration.

[0020] For example, a drug with a half-life of 24 hours can be administered once daily at a peak drug concentration approximately 2 to 3 times the trough concentration. In contrast, a drug with a half-life of 6 hours, when administered once daily, will reach a peak concentration approximately 16 times the trough concentration.

[0021] Generally, a principle of drug development is that a small ratio of peak concentration to trough concentration is desirable in order to maintain drug concentrations within the therapeutic range (see Figure 1). This range is explained by the dose-response relationship between efficacy and toxicity. A low peak / trough ratio helps to maintain drug concentrations at a level that is effective throughout the entire dosing interval without becoming toxic.

[0022] During the course of medicinal chemistry research, there is evidence that the oxazole carboxamide developed has a short half-life. When the compound in the program was evaluated in rhesus monkeys, a rapid decrease in radioactivity was observed, and this decrease was due to C 11 The rate of decay was more rapid than expected based on the half-life (see Figure 2). When the same compound was injected into mice at a dose of 50 mg / kg, the concentrations in plasma and brain decreased rapidly every hour (see Figure 3).

[0023] Throughout the entire 7 hours of measurement, the level remained consistently IC 50 The result was higher, but this was due to the larger dose administered. The results were consistent with the peak / trough ratio of approximately 100 in mice administered every 6 hours. Compounds that are potent and selective inhibitors of GSK3β would be more suitable for therapeutic use if they have a superior pharmacokinetic profile, such as high stability and a low peak / trough ratio.

[0024] Therefore, one aspect of the present invention includes administering the following compounds 2 to 38 (compound 1 being OCM-51) by injection at a total daily dose of about 0.1 to about 4 mg / kg, or by oral administration at a dose of about 0.125 to about 10 mg / kg.

[0025] As part of the medicinal chemistry studies of OCM-51 lead compound 1, phenyl group substitution was investigated in compounds 2-10, distal heterocycles were investigated in compounds 11-17, central carboxamides were investigated in compounds 18-20, linkers were investigated in compounds 21-24, and core heterocycles were investigated in compounds 25-38. Surprisingly and unexpectedly, the compounds of the present invention were found to possess excellent efficacy and selectivity against GSK-3β while providing the necessary improvement in stability (delayed clearance) for therapeutic use.

[0026] Those skilled in the art, without wishing to be bound by any particular theory, will recognize that ATP-competitive kinase inhibitors generally interact with the "hinge region" of a particular kinase. The kinase hinge region is a critical region for the binding of ATP, the natural kinase substrate. Typically, the hinge region provides hydrogen bond donors and hydrogen bond acceptors, which are generally present as part of the kinase protein backbone. To leverage this feature, a common strategy in the design of kinase inhibitors is to include a combination of hydrogen bond donors and acceptors complementary to the kinase hinge region. Specifically, the inhibitor's hydrogen bond donors form hydrogen bonds with the hydrogen bond acceptors in the kinase hinge region. Simultaneously, the inhibitor's hydrogen bond acceptors form hydrogen bonds with the hydrogen bond donors in the kinase hinge region. In the case of kinases, the hinge region is defined as the amino acid sequence connecting the C-terminal lobe and the N-terminal lobe.

[0027] Since all kinases possess a hinge region, simply binding to the hinge region is generally insufficient for developing effective kinase inhibitory therapies. To give specific inhibitors drug-worthy properties, substituents on both sides of the hinge-binding agent are optimized for the structure of the specific kinase. In this way, selective inhibition can be achieved between different kinases and between specific kinase isoforms.

[0028] The compounds of the present invention utilize amides, amidines, acylated heteroaromatic groups, aminopyridines, aminopyrimidines, and related structures as hinge region binders. Those skilled in the art will recognize that additional functional groups and structures useful for kinase inhibitor hinge region binding exist.

[0029] The compounds of the present invention are generally represented by the structure of formula I or a pharmaceutically acceptable salt thereof.

Chemical formula

[0030] The compounds of the present invention include those generally described above and are further described by the classes, subclasses, and species disclosed herein. Unless otherwise specified, the following definitions shall apply as used herein. In at least some embodiments, chemical elements are identified according to the periodic table of elements in the CAS edition of the Handbook of Chemistry and Physics, supplementally edited in the 75th edition. Furthermore, the general principles of organic chemistry are described in "Organic Chemistry" by Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Organic Chemistry," 5th edition, edited by Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0031] In one embodiment, the "alkyl" group refers to a saturated aliphatic hydrocarbon, including linear, branched, and cyclic alkyl groups. In one embodiment, the alkyl group has 1 to 12 carbon atoms. In another embodiment, the alkyl group has 1 to 7 carbon atoms. In yet another embodiment, the alkyl group has 1 to 6 carbon atoms. In yet another embodiment, the alkyl group has 1 to 4 carbon atoms. The alkyl group may be unsubstituted or may be substituted with one or more groups selected from halogen, hydroxy, alkoxy, carboxylic acid, aldehyde, carbonyl, amide, cyano, alkylamide, dialkylamide, nitro, amino, alkylamino, dialkylamino, carboxyl, thio, and thioalkyl groups.

[0032] In one embodiment, the term "halogen" refers to F, in another embodiment to Cl, in yet another embodiment to Br, and in yet another embodiment to I.

[0033] In one embodiment, the "cycloalkyl" group refers to a saturated or unsaturated hydrocarbon ring. In one embodiment, the cycloalkyl group has 3 to 12 carbon atoms. In some embodiments, the cycloalkyl group has 3 to 8 carbon atoms. In some embodiments, the cycloalkyl group has 4 to 8 carbon atoms. In another embodiment, the cycloalkyl group includes 2 to 3 fused rings. The cycloalkyl group may be unsubstituted or substituted with one or more groups selected from halogens, hydroxy, alkoxy, carboxylic acids, aldehydes, carbonyls, amides, cyanos, alkylamides, dialkylamides, nitros, aminos, alkylaminos, dialkylaminos, carboxyls, thios, and thioalkyls. The carbon ring may be substituted with one or more groups selected from halogens, hydroxy, alkoxy, carboxylic acids, aldehydes, carbonyls, amides, cyanos, alkylamides, dialkylamides, nitros, aminos, alkylaminos, dialkylaminos, carboxyls, thios, and thioalkyls.

[0034] In one embodiment, a "heterocyclic" group refers to a ring structure that, in addition to carbon atoms, includes sulfur, oxygen, nitrogen, or any combination thereof as part of the ring. In another embodiment, the heterocyclic group is a 3- to 12-membered ring. In another embodiment, the heterocyclic group is a 6-membered ring. In another embodiment, the heterocyclic group is a 5- to 7-membered ring. In another embodiment, the heterocyclic group is a 4- to 8-membered ring. In another embodiment, the heterocyclic group may be unsubstituted, or may be substituted with halogens, haloalkyls, hydroxyls, alkoxys, carbonyls, amides, alkylamides, dialkylamides, cyanos, nitros, CO2H, aminos, alkylaminos, dialkylaminos, carboxyls, thios, and / or thioalkyls. In another embodiment, the heterocyclic group may be condensed into another saturated or unsaturated cycloalkyl or heterocyclic 3- to 8-membered ring. In another embodiment, the heterocyclic group is a saturated ring. In another embodiment, the heterocyclic ring is an unsaturated ring.

[0035] In one embodiment, the "aryl" group refers to an aromatic ring structure containing 6 to 14 carbon atoms. In one embodiment, the aryl group has 6 carbon atoms. In another embodiment, the aryl group has 12 carbon atoms. In yet another embodiment, the aryl group has 14 carbon atoms. The aryl group may be unsubstituted or may be substituted with one or more groups selected from halogens, hydroxy, alkoxy, carboxylic acids, aldehydes, carbonyls, amides, cyanos, alkylamides, dialkylamides, nitros, aminos, alkylaminos, dialkylaminos, carboxyls, thios, and thioalkyls. The carbocyclic ring may be substituted with one or more groups selected from halogens, hydroxy, alkoxy, carboxylic acids, aldehydes, carbonyls, amides, cyanos, alkylamides, dialkylamides, nitros, aminos, alkylaminos, dialkylaminos, carboxyls, thios, and thioalkyls.

[0036] In one embodiment, a "heteroaryl" group refers to an aromatic ring structure that, in addition to carbon atoms, includes sulfur, oxygen, nitrogen, or any combination thereof as part of the ring. In another embodiment, the heteroaryl group is a 5- to 14-membered ring. In yet another embodiment, the heteroaryl group is a 5-membered ring. In yet another embodiment, the heteroaryl group is a 6-membered ring. In yet another embodiment, the heteroaryl group is a bicyclic ring structure containing 9 atoms. In yet another embodiment, the heteroaryl group is a bicyclic ring structure containing 10 atoms. In yet another embodiment, the heteroaryl group is a bicyclic ring structure containing 14 atoms. The heteroaryl group may be unsubstituted or may be substituted with one or more groups selected from halogens, hydroxyl, alkoxy, carboxylic acids, aldehydes, carbonyls, amides, cyanos, alkylamides, dialkylamides, nitros, aminos, alkylaminos, dialkylaminos, carboxyls, thios, and thioalkyls. The carbocyclic ring may be substituted with one or more groups selected from halogens, hydroxyl, alkoxy, carboxylic acids, aldehydes, carbonyls, amides, cyanos, alkylamides, dialkylamides, nitros, aminos, alkylaminos, dialkylaminos, carboxyls, thios, and thioalkyls.

[0037] A "pharmaceutically acceptable salt" refers to a salt that, within the bounds of sound medical judgment, is suitable for use in contact with human and lower animal tissues without causing excessive toxicity, irritation, or allergic reactions, and that is commensurate with a reasonable benefit / risk ratio. pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. described pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which are incorporated herein by reference. Examples of pharmaceutically acceptable salts of the compounds of the present invention include salts derived from appropriate inorganic acids and inorganic bases, as well as organic acids and organic bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptone, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-hydroxyethanes. Examples include ruhonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.

[0038] References to disorders involving "abnormal signaling" of GSK-3 or GSK-3 beta mean that the type of disorder is related to abnormal regulation and expression of the GSK-3 or GSK-3 beta enzyme by the corresponding gene encoding the enzyme, or that the disorder is related to biomarkers (such as blood tests, tumor biopsy results, or PET imaging tests) indicating an increase in GSK-3 or GSK-3 beta activity.

[0039] As used herein, the term "subject" is intended to include humans and non-human animals. Non-human animals include all vertebrates, such as mammals and non-mammals (non-human primates, sheep, dogs, cats, cows, horses, chickens, amphibians, reptiles, etc.), with mammals such as non-human primates, sheep, dogs, cats, cows, horses, etc. being preferred.

[0040] Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, N + (C 1~4 alkyl)4 salts and the like. Representative alkali metal salts or alkaline earth metal salts include salts of sodium, lithium, potassium, calcium, magnesium, etc. Further, pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, aryl sulfonates, etc.

[0041] Unless otherwise specified, the structures shown herein include all isomers of the structure (e.g., enantiomers, diastereomers, and geometric (or conformational) forms), including the R and S configurations of each chiral center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers of the compounds of the present invention, as well as mixtures of enantiomers, diastereomers, and geometric (or conformational) forms, are within the scope of the present invention. Unless otherwise specified, all tautomer forms of the compounds of the present invention are within the scope of the present invention. Furthermore, unless otherwise specified, the structures shown herein include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds in which hydrogen is substituted with deuterium or tritium, or carbon 13 C or 14 Compounds substituted with carbon-rich carbon atoms are also within the scope of the present invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the present invention.

[0042] At least one embodiment of the present invention provides a structure of formula I or a pharmaceutically acceptable salt thereof. [ka] (In the formula, R 1 L 1 ~R 5 And, R 2 L 2 ~R 6 And, R 3 is H or C1-C6 alkyl, R 4 is H or C1-C6 alkyl, R 5 R is a 5-membered heteroaryl ring, a 6-membered aryl ring, a 6-membered heteroaryl ring, or an 8-12 membered fused bicyclic aryl or heteroaryl ring system, where R 5 is -(C=O) q -(C1~C6 alkyl), F, Cl, Br, I, OR 9 , SR9 S(O)R 9 S(O)2R 9 , N(R 9 )2, CN, C(O)OR 10 , C(O)N(R 10 )2, S(O)2OR 10 , P(O)(OR 10 )2, and -(CH2) s -R 11 It is arbitrarily replaced by 1 to 3 elements independently selected from, R 6 R is a 5-6 member heteroaryl ring, a 6 member aryl ring, or a 6 member heteroaryl ring, where R 6 is -(C=O) u -(C1~C6 alkyl), F, Cl, Br, I, NO2, OR 13 , SR 13 S(O)R 13 S(O)2R 13 , S(O)2N(R 13 )2, N(R 13 )2, CN, C(O)OR 14 , C(O)N(R 14 )2, S(O)2OR 14 , and P(O)(OR 14 ) Optionally replaced by 1 to 3 elements independently selected from 2, R 7 H, OR 8 , or N(R 8 )2, Each R 8 These are independently H or -(C=O) p -(C1~C6 alkyl) Each R 9 These are independently H and -(C=O) r -(C1~C6 alkyl), or -(C=O) r -(CH2) x -(C3~C6 cycloalkyl) Each R 10 These are independently H or C1-C6 alkyl groups. Each R 11 H, OR 12 , or N(R 12 )2, Each R12 These are independently H or -(C=O) t -(C1~C6 alkyl) Each R 13 These are independently H and -(C=O) v -(C1~C6 alkyl), or S(O)2R 14 And, Each R 14 These are independently H or C1-C6 alkyl groups. L 1 These are those with direct bonds, -(CH2) n -, a 3-7 membered cycloalkyl or heterocycle, a 5-6 membered heteroaryl ring, or a 6 membered aryl ring, where L 1 Any carbon atom in -(CH2) is one or two -(CH2) o -R 7 It is arbitrarily replaced with, L 2 L is a 5-6 member heteroaryl ring, a 6 member aryl ring, or a 6 member heteroaryl ring, where L 2 It is optionally substituted with 1-2 C1-C6 alkyl groups. X is O or NR 3 And, Y is O or NR 4 And, n is an integer between 1 and 5. o is an integer from 0 to 4. Each p is independently either 0 or 1. Each q is independently either 0 or 1. Each r is independently either 0 or 1. Each s is independently an integer between 0 and 3, Each t is independently either 0 or 1. Each u is independently either 0 or 1. Each v is independently either 0 or 1. Each w is independently either 0 or 1. x is an integer between 0 and 3. Each solid center is independently R, S, or a racemate.

[0043] At least some embodiments of the present invention further provide a method for producing a structure of formula I, a pharmaceutical composition comprising a structure of formula I, and a method for using a structure of formula I to treat various disorders characterized by abnormal signaling of GSK-3.

[0044] As generally defined above, R 1 L 1 ~R 5 That is the case.

[0045] As generally defined above, R 2 L 2 ~R 6 That is the case.

[0046] As generally defined above, R 3 is H or C1-C6 alkyl. In some embodiments, R 3 H is H. In some embodiments, R 3 These are C1-C6 alkyl groups.

[0047] As generally defined above, R 4 is H or C1-C6 alkyl. In some embodiments, R 4 is H. In some embodiments, R 4 These are C1-C6 alkyl groups.

[0048] As generally defined above, R 5 R is a 5-membered heteroaryl ring, a 6-membered aryl ring, a 6-membered heteroaryl ring, or an 8-12 membered fused bicyclic aryl or heteroaryl ring system, where R 5 is -(C=O) q -(C1~C6 alkyl), F, Cl, Br, I, OR 9 , SR 9 S(O)R 9 S(O)2R 9 , N(R 9 )2, CN, C(O)OR 10 , C(O)N(R 10 )2, S(O)2OR 10, P(O)(OR 10 )2, and -(CH2) s -R 11 It is optionally replaced by 1 to 3 groups independently selected from. In some embodiments, R 5 is a 5-membered heteroaryl ring. In some embodiments, R 5 R is a 6-membered aryl ring and a 6-membered heteroaryl ring. In some embodiments, R 5 R is a six-membered heteroaryl ring. In some embodiments, R 5 This is an 8-12 member condensed bicyclic aryl or heteroaryl ring system. In some embodiments, R 5 is non-substitutable. In some embodiments, R 5 is -(C=O) q -(C1~C6 alkyl), F, Cl, Br, I, OR 9 , SR 9 S(O)R 9 S(O)2R 9 , N(R 9 )2, CN, C(O)OR 10 , C(O)N(R 10 )2, S(O)2OR 10 , P(O)(OR 10 )2, and -(CH2) s -R 11 It is replaced by 1 to 3 elements selected independently of it.

[0049] As generally defined above, R 6 R is a 5-6 member heteroaryl ring, a 6 member aryl ring, or a 6 member heteroaryl ring, where R 6 is -(C=O) u -(C1~C6 alkyl), F, Cl, Br, I, NO2, OR 13 , SR 13 S(O)R 13 S(O)2R 13 , S(O)2N(R 13 )2, N(R 13 )2, CN, C(O)OR 14 , C(O)N(R 14 )2, S(O)2OR 14 , and P(O)(OR14 ) is optionally replaced by 1 to 3 groups independently selected from 2. In some embodiments, R 6 is a 5-6 member heteroaryl ring. In some embodiments, R 6 is a 6-membered aryl ring. In some embodiments, R 6 R is a six-membered heteroaryl ring. In some embodiments, R 6 is non-substitutable. In some embodiments, R 6 is -(C=O) u -(C1~C6 alkyl), F, Cl, Br, I, NO2, OR 13 , SR 13 S(O)R 13 S(O)2R 13 , S(O)2N(R 13 )2, N(R 13 )2, CN, C(O)OR 14 , C(O)N(R 14 )2, S(O)2OR 14 , and P(O)(OR 14 ) is replaced by 1 to 3 elements independently selected from 2.

[0050] As generally defined above, R 7 H, OR 8 , or N(R 8 )2. In some embodiments, R 7 is H. In some embodiments, R 7 is OR 8 In some embodiments, R 7 N(R) 8 )2.

[0051] As generally defined above, each R 8 These are independently H or -(C=O) p -(C1~C6 alkyl). In some embodiments, R 8 At least one of them is H. In some embodiments, R 8 At least one of them is -(C=O) p-(C1~C6 alkyl). In some embodiments, each R 8 They are the same. In some embodiments, each R 8 They are different.

[0052] As generally defined above, each R 9 These are independently H and -(C=O) r -(C1~C6 alkyl), or -(C=O) r -(CH2) x -(C3~C6 cycloalkyl). In some embodiments, R 9 At least one of them is H. In some embodiments, R 9 At least one of them is -(C=O) r -(C1~C6 alkyl). In some embodiments, R 9 At least one of them is -(C=O) r -(CH2) x -(C3~C6 cycloalkyl). In some embodiments, R 9 At least two of them are H. In some embodiments, R 9 At least two of them are -(C=O) r -(C1~C6 alkyl). In some embodiments, R 9 At least two of them are -(C=O) r -(CH2) x -(C3~C6 cycloalkyl). In some embodiments, each R 9 They are the same. In some embodiments, each R 9 They are different.

[0053] As generally defined above, each R 10 is independently H or C1-C6 alkyl. In some embodiments, R 10 At least one of them is H. In some embodiments, R 10 At least one of them is a C1-C6 alkyl group. In some embodiments, R 10 At least two of them are H. In some embodiments, R10 At least two of them are C1-C6 alkyl groups. In some embodiments, each R 10 They are the same. In some embodiments, each R 10 They are different.

[0054] As generally defined above, each R 11 H, OR 12 or N(R 12 )2. In some embodiments, R 11 At least one of them is H. In some embodiments, R 11 At least one of them is OR 12 In some embodiments, R 11 At least one of them is N(R 12 )2. In some embodiments, R 11 At least two of them are H. In some embodiments, R 11 At least two of them are OR 12 In some embodiments, R 11 At least two of them are N(R 12 )2. In some embodiments, each R 11 They are the same. In some embodiments, each R 11 They are different.

[0055] As generally defined above, each R 12 These are independently H or -(C=O) t -(C1~C6 alkyl). In some embodiments, R 12 At least one of them is H. In some embodiments, R 12 At least one of them is -(C=O) t -(C1~C6 alkyl). In some embodiments, each R 12 They are the same. In some embodiments, each R 12 They are different.

[0056] As generally defined above, each R 13These are independently H and -(C=O) v -(C1~C6 alkyl), or S(O)2R 14 In some embodiments, R 13 At least one of them is H. In some embodiments, R 13 At least one of them is -(C=O) v -(C1~C6 alkyl). In some embodiments, R 13 At least one of them is S(O)2R 14 In some embodiments, R 13 At least two of them are H. In some embodiments, R 13 At least two of them are -(C=O) v -(C1~C6 alkyl). In some embodiments, R 13 At least two of them are S(O)2R 14 In some embodiments, each R 13 They are the same. In some embodiments, each R 13 They are different.

[0057] As generally defined above, each R 14 is independently H or C1-C6 alkyl. In some embodiments, R 14 At least one of them is H. In some embodiments, R 14 At least one of them is a C1-C6 alkyl group. In some embodiments, R 14 At least two of them are H. In some embodiments, R 14 At least two of them are C1-C6 alkyl groups. In some embodiments, each R 14 They are the same. In some embodiments, each R 14 They are different.

[0058] As generally defined above, L 1 These are those with direct bonds, -(CH2) n -, a 3-7 membered cycloalkyl or heterocycle, a 5-6 membered heteroaryl ring, or a 6 membered aryl ring, where L1 Any carbon atom in -(CH2) o -R 7 It is optionally replaced by L. In some embodiments, 1 This is a direct bond. In some embodiments, L 1 is, -(CH2) n - is. In some embodiments, L 1 is a 3- to 7-membered cycloalkyl ring. In some embodiments, L 1 is a 4- to 7-membered complex ring. In some embodiments, R 1 is a 6-membered aryl ring. In some embodiments, R 1 is non-substitutable. In some embodiments, L 1 Any carbon atom in -(CH2) is one or two carbon atoms. o -R 7 It may be replaced with.

[0059] As generally defined above, L 2 L is a 5-6 member heteroaryl ring, a 6 member aryl ring, or a 6 member heteroaryl ring, where L 2 R is optionally substituted with 1-2 C1-C6 alkyl groups, and in some embodiments, 2 is a 5-6 member heteroaryl ring. In some embodiments, R 2 is a 6-membered aryl ring. In some embodiments, R 2 R is a six-membered heteroaryl ring. In some embodiments, R 2 is non-substitutable. In some embodiments, L 2 It is substituted with 1-2 C1-C6 alkyl groups.

[0060] As generally defined above, X is O or NR 3 In some embodiments, X is O. In some embodiments, X is NR 3 That is the case.

[0061] As generally defined above, Y is O or NR 4In some embodiments, Y is O. In some embodiments, Y is NR 4 That is the case.

[0062] As generally defined above, n is an integer between 1 and 5. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5.

[0063] As generally defined above, o is 0 or an integer from 1 to 4. In some embodiments, o is 0. In some embodiments, o is 1. In some embodiments, o is 2. In some embodiments, o is 3. In some embodiments, o is 4.

[0064] As generally defined above, each p is independently either 0 or 1. In some embodiments, at least one of the p is 0. In some embodiments, at least one of the p is 1. In some embodiments, each p is the same. In some embodiments, each p is different.

[0065] As generally defined above, each q is independently either 0 or 1. In some embodiments, at least one of the qs is 0. In some embodiments, at least one of the qs is 1. In some embodiments, at least two of the qs are 0. In some embodiments, at least two of the qs are 1. In some embodiments, each q is the same. In some embodiments, each q is different.

[0066] As generally defined above, each r is independently either 0 or 1. In some embodiments, at least one of r is 0. In some embodiments, at least one of r is 1. In some embodiments, at least two of r are 0. In some embodiments, at least two of r are 1. In some embodiments, each r is the same. In some embodiments, each r is different.

[0067] As generally defined above, each s is independently an integer between 0 and 3. In some embodiments, at least one of s is 0. In some embodiments, at least one of s is 1. In some embodiments, at least two of s are 2. In some embodiments, at least one of s is 3. In some embodiments, each 3 is the same. In some embodiments, each 3 is different.

[0068] As generally defined above, each t is independently either 0 or 1. In some embodiments, at least one of the t is 0. In some embodiments, at least one of the t is 1. In some embodiments, at least two of the t are 0. In some embodiments, at least two of the t are 1. In some embodiments, each t is the same. In some embodiments, each t is different.

[0069] As generally defined above, each u is independently either 0 or 1. In some embodiments, at least one of the u is 0. In some embodiments, at least one of the u is 1. In some embodiments, at least two of the u are 0. In some embodiments, at least two of the u are 1. In some embodiments, each u is the same. In some embodiments, each u is different.

[0070] As generally defined above, each v is independently either 0 or 1. In some embodiments, at least one of the v is 0. In some embodiments, at least one of the v is 1. In some embodiments, at least two of the v are 0. In some embodiments, at least two of the v are 1. In some embodiments, each v is the same. In some embodiments, each v is different.

[0071] As generally defined above, each w is independently either 0 or 1. In some embodiments, at least one of the w is 0. In some embodiments, at least one of the w is 1. In some embodiments, at least two of the w are 0. In some embodiments, at least two of the w are 1. In some embodiments, each w is the same. In some embodiments, each w is different.

[0072] As generally defined above, each x is independently an integer between 0 and 3. In some embodiments, at least one of the x is 0. In some embodiments, at least one of the x is 1. In some embodiments, at least one of the x is 2. In some embodiments, at least one of the x is 3. In some embodiments, at least two of the x are 0. In some embodiments, at least two of the x are 1. In some embodiments, at least two of the x are 2. In some embodiments, at least three of the x are 3. In some embodiments, each x is the same. In some embodiments, each x is different.

[0073] As generally defined above, each stereocenter is independently either R or S. In some embodiments, at least one stereocenter is R and at least one stereocenter is S. In some embodiments, at least two stereocenters are R and the other stereocenter is S. In some embodiments, at least two stereocenters are S and the other stereocenter is R.

[0074] Another aspect of the present invention relates to a method for producing a compound of formula I or a pharmaceutically acceptable salt thereof. [ka] (In the formula, R 1 L 1 ~R 5 And, R 2 L 2 ~R 6 And, R 3 is H or C1-C6 alkyl, R 4 is H or C1-C6 alkyl, R 5 R is a 5-membered heteroaryl ring, a 6-membered aryl ring, a 6-membered heteroaryl ring, or an 8-12 membered fused bicyclic aryl or heteroaryl ring system, where R 5 is -(C=O) q -(C1~C6 alkyl), F, Cl, Br, I, OR 9 , SR 9 S(O)R 9 S(O)2R 9 , N(R 9 )2, CN, C(O)OR 10 , C(O)N(R 10 )2, S(O)2OR 10 , P(O)(OR 10 )2, and -(CH2) s -R 11 It is arbitrarily replaced by 1 to 3 elements independently selected from, R 6R is a 5-6 member heteroaryl ring, a 6 member aryl ring, or a 6 member heteroaryl ring, where R 6 is -(C=O) u -(C1~C6 alkyl), F, Cl, Br, I, NO2, OR 13 , SR 13 S(O)R 13 S(O)2R 13 , S(O)2N(R 13 )2, N(R 13 )2, CN, C(O)OR 14 , C(O)N(R 14 )2, S(O)2OR 14 , and P(O)(OR 14 ) Optionally replaced by 1 to 3 elements independently selected from 2, R 7 H, OR 8 , or N(R 8 )2, Each R 8 These are independently H or -(C=O) p -(C1~C6 alkyl) Each R 9 These are independently H and -(C=O) r -(C1~C6 alkyl), or -(C=O) r -(CH2) x -(C3~C6 cycloalkyl) Each R 10 These are independently H or C1-C6 alkyl groups. Each R 11 H, OR 12 , or N(R 12 )2, Each R 12 These are independently H or -(C=O) t -(C1~C6 alkyl) Each R 13 These are independently H and -(C=O) v -(C1~C6 alkyl), or S(O)2R 14 And, Each R 14 These are independently H or C1-C6 alkyl groups. L 1 These are those with direct bonds, -(CH2)n -, a 3-7 membered cycloalkyl or heterocycle, a 5-6 membered heteroaryl ring, or a 6 membered aryl ring, where L 1 Any carbon atom in -(CH2) o -R 7 It is arbitrarily replaced with, L 2 L is a 5-6 member heteroaryl ring, a 6 member aryl ring, or a 6 member heteroaryl ring, where L 2 It is optionally substituted with 1-2 C1-C6 alkyl groups. X is O or NR 3 And, Y is O or NR 4 And, n is an integer between 1 and 5. o is an integer from 0 to 4. Each p is independently either 0 or 1. Each q is independently either 0 or 1. Each r is independently either 0 or 1. Each s is independently an integer between 0 and 3, Each t is independently either 0 or 1. Each u is independently either 0 or 1. Each v is independently either 0 or 1. Each w is independently either 0 or 1. x is an integer between 0 and 3. Each solid center is independently R, S, or a racemate. The manufacturing method is (1) A step of reacting the compound of formula II with the compound of formula IV, a. The compound of formula II can be used as is, or b. Compound II of formula is converted to a carboxylic acid, step, (2) If a protecting group is present, the step of removing the protecting group from the compound of formula IV, or, (1) The step of reacting the compound of formula III with the compound of formula IV, (2) If a protecting group is present, the step of removing the protecting group from the compound of formula IV is included. [ka] (In the formula, all substituents are defined according to the structure of formula I, R 15 is H, C1-C6 alkyl, or -(CH2) w -R 16 And, R 16 is a 5-membered heteroaryl group, a 6-membered aryl group, or a 6-membered heteroaryl group, where R 16 It is optionally substituted with 1 to 5 groups independently selected from F, NO2, and OCH3. R 17 This refers to a protecting group selected from a list that includes, but is not limited to, acetyl, benzoyl, 4-nitrobenzoyl, benzyl, p-methoxybenzyl, tolyl, trityl, methoxymethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tert-butylcarbamoyl (Boc), fluorenylmethylcarbamoyl (Fmoc), and benzylcarbamoyl (Cbz). w is either 0 or 1.

[0075] As generally defined above, R 15 is H, C1-C6 alkyl, or -(CH2) w -R 16 In some embodiments, R 15 is H. In some embodiments, R 15 is a C1-C6 alkyl group. In some embodiments, R 15 is, -(CH2) w -R 16 That is the case.

[0076] As generally defined above, R 16 is a 5-membered heteroaryl group, a 6-membered aryl group, or a 6-membered heteroaryl group, where R 16is optionally substituted with 1 to 5 groups independently selected from F, NO2, and OCH3. In some embodiments, R 16 is a 5-membered heteroaryl group. In some embodiments, R 16 is a 6-membered aryl group optionally substituted with 1 to 5 groups independently selected from F, NO2, and OCH3. In some embodiments, R 16 R is a 6-membered heteroaryl group, where R 16 This is optionally substituted with 1 to 5 groups independently selected from F, NO2, and OCH3.

[0077] As generally defined above, R 17 R is a protecting group selected from a list that includes, but is not limited to, acetyl, benzoyl, 4-nitrobenzoyl, benzyl, p-methoxybenzyl, tolyl, trityl, methoxymethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tert-butylcarbamoyl (Boc), fluorenylmethylcarbamoyl (Fmoc), and benzylcarbamoyl (Cbz). In some embodiments, R 17 is acetyl. In some embodiments, R 17 is benzoyl. In some embodiments, R 17 R is 4-nitrobenzoyl. In some embodiments, R 17 is benzyl. In some embodiments, R 17 is p-methoxybenzyl. In some embodiments, R 17 is a trill. In some embodiments, R 17 is trityl. In some embodiments, R 17 R is methoxymethyl. In some embodiments, R 17 is trimethylsilyl. In some embodiments, R 17 is triethylsilyl. In some embodiments, R 17 is triisopropylsilyl. In some embodiments, R 17is tert-butyldimethylsilyl. In some embodiments, R 17 is tert-butyldiphenylsilyl. In some embodiments, R 17 is tert-butylcarbamoyl (Boc). In some embodiments, R 17 is fluorenylmethylcarbamoyl (Fmoc). In some embodiments, R 17 is benzylcarbamoyl (Cbz). In some embodiments, R 17 is a suitable protecting group for hydroxyl functional groups. In some embodiments, R 17 This is a suitable protecting group for amine functional groups. Those skilled in the art will recognize that there are several suitable protecting groups for hydroxyl groups and amines. Such choices are generally available in relevant literature and are described in books such as "Protective Groups in Organic Synthesis" (Wiley, Greene, and Wuts et al.).

[0078] As generally defined above, w is either 0 or 1. In some embodiments, w is 0. In some embodiments, w is 1.

[0079] Those skilled in the art will recognize that combining the structures of formula II and formula IV forms an ester or amide bond. They will also recognize that esters and amides are formed by combining a carboxylic acid with an alcohol or amine using a variety of coupling reagents, including but not limited to isobutylchloroformate, DCC, EDC, CDI, BOP, PyBOP, HATU, HBTU, T3P, and DSC. Furthermore, they will recognize that such coupling reactions are often facilitated by amine bases, including but not limited to triethylamine, diisopropylethylamine, N-methylmorpholine, and pyridine. They will also recognize that such coupling reactions are often catalyzed by compounds, including but not limited to HOBt and DMAP. Furthermore, they will understand that a collection of suitable reagents and reaction conditions for forming esters and amides is generally available in the relevant scientific literature and is described in books such as "Comprehensive Organic Transformation" (VCH, Larock).

[0080] Those skilled in the art will recognize that combining the structures of formula II and formula IV forms an ester bond or an amide bond. Those skilled in the art will also recognize that combining an active ester of a carboxylic acid with an alcohol or amine forms esters and amides. Those skilled in the art will understand that such active esters include, but are not limited to, acylimidazoles, nitrophenyl esters, pentafluorophenyl esters, succinimidyl esters, and others. Furthermore, those skilled in the art will recognize that such coupling reactions are often facilitated by amine bases, including, but not limited to, triethylamine, diisopropylethylamine, N-methylmorpholine, and pyridine. Those skilled in the art will also recognize that such coupling reactions are often catalyzed by compounds, including, but not limited to, DMAPs. Furthermore, those skilled in the art will understand that a collection of suitable reagents and reaction conditions for forming esters and amides from active esters of carboxylic acids is generally available in the relevant scientific literature and is described in books such as "Comprehensive Organic Transformation" (VCH, Larock).

[0081] Those skilled in the art will recognize that amidine is formed by combining the structures of formula III and formula IV. Those skilled in the art will also recognize that amidine is formed by combining a nitrile and an amine. Those skilled in the art will understand that a collection of appropriate reagents and reaction conditions for forming amidine from active nitriles and amines is generally available in the relevant scientific literature and is described in books such as "Comprehensive Organic Transformation" (VCH, Larock).

[0082] In at least some embodiments, the exemplary compounds of formula I include compounds 2 to 101. [ka] [ka] [ka] [ka]

[0083] In the spirit of the present invention, compounds 2 to 101 progressively address key issues related to parent compound 1. Such issues include, but are not limited to, metabolic stability and general pharmacological properties. Compounds 2 to 101 are not representative of the compounds of the present invention and should be considered only as examples.

[0084] The compounds and pharmaceutical compositions of the present invention are useful in the treatment of bipolar disorder, depression, Alzheimer's disease, autism spectrum disorder, fragile X syndrome, Pitt-Hopkins syndrome, Rett syndrome, traumatic brain injury, stroke, acute spinal cord injury, schizophrenia, Parkinson's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), neurofibromatosis type 1, neuronal ceroid lipofuscinosis, chronic pain, neuropathic pain, chemotherapy-induced neuropathy, and chemotherapy-induced cognitive impairment. These compounds and their pharmaceutical compositions are also useful in treating conditions for which inhibition of GSK-3β and / or enhancement of WNT signaling have been identified or proposed, including alopecia, osteoarthritis, osteoporosis, alcoholic hepatitis, inflammatory bowel disease, exudative age-related macular degeneration, atrophic age-related macular degeneration, diabetic macular edema, Fuchs corneal endothelial dystrophy, corneal epithelial cell deficiency, dry eye, glaucoma, familial exudative vitreoretinopathy (FEVR), Norie's disease, Coats' disease, retinopathy of prematurity, macular telangiectasia, retinal vein occlusion, Sjögren's syndrome, sensorineural hearing loss, conductive hearing loss, schizophrenia, Parkinson's disease, polycystic kidney disease, focal segmental glomerulosclerosis, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, short bowel syndrome, melanoma, pancreatic cancer, prostate cancer, colon cancer, leukemia, septic shock, and ischemia / reperfusion injury.

[0085] In some embodiments, the compound of formula I is administered to subjects once daily (QD) in an amount of approximately 32 mg to approximately 320 mg. In some embodiments, the compound of formula I is administered to subjects twice daily (BID) in an amount of approximately 16 mg to approximately 160 mg.

[0086] The compounds of this disclosure may also be administered in combination with lithium. In some embodiments, the subject is unresponsive to lithium. In some embodiments, the subject is responsive to lithium. Lithium may be administered in amounts less than the effective dose for monotherapy, in which case the compound of formula I is administered in amounts less than the effective dose for monotherapy. In some embodiments, the less than effective dose of lithium is administered as a QD of about 60 mg to about 600 mg or as a BID of about 30 mg to about 300 mg. In some embodiments, the less than effective dose of the compound of formula I is administered as a QD of about 8 mg to about 32 mg or as a BID of about 4 to about 16 mg.

[0087] The Disclosure also provides a method for establishing a diagnosis of bipolar disorder or other conditions for which GSK-3 inhibition is clinically useful, comprising administering a therapeutically effective dose of the compound of formula I to a subject under evaluation and evaluating the subject's clinical response. Furthermore, in some embodiments, the Disclosure provides a method for establishing an appropriate therapeutic dose of the compound of formula I in a subject, comprising administering an escalating dose of the compound and evaluating the response using GSK-3 imaging or GSK-3 serology.

[0088] In some embodiments, the Disclosure provides a method for treating a subject having Alzheimer's disease, bipolar disorder, or depression showing evidence of elevated GSK-3, comprising administering the subject a therapeutically effective dose of the compound of Formula I and evaluating and monitoring the subject using positron emission tomography (PET) or serology. In some embodiments, the Disclosure provides a method for establishing a diagnosis of bipolar disorder or other conditions for which GSK-3 inhibition is clinically useful, comprising administering a therapeutically effective dose of the compound of Formula I together with a therapeutically effective dose of lithium to a subject under evaluation and evaluating the subject's clinical response. In some embodiments, the doses of both the compound of Formula I and lithium are less than the effective dose for monotherapy.

[0089] In some embodiments, the Disclosure provides a method for treating a subject with Alzheimer's disease who has evidence of elevated GSK-3 beta activity, comprising administering to the subject a therapeutically effective dose of a compound of formula I or a pharmaceutically acceptable salt, solvate, or polymorph thereof, and a therapeutically effective dose of lithium, and monitoring the subject using positron emission tomography (PET). In some embodiments, the doses of both the compound of formula I and lithium are less than the effective dose for monotherapy.

[0090] In some embodiments, the present disclosure provides a method for establishing an appropriate therapeutic dose of a compound of formula I in a subject, comprising administering the subject an increasing dose of the compound of formula I and lithium, and evaluating the response using positron emission tomography (PET).

[0091] Examples While certain features of the present invention are illustrated and described herein, many modifications, substitutions, alterations, and equivalents will readily come to mind for those skilled in the art. Therefore, it should be understood that the appended claims are intended to encompass all such modifications and alterations that fall within the true spirit of the invention.

[0092] While the following claims describe specific reactions, please understand that the following examples are based on laboratory-scale reactions rather than manufacturing processes, and therefore variability in the final results is to be expected. Furthermore, it should be understood that in many cases, the amount of isolated product is the amount isolated from multiple repeated batches of the reaction, rather than from a single reaction.

