Process for the preparation of thiazolylpyrazole carboxylic acids and intermediates thereof

Abstract

The present disclosure relates generally to improved processes for preparing pyrazolylthiazole-containing compounds and intermediates thereof.

Description

[0001] Cross-referencing of related patent applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 62 / 855652, filed May 31, 2019, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This disclosure generally relates to improved methods for preparing compounds containing pyrazolylthiazoles and intermediates that can be used therein. Background Technology

[0004] Cancer is the uncontrolled proliferation of cells, a multifactorial disease characterized by the formation, growth, and, in some cases, metastasis of tumors. In the United States, more than 1.5 million people will be diagnosed with cancer this year, and more than 500,000 will die from it. Overall, it is estimated that at least one-third of all people will develop some form of cancer in their lifetime. There are more than 200 different histopathological types of cancer, with breast, lung, colorectal, and prostate cancer accounting 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 a combination of surgery, systemic therapy, radiation therapy, and chemotherapy. Despite researchers' efforts to develop anti-cancer strategies, many remain ineffective against specific cancers.

[0005] Uncontrolled cell proliferation, a hallmark of cancer, involves not only dysregulated cell proliferation but also corresponding adjustments to energy metabolism to promote cell growth and division. Reprogramming of cellular metabolism is becoming a key molecular marker of cancer cells. Under aerobic conditions, normal cells process glucose, first producing pyruvate via glycolysis in the cytoplasm, and then carbon dioxide in the mitochondria. Under anaerobic conditions, glycolysis is favored, and relatively less pyruvate is transported to the oxygen-consuming mitochondria. When growth factors and nutrients are abundant, oncogenic signaling pathways guide enhanced metabolism, leading to increased synthesis of macromolecules such as lipids, proteins, and nucleic acids. The net effect supports cell growth and proliferation. However, the harsh hypoxic and nutrient-deficient environment during tumorigenesis challenges cells and their ability to maintain metabolic homeostasis. Cancer cells can reprogram their glucose metabolism, thereby reprogramming their energy production, by restricting their energy metabolism primarily to glycolysis—a process initially considered primitive and inefficient by biochemists. Despite these early ideas, the metabolic characteristics of cancer cells are not a passive response to damaged mitochondria, but rather a result of metabolic reprogramming guided by oncogenes that support anabolic growth. Mutations in oncogenes allow for increased and more efficient utilization of scarce nutrients, a unique target in cancer treatment.

[0006] Particularly useful annelated pyrazolothiazole compounds for treating cancer are disclosed in International Publication Nos. WO 2018 / 102452 and WO 2018 / 102453, the entireties of each of which are hereby incorporated by reference. One example of such a compound is 4-(3-fluorophenyl)-l-(5-(isopropylthio)-4-(4- (trifluoromethyl)cyclohex-l-en-l-yl)thiazol-2-yl)-3-methyl-lH-pyrazole-5-carboxylic acid. These compounds are believed to be active against cancer cells by arresting the cell cycle at the G0 / G1 phase thereby inducing apoptosis of cancer cells, and are also believed to inhibit glutathione synthesis in cancer cells. Thus, annelated pyrazolothiazole compounds show promise for treating cancer, and efficient methods are needed for preparing these compounds. SUMMARY

[0007] The present disclosure provides improved methods of preparing annelated pyrazolothiazole compounds, such as compounds of Formula (I):

[0008]

[0009] in the form of a pharmaceutically acceptable salt or N-oxide and / or solvate or hydrate, wherein

[0010] 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 -;

[0011] R 1 is selected from the group consisting of C1-C8alkyl, C1-C8alkenyl, and C1-C8alkynyl, each of which is unsubstituted or fluorinated;

[0012] Q is selected from the group consisting of -C(O)OR 2A , -C(O)NR 2B R2A -C(O)NR 2B S(O)2R 2A -C(O)NR 2B S(O)2NR 2B R 2A -S(O)2R 2A -N(R 2B )S(O)2R 2A -S(O)2NR 2B R 2A and -C(O)NH-O(C1-C3 alkyl), wherein

[0013] each R 2A is independently selected from H, C1-C3 alkyl, and a protecting group, and

[0014] each R 2B is independently selected from H and C1-C3 alkyl;

[0015] R 3 is phenyl or heteroaryl, each of which (i) is optionally substituted with a single substituent selected from -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 (ii) is optionally substituted with 1-5 R 3E ,

[0016] wherein

[0017] each L 3C is a bond, methylene, ethylene, -C(O)-, -S-, -S(O) 1-2 -, -O-, or -NR 3G -;

[0018] each R 3D is independently selected from oxo, optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, -SF5, -N3, -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 ;

[0019] each R 3E is independently selected from oxo, optionally substituted C1-C4alkyl, C1-C4fluoroalkyl, halogen, -CN, -SF5, -N3, -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)R3F -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 ;

[0020] each R 3F is independently selected from H, C1-C3 alkyl, and C1-C3 fluoroalkyl, and

[0021] each R 3G is independently selected from H, C1-C3 alkyl, and C1-C3 fluoroalkyl;

[0022] R 4 is selected from the group consisting of hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkenyl, and optionally substituted C1-C8 alkynyl; and

[0023] R 5 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted with 1-5 R 5E ,

[0024] wherein

[0025] each R 5E is independently selected from oxo, optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, -SF5, -N3, -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 ;

[0026] each R 5F is independently selected from H, C1-C3 alkyl, and C1-C3 fluoroalkyl, and

[0027] each R 5G is independently selected from H and C1-C3 alkyl;

[0028] wherein

[0029] each R 6 is selected from the group consisting of hydrogen, C1-C3 alkyl, and -C(O)(C1-C3 alkyl);

[0030] each optionally substituted alkyl, alkenyl, and alkynyl is unsubstituted, fluorinated, or substituted with one or two hydroxyl groups;

[0031] each cycloalkyl has 3-10 ring carbons and is unsaturated or partially unsaturated;

[0032] each heterocycloalkyl has 3-10 ring members and 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and is unsaturated or partially unsaturated;

[0033] each heteroaryl is a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0034] Such methods include coupling a pyrazolylthiazole (e.g., a pyrazolylthiazole of Formula (la)) optionally in a solvent with an organoboron compound comprising a desired ring substituent moiety (e.g., comprising R 5 moiety).

[0035] The present disclosure also provides pyrazolylthiazole compounds useful as intermediates in the synthesis of compounds of Formula (I) and methods of making the same. Thus, in another aspect, there is provided a pyrazolylthiazole of Formula (la):

[0036]

[0037] wherein

[0038] X is halogen;

[0039] Q 1 is selected from the group consisting of -C(O)OR 2C , -C(O)NR 2B R 2C , -C(O)NR 2B S(O)2R 2C , -C(O)NR 2B S(O)2NR 2B R 2C , -S(O)2R 2C , -N(R 2B )S(O)2R 2C , -S(O)2NR 2B R 2C , and -C(O)NH-O(C1-C3alkyl), wherein each R 2B is independently selected from H and C1-C3alkyl, and each R 2C is independently selected from C1-C3alkyl and a protecting group; and

[0040] L 1 , R 1 , R 3 , and R 4 are as described for Formula (I).

[0041] Another aspect of the present disclosure provides a method of making a halopyrazolylthiazole of the present disclosure (e.g., a halopyrazolylthiazole of Formula (la)). Such a method includes reacting a thiazolylhydrazine (e.g., a thiazolylhydrazine of Formula (lb)) with a diketone, optionally in a solvent, under conditions sufficient to form a hydrazone; and reacting the hydrazone with a compound of Formula X 1 -CH2-Q 1 , wherein Q 1 is as described above, and X 1 is halogen or a leaving group.

[0042] Another aspect provides a method of making a thiazolylhydrazine (e.g., a thiazolylhydrazine of Formula (lb)). Such a method includes: reacting a dihalothiazole, optionally in a solvent, with an aqueous solution of hydrazine to yield a crude product; and crystallizing the crude product, e.g., from a hydrocarbon solvent (e.g., hexanes, heptanes, or a combination thereof), to yield the thiazolylhydrazine.

[0043] In another aspect, there is provided 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.

[0044] Other aspects and embodiments of the disclosure will be apparent in view of the detailed description provided herein. DETAILED DESCRIPTION

[0045] The inventors have invented an improved and efficient process for preparing the compound of formula (I). For example, the current process allows for the preparation of compound 1 in an overall yield of more than 30%, in comparison to the currently known processes such as those disclosed in WO 2018 / 102453, in which the overall yield for preparing the same compound is 2.5%. For example, the process of the present disclosure also provides a relatively pure compound of formula (I) (e.g., a purity of at least 98%). However, in certain embodiments, this purity is achieved without performing chromatography. Since the pyrazolylthiazole of formula (la) is useful in the process for preparing the compound of formula (I), and in turn the thiazolylhydrazine of formula (lb) is useful in the process for preparing the pyrazolylthiazole, it has also been found important by the inventors to develop an efficient process for preparing the pyrazolylthiazole of formula (la) and / or the thiazolylhydrazine of formula (lb).

[0046] Accordingly, one aspect provides an improved process for preparing the thiazolylhydrazine of formula (lb):

[0047]

[0048] wherein

[0049] X is halogen (e.g., chloro, bromo, or iodo);

[0050] 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 -;

[0051] R 1 is selected from the group consisting of C1-C8alkyl, C1-C8alkenyl, and C1-C8alkynyl, each of which is unsubstituted or fluorinated;

[0052] wherein

[0053] each R 6 is selected from the group consisting of hydrogen, C1-C3alkyl, and -C(O)(C1-C3alkyl);

[0054] each optionally substituted alkyl is unsubstituted, fluorinated, or substituted with one or two hydroxyl groups;

[0055] each cycloalkyl has 3-10 ring carbons and is unsaturated or partially unsaturated;

[0056] each monocyclic heteroaryl is a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur,

[0057] Such methods include:

[0058] reacting a dihalothiazole of the formula

[0059]

[0060] wherein X, R 1 and L 1 are as described for formula (lb), and X a is halogen (e.g., chloro, bromo, or iodo), optionally in a solvent, with an aqueous solution of hydrazine to give a crude product; and

[0061] crystallizing the crude product, e.g., from a hydrocarbon solvent (e.g., hexanes, heptanes, or a combination thereof), to give a thiazolylhydrazine of formula (lb).

[0062] In certain embodiments, X a is chloro. In certain such embodiments, X is bromo or iodo.

[0063] In the process of preparing a thiazolylhydrazine of Formula (Ib), the inventors have found it advantageous to use hydrazine in an amount of at least 6 molar equivalents based on the amount of the 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, all based on the amount of the dihalothiazole. In certain embodiments, the amount of hydrazine is in the range of 6-20 equivalents, such as, 6-15 equivalents, or 7-20 equivalents, or 7-15 equivalents, based on the amount of the dihalothiazole.

[0064] A variety of polar aprotic solvents are suitable for use in the process of preparing a thiazolylhydrazine of Formula (Ib). Examples include tetrahydrofuran (THF), ethyl acetate, acetone, dimethylformamide (DMF), acetonitrile (MeCN), dimethylsulfoxide (DMSO), and the like. In certain embodiments, the solvent is THF.

[0065] The reaction of the dihalothiazole with the aqueous hydrazine can be carried out at a variety of temperatures, including at about 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. In other embodiments, the dihalothiazole is reacted with the aqueous hydrazine at a temperature in the range of 5 °C to 20 °C. In other embodiments, the reaction of the dihalothiazole with the aqueous hydrazine is carried out at a temperature in the 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.

[0066] The reaction of the dihalothiazole with the aqueous hydrazine is carried out for a time sufficient to provide a crude product (i.e., containing the crude thiazolylhydrazine). In certain embodiments, the dihalothiazole is reacted with the aqueous 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 hydrazine for a time in the range of 10 hours to 100 hours, such as, in the range of 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 substantial amount of the crude thiazolylhydrazine.

[0067] The crude product is crystallized to obtain the thiazolylhydrazine of formula (lb). Particularly useful crystallization solvents are hydrocarbon solvents such as hexanes, heptanes, or combinations thereof. In certain embodiments, the crystallization solvent is hexanes. In certain embodiments, the crystallization solvent is heptanes. The crystallization solvent can be used in any volume sufficient to induce crystal formation. In certain embodiments, the crystallization solvent is used in an amount of about 100% v / v to 300% v / v, e.g., 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.

