Pyrazole compounds, formulations thereof, and methods for using the compounds and / or formulations.

Abstract

The present invention provides compounds useful for delivering interleukin receptor-related kinase (IRAK) inhibitors to targets that require them, and compositions containing such compounds. [Solution] Embodiments of pyrazole compounds according to formula (I) are disclosed herein. In one embodiment, the compound is a prodrug and / or salt of an IRAK inhibitor compound. The composition may include a carrier such as a polymer and may be a spray-dried formulation. JPEG2026053335000104.jpg45170 (wherein R is an aliphatic, acyl, heterocyclyl, carboxyl ester, amide, alkylphosphoamide, or alkyl phosphate; or R is H, and the compound is a salt.)

Description

[Technical Field]

[0001] Cross-reference of related applications This application seeks the benefit of retroactive application to the filing date of U.S. Provisional Patent Application No. 62 / 894,547, filed on 30 August 2019, which is incorporated herein by reference in its entirety.

[0002] This disclosure relates to the compound, its formulation, and embodiments of methods of using the compound, including for inhibiting interleukin receptor-associated kinase (IRAK) and / or delivering IRAK inhibitors to a target, and for treating IRAK-related diseases and conditions. [Background technology]

[0003] Interleukin-1 receptor-related kinases (IRAKs) are important mediators in signal transduction processes, including Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling pathways. IRAKs are involved in regulating signaling networks that control inflammation, apoptosis, and cell differentiation. Four IRAK genes have been identified in the human genome (IRAK1, IRAK2, IRAK3, and IRAK4), and studies have revealed their distinct essential biological roles. IRAK1 and IRAK4 have been shown to exhibit kinase activity. [Overview of the Initiative] [Means for solving the problem]

[0004] overview In particular, compounds and compositions comprising such compounds that are useful as kinase inhibitors, such as IRAK inhibitors, and / or for delivering IRAK inhibitors to targets requiring them are disclosed herein. In some embodiments, the compound is a prodrug and / or salt of an IRAK inhibitor compound. A specific embodiment disclosed is of formula I: [ka] (wherein, R is hydrogen, aliphatic, acyl, heterocyclyl, carboxyl ester, amide, alkyl phosphoramidate or alkyl phosphate such as alkyl, acyl, carboxyl ester, amide, non-aromatic heterocyclyl, alkyl phosphoramidate or alkyl phosphate) relates to a compound having. Instead, R is hydrogen and the compound is a salt. In certain embodiments, R is C a , g alkyl phosphate, C 1~4 alkyl phosphoramidate, C 1~6 alkyl, C 1~6 acyl, -C(O)O-C 1~6 aliphatic, -C(O)N(R b )2 or a 5- or 6-membered non-aromatic heterocyclyl. Also, each R b is independently H, unsubstituted C alkyl, C substituted with -N(R 1~6 )2 g alkyl, carboxyl ester or a 5- or 6-membered non-aromatic heterocyclyl, or two R 1~6 are together with the nitrogen to which they are attached, a C b non-aromatic heterocyclyl moiety optionally intervened by one or two -O- or -N(R g ), where R 3~6 is H or C g alkyl. R can be C optionally substituted with a 5- or 6-membered non-aromatic heterocyclyl, OH, -OC(O)-R 1~4 , -N(R a )2, -OC(O)-R b [[ID=三十八]]、カルボキシル又はそれらの組合せで任意選択的に置換されるC c alkyl, where R 1~6 is a 5-membered non-aromatic heterocyclyl, aryl substituted with -CH2N(R a )2, cycloalkyl substituted with carboxyl, C b alkoxy, unsubstituted C 3~6 alkyl or N(R<00000—23>), carboxyl, carboxyl ester, -OC ' 1~6 alkyl or N(R b )2, carboxyl, carboxyl ester, -OC 1~6Acyl, -NHC(O)(NH2)C 1~6 Alkyl or -(OCH2CH2) 1~8 N(R b )C is replaced by one or more of the above. 1~6 It is alkyl. Also, -OC(O)-R c It is derived from amino acids, where -OC(O)-R c The -OC(O)- portion corresponds to the acid portion of the amino acid, and R c is -N(R b )2 or nitrogen-containing non-aromatic heterocycline. The amino acids may be naturally occurring amino acids and / or may be selected from glycine, valine, alanine, leucine, isoleucine, methionine, phenylalanine, tryptophan, tyrosine, serine, threonine, asparagine, glutamine, arginine, histidine, lysine, aspartic acid, glutamic acid, cysteine, or proline.

[0005] Instead, R is -C(O)OC 1~4 Alkyl, -C(O)OC 1~4 Alkyl-N(R b )2, N(R b )2,-NHC(O)C 1~4 C is optionally substituted with alkyl or a combination thereof. 1~6 It may be an acyl moiety. In one embodiment, R is a 5 or 6-membered non-aromatic heterocyclyl moiety that is optionally substituted with hydroxyl, hydroxymethyl, or a combination thereof. However, in other embodiments, R is -OC(O)C 1~4 Alkyl or N(R) b -C(O)OC is optionally substituted in )2. 1~6 It is alkyl, or R is C 1~4 -C(O)OC that can be optionally substituted with alkyl groups. 3~6 It is a cycloalkyl group.

[0006] In certain embodiments, R is hydrogen, and the salt is a hydrochloride, citrate, hemicitrate, hemitartrate, tartrate, benzenesulfonate, mesylate, sodium salt, hemisuccinate, or succinate. However, in other embodiments, R is not a salt, and / or the compound is [ka] It could be a prodrug.

[0007] Embodiments of compositions comprising a compound and a pharmaceutically acceptable carrier are also disclosed herein. The composition may be a spray-drying composition comprising a carrier and a compound according to formula I. However, with respect to the spray-drying composition, R may be H, alkyl, acyl, carboxyl ester, amide, non-aromatic heterocyclyl, alkylphosphoramidate or alkyl phosphate, etc. They may be rhamidates or alkyl phosphates. Typically, compounds according to formula I are not in salt form when spray-dried. For example, suitable compounds for the spray-dried formulations disclosed herein include compounds of formula I in which R is hydrogen, aliphatic, acyl, heterocyclyl, carboxyl ester, or amide.

[0008] The carrier may be a polymer, such as a cellulose derivative, a vinyl polymer, a lactide polymer, a sugar, or a combination thereof. In some embodiments, the cellulose derivative may be hydroxypropyl methylcellulose succinate acetate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose (HPMC), or a combination thereof; the vinyl polymer may be poly(vinylpyrrolidone) (PVP), poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA), or a combination thereof; the lactide polymer may be polylactide (PLA), polylactide-co-glycolide (PLGA), or a combination thereof; or the sugar may be sucrose, trehalose, or a combination thereof. In certain embodiments, the carrier may be hydroxypropyl methylcellulose succinate acetate, and may be M-grade and / or fine-grade hydroxypropyl methylcellulose succinate acetate.

[0009] The composition may contain an effective amount of the compound according to Formula I, such as 1% to 50% w / w relative to the carrier or 10% to 35% w / w relative to the carrier. Furthermore, or alternatively, the spray-dried composition may further contain a flavoring agent, a stabilizer, a filler, or a combination thereof. Also, in any embodiment, the composition may be amorphous and / or have a glass transition temperature of 100°C to 120°C, such as 105°C to 110°C or 107°C to 110°C.

[0010] In a particular embodiment, the composition comprises 20% of the disclosed compound and 80% of HPMCAS-MF.

[0011] Embodiments of a method for producing a spray-dried composition are also disclosed herein. The method may include forming a mixture of a compound according to formula I, a carrier, and a solvent, and spray-drying the mixture to form a spray-dried formulation comprising the compound and the carrier.

[0012] Embodiments of methods for using the disclosed compounds and / or compositions containing the compounds are also disclosed. The methods may include administering the compounds of a composition containing the compounds to a subject, such as administering an effective amount of the compound or composition to a subject that requires it. The methods may be methods for treating diseases or conditions for which an IRAK inhibitor is indicated. In some embodiments, the diseases are autoimmune diseases, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergic diseases, multiple organ failure, kidney disease, platelet aggregation, cancer, transplantation, sperm motility, red blood cell deficiency, graft rejection, lung injury, respiratory diseases, ischemic conditions, bacterial infections, viral infections, immunomodulatory diseases, or combinations thereof.

[0013] The method may include administering a second therapeutic agent. The second therapeutic agent may be an analgesic, antibiotic, anticoagulant, antibody, anti-inflammatory agent, immunosuppressant, guanylate cyclase-C agonist, intestinal secretagogue, antiviral agent, anticancer agent, antifungal agent, or a combination thereof. In some embodiments, the second therapeutic agent is administered substantially simultaneously with the compound or composition. In other embodiments, the second therapeutic agent is administered sequentially with the compound or composition in any order, and the compound or composition and the second therapeutic agent may be administered such that the effective period of the compound or composition overlaps with the effective period of the second therapeutic agent.

[0014] Furthermore, embodiments of a method for inhibiting the IRAK protein are disclosed, comprising contacting the IRAK protein with an effective amount of the disclosed compound or a composition containing the compound. In one embodiment, the IRAK protein is present in the subject.

[0015] The above and other objects, features and advantages of the present invention will become more apparent from the following detailed description, which proceeds with reference to the accompanying figures. [Brief explanation of the drawing]

[0016] Brief explanation of the drawing [Figure 1]This is a dynamic water vapor sorbent (DVS) plot of the percentage change in mass with respect to target relative humidity (RH), representing the change in mass of one embodiment of the disclosed spray-dried formulation under various relative humidity conditions at 25°C. The plot gives two isotherms: 1 is an sorbent plot representing the change in mass with increasing relative humidity steps; 2 is a desorption plot representing the change in mass with decreasing relative humidity steps. [Figure 2] This is a digital image showing a 400x polarized light microscopy (PLM) image of one embodiment of the disclosed spray-dried formulation. [Figure 3] This is a graph of intensity against scattering angle, representing the X-ray powder diffraction pattern of one embodiment of the disclosed spray-dried formulation. [Figure 4] This graph shows weight and heat flow against temperature, providing both thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) plots of one embodiment of a spray-dried formulation, illustrating the weight change and heat flow of the dispersion at different temperatures. [Figure 5] This is a modulated DSC (mDSC) plot of reversible heat flow against temperature, showing the heat flow of one embodiment of a spray-dried formulation and indicating that the glass transition temperature (Tg) of that embodiment is 108.3°C. [Figure 6] This is a DVS plot of the percentage change in mass with respect to target relative humidity, representing the change in mass of one embodiment of a crystalline sample of compound I-1 under various relative humidity conditions at 25°C. The plot gives two isotherms: 1 is an sorption plot representing the change in mass with increasing relative humidity steps; 2 is a desorption plot representing the change in mass with decreasing relative humidity steps. [Figure 7] This is a digital image showing a PLM image of a crystalline sample of compound I-1 at a magnification of 400x. [Figure 8] This graph shows the intensity against scattering angle, representing the X-ray powder diffraction pattern of a crystalline sample of compound I-1. [Figure 9] This graph shows weight and heat flow against temperature, providing both thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) plots of a crystalline sample of compound I-1, representing the weight change and heat flow of the formulation at different temperatures. [Figure 10] This is an mDSC plot of reversible heat flow against temperature, showing the heat flow of a crystalline sample of compound I-1 and indicating that the glass transition temperature (Tg) of the crystalline sample is 106.1°C. [Figure 11] The graph shows the individual and mean plasma concentrations obtained by administering compound I-1 as a succinate cocrystal (compound I-106) to each of three subjects, representing plasma concentration against time. The results were normalized to a dose of 5 mg / kg of compound I-1. [Figure 12] This graph shows the individual and mean plasma concentrations resulting from the administration of compound I-1 as a phosphate cocrystal (compound I-104) to each of three subjects, representing plasma concentration against time. The results were normalized to a dose of 5 mg / kg of compound I-1. [Figure 13] This graph shows the individual and mean plasma concentrations obtained by administering compound I-1 as a gentisic acid cocrystal (compound I-105) to each of three subjects, representing plasma concentration against time. The results were normalized to a dose of 5 mg / kg of compound I-1. [Figure 14] This graph shows the individual and mean plasma concentrations obtained by administering compound I-1 as a tartrate cocrystal (compound I-11) to each of three subjects, representing plasma concentration against time. The results were normalized to a dose of compound I-1 of 5 mg / kg. [Figure 15] This is a graph of plasma concentration over time, showing the plasma concentration of compound I-1 derived from each of three subjects and the mean plasma concentration, resulting from administering a dose of one embodiment of the disclosed spray-dried formulation, which is sufficient to administer a 5 mg / kg dose of compound I-1. [Figure 16] This is a graph of plasma concentration over time, showing the plasma concentration and mean plasma concentration of the metabolite of compound I-1 derived from each of three subjects, resulting from administering a dose of one embodiment of the disclosed spray-dried formulation, which is sufficient to administer a 5 mg / kg dose of compound I-1. [Figure 17] This graph shows the plasma concentration over time, representing the plasma concentration of compound I-1 from each of three subjects and the mean plasma concentration, resulting from the administration of compound I-1 at a stock solution of 5 mg / kg diluted with orange juice. [Figure 18] This graph shows the plasma concentration against time, representing the plasma concentration of compound I-1 metabolites derived from each of three subjects, and the mean plasma concentration, resulting from the administration of compound I-1 at a stock solution of 5 mg / kg diluted with orange juice. [Figure 19] This is a table of pharmacokinetic data for one embodiment of the disclosed spray-dried formulation and the organic solution / organic juice formulation. [Figure 20] This is a DVS isotherm plot of the potassium salt of compound I-18. [Figure 21] This is a DVS isotherm plot of the arginine salt of compound I-18. [Figure 22] This is a DVS isotherm plot of the choline salt of compound I-18. [Figure 23] This is a DVS isotherm plot of the Tris salt of compound I-18. [Modes for carrying out the invention]

[0017] Detailed explanation I. Definition The following definitions of terms are provided to better describe this disclosure and to guide those skilled in the art in the practice of this disclosure. As used herein, “includes” means “inclusive,” and the singular forms “a” or “an” or “it” are otherwise clearly indicated by the context. Unless otherwise specified, it includes multiple references. The term "or" refers to one or more elements of the alternative elements stated, or a combination of two or more elements, unless otherwise clearly indicated by the context.

[0018] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this disclosure pertains. Similar or equivalent methods and materials may be used in the implementation or testing of this disclosure, but preferred methods and materials are described below. Materials, methods and examples are illustrative and not intended to be limiting. Other features of this disclosure are evident from the following detailed description and claims.

[0019] Unless otherwise specified, all figures representing quantities such as components, molecular weights, and percentages used herein or in the claims shall be understood to be modified by the term “approximately.” Therefore, unless otherwise specified, numerical parameters stated, whether express or implied, are approximations that may depend on the desired properties and / or the limits of detection under standard test conditions / methods. Where embodiments are directly and clearly distinguished from the prior art discussed, numerical values ​​in embodiments are not approximations unless the term “approximately” is enumerated.

[0020] Where chemical structures are shown or described, unless otherwise specified, it is assumed that all carbon atoms contain hydrogen atoms so that each carbon atom has a valence of 4. For example, in the left-hand structure of the schematic diagram below, nine hydrogen atoms are implied. The nine hydrogen atoms are shown in the right-hand structure. [ka]

[0021] In some cases, specific atoms in a structure may be described in the formulas as hydrogen or containing a hydrogen atom (e.g., -CH2CH2-). Those skilled in the art will understand that this descriptive method is common in the field of chemistry to provide conciseness and simplicity in describing organic structures.

[0022] Those skilled in the art will understand that definitions can be combined to further describe specific compounds. For example, hydroxyaliphatic refers to an aliphatic group substituted with a hydroxy(-OH) group, and haloalkylaryl refers to an aryl group substituted with an alkyl group, where the alkyl group may also be substituted with a halogen, and the bond to the parent structure is via the aryl moiety, since aryl is the base name of the substituent.

[0023] As used herein, the term “substitution” refers to all subsequent modifications within the term, such as “substitution aryl C 1~8 In the term "alkyl," substitution is "C 1~8 The alkyl portion, the aryl portion, or aryl C 1~8 This can occur at both parts of an alkyl group. For example, alkyl groups include substituted cycloalkyl groups.

[0024] When used to modify a given group or part, “substitution” means that at least one, and possibly two or more, hydrogen atoms of the given group or part are independently substituted with the same or different substituents as defined below. In certain embodiments, a group, part, or substituent may be substituted or unsubstituted unless explicitly defined as either “unsubstituted” or “substituted.” Thus, any of the groups defined herein may or may be unsubstituted. In certain embodiments, a substituent may or may not be explicitly defined as substituted, but it is still considered to be optionally substituted. For example, an “alkyl” substituent may or may be unsubstituted, but an “unsubstituted alkyl” is never substituted.

