Novel compound as glycoprotein 130 inhibitor

Abstract

The present invention relates to a novel compound having a structure of chemical formula 1. The compound of the present invention exhibits inhibitory activity against glycoprotein 130 (gp130). By inhibiting gp130, the compound can be used for preventing or treating gp130-mediated diseases, specifically autoimmune diseases including rheumatoid arthritis and / or autoimmune-related fibrotic diseases and thus is able to be used for this purpose.

Description

Novel compound as a glycoprotein 130 inhibitor

[0001] This application claims priority to Korean Patent Application No. 10-2024-0183356 filed on December 11, 2024, and the entire specification is a reference to this application. The present invention relates to a novel compound having the structure of Formula 1. The compound of the present invention has activity that inhibits glycoprotein 130 (gp130), and by inhibiting gp130, it can prevent or treat diseases mediated by gp130, specifically autoimmune diseases including rheumatoid arthritis and / or autoimmune-derived fibrotic diseases, and can be used for such purposes.

[0002]

[0003] The human immune system plays the role of protecting the body from invading external antigens, but it possesses self-tolerance and does not attack its own tissues. However, when the immune system's self-tolerance is compromised, immune cells recognize proteins normally expressed by one's own genes as targets for attack, producing antibodies or triggering T-cell responses that destroy normal tissues; this condition is called autoimmunity, and when specific symptoms appear, it is referred to as an autoimmune disease.

[0004] Rheumatoid arthritis is a representative autoimmune disease. Rheumatoid arthritis can primarily be caused by autoimmune abnormalities, and inflammation can occur due to abnormally functioning immune systems. Major cells involved in inflammatory responses within the joints are known to include T cells, B cells, and macrophages, and tumor necrosis factor-α (TNF-α) secreted by these cells can act as a factor that exacerbates rheumatoid arthritis. Additionally, M1 macrophages that secrete interleukin (IL)-1β and inflammatory helper T-17 (Th17) cells that secrete IL-17 are known to further worsen rheumatoid arthritis.

[0005] In particular, IL-6 and IL-6 family cytokines (IL-11, OSM (oncostatin M), and LIF (leukemia inhibitory factor)) act on T cells, hepatocytes, hematopoietic stem cells, and neurons to participate in important immune, hematopoietic, and inflammatory responses. IL-6 levels increase rapidly during bacterial and viral infections, inflammation, and trauma; it exhibits high serum concentrations in rheumatoid arthritis and autoimmune diseases and is also associated with multiple myeloma. IL-6 family cytokines are known to play a significant role in autoimmune-derived fibrosis. Cytokines secreted by inflammatory cells residing in tissues activated by the inflammatory response activate vascular endothelial cells and recruit immune cells from the blood to maximize the inflammatory response; furthermore, they induce the activation, proliferation, and differentiation of stromal cells, thereby causing tissue fibrosis (Fig. 1).

[0006] gp130 is a common receptor for IL-6 and IL-11 as described above. IL-6 and IL-11 form complexes with their respective receptors (IL-6R and IL-11R) and gp130, forming a trimer composed of IL-6 / IL-6R / gp130, or a trimer composed of IL-11 / IL-11R / gp130 that forms a dimer to form a hexamer. OSM and LIF form complexes with their receptors, OSMR and LIFR, respectively, forming a trimer of OSM / OSMR / gp130 or a trimer of LIF / LIFR / gp130 to transmit signals into the cell. Downstream of these, proteins such as signal transducer and activator of transcription 3 (STAT3), protein kinase B (PKB; Akt), and extracellular signal-regulated kinase (ERK) are known to be involved in mediating inflammatory responses (Fig. 2).

[0007] Currently, various treatments for autoimmune diseases, including rheumatoid arthritis, have been developed and are in use, but they are not fundamental treatments, are accompanied by side effects such as itching and respiratory infections, and are focused only on reducing pain through the suppression of inflammation.

[0008] Recently, monoclonal antibodies against IL-6 family cytokines and their receptors, as shown in Table 1 below, have been developed or are currently in use as treatments for autoimmune diseases. However, due to the complex mechanisms of IL-6 family cytokines that contribute to fibrosis, treatments that inhibit a single target have limitations in their effectiveness against autoimmune-fibrosis. Furthermore, antibody drugs have limitations such as the presence of refractory patients, relapsed patients, and the difficulty of adjusting dosing schedules to account for individual differences in immune response.

[0009] Target Name Drug Type Development Status IL-6 Sylvant IL-6 monoclonal antibody Approved as a treatment for multiple Castleman disease IL-6 RA ctemra IL-6R monoclonal antibody Approved as a treatment for rheumatoid arthritis, systemic juvenile idiopathic arthritis, juvenile idiopathic arthritis, giant cell arteritis, interstitial lung disease derived from systemic sclerosis, and COVID-19 Kevzara IL-6R monoclonal antibody Approved as a treatment for rheumatoid arthritis IL-6 / IL-6 ROlamkicept (Ferring Pharmaceuticals) sgp130-IgG1Fc conjugate In Phase 2 clinical trials as a treatment for inflammatory bowel disease IL-11 BI765423 (Boehringer Ingelheim) IL-11 monoclonal antibody In Phase 1 clinical trials as a treatment for idiopathic interstitial lung disease and idiopathic pulmonary disease OS MGS SK2330811 (GSK) OSM monoclonal antibody In Phase 2 clinical trials as a treatment for systemic sclerosis and inflammatory bowel disease LIFAZD0171 (AstraZeneca) is currently in Phase 2 clinical trials as a LIF monoclonal antibody for the treatment of non-small cell lung cancer.

[0010] Accordingly, the inventors of the present invention developed a small molecule compound having activity that inhibits multiple IL-6 family cytokines by inhibiting gp130, and completed the present invention by developing a novel compound and its use that can be usefully utilized as a therapeutic agent with excellent therapeutic effects on autoimmune diseases including rheumatoid arthritis and autoimmune-derived fibrotic diseases, and with easy adjustment of dosage and administration schedule according to individual immune response.

[0011]

[0012] The present invention aims to provide a novel compound having inhibitory activity against gp130.

[0013] In addition, the present invention aims to provide a pharmaceutical composition for preventing or treating gp130-mediated diseases.

[0014] In addition, the present invention aims to provide an intermediate for synthesizing a novel compound having inhibitory activity against the g130.

[0015] In addition, the present invention aims to provide a use of the compound for preparing a pharmaceutical composition for preventing or treating the gp130-mediated disease.

[0016] In addition, the present invention aims to provide a method for treating a gp130-mediated disease comprising administering an effective amount of a composition containing the above compound as an active ingredient to an individual in need thereof.

[0017]

[0018] To achieve the above objective, one aspect of the present invention provides a compound of the following formula 1 or a pharmaceutically acceptable salt thereof.

[0019] [Chemical Formula 1]

[0020]

[0021] In the above formula,

[0022] X is -NH-C(=O)-, -NH-C(=O)-CH2-, -NH-C(=O)-CH2-CH2-, -NH-CH2-, or sulfonamide, and

[0023] Ring A is a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl, and

[0024] n is an integer from 0 to 2, and

[0025] R1, R2, R3, R4, and R5 are each independently selected from hydrogen or the following substituent group I, and

[0026] R1 are identical or different from each other when n is 2, each independently selected from hydrogen or the following substituent group I, or fuses with each other to form a substituted or unsubstituted C3-8 carbocycle group or a substituted or unsubstituted 3 to 8-membered heterocycle group together with the carbon bonded thereto, and

[0027] The above substituent group I is -OH, substituted or unsubstituted C 1-10 Alkyl groups, substituted or unsubstituted C 2-10 Alkenyl group, substituted or non-substituted C 3-20 Carbocycle group, substituted or non-substituted C 3-20 Cycloalkyl group, substituted or unsubstituted C 6-30 Aryl group, substituted or unsubstituted 3 to 30-membered heterocyclic group, substituted or unsubstituted C 1-10 Alkoxy group, substituted or non-substituted C 2-10 Alkenyloxy group, substituted or unsubstituted C 3-10 Cycloalkyloxy group, substituted or unsubstituted C 6-30 Aryloxy group, substituted or unsubstituted 3 to 30-membered heterocyclooxy group, substituted or unsubstituted C 1-10 Alkyl carbonyl group, substituted or unsubstituted C 2-10 Alkenyl carbonyl group, substituted or unsubstituted C 3-10 Cycloalkylcarbonyl group, substituted or unsubstituted C 6-30 Aryl carbonyl group, substituted or unsubstituted 3 to 30-membered heterocyclic carbonyl group, substituted or unsubstituted C 1-10 Alkylthio groups, substituted or unsubstituted C 2-10 Alkenylthio group, substituted or non-substituted C 3-10 Cycloalkylthio groups, substituted or unsubstituted C 6-30 Arylthio group, substituted or unsubstituted 3 to 30-membered heterocyclic thio group, aldehyde group, carboxyl group, halogen group, C 1-10It consists of a haloalkyl group, a hydroxyl group, a substituted or unsubstituted amino group, an imine group, a cyano group, a nitro group, an amide group, a thiol group, a sulfonyl group, a sulfino group, and a phosphate group.

[0028]

[0029] In addition, another aspect of the present invention provides a pharmaceutical composition for the prevention or treatment of gp130-mediated diseases comprising the compound or a pharmaceutically acceptable salt thereof.

[0030] The above gp130-mediated disease may be an autoimmune disease or an autoimmune-derived fibrotic disease. Specifically, the above gp130-mediated disease may be any one selected from the group consisting of rheumatoid arthritis, interstitial lung disease, idiopathic pulmonary fibrosis, hepatic fibrosis, non-alcoholic fatty liver disease, systemic sclerosis, multiple sclerosis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, atopic dermatitis, rhinitis, psoriatic arthritis, psoriasis, rhinitis, and allergic conjunctivitis, but is not limited thereto.

[0031]

[0032] In the present invention, the content of the composition is not significantly limited depending on the purpose or aspect of use, and may, for example, be 0.01 to 99 weight%, preferably 0.5 to 50 weight%, and more preferably 1 to 30 weight% based on the total weight of the composition. In addition, the pharmaceutical composition according to the present invention may further include additives such as pharmaceutically acceptable carriers, excipients, or diluents in addition to the active ingredient. The pharmaceutical composition of the present invention may contain 0.1 to 99.9 weight% of a compound represented by Formulas 1 to 223 prepared by the method of the present invention, and may contain 99.9% to 0.1 weight% of a carrier.

[0033]

[0034] In addition, another aspect of the present invention provides an intermediate of the following chemical formula 2 for synthesizing the compound.

[0035] [Chemical Formula 2]

[0036]

[0037] In the above formula,

[0038] Y is a halogen group, and

[0039] R2 is selected from hydrogen or the above substituent group I.

[0040] In addition, another aspect of the present invention provides the use of the compound for preparing a pharmaceutical composition for preventing or treating the gp130-mediated disease.

[0041] In addition, another aspect of the present invention provides a method for treating a gp130-mediated disease comprising administering an effective amount of a composition containing the compound as an active ingredient to an individual in need thereof.

[0042] The "effective amount" of the present invention refers to an amount that, when administered to an individual, produces an effect of improving, treating, detecting, diagnosing, or suppressing or reducing a gp130-mediated disease. The "individual" may be an animal, preferably a mammal, including humans in particular, and may also be a cell, tissue, organ, etc. derived from an animal. The individual may be a patient requiring the said effect.

[0043]

[0044] The novel compound of the present invention has activity that inhibits gp130. gp130 forms complexes with ligands such as IL-6, IL-11, OSM, and LIF, and expresses genes that induce inflammatory responses through intracellular signaling, which can result in the development of various autoimmune diseases or fibrotic diseases derived from autoimmune diseases. Therefore, by targeting and inhibiting gp130, the compound of the present invention can prevent or treat diseases mediated by gp130, more specifically autoimmune diseases and / or fibrotic diseases derived from autoimmune diseases.

[0045] In particular, since the compound of the present invention has activity that inhibits gp130, which binds to various types of IL-6 family cytokine ligands, it can perform multiple inhibitory functions compared to existing autoimmune disease treatment drugs that target only one, thereby allowing for the expectation of superior efficacy and fundamental therapeutic effects.

[0046] However, the effects of the present invention are not limited to those mentioned above, and other unmentioned effects will be clearly understood by those skilled in the art from the description below.

[0047]

[0048] Figure 1 is a diagram illustrating the pathogenesis of autoimmune diseases and fibrotic diseases.

[0049] Figure 2 is a diagram illustrating the mechanism of gp130 and related intracellular signaling.

[0050] Figures 3a and 3b show the results of recording the survival rate (Figure 3a) and body weight (Figure 3b) of CIA mice after administering the test substance for 19 days.

[0051] Figures 4a and 4b show the results of recording the clinical arthritis index (CAI) of CIA mice after administering the test substance for 19 days (Figure 4a) and the results of recording the AUC value thereof (Figure 4b).

[0052] Figures 5a and 5b show the results of recording the incidence of arthritis in CIA mice after administering the test substance for 19 days (Figure 5a) and the results of recording the AUC value (Figure 5b).

[0053] Figures 6a and 6b show the results of measuring the paw pad volume (%) of CIA mice on day 23 and day 42 after administering the test substance for 19 days (Figure 6a) and the results of measuring on day 42 (Figure 6b).

[0054] Figures 7a to 7c show the results of recording the body weight change (Figure 7a), body weight after the test (Figure 7b), and lung weight / body weight value (Figure 7c) of a PHMG-IPF mouse model administered with the test substance.

[0055] Figure 8 shows the results of measuring the expression levels of each mRNA in a PHMG-IPF mouse model administered with the test substance.

[0056] Figure 9 shows the results of lung histological observation of the collagen-deposited area in a PHMG-IPF mouse model administered the test substance.

[0057]

[0058] The present invention will be described in detail below.

[0059]

[0060] As used in the present invention, the term “alkyl” is a hydrocarbon having a substituted or unsubstituted primary, secondary, tertiary, and / or quaternary carbon atom and comprises a saturated aliphatic group having a straight-chain, branched, cyclic, or a combination thereof, or a stereochemical structure thereof. For example, the alkyl group may have 1 to 20 carbon atoms (i.e., C1-C20 alkyl), 1 to 10 carbon atoms (i.e., C1-C10 alkyl), or 1 to 6 carbon atoms (i.e., C1-C6 alkyl). Unless otherwise defined, in a preferred embodiment, alkyl refers to a C1-C6 alkyl.Examples of suitable alkyl groups include methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), and 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), Examples include 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), and octyl (-(CH2)7CH3), but are not limited thereto. Furthermore, the term "alkyl" used throughout the specification, examples, and claims is intended to include both unsubstituted and substituted alkyl groups, the latter of which refers to alkyl residues having substituents that replace one or more hydrogens on a carbon of a hydrocarbon backbone, such as haloalkyl groups like trifluoromethyl.

[0061] The terms "Cx-y" or "Cx-Cy" used in the present invention mean that, when used with chemical residues such as acyl, acyloxy, alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, or alkoxy, they comprise a group containing x to y carbons within the chain. C0 alkyl means hydrogen when the substituent is at the terminal position, and a bond when it is internal. Additionally, for example, a C1-C6 alkyl group contains 1 to 6 carbon atoms within the chain.

[0062] The term "alkenyl" as used in the present invention is a hydrocarbon having primary, secondary, tertiary and / or quaternary carbon atoms, comprising a straight-chain, branched and cyclic structure, or a combination thereof, and having one or more unsaturated regions, i.e., carbon-carbon sp2 double bonds. For example, the alkenyl group may have 2 to 20 carbon atoms (i.e., C2-C20 alkenyl), 2 to 12 carbon atoms (i.e., C2-C12 alkenyl), 2 to 10 carbon atoms (i.e., C2-C10 alkenyl), or 2 to 6 carbon atoms (i.e., C2-C6 alkenyl). Examples of suitable alkenyl groups include vinyl (-CH=CH2), allyl (-CH2CH=CH2), cyclopentenyl (-C5H7), and 5-hexenyl (-CH2CH2CH2CH2CH=CH2), but are not limited thereto.

[0063] As used in the present invention, the term "alkynyl" refers to a hydrocarbon having primary, secondary, tertiary, and / or quaternary carbon atoms, comprising straight-chain, branched, and cyclic groups, or combinations thereof, and having one or more carbon-carbon sp³ triple bonds. For example, the alkynyl group may have 2 to 20 carbon atoms (i.e., C2-C20 alkynyl), 2 to 12 carbon atoms (i.e., C2-C12 alkynyl), 2 to 10 carbon atoms (i.e., C2-C10 alkynyl), or 2 to 6 carbon atoms (i.e., C2-C6 alkynyl). Examples of suitable alkynyl groups include, but are not limited to, acetylenic (-C≡) and propargyl (-CH2C≡).

[0064] The term "alkoxy" as used in the present invention refers to an alkyl group attached to a parent compound via an oxygen atom, which may be represented as -O-alkyl, wherein the alkyl group is as defined herein and may be substituted or unsubstituted. The alkyl group of the alkoxy group may have, for example, 1 to 20 carbon atoms (i.e., C1-C20 alkoxy), 1 to 12 carbon atoms (i.e., C1-C12 alkoxy), 1 to 10 carbon atoms (i.e., C1-C10 alkoxy), or 1 to 6 carbon atoms (i.e., C1-C6 alkoxy). Suitable examples of alkoxy groups may include, but are not limited to, methoxy (-O-CH3 or -OMe), ethoxy (-OCH2CH3 or -OEt), and t-butoxy (-OC(CH3)3 or -O-tBu).

[0065] The term "oxo" used in the present invention refers to an oxygen atom (i.e., =O) as a substituent that forms a carbonyl group (e.g., C=O or C(O)) when bonded to carbon, and forms a nitroso, sulfinyl, or sulfonyl group when bonded to a nitrogen or sulfur atom.

[0066] The term "alkoxyalkyl" used in the present invention refers to an alkyl group substituted with an alkoxy group as defined herein, and may be represented as -alkyl-O-alkyl.

[0067] The term "acyl" as used in the present invention refers to -CO-alkyl or -C(=O)-alkyl unless otherwise indicated, and said alkyl may be substituted.

[0068] The term "aryl acyl" used in the present invention refers to an acyl group as defined in the present specification, in which at least one hydrogen atom is substituted with an aryl group as defined in the present specification.

[0069] As used herein, the term "alkylene" refers to a saturated hydrocarbon group having two valencies, which may be branched, straight-chain, cyclic, or a combination thereof, and is derived by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane. For example, the alkylene group may have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Examples of suitable alkylene groups include, but are not limited to, methylene (-CH2-) and 1,2-ethylene (-CH2-CH2-).

[0070] "Used in the present invention" According to industry conventions, "R" means that a residue or substituent "R" is attached to the skeletal structure.

[0071] The term "cycloalkyl" as used in the present invention refers to a non-aromatic saturated or unsaturated ring that is substituted or unsubstituted monocyclic, bicyclic, or polycyclic, in which each atom of the ring is carbon. A cycloalkyl may be a polycyclic cycloalkyl composed of two or more rings in which one or more carbons are common to adjacent rings. A polycyclic cycloalkyl may be a fused ring system, a spirocyclic ring system, or a bridged ring system, and one or more of the rings may be cycloalkyl, and the other rings may be, for example, the cycloalkyl, aryl, heteroaryl, and / or heterocycloalkyl defined herein. Examples of suitable cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.

[0072] The terms “heterocyclil,” “heterocycle,” “heterocyclic,” and “heterocycloalkyl” as used in the present invention refer to substituted or unsubstituted, monovalent or divalent, saturated or partially saturated non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, wherein the ring structure comprises one or more heteroatoms, preferably 1 to 4 heteroatoms, more preferably 1 to 2 heteroatoms. Substituted heterocycles comprise, for example, heterocyclic rings substituted with any substituent disclosed herein, including carbonyl groups. Heterocyclil groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactone, lactam, etc. Additionally, exemplary heterocyclos include dihydropyridyl, dihydroindolyl, tetrahydropyridyl (piperidyl), tetrahydrothiophenyl, sulfur-oxidized tetrahydrothiophenyl, indolenyl, piperidinyl, 4-piperidinyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranil, tetrahydroquinolinil, tetrahydroisoquinolinil, decahydroquinolinil, octahydroisoquinolinil, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, pyranil, cropnyl, xanthenyl, phenoxatinyl, 2H-pyrrolil, 3H-indolyl, 4H-quinolizinyl, phthalazinyl, naftiridinyl, quinoxalinyl, Examples include, but are not limited to, quinazolininil, cinnolinil, pteridinil, 4aH-carbazolil, carbazolil, β-carbolinil, phenanthridinil, acridinil, phenanthrolinil, phenazinil, phenothiazinil, furazanil, phenoxazinil, isochromatinil, chromatinil, imidazolidinil, imidazolininil, pyrazolidinil, pyrazolidinil, piperazinil, quinuclidinil, morpholinil, and oxazolidinil (each of which may be substituted or unsubstituted).

[0073] The term "heterocycloalkyl" as used in the present invention refers to a substituted or unsubstituted monovalent or divalent, saturated or partially saturated non-aromatic ring that is monocyclic, bicyclic, or polycyclic and contains one or more heteroatoms, preferably 1 to 4 heteroatoms, more preferably 1 to 2 heteroatoms, within the ring. Additionally, "heterocycloalkyl" refers to a bicyclic or polycyclic ring system having two or more cyclic rings in which two or more carbons are common to two adjacent rings, wherein one or more of the rings are heterocyclic and the other cyclic rings may be, for example, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocycloalkyl. The bicyclic or polycyclic ring system may be a fused, bridged, or spirocyclic ring system. “Heterocycloalkyl” includes, for example, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, lactonyl, lactamil, azetidinyl, dihydropyridinyl, dihydroindolyl, tetrahydropyridinyl (piperidinyl), tetrahydrothiophenyl, sulfur-oxidized tetrahydrothiophenyl, indolenyl, 4-piperidinyl, 2-pyrrolidonyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, pyranyl, cropnyl, xanthenyl, phenoxatinyl, 2H-pyrrolyl, 3H-indolyl, It includes 4H-quinolidinyl, phthalazinyl, naftiridinyl, quinoxalinyl, quinazolidinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, pyrazolidinyl, pyrazolidinyl, quinuclidinyl, and oxazolidinyl, piperidine, piperazine, pyrrolidine, morpholine, lactone, lactam, etc. (each of which may be substituted or unsubstituted).

[0074] The term "aryl" as used in the present invention comprises a substituted or unsubstituted monovalent or divalent aromatic hydrocarbon group that is monocyclic, bicyclic, or polycyclic, in which each atom of the ring is carbon. Preferably, the aryl ring is a 6- to 20-membered ring, a 6- to 14-membered ring, a 6- to 10-membered ring, or more preferably a 6-membered ring. The aryl group may be a polycyclic ring system having two or more cyclic rings in which two or more carbons are common to two adjacent rings, wherein one or more of the rings are aromatic, and, for example, the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocycloalkyl. Examples of aryl groups include benzene, naphthalene, phenanthrene, anthracene, indene, indan, phenol, aniline, etc.

[0075] The term "arylene" used in the present invention refers to an aryl group having two valencies derived by removing two hydrogen atoms from the same constituent atom of a mother aryl or from two different constituent atoms.

[0076] The term "arylalkyl" used in the present invention includes an alkyl group as defined in the present specification in which at least one hydrogen atom is substituted with an aryl group as defined in the present specification.

[0077] The term “heteroaryl” as used in the present invention refers to a substituted or unsubstituted monovalent or divalent aromatic group that is monocyclic, bicyclic, or polycyclic and contains one or more heteroatoms within the ring. Non-limiting examples of suitable heteroatoms that may be contained in the aromatic ring include oxygen, sulfur, and nitrogen. “Heteroaryl” is a bicyclic or polycyclic ring system having two or more cyclic rings common to two adjacent rings, where one or more of the rings are heteroaromatic and the other cyclic ring may be, for example, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclic. “Heteroaryl” includes, for example, benzofuran, benzothiophen, pyrrole, furan, thiophene, imidazole, indole, isoindole, isoxazole, isothiaazole, oxazole, thiazole, quinoline, isoquinoline, pyrazol, pyridine, pyrazine, pyridazine, and pyrimidine, etc. (each of which may be substituted or unsubstituted).

[0078] The terms "amino" or "amine" used in the present invention refer to -NH2 in which a hydrogen atom is substituted or unsubstituted with a substituent such as an alkyl or aryl group. The substituents such as alkyl or aryl groups that substitute the hydrogen atom are defined in this invention and may be substituted or unsubstituted, and may form a ring structure together with the N atom. Examples of suitable amino groups include -NH2, -N(CH3)2, -N(CH3)-CH2CH2-N(CH3)2, etc., but are not limited thereto. The term "aminealkyl" used in the present invention refers to an alkyl group as defined in this specification in which at least one hydrogen atom is substituted with an amine group as defined in this specification.

[0079] The terms "halo" and "halogen" used in the present invention both mean halogen and include chloro, fluoro, bromo, and iodo.

[0080] The term "cyano" used in the present invention refers to the -CN group.

[0081] The term "nitro" used in the present invention refers to a -NO2 group.

[0082] The term "carboxyl" used in the present invention represents a -C(O)OH group.

[0083] The term "aldehyde" used in the present invention represents a -CHO group.

[0084] The term "alkoxycarbonyl" used in the present invention represents a -C(O)O(alkyl) or -C(O)O(cycloalkyl) group, wherein the alkyl and cycloalkyl are as defined above.

[0085] The term "acyl halide" as used in the present invention refers to a compound containing a -C(O)-halogen group.

[0086] The term "acylamino" as used in the present invention refers to -NHCO- or -NHC(=O)- unless otherwise indicated, and, for example, when substituted with an aryl or heteroaryl, becomes -NHCO-aryl (or NHC(=O)-aryl) or NHCO-heteroaryl (or NHC(=O)-heteroaryl).

[0087] The term "haloalkyl" as used in the present invention is an alkyl group in which one or more of the hydrogen atoms of the alkyl group as defined above are replaced by halogen atoms. The alkyl residue of the haloalkyl group may have 1 to 20 carbon atoms (i.e., C1-C20 haloalkyl), 1 to 12 carbon atoms (i.e., C1-C12 haloalkyl), 1 to 10 carbon atoms (i.e., C1-C10 haloalkyl), or 1 to 6 carbon atoms (i.e., C1-C6 haloalkyl). Examples of suitable haloalkyl groups include, but are not limited to, -CF3, -CHF2, -CFH2, and -CH2CF3.

[0088] As used in the present invention, the term “cycloalkenyl” refers to a non-aromatic monocyclic or polycyclic hydrocarbon containing at least one carbon-carbon double bond. In some embodiments, the cycloalkenyl comprises 3 to 20 carbon atoms, 3 to 10 carbon atoms, or 3 to 7 carbon atoms. The cycloalkenyl comprises monocyclic and polycyclic groups (including fused, cross-linked, and spirocyclic groups). Examples of suitable cycloalkenyl groups include, but are not limited to, cyclopentenyl (-C5H7).

[0089] The term “substituted,” e.g., “substituted alkyl,” as used in the present invention means that one or more hydrogen atoms of an alkyl group are each independently replaced by non-hydrogen substituents. Unless otherwise indicated, the meaning of “substituted” may be that it is substituted by one or more substituents. The substituents may include, but are not limited to, any of the substituents described herein, e.g., halogen, hydroxyl, alkyl, hydroxyalkyl, haloalkyl, cyanoalkyl, alkoxyalkyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (e.g., thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidin, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, aryl, or heteroaryl. The substituted residue on the hydrocarbon chain may, in some cases, be substituted itself.

[0090] As used herein, the term "pharmaceuticalally acceptable salt" refers to any acid-addition salt or base-addition salt that is non-toxic and harmless to the patient and whose side effects caused by said salt do not impair the beneficial efficacy of the compound of the present invention. Inorganic acids that form suitable salts include hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, hydrobromide, hydroiodide, nitrous acid, or phosphoric acid, and organic acids that form suitable salts include glycolic acid, lactic acid, pyruvate, malonic acid, succinic acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, benzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, nicotinic acid, tosylic acid, camphosulfonic acid, naphthoic acid, acetic acid, trifluoroacetic acid, oxalic acid, manderic acid, propionic acid, citric acid, lactic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, carboxylic acid, vanillic acid, benzenesulfonic acid, p-toluenesulfonic acid, or methanesulfonic acid, and preferably oxalates, hydrochlorides, It may be benzenesulfonate, hemifumarate, succinate, hemimaleate, nicotinate, tosylate, glycolate, hemisulfonate, tartrate, maleate, aspartate, malate, citrate, malonate, phosphate, glutamate, camphosulfonate, 3-hydroxy-2-naphthoate, mesylate, or 4-hydroxy-benzoate, but is not limited thereto.

[0091] As used herein, the term "isomer" includes diastereomers and enantiomers.

[0092] The term “ ” used herein refers to a tert-butoxycarbonyl group.

[0093] The terms “carbocyclylalkyl”, “cycloalkylalkyl”, or “(cycloalkyl)alkyl” as used herein refer to an alkyl group substituted with a carbocycline group or a cycloalkyl group.

[0094] As used herein, the term “amide” refers to a compound in which a nitrogen atom (N) is connected to a carbonyl group (RC=O), RSO2, or R2PO functional group, and may be, for example, carboxyamide, but is not limited thereto.

[0095] As used herein, the term "prevention" refers to any act of suppressing or delaying the onset of a disease by administering the composition; "treatment" refers to any act of improving or beneficially altering the symptoms of an individual suspected of or suffering from the disease by administering the composition; and "improvement" refers to any act of at least reducing parameters related to the condition, such as the degree of symptoms, by administering the composition.

[0096]

[0097] The present invention will be explained in detail below through manufacturing examples and experimental examples.

[0098]

[0099] However, the following manufacturing examples and experimental examples are intended to specifically illustrate the present invention, and the content of the present invention is not limited by the following examples and experimental examples.

[0100]

[0101] Preparation Example 1

[0102] Scheme 1

[0103]

[0104] Reagents and conditions:(a) i) Acyl chloride, AlCl3, DCE, 0 ℃ to rt; ii) AlCl3, CH2Cl2, 40 ℃; (b) CuBr2, EtOAt / CHCl3, 80 ℃; (c) Thioure, EtOH, 80 ℃; (d) TBDMSCl, imidazole, DMF, rt for 5a, c-f; MOMCl, K2CO3, DMF, -20 ℃ for 6b-c; PMBCl, K2CO3, DMF, 60 ℃ for 6a and 6d-g, h; CH3I, K2CO3, DMF, 60 ℃ for 6h.

[0105]

[0106] Scheme 2

[0107]

[0108] Reagents and conditions:(a) Acyl chloride, AlCl3, DCE, 0 ℃ to rt; (b) CuBr2, EtOAt / CHCl3, 80 ℃; (c) Thioure, EtOH, 80 ℃; (d) TBSCl, imidazole, DMF, rt.

[0109]

[0110] Scheme 3

[0111]

[0112] Reagents and conditions:(a)N,O-Dimethylhydroxylamine hydrochloride, sat. NaHCO3solution, CH2Cl2, rt; (b) 2.0 M solution of ethyl magnesium bromide in THF, THF, 0 ℃ to rt; (c) AlCl3, toluene, 115℃; (d) CuBr2, EtOAc, CHCl3, 80℃; (e) Thiourea, EtOH, 85℃; (f) 4-Methoxybenzyl chloride, K2CO3, DMF, rt to 60℃.

[0113]

[0114] Scheme 4

[0115]

[0116] Reagents and conditions:(a) i) Butyryl chloride, TEA, CH2Cl2, 0 ℃ to rt; ii) AlCl3, 135 ℃ or 70 ℃; (b) CuBr2, EtOAc, CHCl3, 80 ℃; (c) thiourea, EtOH, 85 ℃; (d) PMBCl, K2CO3, DMF, rt to 60 ℃.

[0117]

[0118] Scheme 5

[0119]

[0120] Reagents and conditions:(a) 1M Butylmagnesium chloride in THF, THF, 0 ℃ to rt; (b) CuBr2, EtOAc, CHCl3, 80 ℃; (c) Thiourea, EtOH, 85 ℃.

[0121]

[0122] Scheme 6

[0123]

[0124] Reagents and conditions:(a) >200 ℃; (b)N-Bromosuccinimide, ACN, 50 ℃; (c) NH2NH 2· H2O, EtOH, rt; (d) (Boc)2O, TEA, DMAP, CH2Cl2, rt; (e) PMBCl, Cs2CO3, DMF, 80 ℃.

[0125]

[0126] Scheme 7

[0127]

[0128] Reagents and conditions:(a) Bis(pinacolato)diboron, KOAc, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, 1,4-dioxane, 92 ℃; (b) MOMCl, DIPEA, CH2Cl2, 0 ℃ to rt;

[0129]

[0130] Scheme 8

[0131]

[0132] Reagents and conditions:(a) Boronic ester, Pd(dppf)Cl 2· DCM, K3PO4, DMF / H2O (4:1); (b) TFA, 70 ℃; (c) MOMCl, K2CO3, DMF, -20 ℃ for a; PMBCl, K2CO3, DMF, 70 ℃ for b-d.

[0133]

[0134] Scheme 9

[0135]

[0136] Reagents and conditions:(a) (Boc)2O, TEA, DMAP, THF, 50 ℃; (b) Boronic ester, Pd(dppf)Cl 2· DCM, K3PO4, DMF / H2O (4:1), 80 ℃; (c) i) NaBH4, MeOH, THF, 0 ℃; ii) TFA, CH2Cl2, 0 ℃ to rt.

[0137]

[0138] Scheme 10

[0139]

[0140] Reagents and conditions:(a) Benzoyl chloride, pyridine, rt; (f) 1M TBAF in THF, 0 ℃ to rt; (c) Benzoic acid, HATU, DIPEA, DMF, rt; (d) Amine, NaBH3CN, MeOH, rt; (e) 4M HCl in dioxane, MeOH, THF, 0 ℃ to rt.

[0141]

[0142] Scheme 11

[0143]

[0144] Reagents and conditions:(a) Amine, TEA, CH2Cl2, rt; (b) HATU, pyridine, 50 ℃; (c) 4M HCl in dioxane, MeOH, THF, 0 ℃ to rt.

[0145]

[0146] Scheme 12

[0147]

[0148] Reagents and conditions:(a) SOCl2, MeOH, rt; (b) HATU, DIPEA, DMF, 50 ℃; (c) 4M HCl in dioxane, MeOH, THF, 0 ℃ to rt; (d) LiOH·H2O, THF, H2O, rt; (e) Amine, HATU, DIPEA, DMF, rt.

[0149]

[0150] Scheme 13

[0151]

[0152] Reagents and conditions:(a) Benzoyl chloride, pyridine, rt; benzoic acid, HATU, DIPEA, DMF, rt; (b) 1M TBAF in THF, 0 ℃ to rt; (c) TFA, CH2Cl2, rt.

[0153]

[0154] Scheme 14

[0155]

[0156] Reagents and conditions:(a) Phenethyl bromide, K2CO3, acetone, 50 ℃; LiOH·H2O, THF, H2O, rt; (c) HATU, DIPEA, DMF, rt; (d) 4M HCl in dioxane, MeOH, THF, 0 ℃ to rt.

[0157]

[0158] Scheme 15

[0159]

[0160] Reagents and conditions:(a) NaBH3CN, acetic acid, 0℃ to 15 ℃; (b) AcCl, pyridine, 0 ℃; (c) 1M NaOH, MeOH, 60 ℃; (d) HATU, pyridine, 50 ℃; (e) HCl in dioxane, anhydrous MeOH, THF, 70 ℃.

[0161]

[0162] Scheme 16

[0163]

[0164] Reagents and conditions:(a) NaBH3CN, acetic acid, 0℃ to 15 ℃; (b) AcCl, pyridine, 0 ℃; (c) 1M NaOH, MeOH, 60 ℃; (d) HATU, pyridine, 50 ℃; (e) HCl in dioxane, anhydrous MeOH, THF, 70 ℃.

[0165]

[0166] Scheme 17

[0167]

[0168] Reagents and conditions:(a) Benzoyl chloride, pyridine, rt; (b) 1M TBAF in THF, 0 ℃ to rt.

[0169]

[0170] Scheme 18

[0171]

[0172] Reagents and conditions:(a) Benzoyl chloride, pyridine, 0 ℃ to rt; (b) TFA, CH2Cl2, rt for a-b, f; 1 M TBAF in THF, THF, 0 ℃ to rt for c-e.

[0173]

[0174] Scheme 19

[0175]

[0176] Reagents and conditions:(a) Acid, HATU, DIPEA, DMF, rt; (b) 1M TBAF in THF, 0 ℃ to rt; (c) Acid, EDC·HCl, DIPEA, DMF; Acid chloride, pyridine, rt; (d) 4M HCl in dioxane, MeOH, THF, 0 ℃ to rt.

[0177]

[0178] Scheme 20

[0179]

[0180] Reagents and conditions:(a) DABCO, CH3CN, rt; (b) 1M TBAF in THF, 0 ℃ to rt.

[0181]

[0182] Scheme 21

[0183]

[0184] Reagents and conditions:(a) EtOH, 85 ℃.

[0185]

[0186] Scheme 22

[0187]

[0188] Reagents and conditions:(a) Acid, EDC·HCl, HOBt, DIPEA, DMF, rt; (b) 4 M HCl in dioxane, MeOH, rt.

[0189]

[0190] Scheme 23

[0191]

[0192] Reagents and conditions:(a) Acid chloride, pyridine, rt or DMAP, pyridine, 70 ℃; (b) TFA, CH2CH2, 0 ℃ rt, for a, d-j; 1M TBAF in THF, THF, rt for b-c.

[0193]

[0194] Scheme 24

[0195]

[0196] Reagents and conditions:(a) Acid chloride, pyridine, rt or DMAP, pyridine, 50 ℃; (b) 4M HCl in dioxane, MeOH, THF, rt for a; TFA, CH2CH2, 0 ℃ to rt for b.

[0197]

[0198] Scheme 25

[0199]

[0200] Reagents and conditions:(a) Acid chloride, pyridine, rt or DMAP, pyridine, 70 ℃.

[0201]

[0202] Scheme 26

[0203]

[0204] Reagents and conditions:(a) Acid chloride, DMAP, pyridine, 70 ℃; (b) LiOH·H2O, THF, H2O, rt; (c) 40% CH3NH2in MeOH, rt; (d) NH4Cl, HATU, DIPEA, DMF, rt.

[0205]

[0206] Scheme 27

[0207]

[0208] Reagents and conditions:(a) Acid chloride, DMAP, pyridine, 70 ℃; (b) Fe, NH4Cl, AcOH, THF, H2O, EtOH, 80 ℃; (c) AcCl, CH2Cl2, pyridine, rt.

[0209]

[0210] Scheme 28

[0211]

[0212] Reagents and conditions:(a) i) TBDMSCl, imidazole, CH2Cl2, THF, 0 ℃ to rt; ii) Benzoyl chloride, pyridine, 0 ℃ to rt; (b) 1 M TBAF in THF, THF, 0 ℃ to rt.

[0213]

[0214] Scheme 29

[0215]

[0216] Reagents and conditions:(a) Acid chloride, DMAP, pyridine, rt or 70 ℃.

[0217]

[0218] Scheme 30

[0219]

[0220] Reagents and conditions:(a) Acid chloride, DMAP, pyridine, rt or 70 ℃.

[0221]

[0222] Scheme 31

[0223]

[0224] Reagents and conditions:(a) Acid, HATU, DIPEA, DMF, rt; Acid chloride, pyridine, rt; (b) 1 M TBAF in THF, THF, 0 ℃ to rt; (c) TFA, CH2Cl2, rt.

[0225]

[0226] Scheme 32

[0227]

[0228] Reagents and conditions:(a) 6d or 6e, HATU, DIPEA, DMF, 50 ℃; (b) TFA, CH2Cl2, 0.5 h, rt.

[0229]

[0230] Scheme 33

[0231]

[0232] Reagents and conditions:(a) 6d, HATU, DIPEA, DMF, 50 ℃; (b) Amine, NaBH4, AcOH, THF, MeOH, rt; (C) TFA, CH2Cl2, 0.5 h, rt.

[0233]

[0234] Scheme 34

[0235]

[0236] Reagents and conditions:(a) 6d, HATU, DIPEA, DMF, 50 ℃; (b) TFA, CH2Cl2, 0.5 h, rt.

[0237]

[0238] Scheme 35

[0239]

[0240] Reagents and conditions:(a) CH3I, K2CO3, DMF, 50 ℃; (b) Dimethylamine hydrochloride, K2CO3, DMSO, 50 ℃; (c) Amine, NaBH4, AcOH, THF, MeOH, rt; (d) (Boc)2O, TEA, CH2Cl2, rt; (e) CuCN, K2CO3, Pd(PPh3)4, dioxane, 120 ℃; (f) NaOH, THF, H2O, rt.

[0241]

[0242] Scheme 36

[0243]

[0244] Reagents and conditions:(a) Dimethylamine hydrochloride, K2CO3, DMSO, 50 ℃; (b) NaOH, THF, H2O, rt.

[0245]

[0246] Scheme 37

[0247]

[0248] Reagents and conditions:(a) 6e, HATU, DIPEA, DMF, 50 ℃, overnight; (b) TFA, CH2Cl2, 0.5 h, rt.

[0249]

[0250] Scheme 38

[0251]

[0252] Reagents and conditions:(a) 6d, HATU, DIPEA, DMF, 50 ℃; (b) Fe, NH4Cl, AcOH, THF, MeOH, rt; (c) TFA, CH2Cl2, 0.5 h, rt.

[0253]

[0254] Scheme 39

[0255]

[0256] Reagents and conditions:(a) 6d-e, HATU, DIPEA, DMF, 50 ℃; (b) TFA, CH2Cl2, 0.5 h, rt.

[0257]

[0258] Scheme 40

[0259]

[0260] Reagents and conditions:(a) 6d,37v-w, HATU, DIPEA, DMF, 50 ℃; (b) TFA, CH2Cl2, 0.5 h, rt; (c) Amine, DIPEA, DMF, 125 ℃.

[0261]

[0262] Scheme 41

[0263]

[0264] Reagents and conditions:(a) 6d, HATU, DIPEA, DMF, 50 ℃; (b) Amine, DIPEA, DMF, 125 ℃; (b) TFA, CH2Cl2, 0.5 h, rt.

[0265]

[0266] Scheme 42

[0267]

[0268] Reagents and conditions:(a) Morpholine, DIPEA, DMF, 125 ℃; (b) NaOH, THF, H2O, 50 ℃; (c) 6d, HATU, DIPEA, DMF, 70 ℃.

[0269]

[0270] Scheme 43

[0271]

[0272] Reagents and conditions:(a) NaOH, THF, H2O, 50 ℃ for 142a; 40% CH3NH2in MeOH, THF for 142b-d, 142e-f: hydrazine monohydrate, EtOH, 90 ℃ for d; (b) 136a, amine or NH4Cl, HATU, DIPEA, DMF, rt.

[0273]

[0274] Scheme 44

[0275]

[0276] Reagents and conditions:(a) Fe, NH4Cl, AcOH, THF, H2O, EtOH, 80 ℃; (c) Acid chloride, CH2Cl2, pyridine, rt.

[0277]

[0278] Scheme 45

[0279]

[0280] Reagents and conditions:(a) Boronic acid, Pd(dppf)Cl2·DCM, K3PO4, DMF / H2O (4:1), 70 ℃; (b) i) Ethyl bromoacetate, K2CO3, DMF, 70 ℃; ii) TFA, 70 ℃; (c) 132, HATU, DIPEA, DMF, 70 ℃; (d) Fe, AcOH, DMF, 70 ℃.

[0281]

[0282] Scheme 46

[0283]

[0284] Reagents and conditions:(a) Methyl azetidine-3-carboxylate hydrochloride, K2CO3, DMSO, 40 ℃; (b) i) NaOH, THF, H2O, 50 ℃; ii) Thionyl chloride, MeOH, rt; (c) 6d, HATU, DIPEA, DMF, 50 ℃; (d) TFA, CH2Cl2, rt; (e) LiOH·H2O, THF, H2O, rt; (f) Amine, HATU, DIPEA, DMF.

[0285]

[0286] Scheme 47

[0287]

[0288] Reagents and conditions:(a) Sarcosine, DIPEA, DMF, 125 ℃ for 6d, (b) Thionyl chloride, MeOH, rt; (c) 40% CH3NH2in MeOH, rt; (d) Morpholine, HATU, DIPEA, DMF, rt.

[0289]

[0290] Scheme 48

[0291]

[0292] Reagents and conditions:(a) 6e, HATU, DIPEA, DMF, 50 ℃; (b) TFA, CH2Cl2, rt.

[0293]

[0294] Scheme 49

[0295]

[0296] Reagents and conditions:(a) 6d-e, g, HATU, DIPEA, DMF, 50 ℃; (b) Amine, DIPEA, DMF; (c) TFA, CH2Cl2, rt.

[0297]

[0298] Scheme 50

[0299]

[0300] Reagents and conditions:(a) Amine, DIPEA, DMF, 125 ℃; (b) TFA, CH2Cl2, 0.5 h, rt.

[0301]

[0302] Scheme 51

[0303]

[0304] Reagents and conditions:(a) 40% CH3NH2in MeOH, rt; (b) 3-Cyano-4-fluorobenzoic acid, HATU, DIPEA, DMF, rt; (c) Methyl azetidine-3-carboxylate hydrochloride or azetidine, K2CO3, DMSO, 60 ℃.

[0305]

[0306] Scheme 52

[0307]

[0308] Reagents and conditions:(a) Benzoyl chloride, DMAP, pyridine, 70 ℃; (b) Fe, NH4Cl, AcOH, THF, EtOH, H2O, 80 ℃; (c) 40% CH3NH2in MeOH, 50 ℃; (d) Boc-glycine, HATU, DIPEA, DMF, rt; (e) TFA, CH2Cl2, rt.

[0309]

[0310] Scheme 53

[0311]

[0312] Reagents and conditions: (a) Sarcosine, DIPEA, DMF, 125°C; (b) i) NaOH, THF, HO, rt; ii) 1 M SOCl2in CH2Cl2, MeOH, rt; (c) 37d, HATU. DIPEA, DMF, 70°C; (d) Fe, glacial acetic acid, 80℃.

[0313]

[0314] Scheme 54

[0315]

[0316] Reagents and conditions: (a) Morpholine, DIPEA, DMF, 0 °C; (b) NaOH, THF, HO, 50 °C; (c) 6d, HATU, DIPEA, DMF, 70 °C; (d) Fe, NH4Cl, AcOH, THF, EtOH, HO, 80 °C.

[0317]

[0318] Preparation Example 2

[0319] 1-(3-chloro-4-hydroxyphenyl)pentan-1-one

[0320] 1-(3-Chloro-4-hydroxyphenyl)pentan-1-one

[0321]

[0322]

[0323] Aluminum chloride (981.4 mg, 7.36 mmol) was added to a 10 mL solution of dichloromethane containing 2-chloroanisole (1.0 g, 0.89 mL, 7.01 mmol) at 0°C, and the reaction mixture was stirred at the same temperature for 0.5 hours. Then, valeroyl chloride (887.4 mg, 873.5 μL, 7.36 mmol) was slowly added at 0°C and stirred for 30 minutes at this temperature and for an additional 2.5 hours at room temperature. After the reaction was complete, the mixture was cooled to room temperature and volatile substances were removed. Dichloromethane (10 mL) and aluminum chloride (981.4 mg) were sequentially added to this mixture at 0°C and stirred at 40°C for 16 hours. After the reaction was completed, the mixture was poured into a 2-normal hydrochloric acid solution, extracted with dichloromethane, washed with sodium bicarbonate and saturated brine, dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate:n-hexane, 1:5) to obtain the compound as a pale yellow solid (1.177 g, 79.0%).

[0324] 1 H NMR (500 MHz, CDCl3) δ 7.98 (d,J= 1.8 Hz, 1H), 7.82 (m, 1H), 7.07 (d,J= 8.5 Hz, 1H), 6.21 (s, 1H), 2.89 (t,J= 7.4 Hz, 2H), 1.70 (dd,J= 15.0, 7.4 Hz, 2H), 1.39 (m, 2H), 0.94 (t,J= 7.3 Hz, 3H).

[0325]

[0326] Preparation Example 3

[0327] 1-(3-fluoro-4-hydroxyphenyl)butan-1-one

[0328] 1-(3-Fluoro-4-hydroxyphenyl)butan-1-one

[0329]

[0330]

[0331] The above compound was obtained from 2-fluoroanisole and butyryl chloride as a beige solid (11.67 g, quantitative yield).

[0332] 1 H NMR (500 MHz, DMSO-d6) δ 10.83 (s, 1H), 7.69 (t,J= 10.5 Hz, 2H), 7.03 (t,J= 8.4 Hz, 1H), 2.89 (t,J= 7.1 Hz, 2H), 1.64 - 1.55 (m, 2H), 0.90 (t,J= 7.4 Hz, 3H).

[0333]

[0334] Preparation Example 4

[0335] 1-(3-chloro-4-hydroxyphenyl)butan-1-one

[0336] 1-(3-Chloro-4-hydroxyphenyl)butan-1-one

[0337]

[0338] The above compound was obtained from 2-chloroanisole and butyryl chloride as a beige solid (10.88 g, 78.1%).

[0339] 1 H NMR (500 MHz, CDCl3) δ 7.98 (d,J= 1.9 Hz, 1H), 7.82 (dd,J= 8.5, 1.8 Hz, 1H), 7.07 (d,J= 8.5 Hz, 1H), 6.15 (s, 1H), 2.87 (t,J= 7.3 Hz, 2H), 1.80 - 1.69 (m, 2H), 0.99 (t,J= 7.4 Hz, 3H).

[0340]

[0341] Preparation Example 5

[0342] 1-(3-chloro-4-hydroxyphenyl)-3-methylbutan-1-one

[0343] 1-(3-Chloro-4-hydroxyphenyl)-3-methylbutan-1-one

[0344]

[0345] The above compound was obtained from 2-chloroanisole and isovaleroyl chloride as a white solid (10.60 g, 71.1%).

[0346] 1 H NMR (500 MHz, CDCl3) δ 7.98 (s, 1H), 7.81 (d,J= 7.8 Hz, 1H), 7.07 (d,J= 8.0 Hz, 1H), 6.03 (s, 2H), 2.75 (m, 2H), 2.27 (m, 1H), 0.98 (s, 6H).

[0347]

[0348] Preparation Example 6

[0349] 1-(3-chloro-4-hydroxyphenyl)-4-methylpentan-1-one

[0350] 1-(3-Chloro-4-hydroxyphenyl)-4-methylpentan-1-one

[0351]

[0352] The above compound was obtained from 2-chloroanisole and 4-methylpentanoyl chloride as a white solid (2.99 g, 94.3%).

[0353] 1 H NMR (500 MHz, DMSO-d6) δ 11.13 (s, 1H), 7.92 (s, 1H), 7.79 (d,J= 8.4 Hz, 1H), 7.03 (d,J= 8.6 Hz, 1H), 2.90 (t,J= 7.5 Hz, 2H), 1.54 (m, 1H), 1.45 (q,J= 7.0 Hz, 2H), 0.87 (d,J= 6.5 Hz, 6H).

[0354]

[0355] Preparation Example 7

[0356] 1-(3-chloro-4-hydroxyphenyl)ethanol

[0357] 1-(3-Chloro-4-hydroxyphenyl)ethenone

[0358]

[0359] The above compound was obtained from 2-chloroanisole and acetyl chloride as an orange solid (394.7 mg, 85.0%).

[0360] 1 H NMR (500 MHz, CDCl3) δ 7.99 (s, 1H), 7.82 (d,J= 8.4 Hz, 1H), 7.08 (d,J= 6.9 Hz, 1H), 6.01 (s, 1H), 2.56 (s, 3H).

[0361]

[0362] Preparation Example 8

[0363] 2-bromo-1-(3-chloro-4-hydroxyphenyl)pentan-1-one

[0364] 2-Bromo-1-(3-chloro-4-hydroxyphenyl)pentan-1-one

[0365]

[0366] A mixture of 1-(3-chloro-4-hydroxyphenyl)pentan-1-one (920.0 mg, 4.33 mmol) and copper(II) bromide (1.93 g, 8.65 mmol) dissolved in ethyl acetate and chloroform (40 mL, 1:1, v / v) was refluxed for 16 hours. After the reaction was complete, the reaction mixture was filtered through Celite. The filtrate was evaporated under reduced pressure, water was added to the resulting mixture, the aqueous layer was extracted with dichloromethane, dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate:n-hexane, 1:3) to obtain the compound as a white solid (1.21 g, 96.2%).

[0367] 1H NMR (500 MHz, DMSO-d6) δ 11.40 (s, 1H), 8.04 (d,J= 1.6 Hz, 1H), 7.87 (dd,J= 8.5, 1.6 Hz, 1H), 7.06 (d,J= 8.6 Hz, 1H), 5.62 (t,J= 7.0 Hz, 1H), 2.04 - 1.85 (m, 2H), 1.48 - 1.29 (m, 2H), 0.90 (t,J= 7.4 Hz, 3H).