[0093] Example 1 - Preparation of Compound 1 (OCM-51) Compound 1 was prepared according to the following scheme, via the numbered intermediate structures shown in the scheme. [ka]

[0094] Intermediate 2: To a stirred suspension of compound 1(1) (10 g, 0.034 mol) in dichloromethane (100 mL), oxalyl chloride (4.6 mL, 0.050 mol) and 3 drops of DMF were added at 0°C. The resulting reaction mixture was heated to room temperature and stirred for 2 hours. After the reaction was completed by TLC, the reaction mixture was evaporated under reduced pressure in a nitrogen atmosphere to obtain the crude residue. The obtained crude compound 2 (10.6 g) was used in the next step without further purification.

[0095] Intermediate 4: To a stirred solution of compound 3 (4.2 mL, 0.033 mmol) in dry THF (100 mL), tert-butoxide potassium (12 g, 0.10 mol) was gradually added at 0°C and stirred for 15 minutes. Then, compound 2 (10.6 g, 1.79 mmol) in dry THF (100 mL) was dissolved in dry THF (100 mL) and added dropwise at the same temperature. The resulting reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed by TLC, the reaction mixture was diluted with water and extracted with SiO2 (2 x 100 mL). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and evaporated to obtain the crude residue. The obtained crude residue was further purified by silica gel (100-200 mesh) column chromatography using ethyl acetate / hexane (30:70) as the eluent to obtain compound 4 (3.6 g) as a pale yellow solid.1 H NMR(400MHz, CDCl3): δ8.51(d,J=2.0Hz,1H),8.16(dd,J=8.8Hz,J=2Hz,1H),7.87(s, 1H), 6.9(d,J=8.8Hz,1H),4.42(q,J=7.2Hz,2H),3.95(s,3H),1.43(t,J=7.2Hz,3H).

[0096] Intermediate 5: Compound 4 (7 g, 0.018 mol) in THF (15 ml) was stirred, and a 1 M NaOH solution (6 mL, 0.028 mmol) was added at 0°C. The resulting reaction mixture was heated to room temperature and stirred for 16 hours. After the reaction was completed by TLC, the reaction mixture was evaporated under reduced pressure to obtain the crude residue. The crude residue was placed in water and extracted with diethyl ether. The aqueous layer was acidified with 1 N HCl, and the aqueous layer was extracted with SiO2 (2 x 100 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and evaporated to obtain the crude residue. The crude residue was ground with n-pentane, filtered, and dried under high vacuum to obtain compound 5 (4.8 g) as an off-white solid. 1 H NMR (400MHz, DMSO6): δ13.13(br,s,1H),8.49(s,1H),8.46(d,J=2.0Hz,1H),8.03(dd,J=8.8Hz,J=2.4Hz,1H),7.15(d,J=8.8Hz 1H),3.91(s,3H).

[0097] Intermediate 8: Propa-2-in-1-ol (9.5 g, 0.17 mmol) was added to a stirred solution of 3-bromo-5-fluoropyridine (7) (15 g, 0.08 mmol) in triethylamine (150 mL), and the reaction mixture was degassed at room temperature under a nitrogen atmosphere for 25 minutes. Next, Pd(PPh3)2Cl2 (2.9 g, 0.004 mol) and CuI (1.6 g, 0.008 mmol) were added at room temperature, and the resulting reaction mixture was stirred at 100 °C for 16 hours. After the reaction was completed by TLC, the reaction mixture was filtered through a Celite pad. The filtered cake was thoroughly washed with dichloromethane, and the filtrate was evaporated under reduced pressure to obtain the crude residue. The obtained crude residue was further purified by silica gel (100-200 mesh) column chromatography using ethyl acetate / hexane (50:50) as the eluent to obtain compound 8 (10.4 g) as a pale yellow solid. 1 H NMR (400MHz, CDCl3): δ8.50(s,1H),8.41(d,J=2.8Hz,1H),7.46-7.42(m,1H),4.52(d,J=6.0Hz,1H),1.96(t,J=6.4Hz,1H).

[0098] Intermediate 9: Compound 8 (10.2 g, 0.067 mmol) was added to a stirred suspension of palladium carbon (10% wet) (2.0 g) in methanol (180 mL). The resulting reaction mixture was stirred at room temperature for 16 hours under a hydrogen (60 Psi) atmosphere. After the reaction was completed by TLC, the mixture was filtered through a Celite pad. The filtered cake was thoroughly washed with MeOH (5 mL), and the filtrate was evaporated under reduced pressure to obtain the crude residue. The obtained crude residue was purified by silica gel column chromatography (100-200 mesh) using ethyl acetate (50:50) in hexane as the eluent to obtain compound 9 (8.4 g) as a pale yellow liquid. 1 H NMR (400MHz, CDCl3): δ8.32-8.29(m,2H),7.28-7.24(m,1H),3.69(t,J=6.0Hz,2H),2.77(t,J=7.6Hz,2H),2.04-1.86(m,2H).

[0099] Intermediate 10: Compound 9 (8.2 g, 0.052 mol) in THF (100 mL) was stirred, to which PPh3 (27.8 g, 0.105 mol) and phthalimide (7.75 g, 0.052 mol) were sequentially added at room temperature, and the mixture was stirred for 10 minutes. The reaction mixture was then cooled to 0°C, and DIAD (20.8 mL, 0.105 mol) was added dropwise at 0°C. The resulting reaction mixture was heated to room temperature and stirred for 16 hours. After the reaction was completed by TLC, the reaction mixture was evaporated under reduced pressure to obtain the crude residue. The crude residue was purified by silica gel column chromatography (100-200 mesh) using ethyl acetate in hexane (50:50) as the eluent to obtain compound 10 (17.1 g) as a pale yellow solid.

[0100] Intermediate 6: Compound 10 (12.0 g, 0.042 mol) in MeOH (36 mL) was stirred, to which N2H4.H2O (5.5 g, 0.109 mol) was added at room temperature and stirred for 16 hours. After the reaction was completed by TLC, the reaction mixture was evaporated under reduced pressure to obtain the crude residue. The obtained crude residue was washed with SiO2 and filtered. The filtrate was evaporated under reduced pressure to obtain the crude residue, and the obtained crude residue was purified by silica gel column chromatography (100-200 mesh) using (Aq.NH3:MeOH:DCM) as the eluent (5:10:85) to obtain Int-6 (1.2 g) as a colorless liquid. 1 H NMR (400MHz, CDCl3): δ8.31-8.28(m,2H),7.28-7.23(m,1H),2.76(t,J=7.2Hz,2H),2.70(t,J=7.6Hz,2H),1.82-1.74(m,2H).

[0101] Compound 1: To a stirred solution of Compound 5 (3.8 g, 0.011 mol) and Int-6 (2 g, 0.013 mol) in DMF (40 mL), HATU (4.95 g, 0.013 mol) and triethylamine (7.7 mL, 0.055 mol) were added at 0°C. The resulting reaction mixture was heated to room temperature and stirred for 16 hours. After the reaction was completed by TLC, the reaction mixture was quenched with water, and the aqueous layer was extracted with HCl (2 x 50 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and evaporated to obtain the crude residue. The crude residue was purified by silica gel column chromatography (100-200 mesh) using (50:50) HCl in hexane as the eluent to obtain Compound 1 (3.2 g) as an off-white solid. 1 H NMR(400MHz,CDCl3):δ8.64(d,J=2.4Hz 1H),8.49(dd,J=8.4Hz,8.8Hz,1H),8.32-8.30(m,2H),7.80(s,1H),7.38-7.32(m,1H),7.28-7.26(m,1H),6.89(d,J=8.8Hz 1H),3.94(s,3H),3.5(q,J=6.8Hz,2H),2.75(t,J=6.8Hz,2H),1.99-1.96(m,2H).

[0102] Example 2 - General scheme for the production of compounds 2-10 Compounds 2 to 10 were prepared according to the following scheme via the numbered intermediate structures shown in the scheme. [ka]

[0103] Example 3 - Preparation of Compound 2 Compound 2 was prepared according to the general scheme of Example 2, via the numbered intermediate structures shown in the scheme.

[0104] Intermediate 2: To a stirred suspension of substituted benzoic acid (1) (1.79 mmol) in DCM (5 mL), oxalyl chloride (2.69 mmol) and a few drops of DMF were added at 0°C. The resulting reaction mixture was heated to room temperature and stirred for 2-4 hours. After the reaction was complete (monitored by TLC), the reaction mixture was evaporated under reduced pressure in a nitrogen atmosphere to obtain the crude residue. The crude residue of compound 2 (1.2 g) was used directly in the next step without further purification.

[0105] Intermediate 4: To a stirred solution of compound 3 (1.79 mmol) in dry THF (5 mL), tert-butoxide potassium (5.37 mmol) was gradually added at 0°C and stirred for 15 minutes. Then, compound 2 (1.79 mmol) dissolved in dry THF (5 mL) was added dropwise to the reaction mixture at the same temperature. The resulting reaction mixture was stirred at room temperature for 2-4 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with saturated ammonium chloride (5 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic phases were washed with brine (2 mL), dried over anhydrous Na₂SO₄, filtered, and evaporated to obtain the crude residue. The crude residue was further purified by silica gel (100-200 mesh) column chromatography by elution with ethyl acetate in hexane to obtain compound 4 (0.8 g). 1 H NMR (400MHz, CDCl3): δ8.09-8.06(m,2H),7.92(s,1H),7.51-7.45(m,3H),4.42(q,J=7.2Hz,2H),1.41(t,J=7.2Hz,3H).

[0106] Intermediate 5: Compound 4 (0.34 mmol) in THF (5 mL) was stirred, and 1 M NaOH solution (0.5 mL, 0.52 mmol) was added at 0°C. The resulting reaction mixture was stirred at room temperature for 12-16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was evaporated under reduced pressure to obtain the crude residue. The crude residue was placed in water (5 mL), extracted with ethyl acetate (10 mL), the organic layer was separated, the aqueous layer was acidified with 1 N HCl (pH 1-2), the precipitated solid was filtered, washed with water (5 mL), and the product was dried under vacuum at 45-50°C to obtain compound 5 (0.5 g). 1 H NMR (400MHz, DMSO-d6): δ13.18 (br s, 1H), 8.54 (s, 1H), 8.00-7.98 (m, 2H), 7.55-7.50 (m, 3H).

[0107] Compound 2: To a stirred solution of Compound 5 (0.58 mmol) and Int-6 (0.69 mmol) in DMF (5 mL), HATU (0.69 mmol) and triethylamine (4.9 mL, 2.90 mmol) were added at 0°C. The resulting reaction mixture was heated to room temperature and stirred for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was partitioned with water (5 mL) and ethyl acetate (10 mL). The organic layer was separated and washed with brine (5 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated to obtain the crude residue. The crude residue was purified by silica gel column chromatography (100-200 mesh) by elution with ethyl acetate in hexane to obtain Compound 2 (130 mg). 1 H NMR(400MHz,DMSO-d6):δ8.59(s,1H),8.51(t,J=6.0Hz 1H),8.39(d,J=2.8Hz,1H),8.35(t,J=1.6Hz,1H),8.21-8.20(m,1H),8.18(d,J=1.2Hz,1H),7.67 -7.64(m,1H),7.52-7.46(m,3H),3.29(q,J=6.8Hz,2H),2.68(t,J=7.6Hz,2H),1.90-1.83(m,2H).

[0108] Example 4 - Preparation of Compound 3 Compound 3 was prepared according to the general scheme of Example 2, via the numbered intermediate structures shown in the scheme.

[0109] Intermediate 2 of compound 3 was prepared by replacing benzoic acid with 4-methylbenzoic acid according to the protocol described in Example 3, thereby obtaining 1.2 grams of the desired product.

[0110] According to the protocol described in Example 3, intermediate 4 of compound 3 was prepared using intermediate 2 of this example. 0.7 grams of the desired product was isolated. 1 H NMR (400MHz, CDCl3): δ7.98(dd,J=6.4,1.6Hz,2H),7.89(s,1H),7.28(d,J=8.0Hz,2H),4.42(q,J=7.2Hz,2H),1.41(t,J=7.2Hz,3H).

[0111] According to the protocol described in Example 3, intermediate 5 of compound 3 was prepared using intermediate 4 of this example. 180 mg of the desired product was isolated. 1 H NMR (400MHz, DMSO-d6): δ13.13 (br s, 1H), 8.50 (s, 1H), 7.89 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H).

[0112] Compound 3 was prepared using intermediate 5 of this example according to the protocol described in Example 3. 0.4 grams of the desired product was isolated. 1 H NMR(400MHz,DMSO-d6):δ8.55(s,1H),8.47(t,J=6.0Hz 1H),8.39(d,J=2.8Hz,1H),8.35(t,J=1.6Hz,1H),8.10(d,J=8.4Hz,2H),7.67-7.63(m,1H),7.3 0(d,J=8.0Hz,2H),3.28(q,J=6.8Hz,2H),2.68(t,J=7.6Hz,2H),2.36(s,3H),1.90-1.82(m,2H).

[0113] Example 5 - Preparation of Compound 4 Compound 4 was prepared according to the general scheme of Example 2, via the numbered intermediate structures shown in the scheme.

[0114] Intermediate 2 of compound 4 was prepared by replacing benzoic acid with 4-methoxybenzoic acid according to the protocol described in Example 4, thereby obtaining 1.25 grams of the desired product.

[0115] According to the protocol described in Example 3, intermediate 4 of compound 4 was prepared using intermediate 2 of this example. 0.7 grams of the desired product was isolated. 1 H NMR (400MHz, CDCl3): δ8.07(dd,J=6.8,2.0Hz,2H),7.86(s,1H),6.99(dd,J=6.8,2.0Hz,2H),4.42(q,J=7.2Hz,2H),1.42(t,J=7.2Hz,3H).

[0116] According to the protocol described in Example 3, intermediate 5 of compound 4 was prepared using intermediate 4 of this example. 0.4 grams of the desired product was isolated. 1 H NMR (400MHz, DMSO-d6): δ13.10(brs,1H),8.47(s,1H),7.98(dd,J=7.2,2.0Hz,2H),7.07(dd,J=7.2,2.0Hz,2H).

[0117] Compound 4 was prepared using intermediate 5 of this example according to the protocol described in Example 3. 180 mg of the desired product was isolated. 1 H NMR(400MHz,DMSO-d6):δ8.42(s,1H),8.40-8.36(m,2H),8.20(d,J=10.0Hz,2H),7.67-7.63(m,1H), 7.06(d,J=10.0Hz,2H),3.83(s,3H),3.30(t,J=6.8Hz,2H),2.70(t,J=7.6Hz,2H),1.90-1.83(m,2H).

[0118] Example 6 - Preparation of Compound 5 Compound 5 was prepared according to the general scheme of Example 2, via the numbered intermediate structures shown in the scheme.

[0119] Intermediate 2 of compound 5 was prepared by replacing benzoic acid with 4-chlorobenzoic acid according to the protocol described in Example 3, thereby obtaining 1.3 grams of the desired product.

[0120] According to the protocol described in Example 3, intermediate 4 of compound 5 was prepared using intermediate 2 of this example. 0.5 grams of the desired product was isolated. 1 H NMR (400MHz, CDCl3): δ8.08-8.05(m,2H),7.92(s,1H),7.47-7.44(m,2H),4.43(q,J=7.2Hz,2H),1.42(t,J=7.2Hz,3H).

[0121] According to the protocol described in Example 3, intermediate 5 of this example was used to prepare intermediate 5 of compound 5. 0.2 grams of the desired product was isolated. 1 H NMR (400MHz, DMSO-d6): δ13.26 (br s, 1H), 8.57 (s, 1H), 8.03 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 8.0 Hz, 2H).

[0122] Compound 5 was prepared using intermediate 5 of this example according to the protocol described in Example 3. 120 mg of the desired product was isolated. 1 H NMR(400MHz,DMSO-d6):δ8.63(s,1H),8.57(t,J=5.6Hz,1H),8.38(d,J=2.8Hz,1H),8.35(t,J=1.6Hz,1H),8.27(d,J= 9.6Hz,2H),7.67-7.63(m,1H),7.58(d,J=9.6Hz,2H),3.30(q,J=6.8Hz,2H),2.69(t,J=7.6Hz,2H),1.89-1.86(m,2H).

[0123] Example 7 - Preparation of Compound 6 Compound 6 was prepared according to the general scheme of Example 2, via the numbered intermediate structures shown in the scheme.

[0124] Intermediate 2 of compound 6 was prepared by replacing benzoic acid with 3,4-dichlorobenzoic acid according to the protocol described in Example 3, thereby obtaining 1.3 grams of the desired product.

[0125] According to the protocol described in Example 3, intermediate 4 of compound 6 was prepared using intermediate 2 of this example. 0.5 grams of the desired product was isolated.

[0126] According to the protocol described in Example 3, intermediate 5 of compound 6 was prepared using intermediate 4 of this example. 0.2 grams of the desired product was isolated. 1 H NMR (400MHz, DMSO-d6): δ13.41(brs,1H),8.61(s,1H),8.34(d,J=2.0Hz,1H),7.97(dd,J=8.4,2.0Hz,1H),7.82(d,J=8.8Hz,1H).

[0127] Compound 6 was prepared using intermediate 5 of this example according to the protocol described in Example 3. 120 mg of the desired product was isolated. 1 H NMR(400MHz,DMSO-d6):δ8.70(d,J=2.0Hz,1H),8.66(s,1H),8.61(t,J=6.0Hz,1H),8.38(d,J=2.4Hz,1H),8.35(s,1H),8.14(dd,J=8.8, 2.0Hz,2H),7.78(d,J=8.4Hz,1H),7.66-7.63(m,1H),7.58(d,J=9.6Hz,2H),3.30-3.28(m,2H),2.68(t,J=7.6Hz,2H),1.91-1.84(m,2H).

[0128] Example 8 - Preparation of Compound 7 Compound 7 was prepared according to the general scheme of Example 2, via the numbered intermediate structures shown in the scheme.

[0129] Intermediate 2 of compound 7 was prepared by replacing benzoic acid with 3-iodo-4-isopropylbenzoic acid according to the protocol described in Example 3, thereby obtaining 1.2 grams of the desired product.

[0130] According to the protocol described in Example 3, intermediate 4 of compound 7 was prepared using intermediate 2 of this example. 0.6 grams of the desired product was isolated.

[0131] According to the protocol described in Example 3, intermediate 5 of compound 7 was prepared using intermediate 4 of this example. 0.2 grams of the desired product was isolated. 1 H NMR(400MHz,DMSO-d6):δ13.13(s,1H),8.48(s,1H),8.45(d,J=2.0Hz,1H),8.00(dd ,J=8.8,2.4Hz,1H),7.17(d,J=8.8Hz,1H),4.81-4.75(m,1H),1.33(d,J=6.0Hz,6H).

[0132] Compound 7 was prepared using intermediate 5 of this example according to the protocol described in Example 3. 170 mg of the desired product was isolated. 1 H NMR (400MHz, DMSO-d6): δ8.77(d,J=2.4Hz,1H),8.53(s,1H),8.46(t,J=6.4Hz,1H),8.38(d,J=2.8Hz,1H),8.35(t,J=2.0Hz,1H),8.16(dd ,J=8.8,2.0Hz,1H),7.67-7.63(m,1H),7.14(d,J=8.8Hz,2H),4.79-4.75(m,1H),3.30-3.27(m,2H),2.70-2.66(m,2H),1.88-1.84(m,2H).

[0133] Example 9 - Preparation of Compound 8 Compound 8 was prepared according to the general scheme of Example 2, via the numbered intermediate structures shown in the scheme.

[0134] Intermediate 2 of compound 8 was prepared by replacing benzoic acid with 3-iodo-4-cyclopropylmethoxybenzoic acid (prepared as described in Example 12) according to the protocol described in Example 3, to obtain 1 gram of the desired product.

[0135] According to the protocol described in Example 3, intermediate 4 of compound 8 was prepared using intermediate 2 of this example. 0.7 grams of the desired product was isolated.

[0136] According to the protocol described in Example 3, intermediate 5 of compound 8 was prepared using intermediate 4 of this example. 0.2 grams of the desired product was isolated. 1 H NMR(400MHz,DMSO-d6):δ13.12(br s,1H),8.47(s,1H),8.45(d,J=2.0Hz,1H),7.99(dd,J=8.8,2.0Hz,1H),7.12(d,J=8.8H z,1H),4.00(d,J=6.8Hz,2H),1.30-1.25(m,1H),0.62-0.57(m,2H),0.43-0.38(m,2H).

[0137] Compound 8 was prepared using intermediate 5 of this example according to the protocol described in Example 3. 115 mg of the desired product was isolated. 1 H NMR(400MHz,DMSO-d6):δ8.78(d,J=2.0Hz,1H),8.52(s,1H),8.46(t,J=6.0Hz 1H),8.38(d,J=2.8Hz,1H),8.35(s,1H),8.16(dd,J=8.8,2.0Hz,1H),7.67-7.63(m,1H),7.09(d,J=8.8Hz,1H),m,3H),3.99(d,J= 6.4Hz,2H),3.29-3.27(m,2H),2.68(t,J=7.6Hz,2H),1.90-1.83(m,2H),1.29-1.23(m,1H),0.62-0.57(m,2H),0.41-0.40(m,2H).

[0138] Example 10 - Preparation of Compound 9 Compound 9 was prepared according to the general scheme of Example 2, via the numbered intermediate structures shown in the scheme.

[0139] Intermediate 2 of compound 9 was prepared by replacing benzoic acid with 3-isopropyl-4-methoxybenzoic acid according to the protocol described in Example 3, thereby obtaining 1.2 grams of the desired product.

[0140] According to the protocol described in Example 3, intermediate 4 of compound 9 was prepared using intermediate 2 of this example. 0.6 grams of the desired product was isolated.

[0141] According to the protocol described in Example 3, intermediate 5 of compound 9 was prepared using intermediate 4 of this example. 0.3 grams of the desired product was isolated. 1 H NMR(400MHz,DMSO-d6):δ13.01(s,1H),8.44(s,1H),7.91(d,J=2.0Hz,1H),7.85(dd,J=8.4 ,2.0Hz,1H),7.09(d,J=8.4Hz,1H),3.86(s,3H),3.32-3.29(m,1H),1.18(d,J=6.8Hz,6H).

[0142] Compound 9 was prepared using intermediate 5 of this example according to the protocol described in Example 3. 140 mg of the desired product was isolated. 1 H NMR(400MHz,DMSO-d6):δ8.48(s,1H),8.39(d,J=6.4Hz,2H),8.35(s,1H),8.15(d,J=2.0Hz,1H),8.05(dd,J=8.8,2.0Hz,1H),7.68- 7.65(m,1H),7.06(d,J=8.8Hz,1H),3.85(s,3H),3.30-3.23(m,3H),2.68(t,J=7.6Hz,2H),1.90-1.83(m,2H),1.19(d,J=7.2Hz,6H).

[0143] Example 11 - Preparation of Compound 10 Compound 10 was prepared according to the general scheme of Example 2, via the numbered intermediate structures shown in the scheme.

[0144] Intermediate 2 of compound 10 was prepared by replacing benzoic acid with 3-(tert-butyl)-4-methoxybenzoic acid according to the protocol described in Example 3, thereby obtaining 1.2 grams of the desired product.

[0145] According to the protocol described in Example 3, intermediate 4 of compound 10 was prepared using intermediate 2 of this example. 0.6 grams of the desired product was isolated. 1 H NMR (400MHz, DMSO-d6): δ8.04-7.98(m,2H),7.85(s,1H),6.95(d,J=8.8Hz,1H),4.42(q,J=7.2Hz,1H),3.90(s,3H),1.40(s,9H).

[0146] According to the protocol described in Example 3, intermediate 5 of compound 10 was prepared using intermediate 4 of this example. 210 mg of the desired product was isolated. 1 H NMR(400MHz,DMSO-d6):δ12.96(br s,1H),8.44(s,1H),8.02(d,J=2.4Hz,1H),7.86(dd,J=8.8,2.4Hz,1H),7.12(d,J=8.8Hz,1H),3.88(s,3H),1.36(s,9H).

[0147] Compound 10 was prepared using intermediate 5 of this example according to the protocol described in Example 3. 142 mg of the desired product was isolated. 1 H NMR(400MHz,DMSO-d6):δ8.48(s,1H),8.39(d,J=2.8Hz,2H),8.35(s,1H),8.24(d,J=2.4Hz,1H),8.03(dd,J=8.8,2.4Hz,1H), 7.68-7.63(m,1H),7.09(d,J=8.8Hz,1H),3.87(s,3H),3.29-3.28(m,2H),2.69-2.66(m,2H),1.88-1.84(m,2H),1.35(s,9H).

[0148] Example 12-3: Preparation of 3-iodo-4-cyclopropylmethoxybenzoic acid (starting material from Example 9) 3-iodo-4-cyclopropylmethoxybenzoic acid was prepared according to the following scheme. [ka]

[0149] Intermediate 1b: To a stirred solution of compound 1a (1.0 g, 3.78 mmol) in DMF (15 mL), potassium carbonate (2.1 g, 15.15 mmol) and (bromomethyl)cyclopropane (1.53 g, 11.36 mmol) were added in a sealed tube. The resulting reaction contents were heated to 60°C and stirred for 16 hours. After the reaction was complete (monitored by TLC), the reaction products were cooled to room temperature and partitioned with ethyl acetate (30 mL) and water (15 mL). The organic layer was separated, washed with brine (15 mL), separated again, dried over sodium sulfate, filtered, and evaporated under vacuum to obtain compound 1b as a brown liquid (1.6 g of isolated product). 1 H NMR (400MHz, CDCl3): δ8.47(d,J=2.0Hz,1H),8.01(d,J=2.0Hz,1H),7.98(d,J=2.0Hz,1H),6.78(d,J=8.8Hz,1H),4.12(d,J=7.2Hz,2H),3.9 6(d,J=6.4Hz,2H),2.96(s,2H),2.88(s,2H),1.34-1.22(m,2H),0.69- 0.66(m,2H),0.64-0.59(m,2H),0.46-0.42(m,2H),0.37-0.33(m,2H). To a stirred solution of compound 1b (1.6 g, 6.06 mmol) in intermediate 1:THF:MeOH:H2O (3:1:1) (10 mL), lithium hydroxide monohydrate (0.54 g, 18.18 mmol) was added and the mixture was stirred at room temperature for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was evaporated under reduced pressure to obtain the crude residue. The crude residue was placed in water (5 mL), extracted with ethyl acetate (10 mL), the organic layer was separated, the aqueous layer was acidified with 1N HCl (pH 1-2), the precipitated solid was filtered, washed with water (10 mL), and the compound was dried under vacuum at 45-50°C to obtain compound 1 as a white solid (0.85 g isolation product). 1 H NMR(400MHz,DMSO-d6):δ12.86(s,1H),8.26(d,J=2.0Hz,1H),7.91(dd,J=8.8,2.0Hz,1H),7.05( d,J=8.8Hz,1H),4.00(d,J=6.8Hz,2H),1.28-1.24(m,1H),0.62-0.57(m,2H),0.42-0.37(m,2H).

[0150] Example 13 - Preparation of Compound 11 Compound 11 was prepared according to the following scheme. [ka]

[0151] Intermediate 3: To a stirred solution of 3-(pyridine-4-yl)propan-1-ol 1 (1.415 mL, 10.93 mmol, 1.0 eq), phthalimide 2 (1.931 g, 13.12 mmol, 1.2 eq), and triphenylphosphine (3.58 g, 13.67 mmol, 1.25 eq) in THF (20.0 mL), DIAD (4.29 mL, 21.87 mmol, 2 eq) was added at 0°C. The reaction mixture was heated to room temperature and then stirred overnight under a nitrogen atmosphere. After the reaction was complete (confirmed by TLC, 100% ethyl acetate Rf approximately 0.3), the reaction mixture was acidified with 1.5N HCl (50 mL) and diluted with MTBE (2 × 20 mL). The resulting organic layer was basicized to pH 9-10 with saturated sodium bicarbonate (50.0 mL). The precipitated solid was filtered and dried under vacuum for 45 minutes to obtain 2-(3-(pyridine-4-yl)propyl)isoindoline-1,3-dione 3 (2.01 g, 7.51 mmol, yield 68.7%) as an off-white solid. 1 H-NMR(400MHz,DMSO-d6):δ8.43-8.41(m,1H),7.87-7.82(m,2H),7.25(d,J=6 .00Hz,1H),3.61(t,J=6.80Hz,1H),2.65(t,J=7.60Hz,1H),1.97-1.90(m,1H).

[0152] Intermediate 4: To a stirred solution of 2-(3-(pyridine-4-yl)propyl)isoindoline-1,3-dione 3 (2.0 g, 7.51 mmol, 1.0 eq) in ethanol (40.0 mL), hydrazine hydrate (50-60% solution in H2O, 3.42 g, 37.6 mmol, 5.0 eq) was added at room temperature, and the resulting solution was stirred overnight at 80°C. After the reaction was complete (confirmed by LC-MS analysis), the reaction mixture was concentrated under reduced pressure, ground through DCM (2 x 15 mL), and filtered. The filtrate was concentrated under reduced pressure to obtain crude 3-(pyridine-4-yl)propan-1-amine 4 (0.850 g, 5.48 mmol, yield 73.0%) as a pale yellow oil. 1H-NMR (400MHz, DMSO-d6): δ8.45-8.43(m,2H), 7.24-7.22(m,2H), 2.64-2.53(m,2H), 2.52-2.50(m,2H), 1.68-1.44(m,2H). Compound 11: In a stirred solution of 5-(3-iodo-4-methoxyphenyl)oxazole-4-carboxylic acid 4 (intermediate 5 from Example 1, 0.300 g, 0.869 mmol, 1.0 eq) and 3-(pyridine-4-yl)propan-1-amine (0.178 g, 1.304 mmol, 1.5 eq) in DMF (8.0 mL), DIPEA (0.562 g, 4.35 mmol, 5.0 eq) was added at 0°C under a nitrogen atmosphere, followed by the addition of HATU (0.397 g, 1.043 mmol, 1.2 eq). The reaction mixture was stirred overnight at room temperature. After the reaction was complete (confirmed by LC-MS analysis), the reaction mixture was diluted with ice-cold water (30 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layer was washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product obtained was purified by reverse-phase column chromatography (Grace column: C18 40 μm, 0.330 g, flow rate: 30 mL / min, mobile phase: 0.1% aqueous TFA / MeCN) to obtain 5-(3-iodo-4-methoxyphenyl)-N-(3-(pyridine-4-yl)propyl)oxazole-4-carboxamide 11 (0.248 g, 0.535 mmol, yield 61.5%) as an off-white solid. 1 H-NMR(400MHz,DMSO-d6): 8.82(d,J=2.00Hz,1H),8.75-8.73(m,2H),8.54-8.50(m,2H),8.18(dd,J=2.00,8.80Hz,1H),7.83(dd,J=6.40 ,Hz,2H),7.14(dd,J=8.80,Hz,1H),3.90(s,3H),3.35-3.31(m,2H),2.87(t,J=7.60Hz,2H),1.97-1.90(m,2H).

[0153] Example 14 - Preparation of Compound 12 Compound 12 was prepared according to the following scheme. [ka]

[0154] Intermediate 3: To a stirred suspension of 4-chloropyrimidine in anhydrous DMF (5.0 ml) and triethylamine (1.846 ml, 13.25 mmol, 10.0 eq), HCl 1 (0.2 g, 1.325 mmol), and tert-butylpropa-2-in-1-ylcarbamate 2 (0.411 g, 2.65 mmol, 2.0 eq), copper(I) iodide (0.050 g, 0.265 mmol, 0.2 eq) was added, followed by the addition of PdCl2(PPh3)2 (0.093 g, 0.132 mmol, 0.1 eq). The resulting suspension was degassed under nitrogen for 10 minutes, and the reaction mixture was stirred overnight at room temperature under a nitrogen atmosphere. After the reaction was complete (confirmed by LC-MS analysis), the reaction mixture was filtered through Celite, the bed was washed with SiO2 (1 x 10 mL), and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude compound was purified by reverse-phase column chromatography (Grace column: C18 40 μm, 120 g, flow rate: 20 mL / min, mobile phase: 0.1% aqueous TFA / MeCN). The fractions were combined, and volatile substances were removed under reduced pressure. To the residue, ice-cold saturated NaHCO3 aqueous solution (75 mL) was added, followed by DCM (70 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (2 × 40 mL). The combined organic layers were washed with brine (1 × 50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain tert-butyl(3-(pyrimidine-4-yl)prop-2-in-1-yl)carbamate 3 (0.200 g, 0.857 mmol, yield 64.6%) as a light brown viscous liquid. 1 H-NMR (400MHz, DMSO-d6): δ9.17(s,1H),8.82(d,J=4.80Hz,1H),7.59-7.57(m,1H),7.48(m,1H),4.06(d,J=5.60Hz,2H),1.41(s,9H).

[0155] Intermediate 4: A stirred solution of tert-butyl(3-(pyrimidine-4-yl)propyl-2-in-1-yl)carbamate 3 (0.200 g, 0.857 mmol, 1.0 eq) in methanol (10 mL) was degassed and purged with nitrogen. Pd / C (10% w / w) (0.912 g, 0.857 mmol, 0.1 eq) was added to the solution, and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. After the reaction was complete (confirmed by LC-MS analysis), the reaction mixture was filtered through a Celite bed, and the filtrate was concentrated under reduced pressure to obtain crude tert-butyl(3-(pyrimidine-4-yl)propyl)carbamate 4 (0.130 g, 0.456 mmol, yield 53.2%) as a brownish viscous liquid. The crude product was used directly in the next step without further purification. 1 H-NMR(400MHz,DMSO-d6):δ9.07(d,J=1.20Hz,1H),8.67(d,J=5.20Hz,1H),7.43-7.41(m,1H),6.8 9-6.87(m,1H),2.99-2.94(m,2H),2.73-2.68(m,2H),1.78(quintet,J=7.20Hz,2H),1.38(s,9H).

[0156] Intermediate 5: To a stirred solution of tert-butyl(3-(pyrimidine-4-yl)propyl)carbamate 4 (0.132 g, 0.556 mmol, 1.0 eq) in DCM (3 mL), HCl (4 M solution in 1,4-dioxane, 2.78 ml, 11.13 mmol, 20.0 eq) was added at 0°C. The resulting solution was stirred at room temperature for 2 hours under a nitrogen atmosphere. After the reaction was complete (confirmed by TLC, 70% ethyl acetate in petroleum ether, product Rf ~ 0.0), the reaction mixture was concentrated under reduced pressure, titrated with MTBE (2 × 3 ml), and dried under reduced pressure to obtain crude 3-(pyrimidine-4-yl)propan-1-amine, HCl 5 (0.095 g, 0.141 mmol, yield 25.4%) as a brown, viscous solid. The crude product was used directly in the next step without further purification.

[0157] Compound 12: In a stirred solution of 5-(3-iodo-4-methoxyphenyl)oxazole-4-carboxylic acid 5 (intermediate 5 from Example 1, 0.2 g, 0.580 mmol, 1.0 eq) and 3-(pyrimidine-4-yl)propan-1-amine (0.095 g, 0.695 mmol, 1.2 eq) in DMF (8 ml), DIPEA (0.516 ml, 2.90 mmol, 5.0 eq) was added at 0°C under a nitrogen atmosphere, followed by the addition of HATU (0.331 g, 0.869 mmol, 1.5 eq). The reaction mixture was stirred overnight at room temperature. After the reaction was complete (confirmed by LC-MS analysis), ice-cold water (15 mL) was added to the reaction mixture and diluted with ethyl acetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (column: XBRIDGE C18-150, 500 μl, mobile phase: A: 100 ml aqueous ammonium bicarbonate solution, B: MeCN, flow rate: 15 mL / min, retention time: 11.0 min) to obtain the final compound 12 [5-(3-iodo-4-methoxyphenyl)-N-(3-(pyrimidine-4-yl)propyl)oxazole-4-carboxamide (0.018 g, 0.037 mmol, yield 6.3%)] as a beige solid. 1 H-NMR(400MHz,DMSO-d6):δ9.07(d,J=1.20Hz,1H),8.81(d,J=2.40Hz,1H),8.66(d,J=5.20Hz,1H),8.53(s,1H),8.51-8.47(m,1H),8. 20(dd,J=2.40,8.60Hz,1H),7.45(m,1H),7.14(d,J=9.20Hz,1H),3.90(s,3H),3.33(m,2H),2.77(t,J=8.00Hz,2H),1.88-1.97(m,2H).

[0158] Example 15 - Preparation of Compound 13 Compound 13 was prepared according to the following scheme. [ka]

[0159] Intermediate 3: Diisopropylamine (1.343 ml, 9.43 mmol, 1.5 eq), CuI (0.120 g, 0.629 mmol, 0.1 eq), and tetrakis(triphenylphosphine)palladium(0) (0) (0.727 g, 0.629 mmol, 0.1 eq) were added to a stirred suspension of 5-bromopyrimidine 1 (1.00 g, 6.29 mmol, 1.0 eq) and tert-butylpropa-2-in-1-ylcarbamate 2 (1.074 g, 6.92 mmol, 1.1 eq) in anhydrous acetonitrile (20.0 ml). After the reaction was complete (confirmed by TLC analysis, 60% ethyl acetate in petroleum ether, and Rf of the product approximately 0.1, as confirmed by LC-MS analysis), the reaction mixture was diluted with ethyl acetate (10 mL), filtered through a Celite bed, and washed with ethyl acetate (1 x 10 mL). The filtrate was concentrated under reduced pressure to obtain the crude product as a light brown viscous solid. The obtained crude product was purified by column chromatography (Isolera, silica mesh size 230-400, flow rate 35 mL / min). The column was eluted with 25% ethyl acetate in petroleum ether to obtain tert-butyl(3-(pyrimidine-5-yl)prop-2-in-1-yl)carbamate 3 (1.1 g, 4.56 mmol, yield 72.5%) as a brown viscous liquid.

[0160] Intermediate 4: A solution of tert-butyl(3-(pyrimidine-5-yl)propyl-2-in-1-yl)carbamate 3 (1.1 g, 4.72 mmol, 1.0 eq) in methanol (30 mL) was degassed, purged with argon, and PdOH2 (20% w / w) (0.331 g, 0.472 mmol, 0.1 eq) was added. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. After the reaction was complete (confirmed by LC-MS analysis), the reaction mixture was filtered through a Celite bed, the bed was washed with methanol (2 x 20 ml), and the filtrate was concentrated under reduced pressure to obtain the crude product tert-butyl(3-(pyrimidine-5-yl)propyl)carbamate 4 (0.750 g, 2.279 mmol, yield 48.3%) as a light brown viscous liquid. The obtained crude compound was used directly in the next step without further purification. 1 H-NMR (400MHz, DMSO-d6): δ9.03(s,1H),8.69(s,2H),6.89(s,1H),4.11-4.07(m,1H),3.18(d,J=5.2 0Hz,1H),2.97-2.92(m,2H),2.59(t,J=7.60Hz,2H),1.71(t,J=7.20Hz,2H),1.39(d,J=9.60Hz,12H).

[0161] Intermediate 5: To a stirred solution of tert-butyl(3-(pyrimidine-5-yl)propyl)carbamate 4 (0.300 g, 1.264 mmol, 1.0 eq) in DCM (6 ml), HCl (4 M dioxane solution, 6.32 ml, 25.3 mmol, 20.0 eq) was added at 0°C. The resulting solution was stirred overnight at room temperature under a nitrogen atmosphere. After the reaction was complete (confirmed by LC-MS), the reaction mixture was concentrated under reduced pressure to obtain the crude compound as a brown semi-solid. The crude compound was pulverized with MTBE (2 x 5 ml), the solvent was decanted, and the solid was dried under reduced pressure to obtain the crude product 3-(pyrimidine-5-yl)propan-1-amine, HCl 5 (0.205 g, 1.171 mmol, yield 93%) as a light brown semi-solid. 1H-NMR (400MHz, DMSO-d6): δ9.08(s,1H),8.76(s,2H),8.14(d,J=12.80Hz,4H),3.57(s,1H),2.81-2.70(m,5H),1.95-1.88(m,2H).