[0025] Unless otherwise specified, a "substituent" or "substituent group" for substituting one or more hydrogen atoms in a saturated carbon atom in a given group or part is -R 60 , halo, =O, -OR 70 , -SR 70 , -N(R 80)2. Haloalkyl, perhaloalkyl, -CN, -NO2, =N2, -N3, -SO2R 70 , -SO3 - M + , -SO3R 70 , -OSO2R 70 , -OSO3 - M + , -OSO3R 70 , -P(O)(O - )(2(M + )(2, -P(O)(O - )(2M 2+ , -P(O)(OR 70 )O - M + , -P(O)(OR 70 )2, -C(O)R 70 , -C(S)R 70 , -C(NR 70 )R 70 , -CO2 - M + , -CO2R 70 , -C(S)OR 70 , -C(O)N(R 80 )(2, -C(NR 70 )(R 80 )(2, -OC(O)R 70 , -OC(S)R 70 , -OCO2 - M + , -OCO2R 70 , -OC(S)OR 70 , -NR 70 C(O)R 70 , -NR 70 C(S)R 70 , -NR 70 CO2 - M + , -NR 70 CO2R 70 , -NR 70 C(S)OR 70 , -NR 70 C(O)N(R 80 )(2, -NR 70 C(NR 70 )R 70 and -NR 70 C(NR 70 )(N(R 80 )(2, where R60 However, C is optionally substituted with 1, 2, or 3 OH groups. 1~6 It is alkyl; each R 70 However, for each appearance, independently of hydrogen or R 60 and; each R 80 However, R 70 or, instead, two R 80 The groups, together with the nitrogen atom to which they are bonded, are O, N, and S, of which N is optionally H or Forming 3- to 7-membered non-aromatic heteroallic cyclyls having C1-C3 alkyl substitutions and optionally containing 1-4 additional heteroatoms of the same or different type selected from O, N, and S; and each M + However, each M is a counterion with a single positive charge. + Each occurrence is independent, for example, K + kaNa + Li + alkali metal ions such as; + NH4 or + N(R 60 ) Ammonium ions such as 4; protonated amino acid ions such as lysine ions (e.g., L-lysine ions) or L-arginine ions, or arginine ions, or naturally occurring amino acid counterions such as meglumine; amino sugars such as meglumine; or [Ca 2+ ] 0.5 [Mg 2+ ] 0.5 Or [Ba 2+ ] 0.5 (The subscript "0.5" means, for example, that one of the counterions of such a divalent alkaline earth ion may be the ionized form of the compound of the present invention and the other may be a typical counterion such as a chloride, or that two ionized compounds may function as counterions of such a divalent alkaline earth ion, or that a doubly ionized compound may function as a counterion of such a divalent alkaline earth ion) such alkaline earth metal ions.Specific examples include -N(R 80Examples of )2 include -NH2, -NH-alkyl, -NH-pyrrolidine-3-yl, N-pyrrolidine, N-piperazinyl, 4N-methylpiperazin-1-yl, and N-morpholinyl. Any two hydrogen atoms on a single carbon are =O, =NR 70 、=N-OR 70 , can be replaced with =N2 or =S.

[0026] Substituents for substituting hydrogen atoms in unsaturated carbon atoms within a group containing unsaturated carbon are, unless otherwise specified, -R 60 Hello, -O - M + , -OR 70 , -SR 70 , -S - M + , -N(R 80 )2, perhaloalkyl, -CN, -OCN, -SCN, -NO, -NO2, -N3, -SO2R 70 , -SO3 - M + , -SO3R 70 , -OSO2R 70 , -OSO3 - M + -OSO3R 70 , -PO3 -2 (M + )2, -PO3 -2 M 2+ , -P(O)(OR 70 )O - M + , -P(O)(OR 70 )2, -C(O)R 70 ,-C(S)R 70 -C(NR 70 )R 70 , -CO2 - M + , -CO2R 70 , -C(S)OR 70 -C(O)NR 80 R 80 -C(NR 70 )N(R 80 )2, -OC(O)R 70 ,-OC(S)R 70 , -OCO2 - M +, -OCO2R 70 , -OC(S)OR 70 , -NR 70 C(O)R 70 , -NR 70 C(S)R 70 , -NR 70 CO2 - M + , -NR 70 CO2R 70 , -NR 70 C(S)OR 70 , -NR 70 C(O)N(R 80 )2, -NR 70 C(NR 70 )R 70 and -NR 70 C(NR 70 )N(R 80 )2, and here, R 60 , R 70 , R 80 and M + As previously defined, except in the case of substituted alkenes or alkynes, the substituent is -O - M + , -OR 70 , -SR 70 or -S - M + isn't it.

[0027] Substituents for replacing a hydrogen atom in such a nitrogen atom in a nitrogen atom-containing group are, unless otherwise specified, -R 60 , -O - M + , -OR 70 , -SR 70 , -S - M + , -N(R 80 )2, perhaloalkyl, -CN, -NO, -NO2, -S(O)2R 70 , -SO3 - M + , -SO3R 70 -OS(O)2R 70 , -OSO3 - M + -OSO3R 70 , -PO3 2- (M +)2, -PO3 2- M 2+ , -P(O)(OR 70 )O - M + , -P(O)(OR 70 )(OR 70 ), -C(O)R 70 ,-C(S)R 70 -C(NR 70 )R 70 , -CO2R 70 , -C(S)OR 70 -C(O)NR 80 R 80 -C(NR 70 )NR 80 R 80 -OC(O)R 70 ,-OC(S)R 70 , -OCO2R 70 , -OC(S)OR 70 , -NR 70 C(O)R 70 , -NR 70 C(S)R 70 , -NR 70 CO2R 70 , -NR 70 C(S)OR 70 , -NR 70 C(O)N(R 80 )2, -NR 70 C(NR 70 )R 70 and -NR 70 C(NR 70 )N(R 80 )2, and here, R 60 , R 70 , R 80 and M + This is as previously defined.

[0028] In one embodiment, the substituted group has one substituent, two substituents, a substituent, or four substituents.

[0029] Furthermore, in embodiments in which a group or moiety is substituted with a substituent to be substituted, the nesting of such substituents is limited to three, thereby preventing polymer formation. Thus, in a group or moiety comprising a first group which is a substituent in a second group which is itself a substituent in a third group and is bonded to the parent structure, the first (outermost) group can only be substituted with an unsubstituted substituent. For example, in a group comprising -(aryl-1)-(aryl-2)-(aryl-3), aryl-3 can only be substituted with an unsubstituted substituent.

[0030] "Acyl" refers to the group -C(O)R, where R is H, aliphatic, heteroaliphatic, heterocyclic, or aryl. Examples of acyl moieties, though not limited to them, include -C(O)H, -C(O)alkyl, -C(O)C1~C6alkyl, -C(O)C1~C6 haloalkyl-C(O)cycloalkyl, -C(O)alkenyl, -C(O)cycloalkenyl, -C(O)aryl, -C(O)heteroaryl, or -C(O)heterocyclyl. Specific examples include -C(O)H, -C(O)Me, -C(O)Et, or -C(O)cyclopropyl.

[0031] "Aliphatic" refers to substantially hydrocarbon-based groups or parts, including alkyl, alkenyl, and alkynyl groups, and their cyclic forms (such as cycloalkyl, cycloalkenyl, or cycloalkynyl), and further including linear and branched configurations, as well as all stereoisomers and positional isomers. Unless explicitly stated otherwise, aliphatic groups contain 1 to 25 carbon atoms; for example, 1 to 15, 1 to 10, 1 to 6, or 1 to 4 carbon atoms, and cyclic aliphatic groups contain 3 to 25 carbon atoms; for example, 3 to 15, 3 to 10, 3 to 6, or 3 to 4 carbon atoms.

[0032] "Alkyl" refers to a saturated aliphatic hydrocarbyl group having 1 to 25 carbon atoms, typically 1 to 10 carbon atoms (1 to 6 carbon atoms (C1-6 alkyl) or 1 to 4 carbon atoms (C1-4 alkyl)). The alkyl portion may be substituted or unsubstituted. This term includes linear and branched hydrocarbyl groups such as methyl (CH3), ethyl (-CH2CH3), n-propyl (-CH2CH2CH3), isopropyl (-CH(CH3)2), n-butyl (-CH2CH2CH2CH3), isobutyl (-CH2CH2(CH3)2), sec-butyl (-CH(CH3)(CH2CH3), t-butyl (-C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), and neopentyl (-CH2C(CH3)3).

[0033] "Alkoxy" refers to the -O-alkyl group.

[0034] "Amino" refers to the group -NH2, -NHR, or -NRR, where each R is independently selected from H, aliphatic, aryl, or heterocyclic, or two R groups, together with the nitrogen to which they are bonded, form a heterocycle. An example of such a heterocycle is two R groups, together with the nitrogen to which they are bonded, forming the following groups [ka] In the middle, -O- or -N(R g -(CH2) is optionally interposed by one or two heteroatom groups such as ) 2~5 -Examples include those that form a ring, where R g However, R 70 , -C(O)R 70 , -C(O)OR 60 or -C(O)N(R 80 )2.

[0035] "Amide" refers to the group -N(H)acyl or -C(O)amino.

[0036] "Aromatic aliphatic" refers to an aryl group bonded to the parent compound via an aliphatic moiety. Aromatic aliphatic compounds include aralkyl or arylalkyl groups such as benzyl and phenylethyl.

[0037] "Aryl" refers to an aromatic group having 5 to 15 ring atoms, unless otherwise specified, having a monocyclic ring (e.g., phenyl) or a plurality of fused rings (e.g., naphthyl) in which at least one ring is aromatic. In the case of a group having plurality of rings in which at least one is aromatic and one is not, such a group is still called "aryl" insofar as the bonding sites to the rest of the compound are through atoms of the aromatic part of the aryl group. Aryl groups can be monocyclic, bicyclic, tricyclic, or tetracyclic. Unless otherwise specified, aryl groups can be substituted or unsubstituted.

[0038] "Carboxyl," "carboxy," or "carboxylate" are derived from -CO2H, -C(O)O - Or it refers to the salt.

[0039] Combinations: A combination comprises two or more components administered such that the effective period of at least one component overlaps with the effective period of at least one other component. A combination or its components may be a composition. In one embodiment, the effective periods of all administered components overlap with each other. In an exemplary embodiment of a combination containing three components, the effective period of the first administered component may overlap with the effective periods of the second and third components, but the effective periods of the second and third components may or may not overlap independently. In another exemplary embodiment of a combination containing three components, the effective period of the first administered component overlaps with the effective period of the second component but not with the effective period of the third component; the effective period of the second component overlaps with the effective periods of the first and third components. A combination may be a composition containing components, a composition containing one or more components and another individual component (or component), or a composition containing the remaining components, or a combination may be two or more individual components. In one embodiment, the two or more components may include the same component administered at two or more different times, two or more different components administered substantially simultaneously or sequentially in any order, or a combination thereof.

[0040] "Carboxyl ester" or "carboxyester" refers to the group -C(O)OR, where R is aliphatic, heteroaliphatic, or heterocyclic (including aryl and heteroaryl groups).

[0041] "Alicyclic" refers to a monocyclic (e.g., cyclohexyl) or multi-ring (such as in a condensed, cross-linked, or spirocyclic system) group in which at least one ring is aliphatic, insofar as the bonding site is mediated by an atom in the aliphatic region of the alicyclic group. Alicyclic groups include saturated and unsaturated systems, including cycloalkyl, cycloalkenyl, and cycloalkynyl groups. Examples of alicyclic groups, though not limited to them, include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, or cyclohexenyl.

[0042] "Heteroaliphatic" refers to an aliphatic compound or group having at least one heteroatom and at least one carbon atom, i.e., one or more carbon atoms from an aliphatic compound or group containing at least two carbon atoms are replaced by an atom having at least one lone pair of electrons, typically nitrogen, oxygen, phosphorus, silicon or sulfur. The heteroaliphatic compound or group can be substituted or unsubstituted, branched or unbranched, chiral or achiral and / or acyclic or cyclic, such as a heterocycloaliphatic group.

[0043] "Heterocyclyl" and "heterocycle" refer to aromatic and non-aromatic ring systems, and more specifically, to stable 3- to 15-membered ring portions containing a carbon atom and at least one (e.g., 1 to 5) heteroatoms. A heterocyclyl portion may be a monocyclic portion or may contain multiple rings, such as in a bicyclic or tricyclic ring system, provided that at least one of the rings contains a heteroatom. Such multiple ring portions may include condensed or bridging ring systems and spirocycle systems; nitrogen, phosphorus, carbon, silicon, or sulfur atoms in the heterocyclyl portion may be optionally oxidized to various oxidation states. For convenience, nitrogen, but not limited to, those specifically defined as cyclic aromatic nitrogen, is intended to include their corresponding N-oxide forms, although in certain examples they are not explicitly defined. Furthermore, cyclic nitrogen atoms may be optionally quaternized. Heterocycles include heteroaryl or aromatic heterocyclyl portions and non-aromatic heteroaryl cyclyl portions, which are partially or completely saturated heterocyclyl rings.Examples of heterocyclyl groups, though not limited to them, include azetidinil, oxetanil, acridinil, benzodioxolyl, benzodioxanil, benzofuranil, carbazolyl, synnolinil, dioxolanil, indolidinil, naphthilidinil, perhydroazepinil, phenadinil, phenothiazinil, phenoxadinil, phthalazinil, pteridinil, purinil, quinazolinil, quinoxalinil, and quinolinil. Isoquinolinyl, tetrazolyl, tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperizinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, pyridinyl, pyrazi Examples include nyl, pyrimidinyl, pyridadinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranil, benzothiazolyl, benzoxazolyl, furyl, diazabicycloheptane, diazapan, diazepine, tetrahydrofuryl, tetrahydropyranil, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphosphoranyl, and oxadiazolyl.

[0044] "Hydroxyl" refers to the -OH group.

[0045] "Pharmaceutically acceptable excipient" refers to substances other than the active ingredient or its prodrug that are included in the formulation of the active ingredient. As used herein, an excipient can be incorporated within the particles of the pharmaceutical composition or it can be physically mixed with the particles of the pharmaceutical composition. Excipients can be used, for example, to dilute the active agent and / or to adjust the properties of the pharmaceutical composition. Excipients include, but are not limited to, anti-adhesion agents, binders, coatings, enteric coatings, disintegrants, flavors, sweeteners, colorants, lubricants, glidants, adsorbents, preservatives, adjuvants, carriers or vehicles. Excipients can be starch and modified starch, cellulose and cellulose derivatives, saccharides and their derivatives (such as disaccharides, polysaccharides and sugar alcohols), proteins, synthetic polymers, cross-linked polymers, antioxidants, amino acids or preservatives. Exemplary excipients include, but are not limited to, magnesium stearate, stearic acid, vegetable stearin, sucrose, lactose, starch, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, xylitol, sorbitol, maltitol, gelatin, polyvinyl pyrrolidone (PVP), polyethylene glycol (PEG), tocopheryl polyethylene glycol 1000 succinate (also known as vitamin E TPGS or TPGS), carboxymethyl cellulose, dipalmitoyl phosphatidylcholine (DPPC), vitamin A, vitamin E, vitamin C, retinyl palmitate, selenium, cysteine, methionine, citric acid, sodium citrate, me thylparaben, propylparaben, sugar, silica, talc, magnesium carbonate, sodium starch glycolate, tartrazine, aspartame, benzalkonium chloride, sesame oil, propyl gallate, sodium metabisulfite or lanolin are included.

[0046] An "adjuvant" is an excipient that modifies the effects of other drugs, typically the active ingredient. Adjuvants are often pharmacological and / or immunological agents. Adjuvants can modulate the effects of the active ingredient by increasing the immune response. Adjuvants can also act as stabilizers for the formulation. Exemplary adjuvants, but not limited to, include aluminum hydroxide, alum, aluminum phosphate, dead bacteria, squalene, detergents, cytokines, paraffin oil, and combination adjuvants (such as complete or incomplete Freund's adjuvants).

[0047] "Pharmacologically acceptable salts" refer to pharmaceutically acceptable salts of compounds derived from various organic and inorganic counterions, as is well known to those skilled in the art, and include, but are merely examples, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, tris(hydroxymethyl)aminomethane (Tris), etc.; and, if the molecule contains a basic functional group, salts of organic or inorganic acids (hydrochloride, hydrobromide, tartrate, mesylate, benzenesulfonate, tosylate, succinate, acetate, maleate, oxalate, etc.). "Pharmacologically acceptable acid addition salts" are a subset of "pharmaceutically acceptable salts" that are formed by an acid partner while retaining the biological efficacy of the free base. In particular, the disclosed compounds form salts with a variety of pharmaceutically acceptable acids, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, as well as organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, benzenesulfonic acid, isethionic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, xinafoic acid, and gentisic acid. "Pharmacologically acceptable base addition salts" are a subset of "pharmaceutically acceptable salts" derived from inorganic bases, such as sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, and aluminum salts. Exemplary salts are ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.Examples of pharmaceutically acceptable salts derived from organic bases include, but are not limited to, salts of isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, tris(hydroxymethyl)aminomethane (tris), ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine (e.g., L-lysine), arginine (e.g., L-arginine), histidine, caffeine, procaine, hydravamin, choline, betaine, ethylenediamine, glucosamine, meglumine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and other primary, secondary, and tertiary amines, substituted amines including naturally substituted amines, cyclic amines, and basic ion exchange resins. Exemplary organic bases include isopropylamine, diethylamine, tris(hydroxymethyl)aminomethane (tris), ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine (see, for example, SM Berge, et al., “Pharmaceutical Salts”, J. Pharm. Sci., 1977; 66: 1-19, incorporated herein by reference). In certain disclosed embodiments, the compounds are in the form of benzenesulfonates, hydrochlorides, sodium salts, succinates, tris, mesylates, or tartrates.

[0048] "Phosphate" refers to the group -OP(O)(OR')2, where each -OR' is independently an -O-aliphatic such as -OH, -O-alkyl, -O-aryl, or -O-aralkyl, or -OR' is -O - M + And here, M + is a single positively charged counterion disclosed herein. For example, each M + is, K + kaNa + , L i + Alkaline ions such as; +Ammonium ions such as N(R'')4 (where each R'' is independently aliphatic, heterocyclyl, or aryl such as H, alkyl, hydroxyalkyl, or a combination thereof); amino acids such as arginine or lysine; amino sugars such as meglumine; or [Ca 2+ ] 0.5 [Mg 2+ ] 0.5 Or [Ba 2+ ] 0.5 These can be alkaline earth ions such as -CH2O-P(O)(OR')2 or -CH2(CH3)OP(O)(OR')2, for example -CH2OP(O)(O-isopropyl)2, -CH2OP(O)(OH)(O-tert-butyl), -CH2OP(O)(O-tert-butyl)2, -CH2OP(O)(OCH2OCO2isopropyl)2, -CH2OP(O)(OH)2 or -CH2OP(O)(O - Na + )2, -CH2OP(O)(O - )2Mg 2+ Alternatively, -CH2OP(O)(OH)(O - Na + This refers to group-alkyl phosphates, such as salts of ) and others.

[0049] "Phosphoreamide" refers to the group -OP(O)(OR')(N(R')2), where each R' is independently an aliphatic such as H, alkyl, aryl, or aralkyl, or -OR' is -O - M + And here, M + is a single positively charged counterion disclosed herein. For example, each M + is, K + kaNa + Li + Alkaline ions such as; + Ammonium ions such as N(R'')4 (where each R'' is independently aliphatic, heterocyclyl, or aryl such as H, alkyl, hydroxyalkyl, or a combination thereof); amino acids such as arginine or lysine; amino sugars such as meglumine; or [Ca 2+ ]0.5 [Mg 2+ ] 0.5 Or [Ba 2+ ] 0.5 These can be alkaline earth ions such as -CH2OP(O)(O-phenyl)[NHC(CH3)CO2 isopropyl] or -CH2OP(O)(OH)(N(H)alkyl) or -CH2OP(O)(O - Na + This refers to the group-alkyl-phosphoroamide, such as salts of (N(H)alkyl) or -CH2O-P(O)(OR')(N(R'2)) or -CH2(CH3)OP(O)(OR')(N(R'2)).

