Methods for making thiazolylpyrazole carboxylic acids and intermediates therefor

Abstract

To solve the problem that ring-substituted pyrazolylthiazole compounds are considered to be promising for the treatment of cancer, and that there is a need for efficient methods for preparing these compounds.SOLUTION: This disclosure relates generally to improved methods of preparing pyrazolylthiazole-containing compounds and their intermediates.SELECTED DRAWING: None

Description

Cross - reference to related applications

[0001] This application claims the benefit of priority of U.S. Provisional Patent Application No. 62 / 855,652, filed on May 31, 2019, the entire content of which is incorporated herein by reference.

Technical Field

[0002] The present disclosure generally relates to improved methods for preparing pyrazolylthiazole - containing compounds and intermediates useful therefor.

Background Art

[0003] Cancer, which is uncontrolled cell growth, is a multifactorial disease characterized by tumor formation, growth, and in some cases metastasis. In the United States, more than 1.5 million people will be diagnosed with cancer this year, and more than 500,000 people will die from cancer. Overall, at least 1 in 3 people will develop some form of cancer during their lifetime. There are more than 200 histologically different types of cancer, and breast cancer, colorectal cancer, and prostate cancer account for more than half of all new cases in the United States. Current cancer treatments vary depending on the location and stage of the cancer but generally include surgery, systemic therapy, radiation therapy, and chemotherapy. Despite the efforts devoted to the development of anticancer methods, many of these still remain ineffective against certain cancers.

[0004] The uncontrolled cell growth that characterizes cancer involves not only the disorderly regulation of cell proliferation but also the corresponding adjustment of energy metabolism to stimulate cell growth and division. The reprogramming of cell metabolism has emerged as a crucial molecular hallmark of cancer cells. Under aerobic conditions, normal cells process glucose in the cytosol via glycolysis, first to pyruvate and then to carbon dioxide within the mitochondria. Under hypoxic conditions, glycolysis is favored and relatively little pyruvate is sent to the mitochondria, which consume oxygen. When growth factors and nutrients are abundant, the oncogenic signaling process is directed towards enhanced metabolism, leading to an increase in the synthesis of macromolecules such as lipids, proteins, and nucleic acids. The ultimate effect is to support cell growth and proliferation. However, during tumor formation, a harsh hypoxic and nutrient-deprived environment exists, which forces cells and their ability to cope to maintain metabolic homeostasis. Cancer cells can reprogram their glucose metabolism, and thus their energy production, by predominantly restricting their energy metabolism to glycolysis, which was considered primitive and inefficient by early biochemists. Despite these early theories, the metabolic signature of cancer cells results in oncogene-directed metabolic reprogramming necessary to support anabolic growth rather than a passive response to damaged mitochondria. Oncogene mutations that allow for increased and more efficient utilization of scarce nutrients present unique targets in cancer therapy.

[0005] Cyclic substituted pyrazolylthiazole compounds that are particularly useful for the treatment of cancer are disclosed in International Publication Nos. 2018 / 102452 and 2018 / 102453, each of which is incorporated herein by reference in its entirety. One example of such a compound is 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid. These compounds are thought to be active against cancer cells by arresting the cell cycle at the G0 / G1 phase, thereby inducing apoptosis of cancer cells, and also by inhibiting glutathione synthesis in cancer cells. As a result, cyclic substituted pyrazolylthiazole compounds are considered promising for the treatment of cancer, and there is a need for an efficient method for preparing these compounds.

Summary of the Invention

[0006] The present disclosure provides an improved method for preparing cyclic substituted pyrazolylthiazole compounds such as the compounds of formula (I),

Chemical Formula

[0007] Such a method involves coupling a pyrazolylthiazole (e.g., of formula (Ia)) with an organoboron compound optionally in a solvent and containing the desired ring substituent moiety (e.g., an R 5 moiety).

[0008] The present disclosure also provides pyrazolylthiazole compounds useful as intermediates in the synthesis of compounds of formula (I) and methods for preparing them. Accordingly, another aspect provides a pyrazolylthiazole of formula (Ia),

Chemical Formula

[0009] Another aspect of the present disclosure provides a method for preparing a halopyrazolylthiazole of the present disclosure (e.g., of formula (Ia)). Such a method involves reacting a thiazolylthiazole (e.g., of formula (Ib)) with a dione optionally in a solvent under conditions sufficient to form a hydrazone, and then reacting the hydrazone with a compound of formula X1 -CH2-Q 1 (wherein Q 1 is as described above, and X 1 is a halogen or a leaving group) with a compound to obtain pyrazolylthiazole.

[0010] Another aspect provides a method for preparing thiazolylhydrazine (e.g., of formula (Ib)). Such a method involves reacting a dihalothiazole, optionally in a solvent, with an aqueous solution of hydrazine to obtain a crude product, and crystallizing the crude product from, for example, a hydrocarbon solvent (e.g., hexane, heptane, or a combination thereof) to obtain thiazolylhydrazine.

[0011] Another aspect provides C1-C3 alkyl 1-(4-halo-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylate. One embodiment of this aspect provides ethyl 1-(4-bromo-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylate.

[0012] Other aspects and embodiments of the present disclosure will be apparent in view of the modes for carrying out the invention provided herein.

Modes for Carrying Out the Invention

[0013] The inventors have found an improved and efficient method for preparing the compounds of formula (I). For example, compared to currently known methods such as those disclosed in WO2018 / 102453, the method of the present invention enables a total yield of over 30% for the preparation of Compound 1, compared to the 2.5% total yield disclosed in WO2018 / 102453 for the preparation of the same compound. The method of the present disclosure also provides, for example, a relatively pure (e.g., at least 98% pure) compound of formula (I). Further, in certain embodiments, this purity can be achieved without the need to perform chromatography. Pyrazolylthiazole of formula (Ia) can be used in the method for preparing the compound of formula (I), and thus thiazolylhydrazine of formula (Ib) can be used in the method for preparing pyrazolylthiazole. Therefore, the inventors have found that it is also important for developing an efficient method for preparing pyrazolylthiazole of formula (Ia) and / or thiazolylhydrazine of formula (Ib).

[0014] Accordingly, one aspect provides an improved method for preparing thiazolylhydrazine of formula (Ib),

Chemical formula

[0015] Such a method comprises reacting a dihalothiazole of the formula

Chemical formula

[0016] In certain embodiments, X a is chloro. In certain such embodiments, X is bromo or iodo.

[0017] In the method for preparing thiazolyl hydrazine of formula (Ib), the inventors have found that it is advantageous to use an amount of hydrazine that is at least 6 molar equivalents based on the amount of dihalothiazole of formula (Ic). For example, in certain embodiments, the amount of hydrazine is at least 6.25 molar equivalents, such as at least 6.5 molar equivalents, or at least 7 molar equivalents, based on the amount of all dihalothiazole. In certain embodiments, the amount of hydrazine ranges from 6 to 20 equivalents, such as 6 to 15 equivalents, or 7 to 20 equivalents or 7 to 15 equivalents, based on the amount of dihalothiazole.

[0018] A variety of polar aprotic solvents are suitable for use in the method for preparing thiazolyl hydrazine of formula (Ib). Examples include tetrahydrofuran (THF), ethyl acetate, acetone, dimethylformamide (DMF), acetonitrile (MeCN), dimethyl sulfoxide (DMSO), and the like. In certain embodiments, the solvent is THF.

[0019] Reacting the dihalothiazole with an aqueous solution of hydrazine may be carried out at various temperatures including approximately room temperature. For example, in certain embodiments, this reaction is carried out at a temperature in the range of 20°C to 25°C, or 20°C to 23°C. In other embodiments, the dihalothiazole is reacted with an aqueous solution of hydrazine at a temperature in the range of 5°C to 20°C. In other embodiments, the dihalothiazole is reacted with an aqueous solution of hydrazine, which is carried out at a temperature range of 25°C to 40°C, such as 30°C to 40°C or 35°C to 40°C or 30°C to 35°C.

[0020] The reaction of the dihalothiazole with an aqueous solution of hydrazine is carried out for a time sufficient to obtain a crude product (i.e., containing crude thiazolylhydrazine). In certain embodiments, the dihalothiazole is reacted with the aqueous solution of hydrazine for at least 10 hours, such as at least 20 hours, or at least 24 hours, or at least 48 hours, or at least 72 hours. In certain embodiments, the dihalothiazole is reacted with the aqueous solution of hydrazine for a time in the range of 10 hours to 100 hours, such as 24 hours to 100 hours, or 48 hours to 100 hours, or 72 hours to 100 hours, or 10 hours to 72 hours, or 24 hours to 72 hours, or 48 hours to 72 hours, or 10 hours to 48 hours, or 24 hours to 48 hours. The reaction time and reaction temperature can be selected to provide a crude product having a large amount of crude thiazolylhydrazine.

[0021] The crude product is crystallized to obtain thiazolylhydrazine of formula (Ib). Particularly useful crystallization solvents are hydrocarbon solvents such as hexane, heptane, or combinations thereof. In certain embodiments, the crystallization solvent is hexane. In certain embodiments, the crystallization solvent is heptane. The crystallization solvent may be used in any volume sufficient to effect crystal formation. In certain embodiments, the crystallization solvent is used in an amount of 100 v / v% to 300 v / v%, such as 100 v / v% to 200 v / v%, or 100 v / v% to 150 v / v%, or 200 v / v% to 300 v / v%, or 200 v / v% to 250 v / v%, or 250 v / v% to 300 v / v%, based on the total volume of the crude product. In certain embodiments, the crystallization solvent is added in an amount of about 50 v / v% to 99 v / v% based on the total volume of the crude product. In certain embodiments, the crystallization solvent is added in an amount greater than 300 v / v% based on the total volume of the crude product.

[0022] The present disclosure also provides halopyrazolylthiazoles and methods for preparing them. Accordingly, another aspect of the present disclosure provides halopyrazolylthiazoles of formula (Ia),

Chemical formula

[0023] A method for preparing the pyrazolylthiazole of formula (Ia) is reacting the thiazolylhydrazine of formula (Ib) described herein with a dione of formula (II)

Chemical formula

[0024] The hydrazone can have the following structure (III):

Chemical formula

[0025] Contacting the hydrazone with an alkyl halide of formula X 1 -CH2-Q 1 can form an intermediate having the formula (IV):

Chemical formula

[0026] reacting the dihalothiazole of formula (1c) described herein, optionally in a solvent, with an aqueous solution of hydrazine to obtain a crude product (i.e., containing crude thiazolylhydrazine); crystallizing the crude product (from a hydrocarbon solvent such as hexane, heptane, or combinations thereof) to obtain the thiazolylhydrazine of formula (Ib) described herein; reacting the thiazolylhydrazine of formula (Ib) described herein, optionally in a solvent, with a dione described herein under conditions sufficient to form a hydrazone; reacting the hydrazone with an alkylhalogenide described herein to obtain the halopyrazolylthiazole of formula (Ia).