[0368]

[0369] Preparation Example 9

[0370] 2-bromo-1-(3-fluoro-4-hydroxyphenyl)pentan-1-one

[0371] 2-Bromo-1-(3-fluoro-4-hydroxyphenyl)pentan-1-one

[0372]

[0373] The above compound was obtained from 1-(3-fluoro-4-hydroxyphenyl)butan-1-one as a bright yellow solid (1.44 g, 60.5%).

[0374] 1 H NMR (500 MHz, DMSO-d6) δ 11.10 (s, 1H), 7.83 (d,J= 13.2 Hz, 1H), 7.78 (d,J= 8.5 Hz, 1H), 7.07 (t,J= 8.6 Hz, 1H), 5.59 (t,J= 6.9 Hz, 1H), 2.08 (m, 1H), 1.94 (m, 1H), 0.98 (t,J= 7.2 Hz, 3H).

[0375]

[0376] Preparation Example 10

[0377] 2-bromo-1-(3-chloro-4-hydroxyphenyl)butan-1-one

[0378] 2-Bromo-1-(3-chloro-4-hydroxyphenyl)butan-1-one

[0379]

[0380] The above compound was obtained from 1-(3-chloro-4-hydroxyphenyl)butan-1-one as a bright yellow solid (9.93 g, 71.2%).

[0381] 1 H NMR (500 MHz, CDCl3) δ 8.05 (d,J= 1.9 Hz, 1H), 7.88 (dd,J= 8.5, 1.7 Hz, 1H), 7.10 (d,J= 8.6 Hz, 1H), 6.05 (s, 1H), 4.96 (t,J= 7.0 Hz, 1H), 2.29 - 2.05 (m, 2H), 1.07 (t,J= 7.3 Hz, 3H).

[0382]

[0383] Preparation Example 11

[0384] 2-bromo-1-(3-chloro-4-hydroxyphenyl)-3-methylbutan-1-one

[0385] 2-Bromo-1-(3-chloro-4-hydroxyphenyl)-3-methylbutan-1-one

[0386]

[0387] The above compound was obtained from 1-(3-chloro-4-hydroxyphenyl)-3-methylbutan-1-one as a beige solid (12.62 g, 62.3%).

[0388] 1 H NMR (500 MHz, DMSO-d6) δ 11.14 (s, 1H), 7.90 (d,J= 2.0 Hz, 1H), 7.77 (dd,J= 8.5, 2.0 Hz, 1H), 7.03 (d,J= 8.5 Hz, 1H), 2.77 (d,J= 6.8 Hz, 1H), 2.16 - 2.00 (m, 1H), 0.89 (d,J= 6.6 Hz, 6H).

[0389]

[0390] Preparation Example 12

[0391] 2-bromo-1-(3-chloro-4-hydroxyphenyl)-4-methylpentan-1-one

[0392] 2-Bromo-1-(3-chloro-4-hydroxyphenyl)-4-methylpentan-1-one

[0393]

[0394] The above compound was obtained from 1-(3-chloro-4-hydroxyphenyl)-4-methylpentan-1-one as a light gray solid (6.39 g, 99.0%).

[0395] 1 H NMR (500 MHz, DMSO-d6) δ 11.38 (s, 1H), 8.09 (s, 1H), 7.91 (d,J= 8.6 Hz, 1H), 7.06 (d,J= 8.6 Hz, 1H), 5.61 (t,J= 7.0 Hz, 1H), 1.89 (t,J= 6.5 Hz, 2H), 1.68 (m, 1H), 0.89 (m, 6H).

[0396]

[0397] Preparation Example 13

[0398] 2-bromo-1-(3-chloro-4-hydroxyphenyl)ethane-1-one

[0399] 2-Bromo-1-(3-chloro-4-hydroxyphenyl)ethenone

[0400]

[0401] The above compound was obtained from 1-(3-chloro-4-hydroxyphenyl)ethanol as a brown solid (497.2 mg, 86.0%).

[0402] 1 H NMR (500 MHz, CDCl3) δ 8.03 (s, 1H), 7.98 (d,J= 8.5 Hz, 1H), 7.85 (d,J= 8.5 Hz, 1H), 6.16 (s, 1H), 4.37 (s, 2H).

[0403]

[0404] Preparation Example 14

[0405] 4-(2-amino-5-propylthiazole-4-yl)-2-chlorophenol

[0406] 4-(2-Amino-5-propylthiazol-4-yl)-2-chlorophenol

[0407]

[0408] Thiourea (85.7 mg, 1.1 mmol) was added to a 5 mL ethanol solution of 2-bromo-1-(3-chloro-4-hydroxyphenyl)pentan-1-one (320.7 mg, 1.10 mmol), and the reaction mixture was stirred in a sealed tube at 90°C for 3.5 hours. After the reaction was complete, the volatile solvent was removed under reduced pressure. Water was added to the resulting mixture, the aqueous layer was extracted with ethyl acetate, dried with magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the compound as a beige solid (180.0 mg, 60.9%).

[0409] 1 H NMR (500 MHz, DMSO-d6) δ 10.24 (s, 1H), 7.41 (d,J= 1.3 Hz, 1H), 7.24 (m, 1H), 6.95 (d,J= 8.4 Hz, 1H), 6.77 (s, 1H), 2.62 (t,J= 7.5 Hz, 2H), 1.52 (m, 2H), 0.88 (t,J= 7.3 Hz, 3H).

[0410]

[0411] Preparation Example 15

[0412] 4-(2-amino-5-ethylthiazole-4-yl)-2-fluorophenol

[0413] 4-(2-Amino-5-ethylthiazol-4-yl)-2-fluorophenol

[0414]

[0415] The above compound was obtained from 2-bromo-1-(3-fluoro-4-hydroxyphenyl)butan-1-one as a yellow solid (1.18 g, 89.6%).

[0416] 1 H NMR (500 MHz, DMSO) δ 9.91 (s, 1H), 7.22 (d,J= 12.8 Hz, 1H), 7.13 (d,J= 8.4 Hz, 1H), 6.95 (t,J= 8.8 Hz, 1H), 6.77 (s, 2H), 2.70 (q,J= 7.4 Hz, 2H), 1.16 (t,J= 7.3 Hz, 3H).

[0417]

[0418] Preparation Example 16

[0419] 4-(2-amino-5-ethylthiazole-4-yl)-2-chlorophenol

[0420] 4-(2-Amino-5-ethylthiazol-4-yl)-2-chlorophenol

[0421]

[0422] The above compound was obtained from 2-bromo-1-(3-chloro-4-hydroxyphenyl)butan-1-one as a beige solid (8.43 g, 92.0%).

[0423] 1 H NMR (500 MHz, DMSO-d6) δ 10.73 (s, 1H), 8.75 (s, 2H), 7.49 (s, 1H), 7.27 (d,J= 8.5 Hz, 1H), 7.08 (d,J= 8.4 Hz, 1H), 2.64 (q,J= 7.4 Hz, 2H), 1.14 (t,J= 7.4 Hz, 3H).

[0424]

[0425] Preparation Example 17

[0426] 4-(2-amino-5-isopropylthiazole-4-yl)-2-chlorophenol

[0427] 4-(2-Amino-5-isopropylthiazol-4-yl)-2-chlorophenol

[0428]

[0429] The above compound was obtained from 2-bromo-1-(3-chloro-4-hydroxyphenyl)-3-methylbutan-1-one as a yellow solid (1.81 g, 39.1%).

[0430] 1 H NMR (500 MHz, DMSO-d6) δ 10.23 (s, 1H), 7.38 (s, 1H), 7.21 (d,J= 8.3 Hz, 1H), 6.96 (d,J= 8.4 Hz, 1H), 6.75 (s, 2H), 3.18 (m, 1H), 1.17 (d,J= 6.6 Hz, 6H).

[0431]

[0432] Preparation Example 18

[0433] 4-(2-amino-5-isobutylthiazole-4-yl)-2-chlorophenol

[0434] 4-(2-Amino-5-isobutylthiazol-4-yl)-2-chlorophenol

[0435]

[0436] The above compound was obtained from 2-bromo-1-(3-chloro-4-hydroxyphenyl)-4-methylpentan-1-one as a grayish-brown solid (1.61 g, 50.3%).

[0437] 1 H NMR (500 MHz, DMSO-d6) δ 10.23 (s, 1H), 7.40 (s, 1H), 7.24 (d,J= 8.5 Hz, 1H), 6.95 (d,J= 8.1 Hz, 1H), 6.77 (s, 2H), 2.52 (d,J= 6.9 Hz, 2H), 1.77 - 1.63 (m, 1H), 0.86 (d,J= 6.4 Hz, 6H).

[0438]

[0439] Preparation Example 19

[0440] 4-(2-aminothiazole-4-yl)-2-chlorophenol

[0441] 4-(2-Aminothiazol-4-yl)-2-chlorophenol

[0442]

[0443] The above compound was obtained from 2-bromo-1-(3-chloro-4-hydroxyphenyl)ethanol as a yellow solid (144.9 mg, 32.0%).

[0444] 1 H NMR (500 MHz, DMSO-d6) δ 10.22 (s, 1H), 7.74 (s, 1H), 7.56 (d,J= 8.5 Hz, 1H), 7.02 (s, 2H), 6.94 (d,J= 8.4 Hz, 1H), 6.87 (s, 1H).

[0445]

[0446] Preparation Example 20

[0447] 4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-propylthiazole-2-amine

[0448] 4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)-5-propylthiazol-2-amine

[0449]

[0450] Imidazole (190.0 mg, 2.79 mmol) was added to a solution of 4-(2-amino-5-propylthiazole-4-yl)-2-chlorophenol (0.25 g, 0.93 mmol) dissolved in anhydrous N,N-dimethylformamide (3.5 mL), followed by the addition of tert-butyldimethylsilyl chloride (280.3 mg, 1.86 mmol) at room temperature, and the mixture was stirred at room temperature for 1 day. After the reaction was complete, water was added to the resulting mixture, and the aqueous layer was washed with dichloromethane. The bound organic phase was washed with water and saturated salt water, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate:n-hexane, 1:3) to obtain the compound as a white solid (236.0 mg, 66.4%).

[0451] 1 H NMR (500 MHz, CDCl3) δ 7.51 (d,J= 2.0 Hz, 1H), 7.26 (m, 1H), 6.89 (d,J= 8.4 Hz, 1H), 5.01 (s, 2H), 2.69 (m, 2H), 1.62 (m, 2H), 1.03 (s, 9H), 0.95 (t,J= 7.3 Hz, 3H), 0.23 (s, 6H).

[0452]

[0453] Preparation Example 21

[0454] 4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-ethylthiazole-2-amine

[0455] 4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)-5-ethylthiazol-2-amine

[0456]

[0457] The above compound was obtained from 4-(2-amino-5-ethylthiazole-4-yl)-2-chlorophenol as a yellow liquid (12.88 g, 98.9%).

[0458] 1 H NMR (500 MHz, DMSO-d6) δ 7.52 (s, 1H), 7.34 (d,J= 9.3 Hz, 1H), 7.01 (d,J= 8.4 Hz, 1H), 6.79 (s, 2H), 2.70 (q,J= 14.6, 7.3 Hz, 2H), 1.15 (t,J= 7.4 Hz, 3H), 0.98 (s, 9H), 0.22 (s, 6H).

[0459]

[0460] Preparation Example 22

[0461] 4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-isopropylthiazole-2-amine

[0462] 4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)-5-isopropylthiazol-2-amine

[0463]

[0464] The above compound was obtained from 4-(2-amino-5-isopropylthiazole-4-yl)-2-chlorophenol as a yellow paraffin liquid (2.13 g, 99.0%).

[0465] 1 H NMR (500 MHz, DMSO-d6) δ 7.47 (s, 1H), 7.30 (d,J= 7.7 Hz, 1H), 7.01 (d,J= 8.1 Hz, 1H), 6.79 (s, 2H), 3.20 (m, 1H), 1.18 (d,J= 5.7 Hz, 6H), 0.98 (s, 9H), 0.22 (s, 6H).

[0466]

[0467] Preparation Example 23

[0468] 4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-isobutylthiazole-2-amine

[0469] 4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)-5-isobutylthiazol-2-amine

[0470]

[0471] The above compound was obtained as a brown liquid (1.54 g, 72.3%) from 4-(2-amino-5-isobutylthiazole-4-yl)-2-chlorophenol.

[0472] 1H NMR (500 MHz, DMSO-d6) δ 7.50 (s, 1H), 7.33 (d,J= 8.2 Hz, 1H), 7.01 (d,J= 8.4 Hz, 1H), 6.80 (s, 2H), 2.54 (d,J= 7.0 Hz, 2H), 1.77 - 1.64 (m, 1H), 0.98 (s, 9H), 0.86 (d,J= 6.5 Hz, 6H), 0.22 (s, 6H).

[0473]

[0474] Preparation Example 24

[0475] 4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)thiazole-2-amine

[0476] 4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)thiazol-2-amine

[0477]

[0478] The above compound was obtained from 4-(2-aminothiazole-4-yl)-2-chlorophenol as a white solid (96.1 mg, 26.0%).

[0479] 1 H NMR (500 MHz, DMSO-d6) δ 7.83 (s, 1H), 7.64 (d,J= 8.1 Hz, 1H), 7.07 (s, 2H), 6.99 (d,J= 11.6 Hz, 2H), 1.00 (s, 9H), 0.23 (s, 6H).

[0480]

[0481] Preparation Example 25

[0482] 5-ethyl-4-(3-fluoro-4-((4-methoxybenzyl)oxy)phenyl)thiazole-2-amine

[0483] 5-Ethyl-4-(3-fluoro-4-((4-methoxybenzyl)oxy)phenyl)thiazol-2-amine

[0484]

[0485] 4-(2-amino-5-ethylthiazole-4-yl)-2-fluorophenol (1.18 g, 4.95 mmol) was dissolved in anhydrous N,N-dimethylformamide (20.0 mL) under nitrogen packing. Potassium carbonate (1.03 g, 7.43 mmol) was added at room temperature, and the mixture was stirred for 1 hour. After 1 hour, 4-methoxybenzyl chloride (0.74 mL, 5.45 mmol) was added at 0°C, and the mixture was stirred at 60°C for 4 hours. After the reaction was complete, the mixture was poured into cold water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried with anhydrous magnesium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (EtOAc:hexane, 1:5) to obtain the compound (641.6 mg, 36.2%) as a beige solid.

[0486] 1 H NMR (500 MHz, DMSO) δ 7.40 (d,J= 7.9 Hz, 2H), 7.29 (d,J= 13.0 Hz, 1H), 7.25 (s, 2H), 6.96 (d,J= 8.0 Hz, 2H), 6.81 (s, 2H), 5.10 (s, 2H), 3.76 (s, 3H), 2.71 (m, 2H), 1.16 (t,J= 7.2 Hz, 3H).

[0487]

[0488] Preparation Example 26

[0489] 4-(3-chloro-4-(methoxymethoxy)phenyl)-5-propylthiazole-2-amine

[0490] 4-(3-Chloro-4-(methoxymethoxy)phenyl)-5-propylthiazol-2-amine

[0491]

[0492] 4-(2-amino-5-propylthiazole-4-yl)-2-chlorophenol (0.5 g, 1.86 mmol), potassium carbonate (385.7 mg, 2.79 mmol), and anhydrous N,N-dimethylformamide (5 mL) were added to a dried flask. After stirring at room temperature for 1 hour, chloromethyl methyl ether (164.8 mg, 156.0 μl, 2.05 mmol) was added dropwise to the residue at -20 °C. The mixture was stirred at -20 °C for 1 hour. Subsequently, the mixture was poured into cold water, extracted with ethyl acetate, washed with saturated saline, dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate:hexane = 1:3) to obtain the compound (300.2 mg, 51.6%) as yellow gelatin.

[0493] 1 H NMR (500 MHz, DMSO-d6) δ 7.55 (s, 1H), 7.40 (d,J= 8.6 Hz, 1H), 7.26 (d,J= 8.6 Hz, 1H), 7.01 (s, 2H), 5.31 (s, 2H), 3.42 (s, 3H), 2.66 (t,J= 7.5 Hz, 2H), 1.55 (m, 2H), 0.90 (t,J= 7.2 Hz, 3H).

[0494]

[0495] Preparation Example 27

[0496] 4-(3-chloro-4-(methoxymethoxy)phenyl)-5-ethylthiazole-2-amine

[0497] 4-(3-Chloro-4-(methoxymethoxy)phenyl)-5-ethylthiazol-2-amine

[0498]

[0499] The above compound (1.2 g, 25.0%) as a yellow solid was obtained from 4-(2-amino-5-ethylthiazole-4-yl)-2-chlorophenol.

[0500] 1 H NMR (500 MHz, DMSO-d6) δ 7.55 (s, 1H), 7.41 (d,J= 8.4 Hz, 1H), 7.25 (d,J= 6.8 Hz, 1H), 6.83 (s, 2H), 5.30 (s, 2H), 3.42 (s, 3H), 2.72 (q,J= 6.1 Hz, 2H), 1.17 (t,J= 6.1 Hz, 3H).

[0501]

[0502] Preparation Example 28

[0503] 4-(3-chloro-4-((4-methoxybenzyl)oxy)phenyl)-5-ethylthiazole-2-amine

[0504] 4-(3-Chloro-4-((4-methoxybenzyl)oxy)phenyl)-5-ethylthiazol-2-amine

[0505]

[0506] The above compound (2.75 g, 26.4%) as a yellow solid was obtained using 4-methoxybenzyl chloride from 4-(2-amino-5-ethylthiazole-4-yl)-2-chlorophenol.

[0507] 1 H NMR (500 MHz, DMSO-d6) δ 7.54 (s, 1H), 7.40 (m, 3H), 7.26 (d,J= 8.4 Hz, 1H), 6.97 (d,J= 7.8 Hz, 2H), 6.82 (s, 2H), 5.13 (s, 2H), 3.76 (s, 3H), 2.66 (m, 2H), 1.55 (m, 2H), 0.90 (m, 3H).

[0508]

[0509] Preparation Example 29

[0510] 4-(3-chloro-4-((4-methoxybenzyl)oxy)phenyl)-5-propylthiazole-2-amine

[0511] 4-(3-Chloro-4-((4-methoxybenzyl)oxy)phenyl)-5-ethylthiazol-2-amine

[0512]

[0513] The above compound (3.15 g, 35.4%) as a yellow solid was obtained using 4-methoxybenzyl chloride from 4-(2-amino-5-propylthiazole-4-yl)-2-chlorophenol.

[0514] 1 H NMR (500 MHz, CD3OD) δ 7.47 (d,J= 2.1 Hz, 1H), 7.40 (d,J= 8.6 Hz, 2H), 7.32 (m, 1H), 7.15 (d,J= 8.5 Hz, 1H), 6.94 (m, 2H), 5.12 (s, 2H), 3.80 (s, 3H), 2.66 (m, 2H), 1.61 (m, 2H), 0.94 (t,J= 7.3 Hz, 3H).

[0515]

[0516] Preparation Example 30

[0517] 4-(3-chloro-4-((4-methoxybenzyl)oxy)phenyl)-5-isobutylthiazole-2-amine

[0518] 4-(3-Chloro-4-((4-methoxybenzyl)oxy)phenyl)-5-isobutylthiazol-2-amine

[0519]

[0520] The above compound (514.2 mg, 48.7%) as a yellow solid was obtained using 4-methoxybenzyl chloride from 4-(2-amino-5-isobutylthiazole-4-yl)-2-chlorophenol.

[0521] 1H NMR (500 MHz, DMSO-d6) δ 7.53 (d,J= 1.3 Hz, 1H), 7.41 (m, 3H), 7.26 (d,J= 8.6 Hz, 1H), 6.97 (d,J= 8.4 Hz, 2H), 6.83 (s, 2H), 5.13 (s, 2H), 3.76 (s, 3H), 2.56 (d,J= 7.1 Hz, 2H), 1.73 (m, 1H), 0.88 (d,J= 6.5 Hz, 6H).

[0522]

[0523] Preparation Example 31

[0524] 4-(3-chloro-4-((4-methoxybenzyl)oxy)phenyl)thiazole-2-amine

[0525] 4-(3-Chloro-4-((4-methoxybenzyl)oxy)phenyl)thiazol-2-amine

[0526]

[0527] The above compound (2.59 g, 63.8%) as a yellow solid was obtained using 4-methoxybenzyl chloride from 4-(2-aminothiazole-4-yl)-2-chlorophenol.

[0528] 1 H NMR (500 MHz, DMSO-d6) δ 7.84 (s, 1H), 7.70 (d,J= 8.5 Hz, 1H), 7.40 (d,J= 7.8 Hz, 2H), 7.23 (d,J= 8.5 Hz, 1H), 7.07 (s, 2H), 6.97 (m, 3H), 5.13 (s, 2H), 3.75 (s, 3H).

[0529]

[0530] Preparation Example 32

[0531] 4-(3-chloro-4-methoxyphenyl)-5-ethylthiazole-2-amine

[0532] 4-(3-Chloro-4-methoxyphenyl)-5-ethylthiazol-2-amine

[0533]

[0534] 5-(2-amino-5-ethylthiazole-4-yl)-2-chlorophenol (0.20 g, 0.79 mmol), potassium carbonate (162.8 mg, 1.18 mmol), and anhydrous N,N-dimethylformamide (3 mL) were added to a flame-dried flask. After stirring at room temperature for 1 hour, iodomethane (134.6 mg, 59.0 μL, 0.95 mmol) was added dropwise to the residue at 0°C. The mixture was stirred at 60°C for 4 hours. Then, the mixture was poured into cold water, extracted with ethyl acetate, washed with brine, dried with anhydrous magnesium sulfate, filtered, and concentrated. The crude product was purified by flash column chromatography (EtOAc:hexane, 1:3) to obtain the title compound (102.3 mg, 48.2%) as a yellow solid.

[0535] 1 H NMR (500 MHz, CDCl3) δ 7.55 (s, 1H), 7.38 (d,J= 8.5 Hz, 1H), 6.94 (d,J= 8.5 Hz, 1H), 5.03 (s, 2H), 3.92 (s, 3H), 2.77 (q,J= 7.4 Hz, 2H), 1.24 (t,J= 7.4 Hz, 3H).

[0536]

[0537] Preparation Example 33

[0538] 1-(p-tholyl)butane-1-on

[0539] 1-(p-Tolyl)butan-1-one

[0540]

[0541] Toluene (10.0 g, 11.5 mL, 108.5 mmol) was dissolved in dichloromethane (50.0 mL) under nitrogen gas filling. Aluminum chloride (21.7 g, 162.8 mmol) was added at 0°C, and the mixture was stirred at 0°C for 0.5 hours. Then, butyryl chloride (11.8 mL, 114.0 mmol) was added dropwise at 0°C, and the mixture was stirred at 0°C for 0.5 hours. Subsequently, the mixture was stirred at room temperature for 2.5 hours. After the reaction was complete, the mixture was poured into a 2N hydrochloric acid solution and extracted with dichloromethane; the organic layer was washed with water, then dried, filtered, and concentrated with anhydrous MgSO4. The residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:100) to obtain the compound (3.30 g, 19.0%) in the form of a yellow liquid.

[0542] 1 ¹H NMR (500 MHz, CDCl₃) 1 H NMR (500 MHz, CDCl3) δ 7.83 (d,J= 8.0 Hz, 2H), 7.20 (d,J= 7.8 Hz, 2H), 2.87 (t,J= 7.3 Hz, 2H), 2.36 (s, 3H), 1.72 (m, 2H), 0.97 (t,J= 7.4 Hz, 3H).

[0543]

[0544] Preparation Example 34

[0545] 2-bromo-1-(p-tholyl)pentan-1-one

[0546] 2-Bromo-1-(p-tolyl)pentan-1-one

[0547]

[0548] 4-methylvalerophenone (500 mg, 2.8 mmol) and copper(II) bromide (760.3 mg, 3.4 mmol) were dissolved in ethyl acetate (2.0 mL) under nitrogen gas filling. The mixture was stirred at room temperature for 24 hours. After cooling the mixture to room temperature, it was filtered through a Celite pad. The organic layer was washed with water and an aqueous sodium bicarbonate solution, then dried, filtered, and concentrated with anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:5) to obtain the compound (362 mg, 50.0%) in the form of a brown solid.

[0549] 1 H NMR (500 MHz, CDCl3) δ 7.88 (d,J= 8.0 Hz, 2H), 7.82 (d,J= 8.0 Hz, 1H), 7.23 (d,J= 7.9 Hz, 2H), 7.20 (d,J= 7.9 Hz, 1H), 5.1 (t,J= 7.4 Hz, 1H), 2 (q,J= 7.4 Hz, 1H), 2.37 (s, 3H), 1.67 (m, 2H), 1.38(m, 2H), 0.94 (t,J= 7.4 Hz, 3H).

[0550]

[0551] Preparation Example 35

[0552] 2-bromo-1-(p-tolyl)butane-1-on

[0553] 2-Bromo-1-(p-tolyl)butan-1-one

[0554]

[0555] The above compound (659.5 mg, 50.0%) was obtained as a yellow liquid from 1-(p-tolyl)butan-1-one.

[0556] 1H NMR (500 MHz, CDCl3) δ 7.84 (d,J= 8.0 Hz, 2H), 7.19 (d,J= 7.6 Hz, 2H), 5.00 (t,J= 4.2 Hz, 1H), 2.33 (s, 3H), 2.16 (m, 1H), 2.04 (m, 1H), 0.99 (t,J= 4.6 Hz, 3H).

[0557]

[0558] Preparation Example 36

[0559] 2-bromo-1-phenylbutan-1-one

[0560] 2-Bromo-1-phenylbutan-1-one

[0561]

[0562] The above compound (1.03 g, 68.7%) was obtained from 1-phenylbutan-1-one as a transparent viscous liquid.

[0563] 1 H NMR (500 MHz, DMSO-d6) δ 8.03 (t,J= 7.4 Hz, 2H), 7.66 (t,J= 7.4 Hz, 1H), 7.55 (t,J= 7.7 Hz, 2H), 5.66 (t,J= 7.6, 6.1 Hz, 1H), 2.11 (m, 7.1 Hz, 1H), 1.97 (m, 1H), 1.00 (t,J= 7.3 Hz, 3H).

[0564]

[0565] Preparation Example 37

[0566] 2-bromo-1-(4-chlorophenyl)butan-1-one

[0567] 2-Bromo-1-(4-chlorophenyl)butan-1-one

[0568]

[0569] The above compound (1.40 g, 97.6%) was obtained as a gray solid from 1-(4-chlorophenyl)butan-1-one.

[0570] 1H NMR (500 MHz, DMSO-d6) δ 8.03 (t,J= 7.4 Hz, 2H), 7.66 (t,J= 7.4 Hz, 1H), 7.55 (t,J= 7.7 Hz, 2H), 5.66 (t,J= 7.6, 6.1 Hz, 1H), 2.11 (m, 7.1 Hz, 1H), 1.97 (m, 1H), 1.00 (t,J= 7.3 Hz, 3H).

[0571]

[0572] Preparation Example 38

[0573] 2-bromo-1-(4-hydroxyphenyl)butan-1-one

[0574] 2-Bromo-1-(4-hydroxyphenyl)butan-1-one

[0575]

[0576] The above compound (1.12 g, 63.1%) was obtained as a white solid from 1-(4-hydroxyphenyl)butan-1-one.

[0577] 1 H NMR (500 MHz, DMSO-d6) δ 8.03 (t,J= 7.4 Hz, 2H), 7.66 (t,J= 7.4 Hz, 1H), 7.55 (t,J= 7.7 Hz, 2H), 5.66 (t,J= 7.6, 6.1 Hz, 1H), 2.11 (m, 7.1 Hz, 1H), 1.97 (m, 1H), 1.00 (t,J= 7.3 Hz, 3H).

[0578]

[0579] Preparation Example 39

[0580] 5-propyl-4-(p-tolyl)thiazole-2-amine

[0581] 5-Propyl-4-(p-tolyl)thiazol-2-amine

[0582]

[0583] The above compound (570.6 mg, 99.9%) was obtained as a yellow solid from 2-bromo-1-(p-tolyl)pentan-1-one.

[0584] 1 H NMR (500 MHz, DMSO-d6) δ 8.03 (t,J= 7.4 Hz, 2H), 7.66 (t,J= 7.4 Hz, 1H), 7.55 (t,J= 7.7 Hz, 2H), 5.66 (t,J= 7.6, 6.1 Hz, 1H), 2.11 (m, 7.1 Hz, 1H), 1.97 (m, 1H), 1.00 (t,J= 7.3 Hz, 3H).

[0585]

[0586] Preparation Example 40

[0587] 5-ethyl-4-(p-tolyl)thiazole-2-amine

[0588] 5-Ethyl-4-(p-tolyl)thiazol-2-amine

[0589]

[0590] The above compound (788.9 mg, 99.9%) was obtained as a yellow solid from 2-bromo-1-(p-tolyl)butan-1-one.

[0591] 1 H NMR (500 MHz, DMSO-d6) δ 7.38 (d,J= 6.6 Hz, 2H), 7.18 (d,J= 6.9 Hz, 2H), 6.76 (s, 2H), 2.71 (q,J= 6.7 Hz, 2H), 2.31 (s, 3H), 1.17 (t,J= 6.5 Hz, 3H).

[0592]

[0593] Preparation Example 41

[0594] 5-ethyl-4-phenylthiazole-2-amine

[0595] 5-Ethyl-4-phenylthiazol-2-amine

[0596]

[0597] The above compound (723.4 mg, 78.5%) was obtained as a yellow solid from 2-bromo-1-phenylbutan-1-one.

[0598] 1 H NMR (500 MHz, DMSO-d6) δ 7.48 (d,J= 7.8 Hz, 2H), 7.36 (t,J= 7.4 Hz, 2H), 7.27 (t,J= 6.9 Hz, 1H), 6.80 (s, 2H), 2.71 (q,J= 7.3 Hz, 2H), 1.16 (t,J= 7.2 Hz, 3H).

[0599]

[0600] Preparation Example 42

[0601] 4-(4-chlorophenyl)-5-ethylthiazole-2-amine

[0602] 4-(4-Chlorophenyl)-5-ethylthiazol-2-amine

[0603]

[0604] The above compound (724.0 mg, 79.3%) was obtained as a yellow solid from 2-bromo-1-(4-chlorophenyl)butan-1-one.

[0605] 1 H NMR (500 MHz, DMSO-d6) δ 7.50 (d,J= 8.5 Hz, 2H), 7.42 (d,J= 8.5 Hz, 2H), 6.83 (s, 2H), 2.70 (q,J= 7.4 Hz, 2H), 1.16 (t,J= 7.4 Hz, 3H).

[0606]

[0607] Preparation Example 43

[0608] 4-(2-amino-5-ethylthiazole-4-yl)phenol

[0609] 4-(2-Amino-5-ethylthiazol-4-yl)phenol

[0610]

[0611] The above compound (599.2 mg, quantitative yield) was obtained as a yellow solid from 2-bromo-1-(4-hydroxyphenyl)butan-1-one.

[0612] 1 H NMR (500 MHz, DMSO-d6) δ 9.44 (s, 1H), 7.28 (d,J= 8.2 Hz, 2H), 6.74 (d,J= 8.3 Hz, 2H), 6.69 (s, 2H), 2.66 (q,J= 7.3 Hz, 2H), 1.14 (t,J= 7.3 Hz, 3H).

[0613]

[0614] Preparation Example 44

[0615] 4-(4-((tert-butyldimethylsilyl)oxy)phenyl)-5-ethylthiazole-2-amine

[0616] 4-(4-((tert-Butyldimethylsilyl)oxy)phenyl)-5-ethylthiazol-2-amine

[0617]

[0618] The above compound (317.8 mg, 35.0%) was obtained from 4-(2-amino-5-ethylthiazole-4-yl)phenol as a yellow viscous liquid.

[0619] 1 H NMR (500 MHz, DMSO-d6) δ 7.37 (d,J= 8.6 Hz, 2H), 6.83 (d,J= 8.6 Hz, 2H), 6.72 (s, 2H), 2.68 (q,J= 7.3 Hz, 2H), 1.15 (t,J= 7.4 Hz, 3H), 0.94 (s, 9H), 0.18 (s, 6H).

[0620]

[0621] Preparation Example 45

[0622] N,3-Dimethoxy-N-methylbenzamide

[0623] N,3-Dimethoxy-N-methylbenzamide

[0624]

[0625] N,O-dimethylhydroxylamine hydrochloride (1.89 g, 19.35 mmol) was dissolved in 100 mL of dichloromethane and 100 mL of saturated sodium bicarbonate aqueous solution and stirred at room temperature for 5 minutes. 3-methoxybenzoyl chloride (3.0 g, 2.47 mL, 17.59 mmol) was added over 20 minutes, and the reaction mixture was stirred at room temperature for 4 hours. The organic layer was separated, and the aqueous layer was washed with dichloromethane. The combined organic layer was washed with water and saturated saline, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate:hexane = 1:2) to obtain the compound (3.43 g, quantitative yield) in the form of a colorless liquid.

[0626] 1 H NMR (500 MHz, CDCl3) δ 7.25 (t,J= 7.9 Hz, 1H), 7.18 (d,J= 7.4 Hz, 1H), 7.14 (s, 1H), 6.93 (d,J= 8.2 Hz, 1H), 3.76 (s, 3H), 3.51 (s, 3H), 3.28 (s, 3H).

[0627]

[0628] Preparation Example 46

[0629] 4-fluoro-N-methoxy-N-methyl-3-(trifluoromethyl)benzamide

[0630] 4-Fluoro-N-methoxy-N-methyl-3-(trifluoromethyl)benzamide

[0631]

[0632] The above compound (5.21 g, 94.0%) was obtained from 4-fluoro-3(trifluoromethyl)benzyl chloride as a colorless viscous liquid.

[0633] 1H NMR (500 MHz, CDCl3) δ 8.01 (d,J= 6.7 Hz, 1H), 7.93 (m, 1H), 7.21 (t,J= 9.3 Hz, 1H), 3.51 (s, 3H), 3.35 (s, 3H).

[0634]

[0635] Preparation Example 47

[0636] 1-(3-methoxyphenyl)butan-1-one

[0637] 1-(3-Methoxyphenyl)butan-1-one

[0638]

[0639] A tetrahydrofuran solution of 2.0 molar propyl magnesium bromide (13.2 mL, 26.39 mmol) was slowly added at 5 °C to a stirred solution in which N,3-dimethoxy-N-methylbenzamide (3.43 g, 17.59 mmol) was dissolved in tetrahydrofuran (100 mL). The resulting reaction mixture was stirred at room temperature for 2.5 hours. The reaction mixture was poured into a 20% aqueous hydrochloric acid solution and extracted with ethyl acetate. The combined organic layer was washed with saturated saline, dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the compound (3.14 g, quantitative yield) in liquid form.

[0640] 1 H NMR (500 MHz, CDCl3) δ 7.50 (d,J= 7.6 Hz, 1H), 7.48 - 7.42 (m, 1H), 7.32 (t,J= 7.9 Hz, 1H), 7.07 - 7.05 (m, 1H), 3.81 (s, 3H), 2.89 (t,J= 7.3 Hz, 2H), 1.73 (m, 2H), 0.97 (t,J= 7.4 Hz, 3H).

[0641]

[0642] Preparation Example 48

[0643] 1-(4-fluoro-3-(trifluoromethyl)phenyl)butan-1-one

[0644] 1-(4-Fluoro-3-(trifluoromethyl)phenyl)butan-1-one

[0645]

[0646] The above compound (4.43 g, 91.1%) was obtained from 4-fluoro-N-methoxy-N-methyl-3(trifluoromethyl)benzamide as a colorless viscous liquid.

[0647] 1 H NMR (500 MHz, CDCl3) δ 8.20 (m, 1H), 8.15 (m, 1H), 7.26 (dd,J= 11.1, 7.3 Hz, 1H), 2.93 (t,J= 7.2 Hz, 2H), 1.75 (m, 2H), 0.99 (t,J= 7.4 Hz, 3H).

[0648]

[0649] Preparation Example 49

[0650] 1-(3-hydroxyphenyl)butan-1-one

[0651] 1-(3-Hydroxyphenyl)butan-1-one

[0652]

[0653] Aluminum chloride (3.52 g, 26.39 mmol) was added at 0°C to a solution in which 1-(3-methoxyphenyl)butan-1-one (3.14 g, 17.59 mmol) was dissolved in toluene (50 mL), and the reaction mixture was stirred at 115°C for 9 hours. Additionally, aluminum chloride (3.52 g, 26.39 mmol) was added at 0°C, and the reaction mixture was stirred at 115°C for 15 hours. After the reaction was complete, the mixture was poured into a 2-normal aqueous hydrochloric acid solution, extracted with ethyl acetate, and washed with a saturated aqueous sodium bicarbonate solution and saturated saline solution. The organic layer was dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate:hexane = 1:7) to obtain the compound (2.43 g, 84.1%) in the form of a light brown solid.

[0654] 1 H NMR (500 MHz, CDCl3) δ 7.58 (s, 1H), 7.51 (d,J= 7.7 Hz, 1H), 7.33 (t,J= 7.9 Hz, 1H), 7.09 (dd,J= 8.0, 2.2 Hz, 1H), 6.57 (s, 1H), 2.94 (t,J= 7.3 Hz, 2H), 1.77 (m, 2H), 0.99 (t,J= 7.4 Hz, 3H).

[0655]

[0656] Preparation Example 50

[0657] 2-bromo-1-(3-hydroxyphenyl)butan-1-one

[0658] 2-Bromo-1-(3-Hydroxyphenyl)butan-1-one

[0659]

[0660] The above compound (3.40 g, 94.5%) was obtained from 1-(3-hydroxyphenyl)butan-1-one as a dark brown solid.

[0661] 1H NMR (500 MHz, CDCl3) δ 7.58 (s, 1H), 7.51 (d,J= 7.7 Hz, 1H), 7.33 (t,J= 7.9 Hz, 1H), 7.09 (dd,J= 8.0, 2.2 Hz, 1H), 6.57 (s, 1H), 2.94 (t,J= 7.3 Hz, 2H), 1.77 (m, 2H), 0.99 (t,J= 7.4 Hz, 3H).

[0662]

[0663] Preparation Example 51

[0664] 2-bromo-1-(4-fluoro-3-(trifluoromethyl)phenyl)pentan-1-one

[0665] 2-Bromo-1-(4-fluoro-3-(trifluoromethyl)phenyl)pentan-1-one

[0666]

[0667] The above compound (1.84 g, quantitative yield) was obtained as a brown solid from 1-(4-fluoro-3-(trifluoromethyl)phenyl)butan-1-one.

[0668] 1 H NMR (500 MHz, DMSO-d6) δ 8.43 (m, 1H), 8.36 (d,J= 6.6 Hz, 1H), 7.72 (t,J= 9.6 Hz, 1H), 5.79 (m, 1H), 2.12 (m, 1H), 1.95 (m, 1H), 1.02 (t,J= 7.2 Hz, 3H).

[0669]

[0670] Preparation Example 52

[0671] 3-(2-amino-5-ethylthiazole-4-yl)phenol

[0672] 3-(2-Amino-5-ethylthiazol-4-yl)phenol

[0673]

[0674] The above compound (2.67 g, 87.3%) was obtained as a dark yellow jelly from 2-bromo-1-(3-hydroxyphenyl)butan-1-one.

[0675] 1 H NMR (500 MHz, DMSO-d6) δ 9.38 (s, 1H), 7.14 (t,J= 7.8 Hz, 1H), 6.93 (s, 1H), 6.89 (d,J= 7.6 Hz, 1H), 6.74 (s, 2H), 6.66 (d,J= 6.4 Hz, 1H), 2.70 (q,J= 7.3 Hz, 2H), 1.15 (t,J= 7.3 Hz, 3H).

[0676]

[0677] Preparation Example 53

[0678] 4-(4-fluoro-3-(trifluoromethyl)phenyl)-5-propylthiazole-2-amine

[0679] 4-(4-Fluoro-3-(trifluoromethyl)phenyl)-5-propylthiazol-2-amine

[0680]

[0681] The above compound (1.58 g, 92.4%) was obtained as a beige solid from 2-bromo-1-(4-fluoro-3-(trifluoromethyl)phenyl)pentan-1-one.

[0682] 1 H NMR (500 MHz, DMSO-d6) δ 7.84 (m, 2H), 7.53 (t,J= 9.6 Hz, 1H), 6.94 (s, 2H), 2.74 (q,J= 7.4 Hz, 2H), 1.19 (t,J= 7.4 Hz, 3H).

[0683]

[0684] Preparation Example 54

[0685] 5-ethyl-4-(3-((4-methoxybenzyl)oxy)phenyl)thiazole-2-amine

[0686] 5-Ethyl-4-(3-((4-methoxybenzyl)oxy)phenyl)thiazol-2-amine

[0687]

[0688] 3-(2-amino-5-ethylthiazole-4-yl)phenol (1.44 g, 6.53 mmol), potassium carbonate (9.79 g, 9.80 mmol), and anhydrous N,N-dimethylformamide (15 mL) were added to a flame-dried flask. After stirring the mixture at room temperature for 1 hour, 4-methoxybenzyl chloride (1.23 g, 1.06 mL, 7.84 mmol) was added dropwise to the residue at 0 °C. The mixture was stirred at 60 °C for 4 hours. Subsequently, the mixture was poured into cold water, extracted with ethyl acetate, and washed with saturated saline solution. The organic layer was dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate:hexane = 1:3) to obtain the compound (1.68 g, 75.4%) in the form of a brown solid.

[0689] 1 H NMR (500 MHz, CDCl3) δ 7.36 (d,J= 8.3 Hz, 2H), 7.29 (t,J= 7.8 Hz, 1H), 7.15 (s, 1H), 7.11 (d,J= 7.5 Hz, 1H), 6.92 - 6.92 (m, 3H), 5.02 (s, 2H), 4.85 (s, 2H), 3.82 (s, 3H), 2.78 (q,J= 7.5 Hz, 2H), 1.23 (t,J= 7.4 Hz, 3H).

[0690]

[0691] Preparation Example 55

[0692] 1-(2-hydroxyphenyl)butan-1-one

[0693] 1-(2-Hydroxyphenyl)butan-1-one

[0694]

[0695] Triethylamine (3.23 g, 4.44 mL, 31.88 mmol) was added to a solution of phenol (2.0 g, 21.25 mmol) dissolved in dichloromethane (90 mL), and then butyroyl chloride (2.72 g, 2.64 mL, 25.50 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was poured into cold water, extracted with dichloromethane, washed with saturated saline, dried with anhydrous magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure to obtain the product, which was used immediately in the next step.

[0696] A mixture of anhydrous aluminum chloride powder (5.67 g, 42.50 mmol) and phenyl chloroacetate (21.25 mmol) was heated at 135 °C for 30 minutes. The reaction mixture was stopped with water cooled to 0 °C, after which a cold aqueous hydrochloric acid solution was added. The resulting mixture was extracted with dichloromethane, washed with saturated saline solution, and then dried and concentrated with anhydrous magnesium sulfate. The residue was purified by flash column chromatography (diethyl ether:hexane = 1:50) to obtain the compound (964.4 mg, 27.6%) in the form of a pale yellow liquid.

[0697] 1 H NMR (500 MHz, CDCl3) δ 12.41 (s, 1H), 7.75 (d,J= 6.5 Hz, 1H), 7.44 (t,J= 6.7 Hz, 1H), 6.96 (d,J= 7.5 Hz, 1H), 6.88 (m, 1H), 2.97 - 2.94 (m, 2H), 1.79 - 1.73 (m, 2H), 1.01 (m, 3H).

[0698]

[0699] Preparation Example 56

[0700] 1-(4-chloro-2-hydroxyphenyl)butan-1-one

[0701] 1-(4-Chloro-2-hydroxyphenyl)butan-1-one

[0702]

[0703] A mixture of aluminum chloride (1.92 g, 14.39 mmol) and 1,2-dichloroethane (25 mL) was cooled to 0°C, and butyroyl chloride (1.04 g, 1.01 mL, 9.73 mmol) was dissolved in 1,2-dichloroethane (15 mL) and added. Subsequently, 3-chlorophenol (1.0 g, 7.78 mmol) was dissolved in 1,2-dichloroethane (10 mL) and slowly added at 0°C, and the mixture was stirred at 0°C for 30 minutes and at room temperature for 3 hours. After the reaction was complete, the mixture was poured into a cold aqueous hydrochloric acid solution, extracted with ethyl acetate, and washed with sodium bicarbonate and saturated saline solution. The organic layer was dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the compound in the form of a colorless liquid (quantitative yield), which was used immediately in the next step.

[0704] A mixture of 3-chlorophenyl butyrate (7.78 mmol) and anhydrous aluminum chloride powder (3.11 g, 23.34 mmol, 3 eq.) was heated at 70 °C for 6 hours. The resulting mixture was poured into a cold aqueous hydrochloric acid solution, extracted with ethyl acetate, and washed with water (20 mL) and saturated saline solution. The organic layer was dried and concentrated with anhydrous magnesium sulfate. The residue was purified by flash column chromatography (diethyl ether:hexane = 1:50) to obtain the compound (1.52 g, 98.5%) in the form of a colorless syrup.

[0705] 1 H NMR (500 MHz, CDCl3) δ 12.52 (s, 1H), 7.67 (d,J= 8.6 Hz, 1H), 6.98 (m, 1H), 6.87 - 6.85 (m, 1H), 2.92 (t,J= 7.3 Hz, 2H), 1.76 (m, 2H), 1.01 (t,J= 7.4 Hz, 3H).

[0706]

[0707] Preparation Example 57

[0708] 2-bromo-1-(2-hydroxyphenyl)butan-1-one

[0709] 2-Bromo-1-(2-hydroxyphenyl)butan-1-one

[0710]

[0711] The above compound (1.42 g, quantitative yield) was obtained as a brown solid from 1-(2-hydroxyphenyl)butan-1-one.

[0712] 1 H NMR (500 MHz, CDCl3) δ 11.97 (d,J= 2.4 Hz, 1H), 7.79 (d,J= 8.0 Hz, 1H), 7.51 (t,J= 7.7 Hz, 1H), 7.02 (d,J= 8.4 Hz, 1H), 6.93 (m, 1H), 5.11 (m, 1H), 2.27 - 2.12 (m, 2H), 1.09 (td,J= 7.3, 2.4 Hz, 3H).

[0713]

[0714] Preparation Example 58

[0715] 2-bromo-1-(4-chloro-2-hydroxyphenyl)butan-1-one

[0716] 2-Bromo-1-(4-chloro-2-hydroxyphenyl)butan-1-one

[0717]

[0718] The above compound (3.35 g, quantitative yield) was obtained as a brown solid from 1-(4-chloro-2-hydroxyphenyl)butan-1-one.

[0719] 1H NMR (500 MHz, CDCl3) δ 12.08 (d,J= 3.7 Hz, 1H), 7.72 (m, 1H), 7.04 (s, 1H), 6.90 (d,J= 6.8 Hz, 1H), 5.01 (m, 1H), 2.22 - 2.12 (m, 2H), 1.09 (m, 3H).

[0720]

[0721] Preparation Example 59

[0722] 2-(2-amino-5-ethylthiazole-4-yl)phenol

[0723] 2-(2-Amino-5-ethylthiazol-4-yl)phenol

[0724]

[0725] The above compound (1.23 g, quantitative yield) was obtained as a white solid from 2-bromo-1-(2-hydroxyphenyl)butan-1-one.

[0726] 1 H NMR (500 MHz, CDCl3) δ 10.65 (s, 1H), 7.36 (d,J= 7.7 Hz, 1H), 7.21 (t,J= 7.7 Hz, 1H), 6.99 (d,J= 8.1 Hz, 1H), 6.88 (t,J= 7.5 Hz, 1H), 4.98 (s, 2H), 2.92 (q,J= 7.4 Hz, 1H), 1.31 (t,J= 7.5 Hz, 3H).

[0727]

[0728] Preparation Example 60

[0729] 2-(2-amino-5-ethylthiazole-4-yl)-5-chlorophenol

[0730] 2-(2-Amino-5-ethylthiazol-4-yl)-5-chlorophenol

[0731]

[0732] The above compound (2.55 g, 83.0%) was obtained as a white solid from 2-bromo-1-(4-chloro-2-hydroxyphenyl)butan-1-one.

[0733] 1 H NMR (500 MHz, DMSO-d6) δ 11.57 (s, 1H), 7.32 - 7.31 (m, 1H), 7.21 (s, 2H), 6.88 (s, 1H), 6.87 - 6.85 (m, 1H), 2.71 (m, 2H), 1.16 (m, 3H).

[0734]

[0735] Preparation Example 61

[0736] 5-ethyl-4-(2-((4-methoxybenzyl)oxy)phenyl)thiazole-2-amine

[0737] 5-Ethyl-4-(2-((4-methoxybenzyl)oxy)phenyl)thiazol-2-amine

[0738]

[0739] The above compound (359.3 mg, 18.0%) was obtained as a yellow solid from 2-(2-amino-5-ethylthiazole-4-yl)phenol.

[0740] 1 H NMR (500 MHz, CDCl3) δ 7.34 (d,J= 7.5 Hz, 1H), 7.28 - 7.24 (m, 3H), 7.01 - 6.98 (m, 2H), 6.85 (d,J= 7.3 Hz, 2H), 4.98 (s, 2H), 4.97 (s, 2H), 3.79 (d,J= 1.3 Hz, 3H), 2.64 - 2.39 (m, 2H), 1.08 (td,J= 7.4, 1.2 Hz, 3H).

[0741]

[0742] Preparation Example 62

[0743] 4-(4-chloro-2-((methoxybenzyl)oxy)phenyl)-5-ethylthiazole-2-amine

[0744] 4-(4-Chloro-2-((4-methoxybenzyl)oxy)phenyl)-5-ethylthiazol-2-amine

[0745]

[0746] The above compound (1.26 g, 34.3%) was obtained as a dark brown jelly from 2-(2-amino-5-ethylthiazole-4-yl)-5-chlorophenol.

[0747] 1 H NMR (500 MHz, CDCl3) δ 7.23 - 7.19 (m, 3H), 6.95 (s, 1H), 6.93 (d,J= 7.8 Hz, 1H), 6.80 (d,J= 5.3 Hz, 2H), 5.39 (s, 2H), 4.91 (s, 2H), 3.73 (s, 3H), 2.45 (m, 2H), 1.01 (m, 3H).

[0748]

[0749] Preparation Example 63

[0750] 1-(4-fluorophenyl)penta-1-one

[0751] 1-(4-Fluorophenyl)pentan-1-one

[0752]

[0753] 4-fluorobenzonitrile (2.0 g, 16.51 mmol) and zinc chloride (450.2 mg, 3.303 mmol) were dissolved in anhydrous tetrahydrofuran (30 mL). Butyl magnesium bromide (4.0 g, 24.8 mmol) was added to this solution, and the reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was acidified with dilute hydrochloric acid, extracted with ethyl acetate, washed with brine, dried with magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (EtOAc:hexane, 1:50) to obtain the compound (2.01 g, 67.6%) in the form of a colorless oil.

[0754] 1 H NMR (500 MHz, DMSO-d6) δ 8.06 - 7.99 (m, 2H), 7.32 (t,J= 8.0 Hz, 2H), 2.98 (t,J= 7.0 Hz, 2H), 1.56 (dt,J= 13.6, 6.8 Hz, 2H), 1.32 (dt,J= 14.7, 7.4 Hz, 2H), 0.88 (t,J= 7.2 Hz, 3H).

[0755]

[0756] Preparation Example 64

[0757] 1-(3-chloro-4-fluorophenyl)pentan-1-one

[0758] 1-(3-Chloro-4-fluorophenyl)pentan-1-one

[0759]

[0760] The above compound (2.25 g, 81.1%) was obtained as a brown oil from 3-chloro-4-fluorobenzonitrile.

[0761] 1 H NMR (500 MHz, CDCl3) δ 8.02 (m, 1H), 7.86 (m, 1H), 7.74 (m, 1H), 2.92 (t,J= 7.4 Hz, 2H), 1.70 (m, 2H), 1.40 (m, 2H), 0.95 (t,J= 7.3) Hz, 3H).

[0762]

[0763] Preparation Example 65

[0764] 1-(3-fluoro-4-methylphenyl)pentan-1-one

[0765] 1-(3-Fluoro-4-methylphenyl)pentan-1-one

[0766]

[0767] The above compound (1.32 g, 45.9%) was obtained as a colorless oil from 3-fluoro-4-methylbenzonitrile.

[0768] 1H NMR (500 MHz, DMSO-d6) δ 7.72 (d,J= 7.8 Hz, 1H), 7.66 (d,J= 10.7 Hz, 1H), 7.44 (t,J= 7.8 Hz, 1H), 2.99 (t,J= 7.2 Hz, 2H), 2.30 (s, 3H), 1.57 (m, 2H), 1.32 (m, 2H), 0.89 (t,J= 7.3 Hz, 3H).

[0769]

[0770] Preparation Example 66

[0771] 1-(3-chloro-4-methylphenyl)pentan-1-one

[0772] 1-(3-Chloro-4-methylphenyl)pentan-1-one

[0773]

[0774] The above compound (2.18 g, 77.2%) was obtained as a white solid from 3-chloro-4-methylbenzonitrile.