[0050] "Pharmacologically acceptable carriers" refer to excipients that are carriers or vehicles, such as suspension aids, solubilizers, or aerosolizing aids. Pharmaceutically acceptable carriers are conventional ones. (Remington: The Science and Practice of Pharmacy, The University of the Sciences in Philadelphia, Editor, Lippincott, Williams, & Wilkins, Philadelphia, PA, 21) st Edition (2005) includes combinations suitable for the delivery of one or more therapeutic compositions and additional pharmaceuticals. The product and formulation are described.

[0051] Generally, the properties of the carrier will depend on the specific mode of administration used. For example, parenteral formulations typically contain an injectable fluid that includes a pharmaceutically and physiologically acceptable fluid as a vehicle, such as water, saline, equilibrium salt solution, dextrose aqueous solution, or glycerol. In some cases, the pharmaceutically acceptable carrier may be sterilized to be suitable for administration to the subject (e.g., by parenteral, intramuscular, or subcutaneous injection). In addition to a biologically neutral carrier, the administered pharmaceutical composition may contain smaller amounts of non-toxic auxiliary substances such as wetting agents or emulsifiers, preservatives, and pH buffers, such as sodium acetate or sorbitan monolaurate.

[0052] With respect to a compound or composition, “effective amount” means an amount of the compound or composition sufficient to inhibit a protein or enzyme, particularly interleukin-1 receptor-associated kinase; to elicit a desired biological or medical response in a tissue, system, subject or patient; to treat a particular disorder or disease; to alleviate or eliminate one or more of its symptoms; and / or to prevent the onset of a disease or disorder. The amount of compound constituting the “effective amount” may vary depending on the compound, the desired outcome, the condition and its severity, the age of the patient being treated, and other factors.

[0053] A "prodrug" refers to a compound that is converted in vivo to produce a biologically active compound, particularly a parent compound, by hydrolysis or enzymatic conversion in the intestines, for example. Typically, the prodrug compound of a compound has lower activity with respect to the desired biological target than the parent compound. The prodrug has little to no activity with respect to the desired target until it is metabolized to the active form. Common examples of prodrug moieties include, but are not limited to, esters, amides, carbamates, and urea forms of compounds having an active form with a carboxylic acid moiety. Examples of pharmaceutically acceptable esters of the compounds of the present invention include, but are not limited to, aliphatic esters, particularly alkyl esters (e.g., C 1~6 Examples include esters of phosphate groups and carboxylic acids, such as alkyl esters. Other prodrug moieties include -CH2-OP(O)(OR')2 (where each R' is independently H or C). 1~6 (It is alkyl) etc., -(CH2) n -OP(O)(OR')2(where n is 1 or 2 and R' is H or C) 1~6Examples include phosphate esters (which are alkyl), where at least one R' is H, and the phosphate moiety may be in the form of a salt, such as a mono- or dianionic salt having an organic or inorganic cation counterion. Acceptable esters include, but are not limited to, cycloalkyl esters such as benzyl and arylalkyl esters. Examples of pharmaceutically acceptable amides of the compounds of the present invention include, but are not limited to, primary amides and secondary and tertiary alkylamides (e.g., having 1 to 6 carbon atoms). The amides and esters of the exemplary embodiments disclosed of the compounds of the present invention may be prepared according to conventional methods. A full description of prodrugs is provided in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems”, Vol 14 of the ACS Symposium Series and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987. Both are incorporated herein by reference for all purposes.

[0054] A "spray-dried dispersion" refers to a single-phase dispersion of one or more compounds in a polymer matrix. Typically, one or more of the compounds are amorphous.

[0055] "Subject" refers to both human and non-human subjects.

[0056] A “solvate” refers to a complex formed by a combination of a solvent molecule and a solute molecule or ion. The solvent may be an organic compound, an inorganic compound, or a mixture of both. Some examples of solvents, but not limited to, include methanol, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, and water. The compounds described herein may exist in both non-solvated and solvated forms when combined with solvents such as water and ethanol, whether pharmaceutically acceptable or not. The solvated forms of the compounds disclosed herein are within the scope of the embodiments disclosed herein.

[0057] The above definitions and the following general formulas are not intended to include unacceptable substitution patterns (e.g., methyl substituted with five fluoro groups). Such unacceptable substitution patterns are readily recognizable to those skilled in the art.

[0058] Any of the groups referred to herein may be optionally substituted with at least one, possibly two or more substituents as defined herein. That is, unless otherwise indicated in the context or a particular structural formula excludes substitution, the substituted group has at least one, possibly two or more substituted hydrogens that are substituted with one or more substituents as defined herein.

[0059] Those skilled in the art will understand that compounds may exhibit phenomena of tautomerism, conformational isomerism, geometric isomerism and / or optical isomerism. For example, certain disclosed compounds may contain one or more chiral centers and / or double bonds, resulting in double bond isomers (i.e., geometric isomerism). Atropisomers may exist as stereoisomers such as enantiomers, diastereomers, and mixtures thereof, including racemic mixtures. As another example, certain disclosed compounds may exist as several tautomers, including enol forms, keto forms, and mixtures thereof. Since various compound names, formulas, and compound figures in this specification and claims may represent only one of the possible tautomers, conformatorisomers, optical isomers, or geometric isomers, it will be understood that the disclosed compounds encompass any tautomers, conformatorisomers, optical isomers, and / or geometric isomers of the compounds described herein, as well as mixtures of these various different isomers. Atropisomers are also possible, and are particularly included in the compounds of the present invention, in the case of restricted rotations, for example, around an amide bond or between two directly bonded rings, such as pyrazole and pyridinyl rings.

[0060] Certain examples of the compounds currently disclosed contain one or more chiral centers. Therefore, these compounds may exist in different stereoisomers. Accordingly, compounds and compositions may be provided as individual pure enantiomers or diastereomers or as stereoisomer mixtures including racemic mixtures. In certain embodiments, the compounds disclosed herein are synthesized or purified to substantially high optical purity forms, such as high optical purity forms, including at least 90% enantiomeric excess, 95% enantiomeric excess, 97% enantiomeric excess, 98% enantiomeric excess, 99% enantiomeric excess, 99.5% enantiomeric excess, or greater than 99.5% enantiomeric excess.

[0061] In any embodiment, any or all of the hydrogen atoms present in the compound or in a particular group or part within the compound may be substituted with deuterium or tritium. Thus, the description of alkyl includes deuterated alkyl, where one to a maximum number of hydrogen atoms present may be substituted with deuterium. For example, ethyl may be C2H5 or C2H5, where one to five hydrogen atoms are substituted with deuterium.

[0062] II. Compounds A pyrazole compound, a method for producing this compound, and a method for using this compound are disclosed herein. In one embodiment, the disclosed compound is a tyrosine kinase inhibitor and / or may be useful for inhibiting one or more cytokine signaling pathways such as the IL-17 signaling pathway. In certain embodiments, the pyrazole compound is useful for treating a condition in which inhibition of the interleukin-1 receptor-associated kinase (IRAK) pathway is therapeutically useful. In one embodiment, the compound inhibits an IRAK protein such as IRAK1, IRAK2, IRAK3 or IRAK4. In other embodiments, the compound is useful for delivering an IRAK inhibitor compound and / or may be a prodrug of an IRAK inhibitor. In certain embodiments, the pyrazole compound is [Chemical formula] a prodrug of.

[0063] In one embodiment, the pyrazole compound has the general formula I [Chemical formula] wherein, for formula I, R is H, aliphatic, acyl, heterocyclyl, carboxyl ester, amide, alkyl phosphoramidate or alkyl phosphate. Those skilled in the art will understand that formula I includes solvates, co-crystals, salts and / or N-oxides of the compound as well as the free base compound. In one embodiment, R is not H, or alternatively, R is hydrogen. When R is hydrogen, the compound may be in the form of a free base or a salt. In other embodiments, R is alkyl, acyl, carboxyl ester, amide, non-aromatic heterocyclyl, alkyl phosphoramidate or alkyl phosphate. Those skilled in the art will understand that a compound in which R is not H may act as a prodrug of a compound in which R is H, for example, when administered to a subject.

[0064] In one embodiment, the compound of formula I exists in the form of a cocrystal. Examples of cocrystals include, but are not limited to, succinate cocrystals, phosphate cocrystals, gentisidine cocrystals, or tartrate cocrystals.

[0065] In one embodiment, R is H, C 1~4 Alkyl phosphate, C 1~4 Alkyl phosphoramide, C 1~6 Alkyl, C 1~6 Acyl, -C(O)OC 1~6 Aliphatic, -C(O)N(R b ) A 2- or 5- or 6-membered non-aromatic heterocycline, but in certain embodiments, R is not H, or R is H, and the compound is a salt.

[0066] Regarding the R portion, C 1~6 The alkyl portion may be unsubstituted, or a 5-membered or 6-membered non-aromatic heterocycline, OH, -OC(O)-R a , -N(R b )2, -OC(O)-R c Can it be substituted with carboxyl or a combination thereof? C 1~6 The acyl moiety may be unsubstituted or -C(O)OC 1~4 Alkyl, -C(O)OC 1~4 Alkyl-N(R b )2, N(R b )2,-NHC(O)C 1~4 Can it be substituted with alkyl or a combination thereof? The 5-membered or 6-membered heterocyclyl portion may be a 5-membered or 6-membered oxygen-containing heterocyclyl and / or may be substituted with hydroxyl, hydroxymethyl or a combination thereof; or -C(O)OC 1~6 Aliphatic is -OC(O)C 1~4 Alkyl or N(R) b -C(O)OC is optionally substituted in )2. 1~6 It may be alkyl, or -C(O)OC 1~6 Aliphatic is C 1~4-C(O)OC that can be optionally substituted with alkyl groups. 3~6 It may be a cycloalkyl group.

[0067] In each embodiment, each R a It is independently a 5-membered non-aromatic heterocycline, -CH2N(R b ) Aryl substituted with 2, C substituted with carboxyl 3~6 Cycloalkyl, C 1~6 alkoxy, unsubstituted C 1~6 Alkyl or N(R) b )2, carboxyl, cal Boxyl ester, -OC 1~6 Acyl, -NHC(O)(NH2)C 1~6 Alkyl or -(OCH2CH2) 1~8 N(R b )C is replaced by one or more of the following: 1, 2, or 3 of 2. 1~6 It is alkyl; Each R b These are H and unsubstituted C, independently. 1~6 Alkyl, -N(R g )C is replaced by 2 1~6 Alkyl, carboxyl ester or 5-membered or 6-membered non-aromatic heterocycline, or two R b Along with the nitrogen to which they are bonded, one or two -O- or -N(R) g ) C is optionally intervened in 3~6 It forms a non-aromatic heterocycline moiety, where R g H or C 1~4 It is alkyl; and -OC(O)-R c It is derived from amino acids, where -OC(O)-R c The -OC(O)- portion corresponds to the acid portion of the amino acid, and R c is -N(R b)Includes nitrogen-containing non-aromatic heterocyclines such as 2- or 5- or 6-membered unsaturated nitrogen-containing heterocyclines, e.g., pyrrolidinyl. The amino acid can be any amino acid, such as naturally occurring amino acids, and may be an amino acid selected from glycine, valine, alanine, leucine, isoleucine, methionine, phenylalanine, tryptophan, tyrosine, serine, threonine, asparagine, glutamine, arginine, histidine, lysine, aspartic acid, glutamic acid, cysteine, or proline. Those skilled in the art will understand that if the amino acid contains one or more chiral centers, its whole enantiomer, diastereomer and / or mixtures are intended. For example, the amino acid may be an L-amino acid, a D-amino acid or a mixture thereof. In one embodiment, the amino acid is an L-amino acid. Also, in a particular embodiment, -OC(O)-R c is -OC(O)CH(NH2)R d , [ka] or -OC(O)-(CH2) 1~2 C(NH2)CO2H (where R d (is an amino acid side chain), and / or H, -CH3, isopropyl, -CH2CH(CH3)2, -CH(CH3)Et, -CH2CH2SCH3, [ka] , -CH2OH, -CH(OH)CH3, -CH2C(O)NH2, -CH2CH2C(O)NH2, -CH2SH, -CH2CH2CH2NHC(O)(NH)NH2, [ka] -CH2CH2CH2CH2NH2, -CH2CO2H, or CH2CH2CO2H may be present.

[0068] In any embodiment, the compound may be a salt such as a pharmaceutically acceptable salt as defined herein, and in some embodiments, the salt may be a hydrochloride, citrate, hemicitrate, hemitartrate, tartrate, benzenesulfonate, mesylate, sodium salt, hemisuccinate, or succinate.

[0069] Some exemplary compounds represented by formula I include the following: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0070] Examples of compounds represented by Formula I include the following: I-1:N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1H-pyrazole-4-yl)thiazole-4-carboxamide; I-2: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyldihydrogen phosphate; I-3: Di-tert-butyl((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl)phosphate; I-4: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methylphosphate disodium salt; I-5:N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1-methyl-1H-pyrazole-4-yl)thiazole-4-carboxamide; I-6: 2-(1-(acetyl-L-leucyl)-1H-pyrazole-4-yl)-N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)thiazol-4-carboxamide; I-7: 1-methylcyclopropyl 4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate; I-8: 1-(isobutyryloxy)ethyl 4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate; I-9:N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)-1H-pyrazole-4-yl)thiazole-4-carboxamide; I-10: 2-Morpholinoethyl 4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate; I-11:N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1H-pyrazole-4-yl)thiazol-4-carboxamide hemitartrate; I-12:N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1-(morpholine-4-carbonyl)-1H-pyrazole-4-yl)thiazole-4-carboxamide; I-13:N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1-((3-morpholinopropyl)carbamoyl)-1H-pyrazole-4-yl)thiazol-4-carboxamide; I-14:N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1-((3-(dimethylamino)propyl)carbamoyl)-1H-pyrazole-4-yl)thiazole-4-carboxamide; I-15: 3-Morpholinopropyl 4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate; I-16: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl L-valinate hydrochloride; I-17: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl L-proline hydrochloride; I-18:1-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-yl)ethyldihydrogen phosphate; I-19: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-yl)methylglycinate hydrochloride; I-20: 1-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)ethylphosphate disodium salt; I-21: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl(S)-2-amino-3,3-dimethylbutanoate hydrochloride; I-22:2-(1-acetyl-1H-pyrazole-4-yl)-N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)thiazole-4-carboxamide; I-23: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl 2-amino-2-methylpropanoate hydrochloride; I-24:4-((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methoxy)-4-oxobutanoic acid; I-25: Methyl 4-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)-4-oxobutanoate; I-26:N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1-(2-morpholinoacetyl)-1H-pyrazole-4-yl)thiazole-4-carboxamide; I-27:N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1-(2-hydroxy-3-morpholinopropyl)-1H-pyrazole-4-yl)thiazole-4-carboxamide; I-28: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl 2-morpholinoacetate; I-29: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl L-valinate; I-30: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl L-valinate benzene sulfonate; I-31: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl L-valinate mesylate; I-32: 2-(4-methylpiperazine-1-yl)ethyl 4-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)-4-oxobutanoate; I-33:1-((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-yl)methyl)4-methyl L-aspartate hydrochloride; I-34: Methyl N-(2-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)-2-oxoethyl)-N-methylglycinate; I-35: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl(S)-2-amino-3,3-dimethylbutanoate; I-36:(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl(S)-2-amine No-3,3-dimethylbutanoatebenzenesulfonate; I-37: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl-4-(morpholinomethyl)benzoate; I-38:4-((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl)1-methyl L-aspartate hydrochloride; I-39:(1R,2R)-2-(((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methoxy)carbonyl)cyclohexane-1-carboxylic acid; I-40: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl(S)-2-amino-3,3-dimethylbutanoate mesylate; I-41:(S)-2-amino-4-((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-yl)methoxy)-4-oxobutanoate; I-42:N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4S)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1-((2S,3S,4R,5R,6S)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-yl)thiazole-4-carboxamide; I-43:N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4R)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1-((2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-yl)thiazole-4-carboxamide; I-44: tert-butyl(1-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)ethyl)hydrogen phosphate sodium acetate salt; I-45: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methylisopropyl carbonate; I-46: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyldi(((isopropoxycarbonyl)oxy)methyl)phosphate; I-47:1-((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl)4-methyl L-aspartate; I-48:1-((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl)4-meth L-aspartate benzenesulfonate; I-49:1-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)ethyldihydrogenphosphate tris salt; I-50: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methylglycinate benzene sulfonate; I-51: 2-(4-methylpiperazine-1-yl)ethyl 4-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)-4-oxobutanoatebenzenesulfonate; I-52: 2-(4-methylpiperazine-1-yl)ethyl 4-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-yl)-4-oxobutanoate succinate; I-53:(2R,3R)-2,3-diacetoxy-4-((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methoxy)-4-oxobutanoic acid; I-54: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methylacetate; I-55:4-((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl)1-methyl-L-aspartate benzene sulfonate; I-56:4-((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methoxy)-4-oxobutanoate tris salt; I-57: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl4-((S)-2-amino-3-methylbutanamide)butanoate hydrochloride; I-58: N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1-(2-hydroxyethyl)-1H-pyrazole-4-yl)thiazole-4-carboxamide; I-59: 2-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)acetic acid; I-60: ((((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methoxy)(hydroxy)phosphoryl)oxy)methylisopropyl carbonate; I-61: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl-1-amino-3,6,9,12,15,18-hexaoxahenicosan-21-oate hydrochloride; I-62: Isopropyl(((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; I-63: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyldihydrogenphosphate tris salt; I-64:N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1H-pyrazole-4-yl)thiazol-4-carboxamide hydrochloride; I-65:N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1H-pyrazole-4-yl)thiazole-4-carboxamidebenzenesulfonate; I-66:N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1H-pyrazole-4-yl)thiazol-4-carboxamide tartrate; I-67:N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1H-pyrazole-4-yl)thiazole-4-carboxamide sodium salt; I-68:N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1H-pyrazole-4-yl)thiazole-4-carboxamide hemicitrate; I-69: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyldihydrogenphosphate ditris salt; I-70: Benzyl((S)-1-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)-4-methyl-1-oxopentan-2-yl)carbamate; I-71: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl L-proline; I-72: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methylglycinate; I-73:(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl(R)-2-amino-3,3-dimethylbutanoate; I-74: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl 2-amino-2-methylpropanoate; I-75:4-((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl)1-methyl L-aspartate; I-76:(S)-2-amino-4-((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methoxy)-4-oxobutanoic acid; I-77: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl4-((S)-2-amino-3-methylbutanamide)butanoate; I-78:(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl-1-amino-3,6,9,12,15,18-hexaoxahenicosan-21-oate; I-79:2-(1-(acetyl-D-leucyl)-1H-pyrazole-4-yl)-N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)thiazole-4-carboxamide; I-80:2-(1-(acetylleucyl)-1H-pyrazole-4-yl)-N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)thiazole-4-carboxamide; I-81: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl D-valinate; I-82: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl valinate; I-83: ​​(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl D-proline; I-84: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methylproline; I-85: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl2-amino-3,3-dimethylbutanoate; I-86:(1S,2S)-2-(((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methoxy)carbonyl)cyclohexane-1-carboxylic acid; I-87:(1R,2S)-2-(((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methoxy)carbonyl)cyclohexane-1-carboxylic acid; I-88:(1S,2R)-2-(((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methoxy)carbonyl)cyclohexane-1-carboxylic acid; I-89:2-(((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl) Carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methoxy)carbonyl)cyclohexane-1-carboxylic acid; I-90:(R)-2-amino-4-((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methoxy)-4-oxobutanoic acid; I-91:2-amino-4-((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methoxy)-4-oxobutanoic acid; I-92:4-((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl)1-methyl D-aspartate; I-93:4-((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl)1-methylaspartate; I-94:1-((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl)4-methyl D-aspartate; I-95:1-((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl)4-methylaspartate; I-96: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl4-((R)-2-amino-3-methylbutanamide)butanoate; I-97: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl4-(2-amino-3-methylbutanamide)butanoate; I-98: Isopropyl(((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methoxy)(phenoxy)phosphoryl)-D-alaninate; I-99: Isopropyl(((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methoxy)(phenoxy)phosphoryl)alaninate; I-100: (2R,3S)-2,3-diacetoxy-4-((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methoxy)-4-oxobutanoic acid; I-101: (2S,3R)-2,3-diacetoxy-4-((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methoxy)-4-oxobutanoic acid; I-102: (2S,3S)-2,3-diacetoxy-4-((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methoxy)-4-oxobutanoic acid; I-103: 2,3-diacetoxy-4-((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methoxy)-4-oxobutanoic acid; I-104:N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1H-pyrazole-4-yl)thiazole-4-carboxamide phosphate; I-105:N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1H-pyrazole-4-yl)thiazole-4-carboxamide gentisinate; I-106:N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1H-pyrazole-4-yl)thiazol-4-carboxamide succinate; I-107: Sodium 1-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)ethyl hydrogen phosphate; I-108: Potassium 1-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)ethyl hydrogen phosphate; I-109: Potassium 1-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)ethyl phosphate; I-110: 1-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)ethyldihydrogenphosphate arginine salt; I-111:1-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)ethyldihydrogenphosphate choline salt; I-112: Ammonium 1-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)ethylhydrogen phosphate; I-113:1-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)ethyldihydrogenphosphate lysine salt; I-114: 1-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)ethyldihydrogenphosphate meglumine salt; I-115: Magnesium 1-(4-(4-((3-(3,6-difluoropyridine-2 -yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)ethyl phosphate; or I-116: Calcium 1-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)ethyl phosphate.