[0162] Compound 13: To a stirred solution of 5-(3-iodo-4-methoxyphenyl)oxazole-4-carboxylic acid 4a (intermediate 5 from Example 1, 0.200 g, 0.580 mmol, 1.0 eq) and 3-(pyrimidine-5-yl)propan-1-amine 5 (0.080 g, 0.580 mmol, 1.0 eq) in DMF (3.0 mL), DIPEA (0.506 mL, 2.90 mmol, 5.0 eq) was added at 0°C under a nitrogen atmosphere, followed by the addition of HATU (0.264 g, 0.695 mmol, 1.2 eq). The reaction mixture was stirred overnight at room temperature. After the reaction was complete (confirmed by LC-MS analysis), the reaction mixture was diluted with water (20 mL) and extracted with siRNA (2 x 20 mL). The combined organic extracts were washed with brine (1 x 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product as a yellow liquid. The crude product was purified by reverse-phase column chromatography (Grace column: C18 40 μm, 120 g, flow rate: 20 mL / min, mobile phase: 0.1% aqueous TFA / MeCN) to obtain [5-(3-iodo-4-methoxyphenyl)-N-(3-(pyrimidine-5-yl)propyl)oxazole-4-carboxamide 13 (0.11 g, 0.234 mmol, yield 40.34%)] as an off-white solid. 1 H-NMR(400MHz,DMSO-d6):δ9.02(s,1H),8.81(d,J=2.40Hz,1H),8.72(s,2H),8.54-8.48(m,2H),8.22- 8.19(m,1H),7.14(d,J=8.80Hz,1H),(s,1H),3.33-3.28(m,2H),2.68-2.63(m,2H),1.91-1.87(m,2H).

[0163] Example 16 - Preparation of Compound 14 Compound 14 was prepared according to the following scheme. [ka]

[0164] Intermediate 2: To a stirred solution of 3-fluoroquinoline-5-carboxylic acid 1 (1.0 g, 5.23 mmol, 1.0 eq) in THF (12.0 ml), BH3.THF (1.0 M THF solution, 15.69 ml, 15.69 mmol, 3.0 eq) was added under a nitrogen atmosphere at 0°C and stirred for 10 minutes. The reaction mixture was then heated to room temperature and stirred overnight. After the reaction was complete (confirmed by LC-MS analysis), the reaction mixture was quenched at 0°C with 1N HCl solution (10 mL) and stirred for 10 minutes. Then, saturated NaHCO3 aqueous solution (35 mL) was added to the reaction mixture and diluted with ethyl acetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with brine (1 × 50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The obtained crude compound was purified by reverse-phase column chromatography (Grace column: C18 40 μm, 120 g, flow rate: 20 mL / min, mobile phase: 0.1% aqueous HCOOH / MeCN). The fractions containing the product were combined and concentrated under reduced pressure to obtain (3-fluoroquinoline-5-yl)methanol 2 (0.605 g, 3.37 mmol, yield 64.4%) as a pale yellow solid. 1 H-NMR(400MHz,DMSO-d6):δ8.96(d,J=2.80Hz,1H),8.34-8.31(m,1H),7.98(d,J =8.00Hz,1H),7.74-7.67(m,2H),5.44(t,J=5.60Hz,1H),4.94(d,J=5.60Hz,2H).

[0165] Intermediate 3: To a stirred solution of (3-fluoroquinoline-5-yl)methanol 2 (0.6 g, 3.39 mmol, 1.0 eq) in dichloromethane (6.0 mL), triethylamine (1.028 g, 10.16 mmol, 3.0 eq) was added at 0°C under a nitrogen atmosphere, followed by the addition of mesylchloride (0.465 g, 4.06 mmol, 1.2 eq). The resulting reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete (confirmed by TLC, 50% ethyl acetate in petroleum ether, Rf value of 0.6 for the desired product), ice-cooled saturated NaHCO3 solution (15 mL) was added to the reaction mixture and diluted with DCM (10 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (2 × 10 mL). The combined organic layers were washed with brine (1 x 30 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain 5-(chloromethyl)-3-fluoroquinoline 3 (0.71 g, 3.62 mmol, yield 107.2%) as a light brown solid. The crude compound was used in the next step without further purification. 1 H-NMR(400MHz,DMSO-d6):δ9.03(d,J=3.60Hz,1H),8.48-8.44(m,1H),8.10 (d,J=11.20Hz,1H),7.83(d,J=9.20Hz,1H),7.78-7.72(m,1H),5.31(s,2H).

[0166] Intermediate 4: To a stirred solution of 5-(chloromethyl)-3-fluoroquinoline 3 (0.7 g, 3.57 mmol, 1.0 eq) in DMSO (5.0 mL), sodium cyanide (0.269 g, 5.48 mmol, 2.0 eq) was added at room temperature under a nitrogen atmosphere, and the solution was stirred overnight at room temperature. After the reaction was complete (confirmed by TLC, 30% ethyl acetate in petroleum ether, Rf value of 0.2 for the desired product), ice-cold water (15 mL) was added to the reaction mixture and diluted with ethyl acetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (1 × 50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product as a yellow viscous liquid. The crude product was purified by column chromatography (Isolera, silica mesh size 230-400, flow rate 35 mL / min). The column was eluted with 17-19% ethyl acetate in petroleum ether to obtain 2-(3-fluoroquinoline-5-yl)acetonitrile 4 (0.4 g, 2.140 mmol, yield 59.9%) as a pale yellow solid. 1 H-NMR (400MHz, DMSO-d6): δ9.04(d,J=2.80Hz,1H),8.41-8.38(m,1H),8.09(d,J=8.40Hz,1H),7.81-7.75(m,2H),4.54(s,2H).

[0167] Intermediate 5: Raney nickel (10.58 mg, 0.124 mmol, 0.1 eq) was slowly added to a stirred solution of 2-(3-fluoroquinoline-5-yl)acetonitrile 4 (0.23 g, 1.235 mmol) in a mixture of methanol (6.0 ml) and ammonia (7N MeOH solution, 6.0 mL) at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. After the reaction was complete (confirmed by LC-MS analysis), the reaction mixture was filtered through a Celite bed and washed with methanol (2 x 5 mL). The filtrate was concentrated under reduced pressure to obtain crude 2-(3-fluoroquinoline-5-yl)ethane-1-amine 5 (0.22 g, 1.054 mmol, yield 85%) as a pale yellow viscous solid. The crude product was used in the next step without further purification. 1H-NMR(400MHz,DMSO-d6):δ8.94(d,J=2.80Hz,1H),8.42(dd,J=2.40,10.80Hz,1H),7.93(d,J=8.40Hz,1H ),7.67(t,J=8.40Hz,1H),7.52(d,J=6.80Hz,1H),3.10(t,J=7.20Hz,2H),2.82(t,J=7.20Hz,2H),1.44(br s,H).

[0168] Compound 14: In a stirred solution of 5-(3-iodo-4-methoxyphenyl)oxazole-4-carboxylic acid 4a (intermediate 5 from Example 1, 0.35 g, 1.014 mmol, 1.0 eq) and 2-(3-fluoroquinoline-5-yl)ethane-1-amine 5 (0.232 g, 1.217 mmol, 1.2 eq) in N,N-dimethylformamide (8.0 mL), N,N-diisopropylethylamine (0.903 mL, 5.07 mmol) was added at 0°C under a nitrogen atmosphere, followed by the addition of HATU (0.578 g, 1.521 mmol). The mixture was heated to room temperature and stirred overnight. After the reaction was complete (confirmed by LC-MS analysis), ice-cold water (15 mL) was added to the reaction mixture and diluted with ethyl acetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (column: XSelect C18 150, 500 μl, mobile phase: A: 10 Mm aqueous ammonium bicarbonate solution, B: MeCN, flow rate: 15 mL / min, retention time: 14.0 min) to obtain [N-(2-(3-fluoroquinoline-5-yl)ethyl)-5-(3-iodo-4-methoxyphenyl)oxazole-4-carboxamide 14 (0.204 g, 0.393 mmol, yield 38.7%)] as a pale beige solid. 1H-NMR(400MHz,DMSO-d6):δ8.95(d,J=2.40Hz,1H),8.80(d,J=2.40Hz,1H),8. 67(t,J=6.00Hz,1H),8.61(dd,J=2.40,10.80Hz,1H),8.55(s,1H),8.21-8.18 (m,1H),7.96(d,J=8.40Hz,1H),7.68(t,J=8.40Hz,1H),7.57(d,J=7.20Hz,1H ),7.14(d,J=8.80Hz,1H),3.91(s,3H),3.59-3.54(m,2H),3.29-3.28(m,2H).

[0169] Example 17 - Preparation of Compound 15 Compound 15 was prepared according to the following scheme. [ka]

[0170] Intermediate 2: POCl3 (2.67 ml, 28.6 mmol, 10.0 eq) was added dropwise to a solution of 7-amino-4-fluoroisoquinoline-1(2H)-one 1 (0.510 g, 2.86 mmol, 1.0 eq) in toluene (3.0 mL), and the reaction mixture was heated overnight at 110 °C under a nitrogen atmosphere. After the reaction was complete (confirmed by LC-MS analysis), the reaction mixture was concentrated to dryness under reduced pressure. Ice-cooled saturated NaHCO3 solution (55 mL) was added to the reaction mixture and diluted with DCM (40 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (2 × 40 mL). The combined organic layers were washed with brine (1 × 50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The obtained crude product was purified by column chromatography (Isolera, silica mesh size 230-400, flow rate 35 mL / min). The column was eluted with 20-25% ethyl acetate in petroleum ether to obtain 1-chloro-4-fluoroisoquinoline-7-amine 2 (0.098 g, 0.496 mmol, yield 17.33%) as a pale yellow solid. 1H-NMR (400MHz, DMSO-d6): δ7.90-7.85 (m, 2H), 7.34 (dd, J=2.00, 9.00Hz, 1H), 7.15-7.14 (m, 1H), 6.33 (br s, 2H).

[0171] Intermediate 3: To a stirred solution of 1-chloro-4-fluoroisoquinoline-7-amine 2 (0.095 g, 0.483 mmol, 1.0 eq) in a mixture of ethanol (1.5 ml) and ammonia (7N solution in methanol, 0.209 ml, 9.66 mmol, 20.0 eq), Pd / C (0.051 g, 0.048 mmol, 0.1 eq) was added under a nitrogen atmosphere at room temperature, and the solution was stirred overnight under a hydrogen atmosphere at room temperature. After the reaction was complete (confirmed by LC-MS analysis), the reaction mixture was filtered through Celite and washed with MeOH (1 x 5 mL). The filtrate was concentrated under reduced pressure to obtain crude 4-fluoroisoquinoline-7-amine 3 (0.080 g, 0.478 mmol, yield 99%) as a pale yellow solid. 1 H-NMR(400MHz,DMSO-d6):δ8.77(s,1H),8.04(d,J=2.40Hz,1H),7.79(d,J=8.80Hz,1H),7.28(d,J=2.00Hz,1H),7.26(br s,4H),7.00(t,J=2.00Hz,1H),5.97(br s,2H).

[0172] Intermediate 4: To a stirred solution of 4-fluoroisoquinoline-7-amine 3 (0.230 g, 1.418 mmol, 1.0 eq) in water (1.0 mL) and Conc.HCl (1.0 mL), a solution of sodium nitrite (0.117 g, 1.702 mmol, 1.2 eq) in water (1.0 mL) was added dropwise at 0°C and the mixture was stirred for 30 minutes. Next, a solution of potassium iodide (0.330 g, 1.986 mmol, 1.4 eq) in water (1.0 mL) was added to the reaction mixture at 0°C and the mixture was stirred at room temperature for 4 hours. After the reaction was complete (confirmed by TLC, 15% ethyl acetate in petroleum ether, Rf value of 0.7 for the desired product), an ice-cooled saturated NaHCO3 solution (25 mL) was added to the reaction mixture and diluted with DCM (10 mL). The organic layer was separated and the aqueous layer was extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (Isolera, silica mesh size 230-400, flow rate 35 mL / min). The column was eluted with 7% ethyl acetate in petroleum ether to obtain 4-fluoro-7-iodoisoquinoline 4 (0.170 g, 0.620 mmol, yield 43.7%) as a pale yellow solid. 1 H-NMR (400MHz, DMSO-d6): δ9.18(s,1H),8.75(t,J=1.60Hz,1H),8.56(d,J=2.40Hz,1H),8.18(dd,J=1.60,8.80Hz,1H),7.90(d,J=8.80Hz,1H).

[0173] Intermediate 5: A solution of 4-fluoro-7-iodoisoquinoline 4 (0.21 g, 0.769 mmol, 1.0 eq), zinc(II) cyanide (0.135 g, 1.154 mmol, 1.5 eq), and dppf (0.021 g, 0.038 mmol, 0.05 eq) dissolved in DMF (5.00 mL) was stirred. The resulting solution was degassed under nitrogen for 10 minutes. Next, Pd2(dba)3 (0.070 g, 0.077 mmol, 0.1 eq) was added to the mixture under a nitrogen atmosphere, and the resulting solution was again degassed under nitrogen for 10 minutes. The resulting solution was heated to 130°C overnight. After the reaction was complete (confirmed by LC-MS analysis), ice-cold water (25 mL) was added to the reaction mixture and diluted with ethyl acetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude compound. The crude product was purified by column chromatography (Isolera, silica mesh size 230-400, flow rate 35 mL / min). The column was eluted with 23-25% ethyl acetate in petroleum ether to obtain 4-fluoroisoquinoline-7-carbonitrile 5 (0.11 g, 0.638 mmol, yield 83%) as a yellow solid. 1 H-NMR (400MHz, DMSO-d6): δ9.35(s,1H),8.95(s,1H),8.73(d,J=2.40Hz,1H),8.29(d,J=8.40Hz,1H),8.22-8.20(m,1H).

[0174] Intermediate 6: To a stirred solution of 4-fluoroisoquinoline-7-carbonitrile 5 (0.110 g, 0.639 mmol, 1.0 eq) in ammonia (7N in methanol, 4.0 mL), Raney nickel (5.47 mg, 0.064 mmol, 0.1 eq) was slowly added at room temperature under a nitrogen atmosphere. The mixture was stirred overnight at room temperature under a hydrogen atmosphere. After the reaction was complete (confirmed by LC-MS analysis), the reaction mixture was filtered through Celite, washed with methanol (2 x 5 mL), and the filtrate was concentrated under reduced pressure to obtain crude (4-fluoroisoquinoline-7-yl)methaneamine 6 (0.115 g, 0.599 mmol, yield 94%) as a light brown viscous solid. The crude compound was used in the next step without further purification.

[0175] Compound 15: To a stirred solution of 5-(3-iodo-4-methoxyphenyl)oxazole-4-carboxylic acid 4a (intermediate 5 from Example 1, 0.150 g, 0.435 mmol, 1.0 eq) and (4-fluoroisoquinoline-7-yl)methaneamine 6 (0.092 g, 0.522 mmol, 1.2 eq) in DMF (5.0 mL), N,N-diisopropylethylamine (0.228 mL, 1.304 mmol, 3.0 eq) was added, followed by the addition of HATU (0.248 g, 0.652 mmol, 1.5 eq) under a nitrogen atmosphere at 0°C. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete (confirmed by LC-MS analysis), ice-cold water (15 mL) was added to the reaction mixture and diluted with ethyl acetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (column: XBRIDGE C18-150, 500 μl, mobile phase: A: 10 Mm aqueous ammonium bicarbonate solution, B: MeCN, flow rate: 15 mL / min, retention time: 10.1 min) to obtain 15[N-((4-fluoroisoquinoline-7-yl)methyl)-5-(3-iodo-4-methoxyphenyl)oxazole-4-carboxamide (0.059 g, 0.116 mmol, yield 26.6%)] as a pale yellow solid. 1H-NMR (400MHz, DMSO-d6): δ9.20(m,2H),8.80(d,J=2.40Hz,1H),8.59(s,1H),8.47(d,J=2.40Hz,1H),8.21(dd,J=2.40,8. 60Hz,1H),8.12-8.09(m,2H),7.92(dd,J=1.20,8.60Hz,1H),7.13(d,J=8.80Hz,1H),4.71(d,J=6.40Hz,2H),3.90(s,3H).

[0176] Example 18 - Preparation of Compound 16 Compound 16 was prepared according to the following scheme. [ka]

[0177] Intermediate 2: To a stirred solution of 8-bromoisoquinoline-3(2H)-one 1 (4.0 g, 17.85 mmol, 1.0 eq) in methanol (25.00 mL) and CH3CN (25.00 mL), selectfluor (7.59 g, 21.42 mmol, 1.2 eq) was added at room temperature, and the mixture was stirred at 50°C for 1 hour under a nitrogen atmosphere. The reaction mixture was concentrated and dissolved in DCE (20 mL) under a nitrogen atmosphere. POCl3 (3.33 ml, 35.7 mmol, 2.0 eq) was added to the resulting solution, and the mixture was stirred overnight at 50°C. After the reaction was complete (confirmed by LC-MS analysis), ice-cold water (30 mL) was added to the reaction mixture, and it was diluted with ethyl acetate (20 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (1 x 50 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (Isolera, silica mesh size 230-400, flow rate 35 mL / min) to obtain 8-bromo-4-fluoroisoquinoline-3(2H)-one 2 (4.2 g, 11.87 mmol, yield 66%) as a light brown solid. 1H-NMR (400MHz, DMSO-d6): δ8.83 (br s, 1H), 7.89 (d, J = 8.80Hz, 1H), 7.72 (d, J = 7.20Hz, 1H), 7.59-7.54 (m, 2H).

[0178] Intermediate 3: To a stirred solution of 8-bromo-4-fluoroisoquinoline-3(2H)-one 2 (4.02 g, 16.61 mmol, 1.0 eq) in a mixture of methanol (20 mL) and DMF (20 mL), triethylamine (4.63 mL, 33.2 mmol, 2.0 eq) was added and the mixture was purged with nitrogen. PdCl2 (dppf).CH2Cl2 (1.356 g, 1.661 mmol, 0.1 eq) was added, and the mixture was diluted to 4 kg / cm³. 2 The mixture was heated overnight at 100°C under a carbon monoxide atmosphere. After the reaction was complete (confirmed by TLC, 60% ethyl acetate in petroleum ether, and an Rf value of 0.2 for the desired product), the reaction mixture was filtered through a Celite bed, and the filtrate was concentrated to dryness under reduced pressure. 70 mL of ice-cold water was added to the residue, and it was diluted with ethyl acetate (100 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine (1 × 100 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (Isolera, silica mesh size 230-400, flow rate 35 mL / min, eluted with 60% ethyl acetate in petroleum ether) to obtain the desired product, methyl 4-fluoro-3-oxo-2,3-dihydroisoquinoline-8-carboxylate 3 (1.1 g, 4.34 mmol, yield 26.1%), as a yellow solid. 1 H-NMR (400MHz, DMSO-d6): δ12.02(brs,1H),9.39(s,1H),8.10(d,J=8.80Hz,1H),7.97(t,J=5.20Hz,1H),7.77-7.73(m,1H),3.96(s,3H).

[0179] Intermediate 4: To a stirred solution of methyl 4-fluoro-3-oxo-2,3-dihydroisoquinoline-8-carboxylate 3 (1.1 g, 4.97 mmol, 1.0 eq) in DCM (20.00 mL), trifluoromethanesulfonic anhydride (2.088 mL, 12.43 mmol, 2.5 eq) and triethylamine (2.080 mL, 14.92 mmol, 3.0 eq) were added under a nitrogen atmosphere at 25°C. The reaction mixture was stirred overnight under a nitrogen atmosphere at 25°C. After the reaction was complete (confirmed by LC-MS analysis), ice-cold water (25 mL) was added to the reaction mixture and diluted with DCM (15 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (2 × 20 mL). The combined organic layers were washed with sodium bicarbonate solution (1 x 10 mL), then with brine (1 x 50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product methyl 4-fluoro-3-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydroisoquinoline-8-carboxylate 4 (2.5 g, 5.59 mmol, yield 112%) as a brownish viscous liquid. 1 H-NMR (400MHz, DMSO-d6): δ9.79(d,J=0.80Hz,1H),8.56(d,J=8.40Hz,1H),8.47(t,J=0.80Hz,1H),8.17-8.13(m,1H),4.02(s,3H).

[0180] Intermediate 5: A stirred solution of methyl-4-fluoro-3-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydroisoquinoline-8-carboxylate 4 (2.5 g, 7.04 mmol, 1.0 eq), formic acid (0.972 g, 21.11 mmol, 3.0 eq), and DIPEA (3.69 ml, 21.11 mmol, 3.0 eq) in NMP (12.0 mL) was degassed with nitrogen for 10 minutes. Next, tetrakis(triphenylphosphine)palladium (0) (0.813 g, 0.704 mmol, 0.1 eq) was added to the reaction mixture, and after further degassing with nitrogen for 5 minutes, the mixture was heated to 80°C for 4 hours under a nitrogen atmosphere. After the reaction was complete (confirmed by LC-MS analysis), ice-cold water (15 mL) was added to the reaction mixture and diluted with ethyl acetate (40 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 40 mL). The combined organic layers were washed with brine (1 × 150 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The obtained crude product was purified by column chromatography (Isolera, silica mesh size 230-400, flow rate: 35 mL / min, eluted with 7-8% ethyl acetate in petroleum ether) to obtain methyl 4-fluoroisoquinoline-8-carboxylate 5 (0.425 g, 1.921 mmol, yield 27.3%) as a pale yellow solid. 1 H-NMR (400MHz, DMSO-d6): δ9.93 (s, 1H), 8.65 (d, J = 2.00Hz, 1H), 8.41-8.36 (m, 1H), 8.04-8.01 (m, 1H), 4.01 (s, 3H).

[0181] Intermediate 6: To a solution of methyl 4-fluoroisoquinoline-8-carboxylate 5 (0.44 g, 2.144 mmol, 1.0 eq) in anhydrous dichloromethane (6.0 mL) in a round-bottom flask at -78°C, DIBAL-H (1.2 M toluene solution, 5.36 ml, 6.43 mmol, 3.0 eq) was added dropwise at -78°C under an inert atmosphere (N2). The reaction mixture was stirred at -20°C for 2 hours under a nitrogen atmosphere. After the reaction was complete, (TLC, 30% ethyl acetate in petroleum ether, R of the desired product) f(Confirmed by a value of 0.1), the reaction mixture was carefully quenched at -10°C with saturated potassium sodium tartrate aqueous solution (3 mL) and stirred for 15 minutes. The reaction mixture was diluted with DCM (3 mL), the organic layer was separated, and the aqueous layer was extracted with DCM (2 × 4 mL). The combined organic layers were washed with brine (1 × 10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The obtained crude product was purified by column chromatography (Isolera, silica mesh size 230-400, flow rate: 35 mL / min, elution with 4% MeOH in DCM) to obtain (4-fluoroisoquinoline-8-yl)methanol 6 (0.185 g, 0.975 mmol, yield 45.5%) as a pale yellow viscous liquid. 1 H-NMR(400MHz,DMSO-d6):δ9.39(s,1H),8.54(d,J=2.40Hz,1H),8.03(d,J=8.40Hz,1H),7.8 8(t,J=8.40Hz,1H),7.80(d,J=6.80Hz,1H),5.58(t,J=5.60Hz,1H),5.10(d,J=5.60Hz,2H).

[0182] Intermediate 7: To a stirred solution of (4-fluoroisoquinoline-8-yl)methanol 6 (0.180 g, 1.016 mmol, 1.0 eq) in dichloromethane (3.0 mL), triethylamine (0.425 mL, 3.05 mmol, 3.0 eq) was added, followed by mesyl-Cl (0.158 mL, 2.032 mmol, 2.0 eq), and the mixture was stirred at 0°C for 10 minutes. The reaction mixture was heated to room temperature and stirred for 2 hours. After the reaction was complete, the mixture was analyzed by TLC (50% ethyl acetate in petroleum ether, R of the desired product). f A saturated NaHCO3 aqueous solution (5 mL), cooled on ice (confirmed by LC-MS analysis), was added to the reaction mixture and diluted with DCM (5 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (2 × 5 mL). The combined organic layers were washed with brine (1 × 10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain crude (4-fluoroisoquinoline-8-yl)methylmethanesulfonate 7 (0.345 g, 0.840 mmol, yield 83%) as a yellow viscous liquid. The crude compound was used in the next step without further purification.

[0183] Intermediate 8: To a stirred solution of (4-fluoroisoquinoline-8-yl)methylmethanesulfonate 7 (0.32 g, 1.254 mmol, 1.0 eq) in DMSO (2.00 mL), sodium cyanide (0.123 g, 2.507 mmol, 2.0 eq) was added at 25°C and stirred overnight at 25°C under a nitrogen atmosphere. After the reaction was complete (confirmed by LC-MS analysis), ice-cold water (15 mL) was added to the reaction mixture and diluted with ethyl acetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 10 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product obtained was purified by column chromatography (Isolera, silica mesh size 230-400, flow rate: 25 mL / min, elution with 18-20% ethyl acetate in petroleum ether) to obtain 2-(4-fluoroisoquinoline-8-yl)acetonitrile 8 (0.06 g, 0.319 mmol, yield 25.5%) as a light brown solid.

[0184] Intermediate 9: Raney nickel (0.014 g, 0.161 mmol, 0.5 eq) was slowly added to a stirred solution of 2-(4-fluoroisoquinoline-8-yl)acetonitrile 8 (0.060 g, 0.322 mmol, 1.0 eq) in a mixture of ammonia (7N solution in methanol, 2.0 mL) and ethanol (2.0 mL) at room temperature under a nitrogen atmosphere. The mixture was stirred overnight at room temperature under a hydrogen atmosphere. After the reaction was complete, the desired product was analyzed by TLC (50% ethyl acetate in petroleum ether, R). f (Confirmed by a value of 0.1), the reaction mixture was filtered through Celite, the bed was washed with methanol (2 x 5 mL), and the filtrate was concentrated under reduced pressure to obtain crude 2-(4-fluoroisoquinoline-8-yl)ethane-1-amine 9 (0.053 g, 0.261 mmol, yield 81%) as a pale yellow viscous liquid. The crude compound was used in the next step without further purification.

[0185] Compound 16: In a stirred solution of 2-(4-fluoroisoquinoline-8-yl)ethane-1-amine 9 (0.05 g, 0.263 mmol, 1.0 eq) and 5-(3-iodo-4-methoxyphenyl)oxazole-4-carboxylic acid 4a (intermediate 5 from Example 1, 0.091 g, 0.263 mmol, 1.0 eq) in DMF (1.5 mL), DIPEA (0.138 mL, 0.789 mmol, 3.0 eq) was added, followed by the addition of HATU (0.150 g, 0.394 mmol, 1.5 eq) under a nitrogen atmosphere at 0°C, and the mixture was stirred for 10 minutes. The reaction mixture was then heated to room temperature and stirred overnight. After the reaction was complete (confirmed by LC-MS analysis), ice-cold water (5 mL) was added to the reaction mixture and diluted with ethyl acetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 5 mL). The combined organic layers were washed with brine (1 x 20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (Isolera, silica mesh size 230-400, flow rate: 35 mL / min, eluted with 30-32% ethyl acetate in petroleum ether) to obtain the final compound 16 [N-(2-(4-fluoroisoquinoline-8-yl)ethyl)-5-(3-iodo-4-methoxyphenyl)oxazole-4-carboxamide (0.065 g, 0.122 mmol, yield 46.2%)] as an off-white solid. 1 H-NMR(400MHz,DMSO-d6):δ9.59(s,1H),8.73(d,J=2.00Hz,1H),8.68(t,J=6.00Hz,1H),8.54-8.51(m,2H),8.19(dd,J=2.40,8.60Hz,1H),8.0 0(d,J=8.40Hz,1H),7.83(t,J=8.40Hz,1H),7.66(d,J=7.20Hz,1H),7.1 4(d,J=8.80Hz,1H),3.91(s,3H),3.67-3.62(m,2H),3.47-3.43(m,2H).

[0186] Example 19 - Preparation of Compound 17 Compound 17 was prepared according to the following scheme. [ka]

[0187] Intermediate 2: Hydrochloric acid (6N aq.HCl, 3.59 ml, 21.52 mmol, 8.0 eq) was added to 6-bromoquinoline-3-amine 1 (0.6 g, 2.69 mmol, 1.0 eq) at room temperature, and the resulting solution was cooled to 0°C. Next, a solution of sodium nitrite (0.278 g, 4.03 mmol, 1.5 eq) in water (1.5 mL) was slowly added to the reaction mixture over 5 minutes, and the resulting mixture was stirred at 0°C for 30 minutes. Then, tetrafluoroboric acid (48% solution in water, 9.84 g, 53.8 mmol, 20.0 eq) was slowly added to the reaction mixture, stirred for 1 hour, and then heated overnight at 50°C. After the reaction was complete (confirmed by LC-MS analysis), RM was cooled to 0°C and basicized to approximately pH 10 with saturated NaHCO3 solution. The obtained solid was filtered, washed with water (2 x 20 mL), and dried under vacuum for 1 hour to obtain the crude product. The crude product was purified by reverse-phase column chromatography (Grace column: C18 40 μm, 120 g, flow rate: 20 mL / min, mobile phase: 0.1% aqueous HCOOH / MeCN) to obtain 6-bromo-3-fluoroquinoline 2 (0.130 g, 0.404 mmol, yield 15%) as a pale beige solid. 1 H-NMR (400MHz, DMSO-d6): δ9.00(d,J=4.00Hz,1H),8.31-8.30(m,1H),8.25(dd,J=4.00,12.40Hz,1H),8.04-8.00(m,1H),7.92-7.87(m,1H).

[0188] Intermediate 3: Add 6-bromo-3-fluoroquinoline 2 (0.15 g, 0.664 mmol, 1.0 eq), zinc cyanide (0.117 g, 0.995 mmol, 1.5 eq), and dppf (0.018 g, 0.033 mmol, 0.05 eq) to a stirred solution in DMF (5.0 mL). The resulting solution was degassed by nitrogen bubbling for 10 minutes. Next, Pd2(dba)3 (0.061 g, 0.066 mmol, 0.1 eq) was added to the mixture under a nitrogen atmosphere, and the resulting solution was again degassed by nitrogen bubbling for 10 minutes. The resulting solution was heated overnight to 130°C. After the reaction was complete (confirmed by LC-MS analysis), ice-cold water (25 mL) was added to the reaction mixture and diluted with ethyl acetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (Isolera, silica mesh size 230-400, flow rate: 35 mL / min, eluted with 15-17% ethyl acetate in petroleum ether) to obtain 3-fluoroquinoline-6-carbonitrile 3 (0.07 g, 0.407 mmol, yield 61.3%) as a pale yellow solid. 1 H-NMR (400MHz, DMSO-d6): δ9.16(d,J=2.80Hz,1H),8.66(d,J=2.00Hz,1H),8.41-8.38(m,1H),8.24(d,J=8.80Hz,1H),8.08-8.05(m,1H).

[0189] Intermediate 4: To a stirred solution of 3-fluoroquinoline-6-carbonitrile 3 (0.07 g, 0.407 mmol, 1.0 eq) in ammonia (7N solution in MeOH, 6.0 mL), Raney nickel (3.48 mg, 0.041 mmol, 0.1 eq) was slowly added at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. After the reaction was complete (confirmed by LC-MS analysis), the reaction mixture was filtered through a Celite bed, the bed was washed with methanol (2 x 5 mL), and the filtrate was concentrated under reduced pressure to obtain crude (3-fluoroquinoline-6-yl)methaneamine 4 (0.055 g, 0.256 mmol, yield 63.0%) as a light brown viscous solid. The crude compound was used in the next step without further purification.

[0190] Compound 17: A stirred solution of (3-fluoroquinoline-6-yl)methaneamine 4 (0.05 g, 0.284 mmol, 1.0 eq) and 5-(3-iodo-4-methoxyphenyl)oxazole-4-carboxylic acid 4a (intermediate 5 from Example 1, 0.098 g, 0.284 mmol, 1.0 eq) in DMF (2.0 mL) was prepared by adding DIPEA (0.149 mL, 0.851 mmol, 3.0 eq) at 0°C under a nitrogen atmosphere, followed by the addition of HATU (0.162 g, 0.426 mmol, 1.5 eq). The reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete (confirmed by LC-MS analysis), ice-cold water (15 mL) was added to the reaction mixture and diluted with ethyl acetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (column: Atlantis T3 250, 500 μl, mobile phase: A: 0.1% TFA aqueous solution, B: MeCN, flow rate: 15 mL / min, retention time: 10.1 min) to obtain the final compound 17 [N-((3-fluoroquinoline-6-yl)methyl)-5-(3-iodo-4-methoxyphenyl)oxazole-4-carboxamide, TFA (0.038 g, 0.062 mmol, yield 21.8%)] as an off-white solid. 1H-NMR(400MHz,DMSO-d6):δ9.14-9.18(m,1H),8.90(d,J=3.60Hz,1H),8.81(d,J=3.20Hz,1H),8.59(s,1H),8.30-8.20(m,2 H),8.04(d,J=11.60Hz,1H),7.87(m,1H),7.76-7.73(m,1H),7.13(d,J=12.00Hz,1H),4.67(d,J=8.40Hz,2H),3.90(s,3H).

[0191] Example 20 - Preparation of Compound 18 Compound 18 was prepared according to the following scheme. [ka]

[0192] Intermediate 6a: Triethylamine (0.47 mL, 3.40 mmol) was added to a stirred solution of Int-6 (250 mg, 1.62 mmol) in DCM (10 mL), cooled to 0°C, and then Boc2O (0.41 mL, 1.78 mmol) was added. The resulting reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete (monitored by TLC), water (5 mL) was added to the reaction mixture, extracted with DCM (2 x 10 mL), the combined organic layers were dried over sodium sulfate, filtered, and evaporated under vacuum to obtain crude compound 6a as a pale yellow liquid (400 mg of isolated product). 1 H NMR (400MHz, CDCl3): δ8.31(d,J=2.4Hz,1H),8.27(s,1H),7.26-7.23(m,2H),4.60(br s, 1H), 3.19-3.17 (m, 2H), 2.68 (t, J=7.6Hz, 1H), 1.86-1.81 (m, 2H). 1.45(s,9H).

[0193] Intermediate 6b: To a stirred solution of compound 6a (100 mg, 0.39 mmol) in dry THF (5 mL), KHMDS (1 M in THF) (1.56 mL, 1.56 mmol) was added at 0°C under a nitrogen atmosphere, and the mixture was stirred for 1 hour. Methyl iodide (0.05 mL, 0.63 mmol) was added at 0°C, and the resulting reaction mixture was heated to room temperature and stirred for 16 hours. After the reaction was complete (monitored by TLC), the mixture was quenched with saturated NH4Cl (3 mL), extracted with ethyl acetate (2 × 10 mL), the organic layers were dried over sodium sulfate, filtered, and evaporated under vacuum to obtain crude compound 6b as a pale yellow liquid (100 mg of isolated product). 1 H NMR(400MHz,DMSO-d6):δ8.40(d,J=2.8Hz,1H),8.34(t,J=1.6Hz,1H),7.66-7.63(m,1H),7.28-7.24(m,2H),7.18-7.14(m,2H),3.16(br s,2H),2.76(s,3H),2.61-2.59(m,2H),1.79(br s,2H).

[0194] Intermediate E18: To a solution of compound 6b (100 mg, 0.37 mmol) in dioxane (1 mL), 4 M HCl in dioxane (2 mL) was added at 0°C. The resulting reaction mixture was gradually heated to room temperature and stirred for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was evaporated under vacuum at 45-50°C, the resulting residue was pulverized with diethyl ether (5 mL), the solvent was decanted, and the residue was dried under vacuum at 45-50°C to obtain crude Int-E18 as a brown semi-solid (90 mg of isolated product).

[0195] Compound 18: In a stirred solution of Int-5 (intermediate 5 from Example 1, 170 mg, 0.49 mmol) in DMF (3 mL), triethylamine (0.35 mL, 2.46 mmol) was added at 0°C, followed by the addition of Int-E18 (120 mg, 0.59 mmol). The mixture was stirred at 0°C for 15 minutes, and then HATU (230 mg, 0.59 mmol) was added. The resulting reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed by TLC, the reaction mixture was partitioned with water (5 mL) and ethyl acetate (10 mL). The aqueous layer was extracted with ethyl acetate (2 × 10 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and evaporated to obtain the crude residue. The crude residue was purified by silica gel column chromatography (100-200 mesh), and eluted with 2-4% methanol in DCM to obtain compound 18 as a pale yellow semi-solid (120 mg of isolated product). 1 H NMR(400MHz,DMSO-d6):δ8.33(s,2H),8.15-8.11(m,2H),7.72(d,J=7.6Hz,1H),7.55-7.35(m,1H ),7.10(d,J=8.8Hz,1H),3.87(s,3H),3.49-3.34(m,2H),3.00(s,3H),2.82-2.79(m,2H),1.88(br s,2H).

[0196] Example 21 - Preparation of Compound 19 Compound 19 was prepared according to the following scheme. [ka]

[0197] Intermediate 11: To a solution of compound 4 (intermediate 4 from Example 1, 500 mg, 1.34 mmol) in methanol (10 mL), 7 M NH3 in methanol (15 mL, 30 vol) was added in a sealed tube at 0°C. The resulting reaction contents were heated to 50°C for 16 hours. After the reaction was complete (monitored by TLC), it was cooled to room temperature, the precipitated solid was filtered, the solid was washed with methanol (1 mL), and dried under vacuum at 40-45°C to obtain compound 11 (180 mg of isolated product) as an off-white solid.

[0198] Intermediate 12: To a solution of triethylamine (1.25 mL, 8.72 mmol) in dichloromethane (12 mL), trifluoroacetic anhydride (1.14 g, 5.45 mmol) was added at 0°C and the mixture was stirred for 10 minutes. Then, compound 11 (750 mg, 2.18 mmol) in dichloromethane (10 mL) was added to the reaction mixture and the mixture was stirred at 0°C for 2 hours. After the reaction was complete (monitored by TLC), water (10 mL) was added, and the compound was extracted into dichloromethane. The organic layer was dried over sodium sulfate, filtered, and evaporated under vacuum to obtain crude compound 12 (1.35 g). The crude compound 12 was further purified by silica gel column chromatography (100-200 mesh) by elution with 15-20% ethyl acetate in hexane to obtain compound 12 (200 mg of isolated product) as an off-white solid. 1 H NMR (400MHz, CDCl3): δ8.32(d,J=2.0Hz,1H),8.00(dd,J=8.4,2.0Hz,1H),7.87(s,1H),6.94(d,J=8.4Hz,1H),3.97(s,3H).

[0199] Compound 19: In a stirred solution of Compound 12 (500 mg, 1.53 mmol) in THF (5 mL), Int-6 (236 mg, 1.53 mmol) was added in a sealed tube, followed by the addition of DABAL-Me3 (1.96 g, 7.64 mmol) in five portions over 15 minutes. The resulting reaction mixture was heated to 120°C and stirred for 4 hours. After the reaction was complete (monitored by TLC), the mixture was quenched with 1 N HCl (1 mL), extracted with ethyl acetate (10 mL), the organic layer was separated, dried over sodium sulfate, filtered, and evaporated under vacuum to obtain crude compound 19 (700 mg). Crude compound 19 was further purified by Grace (reverse phase) to obtain compound 19 (200 mg) as an off-white solid. The solid was pulverized with IPA (2 mL), decanted, and dried under vacuum at 40-45°C to obtain compound 19 as a pale yellow solid (105 mg of isolation product). 1H NMR(400MHz,DMSO-d6):δ8.92(d,J=2.0Hz,1H),8.43(dd,J=8.8,2.0Hz,1H),8.39(d,J=2.8Hz,1H),8.34(br s,1H),7.64-7.62(m,1H),7.28(s,1H),7.11-7.07(m,3H,2H exchanged in D2O),3.93-3.91(m,2H),3.90(s,3H),2.70-2.68(m,2H),2.05-2.01(m,2H).