[0027] ​The inventors have found that halopyrazolylthiazoles of formula (Ia) in which X is Cl, Br or I are advantageous, especially when used for preparing compounds of formula (I). In certain embodiments, as described elsewhere herein, in the halopyrazolylthiazole of formula (Ia), X is Br. In certain embodiments, as described elsewhere herein, in the halopyrazolylthiazole of formula (Ia), X is Cl. In certain embodiments, as described elsewhere herein, in the halopyrazolylthiazole of formula (Ia), X is I.

[0028] The inventors have also found that it is advantageous to use an amount of dione of at least 1 molar equivalent, based on the amount of thiazolylhydrazine. For example, in certain embodiments, the amount of dione is at least 1.1 molar equivalents, such as at least 1.25 molar equivalents, or at least 1.5 molar equivalents, all based on the amount of thiazolylhydrazine.

[0029] The thiazolylhydrazine and the dione, as described elsewhere herein, can be reacted in a solvent in certain embodiments. Suitable solvents include, but are not limited to, dioxane, toluene, THF, DMF, and dichloromethane.

[0030] The reaction of thiazolyl hydrazine with dione may be carried out at various temperatures including room temperature. For example, in certain embodiments, the reaction is carried out at a temperature in the range of 20°C to 25°C, or 20°C to 23°C. The reaction of thiazolyl hydrazine with dione may be carried out for a time sufficient to obtain hydrazone. In certain embodiments, thiazolyl hydrazine is reacted with dione for at least 8 hours, such as at least 10 hours, or at least 12 hours, or at least 14 hours, or at least 16 hours. In certain embodiments, thiazolyl hydrazine is reacted with dione at approximately room temperature for a time in the range of 8 hours to 20 hours, such as 8 hours to 16 hours, or 8 hours to 14 hours, or 8 hours to 12 hours, or 8 hours to 10 hours, or 10 hours to 20 hours, or 10 hours to 16 hours, or 10 hours to 14 hours, or 10 hours to 12 hours, or 14 hours to 20 hours, or 14 hours to 18 hours, or 14 hours to 16 hours, or 16 hours to 20 hours, or 16 hours to 18 hours, or 18 hours to 20 hours. The reaction of thiazolyl hydrazine with dione may alternatively be carried out at a temperature above room temperature. For example, the reaction of thiazolyl hydrazine with dione may be at a temperature of at least 40°C, such as at least 45°C, or at least 50°C, or at least 60°C, or at least 65°C. In certain embodiments, the reaction of thiazolyl hydrazine with dione is in the range of 40°C to 80°C, such as 40°C to 70°C, or 40°C to 60°C, or 40°C to 50°C, 50°C to 80°C, or 50°C to 70°C, or 50°C to 60°C, or 60°C to 80°C, or 60°C to 70°C. In certain embodiments, thiazolyl hydrazine and dione are reacted at a temperature above room temperature for at least 30 minutes (such as at least 45 minutes, or at least 1 hour).

[0031] In the method described herein, the hydrazone is reacted with the alkyl halide described herein to prepare a halopyrazolylthiazole of formula (Ia). The hydrazone and the alkyl halide may be reacted, for example, in the presence of an inorganic iodide and a base. The inorganic iodide can be, in certain embodiments, KI or NaI. In certain embodiments, the hydrazone is contacted with the alkyl halide in the presence of an inorganic iodide that is KI. The base can be, in certain embodiments, a carbonate (e.g., potassium carbonate, sodium carbonate, cesium carbonate, thallium(I) carbonate, etc.), a hydroxide (e.g., potassium hydroxide, sodium hydroxide, etc.), an ethoxide (e.g., sodium ethoxide, potassium tert-butoxide, thallium(I) ethoxide, etc.), an amine (e.g., trimethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, N,N-dimethylethylamine, etc.), or a hydride (e.g., sodium hydride and potassium hydride). In certain embodiments, the hydrazone is contacted with the alkyl halide in the presence of a base that is a carbonate (such as potassium carbonate).

[0032] In certain embodiments, the inorganic iodide is provided in a catalytic amount. For example, in certain embodiments, the amount of the inorganic iodide is 20 mol% or less, such as 15 mol% or less, or 10 mol% or less, based on the amount of the hydrazone. In certain embodiments, the amount of the inorganic iodide is in the range of 5 mol% to 20 mol%, such as in the range of 5 mol% to 15 mol%, or in the range of 5 mol% to 10 mol%, or in the range of 8 mol% to 20 mol%, or in the range of 8 mol% to 15 mol%, or in the range of 8 mol% to 12 mol%, or in the range of 8 mol% to 10 mol%, or in the range of 10 mol% to 20 mol%, or in the range of 10 mol% to 15 mol%, based on the amount of the thiazolylhydrazine.

[0033] In certain embodiments, the inorganic iodide is provided in stoichiometric amounts. For example, in certain embodiments, the amount of inorganic iodide is at least 1 molar equivalent, such as at least 1.1 molar equivalents, or at least 1.25 molar equivalents, or at least 1.5 molar equivalents, or at least 2 molar equivalents, based on the amount of hydrazone.

[0034] The hydrazone and the alkyl halide can be contacted at a temperature and for a time sufficient to obtain halopyrazolylthiazole.

[0035] For example, in certain embodiments, the hydrazone and the alkyl halide are reacted at a temperature of at least 80°C, such as at least 85°C, or at least 90°C, or at least 95°C, or at least 100°C, or at least 110°C. In certain embodiments, the hydrazone and the alkyl halide are reacted at a temperature in the range of 80°C to 120°C, such as 80°C to 110°C, or 80°C to 100°C, or 80°C to 90°C, or 90°C to 120°C, or 90°C to 110°C, or 90°C to 100°C, or 100°C to 120°C, or 100°C to 110°C.

[0036] In certain embodiments, the hydrazone and the alkyl halide are reacted for at least 8 hours. For example, the hydrazone and the alkyl halide may be reacted for at least 10 hours, such as at least 12 hours, or at least 14 hours, or at least 16 hours. In another embodiment, the hydrazone and the alkyl halide are reacted for a time in the range of 8 to 24 hours. For example, in various embodiments, the hydrazone and the alkyl halide are reacted for 8 to 20 hours, or 8 to 16 hours, or 8 to 14 hours, or 8 to 12 hours, or 8 to 10 hours, or 10 to 24 hours, or 10 to 20 hours, or 10 to 16 hours, or 10 to 14 hours, or 10 to 12 hours, or 14 to 24 hours, or 14 to 20 hours, or 14 to 18 hours, or 14 to 16 hours, or 16 to 24 hours, or 16 to 20 hours, or 16 to 18 hours, or 18 to 24 hours, or 18 to 20 hours.

[0037] As described in more detail below, the reaction of the hydrazone of formula X 1 -CH2-Q 1 with the alkyl halide results in substitution of -CH2-Q at the substitutable nitrogen of the hydrazone, and then this intermediate cyclizes through water removal to construct the pyrazole ring of the halopyrazolylthiazole. 1 Specifically, the reaction of the thiazolylhydrazine dione to form the hydrazone (e.g., of formula (III)), the subsequent reaction of the hydrazone of formula X

[0038] -CH2-Q 1 with the alkyl halide to form the substituted hydrazone intermediate (e.g., of formula (IV)), and the cyclization of that hydrazone intermediate to form the halopyrazolylthiazole can be carried out without isolating or purifying any of the intermediates. 1

[0039] In certain embodiments, the method for preparing the halopyrazolylthiazole of formula (Ia) described herein may further include crystallizing the halopyrazolylthiazole. For example, the pyrazolylthiazole can be crystallized to form an alcohol (such as ethanol), and a compound having a purity of at least 98% can be obtained.

[0040] In another aspect, the present disclosure provides a method for preparing a compound of formula (I). Such a method comprises coupling a halopyrazolylthiazole of formula (Ia) described herein, optionally in a solvent, with an organoboron containing an R 5 moiety to obtain a compound of formula (I).

[0041] In certain embodiments, the method for preparing a compound of formula (I) further comprises preparing a halopyrazolylthiazole of formula (Ia) according to the method described herein. For example, in certain embodiments, the method for preparing a compound of formula (I) comprises reacting a thiazolylhydrazine of formula (Ib) described herein with a dione described herein, optionally in a solvent, under conditions sufficient to form a hydrazone, reacting the hydrazone with an alkyl halide described herein to obtain a halopyrazolylthiazole of formula (Ia), and coupling the halopyrazolylthiazole of formula (Ia) described herein, optionally in a solvent, with an organoboron containing an R 5 moiety to obtain a compound of formula (I).

[0042] In certain embodiments, the method for preparing a compound of formula (I) further comprises preparing a halopyrazolylthiazole of formula (Ia) and a thiazolylhydrazine of formula (Ib) according to the method described herein. For example, in certain embodiments, the method for preparing a compound of formula (I) The dihalothiazole described in this specification is optionally reacted in a solvent with an aqueous solution of hydrazine to obtain a crude product (i.e., containing crude thiazolylhydrazine), The crude product is crystallized (from a hydrocarbon solvent such as hexane, heptane, or a combination thereof) to obtain the thiazolylhydrazine of formula (Ib) described in this specification, The thiazolylhydrazine of formula (Ib) described in this specification is optionally reacted in a solvent with a dione described in this specification under conditions sufficient to form a hydrazone, The hydrazone is reacted with an alkyl halide described in this specification to obtain a halopyrazolylthiazole of formula (Ia), The halopyrazolylthiazole of formula (Ia) described in this specification is optionally reacted in a solvent with an organic boron containing an R 5 moiety to obtain a compound of formula (I), and includes.

[0043] The inventors have found that the Suzuki coupling is particularly advantageous for preparing the compounds of formula (I). The Suzuki coupling is well known to those skilled in the art, and a comprehensive guide to suitable catalysts and coupling conditions can be found in J.P. Wolfe and J.S. Nakhla, Name Reactions for Homologations. The Suzuki Reaction. John Wiley & Sons, Inc. (2009), Pt. 1: 163 - 184, which is hereby incorporated by reference in its entirety.