[0071] III. Compositions and / or combinations containing pyrazole compounds A. Combination with other therapeutic agents The pyrazole compounds of the present invention may be used alone, in combination with each other, or as an adjunct to or in combination with other established therapeutic agents. In another embodiment, the compounds of the present invention may be used in combination with other therapeutic agents useful for the disease or condition being treated. These compounds may be administered simultaneously and sequentially in any order, either via the same route of administration or via different routes.

[0072] In some embodiments, the second therapeutic agent is an analgesic, antibiotic, anticoagulant, antibody, anti-inflammatory agent, immunosuppressant, guanylate cyclase-C agonist, intestinal secretion stimulant, antiviral agent, anticancer agent, antifungal agent, cell therapy, or a combination thereof. The anti-inflammatory agent may be a steroidal or nonsteroidal anti-inflammatory agent. In certain embodiments, the nonsteroidal anti-inflammatory agent is selected from aminosalicylates, cyclooxygenase inhibitors, diclofenac, etodolac, famotidine, fenoprofen, flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin, meclofenamete, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, sarsalat, sulindac, tolmetine, or a combination thereof. In one embodiment, the immunosuppressant is mercaptopurine, corticosteroid, alkylating agent, calcineurin inhibitor, inosine monophosphate dehydrogenase inhibitor, anti-lymphocyte globulin, anti-thymocyte globulin, anti-T cell antibody, or a combination thereof. In one embodiment, the antibody is infliximab.

[0073] In some embodiments, the compounds of the present invention may be used in conjunction with anticancer or cytotoxic agents. Examples of various types of anticancer and antitumor compounds include, but are not limited to, alkylating agents, antimetabolites, BCL-2 inhibitors, vinca alkaloids, taxanes, antibiotics, enzymes, cytokines, platinum-coordinated complexes, proteasome inhibitors, substituted ureas, kinase inhibitors, hormones and hormone antagonists, and hypomethylating agents, such as DNMT inhibitors including azacitidine and decitabine. Exemplary alkylating agents include, but are not limited to, mechloretamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, ethyleneimine, methylmelamine, alkyl sulfonates (e.g., busulfan), and carmustine. Exemplary antimetabolites include, but are not limited to, the folic acid analog methotrexate; the pyrimidine analogs fluorouracil and cytosine arabinoside; and the purine analogs mercaptopurine, thioguanine, and azathioprine. Exemplary vinca alkaloids include, but are not limited to, vinblastine, vincristine, paclitaxel, and colchicine. Exemplary antibiotics include, but are not limited to, actinomycin D, daunorubicin, and bleomycin. An exemplary enzyme effective as an antitumor agent is L-asparaginase. Exemplary coordination compounds include, but are not limited to, cisplatin and carboplatin. Exemplary hormones and hormone-related compounds include, but are not limited to, the corticosteroids prednisone and dexamethasone; the aromatase inhibitors aminoglutethimide, formestan, and anastrozole; the progestin compounds hydroxyprogesterone caproate and medroxyprogesterone; and anti-estrogen compounds. Tamoxifen is one example.

[0074] These and other useful anticancer compounds are described in Merck Index, 13th Ed. (O'Neil MJ et al., ed.) Merck Publishing Group (2001) and Goodman and Gilman's The Pharmacological Basis of Therapeutics, 12th Edition, Brunton L.L. ed., Chapters 60-63, McGraw Hill, (2011), both of which are incorporated herein by reference.

[0075] One of the CTLA 4 antibodies that may be used in combination with the inhibitors of this disclosure is ipilimumab, marketed by Bristol-Myers Squibb as YERVOY®.

[0076] Other chemotherapeutic agents for combination therapy include checkpoint pathway inhibitors, such as PD-1 inhibitors like nivolumab and lambrolizumab, and immuno-oncological agents such as PD-L1 inhibitors like pembrolizumab, MEDI-4736, and MPDL3280A / RG7446. Further checkpoint inhibitors for combination therapy with the compounds disclosed herein include anti-LAG-3 agents such as BMS-986016 (MDX-1408).

[0077] Further chemotherapeutic agents for combination with the inhibitors of this disclosure include anti-SLAMF7 agents such as the humanized monoclonal antibody elotuzumab (BMS-901608), anti-KIR agents such as the anti-KIR monoclonal antibody lirirumab (BMS-986015), and anti-CD137 agents such as the fully human monoclonal antibody urelumab (BMS-663513).

[0078] Further antiproliferative compounds useful in combination with the compounds of the present invention include, but are not limited to, antibodies against growth factor receptors (e.g., anti-Her2); as well as cytokines such as interferon-α and interferon-γ, interleukin-2, and GM-CSF.

[0079] Further chemotherapeutic agents useful in combination with the pyrazole compounds of the present invention include proteasome inhibitors such as bortezomib, carfilzomib, and marizomib.

[0080] Examples of cell therapies include, but are not limited to, cells expressing chimeric antigen receptors (CARs) and / or T cell receptors (TCRs). YESCARTA and KYMRIAH are 2 Here are some commercially available examples.

[0081] Examples of kinase inhibitors useful in combination with the compounds of this disclosure, particularly when treating malignant tumors, include Btk inhibitors such as ibrutinib, CDK inhibitors such as palbocyclib, EGFR inhibitors such as afatinib, erlotinib, gefitinib, lapatinib, osimertinib, and vandetanib, Mek inhibitors such as trametinib, Raf inhibitors such as dabrafenib, sorafenib, and vemurafenib, VEGFR inhibitors such as axitinib, lenvatinib, nintedanib, and pazopanib, BCR-Abl inhibitors such as bosutinib, dasatinib, imatinib, and nilotinib, Syk inhibitors such as hostamatinib, and JAK inhibitors such as ruxolitinib. In other embodiments, the second therapeutic agent may be selected from any of the following: Pain relievers - Morphine, fentanyl, hydromorphone, oxycodone, codeine, acetaminophen, hydrocodone, buprenorphine, tramadol, venlafaxine, flupirin, meperidine, pentazocine, dextromoramide, dipipanone; Antibiotics - Aminoglycosides (e.g., amikacin, gentamicin, kanamycin, neomycin, netylmycin, tobramycin, and paromomycin), carbapenems (e.g., ertapenem, doripenem, imipenem, cilastatin, and meropenem), cephalosporins (e.g., cefadroxil, cefazolin, cephalothin, cephalexin) (e.g., cefaclor, cefamandol, cefoxitin, cefprodil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime and ceftobiprole), glycopeptides (e.g., teicoplanin, vancomycin and teravancin), lincosamides (e.g., clindamycin and lincomycin), lipopeptides (e.g., daptomycin), macrolides (e.g., azithromycin, clarithromycin, di) Risromycin, erythromycin, roxithromycin, troleandmycin, telithromycin and spectinomycin), monobactams (e.g., aztreonam), nitrofurans (e.g., furazolidone and nitrofurantoin), penicillins (e.g., amoxicillin, ampicillin, azurocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin, nafcillin, oxacillin, penicillin G, penicillin V, piperacillin, temocillin and ticalcillin), combinations of penicillins (e.g.) For example, amoxicillin / clavulanate, ampicillin / sulbactam, piperacillin / tazobactam and ticarcillin / clavulanate), polypeptides (e.g., bacitracin, colistin and polymyxin B), quinolones (e.g., ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, trovafloxacin, glepafloxacin, sparfloxacin and temafloxacin), sulfonamides (e.g., mafenides, sulfonamides) Lysoidine, sulfacetamide, sulfadiazine, silver sulfadiazine, sulfamethizol, sulfamethoxazole, sulfanilimide, sulfasalazine, sulfisoxazole, trimethoprim and trimethoprim-sulfamethoxazole), tetracyclines (e.g., demeclocycline, doxycycline, minocycline, oxytetracycline and tetracycline), anti-acid-fast bacilli compounds (e.g., clofazimine, dapsone, capreomycin, cycloserine, ethambutol, ethionamide, isoniazid, pyrazinamide,Rifampicin (rifampin), rifabutin, rifapentin, and streptomycin), and others (arsphenamine, chloramphenicol, fosfomycin, fusidic acid, linezolid, metronidazole, mupirocin, platensimycin, quinupristin / dalfopristin, rifaximin, thianphenicol, tigecycline, and thymidazole, etc.); Antibodies - Anti-TNF-α antibodies, e.g., infliximab (Remicade®), adalimumab, golimumab, certolizumab; anti-B cell antibodies, e.g., rituximab; anti-IL-6 antibodies, e.g., tocilizumab; anti-IL-1 antibodies, e.g., anakinra; anti-PD-1 and / or anti-PD-L1 antibodies, e.g., nivolumab, pembrolizumab, pidilizumab, BMS-936559, MPDL3280A, AMP-224, MEDI4736; ixekizumab, brodalumab, ofatumumab, silkumab, clenoliximab, crazakizumab, fezakinumab, fleticumab, mabrilimumab, ocrelizumab, sarilumab, secukinumab, tralizumab, zanolimumab; Anticoagulants - Warfarin (Coumadin®), Asenocumarol, Fenprocum, Atromentin, Phenindione, Heparin, Fondaparinux, Hydraparinax, Rivaroxaban, Apixaban, Hirudin, Repirudine, Bivalirudine, Argatroban, Dabigatran, Ximelagatran, Batroxobin, Hementin; Anti-inflammatory agents - steroids, e.g., budesonide; non-steroidal anti-inflammatory drugs, e.g., aminosalicylates (e.g., sulfasalazine, mesalamine, orsalazine, and valsalidide); cyclooxygenase inhibitors (COX-2 inhibitors such as rofecoxib and celecoxib); diclofenac, etodolac, famotidine, fenoprofen, flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin, meclofenamete, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, sarsalate, sulindac, tolmetin; Immunosuppressants - mercaptopurine, dexamethasone, hydrocortisone, prednisone corticosteroids such as methylprednisolone and prednisolone, alkylating agents such as cyclophosphamide, calcineurin inhibitors such as cyclosporine, sirolimus and tacrolimus, inosine monophosphate dehydrogenase (IMPDH) inhibitors such as mycophenolate, mycophenolate mofetil and azathioprine, and agents designed to suppress cellular immunity without impairing the recipient's humoral immune response (including various antibodies (e.g., anti-lymphocyte globulin (ALG), anti-thymocyte globulin (ATG), monoclonal anti-T cell antibody (OKT3)) and irradiation). Azathioprine is currently available from Salix Pharmaceuticals, Inc. under the trademark Azasan; mercaptopurine is currently available from Gate Pharmaceuticals, Inc. under the trademark Purinethol; prednisone and pre Donisolone is currently available from Roxane Laboratories, Inc.; methylprednisolone Ron is currently available from Pfizer; sirolimus (rapamycin) is currently available from Wyeth-Ayerst under the brand name Rapamune; and tacrolimus is available from Fujisawa under the brand name Prograf. Currently available from; Cyclosporine is currently available from Novartis under the brand name Sandimmune and from Abbott under the brand name Gengraf; Mycophenolate mofetil and Mycophe IMPDH inhibitors such as nolic acid are currently available from Roche under the brand name Cellcept and from Novartis under the brand name Myfortic; azathioprine is currently available from Glaxo Smith Kline under the brand name Imuran; antibodies are available from Ortho Biotech under the brand name Orthoclone, from Novartis under the brand name Simulect (basiliximab) and from Roche under the brand name Zenapax (daclizumab). Currently available; and Guanylate cyclase - C receptor agonist or intestinal secretion stimulant - for example, Linzess Linaclotide, sold under a specific name.

[0082] These various drugs are as specified in the prescribing information accompanying the commercially available forms of the drugs (the disclosure is incorporated herein by reference in the 2006 Edition of the Physician (See also the prescribing information in 's Desk Reference), and it may be used according to those standard or common dosages.

[0083] B. Compositions containing pyrazole compounds The disclosed pyrazole compounds may be used alone, in any combination, and in combination with or as an adjunct to at least one second therapeutic agent, and further pyrazole compounds and at least one second therapeutic agent may be used in combination with any suitable additives useful for forming a composition for administration to a subject, if present. Additives may be included in the pharmaceutical composition for a variety of purposes, such as diluting the composition for delivery to a subject, facilitating the formulation process, imparting favorable material properties to the formulation, facilitating dispersion from the delivery device, stabilizing the formulation (e.g., antioxidants or buffers), or imparting a favorable or palatable taste or consistency to the formulation. Typical additives include, but are not limited to, pharmaceutically acceptable excipients; pharmaceutically acceptable carriers; and / or auxiliary agents such as monosaccharides, disaccharides and polysaccharides, sugar alcohols and other polyols, such as lactose, glucose, raffinose, melegitose, lactitol, maltitol, trehalose, sucrose, mannitol, starch or combinations thereof; surfactants such as sorbitol, diphosphatidylcholine and lecithin; fillers; buffers such as phosphate buffer and citrate buffer; anti-adhesion agents such as magnesium stearate; sugars (including disaccharides such as sucrose and lactose), polysaccharides (starch, cellulose) Binders such as cellulose, microcrystalline cellulose, cellulose ethers (such as hydroxypropyl cellulose), gelatin, synthetic polymers (such as polyvinylpyrrolidone, polyalkylene glycol); coatings (such as cellulose ether containing hydroxypropyl methylcellulose, shellac, corn protein zein, and gelatin); release aids (such as enteric coatings); disintegrants (such as crospovidone, cross-linked sodium carboxymethylcellulose, and sodium starch glycolate); fillers (such as dicalcium phosphate, vegetable oils, lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, and Examples include: magnesium stearate, etc.; flavorings and sweeteners (mint, cherry, anise, peach, apricot or licorice, raspberry and vanilla, etc.); lubricants (minerals exemplified by talc or silica, vegetable stearin, fats exemplified by magnesium stearate or stearic acid, etc.); preservatives (antioxidants exemplified by vitamin A, vitamin E, vitamin C, retinyl palmitate and selenium, amino acids exemplified by cysteine ​​and methionine, citric acid and sodium citrate, parabens exemplified by methylparaben and propylparaben, etc.); colorants; compression aids; emulsifiers; encapsulants; gums; granulators; and combinations thereof.