[0200] Example 22 - Preparation of Compound 21 Compound 21 was prepared according to the following scheme. [ka]

[0201] Intermediate 13: To a solution of compound 7 (2.0 g, 11.36 mmol) in DMF (10 mL), methyl acrylate (1.54 mL, 17.04 mmol), potassium carbonate (1.57 g, 11.36 mmol), and DABCO (50 mg, catalyst) were added at room temperature. The reaction mixture was degassed under nitrogen for 15 minutes, then Pd(OAc)2 (50 mg, 0.23 mmol) was added, and the mixture was degassed again for 10 minutes. The sealed tube was capped, and the resulting reaction contents were heated to 125°C and stirred for 16 hours. After the reaction was complete (monitored by TLC), it was cooled to room temperature, filtered through a Celite bed, and the Celite bed was washed with ethyl acetate (20 mL). The filtrate was washed with water (10 mL), the separated organic layer was dried over sodium sulfate, filtered, and evaporated under vacuum to obtain crude compound 13 as an off-white solid (1.5 g of isolated product). 1 H NMR (400MHz, CDCl3): δ8.56(t,J=1.6Hz,1H),8.48(d,J=2.8Hz,1H),7.68(br d,J=16.0Hz,1H),7.57-7.53(m,1H),6.52(br d,J=16.0Hz,1H),3.84(s,3H).

[0202] Intermediate 14: To a solution of compound 13 (1.7 g, 9.39 mmol) in methanol (17 mL), nickel chloride hexahydrate (0.67 g, 2.82 mmol) was added at 0°C. After stirring for 15 minutes, sodium borohydride (0.89 g, 23.48 mmol) was gradually added over 15 minutes. The resulting reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete (monitored by TLC), the solvent was evaporated under vacuum at 40-45°C, and the residue was partitioned with 10% MeOH (30 mL) and water (10 mL) in DCM. The organic layer was separated, dried over sodium sulfate, and evaporated under vacuum to obtain crude compound 14 (1.0 g). Crude compound 14 was further purified by silica gel column chromatography (100-200 mesh) by elution with 20-25% ethyl acetate in hexane to obtain compound 14 as a brown oily compound (0.8 g of isolated product). 1 H NMR (400MHz, CDCl3): δ8.34-8.31(m,2H),7.29-7.27(m,1H),3.68(s,3H),2.99(t,J=7.6Hz,2H),2.66(t,J=7.6Hz,2H).

[0203] Intermediate 15: To a solution of compound 14 (800 mg, 4.37 mmol) in dry THF (10 mL), CH3MgBr (1 M in THF) (17.5 mL, 17.48 mmol) was added dropwise at 0°C and the mixture was stirred for 15 minutes. The resulting reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete (monitored by TLC), the mixture was quenched with saturated NH4Cl solution (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic extracts were washed with brine (5 mL), separated, dried over sodium sulfate, filtered, and evaporated under vacuum to obtain crude compound 15 as a brown semi-solid (0.7 g isolation product).

[0204] Intermediate 16: To a solution of compound 15 (100 mg, 0.54 mmol) in TFA (5 mL), chloroacetonitrile (0.06 mL, 1.08 mmol) was added. The resulting reaction mixture was heated to 70°C and stirred for 4 hours. After the reaction was complete (monitored by TLC), it was quenched with saturated sodium bicarbonate solution (10 mL) to pH 8 and extracted with ethyl acetate (2 x 10 mL). The combined organic extracts were washed with brine (5 mL), separated, dried over sodium sulfate, filtered, and evaporated under vacuum to obtain crude compound 16 as a brown semi-solid (130 mg of isolated product).

[0205] Intermediate 21: To a solution of compound 16 (120 mg, 0.46 mmol) in ethanol (10 mL), thiourea (40 mg, 0.55 mmol) and acetic acid (0.3 mL, 2.5 vol) were added. The resulting reaction mixture was heated to 80°C and stirred for 16 hours. After the reaction was complete (monitored by TLC), the reaction products were evaporated under vacuum, and the resulting residue was partitioned with ethyl acetate (10 mL) and water (5 mL). The aqueous layer was basicized with aqueous sodium hydroxide solution (to pH 8), extracted with ethyl acetate (2 x 10 mL), the organic extracts were combined, dried over sodium sulfate, filtered, and evaporated under vacuum to obtain crude Int-E21 as a brown semi-solid, which was used directly in the next step (130 mg of isolated product).

[0206] Compound 21: Int-E21 (320 mg, 1.78 mmol) was added to a stirred solution of Int-5 (intermediate 5 from Example 1, 615 mg, 1.78 mmol) in DMF (3.2 mL). After cooling to 0°C, HATU (770 mg, 2.14 mmol) was added and stirred for 10 minutes, then triethylamine (1.19 mL, 8.91 mmol) was added. The resulting reaction mixture was heated to room temperature and stirred for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was partitioned with water (5 mL) and ethyl acetate (10 mL). The aqueous layer was extracted with ethyl acetate (2 x 10 mL), and the combined organic phase was dried over anhydrous Na2SO4, filtered, and evaporated to obtain the crude residue. The resulting crude residue was purified by silica gel column chromatography (100-200 mesh) by elution with 25-30% ethyl acetate in hexane to obtain compound 21 (isolated product 160 mg) as a pale green semi-solid. 1 H NMR(400MHz,DMSO-d6):δ8.63(d,J=2.0Hz,1H),8.51(s,1H),8.32(d,J=2.8Hz,1H),8.30(s,1H),8.18(dd,J=8.8,2.0Hz,1 H),7.59-7.56(m,1H),7.47(s,1H),7.14(d,J=8.8Hz,1H),3.90(s,3H),2.67-2.63(m,2H),2.13-2.07(m,2H),1.42(s,6H).

[0207] Example 23 - Preparation of Compound 22 and Compound 23 Compounds 21 and 23 were prepared according to the following scheme. [ka]

[0208] Intermediate 7B: Compound 7A (1.0 g, 8.92 mmol) was stirred in DCM (25 mL), to which DMF (catalyst) was added. Then, oxalyl chloride (0.76 mL, 8.92 mmol) was added dropwise at 0°C. The resulting reaction mixture was heated to room temperature and stirred for 2 hours. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under vacuum to obtain crude compound 7B as a yellow liquid (1 gram of isolated product), which was then used directly in the next reaction.

[0209] Intermediate 18A: Compound 7B (1.0 g, 7.63 mmol) in 1,4-dioxane (40 mL) and water (10 mL) was stirred, to which (5-fluoropyridine-3-yl)boronic acid (1.16 g, 8.39 mmol) was added, followed by the addition of potassium carbonate (3.1 g, 22.9 mmol). The reaction mixture was degassed under nitrogen for 15 minutes, PdCl2(dppf)DCM complex (620 mg, 0.76 mmol) was added, and the mixture was degassed again for 10 minutes. The sealed tube was then capped, and the resulting reaction contents were heated at 80°C for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was cooled to room temperature and filtered through a Celite pad. The filtrate was extracted with ethyl acetate (50 mL), the organic layer was dried with sodium sulfate, and evaporated under vacuum to obtain crude compound 18A (1.2 g). Crude compound 18A was purified by silica gel column chromatography (100-200 mesh) by elution with 30-35% ethyl acetate in hexane to obtain compound 18A as a pale yellow solid (980 mg of isolation product). 1 H NMR(400MHz,DMSO-d6):δ8.62(s,1H),8.51(t,J=2.8Hz,1H),7.54-7.51(m,1 H),6.43(s,1H),2.78-2.75(m,2H),2.53(t,J=6.8Hz,1H),2.24-2.17(m,2H).

[0210] Intermediate 18B: To a stirred solution of compound 18A (1.0 g, 5.23 mmol) in methanol (10 mL), 20% Pd(OH)2 (0.1 g, 0.52 mmol) was added at room temperature. The resulting reaction mixture was stirred for 2 hours under hydrogen pressure (60 psi). After the reaction was complete (monitored by TLC), the reaction product was filtered through a Celite pad. The filtrate was evaporated under vacuum to obtain crude compound 18B (1.2 g). The crude compound 18B was purified by silica gel column chromatography (100-200 mesh) by elution with 20-25% ethyl acetate in hexane to obtain compound 18B as a brown semi-solid (980 mg of isolated product). 1 H NMR(400MHz,DMSO-d6):δ8.37(d,J=2.4Hz,1H),8.34(s,1H),7.34-7.28(m,1H),3.13-3.06(m,1H) ),2.65-2.60(m,1H),2.53-2.50(m,2H),2.44-2.36(m,1H),2.22-2.14(m,2H),1.92-1.79(m,2H).

[0211] Intermediate E22 (racemic mixture): To a stirred solution of compound 18B (360 mg, 1.86 mmol) in ethanol (10 mL), titanium isopropoxide (1.1 mL, 3.72 mmol) was added in a sealed tube at room temperature. After cooling the reaction mixture to 0°C, 7M NH3 (2.6 mL, 18.6 mmol) in MeOH was added dropwise. The resulting reaction mixture was stirred at room temperature for 16 hours. Then, the reaction mixture was cooled to 0°C, sodium borohydride (105 mg, 2.79 mmol) was added, and the resulting reaction mixture was heated to room temperature and stirred for 2 hours. After the reaction was complete (monitored by TLC), the reaction mixture was filtered through a Celite pad. The filtrate was evaporated under vacuum to obtain crude Int-E22 as a pale yellow semi-solid (520 mg of isolated product).

[0212] Intermediate 17 (racemic): To a stirred solution of Int-5 (Intermediate 5 from Example 1, 450 mg, 1.30 mmol) in DMF (4.5 mL), triethylamine (0.91 mL, 6.52 mmol) was added at 0°C, followed by the addition of Int-E22 (300 mg, 1.54 mmol). After stirring at 0°C for 15 minutes, HATU (590 mg, 1.54 mmol) was added and the mixture was stirred for 10 minutes. The resulting reaction mixture was heated to room temperature and stirred for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was partitioned with water (10 mL) and ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and evaporated to obtain the crude residue. The resulting crude residue was purified by silica gel column chromatography (100-200 mesh) by elution with 25-30% ethyl acetate in hexane to obtain compound 17 as an off-white solid (360 mg of isolation product). 1 H NMR(400MHz,DMSO-d6):δ8.82(d,J=2.4Hz,1H),8.53(s,1H),8.41-8.38(m,2H),8.15-8.13(m,2H),7.63-7.60(m,1H),7.14 -7.11(m,1H),3.99-3.96(m,1H),3.89(s,3H),2.86-2.80(m,1H),1.95-1.79(m,4H),1.68-1.69(m,1H),1.48-1.38(m,3H).

[0213] Compounds 22A, 22B, 23A, and 23B: [ka] 1.0 g of racemic intermediate 17 was separated by chiral SFC HPLC (column: Chiralcel OX-H (250x4.6) 5u, MP: CO2: ethanol (100%) 80-20, BPR: 102 KGF, flow rate: 3.0 ml / min, UV: 280 nm) to obtain four isomers. The structures were verified by nOe analysis, and the stereochemistry of each cis and trans component was arbitrarily assigned as follows: Isomer 1 (trans-A), Isomer 2 (cis-A), Isomer 3 (cis-B), Isomer 4 (trans-B). Compound 22A: 1 H NMR (400MHz, DMSO-d6): δ8.81(d,J=2.0Hz,1H),8.53(s,1H),8.41-8.38(m,2H),8.15(dd,J=8.4,2.0Hz,1H),8.11(d,J=8.4Hz,1H),7.63-7.6 0(m,1H),7.12(d,J=8.8Hz,1H),3.99-3.94(m,1H),3.89(s,3H),2.86- 2.80(m,1H),1.99-1.79(m,4H),1.68-1.59(m,1H),1.53-1.38(m,3H). Compound 22B: 1 H NMR (400MHz, DMSO-d6): δ8.82(d,J=2.4Hz,1H),8.54(s,1H),8.41-8.39(m,2H),8.17-8.12(m,2H),7.64-7.60(m,1H),7.12( d,J=9.2Hz,1H),3.99-3.97(m,1H),3.89(s,3H),2.86-2.80(m,1H),1.99-1.79(m,4H),1.68-1.59(m,1H),1.50-1.46(m,3H). Compound 23A: 1 H NMR (400MHz, DMSO-d6): δ8.75(d,J=2.4Hz,1H),8.57(s,1H),8.41-8.39(m,2H),8.18(dd,J =8.8,2.0Hz,1H),8.01(d,J=7.2Hz,1H),7.70-7.67(m,1H),7.14(d,J=8.8Hz,1H),4.26(br s,1H),3.89(s,3H),3.03(br s,1H),1.95-1.91(m,2H),1.87-1.83(m,2H),1.63(br s,4H). Compound 23B: 1H NMR(400MHz,DMSO-d6):δ8.75(d,J=2.4Hz,1H),8.58(s,1H),8.42(br s,2H),8.18(dd,J=8.8,2.0Hz,1H),8.02(d,J=7.2Hz,1H),7.71-7.67(m,1H),7.13(dd,J=8.8,1.2Hz,1H),4.26(br s,1H),3.89(s,3H),3.03(br s,1H),1.98-1.91(m,2H),1.88-1.83(m,2H),1.63(br s,4H).

[0214] Example 24 - Preparation of Compound 24 Compound 24 was prepared according to the following scheme. [ka]

[0215] Intermediate 7b: Compound 7a (500 mg, 3.64 mmol) was stirred in acetonitrile (5 mL), to which anhydrous Boc (870 mg, 4.01 mmol) and DMAP (catalyst) were added. The resulting reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed by TLC, the reaction mixture was evaporated under vacuum, and the resulting residue was partitioned with 1N HCl (5 mL) and ethyl acetate (10 mL). The separated organic layer was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and the solvent was evaporated under reduced pressure to obtain crude compound 7b as a colorless viscous liquid (isolated product 610 mg). 1 H NMR (400MHz, DMSO-d6): δ9.22(d,J=4.0Hz,1H),7.95(s,1H),7.85-7.81(m,1H),7.54-7.37(m,2H),7.26-7.17(m,1H),1.47(d,J=1.6Hz,9H).

[0216] Intermediate 7c: Compound 7b (600 mg, 2.55 mmol) was added to a stirred solution of compound 7 (450 mg, 2.55 mmol) in 1,4-dioxane (12 mL) and water (3 mL), followed by the addition of KCl (1.39 g, 10.07 mmol). The reaction mixture was degassed under nitrogen for 15 minutes, Pd(PPh3)4 (20 mg, 0.13 mmol) was added, and the mixture was degassed again for 10 minutes. The sealed tube was capped, and the resulting reaction contents were heated at 100°C for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was cooled to room temperature and filtered through a Celite pad. The filtrate was evaporated under vacuum, and the resulting residue was purified by silica gel column chromatography (100-200 mesh) by elution with 20-25% ethyl acetate in hexane to obtain compound 7c (810 mg of isolated product) as a viscous semi-solid.

[0217] Intermediate E24: A solution (4 mL) of compound 7c (800 mg, 2.77 mmol) in 4M HCl dioxane was stirred at room temperature for 16 hours. After the reaction was complete (monitored by TLC), the precipitated solid was filtered, washed with dioxane (2 mL), and dried under vacuum at 45-50°C to obtain Int-E24 (300 mg of isolated product) as a cream-colored solid. 1 H NMR(400MHz,DMSO-d6):δ8.80(t,J=1.6Hz,1H),8.69(d,J=2.8Hz,1H),8.14-8.11(m,1H),7.85- 7.83(m,1H),7.80(t,J=1.6Hz,1H),7.65(t,J=7.6Hz,1H),7.52-7.49(m,1H),6.60-5.70(m,2H).

[0218] Compound 24: In a stirred solution of Int-5 (intermediate 5 from Example 1, 200 mg, 0.58 mmol) in DMF (2.0 mL), triethylamine (0.57 mL, 4.05 mmol) was added at 0°C, followed by the addition of Int-E24 (130 mg, 0.69 mmol). The mixture was stirred at 0°C for 15 minutes, then HATU (264 mg, 0.69 mmol) was added and stirred for 10 minutes. The resulting reaction mixture was heated to room temperature and stirred for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was partitioned with water (5 mL) and ethyl acetate (10 mL). The aqueous layer was extracted with ethyl acetate (2 × 10 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and evaporated to obtain the crude residue. The resulting crude residue was purified by silica gel column chromatography (100-200 mesh) by elution with 30-35% ethyl acetate in hexane to obtain compound 24 as an off-white solid (150 mg of isolation product). 1 H NMR(400MHz,DMSO-d6):δ10.32(s,1H),8.79(t,J=2.0Hz,1H),8.70-8.69(m,2H),8.61(d,J=2.4Hz,1H),8.23(dd ,J=8.4,2.0Hz,1H),8.20-8.19(m,1H),8.07-8.00(m,2H),7.56-7.51(m,2H),7.18(d,J=9.2Hz,1H),3.91(s,3H).

[0219] Example 25 - Preparation of Compound 25 Compound 25 was prepared according to the following scheme. [ka]

[0220] Intermediate 1b: To a stirred solution of methyl 5-bromo-1H-imidazole-4-carboxylate 1 (1.0 g, 4.88 mmol, 1.0 eq) in DMF (8.0 mL), sodium hydride (60% w / w in mineral oil, 0.273 g, 6.83 mmol, 1.4 eq) was added at 0°C and the mixture was stirred for 30 minutes under an N2 atmosphere. SEM-Cl (0.952 mL, 5.37 mmol, 1.1 eq) was added at 0°C and the mixture was stirred overnight. After the reaction was complete (confirmed by LC-MS analysis), the reaction mixture was quenched with saturated NH4Cl solution at 0°C and diluted with ethyl acetate (20 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (Isolera, silica mesh size 230-400, flow rate 18 mL / min). The column was eluted with 10% ethyl acetate in petroleum ether to obtain methyl 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate 1b (1.15 g, 3.33 mmol, yield 68.4%) as a pale yellow viscous liquid. 1 H-NMR (400MHz, DMSO-d6): δ8.17(s,1H),5.61(s,2H),3.82(s,3H),3.48(t,J=8.00Hz,2H),0.82(t,J=7.60Hz,2H),-0.01(t,J=Hz,10H).

[0221] Intermediate 3: To a stirred solution of methyl 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate 1b (1.15 g, 3.43 mmol, 1.0 eq) and 2-(4-methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 2 (1.436 g, 5.15 mmol, 1.5 eq) in dioxane (10.0 mL) and water (1.0 mL), potassium carbonate (0.948 g, 6.86 mmol, 2.0 eq) was added under a nitrogen atmosphere. The reaction mixture was degassed under nitrogen for 10 minutes, and PdCl2 (dppf) (0.251 g, 0.343 mmol, 0.1 eq) was added. The reaction mixture was heated to 80°C overnight. After the reaction was complete (confirmed by LC-MS analysis), the reaction mixture was diluted with ethyl acetate (10 mL), filtered through Celite, and washed with ethyl acetate (2 x 10 mL). Water (20 mL) was added to the filtrate, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The obtained crude product was purified by column chromatography (Isolera, silica mesh size 230-400, flow rate 35 mL / min, eluted with 40-45% ethyl acetate in petroleum ether) to obtain methyl 5-(4-methoxy-3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate 3 (1.13 g, 2.485 mmol, yield 72.5%) as a brownish viscous liquid. 1 H-NMR(400MHz,DMSO-d6):δ8.23(t,J=6.40Hz,2H),8.03-8.00(m,1H),7.42(d,J=9.20Hz,1H),5.64(s,2H) ,4.04(t,J=7.20Hz,3H),3.76(s,3H),3.50(t,J=8.00Hz,2H),1.18(t,J=6.80Hz,2H),-0.02(t,J=Hz,9H).

[0222] Intermediate 4: To a stirred solution of methyl 5-(4-methoxy-3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate 3 (1.39 g, 3.41 mmol, 1.0 eq) in ethanol (15.0 mL) and water (6.0 mL), ammonium chloride (1.460 g, 27.3 mmol, 8.0 eq) and iron (0.952 g, 17.06 mmol, 5.0 eq) were added at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 85 °C for 8 hours. After the reaction was complete (confirmed by LC-MS analysis), the reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was diluted with 10% MeOH (20 mL) and water (20 mL) in DCM. The organic layer was separated, and the aqueous layer was extracted with 10% MeOH (2 × 10 mL) in DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain crude methyl 5-(3-amino-4-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate 4 (0.980 g, 2.53 mmol, yield 74.2%) as a black, viscous liquid.

[0223] Intermediate 5: To a stirred solution of copper(I) 4 iodide (0.515 g, 2.70 mmol, 1.2 eq) in acetonitrile (8.0 mL), tert-butyl nitrite (0.279 g, 2.70 mmol, 1.2 eq) was added, followed by the addition of a solution of methyl 5-(3-amino-4-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (0.850 g, 2.252 mmol, 1.0 eq) in acetonitrile (8.0 mL) at 0°C. The resulting solution was stirred at 0°C for 15 minutes. The reaction mixture was then heated to room temperature and stirred overnight under a nitrogen atmosphere. After the reaction was complete (confirmed by LC-MS analysis), the reaction mixture was basicized with saturated sodium bicarbonate solution (20 mL) and diluted with DCM (20 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (2 × 20 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (Isolera, silica mesh size 230-400, flow rate 35 mL / min). The column was eluted with 30-40% ethyl acetate in petroleum ether to obtain methyl 5-(3-iodo-4-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate 5 (0.390 g, 0.702 mmol, yield 31.2%) as a yellow viscous liquid.

[0224] Intermediate 6: Methyl 5-(3-iodo-4-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate 5 (0.390 g, 0.799 mmol, 1.0 eq) was stirred in a mixture of MeOH (6.0 mL), THF (4.0 mL), and water (2.0 mL). LiOH.H2O (0.076 g, 3.19 mmol, 4.0 eq) was added at 0°C and the mixture was stirred overnight at room temperature. After the reaction was complete (confirmed by LC-MS analysis), the reaction mixture was acidified with saturated citric acid solution (5.0 mL) and diluted with ethyl acetate (10.0 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 5-(3-iodo-4-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylic acid 6 (0.880 g, 1.552 mmol, yield 194%) as an off-white solid.

[0225] Intermediate 7a: In a stirred solution of 5-(3-iodo-4-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylic acid 6 (0.090 g, 0.190 mmol, 1.0 eq) and 3-(5-fluoropyridine-3-yl)propan-1-amine 7 (Intermediate 6 from Example 1, 0.044 g, 0.285 mmol, 1.5 eq) in DMF (3.0 mL), DIPEA (0.166 mL, 0.949 mmol, 1.2 eq) was added, followed by the addition of HATU (0.087 g, 0.228 mmol, 5.0 eq) under a nitrogen atmosphere at 0°C. The reaction mixture was stirred overnight at room temperature. After the reaction was complete (confirmed by LC-MS analysis), ice-cold water (10.0 mL) was added to the reaction mixture and diluted with ethyl acetate (10.0 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 10 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain N-(3-(5-fluoropyridine-3-yl)propyl)-5-(3-iodo-4-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxamide 7a (0.200 g, 0.263 mmol, yield 138%) as a pale yellow liquid.

[0226] Compound 25: To a stirred solution of N-(3-(5-fluoropyridine-3-yl)propyl)-5-(3-iodo-4-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxamide 7a (0.200 g, 0.328 mmol, 1.0 eq) in THF (5.0 mL), TBAF (1 M in THF, 1.638 mL, 1.638 mmol, 5 eq) was added at 0°C under a nitrogen atmosphere. The reaction mixture was stirred overnight at room temperature. LC-MS analysis showed unreacted starting material. 2.0 mL of TBAF was added to the reaction mixture at 0°C and stirred at room temperature for 5 hours. After the reaction was complete (confirmed by LC-MS analysis), the reaction mixture was concentrated to dryness under reduced pressure. The crude product obtained was purified by preparative HPLC (column: X Bridge C18-150, 500 ul; mobile phase: A: 0.1% FA aqueous solution, B: MeCN; flow rate: 15 mL / min; retention time: 10.2 min) to obtain the final compound N-(3-(5-fluoropyridine-3-yl)propyl)-5-(3-iodo-4-methoxyphenyl)-1H-imidazole-4-carboxamide 25 (0.040 g, 0.083 mmol, yield 25.30%) as an off-white solid. 1 H-NMR (400MHz, DMSO-d6): δ12.75(s,1H),8.38(t,J=16.40Hz,3H),8.12(s,1H),7.90-7.87(m,1H),7.79(s,1H),7. 67-7.63(m,1H),7.06(d,J=8.40Hz,1H),3.87(s,3H),3.28-3.23(m,2H),2.68(t,J=8.00Hz,2H),1.87-1.80(m,2H).

[0227] Example 26 - Preparation of Compound 27 Compound 27 was prepared according to the following scheme. [ka]

[0228] Intermediate 3: To a stirred solution of ethyl ¹H-imidazole-2-carboxylate 1 (2.00 g, 14.27 mmol) in DCM (60.00 mL), copper(II) acetate (3.89 g, 21.41 mmol, 1.5 eq), pyridine (2.309 mL, 28.5 mmol, 2.0 eq), and (4-methoxyphenyl)boronic acid (4.34 g, 28.5 mmol, 2.0 eq) were added at 25°C. The mixture was stirred overnight at 25°C under an oxygen atmosphere. After the reaction was complete (confirmed by TLC, 70% ethyl acetate in petroleum ether, Rf value of the desired product 0.5, and LCMS analysis), the reaction mixture was concentrated under reduced pressure to obtain the crude product as a blue viscous liquid. The crude product was purified by column chromatography (Isolera, silica mesh size 230-400, flow rate 35 mL / min, elution with 60% ethyl acetate in petroleum ether) to obtain ethyl 1-(4-methoxyphenyl)-1H-imidazole-2-carboxylate 3 (1.00 g, 3.06 mmol, yield 21.45%) as a yellow solid. 1 H-NMR (400MHz, DMSO-d6): δ7.56(s,1H),7.35-7.32(m,2H),7.22(s,1H),7.04-7.01(m,2H),4.15-4.10(m,2H),3.82(s,3H),1.14(t,J=9.60Hz,3H).

[0229] Intermediate 4: To a stirred solution of ethyl 1-(4-methoxyphenyl)-1H-imidazole-2-carboxylate 3 (1.00 g, 4.06 mmol, 1.0 eq) and chloroform (10.0 mL) in trifluoroacetic acid (3.0 mL), silver trifluoroacetate (0.897 g, 4.06 mmol, 1.0 eq) and iodine (1.031 g, 4.06 mmol, 1.0 eq) were added, and the reaction mixture was stirred overnight at 25°C. After the reaction was complete (confirmed by LC-MS analysis), the reaction mixture was concentrated under reduced pressure, basicized to pH=12 using aqueous ammonia (30 solution, 10 mL), and extracted with DCM (2 x 10 mL). The combined organic layers were washed with aqueous Na2S2O3 solution (2 x 40 mL), water (1 x 50 mL), and then brine (1 x 50 mL). The organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase column chromatography (Grace column: C18 40 μm, 120 g, flow rate: 20 mL / min, mobile phase: 0.1% aqueous TFA / MeCN) to obtain ethyl 1-(3-iodo-4-methoxyphenyl)-1H-imidazole-2-carboxylate 4 (1.00 g, 2.66 mmol, yield 65.5%) as a pale yellow solid. 1 H-NMR(400MHz,DMSO-d6):δ7.86(d,J=3.20Hz,1H),7.63(d,J=1.60Hz,1H),7.45(dd,J=3.60,11.80Hz,1H) ,7.29(d,J=1.20Hz,1H),7.09(d,J=12.00Hz,1H),4.19-4.12(m,2H),3.89(s,3H),1.14(t,J=9.60Hz,3H).

[0230] Compound 27: A mixture of 3-(5-fluoropyridine-3-yl)propan-1-amine 7 (intermediate 6 from Example 1, 0.414 g, 2.69 mmol, 2.5 eq) and DIPEA (0.478 ml, 2.69 mmol, 2.5 eq) in methanol (10 mL) was stirred at 25°C for 1 hour under a nitrogen atmosphere. Ethyl 1-(3-iodo-4-methoxyphenyl)-1H-imidazole-2-carboxylate 4 (0.4 g, 1.075 mmol, 1.0 eq) and calcium chloride (0.119 g, 1.075 mmol, 1.0 eq) were added to the reaction mixture at 25°C under a nitrogen atmosphere, and the mixture was stirred overnight at 25°C. After the reaction was complete (confirmed by LC-MS analysis), the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product obtained was purified by preparative HPLC (column: Agilent 50 mm, 500 ul; mobile phase: A: 10 mm aqueous ammonium bicarbonate solution, B: MeCN; flow rate: 15 mL / min; retention time: 11.0 min) to obtain the final compound 27 [N-(3-(5-fluoropyridine-3-yl)propyl)-1-(3-iodo-4-methoxyphenyl)-1H-imidazole-2-carboxamide (0.117 g, 0.243 mmol, yield 28.7%)] as a light brown, viscous solid. 1 H-NMR(400MHz,DMSO-d6):δ8.60(t,J=6.00Hz,1H),8.38(d,J=2.80Hz,1H), 8.32(t,J=1.60Hz,1H),7.76(d,J=2.80Hz,1H),7.63-7.60(m,1H),7.48(d,J =0.80Hz,1H),7.39-7.37(m,1H),7.13(d,J=0.80Hz,1H),7.05(d,J=8.80Hz ,1H),3.88(s,3H),3.19-3.14(m,2H),2.68-2.66(m,2H),1.84-1.77(m,2H).

[0231] Example 27 - Preparation of Compound 28 Compound 28 was prepared according to the following scheme. [ka]

[0232] Intermediate 2: To a solution of 3-iodo-4-methoxyaniline 1 (1.0 g, 4.02 mmol, 1.0 eq) in methanol (15 mL), ethyl 2-oxoacetate (40% in toluene, 1.230 g, 4.82 mmol, 1.2 eq) was added, and the resulting mixture was heated under reflux for 3.5 hours. The mixture was concentrated under vacuum, and the resulting residue was reconstituted with anhydrous ethanol (15.0 mL) and treated with potassium carbonate (1.110 g, 8.03 mmol, 2.0 eq) and 1-((isocyanomethyl)sulfonyl)-4-methylbenzene 1a (1.176 g, 6.02 mmol, 1.5 eq). The resulting mixture was heated at 65°C for 4 hours under a nitrogen atmosphere. After the reaction was complete (confirmed by LC-MS analysis), the reaction mixture was concentrated to dryness under reduced pressure. Ice-cold water (50 mL) was added to the residue, and it was diluted with ethyl acetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (1 × 50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (Isolera, silica mesh size 230-400, flow rate 35 mL / min, eluted with 37-40% ethyl acetate in petroleum ether) to obtain ethyl 1-(3-iodo-4-methoxyphenyl)-1H-imidazole-5-carboxylate 2 (0.810 g, 1.918 mmol, yield 47.8%) as a yellow solid. 1 H-NMR(400MHz,DMSO-d6):δ8.05(d,J=0.80Hz,1H),7.86(d,J=2.40Hz,1H),7.77(d,J=0.80Hz,1H),7.47- 7.44(m,1H),7.09(d,J=8.80Hz,1H),4.16-4.11(m,2H),3.87(t,J=37.20Hz,3H),1.15(t,J=6.80Hz,3H).

[0233] Intermediate 3: To a stirred solution of ethyl 1-(3-iodo-4-methoxyphenyl)-1H-imidazole-5-carboxylate 2 (0.800 g, 2.150 mmol, 1.0 eq) in a mixture of ethanol (10.0 mL), THF (6.67 mL), and water (3.33 mL), LiOH.H2O (0.206 g, 8.60 mmol, 4.0 eq) was added at 0°C and the mixture was stirred overnight at room temperature. After the reaction was complete (confirmed by LC-MS analysis), the reaction product was concentrated under reduced pressure. The resulting residue was acidified with acetic acid (3.0 mL) and concentrated under reduced pressure to obtain the crude product. The crude compound was purified by reverse-phase column chromatography (Grace column: C18 40 μm, 870 g, flow rate: 25 mL / min, mobile phase: water / 35% HCOOH in MeCN) to obtain 1-(3-iodo-4-methoxyphenyl)-1H-imidazole-5-carboxylic acid 3 (0.720 g, 1.817 mmol, yield 84.5%) as an off-white solid.

[0234] Compound 28: To a stirred solution of 1-(3-iodo-4-methoxyphenyl)-1H-imidazole-5-carboxylic acid 3 (0.250 g, 0.727 mmol, 1.0 eq) and 3-(5-fluoropyridine-3-yl)propan-1-amine (intermediate 6 from Example 1, 0.168 g, 1.090 mmol, 1.5 eq) in DMF (4.0 mL), DIPEA (0.469 g, 3.63 mmol, 5.0 eq) was added, followed by the addition of HATU (0.331 g, 0.872 mmol, 1.2 eq) under a nitrogen atmosphere at 0°C. The reaction mixture was stirred overnight at room temperature. After the reaction was complete (confirmed by LC-MS analysis), the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was diluted with ethyl acetate (10 mL) by adding ice-cold water (20 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 10 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The obtained crude product was purified by preparative HPLC (column: XSELECT C18-250, 500 μl, mobile phase: A: 10 mm aqueous ammonium bicarbonate solution, B: MeCN, flow rate: 14 mL / min, retention time: 13.0 min) to obtain N-(3-(5-fluoropyridine-3-yl)propyl)-1-(3-iodo-4-methoxyphenyl)-1H-imidazole-5-carboxamide 28 (0.113 g, 0.232 mmol, yield 31.9%) as an off-white solid. 1 H-NMR(400MHz,DMSO-d6):δ8.40-8.37(m,2H),8.33(t,J=2.00Hz,1H),7.90(d,J=0.80Hz,1H),7.75(d,J=2.40Hz,1H),7.62(t,J=2.00Hz,1H), 7.61-7.58(m,1H),7.37-7.34(m,1H),7.06(d,J=8.80Hz,1H),3.87(s, 3H),3.17-3.12(m,2H),2.65(t,J=7.60Hz,2H),1.78(t,J=7.20Hz,2H).

[0235] Example 28 - Preparation of Compound 29 Compound 29 was prepared according to the following scheme. [ka]

[0236] Intermediate 2: To a stirred solution of 4-methoxybenzaldehyde (1.0 g, 7.34 mmol, 1.0 eq) in glacial acetic acid (10.0 mL), ICl (0.442 mL, 8.81 mmol, 1.2 eq) was added at room temperature under a nitrogen atmosphere, and the resulting solution was stirred overnight at 140 °C. The progress of the reaction was monitored by TLC (15% ethyl acetate in petroleum ether, Rf value approximately 0.2). After the reaction was complete, the reaction mixture was cooled to room temperature and poured into a solution of sodium metabisulfite (15.0 g) in ice-cold water (250 mL). The suspension was stirred for 10 minutes, filtered, washed with water (20 mL), and air-dried for 30 minutes. The resulting crude product was purified by column chromatography (Isolera, silica mesh size 230-400, flow rate 35 mL / min). The column was eluted with 15% ethyl acetate in petroleum ether to obtain 3-iodo-4-methoxybenzaldehyde 2 (1.0 g, 2.98 mmol, yield 40.5%) as an off-white solid. 1 H-NMR (400MHz, CDCl3): δ9.85(s,1H),8.33(d,J=2.00Hz,1H),7.90-7.87(m,1H),6.95(d,J=8.40Hz,1H),4.00(s,3H).

[0237] Intermediate 4: To a stirred solution of 3-iodo-4-methoxybenzaldehyde 2 (0.8 g, 3.05 mmol, 1.0 eq) in DMF (10.0 ml), methylcyanoacetate 3 (0.270 ml, 3.05 mmol, 1.0 eq), sodium azide (0.595 g, 9.16 mmol, 3.0 eq), and triethylamine hydrochloride (1.051 g, 7.63 mmol, 2.5 eq) were added at room temperature under a nitrogen atmosphere, and the resulting reaction mixture was stirred overnight at 70°C. The progress of the reaction was monitored by TLC (20% ethyl acetate in petroleum ether, Rf value approximately 0.1). After the reaction was complete (confirmed by TLC, 20% ethyl acetate in petroleum ether, Rf value of product approximately 0.1), the reaction mixture was cooled to room temperature, quenched with ice-cold saturated NaHCO3 solution (45 mL), and diluted with ethyl acetate (20 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (1 × 50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product as a yellow viscous liquid. The obtained crude product was purified by column chromatography (Isolera, silica mesh size 230-400, flow rate 35 mL / min). The column was eluted with 45-49% ethyl acetate in petroleum ether to obtain methyl 5-(3-iodo-4-methoxyphenyl)-1H-1,2,3-triazole-4-carboxylate 4 (0.43 g, 1.132 mmol, yield 37.1%) as a yellow viscous oil. 1 H-NMR(400MHz,DMSO-d6):δ15.83(d,J=60.80Hz,1H),8.23(br s,1H),7.98(d,J=14.80Hz,1H),7.82(s,1H),7.13(d,J=8.40Hz,1H),3.90(s,3H),3.83(s,3H).

[0238] Intermediate 5: A stirred solution of methyl 5-(3-iodo-4-methoxyphenyl)-1H-1,2,3-triazole-4-carboxylate 4 (0.430 g, 1.197 mmol, 1.0 eq) in a mixture of methanol (9.0 ml), tetrahydrofuran (6.0 ml), and water (3.00 ml) was to which lithium hydroxide (0.201 g, 4.79 mmol, 4.0 eq) was added at 0°C. The resulting solution was stirred at 0°C for 10 minutes. The reaction mixture was then adjusted to room temperature and stirred overnight. After the reaction was complete (confirmed by LC-MS analysis), the reaction mixture was concentrated to dryness under reduced pressure. The resulting residue was dissolved in water (5 mL), acidified with acetic acid to approximately pH 5-6, and concentrated under reduced pressure to obtain the compound. The crude product obtained was purified by preparative HPLC (column: Agilent 50 mm, 500 ul; mobile phase: A: 0.1% TFA aqueous solution, B: MeCN; flow rate: 15 mL / min; retention time: 8.0 min) to obtain the desired compound 5-(3-iodo-4-methoxyphenyl)-1H-1,2,3-triazole-4-carboxylic acid 5 (0.255 g, 0.721 mmol, yield 60%) as an off-white solid. 1 H-NMR (400MHz, DMSO-d6): δ8.52 (br s, 1H), 8.10 (br s, 1H), 7.07 (d, J = 8.80Hz, 1H), 3.88 (s, 3H).

[0239] Compound 29: To a stirred solution of 5-(3-iodo-4-methoxyphenyl)-1H-1,2,3-triazole-4-carboxylic acid 5 (0.2 g, 0.580 mmol, 1.0 eq), 3-(5-fluoropyridine-3-yl)propan-1-amine, and HCl 7 (intermediate 6 from Example 1, 0.166 g, 0.869 mmol, 1.5 eq) in DMF (3.5 ml), N,N-diisopropylethylamine (0.375 g, 2.90 mmol, 5.0 eq), EDC (0.167 g, 0.869 mmol, 1.5 eq), and HOBt (0.133 g, 0.869 mmol, 1.5 eq) were added under a nitrogen atmosphere at 0°C, and the solution was stirred overnight at room temperature. After the reaction was complete (confirmed by LC-MS analysis), ice-cold water (45 mL) was added to the reaction mixture and diluted with ethyl acetate (30 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine (1 × 50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude compound. The obtained crude product was purified by preparative HPLC (column: SUNFIRE C-18 19.1 × 250, 500 μl, mobile phase: A: 0.1% FA aqueous solution, B: MeCN, flow rate: 15 mL / min, retention time: 10.1 min). The fractions containing the product were combined and freeze-dried to obtain the TFA salt of compound 29 as an off-white solid. The obtained TFA salt of compound 29 was basicized with saturated aqueous solution of NaHCO₃ (4 mL) and diluted with DCM (4 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (2 × 4 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a yellow, viscous liquid. The compounds were freeze-dried to obtain the final compound 29[N-(3-(5-fluoropyridine-3-yl)propyl)-5-(3-iodo-4-methoxyphenyl)-1H-1,2,3-triazole-4-carboxamide (0.045 g, 0.092 mmol, yield 15.8%)] as a pale beige solid. 1H-NMR(400MHz,DMSO-d6):15.56(br s,1H),8.61(s,1H),8.42-8.35(m,3H),7.98(t,J=6.80Hz,1H),7.67-7.64(m,1H),7.10(d, J=8.80Hz,1H),3.88(s,3H),3.28(t,J=6.40Hz,2H),2.71-2.68(m,2H),1.90-1.85(m,2H).