[0044] Generally, the coupling reaction is carried out in the presence of a catalyst, optionally in the presence of a base. Catalysts suitable for the Suzuki coupling include palladium catalysts. Examples of palladium catalysts include tetrakis(triphenyl-phosphine)palladium(0) (Pd(PPh3)4), tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2), bis(triphenylphosphine)palladium(II) dichloride (PdCl2(PPh3)2), palladium(II) acetate (Pd(OAc)2, (Pd(OAc)2 / triphenylphosphine (PPh3), (Pd(OAc)2 / tricyclohexylphosphine (PCy3), (Pd(OAc)2 / tri(o-tolyl)phosphine (PTol3), etc., but are not limited thereto. Catalysts suitable for the Suzuki coupling also include nickel catalysts, for example, bis(1,5-cyclooctadiene)nickel(0) (Ni(cod)2), nickel(II) chloride ethylene glycol dimethyl ether complex (NiCl2-glyme), bis(triphenylphosphine)nickel(II) dichloride (NiCl2(PPh3)2), etc.

[0045] The catalyst is provided in an amount sufficient to catalyze the coupling reaction. For example, in certain embodiments, the amount of the catalyst is 20 mol% or less, such as 15 mol% or less, or 10 mol% or less, or 5 mol% or less, or 3 mol% or less, based on the amount of the halopyrazolylthiazole. In certain embodiments, the amount of the catalyst is in the range of 0.1 mol% to 20 mol%, such as 0.1 mol% to 15 mol%, or 0.1 mol% to 10 mol%, or 0.1 mol% to 5 mol%, 0.1 mol% to 1 mol%, or 1 mol% to 20 mol%, or 1 mol% to 15 mol% or 1 mol% to 10 mol%, or 1 mol% to 5 mol%, or 5 mol% to 20 mol%, or 5 mol% to 15 mol%, or 5 mol% to 10 mol%, based on the amount of the halopyrazolylthiazole. In certain embodiments, the amount of the catalyst is in the range of 8 mol% to 20 mol%, such as 8 mol% to 15 mol%, or 8 mol% to 12 mol%, or 8 mol% to 10 mol%, or 10 mol% to 20 mol%, or 10 mol% to 15 mol%, or 15 mol% to 20 mol%, based on the amount of the halopyrazolylthiazole.

[0046] Suitable bases for use in the Suzuki coupling include, for example, carbonates (such as potassium carbonate, sodium carbonate, cesium carbonate, thallium(I) carbonate, etc.), acetates (such as potassium acetate, cesium acetate, etc.), phosphates (such as tripotassium phosphate), hydroxides (such as potassium hydroxide, sodium hydroxide, etc.), alkoxides (such as sodium ethoxide, thallium(I) ethoxide, etc.), amines (such as triethylamine), and basic fluoride salts (potassium fluoride, sodium fluoride, and cesium fluoride).

[0047] In certain embodiments, the suitable base can be provided in a stoichiometric amount. For example, in certain embodiments, the amount of the base is at least 1 molar equivalent, such as at least 1.5 molar equivalents, or at least 2 molar equivalents, or at least 2.5 molar equivalents, or at least 3 molar equivalents, based on the amount of the halopyrazolylthiazole.

[0048] In certain embodiments, the coupling of the halopyrazolylthiazole with the organoboron can be carried out in the presence of Pd(dppf)Cl2 and a carbonate (e.g., potassium carbonate).

[0049] The coupling of the halopyrazolylthiazole with the organoboron as described elsewhere herein can, in certain embodiments, be reacted in a solvent. Suitable solvents include, but are not limited to, dioxane, toluene, THF, DMF, dichloromethane, water, and combinations thereof. In certain embodiments, the solvent is one or more of water and dioxane, toluene, or DMF. In some embodiments, the ratio of water to one or more of dioxane, toluene, or DMF in the solvent is from 2:1 to 1:5, such as the ratio is from 1:1 to 1:5, or from 1:1 to 1:4, or from 1:2 to 1:5, or from 1:2 to 1:4, or from 1:3 to 1:5, or from 2:1 to 1:2, or from 2:1 to 1:2.

[0050] In the method for preparing the compound of formula (I), any organoboron carrying the R 5 moiety optimal for the Suzuki reaction may be used. For example, specific organoborons suitable for the methods of the present disclosure include boronic acids and boronic esters having R 5 substituted on boron,

Chemical formula

[0051] In certain embodiments, the organoboron is 2-R 5 -4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 2-R 5 -boronic acid, 2-R 5 -5,5-dimethyl-1,3,2-dioxaborinane, or 2-R 5 -1,3,2-dioxaborinane. In certain embodiments, the organoboron is 2-R 5 -4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0052] The halopyrazolylthiazole and the organoboron can be coupled at a temperature and for a time sufficient to obtain the compound of formula (I).

[0053] For example, in certain embodiments, the halopyrazolylthiazole and the organoboron are coupled at a temperature of at least 80°C, such as at least 85°C, or at least 90°C, or at least 95°C, or at least 100°C, or at least 110°C. In certain embodiments, the halopyrazolylthiazole and the organoboron are coupled at a temperature in the range of 80°C to 120°C, such as 80°C to 110°C, or 80°C to 100°C, or 80°C to 90°C, or 90°C to 120°C, or 90°C to 110°C, or 90°C to 100°C, or 100°C to 120°C, or 100°C to 110°C.

[0054] In certain embodiments, the halopyrazolyl thiazole and the organoboron are coupled for at least 8 hours. For example, in various embodiments, the halopyrazolyl thiazole and the organoboron may be coupled for at least 10 hours, such as at least 12 hours, or at least 14 hours, or at least 16 hours. In another embodiment, the halopyrazolyl thiazole and the organoboron are coupled for a time ranging from 8 hours to 24 hours. For example, in various embodiments, the halopyrazolylthiazole and organoborane may be coupled for a time ranging from 8 hours to 20 hours, or from 8 hours to 16 hours, or from 8 hours to 14 hours, or from 8 hours to 12 hours, or from 8 hours to 10 hours, or from 10 hours to 24 hours, or from 10 hours to 20 hours, or from 10 hours to 16 hours, or from 10 hours to 14 hours, or from 10 hours to 12 hours, or from 14 hours to 24 hours, or from 14 hours to 20 hours, or from 14 hours to 18 hours, or from 14 hours to 16 hours, or from 16 hours to 24 hours, or from 16 hours to 20 hours, or from 16 hours to 18 hours, or from 18 hours to 24 hours, or from 18 hours to 20 hours.

[0055] In certain embodiments of the methods described herein, the desired compound of formula (I) is a compound where Q is -C(O)OH, e.g., a compound of formula [ka] Compounds of or a pharma- ceutically acceptable salt thereof. Such methods include, for example, hydrolysis (e.g., Q 1 But -C(O)OR 2C and R 2C In certain embodiments, the methods described herein may further comprise converting the coupling reaction product to the corresponding carboxylic acid by hydrolyzing the compound of formula (I) where Q is a C1-C3 alkyl or a protecting group. 1 is -C(O)O(C1-C3 alkyl) to provide the corresponding carboxylic acid or carboxylate.

[0056] In certain embodiments, the methods described herein are Q 1 further comprising hydrolyzing a compound of formula (I) wherein Q is -C(O)O(C1-C3 alkyl) to obtain a carboxylate salt of the compound of formula (I) and crystallizing the salt of the compound of formula (I).

[0057] The method can further comprise converting the salt to the corresponding carboxylic acid. In certain embodiments, the salt is treated with an acid to obtain the carboxylic acid compound of formula (I). In certain embodiments of this method, the compound of formula (I) is obtained with a purity of at least 98%.

[0058] Certain embodiments of the methods described herein are when the compound has any of the above structural formulas (I)-(Ib), for example, structural formula (I), (Ia), or (Ib), wherein the variables are as described elsewhere in any of the embodiments herein, and R 1 is optionally substituted C1-C8 alkyl. In certain embodiments, R 1 is unsubstituted C1-C8 alkyl or fluorinated C1-C8 alkyl. In certain embodiments, R 1 is unsubstituted C1-C8 alkyl. In certain embodiments, R 1 is optionally substituted C1-C5 alkyl. In certain embodiments, R 1 is unsubstituted C1-C5 alkyl or fluorinated C1-C5 alkyl. In certain embodiments, R 1 is unsubstituted C1-C5 alkyl. In certain embodiments, R 1 is optionally substituted C2-C5 alkyl. In certain embodiments, R 1 is unsubstituted C2-C5 alkyl or fluorinated C2-C5 alkyl. In certain embodiments, R 1 is unsubstituted C2-C5 alkyl. In certain embodiments, R 1 is hydroxymethyl, methoxymethyl, hydroxyethyl, or methoxyethyl. In certain embodiments, R 1is methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl. In certain embodiments, R 1 is propyl, isopropyl, butyl, or tert-butyl. In certain embodiments, R 1 is isopropyl.

[0059] Other embodiments of the methods described elsewhere herein are those in which the compound has any of the above structural formulas (I)-(Ib), wherein the variables are as otherwise described in any of the embodiments herein, and L 1 is a bond, -O-, -S-, -S(O)-, or -S(O)2-. In certain embodiments, L 1 is -O-, -S-, -S(O)-, or -S(O)2-. In certain embodiments, L 1 is -S-, -S(O)-, or -S(O)2-. In certain embodiments, L 1 is -S-. In certain embodiments, L 1 is a bond. In certain embodiments, L 1 is -O- or L 1 is -NR 6 -.