[0775] 1 H NMR (500 MHz, DMSO-d6) δ 7.81 (d,J= 7.7 Hz, 1H), 7.71 (d,J= 7.7 Hz, 1H), 7.55 (d,J= 7.6 Hz, 1H), 7.48 (d,J= 7.7 Hz, 1H), 2.97 (dd,J= 9.5, 4.8 Hz, 2H), 2.38 (s, 3H), 1.59 - 1.50 (m, 2H), 1.31 (dd,J= 13.5, 6.5 Hz, 2H), 0.87 (dd,J= 9.6, 4.9 Hz, 3H).

[0776]

[0777] Preparation Example 67

[0778] 2-bromo-1-(4-fluorophenyl)pentan-1-one

[0779] 2-Bromo-1-(4-fluorophenyl)pentan-1-one

[0780]

[0781] The above compound (2.84 g, quantitative yield) was obtained as a white solid from 1-(4-fluorophenyl)pentan-1-one.

[0782] 1 H NMR (500 MHz, DMSO-d6) δ 8.16 - 8.10 (m, 2H), 7.38 (t,J= 8.8 Hz, 2H), 5.69 (t,J= 6.9 Hz, 1H), 2.04 (tt,J= 11.5, 5.8 Hz, 1H), 1.95 - 1.87 (m, 1H), 1.53 - 1.42 (m, 1H), 1.36 (dt,J= 29.3, 9.9 Hz, 1H), 0.92 (t,J= 7.4 Hz, 3H).

[0783]

[0784] Preparation Example 68

[0785] 2-bromo-1-(3-chloro-4-fluorophenyl)pentan-1-one

[0786] 2-Bromo-1-(3-chloro-4-fluorophenyl)pentan-1-one

[0787]

[0788] The above compound (2.46 g, 80.2%) was obtained as a yellow solid from 1-(3-chloro-4-fluorophenyl)pentan-1-one.

[0789] 1 H NMR (500 MHz, DMSO-d6) δ 8.30 (m, 1H), 8.09 (m, 1H), 7.96 (m, 1H), 7.67 (t,J= 8.9 Hz, 1H), 5.76 (m, 1H), 2.04 (m, 1H), 1.94 (m, 1H), 1.50 (m, 1H), 1.40 (m, 1H), 0.94 (t,J= 7.4 Hz, 3H).

[0790]

[0791] Preparation Example 69

[0792] 2-bromo-1-(3-fluoro-4-methylphenyl)pentan-1-one

[0793] 2-Bromo-1-(3-fluoro-4-methylphenyl)pentan-1-one

[0794]

[0795] The above compound (2.47 g, quantitative yield) was obtained as a yellow solid from 1-(3-fluoro-4-methylphenyl)pentan-1-one.

[0796] 1 H NMR (500 MHz, DMSO-d6) δ 7.81 (d,J= 7.9 Hz, 1H), 7.77 (d,J= 10.0 Hz, 1H), 7.61 (d,J= 7.8 Hz, 1H), 5.70 (m, 1H), 2.31 (s, 3H), 2.05 (m, 1H), 1.95 (m, 1H), 1.48 (m, 1H), 1.37 (m, 1H), 0.93 (t,J= 7.4 Hz, 3H).

[0797]

[0798] Preparation Example 70

[0799] 2-bromo-1-(3-chloro-4-methylphenyl)pentan-1-one

[0800] 2-Bromo-1-(3-chloro-4-methylphenyl)pentan-1-one

[0801]

[0802] The above compound (2.9 g, quantitative yield) was obtained as a white solid from 1-(3-chloro-4-methylphenyl)pentan-1-one.

[0803] 1H NMR (500 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.91 (d,J= 7.9 Hz, 1H), 7.72 (d,J= 7.9 Hz, 1H), 5.73 - 5.68 (m, 1H), 2.39 (s, 3H), 2.03 (dt,J= 14.8, 5.7 Hz, 1H), 1.97 - 1.88 (m, 1H), 1.53 - 1.42 (m, 1H), 1.42 - 1.31 (m, 1H), 0.92 (t,J= 7.3 Hz, 3H).

[0804]

[0805] Preparation Example 71

[0806] 4-(4-fluorophenyl)-5-propylthiazole-2-amine

[0807] 4-(4-Fluorophenyl)-5-propylthiazol-2-amine

[0808]

[0809] 2-bromo-1-(4-fluorophenyl)pentan-1-one (2.8 g, 10.9 mmol) and thiourea (829.7 mg, 10.9 mmol) were dissolved in ethanol (20 mL). The reaction mixture was stirred at 85°C for 1.5 hours. After the reaction was complete, the mixture was based with an aqueous sodium bicarbonate solution, extracted with ethyl acetate, washed with brine, dried with magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (EtOAc:hexane, 1:5) to obtain the compound (1.45 g, 56.3%).

[0810] 1 H NMR (500 MHz, DMSO-d6) δ 7.53 - 7.46 (m, 2H), 7.19 (t,J= 8.7 Hz, 2H), 6.80 (s, 2H), 2.63 (t,J= 7.5 Hz, 2H), 1.53 (dd,J= 14.7, 7.4 Hz, 2H), 0.88 (t,J= 7.2 Hz, 3H).

[0811]

[0812] Preparation Example 72

[0813] 4-(3-chloro-4-fluorophenyl)-5-propylthiazole-2-amine

[0814] 4-(3-Chloro-4-fluorophenyl)-5-propylthiazol-2-amine

[0815]

[0816] The above compound (1.20 g, 53.0%) was obtained as a bright red solid from 2-bromo-1-(3-chloro-4-fluorophenyl)pentan-1-one.

[0817] 1 H NMR (500 MHz, DMSO-d6) δ 7.64 (d,J= 7.3 Hz, 1H), 7.48 (m, 1H), 7.43 (t,J= 8.9 Hz, 1H), 6.89 (s, 2H), 2.67 (t,J= 7.5 Hz, 2H), 1.56 (m, 2H), 0.90 (t,J= 7.3 Hz, 3H).

[0818]

[0819] Preparation Example 73

[0820] 4-(3-fluoro-4-methylphenyl)-5-propylthiazole-2-amine

[0821] 4-(3-Fluoro-4-methylphenyl)-5-propylthiazol-2-amine

[0822]

[0823] The above compound (1.14 g, 50.2%) was obtained as a bright red solid from 2-bromo-1-(3-fluoro-4-methylphenyl)pentan-1-one.

[0824] 1H NMR (500 MHz, DMSOv) δ 7.28 (t,J= 7.9 Hz, 1H), 7.21 (t,J= 9.2 Hz, 2H), 6.84 (s, 2H), 2.68 (t,J= 7.5 Hz, 2H), 2.24 (s, 3H), 1.56 (m, 2H), 0.90 (t,J= 7.2 Hz, 3H).

[0825]

[0826] Preparation Example 74

[0827] 4-(3-chloro-4-methylphenyl)-5-propylthiazole-2-amine

[0828] 4-(3-Chloro-4-methylphenyl)-5-propylthiazol-2-amine

[0829]

[0830] The above compound (1.24 g, 46.0%) was obtained as a yellow solid from 2-bromo-1-(3-chloro-4-methylphenyl)pentan-1-one.

[0831] 1 H NMR (500 MHz, DMSO-d6) δ 7.49 (s, 1H), 7.33 (s, 2H), 6.83 (s, 2H), 2.69 - 2.62 (m, 2H), 2.31 (s, 3H), 1.53 (dd,J= 14.7, 7.3 Hz, 2H), 0.88 (t,J= 7.2 Hz, 3H).

[0832]

[0833] Preparation Example 75

[0834] 2-(5-ethylthiazole-2-yl)isoindolin-1,3-dione

[0835] 2-(5-Ethylthiazol-2-yl)isoindoline-1,3-dione

[0836]

[0837] A mixture of 5-ethylthiazole-2-amine (1.58 g, 12.32 mmol) and isobutanzofuran-1,3-dione (1.83 g, 12.32 mmol) was stirred at 210 °C for 7 minutes under a nitrogen atmosphere. After the reaction was complete, distilled water and ethyl acetate were added, the organic layer was separated, and the aqueous layer was washed with ethyl acetate. The combined organic layer was washed with distilled water and brine, dried with anhydrous magnesium sulfate, and then vacuum concentrated. The residue was ground and purified with ethyl acetate and hexane to obtain the title compound. The filtrate was concentrated, and the residue was purified by flash column chromatography (EtOAc:hexane, 1:3) to obtain the above compound (3.00 g, 94.3%) as a pale yellow solid.

[0838] 1 H NMR (500 MHz, DMSO-d6) δ 7.99 - 7.96 (m, 2H), 7.93 - 7.90 (m, 2H), 7.53 (s, 1H), 2.87 (q,J= 7.4 Hz, 2H), 1.27 (t,J= 7.5 Hz, 3H).

[0839]

[0840] Preparation Example 76

[0841] 2-(5-(tert-butyl)thiazole-2-yl)isoindolin-1,3-dione

[0842] 2-(5-(tert-Butyl)thiazol-2-yl)isoindoline-1,3-dione

[0843]

[0844] The above compound (1.69 g, 89.3%) was obtained as a white solid from 5-(tert-butyl)thiazole-2-amine.

[0845] 1H NMR (500 MHz, DMSO-d6) δ 7.99 - 7.96 (m, 2H), 7.93 - 7.90 (m, 2H), 7.53 (s, 1H), 2.87 (q,J= 7.4 Hz, 2H), 1.27 (t,J= 7.5 Hz, 3H).

[0846]

[0847] Preparation Example 77

[0848] 2-(4-bromo-5-ethylthiazole-2-yl)isoindolin-1,3-dione

[0849] 2-(4-Bromo-5-ethylthiazol-2-yl)isoindoline-1,3-dione

[0850]

[0851] A solution of 2-(5-ethylthiazole-2-yl)isoindolin-1,3-dione (300.1 mg, 1.16 mmol) dissolved in anhydrous acetonitrile (2 mL) was placed in a foil-covered flask, and N-bromosuccinimide (248.1 mg, 1.39 mmol) was added at room temperature. After vigorously stirring at 50 °C for 9 hours, the mixture was concentrated. The residue was distributed between water and ethyl acetate, extracted with ethyl acetate, dried with magnesium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (EtOAc:hexane, 1:5) to obtain the compound (310.0 mg, 79.3%) in the form of a yellow solid.

[0852] 1H NMR (500 MHz, DMSO-d6) δ 8.01 - 7.99 (m, 2H), 7.93 - 7.92 (m, 2H), 2.80 (q,J= 7.5 Hz, 2H), 1.23 (t,J= 7.5 Hz, 3H).

[0853]

[0854] Preparation Example 78

[0855] 2-(4-bromo-5-(tert-butyl)thiazole-2-yl)isoindolin-1,3-dione

[0856] 2-(4-Bormo-5-(tert-butyl)thiazol-2-yl)isoindoline-1,3-dione

[0857]

[0858] The above compound (2.11 g, quantitative yield) was obtained as a bright yellow solid from 2-(5-(tert-butyl)thiazole-2-yl)isoindolin-1,3-dione.

[0859] 1 H NMR (500 MHz, DMSO-d6) δ 8.00 - 7.99 (m, 2H), 7.93 - 7.91 (m, 2H), 1.48 (s, 9H).

[0860]

[0861] Preparation Example 79

[0862] 4-Bromo-5-ethylthiazole-2-amine

[0863] 4-Bromo-5-ethylthiazol-2-amine

[0864]

[0865] N2H4·H2O (2.78 g, 2.70 mL, 55.60 mmol) was added dropwise at room temperature to a solution of 2-(4-bromo-5-ethylthiazole-2-yl)isoindolin-1,3-dione (3.75 g, 11.12 mmol) dissolved in ethanol (72 mL). After stirring overnight at room temperature, the mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (EtOAc:hexane, 1:3) to obtain the compound (2.10 g, 91.2%) in the form of a pale yellow solid.

[0866] 1H NMR (500 MHz, CDCl3) δ 5.05 (s, 2H), 2.63 (q,J= 7.5 Hz, 2H), 1.19 (t,J= 7.5 Hz, 3H).

[0867]

[0868] Preparation Example 80

[0869] 4-Bromo-5-(tert-butyl)thiazole-2-amine

[0870] 4-Bromo-5-(tert-butyl)thiazol-2-amine

[0871]

[0872] The above compound (1.24 g, 91.7%) was obtained in the form of a pale yellow solid from 2-(4-bromo-5-(tert-butyl)thiazole-2-yl)isoindolin-1,3-dione.

[0873] 1H NMR (500 MHz, DMSO-d6) δ 6.98 (s, 2H), 1.32 (s, 9H).

[0874]

[0875] Preparation Example 81

[0876] Tert-butyl(4-bromo-5-ethylthiazole-2-yl)carbamate

[0877] tert-Butyl (4-bromo-5-ethylthiazol-2-yl)carbamate

[0878]

[0879] (Boc)2O (5.68 g, 26.02 mmol) was added to a solution of 4-bromo-5-ethylthiazole-2-amine (2.245 g, 10.84 mmol), DMAP (132.5 mg, 1.084 mmol), and triethylamine (2.633 g, 3.63 mL, 26.02 mmol) dissolved in tetrahydrofuran (40 mL). The reaction mixture was stirred overnight at 50°C. The solvent was evaporated. The residue was partitioned between distilled water and ethyl acetate, extracted with ethyl acetate, dried with magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (EtOAc:hexane, 1:50–1:30) to obtain the compound (3.12 g, 70.66%) as a yellow liquid.

[0880] 1H NMR (500 MHz, CDCl3 / CD3OD) δ 2.71 (q,J= 7.5 Hz, 2H), 1.53 (s, 9H), 1.25 (t,J= 7.5 Hz, 3H).

[0881]

[0882] Preparation Example 82

[0883] Tert-butyl(4-bromo-5-(tert-butyl)thiazole-2-yl)carbamate

[0884] tert-Butyl (4-bromo-5-(tert-Butyl)thiazol-2-yl)carbamate

[0885]

[0886] 4-bromo-5-(tert-butyl)thiazole-2-amine (1.11 g, 4.704 mmol), DMAP (28.8 mg, 0.24 mmol), and triethylamine (714.0 mg, 983.5 μL, 7.06 mmol), which were dissolved in dichloromethane (15 mL) of (Boc)2O (1.13 g, 5.17 mmol), were added to the solution. The reaction mixture was stirred overnight at room temperature. The solvent was evaporated. The residue was partitioned with distilled water and ethyl acetate, then extracted with ethyl acetate, dried with magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (EtOAc:hexane, 1:10) to obtain the compound (1.40 g, 88.5%) as a white solid.

[0887] 1H NMR (500 MHz, DMSO-d6) δ 11.51 (s, 1H), 1.44 (s, 9H), 1.39 (s, 9H).

[0888]

[0889] Preparation Example 83

[0890] Tert-butyl(4-bromo-5-ethylthiazole-2-yl)(4-methoxybenzyl)carbamate

[0891] tert-Butyl (4-bromo-5-ethylthiazol-2-yl)(4-methoxybenzyl)carbamate

[0892]

[0893] Tert-butyl(4-bromo-5-ethylthiazole-2-yl)carbamate (6.87 g, 22.4 mmol) was dissolved in N,N-dimethylformamide (35 mL). Cesium carbonate (8.74 g, 26.83 mmol) was added to the solution, followed by the addition of 4-methoxybenzyl chloride (4.2 g, 3.64 mL, 26.83 mmol). The mixture was stirred at 80°C for 1 hour. The reaction mixture was cooled to 25°C, water was added, and the mixture was extracted with ethyl acetate. The organic extract was dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (diethyl ether:hexane, 1:20) to obtain the compound (8.49 g, 88.8%) in the form of a colorless oil.

[0894] 1H NMR (500 MHz, CDCl3) δ 7.32 (d,J= 8.3 Hz, 2H), 6.82 (d,J= 8.6 Hz, 2H), 5.17 (s, 2H), 3.78 (s, 3H), 2.69 (q,J= 7.5 Hz, 2H), 1.52 (s, 3H), 1.50 (s, 9H), 1.24 (t,J= 7.6 Hz, 3H).

[0895]

[0896] Preparation Example 84

[0897] Tert-butyl(4-bromo-5-(tert-butyl)thiazole-2-yl)(4-methoxybenzyl)carbamate

[0898] tert-Butyl (4-bromo-5-(tert-butyl)thiazol-2-yl)(4-methoxybenzyl)carbamate

[0899]

[0900] The above compound (1.85 g, 99.5%) was obtained in the form of a colorless oil from tert-butyl(4-bromo-5-(tert-butyl)thiazole-2-yl)carbamate.

[0901] 1H NMR (500 MHz, CDCl3) δ 7.33 (d, J= 8.3 Hz, 2H), 6.83 (d, J= 8.6 Hz, 2H), 5.14 (s, 2H), 3.78 (s, 3H), 1.50 (s, 9H), 1.46 (s, 9H).

[0902]

[0903] Preparation Example 85

[0904] Tert-butyl (4-bromo-5-propylthiazole-2-yl)(4-methoxybenzyl)carbamate

[0905] tert-Butyl (4-bromo-5-propylthiazol-2-yl)(4-methoxybenzyl)carbamate (27)

[0906]

[0907] Di-tert-butyldicarbonate (987.2 mg, 4.523 mmol) was added to a solution of 4-bromo-5-propylthiazole-2-amine (1.0 g, 4.523 mmol) and 4-dimethylaminopyridine (55.4 mg, 0.453 mmol) dissolved in dichloromethane (15 mL). The reaction mixture was stirred at room temperature for 2 days. The solvent was evaporated, and the residue was purified by flash column chromatography (ethyl acetate:hexane = 1:5) to obtain the compound (1.17 g, 80.14% yield) in the form of a yellow gel.

[0908] Next, tert-butyl(4-bromo-5-propylthiazole-2-yl)carbamate (1.16 g, 3.63 mmol) was dissolved in N,N-dimethylformamide (5 mL). Cesium carbonate (1.42 g, 4.35 mmol) was added to the solution, followed by the addition of 4-methoxybenzyl chloride (676.6 mg, 585.8 μL, 4.35 mmol). The mixture was stirred at 80 °C for 1 hour. The reaction mixture was cooled to room temperature, the reaction was stopped with water, and the mixture was extracted with ethyl acetate. The organic extract was dried with anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (diethyl ether:hexane = 1:20) to obtain the compound (1.33 g, 83.0%) in the form of a colorless liquid.

[0909] 1 H NMR (500 MHz, CDCl3) δ 7.33 (d,J= 7.7 Hz, 2H), 6.83 (d,J= 8.3 Hz, 2H), 5.17 (s, 2H), 3.78 (s, 3H), 2.65 (t,J= 7.4 Hz, 2H), 1.65 (m, 2H), 1.51 (s, 9H), 0.98 (t,J= 7.3 Hz, 3H).

[0910]

[0911] Preparation Example 86

[0912] 4-(4,4,5,5-tetramethyl-1,3,5-diosavorolan-2-yl)-2-(trifluoromethyl)phenol

[0913] 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenol

[0914]

[0915] A mixture of 4-bromo-2-(trifluoromethyl)phenol (10.0 g, 41.493 mmol), potassium acetate (12.22 g, 124.5 mmol), bis(pinacolato)diborone (12.64 g, 49.79 mmol), [1,1´-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (1.02 g, 1.24 mmol) and dioxane (500 mL) was stirred at 92 °C for 5 hours under nitrogen gas filling. After the reaction was complete, the mixture was cooled to room temperature and filtered by passing it through a Celite pad. After removing volatile substances, the concentrate was redissolved in ethyl acetate, washed with saturated saline, dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate:hexane = 1:10) to obtain the compound (12.02 g, quantitative yield) in the form of a white solid.

[0916] 1 H NMR (500 MHz, CDCl3) δ 7.98 (s, 1H), 7.81 (d,J= 8.1 Hz, 1H), 6.90 (d,J= 8.2 Hz, 1H), 1.34 (s, 9H).

[0917]

[0918] Preparation Example 87

[0919] 2-(4-(methoxymethoxy)-3-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-diosavorore

[0920] 2-(4-(Methoxymethoxy)-3-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0921]

[0922] Methoxymethyl chloride (1.85 g, 1.75 mL, 22.98 mmol) was added at 0 °C to a stirred solution in which 4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)-2-(trifluoromethyl)phenol (3.31 g, 11.49 mmol) and diisopropylethylamine (2.97 g, 4.01 mL, 22.98 mmol) were dissolved in anhydrous dichloromethane (50 mL). The mixture was stirred at room temperature for 1 hour. The reaction was stopped using water, and the product was extracted with ethyl acetate. The organic extract was washed with saturated saline, dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (diethyl ether:hexane = 1:20) to obtain the compound (8.22 g, 84.5%) in the form of a colorless liquid.

[0923] 1 H NMR (500 MHz, DMSO-d6) δ 7.86 (d, J= 8.4 Hz, 1H), 7.82 (s, 1H), 7.31 (d, J= 8.4 Hz, 1H), 5.36 (s, 2H), 3.37 (s, 3H), 1.25 (s, 12H).

[0924]

[0925] Preparation Example 88

[0926] Tert-butyl 4-methoxybenzyl(4-(4-(methoxymethoxy)-3-(trifluoromethyl)phenyl)-5-propylthiazole-2-yl)carbamate

[0927] tert-Butyl 4-methoxybenzyl(4-(4-(methoxymethoxy)-3-(trifluoromethyl)phenyl)-5-propylthiazol-2-yl)carbamate

[0928]

[0929] Aryl bromide (0.5 g, 1.133 mmol, 100 mol%), potassium triphosphate (481.9 mg, 2.27 mmol), 2-(4-(methoxymethoxy)-3-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-diosbororan (451.7 mg, 1.36 mmol, 120 mol%), and N,N-dimethylformamide:water (4:1, 10 mL) were added to a heat-dried flask. After purging the flask with nitrogen for 10 minutes, a complex of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane (46.3 mg, 0.057 mmol) was added to the mixture. The mixture was covered with foil and stirred at 80 °C for 2 hours. The reaction mixture was cooled to room temperature, filtered by passing it through a Celite pad, washed with a large amount of ethyl acetate, and concentrated under reduced pressure. The residue was purified by flash column chromatography (diethyl ether:hexane = 1:15) to obtain the compound (536.1 mg, 83.5%) in the form of a colorless liquid.

[0930] 1 H NMR (500 MHz, DMSO-d6) δ 7.80 (m, 2H), 7.40 (d,J= 8.6 Hz, 1H), 7.29 (d,J= 8.5 Hz, 2H), 6.87 (d,J= 8.5 Hz, 2H), 5.37 (s, 2H), 5.14 (s, 2H), 3.69 (s, 3H), 3.39 (s, 3H), 2.80 (m, 2H), 1.62 (m, 2H), 1.48 (s, 9H), 0.92 (t,J= 7.3 Hz, 3H).

[0931]

[0932] Preparation Example 89

[0933] Tert-butyl(5-(tert-butyl)-4-(3-chloro-4-(methoxymethoxy)phenyl)thiazole-2-yl)(4-methoxybenzyl)carbamate

[0934] tert-Butyl (5-(tert-butyl)-4-(3-chloro-4-(methoxymethoxy)phenyl)thiazol-2-yl)(4-methoxybenzyl)carbamate

[0935]

[0936] The above compound (2.18 g, quantitative yield) was obtained in the form of a colorless liquid from tert-butyl(4-bromo-5-(tert-butyl)thiazole-2-yl)(4-methoxybenzyl)carbamate and 2-(3-chloro-4-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0937] 1 H NMR (500 MHz, CDCl3) δ 7.39 (s, 1H), 7.31 (d,J= 8.3 Hz, 2H), 7.26 (s, 1H), 7.22 (dd,J= 8.5, 1.6 Hz, 1H), 7.18 (d,J= 8.4 Hz, 1H), 6.81 (d,J= 8.5 Hz, 2H), 5.29 (s, 2H), 5.16 (s, 2H), 3.79 (s, 3H), 3.55 (s, 3H), 1.51 (s, 9H), 1.26 (s, 9H).

[0938]

[0939] Preparation Example 90

[0940] Tert-butyl(4-(4-chloro-3-hydroxyphenyl)-5-ethylthiazole-2-yl)(4-methoxybenzyl)carbamate

[0941] tert-Butyl (4-(4-chloro-3-hydroxyphenyl)-5-ethylthiazol-2-yl)(4-methoxybenzyl)carbamate

[0942]

[0943] The above compound was obtained from tert-butyl(4-bromo-5-ethylthiazole-2-yl)(4-methoxybenzyl)carbamate and (4-chloro-3-hydroxyphenyl)boronic acid in the form of a colorless gel (805.7 mg, 72.6%).

[0944] 1 H NMR (500 MHz, CDCl3) δ 7.36 (d,J= 8.2 Hz, 2H), 7.34 (d,J= 8.4 Hz, 1H), 7.31 (s, 1H), 7.16 (d,J= 8.3 Hz, 1H), 6.83 (d,J= 8.5 Hz, 2H), 5.25 (s, 2H), 3.78 (s, 3H), 2.90 (q,J= 7.4 Hz, 2H), 1.53 (s, 9H), 1.32 (t,J= 7.5 Hz, 3H).

[0945]

[0946] Preparation Example 91

[0947] Methyl 4-(2-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-5-ethylthiazole-4-yl)benzoate

[0948] Methyl 4-(2-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-5-ethylthiazol-4-yl)benzoate

[0949]

[0950] The above compound was obtained as a bright yellow solid (1.07 g, 92.0%) from tert-butyl(4-bromo-5-ethylthiazole-2-yl)(4-methoxybenzyl)carbamate and (4-(methoxycarbonyl)phenyl)boronic acid.

[0951] 1H NMR (500 MHz, DMSO-d6) δ 8.01 (d,J= 7.0 Hz, 2H), 7.75 (d,J= 6.7 Hz, 2H), 7.28 (d,J= 6.7 Hz, 2H), 6.88 (d,J= 6.7 Hz, 2H), 5.17 (s, 2H), 3.85 (s, 3H), 3.68 (s, 3H), 2.91 (d,J= 6.6 Hz, 2H), 1.46 (s, 9H), 1.24 (s, 3H).

[0952]

[0953] Preparation Example 92

[0954] Methyl 4-(2-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-5-ethylthiazole-4-yl)-2-fluorobenzoate

[0955] Methyl 4-(2-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-5-ethylthiazol-4-yl)-2-fluorobenzoate

[0956]

[0957] The above compound was obtained as a bright yellow solid (464.7 mg, 79.3%) from tert-butyl(4-bromo-5-ethylthiazole-2-yl)(4-methoxybenzyl)carbamate and (3-fluoro-4-(methoxycarbonyl)phenyl)boronic acid.

[0958] 1 H NMR (500 MHz, DMSO-d6) δ 7.95 (t,J= 7.9 Hz, 1H), 7.58 (d,J= 8.1 Hz, 1H), 7.52 (d,J= 12.2 Hz, 1H), 7.27 (d,J= 8.3 Hz, 2H), 6.88 (d,J= 8.2 Hz, 2H), 5.17 (s, 2H), 3.86 (d,J= 7.3 Hz, 3H), 3.68 (s, 3H), 2.94 (dd,J= 14.6, 7.2 Hz, 2H), 1.47 (s, 9H), 1.25 (t,J= 7.3 Hz, 3H).

[0959]

[0960] Preparation Example 93

[0961] Methyl 4-(2-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-5-ethylthiazole-4-yl)-2-chlorobenzoate

[0962] Methyl 4-(2-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-5-ethylthiazol-4-yl)-2-chlorobenzoate

[0963]

[0964] The above compound was obtained as a bright yellow solid (471.9 mg, 78.0%) from tert-butyl(4-bromo-5-ethylthiazole-2-yl)(4-methoxybenzyl)carbamate and (3-chloro-4-(methoxycarbonyl)phenyl)boronic acid.

[0965] 1 H NMR (500 MHz, DMSO-d6) δ 7.89 (d,J= 8.1 Hz, 1H), 7.74 (s, 1H), 7.67 (d,J= 8.1 Hz, 1H), 7.27 (d,J= 8.5 Hz, 2H), 6.88 (d,J= 8.6 Hz, 2H), 5.16 (s, 2H), 3.90 - 3.82 (m, 3H), 3.68 (s, 3H), 2.91 (q,J= 7.4 Hz, 2H), 1.48 (d,J= 9.7 Hz, 9H), 1.24 (t,J= 7.5 Hz, 3H).

[0966]

[0967] Preparation Example 94

[0968] methyl 4-(2-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-5-ethylthiazole-4-yl)-2-methylbenzoate

[0969] Methyl 4-(2-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-5-ethylthiazol-4-yl)-2-methylbenzoate

[0970]

[0971] The above compound was obtained as a bright yellow solid (492.2 mg, 84.7%) from tert-butyl(4-bromo-5-ethylthiazole-2-yl)(4-methoxybenzyl)carbamate and (3-methyl-4-(methoxycarbonyl)phenyl)boronic acid.

[0972] 1 H NMR (500 MHz, DMSO-d6) δ 7.88 (d,J= 8.3 Hz, 1H), 7.52 (s, 2H), 7.28 (d,J= 8.1 Hz, 2H), 6.87 (d,J= 8.1 Hz, 2H), 5.16 (s, 2H), 3.81 (s, 3H), 3.68 (s, 3H), 2.89 (d,J= 7.3 Hz, 2H), 2.55 (s, 3H), 1.47 (s, 9H), 1.24 (d,J= 7.1 Hz, 3H).

[0973]

[0974] Preparation Example 95

[0975] Methyl 3-(2-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-5-ethylthiazole-4-yl)benzoate

[0976] Methyl 3-(2-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-5-ethylthiazol-4-yl)benzoate

[0977]

[0978] The above compound was obtained as a colorless jelly (1.46 g, 86.2%) from tert-butyl(4-bromo-5-ethylthiazole-2-yl)(4-methoxybenzyl)carbamate and (3-(methoxycarbonyl)phenyl)boronic acid.

[0979] 1H NMR (500 MHz, CDCl3) δ 8.32 (s, 1H), 7.99 (m, 1H), 7.84 (m, 1H), 7.49 (m, 1H), 7.41 (m, 1H), 6.85 (m, 1H), 5.27 (s, 2H), 3.94 (m, 3H), 3.78 (m, 3H), 2.93 (m, 2H), 1.55 (s, 9H), 1.34 (m, 3H).

[0980]

[0981] Preparation Example 96

[0982] Isopropyl 3-(2-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-5-ethylthiazole-4-yl)benzoate

[0983] Isopropyl 3-(2-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-5-ethylthiazol-4-yl)benzoate

[0984]

[0985] The above compound was obtained as a colorless jelly (527.0 g, 88.2%) from tert-butyl(4-bromo-5-ethylthiazole-2-yl)(4-methoxybenzyl)carbamate and (3-(isoproxycarbonyl)phenyl)boronic acid.

[0986] 1 H NMR (500 MHz, CDCl3) δ 8.30 (s, 1H), 7.98 (d,J= 7.8 Hz, 1H), 7.82 (d,J= 7.8 Hz, 1H), 7.48 (t,J= 7.7 Hz, 2H), 7.40 (d,J= 8.4 Hz, 2H), 6.84 (d,J= 8.7 Hz, 2H), 5.27 (m, 3H), 3.78 (s, 3H), 2.93 (m, 2H), 1.54 (s, 9H), 1.38 (d,J= 6.2 Hz, 6H), 1.34 (t,J= 7.6 Hz, 3H).

[0987]

[0988] Preparation Example 97

[0989] Methyl 5-(2-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-5-ethylthiazole-4-yl)-2-fluorobenzoate

[0990] Methyl 4-(2-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-5-ethylthiazol-4-yl)-2-fluorobenzoate

[0991]

[0992] The above compound was obtained as a bright yellow solid (468.7 mg, 80.0%) from tert-butyl(4-bromo-5-ethylthiazole-2-yl)(4-methoxybenzyl)carbamate and (4-fluoro-3-(methoxycarbonyl)phenyl)boronic acid.

[0993] 1 H NMR (500 MHz, DMSO-d6) δ 8.10 (d,J= 6.6 Hz, 1H), 7.85 (s, 1H), 7.44 - 7.37 (m, 1H), 7.29 (d,J= 8.1 Hz, 2H), 6.88 (d,J= 8.1 Hz, 2H), 5.15 (s, 2H), 3.87 (s, 3H), 3.69 (s, 3H), 2.85 (dd,J= 14.6, 7.1 Hz, 2H), 1.47 (s, 9H), 1.23 (t,J= 7.4 Hz, 3H).

[0994]

[0995] Preparation Example 98

[0996] Methyl 5-(2-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-5-ethylthiazole-4-yl)-2-chlorobenzoate

[0997] Methyl 5-(2-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-5-ethylthiazol-4-yl)-2-chlorobenzoate

[0998]

[0999] The above compound was obtained as a bright yellow solid (360.4 mg, 59.0%) from tert-butyl(4-bromo-5-ethylthiazole-2-yl)(4-methoxybenzyl)carbamate and (4-chloro-3-(methoxycarbonyl)phenyl)boronic acid.

[1000] 1 H NMR (500 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.77 (d,J= 8.4 Hz, 1H), 7.63 (d,J= 8.4 Hz, 1H), 7.28 (d,J= 8.5 Hz, 2H), 6.87 (d,J= 8.5 Hz, 2H), 5.15 (s, 2H), 3.87 (s, 3H), 3.69 (s, 3H), 2.87 (q,J= 7.4 Hz, 2H), 1.47 (s, 9H), 1.23 (t,J= 7.5 Hz, 3H).

[1001]

[1002] Preparation Example 99

[1003] methyl 5-(2-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-5-ethylthiazole-4-yl)-2-methylbenzoate

[1004] Methyl 5-(2-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-5-ethylthiazol-4-yl)-2-methylbenzoate

[1005]

[1006] The above compound was obtained as a bright yellow solid (582.5 mg, quantitative yield) from tert-butyl(4-bromo-5-ethylthiazole-2-yl)(4-methoxybenzyl)carbamate and (4-methyl-3-(methoxycarbonyl)phenyl)boronic acid.

[1007] 1H NMR (500 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.68 (d,J= 7.7 Hz, 1H), 7.39 (d,J= 7.6 Hz, 1H), 7.30 (d,J= 8.1 Hz, 2H), 6.88 (d,J= 8.1 Hz, 2H), 5.15 (s, 2H), 3.84 (s, 3H), 3.69 (s, 3H), 2.86 - 2.81 (m, 2H), 2.52 (s, 3H), 1.48 (s, 9H), 1.23 (t,J= 7.3 Hz, 3H).

[1008]

[1009] Preparation Example 100

[1010] Tert-butyl(5-ethyl-4-(4-nitrophenyl)thiazole-2-yl)(4-methoxybenzyl)carbamate

[1011] tert-Butyl (5-ethyl-4-(4-nitrophenyl)thiazol-2-yl)(4-methoxybenzyl)carbamate

[1012]

[1013] The above compound was obtained as a yellow liquid (4.37 g, quantitative yield) from tert-butyl(4-bromo-5-ethylthiazole-2-yl)(4-methoxybenzyl)carbamate and (4-nitrophenyl)boronic acid.

[1014] 1 H NMR (500 MHz, DMSO-d6) δ 8.28 (d,J= 8.4 Hz, 2H), 7.88 (d,J= 8.4 Hz, 2H), 7.29 (d,J= 8.2 Hz, 2H), 6.88 (d,J= 8.2 Hz, 2H), 5.17 (s, 2H), 3.68 (s, 3H), 2.96 (dd,J= 18.8, 11.8 Hz, 2H), 1.48 (d,J= 7.4 Hz, 9H), 1.26 (t,J= 7.1 Hz, 3H).

[1015]

[1016] Preparation Example 101

[1017] Tert-butyl(5-ethyl-4-(3-nitrophenyl)thiazole-2-yl)(4-methoxybenzyl)carbamate

[1018] tert-Butyl (5-ethyl-4-(3-nitrophenyl)thiazol-2-yl)(4-methoxybenzyl)carbamate

[1019]

[1020] The above compound was obtained as a yellow liquid (1.01 g, 79.3%) from tert-butyl(4-bromo-5-ethylthiazole-2-yl)(4-methoxybenzyl)carbamate and (3-nitrophenyl)boronic acid.

[1021] 1 H NMR (500 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.17 (d,J= 7.9 Hz, 1H), 8.04 (d,J= 7.7 Hz, 1H), 7.73 (t,J= 8.0 Hz, 1H), 7.31 (d,J= 8.4 Hz, 2H), 6.89 (d,J= 8.4 Hz, 2H), 5.16 (s, 2H), 3.69 (s, 3H), 2.92 (q,J= 7.4 Hz, 2H), 1.48 (s, 9H), 1.26 (t,J= 7.4 Hz, 3H).

[1022]

[1023] Preparation Example 102

[1024] Tert-butyl(5-ethyl-4-(4-cyanophenyl)thiazole-2-yl)(4-methoxybenzyl)carbamate

[1025] tert-Butyl (5-ethyl-4-(4-cyanophenyl)thiazol-2-yl)(4-methoxybenzyl)carbamate

[1026]

[1027] The above compound was obtained as a yellow liquid (856.6 mg, quantitative yield) from tert-butyl(4-bromo-5-ethylthiazole-2-yl)(4-methoxybenzyl)carbamate and (4-cyanophenyl)boronic acid.

[1028] 1 H NMR (500 MHz, CDCl3) δ 7.75 (d,J= 8.3 Hz, 2H), 7.69 (t,J= 7.0 Hz, 2H), 7.35 (d,J= 8.5 Hz, 2H), 6.83 (d,J= 8.6 Hz, 2H), 5.25 (s, 2H), 3.78 (s, 3H), 2.93 (q,J= 7.4 Hz, 2H), 1.54 (s, 9H), 1.35 (m, 3H).

[1029] Preparation Example 103

[1030] Tert-butyl(5-ethyl-4-(3-cyanophenyl)thiazole-2-yl)(4-methoxybenzyl)carbamate

[1031] tert-Butyl (5-ethyl-4-(3-cyanophenyl)thiazol-2-yl)(4-methoxybenzyl)carbamate

[1032]

[1033] The above compound was obtained as a colorless liquid (705.5 mg, quantitative yield) from tert-butyl(4-bromo-5-ethylthiazole-2-yl)(4-methoxybenzyl)carbamate and (3-cyanophenyl)boronic acid.

[1034] 1 H NMR (500 MHz, DMSO-d6) δ 7.99 (m, 1H), 7.68 (m, 2H), 7.28 (d,J= 8.7 Hz, 2H), 6.90 (m, 2H), 5.19 (s, 2H), 3.70 (s, 3H), 2.96 (q,J= 7.5 Hz, 2H), 1.49 (s, 9H), 1.27 (t,J= 5.1 Hz, 3H).

[1035]

[1036] Preparation Example 104

[1037] Tert-butyl(4-(4-cyano-3-fluorophenyl)-5-ethylthiazole-2-yl)(4-methoxybenzyl)carbamate

[1038] tert-Butyl (4-(4-cyano-3-fluorophenyl)-5-ethylthiazol-2-yl)(4-methoxybenzyl)carbamate

[1039]

[1040] The above compound was obtained as a white solid (745.7 mg, quantitative yield) from tert-butyl(4-bromo-5-ethylthiazole-2-yl)(4-methoxybenzyl)carbamate and (4-cyano-3-fluorophenyl)boronic acid.

[1041] 1 H NMR (500 MHz, DMSO-d6) δ 7.99 (m, 1H), 7.68 (m, 2H), 7.28 (d,J= 8.7 Hz, 2H), 6.90 (m, 2H), 5.19 (s, 2H), 3.70 (s, 3H), 2.96 (q,J= 7.5 Hz, 2H), 1.49 (s, 9H), 1.27 (t,J= 5.1 Hz, 3H).

[1042]

[1043] Preparation Example 105

[1044] Tert-butyl(5-ethyl-4-(3-sulfamoylphenyl)thiazole-2-yl)(4-methoxybenzyl)carbamate

[1045] tert-Butyl (5-ethyl-4-(3-sulfamoylphenyl)thiazol-2-yl)(4-methoxybenzyl)carbamate

[1046]

[1047] The above compound was obtained as a colorless liquid (570.2 mg, 85.4%) from tert-butyl(4-bromo-5-ethylthiazole-2-yl)(4-methoxybenzyl)carbamate and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide.

[1048] 1H NMR (500 MHz, DMSO-d6) δ 8.08 (s, 1H), 7.79 (m, 2H), 7.64 (t,J= 7.8 Hz, 1H), 7.42 (s, 2H), 7.31 (d,J= 8.5 Hz, 2H), 6.89 (d,J= 8.5 Hz, 2H), 5.17 (s, 2H), 3.69 (s, 3H), 2.89 (q,J= 7.4 Hz, 2H), 1.48 (s, 9H), 1.25 (t,J= 7.5 Hz, 3H).

[1049]

[1050] Preparation Example 106

[1051] tert-butyl(4-(4-(dimethylamino)phenyl)-5-ethylthiazole-2-yl)(4-methoxybenzyl)carbamate

[1052] tert-Butyl (4-(4-(dimethylamino)phenyl)-5-ethylthiazol-2-yl)(4-methoxybenzyl)carbamate

[1053]

[1054] The above compound was obtained as a white solid (611.4 mg, quantitative yield) from tert-butyl(4-bromo-5-ethylthiazole-2-yl)(4-methoxybenzyl)carbamate and (4-dimethylaminophenyl)boronic acid.

[1055] 1 H NMR (500 MHz, DMSO-d6) δ 7.44 (d,J= 8.6 Hz, 2H), 7.30 (d,J= 8.5 Hz, 2H), 6.89 (d,J= 8.4 Hz, 2H), 6.77 (d,J= 8.6 Hz, 2H), 5.17 (s, 2H), 3.71 (s, 3H), 2.92 (s, 6H), 2.84 (q,J= 7.5 Hz, 2H), 1.48 (s, 9H), 1.24 (m, 3H).

[1056]

[1057] Preparation Example 107

[1058] Tert-butyl(5-ethyl-4-(3-(methoxymethyl)phenyl)thiazole-2-yl)(4-methoxybenzyl)carbamate

[1059] tert-Butyl (5-ethyl-4-(3-(methoxymethyl)phenyl)thiazol-2-yl)(4-methoxybenzyl)carbamate

[1060]

[1061] The above compound was obtained as a colorless liquid (1.54 g, 98.4%) from tert-butyl(4-bromo-5-ethylthiazole-2-yl)(4-methoxybenzyl)carbamate and (4-methoxymethylphenyl)boronic acid.

[1062] 1 H NMR (500 MHz, DMSO-d6) δ 7.53 (s, 1H), 7.48 (s, 1H), 7.41 (dd,J= 9.0, 6.1 Hz, 1H), 7.29 (d,J= 8.7 Hz, 3H), 6.89 - 6.84 (m, 2H), 5.16 (s, 2H), 4.45 (s,J= 2.6 Hz, 2H), 3.69 (s,J= 2.9 Hz, 3H), 3.29 (s,J= 9.4, 2.9 Hz, 3H), 2.86 (dd,J= 7.4, 2.9 Hz, 2H), 1.47 (s,J= 2.4 Hz, 9H), 1.27 - 1.20 (t, 3H).

[1063]

[1064] Preparation Example 108

[1065] methyl 2-(4-(2-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-5-ethylthiazole-4-yl)phenyl)acetate

[1066] Methyl 2-(4-(2-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-5-ethylthiazol-4-yl)phenyl)acetate

[1067]

[1068] The above compound was obtained as a colorless gel (423.5 mg, 72.9%) from tert-butyl(4-bromo-5-ethylthiazole-2-yl)(4-methoxybenzyl)carbamate and 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate.

[1069] 1 H NMR (500 MHz, CDCl3) δ 7.62 (d,J= 8.0 Hz, 2H), 7.41 (d,J= 8.4 Hz, 2H), 7.34 (d,J= 8.0 Hz, 2H), 6.84 (d,J= 8.4 Hz, 2H), 5.28 (s, 2H), 3.77 (s, 3H), 3.70 (s, 3H), 3.67 (s, 2H), 2.93 (q,J= 7.5 Hz, 2H), 1.55 (s, 9H), 1.34 (t,J= 7.5 Hz, 3H).

[1070]

[1071] Preparation Example 109

[1072] Tert-butyl(4-(4-acetylphenyl)-5-ethylthiazole-2-yl)(4-methoxybenzyl)carbamate

[1073] tert-Butyl (4-(4-acetylphenyl)-5-ethylthiazol-2-yl)(4-methoxybenzyl)carbamate

[1074]

[1075] The above compound was obtained as a colorless liquid (192.9 mg, 89.4%) from tert-butyl(4-bromo-5-ethylthiazole-2-yl)(4-methoxybenzyl)carbamate and (4-acetylphenyl)boronic acid.

[1076] 1H NMR (500 MHz, CDCl3) δ 8.01 (d,J= 8.1 Hz, 2H), 7.74 (d,J= 8.1 Hz, 2H), 7.38 (d,J= 7.8 Hz, 2H), 6.83 (d,J= 8.4 Hz, 2H), 5.26 (s, 2H), 3.78 (s, 3H), 2.94 (q,J= 7.4 Hz, 2H), 2.63 (s, 3H), 1.54 (s, 9H), 1.35 (t,J= 7.3 Hz, 3H).

[1077]

[1078] Preparation Example 110

[1079] Tert-butyl(5-ethyl-4-(4-formylphenyl)thiazole-2-yl)(4-methoxybenzyl)carbamate

[1080] tert-Butyl (5-ethyl-4-(4-formylphenyl)thiazol-2-yl)(4-methoxybenzyl)carbamate

[1081]

[1082] The above compound was obtained as a colorless liquid (192.9 mg, 89.4%) from tert-butyl(4-bromo-5-ethylthiazole-2-yl)(4-methoxybenzyl)carbamate and (4-formylphenyl)boronic acid.

[1083] 1 H NMR (500 MHz, CDCl3) δ 10.03 (s, 1H), 7.92 (d,J= 8.1 Hz, 2H), 7.82 (t,J= 9.1 Hz, 2H), 7.37 (d,J= 8.4 Hz, 2H), 6.84 (d,J= 8.5 Hz, 2H), 5.28 (d,J= 13.6 Hz, 2H), 3.78 (s, 3H), 2.96 (q,J= 7.5 Hz, 2H), 1.54 (d,J= 3.2 Hz, 9H), 1.36 (t,J= 9.8, 5.2 Hz, 3H).

[1084]

[1085] Preparation Example 111

[1086] Tert-butyl(4-([1,1'-biphenyl]-4-yl)-5-ethylthiazole-2-yl)(4-methoxybenzyl)carbamate

[1087] tert-Butyl (4-([1,1'-biphenyl]-4-yl)-5-ethylthiazol-2-yl)(4-methoxybenzyl)carbamate

[1088]

[1089] The above compound was obtained as a colorless gel (326.2 mg, 51.7%) from tert-butyl(4-bromo-5-ethylthiazole-2-yl)(4-methoxybenzyl)carbamate and [1,1'-biphenyl]-4-ylboronic acid.

[1090] 1 H NMR (500 MHz, cdcl3) δ 7.72 (d,J= 8.3 Hz, 2H), 7.66 - 7.33 (m, 4H), 7.46 (t,J= 7.7 Hz, 2H), 7.41 (d,J= 8.5 Hz, 2H), 7.35 (t,J= 7.4 Hz, 1H), 6.84 (d,J= 8.6 Hz, 2H), 5.29 (s, 2H), 3.79 (s, 3H), 2.97 (q,J= 7.5 Hz, 2H), 1.54 (s, 9H), 1.36 (t,J= 7.5 Hz, 3H).

[1091]

[1092] Preparation Example 112

[1093] Tert-butyl(5-ethyl-4-(4-(1-methyl-1H-pyrazol-5-yl)phenyl)thiazole-2-yl)(4-methoxybenzyl)carbamate

[1094] tert-Butyl (5-ethyl-4-(4-(1-methyl-1H-pyrazol-5-yl)phenyl)thiazol-2-yl)(4-methoxybenzyl)carbamate

[1095]

[1096] The above compound was obtained as a colorless gel (524.0 mg, 88.8%) from tert-butyl(4-bromo-5-ethylthiazole-2-yl)(4-methoxybenzyl)carbamate and 1-methyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole.

[1097] 1 H NMR (500 MHz, CDCl3) δ 7.73 (d,J= 8.2 Hz, 2H), 7.50 (d,J= 1.7 Hz, 1H), 7.45 (d,J= 8.1 Hz, 2H), 7.39 (d,J= 8.3 Hz, 2H), 6.83 (d,J= 8.6 Hz, 2H), 6.32 (d,J= 1.7 Hz, 1H), 5.28 (s, 2H), 3.91 (s, 3H), 3.74 (s, 3H), 2.95 (q,J= 7.4 Hz, 2H), 1.52 (s, 9H), 1.35 (t,J= 7.5 Hz, 3H).

[1098]

[1099] Preparation Example 113

[1100] Tert-butyl(5-ethyl-4-(4-(1-methyl-1H-pyrazol-3-yl)phenyl)thiazole-2-yl)(4-methoxybenzyl)carbamate

[1101] tert-Butyl (5-ethyl-4-(4-(1-methyl-1H-pyrazol-3-yl)phenyl)thiazol-2-yl)(4-methoxybenzyl)carbamate

[1102]

[1103] The above compound was obtained as a colorless gel (574.3 mg, 97.4%) from tert-butyl(4-bromo-5-ethylthiazole-2-yl)(4-methoxybenzyl)carbamate and 1-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole.

[1104] 1H NMR (500 MHz, CDCl3) δ 7.85 (d,J= 8.1 Hz, 2H), 7.69 (d,J= 7.9 Hz, 2H), 7.40 (d,J= 8.1 Hz, 2H), 7.27 (s, 1H), 6.82 (d,J= 8.3 Hz, 2H), 6.51 (d,J= 1.8 Hz, 1H), 5.27 (s, 2H), 3.84 (s, 3H), 3.71 (s, 3H), 2.93 (q,J= 7.4 Hz, 2H), 1.51 (s, 9H), 1.32 (t,J= 7.4 Hz, 3H).

[1105]

[1106] Preparation Example 114

[1107] Tert-butyl(4-(dibenzo[b,d]furan-4-yl)-5-ethylthiazole-2-yl)(4-methoxybenzyl)carbamate

[1108] tert-Butyl (4-(dibenzo[b,d]furan-4-yl)-5-ethylthiazol-2-yl)(4-methoxybenzyl)carbamate

[1109]

[1110] The above compound was obtained as a colorless gel (602.1 mg, quantitative yield) from tert-butyl(4-bromo-5-ethylthiazole-2-yl)(4-methoxybenzyl)carbamate and dibenzofuran-4-boronic acid.

[1111] 1H NMR (500 MHz, CDCl3) δ 7.99 (d,J= 7.7 Hz, 1H), 7.96 (dd,J= 7.7, 1.2 Hz, 1H), 7.60 (dd,J= 7.5, 1.2 Hz, 1H), 7.56 (d,J= 8.2 Hz, 1H), 7.47 - 7.43 (m, 3H), 7.42 (t,J= 7.6 Hz, 1H), 7.38 - 7.33 (m, 1H), 6.87 - 6.84 (m, 2H), 5.28 (s, 2H), 3.80 (s, 3H), 2.83 (q,J= 7.5 Hz, 2H), 1.56 (s, 9H), 1.32 (t,J= 7.5 Hz, 3H).

[1112]

[1113] Preparation Example 115

[1114] tert-butyl(4-(4-((dimethylamino)methyl)phenyl)-5-ethylthiazole-2-yl)(4-methoxybenzyl)carbamate

[1115] tert-Butyl (4-(4-((dimethylamino)methyl)phenyl)-5-ethylthiazol-2-yl)(4-methoxybenzyl)carbamate

[1116]

[1117] The above compound was obtained as a colorless gel (179.0 mg, 44.2%) from tert-butyl(5-ethyl-4-(4-formylphenyl)thiazole-2-yl)(4-methoxybenzyl)carbamate.

[1118] 1H NMR (500 MHz, CDCl3) δ 7.59 (d,J= 7.0 Hz, 2H), 7.39 (d,J= 7.5 Hz, 2H), 7.35 (d,J= 7.1 Hz, 2H), 6.83 (d,J= 7.3 Hz, 2H), 5.26 (s, 2H), 3.78 (d,J= 1.2 Hz, 3H), 3.48 (s, 2H), 2.96 - 2.87 (m, 2H), 2.28 (s, 6H), 1.53 (s, 9H), 1.32 (t,J= 6.9 Hz, 3H).