[0240] Example 29 - Preparation of Compound 30 Compound 30 was prepared according to the following scheme. [ka]

[0241] Intermediate 2: To a stirred solution of 4-bromo-1-methoxy-2-nitrobenzene 1 (5.5 g, 23.70 mmol, 1.0 eq) and bis(pinacolato)diborone (12.04 g, 47.4 mmol, 2.eq) in 1,4-dioxane (30.0 ml), potassium acetate (13.38 g, 136 mmol, 5.75 eq) was added under a nitrogen atmosphere. The reaction mixture was degassed under nitrogen for 10 minutes, and PdCl2 (dppf) (0.520 g, 0.711 mmol, 0.03 eq) was added. The mixture was then degassed again under nitrogen for 10 minutes. The reaction mixture was heated at 100°C overnight. The progress of the reaction was monitored by TLC (10% siRNA in petroleum ether, Rf value approximately 0.4). After the reaction was complete, the reaction mixture was filtered through Celite, the bed was washed with siRNA (1 x 10 mL), and the filtrate was concentrated to dryness under reduced pressure. Water (150 mL) was added to the residue and diluted with ethyl acetate (100 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 70 mL). The combined organic layers were washed with brine (1 x 150 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product as a black, viscous liquid. The obtained crude product was purified by column chromatography (Isolera, silica mesh size 230-400, flow rate: 35 mL / min, eluted with 12-14% ethyl acetate in petroleum ether) to obtain 2-(4-methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 2 (8.1 g, 23.06 mmol, yield 97%) as a pale yellow solid. 1 H-NMR (400MHz, DMSO-d6): δ8.03(d,J=1.60Hz,1H),7.90(dd,J=1.60,8.40Hz,1H),7.38(d,J=8.40Hz,1H),3.96(s,3H),1.30(s,12H).

[0242] Intermediate 4: A stirred solution of 2-(4-methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 2 (0.4 g, 1.433 mmol, 1.0 eq), ethyl 5-bromothiazole-4-carboxylate 3 (0.305 g, 1.290 mmol, 0.9 eq), and K2CO3 (0.396 g, 2.87 mmol, 2.0 eq) in a mixture of 1,4-dioxane (4.0 mL) and water (0.5 mL) was degassed under nitrogen for 10 minutes. Then, PdCl2 (dppf) (10.49 mg, 0.014 mmol, 0.01 eq) was added to the mixture and degassed under nitrogen for 3 hours under a nitrogen atmosphere. The progress of the reaction was monitored by LC-MS analysis, and after the reaction was complete, the reaction mixture was filtered through Celite and washed with ELISA (1 x 10 mL). The filtrate was concentrated to dryness under reduced pressure. Ice-cold water (15 mL) was added to the reaction mixture and diluted with ethyl acetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with brine (1 × 50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product as a black, viscous liquid. The obtained crude product was purified by column chromatography (Isolera, silica mesh size 230-400, flow rate 35 mL / min). The column was eluted with 40-43% ethyl acetate in petroleum ether to obtain ethyl 5-(4-methoxy-3-nitrophenyl)thiazole-4-carboxylate 4 (0.435 g, 1.344 mmol, yield 94%) as a pale yellow solid. 1 H-NMR(400MHz,DMSO-d6):δ9.16(s,1H),8.10(d,J=2.00Hz,1H),7.82(dd,J=2.40,8.80 Hz,1H),7.44(d,J=8.80Hz,1H),4.22-4.17(m,2H),3.99(s,3H),1.15(t,J=7.20Hz,3H).

[0243] Intermediate 5: To a stirred solution of ethyl 5-(4-methoxy-3-nitrophenyl)thiazole-4-carboxylate 4 (0.415 g, 1.346 mmol, 1.0 eq) in a mixture of EtOH (10.0 ml) and water (2.00 ml), iron (0.376 g, 6.73 mmol, 5.0 eq) and ammonium chloride (0.864 g, 16.15 mmol, 12.0 eq) were added under a nitrogen atmosphere at room temperature, and the solution was stirred at 80°C for 8 hours. The progress of the reaction was monitored by LC-MS analysis. After the reaction was complete, the reaction mixture was filtered through Celite, washed with EtOH (2 x 10 mL), and the filtrate was concentrated to dryness under reduced pressure. Water (25 mL) was added to the residue and diluted with DCM (50 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (2 x 20 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain crude ethyl 5-(3-amino-4-methoxyphenyl)thiazole-4-carboxylate 5 (0.260 g, 0.832 mmol, yield 61.8%) as a pale yellow, viscous oil. The obtained crude compound was used in the next step without further purification. 1 H-NMR(400MHz,DMSO-d6):δ9.02(s,1H),6.84(d,J=8.40Hz,1H),6.76(d,J=2.00Hz,1H), 6.68-6.65(m,1H),4.91(s,2H),4.23-4.18(m,2H),3.81(s,3H),1.18(t,J=6.80Hz,3H).

[0244] Intermediate 6: To a stirred solution of ethyl 5-(3-amino-4-methoxyphenyl)thiazole-4-carboxylate 5 (0.16 g, 0.575 mmol, 1.0 eq) in Conc.HCl (2.0 ml), a solution of sodium nitrite (0.048 g, 0.690 mmol, 1.2 eq) in H2O (1.0 mL) at 0°C was added. The resulting diazonium salt was stirred at 0°C for 1.5 hours. Next, a solution of potassium iodide (0.382 g, 2.299 mmol, 4.0 eq) in H2O (1.0 mL) was added dropwise over 10 minutes. The reaction mixture was heated to room temperature and stirred for 3 hours. The progress of the reaction was monitored by TLC (60% ethyl acetate in petroleum ether, Rf value approximately 0.6). After the reaction was complete, ice-cold water (5 mL) was added to the reaction mixture and diluted with ethyl acetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (1 × 5 mL). The combined organic layers were washed with saturated aqueous Na₂S₂O₃ solution (1 × 50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product as a yellow, viscous solid. The obtained crude product was purified by column chromatography (Isolera, silica mesh size 230-400, flow rate 35 mL / min). The column was eluted with 27-29% ethyl acetate in petroleum ether to obtain ethyl 5-(3-iodo-4-methoxyphenyl)thiazole-4-carboxylate 6 (0.142 g, 0.365 mmol, yield 63.5%) as a pale yellow solid. 1 H-NMR(400MHz,DMSO-d6):δ9.11(s,1H),7.92(d,J=2.00Hz,1H),7.53(dd,J=2.00,8.60 Hz,1H),7.07(d,J=8.40Hz,1H),4.22-4.17(m,2H),3.89(s,3H),1.17(t,J=6.80Hz,3H).

[0245] Intermediate 7: To a stirred solution of ethyl 5-(3-iodo-4-methoxyphenyl)thiazole-4-carboxylate 6 (0.32 g, 0.822 mmol, 1.0 eq) in a mixture of ethanol (6.0 ml), tetrahydrofuran (4.0 ml), and water (2.00 ml), lithium hydroxide (0.138 g, 3.29 mmol, 4.0 eq) was added at 0°C. The resulting solution was stirred at room temperature for 3 hours. The progress of the reaction was monitored by TLC & LC-MS analysis, and after the reaction was complete, the reaction mixture was concentrated to dryness under reduced pressure. The resulting residue was acidified to approximately pH 4 with 1.5 N HCl solution and diluted with ethyl acetate (20 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain crude 5-(3-iodo-4-methoxyphenyl)thiazole-4-carboxylic acid 7 (0.28 g, 0.722 mmol, yield 88%) as a pale yellow solid. The obtained crude compound was used directly in the next step without further purification. 1 H-NMR (400MHz, DMSO-d6): δ12.97(br s,1H),9.08(s,1H),7.92(d,J=2.00Hz,1H),7.53(dd,J=2.40,8.60Hz,1H),7.07(d,J=8.40Hz,1H),3.88(s,3H).

[0246] Compound 30: In a stirred solution of 5-(3-iodo-4-methoxyphenyl)thiazole-4-carboxylic acid 7 (0.28 g, 0.775 mmol, 1.0 eq) and 3-(5-fluoropyridine-3-yl)propan-1-amine and HCl 8 (intermediate 6 from Example 1, 0.222 g, 1.163 mmol, 1.5 eq) in DMF (6.0 ml), N,N-diisopropylethylamine (0.406 ml, 2.326 mmol, 3.0 eq) was added, followed by the addition of HATU (0.442 g, 1.163 mmol, 1.5 eq) under a nitrogen atmosphere at 0°C. The resulting solution was stirred at room temperature for 4 hours. After the reaction was complete (confirmed by TLC analysis, 70% ethyl acetate in petroleum ether, and an Rf value of approximately 0.5 for the product), ice-cold water (50 mL) was added to the reaction mixture, and it was diluted with ethyl acetate (20 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (1 × 60 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude compound was purified by reverse-phase column chromatography (Grace column: C18 40 μm, 120 g, flow rate: 20 mL / min, mobile phase 0.1% aqueous TFA / MeCN) to obtain the desired final compound N-(3-(5-fluoropyridine-3-yl)propyl)-5-(3-iodo-4-methoxyphenyl)thiazole-4-carboxamide 30 (0.180 g, 0.362 mmol, yield 46.7%) as a pale pink solid. 1 H-NMR(400MHz,DMSO-d6):δ9.10(s,1H),8.55(t,J=6.00Hz,1H),8.40(d,J=2.80Hz,1H),8.34(s,1H),7.97(d,J=2.00Hz,1H),7.65-7.63 (m,1H),(dd,J=3018.00,8.40Hz,1H),7.04(d,J=8.40Hz,1H),3.87(s,3H),3.26-3.21(m,2H),2.65(t,J=7.60Hz,2H),0.00-1.84(m,2H).

[0247] Example 30 - Preparation of Compound 31 Compound 31 was prepared according to the following scheme. [ka]

[0248] Intermediate 1a: To a stirred solution of furan-3-carboxylic acid 1 (2.0 g, 17.84 mmol, 1.0 eq) in THF (15 mL), n-BuLi (2.5 M solution in hexane, 14.28 mL, 35.7 mmol, 2.0 eq) was added at -78°C under a nitrogen atmosphere (formation of a white precipitate was observed during addition). The reaction mixture was stirred at -78°C for 2 hours, after which bromine (1.011 mL, 19.63 mmol, 1.1 eq) was added dropwise. The reaction mixture was stirred further at -78°C for 2 hours under a nitrogen atmosphere. After the reaction was complete (confirmed by LC-MS analysis), ice-cooled 2N HCl aqueous solution (15.0 mL) was added to the reaction mixture and diluted with ethyl acetate (20 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase column chromatography (Grace column: C18 40 μm, 120 g, flow rate: 20 mL / min, mobile phase: 0.1% aqueous HCO₂H / MeCN). The fractions containing the product were combined and concentrated under reduced pressure to obtain 2-bromofuran-3-carboxylic acid 1a (1.4 g, 7.29 mmol, yield 40.86%) as a pale yellow solid. 1 H-NMR (400MHz, DMSO-d6): δ13.04 (s, 1H), 7.89 (d, J = 2.00Hz, 1H), 6.82 (d, J = 2.40Hz, 1H).

[0249] Intermediate 1b: To a stirred solution of 2-bromofuran-3-carboxylic acid 1a (1.38 g, 7.23 mmol, 1.0 eq) in DMF (10 mL), potassium carbonate (3.00 g, 21.68 mmol, 3.0 eq) and methyl iodide (0.900 mL, 14.45 mmol, 2.0 eq) were added at room temperature under a nitrogen atmosphere, and the reaction mixture was stirred overnight. After the reaction was complete (confirmed by TLC analysis, 15% ethyl acetate in petroleum ether, Rf value approximately 0.7), ice-cold water (15 mL) was added to the reaction mixture and diluted with MTBE (10 mL). The organic layer was separated, and the aqueous layer was extracted with MTBE (2 × 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain crude methyl 2-bromofuran-3-carboxylate 1b (1.4 g, 6.82 mmol, 94% yield) as a brown solid. 1 H-NMR (400MHz, DMSO-d6): δ7.93 (d, J = 2.80 Hz, 1H), 6.88 (d, J = 2.80 Hz, 1H), 3.79 (s, 3H).

[0250] Intermediate 3: Methyl 2-bromofuran-3-carboxylate 1b (1.4 g, 6.83 mmol, 1.0 eq) and methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 2 (2.86 g, 10.24 mmol, 1.5 eq) were stirred in a mixture of dioxane (15 mL) and water (1 mL). Potassium carbonate (1.888 g, 13.66 mmol, 2.0 eq) was added under a nitrogen atmosphere. The reaction mixture was degassed under nitrogen for 10 minutes, and PdCl2 (dppf) (0.500 g, 0.683 mmol, 0.1 eq) was added. The mixture was then purged again under nitrogen for 10 minutes and stirred overnight at 80°C. After the reaction was complete (confirmed by TLC, 15% ethyl acetate in petroleum ether, Rf value approximately 0.7), the reaction mixture was diluted with ethyl acetate (20 mL), filtered through a Celite bed, washed with ethyl acetate (2 x 10 mL), and ice-cold water (20 mL) was added to the filtrate. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The obtained crude product was purified by column chromatography (Isolera, silica mesh size 230-400, flow rate 35 mL / min). The column was eluted with 10-15% ethyl acetate in petroleum ether to obtain methyl 2-(4-methoxy-3-nitrophenyl)furan-3-carboxylate 3 (1.4 g, 4.58 mmol, yield 67.1%) as a yellow solid. 1 H-NMR(400MHz,DMSO-d6):δ8.57(d,J=2.40Hz,1H),8.23-8.20(m,1H),7.90(d,J=2.00H z,1H),7.51(d,J=8.80Hz,1H),6.92(d,J=2.00Hz,1H),4.01(s,3H),3.82-3.76(m,3H).

[0251] Intermediate 4: To a stirred solution of methyl 2-(4-methoxy-3-nitrophenyl)furan-3-carboxylate 3 (1.4 g, 5.05 mmol, 1.0 eq) in a mixture of ethanol (15.0 mL) and water (7.50 mL), ammonium chloride (2.161 g, 40.4 mmol, 8.0 eq) and iron (1.410 g, 25.2 mmol, 5.0 eq) were added at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 85 °C for 5 hours. After the reaction was complete (confirmed by LC-MS analysis), the reaction mixture was filtered through Celite, and the filtrate was concentrated to dryness under reduced pressure. The resulting residue was diluted with 10% MeOH (20 mL) and water (20 mL) in DCM. The organic layer was separated, and the aqueous layer was extracted with 10% MeOH (2 × 20 mL) in DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain methyl 2-(3-amino-4-methoxyphenyl)furan-3-carboxylate 4 (1.13 g, 4.42 mmol, yield 88%) as a brown, viscous liquid. The crude product was used in the next step without further purification. 1 H-NMR(400MHz,DMSO-d6):δ7.74(d,J=2.80Hz,1H),7.23-7.19(m,2H),6.88(d, J=11.20Hz,1H),6.81(d,J=2.80Hz,1H),4.88(s,2H),3.82(s,3H),3.76(s,3H).

[0252] Intermediate 5: To a stirred solution of methyl 2-(3-amino-4-methoxyphenyl)furan-3-carboxylate 4 (0.830 g, 3.36 mmol, 1.0 eq) in Conc.HCl (3.5 mL), a solution of sodium nitrite (0.278 g, 4.03 mmol, 1.2 eq) in water (1.0 mL) was added at 0°C. The resulting diazonium salt was stirred at 0°C for 30 minutes. Then, a solution of potassium iodide (2.229 g, 13.43 mmol, 4.0 eq) in water (1.0 mL) was added at 0°C. The reaction mixture was heated to room temperature and stirred overnight. After the reaction was complete (confirmed by TLC analysis, 50% EtOAC in petroleum ether, Rf value approximately 0.5), the reaction mixture was basicized at 0°C with saturated sodium bicarbonate solution (20 mL) and diluted with DCM (20 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (2 × 20 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The obtained crude product was purified by column chromatography (Isolera, silica mesh size 230-400, flow rate: 50 mL / min, eluted with 30% ethyl acetate in petroleum ether) to obtain methyl 2-(3-iodo-4-methoxyphenyl)furan-3-carboxylate 5 (0.375 g, 0.946 mmol, yield 28.2%) as a yellow viscous liquid. 1 H-NMR (400MHz, DMSO-d6): δ8.42(d,J=2.00Hz,1H),7.97-7.94(m,1H),7.82(d,J=2. 00Hz,1H),7.12(d,J=8.80Hz,1H),6.87(d,J=2.00Hz,1H),3.90(s,3H),3.78(s,3H).

[0253] Intermediate 6: To a stirred solution of methyl 2-(3-iodo-4-methoxyphenyl)furan-3-carboxylate 5 (0.470 g, 1.312 mmol, 1.0 eq) in a mixture of methanol (20 mL), THF (13 mL), and water (7 mL), LiOH.H2O (0.220 g, 5.25 mmol, 4.0 eq) was added at 0°C and stirred overnight at room temperature. Further, 4 eq of LiOH.H2O (0.220 g, 5.25 mmol) were added, and the reaction mixture was heated at 45°C for 2 hours. After the reaction was complete (confirmed by TLC analysis, 50% ethyl acetate in petroleum ether, Rf value approximately 0.2), the reaction product was concentrated to dryness under reduced pressure. The resulting residue was acidified to approximately pH 2 with aqueous HCl (1.5 N, 10 mL) at 0°C and extracted with ethyl acetate (2 × 15 mL). The combined organic layers were washed with brine (1 x 30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain crude 2-(3-iodo-4-methoxyphenyl)furan-3-carboxylic acid 6 (0.370 g, 1.075 mmol, yield 82%) as a pale yellow, sticky solid. 1 H-NMR(400MHz,DMSO-d6):δ12.75(s,1H),8.40(d,J=2.00Hz,1H),8.00-7.91( m,1H),7.78-7.75(m,1H),7.13-7.02(m,1H),6.83-6.81(m,1H),3.90(s,3H).

[0254] Compound 31: In a stirred solution of 2-(3-iodo-4-methoxyphenyl)furan-3-carboxylic acid 6 (0.390 g, 1.133 mmol, 1.0 eq) and 3-(5-fluoropyridine-3-yl)propan-1-amine (intermediate 6 from Example 1, 0.262 g, 1.700 mmol, 1.5 eq) in DMF (5.0 mL), DIPEA (0.732 g, 5.67 mmol, 5.0 eq) was added at 0°C under a nitrogen atmosphere, followed by the addition of HATU (0.517 g, 1.360 mmol, 1.2 eq). The reaction mixture was stirred overnight at room temperature. After the reaction was complete (confirmed by LC-MS analysis), ice-cold water (20 mL) was added to the reaction mixture and diluted with ethyl acetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (column: XSELECT C18-250, 500 ul, mobile phase: A: 10 mm aqueous ammonium bicarbonate solution, B: MeCN, flow rate: 14 mL / min, retention time: 13.0 min) to obtain N-(3-(5-fluoropyridine-3-yl)propyl)-2-(3-iodo-4-methoxyphenyl)furan-3-carboxamide 31 (0.245 g, 0.508 mmol, yield 44.8%) as an off-white solid. 1 H-NMR(400MHz,DMSO-d6):δ8.41-8.36(m,3H),8.27(t,J=5.60Hz,1H),7.92-7.90(m,1H),7.75(d,J=2.00Hz,1H),7.66-7.63(m,1H) ),7.08(d,J=8.80Hz,1H),6.86(d,J=2.00Hz,1H),3.87(s,3H),3.26-3.22(m,2H),2.70(t,J=8.00Hz,2H),1.84(t,J=7.20Hz,2H).

[0255] Example 31 - Preparation of Compound 32 Compound 32 was prepared according to the following scheme. [ka]

[0256] Intermediate 1b: To a stirred solution of 3,4-dibromofuran 1 (2.0 g, 8.85 mmol, 1.0 eq) in tetrahydrofuran (10 mL), isopropyl magnesium chloride (2.0 M solution in THF, 4.87 ml, 9.74 mmol, 1.1 eq) was added dropwise over 30 minutes at 0°C. The reaction mixture was then heated to room temperature and stirred for 5 hours. After cooling the reaction mixture to 0°C, methyl chloroformate (0.823 mL, 10.63 mmol, 1.2 eq) in anhydrous tetrahydrofuran (10 mL) was added dropwise over 10 minutes. The reaction mixture was heated to room temperature and stirred overnight. After the reaction was complete, (TLC analysis, 10% siRNA in petroleum ether, R of the product) f (Confirmed by a value of approximately 0.3), saturated ammonium chloride aqueous solution (15 mL) was added to the reaction mixture and diluted with ethyl acetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (1 × 50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product as a brownish viscous liquid. The obtained crude product was purified by column chromatography (Isolera, silica mesh size 230-400, flow rate 35 mL / min, eluted with 4-5% ethyl acetate in petroleum ether) to obtain methyl 4-bromofuran-3-carboxylate 1b (1.1 g, 5.17 mmol, yield 58.4%) as a pale yellow liquid. 1 H-NMR (400MHz, DMSO-d6): δ8.49 (t, J = 1.20 Hz, 1H), 8.10 (t, J = 1.20 Hz, 1H), 3.79 (s, 3H), 3.67 (s, 1H).

[0257] Intermediate 3: Methyl 4-bromofuran-3-carboxylate 1b (0.900 g, 4.39 mmol, 1.0 eq) and 2-(4-methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 2 (2.451 g, 8.78 mmol, 2.0 eq) in a stirred solution of water (2 mL) and 1,4-dioxane (40 mL) were mixed with K2CO3 (1.213 g, 8.78 mmol, 2.0 eq) under a nitrogen atmosphere. The reaction mixture was degassed under nitrogen for 10 minutes, and then PdCl2 (dppf) (0.321 g, 0.439 mmol, 0.1 eq) was added. The mixture was then purged again under nitrogen for 10 minutes. The reaction mixture was heated overnight to 80°C. After the reaction was complete, (TLC analysis, 10% siRNA in petroleum ether, R of the product) f (Confirmed by a value of approximately 0.2), the reaction mixture was filtered through Celite and washed with ethyl acetate (2 x 30 mL). Ice-cold water (45 mL) was added to the filtrate to separate the organic layer, and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The obtained crude compound was purified by column chromatography (Isolera, silica mesh size 230-400, flow rate: 20 mL / min, eluted with 9% ethyl acetate in petroleum ether) to obtain the desired product, methyl 4-(4-methoxy-3-nitrophenyl)furan-3-carboxylate 3 (0.760 g, 1.875 mmol, yield 42.7%), as a yellow solid. 1 H-NMR(400MHz,DMSO-d6):δ8.49(d,J=1.60Hz,1H),8.10(d,J=1.60Hz,1H),8.03(d,J=2.40Hz ,1H),7.80-7.77(m,1H),7.41-7.38(m,1H),3.96(s,3H),3.78(s,1H),3.73(d,J=9.20Hz,2H).

[0258] Intermediate 4: To a stirred solution of methyl 4-(4-methoxy-3-nitrophenyl)furan-3-carboxylate 3 (0.700 g, 2.52 mmol, 1.0 eq) in methanol (40 mL) and water (5 mL), ammonium chloride (1.080 g, 20.20 mmol, 8.0 eq) and iron (0.705 g, 12.62 mmol, 5.0 eq) were added at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 85 °C for 4 hours. After the reaction was complete, (TLC analysis, 50% siRNA in petroleum ether, R of the product) f The reaction mixture was filtered through Celite (value approximately 0.4, confirmed by LC-MS analysis), and the filtrate was concentrated. The residue was diluted with 10% methanol in DCM (20 mL), and water (25 mL) was added to the organic layer. The organic layer was separated, and the aqueous layer was extracted with 10% methanol in DCM (2 × 20 mL). The combined organic layers were washed with brine (1 × 50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product methyl 4-(3-amino-4-methoxyphenyl)furan-3-carboxylate 4 (0.550 g, 1.907 mmol, yield 76%) as a brownish viscous liquid. The crude compound was used in the next step without further purification. 1 H-NMR(400MHz,DMSO-d6):δ8.39-8.36(m,1H),7.85-7.80(m,1H),6.79(d,J=8.40Hz,1H),6.72-6.70 (m,1H),6.63-6.60(m,1H),4.69(d,J=19.20Hz,2H),3.76(t,J=4.00Hz,2H),3.72(d,J=1.60Hz,3H).

[0259] Intermediate 5: To a stirred solution of methyl 4-(3-amino-4-methoxyphenyl)furan-3-carboxylate 4 (0.500 g, 2.022 mmol, 1.0 eq) in Conc.HCl (4.00 ml), a solution of sodium nitrite (0.167 g, 2.427 mmol, 1.2 eq) in water (2.00 mL) was added at 0°C. The resulting diazonium salt was stirred at 0°C for 1.5 hours. Next, a solution of potassium iodide (1.343 g, 8.09 mmol, 4.0 eq) in water (2.00 mL) was added dropwise over 10 minutes. The reaction mixture was heated to room temperature and stirred for 4 hours. After the reaction was complete, (TLC analysis, 50% siRNA in petroleum ether, R of the product) f (Confirmed by a value of approximately 0.6), the reaction mixture was basicized to pH=12 with saturated sodium bicarbonate solution (10 mL) and diluted with DCM (20 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (2 × 10 mL). The combined organic layers were washed with saturated Na₂S₂O₃ aqueous solution (1 × 30 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product as a brown viscous liquid. The crude product was purified by column chromatography (Isolera, silica mesh size 230-400, flow rate 20 mL / min, eluted with 28% ethyl acetate in petroleum ether) to obtain the desired product, methyl 4-(3-iodo-4-methoxyphenyl)furan-3-carboxylate 5 (0.370 g, 1.019 mmol, yield 50.4%), as a yellow viscous solid. 1 H-NMR(400MHz,DMSO-d6):δ8.44(d,J=3.20Hz,1H),8.00(d,J=3.60Hz,1H),7.90(d,J=5.20H) z,1H),7.50-7.47(m,1H),7.05-7.02(m,1H),3.86(t,J=2.00Hz,4H),3.73(t,J=1.60Hz,4H).

[0260] Intermediate 6: To a stirred solution of methyl 4-(3-iodo-4-methoxyphenyl)furan-3-carboxylate 5 (0.370 g, 1.033 mmol, 1.0 eq) in a mixture of methanol (20 mL), THF (13.0 mL), and water (6.5 mL), LiOH.H2O (0.173 g, 4.13 mmol, 4.0 eq) was added at 0°C and stirred overnight at room temperature. The reaction mixture was then heated at 45°C for 1 hour. After the reaction was complete, (TLC analysis showed 50% siRNA in petroleum ether, and the R of the product) f (Confirmed by a value of approximately 0.0), the reaction mixture was concentrated to dryness under reduced pressure. The resulting residue was acidified to approximately pH 2 with 10 mL of 1.5 N HCl aqueous solution at 0°C and extracted with ethyl acetate (2 × 15 mL). The combined organic layers were washed with brine (1 × 30 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product 4-(3-iodo-4-methoxyphenyl)furan-3-carboxylic acid 6 (0.330 g, 0.945 mmol, yield 92%) as a pale yellow solid. The crude compound was used directly in the next step without further purification. 1 H-NMR(400MHz,DMSO-d6):δ12.61(s,1H),8.35(d,J=2.40Hz,1H),7.95(d,J=2.00Hz, 1H),7.89(d,J=3.20Hz,1H),7.52-7.48(m,1H),7.03(d,J=11.60Hz,1H),3.86(s,3H).

[0261] Compound 32: In a stirred solution of 4-(3-iodo-4-methoxyphenyl)furan-3-carboxylic acid 6 (0.330 g, 0.959 mmol, 1.0 eq), 3-(5-fluoropyridine-3-yl)propan-1-amine, and HCl 7 (intermediate 6 from Example 1, 0.274 g, 1.439 mmol, 1.5 eq) in DMF (6.0 ml), N,N-diisopropylethylamine (0.837 ml, 4.80 mmol, 5.0 eq) was added at 0°C under a nitrogen atmosphere, followed by the addition of HATU (0.547 g, 1.439 mmol, 1.5 eq). The resulting solution was stirred overnight at room temperature. After the reaction was complete, (TLC analysis showed 70% siRNA in petroleum ether, and the R of the product was observed). f(Confirmed by a value of approximately 0.2), ice-cold water (50 mL) was added to the reaction mixture and diluted with ethyl acetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (1 × 20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product as a pale brown viscous liquid. The obtained crude compound was purified by preparative HPLC (column: X-Bridge C8 (50 x 4.6) mm, 3.5 μm; mobile phase: A: 10 mM ammonium bicarbonate aqueous solution, B: acetonitrile; flow rate: 1.0 mL / min; retention time: 12.0 min) to obtain N-(3-(5-fluoropyridine-3-yl)propyl)-4-(3-iodo-4-methoxyphenyl)furan-3-carboxamide 32 (0.22053 g, 0.458 mmol, yield 47.75%) as a light brown, viscous solid. 1 H-NMR(400MHz,DMSO-d6):δ8.41(d,J=2.80Hz,1H),8.35(s,1H),8.27(t,J=5.60Hz,1H),8.06(d,J=1.60Hz,1H),7.97(d,J=1.60Hz,1H),7.91(d,J=2 .00Hz,1H),7.64-7.61(m,1H),7.51-7.48(m,1H),7.01(d,J=8.40Hz,1H), 3.83(s,3H),3.22-3.17(m,2H),2.68(t,J=7.60Hz,2H),1.96-1.75(m,2H).

[0262] Example 32 - Preparation of Compound 33 Compound 33 was prepared according to the following scheme. [ka]

[0263] Intermediate 1a: To a stirred solution of 3-bromofuran-2-carboxylic acid 1 (0.500 g, 2.62 mmol, 1.0 eq) in DMF (10 mL), K2CO3 (0.543 g, 3.93 mmol, 1.5 eq) and methyl iodide (0.327 ml, 5.24 mmol, 2.0 eq) were added at room temperature. The reaction mixture was stirred overnight under a nitrogen atmosphere. After the reaction was complete, (TLC analysis, 50% siRNA in petroleum ether, R of the product) f (Confirmed by a value of approximately 0.6), ice-cold water (15 mL) was added to the reaction mixture and diluted with ethyl acetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product methyl 3-bromofuran-2-carboxylate 1a (0.520 g, 2.54 mmol, yield 97%) as a pale yellow liquid. The crude compound was used directly in the next step without further purification. 1 H-NMR (400MHz, DMSO-d6): δ8.03 (d, J = 2.00 Hz, 1H), 6.96 (d, J = 2.00 Hz, 1H), 3.84-3.83 (m, 3H).

[0264] Intermediate 3: To a stirred solution of methyl 3-bromofuran-2-carboxylate 1a (1.77 g, 8.63 mmol, 1.0 eq) and 2-(4-methoxy-3-nitrophenyl)-4,4,5-trimethyl-1,3,2-dioxaborolane 2 (3.43 g, 12.95 mmol, 1.5 eq) in 1,4-dioxane (50 mL) and water (4.0 mL), potassium carbonate (1.790 g, 12.95 mmol, 1.5 eq) was added under a nitrogen atmosphere. The reaction mixture was degassed under nitrogen for 10 minutes, and PdCl2 (dppf) (0.632 g, 0.863 mmol, 0.1 eq) was added. The mixture was then purged again under nitrogen for 10 minutes and heated overnight to 80°C. After the reaction was complete (TLC analysis, 50% siRNA in petroleum ether, R of the product) f(Confirmed by a value of approximately 0.5), the reaction mixture was filtered through a Celite bed, and the filtrate was extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine (1 × 10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product as a brownish viscous liquid. The crude product was purified by column chromatography (Isolera, silica mesh size 230-400, flow rate: 20 mL / min, eluted with 45% ethyl acetate in petroleum ether) to obtain the desired product, methyl 3-(4-methoxy-3-nitrophenyl)furan-2-carboxylate 3 (4.2 g, 14.22 mmol, yield 165%), as a yellow solid. 1 H-NMR(400MHz,DMSO-d6):δ8.24(d,J=2.80Hz,1H),8.03(d,J=2.40Hz,1H),7.98-7.93(m,1H),7.43(d,J=12.00Hz,1 H),7.02(d,J=2.40Hz,1H),4.07-3.96(m,3H),3.93(s,1H),3.78(t,J=10.80Hz,3H),1.20-1.16(m,1H),1.08(s,3H).

[0265] Intermediate 4: To a stirred solution of methyl 3-(4-methoxy-3-nitrophenyl)furan-2-carboxylate 3 (2.0 g, 7.21 mmol, 1.0 eq) in methanol (50 mL) and water (5 mL), ammonium chloride (4.63 g, 87 mmol, 12.0 eq) and iron (2.014 g, 36.1 mmol, 5.0 eq) were added at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 85 °C for 2 hours. After the reaction was complete, (TLC analysis, 50% siRNA in petroleum ether, R of the product) f(Confirmed by a value of approximately 0.4), the reaction mixture was filtered through Celite and the filtrate was concentrated. Water (20 mL) was added to the resulting residue and extracted with 10% methanol in DCM (2 × 20 mL). The combined organic layers were washed with brine (1 × 20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product as a brown liquid. The crude product was purified by column chromatography (Isolera, silica mesh size 230-400, flow rate: 35 mL / min, eluted with 30-40% ethyl acetate in petroleum ether) to obtain methyl 3-(3-amino-4-methoxyphenyl)furan-2-carboxylate 4 (1.40 g, 5.42 mmol, yield 75%) as a brown liquid. 1 H-NMR(400MHz,DMSO-d6):δ7.94-7.92(m,1H),6.92(t,J=1.20Hz,1H),6.88-6.82(m,2H),6.76(d,J=2.0 0Hz,1H),4.76(s,2H),4.06-4.01(m,1H),3.94(s,3H),3.80(s,1H),3.76(t,J=3.20Hz,3H),1.08(s,2H).

[0266] Intermediate 5: To a stirred solution of methyl 3-(3-amino-4-methoxyphenyl)furan-2-carboxylate 4 (1.1 g, 4.45 mmol, 1.0 eq) in conc.HCl (4.0 mL), a solution of sodium nitrite (0.368 g, 5.34 mmol, 1.2 eq) in water (2.0 mL) was added at 0°C. The resulting diazonium salt was stirred at 0°C for 1.5 hours. Next, a solution of potassium iodide (2.95 g, 17.80 mmol, 4.0 eq) in water (2.0 mL) was added dropwise over 10 minutes. The reaction mixture was heated to room temperature and stirred for 4 hours. After the reaction was complete, (TLC analysis, 50% HCl in petroleum ether, R of the product) f(Confirmed by a value of approximately 0.6), the reaction mixture was basicized to pH=12 with saturated NaHCO3 solution (10 mL) and diluted with DCM (20 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (2 × 10 mL). The combined organic layers were washed with saturated Na2S2O3 aqueous solution (1 × 30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product as a brown viscous liquid. The obtained crude product was purified by column chromatography (Isolera, silica mesh size 230-400, flow rate 20 mL / min). The column was eluted with 28% ethyl acetate in petroleum ether to obtain the desired product, methyl 3-(3-iodo-4-methoxyphenyl)furan-2-carboxylate 5 (1.15 g, 3.03 mmol, yield 68.2%), as a yellow viscous liquid. 1 H-NMR(400MHz,DMSO-d6):δ8.11(d,J=2.00Hz,1H),7.98(d,J=1.60Hz,1H),7.68-7. 65(m,1H),7.06(d,J=8.80Hz,1H),6.94(d,J=1.60Hz,1H),3.88(s,3H),3.78(s,3H).

[0267] Intermediate 6: To a stirred solution of methyl 3-(3-iodo-4-methoxyphenyl)furan-2-carboxylate 5 (1.1 g, 3.07 mmol, 1.0 eq) in a mixture of methanol (20 mL), THF (13.0 mL), and water (6.5 mL), LiOH.H2O (0.516 g, 12.29 mmol, 4.0 eq) was added at 0°C and the mixture was stirred overnight at room temperature. After the reaction was complete (TLC analysis, 50% siRNA in petroleum ether, R of the product) f The reaction mixture was concentrated under reduced pressure (value approximately 0.1, confirmed by LC-MS analysis). The crude product was acidified with 10 mL of 1.5 N HCl aqueous solution and extracted with ethyl acetate (2 x 15 mL). The combined organic layers were washed with brine (1 x 20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3-(3-iodo-4-methoxyphenyl)furan-2-carboxylic acid 6 (1.01 g, 2.83 mmol, yield 92%) as an off-white solid. The obtained crude compound was used directly in the next step without further purification. 1H-NMR(400MHz,DMSO-d6):δ13.02(s,1H),8.07(d,J=3.20Hz,1H),7.92(d,J=2.00Hz, 1H),7.68-7.65(m,1H),7.05(d,J=11.60Hz,1H),6.88(d,J=2.00Hz,1H),3.87(s,3H).

[0268] Compound 33: In a stirred solution of 3-(3-iodo-4-methoxyphenyl)furan-2-carboxylic acid 6 (0.500 g, 1.453 mmol, 1.0 eq), 3-(5-fluoropyridine-3-yl)propan-1-amine, and HCl 7 (0.416 g, 2.180 mmol, 1.5 eq) in DMF (6.0 mL), N,N-diisopropylethylamine (1.269 ml, 7.27 mmol, 5.0 eq) was added at 0°C under a nitrogen atmosphere, followed by the addition of HATU (0.829 g, 2.180 mmol, 1.5 eq). The resulting solution was stirred overnight at room temperature. After the reaction was complete, (TLC analysis, 50% siRNA in petroleum ether, R of the product) f (Confirmed by a value of approximately 0.4), ice-cold water (50 mL) was added to the reaction mixture and diluted with ethyl acetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (1 × 20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The obtained crude product was purified by preparative HPLC (column: X-Bridge C8 (50 × 4.6) mm, 3.5 μm, mobile phase: A: 10 mM ammonium bicarbonate aqueous solution, B: acetonitrile, flow rate: 1.0 mL / min, retention time: 12.0 min) to obtain [N-(3-(5-fluoropyridine-3-yl)propyl)-3-(3-iodo-4-methoxyphenyl)furan-2-carboxamide 33 (0.192 g, 0.399 mmol, yield 29.3%)] as a pale yellow viscous solid. 1H-NMR(400MHz,DMSO-d6):δ8.41-8.38(m,2H),8.35(t,J=2.00Hz,1H),8.27(d,J=2.40Hz,1H),7.85(d,J=1.60Hz,1H),7.78-7.75(m,1H),7. 66-7.63(m,1H),7.02(d,J=8.80Hz,1H),6.91(d,J=2.00Hz,1H),3.86(s,3H),3.27-3.22(m,2H),2.68(t,J=8.00Hz,2H),1.87-1.80(m,2H).