[0068] The present disclosure also provides halopyrazolylthiazoles and methods of making the same. Thus, another aspect of the present disclosure provides a halopyrazolylthiazole of formula (la):

[0069]

[0070] wherein

[0071] X is halogen (e.g., chloro, bromo, or iodo);

[0072] 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 -;

[0073] R 1 is selected from the group consisting of C1-C8alkyl, C1-C8alkenyl, and C1-C8alkynyl, each of which is unsubstituted or fluorinated;

[0074] Q 1-C(O)OR 2C -C(O)NR 2B R 2C -C(O)NR 2B S(O)2R 2C -C(O)NR 2B S(O)2NR 2B R 2C -S(O)2R 2C -N(R 2B )S(O)2R 2C -S(O)2NR 2B R 2C -C(O)NH-O(C1-C3 alkyl), wherein

[0075] each R 2B is independently selected from H and C1-C3 alkyl, and

[0076] each R 2C is independently selected from C1-C3 alkyl and a protecting group;

[0077] R 3 is phenyl or heteroaryl, each of which (i) is optionally substituted with a single substituent selected from -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 (ii) is optionally substituted with 1-5 R 3E , wherein

[0078] each L 3C is a bond, methylene, ethylene, -C(O)-, -S-, -S(O) 1-2 -, -O-, or -NR 3G -;

[0079] each R 3D is independently selected from oxo, optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, -SF5, -N3, -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 ;

[0080] each R 3E is independently selected from oxo, optionally substituted C1-C4alkyl, C1-C4fluoroalkyl, halogen, -CN, -SF5, -N3, -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)SR3F , -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 ;

[0081] each R 3F is independently selected from the group consisting of H, C1-C3 alkyl, and C1-C3 fluoroalkyl, and

[0082] each R 3G is independently selected from the group consisting of H, C1-C3 alkyl, and C1-C3 fluoroalkyl; and

[0083] R 4 is selected from the group consisting of hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkenyl, and optionally substituted C1-C8 alkynyl;

[0084] wherein

[0085] each R 6 is selected from the group consisting of hydrogen, C1-C3 alkyl, and -C(O)(C1-C3 alkyl);

[0086] each optionally substituted alkyl, alkenyl, and alkynyl is unsubstituted, fluorinated, or substituted with one or two hydroxyl groups;

[0087] each cycloalkyl has 3-10 ring carbons and is unsaturated or partially unsaturated;

[0088] each heterocycloalkyl has 3-10 ring members and 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and is unsaturated or partially unsaturated; and

[0089] each heteroaryl is a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0090] A method for preparing a pyrazolothiazole of Formula (Ia) comprises:

[0091] reacting a thiazolylhydrazine of Formula (Ib) as described herein with a diketone of Formula (II)

[0092]

[0093] wherein R 3 and R 4as described for Formula (la),

[0094] optionally in a solvent under conditions sufficient to form a hydrazone; and

[0095] contacting the hydrazone with an alkyl halide of Formula X 1 -CH2-Q 1 where Q 1 is as described for Formula (la), and X 1 is a halogen or leaving group,

[0096] to yield the halopyrazolothiazole of Formula (la).

[0097] The hydrazone can have the following structure (III):

[0098]

[0099] The hydrazone can have the following structure (III): 1 -CH2-Q 1 The contacting of the hydrazone with an alkyl halide of Formula X

[0100]

[0101] The reaction conditions can be selected such that the intermediate is cyclized with elimination of water to form the halopyrazolothiazole of Formula (la).

[0102] In certain embodiments, the method for preparing a halopyrazolothiazole of Formula (la) further comprises preparing a thiazolylhydrazine of Formula (lb) according to the methods described herein. For example, in certain embodiments, the method for preparing a halopyrazolothiazole of Formula (la) comprises:

[0103] reacting a dihalothiazole of Formula (lc) as described herein, optionally in a solvent, with an aqueous solution of hydrazine to yield a crude product (i.e., containing a crude thiazolylhydrazine);

[0104] crystallizing the crude product (e.g., from a hydrocarbon solvent, such as hexanes, heptanes, or a combination thereof) to yield a thiazolylhydrazine of Formula (lb) as described herein;

[0105] reacting a thiazolylhydrazine of Formula (lb) as described herein, optionally in a solvent, with a diketone as described herein under conditions sufficient to form a hydrazone; and

[0106] reacting the hydrazone with an alkyl halide as described herein to yield the halopyrazolothiazole of Formula (la).

[0107] The present inventors have found that halo-pyrazolyl-thiazoles of Formula (la) (where X is CI, Br, or I) are advantageous, particularly when used to make compounds of Formula (I). In certain embodiments as otherwise described herein, in the halo-pyrazolyl-thiazole of Formula (la), X is Br. In certain embodiments as otherwise described herein, in the halo-pyrazolyl-thiazole of Formula (la), X is CI. In certain embodiments as otherwise described herein, in the halo-pyrazolyl-thiazole of Formula (la), X is I.

[0108] The present inventors have also found that it is advantageous to use the diketone in an amount of at least 1 molar equivalent, based on the amount of thiazolylhydrazine. For example, the amount of diketone can be at least 1.1 molar equivalents, for example, at least 1.25 molar equivalents or at least 1.5 molar equivalents, all based on the amount of thiazolylhydrazine.

[0109] In certain embodiments, the thiazolylhydrazine and diketone as otherwise described herein can be reacted in a solvent. For example, suitable solvents include, but are not limited to, dioxane, toluene, THF, DMF, and dichloromethane.

[0110] The reaction of the thiazolyl hydrazine and the diketone can be performed at a variety of temperatures, including at about room temperature. For example, in certain embodiments, the reaction is performed at a temperature in the range of 20 °C to 25 °C, or 20 °C to 23 °C. The reaction of the thiazolyl hydrazine and the diketone can be performed for a time sufficient to yield the hydrazone. In certain embodiments, the thiazolyl hydrazine is reacted with the diketone for at least 8 hours, for example, at least 10 hours, or at least 12 hours, or at least 14 hours, or at least 16 hours. In certain embodiments, the thiazolyl hydrazine is reacted with the diketone at about room temperature for a time in the range of 8 hours to 20 hours, for example, in the range of 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. Alternatively, the reaction of the thiazolyl hydrazine and the diketone can be performed at a temperature above room temperature. For example, the reaction of the thiazolyl hydrazine and the diketone can be performed at a temperature of at least 40 °C, for example, 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 the thiazolyl hydrazine and the diketone can be performed at a temperature in the range of 40 °C to 80 °C, for example, in the range of 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, the thiazolyl hydrazine and the diketone are reacted at said temperature above room temperature for at least 30 minutes (e.g., at least 45 minutes or at least 1 hour).

[0111] In the methods as described herein, the hydrazone is reacted with an alkyl halide as described herein to produce a halopyrazolylthiazole of Formula (la). The hydrazone and the alkyl halide can be reacted, for example, in the presence of an inorganic iodide and a base. In certain embodiments, the inorganic iodide can be KI or Nal. In certain embodiments, the hydrazone is contacted with the alkyl halide in the presence of an inorganic iodide, KI. In certain embodiments, the base can be a carbonate (such as potassium carbonate, sodium carbonate, cesium carbonate, thallium (I) carbonate, and the like), a hydroxide (such as potassium hydroxide, sodium hydroxide, and the like), an alkoxide (such as sodium ethoxide, potassium tert-butoxide, thallium (I) ethoxide, and the like), an amine (such as trimethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, N,N-dimethylethylamine, and the like), a hydride (such as sodium hydride and potassium hydride). In certain embodiments, the hydrazone is contacted with the alkyl halide in the presence of a base, a carbonate (such as potassium carbonate).

[0112] In certain embodiments, the inorganic iodide is provided in catalytic amounts. For example, in certain embodiments, the amount of inorganic iodide is no more than 20 mol%, e.g., no more than 15 mol% or no more than 10 mol%, based on the amount of hydrazone. In certain embodiments, the amount of inorganic iodide is in the range of 5 mol% to 20 mol%, e.g., 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 hydrazone.

[0113] In certain alternative embodiments, the inorganic iodide can be provided in stoichiometric amounts. For example, in certain embodiments, the amount of inorganic iodide is at least 1 molar equivalent, e.g., at least 1.1 molar equivalent, or at least 1.25 molar equivalent, or at least 1.5 molar equivalent, or at least 2 molar equivalents, based on the amount of hydrazone.

[0114] The hydrazone and alkyl halide can be contacted at a temperature and for a time sufficient to obtain the halopyrazolylthiazole.

[0115] For example, in certain embodiments, the hydrazone and alkyl halide are reacted at a temperature of at least 80 °C, e.g., 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 alkyl halide are reacted at a temperature in the range of 80 °C to 120 °C, e.g., in the range of 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.

[0116] In certain embodiments, the hydrazone and alkyl halide are reacted for at least 8 hours. For example, the hydrazone and alkyl halide can be reacted for at least 10 hours, e.g., at least 12 hours, or at least 14 hours, or at least 16 hours. In another embodiment, the hydrazone and alkyl halide are reacted for a time ranging from 8 hours to 24 hours. For example, in various embodiments, the hydrazone and alkyl halide can be reacted for a time ranging from 8 hours to 20 hours, or 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 24 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 24 hours, or 14 hours to 20 hours, or 14 hours to 18 hours, or 14 hours to 16 hours, or 16 hours to 24 hours, or 16 hours to 20 hours, or 16 hours to 18 hours, or 18 hours to 24 hours, or 18 hours to 20 hours.

[0117] As described in greater detail below, the reaction of the hydrazone with an alkyl halide of formula X 1 -CH2-Q 1 results in the hydrazone being substituted at its substitutable nitrogen position with -CH2-Q 1 ; this intermediate then cyclizes by elimination of water to build the pyrazole ring of the halopyrazolothiazole.

[0118] Notably, the thiazolyl hydrazine is reacted with a diketone to form a hydrazone (e.g., a hydrazone of formula (III)), the hydrazone is subsequently reacted with an alkyl halide of formula X 1 -CH2-Q 1 to form a substituted hydrazone intermediate (e.g., a hydrazone intermediate of formula (IV)), and the hydrazone intermediate cyclizes to form the halopyrazolothiazole can be performed without isolating or purifying any intermediates.

[0119] In certain embodiments, the method of preparing a halopyrazolothiazole of formula (la) as described herein can include further crystallizing the halopyrazolothiazole. For example, the pyrazolothiazole can be crystallized from an alcohol, such as ethanol, to yield a compound having a purity of at least 98%.

[0120] In another aspect, the present disclosure provides a method for preparing a compound of formula (I). Such a method includes: reacting a halopyrazolothiazole of formula (la) as described herein, optionally in a solvent, with an organic boron coupling comprising R 5 to yield a compound of formula (I).

[0121] In certain embodiments, the method for preparing a compound of formula (I) further includes preparing a halopyrazolothiazole of formula (la) according to a method as described herein. For example, in certain embodiments, the method for preparing a compound of formula (I) includes:

[0122] reacting a thiazolylhydrazine of Formula (lb) as described herein with a diketone as described herein, optionally in a solvent, under conditions sufficient to form a hydrazone;

[0123] contacting the hydrazone with an alkyl halide as described herein to give a halopyrazolylthiazole of Formula (la); and

[0124] reacting a halopyrazolylthiazole of Formula (la) as described herein, optionally in a solvent, with an organoboron coupling comprising R 5 to give a compound of Formula (I).

[0125] In certain embodiments, the method for preparing a compound of Formula (I) further comprises preparing a halopyrazolylthiazole of Formula (la) and a thiazolylhydrazine of Formula (lb) according to the methods as described herein. For example, in certain embodiments, the method for preparing a compound of Formula (I) comprises:

[0126] reacting a dihalothiazole as described herein, optionally in a solvent, with an aqueous solution of hydrazine to give a crude product (i.e., containing a crude thiazolylhydrazine);

[0127] crystallizing the crude product (e.g., from a hydrocarbon solvent such as hexanes, heptanes, or a combination thereof) to give a thiazolylhydrazine of Formula (lb) as described herein;

[0128] reacting a thiazolylhydrazine of Formula (lb) as described herein with a diketone as described herein, optionally in a solvent, under conditions sufficient to form a hydrazone;

[0129] contacting the hydrazone with an alkyl halide as described herein to give a halopyrazolylthiazole of Formula (la); and

[0130] reacting a halopyrazolylthiazole of Formula (la) as described herein, optionally in a solvent, with an organoboron coupling comprising R 5 to give a compound of Formula (I).

[0131] The present inventors have found that Suzuki coupling is particularly advantageous for preparing compounds of Formula (I). Suzuki coupling is well known to those of skill 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 incorporated by reference herein in its entirety.

[0132] Generally, the coupling reaction is carried out in the presence of a catalyst and optionally in the presence of a base. Suitable catalysts for Suzuki coupling include palladium catalysts. Examples of palladium catalysts include, but are not limited to, tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4), tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2), bis(triphenylphosphine)dichloropalladium(II) (PdCl2(PPh3)2), palladium(II) acetate (Pd(OAc)2), Pd(OAc)2 / triphenylphosphine (PPh3), Pd(OAc)2 / tricyclohexylphosphine (PCy3), Pd(OAc)2 / tris(o-tolyl)phosphine (PTol3), and the like. Suitable catalysts for Suzuki coupling can also include nickel catalysts such as bis(1,5-cyclooctadiene)nickel(0) (Ni(cod)2), nickel(II) chloride ethylene glycol dimethyl ether complex (NiCl2-glyme), bis(triphenylphosphine)nickel(II) chloride (NiCl2(PPh3)2), and the like.

[0133] The catalyst is provided in an amount sufficient to catalyze the coupling reaction. For example, in certain embodiments, the amount of catalyst is no more than 20 mol%, e.g., no more than 15 mol%, or no more than 10 mol%, or no more than 5 mol%, or no more than 3 mol%, based on the amount of halopyrazolylthiazole. In certain embodiments, the amount of catalyst is in the range of 0.1 mol% to 20 mol%, e.g., in the range of 0.1 mol% to 15 mol%, or 0.1 mol% to 10 mol%, or 0.1 mol% to 5 mol%, or 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 halopyrazolylthiazole. In certain embodiments, the amount of catalyst is in the range of 8 mol% to 20 mol%, e.g., in the range of 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 halopyrazolylthiazole.

[0134] Suitable bases for use in Suzuki couplings include, for example, carbonates (e.g., potassium carbonate, sodium carbonate, cesium carbonate, thallium(I) carbonate, and the like), acetates (e.g., potassium acetate, cesium acetate, and the like), phosphates (e.g., tri-potassium phosphate), hydroxides (e.g., potassium hydroxide, sodium hydroxide, and the like), alkoxides (e.g., sodium ethoxide, thallium(I) ethoxide, and the like), amines (e.g., triethylamine), and basic fluoride salts (e.g., potassium fluoride, sodium fluoride, and cesium fluoride).

[0135] In certain embodiments, a suitable base can be provided in stoichiometric amounts. For example, in certain embodiments, the amount of base is at least 1 molar equivalent, e.g., 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 halopyrazolylthiazole.

[0136] In certain embodiments, the coupling of the halopyrazolylthiazole and the organoboron can be performed in the presence of Pd(dppf)Cl2and a carbonate salt (e.g., potassium carbonate).