[0084] IV.How to use This disclosure provides pyrazole compounds, combinations thereof, and / or compositions that may be useful for improving, treating, and / or preventing various diseases and / or disorders. Certain compounds disclosed herein, referred to as active compounds, have activity as IRAK inhibitors and / or provide desired benefits to a subject, but can be used to improve, treat, or prevent diseases and / or disorders when administered in doses that do not cause significant undesirable and / or adverse side effects to the subject. In some embodiments, the diseases and / or disorders to which the IRAK inhibitor is indicated. This disclosure also addresses the problem of administering and / or providing such bioeffective amounts of such active compounds to subjects, such as those requiring IRAK inhibitors. Certain embodiments relate to pyrazole compounds useful for providing and / or delivering bioeffective amounts of the active compound to a subject. Such compounds may be prodrugs of the active compound, salts of the active compound, or combinations thereof. Embodiments of formulations comprising one or more pyrazole compounds useful for delivering the active compound, prodrugs and / or salts thereof, are also disclosed. Certain embodiments of compositions relate to spray-dry formulations.

[0085] A. Disease / Disorder The disclosed pyrazole compounds and combinations and / or compositions thereof may be useful for improving, treating and / or preventing various diseases and / or disorders. In certain embodiments, pyrazole compounds, combinations and / or compositions thereof may be useful for treating or preventing autoimmune diseases, inflammatory diseases, cardiovascular diseases, neurological diseases, neurodegenerative diseases, allergic diseases, asthma, pancreatitis, multiple organ failure, kidney disease, platelet aggregation, cancer, transplantation, sperm motility, red blood cell deficiency, graft rejection, lung injury, respiratory diseases, ischemic conditions, cytokine release syndrome (CRS), and bacterial and viral infections.

[0086] In some embodiments, pyrazole compounds, combinations of pyrazole compounds, and / or compositions thereof may be useful in treating or preventing allergic diseases, amyotrophic lateral sclerosis (ALS), systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves' ophthalmopathy, or asthma.

[0087] Pyrazole compounds, combinations of pyrazole compounds, and / or compositions thereof may also be useful in improving, treating, or preventing immunomodulatory disorders associated with bone marrow or organ transplant rejection or graft-versus-host disease. Examples of inflammatory and immunomodulatory disorders that can be treated with the compounds of the present invention include, but are not limited to, organ or tissue transplantation, graft-versus-host disease caused by transplantation, autoimmune syndromes (including rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, systemic sclerosis, myasthenia gravis, type 1 diabetes mellitus, uveitis, posterior uveitis, allergic encephalomyelitis, and glomerulonephritis), post-infectious autoimmune diseases (including rheumatic fever and post-infectious glomerulonephritis), inflammatory and hyperproliferative skin diseases, psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, and urticaria. Streptococcal disease, angioedema, vasculitis, erythema, cutaneous eosinophilia, lupus erythematosus, acne, alopecia areata, keratoconjunctivitis, vernal keratoconjunctivitis, uveitis associated with Behçet's disease, keratitis, herpetic keratitis, keratoconus, corneal epithelial dystrophy, corneal leukoplakia, pemphigus ophthalmosum, Mohren's ulcer, scleritis, Graves' ophthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, pollen allergy, reversible obstructive airway disease, bronchial asthma, allergic asthma, endogenous asthma, exogenous asthma, dust-induced asthma, chronic or refractory asthma, terminal asthma Asthma and airway hyperresponsiveness, bronchitis, gastric ulcer, ischemic disease and vascular injury caused by thrombus formation, ischemic bowel disease, inflammatory bowel disease, necrotizing enterocolitis, burn-related intestinal lesions, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, migraine, rhinitis, eczema, interstitial nephritis, Goodpasture syndrome, hemolytic uremic syndrome, diabetic nephropathy, polymyositis, Guillain-Barré syndrome, Meniere's disease, polyneuritis, multiple neuritis, mononeuropathy Inflammation, nerve root disorder, hyperthyroidism, Graves' disease, pure red cell adenoma, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, granulocytopenia, pernicious anemia, megaloblastic anemia, erythrocytosis, osteoporosis, sarcoidosis, pulmonary fibrosis, idiopathic interstitial pneumonia, dermatomyositis, vitiligo, ichthyosis vulgaris, photoallergic hypersensitivity, cutaneous T-cell lymphoma, chronic lymphocytic leukemia, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, cardiomyopathy, scleroderma, Wegena - Granulomatous disease, Sjögren's syndrome, steatosis, eosinophilic fasciitis, lesions of the gingiva, periodontal tissue, alveolar bone, and tooth cementum, glomerulonephritis, male pattern baldness or senile alopecia due to prevention of hair loss or provision of hair growth and / or promotion of hair development and growth, muscular dystrophy, pyoderma and Sézary syndrome, Addison's disease, ischemic-reperfusion injury of organs occurring during preservation, transplantation or ischemic disease, endotoxin shock, pseudomembranous colitis, colitis caused by drugs or radiation, ischemic acute renal failure, chronic renal failure Toxicosis caused by oxygen or drugs in the lungs, lung cancer, emphysema, cataracts, iron deposition disease, retinitis pigmentosa, senile macular degeneration, vitreous scarring, corneal alkali damage, dermatitis, erythema multiforme, linear IgA bullous dermatosis and cementodermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution, aging, carcinogenesis, metastasis of carcinomas and altitude sickness, diseases caused by the release of histamine or leukotriene-C4, Behçet's disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing These include cholangitis, partial hepatectomy, acute hepatic necrosis, toxins, viral hepatitis, necrosis caused by shock or oxygen deficiency, hepatitis B virus, non-A / non-B hepatitis, cirrhosis, alcoholic liver disease (including alcoholic cirrhosis), non-alcoholic steatohepatitis (NASH), hepatic failure, fulminant hepatic failure, delayed hepatic failure, hepatic failure that has been "acutely exacerbated from chronic conditions," increased response to chemotherapy, cytomegalovirus infection, HCMV infection, AIDS, cancer, senile dementia, Parkinson's disease, trauma, or chronic bacterial infection.

[0088] In certain embodiments, the compounds of the present invention are useful for treating neuralgia, including neuropathic pain and pain induced by inflammation.

[0089] In certain embodiments, pyrazole compounds, combinations of pyrazole compounds and / or compositions thereof are used to treat rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis, osteoporosis, systemic sclerosis, multiple sclerosis, psoriasis, especially pustular psoriasis, type 1 diabetes, type 2 diabetes, inflammatory bowel disease (Crohn's disease and ulcerative colitis), hyperimmune globulin D emia and periodic fever syndromes, cryopyrin-associated periodic syndromes, Schnitzler syndrome, systemic juvenile idiopathic arthritis, adult-onset Still's disease, gout, gout flare, pseudogout, SAPHO syndrome, Castleman disease, sepsis, stroke, atherosclerosis, and celiac disease. It is useful in treating and / or preventing DIRA (Il-1 receptor antagonist deficiency), Alzheimer's disease, or Parkinson's disease.

[0090] Proliferative disorders that can be treated with pyrazole compounds, combinations of pyrazole compounds and / or compositions thereof include benign or malignant tumors, solid tumors, and tumors of the brain, kidneys, liver, adrenal glands, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lungs, vagina, cervix, testes, and genitourinary tract. Carcinomas of the esophagus, larynx, skin, bone or thyroid, sarcomas, gliablastomas, neuroblastomas, multiple myelomas, gastrointestinal cancers, especially colon cancer or colorectal adenomas, tumors of the head and neck, epithelial hyperplasia, psoriasis, benign prostatic hyperplasia, neoplastic tissue formation, epithelial neoplastic tissue formation, adenomas, adenocarcinomas, keratosacral cell carcinomas, epidermoid carcinomas, large cell carcinomas, non-small cell lung cancers, Hodgkin and non-Hodgkin lymphomas, breast cancers, follicular adenocarcinomas, undifferentiated carcinomas, papillary carcinomas, sperm Epithelioma, melanoma, IL-1-induced diseases, MyD88-induced diseases (such as ABC diffuse large B-cell lymphoma (DLBCL), Waldenström macroglobulinemia, Hodgkin lymphoma, primary cutaneous T-cell lymphoma, or chronic lymphocytic leukemia), smoldering or painless multiple myeloma, or hematological malignancies (leukemia, acute myeloid leukemia (AML), DLBCL, ABC) Examples include DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary exudative lymphoma, Burkitt lymphoma / leukemia, acute lymphoblastic leukemia, B-cell prelymphocytic leukemia, lymphoplasmacytic lymphoma, myelodysplastic syndrome (MDS), myelofibrosis, polycythemia vera, Kaposi's sarcoma, Waldenström macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, or intravascular large B-cell lymphoma. In particular, the compounds of this disclosure are useful for treating drug-resistant malignancies, including those resistant to JAK inhibitors and ibrutinib-resistant malignancies, such as ibrutinib-resistant hematological malignancies (e.g., ibrutinib-resistant CLL and ibrutinib-resistant Waldenström macroglobulinemia).

[0091] Examples of allergic diseases that can be treated with pyrazole compounds, combinations of pyrazole compounds and / or compositions thereof include, but are not limited to, asthma (e.g., atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, non-atopic asthma, bronchial asthma, non-allergic asthma, essential asthma, true asthma, endogenous asthma caused by pathophysiological disorders, essential asthma of unknown or unclear cause, emphysematous asthma, exercise-induced asthma, emotion-induced asthma, and asthma caused by environmental factors). Examples of exogenous asthma, cold-induced asthma, occupational asthma, infectious asthma caused or associated with bacterial, fungal, protozoan or viral infections, early asthma, wheezing infant syndrome, bronchiolitis, cough variant asthma or drug-induced asthma, allergic bronchopulmonary aspergillosis (ABPA), allergic rhinitis, perennial allergic rhinitis, perennial rhinitis, vasomotor rhinitis, postnasal drip, purulent or non-purulent sinusitis, acute or chronic sinusitis, and ethmoid, frontal, maxillary or sphenoid sinusitis.

[0092] As another example, rheumatoid arthritis (RA) typically results in swelling, pain, and decreased movement and flexibility of target joints throughout the body. RA is characterized by a chronically inflamed synovial membrane densely packed with lymphocytes. The synovial membrane, which is typically the thickness of a single cell layer, rapidly increases in cell volume and takes on a lymphatic tissue-like form, containing clusters of dendritic cells, T cells, B cells and NK cells, macrophages and plasma cells. This process, along with numerous immunopathological mechanisms, including the formation of antigen-immunoglobulin complexes, ultimately leads to the destruction of joint integrity, resulting in deformity, permanent loss of function, and / or bone erosion in or near the joint. Pyrazole compounds, combinations of pyrazole compounds, or compositions thereof may be used to treat, improve, or prevent any, some, or all of these symptoms of RA. Therefore, in relation to RA, this compound is considered to have a therapeutic effect when a reduction or improvement in any of the symptoms commonly associated with RA is achieved, whether the treatment results in concomitant therapy with the underlying RA and / or a reduction in the amount of rheumatoid factor ("RF") in the blood.

[0093] The American College of Rheumatology (ACR) has developed criteria to define improvement and clinical remission of RA. In these parameters, ACR20 (ACR criteria for 20% clinical improvement) requires a 20% improvement in the number of tender and swollen joints, as well as a 20% improvement in three of the following five parameters: overall patient assessment, overall physician assessment, patient pain assessment, degree of disability, and levels of acute-phase reactive substances. The criteria were extended to 50% and 70% improvements in ACR50 and ACR70, respectively. Other criteria include Paulu's criteria and progression of radiographic findings (e.g., Sharp score).

[0094] In one embodiment, the therapeutic effect in a patient suffering from RA is achieved when the patient shows an ACR of 20. In a particular embodiment, an ACR improvement of ACRC50 or even ACR70 may be achieved.

[0095] B. Formulation and Administration Pharmaceutical compositions comprising the active compound (or its prodrug) of the present invention can be produced by conventional mixing, dissolution, granulation, sugar coating, polishing, emulsification, encapsulation, incorporation, or freeze-drying processes. The compositions can be formulated in conventional methods with one or more physiologically acceptable excipients, diluents, carriers, auxiliaries, or adjuvants to obtain pharmaceutically usable formulations.

[0096] Active compounds or their prodrugs can be formulated in pharmaceutical compositions either in themselves or in the form of hydrates, solvates, N-oxides, cocrystals, or pharmaceutically acceptable salts. Typically, such salts are more soluble in aqueous solutions than their corresponding free acids and bases, although salts with lower solubility than their corresponding free acids and bases may also be formed.

[0097] The pharmaceutical composition of the present invention may take a form suitable for substantially any method of administration, including, for example, a form suitable for local, ocular, oral, oral, systemic, nasal, intravenous (IV) or intraperitoneal (IP) injection, transdermal, transrectal, transvaginal, or administration by inhalation or blowing.

[0098] For topical administration, the active compound, hydrate, solvate, N-oxide, cocrystal, or pharmaceutically acceptable salt and / or prodrug may be formulated as a liquid, gel, ointment, cream, suspension, etc., as is well known in the art.

[0099] Systemic formulations include those designed for administration by injection, such as subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection, as well as those designed for administration percutaneously, transmucosally, orally, or transpulmonaryly.

[0100] Useful injectable formulations include sterile suspensions, liquids or emulsions of the active compound in aqueous or oily vehicles. The compositions may also contain formulation agents such as suspending agents, stabilizers, and / or dispersants. Injectable formulations may be provided in unit dosage forms, such as ampoules or multi-dose containers, and may contain added preservatives.

[0101] Alternatively, the injectable formulation may be provided in powder form for reconstitution with a suitable vehicle, including but not limited to sterile pyrogenically decontaminated distilled water, buffer solution, or dextrose solution, before use. For this purpose, the pyrazole compound may be dried by any technique known in the art, such as lyophilization, and reconstituted before use.

[0102] For transmucosal administration, a suitable penetrating agent is used in the formulation to address the barrier to penetration. Such penetrating agents are well known in the art.

[0103] For oral administration, the pharmaceutical composition is prepared by conventional means using pharmaceutically acceptable excipients such as binders (e.g., alpha-corn starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., potato starch or sodium starch glycolate); and / or wetting agents (e.g., sodium lauryl sulfate), for example, lozenges. It may take the form of a drug, tablet, or capsule. Tablets may be coated, for example, with sugar, film, or enteric coating by methods well known in the art.

[0104] Liquid formulations for oral administration may take the form of, for example, elixirs, solutions, syrups, or suspensions, or they may be provided as dry products to be reconstituted with water or other suitable vehicles before use. Such liquid formulations may be prepared by conventional means using suspending agents (e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible fats); emulsifiers (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, cremophore®, or fractionated vegetable oils); and pharmaceutically acceptable additives such as preservatives (e.g., methyl or propyl-p-hydroxybenzoate or sorbic acid). The formulations may also contain buffer salts, preservatives, flavorings, colorants, and sweeteners as needed.

[0105] Formulations for oral administration can be suitably formulated to provide controlled release of the active compound or prodrug, as is well known.

[0106] For oral administration, the composition may take the form of tablets or lozenges formulated using conventional methods.

[0107] For transrectal and transvaginal administration routes, pyrazole compounds can be formulated as liquid suppositories (in the case of retained enemas) or ointments containing conventional suppository bases such as cocoa butter or other glycerides.

[0108] For nasal administration or administration by inhalation or inhalation, the active compound, hydrate, solvate, N-oxide, cocrystal, pharmaceutically acceptable salt, and / or prodrug can be conveniently delivered in the form of an aerosol spray from a pressurized pack or atomizer using a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon fluoride, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the administration unit may be determined by providing a valve that provides a metered supply. Capsules and cartridges for use in inhalers or injectors (e.g., capsules and cartridges containing gelatin) may be formulated containing a powder mixture of the compound and a suitable powder such as lactose or starch.

[0109] Specific examples of aqueous suspension formulations suitable for intranasal administration using commercially available nasal sprayers include the following components: active compound or prodrug (0.5-20 mg / ml); benzalkonium chloride (0.1-0.2 mg / ml); polysorbate 80 (TWEEN® 80; 0.5-5 mg / ml) It contains (g / ml) carboxymethylcellulose sodium or microcrystalline cellulose (1-15 mg / ml), phenylethanol (1-4 mg / ml), and dextrose (20-50 mg / ml). The pH of the final suspension can be adjusted to a range of approximately pH 5-7, with a pH of approximately 5.5 being typical.

[0110] Another specific example of an aqueous suspension suitable for administering a compound by inhalation is a 20 mg / mL compound or prodrug, or 1% (v / v) polysorbate 80 (TWEEN® 80). It contains 50 mM citrate and / or 0.9% sodium chloride.

[0111] For intraocular administration, the active compound or prodrug may be formulated as a liquid, emulsion, suspension, or the like, suitable for administration into the eye. Various vehicles suitable for administering the compound into the eye are known in the art. Specific non-limiting examples are incorporated herein by reference of U.S. Patents 6,261,547; 6,197,934; 6,056,950; 5,800,807; 5,776,445; and 5,698,21 It is listed in No. 9; No. 5,521,222; No. 5,403,841; No. 5,077,033; No. 4,882,150; and No. 4,738,851.

[0112] For long-term delivery, pyrazole compounds can be formulated as depot formulations for administration by infusion or intramuscular injection. Pyrazole compounds can be formulated using suitable polymers or hydrophobic materials (e.g., as emulsions in acceptable oils) or ion-exchange resins, or as sparingly soluble derivatives, such as sparingly soluble salts. Alternatively, transdermal delivery systems manufactured as adhesive discs or patches that slowly release the active compound for transdermal absorption may be used. For this purpose, penetration enhancers may be used to facilitate the transdermal penetration of the active compound. Suitable transdermal patches are described, for example, in U.S. Patent Nos. 5,407,713; 5,352,456; 5,332,213; 5,336,168; 5,290,561; 5,254,346; 5,164,189; 5,163,899; 5,088,977; 5,087,240; 5,008,110; and 4,921,475, which are incorporated herein by reference.

[0113] Alternatively, other drug delivery systems may be used. Liposomes and emulsions are well-known examples of delivery vehicles that can be used to deliver pyrazole compounds. Certain organic solvents, such as dimethyl sulfoxide (DMSO), may also be used, although this usually comes at the cost of greater toxicity.

[0114] The pharmaceutical composition may be provided in a pack or dispenser device that may contain, as needed, one or more unit dosage forms containing the active compound. The pack may include, for example, metal or plastic foil such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration.