[0269] Example 33 - Preparation of Compound 34 Compound 34 was prepared according to the following scheme. [ka]

[0270] Intermediate 3: A stirred solution of ethyl 2-iodobenzoate 1 (1.0 g, 3.62 mmol, 1.0 eq), 2-(4-methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 2 (1.011 g, 3.62 mmol, 1.0 eq), and K2CO3 (1.001 g, 7.24 mmol, 2.0 eq) in a mixture of 1,4-dioxane (10.0 mL) and water (0.5 mL) was degassed, purged with nitrogen for 10 minutes, and then PdCl2 (dppf) (0.027 g, 0.036 mmol, 0.01 eq) was added to the mixture, degassed, and purged with nitrogen for 10 minutes. The resulting reaction mixture was stirred overnight at 80°C under a nitrogen atmosphere. After the reaction was complete, (TLC analysis, 10% siRNA in petroleum ether, R of the product) f(Confirmed by a value of approximately 0.1), the reaction mixture was filtered through Celite and washed with ethyl acetate (1 × 10 mL). The filtrate was concentrated under reduced pressure to obtain the crude product as a black, viscous liquid. The obtained crude product was purified by column chromatography (Isolera, silica mesh size 230-400, flow rate: 35 mL / min, eluted with 16% ethyl acetate in petroleum ether) to obtain ethyl 4'-methoxy-3'-nitro-[1,1'-biphenyl]-2-carboxylate 3 (0.85 g, 2.81 mmol, yield 78%) as a pale yellow solid. 1 H-NMR(400MHz,DMSO-d6):δ7.83-7.81(m,1H),7.79(d,J=2.00Hz,1H),7.68-7.64(m,1H),7.61-7.58(m,1H),7.56 -7.52(m,1H),7.48-7.46(m,1H),7.42(d,J=8.80Hz,1H),4.13-4.08(m,2H),3.98(s,3H),1.05(t,J=7.20Hz,3H).

[0271] Intermediate 4: To a stirred solution of ethyl 4'-methoxy-3'-nitro-[1,1'-biphenyl]-2-carboxylate 3 (0.85 g, 2.82 mmol, 1.0 eq) in a mixture of ethanol (15.0 mL) and water (3.00 mL), iron (0.788 g, 14.11 mmol, 5.0 eq) and ammonium chloride (1.811 g, 33.9 mmol, 12.0 eq) were added at room temperature under a nitrogen atmosphere, and the solution was stirred at 80°C for 8 hours. After the reaction was complete (TLC analysis, 80% RINKAN in petroleum ether, R of the product) f(Confirmed by a value of approximately 0.5), the reaction mixture was filtered through Celite, washed with EtOH (2 × 10 mL), and the filtrate was concentrated to dryness under reduced pressure. Then, saturated NaHCO3 solution (45 mL) was added to the reaction mixture and diluted with DCM (50 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine (1 × 50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude compound ethyl 3'-amino-4'-methoxy-[1,1'-biphenyl]-2-carboxylate 4 (0.700 g, 2.58 mmol, yield 91%) as a pale yellow solid. The obtained crude compound was used directly in the next step without further purification. 1 H-NMR(400MHz,DMSO-d6):δ7.61-7.54(m,1H),7.52(d,J=1.20Hz,1H),7.42-7.35(m,2H),6.82(d,J=8.40Hz,1H) ,6.59(d,J=2.00Hz,1H),6.45-6.43(m,1H),4.79(s,2H),4.10-4.03(m,2H),3.79(s,3H),1.02(t,J=7.20Hz,3H).

[0272] Intermediate 5: To a stirred solution of ethyl 3'-amino-4'-methoxy-[1,1'-biphenyl]-2-carboxylate 4 (0.4 g, 1.474 mmol, 1.0 eq) in HCl (5.0 mL), a solution of sodium nitrite (0.122 g, 1.769 mmol, 1.2 eq) in water (2.00 mL) was added at 0°C. The resulting diazonium salt was stirred at 0°C for 1.5 hours. Then, a solution of potassium iodide (0.979 g, 5.90 mmol, 4.0 eq) in water (2.00 mL) was added dropwise over 10 minutes at 0°C. The reaction mixture was heated to room temperature and stirred for 3 hours. After the reaction was complete, (TLC analysis, 0% HCl in petroleum ether, R of the product) fA value of approximately 0.3 (confirmed by LC-MS analysis) was added to the reaction mixture with ice-cold water (5 mL) and diluted with ethyl acetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (1 × 5 mL). The combined organic layers were washed with saturated Na₂S₂O₃ aqueous solution (1 × 50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product as a yellow, viscous solid. The obtained crude product was purified by column chromatography (Isolera, silica mesh size 230-400, flow rate 35 mL / min). The column was eluted with 70-90% ethyl acetate in petroleum ether to obtain ethyl 3'-iodo-4'-methoxy-[1,1'-biphenyl]-2-carboxylate 5 (0.550 g, 1.425 mmol, yield 97%) as a pale yellow, viscous solid. 1 H-NMR(400MHz,DMSO-d6):δ7.73-7.71(m,1H),7.64(d,J=2.00Hz,1H),7.61-7.58(m,1H),7.50-7.46(m,1H),7.43 -7.41(m,1H),7.33-7.30(m,1H),7.07(d,J=8.40Hz,1H),4.12-4.07(m,2H),3.87(s,3H),1.04(t,J=7.20Hz,3H).

[0273] Intermediate 6: To a stirred solution of ethyl 3'-iodo-4'-methoxy-[1,1'-biphenyl]-2-carboxylate 5 (0.550 g, 1.439 mmol, 1.0 eq) in a mixture of ethanol (12 mL), THF (8.00 mL), and water (4.00 mL), LiOH.H2O (0.242 g, 5.76 mmol, 4.0 eq) was added at 0°C and the mixture was stirred overnight at room temperature. LC-MS analysis indicated the presence of unreacted starting material, so 2 eqs of LiOH.H2O were added and the reaction was continued by heating at 50°C. After the reaction was complete (confirmed by LC-MS analysis), the reactants were concentrated under reduced pressure. The resulting crude product was acidified with 1.5 N aqueous HCl (10 mL), extracted with ethyl acetate (2 × 15 mL), and washed with brine (1 × 50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 3'-iodo-4'-methoxy-[1,1'-biphenyl]-2-carboxylic acid 6 (0.436 g, 1,200 mmol, yield 83%) as a pale yellow solid. The crude compound was used in the next step without further purification. 1 H-NMR(400MHz,DMSO-d6):δ12.84(s,1H),7.73-7.71(m,2H),7.71-7.58(m, 1H), 7.56-7.54(m, 1H), 7.46-7.36(m, 2H), 7.06-7.04(m, 1H), 3.87(s, 3H).

[0274] Compound 34: In a stirred solution of 3'-iodo-4'-methoxy-[1,1'-biphenyl]-2-carboxylic acid 6 (0.400 g, 1.129 mmol, 1.0 eq), 3-(5-fluoropyridine-3-yl)propan-1-amine, and HCl 7 (intermediate 6 from Example 1, 0.258 g, 1.355 mmol, 1.2 eq) in DMF (6.0 mL), N,N-diisopropylethylamine (0.592 mL, 3.39 mmol, 3.0 eq) was added at 0°C under a nitrogen atmosphere, followed by the addition of HATU (0.644 g, 1.694 mmol, 1.5 eq). The resulting solution was stirred overnight at room temperature. After the reaction was complete (confirmed by TLC analysis and 100% siRNA), ice-cold water (50 mL) was added to the reaction mixture, and it was diluted with ethyl acetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (1 × 20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude compound as a light brown viscous liquid. The obtained crude product was purified by preparative HPLC (column: X-Bridge C8 (50 × 4.6) mm, 3.5 μm, mobile phase: A: 10 mM ammonium bicarbonate aqueous solution, B: acetonitrile, flow rate: 1.0 mL / min, retention time: 12.0 min) to obtain N-(3-(5-fluoropyridine-3-yl)propyl)-3'-iodo-4'-methoxy-[1,1'-biphenyl]-2-carboxamide 34 (0.167 g, 0.340 mmol, yield 30.9%) as an off-white solid. 1 H-NMR(400MHz,DMSO-d6):δ8.40(d,J=2.80Hz,1H),8.25-8.21(m,2H),7.77(d,J=2.00Hz,1H),7.46-7.49(m,2H),7. 41-7.37(m,4H),7.02(d,J=8.80Hz,1H),(s,3H),3.10(q,J=6.40Hz,2H),2.42(t,J=8.00Hz,2H),1.67-1.60(m,2H).

[0275] Example 34 - Preparation of Compound 35 Compound 35 was prepared according to the following scheme. [ka]

[0276] Intermediate 1a: 2-bromonicotinic acid 1 (2 g, 9.90 mmol, 1.0 eq) was stirred in DMF (20.0 mL) and potassium carbonate (1.505 g, 10.89 mmol, 1.1 eq) and methyl iodide (1.238 mL, 19.80 mmol, 2.0 eq) were added at room temperature. The reaction mixture was stirred overnight at room temperature. After the reaction was complete (confirmed by TLC analysis, 50% ethyl acetate in petroleum ether, Rf value approximately 0.8), ice-cold water (15 mL) was added to the reaction mixture and diluted with ethyl acetate (20 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (2 × 25 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain crude methyl 2-bromonicotinate 1a (2.0 g, 7.47 mmol, yield 75%) as a pale yellow liquid. 1 H-NMR (400MHz, DMSO-d6): δ8.57-8.55 (m, 1H), 8.19-8.17 (m, 1H), 7.61-7.58 (m, 1H), 3.89 (s, 3H).

[0277] Intermediate 3: Methyl 2-bromonicotinate 1a (2.330 g, 10.79 mmol, 1.0 eq) and 2-(4-methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 2 (4.52 g, 16.18 mmol, 1.5 eq) were stirred in a mixture of dioxane (40.0 mL) and water (2.0 mL), to which potassium carbonate (2.98 g, 21.57 mmol, 2.0 eq) was added. The reaction mixture was degassed under nitrogen for 10 minutes, and PdCl2 (dppf) (0.789 g, 1.079 mmol, 0.1 eq) was added. The mixture was then purged again under nitrogen for 10 minutes, and the reaction mixture was heated overnight to 80°C. After the reaction was complete (confirmed by LC-MS analysis), ice-cold water (40 mL) was added to the reaction mixture and diluted with ethyl acetate (30 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (Isolera, silica mesh size 230-400, flow rate: 40 mL / min, eluted with 33% ethyl acetate in petroleum ether) to obtain methyl 2-(4-methoxy-3-nitrophenyl)nicotinic acid 3 (2.350 g, 8.13 mmol, yield 75%) as an off-white solid. 1 H-NMR(400MHz,DMSO-d6): δ8.84-8.82(m,1H),8.23-8.21(m,1H),8.06(d,J=2.00Hz,1H),7.82-7.79( m,1H),7.58-7.55(m,1H),7.45(d,J=8.80Hz,1H),4.00(s,3H),3.74(s,3H).

[0278] Intermediate 4: To a stirred solution of methyl 2-(4-methoxy-3-nitrophenyl)nicotinic acid 3 (1.15 g, 3.99 mmol, 1.0 eq) in a mixture of EtOH (40 mL) and water (20 mL), ammonium chloride (1.707 g, 31.9 mmol, 8.0 eq) and iron (1.114 g, 19.95 mmol, 5.0 eq) were added at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 85 °C for 3 hours. After the reaction was complete (confirmed by LC-MS analysis), the reaction mixture was filtered through Celite, and the filtrate was concentrated to dryness under reduced pressure. The residue was diluted with 10% MeOH (20 mL) and water (20 mL) in DCM. The organic layer was separated, and the aqueous layer was extracted with 10% MeOH (2 × 30 mL) in DCM. The combined organic layers were washed with brine (2 x 20 mL) and NaHCO3 (2 x 20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain crude methyl 2-(3-amino-4-methoxyphenyl)nicotinic acid 4 (1.22 g, 4.42 mmol, yield 111%) as a brown solid. 1 H-NMR(400MHz,DMSO-d6):δ8.72-8.71(m,1H),8.00-7.98(m,1H),7.41-7.38(m,1H),6.92(d,J= 2.40Hz, 1H), 6.85 (d, J=8.00Hz, 1H), 6.69-6.66 (m, 1H), 4.85 (s, 2H), 3.81 (s, 3H), 3.70 (s, 3H).

[0279] Intermediate 5: To a stirred solution of methyl 2-(3-amino-4-methoxyphenyl)nicotinic acid 4 (1.22 g, 4.72 mmol, 1.0 eq) in Conc.HCl (4.0 mL), a solution of sodium nitrite (0.391 g, 5.67 mmol, 1.2 eq) in water (2.0 mL) was added at 0°C. The resulting diazonium salt was stirred at 0°C for 1.5 hours. Then, a solution of potassium iodide (3.14 g, 18.89 mmol, 4.0 eq) in water (2 mL) was added dropwise at 0°C. The reaction mixture was heated to room temperature and stirred for 4 hours. After the reaction was complete (confirmed by TLC analysis, 50% EtOAC in petroleum ether, Rf value approximately 0.6), the reaction mixture was basicized with saturated sodium bicarbonate solution (30 mL) and diluted with DCM (20 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (2 × 20 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (Isolera, silica mesh size 230-400, flow rate: 40 mL / min, eluted with 35% ethyl acetate in petroleum ether) to obtain methyl 2-(3-iodo-4-methoxyphenyl)nicotinic acid 5 (0.610 g, 1.289 mmol, yield 27.3%) as a brownish viscous liquid. 1 H-NMR (400MHz, DMSO-d6): δ8.79-8.76(m,1H),8.13-8.07(m,1H),7.94(d,J=2. 00Hz,1H),7.53-7.44(m,2H),7.09(d,J=8.80Hz,1H),3.90(s,3H),3.72(s,3H).

[0280] Intermediate 6: To a stirred solution of methyl 2-(3-iodo-4-methoxyphenyl)nicotinic acid 5 (0.610 g, 1.652 mmol, 1.0 eq) in a mixture of MeOH (8.0 mL), THF (5.33 mL), and water (2.67 mL), LiOH.H2O (0.158 g, 6.61 mmol, 4.0 eq) was added at 0°C and the mixture was stirred overnight at room temperature. After the reaction was complete (confirmed by LC-MS analysis), the reaction mixture was concentrated under reduced pressure. The resulting crude product was acidified with HCl (4.0 M solution in ethyl acetate, 3.0 mL) and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase column chromatography (Grace column: C18 40 μm, 870 g, flow rate: 20 mL / min, mobile phase: water / 0.1% TFA in MeCN) to obtain 2-(3-iodo-4-methoxyphenyl)nicotinic acid 6 (0.560 g, 1.542 mmol, yield 93.3%) as a light brown solid. 1 H-NMR(400MHz,DMSO-d6):δ8.74-8.72(m,1H),8.11-8.07(m,1H),7.96(d,J=3.2 0Hz, 1H), 7.58-7.51 (m, 1H), 7.48-7.44 (m, 1H), 7.10-7.00 (m, 1H), 3.89 (s, 3H).

[0281] Compound 35: In a stirred solution of 2-(3-iodo-4-methoxyphenyl)nicotinic acid 6 (0.460 g, 1.295 mmol, 1.0 eq) and 3-(5-fluoropyridine-3-yl)propan-1-amine 7 (intermediate 6 from Example 1, 0.300 g, 1.943 mmol, 1.5 eq) in DMF (10.0 mL), DIPEA (0.837 g, 6.48 mmol, 5.0 eq) was added at 0°C under a nitrogen atmosphere, followed by the addition of HATU (0.591 g, 1.554 mmol, 1.2 eq). The reaction mixture was stirred overnight at room temperature. After the reaction was complete (confirmed by LC-MS analysis), the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was diluted with ethyl acetate (20 mL) by adding ice-cold water (20 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (column: XSELECT C18-250, 500 μl, mobile phase: A: 10 mm aqueous ammonium bicarbonate solution, B: MeCN, flow rate: 14 mL / min, retention time: 13.0 min) to obtain N-(3-(5-fluoropyridine-3-yl)propyl)-2-(3-iodo-4-methoxyphenyl)nicotinamide 35 (0.174 g, 0.353 mmol, 27.25%) as an off-white solid. 1 H-NMR(400MHz,DMSO-d6):δ8.69-8.68(m,1H),8.46(t,J=5.20Hz,1H),8.41( d,J=2.40Hz,1H),8.27(s,1H),8.06(d,J=2.00Hz,1H),7.82-7.80(m,1H),7. 69-7.67(m,1H),7.51-7.52(m,1H),7.43-7.40(m,1H),7.05(d,J=8.80Hz,1H ),3.82(s,3H),3.33-3.14(m,2H),2.52-2.47(m,2H),1.72(t,J=8.00Hz,2H).

[0282] Example 35 - Preparation of Compound 36 Compound 36 was prepared according to the following scheme. [ka]

[0283] Intermediate 1a: To a stirred solution of 3-bromoisonicotinic acid 1 (3.0 g, 14.85 mmol, 1.0 eq) in DMF (25.0 mL), K2CO3 (4.52 g, 32.7 mmol, 2.2 eq) and methyl iodide (1.857 mL, 29.7 mmol, 2.0 eq) were added under a nitrogen atmosphere. The reaction mixture was stirred overnight at room temperature. After the reaction was complete (confirmed by TLC analysis, 20% EtOAC in petroleum ether, Rf value approximately 0.5), ice-cold water (15 mL) was added to the reaction mixture and diluted with ethyl acetate (40 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain crude methyl 3-bromoisonicotinate 1a (1.3 g, 4.86 mmol, yield 32.8%) as a brown liquid. 1 H-NMR (400MHz, DMSO-d6): δ8.93 (s, 1H), 8.71 (d, J = 4.80Hz, 1H), 7.75-7.74 (m, 1H), 3.92 (s, 3H).

[0284] Intermediate 3: A stirred solution of methyl 3-bromoisonicotinate 1a (0.400 g, 1.852 mmol, 1.0 eq) and 2-(4-methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 2 (0.517 g, 1.852 mmol, 1.5 eq) in 1,4-dioxane (40 mL) and water (2 mL) was prepared by adding potassium carbonate (0.256 g, 1.852 mmol, 2.0 eq) under a nitrogen atmosphere. The reaction mixture was degassed under nitrogen for 10 minutes, then PdCl2 (dppf) (1.355 g, 1.852 mmol, 0.1 eq) was added, and the mixture was purged under nitrogen for another 10 minutes. The reaction mixture was heated to 80°C overnight. After the reaction was complete (confirmed by LC-MS analysis), ice-cold water (15 mL) was added to the reaction mixture and diluted with ethyl acetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (Isolera, silica mesh size 230-400, flow rate: 20 mL / min, eluted with 45% ethyl acetate in petroleum ether) to obtain methyl 4-(4-methoxy-3-nitrophenyl)nicotinic acid 3 (0.296 g, 0.919 mmol, yield 49.6%) as a pale yellow viscous liquid. 1 H-NMR(400MHz,DMSO-d6):δ8.78-8.75(m,2H),7.94(d,J=2.00Hz,1H),7.76(d,J= 4.80Hz, 1H), 7.70-7.67 (m, 1H), 7.46 (d, J=8.40Hz, 1H), 3.99 (s, 3H), 3.73 (s, 3H).

[0285] Intermediate 4: To a stirred solution of methyl 3-(4-methoxy-3-nitrophenyl)isonicotinic acid 3 (1.35 g, 4.68 mmol, 1.0 eq) in ethanol (30.0 mL) and water (15.0 mL), ammonium chloride (2.004 g, 37.5 mmol, 8.0 eq) and iron (1.308 g, 23.42 mmol, 5.0 eq) were added at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 85 °C for 8 hours. After the reaction was complete (confirmed by LC-MS analysis), the reaction mixture was filtered through Celite, and the resulting filtrate was concentrated to dryness under reduced pressure. The residue was diluted with 10% MeOH in DCM (20 mL) and saturated NaHCO3 aqueous solution (40 mL). The organic layer was separated, and the aqueous layer was extracted with 10% MeOH in DCM (2 × 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure to obtain crude methyl 3-(3-amino-4-methoxyphenyl)isonicotinic acid 4 (1.15 g, 4.33 mmol, yield 93%) as a brownish viscous liquid.

[0286] Intermediate 5: To a stirred solution of methyl 3-(3-amino-4-methoxyphenyl)isonicotinic acid 4 (1.15 g, 4.45 mmol, 1.0 eq) in Conc.HCl (4.0 mL), a solution of sodium nitrite (0.369 g, 5.34 mmol, 1.2 eq) in water (2.0 mL) was added at 0°C. The resulting diazonium salt was stirred at 0°C for 1.5 hours. Then, a solution of potassium iodide (2.96 g, 17.81 mmol, 4.0 eq) in water (2.0 mL) was added dropwise at 0°C. The reaction mixture was heated to room temperature and stirred for 4 hours. After the reaction was complete (confirmed by TLC analysis, 50% EtOAC in petroleum ether, Rf value approximately 0.5), the reaction mixture was basicized to approximately pH 11 with saturated sodium bicarbonate solution and diluted with DCM (20 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (2 × 10 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The obtained crude product was purified by column chromatography (Isolera, silica mesh size 230-400, flow rate: 50 mL / min, eluted with 30% ethyl acetate in petroleum ether) to obtain methyl 3-(3-iodo-4-methoxyphenyl)isonicotinate 5 (0.360 g, 0.824 mmol, yield 18.52%) as a yellow viscous liquid. 1 H-NMR(400MHz,DMSO-d6):δ8.72-8.69(m,2H),7.77(d,J=2.40Hz,1H),7.68- 7.67(m,1H),7.41-7.38(m,1H),7.12-7.03(m,1H),3.89(s,3H),3.71(s,3H).

[0287] Intermediate 6: To a stirred solution of methyl 3-(3-iodo-4-methoxyphenyl) isonicotinate 5 (0.360 g, 0.975 mmol, 1.0 eq) in a mixture of MeOH (6.0 mL), THF (4.0 mL), and water (2.0 mL), LiOH.H2O (0.093 g, 3.90 mmol, 4.0 eq) was added at 0°C and the mixture was stirred overnight at room temperature. After the reaction was complete (confirmed by LC-MS analysis), the reaction mixture was concentrated to dryness under reduced pressure. The resulting residue was acidified with 1.5 N HCl (3.0 mL) and concentrated under reduced pressure to obtain the crude product. The crude compound was purified by reverse-phase column chromatography (Grace column: C18 40 μm, 100 g, flow rate: 40 mL / min, mobile phase: water / 35% FA in MeCN) to obtain 3-(3-iodo-4-methoxyphenyl)isonicotinic acid 6 (0.200 g, 0.556 mmol, yield 57.0%) as an off-white solid. 1 H-NMR(400MHz,DMSO-d6):δ13.57(s,1H),8.66(t,J=10.00Hz,2H),7.79(d,J=2.80Hz, 1H),7.63(d,J=6.40Hz,1H),7.44-7.41(m,1H),7.10(d,J=11.20Hz,1H),3.89(s,3H).

[0288] Compound 36: In a stirred solution of 3-(3-iodo-4-methoxyphenyl)isonicotinic acid 6 (0.200 g, 0.563 mmol, 1.0 eq) and 3-(5-fluoropyridine-3-yl)propan-1-amine 7 (0.130 g, 0.845 mmol, 1.5 eq) in DMF (2.0 mL), N,N-diisopropylethylamine (0.492 mL, 2.82 mmol, 5.0 eq) was added at 0°C under a nitrogen atmosphere, followed by the addition of HATU (0.257 g, 0.676 mmol, 1.2 eq). The reaction mixture was stirred overnight at room temperature. After the reaction was complete (confirmed by LC-MS analysis), ice-cold water (20 mL) was added to the reaction mixture and diluted with ethyl acetate (20 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with saturated brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (column: XSELECT C18-250, 500 μl, mobile phase: A: 10 mm aqueous ammonium bicarbonate solution, B: MeCN, flow rate: 14 mL / min, retention time: 13.0 min) to obtain the final compound N-(3-(5-fluoropyridine-3-yl)propyl)-3-(3-iodo-4-methoxyphenyl)isonicotinamide 36 (0.087 g, 0.176 mmol, yield 31.2%) as an off-white solid. 1 H-NMR(400MHz,DMSO-d6):δ8.63-8.61(m,2H),8.47(t,J=5.60Hz,1H),8.40(d,J=2.80Hz,1H),8.25(d,J=1.60Hz,1H),7.83(d,J=2.40Hz,1H) ),7.51-7.46(m,2H),7.41-7.39(m,1H),7.07(d,J=8.40Hz,1H),3.80(s,3H),3.15-3.11(m,2H),2.41(d,J=8.00Hz,2H),1.69-1.61(m,2H).

[0289] Example 36 - Preparation of Compound 37 Compound 37 was prepared according to the following scheme. [ka]

[0290] Intermediate 1b: To a stirred solution of 4-chloronicotinic acid 1a (1.0 g, 6.35 mmol, 1.0 eq) in dichloromethane (10 mL) and DMF (0.2 mL), oxalyl chloride (1.389 mL, 15.87 mmol, 2.5 eq) was added dropwise at 0°C. After addition, the mixture was stirred at room temperature for 2 hours. Then, it was cooled to 0°C, and MeOH (4.0 mL) was slowly added, and the clear solution was stirred for a further 30 minutes. After the reaction was complete (TLC analysis, 30% HCl, R in petroleum ether) f (Confirmed by a value of approximately 0.5), the reaction mixture was quenched with a saturated NaHCO3 solution (35 mL) cooled on ice at 0°C and diluted with DCM (20 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine (1 × 50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain crude methyl 4-chloronicotinate 1b (1.2 g, 3.57 mmol, yield 56.2%) as a yellow viscous liquid. 1 H-NMR (400MHz, DMSO-d6): δ8.99 (t, J = 6.40 Hz, 1H), 8.71 (d, J = 5.20 Hz, 1H), 7.74-7.73 (m, 1H), 3.91 (s, 3H).

[0291] Intermediate 3: Methyl 4-chloronicotinate 1b (1.0 g, 5.83 mmol, 1.0 eq) and 2-(4-methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 2 (2.440 g, 8.74 mmol, 1.5 eq) were stirred in a mixture of dioxane (20.0 mL) and water (2.0 mL). Potassium carbonate (1.611 g, 11.66 mmol, 2.0 eq) was added under a nitrogen atmosphere. The reaction mixture was degassed under nitrogen for 10 minutes, then PdCl2 (dppf) (0.426 g, 0.583 mmol, 0.1 eq) was added, and the mixture was purged under nitrogen for 10 minutes. The reaction mixture was heated to 80°C overnight. After the reaction was complete (confirmed by LC-MS analysis), the reaction mixture was filtered through Celite, and the filtrate was diluted with ethyl acetate (2 x 15 mL) and water (25 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The obtained crude product was purified by column chromatography (Isolera, silica mesh size 230-400, flow rate 20 mL / min). The column was eluted with 48-52% ethyl acetate in petroleum ether to obtain the desired product, methyl 4-(4-methoxy-3-nitrophenyl)nicotinic acid 3 (1.1 g, 3.14 mmol, yield 53.9%), as a yellow solid. 1 H-NMR(400MHz,DMSO-d6):δ8.98(s,1H),8.80(d,J=5.20Hz,1H),7.96(d,J=2.00Hz,1H),7. 71-7.68(m,1H),7.56(d,J=5.20Hz,1H),7.47-7.41(m,1H),4.10(s,3H),3.73-3.70(m,3H).

[0292] Intermediate 4: To a stirred solution of methyl 4-(4-methoxy-3-nitrophenyl)nicotinic acid 3 (1.1 g, 3.82 mmol, 1.0 eq) in ethanol (15.0 mL) and water (5.0 mL), ammonium chloride (1.633 g, 30.5 mmol, 8.0 eq) and iron (1.066 g, 19.08 mmol, 5.0 eq) were added at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 85 °C for 5 hours. After the reaction was complete (confirmed by LC-MS analysis), the reaction mixture was filtered through Celite, and the resulting filtrate was concentrated to dryness under reduced pressure. The resulting residue was diluted with 10% MeOH in DCM (20 mL). The organic layer was separated, and the aqueous layer was extracted with 10% MeOH in DCM (2 × 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain crude methyl 4-(3-amino-4-methoxyphenyl)nicotinic acid 4 (1.01 g, 3.89 mmol, yield 102%) as a brown, viscous liquid. 1 H-NMR(400MHz,DMSO-d6):δ8.75(s,1H),8.67(d,J=5.20Hz,1H),7.42(d,J=5.20Hz,1H),6.88(d,J= 8.40Hz,1H),6.66(d,J=2.00Hz,1H),6.54(d,J=2.40Hz,1H),4.92(s,2H),3.81(s,3H),3.69(s,3H).

[0293] Intermediate 5: To a stirred solution of methyl 4-(3-amino-4-methoxyphenyl)nicotinic acid 4 (1.01 g, 3.91 mmol, 1.0 eq) in Conc.HCl (4.0 mL), a solution of sodium nitrite (0.324 g, 4.69 mmol, 1.2 eq) in water (2.0 mL) was added at 0°C. The resulting diazonium salt was stirred at 0°C for 30 minutes. Next, a solution of potassium iodide (2.60 g, 15.64 mmol, 4 eq) in water (2.0 mL) was added dropwise at 0°C. The reaction mixture was heated to room temperature and stirred for 4 hours. After the reaction was complete (confirmed by LC-MS analysis), the reaction mixture was basicized with saturated sodium bicarbonate solution and diluted with DCM (20 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (2 × 20 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product obtained was purified by column chromatography (Isolera, silica mesh size 230-400, flow rate: 35 mL / min, elution with 30-35% ethyl acetate in petroleum ether) to obtain methyl 4-(3-iodo-4-methoxyphenyl)nicotinic acid 5 (0.330 g, 0.792 mmol, yield 20.26%) as a yellow viscous liquid. 1 H-NMR (400MHz, DMSO-d6): δ8.86(d,J=16.00Hz,1H),8.73(d,J=6.80Hz,1H),7.78(d,J=3.20Hz,1H),7. 50(t,J=7.20Hz,1H),7.42-7.39(m,1H),7.11(d,J=11.60Hz,1H),3.90(s,3H),3.70(d,J=6.40Hz,3H).

[0294] Intermediate 6: To a stirred solution of methyl 4-(3-iodo-4-methoxyphenyl)nicotinic acid 4 (0.330 g, 0.894 mmol, 1.0 eq) in a mixture of methanol (6 mL), THF (4 mL), and water (2 mL), LiOH.H2O (0.086 g, 3.58 mmol, 4.0 eq) was added at 0°C, and the mixture was stirred at 45°C for 5 hours. After the reaction was complete (confirmed by LC-MS analysis), the reaction product was concentrated under reduced pressure. The resulting crude product was acidified with 1.5 N HCl (3.0 mL) and concentrated under reduced pressure to obtain the crude product. The crude compound was purified by reverse-phase column chromatography (Grace column: C18 40 μm, 100 g, flow rate: 25 mL / min, mobile phase: water / 35% ammonium bicarbonate aqueous solution in MeCN) to obtain 4-(3-iodo-4-methoxyphenyl)nicotinic acid 6 (0.290 g, 0.698 mmol, yield 78.0%) as a pale yellow solid. 1 H-NMR (400MHz, DMSO-d6): δ8.50(s,1H),8.40(s,1H),7.93(d,J=2.80Hz,1H),7.56-7. 53(m,1H),7.25(d,J=5.60Hz,1H),7.03(t,J=17.20Hz,1H),3.87(s,3H),3.80(s,1H).

[0295] Compound 37: A stirred solution of 4-(3-iodo-4-methoxyphenyl)nicotinic acid 5 (0.290 g, 0.817 mmol, 1.0 eq) and 3-(5-fluoropyridine-3-yl)propan-1-amine 7 (intermediate 6 from Example 1, 0.189 g, 1.225 mmol, 1.5 eq) in DMF (5 mL) was prepared by adding DIPEA (0.713 mL, 4.08 mmol, 5 eq) at 0°C under a nitrogen atmosphere, followed by the addition of HATU (0.373 g, 0.980 mmol, 1.2 eq). The reaction mixture was stirred overnight at room temperature. After the reaction was complete (confirmed by LC-MS analysis), ice-cold water was added to the reaction mixture and diluted with ethyl acetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 10 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (column: XSELECT C18-250, 500 μl; mobile phase: A: 10 mm aqueous ammonium bicarbonate solution, B: MeCN; flow rate: 14 mL / min; retention time: 13.0 min) to obtain N-(3-(5-fluoropyridine-3-yl)propyl)-4-(3-iodo-4-methoxyphenyl)nicotinamide 37 (0.057 g, 0.114 mmol, yield 13.95%) as an off-white solid. 1 H-NMR(400MHz,DMSO-d6):δ8.64(d,J=5.20Hz,1H),8.56(s,1H),8.50(t,J=6.00Hz,1H),8.40(d,J=2.80Hz,1H),8.27(s,1H),7.86( d,J=2.00Hz,1H),7.55-7.46(m,3H),7.08(d,J=8.40Hz,1H),3.81(s,3H),3.18-3.14(m,2H),2.52-2.46(m,2H),1.73-1.66(m,2H).

[0296] Example 37 - Preparation of Compound 38 Compound 38 was prepared according to the following scheme. [ka]

[0297] Intermediate 1a: To a stirred solution of 3-bromopicolinic acid 1 (1.5 g, 7.43 mmol, 1.0 eq) in dichloromethane (10 mL), oxalyl chloride (1.592 mL, 18.56 mmol, 2.5 eq) was added dropwise at room temperature, followed by the addition of DMF (0.200 mL). The reaction mixture was stirred at room temperature for 2 hours. Next, the reaction mixture was cooled to 0°C, and methanol (10 mL) was added dropwise under a nitrogen atmosphere. The reaction mixture was stirred for 20 minutes. After the reaction was complete (TLC analysis, 50% ethyl acetate in petroleum ether, R of the product) f The reaction mixture was concentrated to dryness under reduced pressure (value approximately 0.3, confirmed by LC-MS analysis), quenched to approximately pH 10 with saturated NaHCO3 solution (approximately 55 mL) at 0°C, and diluted with ethyl acetate (30 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (Isolera, silica mesh size 230-400, flow rate: 35 mL / min, eluted with 10-12% ethyl acetate in petroleum ether) to obtain methyl 3-bromopicolinate 1a (1.3 g, 5.99 mmol, yield 81%) as a pale yellow liquid. 1 H-NMR (400MHz, DMSO-d6): δ8.64-8.62 (m, 1H), 8.27-8.25 (m, 1H), 7.55-7.52 (m, 1H), 3.91 (s, 3H).

[0298] Intermediate 3: To a stirred solution of methyl 3-bromopicolinate 1a (1 g, 4.63 mmol, 1.0 eq) and 2-(4-methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 2 (1.938 g, 6.94 mmol, 1.5 eq) in 1,4-dioxane (50 mL) and water (4 mL), potassium carbonate (0.960 g, 6.94 mmol, 1.5 eq) was added under a nitrogen atmosphere. The reaction mixture was degassed under nitrogen for 10 minutes, and PdCl2 (dppf) (0.339 g, 0.463 mmol, 0.1 eq) was added. The mixture was purged again under nitrogen for 10 minutes and heated overnight to 80°C. After the reaction was complete (TLC analysis, 50% siRNA in petroleum ether, R of the product),f (Confirmed by a value of approximately 0.2), the reaction mixture was filtered through Celite. Ice-cold water (50 mL) was added to the filtrate and diluted with ethyl acetate (20 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (1 × 50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The obtained crude product was purified by column chromatography (Isolera, silica mesh size 230-400, flow rate: 20 mL / min, eluted with 45% ethyl acetate in petroleum ether) to obtain the desired product, methyl 3-(4-methoxy-3-nitrophenyl) picolinate 3 (1.5 g, 4.38 mmol, yield 95%), as a pale beige solid. 1 H-NMR(400MHz,DMSO-d6):δ8.68-8.66(m,1H),8.03-8.00(m,1H),7.92(d,J=3.20Hz,1 H),7.71-7.64(m,2H),7.48(d,J=12.00Hz,1H),3.99(s,3H),3.74(t,J=14.00Hz,3H).

[0299] Intermediate 4: To a stirred solution of methyl 3-(4-methoxy-3-nitrophenyl) picolinate 3 (2.0 g, 6.94 mmol, 1.0 eq) in methanol (40 mL) and water (20.00 mL), ammonium chloride (2.97 g, 55.5 mmol, 8.0 eq) and iron (1.937 g, 34.7 mmol, 5.0 eq) were added at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 85 °C for 2 hours. After the reaction was complete (confirmed by TLC analysis), the reaction mixture was filtered through Celite, and the filtrate was concentrated to dryness under reduced pressure. The residue was basicized to approximately pH 12 with 10% NaHCO3 aqueous solution and diluted with ethyl acetate (75 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 40 mL). The combined organic layers were washed with brine (1 × 150 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product methyl 3-(3-amino-4-methoxyphenyl)picolinate 4 (0.400 g, 1.469 mmol, yield 21%) as a brown, viscous liquid. The obtained crude compound was used directly in the next step without further purification. 1H-NMR (400MHz, DMSO-d6): δ8.54-8.53(m,1H),7.85-7.83(m,1H),7.65-7.54(m,2H),6.85(t,J=14. 80Hz, 1H), 6.65 (d, J=2.00Hz, 1H), 6.53-6.50 (m, 1H), 4.88 (s, 2H), 4.19-4.03 (s, 3H), 3.80 (s, 3H).

[0300] Intermediate 5: To a stirred solution of methyl 3-(3-amino-4-methoxyphenyl) picolinate 4 (0.400 g, 1.469 mmol, 1.0 eq) in Conc.HCl (2.0 mL), a solution of sodium nitrite (0.122 g, 1.763 mmol, 1.2 eq) in water (1.0 mL) was added at 0°C. The resulting diazonium salt was stirred at 0°C for 1.5 hours. Next, a solution of potassium iodide (0.975 g, 5.88 mmol, 4.0 eq) in water (1.0 mL) was added dropwise over 10 minutes. The reaction mixture was heated to room temperature and stirred for 4 hours. After the reaction was complete (confirmed by LC-MS analysis), the reaction mixture was basicized with saturated NaHCO3 (40 mL) and diluted with DCM (20 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (2 × 10 mL). The combined organic layers were washed with saturated Na2S2O3 aqueous solution (1 × 30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product as a brownish viscous liquid. The crude product was purified by column chromatography (Isolera, silica mesh size 230-400, flow rate 20 mL / min). The column was eluted with 28% ethyl acetate in petroleum ether to obtain the desired product, methyl 3-(3-iodo-4-methoxyphenyl) picolinate 5 (0.211 g, 0.527 mmol, yield 35.9%), as a yellow liquid. 1 H-NMR(400MHz,DMSO-d6):δ8.61-8.60(m,1H),7.96-7.94(m,1H),7.75(d,J=2.40Hz,1H),7. 64-7.61(m,1H),7.41-7.39(m,1H),7.12(d,J=8.40Hz,1H),4.21-4.15(s,3H),3.88(s,3H).

[0301] Intermediate 6: To a stirred solution of methyl 3-(3-iodo-4-methoxyphenyl) picolinate 5 (0.211 g, 0.572 mmol, 1.0 eq) in a mixture of methanol (12 mL), THF (8.00 mL), and water (4.00 mL), LiOH.H2O (0.096 g, 2.286 mmol, 4.0 eq) was added at 0°C and stirred overnight at room temperature. After the reaction was complete (TLC analysis, 50% siRNA in petroleum ether, R of the product) f The reaction mixture was concentrated to dryness under reduced pressure (confirmed by LC-MS analysis with a value of approximately 0.0). The resulting residue was acidified to approximately pH 5 with 10 mL of 1.5 N HCl aqueous solution, concentrated under reduced pressure, and the crude product was obtained as a yellow solid. The crude compound was purified by reverse-phase column chromatography (Grace column: C18 40 μm, 120 g, flow rate: 20 mL / min, mobile phase: 0.1% aqueous TFA / MeCN) to obtain 3-(3-iodo-4-methoxyphenyl)picolinic acid 6 (0.150 g, 0.383 mmol, yield 68.0%) as an off-white solid. 1 H-NMR(400MHz,DMSO-d6):δ13.34(s,1H),8.58-8.56(m,1H),7.91-7.87(m,1H),7.81(d,J=2.80Hz,1H),7. 59-7.55(m,1H),7.45-7.41(m,1H),7.26(s,1H),7.23(s,1H),7.19-7.09(m,1H),3.88(s,3H),2.31(s,1H).