[0137] As described elsewhere herein, the coupling of the pyrazolylthiazole and the organoboron can be performed in a solvent in certain embodiments. Suitable solvents include, but are not limited to, dioxane, toluene, THF, DMF, dichloromethane, water, and combinations thereof. In certain embodiments, the solvent is water and one or more of 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, e.g., 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.

[0138] In the methods of making compounds of Formula (I), any organoboron bearing an R 5 group on boron can be used that is well suited for Suzuki reactions. For example, certain organoborons suitable for use in the methods of the present disclosure include boronic acids and boronic esters having a substituted R 5 group on boron, including those of the following formula:

[0139]

[0140] wherein

[0141] R 5 is as described for Formula (I), and

[0142] Y 1 and Y 2 are independently hydroxyl or C1-C4alkoxy, or Y 1 and Y 2 together with the B atom form a 5-6 membered ring, wherein one or both oxygens in the ring are bound to boron.

[0143] In certain embodiments, the organoboron is 2-R 5 -4,4,5,5-tetramethyl-l,3,2-dioxaborolane, 2-R 5 - boronic acid, 2-R 5 -5,5-dimethyl-l,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-l,3,2-dioxaborolane.

[0144] The halo-pyrazolylthiazole and the organoboron can be coupled at a temperature and for a time sufficient to obtain a compound of Formula (I).

[0145] For example, in certain embodiments, the pyrazolylthiazole and the organoboron are coupled at a temperature of at least 80 °C, e.g., 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 halo-pyrazolylthiazole and the organoboron are coupled at a temperature ranging from 80 °C to 120 °C, e.g., at a temperature ranging from 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.

[0146] In certain embodiments, the halo-pyrazolylthiazole and the organoboron can be coupled for at least 8 hours. For example, in various embodiments, the halo-pyrazolylthiazole and the organoboron are coupled for at least 10 hours, e.g., at least 12 hours, or at least 14 hours, or at least 16 hours. In another embodiment, the halo-pyrazolylthiazole and the organoboron are coupled for a time ranging from 8 hours to 24 hours. For example, in various embodiments, the halo-pyrazolylthiazole and the organoboron can be coupled for a time ranging from 8 hours to 20 hours, or 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 24 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 24 hours, or 14 hours to 20 hours, or 14 hours to 18 hours, or 14 hours to 16 hours, or 16 hours to 24 hours, or 16 hours to 20 hours, or 16 hours to 18 hours, or 18 hours to 24 hours, or 18 hours to 20 hours.

[0147] In certain embodiments of the methods as described herein, the desired compound of Formula (I) is a compound in which Q is -C(O)OH, e.g., a compound of the following formula:

[0148]

[0149] or a pharmaceutically acceptable salt thereof. Such methods can further include converting the coupling reaction product to the corresponding formic acid, for example, by hydrolysis (e.g., hydrolyzing a compound of Formula (I) wherein Q 1 is -C(O)OR 2C and R 2C is C1-C3 alkyl or a protecting group). In certain embodiments, the methods as described herein further include hydrolyzing a compound of Formula (I) wherein Q 1 is -C(O)O(C1-C3 alkyl) to provide the corresponding formic acid or formate.

[0150] In certain embodiments, the methods as described herein further include hydrolyzing a compound of Formula (I) wherein Q 1 is -C(O)O(C1-C3 alkyl) to provide a formate salt of a compound of Formula (I); and crystallizing the salt of a compound of Formula (I).

[0151] The methods can further include converting the salt to the corresponding formic acid. In certain embodiments, the salt is treated with an acid to provide a formic acid compound of Formula (I). In certain embodiments of the methods, a compound of Formula (I) is obtained having a purity of at least 98%.

[0152] Certain embodiments of the methods as otherwise described herein are those wherein the compound has any of the above structural Formulae (I)-(Ib), e.g., structural Formula (I), (Ia), or (Ib), wherein the variables are as otherwise described in any embodiment 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, R1 It is methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl. In some embodiments, R 1 It is propyl, isopropyl, butyl, or tert-butyl. In some embodiments, R 1 It is isopropyl.

[0153] Other embodiments of the method described herein are as follows, wherein the compound has any of the above structural formulas (I)-(Ib), wherein the variables are as otherwise described in any embodiment herein, and L 1 For a key, -O-, -S-, -S(O)-, or -S(O)2-. In some embodiments, L 1 It can be -O-, -S-, -S(O)-, or -S(O)2-. In some embodiments, L 1 It can be -S-, -S(O)-, or -S(O)2-. In some embodiments, L 1 For -S-. In some embodiments, L 1 For the key. In some embodiments, L 1 For -O-, or where L 1 For -NR 6 -

[0154] Other embodiments of the method described herein are as follows, wherein the compound has any of the above structural formulas (I)-(Ib), wherein the variables are as otherwise described in any embodiment herein, and R 3 It is a phenyl or heteroaryl group (each (i) optionally substituted by a single substituent selected from -L). 3C -(Choose any 1-5 R's) 3D Substituted phenyl), -L 3C -(Choose any 1-5 R's) 3D Substituted heteroaryl), -L 3C -(Choose any 1-5 R's) 3D Substituted cycloalkyl), -L 3C -(Choose any 1-5 R's) 3D (ii) substituted heterocyclic alkyl groups; and optionally via 1-5 R groups. 3E Replacement. In some embodiments, R 3 It is a phenyl group, (i) which is substituted by a single substituent selected from -L 3C -(Choose any 1-5 R's) 3D Substituted phenyl), -L 3C -(Choose any 1-5 R's) 3D Substituted heteroaryl), -L 3C -(Choose any 1-5 R's) 3D Substituted cycloalkyl), -L 3C-(Choose any 1-5 R's) 3D (ii) substituted heterocyclic alkyl groups; and optionally via 1-5 R groups. 3E Replacement. In some embodiments, R 3 It is a phenyl group, (i) which is substituted by a single substituent selected from -L 3C -(Choose any 1-5 R's) 3D Substituted phenyl), -L 3C -(Choose any 1-5 R's) 3D Substituted heteroaryl), -L 3C -(Choose any 1-5 R's) 3D Substituted cycloalkyl), -L 3C -(Choose any 1-5 R's) 3D (ii) substituted heterocyclic alkyl groups; and optionally via 1-5 R groups. 3E Replacement. In some embodiments, R 3 It is a heteroaryl group (e.g., isothiazole, pyridone, thiadiazole, pyrazine, imidazole, benzofuran, indole, pyridine, pyrazole, isoxazole, thiophene, furan, or pyrimidine), which (i) is substituted by a single substituent selected from -L 3C -(Choose any 1-5 R's) 3D Substituted phenyl), -L 3C -(Choose any 1-5 R's) 3D Substituted heteroaryl), -L 3C -(Choose any 1-5 R's) 3D Substituted cycloalkyl), -L 3C -(Choose any 1-5 R's) 3D (ii) substituted heterocyclic alkyl groups; and optionally via 1-5 R groups. 3E Replacement. In some embodiments, R 3 It is a heteroaryl group (e.g., isothiazole, pyridone, thiadiazole, pyrazine, imidazole, benzofuran, indole, pyridine, pyrazole, isoxazole, thiophene, furan, or pyrimidine), which (i) is substituted by a single substituent selected from -L 3C -(Choose any 1-5 R's) 3D Substituted phenyl), -L 3C -(Choose any 1-5 R's) 3D Substituted monocyclic heteroaryl), -L 3C -(Choose any 1-5 R's) 3D Substituted cycloalkyl), -L 3C -(Choose any 1-5 R's) 3D (ii) substituted heterocyclic alkyl groups; and optionally via 1-5 R groups. 3E Replacement. In some embodiments, R 3The following are selected from the group consisting of: phenyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, pyridyl, pyrazinyl, pyridonel, thiadiazolyl, pyrazolyl, triazolopyridyl, thiophenyl, furanyl, and pyrimidinyl, each of which (i) is optionally substituted by a single substituent selected from -L 3C -(Choose any 1-5 R's) 3D Substituted phenyl), -L 3C -(Choose any 1-5 R's) 3D Substituted heteroaryl), -L 3C -(Choose any 1-5 R's) 3D Substituted cycloalkyl), -L 3C -(Choose any 1-5 R's) 3D (ii) substituted heterocyclic alkyl groups; and optionally via 1-5 R groups. 3E replace.

[0155] In certain other embodiments of the methods otherwise described herein, the compound has any of the above structural formulas (I)-(Ia), wherein the variables are as otherwise described in any embodiment herein, and R 3 For any location, travel via 1-5 R... 3E Substituted phenyl groups. In some embodiments, R 3 For any location, take 1-2 R... 3E Substituted phenyl groups. In some embodiments, R 3 For optional location R 3E Substituted phenyl groups. In some embodiments, R 3 For 1-2 R 3E Substituted phenyl groups. In some embodiments, R 3 For R 3E Substituted phenyl groups. In some embodiments, R 3 For any location, travel via 1-5 R... 3E Substituted heteroaryl groups (e.g., isothiazole, pyridone, thiadiazole, pyrazine, imidazole, benzofuran, indole, pyridine, pyrazole, isoxazole, thiophene, furan, or pyrimidine). In some embodiments, R 3 Selected from the group consisting of phenyl and heteroaryl groups (e.g., pyridyl, pyrazolyl), optionally hydroxylated by 1-5 R groups. 3E Replacement. In some embodiments, R 3 It is a halogen-substituted phenyl group. In some embodiments, R 3 It is 3-fluorophenyl.

[0156] Other embodiments of the method described herein are as follows, wherein the compound has any of the above structural formulas (I)-(Ia), wherein the variables are as otherwise described in any embodiment herein, and each R 3Eindependently selected from C1-C4alkyl, C1-C4fluoroalkyl, halogen, -OR 3F and -NR 3G R 3F In certain embodiments, each R 3E is independently selected from halogen, -OR 3F and -NR 3G R 3F In certain embodiments, each R 3E is independently selected from C1-C4alkyl, C1-C4fluoroalkyl, and halogen. In certain embodiments, each R 3E is independently selected from C1-C4alkyl, halogen, -OR 3F and -NR 3G R 3F In certain embodiments, each R 3E is independently selected from C1-C4fluoroalkyl and halogen. In certain embodiments, each R 3E is independently halogen.

[0157] Certain embodiments of the methods as otherwise described herein are such wherein the compound has any of the above structural formulae (I)-(Ia), wherein the variables are as otherwise described in any embodiment herein, and R 4 is optionally substituted C1-C8alkyl, optionally substituted C1-C8alkenyl, or optionally substituted C1-C8alkynyl. In certain embodiments, R 4 is optionally substituted C1-C8alkyl. In certain embodiments, R 4 is hydrogen or unsubstituted C1-C6alkyl. In certain embodiments, R 4 is unsubstituted C1-C3alkyl. In certain embodiments, R 4 is unsubstituted methyl.

[0158] Certain embodiments of the methods as otherwise described herein are such wherein the compound has any of the above structural formulae (I), wherein the variables are as otherwise described in any embodiment herein, and R 5 is phenyl or heteroaryl (e.g., isoxazolyl, pyridinyl, pyrazolyl), each optionally substituted with 1-5 R 5E In certain embodiments, R 5 is heterocycloalkyl optionally substituted with 1-5 R 5E In certain embodiments, R 5 is cycloalkyl optionally substituted with 1-5 R 5E In certain embodiments, R 5 is cycloalkyl substituted with 1-5 R 5E In certain embodiments, R 5 is cycloalkyl optionally substituted with 1-5 R5E substituted unsaturated cycloalkyl. In certain embodiments, R 5 is substituted with 1-5 R 5E substituted unsaturated cycloalkyl. In certain embodiments, R 5 is substituted with R 5E substituted cyclohexenyl. In certain embodiments, R 5 is 4-(trifluoromethyl)cyclohexen-1-en-1-yl.

[0159] Certain embodiments of the methods as otherwise described herein are such wherein the compound has any of the above structural Formula (I), wherein the variables are as otherwise described in any embodiment 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.

[0160] In certain embodiments of the methods of the disclosure, the compound of Formula (I) is: 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohexen-1-en-1- yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid, optionally in the form of a pharmaceutically acceptable salt and / or solvate or hydrate.

[0161] In certain embodiments of the methods of the disclosure, the compound of Formula (I) is: 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohexen-1-en-1- yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid C1-C3 alkyl ester, optionally in the form of a solvate or hydrate. In certain embodiments of the methods of the disclosure, the compound of Formula (I) is: 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohexen-1-en-1- yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid ethyl ester, optionally in the form of a solvate or hydrate.

[0162] Certain embodiments of the methods as otherwise described herein are such wherein the compound has any of the above structural Formula (Ia), wherein the variables are as otherwise described in any embodiment herein, and Q 1 is -C(O)OR 2C or -C(O)NR 2B R 2C . In certain embodiments, Q 1 is -C(O)OR2C In certain embodiments, Q is -C(O)O(Ci-C3alkyl). In certain embodiments, Q is -C(O)O(ethyl). In certain embodiments, Q is -C(O)O(Ci-C3alkyl). In certain embodiments, Q is -C(O)O(ethyl). 1 In certain embodiments, Q is -C(O)O(Ci-C3alkyl). In certain embodiments, Q is -C(O)O(ethyl). In certain embodiments, Q is -C(O)O(Ci-C3alkyl). In certain embodiments, Q is -C(O)O(ethyl). 1 In certain embodiments, Q is -C(O)O(Ci-C3alkyl). In certain embodiments, Q is -C(O)O(ethyl). In certain embodiments, Q is -C(O)O(Ci-C3alkyl). In certain embodiments, Q is -C(O)O(ethyl). 1 In certain embodiments, Q is -C(O)O(Ci-C3alkyl). In certain embodiments, Q is -C(O)O(ethyl). In certain embodiments, Q is -C(O)O(Ci-C3alkyl). In certain embodiments, Q is -C(O)O(ethyl). 2C In certain embodiments, Q is -C(O)O(Ci-C3alkyl). In certain embodiments, Q is -C(O)O(ethyl). In certain embodiments, Q is -C(O)O(Ci-C3alkyl). In certain embodiments, Q is -C(O)O(ethyl). 2C In certain embodiments, Q is -C(O)O(Ci-C3alkyl). In certain embodiments, Q is -C(O)O(ethyl). In certain embodiments, Q is -C(O)O(Ci-C3alkyl). In certain embodiments, Q is -C(O)O(ethyl).