[0115] I. Spray-dried formulations Embodiments of spray-dried formulations comprising one or more compounds according to Formula I are disclosed herein. A spray-dried formulation may be a dispersion, such as a spray-dried dispersion of a compound according to Formula I in a matrix, such as a carrier or a polymer matrix. Typically, a spray-dried formulation comprises a single-phase amorphous dispersion of the disclosed compound in a carrier, such as a polymer matrix.

[0116] Embodiments of spray-dried formulations include, are based on, or consist of, an effective amount of one or more compounds according to Formula I and a sufficient amount of carrier to form the spray-dried formulation. Those skilled in the art will recognize that the effective amount of compound can vary, typically ranging from 0.1% to 50% (w / w relative to the carrier) or more, such as 1% to 50%, 5% to 40%, 10% to 35%, 15% to 30%, or 15% to 25%. In particular embodiments, the spray-dried formulation includes, is based on, or consists of 20% w / w of the disclosed compound and 80% w / w of a carrier, such as a polymer matrix.

[0117] In one embodiment, the carrier is a polymer, such as a polymer, that is suitable for forming a spray-drying formulation together with the disclosed compound. Suitable polymers include cellulose derivatives such as hydroxypropyl methylcellulose succinate acetate (hypromellose acetate succinate; HPMCAS), hydroxypropyl methylcellulose phthalate (hypromellose phthalate; HPMCP), or hydroxypropyl methylcellulose (HPMC); vinyl polymers such as poly(vinylpyrrolidone) (PVP) or poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA); lactide polymers such as polylactide (PLA) or polylactide-co-glycolide (PLGA); sugars such as sucrose or trehalose; or any combination thereof. It is not limited to these. In certain embodiments, the carrier is HPMCAS. The polymer, such as HPMCAS, may be any grade suitable for forming a spray-drying formulation, such as L grade, M grade, or H grade. In certain embodiments, M grade is used. Furthermore, HPMCAS may be fine grade (F) or granular grade (G), and in certain embodiments, fine grade is used. Also, in certain practical embodiments, the carrier is HPMCAS-MF.

[0118] In one embodiment, the spray-dried formulation has a suitable glass transition temperature. The glass transition temperature may be between 100°C and 120°C, such as 105°C to 110°C or 107°C to 110°C. In a particular practical embodiment, the glass transition temperature is 108°C to 109°C.

[0119] In some embodiments, the formulation may include additional components. These additional components may be included in the pharmaceutical composition for various purposes, such as diluting the composition for delivery to a target, facilitating the processing of the formulation, providing the formulation with desirable material properties, facilitating dispersion from a delivery device, stabilizing the formulation (e.g., antioxidants or buffers), or providing the formulation with a pleasant or palatable taste or viscosity.Typical additional components include, but are not limited to, pharmaceutically acceptable excipients; pharmaceutically acceptable carriers; and / or auxiliary agents, such as monosaccharides, disaccharides and polysaccharides, sugar alcohols such as lactose, glucose, raffinose, melegitose, lactitol, maltitol, trehalose, sucrose, mannitol, starch, and other polyols or combinations thereof; surfactants such as sorbitol, diphosphatidylcholine and lecithin; fillers; buffers such as phosphoric acid and citrate buffers; anti-tackifying agents such as magnesium stearate; binders such as sugars (including disaccharides such as sucrose and lactose), polysaccharides (starch, cellulose, microcrystalline cellulose, cellulose ethers (such as hydroxypropyl cellulose), gelatin, and synthetic polymers (such as polyvinylpyrrolidone and polyalkylene glycol); coatings (cellulose ethers containing hydroxypropyl methylcellulose, shellac, corn protein zein and zein). Examples include: latin, etc.; release aids (enteric coatings, etc.); disintegrants (crospovidone, cross-linked sodium carboxymethylcellulose, and sodium starch glycolate, etc.); fillers (calcium hydrogen phosphate, vegetable oils, lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, and magnesium stearate, etc.); flavorings and sweeteners (mint, cherry, anise, peach, apricot or licorice, raspberry, and vanilla, etc.); lubricants (minerals such as talc or silica, vegetable stearin, magnesium stearate, or fats such as stearic acid, etc.); preservatives (antioxidants such as vitamin A, vitamin E, vitamin C, retinyl palmitate, and selenium, amino acids such as cysteine ​​and methionine, citric acid and sodium citrate, parabens such as methylparaben and propylparaben, etc.); colorants; compression aids; emulsifiers; encapsulants; gums; granulators; and combinations thereof.

[0120] II. Method for producing spray-dried formulations Embodiments of methods for producing spray-dried formulations are also disclosed herein. In one embodiment, one or more compounds and polymers according to Formula I are dissolved in a suitable solvent or mixture of solvents and then spray-dried. Suitable solvents include any solvent or mixture of solvents that dissolves the disclosed compounds and carriers and is suitable for the spray-drying process. Exemplary solvents include, but are not limited to, alcohols such as methanol, ethanol, isopropanol, and n-propanol; and chlorinated solvents such as dichloromethane and chloroform. In one embodiment, the disclosed compounds are dissolved in the solvent or mixture of solvents, and the polymer is added to the mixture. However, in other embodiments, the polymer is dissolved first, and the compounds are added thereafter, or the compounds and polymers are mixed with the solvent or mixture of solvents substantially simultaneously. Regardless of the order of addition, the mixture is typically, The disclosed compounds and polymers are mixed until they dissolve and / or the mixture has a uniform appearance. In one embodiment, the resulting mixture is stored at low temperatures, typically around 5°C, such as below 25°C, below 25°C to 0°C, 15°C to 0°C, 10°C to 0°C, or 7°C to 3°C. The solution may also be stored protected from light, i.e., in a dark environment.

[0121] The solution is then spray-dried using a spray drying apparatus. Suitable spray drying apparatuses are known to those skilled in the art. In some embodiments, parameters of the spray drying apparatus, such as the supply temperature, inlet temperature, target outlet temperature, and suction, are set to values ​​suitable for the disclosed compounds and polymers, as will be understood by those skilled in the art. In certain embodiments, the supply temperature is between 15°C and 35°C, such as 20°C to 25°C. The inlet temperature may be between 40°C and 60°C, such as 45°C to 55°C. The target outlet temperature may be between 30°C and 45°C, such as 32°C to 42°C or 34°C to 40°C. And / or, the aspirator may be between 50% and 100%, such as 70% to 100% or 80% to 100%.

[0122] The resulting spray-dried solid may be further dried at a temperature suitable for removing at least some, perhaps substantially all, of the residual solvent without substantially decomposing the disclosed compound and / or carrier. In one embodiment, the solid is dried at a temperature of 25°C to 100°C or higher, such as 30°C to 75°C or 35°C to 50°C. The dispersion may be dried until substantially all of the residual solvent is removed and / or until no further weight loss is obtained. Drying may continue for 1 to 48 hours or more, such as 6 to 36 hours, 12 to 32 hours or 18 to 24 hours. The resulting solid formulation may be stored at low temperatures, typically around 5°C, such as below 25°C or below 25°C to 0°C, 15°C to 0°C, 10°C to 0°C or 7°C to 3°C. The solution may be stored protected from light, i.e., in a dark environment, and / or in a dry state, such as in the presence of a desiccant and / or in a dry atmosphere.

[0123] C. Dosage Pyrazole compounds or combinations thereof are generally used in amounts effective to achieve the intended result, for example, in amounts effective to treat and / or prevent a particular disease or disorder. Pyrazole compounds or compositions thereof may be administered therapeutically to obtain a therapeutic effect or prophylactically to obtain a preventive effect. A therapeutic effect means the eradication or improvement of the underlying disease being treated and / or the eradication or improvement of one or more symptoms associated with the underlying disease, to the extent that the patient may still be suffering from the underlying disease, but the patient reports an improvement in mood or condition. For example, administration of a compound to a patient suffering from allergies provides a therapeutic effect not only when the underlying allergic reaction is eradicated or improved, but also when the patient reports a reduction in the severity or duration of allergy-related symptoms after exposure to the allergen. As another example, a therapeutic effect related to asthma includes improvement in breathing after an asthma attack or a reduction in the frequency or severity of asthma attacks. A therapeutic effect also includes the cessation or slowing of disease progression, whether improvement is achieved or not.

[0124] As is known to those skilled in the art, the preferred dose of a pyrazole compound also depends on various factors, including the age, weight, overall health, and severity of the condition of the patient or subject being treated. In the case of inhalation administration, the dose may also need to be tailored to the individual's sex and / or lung capacity. The dose may also be tailored to individuals suffering from two or more conditions or further conditions affecting lung capacity and the ability to breathe normally, such as emphysema, bronchitis, pneumonia, and respiratory infections. The dose and frequency of administration of the disclosed pyrazole compound or its composition also depends on whether the pyrazole compound is formulated for the treatment of an acute exacerbation of a condition or for the prophylactic treatment of a disease. Those skilled in the art will be able to determine the optimal dose for a particular individual.

[0125] In prophylactic administration, pyrazole compounds, combinations of pyrazole compounds, or compositions thereof are used. It may be administered to patients or subjects at risk of developing one of the conditions described. For example, if it is unknown whether a patient or subject is allergic to a particular drug, a pyrazole compound, a combination of pyrazole compounds, or a composition thereof may be administered before administration of the drug to avoid or improve an allergic reaction to the drug. Alternatively, prophylactic administration may be used to avoid or improve the onset of symptoms in patients diagnosed with an underlying disease. For example, a pyrazole compound or a composition thereof may be administered to allergic patients before anticipated exposure to an allergen. Pyrazole compounds, combinations of pyrazole compounds, or a composition thereof may also be administered prophylactically to healthy individuals who are repeatedly exposed to a drug known to cause one of the diseases described above, in order to prevent the onset of the disease. For example, a pyrazole compound, a combination of pyrazole compounds, or a composition thereof may be administered to healthy individuals who are repeatedly exposed to an allergen known to induce allergies, such as latex, in order to prevent the individual from developing an allergy. Alternatively, pyrazole compounds, combinations of pyrazole compounds, or compositions thereof may be administered to patients with asthma before engaging in activities that could trigger an asthma attack, in order to reduce the severity of an asthma attack or to completely avoid an asthma attack.

[0126] The effective dose can be initially estimated from an in vitro assay. For example, the initial dose to be used for a subject is determined when measured in an in vitro assay for a particular compound. 50 or EC 50 Alternatively, the formulation may be designed to achieve circulating blood or serum concentrations of the active compound that exceed or exceed those levels. Dosages may be calculated to achieve such circulating blood or serum concentrations, taking into account the bioavailability of the specific compound. Fingl & Woodbury, “General Principles”, In: Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, Chapter 1, pages 1-46, Pergamon Press, and the references cited therein are relevant. Further guidance regarding dosage will be provided.

[0127] In one embodiment, the disclosed compound has an EC of greater than 0 to 20 μM, for example, greater than 0 to 10 μM, greater than 0 to 5 μM, greater than 0 to 1 μM, greater than 0.5 μM, or greater than 0.1 μM. 50 It has.

[0128] Initial doses can also be estimated from in vivo data such as animal models. Animal models useful for testing the efficacy of compounds for treating or preventing the various diseases described above are well known in the art. Suitable animal models for hypersensitivity or allergic reactions are described in Foster, (1995) Allergy 50 (21Suppl): 6-9, discussion 34-38 and Tumas et al., (2001), J. This is described in Allergy Clin. Immunol. 107 (6): 1025-1033. Suitable animal models of allergic rhinitis are described in Szelenyi et al., (2000), Arzneimittelforschung 50 (11): 1037-42; Kawaguchi et al., (1994), Clin. Exp. Allergy 24 (3): 238-244 and Sugimoto et al., (2000), Immunopharmacology 48 (1): 1-7. Those skilled in the art can adapt this information to determine suitable dosages for administration to humans.

[0129] The doses of the disclosed pyrazole compounds will typically be in the range of greater than 0 mg / kg / day, e.g., 0.0001 mg / kg / day or 0.001 mg / kg / day or 0.01 mg / kg / day, and at least 100 mg / kg / day. More typically, the dose (or effective dose) may be in the range of 0.0025 mg / kg to 1 mg / kg, e.g., 0.01 mg / kg to 0.5 mg / kg or 0.05 mg / kg to 0.15 mg / kg, administered at least once per day. The total daily dose will typically be in the range of 0.1 mg / kg to 5 mg / kg or up to 20 mg / kg / day, e.g., 0.5 mg / kg to 10 mg / kg / day or 0.7 mg / kg / day to 2.5 mg / kg / day. The dosage may be higher or lower depending on various factors, particularly the activity of the pyrazole compound, its bioavailability, the method of administration, and the various factors mentioned above.

[0130] The dosage and administration interval should be sufficient to maintain the therapeutic or prophylactic effect of the pyrazole compound. The dosage can be adjusted for each individual to provide a suitable plasma concentration. For example, the compound may be administered once daily, multiple times daily, once weekly, multiple times weekly (e.g., every other day), once monthly, multiple times monthly, or once a year, depending in particular on the method of administration, the specific indication being treated, and the prescribing physician's discretion. Those skilled in the art will be able to optimize the effective local dose without excessive experimentation.

[0131] A composition comprising one or more of the disclosed pyrazole compounds typically contains more than 0 to 99% by total weight of the pyrazole compound or compound and / or other therapeutic agent. More typically, a composition comprising one or more of the disclosed pyrazole compounds contains 1 to 20% by total weight of the pyrazole compound and other therapeutic agent and 80 to 99% by weight of pharmaceutically acceptable additives.

[0132] Preferably, pyrazole compounds, combinations of pyrazole compounds, and / or compositions thereof will provide therapeutic or preventive effects without causing significant toxicity. The toxicity of pyrazole compounds can be determined using standard pharmaceutical procedures. The dose-to-toxicity ratio is the therapeutic index. Pyrazole compounds exhibiting a high therapeutic index are preferred. [Examples]

[0133] IV. Examples Example 1 Compound I-1 (8 g, 20% w / w) was slowly added to a mixture of methylene chloride (360 g) and methanol (40 g) while mixing, and mixing continued until compound I-1 dissolved. Next, HPMCAS-MF (32 g) was slowly added to the mixture while mixing, and the resulting mixture was mixed until HPMCAS-MF dissolved. The solution was visually homogeneous. The solution was stored at 5°C and protected from light.

[0134] A spray drying apparatus (Buchi B290) was prepared with a supply temperature of 25°C, an inlet temperature of 50°C, and a target outlet temperature of 38°C. During spray drying, the outlet temperature was 34-40°C, the inlet temperature was 45-51°C, and the aspirator was 80-100%. The yield was 32g, 90%.

[0135] The resulting solid dispersion was collected and further dried in an oven set to 40°C for 24 hours. The resulting powder was stored at 5°C in the presence of a desiccant. The yield after secondary drying was 27 g, 67.5%. Table 1 shows the stability data of the solid dispersion.

[0136] [Table 1]

[0137] Figures 1-10 provide structural and stability data for the spray-dried formulation (Figures 1-5) and the crystalline sample of compound I-1 (Figures 6-10). Figures 1 and 6 show DVS isotherm plots for the spray-dried formulation and the crystalline compound, respectively. Figures 1 and 6 clearly show that the crystalline compound exhibits a significantly smaller mass change than the dispersion when exposed to higher relative humidity. Figures 2 and 3 show that the dispersion has substantially no crystalline structure, while Figures 7 and 8 clearly show that compound I-1 has a crystalline structure.

[0138] Example 2 Two groups of male cynomolgus monkeys (n=3 / group) were administered the test substance using the three-way crossover design shown in Table 2. The drug-free interval between administrations was 3–4 days. Test substance capsules were prepared so that each capsule contained an equal amount of 25 mg of free base compound I-1. An organic stock solution of compound I-1 was prepared at a concentration of 5 mg / ml using TPGS / PEG400 / PG and diluted with apple juice within 1 hour of administration (PO) using 1 part stock solution in 3 parts apple juice.

[0139] [Table 2]

[0140] Figures 11-14 show graphs of plasma concentrations obtained from administration of the co-crystal formulation of compound I-1 to monkeys. Table 3 shows pharmacokinetic (PK) data of the co-crystal formulation, including the mean area under the curve (AUC) and bioavailability percentage.

[0141] [Table 3]

[0142] Figure 19 shows one embodiment of the disclosed spray-dried formulation and the PK data of the organic / juice formulation. Figure 19 shows that administration of the spray-dried formulation resulted in 88% bioavailability of compound I-1.

[0143] Example 3 Rats were administered either compound I-1 or a prodrug form potentially derived from compound I-1. The area under the curve (AUC) and bioavailability percentage (%F) data for compound I-1 resulting from prodrug administration were determined using standard techniques known to those skilled in the art (Table 4).

[0144] [Table 4]

[0145] Example 4 Formation of N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1H-pyrazole-4-yl)thiazole-4-carboxamidebenzenesulfonate (I-65) [ka] N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1H-pyrazole- 4-Il)thiazole-4-carboxamide (0.050 g, 0.100 mmol, 1.0 equivalent) was dissolved in chloroform (1.0 equivalent) to obtain a clear, colorless solution. When benzenesulfonic acid (0.019 g, 0.120 mmol, 1.2 equivalents) was added, a precipitate formed over the next 15 minutes. The reaction mixture was stirred at room temperature for 1 hour, and the precipitate was isolated by filtration to obtain the marked compound (0.038 g) as a white solid. 1H nmr (400MHz, D6-DMSO) δ 8.53 (1H,s, thiazole H-5 or pyrazole H-5), 8.30 (1H,s, thiazole H-5 or pyrazole H-5, pyrazole H-3, H-5 1H), 8.29 (1H,s, thiazole H-5 or pyrazole H-5, pyrazole H-3, H-5 1H), 8.28 (1H,s, thiazole H-5 or pyrazole H-5, pyrazole H-3, H-5 1H), 8.08 (1H,dt,J 9.0,6.5Hz, pyridine H-4 or H-5), 7.59-7.56 (2H,m, 2H of C6H5SO3H), 7.32-7.27 (4H,m, pyridine H-4 or H-5, 3H of C6H5SO3H), 4.33 (1H,tt,J 11.5,3.5Hz, cyclohexane H-1 or H-4), 3.47 (2H,q,J 7.0Hz, OCH2CH3), 3.34 (1H,tt,J 10.5, 3.5 Hz, cyclohexane H-1 or H-4), 2.08 (4H, m, 4H of cyclohexane H-2, H-3, H-5, H-6), 1.85 (2H, m, cyclohexane H-2, H-3, H-5, H-6), 1.35 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.10 (3H, t, J 7.0 Hz, OCH2CH3); 19 F nmr(380MHz,D6-DMSO)δ -73.0(dd,24.5,2.5Hz),-124.2(ddd,J 26.0,9.5,1.5Hz);m / z:500[M+H] + .