[0302] Compound 38: In a stirred solution of 3-(3-iodo-4-methoxyphenyl)picolinic acid 6 (0.150 g, 0.422 mmol, 1.0 eq) and 3-(5-fluoropyridine-3-yl)propan-1-amine 7 (0.098 g, 0.634 mmol, 1.5 eq) in DMF (3.0 mL), DIPEA (0.369 ml, 2.112 mmol, 5.0 eq) was added at 0°C under a nitrogen atmosphere, followed by the addition of HATU (0.241 g, 0.634 mmol, 1.5 eq). The reaction mixture was stirred overnight at room temperature. After the reaction was complete, (TLC analysis, 50% siRNA in petroleum ether, R of the product) fA value of approximately 0.3 (confirmed by LC-MS analysis) was added to the reaction mixture with ice-cold water (10 mL) and diluted with ethyl acetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (1 × 20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product as a brownish viscous liquid. The crude compound was purified by preparative HPLC (column: X-Bridge C8 (50 × 4.6) mm, 3.5 μm, mobile phase: A: 10 mM ammonium bicarbonate aqueous solution, B: acetonitrile, flow rate: 1.0 mL / min, retention time: 12.0 min) to obtain the final compound N-(3-(5-fluoropyridine-3-yl)propyl)-3-(3-iodo-4-methoxyphenyl)picolinamide 38 (0.092 g, 0.187 mmol, yield 44.31%) as a pale orange solid. 1 H-NMR(400MHz,DMSO-d6):δ8.57-8.55(m,2H),8.40(d,J=2.40Hz,1H),8.28(t,J=1.60Hz,1H),7.86-7.84(m,1H),7.80(d,J=2.40Hz,1H) ),7.56-7.53(m,2H),7.43-7.41(m,1H),7.04(d,J=8.40Hz,1H),3.82(s,3H),3.19-3.14(m,2H),2.55-2.50(m,2H),1.77-1.69(m,2H).

[0303] Example 38 - Preparation of Compound 39 Compound 39 was prepared according to the following scheme. [ka]

[0304] Intermediate 2: To a stirred solution of triphenylphosphine (8.14 g, 31.0 mmol, 1.0 eq) and imidazole (2.112 g, 31.0 mmol, 1.0 eq) in DCM (30.0 mL), iodine (9.45 g, 37.2 mmol, 1.2 eq) was gradually added at 25°C and the mixture was stirred for 1 hour. Next, a solution of tert-butyl(2-hydroxyethyl) carbamate 1 (5.0 g, 31.0 mmol, 1.0 eq) in DCM (10 mL) was added dropwise to the reaction mixture and the mixture was stirred at room temperature for 2 hours. After the reaction was complete (confirmed by LC-MS analysis), water (30 mL) was added to the reaction mixture and diluted with DCM (30 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (2 × 30 mL). The combined organic layers were washed with sodium thiosulfate solution (2 x 15 mL) and brine (1 x 50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The obtained crude product was purified by column chromatography (Isolera, silica mesh size 230-400, flow rate: 35 mL / min, eluted with 8-10% ethyl acetate in petroleum ether) to obtain tert-butyl(2-iodoethyl)carbamate 2 (5.3 g, 17.97 mmol, yield 57.9%) as an orange viscous liquid. 1 H-NMR (400MHz, DMSO-d6): δ7.15 (t, J=5.20Hz, 1H), 3.27-3.22 (m, 2H), 3.18-3.15 (m, 2H), 1.39 (s, 9H).

[0305] Intermediate 4: 5-bromoquinoline 3 (0.250 g, 1.202 mmol, 1.0 eq), zinc (0.236 g, 3.60 mmol, 3.0 eq, newly activated with 1N HCl and dried), pyridine-2,6-bis(carboxyimidamide) dihydrochloride (0.057 g, 0.240 mmol, 0.2 eq), TBAI (0.133 g, 0.360 mmol, 0.3 eq), and NiCl2(dme) (0.053 g, 0.240 mmol, 0.2 eq) were stirred in a RB under an N2 atmosphere. Next, the RB was evacuated and refilled with N2 (3 times) using a two-way adapter. tert-butyl(2-iodoethyl)carbamate 2 (0.391 g, 1.442 mmol, 1.2 eq) was placed in a separate vial, evacuated, and refilled with N2. Then, separately degassed N,N-dimethylacetamide (6.0 mL) was added to the vial containing the alkyl iodide compound. The alkyl iodide solution was transferred to a vial containing the aryl iodide reaction mixture under N2 conditions. The reaction mixture was heated at 100°C for 1 hour under a nitrogen atmosphere. After the reaction was complete (confirmed by LC-MS analysis), the reaction mixture was quenched with water (20.0 mL) and extracted with SiO2 (2 x 15 mL). The combined organic layers were dried over Na2SO4 and concentrated to obtain the crude product. The crude product was purified by reverse-phase column chromatography (Grace column: C18 40 μm, 120 g, flow rate: 20 mL / min, mobile phase: 0.1% aqueous HCOOH / MeCN) to obtain tert-butyl(2-(quinoline-5-yl)ethyl)carbamate 4 (0.092 g, 0.332 mmol, yield 27.6%) as a pale yellow viscous liquid. 1 H-NMR(400MHz,DMSO-d6):δ8.91-8.90(m,1H),8.58(d,J=8.00Hz,1H),7.90(d,J=8.00Hz,1H),7.70- 7.66(m,1H),7.59-7.56(m,1H),7.45(d,J=8.00Hz,1H),6.99(s,1H),3.23-3.17(m,4H),1.37(s,9H).

[0306] Intermediate 5: To a stirred solution of tert-butyl(2-(quinoline-5-yl)ethyl)carbamate 4 (0.09 g, 0.330 mmol, 1.0 eq) in DCM (3.0 mL), HCl (4.0 M solution in 1,4-dioxane, 1.487 mL, 5.95 mmol, 18.0 eq) was added at 0°C. The resulting solution was stirred at room temperature for 2 hours. After the reaction was complete (confirmed by LC-MS analysis), the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was pulverized with petroleum ether (2 x 5 mL), the solvent was decanted, and the mixture was dried under reduced pressure to obtain 2-(quinoline-5-yl)ethane-1-amine, HCl 5 (0.07 g, 0.328 mmol, yield 99%) as an off-white solid. 1 H-NMR (400MHz, DMSO-d6): δ9.06(d,J=3.60Hz,1H),8.83(d,J=8.00Hz,1H),8.06(d,J=8.00Hz,1H),7. 99(s,2H),7.84(t,J=8.80Hz,1H),7.79-7.77(m,1H),7.63(d,J=7.20Hz,1H),3.45(t,J=7.60Hz,4H). Compound 39: In a stirred solution of 2-(quinoline-5-yl)ethane-1-amine, HCl 5 (0.07 g, 0.335 mmol, 1.0 eq) and 5-(3-iodo-4-methoxyphenyl)oxazole-4-carboxylic acid 6 (intermediate 5 from Example 1, 0.116 g, 0.335 mmol, 1.0 eq) in DMF (3.0 mL), DIPEA (0.293 mL, 1.677 mmol, 5.0 eq) was added at 0°C under a nitrogen atmosphere, followed by the addition of HATU (0.153 g, 0.403 mmol, 1.2 eq). The reaction mixture was stirred overnight at room temperature. After the reaction was complete (confirmed by LC-MS analysis), the crude product was diluted with ethyl acetate (10 mL) by adding ice-cold water (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (Isolera, silica mesh size 230-400, flow rate: 35 mL / min, eluted with 60-62% ethyl acetate in petroleum ether) to obtain 5-(3-iodo-4-methoxyphenyl)-N-(2-(quinoline-5-yl)ethyl)oxazole-4-carboxamide 39 (0.043 g, 0.086 mmol, yield 21.48%) as an off-white solid. 1 H-NMR(400MHz,DMSO-d6):δ8.92-8.90(m,1H),8.79(d,J=2.40Hz,1H),8.74(d, J=8.40Hz,1H),8.65(t,J=6.00Hz,1H),8.55(s,1H),8.23-8.20(m,1H),7.91(d ,J=8.40Hz,1H),7.71-7.67(m,1H),7.59-7.56(m,1H),7.51(d,J=6.40Hz,1H), 7.15(d,J=8.80Hz,1H),3.91(s,3H),3.61-3.56(m,2H),3.33(t,J=6.80Hz,2H).

[0307] Example 39 - Preparation of Compound 40 Compound 40 was prepared according to the following scheme. [ka]

[0308] Intermediate 3: 5-bromoisoquinoline 1 (0.25 g, 1.202 mmol, 1.0 eq), zinc (0.236 g, 3.60 mmol, 3.0 eq, newly activated with 1N HCl and dried), pyridine-2,6-bis(carboxyimidamide) dihydrochloride (0.057 g, 0.240 mmol, 0.2 eq), TBAI (0.133 g, 0.360 mmol, 0.3 eq), and NiCl2(dme) (0.053 g, 0.240 mmol, 0.2 eq) were stirred in a RB under an N2 atmosphere. The RB was then vacuumed and refilled with N2 (three times) using a two-way adapter. tert-butyl(2-iodoethyl)carbamate 2 (0.391 g, 1.442 mmol, 1.2 eq) was placed in a separate vial, evacuated, and refilled with N2. Then, separately degassed N,N-dimethylaniline (6.0 mL) was added to the vial containing the alkyl iodide compound. The alkyl iodide solution was transferred to a vial containing the aryl iodide reaction mixture under N2 conditions. The reaction mixture was heated at 100°C for 1 hour under a nitrogen atmosphere. After the reaction was complete (confirmed by LC-MS analysis), the reaction mixture was quenched with water (20 mL) and extracted with SiO2 (2 x 15 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to obtain the crude product. The obtained crude compound was purified by reverse-phase column chromatography (Grace column: C18 40 μm, 120 g, flow rate: 20 mL / min, mobile phase: 0.1% aqueous HCOOH / MeCN) to obtain the desired product, tert-butyl(2-(isoquinoline-5-yl)ethyl)carbamate 3 (0.095 g, 0.330 mmol, yield 27.4%), as a pale yellow viscous liquid. 1 H-NMR(400MHz,DMSO-d6):δ9.30(s,1H),8.55(d,J=4.00Hz,1H),7.99(d,J=8.00Hz,2H),7.61 (t,J=0.00Hz,2H),6.99(t,J=4.00Hz,1H),3.34-3.24(m,2H),3.23-3.16(m,2H),1.36(s,9H).

[0309] Intermediate 4: To a stirred solution of tert-butyl(2-(isoquinoline-5-yl)ethyl)carbamate 4 (0.09 g, 0.330 mmol, 1.0 eq) in DCM (3.0 mL), HCl (4.0 M solution in 1,4-dioxane, 1.487 mL, 5.95 mmol, 18.0 eq) was added at 0°C. The resulting solution was stirred at room temperature for 2 hours under a nitrogen atmosphere. After the reaction was complete (confirmed by LC-MS analysis), the reaction mixture was concentrated under reduced pressure to obtain the crude product. The obtained crude compound was pulverized with petroleum ether (2 x 5 mL), the solvent was decanted, and the mixture was dried under reduced pressure to obtain 2-(isoquinoline-5-yl)ethane-1-amine, HCl 4 (0.08 g, 0.276 mmol, yield 84%) as an off-white solid. Compound 40: In a stirred solution of 2-(isoquinoline-5-yl)ethane-1-amine, HCl 4 (0.08 g, 0.383 mmol, 1.0 eq) and 5-(3-iodo-4-methoxyphenyl)oxazole-4-carboxylic acid 6 (intermediate 5 from Example 1, 0.132 g, 0.383 mmol, 1.0 eq) in DMF (3.0 mL), DIPEA (0.335 mL, 1.917 mmol, 5.0 eq) was added at 0°C under a nitrogen atmosphere, followed by the addition of HATU (0.175 g, 0.460 mmol, 1.2 eq). The reaction mixture was stirred overnight at room temperature. After the reaction was complete (confirmed by LC-MS analysis), the crude product was diluted with ice-cold water (10 mL) and ethyl acetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with brine (10 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (Isolera, silica mesh size 230-400, flow rate 35 mL / min). The column was eluted with 60-62% ethyl acetate in petroleum ether to obtain 5-(3-iodo-4-methoxyphenyl)-N-(2-(isoquinoline-5-yl)ethyl)oxazole-4-carboxamide 40 (0.032 g, 0.064 mmol, yield 16.57%) as an off-white solid. 1H-NMR(400MHz,DMSO-d6):δ9.31(s,1H),8.77(d,J=4.00Hz,1H),8.64(t,J= 4.00Hz,1H),8.55(t,J=0.00Hz,2H),8.22-8.19(m,1H),8.16(d,J=4.00Hz, 1H),8.01(d,J=8.00Hz,1H),7.68(t,J=0.00Hz,1H),7.62(t,J=8.00Hz,1H) ,7.15(d,J=8.00Hz,1H),3.91(s,3H),3.62-3.57(m,2H),2.56-2.50(m,2H).

[0310] Example 40 - Preparation of Compound 41 Compound 41 was prepared according to the following scheme. [ka]

[0311] Intermediate 3: 8-bromoisoquinoline 1 (0.5 g, 2.403 mmol, 1.0 eq), zinc (0.471 g, 7.21 mmol, 3.0 eq) (freshly activated with 1N HCl and dried), pyridine-2,6-bis(carboxyimidamide) dihydrochloride (0.113 g, 0.481 mmol, 0.2 eq), TBAI (0.266 g, 0.721 mmol, 0.3 eq), and NiCl2(dme) (0.106 g, 0.481 mmol, 0.2 eq) were stirred in RB under an N2 atmosphere. RB was then vacuumed and repacked with N2. 0.782 g, 2.88 mmol, 1.2 eq of tert-butyl(2-iodoethyl)carbamate 2 was placed in a separate vial, evacuated, and refilled with N2. Separately degassed DMA (6.00 mL) was then added. The DMA solution was transferred to RB under a nitrogen atmosphere. The reaction mixture was heated at 100°C for 1 hour under a nitrogen atmosphere. After the reaction was complete, (TLC analysis showed 40% siRNA in petroleum ether, and the R of the product) fThe reaction mixture was quenched with ice-cold water (10 mL) and extracted with ethyl acetate (2 x 15 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product. The crude compound was purified by reverse-phase column chromatography (Grace column: C18 40 μm, 120 g, flow rate: 20 mL / min, mobile phase: 0.1% aqueous HCOOH / MeCN) to obtain tert-butyl(2-(isoquinoline-8-yl)ethyl)carbamate 3 (0.220 g, 0.752 mmol, yield 31.2%) as a pale yellow viscous liquid. 1 H-NMR(400MHz,DMSO-d6):δ9.57(s,1H),8.52(d,J=5.60Hz,1H),8.17(s,1H),7.83(t,J=4.80Hz,2H),7.71-7.67(m,1H) ),7.49(d,J=6.80Hz,1H),7.02(s,1H),3.27(d,J=2.40Hz,4H),3.17(s,1H),3.00-2.88(m,1H),1.36(d,J=7.20Hz,9H).

[0312] Intermediate 4: To a stirred solution of tert-butyl(2-(isoquinoline-8-yl)ethyl)carbamate 3 (0.210 g, 0.771 mmol, 1.0 eq) in dichloromethane (3.0 mL), HCl (4.0 M solution in 1,4-dioxane, 3.47 mL, 13.88 mmol, 18.0 eq) was added at 0°C. The resulting solution was stirred at room temperature under a nitrogen atmosphere for 1.5 hours. After the reaction was complete, (TLC analysis, 60% siRNA in petroleum ether, R of the product) f (Confirmed by a value of approximately 0.0), the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude compound was pulverized with MTBE (2 × 3 mL), the solvent was decanted, and the mixture was dried under reduced pressure to obtain 2-(isoquinoline-8-yl)ethane-1-amine, HCl 4 (0.160 g, 0.731 mmol, yield 95%) as an off-white solid. 1H-NMR(400MHz,DMSO-d6):δ10.08(s,1H),8.70(t,J=3.20Hz,1H),8.48(d,J=6.40Hz,1H),8.23(d,J =8.00Hz,3H),8.12(t,J=8.40Hz,1H),7.90(d,J=7.20Hz,1H),3.96-3.57(m,2H),3.21-3.16(m,2H).

[0313] Compound 41: In a stirred solution of 2-(isoquinoline-8-yl)ethane-1-amine, HCl4 (0.160 g, 0.767 mmol, 1.0 eq) and 5-(3-iodo-4-methoxyphenyl)oxazole-4-carboxylic acid 4a (intermediate 5 from Example 1, 0.265 g, 0.767 mmol, 1.0 eq) in DMF (3.0 mL), DIPEA (0.682 ml, 3.83 mmol, 5.0 eq) was added at 0°C under a nitrogen atmosphere, followed by the addition of HATU (0.350 g, 0.920 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 6 hours. After the reaction was complete, (TLC analysis showed 60% siRNA in petroleum ether, and the product was R) f (Confirmed by a value of approximately 0.2), the crude product obtained was diluted with ice-cold water (10 mL) and ethyl acetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The obtained crude compound was purified by column chromatography (Isolera, silica mesh size 230-400, flow rate 35 mL / min). The column was eluted with 35-40% ethyl acetate in petroleum ether to obtain the final compound 5-(3-iodo-4-methoxyphenyl)-N-(2-(isoquinoline-8-yl)ethyl)oxazole-4-carboxamide 41 (0.1962 g, 0.386 mmol, yield 50.3%) as an off-white solid. 1H-NMR(400MHz,DMSO-d6):δ9.71(s,1H),8.75(d,J=2.40Hz,1H),8.69(t,J=6.40Hz,1H),8.53(t,J=5.60Hz,2H),8.24-8.21(m,1H),7.86-7.82( m,2H),7.72-7.68(m,1H),7.55(d,J=6.40Hz,1H),7.15(d,J=8.80Hz,1H ),3.91(s,3H),3.66-3.61(m,2H),3.43(t,J=6.80Hz,2H),(t,J=Hz,2H).

[0314] Example 41 - Preparation of Compound 42 Compound 42 was prepared according to the following scheme. [ka]

[0315] Intermediate 2: To a stirred solution of 8-(bromomethyl)quinoline 1 (1.00 g, 4.50 mmol, 1.0 eq) in DMSO (10 mL), tetrabutylammonium bromide (0.073 g, 0.225 mmol, 0.05 eq) and sodium cyanide (0.441 g, 9.01 mmol, 2.0 eq) were added at 25°C and stirred overnight under a nitrogen atmosphere. After the reaction was complete (TLC analysis, 20% siRNA in petroleum ether, R of the product) f (Confirmed by a value of approximately 0.3), ice-cold water (15 mL) was added to the reaction mixture and diluted with ethyl acetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 5 mL). The combined organic layers were washed with brine (1 × 10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude compound. The obtained crude product was purified by column chromatography (Isolera, silica mesh size 230-400, flow rate: 35 mL / min, eluted with 8-9% ethyl acetate in petroleum ether) to obtain the desired product 2-(quinoline-8-yl)acetonitrile 2 (0.610 g, 3.60 mmol, yield 80%) as an off-white solid. 1H-NMR (400MHz, DMSO-d6): δ9.02-9.00(m,1H),8.47-8.44(m,1H),8.03-8.01(m,1H),7.88(t,J=6.00Hz,1H),7.67-7.63(m,2H),4.49(s,2H).

[0316] Intermediate 3: Raney nickel (0.022 g, 0.357 mmol, 0.1 eq) was added to a stirred solution of 2-(quinoline-8-yl)acetonitrile 2 (0.60 g, 3.57 mmol, 1.0 eq) in a mixture of 7N methanolic ammonia (3.00 mL) and ethanol (5.0 mL) under a nitrogen atmosphere at room temperature. The mixture was stirred overnight at room temperature under a hydrogen atmosphere. After the reaction was complete (confirmed by LC / MS and TLC analysis, and by 30% Â in petroleum ether), the reaction mixture was filtered through Celite, washed with methanol (2 x 5 mL), and the filtrate was concentrated under reduced pressure to obtain the desired crude product 2-(quinoline-8-yl)ethane-1-amine 3 (0.530 g, 2.89 mmol, yield 81%) as a pale yellow viscous liquid. The obtained crude compound was used directly in the next step without further purification. 1 H-NMR(400MHz,DMSO-d6):δ8.93-8.92(m,1H),8.35-8.33(m,1H),7.84-7.81(m,1H),7.63-7.61(m,1H),7.55-7.51(m,2H),3.4 7-3.20(m,1H),3.17(s,3H),2.95-2.87(m,2H),2.70-2.64(m,1H),1.77(t,J=5.60Hz,1H),1.44(s,1H),1.06(t,J=6.80Hz,1H).

[0317] Compound 42: In a stirred solution of 2-(quinoline-8-yl)ethane-1-amine 3 (0.150 g, 0.869 mmol, 1.2 eq) and 5-(3-iodo-4-methoxyphenyl)oxazole-4-carboxylic acid 4 (intermediate 5 from Example 1, 0.250 g, 0.724 mmol, 1.0 eq) in DMF (6.0 ml), DIPEA (0.633 ml, 3.62 mmol, 5.0 eq) was added at 0°C under a nitrogen atmosphere, followed by the addition of HATU (0.413 g, 1.087 mmol, 1.5 eq). The reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete (confirmed by LC-MS analysis), ice-cold water (20 mL) was added to the reaction mixture and diluted with ethyl acetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with brine (10 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude compound was purified by column chromatography (Isolera, silica mesh size 230-400, flow rate: 35 mL / min, eluted with 35-40% ethyl acetate in petroleum ether) to obtain the final compound 5-(3-iodo-4-methoxyphenyl)-N-(2-(quinoline-8-yl)ethyl)oxazole-4-carboxamide 42 (0.1363 g, 0.271 mmol, yield 37.43%) as an off-white solid. 1 H-NMR(400MHz,DMSO-d6):δ8.99-8.98(m,1H),8.75(d,J=2.00Hz,1H),8.58(t,J=5.60Hz,1H),8.51(s,1H),8.39-8.36(m,1H),8.19-8.16(m,1H) ),7.88-7.85(m,1H),7.67(d,J=6.00Hz,1H),7.58-7.52(m,2H),7.12(d ,J=8.80Hz,1H),3.90(s,3H),3.71-3.66(m,2H),3.50(t,J=7.20Hz,2H).

[0318] Example 42 - Preparation of Compound 43 and Compound 44 Compounds 43 and 44 were prepared according to the following scheme. [ka]

[0319] Intermediate 7B: Compound 7A (1.0 g, 8.92 mmol) was added to a stirred solution of compound 7A in DCM (25 mL) with DMF (catalyst), and then oxalyl chloride (0.76 mL, 8.92 mmol) was added dropwise at 0°C. The resulting reaction mixture was heated to room temperature and stirred for 2 hours. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under vacuum to obtain crude intermediate 7B as a yellow liquid, which was then used directly in the next reaction.

[0320] Intermediate 18A: To a stirred solution of intermediate 7B (1.0 g, 7.63 mmol) in 1,4-dioxane (40 mL) and water (10 mL), (5-fluoropyridine-3-yl)boronic acid (1.16 g, 8.39 mmol) was added, followed by the addition of potassium carbonate (3.1 g, 22.9 mmol). The reaction mixture was degassed under nitrogen for 15 minutes, PdCl2(dppf)DCM complex (620 mg, 0.76 mmol) was added, and the mixture was degassed again for 10 minutes. The sealed tube was then capped, and the resulting reaction contents were heated at 80°C for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was cooled to room temperature and filtered through a Celite pad. The filtrate was extracted with ethyl acetate (50 mL), the organic layer was dried with sodium sulfate, and evaporated under vacuum to obtain crude compound 18A (1.2 g). Crude compound 18A was purified by silica gel column chromatography (100-200 mesh) by elution with 30-35% ethyl acetate in hexane to obtain intermediate 18A (850 mg, yield 73%) as a pale yellow solid. 1 H-NMR(400MHz,DMSO-d6):δ8.76(t,J=1.6Hz,1H),8.64(d,J=2.8Hz,1H),8.09-8.05(m ,1H),6.53(s,J=1.2Hz,1H),2.82-2.78(m,2H),2.43-2.39(m,2H),2.10-2.03(m,2H).

[0321] Intermediate 19A: To a stirred solution of intermediate 18A (200 mg, 1.0 mmol) in THF (4 mL), R-tert-butylsulfonamide (140 mg, 1.1 mmol) was added under a nitrogen atmosphere, followed by the addition of titanium tetraethoxide (1.07 g, 4.7 mmol). The resulting reaction mixture was heated to 70°C and stirred for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with saturated NaHCO3 solution (5 mL) and stirred for 10 minutes. The reaction mixture was then filtered through a Celite bed and washed with ethyl acetate (10 mL). The filtrate was separated into layers, and the organic layer was evaporated under vacuum to obtain 120 mg of the imino compound as a yellow liquid. Next, the obtained imino compound was dissolved in THF (2.5 mL), cooled to -78°C, and DiBAL-H (1.0 M in toluene) (1.3 mL, 1.2 mmol) was added dropwise to the reaction mixture over 10-15 minutes. The reaction mixture was stirred at -78°C for 2 hours. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with saturated NH4Cl solution (5 mL), stirred for 10 minutes, and then extracted with ethyl acetate (10 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated under vacuum to obtain crude compound 19 (300 mg). Crude compound 19 was purified by silica gel (100-200 mesh) column chromatography by elution with 2-4% methanol in DCM to obtain racemic intermediate 19 (80 mg, yield 66%) as a yellow liquid. Intermediate 19A was isolated with 99.33% enantiomer purity by chiral preparative HPLC.

[0322] Intermediate 20: To a stirred solution of intermediate 19A (1 g, 3.3 mmol) in 1,4-dioxane (5 mL), 4 M HCl (20 mL) in dioxane was added, and the resulting reaction mixture was stirred for 2-3 hours. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under vacuum to obtain 1 g of compound 20 as an off-white solid (HCl salt). Compound 20 was further basicized with aqueous NaOH solution and then extracted in DCM (30 mL). The organic layer was separated and evaporated under vacuum to obtain intermediate 20 (650 mg, crude yield 100%) as a free base. 1H NMR(400MHz,DMSO-d6):δ8.52(t,J=2.0Hz,1H),8.44(d,J=2.8Hz,1H),7.74-7.70(m,1H),6.23(s,1H),2.27(br s, 2H), 1.90-1.84 (m, 3H), 1.65-1.61 (m, 1H).

[0323] Intermediate 18: To a stirred solution of intermediate 20 (600 mg, 3.0 mmol) in methanol (10 mL), 20% Pd(OH)2 (1.2 g, 200% w / w) was added at room temperature. The resulting reaction mixture was stirred for 16 hours under hydrogen pressure (60 psi). After the reaction was complete (monitored by TLC), the reaction product was filtered through a Celite pad. The filtrate was evaporated under vacuum to obtain intermediate 18 (470 mg, yield 81%) as an off-white liquid.

[0324] Compounds 43 and 44: Intermediate 10 (intermediate 5 from Example 1, 670 mg, 1.9 mmol) was combined with intermediate 18 (450 mg, 2.3 mmol) using the general procedure for compound 1 (Example 1) to obtain intermediate 20A (a mixture of compounds 43 / 44, 400 mg, yield 78%) as an off-white solid. Separation of isomers by SFC chromatography yielded compound 43 (158 mg) and compound 44 (125 mg). Compound 43: 1 H NMR(400MHz,DMSO-d6):δ8.82(d,J=2.4Hz,1H),8.53(s,1H),8.41(d,J=2.8Hz, 1H),8.38(t,J=1.6Hz,1H),8.16(dd,J=8.8,2.0Hz,1H),8.11(d,J=8.4Hz,1H),7 .63-7.59(m,1H),7.12(d,J=8.8Hz,1H),3.99-3.97(m,1H),3.89(s,3H),2.83( t,J=12.0Hz,2H),1.99-1.79(m,4H),1.64(q,J=12.0Hz,2H),1.53-1.38(m,3H). Compound 44: 1H NMR(400MHz,DMSO-d6):δ8.76(d,J=2.0Hz,1H),8.58(s,1H),8.42-8.40(m,2H), 8.18(dd,J=8.8,2.0Hz,1H),8.01(d,J=7.6Hz,1H),7.69-7.67(m,1H),7.14(d,J=8.8Hz,1H),4.27(br s,1H),3.90(s,3H),3.03(br s,1H),1.99-1.91(m,2H),1.88-1.83(m,2H),1.63(br s,4H).

[0325] Example 43 - General preparation of compounds 45-49 Compounds 45-49 were prepared according to the following scheme. [ka]

[0326] General procedure: To a stirred solution of intermediate 10 (intermediate 5 from Example 1, 0.58 mmol) and amino compounds (intermediates 11-15, 0.69 mmol) in DMF (5 mL), HATU (0.69 mmol) and triethylamine (4.9 mL, 2.90 mmol) were added at 0°C. The resulting reaction mixture was heated to room temperature and stirred for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was partitioned with water (5 mL) and ethyl acetate (10 mL). The organic layer was separated and washed with brine (5 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and evaporated to obtain the crude residue. The crude residue was purified by silica gel column chromatography (100-200 mesh) by elution with ethyl acetate in hexane to obtain compounds 45-49.

[0327] Example 44 - Preparation of Compound 45 According to Example 43, compound 45 was prepared using intermediate 10 (intermediate 5 from Example 1, 300 mg, 0.87 mmol), intermediate 11 (141 mg, 1.04 mmol), HATU (363 mg, 1.04 mmol), and triethylamine (0.6 mL, 4.35 mmol) in DMF (5 mL) to obtain the target compound (220 mg, yield 55%) as a white solid. 1 NMR(400MHz,DMSO-d6):δ8.79(d,J=2.0Hz,1H),8.52(s,1H),8.43(t,J=6.0Hz 1H),8.19(dd,J=8.8,2.8Hz,1H),7.29-7.26(m,2H),7.23-7.21(m,2H),7.19-7.12 (m,2H),3.89(s,3H),3.30-3.26(m,2H),2.61(t,J=6.4Hz,2H),1.86-1.79(m,2H).

[0328] Example 45 - Preparation of Compound 46 According to Example 43, compound 46 was prepared using intermediate 10 (intermediate 5 from Example 1, 200 mg, 0.58 mmol), intermediate 12 (103 mg, 0.69 mmol), HATU (264 mg, 0.69 mmol), and triethylamine (0.4 mL, 2.90 mmol) in DMF (5 mL) to obtain the target compound (135 mg, yield 49%) as a white solid. NMR(400MHz,DMSO-d6):δ8.79(d,J=2.0Hz,1H),8.52(s,1H),8.40(t,J=6.0Hz 1H),8.19(dd,J=8.8,2.4Hz,1H),7.14-7.11(m,1H),7.11-7.06(m,4H),3.89(s ,3H),3.28-3.25(m,2H),2.56(t,J=7.6Hz,2H),2.32(s,3H),1.81-1.78(m,2H).

[0329] Example 46 - Preparation of Compound 47 According to Example 43, compound 47 was prepared using intermediate 10 (intermediate 5 from Example 1, 200 mg, 0.58 mmol), intermediate 13 (0.11 mL, 0.69 mmol), HATU (264 mg, 0.69 mmol), and triethylamine (0.4 mL, 2.90 mmol) in DMF (3 mL) to obtain the target compound (127 mg, yield 45%) as an off-white solid. NMR(400MHz,DMSO-d6):δ8.79(d,J=2.4Hz,1H),8.52(s,1H),8.40(t,J=6.0Hz 1H),8.19(dd,J=8.8,2.0Hz,1H),7.13(d,J=8.8Hz,3H),6.85-6.81(m,2H),3.89( s,3H),3.71(s,3H),3.29-3.24(m,2H),2.54(t,J=7.2Hz,2H),1.82-1.75(m,2H).

[0330] Example 47 - Preparation of Compound 48 According to Example 43, compound 48 was prepared using intermediate 10 (intermediate 5 from Example 1, 200 mg, 0.58 mmol), intermediate 14 (117 mg, 0.69 mmol), HATU (264 mg, 0.69 mmol), and triethylamine (0.4 mL, 2.90 mol) in DMF (3 mL) to obtain the target compound (160 mg, yield 56%) as a white solid. NMR(400MHz,DMSO-d6):δ8.79(d,J=2.4Hz,1H),8.52(s,1H),8.40(t,J=6.0Hz 1H),8.19(dd,J=8.8,2.0Hz,1H),7.32(d,J=8.4Hz,2H),7.25(d,J=8.4Hz,2H),7.13(d, J=8.8Hz,1H),3.89(s,3H),3.28-3.25(m,2H),2.60(t,J=7.2Hz,2H),1.85-1.77(m,2H).

[0331] Example 48 - Preparation of Compound 49 According to Example 43, compound 49 was prepared using intermediate 10 (intermediate 5 from Example 1, 300 mg, 0.87 mmol), intermediate 15 (0.16 mL, 1.04 mmol), HATU (363 mg, 1.04 mmol), and triethylamine (0.6 mL, 4.35 mol) in DMF (5 mL) to obtain the target compound (210 mg, yield 46%) as a white solid. NMR(400MHz,DMSO-d6):δ8.80(d,J=2.4Hz,1H),8.52(s,1H),8.43(t,J=5.6Hz 1H),8.19(dd,J=8.4,2.0Hz,1H),7.53-7.50(m,2H),7.24(dd,J=8.0,1.6Hz,1H),7.13(d,J =8.8Hz,1H),3.90(s,3H),3.28(q,J=6.4Hz,2H),2.63(t,J=7.6Hz,2H),1.85-1.81(m,2H). Example 49 - General synthesis route of compounds 50-53 and 55-58 [ka]

[0332] Generally, compounds 50-53 and 55-58 were prepared according to the above scheme. As shown in the figure, carboxylic acid starting material 1 was converted to acid chloride intermediate 2 by reaction with oxalyl chloride and catalyst DMF. Subsequently, cyclization to oxazole intermediate 4 occurred by reaction of intermediate 2 with isocyanate 3. Intermediate 4 was esterified hydrolyzed with NaOH to produce carboxylic acid intermediate 5. Finally, the target compound was obtained by coupling with amine intermediate 6. Specific conditions and analytical data are described in Examples 50-60.

[0333] General preparation procedure for intermediate 2: To a stirred suspension of substituted benzoic acid (1) (1.79 mmol) in DCM (5 mL), oxalyl chloride (2.69 mmol) and a few drops of DMF were added at 0°C. The resulting reaction mixture was heated to room temperature and stirred for 2-4 hours. After the reaction was complete (monitored by TLC), the reaction mixture was evaporated under reduced pressure in a nitrogen atmosphere to obtain the crude residue. The crude residue of intermediate 2 obtained was used directly in the next step without further purification.

[0334] General preparation procedure for intermediate 4: To a stirred solution of intermediate 3 (1.79 mmol) in dry THF (5 mL), tert-butoxide potassium (5.37 mmol) was gradually added at 0°C and stirred for 15 minutes. Then, intermediate 2 (1.79 mmol) dissolved in dry THF (5 mL) was added dropwise to the reaction mixture at the same temperature. The resulting reaction mixture was stirred at room temperature for 2-4 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with saturated ammonium chloride (5 mL) and extracted with SiO2 (2 x 10 mL). The combined organic phases were washed with brine (2 mL), dried over anhydrous Na2SO4, filtered, and evaporated to obtain the crude residue. The crude residue was further purified by silica gel (100-200 mesh) column chromatography by elution with ethyl acetate in hexane to obtain intermediate 4.

[0335] General preparation procedure for intermediate 5: To a stirred solution of intermediate 4 (0.34 mmol) in THF (5 mL), 1 M NaOH solution (0.5 mL, 0.52 mmol) was added at 0°C. The resulting reaction mixture was stirred at room temperature for 12-16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was evaporated under reduced pressure to obtain the crude residue. The crude residue was placed in water (5 mL), extracted with ethyl acetate (10 mL), the organic layer was separated, the aqueous layer was acidified with 1 N HCl (pH 1-2), the precipitated solid was filtered, washed with water (5 mL), and the product was dried under vacuum at 45-50°C to obtain intermediate 5.

[0336] General preparation procedure for compounds 50-53 and 55-58: Intermediate 5 (0.58 mmol) and intermediate 6 (0.69 mmol) were stirred in DMF (5 mL), to which HATU (0.69 mmol) and triethylamine (4.9 mL, 2.90 mmol) were added at 0°C. The resulting reaction mixture was heated to room temperature and stirred for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was partitioned with water (5 mL) and ethyl acetate (10 mL). The organic layer was separated and washed with brine (5 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and evaporated to obtain the crude residue. The crude residue was purified by silica gel column chromatography (100-200 mesh) by elution with ethyl acetate in hexane to obtain the desired target compound.

[0337] Preparation of Intermediate 6 from Examples 50-49 Intermediate 6 from Example 49 was prepared according to the following scheme. [ka]

[0338] Intermediate 2: To a stirred solution of 3-bromo-5-fluoropyridine (1) (12.0 g, 68.18 mmol) in triethylamine (120 mL), propa-2-in-1-ol (7.6 g, 137.13 mmol) was added in a sealed tube, and the reaction mixture was degassed under a nitrogen atmosphere for 15 minutes. Next, Pd(PPh3)2Cl2 (2.38 g, 3.40 mmol) and CuI (1.29 g, 6.85 mmol) were added, and the mixture was degassed for 15 minutes. The resulting reaction mixture was heated to 100°C and stirred for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was filtered through a Celite pad. The filter cake was thoroughly washed with DCM, and the filtrate was evaporated under reduced pressure to obtain the crude residue (21.0 g). The resulting residue was further purified by silica gel (100-200 mesh) column chromatography by elution with 45-50% ethyl acetate in hexane to obtain intermediate 2 (8.6 g, yield 83%) as a pale yellow liquid. ¹H NMR (400 MHz, DMSO-d6): δ 8.59 (d, J=2.4 Hz, 1 H), 8.51 (br s, 1 H), 7.89-7.75 (m, 1 H), 5.46 (t, J=6.0 Hz, 1 H), 4.34 (d, J=6.0 Hz, 1 H).

[0339] Intermediate 3: To a stirred suspension of palladium carbon (10% wet) (1.8 g) in methanol (100 mL), 3-(5-fluoropyridine-3-yl)prop-2-in-1-ol (2) (8.5 g, 56.23 mmol) was added at room temperature, and the resulting reaction mixture was stirred for 16 hours under hydrogen pressure (60 Psi). After the reaction was complete (monitored by TLC), the mixture was filtered through a Celite pad. The filtrate cake was thoroughly washed with MeOH (50 mL), and the filtrate was evaporated under reduced pressure to obtain the crude residue (8.2 g). The obtained crude residue was purified by silica gel column chromatography (100-200 mesh) by elution with 50-55% ethyl acetate in hexane to obtain Intermediate 3 (6.4 g, yield 73%) as an off-white solid. 1H NMR (400MHz, DMSO-d6): δ8.38(d,J=2.8Hz,1H),8.32(s,1H),7.61-7.57(m,1H),4.53(t,J=5.2 Hz,1H),3.41(q,J=6.0Hz,2H)2.77(t,J=5.2Hz,2H),2.67(t,J=7.6Hz,2H),1.77-1.70(m,2H).