[1119]

[1120] Preparation Example 116

[1121] 4-(2-amino-5-propylthiazole-4-yl)-2-(trifluoromethyl)phenol

[1122] 4-(2-Amino-5-propylthiazol-4-yl)-2-(trifluoromethyl)phenol

[1123]

[1124] Trifluoroacetic acid (4 mL, 4 mL per 1 mmol of reactant unless otherwise noted) was added to tert-butyl 4-methoxybenzyl(4-(4-(methoxymethoxy)-3-(trifluoromethyl)phenyl)-5-propylthiazole-2-yl)carbamate (536.1 mg, 0.95 mmol) and stirred at 70 °C for 2 hours. Subsequently, the solvent was evaporated under reduced pressure. The residue was treated with an aqueous solution of saturated sodium bicarbonate and then extracted with ethyl acetate. The combined organic layer was dried with magnesium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (ethyl acetate:hexane = 1:2) to obtain the compound (205.3 mg, 71.8%) in the form of a yellow solid.

[1125] 1H NMR (500 MHz, CD3OD / CDCl3) δ 7.56 (s, 1H), 7.40 (d,J= 8.3 Hz, 1H), 6.91 (d,J= 8.3 Hz, 1H), 2.60 (t,J= 7.4 Hz, 2H), 1.57 (m, 2H), 0.90 (t,J= 7.0 Hz, 3H).

[1126]

[1127] Preparation Example 117

[1128] 4-(2-amino-5-(tert-butyl)thiazole-4-yl)-2-chlorophenol

[1129] 4-(2-Amino-5-(tert-butyl)thiazol-4-yl)-2-chlorophenol

[1130]

[1131] The above compound was obtained as a bright yellow solid (1.13 g, quantitative yield) from tert-butyl(5-(tert-butyl)-4-(3-chloro-4-(methoxymethoxy)phenyl)thiazole-2-yl)(4-methoxybenzyl)carbamate.

[1132] 1 H NMR (500 MHz, DMSO-d6) δ 10.21 (s, 1H), 7.16 (d,J= 1.6 Hz, 1H), 7.03 (dd,J= 8.3, 1.7 Hz, 1H), 6.91 (d,J= 8.3 Hz, 1H), 6.62 (s, 2H), 1.11 (s, 9H).

[1133]

[1134] Preparation Example 118

[1135] 4-(2-amino-5-ethylthiazole-4-yl)-2-chlorophenol

[1136] 4-(2-Amino-5-ethylthiazol-4-yl)-2-chlorophenol

[1137]

[1138] The above compound was obtained as a yellow solid (531.5 mg, quantitative yield) from tert-butyl(4-(4-chloro-3-hydroxyphenyl)-5-ethylthiazole-2-yl)(4-methoxybenzyl)carbamate.

[1139] 1 H NMR (500 MHz, DMSO-d6) δ 10.56 (s, 1H), 8.47 (s, 2H), 7.41 (d,J= 8.2 Hz, 1H), 7.08 (s, 1H), 6.90 (d,J= 8.2 Hz, 1H), 2.65 (q,J= 7.4 Hz, 2H), 1.15 (t,J= 7.4 Hz, 3H).

[1140]

[1141] Preparation Example 119

[1142] Methyl 4-(2-amino-5-ethylthiazole-4-yl)benzoate

[1143] Methyl 4-(2-amino-5-ethylthiazol-4-yl)benzoate

[1144]

[1145] The above compound was obtained from methyl 4-(2-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-5-ethylthiazole-4-yl)benzoate as a bright yellow solid (551.8 mg, 94.8%).

[1146] 1 H NMR (500 MHz, DMSO-d6) δ 7.96 (d,J= 7.2 Hz, 2H), 7.64 (d,J= 7.4 Hz, 2H), 7.10 (s, 2H), 3.84 (s, 3H), 2.75 (q,J= 6.9 Hz, 2H), 1.17 (t,J= 7.2 Hz, 3H).

[1147]

[1148] Preparation Example 120

[1149] Methyl 4-(2-amino-5-ethylthiazole-4-yl)-2-fluorobenzoate

[1150] Methyl 4-(2-amino-5-ethylthiazol-4-yl)-2-fluorobenzoate

[1151]

[1152] The above compound was obtained from methyl 4-(2-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-5-ethylthiazole-4-yl)-2-fluorobenzoate as a bright yellow solid (249.2 mg, 95.6%).

[1153] 1 H NMR (500 MHz, DMSO-d6) δ 7.92 (t,J= 8.0 Hz, 1H), 7.44 (dd,J= 14.9, 10.4 Hz, 2H), 3.84 (s, 3H), 2.76 (q,J= 7.3 Hz, 2H), 1.17 (t,J= 7.4 Hz, 3H).

[1154]

[1155] Preparation Example 121

[1156] Methyl 4-(2-amino-5-ethylthiazole-4-yl)-2-chlorobenzoate

[1157] Methyl 4-(2-amino-5-ethylthiazol-4-yl)-2-chlorobenzoate

[1158]

[1159] The above compound was obtained from methyl 4-(2-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-5-ethylthiazole-4-yl)-2-chlorobenzoate as a bright yellow solid (206.0 mg, 76.3%).

[1160] 1 H NMR (500 MHz, DMSO-d6) δ 7.84 (d,J= 8.1 Hz, 1H), 7.67 (s, 1H), 7.57 (d,J= 8.1 Hz, 1H), 6.94 (s, 2H), 3.84 (s, 3H), 2.77 (q,J= 7.2 Hz, 2H), 1.18 (t,J= 7.4 Hz, 3H).

[1161]

[1162] Preparation Example 122

[1163] Methyl 4-(2-amino-5-ethylthiazole-4-yl)-2-methylbenzoate

[1164] Methyl 4-(2-amino-5-ethylthiazol-4-yl)-2-methylbenzoate

[1165]

[1166] The above compound was obtained from methyl 4-(2-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-5-ethylthiazole-4-yl)-2-methylbenzoate as a bright yellow solid (267.0 mg, 96.6%).

[1167] 1 H NMR (500 MHz, DMSO-d6) δ 7.83 (d,J= 8.1 Hz, 1H), 7.45 (s, 1H), 7.42 (d,J= 8.0 Hz, 1H), 6.86 (s, 2H), 3.80 (s, 3H), 2.75 (dd,J= 14.7, 7.3 Hz, 2H), 2.53 (s, 3H), 1.17 (t,J= 7.4 Hz, 3H).

[1168]

[1169] Preparation Example 123

[1170] Methyl 3-(2-amino-5-ethylthiazole-4-yl)benzoate

[1171] Methyl 3-(2-amino-5-ethylthiazol-4-yl)benzoate

[1172]

[1173] The above compound was obtained from methyl 3-(2-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-5-ethylthiazole-4-yl)benzoate as a bright yellow solid (794.9 mg, quantitative yield).

[1174] 1H NMR (500 MHz, DMSO-d6) δ 8.08 (s, 1H), 7.96 (d,J= 7.8 Hz, 1H), 7.75 (d,J= 7.7 Hz, 1H), 7.62 (t,J= 7.8 Hz, 1H), 3.86 (s, 3H), 2.69 (q,J= 7.4 Hz, 2H), 1.16 (t,J= 7.4 Hz, 3H).

[1175]

[1176] Preparation Example 124

[1177] Isopropyl 3-(2-amino-5-ethylthiazole-4-yl)benzoate

[1178] Isopropyl 3-(2-amino-5-ethylthiazol-4-yl)benzoate

[1179]

[1180] The above compound was obtained as a white solid (174.7 mg, 59.1%) from isopropyl 3-(2-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-5-ethylthiazole-4-yl)benzoate.

[1181] 1 H NMR (500 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.84 (d,J= 7.7 Hz, 1H), 7.73 (d,J= 7.7 Hz, 1H), 7.51 (t,J= 7.7 Hz, 1H), 6.88 (s, 2H), 5.13 (m, 1H), 2.72 (q,J= 7.4 Hz, 2H), 1.30 (d,J= 6.2 Hz, 6H), 1.18 (t,J= 7.4 Hz, 3H).

[1182]

[1183] Preparation Example 125

[1184] Methyl 5-(2-amino-5-ethylthiazole-4-yl)-2-fluorobenzoate

[1185] Methyl 5-(2-amino-5-ethylthiazol-4-yl)-2-fluorobenzoate

[1186]

[1187] The above compound was obtained from methyl 5-(2-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-5-ethylthiazole-4-yl)-2-fluorobenzoate as a bright yellow solid (333.2 mg, quantitative yield).

[1188] 1 H NMR (500 MHz, DMSO-d6) δ 8.08 (s, 2H), 8.00 (d,J= 6.7 Hz, 1H), 7.79 - 7.73 (m, 1H), 7.47 - 7.40 (m, 1H), 3.85 (s, 3H), 2.67 (q,J= 7.4 Hz, 2H), 1.15 (t,J= 7.4 Hz, 3H).

[1189]

[1190] Preparation Example 126

[1191] Methyl 5-(2-amino-5-ethylthiazole-4-yl)-2-chlorobenzoate

[1192] Methyl 5-(2-amino-5-ethylthiazol-4-yl)-2-chlorobenzoate

[1193]

[1194] The above compound was obtained from methyl 5-(2-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-5-ethylthiazole-4-yl)-2-chlorobenzoate as a bright yellow solid (183.0 mg, 88.1%).

[1195] 1 H NMR (500 MHz, DMSO-d6) δ 7.98 (s, 1H), 7.66 (d,J= 8.4 Hz, 1H), 7.58 (d,J= 8.3 Hz, 1H), 7.02 (s, 2H), 3.85 (s, 3H), 2.73 (q,J= 7.2 Hz, 2H), 1.17 (t,J= 7.3 Hz, 3H).

[1196]

[1197] Preparation Example 127

[1198] Methyl 5-(2-amino-5-ethylthiazole-4-yl)-2-methylbenzoate

[1199] Methyl 5-(2-amino-5-ethylthiazol-4-yl)-2-methylbenzoate

[1200]

[1201] The above compound was obtained from methyl 5-(2-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-5-ethylthiazole-4-yl)-2-methylbenzoate as a bright yellow solid (488.8 mg, quantitative yield).

[1202] 1 H NMR (500 MHz, DMSO-d6) δ 8.30 (s, 2H), 7.94 (s, 1H), 7.57 (d,J= 7.9 Hz, 1H), 7.42 (d,J= 7.8 Hz, 1H), 3.82 (s, 3H), 2.67 (q,J= 7.2 Hz, 2H), 2.53 (s, 3H), 1.15 (t,J= 7.4 Hz, 3H).

[1203]

[1204] Preparation Example 128

[1205] 5-ethyl-4-(4-nitrophenyl)thiazole-2-amine

[1206] 5-Ethyl-4-(4-nitrophenyl)thiazol-2-amine

[1207]

[1208] The above compound was obtained as a yellow solid (1.34 g, quantitative yield) from tert-butyl(5-ethyl-4-(4-nitrophenyl)thiazole-2-yl)(4-methoxybenzyl)carbamate.

[1209] 1H NMR (500 MHz, DMSO-d6) δ 8.28 (d,J= 8.4 Hz, 2H), 7.77 (d,J= 8.4 Hz, 2H), 2.75 (dd,J= 14.6, 7.2 Hz, 2H), 1.18 (t,J= 7.4 Hz, 3H).

[1210]

[1211] Preparation Example 129

[1212] 5-ethyl-4-(3-nitrophenyl)thiazole-2-amine

[1213] 5-Ethyl-4-(3-nitrophenyl)thiazol-2-amine

[1214]

[1215] The above compound was obtained as a yellow solid (462.4 mg, 88.3%) from tert-butyl(5-ethyl-4-(3-nitrophenyl)thiazole-2-yl)(4-methoxybenzyl)carbamate.

[1216] 1 H NMR (500 MHz, DMSO-d6) δ 8.34 (s, 1H), 8.12 (d,J= 8.2 Hz, 1H), 7.94 (d,J= 7.7 Hz, 1H), 7.67 (t,J= 8.0 Hz, 1H), 6.96 (s, 2H), 2.78 (q,J= 7.4 Hz, 2H), 1.20 (t,J= 7.4 Hz, 3H).

[1217]

[1218] Preparation Example 130

[1219] 4-(2-amino-5-ethylthiazole-4-yl)benzonitrile

[1220] 4-(2-Amino-5-ethylthiazol-4-yl)benzonitrile

[1221]

[1222] The above compound was obtained as a yellow solid (70.2 mg, 42.5%) from tert-butyl(5-ethyl-4-(4-cyanophenyl)thiazole-2-yl)(4-methoxybenzyl)carbamate.

[1223] 1 H NMR (500 MHz, DMSO-d6) δ 7.83 (d,J= 8.3 Hz, 2H), 7.70 (d,J= 8.3 Hz, 2H), 6.92 (s, 2H), 2.77 (q,J= 7.4 Hz, 2H), 1.19 (t,J= 7.4 Hz, 3H).

[1224]

[1225] Preparation Example 131

[1226] 3-(2-amino-5-ethylthiazole-4-yl)benzonitrile

[1227] 3-(2-Amino-5-ethylthiazol-4-yl)benzonitrile

[1228]

[1229] The above compound was obtained as a yellow solid (280.6 mg, 77.9%) from tert-butyl(5-ethyl-4-(3-cyanophenyl)thiazole-2-yl)(4-methoxybenzyl)carbamate.

[1230] 1 H NMR (500 MHz, DMSO-d6) δ 7.88 (t,J= 1.5 Hz, 1H), 7.83 (m, 1H), 7.75 (m, 1H), 7.60 (t,J= 7.8 Hz, 1H), 6.91 (s, 2H), 2.75 (m, 2H), 1.18 (t,J= 7.5 Hz, 3H).

[1231]

[1232] Preparation Example 132

[1233] 3-(2-amino-5-ethylthiazole-4-yl)benzenesulfonamide

[1234] 3-(2-Amino-5-ethylthiazol-4-yl)benzenesulfonamide

[1235]

[1236] The above compound was obtained as a yellow solid (297.5 mg, quantitative yield) from tert-butyl(5-ethyl-4-(3-sulfamoylphenyl)thiazole-2-yl)(4-methoxybenzyl)carbamate.

[1237] 1 H NMR (500 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.71 (d,J= 7.7 Hz, 1H), 7.67 (d,J= 7.5 Hz, 1H), 7.56 (t,J= 6.5 Hz, 1H), 7.36 (s, 2H), 6.89 (s, 2H), 2.75 (m, 2H), 1.18 (t,J= 6.2 Hz, 3H).

[1238]

[1239] Preparation Example 133

[1240] 4-(4-(dimethylamino)phenyl)-5-ethylthiazole-2-amine

[1241] 4-(4-(Dimethylamino)phenyl)-5-ethylthiazol-2-amine

[1242]

[1243] The above compound was obtained as a reddish-brown solid (107.3 mg, 33.4%) from tert-butyl(5-ethyl-4-(4-dimethingaminophenyl)thiazole-2-yl)(4-methoxybenzyl)carbamate.

[1244] 1 H NMR (500 MHz, DMSO-d6) δ 7.33 (t,J= 5.8 Hz, 2H), 6.72 (m, 3H), 2.90 (s, 6H), 2.69 (q,J= 7.5 Hz, 2H), 1.16 (t,J= 7.5 Hz, 3H).

[1245]

[1246] Preparation Example 134

[1247] 5-ethyl-4-(3-(methoxymethyl)phenyl)thiazole-2-amine

[1248] 5-Ethyl-4-(3-(methoxymethyl)phenyl)thiazol-2-amine

[1249]

[1250] The above compound was obtained as a reddish-brown liquid (1.05 g, quantitative yield) from tert-butyl(5-ethyl-4-(3-(methoxymethyl)phenyl)thiazole-2-yl)(4-methoxybenzyl)carbamate.

[1251] 1 H NMR (500 MHz, CDCl3) δ 9.15 (s, 2H), 7.47 - 7.44 (m, 1H), 7.43 (s, 1H), 7.39 (s, 1H), 7.34 (d,J= 6.5 Hz, 1H), 4.49 (s, 2H), 3.41 (d,J= 2.3 Hz, 3H), 2.73 (dd,J= 7.4, 2.3 Hz, 2H), 1.33 - 1.18 (m, 3H).

[1252]

[1253] Preparation Example 135

[1254] Methyl 2-(4-(2-amino-5-ethylthiazole-4-yl)phenyl)acetate

[1255] Methyl 2-(4-(2-amino-5-ethylthiazol-4-yl)phenyl)acetate

[1256]

[1257] The above compound was obtained as a bright yellow solid (198.5 mg, 82.0%) from methyl 2-(4-(2-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-5-ethylthiazole-4-yl)phenyl)acetate.

[1258] 1H NMR (500 MHz, CDCl3) δ 7.46 (d,J= 8.1 Hz, 2H), 7.28 (d,J= 8.0 Hz, 2H), 5.47 (s, 2H), 3.69 (s, 3H), 3.63 (s, 2H), 2.77 (q,J= 7.5 Hz, 2H), 1.22 (t,J= 7.5 Hz, 3H).

[1259]

[1260] Preparation Example 136

[1261] 1-(4-(2-amino-5-ethylthiazole-4-yl)phenyl)ethanone

[1262] 1-(4-(2-Amino-5-ethylthiazol-4-yl)phenyl)ethanone

[1263]

[1264] The above compound was obtained from tert-butyl(4-(4-acetylphenyl)-5-ethylthiazole-2-yl)(4-methoxybenzyl)carbamate as a bright yellow solid (93.6 mg, quantitative yield).

[1265] 1 H NMR (500 MHz, CDCl3) δ 7.99 (d,J= 8.0 Hz, 2H), 7.64 (d,J= 8.1 Hz, 2H), 4.99 (s, 2H), 2.83 (dd,J= 14.8, 7.4 Hz, 2H), 2.62 (s, 3H), 1.28 (t,J= 7.5 Hz, 3H).

[1266]

[1267] Preparation Example 137

[1268] 4-([1,1'-biphenyl]-4-yl)-5-ethylthiazole-2-amine

[1269] 4-([1,1'-Biphenyl]-4-yl)-5-ethylthiazol-2-amine

[1270]

[1271] The above compound was obtained as a yellow solid (175.0 mg, 96.0%) from tert-butyl(4-([1,1'-biphenyl]-4-yl)-5-ethylthiazole-2-yl)(4-methoxybenzyl)carbamate.

[1272] 1 H NMR (500 MHz, CDCl3) δ 7.62 (m, 6H), 7.45 (t,J= 7.1 Hz, 2H), 7.35 (t,J= 6.8 Hz, 1H), 5.05 (s, 2H), 2.86 (q,J= 7.4 Hz, 2H), 1.29 (t,J= 7.4 Hz, 3H).

[1273]

[1274] Preparation Example 138

[1275] 5-ethyl-4-(4-(1-methyl-1H-pyrazole-5-yl)phenyl)thiazole-2-amine

[1276] 5-Ethyl-4-(4-(1-methyl-1H-pyrazol-5-yl)phenyl)thiazol-2-amine

[1277]

[1278] The above compound was obtained as a yellow solid (217.8 mg, 73.6%) from tert-butyl(5-ethyl-4-(4-(1-methyl-1H-pyrazole-5-yl)phenyl)thiazole-2-yl)(4-methoxybenzyl)carbamate.

[1279] 1 H NMR (500 MHz, DMSO-d6) δ 7.61 (d,J= 8.3 Hz, 2H), 7.53 (d,J= 8.3 Hz, 2H), 7.45 (d,J= 1.7 Hz, 1H), 6.83 (s, 2H), 6.41 (d,J= 1.7 Hz, 1H), 3.87 (s, 3H), 2.77 (q,J= 7.4 Hz, 2H), 1.19 (t,J= 7.4 Hz, 3H).

[1280]

[1281] Preparation Example 139

[1282] 5-ethyl-4-(4-(1-methyl-1H-pyrazole-3-yl)phenyl)thiazole-2-amine

[1283] 5-Ethyl-4-(4-(1-methyl-1H-pyrazol-3-yl)phenyl)thiazol-2-amine

[1284]

[1285] The above compound was obtained as a yellow solid (323.0 mg, quantitative yield) from tert-butyl(5-ethyl-4-(4-(1-methyl-1H-pyrazole-3-yl)phenyl)thiazole-2-yl)(4-methoxybenzyl)carbamate.

[1286] 1 H NMR (500 MHz, DMSO-d6) δ 7.77 (d,J= 8.3 Hz, 2H), 7.71 (d,J= 2.1 Hz, 1H), 7.51 (d,J= 8.3 Hz, 2H), 6.80 (s, 2H), 6.67 (d,J= 2.2 Hz, 1H), 3.86 (s, 3H), 2.75 (q,J= 7.4 Hz, 2H), 1.18 (t,J= 7.4 Hz, 3H).

[1287]

[1288] Preparation Example 140

[1289] 4-(dibenzo[b,d]furan-4-yl)-5-ethylthiazole-2-amine

[1290] 4-(Dibenzo[b,d]furan-4-yl)-5-ethylthiazol-2-amine

[1291]

[1292] The above compound was obtained as a white solid (269.2 mg, 78.2%) from tert-butyl(4-(dibenzo[b,d]furan-4-yl)-5-ethylthiazole-2-yl)(4-methoxybenzyl)carbamate.

[1293] 1H NMR (500 MHz, CDCl3 / CD3OD) δ 7.91 (d,J= 7.7 Hz, 1H), 7.88 (d,J= 7.7 Hz, 1H), 7.49 (d,J= 8.2 Hz, 1H), 7.45 (d,J= 7.5 Hz, 1H), 7.39 (t,J= 7.7 Hz, 1H), 7.34 - 7.26 (m, 2H), 2.61 (q,J= 7.4 Hz, 2H), 1.17 (t,J= 7.5 Hz, 3H).

[1294]

[1295] Preparation Example 141

[1296] 4-(4-((dimethylamino)methyl)phenyl)-5-ethylthiazole-2-amine

[1297] 4-(4-((Dimethylamino)methyl)phenyl)-5-ethylthiazol-2-amine

[1298]

[1299] The above compound was obtained as a yellow liquid (179.0 mg, 44.2%) from tert-butyl(5-ethyl-4-(4-formylphenyl)thiazole-2-yl)(4-methoxybenzyl)carbamate.

[1300] 1 H NMR (500 MHz, CDCl3) δ 7.59 (d,J= 7.0 Hz, 2H), 7.39 (d,J= 7.5 Hz, 2H), 7.35 (d,J= 7.1 Hz, 2H), 6.83 (d,J= 7.3 Hz, 2H), 5.26 (s, 2H), 3.78 (d,J= 1.2 Hz, 3H), 3.48 (s, 2H), 2.96 - 2.87 (m, 2H), 2.28 (s, 6H), 1.53 (s, 9H), 1.32 (t,J= 6.9 Hz, 3H).

[1301]

[1302] Preparation Example 142

[1303] 4-(4-(methoxymethoxy)-3-(trifluoromethyl)phenyl)-5-propylthiazole-2-amine

[1304] 4-(4-(Methoxymethoxy)-3-(trifluoromethyl)phenyl)-5-propylthiazol-2-amine

[1305]

[1306] 4-(2-amino-5-propylthiazole-4-yl)-2-(trifluoromethyl)phenol (0.15 g, 0.56 mmol), potassium carbonate (115.7 mg, 0.84 mmol), and anhydrous N,N-dimethylformamide (2 mL) were added to a heat-dried flask. After stirring at room temperature for 1 hour, methoxymethoxychloride (49.4 mg, 46.6 μL, 0.61 mmol) was slowly added to the residue at -30°C. The mixture was stirred at room temperature for 20 minutes. Subsequently, the mixture was poured into cold water, extracted with ethyl acetate, washed with saturated salt water, dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate:hexane = 1:3) to obtain the compound (45 mg, 23.3%) in the form of a yellow gel.

[1307] 1 H NMR (500 MHz, DMSO-d6) δ 7.65 (s, 1H), 7.60 (d,J= 8.5 Hz, 1H), 7.07 (d,J= 8.5 Hz, 1H), 3.34 (s, 2H), 2.75 (t,J= 7.5 Hz, 2H), 1.60 (m, 2H), 1.45 (s, 3H), 0.90 (t,J= 7.3 Hz, 3H).

[1308]

[1309] Preparation Example 143

[1310] 4-(4-((4-methoxybenzyl)oxy)-3-(trifluoromethyl)phenyl)-5-propylthiazole-2-amine

[1311] 4-(4-((4-Methoxybenzyl)oxy)-3-(trifluoromethyl)phenyl)-5-propylthiazol-2-amine

[1312]

[1313] 4-(2-amino-5-propylthiazole-4-yl)-2-(trifluoromethyl)phenol (556.3 mg, 1.84 mmol), potassium carbonate (381.5 mg, 2.76 mmol), and anhydrous N,N-dimethylformamide (5 mL) were added to a heat-dried flask. After stirring at room temperature for 1 hour, 4-methoxybenzyl chloride (345.8 mg, 0.30 mL, 2.21 mmol) was slowly added to the residue at 0°C. The mixture was stirred at 60°C for 4 hours. Subsequently, the mixture was poured into cold water, extracted with ethyl acetate, washed with saturated salt water, dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate:hexane = 1:3) to obtain the compound (0.4 g, 51.5%) in the form of a yellow solid.

[1314] 1 H NMR (500 MHz, DMSO-d6) δ 7.72 (d,J= 16.0 Hz, 1H), 7.70 (d,J= 8.6 Hz, 1H), 7.36 (t,J= 7.3 Hz, 3H), 6.95 (d,J= 8.5 Hz, 2H), 6.85 (s, 2H), 5.18 (s, 2H), 3.74 (s, 3H), 2.65 (t,J= 7.6 Hz, 2H), 1.55 (m, 2H), 0.89 (t,J= 7.3 Hz, 3H).

[1315]

[1316] Preparation Example 144

[1317] 5-(tert-butyl)-4-(3-chloro-4-((4-methoxybenzyl)oxy)phenyl)thiazole-2-amine

[1318] 5-(tert-Butyl)-4-(3-chloro-4-((4-methoxybenzyl)oxy)phenyl)thiazol-2-amine

[1319]

[1320] The above compound (658.0 mg, 54.8%) was obtained in the form of a brown solid from 4-(2-amino-5-(tert-butyl)thiazole-4-yl)-2-chlorophenol.

[1321] 1 H NMR (500 MHz, DMSO-d6) δ 7.40 (d,J= 8.5 Hz, 2H), 7.27 (s, 1H), 7.19 (m, 2H), 6.95 (d,J= 8.5 Hz, 2H), 6.62 (s, 2H), 5.11 (s, 2H), 3.74 (s, 3H), 1.12 (s, 9H).

[1322]

[1323] Preparation Example 145

[1324] 4-(4-chloro-3-((4-methoxybenzyl)oxy)phenyl)-5-ethylthiazole-2-amine

[1325] 4-(4-Chloro-3-((4-methoxybenzyl)oxy)phenyl)-5-ethylthiazol-2-amine

[1326]

[1327] The above compound (377.4 mg, 59.8%) was obtained in the form of a yellow solid from 5-(2-amino-5-ethylthiazole-4-yl)-2-chlorophenol.

[1328] 1H NMR (500 MHz, DMSO-d6) δ 7.41 (d,J= 8.2 Hz, 1H), 7.37 (d,J= 8.4 Hz, 2H), 7.24 (s, 1H), 7.06 (d,J= 8.2 Hz, 1H), 6.95 (d,J= 8.5 Hz, 2H), 6.84 (s, 2H), 5.13 (s, 2H), 3.74 (s, 3H), 2.63 (q,J= 7.4 Hz, 2H), 1.12 (t,J= 7.4 Hz, 3H).

[1329]

[1330] Preparation Example 145

[1331] 4-Bromo-N,N-Divac-5-propylthiazole-2-amine

[1332] 4-Bromo-N,N-diBoc-5-propylthiazol-2-amine

[1333]

[1334] Di-tert-butyl dicarbonate (2.25 g, 10.31 mmol, 1.248 mL) was added to a solution in which 4-bromo-5-propylthiazole-2-amine (0.95 g, 4.30 mmol), 4-dimethylaminopyridine (52.6 mg, 0.43 mmol), and triethylamine (1.043 mg, 1.44 mL, 10.31 mmol) were dissolved in tetrahydrofuran (20 mL). The reaction mixture was stirred at 50 °C for 6 hours. After the reaction, the solvent was evaporated, and the residue was purified using flash column chromatography (ether:hexane, 1:20) to obtain the compound (614.2 mg, 33.9%) as a yellow liquid.

[1335] 1 H NMR (500 MHz, CDCl3) δ 2.68 (t,J= 7.4 Hz, 2H), 1.65 (m, 2H), 1.49 (s, 18H), 0.95 (t,J= 7.3 Hz, 3H).

[1336]

[1337] Preparation Example 146

[1338] tert-butyl (4-(4-formylphenyl)-5-propylthiazole-2-yl)carbamate

[1339] tert-Butyl (4-(4-formylphenyl)-5-propylthiazol-2-yl)carbamate

[1340]

[1341] 4-bromo-N,N-divac-5-propylthiazole-2-amine (0.443 g, 1.05 mmol), potassium triphosphate (446.4 mg, 2.103 mmol), (4-formylphenyl)boronic acid (188.9 mg, 1.26 mmol), and N,N-dimethylformamide:water (4:1, 10 mL) were added to a heat-dried flask. After flushing the inside of the flask with nitrogen for 10 minutes, a (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloromethane complex (43.0 mg, 0.053 mmol) was added to the mixture. The mixture was covered with foil and stirred at 80 °C for 1 hour. After cooling the mixture to room temperature, it was filtered using a Celite pad and washed with a sufficient amount of ethyl acetate. Subsequently, water was added to the resulting mixture to separate the organic phase, and the organic phase was washed with H2O and saturated brine, then dried and concentrated with anhydrous magnesium sulfate. The resulting crude raw material was purified using flash column chromatography (ether:hexane, 1:5) to obtain the compound (249.5 mg, 68.6%) as a white solid.

[1342] 1 H NMR (500 MHz, CDCl3) δ 10.03 (s, 1H), 9.83 (s, 1H), 7.91 (d,J= 7.0 Hz, 2H), 7.75 (d,J= 7.4 Hz, 2H), 2.88 (t,J= 7.1 Hz, 2H), 1.74 (m, 2H), 1.33 (s, 9H), 0.99 (t,J= 6.7 Hz, 3H).

[1343]

[1344] Preparation Example 147

[1345] (4-(2-amino-5-propylthiazole-4-yl)phenyl)methanol

[1346] (4-(2-Amino-5-propylthiazol-4-yl)phenyl)methanol

[1347]

[1348] 4-bromo-N,N-divac-5-propylthiazole-2-amine (0.443 g, 1.05 mmol), potassium triphosphate (446.4 mg, 2.103 mmol), (4-formylphenyl)boronic acid (188.9 mg, 1.26 mmol), and N,N-dimethylformamide:water (4:1, 10 mL) were added to a heat-dried flask. After flushing the inside of the flask with nitrogen for 10 minutes, a (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloromethane complex (43.0 mg, 0.053 mmol) was added to the mixture. The mixture was covered with foil and stirred at 80 °C for 1 hour. After cooling the mixture to room temperature, it was filtered using a Celite pad and washed with a sufficient amount of ethyl acetate. Subsequently, water was added to the resulting mixture to separate the organic phase, and the organic phase was washed with H2O and saturated brine, then dried and concentrated with anhydrous magnesium sulfate. The resulting crude raw material was purified using flash column chromatography (ether:hexane, 1:5) to obtain the compound (249.5 mg, 68.6%) as a white solid.

[1349] 1H NMR (500 MHz, CDCl3) δ 7.47 (d,J= 7.8 Hz, 2H), 7.34 (d,J= 7.8 Hz, 2H), 4.89 (s, 2H), 4.70 (s, 2H), 2.72 (t,J= 7.6 Hz, 2H), 1.63 (m, 2H), 0.95 (t,J= 7.3 Hz, 3H).NMR (500 MHz, CDCl3) δ 10.03 (s, 1H), 9.83 (s, 1H), 7.91 (d,J= 7.0 Hz, 2H), 7.75 (d,J= 7.4 Hz, 2H), 2.88 (t,J= 7.1 Hz, 2H), 1.74 (m, 2H), 1.33 (s, 9H), 0.99 (t,J= 6.7 Hz, 3H).

[1350]

[1351] Preparation Example 148

[1352] N-(4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-propylthiazole-2-yl)-4-methoxybenzamide

[1353] N-(4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)-5-propylthiazol-2-yl)-4-methoxybenzamide

[1354]

[1355] 4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-propylthiazole-2-amine (561.5 mg, 1.47 mmol) was dissolved in pyridine (8 mL) and stirred at room temperature for 5 minutes. Anisoyl chloride (350.1 mg, 277.9 μL, 2.05 mmol) was added at 0 °C, and the reaction mixture was stirred overnight at room temperature. After the reaction was complete, water and dichloromethane were added to the resulting mixture, the organic phase was separated, and the aqueous layer was washed with dichloromethane. The combined organic phase was washed with water and brine, dried with anhydrous magnesium sulfate, and concentrated. The resulting residue was purified by flash column chromatography (ethyl acetate:hexane, 1:10) to obtain a compound (600.7 mg, 79.2%) as a white solid.

[1356] 1 H NMR (500 MHz, CDCl3) δ 7.82 (d,J= 8.7 Hz, 2H), 7.44 (d,J= 1.9 Hz, 1H), 7.25 (d,J= 2.0 Hz, 1H), 6.89 (d,J= 8.8 Hz, 2H), 6.84 (d,J= 8.4 Hz, 1H), 3.86 (s, 3H), 2.84 (t,J= 7.6 Hz, 2H), 1.75 (m, 2H), 1.04 (s, 9H), 1.01 (t,J= 7.4 Hz, 3H), 0.23 (s, 6H).

[1357]

[1358] Preparation Example 149

[1359] N-(4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-propylthiazole-2-yl)-4-chlorobenzamide

[1360] N-(4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)-5-propylthiazol-2-yl)-4-chlorobenzamide

[1361]

[1362] The above compound (611.3 mg, 98.0%) was obtained as an orange solid using 4-chlorobenzoyl chloride.

[1363] 1 H NMR (500 MHz, CDCl3) δ 7.78 (s, 1H), 7.64 (d,J= 7.8 Hz, 1H), 7.49 (d,J= 7.9 Hz, 1H), 7.43 (d,J= 7.7 Hz, 1H), 7.34 (t,J= 7.3 Hz, 2H), 7.16 (d,J= 8.3 Hz, 1H), 6.85 (d,J= 7.9 Hz, 1H), 2.84 (t,J= 6.6 Hz, 2H), 1.70 (m, 2H), 1.02 (s, 9H), 0.96 (t,J= 6.9 Hz, 3H), 0.22 (s, 6H).

[1364]

[1365] Preparation Example 150

[1366] N-(4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-propylthiazole-2-yl)-4-bromobenzamide

[1367] N-(4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)-5-propylthiazol-2-yl)-4-bromobenzamide

[1368]

[1369] The above compound (353.2 mg, 80.0%) was obtained as a yellow solid using 4-bromobenzoyl chloride.

[1370] 1H NMR (500 MHz, DMSO-d6) δ 12.69 (s, 1H), 8.03 (d,J= 7.9 Hz, 2H), 7.76 (d,J= 7.9 Hz, 2H), 7.68 (s, 1H), 7.48 (d,J= 8.8 Hz, 1H), 7.11 (d,J= 8.2 Hz, 1H), 2.86 (t,J= 6.7 Hz, 2H), 1.67 (m, 2H), 1.00 (s, 9H), 0.95 (t,J= 6.7 Hz, 3H), 0.26 (s, 6H).

[1371]

[1372] Preparation Example 151

[1373] N-(4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-propylthiazole-2-yl)-4-cyanobenzamide

[1374] N-(4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)-5-propylthiazol-2-yl)-4-cyanobenzamide

[1375]

[1376] The above compound (381.1 mg, 95.0%) was obtained as a bright yellow solid using 4-cyanobenzoyl chloride.

[1377] 1 H NMR (500 MHz, DMSO-d6) δ 12.88 (s, 1H), 8.22 (d,J= 8.0 Hz, 2H), 8.03 (d,J= 8.0 Hz, 2H), 7.68 (s, 1H), 7.48 (d,J= 8.4 Hz, 1H), 7.12 (d,J= 8.4 Hz, 1H), 2.87 (t,J= 7.4 Hz, 2H), 1.68 (m, 2H), 1.01 (s, 9H), 0.95 (t,J= 7.2 Hz, 3H), 0.26 (s, 6H).

[1378]

[1379] Preparation Example 152

[1380] N-(4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-propylthiazole-2-yl)-4-nitrobenzamide

[1381] N-(4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)-5-propylthiazol-2-yl)-4-nitrobenzamide

[1382]

[1383] The above compound (212.0 mg, 99.0%) was obtained as a yellow solid using 4-nitrobenzoyl chloride.

[1384] 1 H NMR (500 MHz, DMSO-d6) δ 12.98 (s, 1H), 8.37 (d,J= 7.7 Hz, 2H), 8.31 (d,J= 8.4 Hz, 2H), 7.68 (s, 1H), 7.49 (d,J= 8.1 Hz, 1H), 7.12 (d,J= 8.3 Hz, 1H), 2.88 (t,J= 7.2 Hz, 2H), 1.68 (m, 2H), 1.02 (s, 9H), 0.96 (t,J= 7.2 Hz, 3H), 0.27 (s, 6H).

[1385]

[1386] Preparation Example 153

[1387] N-(4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-propylthiazole-2-yl)-4-(dimethylamino)benzamide

[1388] N-(4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)-5-propylthiazol-2-yl)-4-(dimethylamino)benzamide

[1389]

[1390] The above compound (196.7 mg, 47.0%) was obtained as an orange-brown solid using 4-(dimethylamino)benzoyl chloride.

[1391] 1 H NMR (500 MHz, DMSO-d6) δ 12.15 (s, 1H), 8.00 (d,J= 7.8 Hz, 2H), 7.68 (s, 1H), 7.47 (d,J= 8.1 Hz, 1H), 7.11 (d,J= 8.1 Hz, 1H), 6.75 (d,J= 8.3 Hz, 2H), 3.01 (s, 6H), 2.84(t, 2H), 1.66 (m, 2H), 1.01 (s, 9H), 0.95 (t,J= 6.4 Hz, 3H), 0.26 (s, 6H).

[1392]

[1393] Preparation Example 154

[1394] N-(4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-propylthiazole-2-yl)-3-chlorobenzamide

[1395] N-(4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)-5-propylthiazol-2-yl)-3-chlorobenzamide

[1396]

[1397] The above compound (522.4 mg, 77.0%) was obtained as a yellow solid using 3-chlorobenzoyl chloride.

[1398] 1 H NMR (500 MHz, DMSO-d6) δ 8.06 (d,J= 9.0 Hz, 2H), 8.01 (d,J= 8.5 Hz, 1H), 7.51 (d,J= 8.6 Hz, 2H), 7.43 (d,J= 6.2 Hz, 1H), 7.30 (d,J= 6.6 Hz, 1H), 6.96 (d,J= 6.5 Hz, 1H), 2.85 (t,J= 6.4 Hz, 2H), 1.76 (m, 2H), 1.06 (s, 9H), 1.02 (t,J= 6.4 Hz, 3H), 0.28 (s, 6H).

[1399]

[1400] Preparation Example 155

[1401] N-(4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-propylthiazole-2-yl)-3-cyanobenzamide

[1402] N-(4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)-5-propylthiazol-2-yl)-3-cyanobenzamide

[1403]

[1404] The above compound (372.4 mg, 93.0%) was obtained as a white solid using 3-cyanobenzoyl chloride.

[1405] 1 H NMR (500 MHz, DMSO-d6) δ 8.02 (s, 2H), 7.75 (s, 1H), 7.46 (d,J= 6.8 Hz, 1H), 7.32 (s, 1H), 7.18 (s, 1H), 6.73 (s,J= 6.8 Hz, 1H), 2.86 (t,J= 6.8 Hz, 2H), 1.76 (m, 2H), 1.05 (m, 12H), 0.23 (s, 6H).

[1406]

[1407] Preparation Example 156

[1408] N-(4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-propylthiazole-2-yl)-3-nitrobenzamide

[1409] N-(4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)-5-propylthiazol-2-yl)-3-nitrobenzamide

[1410]

[1411] The above compound (394.3 mg, 95.0%) was obtained as a bright yellow solid using 3-nitrobenzoyl chloride.

[1412] 1 H NMR (500 MHz, DMSO-d6) δ 13.03 (s, 1H), 8.95 (s, 1H), 8.50 (d,J= 7.9 Hz, 1H), 8.48 (d,J= 7.9 Hz, 1H), 7.86 (t,J= 7.6 Hz, 1H), 7.69 (s, 1H), 7.49 (d,J= 8.2 Hz, 1H), 7.13 (d,J= 7.9 Hz, 1H), 2.88 (t,J= 7.1 Hz, 2H), 1.69 (m, 2H), 1.02 (s, 9H), 0.96 (t,J= 6.6 Hz, 3H), 0.27 (s, 6H).

[1413]

[1414] Preparation Example 157

[1415] N-(4-(3-chloro-4-hydroxyphenyl)-5-propylthiazole-2-yl)-4-methoxybenzamide

[1416] N-(4-(3-Chloro-4-hydroxyphenyl)-5-propylthiazol-2-yl)-4-methoxybenzamide (43a)

[1417]

[1418] N-(4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-propylthiazole-2-yl)-4-methoxybenzamide (773.1 mg, 1.49 mmol) was dissolved in tetrahydrofuran (20 mL), and a 1 molar solution of tetrabutyliluminium fluoride (0.3 mL, 0.30 mmol) was slowly added at 0 °C, after which the reaction mixture was stirred at 30 °C for 5 hours. The reaction was terminated with a saturated ammonium chloride solution, and the aqueous layer was washed with dichloromethane. The combined organic phase was washed with water and brine, dried with anhydrous magnesium sulfate, and concentrated. The resulting residue was purified by flash column chromatography (ethyl acetate:hexane, 1:3) to obtain the compound (525.3 mg, 87.5%) as a white solid.

[1419] 1 H NMR (500 MHz, DMSO-d6) δ 12.39 (s, 1H), 10.36 (s, 1H), 8.09 (d,J= 8.7 Hz, 2H), 7.57 (d,J= 1.6 Hz, 1H), 7.37 (dd,J= 8.4, 1.6 Hz, 1H), 7.05 - 7.02 (m, 3H), 3.82 (s, 3H), 2.81 (t,J= 7.5 Hz, 2H), 1.64 (m, 2H), 0.93 (t,J= 7.3 Hz, 3H).

[1420]

[1421] Preparation Example 158

[1422] N-(4-(3-chloro-4-hydroxyphenyl)-5-propylthiazole-2-yl)-4-chlorobenzamide

[1423] N-(4-(3-Chloro-4-hydroxyphenyl)-5-propylthiazol-2-yl)-4-chlorobenzamide (43b)

[1424]

[1425] The above compound (205.4 mg, 43.0%) was obtained from compound 42b as a light brown solid.

[1426] 1 H NMR (500 MHz, DMSO-d6) δ 12.71 (s, 1H), 10.40 (s, 1H), 8.16 (s, 1H), 8.04 (d,J= 7.6 Hz, 1H), 7.70 (d,J= 7.8 Hz, 1H), 7.57 (d,J= 8.5 Hz, 2H), 7.39 (d,J= 8.3 Hz, 1H), 7.05 (d,J= 8.3 Hz, 1H), 2.84 (t,J= 7.2 Hz, 2H), 1.66 (m, 2H), 0.94 (t,J= 6.9 Hz, 3H).

[1427]

[1428] Preparation Example 159

[1429] N-(4-(3-chloro-4-hydroxyphenyl)-5-propylthiazole-2-yl)-4-bromobenzamide

[1430] N-(4-(3-Chloro-4-hydroxyphenyl)-5-propylthiazol-2-yl)-4-bromobenzamide (43c)

[1431]

[1432] The above compound (141.0 mg, 56.0%) was obtained as a yellow solid from compound 42c.

[1433] 1 H NMR (500 MHz, DMSO-d6) δ 12.68 (s, 1H), 10.39 (s, 2H), 8.03 (d,J= 7.3 Hz, 2H), 7.76 (d,J= 7.2 Hz, 2H), 7.58 (s, 1H), 7.39 (d,J= 8.3 Hz, 1H), 7.05 (d,J= 8.1 Hz, 1H), 2.84 (t,J= 7.1 Hz, 2H), 1.66 (m, 2H), 0.95 (t,J= 6.9 Hz, 3H).

[1434]

[1435] Preparation Example 160

[1436] N-(4-(3-chloro-4-hydroxyphenyl)-5-propylthiazole-2-yl)-4-cyanobenzamide

[1437] N-(4-(3-Chloro-4-hydroxyphenyl)-5-propylthiazol-2-yl)-4-cyanobenzamide (43d)

[1438]

[1439] The above compound (137.4 mg, 47.0%) was obtained from compound 42d as a bright yellow solid.

[1440] 1H NMR (500 MHz, DMSO-d6) δ 12.87 (s, 1H), 10.41 (s, 1H), 8.22 (d,J= 7.8 Hz, 2H), 8.03 (d,J= 7.5 Hz, 2H), 7.58 (s, 1H), 7.39 (d,J= 8.2 Hz, 1H), 7.05 (d,J= 8.3 Hz, 1H), 2.84 (t,J= 6.7 Hz, 2H), 1.66 (m, 2H), 0.94 (t,J= 6.5 Hz, 3H).

[1441]

[1442] Preparation Example 161

[1443] N-(4-(3-chloro-4-hydroxyphenyl)-5-propylthiazole-2-yl)-4-nitrobenzamide

[1444] N-(4-(3-Chloro-4-hydroxyphenyl)-5-propylthiazol-2-yl)-4-nitrobenzamide (43e)

[1445]

[1446] The above compound (137.4 mg, 47.0%) was obtained as a yellow solid from compound 42e.

[1447] 1 H NMR (500 MHz, DMSO-d6) δ 12.96 (s, 1H), 10.41 (s, 1H), 8.36 (d,J= 8.4 Hz, 2H), 8.30 (d,J= 7.4 Hz, 2H), 7.58 (s, 1H), 7.40 (d,J= 8.4 Hz, 1H), 7.05 (d,J= 8.1 Hz, 1H), 2.85 (s, 2H), 1.67 (m, 2H), 0.95 (t,J= 6.6 Hz, 3H).

[1448]

[1449] Preparation Example 162

[1450] N-(4-(3-chloro-4-hydroxyphenyl)-5-propylthiazole-2-yl)-4-(dimethylamino)benzamide

[1451] N-(4-(3-Chloro-4-hydroxyphenyl)-5-propylthiazol-2-yl)-4-(dimethylamino)benzamide (43f)

[1452]

[1453] The above compound (123.3 mg, 80.0%) was obtained from compound 42f as an orange-brown solid.

[1454] 1 H NMR (500 MHz, DMSO-d6) δ 12.12 (s, 1H), 10.36 (s, 1H), 8.00 (d,J= 8.9 Hz, 2H), 7.58 (d,J= 1.8 Hz, 1H), 7.38 (d,J= 8.4, 1.9 Hz, 1H), 7.04 (d,J= 8.4 Hz, 1H), 6.75 (d,J= 9.0 Hz, 2H), 3.01 (s, 6H), 2.81 (t,J= 7.6 Hz, 2H), 1.66 (m, 2H), 0.94 (t,J= 7.3 Hz, 3H).

[1455]

[1456] Preparation Example 163

[1457] N-(4-(3-chloro-4-hydroxyphenyl)-5-propylthiazole-2-yl)-3-chlorobenzamide

[1458] N-(4-(3-Chloro-4-hydroxyphenyl)-5-propylthiazol-2-yl)-3-chlorobenzamide (43g)

[1459]

[1460] The above compound (253.8 mg, 62.0%) was obtained as a white solid from 42 g of the compound.

[1461] 1H NMR (500 MHz, DMSO-d6) δ 12.12 (s, 1H), 10.36 (s, 1H), 8.00 (d,J= 8.9 Hz, 2H), 7.58 (d,J= 1.8 Hz, 1H), 7.38 (d,J= 8.4, 1.9 Hz, 1H), 7.04 (d,J= 8.4 Hz, 1H), 6.75 (d,J= 9.0 Hz, 2H), 3.01 (s, 6H), 2.81 (t,J= 7.6 Hz, 2H), 1.66 (m, 2H), 0.94 (t,J= 7.3 Hz, 3H).

[1462]

[1463] Preparation Example 164

[1464] N-(4-(3-chloro-4-hydroxyphenyl)-5-propylthiazole-2-yl)-3-cyanobenzamide

[1465] N-(4-(3-Chloro-4-hydroxyphenyl)-5-propylthiazol-2-yl)-3-cyanobenzamide (43h)

[1466]

[1467] The above compound (218.1 mg, 75.0%) was obtained as a yellow solid from compound 42h.

[1468] 1 H NMR (500 MHz, DMSO-d6) δ 12.79 (s, 1H), 10.41 (s, 1H), 8.53 (s, 1H), 8.35 (d,J= 7.8 Hz, 1H), 8.10 (d,J= 7.5 Hz, 1H), 7.76 (t,J= 7.8 Hz, 1H), 7.58 (s, 1H), 7.39 (d,J= 7.2 Hz, 1H), 7.05 (d,J= 8.4 Hz, 1H), 2.84 (t,J= 7.4 Hz, 2H), 1.66 (m, 2H), 0.95 (t,J= 7.3 Hz, 3H).

[1469]

[1470] Preparation Example 165

[1471] N-(4-(3-chloro-4-hydroxyphenyl)-5-propylthiazole-2-yl)-3-nitrobenzamide

[1472] N-(4-(3-Chloro-4-hydroxyphenyl)-5-propylthiazol-2-yl)-3-nitrobenzamide (43i)

[1473]

[1474] The above compound (274.8 mg, 89.0%) was obtained as a yellow solid from compound 42i.

[1475] 1 H NMR (500 MHz, DMSO-d6) δ 13.00 (s, 1H), 10.41 (s, 1H), 8.95 (s, 1H), 8.51 (d,J= 7.8 Hz, 1H), 8.46 (d,J= 8.4 Hz, 1H), 7.85 (t,J= 8.0 Hz, 1H), 7.59 (s, 1H), 7.40 (d,J= 8.3 Hz, 1H), 7.06 (d,J= 8.4 Hz, 1H), 2.85 (t,J= 7.1 Hz, 2H), 1.68 (m, 2H), 0.95 (t,J= 7.3 Hz, 3H).

[1476]

[1477] Preparation Example 166

[1478] N-(4-(3-chloro-4-(methoxymethoxy)phenyl)-5-propylthiazole-2-yl)-4-formylbenzamide

[1479] N-(4-(3-Chloro-4-(methoxymethoxy)phenyl)-5-propylthiazol-2-yl)-4-formylbenzamide

[1480]

[1481] To a solution of 4-formylbenzoic acid (128.0 mg, 0.85 mmol) dissolved in N,N-dimethylformamide (DMF, 5 mL), 4-(3-chloro-4-(methoxymethoxy)phenyl)-5-ethylthiazole-2-amine (400.0 mg, 1.28 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 1-oxide hexafluorophosphate (487.0 mg, 1.28 mmol), and diisopropylethylamine (223 μL, 1.28 mmol) were added and stirred overnight at room temperature. The reaction mixture was extracted with ethyl acetate, washed with brine, dried with anhydrous magnesium sulfate, and concentrated. The generated residue was purified by flash column chromatography using silica gel to obtain the compound (351.5 mg, 92.5%) as a green solid.

[1482] 1 H NMR (500 MHz, DMSO-d6) δ 12.84 (s, 1H), 10.10 (s, 1H), 8.25 (d,J= 8.1 Hz, 2H), 8.04 (d,J= 8.1 Hz, 2H), 7.69 (s, 1H), 7.53 (d,J= 8.6 Hz, 1H), 7.32 (d,J= 8.8 Hz, 1H), 5.32 (s, 2H), 3.43 (s, 3H), 2.86 (t, 2H), 1.66 (m, 2H), 0.94 (t,J= 7.4 Hz, 3H).

[1483]

[1484] Preparation Example 167

[1485] N-(4-(3-chloro-4-(methoxymethoxy)phenyl)-5-propylthiazole-2-yl)-4-((methylamino)methyl)benzamide

[1486] N-(4-(3-Chloro-4-(methoxymethoxy)phenyl)-5-propylthiazol-2-yl)-4-((methylamino)methyl)benzamide

[1487]

[1488] Methylamine (40% in methyl alcohol, 102 μL, 1.0 mmol) and sodium borohydride cyanide (63.0 mg, 1 mmol) were added to a solution of N-(4-(3-chloro-4-(methoxymethoxy)phenyl)-5-propylthiazole-2-yl)-4-formylbenzamide (300.0 mg, 0.67 mmol) dissolved in methyl alcohol (10 mL), and the mixture was stirred at room temperature for 20 hours. The reaction mixture was extracted with ethyl acetate, washed with brine, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography using silica gel to obtain the compound (70.0 mg, 22.5%) as a bright yellow solid.

[1489] 1 H NMR (500 MHz, DMSO-d6) δ 8.04 (d,J= 8.1 Hz, 2H), 7.69 (s, 1H), 7.52 (d,J= 8.6 Hz, 1H), 7.45 (d,J= 8.1 Hz, 2H), 7.31 (d,J= 8.6 Hz, 1H), 5.32 (s, 2H), 3.70 (s, 2H), 3.42 (s, 3H), 2.85 (t,J= 7.6 Hz, 2H), 2.25 (s, 3H), 1.71 - 1.60 (m, 2H), 0.94 (t,J= 7.3 Hz, 3H).