[0163] In certain embodiments of the methods of the disclosure, the compound of Formula (Ia) is:

[0164]

[0165] In certain embodiments of the methods of the disclosure, the compound of Formula (Ia) is:

[0166]

[0167] wherein R is Ci-C8alkyl, and R is independently selected from Ci-C4alkyl, Ci-C4fluoroalkyl, halogen, -OR and -NR 1 3E 3F 3G 3F

[0168] In certain embodiments of the methods of the disclosure, the pyrazolylthiazole of Formula (Ia) is 1-(4-bromo-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H- pyrazole-5-carboxylic acid ethyl ester.

[0169] Definitions

[0170] The term "may be located before and / or after a single dash "-", or a double dash "—", as used herein, is intended to indicate the order of bonds between the named substituent and its parent moiety; a single dash represents a single bond, and a double dash represents a double bond or a pair of single bonds in a spiro substituent. In the absence of a single or double dash, it is understood that a single bond is formed between the substituent and its parent moiety; further, unless the dashes are otherwise indicated, substituents referred to in reference to a chemical structure are intended to be read in a "left-to-right" manner. For example, arylalkyl, arylalkyl-, and alkylaryl represent the same functional group.

[0171] ​​​​​For simplicity, chemical moieties are defined throughout the specification and referred to primarily as monovalent chemical moieties (e.g., alkyl, aryl, etc.). However, such terms are also used to express the corresponding multivalent moieties where appropriate to one of skill in the art. For example, an "alkyl" moiety can refer to a monovalent radical (e.g., CH3-CH2-), while in certain instances a divalent linking moiety can also be "alkyl," where one of skill in the art would understand alkyl to be a divalent radical (e.g., -CH2-CH2-), which is equivalent to the term "alkylene." (Similarly, where a divalent moiety is required and is referred to as "aryl," one of skill in the art would understand the term "aryl" to refer to the corresponding divalent moiety, i.e., arylene.) All atoms are to be understood as having their normal bond-forming valency (i.e., carbon is 4-valent, N is 3-valent, O is 2-valent, and S is 2-valent, 4-valent, or 6-valent depending on the oxidation state of S). Nitrogen in the disclosed compounds can have a higher valency, e.g., N-oxides or tetra-substituted ammonium salts. At times, moieties can be defined as, for example, -B-(A) a where a is 0 or 1. In such instances, when a is 0, the moiety is -B, and when a is 1, the moiety is -B-A.

[0172] As used herein, the term "alkyl" includes saturated hydrocarbons having the indicated number of carbon atoms, such as 1 to 10 carbon atoms (i.e., inclusive), 1 to 8 carbon atoms, 1 to 6 carbon atoms, 1 to 3 carbon atoms, or 1, 2, 3, 4, 5, or 6 carbon atoms. Alkyl groups can be straight or branched, and depending on the context, can be a monovalent radical or a divalent radical (i.e., an alkylene group). For example, the moiety "-(C1-C6 alkyl)-O-" indicates that the oxygen is attached through an alkylene bridge having 1 to 6 carbon atoms, and C1-C3 alkyl represents methyl, ethyl, and propyl moieties. Examples of "alkyl" include, for example, methyl, ethyl, propyl, iso-propyl, butyl, iso-, sec- and t-butyl, pentyl, and hexyl.

[0173] The term "alkoxy" represents an alkyl group of the indicated number of carbon atoms attached to the parent molecular moiety through an oxygen bridge. Examples of "alkoxy" include, for example, methoxy, ethoxy, propoxy, and isopropoxy.

[0174] The term "alkenyl" as used herein is an unsaturated hydrocarbon containing 2 to 10 carbon atoms (i.e., inclusive of 2 and 10), 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2, 3, 4, 5, or 6 carbon atoms, and unless otherwise indicated, contains at least one carbon-carbon double bond. Alkenyl groups can be straight or branched, and depending on the context, can be a monovalent radical or a divalent radical (i.e., an alkenylene group). For example, the moiety " -(C2-C6 alkenyl)-0-" indicates that the oxygen is connected by an alkenylene bridge having 2 to 6 carbon atoms. Representative examples of alkenyl groups 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-dimethyloct-2,6-dienyl.

[0175] The term "alkynyl" as used herein is an unsaturated hydrocarbon containing 2 to 10 carbon atoms (i.e., inclusive of 2 and 10), 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2, 3, 4, 5, or 6 carbon atoms, and unless otherwise indicated, contains at least one carbon-carbon triple bond. Alkynyl groups can be straight or branched, and depending on the context, can be a monovalent radical or a divalent radical (i.e., an alkynylene group). For example, the moiety " -(C2-C6 alkynyl)-0-" indicates that the oxygen is connected by an alkynylene bridge having 2 to 6 carbon atoms. Representative examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

[0176] The term "halogen" or "halo" denotes fluorine, chlorine, bromine, and iodine. In certain embodiments of each embodiment otherwise described herein, the term "halogen" or "halo" refers to fluorine, chlorine, or bromine. The term "fluoroalkyl" denotes an alkyl group (i.e., as otherwise described herein) that is substituted with at least one fluorine. "Fluoroalkyl" includes alkyl groups that are 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-hexafluoropropyl-2-yl, and 2,2,3,3,3-pentafluoropropyl-1-yl.

[0177] The term "heteroaryl" refers to an aromatic ring system containing at least one aromatic heteroatom selected from nitrogen, oxygen, and sulfur in the aromatic ring. Most commonly, heteroaryl groups will have 1, 2, or 3 heteroatoms. In one embodiment of the compounds of the invention, the heteroaryl group is bonded to the rest of the structure through an atom in the aromatic ring of the heteroaryl group. In another embodiment, the heteroaryl group is bonded to the rest of the structure through a non-aromatic ring atom.

[0178] The term "heterocycloalkyl" refers to a non-aromatic ring containing at least one heteroatom, preferably selected from nitrogen, oxygen, and sulfur, wherein the heteroatom is present in the non-aromatic ring. A heterocycloalkyl group can have 1, 2, or 3 heteroatoms. A heterocycloalkyl group can be saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., heterocycloalkenyl). In certain embodiments, a heterocycloalkyl group has 3 to 7 members in a single ring. In other embodiments, a heterocycloalkyl group has 5 or 6 members in a single ring. In some embodiments, a heterocycloalkyl group has 3, 4, 5, 6, or 7 members in a single ring. Examples of heterocycloalkyl groups include, for example, morpholinyl, thiomorpholinyl, 2-oxazolidinonyl, piperazinyl, homopiperazinyl, piperazinonyl, pyrrolidinyl, azepanyl, azetidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, homopiperidinyl, homomorpholinyl, homothiomorpholinyl, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrofuranyl, dihydropyranyl, imidazolidinyl, and tetrahydrothiophenyl. Particularly desirable heterocycloalkyl groups include morpholinyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, piperazinyl, azepanyl, azetidinyl, thiomorpholinyl, 2-oxazolidinonyl, imidazolidinonyl, and piperazinonyl.

[0179] The term "cycloalkyl" refers to a non-aromatic carbon ring or ring system, which can be saturated (i.e., cycloalkyl) or partially unsaturated (i.e., cycloalkenyl). Certain examples of cycloalkyl groups present in the disclosed compounds have 3 to 7 members in a single ring, such as 5 or 6 members in a single ring. In some embodiments, a cycloalkyl group has 3, 4, 5, 6, or 7 members in a single ring. Examples of cycloalkyl groups include, for example, cyclohexyl, cyclohexenyl, cyclopentyl, cyclobutyl, and cyclopropyl. Cycloalkyl groups herein are unsubstituted, or when specified as "optionally substituted," can be substituted at one or more substitutable positions with the various groups indicated.

[0180] The term "oxo" refers to a doubly bonded oxygen, sometimes represented as =0, or "C(O)" can be used to show a carbon substituted with oxygen, for example, in describing a carbonyl group.

[0181] Unless otherwise indicated, the term "substituted," as defined below, when used to modify a specified group or radical, indicates that one or more hydrogen atoms of the specified group or radical are each, independently of one another, replaced with the same or a different substituent.

[0182] As used herein, the term "medicinal salt" refers to medicinal acid and base addition salts and solvates. Such medicinal 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, and alkanes (such as acetic acid, HOOC-(CH2)). n -COOH, where n is 0-4), etc. Non-toxic pharmaceutical base addition salts include salts of bases such as sodium, potassium, calcium, ammonium, etc. Those skilled in the art will recognize a variety of non-toxic pharmaceutical addition salts.

[0183] As used herein, "leaving group" (e.g., suitable as X) 1 A leaving group ("leaving group") refers to the portion of a reactant (e.g., an alkyl halide of this disclosure) that is displaced from the first reactant in a chemical reaction. A comprehensive list of suitable leaving groups can be found in J. March, Advanced Organic Chemistry, John Wiley and Sons, NY (2013). Examples of suitable leaving groups include, but are not limited to, halogens (such as Cl or Br), acetoxy groups, and sulfonyloxy groups (such as methanesulfonyloxy, trifluoromethanesulfonyloxy ("trifluoromethanesulfonate"), p-toluenesulfonyloxy ("toluenesulfonate")).

[0184] As used herein, a "protecting group" (e.g., suitable as R) 2A Or R 2C () refers to those groups that remain stable at other positions in the molecule under subsequent reaction conditions, and can be removed at appropriate time points without disturbing the rest of the molecule to obtain unprotected Q or Q'. 1 It can be determined based on the group to be protected (e.g., Q or Q). 1The appropriate protecting group is selected based on the properties of the carboxylic acid moiety and the conditions used in the methods of the disclosure. A comprehensive list of suitable protecting groups can be found in T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. (1999), the disclosure of which is incorporated herein by reference in its entirety. For example, the carboxylic acid moiety can be protected in the form of an ester with an alkyl or substituted alkyl group (e.g., methyl, ethyl, t-butyl allyl, trityl (triphenylmethyl), and the like); or an ester with an arylalkyl or substituted arylalkyl group (e.g., benzyl, such as 4-nitrobenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, and the like) in the form of a thioester (e.g., t-butyl thioester), in the form of a silyl ester (e.g., trimethylsilyl, t-butyldimethylsilyl), and the like. The amide moiety can be protected in the form of a carbamate with an alkyl or substituted alkyl group (e.g., t-butyl carbamate).

[0185] Examples

[0186] The methods of the disclosure are further illustrated by the following examples, which should not be construed as limiting the disclosure in scope or spirit to the specific procedures and agents described herein.

[0187] Example 1: Preparation of 4-bromo-2-hydrazinyl-5-(isopropylthio)thiazole (Compound 4)

[0188]

[0189] To a dry round bottom flask under nitrogen was added 2-chlorothiazole (51 g, 0.43 mol), N,N'-dimethylacrylurea (45.5 mL, 0.378 mol), and anhydrous tetrahydrofuran (1.0 L). The clear, colorless solution was cooled to -74 °C in a dry ice-acetone bath, then n-butyllithium in hexanes (262 mL, 0.43 mol) was added dropwise over 120 min while maintaining the temperature < -72 °C. The brown solution was stirred for 30 min, then a solution of diisopropyl disulfide (61.6 g, 0.410 mol) in anhydrous tetrahydrofuran (200 mL) was added over 120 min and the mixture was stirred for an additional 30 min at < -72 °C. The reaction mixture was then transferred via cannula over 70 min to a 5 L flask containing 3 N HC1 (1 L) cooled to 1 °C. The resulting biphasic mixture was stirred for an additional 30 min, then extracted with heptanes (1 x 1 L, 1 x 500 mL) and washed with brine (100 mL).

[0190] 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 heptanes (100 mL) was added dropwise over 60 min and the solution was stirred for 1 h before allowing it to warm to room temperature (20-22 °C) over 18 h. A solution of sodium thiosulfate (30 g) in water (500 mL) was then added and stirred for 1 h. The aqueous phase was extracted with dichloromethane (200 mL) and the combined organic phases were washed with brine (100 mL) and the solvent was removed under reduced pressure.

[0191] The oil was then dissolved in tetrahydrofuran (1.0 L) and a 50% hydrazine solution in water (150 mL, 2.5 mol) was added. The biphasic mixture was stirred at room temperature (20-23 °C) for 30 h. The organic layer was then concentrated to 175 mL and heptanes (250 mL) were added dropwise over 20 min. Seed crystals of the title compound (10 mg) were added and the mixture was agitated for 1 h. Heptanes (250 mL) were then added, causing rapid crystallization. The mixture was cooled to 5 °C, filtered, and washed with heptanes (2 x 250 mL). The filtrate was concentrated to 700 mL under reduced pressure, cooled to 2 °C overnight, and filtered, washing with heptanes (2 x 100 mL). The combined solids from the filtration steps were dried in air to give the title compound as a light beige solid (79.5 g, 72%). 1 H NMR (500 MHz, CDC13) δ 8.66 (br, 1H), 4.16 (br, 2H), 3.17 (m, 1H), 1.28 (s, 6H). 13 C NMR (500 MHz, CDC13) δ 176.48, 130.48, 111.51, 41.44, 23.06. MS (m / z): 268 [M+1] + .