[0340] Intermediate 4: To a stirred solution of Intermediate 3 (6.4 g, 41.29 mmol) in THF (120 mL), PPh3 (21.6 g, 82.5 mmol) and phthalimide (12.0 g, 41.29 mmol) were sequentially added at room temperature, and the mixture was stirred for 10 minutes. The reaction mixture was then cooled to 0°C, DIAD (16.7 mL, 82.5 mmol) was added dropwise, and the reaction mixture was heated to room temperature and stirred for 16 hours. After the reaction was completed by TLC, the reaction mixture was evaporated under reduced pressure to obtain the crude residue. The obtained crude residue was purified by silica gel column chromatography (100-200 mesh) using ethyl acetate in hexane (50:50) as the eluent to obtain Intermediate 4 (10.4 g, yield 89%) as a pale yellow solid.

[0341] Intermediate 6: To a stirred solution of intermediate 4 (10.0 g, 35.17 mmol) in MeOH (100 mL), N2H4.H2O (4.5 mL, 91.45 mmol) was added at room temperature and the mixture was stirred for 16 hours. After the reaction was completed by TLC, the reaction mixture was evaporated under reduced pressure to obtain the crude residue. The crude residue was washed with SiO2 and filtered. The filtrate was evaporated under reduced pressure to obtain the crude residue, which was further purified by silica gel column chromatography (100-200 mesh) using (5:10:85)(Aq.NH3:MeOH:DCM) as the eluent to obtain intermediate 6 (1.2 g, yield 18.4%) as a colorless liquid. 1 H NMR (400MHz, CDCl3): δ8.40(d,J=2.4Hz,2H),8.34(s,1H),7.65(d,J=9.6Hz,1H),2.77-2.67(m,4H),1.91-1.87(m,2H).

[0342] Example 51 - Preparation of Compound 50 Intermediate 2: Intermediate 2 was prepared according to the general preparation procedure for Intermediate 2 (Example 49) using 4-fluorobenzoic acid (2.0 g, 14.28 mmol) and oxalyl chloride (1.84 mL, 21.42 mmol) in DCM (10 mL) to obtain the target compound (2.4 g, 100% yield).

[0343] Intermediate 4: Intermediate 4 was prepared according to the general preparation procedure for intermediate 4 (Example 49) using intermediate 3 (1.7 g, 15.13 mmol), tert-butoxide potassium (5.1 g, 45.40 mmol), and intermediate 2 (2.4 g, 15.13 mmol) in dry THF (20 mL) to obtain the target compound (1.4 g, yield 39%) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d6): δ8.57(s,1H),8.05-8.01(m,2H),7.42-7.37(m,2H),4.26(q,J=7.2Hz,2H),1.25(t,J=7.2Hz,3H).

[0344] Intermediate 5: Intermediate 5 was prepared according to the general preparation procedure for intermediate 5 (Example 49) using intermediate 4 (1.1 g, 4.68 mmol) in THF (12 mL) and a 1 M NaOH solution (7.0 mL, 7.02 mmol) to obtain the target compound (0.9 g, 62% yield) as an off-white solid. 1 H NMR (400MHz, DMSO-d6): δ13.21 (br s, 1H), 8.53 (s, 1H), 8.08-8.04 (m, 2H), 7.37 (t, J = 8.8Hz, 1H).

[0345] Compound 50: Compound 50 was prepared according to the general manufacturing procedure for target compounds 50-53 and target compounds 55-58 (Example 49) using intermediate 5 (300 mg, 1.45 mmol), intermediate 6 (Example 50, 141 mg, 1.74 mmol), HATU (660 mg, 1.74 mmol), and triethylamine (1.0 mL, 7.25 mmol) in DMF (5 mL) to obtain the target compound (160 mg, yield 32%) as a white solid. 1H NMR(400MHz,DMSO-d6):δ8.58(s,1H),8.51(t,J=6.4Hz,1H),8.38(d,J=2.8Hz,1H),8.35(s,1H),8.31-8.27(m, 2H),7.64(d,J=10.0Hz,1H),7.35(t,J=8.8Hz,2H),3.30-3.27(m,2H),2.68(t,J=7.6Hz,2H),1.88-1.85(m,2H).

[0346] Example 52 - Preparation of Compound 51 Intermediate 2: Intermediate 2 was prepared according to the general manufacturing procedure for Intermediate 2 (Example 49) using 4-(methylsulfonamide)benzoic acid (500 mg, 2.32 mmol) and oxalyl chloride (0.3 mL, 3.48 mmol) in DCM (5 mL) to obtain the target compound (0.6 g, 100% yield).

[0347] Intermediate 4: Intermediate 4 was prepared according to the general preparation procedure for intermediate 4 (Example 49) using intermediate 3 (0.29 g, 2.56 mmol), tert-butoxide potassium (0.87 g, 7.70 mmol), and intermediate 2 (0.6 g, 2.56 mmol) in dry THF (10 mL) to obtain the target compound (0.41 g, yield 51%) as a pale yellow solid.

[0348] Intermediate 5: Intermediate 5 was prepared according to the general preparation procedure for intermediate 5 (Example 49) using intermediate 4 (0.4 g, 1.29 mmol) in THF (5 mL) and a 1 M NaOH solution (1.9 mL, 1.9 mmol) to obtain the target compound (0.25 g, 69% yield) as an off-white solid.

[0349] Compound 51: Compound 51 was prepared using intermediate 5 (200 mg, 0.71 mmol), intermediate 6 (Example 50, 130 mg, 0.85 mmol), HATU (323 mg, 0.85 mmol), and triethylamine (0.5 mL, 3.55 mmol) in DMF (5 mL) according to the general manufacturing procedure for target compounds 50-53 and target compounds 55-58 (Example 49), to obtain the target compound (120 mg, 40% yield) as a white solid. 1H NMR (400MHz, DMSO-d6): δ10.09(s,1H),8.54(s,1H),8.45(t,J=5.6Hz,1H),8.38(d,J=2.8Hz,1H),8.35(s,1H),8.18(d,J=8.8H) z,2H),7.64(d,J=10.0Hz,1H),7.29(d,J=8.8Hz,2H),3.29-3.26(m,2H),3.07(s,3H),2.68(t,J=7.6Hz,2H),1.90-1.83(m,2H).

[0350] Example 53 - Preparation of Compound 52 Intermediate 2: Intermediate 2 was prepared according to the general preparation procedure for Intermediate 2 (Example 49) using 4-acetamidobenzoic acid (1.0 g, 5.58 mmol) and oxalyl chloride (0.71 mL, 8.37 mmol) in DCM (10 mL) to obtain the target compound (1.2 g, 100% yield).

[0351] Intermediate 4: Intermediate 4 was prepared according to the general preparation procedure for intermediate 4 (Example 49) using intermediate 3 (0.69 g, 6.07 mmol), tert-butoxide potassium (2.04 g, 18.21 mmol), and intermediate 2 (1.2 g, 6.07 mmol) in dry THF (20 mL) to obtain the target compound (0.8 g, yield 48%) as a pale yellow solid.

[0352] Intermediate 5: Intermediate 5 was prepared according to the general preparation procedure for intermediate 5 (Example 49) using intermediate 4 (0.8 g, 2.91 mmol) in THF (5 mL) and a 1 M NaOH solution (4.4 mL, 4.37 mmol) to obtain the target compound (0.45 g, 63% yield) as an off-white solid.

[0353] Compound 52: Compound 52 was prepared using intermediate 5 (200 mg, 0.81 mmol), intermediate 6 (Example 50, 150 mg, 0.97 mmol), HATU (370 mg, 0.97 mmol), and triethylamine (0.5 mL, 4.05 mmol) in DMF (5 mL) according to the general preparation procedure for target compounds 50-53 and target compounds 55-58 (Example 49), to obtain the target compound (170 mg, yield 55%) as a white solid. 1 H NMR (400MHz, DMSO-d6): δ10.17(s,1H),8.52(s,1H),8.44(t,J=5.6Hz,1H),8.38(d,J=2.4Hz,1H),8.35(s,1H),8.17(d,J=8.8H) z,2H),7.69(d,J=8.8Hz,2H),7.64(d,J=10.4Hz,1H),3.29-3.26(m,2H),2.68(t,J=7.6Hz,2H),2.07(s,3H),1.90-1.83(m,2H).

[0354] Example 54 - Preparation of intermediate 5 of compound 53 Intermediate 2: Intermediate 2 was prepared using 4-(tert-butoxycarbonyl)benzoic acid (500 mg, 2.25 mmol) and oxalyl chloride (0.3 mL, 3.37 mmol) in DCM (5 mL) according to the general manufacturing procedure for Intermediate 2 (Example 49), to obtain the target compound (580 mg, 100% yield).

[0355] Intermediate 4: Intermediate 4 was prepared according to the general preparation procedure for intermediate 4 (Example 49) using intermediate 3 (0.27 g, 2.41 mmol), tert-butoxide potassium (0.81 g, 7.22 mmol), and intermediate 2 (0.58 g, 2.41 mmol) in dry THF (10 mL) to obtain the target compound (0.35 g, yield 46%) as a pale yellow solid.

[0356] Intermediate 5: Intermediate 5 was prepared according to the general preparation procedure for intermediate 5 (Example 49) using intermediate 4 (0.35 g, 1.10 mmol) in THF (10 mL) and a 1 M NaOH solution (1.6 mL, 1.6 mmol) to obtain the target compound (0.18 g, yield 57%) as an off-white solid.1 H NMR (400MHz, DMSO-d6): δ13.33 (br s, 1H), 8.62 (s, 1H), 8.13 (d, J = 8.4 Hz, 2H), 8.03 (d, J = 8.8 Hz, 2H).

[0357] Example 55 - Preparation of Compound 55 Intermediate 2: Intermediate 2 was prepared according to the general preparation procedure for Intermediate 2 (Example 49) using 4-nitrobenzoic acid (2.0 g, 11.97 mmol) and oxalyl chloride (1.54 mL, 17.96 mmol) in DCM (20 mL) to obtain the target compound (2.4 g, 100% yield).

[0358] Intermediate 4: Intermediate 4 was prepared according to the general preparation procedure for Intermediate 4 (Example 49) using Intermediate 3 (1.46 g, 12.92 mmol), tert-butoxide potassium (4.4 g, 38.76 mmol), and Intermediate 2 (2.4 g, 12.92 mmol) in dry THF (20 mL) to obtain the target compound (1.3 g, yield 38%) as an off-white solid.

[0359] Intermediate 5: Intermediate 5 was prepared according to the general preparation procedure for intermediate 5 (Example 49) using intermediate 4 (1.1 g, 4.19 mmol) in THF (12 mL) and a 1 M NaOH solution (6.3 mL, 6.3 mmol) to obtain the target compound (0.7 g, yield 71%) as an off-white solid.

[0360] Compound 55: Compound 55 was prepared according to the general manufacturing procedure (Example 49) for target compounds 50-53 and target compounds 55-58 using intermediate 5 (200 mg, 0.85 mmol), intermediate 6 (Example 50, 157 mg, 1.02 mmol), HATU (389 mg, 1.02 mmol), and triethylamine (0.6 mL, 5.10 mmol) in DMF (5 mL) to obtain the target compound (170 mg, yield 58%) as a white solid. 1H NMR(400MHz,DMSO-d6):δ8.74(s,1H),8.67(t,J=5.6Hz,1H),8.52(d,J=8.8Hz,1H),8.39-8.3 4(m,4H),7.64(d,J=10.0Hz,1H),3.31-3.29(m,2H),2.69(t,J=7.6Hz,2H),1.92-1.87(m,2H).

[0361] Example 56 - Preparation of Compound 56 Intermediate 2: Intermediate 2 was prepared according to the general preparation procedure for Intermediate 2 (Example 49) using 4-acetylbenzoic acid (1.0 g, 6.09 mmol) and oxalyl chloride (0.78 mL, 9.14 mmol) in DCM (10 mL) to obtain the target compound (1.2 g, 100% yield).

[0362] Intermediate 4: Intermediate 4 was prepared according to the general preparation procedure for intermediate 4 (Example 49) using intermediate 3 (0.75 g, 6.57 mmol), tert-butoxide potassium (2.23 g, 19.71 mmol), and intermediate 2 (1.2 g, 6.57 mmol) in dry THF (20 mL) to obtain the target compound (0.8 g, crude yield 47%) as a brown liquid.

[0363] Intermediate 5: Intermediate 5 was prepared according to the general preparation procedure for intermediate 5 (Example 49) using intermediate 4 (0.75 g, 2.89 mmol) in THF (10 mL) and a 1 M NaOH solution (4.3 mL, 4.3 mmol) to obtain the target compound (0.32 g, yield 48%) as an off-white solid.

[0364] Compound 56: Compound 56 was prepared according to the general manufacturing procedure for target compounds 50-53 and target compounds 55-58 (Example 49) using intermediate 5 (240 mg, 1.04 mmol), intermediate 6 (Example 50, 191 mg, 1.24 mmol), HATU (473 mg, 1.24 mmol), and triethylamine (0.73 mL, 5.20 mmol) in DMF (5 mL) to obtain the target compound (160 mg, yield 42%) as a white solid. 1H NMR (400MHz, DMSO-d6): δ8.67(s,1H),8.59(t,J=5.6Hz,1H),8.38(d,J=2.8Hz,1H),8.37(s,1H),8.35(s,2H),8. 06(d,J=8.4Hz,2H),7.66-7.63(m,1H),3.30-3.28(m,2H),2.69(t,J=7.6Hz,2H),2.62(s,3H),1.89-1.87(m,2H).

[0365] Example 57 - Preparation of Compound 57 Intermediate 2: Intermediate 2 was prepared according to the general manufacturing procedure for Intermediate 2 (Example 49) using 4-(methylsulfonyl)benzoic acid (1.0 g, 5.0 mmol) and oxalyl chloride (0.63 mL, 7.50 mmol) in DCM (10 mL) to obtain the target compound (1.2 g, 100% yield).

[0366] Intermediate 4: Intermediate 4 was prepared according to the general preparation procedure for Intermediate 4 (Example 49) using Intermediate 3 (0.62 g, 5.50 mmol), tert-butoxide potassium (1.85 g, 16.51 mmol), and Intermediate 2 (1.2 g, 5.50 mmol) in dry THF (20 mL) to obtain the target compound (0.7 g, crude yield 43%) as a brown liquid.

[0367] Intermediate 5: Intermediate 5 was prepared according to the general preparation procedure for intermediate 5 (Example 49) using intermediate 4 (0.65 g, 2.20 mmol) in THF (10 mL) and a 1 M NaOH solution (3.5 mL, 3.5 mmol) to obtain the target compound (0.2 g, yield 43%) as an off-white solid.

[0368] Compound 57: Compound 57 was prepared using intermediate 5 (200 mg, 0.75 mmol), intermediate 6 (Example 50, 138 mg, 0.90 mmol), HATU (341 mg, 0.90 mmol), and triethylamine (0.52 mL, 3.75 mmol) in DMF (5 mL) according to the general preparation procedure for target compounds 50-53 and target compounds 55-58 (Example 49), to obtain the target compound (130 mg, yield 43%) as an off-white solid.1 H NMR (400MHz, DMSO-d6): δ8.70(s,1H),8.63(t,J=5.6Hz,1H),8.46(d,J=8.8Hz,2H),8.38(d,J=2.8Hz,1H),8.35(s,1H) ),8.04(d,J=8.4Hz,2H),7.66-7.63(m,1H),3.31-3.29(m,2H),3.27(s,3H),2.69(t,J=7.6Hz,2H),1.91-1.84(m,2H).

[0369] Example 58 - Preparation of intermediate 5 of compound 58

[0370] Intermediate 2: Intermediate 2 was prepared according to the general preparation procedure for Intermediate 2 (Example 49) using 4-(N-(tert-butoxycarbonyl)sulfamoyl)benzoic acid (1.0 g, 3.3 mmol) and oxalyl chloride (0.43 mL, 4.97 mmol) in DCM (10 mL) to obtain the target compound (1.2 g, 100% yield).

[0371] Intermediate 4: Intermediate 4 was prepared according to the general preparation procedure for Intermediate 4 (Example 49) using Intermediate 3 (0.43 g, 3.75 mmol), tert-butoxide potassium (1.26 g, 11.25 mmol), and Intermediate 2 (1.2 g, 3.75 mmol) in dry THF (20 mL) to obtain the target compound (0.6 g, yield 40%) as a pale yellow liquid.

[0372] Intermediate 5: Intermediate 5 was prepared according to the general preparation procedure for intermediate 5 (Example 49) using intermediate 4 (0.6 g, 1.51 mmol) in THF (10 mL) and a 1 M NaOH solution (3.2 mL, 3.2 mmol) to obtain the target compound (0.22 g, yield 39%) as an off-white solid. 1 H NMR (400MHz, DMSO-d6): δ13.39 (s, 1H), 11.80 (s, 1H), 8.63 (s, 1H), 8.22 (d, J = 8.8Hz, 2H), 8.00-7.97 (m, 2H).

[0373] Example 59 - Preparation of Compound 53 and Compound 54 Compounds 53 and 54 were prepared according to the following scheme. [ka]

[0374] Intermediate 5A: Following the general manufacturing procedure for target compounds 50-53 and 55-58 (Example 49), intermediate 5A was prepared using intermediate 5 (Example 54, 200 mg, 0.69 mmol), intermediate 6 (Example 50, 128 mg, 0.83 mmol), HATU (316 mg, 0.83 mmol), and triethylamine (0.49 mL, 3.45 mmol) in DMF (5 mL) to obtain the target compound (180 mg, yield 61%) as an off-white solid.

[0375] Compound 54: To a stirred solution of intermediate 5A (180 mg, 0.42 mmol) in DCM (6 mL), TFA (2 mL) was added at room temperature and the mixture was stirred for 4 hours. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under reduced pressure to obtain compound 54 (180 mg, yield 88%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6):δ13.21(br s,1H),8.66(s,1H),8.58(t,J=6.0Hz,1H),8.41(d,J=2.8Hz,1H),8.36(s,1H),8.34(d,J=8.4Hz,2H),8. 04(d,J=8.4Hz,2H),7.70-7.67(m,1H),3.30(q,J=6.8Hz,2H),2.69(t,J=7.2Hz,2H),1.89-1.86(m,2H).

[0376] Compound 53: To a stirred solution of Compound 54 (180 mg, 0.37 mmol) and ammonium chloride (78 mg, 1.12 mmol) in DMF (3 mL), HATU (222 mg, 0.45 mmol) and triethylamine (0.4 mL, 2.22 mmol) were added at 0°C. The resulting reaction mixture was heated to room temperature and stirred for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was partitioned with water (5 mL) and ethyl acetate (10 mL). The organic layer was separated and washed with brine (5 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and evaporated to obtain a crude residue of 280 mg. The crude residue was purified by silica gel column chromatography (100-200 mesh) by elution with 30% ethyl acetate in hexane to obtain Compound 53 (130 mg, yield 61%). 1 H NMR (400MHz, DMSO-d6): δ8.63(s,1H),8.55(t,J=6.0Hz,1H),8.38(d,J=2.8Hz,1H),8.35(s,1H),8.29(d,J=8.4Hz,1H),8.08(s,1H) ),7.97(d,J=8.8Hz,2H),7.66-7.63(m,1H),7.48(s,1H),3.12-3.27(m,2H),3.27(s,3H),2.67(t,J=7.6Hz,2H),1.91-1.84(m,2H).

[0377] Example 60 - Preparation of Compound 58 Compound 58 was prepared according to the following scheme. [ka]

[0378] Intermediate 5A: Following the general manufacturing procedure for target compounds 50-53 and 55-58 (Example 49), intermediate 5A was prepared using intermediate 5 (Example 58, 200 mg, 0.54 mmol), intermediate 6 (Example 50, 102 mg, 0.65 mmol), HATU (247 mg, 0.65 mmol), and triethylamine (0.4 mL, 2.7 mmol) in DMF (5 mL) to obtain the target compound (130 mg, yield 48%) as an off-white solid.

[0379] Compound 58: To a stirred solution of intermediate 5A (125 mg, 0.25 mmol) in dioxane (1 mL), a 4 M HCl dioxane solution (3 mL) was added at 0°C. The resulting reaction mixture was heated to room temperature and stirred for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was evaporated under vacuum. The resulting crude compound was ground with hexane (10 mL) to precipitate the solid, which was filtered, washed with hexane (5 mL), and dried under vacuum to obtain compound 58 (70 mg, yield 57%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6):δ8.67(s,1H),8.59(t,J=6.0Hz,1H),8.39-8.35(m,4H),7.92(d,J=8.8Hz,2H),8.0 8(s,1H),7.67-7.64(m,1H),7.48(s,2H),3.28(q,J=6.8Hz,2H),2.69(t,J=7.6Hz,2H),1.91-1.84(m,2H). Example 61 - General synthesis routes for compounds 59, 60, 62, 63, 75, and 77 [ka]

[0380] Generally, compounds 59, 60, 62, 63, 75, and 77 were prepared according to the above scheme. As shown in the figure, carboxylic acid starting material 1 was converted to acid chloride intermediate 2 by reaction with oxalyl chloride and catalyst DMF. Subsequently, cyclization to oxazole intermediate 4 occurred by reaction of intermediate 2 with isocyanate 3. Intermediate 4 was esterified hydrolyzed with NaOH to produce carboxylic acid intermediate 5. Finally, the target compound was obtained by coupling with amine intermediate 6. Specific conditions and analytical data are described in Examples 62-67.

[0381] General preparation procedure for intermediate 2: To a stirred suspension of substituted benzoic acid (1) (1.79 mmol) in DCM (5 mL), oxalyl chloride (2.69 mmol) and a few drops of DMF were added at 0°C. The resulting reaction mixture was heated to room temperature and stirred for 2-4 hours. After the reaction was complete (monitored by TLC), the reaction mixture was evaporated under reduced pressure in a nitrogen atmosphere to obtain the crude residue. The crude residue of intermediate 2 obtained was used directly in the next step without further purification.

[0382] General preparation procedure for intermediate 4: To a stirred solution of intermediate 3 (1.79 mmol) in dry THF (5 mL), tert-butoxide potassium (5.37 mmol) was gradually added at 0°C and stirred for 15 minutes. Then, intermediate 2 (1.79 mmol) dissolved in dry THF (5 mL) was added dropwise to the reaction mixture at the same temperature. The resulting reaction mixture was stirred at room temperature for 2-4 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with saturated ammonium chloride (5 mL) and extracted with SiO2 (2 x 10 mL). The combined organic phases were washed with brine (2 mL), dried over anhydrous Na2SO4, filtered, and evaporated to obtain the crude residue. The crude residue was further purified by silica gel (100-200 mesh) column chromatography by elution with ethyl acetate in hexane to obtain intermediate 4.

[0383] General preparation procedure for intermediate 5: To a stirred solution of intermediate 4 (0.34 mmol) in THF (5 mL), 1 M NaOH solution (0.5 mL, 0.52 mmol) was added at 0°C. The resulting reaction mixture was stirred at room temperature for 12-16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was evaporated under reduced pressure to obtain the crude residue. The crude residue was placed in water (5 mL), extracted with ethyl acetate (10 mL), the organic layer was separated, the aqueous layer was acidified with 1 N HCl (pH 1-2), the precipitated solid was filtered, washed with water (5 mL), and the product was dried under vacuum at 45-50°C to obtain intermediate 5.

[0384] General preparation procedure for target compounds 59, 60, 62, 63, 75, and 77: To a stirred solution of intermediate 5 (0.58 mmol) and intermediate 6 (Example 50, 0.69 mmol) in DMF (5 mL), HATU (0.69 mmol) and triethylamine (4.9 mL, 2.90 mmol) were added at 0°C. The resulting reaction mixture was heated to room temperature and stirred for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was partitioned with water (5 mL) and ethyl acetate (10 mL). The organic layer was separated and washed with brine (5 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated to obtain the crude residue. The crude residue was purified by silica gel column chromatography (100-200 mesh) by elution with ethyl acetate in hexane to obtain the target compounds.

[0385] Example 62 - Preparation of Compound 59 Preparation of Intermediate 2: Following the general preparation procedure for Intermediate 2 in Example 61, Intermediate 2 was prepared using 3-bromo-4-methoxybenzoic acid (1.0 g, 4.32 mmol) and oxalyl chloride (0.55 mL, 6.49 mmol) in DCM (5 mL) to obtain the target compound (1.2 g, crude yield 100%).

[0386] Preparation of Intermediate 4: Following the general preparation procedure for Intermediate 4 in Example 61, Intermediate 4 was prepared using Intermediate 3 (0.54 g, 4.80 mmol), tert-butoxide potassium (1.7 g, 14.43 mmol), and Intermediate 2 (1.2 g, 4.80 mmol) in dry THF (12 mL) to obtain the target compound (0.6 g, yield 38%).

[0387] Preparation of Intermediate 5: Following the general preparation procedure for Intermediate 5 in Example 61, Intermediate 5 was prepared using Intermediate 4 (0.5 g, 1.53 mmol) in THF (5 mL) and a 1 M NaOH solution (1.96 mL, 1.96 mmol) to obtain the target compound (0.3 g, 67% yield) as an off-white solid.

[0388] Preparation of Compound 59: Following the general preparation procedure for the target compound of Example 61, Compound 59 was prepared using intermediate 5 (200 mg, 0.67 mmol), intermediate 6 (Example 50, 124 mg, 0.80 mmol), HATU (306 mg, 0.80 mmol), and triethylamine (0.47 mL, 3.35 mmol) in DMF (2 mL) to obtain Compound 59 (94 mg, yield 29%) as an off-white solid. 1 H NMR (400MHz, DMSO-d6): δ8.67(d,J=2.0Hz,1H),8.55(s,1H),8.49(t,J=6.0Hz,1H),8.38(d,J=2.8Hz,1H),8.35(s,1H),8.15(dd,J=8 .8Hz,2.4Hz,1H),7.67-7.63(m,1H),7.25(d,J=8.8Hz,1H),3.92(s,3H),3.31-3.27(m,2H),2.68(t,J=7.2Hz,2H),1.88-1.85(m,2H).

[0389] Example 63 - Preparation of Compound 60 Preparation of Intermediate 2: Following the general preparation procedure for Intermediate 2 in Example 61, Intermediate 2 was prepared using 3-chloro-4-methoxybenzoic acid (1 g, 5.36 mmol) and oxalyl chloride (0.69 mL, 8.04 mmol) in DCM (5 mL) to obtain the target compound (1.2 g, crude yield 100%).

[0390] Preparation of Intermediate 4: Following the general preparation procedure for Intermediate 4 in Example 61, Intermediate 4 was prepared using Intermediate 3 (0.66 g, 5.85 mmol), tert-butoxide potassium (1.97 g, 17.55 mmol), and Intermediate 2 (1.2 g, 5.85 mmol) in dry THF (12 mL) to obtain the target compound (0.41 g, yield 38%).

[0391] Preparation of Intermediate 5: Following the general preparation procedure for Intermediate 5 in Example 61, Intermediate 5 was prepared using Intermediate 4 (0.6 g, 2.13 mmol) in THF (6 mL) and 1 M NaOH (3.1 mL, 3.1 mmol) to obtain the target compound (0.33 g, 61% yield) as an of...

Claims

1. A GSK-3β inhibitor for therapeutic use having the structure of formula I. 【Chemistry 1】 (In the formula, R １ is, L １ ~R ５ And, R ２ is, L ２ ~R ６ And, R ３ is H or C １ -C ６ alkyl, R ４ is H or C １ ~C ６ It is alkyl, R ５ R is a 5-membered heteroaryl ring, a 6-membered aryl ring, a 6-membered heteroaryl ring, or an 8-12 membered fused bicyclic aryl or heteroaryl ring system, where R ５ is -(C=O) ｑ - (C １ ~C ６ Alkyl), F, Cl, Br, I, OR ９ , SR ９ S(O)R ９ , S(O) ２ R ９ , N(R ９ ) ２ ,CN,C(O)OR １０ , C(O)N(R １０ ) ２ , S(O) ２ OR １０ , P(O)(OR １０ ) ２ , and - (CH ２ ) ｓ -R １１ It is arbitrarily replaced by 1 to 3 elements independently selected from, R ６ R is a 5-6 member heteroaryl ring, a 6 member aryl ring, or a 6 member heteroaryl ring, where R ６ is -(C=O) ｕ - (C １ ~C ６ Alkyl), F, Cl, Br, I, NO ２ , OR １３ , SR １３ S(O)R １３ , S(O) ２ R １３ , S(O) ２ N(R) １３ ) ２ , N(R １３ ) ２ ,CN,C(O)OR １４ , C(O)N(R １４ ) ２ , S(O) ２ OR １４ , and P(O)(OR １４ ) ２ It is arbitrarily replaced by 1 to 3 elements independently selected from, R ７ H, OR ８ , or N(R ８ ) ２ And, Each R ８ These are independently H or -(C=O) ｐ - (C １ ~C ６ It is alkyl, Each R ９ These are independently H, -(C=O) ｒ - (C １ ~C ６ Alkyl), or -(C=O) ｒ - (CH ２ ) ｘ - (C ３ ~C ６ It is a cycloalkyl group, Each R １０ H or C １ ~C ６ It is alkyl, Each R １１ H, OR １２ , or N(R １２ ) ２ And, Each R １２ These are independently H or -(C=O) ｔ - (C １ ~C ６ It is alkyl, Each R １３ is independently H, -(C=O) ｖ -(C １ ~C ６ alkyl), or S(O) ２ R １４ and is Each R １４ H or C １ ~C ６ It is alkyl, L １ is a directly bonded one, -(CH ２ ) ｎ -, a 3- to 7-member cycloalkyl or heterocyclic ring, a 5- to 6-member heteroaryl ring or a 6-member aryl ring, where any carbon atom of L １ is optionally substituted by one or two -(CH ２ ) ｏ -R ７ and L ２ L is a 5-6 member heteroaryl ring, a 6 member aryl ring, or a 6 member heteroaryl ring, where L ２ is 1 to 2 C １ ~C ６ Optionally substituted with alkyl groups, X is O or N-R ３ And, Y is O or N-R ４ And, n is an integer between 1 and 5. o is 0 or an integer from 1 to 4. Each p is independently either 0 or 1. Each q is independently either 0 or 1. Each r is independently either 0 or 1. Each s is independently 0 or an integer from 1 to 3. Each t is independently either 0 or 1. Each u is independently either 0 or 1. Each v is independently either 0 or 1. Each w is independently either 0 or 1. x is an integer between 0 and 3. Each solid center is independently R, S, or a racemate. 【Request Item 2】 【Chemistry 2】 【Transformation 3】 【Chemistry 4】 【Transformation 5】 The GSK-3β inhibitor according to claim 1, having one of the structures 2 to 101.

3. A method for producing a GSK-3β inhibitor for therapeutic use having the structure of formula I, 【Transformation 6】 (In the formula, R １ is, L １ ~R ５ And, R ２ is, L ２ ~R ６ And, R ３ is H or C １ ~C ６ It is alkyl, R ４ is H or C １ ~C ６ It is alkyl, R ５ R is a 5-membered heteroaryl ring, a 6-membered aryl ring, a 6-membered heteroaryl ring, or an 8-12 membered fused bicyclic aryl or heteroaryl ring system, where R ５ is -(C=O) ｑ - (C １ ~C ６ Alkyl), F, Cl, Br, I, OR ９ , SR ９ S(O)R ９ , S(O) ２ R ９ , N(R ９ ) ２ ,CN,C(O)OR １０ , C(O)N(R １０ ) ２ , S(O) ２ OR １０ , P(O)(OR １０ ) ２ , and - (CH ２ ) ｓ -R １１ It is arbitrarily replaced by 1 to 3 elements independently selected from, R ６ R is a 5-6 member heteroaryl ring, a 6 member aryl ring, or a 6 member heteroaryl ring, where R ６ is -(C=O) ｕ - (C １ ~C ６ Alkyl), F, Cl, Br, I, NO ２ , OR １３ , SR １３ S(O)R １３ , S(O) ２ R １３ , S(O) ２ N(R) １３ ) ２ , N(R １３ ) ２ ,CN,C(O)OR １４ , C(O)N(R １４ ) ２ , S(O) ２ OR １４ , and P(O)(OR １４ ) ２ It is arbitrarily replaced by 1 to 3 elements independently selected from, R ７ H, OR ８ , or N(R ８ ) ２ And, Each R ８ These are independently H or -(C=O) ｐ - (C １ ~C ６ It is alkyl, Each R ９ These are independently H, -(C=O) ｒ - (C １ ~C ６ Alkyl), or -(C=O) ｒ - (CH ２ ) ｘ - (C ３ ~C ６ It is a cycloalkyl group, Each R １０ H or C １ ~C ６ It is alkyl, Each R １１ H, OR １２ , or N(R １２ ) ２ And, Each R １２ These are independently H or -(C=O) ｔ - (C １ ~C ６ It is alkyl, Each R １３ These are independently H, -(C=O) ｖ - (C １ ~C ６ Alkyl), or S(O) ２ R １４ And, Each R １４ H or C １ ~C ６ It is alkyl, L １ These are those with direct bonds, -(CH ２ ) ｎ -, a 3- to 7-membered cycloalkyl or heterocycle, a 5- to 6-membered heteroaryl ring, or a 6-membered aryl ring, where L １ Any carbon atom in the compound is one or two - (CH ２ ) ｏ -R ７ It is arbitrarily replaced with, L ２ L is a 5-6 member heteroaryl ring, a 6 member aryl ring, or a 6 member heteroaryl ring, where L ２ is 1 to 2 C １ ~C ６ Optionally substituted with alkyl groups, X is O or N-R ３ And, Y is O or N-R ４ And, n is an integer between 1 and 5. o is 0 or an integer from 1 to 4. Each p is independently either 0 or 1. Each q is independently either 0 or 1. Each r is independently either 0 or 1. Each s is independently 0 or an integer from 1 to 3. Each t is independently either 0 or 1. Each u is independently either 0 or 1. Each v is independently either 0 or 1. Each w is independently either 0 or 1. x is an integer from 0 to 3. Each solid center is independently R, S, or a racemate. (1) A step of reacting the compound of formula II with the compound of formula IV, a. The compound of formula II can be used as is, or b. The compound of formula II is converted to a carboxylic acid, step, (2) If a protecting group is present, the step of removing the protecting group from the compound of formula IV, or, (1) The step of reacting the compound of formula III with the compound of formula IV, (2) A method for producing a GSK-3β inhibitor, comprising the step of removing a protecting group from a compound of formula IV if a protecting group is present. 【Transformation 7】 (In the formula, all substituents are defined according to the structure of formula I, R １５ H, C １ ~C ６ Alkyl, or -(CH ２ ) ｗ -R １６ And, R １６ is a 5-membered heteroaryl group, a 6-membered aryl group, or a 6-membered heteroaryl group, where R １６ F, NO ２ and OCH ３ It is arbitrarily replaced by 1 to 5 elements independently selected from, R １７ This refers to a protecting group selected from a list that includes, but is not limited to, acetyl, benzoyl, 4-nitrobenzoyl, benzyl, p-methoxybenzyl, tolyl, trityl, methoxymethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tert-butylcarbamoyl (Boc), fluorenylmethylcarbamoyl (Fmoc), and benzylcarbamoyl (Cbz). w is either 0 or 1.

4. A method for producing a GSK-3β inhibitor according to claim 3, having any one of structures 2 to 101. 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】

5. A method for treating a disorder involving abnormal signaling of GSK-3, comprising administering a therapeutically effective dose of the compound according to claim 1 to a subject in need thereof.

6. The method according to claim 5, wherein the subject has a neurological disorder and / or mental disorder.

7. The method according to claim 6, wherein the disease / disorder is selected from Alzheimer's disease, frontotemporal dementia, behavioral complications of dementia, bipolar disorder, depression, schizophrenia, Parkinson's disease, neuroinflammation, autism spectrum disorder, fragile X syndrome, Pitt-Hopkins syndrome, Rett syndrome, traumatic brain injury, stroke, acute spinal cord injury, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), neurofibromatosis type 1, neuronal ceroid lipofuscinosis, chronic pain, neuropathic pain, chemotherapy-induced neuropathy and / or chemotherapy-induced cognitive impairment.

8. The method according to claim 5, wherein the disease / disorder is selected from type 2 diabetes, diabetic retinopathy, diabetic neuropathy, diabetic macular edema, diabetic nephropathy, chronic kidney disease, polycystic kidney disease and / or focal segmental glomerulosclerosis.

9. The method according to claim 5, wherein the disease / disorder is selected from bone and joint disorders including atherosclerosis, alopecia, osteoarthritis and osteoporosis, inflammatory disorders including alcoholic hepatitis and inflammatory bowel disease, and septic shock.

10. The method according to claim 5, wherein the disease / disorder is selected from eye disorders including exudative age-related macular degeneration, atrophic age-related macular degeneration, Fuchs corneal endothelial dystrophy, corneal epithelial cell deficiency, dry eye, glaucoma, familial exudative vitreoretinopathy (FEVR), Norie's disease, Coats' disease, retinopathy of prematurity, macular telangiectasia, retinal vein occlusion and Sjögren's syndrome, and / or ear disorders including sensorineural hearing loss and conductive hearing loss.

11. The method according to claim 5, wherein the disease / disorder is selected from lung disorders including chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, and pulmonary hypertension, and / or cancers including melanoma, pancreatic cancer, prostate cancer, colon cancer, and leukemia, and / or short bowel syndrome, ischemia, inflammation, cardiovascular disease, congestive heart failure, skin disease, inflammation, or GM2 gangliosidosis.

12. The method according to any one of the above claims, wherein the compound is administered once daily in an amount of about 32 to about 320 mg of the compound, or twice daily in an amount of about 16 to about 160 mg of the compound.

13. The method according to any one of claims 5 to 11, wherein the compound is administered in combination with lithium.

14. The method according to any one of claims 5 to 11, wherein the subject does not react to lithium.

15. The method according to claim 13, wherein the subject reacts to lithium.

16. The method according to claim 13, wherein lithium is administered in a dose less than the effective dose used in monotherapy, and the compound is administered in a dose less than the effective dose used in monotherapy.

17. The method according to claim 16, wherein a dose of lithium less than an effective dose is administered once daily at a dose of approximately 60 mg to approximately 600 mg, or twice daily at a dose of approximately 30 mg to approximately 300 mg.

18. The method according to claim 16, wherein an amount less than an effective amount of the compound is administered once daily at a dose of about 8 to about 32 mg, or twice daily at a dose of about 4 to about 16 mg.

19. A method for establishing a diagnosis of bipolar disorder or other conditions for which GSK-3 inhibition is clinically useful, comprising administering a therapeutically effective dose of the compound to a subject to be evaluated, and evaluating the clinical response of the subject.

20. A method for establishing an appropriate therapeutic dose of the compound in a subject, comprising administering the compound in gradually increasing doses and evaluating the response using GSK-3 imaging or GSK-3 serology.

21. A method for treating a subject having Alzheimer's disease, bipolar disorder, or depression who shows evidence of elevated GSK-3, comprising administering to the subject a therapeutically effective dose of the compound of claim 1, and evaluating and monitoring the subject using positron emission tomography (PET) or serology.

22. A method for establishing a diagnosis of bipolar disorder or other conditions for which GSK-3 inhibition is clinically useful, comprising administering a therapeutically effective dose of the compound of claim 1 to a subject to be evaluated together with a therapeutically effective dose of lithium, and evaluating the clinical response of the subject.

23. The method according to claim 21, wherein the doses of both the compound and lithium are less than the effective dose in the case of monotherapy.

24. A method for treating a subject having Alzheimer's disease who has evidence of elevated GSK-3 beta activity, comprising administering to the subject a therapeutically effective dose of the compound of claim 1 or a pharmaceutically acceptable salt, solvate, or polymorph thereof, and a therapeutically effective dose of lithium, and monitoring the subject using positron emission tomography (PET).

25. The method according to claim 24, wherein the doses of both the compound and lithium are less than the effective dose in the case of monotherapy.

26. A method for establishing an appropriate therapeutic dose of the compound of claim 1 in a subject, comprising administering the subject an increasing dose of the compound and lithium, and evaluating the response using positron emission tomography (PET).

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