[1490]

[1491] Preparation Example 168

[1492] N-(4-(3-chloro-4-(methoxymethoxy)phenyl)-5-propylthiazole-2-yl)-4-(((2-dimethylamino)ethyl)amino)methyl)benzamide

[1493] N-(4-(3-Chloro-4-(methoxymethoxy)phenyl)-5-propylthiazol-2-yl)-4-(((2-(dimethylamino)ethyl)amino)methyl)benzamide

[1494]

[1495] The above compound (69.0 mg, 30.4%) was obtained as a yellow liquid using N,N-dimethylethylenediamine.

[1496] 1 H NMR (500 MHz, DMSO-d6) δ 8.03 (d,J= 6.5 Hz, 2H), 7.69 (s, 1H), 7.52 (d,J= 7.4 Hz, 1H), 7.46 (d,J= 7.4 Hz, 2H), 7.31 (d,J= 8.4 Hz, 1H), 5.32 (s, 2H), 3.76 (s, 2H), 3.42 (s, 3H), 2.85 (m, 2H), 2.54 (m, 2H), 2.31 (m, 2H), 2.09 (s, 6H), 1.66 (m, 2H), 0.94 (m, 3H).

[1497]

[1498] Preparation Example 169

[1499] N-(4-(3-chloro-4-hydroxyphenyl)-5-propylthiazole-2-yl)-4-((methylamino)methyl)benzamide

[1500] N-(4-(3-Chloro-4-hydroxyphenyl)-5-propylthiazol-2-yl)-4-((methylamino)methyl)benzamide (46a)

[1501]

[1502] A 4 molar hydrochloric acid / dioxane solution was slowly added at 0°C to a solution of N-(4-(3-chloro-4-(methoxymethoxy)phenyl)-5-propylthiazole-2-yl)-4-((methylamino)methyl)benzamide (70 mg, 0.15 mmol) dissolved in anhydrous methanol. The mixture was stirred at room temperature for 16 hours. The reaction mixture was extracted with ethyl acetate, washed with brine, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The filtrate was purified by flash column chromatography using silica gel to obtain the compound (9.0 mg, 14.2%) as a bright yellow solid.

[1503] 1H NMR (500 MHz, DMSO-d6) δ 12.65 (s, 1H), 10.42 (s, 1H), 8.13 (d,J= 7.9 Hz, 2H), 7.60 (d,J= 8.2 Hz, 2H), 7.57 (s, 1H), 7.37 (d,J= 8.2 Hz, 1H), 7.03 (d,J= 8.4 Hz, 1H), 4.20 (s, 2H), 2.82 (m, 2H), 2.58 (s, 3H), 1.64 (m, 2H), 0.93 (t,J= 7.1 Hz, 3H).

[1504] Preparation Example 170

[1505] N-(4-(3-chloro-4-hydroxyphenyl)-5-propylthiazole-2-yl)-4-(((2-dimethylamino)ethyl)amino)methyl)benzamide

[1506] N-(4-(3-Chloro-4-hydroxyphenyl)-5-propylthiazol-2-yl)-4-(((2-(dimethylamino)ethyl)amino)methyl)benzamide (46b)

[1507]

[1508] Using compound 45b, the above compound (69.0 mg, 30.4%) was obtained as a bright yellow liquid.

[1509] 1 H NMR (500 MHz, DMSO-d6) δ 8.06 (d,J= 6.9 Hz, 2H), 7.58 (s, 1H), 7.49 (d,J= 7.1 Hz, 2H), 7.39 (d,J= 8.1 Hz, 1H), 7.06 (d,J= 8.0 Hz, 1H), 3.82 (s, 2H), 2.84 (m, 2H), 2.61 (m, 2H), 2.16 (m, 2H), 1.66 (q,J= 6.9 Hz, 2H), 0.95 (t,J= 6.6 Hz, 3H).

[1510]

[1511] Preparation Example 171

[1512] 4-(morphorinosulfonyl)benzoic acid

[1513] 4-(Morpholinosulfonyl)benzoic acid

[1514]

[1515] The above compound (1.22 g, 98.8%) was obtained as a white solid using morpholine.

[1516] 1 H NMR (500 MHz, DMSO-d6) δ 13.54 (s, 1H), 8.16 (d,J= 8.2 Hz, 2H), 7.84 (d,J= 8.3 Hz, 2H), 3.61 (m, 4H), 2.87 (m, 4H).

[1517]

[1518] Preparation Example 172

[1519] N-(4-(3-chloro-4-(methoxymethoxy)phenyl)-5-propylthiazole-2-yl)-4-sulfamoylbenzamide

[1520] N-(4-(3-Chloro-4-(methoxymethoxy)phenyl)-5-propylthiazol-2-yl)-4-sulfamoylbenzamide

[1521]

[1522] 4-sulfamoylbenzoic acid (182.6 mg, 0.83 mmol), 4-(3-chloro-4-(methoxymethoxy)phenyl)-5-propylthiazole-2-amine (200.0 mg, 0.63 mmol), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (315.6 mg, 0.83 mmol) were added to a dried flask along with pyridine (3 mL), and the mixture was stirred overnight at 50°C. After the reaction was complete, the solvent was evaporated under reduced pressure. Cold water was added to the mixture, the product was extracted with ethyl acetate, washed with brine, dried with anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (ethyl acetate:hexane, 1:2) to obtain the compound (200.7 mg, 64.2%) as a white solid.

[1523] 1 H NMR (500 MHz, DMSO-d6) δ 12.81 (s, 1H), 8.22 (d,J= 8.3 Hz, 2H), 7.94 (d,J= 8.4 Hz, 2H), 7.69 (d,J= 2.0 Hz, 1H), 7.53 (m, 3H), 7.32 (d,J= 8.6 Hz, 1H), 5.32 (s, 2H), 3.43 (s, 3H), 2.86 (t,J= 7.4 Hz, 2H), 1.66 (m, 2H), 0.94 (t,J= 7.3 Hz, 3H).

[1524]

[1525] Preparation Example 173

[1526] N-(4-(3-chloro-4-(methoxymethoxy)phenyl)-5-propylthiazole-2-yl)-4-(piperidine-1-ylsulfonyl)benzamide

[1527] N-(4-(3-Chloro-4-(methoxymethoxy)phenyl)-5-propylthiazol-2-yl)-4-(piperidin-1-ylsulfonyl)benzamide

[1528]

[1529] The above compound (213.4 mg, 60.0%) was obtained as a white solid using 4-(piperidine-1-ylsulfonyl)benzoic acid with compound 6b.

[1530] 1 H NMR (500 MHz, DMSO-d6) δ 12.88 (s, 1H), 8.29 (d,J= 7.2 Hz, 2H), 7.87 (d,J= 7.6 Hz, 2H), 7.69 (s, 1H), 7.53 (d,J= 8.3 Hz, 1H), 7.33 (d,J= 8.7 Hz, 1H), 5.33 (s, 2H), 3.43 (s, 3H), 2.92 (m, 4H), 2.86 (m, 2H), 1.66 (m, 2H), 1.53 (m, 4H), 1.36 (m, 2H), 0.94 (m, 3H).

[1531]

[1532] Preparation Example 174

[1533] N-(4-(3-chloro-4-(methoxymethoxy)phenyl)-5-propylthiazole-2-yl)-4-(morpholinosulfonyl)benzamide

[1534] N-(4-(3-Chloro-4-(methoxymethoxy)phenyl)-5-propylthiazol-2-yl)-4-(morpholinosulfonyl)benzamide

[1535]

[1536] The above compound (225.2 mg, 63.1%) was obtained as a white solid using 4-(morphorinoylsulfonyl)benzoic acid with compound 6b.

[1537] 1H NMR (500 MHz, dmso) δ 12.88 (s, 1H), 8.31 (d,J= 8.5 Hz, 2H), 7.88 (d,J= 8.5 Hz, 2H), 7.68 (d,J= 2.1 Hz, 1H), 7.52 (dd,J= 8.6, 2.1 Hz, 1H), 7.32 (d,J= 8.6 Hz, 1H), 5.32 (s, 2H), 3.63 (m, 4H), 3.42 (s, 3H), 2.91 (m, 4H), 2.86 (t,J= 7.6 Hz, 2H), 1.66 (m, 2H), 0.94 (t,J= 7.3 Hz, 3H).

[1538]

[1539] Preparation Example 175

[1540] N-(4-(3-chloro-4-hydroxyphenyl)-5-propylthiazole-2-yl)-4-sulfonylbenzamide

[1541] N-(4-(3-Chloro-4-hydroxyphenyl)-5-propylthiazol-2-yl)-4-sulfamoylbenzamide (50a)

[1542]

[1543] N-(4-(3-chloro-4-(methoxymethoxy)phenyl)-5-propylthiazole-2-yl)-4-sulfamoylbenzamide (200.0 mg, 0.403 mmol), anhydrous methanol (3 mL), and tetrahydrofuran (1.5 mL) were added to a dried flask, and a 4 molar solution of dioxane hydrochloride (1.0 mL, 4.03 mmol) was added to the mixture at 0°C. The mixture was stirred at room temperature for 15 hours. After the reaction was complete, volatile substances were evaporated. The residue was neutralized with a saturated sodium bicarbonate solution, the product was extracted with ethyl acetate, washed with brine, dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate:hexane, 1:1) to obtain the compound (155.1 mg, 85.2%) as a beige solid.

[1544] 1 H NMR (500 MHz, DMSO-d6) δ 12.79 (s, 1H), 10.38 (s, 1H), 8.21 (d,J= 8.2 Hz, 2H), 7.93 (d,J= 8.2 Hz, 2H), 7.57 - 7.54 (m, 2H), 7.38 (d,J= 7.6 Hz, 1H), 7.04 (d,J= 8.4 Hz, 1H), 2.83 (t,J= 7.4 Hz, 2H), 1.67 - 1.63 (m, 2H), 0.93 (t,J= 7.3 Hz, 3H).

[1545]

[1546] Preparation Example 176

[1547] N-(4-(3-chloro-4-hydroxyphenyl)-5-propylthiazole-2-yl)-4-(piperidine-1-ylsulfonyl)benzamide

[1548] N-(4-(3-Chloro-4-hydroxyphenyl)-5-propylthiazol-2-yl)-4--(piperidin-1-ylsulfonyl)benzamide (50b)

[1549]

[1550] The above compound (71.9 mg, 52.0%) was obtained as a white solid from compound 49b.

[1551] 1 H NMR (500 MHz, DMSO-d6) δ 12.83 (s, 1H), 10.38 (s, 1H), 8.28 (d,J= 8.5 Hz, 2H), 7.85 (d,J= 8.5 Hz, 2H), 7.56 (d,J= 2.0 Hz, 1H), 7.38 (dd,J= 8.4, 2.0 Hz, 1H), 7.04 (d,J= 8.4 Hz, 1H), 2.92 (m, 4H), 2.82 (t,J= 7.5 Hz, 2H), 1.65 (m, 2H), 1.52 (m, 4H), 1.35 (m, 2H), 0.93 (t,J= 7.3 Hz, 3H).

[1552]

[1553] Preparation Example 177

[1554] N-(4-(3-chloro-4-hydroxyphenyl)-5-propylthiazole-2-yl)-4-(morpholinosulfonyl)benzamide

[1555] N-(4-(3-Chloro-4-hydroxyphenyl)-5-propylthiazol-2-yl)-4--(morpholinosulfonyl)benzamide (50c)

[1556]

[1557] The above compound (99.6 mg, 72.0%) was obtained as a white solid from compound 49c.

[1558] 1 H NMR (500 MHz, DMSO-d6) δ 12.85 (s, 1H), 10.38 (s, 1H), 8.31 (d,J= 8.4 Hz, 2H), 7.87 (d,J= 8.4 Hz, 2H), 7.57 (d,J= 2.0 Hz, 1H), 7.38 (dd,J= 8.4, 2.0 Hz, 1H), 7.04 (d,J= 8.4 Hz, 1H), 3.62 (m, 4H), 2.91 (m, 4H), 2.83 (t,J= 7.5 Hz, 2H), 1.65 (m, 2H), 0.93 (t,J= 7.3 Hz, 3H).

[1559]

[1560] Preparation Example 178

[1561] 4-(2-methoxy-2-oxoethyl)benzoic acid

[1562] 4-(2-Methoxy-2-oxoethyl)benzoic acid

[1563]

[1564] 1 molar concentration of thionyl chloride (0.28 mL, 0.28 mmol) was added to a methanol solution (27.8 mL) of 4-(carboxymethyl)benzoic acid (1.0 g, 5.55 mmol), and the solution was stirred at room temperature for 10 hours. After the reaction was complete, the solvent was evaporated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and water, dried with anhydrous magnesium sulfate, filtered, and concentrated to obtain the compound as a white solid (quantitative yield). The residue proceeded to the next step without purification.

[1565] 1 H NMR (500 MHz, DMSO-d6) δ 12.91 (s, 1H), 7.88 (d,J= 8.0 Hz, 2H), 7.37 (d,J= 8.0 Hz, 2H), 3.76 (s, 2H), 3.60 (s, 3H).

[1566]

[1567] Preparation Example 179

[1568] methyl 2-(4-((4-(3-chloro-4-(methoxymethoxy)phenyl)-5-propylthiazole-2-yl)carbamoyl)phenyl)acetate

[1569] Methyl 2-(4-((4-(3-chloro-4-(methoxymethoxy)phenyl)-5-propylthiazol-2-yl)carbamoyl)phenyl)acetate

[1570]

[1571] 4-(2-methoxy-2-oxoethyl)benzoic acid (273.9 mg, 1.41 mmol), 4-(3-chloro-4-(methoxymethoxy)phenyl)-5-propylthiazole-2-amine (367.7 mg, 1.18 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (536.2 mg, 1.41 mmol), and diisopropylethylamine (228.8 mg, 0.31 mL, 1.77 mmol) were added to a dried flask in N,N-dimethylformamide (5 mL). The mixture was stirred overnight at room temperature. The product was extracted with ethyl acetate, washed with brine, dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate:hexane, 1:3) to obtain the compound (310.0 mg, 53.7%) in the form of yellow gelatin.

[1572] 1 H NMR (500 MHz, CDCl3) δ 7.67 (d,J= 7.5 Hz, 2H), 7.30 (s, 1H), 7.20 - 7.15 (m, 3H), 6.97 (d,J= 8.4 Hz, 1H), 5.18 (s, 2H), 3.69 (s, 3H), 3.65 (s, 2H), 3.51 (s, 3H), 2.80 (t,J= 7.3 Hz, 2H), 1.75 - 1.71 (m, 2H), 0.98 (t,J= 7.0 Hz, 3H).

[1573]

[1574] Preparation Example 180

[1575] methyl 2-(4-((4-(3-chloro-4-hydroxyphenyl)-5-propylthiazole-2-yl)carbamoyl)phenyl)acetate

[1576] Methyl 2-(4-((4-(3-chloro-4-hydroxyphenyl)-5-propylthiazol-2-yl)carbamoyl)phenyl)acetate (54)

[1577]

[1578] Methyl 2-(4-((4-(3-chloro-4-(methoxymethoxy)phenyl)-5-propylthiazole-2-yl)carbamoyl)phenyl)acetate (300.0 mg, 0.61 mmol), anhydrous methanol (5 mL), and tetrahydrofuran (2 mL) were added to a dried flask, and 4 molar hydrochloric acid / dioxane (1.53 mL, 6.14 mmol) was slowly added at 0°C. The mixture was stirred at room temperature for 15 hours. After the reaction was complete, volatile substances were evaporated. The residue was neutralized with a saturated sodium bicarbonate solution, the product was extracted with ethyl acetate, washed with brine, dried with anhydrous magnesium sulfate, and concentrated by filtration. The residue was purified by flash column chromatography (ethyl acetate:hexane, 1:2) to obtain the compound (236.9 mg, 87.3%) as a white foamy solid.

[1579] 1 H NMR (500 MHz, CD3OD) δ 7.95 (d,J= 8.2 Hz, 2H), 7.54 (d,J= 2.0 Hz, 1H), 7.44 (d,J= 8.2 Hz, 2H), 7.34 (dd,J= 8.4, 2.1 Hz, 1H), 6.95 (d,J= 8.4 Hz, 1H), 3.75 (s, 2H), 3.69 (s, 3H), 2.85 (m, 2H), 1.72 (m, 2H), 0.99 (t,J= 7.3 H).

[1580]

[1581] Preparation Example 181

[1582] 2-(4-((4-(3-chloro-4-hydroxyphenyl)-5-propylthiazole-2-yl)carbamoyl)phenyl)acetic acid

[1583] 2-(4-((4-(3-Chloro-4-hydroxyphenyl)-5-propylthiazol-2-yl)carbamoyl)phenyl)acetic acid (55)

[1584]

[1585] A mixture of tetrahydrofuran (3 mL) and water (1 mL) was added to a flask, followed by the addition of methyl 2-(4-((4-(3-chloro-4-hydroxyphenyl)-5-propylthiazole-2-yl)carbamoyl)phenyl)acetate (62.0 mg, 0.14 mmol), and lithium hydroxide hydrate (17.6 mg, 0.42 mmol) at 0°C. The mixture was stirred at room temperature for 40 minutes. After the reaction was complete, 10% hydrochloric acid was added to the mixture to adjust the pH to 2-3, and volatile substances were evaporated. The product was extracted with ethyl acetate, washed with brine, dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the compound (quantitative yield) in the form of a beige solid.

[1586] 1 H NMR (500 MHz, DMSO-d6) δ 12.49 (s, 1H), 10.36 (s, 1H), 8.03 (d,J= 8.0 Hz, 2H), 7.57 (s, 1H), 7.40 (d,J= 8.0 Hz, 2H), 7.38 (d,J= 8.5 Hz, 1H), 7.03 (d,J= 8.4 Hz, 1H), 3.67 (s, 1H), 2.82 (t,J= 7.6 Hz, 2H), 1.68 - 1.41 (m, 2H), 0.93 (t,J= 7.3 Hz, 3H).

[1587]

[1588] Preparation Example 182

[1589] N-(4-(3-chloro-4-hydroxyphenyl)-5-propylthiazole-2-yl)-4-(2-dimethylamino)-2-oxoethyl)benzamide

[1590] N-(4-(3-Chloro-4-hydroxyphenyl)-5-propylthiazol-2-yl)-4-(2-(dimethylamino)-2-oxoethyl)benzamide (56a)

[1591]

[1592] The above compound (45.8 mg, 47.9%) was obtained as a white solid using N,N-dimethylamine in compound 55.

[1593] 1 H NMR (500 MHz, DMSO-d6) δ 12.49 (s, 1H), 10.36 (s, 1H), 8.03 (d,J= 8.0 Hz, 2H), 7.57 (s, 1H), 7.40 (d,J= 8.0 Hz, 2H), 7.38 (d,J= 8.5 Hz, 1H), 7.03 (d,J= 8.4 Hz, 1H), 3.67 (s, 1H), 2.82 (t,J= 7.6 Hz, 2H), 1.68 - 1.41 (m, 2H), 0.93 (t,J= 7.3 Hz, 3H).

[1594]

[1595] Preparation Example 183

[1596] N-(4-(3-chloro-4-hydroxyphenyl)-5-propylthiazole-2-yl)-4-(2-((2-hydroxyethyl)(methyl)amino)-2-oxoethyl)benzamide

[1597] N-(4-(3-Chloro-4-hydroxyphenyl)-5-propylthiazol-2-yl)-4-(2-((2-hydroxyethyl)(methyl)amino)-2-oxoethyl)benzamide (56b)

[1598]

[1599] The above compound (37.6 mg, 36.9%) was obtained as a white solid using 2-(methylamino)ethanol with compound 55.

[1600] 1H NMR (500 MHz, CD3OD / CDCl3) δ 7.95 (dd,J= 8.1, 3.8 Hz, 2H), 7.54 (d,J= 1.9 Hz, 1H), 7.41 (dd,J= 8.1, 3.3 Hz, 2H), 7.33 (dd,J= 8.4, 1.9 Hz, 1H), 6.96 (d,J= 8.4 Hz, 1H), 3.90 (d,J= 36.6 Hz, 2H), 3.70 (t,J= 4.6 Hz, 2H), 3.52 (dd,J= 9.4, 5.3 Hz, 2H), 3.06 (d,J= 77.6 Hz, 3H), 2.85 (t,J= 7.6 Hz, 2H), 1.72 (m, 2H), 0.99 (t,J= 7.3 Hz, 3H).

[1601]

[1602] Preparation Example 184

[1603] N-(4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-ethylthiazole-2-yl)-4-methoxybenzamide

[1604] N-(4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)-5-ethylthiazol-2-yl)-4-methoxybenzamide

[1605]

[1606] The above compound (180.1 mg, 31.8%) was obtained as a white solid using anisoyl chloride in compound 5c.

[1607] 1 H NMR (500 MHz, DMSO-d6) δ 8.06 (d,J= 8.3 Hz, 2H), 7.65 (s, 1H), 7.46 (d,J= 8.0 Hz, 1H), 7.07 (d,J= 8.5 Hz, 1H), 7.04 (d,J= 8.6 Hz, 2H), 3.81 (s, 3H), 2.87 (q,J= 15.1, 7.7 Hz, 2H), 1.25 (t, 3H), 0.98 (s, 9H), 0.23 (s, 6H).

[1608]

[1609] Preparation Example 185

[1610] N-(4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-ethylthiazole-2-yl)benzamide

[1611] N-(4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)-5-ethylthiazol-2-yl)benzamide

[1612]

[1613] The above compound (265.3 mg, 82.0%) was obtained as a white solid using benzoyl chloride in compound 5c.

[1614] 1 H NMR (500 MHz, CDCl3) δ 8.04 (s, 2H), 7.61 (d,J= 4.3 Hz, 1H), 7.52 (s, 3H), 7.32 (d,J= 7.7 Hz, 1H), 6.94 (d,J= 5.2 Hz, 1H), 2.93 (q,J= 4.4 Hz, 2H), 1.37 (t,J= 2.8 Hz, 3H), 1.05 (s,J= 2.5 Hz, 9H), 0.26 (s,J= 2.8 Hz, 6H).

[1615]

[1616] Preparation Example 186

[1617] N-(4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-ethylthiazole-2-yl)-4-chlorobenzamide

[1618] N-(4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)-5-ethylthiazol-2-yl)-4-chlorobenzamide

[1619]

[1620] The above compound (497.4 mg, 67.1%) was obtained as a yellow solid using 4-chlorobenzoyl chloride in compound 5c.

[1621] 1 H NMR (500 MHz, DMSO-d6) δ 12.67 (s, 1H), 8.09 (d,J= 8.5 Hz, 2H), 7.65 (s, 1H), 7.60 (d,J= 8.4 Hz, 2H), 7.47 (d, 1H), 7.09 (d,J= 8.4 Hz, 1H), 2.89 (q,J= 14.8, 7.4 Hz, 2H), 1.26 (t,J= 7.4 Hz, 3H), 0.99 (s, 9H), 0.24 (s, 6H).

[1622]

[1623] Preparation Example 187

[1624] N-(4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-ethylthiazole-2-yl)-4-bromobenzamide

[1625] N-(4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)-5-ethylthiazol-2-yl)-4-bromobenzamide

[1626]

[1627] The above compound (200.0 mg, 89.0%) was obtained as a white solid using 4-bromobenzoyl chloride with compound 5c.

[1628] 1 H NMR (500 MHz, DMSO) δ 12.67 (s, 1H), 8.01 (d,J= 8.4 Hz, 2H), 7.74 (d,J= 8.1 Hz, 2H), 7.67 (s, 1H), 7.47 (d,J= 8.1 Hz, 1H), 7.09 (d,J= 8.2 Hz, 1H), 2.89 (q,J= 7.2 Hz, 2H), 1.26 (t,J= 7.3 Hz, 3H), 0.99 (s, 9H), 0.24 (s, 6H).

[1629]

[1630] Preparation Example 188

[1631] N-(4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-ethylthiazole-2-yl)-4-(trifluoromethoxy)benzamide

[1632] N-(4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)-5-ethylthiazol-2-yl)-4-(trifluoromethoxy)benzamide

[1633]

[1634] The above compound (185.0 mg, 81.5%) was obtained as a white solid using 4-(trifluoromethoxy)benzoyl chloride with compound 5c.

[1635] 1 H NMR (500 MHz, DMSO-d6) δ 12.71 (s, 1H), 8.21 (d,J= 8.1 Hz, 2H), 7.67 (s, 1H), 7.53 (d,J= 7.5 Hz, 2H), 7.47 (d,J= 8.3 Hz, 1H), 7.09 (d,J= 7.9 Hz, 1H), 2.90 (q,J= 7.2 Hz, 2H), 1.27 (t,J= 7.1 Hz, 3H), 0.99 (s, 9H), 0.24 (s, 6H).

[1636]

[1637] Preparation Example 189

[1638] N-(4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-ethylthiazole-2-yl)-4-(trifluoromethyl)benzamide

[1639] N-(4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)-5-ethylthiazol-2-yl)-4-(trifluoromethyl)benzamide

[1640]

[1641] The above compound (82.1 mg, 37.2%) was obtained as a white solid using 4-(trifluoromethyl)benzoyl chloride in compound 5c.

[1642] 1 H NMR (500 MHz, DMSO) δ 12.85 (s, 1H), 8.26 (d,J= 7.9 Hz, 2H), 7.91 (d,J= 7.8 Hz, 2H), 7.67 (s, 2H), 7.48 (d,J= 8.5 Hz, 1H), 7.10 (d,J= 8.6 Hz, 1H), 2.91 (q,J= 7.3 Hz, 2H), 1.27 (t,J= 7.1 Hz, 3H), 1.00 (s, 9H), 0.24 (s, 6H).

[1643]

[1644] Preparation Example 190

[1645] N-(4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-ethylthiazole-2-yl)-4-cyanobenzamide

[1646] N-(4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)-5-ethylthiazol-2-yl)-4-cyanobenzamide

[1647]

[1648] 4-cyanobenzoyl chloride was added to compound 5c to obtain the above compound (130.9 mg, 39.0%) as a yellow solid.

[1649] 1 H NMR (500 MHz, DMSO-d6) δ 12.88 (s, 1H), 8.23 ​​(d,J= 8.1 Hz, 2H), 8.04 (d,J= 8.1 Hz, 2H), 7.69 (s, 1H), 7.49 (d,J= 8.5 Hz, 1H), 7.11 (d,J= 8.3 Hz, 1H), 2.92 (q,J= 7.4 Hz, 2H), 1.29 (t,J= 7.4 Hz, 3H), 1.02 (s, 9H), 0.26 (s, 6H).

[1650]

[1651] Preparation Example 191

[1652] N-(4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-ethylthiazole-2-yl)-4-nitrobenzamide

[1653] N-(4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)-5-ethylthiazol-2-yl)-4-nitrobenzamide

[1654]

[1655] The above compound (405.1 mg, 56.1%) was obtained as a white solid using 4-nitrobenzoyl chloride with compound 5c.

[1656] 1 H NMR (500 MHz, DMSO-d6) δ 12.96 (s, 1H), 8.35 (d,J= 8.5 Hz, 2H), 8.29 (d,J= 8.6 Hz, 2H), 7.67 (s, 1H), 7.47 (d,J= 8.4 Hz, 1H), 7.10 (d,J= 8.4 Hz, 1H), 2.91 (q,J= 14.6, 7.4 Hz, 2H), 1.27 (t,J= 7.4 Hz, 3H), 1.00 (s, 9H), 0.25 (s, 6H).

[1657]

[1658] Preparation Example 192

[1659] N-(4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-ethylthiazole-2-yl)-4-(dimethylamino)benzamide

[1660] N-(4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)-5-ethylthiazol-2-yl)-4-(dimethylamino)benzamide

[1661]

[1662] The above compound (92.9 mg, 44.2%) was obtained as a white solid using 4-(dimethylamino)benzoyl chloride in compound 5c.

[1663] 1 H NMR (500 MHz, DMSO-d6) δ 12.12 (s, 1H), 7.98 (d,J= 7.8 Hz, 2H), 7.67 (s, 1H), 7.46 (d,J= 8.2 Hz, 1H), 7.08 (d,J= 7.1 Hz, 1H), 6.73 (d,J= 8.2 Hz, 2H), 3.00 (s, 6H), 2.87 (q,J= 14.1, 6.6 Hz, 2H), 1.26 (t,J= 7.0 Hz, 3H), 1.00 (s, 9H), 0.24 (s, 6H).

[1664]

[1665] Preparation Example 193

[1666] N-(4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-ethylthiazole-2-yl)-3-chlorobenzamide

[1667] N-(4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)-5-ethylthiazol-2-yl)-3-chlorobenzamide

[1668]

[1669] The above compound was obtained using 3-chlorobenzoyl chloride with compound 5c. It was used directly in the next reaction without separate separation.

[1670]

[1671] Preparation Example 194

[1672] N-(4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-ethylthiazole-2-yl)-3-cyanobenzamide

[1673] N-(4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)-5-ethylthiazol-2-yl)-3-cyanobenzamide

[1674]

[1675] The above compound (227.3 mg, 67.0%) was obtained as a white solid using 3-cyanobenzoyl chloride in compound 5c.

[1676] 1 H NMR (500 MHz, CDCl3) δ 8.20 (s, 1H), 8.15 (d,J= 7.7 Hz, 1H), 7.80 (d,J= 7.5 Hz, 1H), 7.54 (t,J= 7.8 Hz, 1H), 7.39 (s, 1H), 7.21 (d,J= 8.3 Hz, 1H), 6.81 (d,J= 8.3 Hz, 1H), 2.93 (q,J= 7.5 Hz, 2H), 1.38 (t,J= 7.5 Hz, 3H), 1.05 (s, 9H), 0.24 (s, 6H).

[1677]

[1678] Preparation Example 195

[1679] N-(4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-ethylthiazole-2-yl)-3-nitrobenzamide

[1680] N-(4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)-5-ethylthiazol-2-yl)-3-nitrobenzamide

[1681]

[1682] The above compound (550.0 mg, 74.1%) was obtained as a white solid using 3-nitrobenzoyl chloride with compound 5c.

[1683] 1H NMR (500 MHz, DMSO-d6) δ 13.01 (s, 1H), 8.93 (s, 1H), 8.49 (d,J= 7.6 Hz, 1H), 8.45 (d,J= 7.8 Hz, 1H), 7.83 (t,J= 8.0 Hz, 1H), 7.68 (s, 1H), 7.48 (d,J= 8.3 Hz, 1H), 7.10 (d,J= 8.4 Hz, 1H), 2.91 (q,J= 7.4 Hz, 2H), 1.28 (t,J= 7.4 Hz, 3H), 1.00 (s, 9H), 0.25 (s, 6H).

[1684]

[1685] Preparation Example 196

[1686] N-(4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-ethylthiazole-2-yl)-3-(methoxymethoxy)benzamide

[1687] N-(4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)-5-ethylthiazol-2-yl)-3-(methoxymethoxy)benzamide

[1688]

[1689] The above compound (88.0 mg, 23.1%) was obtained as a white solid using 3-(methoxymethoxy)benzoyl chloride in compound 5c.

[1690] 1 H NMR (500 MHz, DMSO-d6) δ 12.58 (s, 1H), 7.72 (d,J= 8.6 Hz, 2H), 7.67 (s, 1H), 7.51 - 7.40 (m,J= 15.7, 8.1 Hz, 2H), 7.26 (d,J= 7.6 Hz, 1H), 7.09 (d,J= 8.5 Hz, 1H), 5.28 (s, 2H), 3.39 (s, 3H), 2.90 (q,J= 7.4 Hz, 2H), 1.27 (t,J= 7.4 Hz, 3H), 1.00 (s, 8H), 0.25 (s, 5H).

[1691]

[1692] Preparation Example 197

[1693] N-(4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-ethylthiazole-2-yl)-3-(dimethylamino)benzamide

[1694] N-(4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)-5-ethylthiazol-2-yl)-3-(dimethylamino)benzamide

[1695]

[1696] Compound 5c was used with 3-(dimethylamino)benzoyl chloride to obtain the compound (98.1 mg, 58.4%) as a yellow foamy solid.

[1697] 1 H NMR (500 MHz, DMSO-d6) δ 12.51 (s, 1H), 7.70 (s, 1H), 7.53 (d,J= 7.0 Hz, 1H), 7.41 (s, 1H), 7.32 (m, 3H), 6.94 (d,J= 8.3 Hz, 1H), 5.32 (s, 3H), 3.42 (s, 2H), 2.96 (s, 6H), 2.90 (q,J= 14.8, 7.4 Hz, 2H), 1.27 (t,J= 7.4 Hz, 3H).

[1698]

[1699] Preparation Example 198

[1700] N-(4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-ethylthiazole-2-yl)-2-(dimethylamino)benzamide

[1701] N-(4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)-5-ethylthiazol-2-yl)-2-(dimethylamino)benzamide

[1702]

[1703] Compound 5c was used with 2-(dimethylamino)benzoyl chloride to obtain the above compound (128.2 mg, 27.8%) as a transparent green gel.

[1704] 1 H NMR (500 MHz, DMSO-d6) δ 13.28 (s, 1H), 7.79 (d,J= 7.4 Hz, 1H), 7.61 (s, 1H), 7.51 (t,J= 7.5 Hz, 1H), 7.44 (d,J= 8.1 Hz, 1H), 7.33 (d,J= 8.0 Hz, 1H), 7.16 (t,J= 7.5 Hz, 1H), 7.08 (d,J= 8.4 Hz, 1H), 2.88 (q,J= 7.1 Hz, 2H), 2.75 (s, 6H), 1.26 (t,J= 7.3 Hz, 3H), 1.00 (s, 9H), 0.24 (s, 6H).

[1705]

[1706] Preparation Example 199

[1707] N-(4-(3-chloro-4-((4-methoxybenzyl)oxy)phenyl)-5-ethylthiazole-2-yl)-3-methoxybenzamide

[1708] N-(4-(3-Chloro-4-((4-methoxybenzyl)oxy)phenyl)-5-ethylthiazol-2-yl)-3-methoxybenzamide

[1709]

[1710] The above compound (481.7 mg, 100%) was obtained as a white solid using 3-methoxybenzoic acid with compound 6d.

[1711] 1H NMR (500 MHz, DMSO-d6) δ 12.61 (s, 1H), 7.70 (m, 3H), 7.54 (d,J= 8.5 Hz, 1H), 7.44 (m, 3H), 7.33 (d,J= 8.6 Hz, 1H), 7.19 (d,J= 7.5 Hz, 1H), 6.98 (d,J= 8.5 Hz, 2H), 5.16 (s, 2H), 3.85 (s, 3H), 3.76 (s, 3H), 2.92 (m, 2H), 1.28 (t,J= 7.5 Hz, 3H).

[1712]

[1713] Preparation Example 200

[1714] N-(4-(3-chloro-4-((4-methoxybenzyl)oxy)phenyl)-5-ethylthiazole-2-yl)-2-methoxybenzamide

[1715] N-(4-(3-Chloro-4-((4-methoxybenzyl)oxy)phenyl)-5-ethylthiazol-2-yl)-2-methoxybenzamide

[1716]

[1717] The above compound (428.6 mg, 100%) was obtained as a white solid using 2-methoxybenzoic acid with compound 6d.

[1718] 1 H NMR (500 MHz, DMSO-d6) δ 11.79 (s, 1H), 7.72 (m, 1H), 7.65 (s, 1H), 7.56 (m, 1H), 7.51 (m, 1H), 7.42 (m, 2H), 7.32 (m, 1H), 7.22 (m, 2H), 6.98 (m, 2H), 5.16 (s, 2H), 3.93 (s, 3H), 3.76 (s, 3H), 2.90 (m, 2H), 1.27 (t,J= 7.4 Hz, 3H).

[1719]

[1720] Preparation Example 201

[1721] Tert-butyl (4-((4-(3-chloro-4-((4-methoxybenzyl)oxy)phenyl)-5-ethylthiazole-2-yl)carbamoyl)phenyl)(methyl)carbamate

[1722] tert-Butyl (4-((4-(3-chloro-4-((4-methoxybenzyl)oxy)phenyl)-5-ethylthiazol-2-yl)carbamoyl) phenyl)(methyl)carbamate

[1723]

[1724] The above compound (262.4 mg, 53.9%) was obtained as a yellow solid using 4-((tert-butoxycarbonyl)(methyl)amino)benzoic acid in compound 6d.

[1725] 1 H NMR (500 MHz, DMSO-d6) δ 12.54 (s, 1H), 8.06 (d,J= 7.9 Hz, 2H), 7.68 (s, 1H), 7.52 (d,J= 8.2 Hz, 1H), 7.45 (d,J= 8.0 Hz, 2H), 7.41 (d,J= 7.9 Hz, 2H), 7.31 (d,J= 8.4 Hz, 1H), 6.96 (d,J= 7.9 Hz, 2H), 5.14 (s, 2H), 3.75 (s, 3H), 2.89 (dd,J= 14.4, 7.1 Hz, 2H), 2.67 (s, 3H), 1.41 (s, 9H), 1.26 (t,J= 7.3 Hz, 3H).

[1726]

[1727] Preparation Example 202

[1728] N-(4-(3-chloro-4-((4-methoxybenzyl)oxy)phenyl)-5-ethylthiazole-2-yl)-4-((4-methylpiperazine N-1-yl)sulfonyl)benzamide

[1729] N-(4-(3-Chloro-4-((4-methoxybenzyl)oxy)phenyl)-5-ethylthiazol-2-yl)-4-((4-methylpiperaziN-1-yl)sulfonyl)benzamide

[1730]

[1731] The above compound (161.2 mg, 35.7%) was obtained as a yellow solid using 4-((4-methylpiperazinon-N-1-yl)sulfonyl)benzoic acid in compound 6d.

[1732] 1 H NMR (500 MHz, DMSO-d6) δ 12.87 (s, 1H), 8.30 (d,J= 8.2 Hz, 2H), 7.87 (d,J= 8.2 Hz, 2H), 7.68 (s, 1H), 7.53 (d,J= 8.5 Hz, 1H), 7.41 (d,J= 8.2 Hz, 2H), 7.32 (d,J= 8.6 Hz, 1H), 6.96 (d,J= 8.3 Hz, 2H), 5.15 (s, 2H), 3.75 (s, 3H), 2.90 (m, 6H), 2.34 (m, 4H), 2.12 (s, 3H), 1.27 (t,J= 7.4 Hz, 3H).

[1733]

[1734] Preparation Example 203

[1735] N-(4-(3-chloro-4-((4-methoxybenzyl)oxy)phenyl)-5-ethylthiazole-2-yl)-4'-fluoro-[1,1'-biphenyl]-4-carboxamide

[1736] N-(4-(3-Chloro-4-((4-methoxybenzyl)oxy)phenyl)-5-ethylthiazol-2-yl)-4'-fluoro-[1,1'-biphenyl]-4-carboxamide

[1737]

[1738] 4'-fluoro-[1,1'-biphenyl]-4-carboxylic acid was added to compound 6d to obtain the above compound (439.4 mg, 65.7%) as a white solid.

[1739] 1H NMR (500 MHz, CDCl3) δ 12.02 (s, 1H), 7.74 (m, 2H), 7.54 (m, 2H), 7.40 (m, 2H), 7.32 (m, 3H), 7.20 (m, 1H), 7.16 (m, 2H), 6.93 (d,J= 7.8 Hz, 2H), 6.76 (d,J= 8.3 Hz, 1H), 4.93 (s, 2H), 3.83 (s, 3H), 2.91 (m, 2H), 1.36 (m, 3H).

[1740]

[1741] Preparation Example 204

[1742] N-(4-(3-(chloro-4-hydroxyphenyl)-5-ethylthiazole-2-yl)-4-methoxybenzamide

[1743] N-(4-(3-Chloro-4-hydroxyphenyl)-5-ethylthiazol-2-yl)-4-methoxybenzamide (58a)

[1744]

[1745] The above compound (27.1 mg, 34.7%) was obtained from compound 57a as a white solid.

[1746] 1 H NMR (500 MHz, DMSO-d6) δ 12.39 (s, 1H), 10.36 (s, 1H), 8.09 (d,J= 8.6 Hz, 2H), 7.58 (s, 1H), 7.38 (d,J= 8.4 Hz, 1H), 7.05 (d,J= 8.9 Hz, 2H), 7.02 (s, 1H), 3.83 (s, 3H), 2.87 (q,J= 7.2 Hz, 2H), 1.25 (t,J= 7.4 Hz, 3H).

[1747]

[1748] Preparation Example 205

[1749] N-(4-(3-(chloro-4-hydroxyphenyl)-5-ethylthiazole-2-yl)benzamide

[1750] N-(4-(3-Chloro-4-hydroxyphenyl)-5-ethylthiazol-2-yl)benzamide (58b)

[1751]

[1752] The above compound (149.0 mg, 74.0%) was obtained as an orange solid from compound 57b.

[1753] 1 H NMR (500 MHz, DMSO-d6) δ 12.58 (s, 1H), 10.38 (s, 1H), 8.10 (d,J= 7.4 Hz, 2H), 7.62 (m, 2H), 7.54 (t,J= 7.6 Hz, 2H), 7.40 (dd,J= 8.4, 1.9 Hz, 1H), 7.05 (d,J= 8.4 Hz, 1H), 2.89 (q,J= 7.4 Hz, 2H), 1.28 (t,J= 7.5 Hz, 3H).

[1754]

[1755] Preparation Example 206

[1756] 4-chloro-N-(4-(3-(chloro-4-hydroxyphenyl)-5-ethylthiazole-2-yl)benzamide

[1757] 4-Chloro-N-(4-(3-chloro-4-hydroxyphenyl)-5-ethylthiazol-2-yl)benzamide (58c)

[1758]

[1759] The above compound (149.0 mg, 74.0%) was obtained as a white solid from compound 57c.

[1760] 1H NMR (500 MHz, DMSO-d6) δ 12.65 (s, 1H), 10.37 (s, 1H), 8.09 (d,J= 8.5 Hz, 2H), 7.59 (m, 3H), 7.38 (d, 1H), 7.03 (d,J= 8.4 Hz, 1H), 2.88 (q,J= 14.8, 7.4 Hz, 2H), 1.26 (t,J= 7.5 Hz, 3H).

[1761]

[1762] Preparation Example 207

[1763] 4-Bromo-N-(4-(3-(chloro-4-hydroxyphenyl)-5-ethylthiazole-2-yl)benzamide

[1764] 4-Bromo-N-(4-(3-chloro-4-hydroxyphenyl)-5-ethylthiazol-2-yl)benzamide (58d)

[1765]

[1766] The above compound (90.0 mg, 76.1%) was obtained as a white solid from compound 57d.

[1767] 1 H NMR (500 MHz, DMSO-d6) δ 12.65 (s, 1H), 10.36 (s, 1H), 8.01 (d,J= 7.7 Hz, 2H), 7.73 (d,J= 7.5 Hz, 2H), 7.57 (s, 1H), 7.38 (d,J= 8.1 Hz, 1H), 7.03 (d,J= 8.2 Hz, 1H), 2.87 (q,J= 7.0 Hz, 2H), 1.23 (t, 3H).

[1768]

[1769] Preparation Example 208

[1770] N-(4-(3-(chloro-4-hydroxyphenyl)-5-ethylthiazole-2-yl)-4-(trifluoromethoxy)benzamide

[1771] N-(4-(3-Chloro-4-hydroxyphenyl)-5-ethylthiazol-2-yl)-4-(trifluoromethoxy)benzamide (58e)

[1772]

[1773] The above compound (12.0 mg, 54.1%) was obtained as a white solid from compound 57e.

[1774] 1 H NMR (500 MHz, DMSO-d6) δ 12.70 (s, 1H), 10.37 (s, 2H), 8.21 (d,J= 8.6 Hz, 1H), 7.57 (s, 1H), 7.52 (d,J= 7.4 Hz, 2H), 7.38 (d,J= 8.7 Hz, 1H), 7.03 (d,J= 8.3 Hz, 1H), 2.87 (q,J= 7.4 Hz, 2H), 1.26 (t,J= 7.3 Hz, 3H).

[1775]

[1776] Preparation Example 209

[1777] N-(4-(3-(chloro-4-hydroxyphenyl)-5-ethylthiazole-2-yl)-4-(trifluoromethyl)benzamide

[1778] N-(4-(3-Chloro-4-hydroxyphenyl)-5-ethylthiazol-2-yl)-4-(trifluoromethyl)benzamide (58f)

[1779]

[1780] The above compound (64.2 mg, quantitative yield) was obtained as a white solid from compound 57f.

[1781] 1H NMR (500 MHz, DMSO-d6) δ 12.83 (s, 1H), 10.38 (s, 1H), 8.26 (d,J= 8.1 Hz, 2H), 7.90 (d,J= 8.3 Hz, 2H), 7.58 (d,J= 1.9 Hz, 1H), 7.39 (dd,J= 8.4, 2.0 Hz, 1H), 7.04 (d,J= 8.4 Hz, 1H), 2.88 (q,J= 7.4 Hz, 2H), 1.26 (t,J= 7.5 Hz, 3H).

[1782]

[1783] Preparation Example 210

[1784] N-(4-(3-(chloro-4-hydroxyphenyl)-5-ethylthiazole-2-yl)-4-cyanobenzamide

[1785] N-(4-(3-Chloro-4-hydroxyphenyl)-5-ethylthiazol-2-yl)-4-cyanobenzamide (58g)

[1786]

[1787] The above compound (84.2 mg, 84.0%) was obtained as a bright yellow solid from 57 g of the compound.

[1788] 1 H NMR (500 MHz, DMSO-d6) δ 12.88 (s, 1H), 10.43 (s, 1H), 8.22 (d,J= 7.5 Hz, 2H), 8.03 (d,J= 7.5 Hz, 2H), 7.59 (s, 1H), 7.40 (d,J= 8.3 Hz, 1H), 7.05 (d,J= 8.3 Hz, 1H), 2.90 (q,J= 7.1 Hz, 2H), 1.27 (t,J= 7.2 Hz, 3H).

[1789]

[1790] Preparation Example 211

[1791] N-(4-(3-(chloro-4-hydroxyphenyl)-5-ethylthiazole-2-yl)-4-nitrobenzamide

[1792] N-(4-(3-Chloro-4-hydroxyphenyl)-5-ethylthiazol-2-yl)-4-nitrobenzamide (58h)

[1793]

[1794] The above compound (40.0 mg, 25.6%) was obtained as a bright green solid from compound 57h.

[1795] 1 H NMR (500 MHz, DMSO-d6) δ 12.94 (s, 1H), 10.39 (s, 1H), 8.35 (d,J= 8.7 Hz, 2H), 8.29 (d,J= 8.7 Hz, 2H), 7.58 (s, 1H), 7.39 (d,J= 8.3 Hz, 1H), 7.04 (d,J= 8.4 Hz, 1H), 2.89 (q,J= 7.2 Hz, 2H), 1.26 (t,J= 7.4 Hz, 3H).

[1796]

[1797] Preparation Example 212

[1798] N-(4-(3-(chloro-4-hydroxyphenyl)-5-ethylthiazole-2-yl)-4-(dimethylamino)benzamide

[1799] N-(4-(3-Chloro-4-hydroxyphenyl)-5-ethylthiazol-2-yl)-4-(dimethylamino)benzamide (58i)

[1800]

[1801] The above compound (31.0 mg, 44.2%) was obtained as a white solid from compound 57i.

[1802] 1H NMR (500 MHz, DMSO-d6) δ 12.09 (s, 1H), 10.33 (s, 1H), 7.98 (d,J= 8.5 Hz, 2H), 7.57 (s, 1H), 7.36 (d, 1H), 7.02 (d,J= 7.6 Hz, 1H), 6.73 (d,J= 7.6 Hz, 2H), 2.99 (s, 6H), 2.85 (q,J= 6.9 Hz, 2H), 1.24 (t,J= 6.9 Hz, 3H).

[1803]

[1804] Preparation Example 213

[1805] N-(4-(3-(chloro-4-hydroxyphenyl)-5-ethylthiazole-2-yl)-3-chlorobenzamide

[1806] N-(4-(3-Chloro-4-hydroxyphenyl)-5-ethylthiazol-2-yl)-3-chlorobenzamide (58j)

[1807]

[1808] The above compound (59.0 mg, 39.0%) was obtained as a white solid from compound 57j.

[1809] 1 H NMR (500 MHz, DMSO-d6) δ 12.69 (s, 1H), 10.38 (s, 1H), 8.15 (s, 1H), 8.03 (d,J= 7.8 Hz, 1H), 7.68 (d, 1H), 7.58 (m, 2H), 7.38 (d,J= 8.6 Hz, 1H), 7.03 (d,J= 9.2 Hz, 1H), 2.88 (q,J= 7.0 Hz, 2H), 1.26 (t,J= 7.0 Hz, 3H).

[1810]

[1811] Preparation Example 214

[1812] N-(4-(3-(chloro-4-hydroxyphenyl)-5-ethylthiazole-2-yl)-3-cyanobenzamide

[1813] N-(4-(3-Chloro-4-hydroxyphenyl)-5-ethylthiazol-2-yl)-3-cyanobenzamide (58k)

[1814]

[1815] The above compound (57.9 mg, 33.0%) was obtained from compound 57k as an orange-brown solid.

[1816] 1 H NMR (500 MHz, DMSO-d6) δ 12.78 (s, 1H), 10.42 (d,J= 14.3 Hz, 1H), 8.53 (s, 1H), 8.36 (d,J= 7.8 Hz, 1H), 8.10 (d,J= 7.6 Hz, 1H), 7.76 (t,J= 7.8 Hz, 1H), 7.59 (s, 1H), 7.40 (d,J= 8.5 Hz, 1H), 7.05 (d,J= 8.4 Hz, 1H), 2.90 (q,J= 14.9, 7.5 Hz, 2H), 1.28 (t,J= 7.5 Hz, 3H).

[1817]

[1818] Preparation Example 215

[1819] N-(4-(3-(chloro-4-hydroxyphenyl)-5-ethylthiazole-2-yl)-3-nitrobenzamide

[1820] N-(4-(3-Chloro-4-hydroxyphenyl)-5-ethylthiazol-2-yl)-3-nitrobenzamide (58l)

[1821]

[1822] The above compound (181.7 mg, 48.9%) was obtained as a yellow solid from 57 liters of compound.

[1823] 1H NMR (500 MHz, DMSO-d6) δ 12.98 (s, 1H), 10.39 (s, 1H), 8.93 (s, 1H), 8.49 (d,J= 7.8 Hz, 1H), 8.45 (d,J= 8.0 Hz, 1H), 7.83 (t,J= 8.1 Hz, 1H), 7.58 (s, 1H), 7.39 (d,J= 8.5 Hz, 1H), 7.04 (d,J= 8.3 Hz, 1H), 2.89 (q,J= 7.2 Hz, 2H), 1.26 (t,J= 7.4 Hz, 3H).

[1824]

[1825] Preparation Example 216

[1826] N-(4-(3-(chloro-4-hydroxyphenyl)-5-ethylthiazole-2-yl)-3-hydroxybenzamide

[1827] N-(4-(3-Chloro-4-hydroxyphenyl)-5-ethylthiazol-2-yl)-3-hydroxybenzamide (58m)

[1828]

[1829] The above compound (22.5 mg, 40.0%) was obtained as a bright yellow solid from compound 57m.

[1830] 1 H NMR (500 MHz, DMSO-d6) δ 12.44 (s, 1H), 10.35 (s, 1H), 9.79 (s, 1H), 7.57 (s, 1H), 7.53 (d,J= 7.1 Hz, 1H), 7.41 (s, 1H), 7.38 (d,J= 8.3 Hz, 1H), 7.30 (t,J= 7.5 Hz, 1H), 7.03 (d,J= 8.8 Hz, 1H), 6.99 (d,J= 7.1 Hz, 1H), 2.87 (q,J= 13.6, 7.2 Hz, 2H), 1.25 (t,J= 7.2 Hz, 3H).

[1831]

[1832] Preparation Example 217

[1833] N-(4-(3-(chloro-4-hydroxyphenyl)-5-ethylthiazole-2-yl)-3-(dimethylamino)benzamide

[1834] N-(4-(3-Chloro-4-hydroxyphenyl)-5-ethylthiazol-2-yl)-3-(dimethylamino)benzamide (58n)

[1835]

[1836] The above compound (50.1 mg, 58.4%) was obtained as a white solid from compound 57n.

[1837] 1 H NMR (500 MHz, DMSO-d6) δ 12.47 (s, 1H), 10.35 (s, 1H), 7.58 (d,J= 1.8 Hz, 1H), 7.35 (m, 4H), 7.03 (d,J= 8.4 Hz, 1H), 6.93 (d,J= 6.9 Hz, 1H), 2.96 (s, 6H), 2.87 (q,J= 7.4 Hz, 2H), 1.26 (t,J= 7.5 Hz, 3H).