[0192] Example 2: Recrystallization of Compound 4

[0193] Compound 4 (186.6 g, 0.6957 mol) and isopropanol (2 L) were charged to a 12 L flask. 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 min, followed by crystallization. The mixture was stirred for 1 h and then water (1.5 L) was added over 1.5 h. 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 x 500 mL), and dried overnight to give the title compound as a light beige solid (166.2 g, 90.2%).

[0194] Example 3: 1stPreparation of 2-(4-bromo-5-isopropylsulfonyl-thiazol-2-yl)-4-(3- fluorophenyl)-5-methyl-pyrazole-3-carboxylic acid ethyl ester (Compound 8)

[0195]

[0196] A solution of compound 4 (6.21 g, 23.2 mmol) and l-(3-fluorophenyl)propane-l,2- dione (5 g, 30.1 mmol) in ethanol (140 mL) was stirred for 16 h. To the reaction was then added ethyl 2-chloroacetate (11.35 g, 92.6 mmol), potassium carbonate (19.2 g, 139 mmol) and potassium iodide (3.84 g, 23.2 mmol). The reaction turned reddish brown and was heated to 90 °C under reflux for 7 h. The reaction was then cooled to 20-25 °C, heptane (40 mL) was added and the reaction was concentrated to 60 mL. To the mixture was then added an aqueous solution of sodium thiosulfate (300 mL) and extracted with heptane (3 x 150 mL). The combined yellow organic layers were dried over sodium sulfate, filtered and concentrated to a viscous orange solution which solidified upon addition of alcohol (10 mL). The mixture was cooled to 0-5 °C, allowed to stand for 1 h and then filtered. The filtered solid was washed with alcohol (3 x 5 mL) and dried under vacuum at 30 °C to yield the title compound (5.9 g, 53%).

[0197] Example 4: 2ndPreparation of Compound 8

[0198]

[0199] To a solution of compound 4 (2.36 g, 8.8 mmol) in dioxane (53 mL) was added l-(3- fluorophenyl)propane-l,2-dione (2.19 g, 13.2 mmol) and stirred at room temperature for 16 h and then heated to 60 °C for 1 h. The reaction was then cooled and ethyl 2-chloroacetate (2.16 g, 17.6 mmol), potassium carbonate (7.30 g, 52.8 mmol) and potassium iodide (146.1 mg, 0.8800 mmol) were added sequentially and heated to 110 °C for 18 h. The reaction was cooled to room temperature, heptane (100 mL) was added and then concentrated to 150 mL under reduced pressure. Water (100 mL) was then added and the mixture was extracted with heptane (3 x 100 mL). The combined organic layers were concentrated to 20 mL and filtered through a pad of silica gel using 10% ethyl acetate in heptane as eluent. The solvent was removed from the resulting yellow solution and crystallized with ethanol (10 mL). The mixture was then cooled to 0 °C and filtered, washed with cold ethanol (2 x 3 mL) and dried under reduced pressure at 35 °C to provide the title compound (2.67 g, 63%).1 H NMR (500 MHz, CDC13) δ 7.4 (m, 1H), 7.2 (d, 1H), 7.1 (m, 1H), 4.35 (q, 2H), 3.3 (quint, 1H), 2.35 (s, 3H), 1.35 (s, 6H), 1.30 (t, 3H). 13 C{ 1 H} NMR (500 MHz, CDC13) δ 163.65, 161.69, 160.73, 160.27, 150.80, 132.16, 131.22, 130.19, 125.06, 124.04, 123.13, 116.35, 115.00, 62.79, 41.85, 23.03, 13.83, 12.63. 19 F NMR (500 MHz, CDC13) δ -112.55 - -112.47 (quint). MS (m / z): 485.65 [M+1] + .

[0200] Example 5: Preparation of 4-(3-fluorophenyl)-2-[5-isopropylsulfonyl-4-[4- (trifluoromethyl)cyclohexen-l-yl]thiazol-2-yl]-5-methyl-pyrazole-3-carboxylic acid ethyl ester (Compound 10)

[0201]

[0202] A 1 L flask was charged with 4,4,5,5-tetramethyl-2-[4-(trifluoromethyl)cyclohexen-l- yl]-l,3,2-dioxaborolane (21.39 g, 77.49 mmol), Compound 8 (31.28 g, 64.57 mmol), Pd(dppf)Cl2-CH2Cl2(1.58 g, 1.94 mmol) and potassium carbonate (26.77 g, 193.7 mmol). Degassed toluene (360 mL) and deionized water (90 mL) were added to the flask and the mixture was heated to 90 °C over the course of 1 h. After 18 h, the reaction mixture was cooled to room temperature and filtered through celite and washed with ethyl acetate (50 mL). The organic layer was separated and dried over sodium sulfate and charged with silica gel (150 g). The resulting slurry was evaporated to dryness, poured onto a silica pad and eluted with 5% ethyl acetate in heptanes (1 L). The organic solvent was evaporated and allowed to stand overnight to give the title compound (36.62 g, 93.4% yield). 1H NMR (500 MHz, CDC13) δ 7.35 (m, 1H), 7.15 (d, 1H), 7.05 (m, 1H), 6.30 (s, 1H), 4.25 (q, 2H), 3.15 (quint, 1H), 2.70 (d, 1H), 2.40 (m, 2H), 2.25 (s, 3H), 2.05 (d, 1H), 1.50-1.60 (m, 3H), 1.20-1.25 (m, 6H), 1.10-1.15 (t, 3H). 13 C{ 1 H} NMR (500 MHz, CDC13) δ 161.23, 159.77, 159.16, 156.09, 153.41, 148.05, 137.15, 130.63, 130.50, 129.52, 127.20, 126.10, 123.12, 118.87, 114.47, 113.11, 60.39, 40.62, 36.46, 25.13, 21.61, 20.80, 19.77, 11.85, 10.66. 19 F NMR (500 MHz, CDC13) δ -73.68, -112.72. MS (m / z): 553.90 [M+1] + .

[0203] Example 6: Preparation of 4-(3-fluorophenyl)-2-[5-isopropylsulfonyl-4-[4- (trifluoromethyl)cyclohexen-l-yl]thiazol-2-yl]-5-methyl-pyrazole-3-carboxylic acid sodium salt (Compound 11)

[0204]

[0205] To a solution of methanol (150 mL), tetrahydrofuran (75 mL) was added compound 10 (17.83 g, 28.79 mmol). Sodium hydroxide aqueous solution (1.0 N, 64 mL) was added and the resulting slurry was heated to 50 °C for 2.5 h. Evaporation under reduced pressure gave a beige solid which was agitated with deionized water (3 x 500 mL) and filtered. The solid was dried under reduced pressure until constant weight and then suspended in acetonitrile (100 mL). The mixture was filtered after 15 min to give the title compound (14.00 g, 89%). 1HNMR (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 (quint, 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 C{ 1 H}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 F NMR (500 MHz, DMSO-d6) δ -72.06 (s), -113.60 (quint). MS (m / z): 525.85 [M-Na+2] + .

[0206] Example 7: Recrystallization of compound 11

[0207] Compound 11 was then recrystallized. 56 g (0.10 mol) of compound 11 was dissolved in tetrahydrofuran (500 mL) and filtered. To this solution was added acetonitrile (250 mL) and the solution was concentrated to 350 mL under reduced pressure at 50 °C. Acetonitrile (250 mL) was added again and the resulting solution was concentrated to 300 mL under reduced pressure at 50 °C, inducing crystallization. To this mixture was added acetonitrile (250 mL) and concentrated again to 500 mL under reduced pressure at 50 °C. The mixture was then left to stand at 50 °C for 1 h, then cooled to 20 °C for 1 hour, then cooled to 0 °C for 30 min. The resulting mixture was filtered and the solid was washed with cold acetonitrile (2 x 100 mL, 0 °C) and dried under reduced pressure at 35 °C to provide compound 11 (54.7 g, 98%). MS (m / z): 525.85 [M-Na+2] + . 1 H NMR (500 MHz, DMSO-d 6) 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). 13 C NMR (126 MHz, DMSO-d 6 ) 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.

[0208] Example 8: Preparation of 4-(3-fluorophenyl)-2-[5-isopropylsulfonyl-4-[4- (trifluoromethyl)-cyclohexen-l-yl]thiazol-2-yl]-5-methyl-pyrazole-3-carboxylic acid (Compound 1)

[0209]

[0210] A solution of compound 11 (52.0 g, 94.9 mmol) and 10% acetonitrile in deionized water (1.0 L) was charged to a 5 L flask. The mixture was stirred for 30 min, then warmed to 50 °C. A seed crystal of the title compound (1.2 g) was added, then 0.1 N HC1 (1.0 L) was added dropwise over 3.75 h. As the addition proceeded, a change in the slurry was noted, which became increasingly thick. A yellow color was also observed to develop with each drop of acid, which dissipated with stirring. After 900 mL of acid was added, the supernatant was monitored for pH. When the amount of addition approached 1.0 equivalent, the pH dropped to ~3, with a target pH <4 to ensure complete protonation.

[0211] The sample was analyzed for assay (XRPD, HPLC), the pH of the sample filtrate was measured by a pH meter to be 4.3, and an additional 20 mL of 0.1 N HC1 was added to the reaction mixture. The heating controller was turned off, and the mixture was allowed to cool to 19 °C and stirred for 18 hours. The reaction was then filtered using a sintered glass funnel and washed with mother liquor, then washed with deionized water (3 x 330 mL). The filter cake was dried in a vacuum oven set to 45 °C and >30 in. vacuum, with slight nitrogen evolution, to give the title compound (51.76 g, 99% yield). 1 H NMR (500 MHz, DMSO-d 6 ) 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 (quint, 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 CNMR (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 (quint). MS (m / z): 526.3 [M+1] + .

[0212] Various exemplary embodiments of the present disclosure include, but are not limited to, the following enumerated embodiments, which can be combined in any number or in any manner that is not technically or logically contradictory.

[0213] Example 1. A process for preparing a halopyrazolylthiazole of formula (la)

[0214]

[0215] wherein

[0216] X is halogen (e.g., chloro, bromo, or iodo);

[0217] L 1is selected from the group consisting of a bond, -C(O)-, -S-, -S(O) 1-2 6 6 6 6 6 1-2 1-2 1-2 6 6 1-2

[0218] R 1 is selected from the group consisting of C1-C8alkyl, C1-C8alkenyl and C1-C8alkynyl, each of which is unsubstituted or fluorinated;

[0219] Q 1 is selected from the group consisting of -C(O)OR 2C 2B R 2C 2B 2C 2B 2B 2C 2C 2B 2C 2B 2C and -C(O)NH-O(C1-C3alkyl), wherein

[0220] each R 2B is independently selected from H and C1-C3alkyl, and

[0221] each R 2C is independently selected from C1-C3alkyl and a protecting group;

[0222] R 3 is phenyl or heteroaryl, each of which (i) is optionally substituted with a single substituent selected from -L 3C -(phenyl optionally substituted with 1-5 R 3D -(phenyl optionally substituted with 1-5 R 3C -(phenyl optionally substituted with 1-5 R​​​​​​​​​​​​​​​​​​​​​​​3D Substituted heteroaryl), -L 3C -(Choose any 1-5 R's) 3D Substituted cycloalkyl), -L 3C -(Choose any 1-5 R's) 3D (ii) substituted heterocyclic alkyl groups; and optionally via 1-5 R groups. 3E replace,

[0223] in

[0224] Each L 3C For bonds, methylene, ethylene, -C(O)-, -S-, -S(O) 1-2 -、-O- or -NR 3G -;

[0225] Each R 3D Independently selected from oxo- or optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, -SF5, -N3, -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 ;

[0226] each R 3E is independently selected from oxo, optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, -SF5, -N3, -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 ;

[0227] each R 3F is independently selected from H, C1-C3 alkyl, and C1-C3 fluoroalkyl, and

[0228] each R 3G is independently selected from H, C1-C3 alkyl, and C1-C3 fluoroalkyl; and

[0229] R 4 is selected from the group consisting of hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkenyl, and optionally substituted C1-C8 alkynyl;

[0230] wherein

[0231] each R 6hydrogen, C1-C3alkyl, and -C(O)(C1-C3alkyl);

[0232] each optionally substituted alkyl, alkenyl, and alkynyl is unsubstituted, fluorinated, or substituted with one or two hydroxyl groups;

[0233] each cycloalkyl has 3-10 ring carbons and is unsaturated or partially unsaturated;

[0234] each heterocycloalkyl has 3-10 ring members and 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and is unsaturated or partially unsaturated; and

[0235] each heteroaryl is a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur,

[0236] the method comprises:

[0237] thiazolylhydrazine of Formula (lb)

[0238]

[0239] wherein X, R 1 and L 1 as described for Formula (la),

[0240] with a diketone of Formula (II)

[0241]

[0242] wherein R 3 and R 4 as described for Formula (la),

[0243] optionally in a solvent under conditions sufficient to form a hydrazone; and

[0244] contacting the hydrazone with a compound of Formula X 1 -CH2-Q 1 to yield the halopyrazolylthiazole of Formula (la), wherein Q 1 as described for Formula (la), and X 1 is halogen or a leaving group.

[0245] Example 2. The method of Example 1, further comprising preparing the thiazolylhydrazine of Formula (lb) according to the method of any one of Examples 37-46.

[0246] Example 3. The method of Example 1 or Example 2, wherein the amount of the diketone is at least 1 molar equivalent (e.g., at least 1.1 molar equivalent, at least 1.25 molar equivalent, or at least 1.5 molar equivalent, based on the amount of thiazolylhydrazine).

[0247] Example 4. The method of Example 1 or Example 2, wherein the thiazolylhydrazine and the diketone are reacted at about room temperature.