[0060] Other embodiments of the methods described elsewhere herein are those in which the compound has any of the above structural formulas (I)-(Ib), wherein the variables are as otherwise described in any of the embodiments herein, and R 3 is (each (i)-L 3C -(phenyl optionally substituted with 1-5 R 3D ), -L 3C -(heteroaryl optionally substituted with 1-5 R 3D ), -L 3C -(cycloalkyl optionally substituted with 1-5 R 3D ), -L 3C -(heterocycloalkyl optionally substituted with 1-5 R 3D ), optionally substituted with one substituent selected from, and (ii) 1-5 R 3Eis optionally substituted and is aryl or heteroaryl. In certain embodiments, R 3 is (i) -L 3C -(phenyl optionally substituted with 1-5 R 3D ), -L 3C -(heteroaryl optionally substituted with 1-5 R 3D ), -L 3C -(cycloalkyl optionally substituted with 1-5 R 3D ), -L 3C -(heterocycloalkyl optionally substituted with 1-5 R 3D ), and is optionally substituted with one substituent selected from the group consisting of, and (ii) phenyl optionally substituted with 1-5 R 3E . In certain embodiments, R 3 is (i) -L 3C -(phenyl optionally substituted with 1-5 R 3D ), -L 3C -(heteroaryl optionally substituted with 1-5 R 3D ), -L 3C -(cycloalkyl optionally substituted with 1-5 R 3D ), -L 3C -(heterocycloalkyl optionally substituted with 1-5 R 3D ), and is optionally substituted with one substituent selected from the group consisting of, and (ii) phenyl optionally substituted with 1-5 R 3E . In certain embodiments, R 3 is (i) -L 3C -(phenyl optionally substituted with 1-5 R 3D ), -L 3C -(heteroaryl optionally substituted with 1-5 R 3D ), -L 3C -(cycloalkyl optionally substituted with 1-5 R 3D ), -L 3C -(heterocycloalkyl optionally substituted with 1-5 R 3D ), and is substituted with one substituent selected from the group consisting of, and (ii) phenyl optionally substituted with 1-5 R 3Eis optionally substituted heteroaryl (e.g., isothiazole, pyridone, thiadiazole, pyrazine, imidazole, benzofuran, indole, pyridine, pyrazole, isoxazole, thiophene, furan, or pyrimidine). In certain embodiments, R 3 is (i) -L 3C -(phenyl optionally substituted with 1-5 R 3D ), -L 3C -(monocyclic heteroaryl optionally substituted with 1-5 R 3D ), -L 3C -(cycloalkyl optionally substituted with 1-5 R 3D ), -L 3C -(heterocycloalkyl optionally substituted with 1-5 R 3D ), and is substituted with one substituent selected from the group consisting of and (ii) heteroaryl (e.g., isothiazole, pyridone, thiadiazole, pyrazine, imidazole, benzofuran, indole, pyridine, pyrazole, isoxazole, thiophene, furan, or pyrimidine) optionally substituted with 1-5 R 3E . In certain embodiments, R 3 is each (i) -L 3C -(phenyl optionally substituted with 1-5 R 3D ), -L 3C -(heteroaryl optionally substituted with 1-5 R 3D ), -L 3C -(cycloalkyl optionally substituted with 1-5 R 3D ), -L 3C -(heterocycloalkyl optionally substituted with 1-5 R 3D ), and is substituted with one substituent selected from the group consisting of and (ii) optionally substituted with 1-5 R 3E , and is selected from the group consisting of phenyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, pyridinyl, pyrazinyl, pyridonyl, thiadiazolyl, pyrazolyl, triazolopyridinyl, thienyl, furanyl, and pyrimidinyl.

[0061] In certain other embodiments of the methods described elsewhere herein, the compound has any of the above structural formulas (I)-(Ia), wherein the variables are as described elsewhere in any of the embodiments herein, and R 3 is phenyl optionally substituted with 1 to 5 R 3E . In certain embodiments, R 3 is phenyl optionally substituted with 1 to 2 R 3E . In certain embodiments, R 3 is phenyl optionally substituted with R 3E . In certain embodiments, R 3 is phenyl substituted with 1 to 2 R 3E . In certain embodiments, R 3 is phenyl substituted with R 3E . R 3 is heteroaryl (e.g., isothiazole, pyridone, thiadiazole, pyrazine, imidazole, benzofuran, indole, pyridine, pyrazole, isoxazole, thiophene, furan, or pyrimidine) optionally substituted with 1 to 5 R 3E . In certain embodiments, R 3 is selected from the group consisting of phenyl and heteroaryl (e.g., pyridyl, pyrazolyl) optionally substituted with 1 to 5 R 3E . In certain embodiments, R 3 is phenyl substituted with halogen. In certain embodiments, R 3 is 3-fluorophenyl.

[0062] Certain other embodiments of the methods described elsewhere herein are those in which the compound has any of the above structural formulas (I)-(Ia), wherein the variables are as described elsewhere in any of the embodiments herein, and each R 3E is independently selected from C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -OR 3F , and -NR 3G R 3F . In certain embodiments, each R 3E is halogen, -OR3F and -NR 3G R 3F is independently selected from. In certain embodiments, each R 3E is independently selected from C1-C4 alkyl, C1-C4 fluoroalkyl, and halogen. In certain embodiments, each R 3E is independently selected from C1-C4 alkyl, halogen, -OR 3F and -NR 3G R 3F is independently selected from. In certain embodiments, each R 3E is independently selected from C1-C4 fluoroalkyl and halogen. In certain embodiments, each R 3E is independently halogen.

[0063] Certain other embodiments of the methods described elsewhere herein are those in which the compound has any of the above structural formulas (I)-(Ia), wherein the variables are as otherwise described in any of the embodiments herein, and each R 4 is optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkenyl, or optionally substituted C1-C8 alkynyl. In certain embodiments, R 4 is optionally substituted C1-C8 alkyl. In certain embodiments, R 4 is hydrogen or unsubstituted C1-C6 alkyl. In certain embodiments, R 4 is unsubstituted C1-C3 alkyl. In certain embodiments, R 4 is unsubstituted methyl.

[0064] Certain other embodiments of the methods described elsewhere herein are those in which the compound has any of the above structural formulas (I), wherein the variables are as otherwise described in any of the embodiments herein, and R 5 is phenyl or heteroaryl (e.g., isoxazolyl, pyridyl, pyrazolyl) each optionally substituted with 1-5 R 5E . In certain embodiments, R 5 is 1-5 R 5Eis a heterocycloalkyl optionally substituted with R. In certain embodiments, R 5 is a cycloalkyl optionally substituted with 1 to 5 R 5E In certain embodiments, R 5 is a cycloalkyl substituted with 1 to 5 R 5E In certain embodiments, R 5 is an unsaturated cycloalkyl optionally substituted with 1 to 5 R 5E In certain embodiments, R 5 is an unsaturated cycloalkyl substituted with 1 to 5 R 5E In certain embodiments, R 5 is cyclohexenyl substituted with R 5E In certain embodiments, R 5 is 4-(trifluoromethyl)cyclohex-1-en-1-yl.

[0065] In certain other embodiments of the methods described herein, the compound has any of the above structural formulas (I), wherein the variables are as otherwise described in any of the embodiments herein, and Q is -C(O)OR 2A or -C(O)NR 2B R 2A In certain embodiments, Q is -C(O)OR 2A In certain embodiments, Q is -C(O)OH, or -C(O)O(C1-C3 alkyl). In certain embodiments, Q is -C(O)OH.

[0066] In certain embodiments of the methods of the present disclosure, the compound of formula (I) is 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid in the form of any pharmaceutically acceptable salt and / or solvate or hydrate.

[0067] In certain embodiments of the methods of the present disclosure, the compound of formula (I) is 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid C1-C3 alkyl, optionally in the form of a solvate or hydrate. In certain embodiments of the methods of the present disclosure, the compound of formula (I) is 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid ethyl, optionally in the form of a solvate or hydrate.

[0068] Certain other embodiments of the methods described herein are those in which the compound has any of the above structural formulas (Ia), wherein the variables are as otherwise described in any of the embodiments herein, and Q 1 is -C(O)OR 2C or -C(O)NR 2B R 2C is. In certain embodiments, Q 1 is -C(O)OR 2C is. In certain embodiments, Q 1 is -C(O)O(C1-C3 alkyl). In certain embodiments, Q 1 is -C(O)O(ethyl). In certain embodiments, Q 1 is -C(O)OR 2C is, and R 2C is a protecting group.

[0069] In certain embodiments of the methods of the present disclosure, the compound of formula (Ia) is

Chemical formula

[0070] In certain embodiments of the methods of the present disclosure, the compound of formula (Ia) is

Chemical formula

[0071] In certain embodiments of the methods of the present disclosure, the pyrazolylthiazole of formula (Ia) is 1-(4-halo-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid C1-C3 alkyl. In certain embodiments of the methods of the present disclosure, the pyrazolylthiazole of formula (Ia) is ethyl 1-(4-bromo-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylate. Definitions

[0072] As used herein, terms can indicate the order of attachment between a named substituent and its parent moiety by the presence of a single line "-", or a double line "=", either preceding or following. A single line indicates a single bond, a double line indicates a double bond, or, in the case of a spiro substituent, a pair of single bonds. In the absence of a single or double line, a single bond is understood to be formed between the substituent and its parent moiety, and further, the substituent is intended to be read "left to right" with respect to the chemical structure, unless otherwise indicated. For example, arylalkyl, arylalkyl-, and -alkylaryl denote the same functional group.

[0073] For simplicity, chemical moieties are consistently defined primarily as monovalent chemical moieties (e.g., alkyl, aryl, etc.) and referred to as such. Nevertheless, such terms are also used to convey the corresponding polyvalent moieties in the context of appropriate structural situations that are clear to those skilled in the art. For example, while an “alkyl” moiety can mean a monovalent group (e.g., CH3-CH2-), in some situations, the divalent linking moiety can be “alkyl,” in which case those skilled in the art will understand that the alkyl is a divalent group equivalent to the term “alkylene” (e.g., -CH2-CH2-). (Similarly, in situations where a divalent moiety is required and described as “aryl,” those skilled in the art will understand that the term “aryl” means arylene, the corresponding divalent moiety.) All atoms are understood to have their normal valences (i.e., carbon is 4, N is 3, O is 2, and S is 2, 4, or 6 depending on the oxidation state of S) to form bonds. Nitrogen in the compounds disclosed herein can have hypervalency, for example, it can be an N-oxide or a tetra-substituted ammonium salt. In some cases, a moiety can be defined, for example, as -B-(A) a , (wherein a is 0 or 1). In such an example, when a is 0, the moiety is -B, and when a is 1, the moiety is -B-A.

[0074] As used herein, the term "alkyl" includes saturated hydrocarbons having the specified number of carbons, e.g., from 1 to 10 carbons (i.e., including 1 and 10), from 1 to 8 carbons, from 1 to 6 carbons, from 1 to 3 carbons, or having 1, 2, 3, 4, 5, or 6 carbons. An "alkyl group" can be straight-chain or branched-chain and, depending on the context, can be a monovalent group or a divalent group (i.e., an alkylene group). For example, the moiety "-(C1-C6 alkyl)-O-" means connection of oxygen via an alkylene bridge having from 1 to 6 carbons, and C1-C3 alkyl represents methyl, ethyl, and propyl moieties. Examples of "alkyl" include, for example, methyl, ethyl, propyl, isopropyl, butyl, iso-, sec-, and tert-butyl, pentyl, and hexyl.

[0075] The term "alkoxy" represents an alkyl group having the indicated number of carbon atoms bonded to the parent molecular moiety via an oxygen bridge. Examples of "alkoxy" include, for example, methoxy, ethoxy, propoxy, and isopropoxy.

[0076] As used herein, the term "alkenyl", unless otherwise specified, is an unsaturated hydrocarbon containing from 2 to 10 carbons (i.e., including 2 and 10), from 2 to 8 carbons, from 2 to 6 carbons, or having 2, 3, 4, 5, or 6 carbons and containing at least one carbon-carbon double bond. An alkenyl group can be straight-chain or branched-chain and, depending on the context, can be a monovalent group or a divalent group (i.e., an alkenylene group). For example, the moiety "-(C2-C6 alkenyl)-O-" means connection of oxygen via an alkenylene bridge having from 2 to 6 carbons. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, 3-decenyl, and 3,7-dimethylocta-2,6-dienyl.