[0146] Example 5 Formation of N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1H-pyrazole-4-yl)thiazole-4-carboxamide sodium salt (I-67) [ka] N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1H-pyrazole-4-yl)thiazole-4-carboxamide (0.062 g, 0.124 mmol, 1.0 equivalent) was dissolved in chloroform (2.0 mL) to obtain a clear solution. Sodium hydroxide (0.05 mL of 3 M aqueous solution, 0.149 mmol, 1.2 equivalents) was added, and the reaction mixture was stirred at room temperature for 3 days. No precipitate formed. The reaction mixture was concentrated and further concentrated in acetonitrile (5 mL) to obtain the marked compound as a white solid; 1 H nmr (400MHz, D6-DMSO)δ 8.53 (1H, s, thiazole H-5 or pyrazole H-5), 8.13 (3H, br s, thiazole H-5 or pyrazole H-5, pyrazole H-3, H-5), 8.08 (1H, dt, J 9.5, 6.5Hz, pyridine H-4 or H-5), 7.28 (1H, ddd, J 9.0, 3.0, 2.5Hz, pyridine H-4 or H-5), 4.33 (1H, tt, J 11.5, 3.0Hz, cyclohexane H-1 or H-4), 3.47 (2H, q, J 7.0Hz, OCH2CH3), 3.35 (1H, tt, J 11.0, 3.5 Hz, cyclohexane H-1 or H-4), 2.08 (4H, m, 4H of cyclohexane H-2, H-3, H-5, H-6), 1.85(2H,m,cyclohexane H-2,H-3,H-5,H-6),1.35(2H,m,2H of cyclohexane H-2,H-3,H-5,H-6),1.10(3H,t,J 7.0Hz,OCH2CH3);m / z:500[M+H] + .

[0147] Example 6 Formation of N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1H-pyrazole-4-yl)thiazole-4-carboxamide tartaric acid cocrystal (I-66) [ka] L-tartaric acid (0.017 g, 0.110 mmol, 1.1 equivalents) was added to a solution of N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1H-pyrazole-4-yl)thiazole-4-carboxamide (0.050 g, 0.100 mmol, 1.0 equivalent) in chloroform (1.0 equivalent). A white solid slowly precipitated. The reaction mixture was stirred at room temperature for 18 hours, and the precipitate was isolated by filtration to obtain the marked compound (0.055 g, 85%) as a white solid; 1 H nmr(400MHz,D6-DMSO)δ 8.53 (1H,s, thiazole H-5 or pyrazole H-5), 8.29 (3H,br s, thiazole H-5 or pyrazole H-5, pyrazole H-3,H-5), 8.08 (1H,dt,J 9.5,6.5Hz, pyridine H-4 or H-5), 7.28 (1H,dt,J 9.0,3.0Hz, pyridine H-4 or H-5), 5.05 (2H,br s,2×OH), 4.33 (1H,tt,J 11.5,3.5Hz, cyclohexane H-1 or H-4), 4.29 (2H,s,COCH(OH)CH(OH)CO), 3.47 (2H,q,J 7.0Hz, OCH2CH3), 3.34 (1H,tt,J 10.5, 3.5 Hz, cyclohexane H-1 or H-4), 2.08 (4H, m, 4H of cyclohexane H-2, H-3, H-5, H-6), 1.85 (2H, m, cyclohexane H-2, H-3, H-5, H-6), 1.35 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.09 (3H, t, J 7.0 Hz, OCH2CH3); 13 C nmr(100MHz,D6-DMSO)δ 173.5,161.7,157.7,157.6(d,J 236.0Hz),153.5(dd,J 259.0,4.0Hz),149.2,138.2(t,J 15.0Hz),132.6(d,J 9.0Hz),131.9(dd,J 22.5,9.0Hz),123.5,121.5,120.2,116.2,109.2(dd,J 43.0,8.5Hz),76.0,72.6,63.0,60.8,30.9,30.9,16.1; 19F nmr(380MHz,D6-DMSO)δ -73.0,-124.2;m / z:500[M+H] + .

[0148] Example 7 Formation of N-(3-(3,6-difluoropyridine-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1H-pyrazole-4-yl)thiazole-4-carboxamide hemi((2R,3R)-2,3-dihydroxysuccinate)(I-11) [ka] A solution of (L)-tartaric acid (750.5 mg, 5 mmol) in MeOH (1.3 mL) was added dropwise to a solution of N-(3-(3,6-difluoropyridine-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1H-pyrazole-4-yl)thiazole-4-carboxamide (5.0 g, 10 mmol) in CH2Cl2-MeOH (60 mL-5 mL) at 35°C. An additional 5 mL of MeOH and 100 mL of CH2Cl2 were added after 15 minutes. The mixture was stirred at 35°C for a further 20 hours and then cooled to room temperature. The solid was collected by filtration, washed with CH2Cl2, and further dried under vacuum. The marked compound was obtained as a white solid: 3.48 g (yield 60.7%). 1 H NMR(400MHz,DMSO-d6)δ 13.32(br s,1H),12.74(br s,1H),11.45(s,1H),8.51(s,1H),8.27(s,1H),8.43-8.14(m,2H),8.07(ddd,J=9.8,8.8,6.3Hz,1H),7.27(ddd,J=8.8,2.9,2.9Hz,1H),5.07(br s,1H),4.31(tt,partially overlapping,J=11.7,3.2Hz,1H),4.27(s,1H),3.45(q,J=7.0Hz,2H),3.33(tt,partially overlapping with H2O) Double, J=10.7,3.6Hz,1H),2.08-2.03(m,4H),1.88-1.78(m,2H),1.38-1.28(m,2H),1.08(t,J=7.0Hz,3H); 19F NMR(376MHz,DMSO-d6)δ -72.97(ddd,J=28.1,6.8,3.8Hz),-124.18(ddd,J=28.1,10.3,3.2Hz);LRMS(M+H)m / z 500.2.

[0149] A second product of the same compound (1.58 g, combined yield: 88%) was obtained from the filtrate after removing the solvent under vacuum, and the solid was resuspended overnight in CH2Cl2-MeOH (25 mL-2 mL) at 35°C.

[0150] Example 8 Preparation of N-(3-(3,6-difluoropyridine-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1H-pyrazole-4-yl)thiazole-4-carboxamide (I-1) - Method 1 [ka] Preparation of 2-bromo-N-(3-(3,6-difluoropyridine-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)thiazole-4-carboxamide C-3 from I.C2.HCl [ka] Diisopropylethylamine (8.5 mL, 48.95 mmol, 3.5 equivalents) was added to a mixture of aminopyrazole C-2.HCl (5.00 g, 13.99 mmol, 1.0 equivalent) and bromothiazole carboxylic acid (3.20 g, 15.38 mmol, 1.1 equivalents) in dichloromethane (50 mL) at 0°C. HATU (5.85 g, 15.38 mmol, 1.1 equivalents) was added. The reaction mixture was stirred at 0°C for 10 minutes, then at room temperature for 4 hours. The reaction mixture was diluted with CH2Cl2 (100 mL). The organic solution was washed with NaHCO3 (150 mL), NH4Cl (150 mL), and brine (100 mL), dried, and concentrated under reduced pressure in (Na2SO4). The residue was suspended in HCl-hexane (1:1, 50 mL), and the resulting solid was isolated by filtration. The solid was suspended in NaHCO3 (50 mL) for 1 hour to remove residual coupling agent, then isolated by filtration and dried under vacuum to obtain C-3 (5.3 g, 74%) as a grayish-white solid; IR ν max (Film) 3290, 3121, 2942, 2865, 1671, 1615, 1552, 1485, 1431, 1377, 1237, 1154, 1104, 1056, 1011, 819, 787, 731 cm -1 ; 1 H nmr (400 MHz, CDCl3) δ 8.42 (1H, d, J 0.5 Hz, thiazole H-5 or pyrazole H-5), 8.09 (1H, s, thiazole H-5 or pyrazole H-5), 7.63 (1H, td, J 9.0, 6.0 Hz, pyridine H-4 or H-5), 6.85 (1H, ddd, J 9.0, 3.5, 2.5 Hz, pyridine H-4 or H-5), 4.26 (1H, tt, J 11.5, 4.0 Hz, cyclohexane H-1 or H-4), 3.55 (2H, q, J 7.0 Hz, OCH2CH3), 3.36 (1H, tt, J 10.5, 4.0 Hz, cyclohexane H-1 or H-4), 2.28 (2H, br d, J 13.0Hz, cyclohexane H-2, H-3, H-5, H-6 (2H), 2.21(2H, m, cyclohexane H-2, H-3, H-5, H-6 (2H)), 1.91, 1.84(2H, 2dd AB system, J 13.0, 3.5Hz, cyclohexane H-2, H-3, H-5, H-6 (2H)), 1.46(2H, m, cyclohexane H-2, H-3, H-5, H-6 (2H)), 1.22(3H, t, J 7.0Hz, OCH2CH3); 13 C nmr(100MHz,CDCl3)δ 157.6(d,J 238.0Hz),156.9,153.3(dd,J 260.0,8.5Hz),150.0,138.6(t,J 14.0Hz),136.1,133.1(d,J 8.5Hz),129.8(dd,J 23.0,8.5Hz),126.7,121.7,119.2,107.8(dd,J 39.5,5.5Hz),76.4,63.6,61.5,31.1,30.9,15.7; 19 F nmr(380MHz,CDCl3)δ -72.3,-124.9;m / z:536,534[M+Na] + ,514,512[M+H] + The filtrate obtained from the initial trituration was purified by column chromatography (20 → 80% siRNA) to obtain a further C-3 (0.8 g, 9%) as a pink foam.

[0151] II. Preparation of N-(3-(3,6-difluoropyridine-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1H-pyrazole-4-yl)thiazole-4-carboxamide (I-1) [ka] Dioxane (400 mL) was added to a mixture of bromothiazole C-3 (25.0 g, 48.8 mmol, 1.0 equivalent) and pyrazole-4-boronic acid (8.2 g, 73.2 mmol, 1.5 equivalents), followed by the addition of an aqueous solution of sodium carbonate (73.3 mL of 2 M solution, 146.5 mmol, 3.0 equivalents). The reaction mixture was degassed by bubbling with argon for 5 minutes. Tetrakis(triphenylphosphine)palladium (1.4 g, 1.2 mmol, 0.025 equivalents) was added, and the reaction mixture was further degassed before heating at 105°C for 6 hours. The reaction mixture was filtered through celite® while still hot and eluted with siRNA (200 mL). The filtrate was concentrated to approximately 150 mL, at which point a precipitate formed. The precipitate was isolated by filtration. The filtrate was concentrated to remove residual organic matter, filtered to remove more precipitate, diluted with water-brine (1:2, 300 mL), and extracted with siRNA (3 × 200 mL). The combined organic solutions were combined, dried (Na₂SO₄), and concentrated under reduced pressure. The combined precipitate and extract were loaded onto silica. Column chromatography (silica, 0 → 10% MeOH-CH₂Cl₂) yielded the marked compound (16.5 g, 68%) as a white solid; IR ν max (Film) 3229, 2938, 2861, 1663, 1615, 1589, 1549, 1482, 1425, 1377,1237,1104,1055,972,930,903,875,820,786,715,664cm -1 ; 1H nmr (400MHz, CDCl3)δ 8.52 (1H,s, thiazole H-5 or pyrazole H-5), 8.24 (2H,s, NH pyrazole H-3, H-5), 8.07 (1H,s, thiazole H-5 or pyrazole H-5), 7.41 (1H,td,J 9.0,6.0Hz, pyridine H-4 or H-5), 6.86 (1H,ddd,J 9.0,3.5,2.5Hz, pyridine H-4 or H-5), 4.28 (1H,tt,J 11.5,4.0Hz, cyclohexane H-1 or H-4), 3.57 (2H,q,J 7.0Hz, OCH2CH3), 3.37 (1H,tt,J 11.0, 4.0 Hz, cyclohexane H-1 or H-4), 2.26 (4H, m, 4H of cyclohexane H-2, H-3, H-5, H-6), 1.92, 1.86 (2H, 2dd AB system, J 13.0, 3.5 Hz, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.50, 1.44 (2H, 2dd AB system, J 13.0, 3.5 Hz, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.23 (3H, t, J 7.0 Hz, OCH2CH3); 13 C nmr(100MHz,CDCl3)δ 160.6,158.6,158.3,156.3,154.8,152.2,150.2,138.9,133.0(d,J 9.0Hz),129.9(dd,J 23.5,9.0Hz),122.0,121.6,119.4,117.2,107.5(dd,J 40.5,5.0Hz),76.4,63.7,61.5,31.1,30.9,15.7; 19 F nmr(380MHz,CDCl3)δ -72.7(dddd,J 27.0,9.5,5.5,4.0Hz),-124.3(ddd,J 27.5,9.5,3.0Hz);m / z:500[M+H] + (Measured value [M+H]) + ,500.1687,C 23 H 23 F2N7O2S is [M+H] + (Requires 500.1675).

[0152] Example 9 Preparation of N-(3-(3,6-difluoropyridine-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1H-pyrazole-4-yl)thiazole-4-carboxamide (I-1) - Method 2 [ka] I. Formation of 2-(1H-pyrazole-4-yl)thiazole-4-carboxylic acid [ka] 2-Bromothiazol-4-carboxylic acid (2.08g, 10 mmol, 1.0 equivalent), (1H-pyrazole-4-yl)boronic acid (3.36g, 30 mmol, 3.0 equivalents), tetrakis(triphenylphosphine)palladium (0.23g, 0.2 mmol, 0. A 1,4-dioxane-H2O (32 mL-8 mL) solution of 0.2 equivalents of 0.2 ohms and sodium carbonate (3.18 g, 30 mmol, 3.0 equivalents) was degassed three times and refilled with nitrogen gas. The turbid solution was stirred at 60°C for 2 hours (by LC-MS, starting material:product approximately 1:1), and then stirred at 100°C for a further 3 hours, monitoring by LC-MS until the reaction was complete. After removing the organic solvent under reduced pressure, the crude mixture was diluted with water (100 mL) and thoroughly mixed. The aqueous solution was passed through a celite® pad and washed with water. With stirring, the filtrate was acidified to pH=1-2 with 6 M aqueous HCl (approximately 11 mL). The precipitate was collected by filtration, washed with water, and dried under vacuum to obtain the marked compound (1.79 g, yield 92%) as a pale yellowish-brown solid; 1 H nmr (400MHz, D6-DMSO) δ 13.11 (2H, br s, NH, OH), 8.28 (1H, s, thiazole H-4), 8.17 (2H, br s, pyrazole H-3, H-5); m / z: 196 [M+H] + .

[0153] II. Preparation of N-(3-(3,6-difluoropyridine-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1H-pyrazole-4-yl)thiazole-4-carboxamide (I-1) [ka] A mixture of C2.HCl aminopyrazole hydrochloride (1.00 g, 2.80 mmol, 1.0 equivalent) and 2-(1H-pyrazole-4-yl)thiazole-4-carboxylic acid (0.65 g, 3.36 mmol, 1.2 equivalents) in dimethylformamide (14 mL) was cooled to 0°C, and diisopropylethylamine (1.22 mL, 6.99 mmol, 2.5 equivalents) was added. A solution was formed, to which HATU (1.17 g, 3.08 mmol, 1.1 equivalents) was added. The solution was stirred at 0°C for 15 minutes and at room temperature for 1 hour, after which the reaction mixture was added to water (75 mL). A solid formed and disintegrated into a gum. The liquid was decanted while the solid was isolated by filtration. The gum and solid were dissolved in siRNA-MeOH (4:1, 100 mL), combined, and concentrated under reduced pressure. The resulting solid was triturated with 10% EtOH-siRNA (4 mL) to obtain the labeled compound I-1 as a grayish-white solid (0.76 g, 55%). The filtrate was concentrated and loaded onto silica. Column chromatography (0 → 10% MeOH-CH2Cl2) yielded a pale yellow solid, which was stirred with NaHCO3 (15 mL). The liquid was decanted, and the residue was triturated with 10% EtOH-siRNA (4 mL) to obtain a further product as a grayish-white solid (0.226 g, 16%). The total yield was 0.99 g, 71%; the data were consistent with those above.