[0248] Example 5. The method of Example 5, wherein the thiazolylhydrazine is reacted with the diketone for at least 8 hours (e.g., at least 10 hours, at least 12 hours, at least 14 hours, or at least 16 hours); or wherein the thiazolylhydrazine is reacted with the diketone for a time in the range of 8 hours to 20 hours (e.g., in the range of 8 hours to 16 hours, 8 hours to 14 hours, 8 hours to 12 hours, 8 hours to 10 hours, 10 hours to 20 hours, 10 hours to 16 hours, 10 hours to 14 hours, 10 hours to 12 hours, 14 hours to 20 hours, 14 hours to 18 hours, 14 hours to 16 hours, 16 hours to 20 hours, 16 hours to 18 hours, or 18 hours to 20 hours).

[0249] Example 6. The method of any one of Examples 1-5, wherein the thiazolylhydrazine and the diketone are reacted at a temperature of at least 40 °C (e.g., at least 45 °C, at least 50 °C, at least 60 °C, or at least 65 °C); or wherein the thiazolylhydrazine and the diketone are reacted at a temperature in the range of 40 °C to 80 °C (e.g., in the range of 40 °C to 70 °C, 40 °C to 60 °C, 40 °C to 50 °C, 50 °C to 80 °C, 50 °C to 70 °C, 50 °C to 60 °C, 60 °C to 80 °C, or 60 °C to 70 °C).

[0250] Example 7. The method of Example 6, wherein the thiazolylhydrazine and the diketone are maintained at the temperature for at least 30 minutes (e.g., at least 45 minutes or at least 1 hour).

[0251] Example 8. The method of any one of Examples 1-7, wherein the hydrazone and alkyl halide are reacted in the presence of an inorganic iodide and a base.

[0252] Example 9. The method of Example 8, wherein the inorganic iodide is KI or NaI.

[0253] Example 10. The method of either of Examples 8 or 9, wherein the amount of inorganic iodide is catalytic based on the amount of the thiazolyl hydrazine (e.g., no more than 20 mol %, or no more than 15 mol %, or no more than 10 mol %, or in the range of 5 mol % to 20 mol %, or 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 thiazolyl hydrazine).

[0254] Example 11. The method of either of Examples 8 or 9, wherein the amount of inorganic iodide is stoichiometric based on the amount of thiazole (e.g., at least 1 molar equivalent based on the amount of thiazole).

[0255] Example 12. The method of any one of Examples 8 to 11, wherein the base is a carbonate salt (e.g., potassium carbonate).

[0256] Example 13. The method of any one of Examples 1 to 12, wherein the hydrazone and alkyl halide are reacted at a temperature of at least 80 °C (e.g., at least 85 °C, at least 90 °C, at least 95 °C, at least 100 °C, or at least 110 °C); or the hydrazone and the alkyl halide are reacted at a temperature in the range of 80 °C to 120 °C (e.g., in the range of 80 °C to 110 °C, 80 °C to 100 °C, 80 °C to 90 °C, 90 °C to 120 °C, 90 °C to 110 °C, 90 °C to 100 °C, 100 °C to 120 °C, or 100 °C to 110 °C).

[0257] Example 14. The method of any one of Examples 1 to 13, wherein the hydrazone and alkyl halide are contacted for at least 8 hours (e.g., at least 10 hours, at least 12 hours, at least 14 hours, or at least 16 hours); or wherein the hydrazone and alkyl halide are contacted for a time in the range of 8 hours to 24 hours (e.g., in the range of 8 hours to 20 hours, 8 hours to 16 hours, 8 hours to 14 hours, 8 hours to 12 hours, 8 hours to 10 hours, 10 hours to 24 hours, 10 hours to 20 hours, 10 hours to 16 hours, 10 hours to 14 hours, 10 hours to 12 hours, 14 hours to 24 hours, 14 hours to 20 hours, 14 hours to 18 hours, 14 hours to 16 hours, 16 hours to 24 hours, 16 hours to 20 hours, 16 hours to 18 hours, 18 hours to 24 hours, or 18 hours to 20 hours).

[0258] Example 15. The method of any one of Examples 1 to 14, wherein the reaction of the thiazolyl hydrazine with the diketone to form the hydrazone and the reaction of the hydrazone with an alkyl halide of formula X 1 -CH2-Q 1 are carried out without isolation or purification of any intermediates.

[0259] Example 16. The method of any one of Examples 1 to 15, further comprising crystallizing the halopyrazolylthiazole of formula (la) from an alcohol to give a compound having a purity of at least 98%.

[0260] Example 17. A halopyrazolylthiazole of formula (la),

[0261]

[0262] wherein

[0263] X is halogen;

[0264] 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 ;

[0265] R 1 is selected from the group consisting of C1-C8alkyl, C1-C8alkenyl, and C1-C8alkynyl, each of which is unsubstituted or fluorinated;

[0266] Q 1 is selected from the group consisting of -C(O)OR 2C , -C(O)NR 2B R 2C , -C(O)NR 2B S(O)2R 2C , -C(O)NR 2B S(O)2NR2B R 2C , -S(O)2R 2C , -N(R 2B )S(O)2R 2C , -S(O)2NR 2B R 2C , and -C(O)NH-O(C1-C3alkyl), wherein

[0267] each R 2B is independently selected from H and C1-C3alkyl, and

[0268] each R 2C is independently selected from C1-C3alkyl and a protecting group;

[0269] R 3 is phenyl or heteroaryl, each of which (i) is optionally substituted with a single substituent selected from -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 (ii) is optionally substituted with 1-5 R 3E ,

[0270] wherein

[0271] each L 3C is a bond, methylene, ethylene, -C(O)-, -S-, -S(O) 1-2 -, -O-, or -NR 3G -;

[0272] each R 3D is independently selected from oxo, optionally substituted C1-C4alkyl, C1-C4fluoroalkyl, halogen, -CN, -SF5, -N3, -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)NR3G R 3F , 3G C(S)R 3F , 3F -OC(O)R 3F , 3F -SC(O)R 3F , 3F -OC(S)R 3F , 3F -SC(S)R 3F , 1-2 OR 3F , 1-2 -OS(O) 3F R 1-2 , 3G -OS(O) 3F R 3G , 1-2 S(O) 3F ;

[0273] each R 3E is independently selected from oxo, optionally substituted C1-C4alkyl, C1-C4fluoroalkyl, halogen, -CN, -SF5, -N3, -C(O)R 3F , 3F -SR 1-2 , 3F -OR 3F , 3G -NR 3F R 3F , 3G -C(O)R 3F , 3G -NR 3F C(O)R 3G , 3F -NR 3G C(S)R 3F , 3F -C(O)OR 3F , 3F -C(O)SR 3F , 3F -C(S)OR 3F , 3F -OC(S)R 3F , 1-2 -SC(S)R 3F , 1-2 -S(O) 3F OR, -S(O) 1-2 NR 3G R 3F and -NR 3G S(O) 1-2 R 3F ;

[0274] each R 3F is independently selected from H, C1-C3 alkyl, and C1-C3 fluoroalkyl, and

[0275] each R 3G is independently selected from H, C1-C3 alkyl, and C1-C3 fluoroalkyl; and

[0276] R 4 is selected from the group consisting of hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkenyl, and optionally substituted C1-C8 alkynyl;

[0277] wherein

[0278] each R 6 is selected from the group consisting of hydrogen, C1-C3 alkyl, and -C(O)(C1-C3 alkyl);

[0279] each optionally substituted alkyl, alkenyl, and alkynyl is unsubstituted, fluorinated, or substituted with one or two hydroxyl groups;

[0280] each cycloalkyl has 3-10 ring carbons and is unsaturated or partially unsaturated;

[0281] each heterocycloalkyl has 3-10 ring members and 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and is unsaturated or partially unsaturated; and

[0282] each heteroaryl is a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur,

[0283] Embodiment 18. The method or compound according to any one of embodiments 1 to 17, wherein X is Cl.

[0284] Embodiment 19. The method or compound according to any one of embodiments 1 to 17, wherein X is Br.

[0285] Embodiment 20. The method or compound according to any one of embodiments 1 to 17, wherein X is I.

[0286] In some embodiments, the compound of Formula (I) is a compound of Formula (Ia):

[0287] In some embodiments, the compound of Formula (I) is a compound of Formula (Ia):

[0288]

[0289] In some embodiments, the compound of Formula (I) is a compound of Formula (Ia):

[0290] L 1 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 ;

[0291] R 1 selected from the group consisting of C1-C8alkyl, C1-C8alkenyl, and C1-C8alkynyl, each of which is unsubstituted or fluorinated;

[0292] Q is selected from the group consisting of -C(O)OR 2A , -C(O)NR 2B R 2A , -C(O)NR 2B S(O)2R 2A , -C(O)NR 2B S(O)2NR 2B R 2A , -S(O)2R 2A , -N(R 2B)S(O)2R 2A , -S(O)2NR 2B R 2A , and -C(O)NH-O(C1-C3alkyl), wherein

[0293] each R 2A is independently selected from H, C1-C3alkyl, and a protecting group, and

[0294] each R 2B is independently selected from H and C1-C3alkyl;

[0295] R 3 is phenyl or heteroaryl, each of which (i) is optionally substituted with a single substituent selected from -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 (ii) is optionally substituted with 1-5 R 3E ,

[0296] wherein

[0297] each L 3C is a bond, methylene, ethylene, -C(O)-, -S-, -S(O) 1-2 -, -O-, or -NR 3G -;

[0298] each R 3D is independently selected from oxo, optionally substituted C1-C4alkyl, C1-C4fluoroalkyl, halogen, -CN, -SF5, -N3, -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)OR3F , -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 ;

[0299] each R 3E is independently selected from oxo, optionally substituted C1-C4alkyl, C1-C4fluoroalkyl, halogen, -CN, -SF5, -N3, -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 ;

[0300] each R 3F is independently selected from H, C1-C3 alkyl, and C1-C3 fluoroalkyl, and

[0301] each R 3G is independently selected from H, C1-C3 alkyl, and C1-C3 fluoroalkyl;

[0302] R 4 is selected from the group consisting of hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkenyl, and optionally substituted C1-C8 alkynyl; and

[0303] R 5 is phenyl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted with 1-5 R 5E substituents,

[0304] wherein

[0305] each R 5E is independently selected from oxo, optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, -SF5, -N3, -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 NR5G R 5F and -NR 5G S(O) 1-2 R 5F ;

[0306] each R 5F is independently selected from H, C1-C3 alkyl, and C1-C3 fluoroalkyl, and

[0307] each R 5G is independently selected from H and C1-C3 alkyl;

[0308] wherein

[0309] each R 6 is selected from the group consisting of hydrogen, C1-C3 alkyl, and -C(O)(C1-C3 alkyl);

[0310] each optionally substituted alkyl, alkenyl, and alkynyl is unsubstituted, fluorinated, or substituted with one or two hydroxyl groups;

[0311] each cycloalkyl has 3-10 ring carbons and is unsaturated or partially unsaturated;

[0312] each heterocycloalkyl has 3-10 ring members and 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and is unsaturated or partially unsaturated;

[0313] each heteroaryl is a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur,

[0314] the method comprising:

[0315] halopyrazolylthiazole of Formula (Ia)

[0316]

[0317] wherein X is a halogen (e.g., Cl, Br, or I);

[0318] Q 1 is selected from the group consisting of -C(O)OR 2C , -C(O)NR 2B R 2C , -C(O)NR 2B S(O)2R 2C , -C(O)NR 2B S(O)2NR 2B R 2C , -S(O)2R 2C , -N(R 2B )S(O)2R 2C , -S(O)2NR2B R 2C and -C(O)NH-O(C1-C3alkyl), wherein

[0319] each R 2B is independently selected from H and C1-C3alkyl, and

[0320] each R 2C is independently selected from C1-C3alkyl and a protecting group;

[0321] and L 1 , R 1 , R 3 and R 4 as described for formula (I),

[0322] optionally in a solvent, with an organic boron coupling to include the R 5 moiety to give the compound of formula (I).

[0323] Example 23. The method of Example 22, further comprising preparing the halopyrazolylthiazole of formula (la) according to the method of any one of Examples 1-21.

[0324] Example 24. The method of Example 22 or 23, wherein the organic boron is a boronic acid or boronic ester having a substituent on the boron atom of R 5 .

[0325] Example 25. The method of Example 24, wherein the organic boron has the following formula:

[0326]

[0327] wherein

[0328] R 5 as described for formula (I), and

[0329] Y 1 and Y 2 are independently hydroxyl or C1-C4alkoxy, or Y 1 and Y 2 together with the B atom form a 5- or 6-membered ring, one or both of the oxygens in the ring being bound to boron.

[0330] Example 26. The method of any one of Examples 22-25, wherein the coupling is performed under Suzuki conditions.

[0331] Example 27. The method of any one of Examples 22-25, wherein the halopyrazolylthiazole of formula (la) and the organic boron are coupled in the presence of a palladium catalyst and a base.

[0332] Example 28. The method of Example 27, wherein the palladium catalyst is [1,1’- bis(diphenylphosphino)ferrocene]dichloropalladium(II).

[0333] Example 29. The method of Example 27 or 28, wherein the base is a carbonate salt (e.g., potassium carbonate).

[0334] Example 30. The method of any one of Examples 22-29, wherein the coupling is performed at a temperature of at least 80 °C (e.g., at least 85 °C, at least 90 °C, at least 95 °C, at least 100 °C, or at least 110 °C); or coupling is performed at a temperature ranging from 80 °C to 120 °C (e.g., ranging from 80 °C to 110 °C, 80 °C to 100 °C, 80 °C to 90 °C, 90 °C to 120 °C, 90 °C to 110 °C, 90 °C to 100 °C, 100 °C to 120 °C, or 100 °C to 110 °C).