[0077] As used herein, the term "alkynyl", unless otherwise specified, contains 2 to 10 carbons (i.e., including 2 and 10), 2 to 8 carbons, 2 to 6 carbons, or 2, 3, 4, 5, or 6, and contains at least one carbon-carbon triple bond, is an unsaturated hydrocarbon. The alkynyl group can be linear or branched and, depending on the context, can be a monovalent group or a divalent group (i.e., an alkynylene group). For example, the moiety "-(C2-C6 alkynyl)-O-" means the connection of oxygen via an alkynylene bridge having 2 to 6 carbons. Representative examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

[0078] The term "halogen" or "halo" refers to fluorine, chlorine, bromine, and iodine. In certain embodiments of any of the embodiments described herein, the term "halogen" or "halo" means fluorine, chlorine, or bromine. The term "fluoroalkyl" refers to an alkyl group substituted with at least one fluorine (i.e., as otherwise described herein). "Fluoroalkyl" includes alkyl groups substituted with multiple fluorines such as perfluoroalkyl groups. Examples of fluoroalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 1,1,1,3,3,3-hexafluoropropan-2-yl, and 2,2,3,3,3-pentafluoropropan-1-yl.

[0079] The term "heteroaryl" means an aromatic ring system containing at least one aromatic heteroatom selected from nitrogen, oxygen, and sulfur within the aromatic ring. Most commonly, the heteroaryl group has 1, 2, or 3 heteroatoms. In one embodiment of the present compound, the heteroaryl group is attached to the rest of the structure via an atom in the heteroaryl group aromatic ring. In another embodiment, the heteroaryl group is attached to the rest of the structure via a non-aromatic ring atom.

[0080] The term "heterocycloalkyl" means a non-aromatic ring containing a heteroatom present in at least one non-aromatic ring, preferably selected from nitrogen, oxygen, and sulfur. Heterocycloalkyl can have 1, 2, or 3 heteroatoms. Heterocycloalkyl can be saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., heterocycloalkenyl). In certain embodiments, the heterocycloalkyl group has 3 to 7 members in one ring. In other embodiments, the heterocycloalkyl group has 5 or 6 members in one ring. In some embodiments, the heterocycloalkyl group has 3, 4, 5, 6, or 7 members in one ring. Examples of heterocycloalkyl groups include, for example, morpholinyl, thiomorpholinyl, 2-oxazolidinonyl, piperazinyl, homopiperazinyl, piperazinonyl, pyrrolidinyl, azepanyl, azetidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, tetrahydrofuranyl, tetrahydrothienyl, homopiperidinyl, homomorpholinyl, homothiomorpholinyl, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, imidazolidinonyl, and tetrahydrothienyl. Particularly desirable heterocycloalkyl groups include morpholinyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, piperazinyl, azepanyl, azetidinyl, thiomorpholinyl, 2-oxazolidinonyl, imidazolidinonyl, and piperazinonyl.

[0081] The term "cycloalkyl" means a non-aromatic carbocyclic ring or ring system that can be saturated (i.e., cycloalkyl) or partially unsaturated (i.e., cycloalkenyl). Specific examples of cycloalkyl groups present in the disclosed compounds have 3 to 7 members in one ring, for example, 5 or 6 members in one ring. In some embodiments, the cycloalkyl group has 3, 4, 5, 6, or 7 members in one ring. Examples of cycloalkyl groups include, for example, cyclohexyl, cyclohexenyl, cyclopentyl, cyclobutyl, and cyclopropyl. The cycloalkyl groups herein are unsubstituted or, when specified as "optionally substituted", can be substituted with various groups as shown at one or more substitutable positions.

[0082] The term "oxo" means double-bonded oxygen and can be represented as =O in some cases or, for example, in the description of carbonyl, "C(O)" can be used to indicate an oxo-substituted carbon.

[0083] When used to modify a particular group or radical, the term "substituted" means that one or more hydrogen atoms of the specified group or radical are each independently replaced with the same or different substituents as defined below, unless otherwise specified.

[0084] As used herein, the term "pharmaceutically acceptable salt" means both pharmaceutically acceptable acid and base addition salts, as well as solvates. Such pharmaceutically acceptable salts include salts of acids such as hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, sulfinic acid, formic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, benzoic acid, citric acid, tartaric acid, maleic acid, hydroiodic acid; acetic acid, HOOC-(CH2) n -COOH [where n is 0 - 4] and other alkanoic acids, and salts of acids. Non-toxic pharmaceutically acceptable base addition salts include salts of bases such as sodium, potassium, calcium, ammonium, etc. Those skilled in the art will recognize various non-toxic, pharmaceutically acceptable addition salts.

[0085] As used herein, a "leaving group" (e.g., suitable as X 1 ) means the portion of a reactant that has been replaced from a first reactant in a chemical reaction (e.g., an alkyl halide of the present disclosure). A comprehensive list of suitable leaving groups can be found in J. March, Advanced Organic Chemistry, John Wiley and Sons, N.Y. (2013). Examples of suitable leaving groups include, but are not limited to, halogen (such as Cl or Br), acetoxy, and sulfonyloxy groups (methylsulfonyloxy, trifluoromethylsulfonyloxy ("triflate"), p-toluenesulfonyloxy ("tosylate"), etc.).

[0086] As used herein, a "protecting group" (e.g., suitable as R 2A or R 2C ) means a group that is stable under the conditions of subsequent reactions at other positions of the molecule and can be removed at an appropriate point without destroying the remainder of the molecule to obtain unprotected Q or Q 1 . Suitable protecting groups are groups that are protected in the methods of the present disclosure (e.g., Q or Q 1It may be selected according to the properties of ) and the conditions used. A comprehensive list of suitable protecting groups can be found in T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. (1999), and this disclosure is hereby incorporated by reference in its entirety. For example, a carboxylic acid moiety may be in the form of an ester having an alkyl or substituted alkyl group (e.g., methyl, ethyl, tert-butyl allyl, triphenylmethyl (trityl), etc.) or an ester having an arylalkyl or substituted arylalkyl group (e.g., benzyl, e.g., 4-nitrobenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, etc.), in the form of a thioester (e.g., tert-butyl thioester), in the form of a silyl ester (e.g., trimethylsilyl, tert-butyldimethylsilyl), etc. The amide moiety may be protected in the form of a carbamate having an alkyl or substituted alkyl group (e.g., tert-butyl carbamate).

Example

[0087] The methods of the present disclosure are further illustrated by the following examples, which should not be construed as limiting the present disclosure in scope and spirit to the specific procedures and reagents described therein.

[0088] Example 1: Preparation of 4-bromo-2-hydrazinyl-5-(isopropylthio)thiazole (Compound 4)

Chem.

[0089] The solvent was removed under reduced pressure, and the resulting oil was dissolved in dichloromethane (850 mL). The resulting solution was cooled to 2 °C in an ice bath, and a solution of bromine (86.8 g, 0.543 mmol) in heptane (100 mL) was added dropwise over 60 minutes. The solution was stirred for 1 hour and then warmed to room temperature (20 - 22 °C) over 18 hours. Then, sodium thiosulfate (30 g) in water (500 mL) was added and the mixture was stirred for 1 hour. The aqueous phase was extracted with dichloromethane (200 mL), the combined organic phases were washed with brine (100 mL), and the solvent was removed under reduced pressure.

[0090] Next, this oily substance was dissolved in tetrahydrofuran (1.0 L), and 50% hydrazine in water (150 mL, 2.5 mol) was added. The two-phase mixture was stirred at room temperature (20 - 23 °C) for 30 hours. Then, the organic layer was concentrated to 175 mL, and heptane (250 mL) was added dropwise over 20 minutes. Seed crystals (10 mg) of the title compound were added, and the mixture was stirred for 1 hour. Then, when heptane (250 mL) was added, rapid crystallization occurred. The mixture was cooled to 5 °C, filtered, and washed with heptane (2 × 250 mL). The filtrate was concentrated under reduced pressure to 700 mL, cooled to 2 °C overnight, filtered, and washed with heptane (2 × 100 mL). The combined solids from the furnace process were air-dried to obtain the title compound (79.5 g, 72%) as a pale beige solid. 1 H NMR (500 MHz, CDCl3) δ 8.66 (br, 1H), 4.16 (br, 2H), 3.17 (m, 1H), 1.28 (s, 6H). 13 C NMR (500 MHz, CDCl3) δ 176.48, 130.48, 111.51, 41.44, 23.06. MS (m / z): 268 [M + 1] + 。

[0091] Example 2: Recrystallization of Compound 4 A 12 L flask was charged with Compound 4 (186.6 g, 0.6957 mol) and isopropyl alcohol (2 L). The slurry was warmed to 65 °C, and water (2 L) was added to form a homogeneous solution. The contents were cooled to 35 °C, and additional water (500 mL) was added dropwise over 30 minutes, upon which crystallization ensued. The mixture was stirred for 1 hour, and then water (1.5 L) was added over 1.5 hours. The resulting slurry was stirred overnight and then cooled to 10 °C. The mixture was filtered, washed with cold (5 °C) isopropanol:water (1:2) (3 × 500 mL), and dried overnight to obtain the title compound as a pale beige solid (166.2 g, 90.2%).

[0092] Example 3: Preparation No.1 of Ethyl 2-(4-bromo-5-isopropylsulfanyl-thiazol-2-yl)-4-(3-fluorophenyl)-5-methyl-pyrazole-3-carboxylate (Compound 8)

Chemical Structure

[0093] Example 4: Preparation No.2 of Compound 8

Chemical Structure

[0094] Example 5: Preparation of Ethyl 4-(3-fluorophenyl)-2-[5-isopropylsulfanyl-4-[4-(trifluoromethyl)cyclohexen-1-yl]thiazol-2-yl]-5-methyl-pyrazole-3-carboxylate (Compound 10)

Chemical formula

[0095] Example 6: Sodium 4-(3-fluorophenyl)-2-[5-isopropylsulfanyl-4-[4-(trifluoromethyl)cyclohex-1-en-1-yl]thiazol-2-yl]-5-methyl-pyrazole-3-carboxylate (Compound 11) [Chemical formula] To a solution of methanol (150 mL) and tetrahydrofuran (75 mL), Compound 10 (17.83 g, 28.79 mmol) was added. An aqueous sodium hydroxide solution (1.0 N, 64 mL) was added, and the resulting slurry was heated at 50 °C for 2.5 hours. It was evaporated under reduced pressure to obtain a beige solid, which was stirred with deionized water (3 × 500 mL) and filtered. The solid was dried under reduced pressure until a constant weight was obtained, and then suspended in acetonitrile (100 mL). After 15 minutes, the mixture was filtered to obtain the title compound (14.00 g, 89%). 1 1H NMR (500 MHz, DMSO-d6) δ 7.40 - 7.50 (m, 1H), 7.35 (t, 2H), 7.10 (t, 2H), 6.40 (s, 1H), 3.25 (quintet, 1H), 2.25 (d, 1H), 2.55 (br, 1H), 2.45 (s, 3H), 2.25 (s, 3H), 2.10 (d, 1H), 1.55 (m, 1H), 1.23 (s, 6H). 13 13C{ 11H NMR (500 MHz, DMSO-d6) δ 163.49, 162.98, 161.56, 158.98, 155.35, 149.20, 143.75, 135.74, 131.92, 130.32, 127.41, 125.02, 118.26, 115.68, 113.44, 42.29, 37.34, 26.85, 24.60, 23.18, 21.75, 13.42. 19 19F NMR (500 MHz, DMSO-d6) δ -72.06 (s), -113.60 (quintet). MS (m / z): 525.85 [M - Na + 2] + .