[1838]

[1839] Preparation Example 218

[1840] N-(4-(3-(chloro-4-hydroxyphenyl)-5-ethylthiazole-2-yl)-2-(dimethylamino)benzamide

[1841] N-(4-(3-Chloro-4-hydroxyphenyl)-5-ethylthiazol-2-yl)-2-(dimethylamino)benzamide (58o)

[1842]

[1843] The above compound (70.1 mg, 70.0%) was obtained from compound 49o as a bright orange solid.

[1844] 1H NMR (500 MHz, DMSO-d6) δ 13.21 (s, 1H), 10.35 (s, 1H), 7.78 (d,J= 6.9 Hz, 1H), 7.52 (s, 2H), 7.34 (m, 2H), 7.15 (t,J= 8.1 Hz, 1H), 7.03 (d,J= 8.0 Hz, 1H), 2.86 (q,J= 7.3 Hz, 2H), 2.75 (s, 6H), 1.25 (t,J= 7.2 Hz, 3H).

[1845]

[1846] Preparation Example 219

[1847] N-(4-(3-chloro-4-hydroxyphenyl)-5-ethylthiazole-2-yl)-3-methoxybenzamide

[1848] N-(4-(3-Chloro-4-hydroxyphenyl)-5-ethylthiazol-2-yl)-3-methoxybenzamide (58p)

[1849]

[1850] N-(4-(3-chloro-4-((4-methoxybenzyl)oxy)phenyl)-5-ethylthiazole-2-yl)-3-methoxybenzamide (481.7 mg, 0.95 mmol) was dissolved in dichloromethane (13.6 mL), then trifluoroacetic acid (1.35 mL) was slowly added and stirred at room temperature for 30 minutes. After the reaction was complete, volatile substances were evaporated. Water was added to the residue, extracted with ethyl acetate, washed with brine, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate:hexane, 1:1) to obtain the compound (143.9 mg, 39.0%) as a pale pink solid.

[1851] 1H NMR (500 MHz, DMSO-d6) δ 12.59 (s, 1H), 10.38 (s, 1H), 7.69 (s, 2H), 7.60 (s, 1H), 7.44 (m, 1H), 7.40 (d,J= 8.2 Hz, 1H), 7.18 (d,J= 7.9 Hz, 1H), 7.05 (d,J= 8.3 Hz, 1H), 3.85 (s, 3H), 2.89 (m, 2H), 1.27 (t,J= 7.2 Hz, 3H).

[1852]

[1853] Preparation Example 220

[1854] N-(4-(3-chloro-4-hydroxyphenyl)-5-ethylthiazole-2-yl)-2-methoxybenzamide

[1855] N-(4-(3-Chloro-4-hydroxyphenyl)-5-ethylthiazol-2-yl)-2-methoxybenzamide (58q)

[1856]

[1857] The above compound (88.0 mg, 26.9%) was obtained as a pink solid from compound 57q.

[1858] 1 H NMR (500 MHz, DMSO-d6) δ 11.77 (s, 1H), 10.38 (s, 1H), 7.71 (d,J= 7.2 Hz, 1H), 7.57 (m, 2H), 7.38 (d,J= 8.1 Hz, 1H), 7.21 (d,J= 8.3 Hz, 1H), 7.09 (t,J= 7.3 Hz, 1H), 7.04 (d,J= 8.3 Hz, 1H), 3.93 (s, 3H), 2.88 (m, 2H), 1.27 (t,J= 7.3 Hz, 3H).

[1859]

[1860] Preparation Example 221

[1861] N-(4-(3-chloro-4-hydroxyphenyl)-5-ethylthiazole-2-yl)-4-(methylamino)benzamide

[1862] N-(4-(3-Chloro-4-hydroxyphenyl)-5-ethylthiazol-2-yl)-4-(methylamino)benzamide (58r)

[1863]

[1864] The above compound (139.1 mg, 86.4%) was obtained as a pink solid from compound 57r.

[1865] 1 H NMR (500 MHz, DMSO-d6) δ 12.01 (s, 1H), 10.33 (s, 1H), 7.91 (d,J= 7.1 Hz, 2H), 7.57 (s, 1H), 7.37 (d,J= 8.3 Hz, 1H), 7.02 (d,J= 8.4 Hz, 1H), 6.56 (d,J= 7.2 Hz, 2H), 6.51 (d,J= 3.2 Hz, 1H), 2.85 (dd,J= 13.8, 6.5 Hz, 2H), 2.72 (s,J= 2.7 Hz, 3H), 1.24 (t,J= 10.2, 4.6 Hz, 3H).

[1866]

[1867] Preparation Example 222

[1868] N-(4-(3-chloro-4-hydroxyphenyl)-5-ethylthiazole-2-yl)-4-(diethylamino)benzamide

[1869] N-(4-(3-Chloro-4-hydroxyphenyl)-5-ethylthiazol-2-yl)-4-(diethylamino)benzamide (58s)

[1870]

[1871] Intermediate 57s was obtained by using 4-(diethylamino)benzoyl chloride with compound 6d in a manner similar to Preparation Example 148, and then the compound (43.5 mg 15.3%, two steps) was obtained as a pink solid from 57s in a manner similar to Preparation Example 157.

[1872] 1 H NMR (500 MHz, DMSO-d6) δ 12.04 (s, 1H), 10.33 (s, 1H), 7.96 (d,J= 8.5 Hz, 2H), 7.57 (s, 1H), 7.37 (d,J= 6.9 Hz, 1H), 7.02 (d,J= 8.1 Hz, 1H), 6.68 (d,J= 8.5 Hz, 2H), 3.40 (m, 4H), 2.85 (m, 2H), 1.25 (t,J= 7.2 Hz, 3H), 1.10 (t,J= 6.6 Hz, 6H).

[1873]

[1874] Preparation Example 223

[1875] N-(4-(3-chloro-4-hydroxyphenyl)-5-ethylthiazole-2-yl)-4-morpholinobenzamide

[1876] N-(4-(3-Chloro-4-hydroxyphenyl)-5-ethylthiazol-2-yl)-4-morpholinobenzamide (58t)

[1877]

[1878] Intermediate 57t was obtained by using morpholinobenzoic acid with compound 6d in a manner similar to Preparation Example 148, and then the compound (55.9 mg, 51.4%, two steps) was obtained as a white solid from 57t in a manner similar to Preparation Example 157.

[1879] 1 H NMR (500 MHz, DMSO-d6) δ 12.22 (s, 1H), 10.35 (s, 1H), 8.01 (d,J= 8.6 Hz, 2H), 7.58 (s, 1H), 7.38 (d,J= 6.4 Hz, 1H), 7.01 (m, 3H), 3.72 (m, 4H), 3.26 (m, 4H), 2.86 (m, 2H), 1.25 (t,J= 7.3 Hz, 3H).

[1880]

[1881] Preparation Example 224

[1882] N-(4-(3-chloro-4-hydroxyphenyl)-5-ethylthiazole-2-yl)-4-((4-methylpiperazine N-1-yl)sulfonyl)benzamide

[1883] N-(4-(3-Chloro-4-hydroxyphenyl)-5-ethylthiazol-2-yl)-4-((4-methylpiperaziN-1-yl)sulfonyl)benzamide (58u)

[1884]

[1885] The above compound (13.0 mg, 11.4%) was obtained as a white solid from compound 57u.

[1886] 1 H NMR (500 MHz, DMSO-d6) δ 12.86 (s, 1H), 10.39 (s, 1H), 8.29 (d,J= 8.1 Hz, 2H), 7.86 (d,J= 8.0 Hz, 2H), 7.58 (s, 1H), 7.39 (d,J= 8.5 Hz, 1H), 7.04 (d,J= 8.4 Hz, 1H), 2.92 - 2.86 (m, 6H), 2.34 (m, 4H), 2.12 (s, 3H), 1.26 (t,J= 7.4 Hz, 3H).

[1887]

[1888] Preparation Example 225

[1889] N-(4-(3-chloro-4-hydroxyphenyl)-5-ethylthiazole-2-yl)-4'-fluoro-[1,1'-biphenyl]-4-carboxamide

[1890] N-(4-(3-Chloro-4-hydroxyphenyl)-5-ethylthiazol-2-yl)-4'-fluoro-[1,1'-biphenyl]-4-carboxamide (58v)

[1891]

[1892] The above compound (160.9 mg, 46.1%) was obtained as a white solid from compound 57v.

[1893] 1 H NMR (500 MHz, DMSO-d6) δ 12.64 (s, 1H), 10.40 (s, 1H), 8.20 (d,J= 7.8 Hz, 2H), 7.84 (m, 4H), 7.61 (s, 1H), 7.41 (d,J= 8.2 Hz, 1H), 7.34 (t,J= 8.3 Hz, 2H), 7.05 (d,J= 8.3 Hz, 1H), 2.90 (m, 2H), 1.28 (t,J= 7.2 Hz, 3H).

[1894]

[1895] Preparation Example 226

[1896] Methyl-4-phenethoxybenzoate

[1897] Methyl-4-phenethoxybenzoate

[1898]

[1899] Methyl-4-hydroxybenzoate (300.3 mg, 2.0 mmol) was dissolved in acetone (3 mL) under nitrogen gas filling. Potassium carbonate (545.2 mg, 3.9 mmol) and phenethyl bromide (0.3 mL, 2.5 mmol) were added to this mixture, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline solution. The bound organic layer was dried with anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified using silica gel column chromatography (ethyl acetate:hexane, 1:5), and the compound was obtained as a colorless liquid (243.8 mg, 48.0%).

[1900] 1 H NMR (500 MHz, CDCl3) δ 8.02 (d,J= 8.5Hz, 2H), 7.36 (d,J= 8.3Hz, 2H), 7.28 (t,J= 8.3Hz, 3H), 6.93 (d,J= 8.4Hz, 2H), 4.22 (t,J= 8.3Hz, 2H), 3.90 (s, 3H), 3.12 (t,J= 8.3Hz, 2H).

[1901]

[1902] Preparation Example 227

[1903] 4-Phenethoxybenzoic acid

[1904] 4-Phenethoxybenzoic acid

[1905]

[1906] Lithium hydroxide hydrate (57.0 mg, 2.4 mmol) was dissolved in water (0.5 mL), and the solution was added to tetrahydrofuran (1.5 mL). Methyl-4-phenethoxybenzoate (243.8 mg, 1.0 mmol) was dissolved in this solution under nitrogen gas filling. The mixture was stirred at room temperature for 1 hour, and if the reaction did not proceed completely, the mixture was stirred for an additional 2 hours at 50°C. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline. The bound organic layer was dried with anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified using silica gel column chromatography (ethyl acetate:hexane, 1:3), and the compound (229.4 mg, quantitative yield) was obtained as a white solid.

[1907] 1 H NMR (500 MHz, DMSO-d6) δ 7.87 (d,J= 6.8 Hz, 2H), 7.33 (s, 4H), 7.23 (s, 1H), 7.01 (d,J= 7.0 Hz, 2H), 4.26 (t,J= 7.0 Hz, 2H), 3.05 (t,J= 7.0 Hz, 2H).

[1908]

[1909] Preparation Example 228

[1910] N-(4-(3-chloro-4-(methoxymethoxy)phenyl)-5-ethylthiazole-2-yl)-4-phenethoxybenzamide

[1911] N-(4-(3-Chloro-4-(methoxymethoxy)phenyl)-5-ethylthiazol-2-yl)-4-phenethoxybenzamide

[1912]

[1913] 4-(3-chloro-4-(methoxymethoxy)phenyl)-5-ethylthiazole-2-amine (166.9 mg, 0.6 mmol) was dissolved in N,N-dimethylformamide (DMF, 1.5 mL) under nitrogen gas charge. 4-phenethoxybenzoic acid (162.4 mg, 0.7 mmol), [1,1´-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (276.8 mg, 0.7 mmol), and diisopropylethylamine (130.0 μL, 0.7 mmol) were added, and the mixture was stirred at room temperature under nitrogen gas charge for 12 hours. After the reaction was complete, the mixture was extracted with ethyl acetate. The organic layer was washed with water and 2 normal hydrochloric acid, dried with anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified using silica gel column chromatography (ethyl acetate:hexane, 1:1), and the compound (145.0 mg, 50.0%) was obtained as a yellow solid.

[1914] 1 H NMR (500 MHz, DMSO-d6) δ 12.40 (s, 1H), 8.07 (d,J= 8.5 Hz, 2H), 7.69 (s, 1H), 7.52 (d,J= 8.6 Hz, 1H), 7.31 (m, 5H), 7.21 (t,J= 6.7 Hz, 1H), 7.05 (d,J= 8.5 Hz, 2H), 5.32 (s, 2H), 4.28 (t,J= 6.7 Hz, 2H), 3.42 (s, 3H), 3.05 (t,J= 6.7 Hz, 2H), 2.89 (q,J= 7.4 Hz, 2H), 1.26 (t,J= 7.4 Hz, 3H).

[1915]

[1916] Preparation Example 229

[1917] N-(4-(3-chloro-4-hydroxyphenyl)-5-ethylthiazole-2-yl)-4-phenethoxybenzamide

[1918] N-(4-(3-Chloro-4-hydroxyphenyl)-5-ethylthiazol-2-yl)-4-phenethoxybenzamide (63)

[1919]

[1920] N-(4-(3-chloro-4-(methoxymethoxy)phenyl)-5-ethylthiazole-2-yl)-4-phenethoxybenzamide (145.0 mg, 0.3 mmol) was dissolved in a mixed solution of methyl alcohol and tetrahydrofuran (1.5 mL, volume ratio 2:1) under nitrogen gas filling. Hydrochloric acid (0.7 mL, 2.8 mmol) at a 4 molar concentration in 1,4-dioxane was added to this solution at 0°C, and the reaction mixture was stirred at room temperature for 15 hours. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline. The bound organic layer was dried with anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified using silica gel column chromatography (ethyl acetate:hexane, 1:1), and the compound (16.3 mg, 12.2%) was obtained as an orange-brown solid.

[1921] 1 H NMR (500 MHz, DMSO-d6) δ 12.38 (s, 1H), 10.36 (s, 1H), 8.08 (d,J= 7.3 Hz, 2H), 7.59 (s, 1H), 7.39 (d,J= 8.5 Hz, 1H), 7.33 (m, 4H), 7.23 (m, 1H), 7.07 - 7.03 (m, 3H), 4.30 (t,J= 6.5 Hz, 2H), 3.07 (t,J= 7.5 Hz, 2H), 2.88 (q,J= 6.7 Hz, 7H), 1.27 (t,J= 6.0 Hz, 3H).

[1922]

[1923] Preparation Example 230

[1924] Methyl indoline-6-carboxylate

[1925] Methyl indoline-6-carboxylate

[1926]

[1927] Methyl 1H-indole-6-carboxylate (1.95 g, 11.13 mmol) and sodium boron cyanohydrogen (3.49 g, 55.65 mmol) were dissolved in acetic acid (20 mL) at 0°C, and the mixture was stirred at 15°C for 2 hours. After the reaction was complete, the solution was alkalized to pH 8 using 1 molar sodium hydroxide and extracted with dichloromethane. The organic layer was washed with saturated saline, dried with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified using silica gel column chromatography (ethyl acetate:hexane, 1:5), and the compound (1.77 g, 90.0%) was obtained as a white solid.

[1928] 1 H NMR (500 MHz, DMSO-d6) δ 7.14 (d,J= 7.5, 1.4 Hz, 1H), 7.10 (d,J= 7.5 Hz, 1H), 6.99 (s,J= 1.0 Hz, 1H), 5.74 (s, 1H), 3.76 (s, 3H), 3.44 (t,J= 8.6, 1.6 Hz, 2H), 2.94 (t,J= 8.5 Hz, 2H).

[1929]

[1930] Preparation Example 231

[1931] Methyl 1-acetylindoline-6-carboxylate

[1932] Methyl 1-acetylindoline-6-carboxylate

[1933]

[1934] Methyl indoline-6-carboxylate (1.06 g, 5.97 mmol) and triethylamine (604.3 mg, 5.97 mmol) were dissolved in dichloromethane (5 mL) at 0°C. Acetyl chloride (937.6 mg, 11.94 mmol) was added to this solution, and the mixture was stirred at 0°C for 2 hours. After the reaction was complete, water was added to the resulting mixture, and the aqueous layer was extracted with dichloromethane. The organic layer was washed with saturated saline, dried with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified using silica gel column chromatography (ethyl acetate:hexane, 1:2), and the compound (1.39 g, 78.0%) was obtained as a white solid.

[1935] 1 H NMR (500 MHz, DMSO-d6) δ 8.59 (s, 1H), 7.60 (d,J= 7.7 Hz, 1H), 7.33 (d,J= 7.7 Hz, 1H), 4.11 (t,J= 8.6 Hz, 2H), 3.81 (s, 3H), 3.18 (t,J= 8.5 Hz, 2H), 2.15 (s, 3H).

[1936]

[1937] Preparation Example 232

[1938] Methyl 1-(methylsulfonyl)indolin-6-carboxylate

[1939] Methyl 1-(methylsulfonyl)indoline-6-carboxylate

[1940]

[1941] The above compound (522.4 mg, 85.0%) was obtained as a white solid from methyl indolin-6-carboxylate.

[1942] 1H NMR (500 MHz, DMSO-d6) δ 7.83 (m,J= 10.6 Hz, 1H), 7.66 (d,J= 7.8 Hz, 1H), 7.46 - 7.39 (d, 1H), 4.00 (t,J= 14.1, 5.4 Hz, 2H), 3.85 (m,J= 11.6 Hz, 3H), 3.24 - 3.15 (t, 2H), 3.04 (m,J= 11.6 Hz, 3H).

[1943]

[1944] Preparation Example 233

[1945] 1-Acetylindolin-6-carboxylic acid

[1946] 1-Acetylindoline-6-carboxylic acid

[1947]

[1948] Methyl 1-acetylindoline-6-carboxylate (1.21 g, 5.54 mmol) was dissolved in methyl alcohol (24 mL). Sodium hydroxide (664.8 mg, 16.62 mmol) at a concentration of 1 molar was added dropwise to this solution, and the mixture was stirred at 60°C for 16 hours. After the reaction was complete, the solution was acidified with hydrochloric acid at a concentration of 2 normal and extracted with dichloromethane. The organic layer was washed with saturated saline, dried with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure to obtain the compound (495.54 mg, 44.3%) as a white solid.

[1949] 1 H NMR (500 MHz, DMSO-d6) δ 12.63 (s, 1H), 8.06 (d,J= 8.1 Hz, 1H), 7.75 (d,J= 7.9 Hz, 2H), 4.12 (t,J= 8.0 Hz, 2H), 3.15 (t,J= 7.9 Hz, 2H), 2.16 (s, 3H).

[1950]

[1951] Preparation Example 234

[1952] 1-(methylsulfonyl)indoline-6-carboxylic acid

[1953] 1-(Methylsulfonyl)indoline-6-carboxylic acid

[1954]

[1955] The above compound (136.5 mg, 28%) was obtained as a white solid from compound 66b.

[1956] 1 H NMR (500 MHz, DMSO-d6) δ 12.64 (s, 1H), 7.80 (d,J= 8.3 Hz, 2H), 7.29 (d,J= 8.3 Hz, 1H), 4.00 (t,J= 8.5 Hz, 2H), 3.24 - 3.15 (t, 2H), 3.05 (s, 3H).

[1957]

[1958] Preparation Example 235

[1959] 1-acetyl-N-(4-(3-chloro-4-(methoxymethoxy)phenyl)-5-ethylthiazole-2-yl)indoline-6-carboxamide

[1960] 1-Acetyl-N-(4-(3-chloro-4-(methoxymethoxy)phenyl)-5-ethylthiazol-2-yl)indoline-6-carboxamide

[1961]

[1962] 4-(3-chloro-4-(methoxymethoxy)phenyl)-5-ethylthiazole-2-amine (120.9 mg, 0.41 mmol), 1-acetylindoline-6-carboxylic acid (107.9 mg, 0.53 mmol), and [1,1´-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (200.0 mg, 0.53 mmol) were dissolved in pyridine (3 mL), and the mixture was stirred at 50°C for 18 hours. After the reaction was complete, the solution was acidified with 2 normal hydrochloric acid and extracted with dichloromethane. The organic layer was washed with saturated saline, dried with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified using silica gel column chromatography (ethyl acetate:hexane, 1:2), and the compound (35.4 mg, 18.1%) was obtained as a white solid.

[1963] 1 H NMR (500 MHz, DMSO-d6) δ 12.39 (s, 1H), 8.08 (d,J= 8.8 Hz, 1H), 7.96 (s, 2H), 7.69 (s, 1H), 7.53 (d,J= 7.4 Hz, 1H), 7.31 (d,J= 8.5 Hz, 1H), 5.32 (s, 2H), 4.15 (t,J= 8.4 Hz, 2H), 3.42 (s, 3H), 3.19 (s, 2H), 2.93 - 2.86 (m, 2H), 2.18 (s, 3H), 1.26 (t,J= 7.4 Hz, 3H).

[1964]

[1965] Preparation Example 236

[1966] 1-Methylsulfonyl-N-(4-(3-chloro-4-(methoxymethoxy)phenyl)-5-ethylthiazole-2-yl)indoline-6-carboxamide

[1967] 1-Methylsulfonyl-N-(4-(3-chloro-4-(methoxymethoxy)phenyl)-5-ethylthiazol-2-yl)indoline-6-carboxamide

[1968]

[1969] The above compound (91.7 mg, 39.1%) was obtained as a white solid from compound 67b.

[1970] 1 H NMR (500 MHz, DMSO-d6) δ 10.22 (s, 1H), 7.82 (s, 1H), 7.72 (d,J= 7.4 Hz, 1H), 7.54 (s, 1H), 7.41 (s, 1H), 7.31 (d,J= 8.6 Hz, 1H), 6.75 (s, 1H), 5.32 (s, 2H), 3.98 (t,J= 8.5 Hz, 2H), 3.42 (s, 3H), 3.20 - 3.14 (t, 2H), 3.11 (s, 3H), 2.90 (m, 2H), 1.26 (t,J= 7.2 Hz, 3H).

[1971]

[1972] Preparation Example 237

[1973] N-(4-(3-chloro-4-hydroxyphenyl)-5-ethylthiazole-2-yl)indolin-6-carboxamide

[1974] N-(4-(3-Chloro-4-hydroxyphenyl)-5-ethylthiazol-2-yl)indoline-6-carboxamide (69a)

[1975]

[1976] 1-acetyl-N-(4-(3-chloro-4-(methoxymethoxy)phenyl)-5-ethylthiazole-2-yl)indoline-6-carboxamide (35.4 mg, 0.07 mmol) was dissolved in anhydrous methyl alcohol / tetrahydrofuran (2:1, 1.5 mL). To this solution, 4 molar concentration of dioxane hydrochloric acid (27.0 mg, 0.73 mmol) was added dropwise, and the mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction was terminated with sodium bicarbonate, and the solution was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified using silica gel column chromatography (ethyl acetate:hexane, 1:2), and the compound (15.0 mg, 50.6%) was obtained as a white solid.

[1977] 1 H NMR (500 MHz, DMSO-d6) δ 11.95 (s, 1H), 10.32 (s, 1H), 7.76 (d,J= 10.1 Hz, 2H), 7.57 (s, 1H), 7.37 (d,J= 8.0 Hz, 1H), 7.02 (d,J= 8.2 Hz, 1H), 6.46 (d,J= 6.8 Hz, 1H), 6.34 (s, 1H), 3.52 (t,J= 8.0 Hz, 2H), 2.96 (t,J= 7.9 Hz, 2H), 2.85 (m, 2H), 1.24 (t,J= 6.2 Hz, 3H).

[1978]

[1979] Preparation Example 238

[1980] N-(4-(3-chloro-4-hydroxyphenyl)-5-ethylthiazole-2-yl)-1-(methylsulfonyl)indoline-6-carboxamide

[1981] N-(4-(3-Chloro-4-hydroxyphenyl)-5-ethylthiazol-2-yl)-1-(methylsulfonyl)indoline-6-carboxamide (69b)

[1982]

[1983] The above compound (16.5 mg, 20.1%) was obtained as a white solid from compound 68b.

[1984] 1 H NMR (500 MHz, DMSO-d6) δ 12.64 (s, 1H), 10.37 (s, 1H), 7.82 (s, 1H), 7.71 (d,J= 7.7 Hz, 1H), 7.57 (d,J= 1.8 Hz, 1H), 7.39 (t,J= 7.3 Hz, 2H), 7.03 (d,J= 8.4 Hz, 1H), 3.98 (t,J= 8.5 Hz, 2H), 3.17 (t,J= 8.3 Hz, 2H), 3.11 (s, 3H), 2.87 (m, 2H), 1.25 (t,J= 7.4 Hz, 3H).

[1985]

[1986] Preparation Example 239

[1987] Methyl indoline-5-carboxylate

[1988] Methyl indoline-5-carboxylate

[1989]

[1990] The above compound (1.27 g, 62.8%) was obtained from methyl indole-5-carboxylate as a bright yellow solid.

[1991] 1 H NMR (500 MHz, DMSO-d6) δ 7.14 (d,J= 7.5, 1.4 Hz, 1H), 7.10 (d,J= 7.5 Hz, 1H), 6.99 (s,J= 1.0 Hz, 1H), 5.74 (s, 1H), 3.76 (s, 3H), 3.44 (t,J= 8.6, 1.6 Hz, 2H), 2.94 (t,J= 8.5 Hz, 2H).

[1992]

[1993] Preparation Example 240

[1994] 1-(methylsulfonyl)indoline-5-carboxylic acid

[1995] 1-(Methylsulfonyl)indoline-5-carboxylic acid

[1996]

[1997] Compound 72, obtained from methyl indoline-5-carboxylate by proceeding with a method similar to Preparation Example 231, was obtained as a white solid (919.2 mg, 99.9%) by using Preparation Example 234 similarly without separate separation.

[1998] 1 H NMR (500 MHz, DMSO-d6) δ 12.65 (s, 1H), 7.80 (d,J= 8.3 Hz, 2H), 7.29 (d,J= 8.3 Hz, 1H), 3.98 (t,J= 8.5 Hz, 2H), 3.14 (t,J= 8.5 Hz, 2H), 3.05 (s, 3H).

[1999]

[2000] Preparation Example 241

[2001] N-(4-(3-chloro-4-(methoxymethoxy)phenyl)-5-ethylthiazole-2-yl)-1-(methylsulfonyl)indoline-5-carboxamide

[2002] N-(4-(3-Chloro-4-(methoxymethoxy)phenyl)-5-ethylthiazol-2-yl)-1-(methylsulfonyl)indoline-5-carboxamide

[2003]

[2004] The above compound (268.3 mg, 38.1%) was obtained as a white solid from compound 73.

[2005] 1H NMR (500 MHz, CDCl3) δ 11.22 (s, 1H), 7.60 (s, 2H), 7.39 (s, 1H), 7.26 (s, 2H), 7.06 (d,J= 8.1 Hz, 1H), 5.22 (s, 2H), 4.04 (t,J= 8.0 Hz, 2H), 3.53 (s, 3H), 3.13 (t,J= 7.7 Hz, 2H), 2.91 (m, 2H), 1.36 (d,J= 6.9 Hz, 3H).

[2006]

[2007] Preparation Example 242

[2008] N-(4-(3-chloro-4-hydroxyphenyl)-5-ethylthiazole-2-yl)-1-(methylsulfonyl)indoline-5-carboxamide

[2009] N-(4-(3-Chloro-4-hydroxyphenyl)-5-ethylthiazol-2-yl)-1-(methylsulfonyl)indoline-5-carboxamide (75)

[2010]

[2011] The above compound (64.3 mg, 27.0%) was obtained as a white solid from compound 74.

[2012] 1 H NMR (500 MHz, DMSO-d6) δ 12.41 (s, 1H), 10.35 (s, 1H), 8.00 (s,J= 6.0 Hz, 2H), 7.57 (d,J= 1.9 Hz, 1H), 7.38 (d,J= 8.4, 1.9 Hz, 1H), 7.32 (d,J= 9.0 Hz, 1H), 7.03 (d,J= 8.4 Hz, 1H), 4.01 (t,J= 8.5 Hz, 2H), 3.17 (t,J= 8.4 Hz, 2H), 3.08 (s, 3H), 2.87 (q,J= 7.4 Hz, 2H), 1.25 (t,J= 7.5 Hz, 3H).

[2013]

[2014] Preparation Example 243

[2015] N-(4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-isopropylthiazole-2-yl)-4-methoxybenzamide

[2016] N-(4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)-5-isopropylthiazol-2-yl)-4-methoxybenzamide

[2017]

[2018] Compound 5d was used with 4-methoxybenzoyl chloride to obtain the above compound (236.2 mg, 88.1%) as a yellow foamy solid.

[2019] 1 H NMR (500 MHz, DMSO-d6) δ 12.38 (s, 1H), 10.36 (s, 1H), 8.08 (d,J= 8.7 Hz, 2H), 7.62 (s, 1H), 7.42 (d,J= 7.9 Hz, 1H), 7.09 (d,J= 8.5 Hz, 1H), 7.05 (d,J= 8.7 Hz, 2H), 3.83 (s, 3H), 3.36 (m, 1H), 1.30 (d,J= 6.5 Hz, 6H), 1.00 (s, 9H), 0.24 (s, 6H).

[2020]

[2021] Preparation Example 244

[2022] N-(4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-isopropylthiazole-2-yl)-4-fluorobenzamide

[2023] N-(4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)-5-isopropylthiazol-2-yl)-4-fluorobenzamide

[2024]

[2025] The above compound (139.2 mg, 86.2%) was obtained as a yellow liquid using 4-fluorobenzoyl chloride in compound 5d.

[2026] 1 H NMR (500 MHz, DMSO-d6) δ 12.61 (s, 1H), 8.18 - 8.13 (m, 2H), 7.61 (s, 1H), 7.42 (d,J= 8.4 Hz, 1H), 7.37 (t,J= 8.7 Hz, 2H), 7.10 (d,J= 8.2 Hz, 1H), 3.40 - 3.34 (m, 1H), 1.30 (d,J= 6.7 Hz, 6H), 0.99 (s, 9H), 0.24 (s, 6H).

[2027]

[2028] Preparation Example 245

[2029] N-(4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-isopropylthiazole-2-yl)-4-chlorobenzamide

[2030] N-(4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)-5-isopropylthiazol-2-yl)-4-chlorobenzamide

[2031]

[2032] The above compound (134.5 mg, 67.6%) was obtained as a yellow solid using 4-chlorobenzoyl chloride in compound 5d.

[2033] 1 H NMR (500 MHz, DMSO-d6) δ 12.67 (s, 1H), 8.08 (d,J= 8.5 Hz, 2H), 7.61 (s, 2H), 7.59 (s, 1H), 7.42 (d,J= 8.4, 1.7 Hz, 1H), 7.09 (d,J= 8.4 Hz, 1H), 3.36 (m, 1H), 1.30 (d,J= 6.7 Hz, 6H), 0.99 (s, 9H), 0.24 (s, 6H).

[2034]

[2035] Preparation Example 246

[2036] N-(4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-isopropylthiazole-2-yl)-4-bromobenzamide

[2037] N-(4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)-5-isopropylthiazol-2-yl)-4-bromobenzamide

[2038]

[2039] The above compound (188.8 mg, 82.5%) was obtained as a yellow liquid using 4-bromobenzoyl chloride in compound 5d.

[2040] 1 H NMR (500 MHz, DMSO-d6) δ 12.67 (s, 1H), 8.00 (d,J= 8.1 Hz, 2H), 7.74 (d,J= 8.1 Hz, 2H), 7.61 (s, 1H), 7.42 (d,J= 8.0 Hz, 1H), 7.09 (d,J= 8.1 Hz, 1H), 3.40 - 3.35 (m, 1H), 1.30 (d,J= 6.4 Hz, 6H), 0.99 (s, 9H), 0.24 (s, 6H).

[2041]

[2042] Preparation Example 247

[2043] N-(4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-isopropylthiazole-2-yl)-4-(trifluoromethoxy)benzamide

[2044] N-(4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)-5-isopropylthiazol-2-yl)-4-(trifluoromethoxy)benzamide

[2045]

[2046] The above compound (154.2 mg, 75.2%) was obtained as a yellow liquid using 4-(trifluoromethoxy)benzoyl chloride with compound 5d.

[2047] 1 H NMR (500 MHz, DMSO-d6) δ 12.71 (s, 1H), 8.20 (d,J= 8.4 Hz, 2H), 7.61 (s, 1H), 7.52 (d,J= 8.1 Hz, 2H), 7.42 (d,J= 8.2 Hz, 1H), 7.10 (d,J= 8.4 Hz, 1H), 3.36 (m, 1H), 1.30 (d,J= 6.5 Hz, 6H), 0.99 (s, 9H), 0.24 (s, 6H).

[2048]

[2049] Preparation Example 248

[2050] N-(4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-isopropylthiazole-2-yl)-4-(trifluoromethyl)benzamide

[2051] N-(4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)-5-isopropylthiazol-2-yl)-4-(trifluoromethyl)benzamide

[2052]

[2053] The above compound (251.7 mg, 99.9%) was obtained as a yellow liquid using 4-(trifluoromethyl)benzoyl chloride in compound 5d.

[2054] 1H NMR (500 MHz, DMSO-d6) δ 12.86 (s, 1H), 8.25 (d,J= 7.8 Hz, 2H), 7.91 (d,J= 7.8 Hz, 2H), 7.62 (s, 1H), 7.42 (d,J= 8.6 Hz, 1H), 7.10 (d,J= 8.2 Hz, 1H), 3.38 (m, 1H), 1.31 (d,J= 6.5 Hz, 6H), 1.00 (s, 9H), 0.25 (s, 6H).

[2055]

[2056] Preparation Example 249

[2057] N-(4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-isopropylthiazole-2-yl)-4-cyanobenzamide

[2058] N-(4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)-5-isopropylthiazol-2-yl)-4-cyanobenzamide

[2059]

[2060] Compound 5d was used with 4-cyanobenzoyl chloride to obtain the above compound (35.0 mg, 26.1%) as a yellow gel.

[2061] 1 H NMR (500 MHz, DMSO-d6) δ 12.86 (s, 1H), 8.20 (d,J= 7.8 Hz, 2H), 8.02 (d,J= 8.1 Hz, 2H), 7.61 (s, 1H), 7.41 (s, 1H), 7.10 (d,J= 8.2 Hz, 1H), 1.31 (d,J= 6.7 Hz, 6H), 1.00 (s, 9H), 0.25 (s, 6H).

[2062]

[2063] Preparation Example 250

[2064] N-(4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-isopropylthiazole-2-yl)-4-nitrobenzamide

[2065] N-(4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)-5-isopropylthiazol-2-yl)-4-nitrobenzamide

[2066]

[2067] 4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-isopropylthiazole-2-amine (110.3 mg, 0.29 mmol) and 4-nitrobenzoyl chloride (80.2 mg, 0.43 mmol) were dissolved in pyridine (2 mL). The reaction mixture was stirred at 0°C for 1 hour, followed by further stirring at room temperature for 18 hours. After the reaction was complete, a 2-normal hydrochloric acid solution was added to the mixture to terminate the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified using silica gel column chromatography (ethyl acetate:hexane, 1:10), and the compound (133.5 mg, 89.5%) was obtained as a yellow solid.

[2068] 1 H NMR (500 MHz, DMSO-d6) δ 12.95 (s, 1H), 8.35 (d,J= 8.6 Hz, 2H), 8.28 (d,J= 8.6 Hz, 2H), 7.61 (s, 1H), 7.42 (d,J= 8.4 Hz, 1H), 7.10 (d,J= 8.4 Hz, 1H), 3.41 - 3.34 (m, 1H), 1.31 (d,J= 6.6 Hz, 6H), 1.00 (s, 9H), 0.25 (s, 6H).

[2069]

[2070] Preparation Example 251

[2071] N-(4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-isopropylthiazole-2-yl)-4-(dimethylamino)benzamide

[2072] N-(4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)-5-isopropylthiazol-2-yl)-4-(dimethylamino)benzamide

[2073]

[2074] The above compound (121.9 mg, 59.0%) was obtained as a yellow liquid using 4-dimethylaminobenzoyl chloride in compound 5d.

[2075] 1 H NMR (500 MHz, DMSO-d6) δ 12.11 (s, 1H), 7.98 (d,J= 8.9 Hz, 2H), 7.61 (s, 1H), 7.41 (d,J= 6.4 Hz, 1H), 7.09 (d,J= 8.4 Hz, 1H), 6.73 (d,J= 9.0 Hz, 2H), 3.34 (m, 1H), 2.99 (s, 6H), 1.30 (d,J= 6.7 Hz, 6H), 1.00 (s, 9H), 0.24 (s, 6H).

[2076]

[2077] Preparation Example 252

[2078] N-(4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-isopropylthiazole-2-yl)-3-methoxybenzamide

[2079] N-(4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)-5-isopropylthiazol-2-yl)-3-methoxybenzamide

[2080]

[2081] The above compound (152.1 mg, 79.1%) was obtained as a yellow solid using 3-methoxybenzoyl chloride with compound 5d.

[2082] 1H NMR (500 MHz, DMSO-d6) δ 12.59 (s, 1H), 7.66 (d,J= 6.9 Hz, 2H), 7.62 (d,J= 1.7 Hz, 1H), 7.43 (t,J= 8.1 Hz, 2H), 7.17 (d,J= 7.5 Hz, 1H), 7.09 (d,J= 8.4 Hz, 1H), 3.83 (s, 3H), 3.37 (m, 1H), 1.30 (d,J= 6.7 Hz, 6H), 0.99 (s, 9H), 0.24 (s, 6H).

[2083]

[2084] Preparation Example 253

[2085] N-(4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-isopropylthiazole-2-yl)-3-chlorobenzamide

[2086] N-(4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)-5-isopropylthiazol-2-yl)-3-chlorobenzamide

[2087]

[2088] The above compound (277.9 mg, 71.3%) was obtained as a yellow solid using 3-chlorobenzoyl chloride in compound 5d.

[2089] 1 H NMR (500 MHz, DMSO-d6) δ 12.70 (s, 1H), 8.13 (s, 1H), 8.02 (d,J= 7.8 Hz, 1H), 7.69 (d,J= 7.8 Hz, 1H), 7.61 (d,J= 1.9 Hz, 1H), 7.56 (t,J= 7.9 Hz, 1H), 7.42 (dd,J= 8.4, 1.9 Hz, 1H), 7.10 (d,J= 8.4 Hz, 1H), 3.40 - 3.34 (m, 1H), 1.30 (d,J= 6.7 Hz, 6H), 0.98 (d,J= 11.4 Hz, 9H), 0.24 (s, 6H).

[2090]

[2091] Preparation Example 254

[2092] N-(4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-isopropylthiazole-2-yl)-3-(trifluoromethoxy)benzamide

[2093] N-(4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)-5-isopropylthiazol-2-yl)-3-(trifluoromethoxy)benzamide

[2094]

[2095] The above compound (257.8 mg, 87.0%) was obtained as a yellow liquid using 3-(trifluoromethoxy)benzoyl chloride with compound 5d.

[2096] 1 H NMR (500 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.47 (s, 1H), 8.35 (d,J= 7.4 Hz, 1H), 7.98 (d,J= 7.0 Hz, 1H), 7.77 (t,J= 7.1 Hz, 1H), 7.52 (s, 1H), 7.34 (d,J= 8.3 Hz, 1H), 7.04 (d,J= 8.3 Hz, 1H), 3.37 (m, 1H), 1.29 (d,J= 6.1 Hz, 6H), 0.81 (s, 9H), -0.07 (s, 6H).

[2097]

[2098] Preparation Example 255

[2099] N-(4-(3-chloro-4-hydroxyphenyl)-5-isopropylthiazole-2-yl)-4-methoxybenzamide

[2100] N-(4-(3-Chloro-4-hydroxyphenyl)-5-isopropylthiazol-2-yl)-4-methoxybenzamide (77a)

[2101]

[2102] The above compound (90.0 mg, 57.1%) was obtained as a white solid from compound 76a.

[2103] 1 H NMR (500 MHz, DMSO-d6) δ 12.38 (s, 1H), 10.36 (s, 1H), 8.08 (d,J= 8.8 Hz, 2H), 7.51 (s, 1H), 7.33 (d,J= 8.5 Hz, 1H), 7.05 (d,J= 9.1 Hz, 2H), 7.02 (s, 1H), 3.83 (s, 3H), 3.35 (m, 1H), 1.29 (d,J= 6.7 Hz, 6H).

[2104]

[2105] Preparation Example 256

[2106] N-(4-(3-chloro-4-hydroxyphenyl)-5-isopropylthiazole-2-yl)-4-fluorobenzamide

[2107] N-(4-(3-Chloro-4-hydroxyphenyl)-5-isopropylthiazol-2-yl)-4-fluorobenzamide (77b)

[2108]

[2109] The above compound (61.4 mg, 57.3%) was obtained as an orange solid from compound 76b.

[2110] 1 H NMR (500 MHz, DMSO-d6) δ 12.59 (s, 1H), 10.38 (s, 1H), 8.15 (dd,J= 8.1, 5.6 Hz, 2H), 7.51 (s, 1H), 7.35 (dd,J= 17.5, 8.6 Hz, 3H), 7.04 (d,J= 8.4 Hz, 1H), 3.36 (m, 1H), 1.29 (d,J= 6.7 Hz, 6H).

[2111]

[2112] Preparation Example 257

[2113] N-(4-(3-chloro-4-hydroxyphenyl)-5-isopropylthiazole-2-yl)-4-chlorobenzamide

[2114] N-(4-(3-Chloro-4-hydroxyphenyl)-5-isopropylthiazol-2-yl)-4-chlorobenzamide (77c)

[2115]

[2116] The above compound (73.2 mg, 73.0%) was obtained from compound 76c as a bright pink solid.

[2117] 1 H NMR (500 MHz, DMSO-d6) δ 12.65 (s, 1H), 10.38 (s, 1H), 8.14 - 8.02 (m, 2H), 7.65 - 7.55 (m, 2H), 7.51 (s, 1H), 7.33 (d,J= 8.3 Hz, 1H), 7.06 - 6.99 (m, 1H), 3.41 - 3.34 (m, 1H), 1.29 (d,J= 6.6 Hz, 6H).

[2118]

[2119] Preparation Example 258

[2120] N-(4-(3-chloro-4-hydroxyphenyl)-5-isopropylthiazole-2-yl)-4-bromobenzamide

[2121] N-(4-(3-Chloro-4-hydroxyphenyl)-5-isopropylthiazol-2-yl)-4-bromobenzamide (77d)

[2122]

[2123] The above compound (99.6 mg, 70.2%) was obtained as a white solid from compound 76d.

[2124] 1H NMR (500 MHz, DMSO-d6) δ 12.65 (s, 1H), 10.39 (s, 1H), 8.00 (d,J= 8.2 Hz, 2H), 7.74 (d,J= 8.1 Hz, 2H), 7.51 (s, 1H), 7.33 (d,J= 8.1 Hz, 1H), 7.04 (d,J= 8.3 Hz, 1H), 1.29 (d,J= 6.4 Hz, 6H).

[2125]

[2126] Preparation Example 259

[2127] N-(4-(3-chloro-4-hydroxyphenyl)-5-isopropylthiazole-2-yl)-4-(trifluoromethoxy)benzamide

[2128] N-(4-(3-Chloro-4-hydroxyphenyl)-5-isopropylthiazol-2-yl)-4-(trifluoromethoxy)benzamide (77e)

[2129]

[2130] The above compound (81.5 mg, 72.1%) was obtained as a white solid from compound 76e.

[2131] 1 H NMR (500 MHz, DMSO-d6) δ 12.70 (s, 1H), 10.38 (s, 1H), 8.20 (d,J= 8.8 Hz, 2H), 7.55 - 7.49 (m, 3H), 7.33 (d,J= 8.4, 2.0 Hz, 1H), 7.04 (d,J= 8.4 Hz, 1H), 3.36 (m, 1H), 1.29 (d,J= 6.7 Hz, 6H).

[2132]

[2133] Preparation Example 260

[2134] N-(4-(3-chloro-4-hydroxyphenyl)-5-isopropylthiazole-2-yl)-4-(trifluoromethyl)benzamide

[2135] N-(4-(3-Chloro-4-hydroxyphenyl)-5-isopropylthiazol-2-yl)-4-(trifluoromethyl)benzamide (77f)

[2136]

[2137] The above compound (200.6 mg, quantitative yield) was obtained as an orange solid from compound 76f.

[2138] 1 H NMR (500 MHz, DMSO-d6) δ 12.84 (s, 1H), 10.39 (s, 1H), 8.25 (d,J= 7.6 Hz, 2H), 7.90 (d,J= 7.6 Hz, 2H), 7.52 (s, 1H), 7.34 (d,J= 8.3 Hz, 1H), 7.05 (d,J= 8.3 Hz, 1H), 3.37 (m, 1H), 1.30 (d,J= 6.4 Hz, 6H).

[2139]

[2140] Preparation Example 261

[2141] N-(4-(3-chloro-4-hydroxyphenyl)-5-isopropylthiazole-2-yl)-4-cyanobenzamide

[2142] N-(4-(3-Chloro-4-hydroxyphenyl)-5-isopropylthiazol-2-yl)-4-cyanobenzamide (77g)

[2143]

[2144] The above compound (24.1 mg, quantitative yield) was obtained as a white solid from 76 g of the compound.

[2145] 1H NMR (500 MHz, DMSO-d6) δ 12.84 (s, 1H), 10.39 (s, 1H), 8.20 (d,J= 7.7 Hz, 2H), 8.01 (d,J= 7.8 Hz, 2H), 7.51 (s, 1H), 7.33 (d,J= 7.8 Hz, 1H), 7.04 (d,J= 7.9 Hz, 1H), 1.29 (d,J= 6.2 Hz, 6H).

[2146]

[2147] Preparation Example 262

[2148] N-(4-(3-chloro-4-hydroxyphenyl)-5-isopropylthiazole-2-yl)-4-nitrobenzamide

[2149] N-(4-(3-Chloro-4-hydroxyphenyl)-5-isopropylthiazol-2-yl)-4-nitrobenzamide (77h)

[2150]

[2151] Tetrabutylammonium fluoride (32.8 mg, 0.13 mmol) and N-(4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-isopropylthiazole-2-yl)-4-nitrobenzamide (133.5 mg, 0.25 mmol) were dissolved in tetrahydrofuran (2 mL). The mixture was stirred at 0°C for 1 hour, followed by further stirring at 30°C for 3 hours. After the reaction was complete, water was added to the resulting mixture, and the aqueous layer was extracted with dichloromethane. The organic layer was washed with saturated saline, dried with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified using silica gel column chromatography (ethyl acetate:hexane, 1:2), and the compound (89.4 mg, 85.0%) was obtained as a yellow solid.

[2152] 1H NMR (500 MHz, DMSO-d6) δ 12.94 (s, 1H), 10.39 (s, 1H), 8.35 (d,J= 8.7 Hz, 2H), 8.28 (d,J= 8.4 Hz, 2H), 7.52 (s, 1H), 7.34 (d,J= 8.1 Hz, 1H), 7.04 (d,J= 8.3 Hz, 1H), 3.36 (m, 1H), 1.30 (d,J= 6.5 Hz, 6H).

[2153]

[2154] Preparation Example 263

[2155] N-(4-(3-chloro-4-hydroxyphenyl)-5-isopropylthiazole-2-yl)-4-(dimethylamino)benzamide

[2156] N-(4-(3-Chloro-4-hydroxyphenyl)-5-isopropylthiazol-2-yl)-4-(dimethylamino)benzamide (77i)

[2157]

[2158] The above compound (74.9 mg, 78.3%) was obtained as an orange solid from compound 76i.

[2159] 1 H NMR (500 MHz, DMSO-d6) δ 12.10 (s, 1H), 10.34 (s, 1H), 7.98 (d,J= 8.5 Hz, 2H), 7.51 (s, 1H), 7.32 (d,J= 7.8 Hz, 1H), 7.03 (d,J= 8.3 Hz, 1H), 6.73 (d,J= 8.6 Hz, 2H), 3.33 (s, 1H), 2.99 (s, 6H), 1.28 (d,J= 6.7 Hz, 6H).

[2160]

[2161] Preparation Example 264

[2162] N-(4-(3-chloro-4-hydroxyphenyl)-5-isopropylthiazole-2-yl)-3-methoxybenzamide

[2163] N-(4-(3-Chloro-4-hydroxyphenyl)-5-isopropylthiazol-2-yl)-3-methoxybenzamide (77j)

[2164]

[2165] The above compound (90.0 mg, 83%) was obtained as a white solid from compound 76j.

[2166] 1 H NMR (500 MHz, DMSO-d6) δ 12.57 (s, 1H), 10.38 (s, 1H), 7.66 (s, 2H), 7.52 (s, 1H), 7.43 (t,J= 7.7 Hz, 1H), 7.34 (d,J= 8.3 Hz, 1H), 7.17 (d,J= 8.1 Hz, 1H), 7.04 (d,J= 8.0 Hz, 1H), 3.83 (s, 3H), 3.35 (m, 1H), 1.29 (d,J= 6.3 Hz, 6H).

[2167]

[2168] Preparation Example 265

[2169] N-(4-(3-chloro-4-hydroxyphenyl)-5-isopropylthiazole-2-yl)-3-chlorobenzamide

[2170] N-(4-(3-Chloro-4-hydroxyphenyl)-5-isopropylthiazol-2-yl)-3-chlorobenzamide (77k)

[2171]

[2172] The above compound (165.6 mg, 77.1%) was obtained as a white solid from compound 76k.

[2173] 1H NMR (500 MHz, DMSO-d6) δ 12.68 (s, 1H), 10.39 (s, 1H), 8.13 (s, 1H), 8.02 (d,J= 7.4 Hz, 1H), 7.68 (d,J= 7.8 Hz, 1H), 7.56 (t,J= 6.8 Hz, 1H), 7.52 (s, 1H), 7.33 (d,J= 8.3 Hz, 1H), 7.04 (d,J= 7.0 Hz, 1H), 3.35 (m, 1H), 1.29 (d,J= 5.0 Hz, 6H).

[2174]

[2175] Preparation Example 267

[2176] N-(4-(3-chloro-4-hydroxyphenyl)-5-isopropylthiazole-2-yl)-3-(trifluoromethoxy)benzamide

[2177] N-(4-(3-Chloro-4-hydroxyphenyl)-5-isopropylthiazol-2-yl)-3-(trifluoromethoxy)benzamide (77l)

[2178]

[2179] The above compound (210.0 mg, 76.3%) was obtained as an orange solid from 76 liters of compound.

[2180] 1 H NMR (500 MHz, DMSO-d6) δ 12.68 (s, 1H), 10.39 (s, 1H), 8.13 (s, 1H), 8.02 (d,J= 7.4 Hz, 1H), 7.68 (d,J= 7.8 Hz, 1H), 7.56 (t,J= 6.8 Hz, 1H), 7.52 (s, 1H), 7.33 (d,J= 8.3 Hz, 1H), 7.04 (d,J= 7.0 Hz, 1H), 3.35 (m, 1H), 1.29 (d,J= 5.0 Hz, 6H).

[2181]

[2182] Preparation Example 268

[2183] N-(5-(tert-butyl)-4-(3-chloro-4-((4-methoxybenzyl)oxy)phenyl)thiazole-2-yl)-4-methoxybenzamide

[2184] N-(5-(tert-Butyl)-4-(3-chloro-4-((4-methoxybenzyl)oxy)phenyl)thiazol-2-yl)-4-methoxybenzamide

[2185]

[2186] The above compound (115.0 mg, 71.4%) was obtained as a white solid using 4-methoxybenzoyl chloride in compound 38c.

[2187] 1 H NMR (500 MHz, DMSO-d6) δ 12.30 (s, 1H), 8.06 (d,J= 8.7 Hz, 2H), 7.41 (m, 2H), 7.30 (d,J= 8.5 Hz, 1H), 7.26 (d,J= 8.5 Hz, 1H), 7.04 (d,J= 8.7 Hz, 2H), 6.96 (d,J= 8.4 Hz, 2H), 5.13 (s, 2H), 3.82 (s, 3H), 3.75 (s, 3H), 1.24 (s, 9H).

[2188]

[2189] Preparation Example 269

[2190] N-(5-(tert-butyl)-4-(3-chloro-4-((4-methoxybenzyl)oxy)phenyl)thiazole-2-yl)-4-(dimethylamino)benzamide

[2191] N-(5-(tert-Butyl)-4-(3-chloro-4-((4-methoxybenzyl)oxy)phenyl)thiazol-2-yl)-4-(dimethylamino)benzamide

[2192]

[2193] The compound (67.3 mg, 37.9%) was obtained as a colorless foam using 4-(dimethylamino)benzoyl chloride in compound 38c.

[2194] 1 H NMR (500 MHz, DMSO-d6) δ 12.01 (s, 1H), 7.95 (d,J= 8.7 Hz, 2H), 7.41 (d,J= 8.2 Hz, 2H), 7.39 (s, 1H), 7.29 (d,J= 8.4 Hz, 1H), 7.25 (d,J= 8.5 Hz, 1H), 6.96 (d,J= 8.2 Hz, 2H), 6.72 (d,J= 8.8 Hz, 2H), 5.13 (s, 2H), 3.75 (s, 3H), 2.98 (s, 6H), 1.23 (s, 9H).