[0335] Example 31. The method of any one of Examples 22-30, wherein the coupling is for a period of at least 8 hours (e.g., at least 10 hours, at least 12 hours, at least 14 hours, or at least 16 hours); or wherein the coupling is for a period ranging from 8 hours to 24 hours (e.g., ranging from 8 hours to 20 hours, 8 hours to 16 hours, 8 hours to 14 hours, 8 hours to 12 hours, 8 hours to 10 hours, 10 hours to 24 hours, 10 hours to 20 hours, 10 hours to 16 hours, 10 hours to 14 hours, 10 hours to 12 hours, 14 hours to 24 hours, 14 hours to 20 hours, 14 hours to 18 hours, 14 hours to 16 hours, 16 hours to 24 hours, 16 hours to 20 hours, 16 hours to 18 hours, 18 hours to 24 hours, or 18 hours to 20 hours).

[0336] Example 32. The method of any one of Examples 22-31, wherein the compound of Formula (I) is

[0337]

[0338] Example 33. The method of Example 32, further comprising hydrolyzing the compound of Formula (I) (e.g., wherein Q 1 is -C(O)O(C1-C3alkyl)) to obtain a carboxylic acid compound of Formula (I).

[0339] Example 34. The method of Example 32, further comprising hydrolyzing the compound of Formula (I) (e.g., wherein Q 1 is -C(O)O(C1-C3alkyl)) to obtain a carboxylate salt of the compound of Formula (I).

[0340] In some embodiments, the method of any one of embodiments 34-35 further comprises crystallizing the salt of the compound of formula (I); and protonating the salt of the compound of formula (I) with an acid to obtain the compound of formula (I) having a purity of at least 98%.

[0341] In some embodiments, the method of any one of embodiments 33-35 is for preparing 4-(3-fluorophenyl)-l-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-l-en-l- yl)thiazol-2-yl)-3-methyl-lH-pyrazole-5-carboxylic acid, optionally in the form of a pharmaceutically acceptable salt and / or solvate or hydrate.

[0342] In some embodiments, the method of any one of embodiments 33-35 is for preparing 4-(3-fluorophenyl)-l-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-l-en-l- yl)thiazol-2-yl)-3-methyl-lH-pyrazole-5-carboxylic acid, optionally in the form of a pharmaceutically acceptable salt and / or solvate or hydrate.

[0343]

[0344] wherein

[0345] X is halogen (e.g., chloro, bromo, or iodo);

[0346] 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 ;

[0347] R 1 is selected from the group consisting of C1-C8alkyl, C1-C8alkenyl, and C1-C8alkynyl, each of which is unsubstituted or fluorinated;

[0348] wherein

[0349] each R 6 is selected from the group consisting of hydrogen, C1-C3alkyl, and -C(O)(C1-C3alkyl);

[0350] The method comprises:

[0351] reacting a dihalothiazole of the formula

[0352]

[0353] wherein X, R 1 and L 1 as described for formula (lb), and X a is halogen (e.g., chloro, bromo, or iodo, e.g., chloro), optionally in a solvent with an aqueous solution of hydrazine to give a crude product; and

[0354] crystallizing the crude product to give the thiazolylhydrazine of formula (lb).

[0355] Example 38. The method of Example 37, wherein X a is chloro.

[0356] Example 39. The method of Example 37, wherein X a is bromo.

[0357] Example 40. The method of Example 37, wherein X a is iodo.

[0358] Example 41. The method of any one of Examples 37-40, wherein the amount of hydrazine is at least 5 molar equivalents based on the amount of the dihalothiazole (e.g., at least 5.25 molar equivalents, e.g., at least 5.5 molar equivalents, at least 5.5 molar equivalents, or at least 6 molar equivalents based on the amount of the dihalothiazole).

[0359] Example 42. The method of any one of Examples 37-41, wherein the solvent is tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile, or dimethylsulfoxide; e.g., tetrahydrofuran.

[0360] Example 43. The method of any one of Examples 37-42, wherein the reaction of the dihalothiazole with the hydrazine is performed at about room temperature (e.g., in the range of 20 °C to 25 °C or 20 °C to 23 °C).

[0361] Example 44. The method of any one of Examples 37-43, wherein the reaction is for at least 10 hours (e.g., at least 20 hours, at least 24 hours, at least 48 hours, or at least 72 hours), e.g., for a time in the range of 10 hours to 100 hours.

[0362] Example 45. The method of any one of Examples 37-44, wherein the crystallization is from a hydrocarbon solvent (e.g., hexanes, heptanes, or a combination thereof).

[0363] In some embodiments, the crystallization from the hydrocarbon solvent (e.g., hexanes, heptanes, or a combination thereof) is from an amount of about 100% v / v to 300% v / v, based on the total volume of the crude product.

[0364] In some embodiments, R is optionally substituted C1-C8alkyl. 1 In some embodiments, R is unsubstituted C1-C8alkyl or fluorinated C1-C8alkyl.

[0365] In some embodiments, R is optionally substituted C1-C8alkyl. 1 In some embodiments, R is unsubstituted C1-C8alkyl or fluorinated C1-C8alkyl.

[0366] In some embodiments, R is optionally substituted C1-C8alkyl. 1 In some embodiments, R is unsubstituted C1-C8alkyl or fluorinated C1-C8alkyl. 1 In some embodiments, R is optionally substituted C1-C5alkyl.

[0367] In some embodiments, R is optionally substituted C1-C8alkyl. 1 In some embodiments, R is unsubstituted C1-C5alkyl or fluorinated C1-C5alkyl.

[0368] In some embodiments, R is optionally substituted C1-C8alkyl. 1 In some embodiments, R is unsubstituted C1-C5alkyl.

[0369] In some embodiments, R is optionally substituted C1-C8alkyl. 1 In some embodiments, R is unsubstituted C2-C5alkyl or fluorinated C2-C5alkyl.

[0370] In some embodiments, R is optionally substituted C1-C8alkyl. 1 In some embodiments, R is unsubstituted C2-C5alkyl or fluorinated C2-C5alkyl.

[0371] In some embodiments, R is optionally substituted C1-C8alkyl. 1 In some embodiments, R is unsubstituted C2-C5alkyl.

[0372] In some embodiments, R is optionally substituted C1-C8alkyl. 1 In some embodiments, R is hydroxymethyl, methoxymethyl, hydroxyethyl, or methoxyethyl.

[0373] In some embodiments, R is optionally substituted C1-C8alkyl.1 is methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl.

[0374] In some embodiments, the compound of Formula (I) is a compound of Formula (II): 1 is propyl, isopropyl, butyl, or tert-butyl.

[0375] In some embodiments, the compound of Formula (I) is a compound of Formula (II): 1 is isopropyl.

[0376] In some embodiments, the compound of Formula (I) is a compound of Formula (II): 1 is a bond, -O-, -S-, -S(O)-, or -S(O)2.

[0377] In some embodiments, the compound of Formula (I) is a compound of Formula (II): 1 is -O-, -S-, -S(O)-, or -S(O)2.

[0378] In some embodiments, the compound of Formula (I) is a compound of Formula (II): 1 is -S-, -S(O)-, or -S(O)2-.

[0379] In some embodiments, the compound of Formula (I) is a compound of Formula (II): 1 is -S-.

[0380] In some embodiments, the compound of Formula (I) is a compound of Formula (II): 1 is a bond.

[0381] In some embodiments, the compound of Formula (I) is a compound of Formula (II): 1 is -O.

[0382] In some embodiments, the compound of Formula (I) is a compound of Formula (II): 1 is -NR 6 -.

[0383] In some embodiments, the compound of Formula (I) is a compound of Formula (II): 3 is aryl (e.g., phenyl) optionally substituted with 1-5 R 3E .

[0384] In some embodiments, the compound of Formula (I) is a compound of Formula (II): 3 is aryl (e.g., phenyl) optionally substituted with 1-2 R 3ESubstituted aryl groups (e.g., phenyl).

[0385] Example 68. The method or compound according to any one of Examples 1 to 35 or 47 to 65, wherein R 3 For optional location R 3E Substituted aryl groups (e.g., phenyl).

[0386] Example 69. The method or compound according to any one of Examples 1 to 35 or 47 to 65, wherein R 3 For 1-2 R 3E Substituted aryl groups (e.g., phenyl).

[0387] Example 70. The method or compound according to any one of Examples 1 to 35 or 47 to 65, wherein R 3 For R 3E Substituted aryl groups (e.g., phenyl).

[0388] Example 71. The method or compound according to any one of Examples 1 to 35 or 47 to 65, wherein R 3 For any location, travel via 1-5 R... 3E Substituted heteroaryl groups (e.g., isothiazole, pyridone, thiadiazole, pyrazine, imidazole, pyridine, pyrazole, isoxazole, thiophene, furan or pyrimidine).

[0389] Example 72. The method or compound according to any one of Examples 1 to 35 or 47 to 65, wherein R 3 Selected from the group consisting of phenyl and monocyclic heteroaryl groups (e.g., pyridyl, pyrazolyl), optionally denoted by 1-5 R groups. 3E Replace; or where R 3 It is a halogen-substituted phenyl group.

[0390] Example 73. The method or compound according to any one of Examples 1 to 35 or 47 to 65, wherein R 3 It is 3-fluorophenyl.

[0391] Example 74. The method or compound according to any one of Examples 1 to 35 or 47 to 65, wherein R 3 It is a phenyl or heteroaryl group, each (i) optionally substituted with a single substituent selected from -L 3C -(Choose any 1-5 R's) 3D Substituted aryl), -L 3C -(Choose any 1-5 R's) 3D Substituted heteroaryl), -L 3C -(Choose any 1-5 R's) 3D Substituted cycloalkyl), -L 3C-(optionally substituted phenyl), -L 3D substituted heteroaryl), -L 3E substituted cycloalkyl), -L

[0392] In some embodiments, R is phenyl, which is (i) substituted with a single substituent selected from -L 3 -(optionally substituted phenyl), -L 3C -(optionally substituted phenyl), -L 3D -(optionally substituted phenyl), -L 3C -(optionally substituted phenyl), -L 3D -(optionally substituted phenyl), -L 3C -(optionally substituted phenyl), -L 3D -(optionally substituted phenyl), -L 3C -(optionally substituted phenyl), -L 3D -(optionally substituted phenyl), -L 3E -(optionally substituted phenyl), -L

[0393] In some embodiments, R is heteroaryl (e.g., isothiazole, pyridinone, thia- diazole, pyrazine, pyridine, pyrazole, isoxazole, thiophene, furan, or pyrimidine), which is (i) substituted with a single substituent selected from -L 3 -(optionally substituted phenyl), -L 3C -(optionally substituted phenyl), -L 3D -(optionally substituted phenyl), -L 3C -(optionally substituted phenyl), -L 3D -(optionally substituted phenyl), -L 3C -(optionally substituted phenyl), -L 3D -(optionally substituted phenyl), -L 3C -(optionally substituted phenyl), -L 3D -(optionally substituted phenyl), -L 3E -(optionally substituted phenyl), -L

[0394] In some embodiments, each R is independently selected from C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -OR and -NR 3E R 3F R 3G R 3F ; or wherein R 3E is independently selected from halogen, -OR 3F and -NR 3G R 3F .

[0395] In embodiments, each R is independently selected from C1-C4alkyl, C1-C4fluoroalkyl, and halogen. 3E In embodiments, each R is independently selected from C1-C4alkyl, C1-C4fluoroalkyl, and halogen.

[0396] In embodiments, each R is independently selected from C1-C4alkyl, C1-C4fluoroalkyl, and halogen. 3E In embodiments, each R is independently selected from C1-C4alkyl, C1-C4fluoroalkyl, and halogen. 3F In embodiments, each R is independently selected from C1-C4alkyl, C1-C4fluoroalkyl, and halogen. 3G In embodiments, each R is independently selected from C1-C4alkyl, C1-C4fluoroalkyl, and halogen. 3F .

[0397] In embodiments, each R is independently selected from C1-C4alkyl, C1-C4fluoroalkyl, and halogen. 3E In embodiments, each R is independently selected from C1-C4alkyl, C1-C4fluoroalkyl, and halogen.

[0398] In embodiments, each R is independently selected from C1-C4alkyl, C1-C4fluoroalkyl, and halogen. 3E In embodiments, each R is independently selected from C1-C4alkyl, C1-C4fluoroalkyl, and halogen.

[0399] In embodiments, each R is independently selected from C1-C4alkyl, C1-C4fluoroalkyl, and halogen. 4 In embodiments, each R is independently selected from C1-C4alkyl, C1-C4fluoroalkyl, and halogen.

[0400] In embodiments, each R is independently selected from C1-C4alkyl, C1-C4fluoroalkyl, and halogen. 4 In embodiments, each R is independently selected from C1-C4alkyl, C1-C4fluoroalkyl, and halogen.

[0401] In embodiments, each R is independently selected from C1-C4alkyl, C1-C4fluoroalkyl, and halogen. 4 In embodiments, each R is independently selected from C1-C4alkyl, C1-C4fluoroalkyl, and halogen.

[0402] In embodiments, each R is independently selected from C1-C4alkyl, C1-C4fluoroalkyl, and halogen. 4 In embodiments, each R is independently selected from C1-C4alkyl, C1-C4fluoroalkyl, and halogen.

[0403] In embodiments, each R is independently selected from C1-C4alkyl, C1-C4fluoroalkyl, and halogen. 4 In embodiments, each R is independently selected from C1-C4alkyl, C1-C4fluoroalkyl, and halogen.

[0404] In embodiments, each R is independently selected from C1-C4alkyl, C1-C4fluoroalkyl, and halogen. 5 In embodiments, each R is independently selected from C1-C4alkyl, C1-C4fluoroalkyl, and halogen. 5E In embodiments, each R is independently selected from C1-C4alkyl, C1-C4fluoroalkyl, and halogen.