[0096] Example 7: Recrystallization of Compound 11 Next, Compound 11 was crystallized. 56 g (0.10 mol) of Compound 11 was dissolved in tetrahydrofuran (500 mL) and filtered. Acetonitrile (250 mL) was added to this solution, and the solution was concentrated to 350 mL at 50 °C under reduced pressure. Acetonitrile (250 mL) was added again, and the resulting solution was concentrated to 300 mL at 50 °C under reduced pressure to cause crystallization. Acetonitrile (250 mL) was added to this mixture, and it was concentrated again to 500 mL at 50 °C under reduced pressure. Then, the mixture was stirred at 50 °C for 1 hour, then cooled to 20 °C for 1 hour, and then to 0 °C for 30 minutes. The resulting mixture was filtered, and the solid was washed with cold acetonitrile (2 × 100 mL, 0 °C) and dried at 35 °C under reduced pressure to give Compound 11 (54.7 g, 98%). MS (m / z): 525.85 [M - Na + 2] + . 1 1H NMR (500 MHz, DMSO-d6) δ 14.16 (br s, 1H), 7.50 - 7.55 (m, 1H), 7.23 - 7.31 (m, 3H), 6.44 (m, 1H), 3.32 (m, 1H), 2.68 - 2.74 (m, 1H), 2.55 - 2.64 (m, 1H), 2.43 - 2.55 (m, 1H), 2.30 (s, 3H), 2.20 - 2.30 (m, 1H), 2.02 - 2.09 (m, 1H), 1.50 - 1.60 (m, 1H), 1.26 (d, 6H, J = 7.5 Hz). 1313C NMR (126 MHz, DMSO-d6) δ 163.51, 162.37, 161.58, 157.70, 154.94, 150.62, 133.49, 132.86, 132.79, 131.44, 131.23, 131.16, 129.80, 127.98, 127.59, 125.55, 125.52, 125.38, 122.20, 120.09, 116.14, 115.96, 115.35, 115.19, 42.50, 26.71, 24.56, 23.15, 23.07, 21.64, 12.76.

[0097] Example 8: 4-(3-Fluorophenyl)-2-[5-isopropylsulfanyl-4-[4-(trifluoromethyl)-cyclohex-1-en-1-yl]thiazol-2-yl]-5-methyl-pyrazole-3-carboxylic acid (Compound 1) [Chemical formula] Into a 5 L flask was placed Compound 11 (52.0 g, 94.9 mmol) and 10% acetonitrile in deionized water (1.0 L). The mixture was stirred for 30 minutes and then warmed to 50 °C. A seed of the title compound (1.2 g) was added, and then 0.1 N HCl (1.0 L) was added dropwise over 3.75 hours. As the addition proceeded, a change to a thicker slurry was observed. Each addition of the acid produced a yellow color, but it was also observed that the color disappeared upon stirring. The pH of the supernatant was monitored after the addition of 900 mL of the acid. As the addition approached 1.0 equivalent, the pH dropped to about 3, and the target pH was <4 to ensure complete protonation.

[0098] Samples were taken for analytical assays (XRPD, HPLC), the pH of the filtrate of the sample was measured to be 4.3 with a pH meter, and an additional 20 mL of 0.1 N HCl was added to the reaction mixture. The heating regulator was turned off and the mixture was cooled to 19 °C and stirred for 18 hours. The reaction product was filtered using a sintered glass funnel and washed with the mother liquor and subsequently deionized water (3 × 330 mL). The cake was dried in a vacuum drying oven set at 45 °C and >30 in. vacuum with a slight nitrogen bleed to obtain the title compound (51.76 g, 99% yield). 1 H NMR (500 MHz, DMSO-d6) δ 14.16 (s, 1H), 7.50 - 7.55 (m, 1H), 7.25 - 7.30 (m, 3H), 6.44 (s, 1H), 3.28 - 3.34 (quintet, 1H), 2.69 - 2.73 (d, 1H), 2.44 - 2.48 (m, 2H), 2.29 (s, 3H) 2.24 - 2.27 (m, 2H), 2.04 - 2.08 (m, 1H), 1.51 - 1.59 (m, 1H), 1.26 (d, 6H). 13 C NMR (500 MHz, CDCl3) δ 163.46, 162.46, 161.51, 156.70, 152.70, 152.35, 133.41, 132.85, 131.94, 131.03, 129.76, 125.39, 121.61, 116.79, 115.22, 42.69, 37.92, 26.89, 24.68, 23.02, 21.48, 12.30. 19 F NMR (500 MHz, CDCl3) δ -73.62 (s), -113.17 (quintet). MS (m / z): 526.3 [M+1] + .

[0099] The various exemplary embodiments of the present disclosure include, but are not limited to, the following listed embodiments, which can be combined in any number and any combination that is not technically or logically inconsistent. Embodiment 1. A method for preparing a halopyrazolylthiazole of formula (Ia) wherein

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0100] Throughout this specification, numerous references have been made to patents and printed publications. The cited references and printed publications are hereby incorporated by reference in their entirety into this specification, individually.

[0101] Finally, it should be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the invention. Other modifications that may be employed are within the scope of the invention. Thus, by way of example, but not limitation, alternative configurations of the invention may also be utilized in accordance with the teachings of this specification. Accordingly, the invention is not precisely limited to that which is shown and described.

Claims

1. A method for preparing a halopyrazolylthiazole of formula (Ia), wherein 【Chemical 1】 in the formula,[[]]END]] X is halogen, L １ is selected from the group consisting of a bond, -C(O)-, -S-, -S(O) １－２ -, -O-, -NR ６ -, -C(O)NR ６ -, -NR ６ C(O)-, -C(S)NR ６ -, -NR ６ C(S)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -C(S)O-, -OC(S)-, -C(S)S-, -SC(S)-, -S(O) １－２ O-, -OS(O) １－２ -, -S(O) １－２ NR ６ -, and -NR ６ S(O) １－２ -; R １ is selected from the group consisting of C １ -C ８ -alkyl, C １ -C ８ -alkenyl, and C １ -C ８ -alkynyl, each of which is unsubstituted or fluorinated, Q １ is -C(O)OR ２Ｃ 、-C(O)NR ２Ｂ R ２Ｃ 、-C(O)NR ２Ｂ S(O) ２ R ２Ｃ 、-C(O)NR ２Ｂ S(O) ２ NR ２Ｂ R ２Ｃ 、-S(O) ２ R ２Ｃ 、-N(R ２Ｂ )S(O) ２ R ２Ｃ 、-S(O) ２ NR ２Ｂ R ２Ｃ 、and -C(O)NH - O(C １ -C ３ alkyl) selected from the group consisting of, where Each R ２Ｂ is independently selected from H and C １ -C ３ alkyl, Each R ２Ｃ is independently selected from C １ -C ３ alkyl and a protecting group, R ３ is each independently (i) -L ３Ｃ -(phenyl optionally substituted with 1 to 5 R ３Ｄ ), -L ３Ｃ -(heteroaryl optionally substituted with 1 to 5 R ３Ｄ ), -L ３Ｃ -(cycloalkyl optionally substituted with 1 to 5 R ３Ｄ ), -L ３Ｃ -(heterocycloalkyl optionally substituted with 1 to 5 R ３Ｄ ), and is optionally substituted with one substituent selected therefrom, and (ii) is phenyl or heteroaryl optionally substituted with 1 to 5 R ３Ｅ ​ wherein,[[]]END]] Each L ３Ｃ is a bond, methylene, ethylene, -C(O)-, -S-, -S(O) １－２ -, -O-, or -NR ３Ｇ -, and Each R ３Ｄ is selected from oxo, optionally substituted C １ -C ４ -alkyl, C １ -C ４ -fluoroalkyl, halogen, -CN, -SF ５ , -N ３ , -C(O)R ３Ｆ , -SR ３Ｆ , -S(O) １－２ R ３Ｆ , -OR ３Ｆ , -NR ３Ｇ R ３Ｆ , -C(O)R ３Ｆ , -C(O)NR ３Ｇ R ３Ｆ , -NR ３Ｇ C(O)R ３Ｆ , -C(S)NR ３Ｇ R ３Ｆ , -NR ３Ｇ C(S)R ３Ｆ , -C(O)OR ３Ｆ , -OC(O)R ３Ｆ , -C(O)SR ３Ｆ , -SC(O)R ３Ｆ , -C(S)OR ３Ｆ , -OC(S)R ３Ｆ , -C(S)SR ３Ｆ , -SC(S)R ３Ｆ , -S(O) １－２ OR ３Ｆ , -OS(O) １－２ R ３Ｆ , -S(O) １－２ NR ３Ｇ R ３Ｆ , and -NR ３Ｇ S(O) １－２ R ３Ｆ and is independently selected from Each R ３Ｅ is selected independently from oxo, optionally substituted C １ -C ４ -alkyl, C １ -C ４ -fluoroalkyl, halogen, -CN, -SF ５ , -N ３ , -C(O)R ３Ｆ , -SR ３Ｆ , -S(O) １－２ R ３Ｆ , -OR ３Ｆ , -NR ３Ｇ R ３Ｆ , -C(O)R ３Ｆ , -C(O)NR ３Ｇ R ３Ｆ , -NR ３Ｇ C(O)R ３Ｆ , -C(S)NR ３Ｇ R ３Ｆ , -NR ３Ｇ C(S)R ３Ｆ , -C(O)OR ３Ｆ , -OC(O)R ３Ｆ , -C(O)SR ３Ｆ , -SC(O)R ３Ｆ , -C(S)OR ３Ｆ , -OC(S)R ３Ｆ , -C(S)SR ３Ｆ , -SC(S)R ３Ｆ , -S(O) １－２ OR ３Ｆ , -OS(O) １－２ R ３Ｆ , -S(O) １－２ NR ３Ｇ R ３Ｆ , and -NR ３Ｇ S(O) １－２ R ３Ｆ and is selected independently from Each R ３Ｆ is independently selected from H, C １ -C ３ alkyl, and C １ -C ３ fluoroalkyl, Each R ３Ｇ is independently selected from H, C １ -C ３ alkyl, and C １ -C ３ fluoroalkyl, R ４ is selected from the group consisting of hydrogen, optionally substituted C １ -C ８ -alkyl, optionally substituted C １ -C ８ -alkenyl, and optionally substituted C １ -C ８ -alkynyl wherein,[[]]END]] Each R ６ is selected from the group consisting of hydrogen, C １ -C ３ -alkyl, and -C(O)(C １ -C ３ -alkyl). each optionally substituted alkyl, alkenyl, and alkynyl is unsubstituted, fluorinated, or substituted with one or two hydroxyl groups; each cycloalkyl has 3 to 10 ring carbons and is unsaturated or partially unsaturated; each heterocycloalkyl has 3 to 10 ring members and 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur and is unsaturated or partially unsaturated; each heteroaryl is a 5- to 6-membered monocyclic heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; said method comprising reacting a thiazolylhydrazine of formula (Ib)[[]]END]] 【Chemical Formula 2】 (wherein X, R １ and L １ are as described for formula (Ia)), with a dione of formula (II)[[]]END]] 【Chemical Formula 3】 (wherein R ３ and R ４ are as described for formula (Ia)), under conditions sufficient to form a hydrazone, optionally in a solvent; Contacting the hydrazone with a compound of formula X １ -CH ２ -Q １ (wherein Q １ is as described for formula (Ia) and X １ is a halogen or a leaving group) to obtain the halopyrazolylthiazole of formula (Ia). A method comprising:

2. The method according to claim 1, wherein said hydrazone and said alkyl halide are reacted in the presence of an inorganic iodide and a base.

3. The method according to claim 2, wherein said inorganic iodide is KI or NaI.

4. The method according to claim 2, wherein the amount of the inorganic iodide is at least 1 molar equivalent based on the amount of said thiazole.

5. The method according to claim 2, wherein said base is a carbonate.

6. A halopyrazolylthiazole of formula (Ia), wherein [Chemical Formula 4] in the formula,[[]]END]] X is halogen, L １ is selected from the group consisting of a bond, -C(O)-, -S-, -S(O) １－２ -, -O-, -NR ６ -, -C(O)NR ６ -, -NR ６ C(O)-, -C(S)NR ６ -, -NR ６ C(S)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -C(S)O-, -OC(S)-, -C(S)S-, -SC(S)-, -S(O) １－２ O-, -OS(O) １－２ -, -S(O) １－２ NR ６ -, and -NR ６ S(O) １－２ -; R １ is selected from the group consisting of C １ -C ８ -alkyl, C １ -C ８ -alkenyl, and C １ -C ８ -alkynyl, each of which is unsubstituted or fluorinated, Q １ is -C(O)OR ２Ｃ 、 -C(O)NR ２Ｂ R ２Ｃ 、 -C(O)NR ２Ｂ S(O) ２ R ２Ｃ 、 -C(O)NR ２Ｂ S(O) ２ NR ２Ｂ R ２Ｃ 、 -S(O) ２ R ２Ｃ 、 -N(R ２Ｂ )S(O) ２ R ２Ｃ 、 -S(O) ２ NR ２Ｂ R ２Ｃ 、 and -C(O)NH -O(C １ -C ３ alkyl) and is selected from the group consisting of, where Each R ２Ｂ is independently selected from H and C １ -C ３ alkyl, Each R ２Ｃ is independently selected from C １ -C ３ alkyl and a protecting group R ３ is each independently (i) -L ３Ｃ -(phenyl optionally substituted with 1 to 5 R ３Ｄ ), -L ３Ｃ -(heteroaryl optionally substituted with 1 to 5 R ３Ｄ ), -L ３Ｃ -(cycloalkyl optionally substituted with 1 to 5 R ３Ｄ ), -L ３Ｃ -(heterocycloalkyl optionally substituted with 1 to 5 R ３Ｄ ), and is optionally substituted with one substituent selected therefrom, and (ii) is phenyl or heteroaryl optionally substituted with 1 to 5 R ３Ｅ ​ wherein,[[]]END]] Each L ３Ｃ is bonding, methylene, ethylene, -C(O)-, -S-, -S(O) １－２ -, -O-, or -NR ３Ｇ -, and Each R ３Ｄ is selected independently from oxo, optionally substituted C １ -C ４ -alkyl, C １ -C ４ -fluoroalkyl, halogen, -CN, -SF ５ , -N ３ , -C(O)R ３Ｆ , -SR ３Ｆ , -S(O) １－２ R ３Ｆ , -OR ３Ｆ , -NR ３Ｇ R ３Ｆ , -C(O)R ３Ｆ , -C(O)NR ３Ｇ R ３Ｆ , -NR ３Ｇ C(O)R ３Ｆ , -C(S)NR ３Ｇ R ３Ｆ , -NR ３Ｇ C(S)R ３Ｆ , -C(O)OR ３Ｆ , -OC(O)R ３Ｆ , -C(O)SR ３Ｆ , -SC(O)R ３Ｆ , -C(S)OR ３Ｆ , -OC(S)R ３Ｆ , -C(S)SR ３Ｆ , -SC(S)R ３Ｆ , -S(O) １－２ OR ３Ｆ , -OS(O) １－２ R ３Ｆ , -S(O) １－２ NR ３Ｇ R ３Ｆ , and -NR ３Ｇ S(O) １－２ R ３Ｆ and is selected independently from Each R ３Ｅ is selected independently from oxo, optionally substituted C １ -C ４ -alkyl, C １ -C ４ -fluoroalkyl, halogen, -CN, -SF ５ , -N ３ , -C(O)R ３Ｆ , -SR ３Ｆ , -S(O) １－２ R ３Ｆ , -OR ３Ｆ , -NR ３Ｇ R ３Ｆ , -C(O)R ３Ｆ , -C(O)NR ３Ｇ R ３Ｆ , -NR ３Ｇ C(O)R ３Ｆ , -C(S)NR ３Ｇ R ３Ｆ , -NR ３Ｇ C(S)R ３Ｆ , -C(O)OR ３Ｆ , -OC(O)R ３Ｆ , -C(O)SR ３Ｆ , -SC(O)R ３Ｆ , -C(S)OR ３Ｆ , -OC(S)R ３Ｆ , -C(S)SR ３Ｆ , -SC(S)R ３Ｆ , -S(O) １－２ OR ３Ｆ , -OS(O) １－２ R ３Ｆ , -S(O) １－２ NR ３Ｇ R ３Ｆ , and -NR ３Ｇ S(O) １－２ R ３Ｆ and is selected independently from Each R ３Ｆ is independently selected from H, C １ -C ３ alkyl, and C １ -C ３ fluoroalkyl Each R ３Ｇ is independently selected from H, C １ -C ３ alkyl, and C １ -C ３ fluoroalkyl, R ４ is selected from the group consisting of hydrogen, optionally substituted C １ -C ８ -alkyl, optionally substituted C １ -C ８ -alkenyl, and optionally substituted C １ -C ８ -alkynyl wherein,[[]]END]] Each R ６ is selected from the group consisting of hydrogen, C １ -C ３ -alkyl, and -C(O)(C １ -C ３ -alkyl), each optionally substituted alkyl, alkenyl, and alkynyl is unsubstituted, fluorinated, or substituted with one or two hydroxyl groups; each cycloalkyl has 3 to 10 ring carbons and is unsaturated or partially unsaturated; each heterocycloalkyl has 3 to 10 ring members and 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur and is unsaturated or partially unsaturated; each heteroaryl is a 5- to 6-membered monocyclic heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

7. The halopyrazolylthiazole of the formula (Ia) is 1-(4-halo-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid C １ -C ３ The compound according to claim 6, wherein it is -C alkyl