[2195]

[2196] Preparation Example 270

[2197] N-(4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-isobutylthiazole-2-yl)-4-methoxybenzamide

[2198] N-(4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)-5-isobutylthiazol-2-yl)-4-methoxybenzamide

[2199]

[2200] The above compound (256.0 mg, 100%) was obtained as a white solid using anisoyl chloride from compound 5e.

[2201] 1 H NMR (500 MHz, DMSO-d6) δ 12.41 (s, 1H), 8.08 (d,J= 8.7 Hz, 2H), 7.65 (s, 1H), 7.45 (d,J= 7.2 Hz, 1H), 7.09 (d,J= 8.4 Hz, 1H), 7.05 (d,J= 8.4 Hz, 2H), 3.83 (s, 3H), 2.73 (d,J= 6.0 Hz, 2H), 1.90 - 1.77 (m, 1H), 0.99 (s, 9H), 0.90 (d,J= 4.9 Hz, 6H), 0.25 (s, 6H).

[2202]

[2203] Preparation Example 271

[2204] N-(4-(3-chloro-4-((4-methoxybenzyl)oxy)phenyl)-5-isobutylthiazole-2-yl)-4-(dimethylamino)benzamide

[2205] N-(4-(3-Chloro-4-((4-methoxybenzyl)oxy)phenyl)-5-isobutylthiazol-2-yl)-4-(dimethylamino)benzamide

[2206]

[2207] The above compound (603.5 mg, 85.7%) was obtained as a yellow solid using 4-(dimethylamino)benzoyl chloride with compound 6f.

[2208] 1 H NMR (500 MHz, DMSO d6) δ 12.15 (s, 1H), 8.00 (d,J= 8.4 Hz, 2H), 7.68 (s, 1H), 7.52 (d,J= 8.4 Hz, 1H), 7.43 (d,J= 8.0 Hz, 2H), 7.33 (d,J= 8.5 Hz, 1H), 6.98 (d,J= 8.0 Hz, 2H), 6.75 (d,J= 8.5 Hz, 2H), 5.15 (s, 2H), 3.77 (s, 3H), 3.01 (s, 6H), 2.73 (d,J= 6.8 Hz, 2H), 1.86 (m, 1H), 0.91 (d,J= 6.3 Hz, 6H).

[2209]

[2210] Preparation Example 272

[2211] N-(4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)thiazole-2-yl)-4-methoxybenzamide

[2212] N-(4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)thiazol-2-yl)-4-methoxybenzamide (89b)

[2213]

[2214] The above compound (156.1 mg, 71.0%) was obtained as an orange solid using anisoyl chloride from compound 5f.

[2215] 1 H NMR (500 MHz, DMSO-d6) δ 12.57 (s, 1H), 8.13 (d,J= 7.9 Hz, 2H), 8.03 (s, 1H), 7.80 (d,J= 8.4 Hz, 1H), 7.65 (s, 1H), 7.09 (d,J= 8.2 Hz, 3H), 3.86 (s, 3H), 1.01 (s, 9H), 0.26 (s, 6H).

[2216]

[2217] Preparation Example 273

[2218] N-(4-(3-chloro-4-((4-methoxybenzyl)oxy)phenyl)thiazole-2-yl)-4-(dimethylamino)benzamide

[2219] N-(4-(3-Chloro-4-((4-methoxybenzyl)oxy)phenyl)thiazol-2-yl)-4-(dimethylamino)benzamide

[2220]

[2221] The above compound (156.1 mg, 71.0%) was obtained as a white solid using 4-(dimethylamino)benzoyl chloride from 6 g of the compound.

[2222] 1 H NMR (500 MHz, CDCl3) δ 7.88 (d,J= 7.5 Hz, 2H), 7.83 (s, 1H), 7.60 (d,J= 8.3 Hz, 1H), 7.39 (d,J= 7.2 Hz, 2H), 7.00 (s, 1H), 6.96 (d,J= 8.2 Hz, 1H), 6.92 (d,J= 7.0 Hz, 2H), 6.70 - 6.65 (m, 2H), 5.10 (s, 2H), 3.81 (s, 3H), 3.05 (s, 6H).

[2223]

[2224] Preparation Example 274

[2225] N-(5-(tert-butyl)-4-(3-chloro-4-hydroxyphenyl)thiazole-2-yl)-4-methoxybenzamide

[2226] N-(5-(tert-Butyl)-4-(3-chloro-4-hydroxyphenyl)thiazol-2-yl)-4-methoxybenzamide (79a)

[2227]

[2228] The above compound (48.1 mg, 77.1%) was obtained as a white solid from compound 78a.

[2229] 1 H NMR (500 MHz, DMSO-d6) δ 12.28 (s, 1H), 10.34 (s, 1H), 8.05 (d,J= 7.9 Hz, 2H), 7.28 (s, 1H), 7.13 (d,J= 8.2 Hz, 1H), 7.04 (d,J= 8.0 Hz, 2H), 6.97 (d,J= 8.1 Hz, 1H), 3.81 (s, 3H), 1.23 (s, 9H).

[2230]

[2231] Preparation Example 275

[2232] N-(5-(tert-butyl)-4-(3-chloro-4-hydroxyphenyl)thiazole-2-yl)-4-(dimethylamino)benzamide

[2233] N-(5-(tert-Butyl)-4-(3-chloro-4-hydroxyphenyl)thiazol-2-yl)-4-methoxybenzamide (79b)

[2234]

[2235] The above compound (18.3 mg, 56.7%) was obtained as a white solid from compound 78b.

[2236] 1H NMR (500 MHz, DMSO-d6) δ 12.00 (s, 1H), 10.32 (s, 1H), 7.95 (d,J= 8.9 Hz, 2H), 7.27 (s, 1H), 7.13 (d,J= 8.3 Hz, 1H), 6.97 (d,J= 8.3 Hz, 1H), 6.72 (d,J= 8.9 Hz, 2H), 2.98 (s, 6H), 1.22 (s, 9H).

[2237]

[2238] Preparation Example 276

[2239] N-(4-(3-chloro-4-hydroxyphenyl)-5-isobutylthiazole-2-yl)-4-methoxybenzamide

[2240] N-(4-(3-Chloro-4-hydroxyphenyl)-5-isobutylthiazol-2-yl)-4-methoxybenzamide (79c)

[2241]

[2242] From compound 78c, the above compound (122.1 mg, 62.2%) was obtained as a colorless, foamy solid.

[2243] 1 H NMR (500 MHz, DMSO-d6) δ 12.40 (s, 1H), 10.35 (s, 1H), 8.08 (d,J= 7.7 Hz, 2H), 7.55 (s, 1H), 7.36 (d,J= 8.2 Hz, 1H), 7.05 (d,J= 7.5 Hz, 2H), 7.02 (d,J= 8.7 Hz, 1H), 3.83 (s, 3H), 2.71 (d,J= 6.4 Hz, 2H), 1.84 (m, 1H), 0.90 (d,J= 5.9 Hz, 6H).

[2244]

[2245] Preparation Example 277

[2246] N-(4-(3-chloro-4-hydroxyphenyl)-5-isobutylthiazole-2-yl)-4-(dimethylamino)benzamide

[2247] N-(4-(3-Chloro-4-hydroxyphenyl)-5-isobutylthiazol-2-yl)-4-methoxybenzamide (79d)

[2248]

[2249] The above compound (165.9 mg, 35.1%) was obtained as a yellow solid from compound 78.

[2250] 1 H NMR (500 MHz, DMSO-d6) δ 12.13 (s, 1H), 10.35 (s, 1H), 8.00 (d,J= 8.8 Hz, 2H), 7.57 (s, 1H), 7.38 (d,J= 8.4 Hz, 1H), 7.04 (d,J= 8.4 Hz, 1H), 6.75 (d,J= 8.8 Hz, 2H), 3.01 (s, 6H), 2.71 (d,J= 7.0 Hz, 2H), 1.85 (m, 1H), 0.91 (d,J= 6.5 Hz, 6H).

[2251]

[2252] Preparation Example 278

[2253] N-(4-(3-chloro-4-hydroxyphenyl)thiazole-2-yl)-4-methoxybenzamide

[2254] N-(4-(3-Chloro-4-hydroxyphenyl)thiazol-2-yl)-4-methoxybenzamide (79e)

[2255]

[2256] The above compound (14.7 mg, 12.1%) was obtained from compound 78e as an orange-brown solid.

[2257] 1H NMR (500 MHz, DMSO-d6) δ 12.51 (s, 1H), 10.43 (s, 1H), 8.11 (d,J= 7.4 Hz, 2H), 7.92 (s, 1H), 7.70 (d,J= 7.9 Hz, 1H), 7.51 (s, 1H), 7.06 (d,J= 8.2 Hz, 2H), 7.00 (d,J= 8.2 Hz, 1H), 3.84 (s, 3H).

[2258]

[2259] Preparation Example 279

[2260] N-(4-(3-chloro-4-hydroxyphenyl)thiazole-2-yl)-4-(dimethylamino)benzamide

[2261] N-(4-(3-Chloro-4-hydroxyphenyl)thiazol-2-yl)-4-(dimethylamino)benzamide (79f)

[2262]

[2263] The above compound (44.0 mg, 45.3%) was obtained as a white solid from compound 78f.

[2264] 1 H NMR (500 MHz, DMSO-d6) δ 12.26 (s, 1H), 10.35 (s, 1H), 8.02 (d,J= 7.9 Hz, 2H), 7.94 (s, 1H), 7.71 (d,J= 8.0 Hz, 1H), 7.48 (s, 1H), 7.01 (d,J= 7.9 Hz, 1H), 6.76 (d,J= 8.0 Hz, 2H), 3.02 (s, 6H).

[2265]

[2266] Preparation Example 280

[2267] N-(4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-ethylthiazole-2-yl)-2-(4-methoxyphenyl)acetamide

[2268] N-(4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)-5-ethylthiazol-2-yl)-2-(4-methoxyphenyl)acetamide

[2269]

[2270] The above compound (218.8 mg, 56.3%) was obtained as a bright yellow solid using 4-methoxyphenylacetic acid from compound 5c.

[2271] 1 H NMR (500 MHz, DMSO-d6) δ 12.26 (s, 1H), 7.61 (s, 1H), 7.42 (d,J= 8.5 Hz, 1H), 7.23 (d,J= 8.3 Hz, 2H), 7.07 (d,J= 8.4 Hz, 1H), 6.87 (d,J= 8.3 Hz, 2H), 3.71 (s, 3H), 3.64 (s, 2H), 2.84 (q,J= 7.4 Hz, 2H), 1.21 (t,J= 7.4 Hz, 3H), 0.99 (s, 9H), 0.24 (s, 6H).

[2272]

[2273] Preparation Example 281

[2274] N-(4-(3-chloro-4-hydroxyphenyl-5-ethylthiazole-2-yl)-2-(4-methoxyphenyl)acetamide

[2275] N-(4-(3-Chloro-hydroxyphenyl)-5-ethylthiazol-2-yl)-2-(4-methoxyphenyl)acetamide (81)

[2276]

[2277] The above compound (55.8 mg, 50.0%) was obtained from compound 80 as a bright yellow solid.

[2278] 1H NMR (500 MHz, DMSO-d6) δ 12.25 (s, 1H), 10.35 (s, 1H), 7.51 (d,J= 2.0 Hz, 1H), 7.33 (d,J= 8.3, 1H), 7.22 (d,J= 8.5 Hz, 2H), 7.01 (d,J= 8.4 Hz, 1H), 6.87 (d,J= 8.6 Hz, 2H), 3.71 (s, 3H), 3.64 (s, 2H), 2.82 (q,J= 7.4 Hz, 2H), 1.20 (t,J= 7.4 Hz, 3H).

[2279]

[2280] Preparation Example 282

[2281] N-(4-(3-chloro-4-(methoxymethoxy)phenyl)-5-ethylthiazole-2-yl)-2-phenylacetamide

[2282] N-(4-(3-Chloro-4-(methoxymethoxy)phenyl)-5-ethylthiazol-2-yl)-2-phenylacetamide

[2283]

[2284] The above compound (60.8 mg, 24.9%) was obtained as a bright yellow liquid using phenacetyl chloride from compound 6c.

[2285] 1 H NMR (500 MHz, DMSO-d6) δ 12.34 (s, 1H), 7.62 (d,J= 2.0 Hz, 1H), 7.48 (dd,J= 8.5, 2.1 Hz, 1H), 7.30 (m, 5H), 7.25 (m, 1H), 5.31 (s, 2H), 3.73 (s, 2H), 3.41 (s, 3H), 2.85 (q,J= 7.3 Hz, 2H), 1.21 (t,J= 7.4 Hz, 3H).

[2286]

[2287] Preparation Example 283

[2288] N-(4-(3-chloro-4-(methoxymethoxy)phenyl)-5-ethylthiazole-2-yl)-2-(4-(dimethylamino)phenyl)acetamide

[2289] N-(4-(3-Chloro-4-(methoxymethoxy)phenyl)-5-ethylthiazol-2-yl)-2-(4-(dimethylamino)phenyl)acetamide

[2290]

[2291] The above compound (130.0 mg, 50.1%) was obtained as an orange solid using (4-dimethylamino)phenylacetic acid from compound 6c.

[2292] 1 H NMR (500 MHz, DMSO-d6) δ 12.22 (s, 1H), 7.62 (s, 1H), 7.48 (d,J= 8.7 Hz, 1H), 7.29 (d,J= 8.6 Hz, 1H), 7.12 (d,J= 8.6 Hz, 2H), 6.66 (d,J= 8.6 Hz, 2H), 5.31 (s, 2H), 3.57 (s, 2H), 3.41 (s, 3H), 2.85 (q,J= 4.4 Hz, 2H), 2.84 (s, 6H), 1.20 (t,J= 7.4 Hz, 3H).

[2293]

[2294] Preparation Example 284

[2295] N-(4-(3-chloro-4-(methoxymethoxy)phenyl)-5-ethylthiazole-2-yl)-2-(pyridine-4-yl)acetamide

[2296] N-(4-(3-Chloro-4-(methoxymethoxy)phenyl)-5-ethylthiazol-2-yl)-2-(pyridine-4-yl)acetamide

[2297]

[2298] To a solution in which 4-(3-chloro-4-(methoxymethoxy)phenyl)-5-ethylthiazole-2-amine (125.0 mg, 0.42 mmol) was dissolved in dichloromethane (10 mL), 2-(pyridine-4-yl)acetic acid (48.0 mg, 0.39 mmol), diisopropylethylamine (152 μL, 0.87 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (35.0 mg, 0.42 mmol), and 4-dimethylaminopyridine (5.13 mg, 0.042 mmol) were added, and the mixture was stirred at 35°C for 26 hours. The reaction mixture was extracted with ethyl acetate, washed with saturated saline, and dried with anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was purified by silica gel flash column chromatography to obtain the compound (40.0 mg, 27.4%) as a beige solid.

[2299] 1 H NMR (500 MHz, DMSO-d6) δ 12.41 (s, 1H), 8.50 (d,J= 5.8 Hz, 2H), 7.62 (s, 1H), 7.48 (d,J= 10.4 Hz, 1H), 7.32 (d,J= 5.7 Hz, 2H), 7.30 (d,J= 8.9 Hz, 1H), 5.31 (s, 2H), 3.80 (s, 2H), 3.41 (s, 3H), 2.85 (q,J= 7.6 Hz, 2H), 1.21 (t,J= 7.4 Hz, 3H).

[2300]

[2301] Preparation Example 285

[2302] N-(4-(3-chloro-4-(methoxymethoxy)phenyl)-5-ethylthiazole-2-yl)-2-(pyridine-3-yl)acetamide

[2303] N-(4-(3-Chloro-4-(methoxymethoxy)phenyl)-5-ethylthiazol-2-yl)-2-(pyridine-3-yl)acetamide

[2304]

[2305] The above compound (46.0 mg, 16.4%) was obtained as a yellow solid using 2-(pyridine-3-yl)acetic acid from compound 6c.

[2306] 1 H NMR (500 MHz, DMSO-d6) δ 12.40 (s, 1H), 8.50 (s, 1H), 8.46 (s, 1H), 7.72 (d,J= 5.8 Hz, 1H), 7.63 (s, 1H), 7.48 (d,J= 7.4 Hz, 1H), 7.35 (s, 1H), 7.30 (d,J= 8.5 Hz, 1H), 5.31 (s, 2H), 3.80 (s, 2H), 3.41 (s, 4H), 2.85 (q,J= 15.5, 8.8 Hz, 3H), 1.20 (t,J= 7.2 Hz, 3H).

[2307]

[2308] Preparation Example 286

[2309] N-(4-(3-chloro-4-(methoxymethoxy)phenyl)-5-ethylthiazole-2-yl)-2-(pyridine-2-yl)acetamide

[2310] N-(4-(3-Chloro-4-(methoxymethoxy)phenyl)-5-ethylthiazol-2-yl)-2-(pyridine-2-yl)acetamide

[2311]

[2312] The above compound (50.0 mg, 15.5%) was obtained as a yellow solid using 2-(pyridine-2-yl)acetic acid from compound 6c.

[2313] 1H NMR (500 MHz, DMSO-d6) δ 12.34 (s, 1H), 8.47 (s, 1H), 7.75 (t,J= 7.4 Hz, 1H), 7.63 (s, 1H), 7.49 (d,J= 7.0 Hz, 1H), 7.38 (d,J= 7.5 Hz, 1H), 7.29 (m, 2H), 5.31 (s, 2H), 3.94 (s, 2H), 3.42 (s, 3H), 2.86 (q,J= 13.8, 8.1 Hz, 2H), 1.21 (t,J= 6.9 Hz, 3H).

[2314]

[2315] Preparation Example 287

[2316] N-(4-(3-chloro-4-hydroxyphenyl)-5-ethylthiazole-2-yl)-2-phenylacetamide

[2317] N-(4-(3-Chloro-4-hydroxyphenyl)-5-ethylthiazol-2-yl)-2-phenylacetamide (83a)

[2318]

[2319] The above compound (32.0 mg, 58.7%) was obtained from compound 82a as an orange foamy solid.

[2320] 1 H NMR (500 MHz, DMSO-d6) δ 12.30 (s, 1H), 10.37 (s, 1H), 7.51 (s, 1H), 7.27 (m, 5H), 7.01 (d,J= 8.2 Hz, 1H), 3.72 (s, 2H), 2.82 (q,J= 7.5 Hz, 2H), 1.19 (s, 3H).

[2321]

[2322] Preparation Example 288

[2323] N-(4-(3-chloro-4-hydroxyphenyl)-5-ethylthiazole-2-yl)-2-(4-(dimethylamino)phenyl)acetamide

[2324] N-(4-(3-Chloro-4-hydroxyphenyl)-5-ethylthiazol-2-yl)-2-(4-(dimethylamino)phenyl)acetamide (83b)

[2325]

[2326] The above compound (75.0 mg, 63.8%) was obtained as a khaki solid from compound 82b.

[2327] 1 H NMR (500 MHz, DMSO-d6) δ 12.18 (s, 1H), 10.34 (s, 1H), 7.51 (s, 1H), 7.33 (d,J= 8.5 Hz, 1H), 7.12 (d,J= 8.7 Hz, 2H), 7.00 (d,J= 8.3 Hz, 1H), 6.66 (d,J= 8.5 Hz, 2H), 3.56 (s, 2H), 2.83 (s, 6H), 2.80 (q,J= 7.6 Hz, 2H), 1.20 (t,J= 7.5 Hz, 3H).

[2328]

[2329] Preparation Example 289

[2330] N-(4-(3-chloro-4-hydroxyphenyl)-5-ethylthiazole-2-yl)-2-(pyridine-4-yl)acetamide

[2331] N-(4-(3-Chloro-4-hydroxyphenyl)-5-ethylthiazol-2-yl)-2-(pyridin-4-yl)acetamide (83c)

[2332]

[2333] The above compound (75.0 mg, 63.8%) was obtained as a khaki solid from compound 82c.

[2334] 1H NMR (500 MHz, DMSO-d6) δ 12.38 (s, 1H), 10.35 (s, 1H), 8.50 (s, 2H), 7.51 (s, 1H), 7.33 (m, 3H), 7.01 (d,J= 8.0 Hz, 1H), 3.79 (s, 2H), 2.83 (q,J= 14.3, 7.3 Hz, 2H), 1.20 (t,J= 6.9 Hz, 3H).

[2335]

[2336] Preparation Example 290

[2337] N-(4-(3-chloro-4-hydroxyphenyl)-5-ethylthiazole-2-yl)-2-(pyridine-3-yl)acetamide

[2338] N-(4-(3-Chloro-4-hydroxyphenyl)-5-ethylthiazol-2-yl)-2-(pyridin-3-yl)acetamide (83d)

[2339]

[2340] The above compound (30.0 mg, 72.7%) was obtained as a yellow solid from compound 82d.

[2341] 1 H NMR (500 MHz, CDCl3) δ 8.41 (d,J= 13.4 Hz, 2H), 7.71 (d,J= 8.4 Hz, 1H), 7.39 (s, 1H), 7.26 (s, 2H), 7.17 (d,J= 8.5 Hz, 1H), 6.91 (d,J= 8.5 Hz, 1H), 3.69 (s, 2H), 2.75 (q,J= 7.2 Hz, 2H), 1.20 (t, 3H).

[2342]

[2343] Preparation Example 291

[2344] N-(4-(3-chloro-4-hydroxyphenyl)-5-ethylthiazole-2-yl)-2-(pyridine-2-yl)acetamide

[2345] N-(4-(3-Chloro-4-hydroxyphenyl)-5-ethylthiazol-2-yl)-2-(pyridin-2-yl)acetamide (83e)

[2346]

[2347] The above compound (19.0 mg, 42.5%) was obtained from compound 82c as a bright yellow solid.

[2348] 1 H NMR (500 MHz, DMSO-d6) δ 12.31 (s, 1H), 10.34 (s, 1H), 8.47 (s, 1H), 7.75 (t, 1H), 7.52 (s, 1H), 7.38 (d,J= 8.0 Hz, 1H), 7.35 (d,J= 8.7 Hz, 1H), 7.27 (s, 1H), 7.02 (d,J= 8.1 Hz, 1H), 3.94 (s, 2H), 2.83 (q,J= 7.5 Hz, 2H), 1.21 (t,J= 6.7 Hz, 3H).

[2349]

[2350] Preparation Example 292

[2351] N-(4-(3-chloro-4-(methoxymethoxy)phenyl)-5-ethylthiazole-2-yl)-3-(4-methoxyphenyl)propinamide

[2352] N-(4-(3-Chloro-4-(methoxymethoxy)phenyl)-5-ethylthiazol-2-yl)-3-(4-methoxyphenyl)propenamide

[2353]

[2354] The above compound (41.1 mg, 16.8%) was obtained as a transparent viscous liquid using 3-(4-methoxyphenyl)propanoic acid from compound 6c.

[2355] 1H NMR (500 MHz, DMSO-d6) δ 12.06 (s, 1H), 7.61 (s, 1H), 7.47 (d,J= 6.1 Hz, 1H), 7.29 (d,J= 8.9 Hz, 1H), 7.13 (d,J= 8.2 Hz, 2H), 6.83 (d,J= 8.7 Hz, 2H), 5.31 (s, 2H), 3.69 (s, 3H), 3.41 (s, 3H), 2.85 (m, 4H), 2.67 (t,J= 6.6 Hz, 2H), 1.23 (t,J= 7.5 Hz, 3H).

[2356]

[2357] Preparation Example 293

[2358] N-(4-(3-chloro-4-hydroxyphenyl)-5-ethylthiazole-2-yl)-3-(4-methoxyphenyl)propinamide

[2359] N-(4-(3-Chloro-4-hydroxyphenyl)-5-ethylthiazol-2-yl)-3-(4-methoxyphenyl)propenamide (83f)

[2360]

[2361] The above compound (26.2 mg, 63.9%) was obtained as an orange solid from compound 82f.

[2362] 1 H NMR (500 MHz, CDCl3) δ 9.57 (s, 1H), 7.50 (s, 1H), 7.32 (d,J= 7.2 Hz, 1H), 7.02 (t,J= 9.6 Hz, 3H), 6.81 (d,J= 8.2 Hz, 2H), 3.78 (s, 3H), 2.88 (m, 4H), 2.45 (t,J= 7.5 Hz, 2H), 1.32 (t,J= 7.4 Hz, 3H).

[2363]

[2364] Preparation Example 294

[2365] N-(4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-propylthiazole-2-yl)-4-methoxybenzenesulfonamide

[2366] N-(4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)-5-propylthiazol-2-yl)-4-methoxybenzenesulfonamide

[2367]

[2368] 4-methoxybenzenesulfonyl chloride (217.6 mg, 1.04 mmol) and triethylenediamine (102.7 mg, 0.85 mmol) were added to a solution in which 4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-propylthiazole-2-amine (260.0 mg, 0.70 mmol) was dissolved in acetonitrile (5 mL), and the mixture was stirred at room temperature for 28 hours. Completion of the reaction was confirmed by NMR. The reaction mixture was extracted with ethyl acetate, washed with saturated saline, and dried with anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was purified using silica gel flash column chromatography (ethyl acetate:hexane, 1:3), yielding the compound (152.6 mg, 39.4%) as a white solid.

[2369] 1 H NMR (500 MHz, DMSO-d6) δ 12.66 (s, 1H), 7.73 (d,J= 8.1 Hz, 2H), 7.49 (s, 1H), 7.26 (d,J= 8.8 Hz, 1H), 7.08 (d, 1H), 7.05 (d,J= 8.1 Hz, 2H), 3.79 (s, 3H), 2.53 (t, 2H), 1.51 (q,J= 6.8 Hz, 2H), 0.97 (s, 9H), 0.84 (t,J= 6.5 Hz, 3H), 0.23 (s, 6H).

[2370]

[2371] Preparation Example 295

[2372] N-(4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-ethylthiazole-2-yl)-4-methoxybenzenesulfonamide

[2373] N-(4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)-5-ethylthiazol-2-yl)-4-methoxybenzenesulfonamide

[2374]

[2375] The compound (37.0 mg, 25.4%) was obtained as a bright yellow solid using 4-methoxybenzenesulfonyl chloride from compound 5c in a manner similar to Preparation Example 188.

[2376] 1 H NMR (500 MHz, DMSO-d6) δ 12.67 (s, 1H), 7.74 (d, 2H), 7.52 (s, 1H), 7.28 (d, 1H), 7.08 (t, 3H), 3.81 (s, 3H), 2.60 (q, 2H), 1.14 (t, 3H), 1.00 (s, 9H), 0.25 (s, 6H).

[2377]

[2378] Preparation Example 296

[2379] N-(4-(3-chloro-4-hydroxyphenyl)-5-propylthiazole-2-yl)-4-methoxybenzenesulfonamide

[2380] N-(4-(3-Chloro-4-hydroxyphenyl)-5-propylthiazol-2-yl)-4-methoxybenzenesulfonamide (86a)

[2381]

[2382] The above compound (35.0 mg, 29.5%) was obtained as a white solid from compound 75a.

[2383] 1H NMR (500 MHz, DMSO-d6) δ 12.62 (s, 1H), 10.62 (s, 1H), 7.72 (d,J= 7.1 Hz, 2H), 7.37 (s, 1H), 7.17 (d,J= 8.3 Hz, 1H), 7.04 (d,J= 7.1 Hz, 2H), 7.00 (d,J= 9.1 Hz, 1H), 3.79 (s, 3H), 2.51 (t, 2H), 1.50 (m, 2H), 0.83 (t,J= 6.9 Hz, 3H).

[2384]

[2385] Preparation Example 297

[2386] N-(4-(3-chloro-4-hydroxyphenyl)-5-ethylthiazole-2-yl)-4-methoxybenzenesulfonamide

[2387] N-(4-(3-Chloro-4-hydroxyphenyl)-5-ethylthiazol-2-yl)-4-methoxybenzenesulfonamide (86b)

[2388]

[2389] The above compound (40.0 mg, 50.9%) was obtained from compound 75b as a bright yellow solid.

[2390] 1 H NMR (500 MHz, DMSO-d6) δ 12.62 (s, 1H), 10.60 (s, 1H), 7.73 (d,J= 7.8 Hz, 2H), 7.38 (s, 1H), 7.17 (s, 1H), 7.04 (d,J= 7.3 Hz, 2H), 7.00 (d,J= 7.9 Hz, 1H), 3.79 (s, 3H), 2.57 (q,J= 13.8, 7.7 Hz, 2H), 1.11 (t,J= 7.4 Hz, 3H).

[2391]

[2392] Preparation Example 298

[2393] 2-chloro-4-(2-((4-methoxybenzyl)amino)-5-propylthiazole-4-yl)phenol

[2394] 2-Chloro-4-(2-((4-methoxybenzyl)amino)-5-propylthiazol-4-yl)phenol (88a)

[2395]

[2396] 1-(4-methoxybenzyl)thiourea (100.0 mg, 0.51 mmol) was added to a solution in which 2-bromo-1-(3-chloro-4-hydroxyphenyl)pentan-1-one (74.3 mg, 0.25 mmol) was dissolved in ethanol (5 mL), and the reaction mixture was stirred at 85°C for 2.5 hours. After the reaction was complete, volatile components were removed under reduced pressure. Subsequently, the aqueous layer was extracted with ethyl acetate, dried with anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified using silica gel flash column chromatography (ethyl acetate:hexane, 1:2), and the compound (70.0 mg, 70.1%) was obtained as an orange solid.

[2397] 1 H NMR (500 MHz, DMSO-d6) δ 10.23 (s, 1H), 7.82 (s, 1H), 7.42 (s, 1H), 7.26 (d,J= 8.0 Hz, 2H), 6.96 (d,J= 8.3 Hz, 1H), 6.87 (d,J= 8.0 Hz, 2H), 4.31 (d,J= 5.1 Hz, 2H), 3.70 (s, 3H), 2.62 (t, 2H), 1.52 (m, 2H), 0.87 (t,J= 7.0 Hz, 3H).

[2398]

[2399] Preparation Example 299

[2400] 2-chloro-4-(2-((4-chlorobenzyl)amino)-5-propylthiazole-4-yl)phenol

[2401] 2-Chloro-4-(2-((4-chlorobenzyl)amino)-5-propylthiazol-4-yl)phenol (88b)

[2402]

[2403] The above compound (107.0 mg, 54.4%) was obtained as an orange gel using 1-(4-chlorobenzyl)thiourea.

[2404] 1 H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 7.94 (s, 1H), 7.36 (m, 4H), 7.25 (d,J= 7.8 Hz, 1H), 6.96 (d,J= 8.2 Hz, 1H), 4.39 (d,J= 4.1 Hz, 2H), 2.62 (m, 2H), 1.52 (m, 2H), 0.87 (t,J= 6.7 Hz, 3H).

[2405]

[2406] Preparation Example 300

[2407] Tert-butyl 4-((4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-isopropylthiazole-2-yl)carbamoyl)piperidine-1-carboxylate

[2408] tert-Butyl 4-((4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-isopropylthiazol-2-yl)carbamoyl)piperidine-1-carboxylate

[2409]

[2410] To a solution of 4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-isopropylthiazole-2-amine (200.0 mg, 0.52 mmol) dissolved in N,N-dimethylformamide (DMF, 5 mL), 1-(tert-butoxycarbonyl)-4-piperidinecarboxylic acid (80.0 mg, 0.35 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 1-oxide hexafluorophosphate (197.0 mg, 0.52 mmol), and diisopropylethylamine (90 μL, 0.52 mmol) were added at room temperature, and the reaction mixture was stirred at this temperature for 24 hours. After the reaction was complete, water was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate, then dried and concentrated with anhydrous magnesium sulfate. The residue was purified by silica gel flash column chromatography (ethyl acetate:hexane, 1:5), and the compound (124.8 mg, 60.0%) was obtained as a yellow solid.

[2411] 1 H NMR (500 MHz, DMSO-d6) δ 12.10 (s, 1H), 7.55 (s, 1H), 7.37 (d,J= 8.3 Hz, 1H), 7.08 (d,J= 8.4 Hz, 1H), 3.93 (s, 1H), 2.76 (s, 2H), 2.63 (t, 1H), 1.76 (d,J= 11.3 Hz, 2H), 1.45 (m,J= 11.5 Hz, 1H), 1.38 (s, 9H), 1.26 (d,J= 6.7 Hz, 6H), 0.99 (s, 9H), 0.24 (s, 6H).

[2412]

[2413] Preparation Example 301

[2414] N-(4-(3-chloro-4-hydroxyphenyl)-5-isopropylthiazole-2-yl)piperidine-4-carboxamide

[2415] N-(4-(3-Chloro-4-hydroxyphenyl)-5-isopropylthiazol-2-yl)piperidine-4-carboxamide (90)

[2416]

[2417] The above compound (12.1 mg, 15.0%) was obtained as a yellow solid from compound 89.

[2418] 1 H NMR (500 MHz, DMSO-d6) δ 7.45 (s, 1H), 7.28 (d,J= 8.5 Hz, 1H), 7.02 (d,J= 8.4 Hz, 1H), 3.12 (d,J= 12.5 Hz, 2H), 2.67 (m, 2H), 1.80 (d,J= 11.5 Hz, 2H), 1.62 (m,J= 11.5 Hz, 2H), 1.25 (d,J= 6.7 Hz, 6H).

[2419]

[2420] Preparation Example 302

[2421] 4-(dimethylamino)-N-(5-ethyl-4-(3-fluoro-4-((4-methoxybenzyl)oxy)phenyl)thiazole-2-yl)benzamide

[2422] 4-(Dimethylamino)-N-(5-ethyl-4-(3-fluoro-4-((4-methoxybenzyl)oxy)phenyl)thiazol-2-yl)benzamide

[2423]

[2424] The above compound was obtained as a beige solid (133.9 mg, 47.3%) from 5-ethyl-4-(3-fluoro-4-((4-methoxybenzyl)oxy)phenyl)thiazole-2-amine and 4-(dimethylamino)benzoyl chloride.

[2425] 1H NMR (500 MHz, CDCl3) δ 7.87 (d,J= 8.5 Hz, 2H), 7.39 (d,J= 8.1 Hz, 2H), 7.29 (t,J= 9.5 Hz, 1H), 7.22 (d,J= 8.3 Hz, 1H), 7.03 (t,J= 8.4 Hz, 1H), 6.93 (d,J= 8.1 Hz, 2H), 6.69 (d,J= 8.5 Hz, 2H), 5.10 (s, 2H), 3.82 (s, 3H), 3.06 (s, 6H), 2.90 (m, 2H), 1.34 (t,J= 7.4 Hz, 3H).

[2426]

[2427] Preparation Example 303

[2428] N-(4-(4-((tert-butyldimethylsilyl)oxy)phenyl)-5-ethylthiazole-2-yl)-4-methoxybenzamide

[2429] N-(4-(4-((tert-Butyldimethylsilyl)oxy)phenyl)-5-ethylthiazol-2-yl)-4-methoxybenzamide

[2430]

[2431] The above compound was obtained as a white solid (355.1 mg, 79.3%) from 4-(4-((tert-butyldimethylsilyl)oxy)phenyl)-5-ethylthiazole-2-amine and anisole chloride.

[2432] 1 H NMR (500 MHz, DMSO-d6) δ 8.06 (d,J= 8.9 Hz, 2H), 7.44 (d,J= 8.6 Hz, 2H), 7.02 (d,J= 8.9 Hz, 2H), 6.93 (d,J= 8.6 Hz, 2H), 3.89 (s, 3H), 2.93 (q,J= 7.5 Hz, 2H), 1.37 (t,J= 7.5 Hz, 3H), 1.00 (s, 9H), 0.23 (s, 6H).

[2433]

[2434] Preparation Example 304

[2435] N-(4-(4-((tert-butyldimethylsilyl)oxy)phenyl)-5-ethylthiazole-2-yl)-4-(dimethylamino)benzamide

[2436] N-(4-(4-((tert-Butyldimethylsilyl)oxy)phenyl)-5-ethylthiazol-2-yl)-4-(dimethylamino)benzamide

[2437]

[2438] The above compound was obtained as a bright yellow solid (93.1 mg, 55.2%) from 4-(4-((tert-butyldimethylsilyl)oxy)phenyl)-5-ethylthiazole-2-amine and 4-(dimethylamino)benzoyl chloride.

[2439] 1 H NMR (500 MHz, DMSO-d6) δ 12.10 (s, 1H), 7.98 (d,J= 8.6 Hz, 2H), 7.49 (d,J= 8.0 Hz, 2H), 6.91 (d,J= 8.1 Hz, 2H), 6.73 (d,J= 8.5 Hz, 2H), 2.99 (s, 6H), 2.85 (d,J= 7.2 Hz, 2H), 1.25 (t,J= 7.2 Hz, 3H), 0.95 (s, 9H), 0.20 (s, 6H).

[2440]

[2441] Preparation Example 305

[2442] N-(5-ethyl-4-(3-((4-methoxybenzyl)oxy)phenyl)thiazole-2-yl)-4-methoxybenzamide

[2443] N-(5-Ethyl-4-(3-((4-methoxybenzyl)oxy)phenyl)thiazol-2-yl)-4-methoxybenzamide

[2444]

[2445] The above compound (135.0 mg, 48.2%) was obtained as a white solid using anisoyl chloride from compound 17.

[2446] 1 H NMR (500 MHz, DMSO-d6) δ 12.41 (s, 1H), 8.10 (d,J= 8.8 Hz, 2H), 7.38 - 7.33 (m, 3H), 7.18 (m, 2H), 7.05 (d,J= 8.8 Hz, 2H), 6.98 (d,J= 7.9 Hz, 1H), 6.94 (d,J= 8.6 Hz, 2H), 5.05 (s, 2H), 3.83 (s, 3H), 3.74 (s, 3H), 2.85 (q,J= 7.4 Hz, 2H), 1.24 (t,J= 7.5 Hz, 3H).

[2447]

[2448] Preparation Example 306

[2449] 4-(dimethylamino)-N-(5-ethyl-4-(3-((4-methoxybenzyl)oxy)phenyl)thiazole-2-yl)benzamide

[2450] 4-(Dimethylamino)-N-(5-ethyl-4-(3-((4-methoxybenzyl)oxy)phenyl)thiazol-2-yl)benzamide

[2451]

[2452] The above compound (146.9 mg, 51.1%) was obtained as a white solid using 4-(dimethylamino)benzoyl chloride from compound 17.

[2453] 1 H NMR (500 MHz, DMSO-d6) δ 12.13 (s, 1H), 7.99 (d,J= 8.7 Hz, 2H), 7.37 (d,J= 8.3 Hz, 2H), 7.33 (t,J= 8.0 Hz, 1H), 7.18 (m, 2H), 6.97 (d,J= 8.1 Hz, 1H), 6.94 (d,J= 8.4 Hz, 2H), 6.73 (d,J= 8.8 Hz, 2H), 5.05 (s, 2H), 3.74 (s, 3H), 2.99 (s, 6H), 2.83 (q,J= 7.3 Hz, 2H), 1.23 (t,J= 7.4 Hz, 3H).

[2454]

[2455] Preparation Example 307

[2456] N-(5-ethyl-4-(2-((4-methoxybenzyl)oxy)phenyl)thiazole-2-yl)-4-methoxybenzamide

[2457] N-(5-Ethyl-4-(2-((4-methoxybenzyl)oxy)phenyl)thiazol-2-yl)-4-methoxybenzamide

[2458]

[2459] The compound (86.0 mg, 64.7%) was obtained as a colorless, foamy solid using anisoyl chloride from compound 22a.

[2460] 1 H NMR (500 MHz, CDCl3) δ 11.54 (s, 1H), 7.73 (d,J= 7.5 Hz, 2H), 7.17 - 7.10 (m, 4H), 6.83 (t,J= 7.3 Hz, 1H), 6.78 (t,J= 7.4 Hz, 5H), 4.85 (s, 2H), 3.78 (s, 3H), 3.71 (s, 3H), 2.65 (q,J= 6.5 Hz, 2H), 1.16 (t,J= 7.1 Hz, 3H).

[2461]

[2462] Preparation Example 308

[2463] 4-(dimethylamino)-N-(5-ethyl-4-(2-((4-methoxybenzyl)oxy)phenyl)thiazole-2-yl)benzamide

[2464] 4-(Dimethylamino)-N-(5-ethyl-4-(2-((4-methoxybenzyl)oxy)phenyl)thiazol-2-yl)benzamide

[2465]

[2466] The compound (134.0 mg, 71.9%) was obtained as a bright yellow foamy solid using 4-(dimethylamino)benzoyl chloride from compound 22a.

[2467] 1 H NMR (500 MHz, CDCl3) δ 7.92 (d,J= 8.4 Hz, 2H), 7.35 - 7.30 (m, 2H), 7.19 (d,J= 8.4 Hz, 2H), 7.03 (m, 2H), 6.81 (d,J= 8.5 Hz, 2H), 6.72 (d,J= 8.8 Hz, 2H), 4.98 (s, 2H), 3.75 (s, 3H), 3.07 (s, 6H), 2.66 (q,J= 7.4 Hz, 2H), 1.18 (t,J= 7.5 Hz, 3H).

[2468]

[2469] Preparation Example 309

[2470] N-(4-(4-chloro-2-((4-methoxybenzyl)oxy)phenyl)-5-ethylthiazole-2-yl)-4-methoxybenzamide

[2471] N-(4-(4-Chloro-2-((4-methoxybenzyl)oxy)phenyl)-5-ethylthiazol-2-yl)-4-methoxybenzamide

[2472]

[2473] The compound (150.0 mg, 77.5%) was obtained as a colorless, foamy solid using anisoyl chloride from compound 22b.

[2474] 1H NMR (500 MHz, CDCl3) δ 10.32 (s, 1H), 7.80 (d,J= 8.8 Hz, 2H), 7.19 - 7.14 (m, 3H), 6.92 - 6.89 (m, 4H), 6.81 (d,J= 8.6 Hz, 2H), 4.90 (s, 2H), 3.86 (s, 3H), 3.75 (s, 3H), 2.62 (q,J= 7.5 Hz, 2H), 1.15 (t,J= 7.5 Hz, 3H).

[2475]

[2476] Preparation Example 310

[2477] N-(4-(4-chloro-2-((4-methoxybenzyl)oxy)phenyl)-5-ethylthiazole-2-yl)-4-(dimethylamino)benzamide

[2478] N-(4-(4-Chloro-2-((4-methoxybenzyl)oxy)phenyl)-5-ethylthiazol-2-yl)-4-(dimethylamino)benzamide

[2479]

[2480] The compound (90.1 mg, 34.3%) was obtained as a bright yellow foamy solid using 4-(dimethylamino)benzoyl chloride from compound 22b.

[2481] 1 H NMR (500 MHz, CDCl3) δ 9.68 (s, 1H), 7.79 (d,J= 8.9 Hz, 2H), 7.24 (d,J= 8.4 Hz, 1H), 7.17 (d,J= 8.5 Hz, 2H), 6.98 (m, 2H), 6.82 (d,J= 8.4 Hz, 2H), 6.68 (d,J= 8.8 Hz, 2H), 4.95 (s, 2H), 3.76 (s, 3H), 3.05 (s, 6H), 2.62 (m, 2H), 1.16 (t,J= 7.5 Hz, 3H).

[2482]

[2483] Preparation Example 311

[2484] 4-(dimethylamino)-N-(5-ethyl-4-(4-hydroxyphenyl)thiazole-2-yl)benzamide

[2485] 4-(Dimethylamino)-N-(5-ethyl-4-(4-hydroxyphenyl)thiazol-2-yl)benzamide (92c)

[2486]

[2487] The above compound (21.4 mg, 30.7%) was obtained as an orange solid from N-(4-(4-((tert-butyldimethylsilyl)oxy)phenyl)-5-ethylthiazole-2-yl)-4-(dimethylamino)benzamide.

[2488] 1 H NMR (500 MHz, DMSO-d6) δ 12.10 (s, 1H), 9.55 (s, 1H), 8.00 (d,J= 8.4 Hz, 2H), 7.37 (d,J= 40.6 Hz, 2H), 6.83 (d,J= 7.9 Hz, 2H), 6.74 (d,J= 8.5 Hz, 2H), 2.95 (s,J= 50.1 Hz, 6H), 2.84 (q,J= 7.3 Hz, 2H), 1.28 - 1.11 (t, 3H).

[2489]

[2490] Preparation Example 312

[2491] N-(5-ethyl-4-(4-hydroxyphenyl)thiazole-2-yl)-4-methoxybenzamide

[2492] N-(5-Ethyl-4-(4-hydroxyphenyl)thiazol-2-yl)-4-methoxybenzamide (92b)

[2493]

[2494] The above compound (105.1 mg, 65.1%) was obtained as a white solid from compound 79e.

[2495] 1H NMR (500 MHz, DMSO-d6) δ 12.39 (s, 1H), 9.56 (s, 1H), 8.09 (d,J= 8.5 Hz, 2H), 7.41 (d,J= 8.2 Hz, 2H), 7.04 (d,J= 8.6 Hz, 2H), 6.82 (d,J= 8.2 Hz, 2H), 3.82 (s, 3H), 2.84 (q,J= 7.3 Hz, 2H), 1.25 (t,J= 7.4 Hz, 3H).

[2496]

[2497] Preparation Example 313

[2498] N-(5-ethyl-4-(3-((4-methoxybenzyl)oxy)phenyl)thiazole-2-yl)-4-methoxybenzamide

[2499] N-(5-Ethyl-4-(3-((4-methoxybenzyl)oxy)phenyl)thiazol-2-yl)-4-methoxybenzamide (92d)

[2500]

[2501] N-(5-ethyl-4-(3-((4-methoxybenzyl)oxy)phenyl)thiazole-2-yl)-4-methoxybenzamide (100 mg, 0.21 mmol) was dissolved in dichloromethane (3 mL) and cooled to 0°C, after which trifluoroacetic acid (0.3 mL) was slowly added. Subsequently, the reaction vessel was removed from the ice bath, and the reaction mixture was stirred at room temperature for 30 minutes. Then, toluene (3 mL) was added, and the mixture was concentrated. The residue was separated into a saturated sodium bicarbonate solution and ethyl acetate, extracted with ethyl acetate, dried with anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified using silica gel flash column chromatography (ethyl acetate:hexane, 1:2), and the compound (62.1 mg, 83.4%) was obtained as a white solid.

[2502] 1H NMR (500 MHz, CDCl3) δ 7.93 (d,J= 8.7 Hz, 2H), 7.32 (t,J= 8.0 Hz, 1H), 7.26 (s, 1H),7.10 (d,J= 7.7 Hz, 1H), 7.00 (d,J= 8.7 Hz, 2H), 6.89 (d,J= 8.2 Hz, 1H), 3.89 (s, 3H), 2.96 (q,J= 7.3 Hz, 2H), 1.35 (t,J= 7.5 Hz, 3H).

[2503]

[2504] Preparation Example 314

[2505] 4-(dimethylamino)-N-(5-ethyl-4-(3-hydroxyoxy)phenyl)thiazole-2-yl)benzamide

[2506] 4-(Dimethylamino)-N-(5-ethyl-4-(3-hydroxyphenyl)thiazol-2-yl)benzamide (92e)

[2507]

[2508] The compound (54.7 mg, 51.3%) was obtained as a white solid from compound 82b in a manner similar to that of Preparation Example 202.

[2509] 1 H NMR (500 MHz, CD3OD / CDCl3) δ 7.87 (d,J= 8.9 Hz, 2H), 7.23 (t,J= 7.7 Hz, 1H), 7.02 - 7.01 (m, 2H), 6.78 (dd,J= 7.6, 1.8 Hz, 1H), 6.74 (d,J= 9.0 Hz, 2H), 3.05 (s, 6H), 2.90 (q,J= 7.5 Hz, 2H), 1.31 (t,J= 7.5 Hz, 3H).

[2510]

[2511] Preparation Example 315

[2512] N-(4-(4-chloro-3-hydroxyphenyl)-5-ethylthiazole-2-yl)-4-(dimethylamino)benzamide

[2513] N-(4-(4-Chloro-3-hydroxyphenyl)-5-ethylthiazol-2-yl)-4-(dimethylamino)benzamide (92f)

[2514]

[2515] 4-(4-chloro-3-((4-methoxybenzyl)oxy)phenyl)-5-ethylthiazole-2-amine (150.0 mg, 0.40 mmol) and DMAP (25.0 mg, 0.2 mmol) were dissolved in pyridine (5 mL) and stirred at room temperature for 5 minutes. 4-(dimethylamino)benzoyl chloride (99.2 mg, 0.60 mmol) was added, and the reaction mixture was stirred overnight at 70°C. After the reaction was complete, toluene (5 mL) was added, and the mixture was concentrated. The residue was distributed between water and EtOAc, extracted with EtOAc, dried with anhydrous magnesium sulfate, and vacuum concentrated. The residue was purified by flash column chromatography (ethyl acetate:hexane, 1:4) to obtain the compound (65.0 mg, 31.1% / residue) as a white solid. The residue was not further purified and proceeded to the next step. Trifluoroacetic acid (0.15 mL) was slowly added to a solution in which the residue (55 mg, 0.106 mmol, 100 mol%, 0.07 M) was dissolved in dichloromethane (1.5 mL) cooled to 0°C. Subsequently, the reaction vessel was removed from the ice bath, and the reaction mixture was stirred at room temperature for 0.5 hours, after which toluene (5 mL) was added and the mixture was concentrated. The residue was distributed between distilled water and ethyl acetate, extracted with ethyl acetate, dried with anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (ethyl acetate:hexane, 1:2) to obtain the compound (14.3 mg, 33.6%) as a white solid.

[2516] 1H NMR (500 MHz, DMSO-d6) δ 12.18 (s, 1H), 10.29 (s, 1H), 7.99 (d,J= 8.7 Hz, 2H), 7.37 (d,J= 8.2 Hz, 1H), 7.22 (s, 1H), 7.04 (d,J= 8.2 Hz, 1H), 6.73 (d,J= 8.8 Hz, 2H), 3.00 (s, 6H), 2.86 (q,J= 7.5 Hz, 2H), 1.26 (t,J= 7.4 Hz, 3H).

[2517]

[2518] Preparation Example 316

[2519] N-(5-ethyl-4-(2-hydroxyphenyl)thiazole-2-yl)-4-methoxybenzamide

[2520] N-(5-Ethyl-4-(2-hydroxyphenyl)thiazol-2-yl)-4-methoxybenzamide (92g)

[2521]

[2522] The above compound (10.0 mg, 15.7%) was obtained as a white solid from compound 83a.

[2523] 1 H NMR (500 MHz, DMSO-d6) δ 12.39 (s, 1H), 10.01 (s, 1H), 8.08 (d,J= 8.8 Hz, 2H), 7.31 (d,J= 7.6 Hz, 1H), 7.19 (t,J= 7.3 Hz, 1H), 7.07 (d,J= 8.7 Hz, 2H), 6.91 (d,J= 8.2 Hz, 1H), 6.85 (t,J= 7.3 Hz, 1H), 3.83 (s, 3H), 2.76 (q,J= 7.0 Hz, 2H), 1.21 (t,J= 7.4 Hz, 3H).

[2524]

[2525] Preparation Example 317

[2526] 4-(dimethylamino)-N-(5-ethyl-4-(2-hydroxyphenyl)thiazole-2-yl)benzamide

[2527] 4-(Dimethylamino)-N-(5-ethyl-4-(2-hydroxyphenyl)thiazol-2-yl)benzamide (92h)

[2528]

[2529] The above compound (21.0 mg, 26.5%) was obtained from compound 83b as a bright yellow solid.

[2530] 1 H NMR (500 MHz, DMSO-d6) δ 12.12 (s, 1H), 10.13 (s, 1H), 7.98 (d,J= 8.6 Hz, 2H), 7.33 (d,J= 7.5 Hz, 1H), 7.18 (t,J= 7.7 Hz, 1H), 6.91 (d,J= 8.1 Hz, 1H), 6.85 (t,J= 7.4 Hz, 1H), 6.75 (d,J= 8.7 Hz, 2H), 3.00 (s, 6H), 2.77 (q,J= 7.4 Hz, 2H), 1.21 (t,J= 7.4 Hz, 3H).

[2531]

[2532] Preparation Example 318

[2533] N-(4-(4-chloro-2-hydroxyphenyl)-5-ethylthiazole-2-yl)-4-methoxybenzamide

[2534] N-(4-(4-Chloro-2-hydroxyphenyl)-5-ethylthiazol-2-yl)-4-methoxybenzamide (92i)

[2535]

[2536] The above compound (104.4 mg, 91.0%) was obtained as a white solid from compound 83c.

[2537] 1H NMR (500 MHz, CD3OD) δ 8.01 (d,J= 8.8 Hz, 2H), 7.39 (d,J= 8.3 Hz, 1H), 7.06 (d,J= 8.8 Hz, 2H), 6.93 (d,J= 1.8 Hz, 1H), 6.90 (dd,J= 8.3, 1.8 Hz, 1H), 3.88 (s, 3H), 2.93 (q,J= 7.5 Hz, 2H), 1.34 (t,J= 7.5 Hz, 3H).