[0405] In some embodiments, R is cycloalkenyl (e.g., cyclohexen-1-yl) optionally substituted with 1-5 R 5 In some embodiments, R is cycloalkenyl (e.g., cyclohexen-1-yl) optionally substituted with 1-5 R 5E In some embodiments, R is cycloalkenyl (e.g., cyclohexen-1-yl) optionally substituted with 1-5 R

[0406] In some embodiments, R is cycloalkenyl (e.g., cyclohexen-1-yl) optionally substituted with 1-5 R 5 In some embodiments, R is cycloalkenyl (e.g., cyclohexen-1-yl) optionally substituted with 1-5 R 5E In some embodiments, R is cycloalkenyl (e.g., cyclohexen-1-yl) optionally substituted with 1-5 R

[0407] In some embodiments, R is cycloalkenyl (e.g., cyclohexen-1-yl) optionally substituted with 1-5 R 5 In some embodiments, R is cycloalkenyl (e.g., cyclohexen-1-yl) optionally substituted with 1-5 R

[0408] In some embodiments, R is cycloalkenyl (e.g., cyclohexen-1-yl) optionally substituted with 1-5 R 5 In some embodiments, R is cycloalkenyl (e.g., cyclohexen-1-yl) optionally substituted with 1-5 R 5E In some embodiments, R is cycloalkenyl (e.g., cyclohexen-1-yl) optionally substituted with 1-5 R

[0409] In some embodiments, R is cycloalkenyl (e.g., cyclohexen-1-yl) optionally substituted with 1-5 R 5 In some embodiments, R is cycloalkenyl (e.g., cyclohexen-1-yl) optionally substituted with 1-5 R 5E In some embodiments, R is cycloalkenyl (e.g., cyclohexen-1-yl) optionally substituted with 1-5 R

[0410] In some embodiments, R is cycloalkenyl (e.g., cyclohexen-1-yl) optionally substituted with 1-5 R 5 In some embodiments, R is cycloalkenyl (e.g., cyclohexen-1-yl) optionally substituted with 1-5 R 5E In some embodiments, R is cycloalkenyl (e.g., cyclohexen-1-yl) optionally substituted with 1-5 R

[0411] In some embodiments, R is cycloalkenyl (e.g., cyclohexen-1-yl) optionally substituted with 1-5 R 5 In some embodiments, R is cycloalkenyl (e.g., cyclohexen-1-yl) optionally substituted with 1-5 R 5E In some embodiments, R is cycloalkenyl (e.g., cyclohexen-1-yl) optionally substituted with 1-5 R

[0412] In some embodiments, R is cycloalkenyl (e.g., cyclohexen-1-yl) optionally substituted with 1-5 R 5 In some embodiments, R is cycloalkenyl (e.g., cyclohexen-1-yl) optionally substituted with 1-5 R 5E In some embodiments, R is cycloalkenyl (e.g., cyclohexen-1-yl) optionally substituted with 1-5 R

[0413] In some embodiments, R is cycloalkenyl (e.g., cyclohexen-1-yl) optionally substituted with 1-5 R 1 In some embodiments, R is cycloalkenyl (e.g., cyclohexen-1-yl) optionally substituted with 1-5 R 2C In some embodiments, R is cycloalkenyl (e.g., cyclohexen-1-yl) optionally substituted with 1-5 R

[0414] In embodiments, Q is -C(O)OR 1 -C(O)NR 2B R 2C .

[0415] In embodiments, Q is -C(O)OR 1 -C(O)O(C1-C3alkyl), e.g., -C(O)O(ethyl).

[0416] In embodiments, Q is -C(O)OR 1 -C(O)OR 2C and R 2C is a protecting group.

[0417] In embodiments, the compound of Formula (Ia) is:

[0418]

[0419] In embodiments, the compound of Formula (Ia) is:

[0420] wherein R 1 is C1-C8alkyl, and R 3E is independently selected from C1-C4alkyl, C1-C4fluoroalkyl, halogen, -OR 3F , and -NR 3G R 3F .

[0421] In embodiments, Q is -C(O)OR 2A or -C(O)NR 2B R 2A ; or wherein Q is -C(O)OR 2A ; or wherein Q is -C(O)OH or -C(O)O(C1-C3alkyl); or wherein Q is -C(O)OH.

[0422] In embodiments, the compound is 1-(4-bromo-5-(isopropylthio)thiazol-2-yl)-4-(3- fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid ethyl ester.

[0423] Numerous references have been made to patents and printed publications throughout this specification. Each of the cited references and printed publications are individually incorporated herein by reference in their entirety.

[0424] In closing, it is to be understood that the embodiments of the application disclosed herein are illustrative of the principles of the present application. Other modifications that can be employed are within the scope of the application. As such, the application is not to be limited to the exact constructional details as set forth above and shown in the accompanying drawings, but can include other alternatives in the spirit or scope of the application. Thus, the present application is not to be limited to the exact details shown and described, for purposes of illustration.

Claims

1. A process for preparing a halo-pyrazolyl-thiazole of formula (la) wherein X is halo; L 1 is selected from the group consisting of a bond, -S-, -S(O) 1-2 -, -O- and -NR 6 -, wherein R 6 is hydrogen or C1-C3alkyl; R 1 selected from the group consisting of C1-C6alkyl; Q 1 selected from the group consisting of -C(O)OR 2C and -C(O)NR 2B S(O)2R 2C wherein R 2B is hydrogen or C1-C3alkyl, R 2C Ci-C3-alkyl; R 3 is phenyl or a 5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said phenyl is optionally substituted with 1-5 substituents selected from the group consisting of halogen, C1-C3alkyl, cyano, -OR 3F and -NR 3G R 3H wherein R 3F is hydrogen or C1-C3alkyl, R 3G and R 3H each independently is hydrogen or C1-C3alkyl, and R 4 selected from the group consisting of hydrogen and C1-C3alkyl; the process comprising: reacting a thiazolylhydrazine of formula (lb) wherein X, R 1 and L 1 as described for formula (Ia), with a diketone of formula (II) wherein R 3 and R 4 as described for formula (Ia), optionally in a solvent under conditions sufficient to form a hydrazone; and with an alkyl halide of formula X 1 -CH2-Q 1 to obtain said halopyrazolylthiazole of formula (la), wherein Q 1 is as described for formula (la), and X 1 is halogen; wherein said hydrazone and alkyl halide are reacted in the presence of a mineral iodide and a base.

2. The process of claim 1, wherein X is chloro or bromo.

3. The method of claim 1, wherein X 1 is chloro or bromo.

4. The process of claim 1, wherein the inorganic iodide is KI or Nal.

5. The process of claim 1, wherein the amount of inorganic iodide is stoichiometric to the amount of thiazolylhydrazine.

6. The process of claim 5, wherein the amount of inorganic iodide is at least 1 molar equivalent based on the amount of thiazolylhydrazine.

7. The process of claim 1, wherein the base is a carbonate salt.

8. The process of claim 7, wherein the base is potassium carbonate.

9. A halo-pyrazolyl-thiazole of formula (la) wherein X is halo; L 1 is selected from the group consisting of a bond, -S-, -S(O) 1-2 -, -O- and -NR 6 -, wherein R 6 is hydrogen or C1-C3 alkyl; R 1 selected from the group consisting of C1-C6 alkyl Q 1 selected from the group consisting of -C(O)OR 2C and -C(O)NR 2B S(O)2R 2C wherein R 2B is hydrogen or C1-C3alkyl, R 2C is C1-C3 alkyl; and R 3 is phenyl or a 5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said phenyl is optionally substituted with 1-5 substituents selected from the group consisting of halogen, C1-C3alkyl, cyano, -OR 3F and -NR 3G R 3H wherein R 3F is hydrogen or C1-C3alkyl, R 3G and R 3H each independently is hydrogen or C1-C3alkyl; and R 4 selected from the group consisting of hydrogen and C1-C3alkyl.

10. The halo-pyrazolyl-thiazole of claim 9, wherein X is chloro or bromo.

11. The halo-pyrazolyl-thiazole of claim 9, wherein the halo-pyrazolyl-thiazole of formula (la) is C1-C3 alkyl ester of l-(4-halo-5-(isopropylthio)thiazol-2-yl)-4-(3- fluorophenyl)-3-methyl-lH-pyrazole-5-carboxylic acid.

12. The halo-pyrazolyl-thiazole of claim 11, wherein the halo-pyrazolyl-thiazole of formula (la) is ethyl l-(4-bromo-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3- methyl-lH-pyrazole-5-carboxylate.

13. A process for preparing a compound of formula (I) the compound optionally in the form of a pharmaceutically acceptable salt, wherein L 1 is selected from the group consisting of a bond, -S-, -S(O) 1-2 -, -O- and -NR 6 -, wherein R 6 is hydrogen or C1-C3alkyl; R 1 selected from the group consisting of C1-C6alkyl; Q is selected from the group consisting of -C(O)OR 2A and -C(O)NR 2B S(O)2R 2A wherein R 2A is H or C1-C3alkyl, R 2B is H or C1-C3alkyl; and R 3 is phenyl or a 5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said phenyl is optionally substituted with 1-5 substituents selected from the group consisting of halogen, C1-C3alkyl, cyano, -OR 3F and -NR 3G R 3H wherein R 3F is hydrogen or C1-C3alkyl, R 3G and R 3H each independently is hydrogen or C1-C3alkyl; R 4 is selected from the group consisting of hydrogen and C1-C3alkyl; and R 5 is cyclohexenyl or phenyl, wherein said cyclohexenyl group is optionally substituted with 1-5 R 5E substituents, said R 5E independently selected from C1-C4 fluoroalkyl, said phenyl is optionally substituted with 1-5 substituents selected from the group consisting of halogen, C1-C3alkyl, -S(O)2R 5D , cyano, -NH2, -OR 5F , or -C(O)NR 5G R 5H , wherein R 5D is hydrogen or C1-C3alkyl, R 5F is C1-C3 alkyl, R 5G and R 5H each independently is hydrogen or C1-C3alkyl; the process comprising: coupling a halo-pyrazolyl-thiazole of formula (la) wherein X, L 1 , R 1 , Q 1 , R 3 and R 4 as described for formula (la) in claim 1, optionally in a solvent, with an organic boron coupling comprising R 5 moieties to give said compound of formula (I).

14. The method of claim 13, wherein R 5 is 4-(trifluoromethyl)cyclohex-1 -en-1 -yl.

15. The process of claim 13, wherein X is chloro or bromo.

16. The method of claim 13, wherein the organoboron is a boronic acid or boronic ester moiety substituted on its boron atom with the R 5 group.

17. The process of claim 16, wherein the organoboron has the formula: wherein R 5 As described for formula (I), and Y 1 and Y 2 independently are hydroxyl or C1-C4alkoxy, or Y 1 and Y 2 together with the B atom form a 5- or 6-membered ring, one or both of the oxygens in the ring being bound to boron.

18. The process of claim 16, wherein the halo-pyrazolyl-thiazole of formula (la) and the organoboron are coupled in the presence of a palladium catalyst and a base.

19. The process of claim 16, wherein the compound of formula (I) is 20. The process of claim 1, wherein the thiazolylhydrazine of formula (lb) is prepared by the process of: reacting a dihalothiazole of the formula wherein X, R 1 and L 1 as described for formula (lb), and X a is halogen, is optionally reacted with an aqueous solution of hydrazine in a solvent to give the crude product; and crystallizing the crude product to yield the thiazolylhydrazine of formula (lb).

21. The method of claim 20, wherein X is chloro or bromo. a is chloro or bromo.

22. The process of claim 20, wherein the crystallization is from a hydrocarbon solvent.

23. The process of claim 22, wherein the hydrocarbon solvent is hexane, heptane, or a combination thereof.

24. The process of claim 13, wherein R 1 is unsubstituted C1-C6alkyl; L 1 -S-; R 3 is phenyl, wherein said phenyl is optionally substituted with 1-5 substituents selected from the group consisting of halogen, C1-C3alkyl, cyano, -OR 3F and -NR 3G R 3H wherein R 3F is hydrogen or C1-C3alkyl, R 3G and R 3H each independently is hydrogen or C1-C3alkyl and R 4 is hydrogen or C1-C3alkyl; R 5 is cyclohexenyl or phenyl, wherein said cyclohexenyl group is optionally substituted with 1-5 R 5E , said R 5E are independently selected from the group consisting of C1-C4 fluoroalkyl, and said phenyl is optionally substituted with 1-5 substituents selected from the group consisting of halogen, C1-C3alkyl, -S(O)2R 5D , cyano, -NH2and -C(O)NR 5G R 5H wherein R 5D is hydrogen or C1-C3alkyl, R 5G and R 5H each independently is hydrogen or C1-C3alkyl; and Q 1 -C(O)OR 2C wherein R 2C is C1-C3 alkyl.

25. The halo-pyrazolyl-thiazole of claim 9, wherein R 1 is unsubstituted C1-C6alkyl; L 1 -S-; R 3 is phenyl, wherein said phenyl is optionally substituted with 1-5 substituents selected from the group consisting of halogen, C1-C3alkyl, cyano, -OR 3F and -NR 3G R 3H wherein R 3F is hydrogen or C1-C3alkyl, R 3G and R 3H each independently is hydrogen or C1-C3alkyl, and R 4 is hydrogen or C1-C3alkyl.

26. The process of any one of claims 1 and 13, wherein the formula (la) is: wherein R 1 is C1-C6alkyl, R C is C1-C3alkyl and R 3E is halogen, C1-C3alkyl, cyano, -OR 3F or -NR 3G R 3H .

27. The halo-pyrazolyl-thiazole of claim 9, wherein the formula (la) is: wherein R 1 is C1-C6alkyl, R C is C1-C3alkyl and R 3E is halogen, C1-C3alkyl, cyano, -OR 3F or -NR 3G R 3H .

28. 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 ester.

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