8. A compound of formula (I)[[]]END]] 【Chemical Formula 5】 Optionally, a method for preparing in the form of a pharmaceutically acceptable salt or N-oxide, and / or a solvate or hydrate, wherein L １ is selected from the group consisting of a bond, -C(O)-, -S-, -S(O) １－２ -, -O-, -NR ６ -, -C(O)NR ６ -, -NR ６ C(O)-, -C(S)NR ６ -, -NR ６ C(S)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -C(S)O-, -OC(S)-, -C(S)S-, -SC(S)-, -S(O) １－２ O-, -OS(O) １－２ -, -S(O) １－２ NR ６ - and -NR ６ S(O) １－２ -; R １ is selected from the group consisting of C １ -C ８ alkyl, C １ -C ８ alkenyl, and C １ -C ８ alkynyl, each of which is unsubstituted or fluorinated, Q is -C(O)OR ２Ａ 、 -C(O)NR ２Ｂ R ２Ａ 、 -C(O)NR ２Ｂ S(O) ２ R ２Ａ 、 -C(O)NR ２Ｂ S(O) ２ NR ２Ｂ R ２Ａ 、 -S(O) ２ R ２Ａ 、 -N(R ２Ｂ )S(O) ２ R ２Ａ 、 -S(O) ２ NR ２Ｂ R ２Ａ 、 and -C(O)NH - O(C １ -C ３ alkyl) selected from the group consisting of, where Each R ２Ａ is independently selected from H, C １ -C ３ alkyl, and a protecting group Each R ２Ｂ is independently selected from H and C １ -C ３ alkyl, R ３ is each independently (i) -L ３Ｃ -(phenyl optionally substituted with 1 to 5 R ３Ｄ ), -L ３Ｃ -(heteroaryl optionally substituted with 1 to 5 R ３Ｄ ), -L ３Ｃ -(cycloalkyl optionally substituted with 1 to 5 R ３Ｄ ), -L ３Ｃ -(heterocycloalkyl optionally substituted with 1 to 5 R ３Ｄ ), and is optionally substituted with one substituent selected therefrom, and (ii) is phenyl or heteroaryl optionally substituted with 1 to 5 R ３Ｅ ​ wherein Each L ３Ｃ is bonding, methylene, ethylene, -C(O)-, -S-, -S(O) １－２ -, -O-, or -NR ３Ｇ -, and Each R ３Ｄ is selected independently from oxo, optionally substituted C １ -C ４ -alkyl, C １ -C ４ -fluoroalkyl, halogen, -CN, -SF ５ , -N ３ , -C(O)R ３Ｆ , -SR ３Ｆ , -S(O) １－２ R ３Ｆ , -OR ３Ｆ , -NR ３Ｇ R ３Ｆ , -C(O)R ３Ｆ , -C(O)NR ３Ｇ R ３Ｆ , -NR ３Ｇ C(O)R ３Ｆ , -C(S)NR ３Ｇ R ３Ｆ , -NR ３Ｇ C(S)R ３Ｆ , -C(O)OR ３Ｆ , -OC(O)R ３Ｆ , -C(O)SR ３Ｆ , -SC(O)R ３Ｆ , -C(S)OR ３Ｆ , -OC(S)R ３Ｆ , -C(S)SR ３Ｆ , -SC(S)R ３Ｆ , -S(O) １－２ OR ３Ｆ , -OS(O) １－２ R ３Ｆ , -S(O) １－２ NR ３Ｇ R ３Ｆ , and -NR ３Ｇ S(O) １－２ R ３Ｆ and is selected independently from Each R ３Ｅ is selected independently from oxo, optionally substituted C １ -C ４ -alkyl, C １ -C ４ -fluoroalkyl, halogen, -CN, -SF ５ , -N ３ , -C(O)R ３Ｆ , -SR ３Ｆ , -S(O) １－２ R ３Ｆ , -OR ３Ｆ , -NR ３Ｇ R ３Ｆ , -C(O)R ３Ｆ , -C(O)NR ３Ｇ R ３Ｆ , -NR ３Ｇ C(O)R ３Ｆ , -C(S)NR ３Ｇ R ３Ｆ , -NR ３Ｇ C(S)R ３Ｆ , -C(O)OR ３Ｆ , -OC(O)R ３Ｆ , -C(O)SR ３Ｆ , -SC(O)R ３Ｆ , -C(S)OR ３Ｆ , -OC(S)R ３Ｆ , -C(S)SR ３Ｆ , -SC(S)R ３Ｆ , -S(O) １－２ OR ３Ｆ , -OS(O) １－２ R ３Ｆ , -S(O) １－２ NR ３Ｇ R ３Ｆ , and -NR ３Ｇ S(O) １－２ R ３Ｆ and is selected independently from Each R ３Ｆ is independently selected from H, C １ -C ３ alkyl, and C １ -C ３ fluoroalkyl, Each R ３Ｇ is independently selected from H, C １ -C ３ alkyl, and C １ -C ３ fluoroalkyl, R ４ is selected from the group consisting of hydrogen, optionally substituted C １ -C ８ -alkyl, optionally substituted C １ -C ８ -alkenyl, and optionally substituted C １ -C ８ -alkynyl R ５ where each is phenyl, heteroaryl, cycloalkyl, or heterocycloalkyl optionally substituted with 1 to 5 R ５Ｅ groups wherein Each R ５Ｅ is selected independently from oxo, optionally substituted C １ -C ４ -alkyl, C １ -C ４ -fluoroalkyl, halogen, -CN, -SF ５ , -N ３ , -C(O)R ５Ｆ , -SR ５Ｆ , -S(O) １－２ R ５Ｆ , -OR ５Ｆ , -NR ５Ｇ R ５Ｆ , -C(O)R ５Ｆ , -C(O)NR ５Ｇ R ５Ｆ , -NR ５Ｇ C(O)R ５Ｆ , -C(S)NR ５Ｇ R ５Ｆ , -NR １Ｇ C(S)R ５Ｆ , -C(O)OR ５Ｆ , -OC(O)R ５Ｆ , -C(O)SR ５Ｆ , -SC(O)R ５Ｆ , -C(S)OR ５Ｆ , -OC(S)R ５Ｆ , -C(S)SR ５Ｆ , -SC(S)R ５Ｆ , -S(O) １－２ OR ５Ｆ , -OS(O) １－２ R ５Ｆ , -S(O) １－２ NR ５Ｇ R ５Ｆ , and -NR ５Ｇ S(O) １－２ R ５Ｆ and is selected independently from Each R ５Ｆ is independently selected from H, C １ -C ３ alkyl, and C １ -C ３ fluoroalkyl, Each R ５Ｇ is independently selected from H and C １ -C ３ alkyl, wherein Each R ６ is selected from the group consisting of hydrogen, C １ -C ３ -alkyl, and -C(O)(C １ -C ３ -alkyl), each optionally substituted alkyl, alkenyl, and alkynyl is unsubstituted, fluorinated, or substituted with one or two hydroxyl groups, each cycloalkyl has 3 to 10 ring carbons and is unsaturated or partially unsaturated, each heterocycloalkyl has 3 to 10 ring members and 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur and is unsaturated or partially unsaturated, each heteroaryl is a 5-6 membered monocyclic heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, said method comprising halopyrazolylthiazole of formula (Ia), 【Chemical Formula 6】 wherein X is halogen, Q １ is -C(O)OR ２Ｃ 、 -C(O)NR ２Ｂ R ２Ｃ 、 -C(O)NR ２Ｂ S(O) ２ R ２Ｃ 、 -C(O)NR ２Ｂ S(O) ２ NR ２Ｂ R ２Ｃ 、 -S(O) ２ R ２Ｃ 、 -N(R ２Ｂ )S(O) ２ R ２Ｃ 、 -S(O) ２ NR ２Ｂ R ２Ｃ 、 and -C(O)NH -O(C １ -C ３ alkyl) selected from the group consisting of, where Each R ２Ｂ is independently selected from H and C １ -C ３ alkyl, Each R ２Ｃ is independently selected from C １ -C ３ alkyl and a protecting group and L １ , R １ , R ３ , and R ４ are as described for formula (I)), Optionally in a solvent, coupling an organoboron containing an R ５ moiety to obtain a compound of formula (I), a method comprising. Claims 9 wherein the organic boron is a boronic acid or boronic ester having R substituted on a boron atom ５ The method according to claim 8, wherein the organic boron is a boronic acid or boronic ester having R substituted on a boron atom Claims 10 said organic boron has the following formula, 【Chemical Formula 7】 wherein R ５ is as described for formula (I), Y １ and Y ２ are independently hydroxy or C １ -C ４ alkoxy, or Y １ and Y ２ together with the B atom form a 5- or 6-membered ring having one or two oxygens in the ring bonded to boron, the method according to claim 9. Claims 11 The method according to claim 9, wherein the halopyrazolylthiazole of formula (Ia) and the organic boron are coupled in the presence of a palladium catalyst and a base. Claims 12 The compound of formula (I) is [Chemical 8] The method according to claim 9. Claims 13 A method for preparing thiazolylhydrazine of formula (Ib), comprising 【Chemical Formula 9】 wherein X is halogen, L １ is selected from the group consisting of a bond, -C(O)-, -S-, -S(O) １－２ -, -O-, -NR ６ -, -C(O)NR ６ -, -NR ６ C(O)-, -C(S)NR ６ -, -NR ６ C(S)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -C(S)O-, -OC(S)-, -C(S)S-, -SC(S)-, -S(O) １－２ O-, -OS(O) １－２ -, -S(O) １－２ NR ６ -, and -NR ６ S(O) １－２ - and is selected from the group consisting of R １ is selected from the group consisting of C １ -C ８ -alkyl, C １ -C ８ -alkenyl, and C １ -C ８ -alkynyl, each of which is unsubstituted or fluorinated, wherein Each R ６ is selected from the group consisting of hydrogen, C １ -C ３ -alkyl, and -C(O)(C １ -C ３ -alkyl). said method comprising dihalothiazole of the following formula, 【Chemical Formula 10】 (wherein X, R １ , and L １ are as described for formula (Ib), X ａ is halogen, and is reacted with an aqueous solution of hydrazine in an optional solvent to obtain a crude product, crystallizing the crude product to obtain thiazolylhydrazine of formula (Ib). Claims 14 X ａ The method according to claim 13, wherein X is chloro or bromo. Claims 15 The method according to claim 13, wherein the crystallization is carried out from a hydrocarbon solvent. Claims 16 wherein R １ is unsubstituted C １ -C ５ alkyl, or fluorinated C １ -C ５ alkyl, and L １ is -S- and R ３ is aryl optionally substituted with 1 to 5 R ３Ｅ wherein each R in the formula ３Ｅ is independently selected from C １ -C ４ alkyl, C １ -C ４ fluoroalkyl, halogen, -OR ３Ｆ and -NR ３Ｇ R ３Ｆ or R ３Ｅ is independently selected from halogen, -OR ３Ｆ and -NR ３Ｇ R ３Ｆ and R ４ is hydrogen or an unsubstituted C １ -C ６ alkyl, R ５ where each is an unsaturated cycloalkyl or phenyl optionally substituted with 1 to 5 R ５Ｅ groups Q １ is -C(O)OR ２Ｃ The method according to any one of claims 1 to 5 and 8 to 15, wherein Claims 17 The method according to any one of claims 1 to 5 and 8 to 16, wherein each halogen and each halo is independently selected from Cl, Br, and I. Claims 18 The compound of formula (Ia) is 【Chemical 11】 The method according to any one of claims 1 to 5 and 8 to 17. Claims 19 The compound of formula (Ia) is 【Chemical 12】 and in the formula, R １ is C １ -C ８ alkyl, and R ３Ｅ is independently selected from C １ -C ４ alkyl, C １ -C ４ fluoroalkyl, halogen, -OR ３Ｆ , and -NR ３Ｇ R ３Ｆ The method according to any one of claims 1 to 5 and 8 to 17 Claims 20 R １ is unsubstituted C １ -C ５ -alkyl or fluorinated C １ -C ５ -alkyl, and L １ is -S- and R ３ is aryl optionally substituted with 1 to 5 R ３Ｅ groups, and wherein R ３Ｅ is selected independently from C １ -C ４ alkyl, C １ -C ４ fluoroalkyl, halogen, -OR ３Ｆ , and -NR ３Ｇ R ３Ｆ or is selected independently from halogen, -OR ３Ｆ and -NR ３Ｇ R ３Ｆ and is selected independently from R ４ is hydrogen or unsubstituted C １ -C ６ alkyl, and R ５ is an unsaturated cycloalkyl or phenyl, each optionally substituted with 1 to 5 R ５Ｅ and may be substituted with Q １ is -C(O)OR ２Ｃ wherein The compound according to claim 6. Claims 21 The compound according to claim 6 or 20, wherein each halogen and each halo is independently selected from Cl, Br, and I. Claims 22 The compound of formula (Ia) is 【Chemical Formula 13】 The compound according to any one of claims 6, 20, and 21. Claims 23 The compound of formula (Ia) is 【Chemical Formula 14】 and Here, R １ is C １ -C ８ alkyl, and R ３Ｅ is C １ -C ４ alkyl, C １ -C ４ fluoroalkyl, halogen, -OR ３Ｆ and -NR ３Ｇ R ３Ｆ independently selected from A compound according to any one of claims 6, 20, and 21. **Claim 24** Ethyl 1-(4-bromo-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylate.

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