[2538]

[2539] Preparation Example 319

[2540] N-(4-(4-chloro-2-hydroxyphenyl)-5-ethylthiazole-2-yl)-4-(dimethylamino)benzamide

[2541] N-(4-(4-Chloro-2-hydroxyphenyl)-5-ethylthiazol-2-yl)-4-(dimethylamino)benzamide (84d) (92j)

[2542]

[2543] The above compound (53.2 mg, 81.7%) was obtained from compound 83d as a bright yellow solid.

[2544] 1 H NMR (500 MHz, CDCl3) δ 10.68 (s, 1H), 9.11 (s, 1H), 7.84 (d,J= 8.7 Hz, 2H), 7.36 (d,J= 7.9 Hz, 1H), 7.04 (s, 1H), 6.90 (d,J= 8.3 Hz, 1H), 6.73 (d,J= 8.8 Hz, 2H), 3.09 (s, 6H), 3.02 (q,J= 7.5 Hz, 2H), 1.41 (t,J= 7.5 Hz, 3H).

[2545]

[2546] Preparation Example 320

[2547] 4-methoxy-N-(4-(4-(methoxymethoxy)-3-(trifluoromethyl)phenyl)-5-propylthiazole-2-yl)benzamide

[2548] 4-Methoxy-N-(4-(4-(methoxymethoxy)-3-(trifluoromethyl)phenyl)-5-propylthiazol-2-yl)benzamide

[2549]

[2550] The above compound (27.9 mg, 44.7%) was obtained as a white solid using anisoyl chloride from compound 30a.

[2551] 1 H NMR (500 MHz, CDCl3) δ 11.29 (s, 11H), 7.70 (d,J= 8.6 Hz, 2H), 7.60 (s, 1H), 7.52 (d,J= 8.2 Hz, 1H), 7.10 (d,J= 8.4 Hz, 1H), 6.77 (d,J= 8.5 Hz, 2H), 5.23 (s, 2H), 3.82 (s, 3H), 3.50 (s, 3H), 2.83 (m, 2H), 1.76 (m, 2H), 1.01 (m, 3H).

[2552]

[2553] Preparation Example 321

[2554] 4-(dimethylamino)-N-(4-(4-((4-methoxybenzyl)oxy)-3-(trifluoromethyl)phenyl)-5-propylthiazole-2-yl)benzamide

[2555] 4-(Dimethylamino)-N-(4-(4-((4-methoxybenzyl)oxy)-3-(trifluoromethyl)phenyl)-5-propylthiazol-2-yl)benzamide

[2556]

[2557] The above compound (140.5 mg, 52.5%) was obtained as a white solid using 4-(dimethylamino)benzoyl chloride from compound 30b.

[2558] 1H NMR (500 MHz, DMSO-d6) δ 12.14 (s, 1H), 7.99 (d,J= 9.0 Hz, 2H), 7.87 (s, 1H), 7.82 (d,J= 9.0 Hz, 1H), 7.43 (d,J= 8.9 Hz, 1H), 7.39 (d,J= 8.5 Hz, 2H), 6.96 (d,J= 8.6 Hz, 2H), 6.73 (d,J= 9.0 Hz, 2H), 5.21 (s, 2H), 3.75 (s, 3H), 3.00 (s, 6H), 2.83 (t,J= 7.5 Hz, 2H), 1.66 (m, 2H), 0.94 (t,J= 7.3 Hz, 3H).

[2559]

[2560] Preparation Example 322

[2561] N-(4-(4-hydroxy-3-(trifluoromethyl)phenyl)-5-propylthiazole-2-yl)-4-methoxybenzamide

[2562] N-(4-(4-Hydroxy-3-(trifluoromethyl)phenyl)-5-propylthiazol-2-yl)-4-methoxybenzamide (94a)

[2563]

[2564] 4-methoxy-N-(4-(4-(methoxymethoxy)-3-(trifluoromethyl)phenyl)-5-propylthiazole-2-yl)benzamide (27.9 mg, 0.06 mmol) was dissolved in anhydrous methyl alcohol (0.5 mL) and tetrahydrofuran (1 mL). Subsequently, a 4 molar hydrogen chloride / dioxane solution (145.2 μL, 0.58 mmol) was added, and the mixture was stirred at room temperature for 40 hours. After the reaction was complete, volatile substances were removed. The concentrate was redissolved in ethyl acetate, washed with saturated saline, dried with anhydrous magnesium sulfate, and concentrated. The residue was purified using silica gel flash column chromatography (ethyl acetate:hexane, 1:4), and the compound (10.3 mg, 40.7%) was obtained as a white solid.

[2565] 1 H NMR (500 MHz, CD3OD) δ 7.99 (d,J= 8.8 Hz, 2H), 7.76 (s, 1H), 7.64 (d,J= 8.5 Hz, 1H), 7.06 (d,J= 8.8 Hz, 2H), 7.00 (d,J= 8.5 Hz, 1H), 3.88 (s, 2H), 2.86 (t,J= 7.6 Hz, 2H), 1.74 (m, 2H), 1.00 (t,J= 7.3 Hz, 3H).

[2566]

[2567] Preparation Example 323

[2568] 4-(dimethylamino)-N-(4-(4-hydroxy-3-(trifluoromethyl)phenyl)-5-propylthiazole-2-yl)benzamide

[2569] 4-(Dimethylamino)-N-(4-(4-hydroxy-3-(trifluoromethyl)phenyl)-5-propylthiazol-2-yl)benzamide (94b)

[2570]

[2571] The above compound (28.5 mg, 28.7%) was obtained as a white solid from compound 85b.

[2572] 1 H NMR (500 MHz, DMSO-d6) δ 12.12 (s, 1H), 10.73 (s, 1H), 7.98 (d,J= 8.9 Hz, 2H), 7.75 (s, 1H), 7.67 (d,J= 8.4 Hz, 1H), 7.09 (d,J= 8.5 Hz, 1H), 6.73 (d,J= 9.0 Hz, 2H), 3.00 (s, 6H), 2.80 (t,J= 7.6 Hz, 2H), 1.65 (m, 2H), 0.93 (t,J= 7.3 Hz, 3H).

[2573]

[2574] Preparation Example 324

[2575] 4-(dimethylamino)-N-(4-(4-fluorophenyl)-5-propylthiazole-2-yl)benzamide

[2576] 4-(Dimethylamino)-N-(4-(4-fluorophenyl)-5-propylthiazol-2-yl)benzamide (95a)

[2577]

[2578] A compound (53.9 mg, 22.3%) was obtained as a bright yellow solid from 4-(4-fluorophenyl)-5-propylthiazole-2-amine and 4-(dimethylamino)benzoyl chloride.

[2579] 1 H NMR (500 MHz, DMSO-d6) δ 12.19 (s, 1H), 8.00 (d,J= 8.8 Hz, 2H), 7.64 (m, 2H), 7.29 (t,J= 8.8 Hz, 2H), 6.75 (d,J= 8.8 Hz, 2H), 3.01 (s, 6H), 2.82 (t,J= 7.6 Hz, 2H), 1.65 (m, 2H), 0.94 (t,J= 7.3 Hz, 3H).

[2580]

[2581] Preparation Example 325

[2582] N-(4-(3-chloro-4-fluorophenyl)-5-propylthiazole-2-yl)-4-(dimethylamino)benzamide

[2583] N-(4-(3-Chloro-4-fluorophenyl)-5-propylthiazol-2-yl)-4-(dimethylamino)benzamide (95b)

[2584]

[2585] A compound (222.1 mg, 96.2%) was obtained as a light beige solid from 4-(3-chloro-4-fluorophenyl)-5-propylthiazole-2-amine and 4-(dimethylamino)benzoyl chloride.

[2586] 1H NMR (500 MHz, DMSO-d6) δ 12.19 (s, 1H), 8.00 (d,J= 8.6 Hz, 2H), 7.80 (d,J= 7.0 Hz, 1H), 7.61 (m, 1H), 7.50 (m, 1H), 6.75 (d,J= 8.6 Hz, 2H), 3.01 (s, 6H), 2.84 (t,J= 7.4 Hz, 2H), 1.66 (m, 2H), 0.94 (t,J= 7.2 Hz, 3H).

[2587]

[2588] Preparation Example 326

[2589] 4-methoxy-N-(5-propyl-4-(p-tolyl)thiazole-2-yl)benzamide

[2590] 4-Methoxy-N-(5-propyl-4-(p-tolyl)thiazol-2-yl)benzamide (95c)

[2591]

[2592] A compound (792.0 mg, quantitative yield) was obtained as a beige solid from 5-propyl-4-(p-tolyl)thiazole-2-amine and anisole chloride.

[2593] 1 H NMR (500 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.10 (d,J= 15.8 Hz, 2H), 7.48 (d,J= 15.8 Hz, 2H), 7.26 (d,J= 6.2 Hz, 2H), 7.07 (d,J= 6.7 Hz, 2H), 3.85 (s, 3H), 2.84 (t,J= 6.2 Hz, 2H), 2.34 (s, 3H), 1.66 (m, 2H), 0.94 (t,J= 7.0, 4.8 Hz, 3H).

[2594]

[2595] Preparation Example 327

[2596] 4-(dimethylamino)-N-(5-propyl-4-(p-tolyl)thiazole-2-yl)benzamide

[2597] 4-(Dimethylamino)-N-(5-propyl-4-(p-tolyl)thiazol-2-yl)benzamide (95d)

[2598]

[2599] A pale yellow solid (570.8 mg, quantitative yield) was obtained from 5-propyl-4-(p-tolyl)thiazole-2-amine and 4-(dimethylamino)benzoyl chloride.

[2600] 1 H NMR (500 MHz, DMSO-d6) δ 12.16 (s, 1H), 8.01 (d,J= 8.8 Hz, 2H), 7.50 (d,J= 7.8 Hz, 2H), 7.26 (d,J= 7.8 Hz, 2H), 6.75 (d,J= 8.8 Hz, 2H), 3.01 (s, 6H), 2.82 (t,J= 7.6 Hz, 2H), 2.34 (s, 3H), 1.65 (m, 2H), 0.93 (t,J= 7.3 Hz, 3H).

[2601]

[2602] Preparation Example 328

[2603] 4-(dimethylamino)-N-(4-(3-fluoro-4-methylphenyl)-5-propylthiazole-2-yl)benzamide

[2604] 4-(Dimethylamino)-N-(4-(3-fluoro-4-methylphenyl)-5-propylthiazol-2-yl)benzamide (95e)

[2605]

[2606] A yellow solid (160.1 mg, 67.1%) was obtained from 4-(3-fluoro-4-methylphenyl)-5-propylthiazole-2-amine.

[2607] 1H NMR (500 MHz, DMSO-d6) δ 12.18 (s, 1H), 8.01 (d,J= 8.6 Hz, 2H), 7.35 (s, 2H), 7.34 (s, 1H), 6.75 (d,J= 8.6 Hz, 2H), 3.01 (s, 6H), 2.84 (t,J= 7.5 Hz, 2H), 2.27 (s, 3H), 1.65 (m, 2H), 0.94 (t,J= 7.2 Hz, 3H).

[2608]

[2609] Preparation Example 329

[2610] N-(4-(3-chloro-4-methylphenyl)-5-propylthiazole-2-yl)-4-(dimethylamino)benzamide

[2611] N-(4-(3-Chloro-4-methylphenyl)-5-propylthiazol-2-yl)-4-(dimethylamino)benzamide (95f)

[2612]

[2613] A bright yellow solid (266.2 mg, quantitative yield) was obtained from 4-(3-chloro-4-methylphenyl)-5-propylthiazole-2-amine.

[2614] 1 H NMR (500 MHz, DMSO-d6) δ 12.19 (s, 1H), 8.00 (d,J= 8.8 Hz, 2H), 7.64 (m, 2H), 7.29 (t,J= 8.8 Hz, 2H), 6.75 (d,J= 8.8 Hz, 2H), 3.00 (d,J= 13.7 Hz, 6H), 2.82 (t,J= 7.6 Hz, 2H), 1.64 (m, 2H), 0.94 (t,J= 7.3 Hz, 3H).

[2615]

[2616] Preparation Example 330

[2617] N-(4-(3-chloro-4-methoxyphenyl)-5-ethylthiazole-2-yl)-4-(dimethylamino)benzamide

[2618] N-(4-(3-Chloro-4-methoxyphenyl)-5-ethylthiazol-2-yl)-4-(dimethylamino)benzamide (96a)

[2619]

[2620] 4-(3-chloro-4-methoxyphenyl)-5-ethylthiazole-2-amine (60.3 mg, 0.23 mmol) and DMAP (14.0 mg, 0.11 mmol) were dissolved in pyridine (2 mL) and stirred at room temperature for 5 minutes. 4-(dimethylamino)benzoyl chloride (62.5 mg, 0.34 mmol) was added, and the reaction mixture was stirred overnight at 70°C. After the reaction was complete, an aqueous solution of saturated sodium carbonate and ethyl acetate were added, and the organic layer was separated; the aqueous solution was then washed with ethyl acetate. The combined organic layer was washed with distilled water and brine, dried with anhydrous magnesium sulfate, and then vacuum concentrated. The residue was purified by flash column chromatography (ethyl acetate:hexane, 1:4) to obtain a compound (44.5 mg, 47.8%) as a white solid.

[2621] 1 H NMR (500 MHz, cdcl3) δ 10.72 (s, 1H), 7.65 (d,J= 8.8 Hz, 2H), 7.40 (d,J= 1.5 Hz, 1H), 7.33 (d,J= 8.4 Hz, 1H), 6.80 (d,J= 8.5 Hz, 1H), 6.53 (d,J= 8.8 Hz, 2H), 3.87 (s, 3H), 3.03 (s, 6H), 2.90 (q,J= 7.5 Hz, 2H), 1.35 (t,J= 7.5 Hz, 3H).

[2622]

[2623] Preparation Example 331

[2624] N-(5-ethyl-4-(p-tolyl)thiazole-2-yl)-4-methoxybenzamide

[2625] N-(5-Ethyl-4-(p-tolyl)thiazol-2-yl)-4-methoxybenzamide (96b)

[2626]

[2627] It was obtained as a white solid (155.2 mg, 32.0%) from 5-ethyl-4-(p-tolyl)thiazole-2-amine and anisoyl chloride.

[2628] 1 H NMR (500 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.11 (d,J= 8.5 Hz, 2H), 7.51 (d,J= 7.7 Hz, 2H), 7.26 (d,J= 7.5 Hz, 2H), 7.07 (d,J= 8.5 Hz, 2H), 3.85 (s, 3H), 2.88 (m, 2H), 2.35 (s, 3H), 1.27 (t,J= 7.3 Hz, 3H).

[2629]

[2630] Preparation Example 332

[2631] 4-(dimethylamino)-N-(5-ethyl-4-(p-tolyl)thiazole-2-yl)benzamide

[2632] 4-(Dimethylamino)-N-(5-ethyl-4-(p-tolyl)thiazol-2-yl)benzamide (96c)

[2633]

[2634] A bright yellow solid (40.1 mg, 13.5%) was obtained from 5-ethyl-4-(p-tolyl)thiazole-2-amine and 4-(dimethylamino)benzoyl chloride.

[2635] 1H NMR (500 MHz, DMSO-d6) δ 12.14 (s, 1H), 7.99 (d,J= 8.5 Hz, 2H), 7.49 (d,J= 7.6 Hz, 2H), 7.24 (d,J= 7.4 Hz, 2H), 6.73 (d,J= 8.5 Hz, 2H), 2.99 (s, 6H), 2.86 (d,J= 7.4 Hz, 2H), 2.32 (s, 3H), 1.25 (t,J= 7.2 Hz, 3H).

[2636]

[2637] Preparation Example 333

[2638] N-(5-ethyl-4-phenylthiazole-2-yl)-4-methoxybenzamide

[2639] N-(5-Ethyl-4-phenylthiazol-2-yl)-4-methoxybenzamide (96d)

[2640]

[2641] It was obtained as a white foamy solid (402.0 mg, 57.7%) from 5-ethyl-4-phenylthiazole-2-amine and anisoyl chloride.

[2642] 1 H NMR (500 MHz, DMSO-d6) δ 12.45 (s, 1H), 8.10 (d,J= 8.7 Hz, 2H), 7.60 (d,J= 7.5 Hz, 2H), 7.45 (t,J= 7.5 Hz, 2H), 7.34 (t,J= 7.3 Hz, 1H), 7.05 (d,J= 8.7 Hz, 2H), 3.83 (s, 3H), 2.89 (q,J= 7.4 Hz, 2H), 1.26 (t,J= 7.4 Hz, 3H).

[2643]

[2644] Preparation Example 334

[2645] N-(4-(4-chlorophenyl)-5-ethylthiazole-2-yl)-4-methoxybenzamide

[2646] N-(4-(4-Chlorophenyl)-5-ethylthiazol-2-yl)-4-methoxybenzamide (96e)

[2647]

[2648] A yellow solid (180.1 mg, 38.1%) was obtained from 4-(4-chlorophenyl)-5-ethylthiazole-2-amine and anisoyl chloride.

[2649] 1 H NMR (500 MHz, DMSO-d6) δ 12.48 (s, 1H), 8.10 (d,J= 8.6 Hz, 2H), 7.63 (d,J= 8.3 Hz, 2H), 7.50 (d,J= 8.2 Hz, 2H), 7.05 (d,J= 8.6 Hz, 2H), 3.83 (s, 3H), 2.89 (q,J= 7.3 Hz, 2H), 1.26 (t,J= 7.4 Hz, 3H).

[2650]

[2651] Preparation Example 335

[2652] 4-(dimethylamino)-N-(5-ethyl-4-(4-fluoro-3-(trifluoromethyl)phenyl)thiazole-2-yl)benzamide

[2653] 4-(Dimethylamino)-N-(5-ethyl-4-(4-fluoro-3-(trifluoromethyl)phenyl)thiazol-2-yl)benzamide (96f)

[2654]

[2655] It was obtained as a light brown solid (799.2 mg, 39.7%) from 4-(4-fluoro-3-(trifluoromethyl)phenyl)-5-propylthiazole-2-amine and 4-(dimethylamino)benzoyl chloride.

[2656] 1H NMR (500 MHz, DMSO-d6) δ 12.20 (s, 1H), 8.01 (d,J= 8.4 Hz, 2H), 7.97 (m, 2H), 7.61 (t,J= 9.6 Hz, 1H), 6.75 (d,J= 8.6 Hz, 2H), 3.01 (s, 6H), 2.92 (m, 2H), 1.29 (t,J= 7.4 Hz, 3H).

[2657]

[2658] Preparation Example 336

[2659] N-(5-ethyl-4-(3-sulfamoylphenyl)thiazole-2-yl)-4-methoxybenzamide

[2660] N-(5-Ethyl-4-(3-sulfamoylphenyl)thiazol-2-yl)-4-methoxybenzamide (96g)

[2661]

[2662] A white solid (53.9 mg, 45.8%) was obtained from 3-(2-amino-5-ethylthiazole-4-yl)benzenesulfonamide and 4-(dimethylamino)benzoyl chloride.

[2663] 1 H NMR (500 MHz, DMSO-d6) δ 12.54 (s, 1H), 8.15 (s, 1H), 8.11 (d,J= 8.6 Hz, 2H), 7.80 (m, 2H), 7.65 (t,J= 7.8 Hz, 1H), 7.41 (s, 2H), 7.06 (d,J= 8.6 Hz, 2H), 3.83 (s, 3H), 2.94 (q,J= 7.4 Hz, 2H), 1.29 (t,J= 7.4 Hz, 3H).

[2664]

[2665] Preparation Example 337

[2666] 4-(dimethylamino)-N-(5-ethyl-4-(3-sulfamoylphenyl)thiazole-2-yl)benzamide

[2667] 4-(Dimethylamino)-N-(5-ethyl-4-(3-sulfamoylphenyl)thiazol-2-yl)benzamide (96h)

[2668]

[2669] A bright yellow solid (20.1 mg, 16.6%) was obtained from 3-(2-amino-5-ethylthiazole-4-yl)benzenesulfonamide and 4-(dimethylamino)benzoyl chloride.

[2670] 1 H NMR (500 MHz, DMSO-d6) δ 12.26 (s, 1H), 8.15 (s, 1H), 8.00 (d,J= 8.5 Hz, 2H), 7.80 (m, 2H), 7.64 (t,J= 7.7 Hz, 1H), 7.40 (s, 2H), 6.74 (d,J= 8.6 Hz, 2H), 3.00 (s, 6H), 2.93 (q,J= 7.3 Hz, 2H), 1.28 (t,J= 7.4 Hz, 3H).

[2671]

[2672] Preparation Example 338

[2673] Methyl 3-(2-(4-(dimethylamino)benzamido)-5-ethylthiazole-4-yl)benzoate

[2674] Methyl 3-(2-(4-(dimethylamino)benzamido)-5-ethylthiazol-4-yl)benzoate (97)

[2675]

[2676] A white solid (234.1 mg, 42.8%) was obtained from methyl 3-(2-amino-5-ethylthiazole-4-yl)benzoate and 4-(dimethylamino)benzoyl chloride.

[2677] 1H NMR (500 MHz, CDCl3) δ 10.05 (s, 1H), 8.18 (s, 1H), 7.93 (d,J= 7.7 Hz, 1H), 7.73 - 7.31 (m, 3H), 7.42 (t,J= 7.7 Hz, 1H), 6.59 (d,J= 8.8 Hz, 2H), 3.93 (s, 3H), 3.00 (s, 6H), 2.95 (q,J= 7.5 Hz, 2H), 1.37 (t,J= 7.5 Hz, 3H).

[2678]

[2679] Preparation Example 339

[2680] 3-(2-(4-(dimethylamino)benzamido)-5-ethylthiazole-4-yl)benzoic acid

[2681] 3-(2-(4-(Dimethylamino)benzamido)-5-ethylthiazol-4-yl)benzoic acid (98)

[2682]

[2683] Lithium hydroxide hydrate (37.0 mg, 0.88 mmol) was added to a solution in which methyl 3-(2-(4-(dimethylamino)benzamido)-5-ethylthiazole-4-yl)benzoate (180 mg, 0.44 mmol) was dissolved in tetrahydrofuran / distilled water (3:1, 10 mL), and then methanol (3 mL) was added at room temperature, and the mixture was stirred overnight at room temperature. After removing volatile substances by evaporation, water was added to the residue and acidified with a 10% aqueous hydrochloric acid solution (pH 3) to obtain the residue. The residue was ground with ethyl acetate to obtain the compound (164.1 mg, 94.4%) as a white solid.

[2684] 1H NMR (500 MHz, DMSO-d6) δ 12.20 (s, 1H), 8.28 (s, 1H), 8.00 (d,J= 8.8 Hz, 2H), 7.90 (d,J= 7.6 Hz, 1H), 7.85 (d,J= 7.7 Hz, 1H), 7.57 (t,J= 7.7 Hz, 1H), 6.75 (d,J= 8.8 Hz, 2H), 3.00 (s, 6H), 2.92 (q,J= 7.4 Hz, 2H), 1.28 (t,J= 7.5 Hz, 3H).

[2685]

[2686] Preparation Example 340

[2687] 3-(2-(4-(dimethylamino)benzamido)-5-ethylthiazole-4-yl)-N-methylbenzamide

[2688] 3-(2-(4-(Dimethylamino)benzamido)-5-ethylthiazol-4-yl)-N-methylbenzamide (99)

[2689]

[2690] A mixture of methyl 3-(2-(4-(dimethylamino)benzamido)-5-ethylthiazole-4-yl)benzoate (93.6 mg, 0.23 mmol) and methylamine (40% methanol solution, 3 mL) was placed in a sealed container and stirred at room temperature for 24 hours. Volatile substances were evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (EtOAc:hexane, 1:1) to obtain the compound (72.1 mg, 76.7%) as a beige solid.

[2691] 1H NMR (500 MHz, DMSO-d6) δ 12.19 (s, 1H), 8.49 (m, 1H), 8.12 (s, 1H), 8.00 (d,J= 8.8 Hz, 2H), 7.78 (d,J= 7.7 Hz, 1H), 7.72 (d,J= 7.6 Hz, 1H), 7.52 (t,J= 7.7 Hz, 1H), 6.74 (d,J= 8.8 Hz, 2H), 3.00 (s, 6H), 2.90 (q,J= 7.5 Hz, 2H), 2.78 (d,J= 4.3 Hz, 3H), 1.27 (t,J= 7.5 Hz, 3H).

[2692]

[2693] Preparation Example 341

[2694] N-(4-(3-carbamoylphenyl)-5-ethylthiazole-2-yl)-4-(dimethylamino)benzamide

[2695] N-(4-(3-Carbamoylphenyl)-5-ethylthiazol-2-yl)-4-(dimethylamino)benzamide (100)

[2696]

[2697] 3-(2-(4-(dimethylamino)benzamido)-5-ethylthiazole-4-yl)benzoic acid (60 mg, 0.152 mmol) was dissolved in N,N-dimethylformamide (2 mL) and stirred at room temperature for 5 minutes. Ammonium chloride (9.0 mg, 0.152 mmol), diisopropylethylamine (59.1 mg, 79.5 μL, 0.152 mmol), and HATU (57.8 mg, 0.152 mmol) were added, and the reaction mixture was stirred overnight at room temperature. After the reaction was complete, the residue was separated into ethyl acetate and distilled water. The organic phase was dried with anhydrous magnesium sulfate, filtered, and concentrated; the residue was then separated into dichloromethane and methanol to obtain the compound (19.3 mg, 32.2%) as a white solid.

[2698] 1H NMR (500 MHz, DMSO-d6) δ 12.19 (s, 1H), 8.16 (s, 1H), 8.03 (s, 1H), 8.00 (d,J= 8.6 Hz, 2H), 7.83 (d,J= 7.6 Hz, 1H), 7.73 (d,J= 7.5 Hz, 1H), 7.51 (t,J= 7.7 Hz, 1H), 7.40 (s, 1H), 6.74 (d,J= 8.6 Hz, 2H), 3.00 (s, 6H), 2.91 (q,J= 7.5 Hz, 2H), 1.27 (t,J= 7.5 Hz, 3H).

[2699]

[2700] Preparation Example 342

[2701] 4-(dimethylamino)-N-(5-ethyl-4-(3-nitrophenyl)thiazole-2-yl)benzamide

[2702] 4-(Dimethylamino)-N-(5-ethyl-4-(3-nitrophenyl)thiazol-2-yl)benzamide (101)

[2703]

[2704] A yellow solid (474.6 mg, quantitative yield) was obtained from 5-ethyl-4-(3-nitrophenyl)thiazole-2-amine and 4-(dimethylamino)benzoyl chloride.

[2705] 1 H NMR (500 MHz, DMSO-d6) δ 12.25 (s, 1H), 8.50 (s, 1H), 8.19 (d,J= 7.8 Hz, 1H), 8.07 (d,J= 7.2 Hz, 1H), 8.00 (d,J= 8.0 Hz, 2H), 7.75 (t,J= 7.6 Hz, 1H), 6.74 (d,J= 8.1 Hz, 2H), 3.00 (s, 6H), 2.96 (d,J= 7.2 Hz, 2H), 1.30 (t,J= 6.9 Hz, 3H).

[2706]

[2707] Preparation Example 343

[2708] N-(4-(3-aminophenyl)-5-ethylthiazole-2-yl)-4-(dimethylamino)benzamide

[2709] N-(4-(3-Aminophenyl)-5-ethylthiazol-2-yl)-4-(dimethylamino)benzamide (102)

[2710]

[2711] Fe powder (350.5 mg, 6.28 mmol), ammonium chloride (56.0 mg, 1.046 mmol), and acetic acid (125.7 mg, 2.093 mmol) were dissolved in ethanol:tetrahydrofuran:distilled water (2 mL:2 mL:2 mL) and stirred at 80°C for 10 minutes. 4-(dimethylamino)-N-(5-ethyl-4-(3-nitrophenyl)thiazole-2-yl)benzamide (414.8 mg, 1.046 mmol) was added to this solution, and the reaction mixture was stirred at 80°C for 1 hour. After the reaction was complete, the mixture was filtered through Celite, extracted with ethyl acetate, washed with brine, dried with anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (ethyl acetate:hexane, 1:2) to obtain the above compound in the form of a yellow solid (60.1 mg, 16.1%).

[2712] 1 H NMR (500 MHz, DMSO-d6) δ 12.12 (s, 1H), 7.99 (d,J= 7.1 Hz, 2H), 7.05 (t, 1H), 6.81 (d, 1H), 6.72 (m, 3H), 6.52 (d,J= 6.2 Hz, 1H), 5.12 (s, 2H), 2.99 (s, 6H), 2.85 (q,J= 5.8 Hz, 2H), 1.25 (t, 3H).

[2713]

[2714] Preparation Example 344

[2715] N-(4-(3-acetamidophenyl)-5-ethylthiazole-2-yl)-4-(dimethylamino)benzamide

[2716] N-(4-(3-Acetamidophenyl)-5-ethylthiazol-2-yl)-4-(dimethylamino)benzamide (103)

[2717]

[2718] N-(4-(3-aminophenyl)-5-ethylthiazole-2-yl)-4-(dimethylamino)benzamide (40 mg, 0.1 mmol) and TEA (9.9 mg, 0.1 mmol) were dissolved in dichloromethane:pyridine (1 mL:1 mL). Acetyl chloride (15.4 mg, 0.196 mmol) was added to this solution, and the reaction mixture was stirred at room temperature for 0.5 hours. After the reaction was complete, the mixture was acidified with a dilute aqueous hydrochloric acid solution, extracted with ethyl acetate, washed with brine, dried with magnesium sulfate, filtered, and concentrated under vacuum to obtain the compound (31.6 mg, 77.4%) as a bright yellow solid.

[2719] 1 H NMR (500 MHz, DMSO-d6) δ 12.18 (s, 1H), 10.04 (s, 1H), 7.99 (d,J= 8.9 Hz, 2H), 7.93 (s, 1H), 7.48 (d,J= 7.9 Hz, 1H), 7.34 (t,J= 7.8 Hz, 1H), 7.26 (d,J= 7.5 Hz, 1H), 6.75 (d,J= 8.8 Hz, 2H), 3.00 (s, 6H), 2.87 (dd,J= 14.8, 7.3 Hz, 2H), 2.05 (s, 3H), 1.26 (t,J= 7.5 Hz, 3H).

[2720]

[2721] Preparation Example 345

[2722] N-(4-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-5-propylthiazole-2-yl)-4-methoxybenzamide

[2723] N-(4-(4-(((tert-Butyldimethylsilyl)oxy)methyl)phenyl)-5-propylthiazol-2-yl)-4-methoxybenzamide

[2724]

[2725] Imidazole (40.2 mg, 0.59 mmol) was added to a solution in which (4-(2-amino-5-propylthiazole-4-yl)phenyl)methanol (97.5 mg, 0.393 mmol) was dissolved in anhydrous dichloromethane (3.5 mL) and tetrahydrofuran (1 mL). Then, tert-butyldimethylsilyl chloride (71.0 mg, 0.47 mmol) was added at room temperature and stirred for 3 hours. Afterward, volatile substances were removed under reduced pressure to obtain the corresponding compound, which was used without further purification. The residue was dissolved in pyridine (2 mL), and anisoyl chloride (181.0 mg, 143.7 μL, 1.061 mmol) was added at 0°C. The reaction mixture was stirred at 5°C for 1 hour and then stirred overnight at room temperature. After the reaction was complete, water and dichloromethane were added to the resulting mixture to separate the organic phase, and the aqueous layer was washed with dichloromethane. The combined organic phase was washed with water and saturated saline solution, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified using silica gel flash column chromatography (ethyl acetate:hexane, 1:5), yielding a colorless gel-like compound (73.8 mg, 37.8%).

[2726] 1 H NMR (500 MHz, CDCl3) δ 10.63 (s, 1H), 7.74 (d,J= 7.2 Hz, 2H), 7.41 (d,J= 6.0 Hz, 2H), 7.26 (d,J= 3.7 Hz, 2H), 6.83 (d,J= 7.2 Hz, 2H), 4.72 (s, 2H), 3.84 (s, 3H), 2.86 (m, 2H), 1.75 (m, 2H), 1.00 (m, 3H), 0.95 (s, 9H), 0.11 (s, 6H).

[2727]

[2728] Preparation Example 346

[2729] N-(4-(4-(hydroxy)phenyl)-5-propylthiazole-2-yl)-4-methoxybenzamide

[2730] N-(4-(4-(Hydroxymethyl)phenyl)-5-propylthiazol-2-yl)-4-methoxybenzamide (105)

[2731]

[2732] Imidazole (40.2 mg, 0.59 mmol) was added to a solution in which (4-(2-amino-5-propylthiazole-4-yl)phenyl)methanol (97.5 mg, 0.393 mmol) was dissolved in anhydrous dichloromethane (3.5 mL) and tetrahydrofuran (1 mL). Then, tert-butyldimethylsilyl chloride (71.0 mg, 0.47 mmol) was added at room temperature and stirred for 3 hours. Afterward, volatile substances were removed under reduced pressure to obtain the corresponding compound, which was used without further purification. The residue was dissolved in pyridine (2 mL), and anisoyl chloride (181.0 mg, 143.7 μL, 1.061 mmol) was added at 0°C. The reaction mixture was stirred at 5°C for 1 hour and then stirred overnight at room temperature. After the reaction was complete, water and dichloromethane were added to the resulting mixture to separate the organic phase, and the aqueous layer was washed with dichloromethane. The combined organic phase was washed with water and saturated saline solution, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified using silica gel flash column chromatography (ethyl acetate:hexane, 1:5), yielding a colorless gel-like compound (73.8 mg, 37.8%).

[2733] 1H NMR (500 MHz, CD3OD / CDCl3) δ 7.97 (d,J= 8.7 Hz, 2H), 7.54 (d,J= 7.9 Hz, 2H), 7.41 (d,J= 7.9 Hz, 2H), 7.02 (d,J= 8.7 Hz, 2H), 4.65 (s, 2H), 3.86 (s, 3H), 2.85 (t,J= 7.6 Hz, 2H), 1.71 (m, 2H), 0.96 (t,J= 7.3 Hz, 3H).

[2734]

[2735] Preparation Example 347

[2736] N-(5-ethylthiazole-2-yl)-4-methoxybenzamide

[2737] N-(5-Ethylthiazol-2-yl)-4-methoxybenzamide (106a)

[2738]

[2739] The compound (120.6 mg, 19.7%) was obtained as a dark brown solid using 4-methoxybenzoyl chloride with compound 27a.

[2740] 1 H NMR (500 MHz, DMSO-d6) δ 8.11 (d,J= 8.7 Hz, 2H), 7.32 (s, 1H), 7.07 (d,J= 8.7 Hz, 2H), 3.84 (s, 3H), 2.77 (q,J= 7.3 Hz, 2H), 1.23 (t,J= 7.5 Hz, 3H).

[2741]

[2742] Preparation Example 348

[2743] N-(4-bromo-5-ethylthiazole-2-yl)-4-methoxybenzamide

[2744] N-(4-Bromo-5-ethylthiazol-2-yl)-4-methoxybenzamide (106b)

[2745]

[2746] The above compound (78.1 mg, 47.7%) was obtained as a white solid using 4-methoxybenzoyl chloride with compound 30a.

[2747] 1 H NMR (500 MHz, DMSO-d6) δ 12.64 (s, 1H), 8.08 (d,J= 8.0 Hz, 2H), 7.07 (d,J= 8.0 Hz, 2H), 3.84 (s, 3H), 2.70 (m, 2H), 1.21 (t,J= 7.1 Hz, 3H).

[2748]

[2749] Preparation Example 349

[2750] N-(4-bromo-5-ethylthiazole-2-yl)-4-(dimethylamino)benzamide

[2751] N-(4-Bromo-5-ethylthiazol-2-yl)-4-(dimethylamino)benzamide (106c)

[2752]

[2753] Compound 30a was used with 4-(dimethylamino)benzoyl chloride to obtain the compound (104.4 mg, 40.9%) as a light yellow solid.

[2754] 1 H NMR (500 MHz, DMSO-d6) δ 12.36 (s, 1H), 7.97 (d,J= 8.7 Hz, 2H), 6.74 (d,J= 8.7 Hz, 2H), 3.01 (s, 6H), 2.69 (q,J= 7.4 Hz, 2H), 1.20 (t,J= 7.5 Hz, 3H).

[2755]

[2756] Preparation Example 350

[2757] N-(4-([1,1'-biphenyl]-4-yl)-5-ethylthiazole-2-yl)-4-(dimethylamino)benzamide

[2758] N-(4-([1,1'-Biphenyl]-4-yl)-5-ethylthiazol-2-yl)-4-(dimethylamino)benzamide (107a)

[2759]

[2760] The above compound (45.1 mg, 33.8%) was obtained as a white solid using 4-(dimethylamino)benzoyl chloride in compound 37u.

[2761] 1 H NMR (500 MHz, CDCl3) δ 7.83 (d,J= 7.3 Hz, 2H), 7.61 (m, 6H), 7.46 (t,J= 6.9 Hz, 2H), 7.36 (t,J= 6.6 Hz, 1H), 6.64 (d,J= 7.5 Hz, 2H), 3.03 (s, 6H), 2.99 (q,J= 8.2 Hz, 2H), 1.39 (t,J= 6.7 Hz, 3H).

[2762]

[2763] Preparation Example 351

[2764] N-(4-(dibenzo[b,d]furan-4-yl)-5-ethylthiazole-2-yl)-4-(dimethylamino)benzamide

[2765] N-(4-(Dibenzo[b,d]furan-4-yl)-5-ethylthiazol-2-yl)-4-(dimethylamino)benzamide (107b)

[2766]

[2767] The above compound (49.5 mg, 36.2%) was obtained as a white solid using 4-(dimethylamino)benzoyl chloride in compound 37x.

[2768] 1H NMR (500 MHz, CDCl3) δ 11.41 (s, 1H), 7.91 (d,J= 7.6 Hz, 1H), 7.75 (d,J= 7.6 Hz, 1H), 7.55 (m, 3H), 7.51 (d,J= 7.4 Hz, 1H), 7.45 (t,J= 7.6 Hz, 1H), 7.35 (t,J= 7.4 Hz, 1H), 7.25 (m, 1H), 6.26 (d,J= 7.5 Hz, 2H), 2.88 (m, 2H), 2.67 (s, 6H), 1.37 (t,J= 7.1 Hz, 3H).

[2769]

[2770] Preparation Example 352

[2771] N-(5-propyl-4-(p-tolyl)thiazole-2-yl)picolineamide

[2772] N-(5-Propyl-4-(p-tolyl)thiazol-2-yl)picolinamide (108a)

[2773]

[2774] Compound 10a was used with 5-propyl-4-(p-tolyl)thiazole-2-amine to obtain the compound (178.9 mg, 62.0%) as a pale yellow solid.

[2775] 1 H NMR (500 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.76 (s, 1H), 8.18 (d,J= 7.8 Hz, 1H), 8.10 (t,J= 7.2 Hz, 1H), 7.72 (s, 1H), 7.51 (d,J= 6.5 Hz, 2H), 7.27 (d,J= 6.8 Hz, 2H), 2.87 (t,J= 6.4 Hz, 2H), 2.35 (s, 3H), 1.67 (m, 2H), 0.94 (t,J= 6.1 Hz, 3H).

[2776]

[2777] Preparation Example 353

[2778] N-(5-propyl-4-(p-tolyl)thiazole-2-yl)picolineamide

[2779] N-(5-Propyl-4-(p-tolyl)thiazol-2-yl)picolinamide (108b)

[2780]

[2781] The above compound (360 mg, 81.0%) was obtained as a white solid using 5-propyl-4-(p-tolyl)thiazole-2-amine in compound 10b.

[2782] 1 H NMR (500 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.76 (s, 1H), 8.18 (d,J= 7.8 Hz, 1H), 8.10 (t,J= 7.2 Hz, 1H), 7.72 (s, 1H), 7.51 (d,J= 6.5 Hz, 2H), 7.27 (d,J= 6.8 Hz, 2H), 2.87 (t,J= 6.4 Hz, 2H), 2.35 (s, 3H), 1.67 (m, 2H), 0.94 (t,J= 6.1 Hz, 3H).

[2783]

[2784] Preparation Example 354

[2785] N-(4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-ethylthiazole-2-yl)fura-N-2-carboxamide

[2786] N-(4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)-5-ethylthiazol-2-yl)furaN-2-carboxamide

[2787]

[2788] Compound 5c was used with 2-furoyl chloride to obtain the above compound (120.1 mg, 63.9%) as a pale yellow solid.

[2789] 1H NMR (500 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.76 (s, 1H), 8.18 (d,J= 7.8 Hz, 1H), 8.10 (t,J= 7.2 Hz, 1H), 7.72 (s, 1H), 7.51 (d,J= 6.5 Hz, 2H), 7.27 (d,J= 6.8 Hz, 2H), 2.87 (t,J= 6.4 Hz, 2H), 2.35 (s, 3H), 1.67 (m, 2H), 0.94 (t,J= 6.1 Hz, 3H).

[2790]

[2791] Preparation Example 355

[2792] N-(4-(4-((tert-butyldimethylsilyl)oxy)-3-chlorophenyl)-5-ethylthiazole-2-yl)picolineamide

[2793] N-(4-(4-((tert-Butyldimethylsilyl)oxy)-3-chlorophenyl)-5-ethylthiazol-2-yl)picolinamide

[2794]

[2795] The above compound (300.1 mg, 57.3%) was obtained as a white solid using picolinic acid in compound 5c.

[2796] 1 H NMR (500 MHz, DMSO-d6) δ 11.91 (s, 1H), 8.74 (d,J= 3.6 Hz, 1H), 8.16 (d,J= 7.5 Hz, 1H), 8.09 (t,J= 7.5 Hz, 1H), 7.69 (m, 2H), 7.48 (dd,J= 8.1, 1.3 Hz, 1H), 7.09 (d,J= 8.4 Hz, 1H), 2.91 (q,J= 14.9, 7.4 Hz, 2H), 1.28 (t,J= 7.4 Hz, 3H), 1.00 (s, 9H), 0.24 (s, 6H).

[2797]

[2798] Preparation Example 356

[2799] N-(4-(3-chloro-4-((4-methoxybenzyl)oxy)phenyl)-5-ethylthiazole-2-yl)-5-methoxypicolinamide

[2800] N-(4-(3-Chloro-4-((4-methoxybenzyl)oxy)phenyl)-5-ethylthiazol-2-yl)-5-methoxypicolin amide

[2801]

[2802] The above compound (241.6 mg, 72.9%) was obtained as a brown solid using 5-methoxypicolinoyl chloride in compound 6d.

[2803] 1 H NMR (500 MHz, DMSO-d6) δ 11.65 (s, 1H), 8.39 (s, 1H), 8.13 (d,J= 8.3 Hz, 1H), 7.66 (s, 1H), 7.61 (d,J= 8.3 Hz, 1H), 7.51 (d,J= 8.8 Hz, 1H), 7.40 (d,J= 7.0 Hz, 2H), 7.30 (d,J= 8.2 Hz, 1H), 6.95 (d,J= 6.6 Hz, 2H), 5.14 (s, 2H), 3.92 (s, 3H), 3.74 (s, 3H), 2.90 (q,J= 6.8 Hz, 2H), 1.26 (t, 3H).

[2804]

[2805] Preparation Example 357

[2806] 5-Bromo-N-(4-(3-chloro-4-((4-methoxybenzyl)oxy)phenyl)-5-ethylthiazole-2-yl)furan-2-carboxamide

[2807] 5-Bromo-N-(4-(3-chloro-4-((4-methoxybenzyl)oxy)phenyl)-5-ethylthiazol-2-yl)furan-2-carboxamide

[2808]

[2809] Compound 6d was used with 5-bromofuran-2-carboxylic acid to obtain the above compound (250.0 mg, 58.0%) as a pale yellow solid.

[2810] 1 H NMR (500 MHz, DMSO-d6) δ 12.60 (s, 1H), 7.66 (d,J= 1.9 Hz, 1H), 7.50 (d,J= 8.6 Hz, 1H), 7.41 (d,J= 8.6 Hz, 2H), 7.31 (d,J= 8.7 Hz,1H), 6.96 (d,J= 8.7 Hz, 2H), 6.86 (d,J= 3.6 Hz, 1H), 5.14 (s, 2H), 3.75 (s, 3H), 2.88 (q,J= 7.5 Hz, 2H), 1.25 (t,J= 7.5 Hz, 3H).

[2811]

[2812] Preparation Example 358

[2813] N-(4-(3-chloro-4-((4-methoxybenzyl)oxy)phenyl)-5-ethylthiazole-2-yl)thiophene-2-carboxamide

[2814] N-(4-(3-Chloro-4-((4-methoxybenzyl)oxy)phenyl)-5-ethylthiazol-2-yl)thiophene-2-carboxamide

[2815]

[2816] The above compound (493.5 mg, 100%) was obtained as a white solid using thiophene-2-carbonyl chloride in compound 6d.

[2817] 1H NMR (500 MHz, DMSO-d6) δ 13.19 (s, 1H), 8.20 (s, 2H), 7.69 (s, 1H), 7.53 (d,J= 8.0 Hz, 1H), 7.43 (d,J= 8.5 Hz, 2H), 7.34 (d,J= 8.6 Hz, 1H), 6.98 (d,J= 8.5 Hz, 2H), 5.17 (s, 2H), 3.77 (s, 3H), 2.91 (m, 2H), 1.27 (t,J= 7.0 Hz, 3H).

[2818]

[2819] Preparation Example 359

[2820] N-(4-(3-chloro-4-((4-methoxybenzyl)oxy)phenyl)-5-ethylthiazole-2-yl)-5-nitrothiophene-2-carboxamide

[2821] N-(4-(3-Chloro-4-((4-methoxybenzyl)oxy)phenyl)-5-ethylthiazol-2-yl)-5-nitrothiophene-2-carboxamide

[2822]

[2823] The above compound (160.0 mg, 57.0%) was obtained as a white solid using thiophene-2-carbonyl chloride with compound 6d.

[2824] 1 H NMR (500 MHz, DMSO-d6) δ 13.19 (s, 1H), 8.20 (s, 2H), 7.69 (s, 1H), 7.53 (d,J= 8.0 Hz, 1H), 7.43 (d,J= 8.5 Hz, 2H), 7.34 (d,J= 8.6 Hz, 1H), 6.98 (d,J= 8.5 Hz, 2H), 5.17 (s, 2H), 3.77 (s, 3H), 2.91 (m, 2H), 1.27 (t,J= 7.0 Hz, 3H).

[2825]

[2826] Preparation Example 360

[2827] N-(4-(3-chloro-4-((4-methoxybenzyl)oxy)phenyl)-5-ethylthiazole-2-yl)oxazole-5-carboxamid...

Claims

1. A compound of the following chemical formula 1 or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the above formula, X is -NH-C(=O)-, -NH-C(=O)-CH2-, -NH-C(=O)-CH2-CH2-, -NH-CH2-, or sulfonamide, and Ring A is a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl, and n is an integer from 0 to 2, and R1, R2, R3, R4, and R5 are each independently selected from hydrogen or the following substituent group I, and R1 are identical or different from each other when n is 2, each independently selected from hydrogen or the following substituent group I, or fuses with each other to form a substituted or unsubstituted C3-8 carbocycle group or a substituted or unsubstituted 3 to 8-membered heterocycle group together with the carbon bonded thereto, and The above substituent group I is -OH, substituted or unsubstituted C 1-10 Alkyl groups, substituted or unsubstituted C 2-10 Alkenyl group, substituted or non-substituted C 3-20 Carbocycle group, substituted or non-substituted C 3-20 Cycloalkyl group, substituted or unsubstituted C 6-30 Aryl group, substituted or unsubstituted 3 to 30-membered heterocyclic group, substituted or unsubstituted C 1-10 Alkoxy group, substituted or non-substituted C 2-10 Alkenyloxy group, substituted or unsubstituted C 3-10 Cycloalkyloxy group, substituted or unsubstituted C 6-30 Aryloxy group, substituted or unsubstituted 3 to 30-membered heterocyclooxy group, substituted or unsubstituted C 1-10 Alkyl carbonyl group, substituted or unsubstituted C 2-10 Alkenyl carbonyl group, substituted or unsubstituted C 3-10 Cycloalkylcarbonyl group, substituted or unsubstituted C 6-30 Aryl carbonyl group, substituted or unsubstituted 3 to 30-membered heterocyclic carbonyl group, substituted or unsubstituted C 1-10 Alkylthio groups, substituted or unsubstituted C 2-10 Alkenylthio group, substituted or non-substituted C 3-10 Cycloalkylthio groups, substituted or unsubstituted C 6-30 Arylthio group, substituted or unsubstituted 3 to 30-membered heterocyclic thio group, aldehyde group, carboxyl group, halogen group, C 1-10 It consists of a haloalkyl group, a hydroxyl group, a substituted or unsubstituted amino group, an imine group, a cyano group, a nitro group, an amide group, a thiol group, a sulfonyl group, a sulfino group, and a phosphate group.

2. In Claim 1, R2 is a substituted or unsubstituted alkyl, and A compound of Formula 1 or a pharmaceutically acceptable salt thereof, wherein R3, R4, and R5 are each independently an alkyl group substituted with -OH, an alkyl group, -alkyl-OH, or a halogen group.

3. In Claim 1, Ring A is a 5- or 6-round ring, and A compound of Formula 1 or a pharmaceutically acceptable salt thereof, wherein the heterocycloalkyl and heteroaryl are composed of one or two heteroatoms, and said heteroatoms are N, O, or S.

4. In Claim 1, A compound of Formula 1 or a pharmaceutically acceptable salt thereof, wherein ring A is substituted or unsubstituted piperidine, substituted or unsubstituted benzene, substituted or unsubstituted furan, substituted or unsubstituted 2-pyridine, substituted or unsubstituted 3-pyridine, or substituted or unsubstituted 4-pyridine.

5. In Claim 1, Compounds selected from the group consisting of the compounds in the table below or pharmaceutically acceptable salts thereof:

6. A pharmaceutical composition for the prevention or treatment of gp130-mediated diseases comprising a compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.

7. In Claim 6, A pharmaceutical composition wherein the above-mentioned gp130-mediated disease is an autoimmune disease or an autoimmune-derived fibrotic disease.

8. In Claim 7, A pharmaceutical composition wherein the above-mentioned gp130-mediated disease is any one selected from the group consisting of rheumatoid arthritis, interstitial lung disease, idiopathic pulmonary fibrosis, hepatic fibrosis, non-alcoholic fatty liver disease, systemic sclerosis, multiple sclerosis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, atopic dermatitis, rhinitis, psoriatic arthritis, psoriasis, rhinitis, and allergic conjunctivitis.

9. An intermediate of the following chemical formula 2 for synthesizing the compound of Claim 1: [Chemical Formula 2] In the above formula, Y is a halogen group, and R2 is selected from hydrogen or the following substituent group I, and The above substituent group I is -OH, substituted or unsubstituted C 1-10 Alkyl groups, substituted or unsubstituted C 2-10 Alkenyl group, substituted or non-substituted C 3-20 Carbocycle group, substituted or non-substituted C 3-20 Cycloalkyl group, substituted or unsubstituted C 6-30 Aryl group, substituted or unsubstituted 3 to 30-membered heterocyclic group, substituted or unsubstituted C 1-10 Alkoxy group, substituted or non-substituted C 2-10 Alkenyloxy group, substituted or unsubstituted C 3-10 Cycloalkyloxy group, substituted or unsubstituted C 6-30 Aryloxy group, substituted or unsubstituted 3 to 30-membered heterocyclooxy group, substituted or unsubstituted C 1-10 Alkyl carbonyl group, substituted or unsubstituted C 2-10 Alkenyl carbonyl group, substituted or unsubstituted C 3-10 Cycloalkylcarbonyl group, substituted or unsubstituted C 6-30 Aryl carbonyl group, substituted or unsubstituted 3 to 30-membered heterocyclic carbonyl group, substituted or unsubstituted C 1-10 Alkylthio groups, substituted or unsubstituted C 2-10 Alkenylthio group, substituted or non-substituted C 3-10 Cycloalkylthio groups, substituted or unsubstituted C 6-30 Arylthio group, substituted or unsubstituted 3 to 30-membered heterocyclic thio group, aldehyde group, carboxyl group, halogen group, C 1-10 It consists of a haloalkyl group, a hydroxyl group, a substituted or unsubstituted amino group, an imine group, a cyano group, a nitro group, an amide group, a thiol group, a sulfonyl group, a sulfino group, and a phosphate group.

10. In Claim 9, Intermediate selected from the group consisting of the compounds in the table below:

11. Use of the compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof for preparing a pharmaceutical composition for the prevention or treatment of gp130-mediated diseases.

12. In Claim 11, The above gp130-mediated disease is an autoimmune disease or an autoimmune-derived fibrotic disease.

13. A method for treating a gp130-mediated disease comprising administering an effective amount of a pharmaceutical composition comprising, as an active ingredient, a compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof to an individual in need thereof.

14. In Claim 13, A treatment method in which the above-mentioned gp130-mediated disease is an autoimmune disease or an autoimmune-derived fibrotic disease.

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