[0154] Example 10 Exemplary synthesis of alkyl phosphate compounds [ka] I. Preparation of di-tert-butyl((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl)phosphate (I-3) [ka] Potassium carbonate (0.41 g, 3.01 mmol, 1.5 equivalents) was added to a suspension of I-1 (1.00 g, 2.00 mmol, 1.0 equivalent) in dimethylformamide (14 mL). The reaction mixture was stirred at room temperature for 30 minutes, after which a solution of chloromethyl di-tert-butyl phosphate (1.04 g, 4.01 mmol, 2.0 equivalents) in dimethylformamide (2 mL) was added. The reaction mixture was stirred at room temperature for 14 hours. Further chloromethyl di-tert-butyl phosphate (0.52 g, 2.00 mmol, 1.0 equivalent) and potassium carbonate (0.21 g, 1.50 mmol, 0.75 equivalents) were added, and the reaction mixture was stirred for a further 24 hours. The reaction mixture was cooled to 0°C, and water (25 mL) was added dropwise over 45 minutes. A viscous solid was formed and isolated by decantation of the liquid. The liquid was added to water (40 mL) and stirred to obtain a solid, which was isolated by filtration. The solid was dried under vacuum and used without further purification (1.76 g, quantitative - theoretical yield 1.44 g); IR ν max (Film) 3308, 2979, 2978, 2864, 1668, 1615, 1592, 1549, 1482, 1374, 1266, 1234, 1104, 998, 965, 822, 787, 714, 666cm -1 ; 1 H nmr(400MHz,C DCl3)δ 8.50 (1H,s, pyrazole H-5, thiazole H-5), 8.34 (1H,s, 1H of pyrazole H-3, H-5), 8.21 (1H,s, 1H of pyrazole H-3, H-5), 8.06 (1H,s 1H of pyrazole H-5, thiazole H-5), 7.65 (1H,td,J 9.0,6.0Hz, pyridine H-4 or H-5), 6.88 (1H,ddd,J 9.0,3.0,2.5Hz, pyridine H-4 or H-5), 5.93 (2H,d,J 12.5Hz, NCH2OP), 4.27 (1H,tt,J 12.0, 4.0 Hz, cyclohexane H-1 or H-4), 3.56 (2H, q, J) 7.0Hz, OCH2CH3), 3.37 (1H, tt, J 10.5, 4.0Hz, cyclohexane H-1 or H-4), 2.29 (2H, br d, J 12.5Hz, 2H of cyclohexane H-2, H-3, H-5, H-6), 2.22 (2H, br d, J 11.0Hz, cyclohexane H-2, H-3, H-5, H-6 (2H), 1.89(2H, m, cyclohexane H-2, H-3, H-5, H-6 (2H)), 1.50(2H, m, cyclohexane H-2, H-3, H-5, H-6 (2H)), 1.45(18H, s, 2×OC(CH3)3), 1.22(3H, t, J 7.0Hz, OCH2CH3); 13 C nmr(100MHz,CDCl3)δ 160.0,158.2,157.5(d,J 236.5Hz),153.5(dd,J 260.0,5.0Hz),150.2,139.5(d,J 6.0Hz),138.9(t,J 15.0Hz),133.0(d,J 9.0Hz),130.0(d,J 4.5Hz),129.8(d,J 9.0Hz),122.0,121.8,119.4,118.6,107.6(dd,J 40.5,5.0Hz),83.9,83.8,77.2,76.4,63.6,61.5,31.1,30.9,29.8,29.7,15.7; 31 P nmr(162MHz,CDCl3)δ -11.1; 19F nmr(380MHz,CDCl3)δ -72.4(dt,J 27.0,5.5Hz),-124.5(dd,J 27.5,9.5Hz);m / z:744[M+Na] + .

[0155] II. Preparation of (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyldihydrogen phosphate (I-2) [ka] To a solution of I-3 (1.58 g crude mass, 1.80 mmol, 1.0 equivalent) in dichloromethane (8.0 mL), trifluoroacetic acid (0.99 mL, 12.80 mmol, 7.1 equivalents) was added. The reaction mixture was stirred at room temperature for 20 hours, during which time a precipitate formed. After 20 hours, the precipitate was isolated by filtration. The solid was washed with CH2Cl2 (2 × 8 mL) to obtain a white solid. The solid was stirred with dioxane-water (10:1, 11 mL) for 5 hours, filtered, and washed with dioxane-water (10:1, 11 mL) to obtain I-2 (0.60 g, 55% in two steps) as a white solid. The filtrate was concentrated and stirred in dioxane-water (10:1, 11 mL) for 18 hours, then isolated by filtration. The solid was washed with dioxane-water (10:1, 2 × 5.5 mL) to obtain an additional product (0.12 g, 0.72 g total, 66%) as a white solid; 1 H nmr(400MHz, D6-DMSO)δ 8.59 (1H,s, pyrazole H-3, H-5 1H), 8.52 (1H,s, pyrazole 1H of zole H-3, H-5), 8.34 (1H, s, 1H of pyrazole H-5, thiazole H-5), 8.19 (1H, s, 1H of pyrazole H-5, thiazole H-5), 8.08 (1H, td, J 9.5, 6.5Hz, pyridine H-4 or H-5), 6.88 (1H, ddd, J 9.0, 3.0, 2.5Hz, pyridine H-4 or H-5), 5.83 (2H, d, J 12.5Hz, NCH2OP), 4.33 (1H, tt, J 12.0, 3.0Hz, cyclohexane H-1 or H-4), 3.47 (2H, q, J 7.0Hz, OCH2CH3), 3.35 (1H, tt, J 10.5, 3.5 Hz, cyclohexane H-1 or H-4), 2.29 (4H, br d, J 11.0 Hz, cyclohexane H-2, H-3, H-5, H-6 4H), 1.85 (2H, m, cyclohexane H-2, H-3, H-5, H-6 2H), 1.35 (2H, m, cyclohexane H-2, H-3, H-5, H-6 2H), 1.10 (3H, t, J 7.0 Hz, OCH2CH3); 13 C nmr(100MHz,CDCl3)δ 160.6,157.6,157.6(d,J 234.5Hz),154.3(dd,J 259.5,4.0Hz),149.4,137.7(d,J 7.0Hz),138.2,132.6(d,J 9.0Hz),131.9(dd,J 22.0,9.0Hz),131.4,124.1,121.4,120.2,117.7,109.2(d,38.0Hz),76.0,75.2,63.0,60.8,30.9(2C),16.1; 31 P nmr(162MHz,D6-DMSO)δ -2.7; 19 F nmr(380MHz,D6-DMSO)δ -72.8,-124.2(ddd,J 27.0,9.5,3.0Hz);m / z:610[M+H] + (Measured value [M+H]) + ,610.1451,C 24 H 26 F2N7O6PS is [M+H] + (Requires 610.1444).

[0156] Other phosphate compounds were prepared using similar methods.

[0157] Example 11 Exemplary synthesis of carbamates and ureas as potential IRAK prodrugs Formation of 1,2-morpholinoethyl(4-nitrophenyl) carbonate [ka] A solution of 4-nitrophenol chloroformate (0.500 g, 2.48 mmol, 1.0 equivalent) in dichloromethane (20 mL) was cooled to -78°C. Diisopropylethylamine (0.65 mL, 3.72 mmol, 1.5 equivalents) was added, followed by 4-(2-hydroxyethyl)morpholine (0.30 mL, 2.48 mmol, 1.0 equivalent), and the reaction mixture was stirred at -78°C to room temperature for 16 hours. The reaction mixture was diluted with dichloromethane (40 mL), washed with NaHCO3 (60 mL) and brine (60 mL), dried, and concentrated under reduced pressure in (Na2SO4) to obtain the marked compound as an orange oil. 1 H nmr(400MHz,CDCl3)δ 8.27 (2H,d,J 9.5Hz, 2H of C6H4NO2), 7.37 (2H,d,J 9.0Hz, 2H of C6H4NO2), 4.39 (2H,t,J 5.5Hz, 2H of COOCH2CH2N), 3.72, 3.71 (4H,2d AB system,J 4.5Hz, 4H of morpholine), 2.72 (2H,t,J 5.5Hz, 2H of COCH2CH2N), 2.54, 2.53 (4H,2d AB system,J 4.5Hz, 4H of morpholine).

[0158] II. Formation of 3-morpholinopropyl(4-nitrophenyl) carbonate [ka] Diisopropylethylamine (0.65 mL, 3.72 mmol, 1.5 equivalents) was added to a solution of 4-nitrophenyl chloroformate (0.500 g, 2.48 mmol, 1.0 equivalent) in dichloromethane (20 mL) at -78°C. 3-(hydroxypropyl)morpholine (0.34 mL, 2.48 mmol, 1.0 equivalent) was added dropwise, and the reaction mixture was stirred at -78°C for 30 minutes. The reaction mixture froze and was warmed to 0°C. After stirring at 0°C for 5 hours, the reaction mixture was left to stand for 16 hours and then warmed to room temperature. The reaction mixture was diluted with dichloromethane (20 mL) and washed with NaHCO3 (3 × 40 mL). The organic solution was dried and concentrated under reduced pressure to obtain the marked compound as a pale yellow oil. 1 H nmr(400MHz,CDCl3)δ 8.26(2H,d,J 9.5Hz,2H of C6H4NO2),7.36(2H,d,J 9.0Hz,2H of C6H4NO2),4.36(2H,t,J 6.5Hz,OCH2CH2CH2N),3.70 3.69(4H,2d AB system,J 4.5Hz, morpholine 4H), 2.49-2.43 (6H, m, morpholine 4H, OCH2CH2CH2N), 1.93 (pentet, J 6.5Hz, OCH2CH2CH2N).

[0159] III. Formation of 2-morpholinoethyl 4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-carboxylate (I-10) [ka] To nitrophenyl carbonate (0.050 g, 0.169 mmol, 1.5 equivalents) in dichloromethane (1.0 mL) at 0°C, N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1H-pyrazole-4-yl)thiazole-4-carboxamide (0.056 g, 0.113 mmol, 1.0 equivalent) and dimethylaminopyridine (0.001 g, 0.011 mmol, 0.1 equivalent) were added. Triethylamine (0.023 mL, 0.169 mmol, 1.5 equivalents) was added, and the reaction mixture was stirred at 0°C for 30 minutes and at room temperature for 1 hour. The reaction mixture was partitioned between CH2Cl2 (30 mL) and NaHCO3 (30 mL). The aqueous phase was extracted with CH2Cl2 (2 × 30 mL). The combined organic solution was dried (Na2SO4) and concentrated under reduced pressure. The marked compound was given as a white solid by MPLC (20 → 80% acetone-hexane, 0.1% triethylamine). 1 H nmr (400MHz, CDCl3)δ 8.75 (1H, s, thiazole H-5, pyrazole H-5, pyrazole H-3, H-5 1H), 8.49 (1H, s, thiazole H-5, pyrazole H-5, pyrazole H-3, H-5 1H), 8.35 (1H, s, thiazole H-5, pyrazole H-5, pyrazole H-3, H-5 1H), 8.13 (1H, s, thiazole H-5, pyrazole H-5, pyrazole H-3, H-5 1H), 7.64 (1H, td, J 9.0, 6.0Hz, pyridine H-4 or H-5), 6.86 (1H, dt, J 8.5, 3.5, 2.5Hz, pyridine H-4 or H-5), 4.63 (2H, t,J 6.0Hz,COOCH2CH2N),4.26(1H,tt,J 11.5,4.0Hz,cyclohexane H-1 or H-4),3.70,3.68(4H,2d AB system,J 4.5Hz, morpholine 4H),3.55(2H,q,J 7.0Hz,OCH2CH3),3.36(1H,tt,J 10.5,4.0Hz,cyclohexane H-1 or H-4),2.84(2H,t,J 6.0Hz,COOCH2CH2N),2.58,2.57(4H,2d AB system,J 4.5Hz, morpholine (4H), 2.28(2H,m, cyclohexane H-2, H-3, H-5, H-6 (2H)), 2.20(2H,m, cyclohexane H-2, H-3, H-5, H-6 (2H)), 1.88(2H,m, cyclohexane H-2, H-3, H-5, H-6 (2H)), 1.45(2H,m, cyclohexane H-2, H-3, H-5, H-6 (2H)), 1.21(3H,t,J 7.0Hz, OCH2CH3); 19 F nmr(380MHz,CDCl3)δ -72.7(ddd,J 27.0,5.5,4.0Hz),-124.3(ddd,27.0,11.0,9.5Hz);m / z:657[M+H] + .

[0160] IV. Formation of 3-morpholinopropyl 4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-carboxylate (I-15) [ka] To a mixture of nitrophenyl carbonate (0.068 g, 0.220 mmol, 1.1 equivalents) and N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1H-pyrazole-4-yl)thiazole-4-carboxamide (0.100 g, 0.200 mmol, 1.0 equivalent) in dichloromethane (2.0 mL) at 0°C, triethylamine (0.031 mL, 0.220 mmol, 1.1 equivalents) and dimethylaminopyridine (0.002 g, 0.020 mmol, 0.1 equivalents) were added. The reaction mixture was stirred at 0°C for 1 hour, then at room temperature for 3 hours, resulting in a nearly clear solution. The reaction products were partitioned between CH2Cl2 (30 mL) and NaHCO3 (30 mL). The aqueous phase was extracted with CH2Cl2 (2 × 30 mL). The combined organic solution was dried (Na2SO4) and concentrated under reduced pressure. The marked compound (0.077 g, 57%) was given as a white solid by MPLC (40 → 100% acetone-hexane, 0.1% triethylamine). 1 H nmr (400MHz, CDCl3)δ 8.75 (1H,s, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 8.49 (1H,s, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 8.34 (1H,s, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 8.12 (1H,s, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 7.64 (1H,td,J 9.0,6.0Hz, pyridine H-4 or H-5), 6.87 (1H,ddd,J 9.0, 3.5, 2.5 Hz, pyridine H-4 or H-5), 4.61 (2H, 6.5 Hz, 2H of OCH2CH2CH2N), 4.26 (1H, tt, J 11.5, 4.0 Hz, cyclohexane H-1 or H-4), 3.66, 3.65 (4H, 2d AB system, J 4.5 Hz, 4H of morpholine), 3.55 (2H, q, J 7.0 Hz, OCH2CH3), 3.35 (1H, tt, J 10.5, 4.0 Hz, cyclohexane H-1 or H-4), 2.52 (2H, J 7.0Hz, 2H of OCH2CH2CH2N, 2.44(4H, m, 4 of morpholine) H), 2.30-2.24 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 2.24-2.17 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 2.05 (2H, penet, J 6.5Hz, OCH2CH2CH2N), 1.93-1.83 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.51-1.41 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.21 (3H, t, J 7.0Hz, OCH2CH3); 19 F nmr(380MHz,CDCl3)δ -72.7(ddd,J 28.5,5.5,4.0Hz),-124.3(ddd,J 28.0,9.5,2.5Hz);m / z:671[M+H] + (Measured value [M+H]) + ,671.2560,C 31 H 36 F2N8O5S is [M+H] + (Requires 671.2570).

[0161] Those skilled in the art will understand that the above method can also be used to produce corresponding urea compounds such as I-13 and I-14 by using an amine instead of the starting hydroxy compound. An exemplary scheme for synthesizing urea compound I-13 is given below. [ka]

[0162] Example 12 Exemplary synthesis of amino acid esters Synthesis of (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl L-valinate hydrochloride (I-16) [ka] I. Preparation of chloromethyl(tert-butoxycarbonyl)-L-valinate [ka] To a 100 mL solution of dichloromethane containing N-Boc-valine (5.00 g, 23.0 mmol, 1.0 equivalent), sodium bicarbonate (7.74 g, 92.2 mmol, 4.0 equivalent) and tetrabutylammonium bisulfate (0.78 g, 2.3 mmol, 0.1 equivalent) were added, followed by the addition of water (100 mL). The mixture was stirred for 10 minutes to dissolve, then cooled to 0°C, and a 20 mL solution of dichloromethane containing chloromethyl chlorosulfate (3.0 mL, 29.0 mmol, 1.3 equivalents) was added dropwise over 20 minutes. The reaction mixture was stirred at 0°C for 1 hour, then at room temperature for 18 hours. The reaction mixture was partitioned, and the aqueous phase was extracted with CH2Cl2 (20 mL). The combined organic phases were washed with water (3 × 100 mL) and brine (100 mL), dried, and concentrated under reduced pressure to obtain the labeled compound (6.10 g, quantitatively) as a colorless oil; 1 H nmr(400MHz,CDCl3)δ 5.87(1H,d,J 6.0Hz,1H of OCH2Cl),5.61(1H,d,J 6.0Hz,OCH2Cl 1H),4.97(1H,br d,J 7.0Hz,NH),4.27(1H,dd,J 9.0,4.5Hz,COCHNH),2.22-2.17(1H,m,CHCH(CH3)2),1.44(9H,s,C(CH3)3),0.99(3H,d,J 6.5Hz, 1×CH3 of CH(CH3)2), 0.92(3H,d,J 7.0Hz, 1×CH3 of CH(CH3)2).

[0163] II. Preparation of (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl(tert-butoxycarbonyl)-L-valinate [ka] Dimethylformamide (50 mL) was added to a mixture of I-1 (5.00 g, 10.0 mmol, 1.0 equivalent) and N-Boc-valinechloromethyl ester (2.93 g, 11.0 mmol, 1.1 equivalents). Cesium carbonate (3.92 g, 12.0 mmol, 1.2 equivalents) was added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was partitioned between SiO (150 mL) and water (150 mL). The organic solution was washed with brine (100 mL). The combined organic solution was back-extracted with SiO (75 mL). The combined organic solution was washed with water (200 mL) and brine (150 mL), dried, and concentrated under reduced pressure using (Na2SO4). The marked compound (6.51 g, 89%) was obtained as a white solid by MPLC (50 → 100% SiO-hexane). 1H nmr (400MHz, CDCl3)δ 8.48 (1H,s, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 8.29 (1H,s, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 8.14 (1H,s, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 8.04 (1H,s, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 7.63 (1H,td,J 9.0,6.0Hz, pyridine H-4 or H-5), 6.87 (1H,ddd,J 9.0,3.5,2.5Hz, pyridine H-4 or H-5), 6.21, 6.02 (2H,2d AB system,J 10.5Hz, NCH2O), 4.94 (1H, d, J 9.0Hz, NHBoc), 4.28-4.21 (2H, m, cyclohexane H-1 or H-4, COCHNH), 3.54 (2H, q, J 7.0Hz, OCH2CH3), 3.43 (1H, tt, J 10.5, 4.0 Hz, cyclohexane H-1 or H-4), 2.30-2.24 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 2.23-2.16 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 2.13-2.04 (1H, m, CHCH(CH3)2), 1.92-1.82 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.49-1.40 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.40 (9H, s, C(CH3)3), 1.20 (3H, t, J 7.0 Hz, OCH2CH3), 0.86 (3H, d, J 6.5Hz, CH(CH3)2 (1×CH3), 0.77(3H,d,J 6.5Hz, CH(CH3)2 (1×CH3); 13C nmr(100MHz,CDCl3)δ 171.9,159.7,158.2,15x(d,J 236.5Hz),155.6,153.x(dd,J 260.5,4.5Hz),150.2,139.8(d,J 5.0Hz),138.9(t,J 14.5Hz),133.0(d,J 8.5Hz),130.5(d,J 5.0Hz),129.9(dd,J 22.5,9.0Hz),122.0,121.8,119.4,118.6,107.6(dd,J 40.5,5.5Hz),80.1,77.2,76.4,72.6,63.6,61.5,58.4,31.1,31.0,30.9,28.3,18.8,17.4,15.7; 19 F nmr(380MHz,CDCl3)δ -72.6,-124.4;m / z:751[M+H] + ,673[M+H-C4H8] + ,629[M+H-C4H8-CO2] + .

[0164] III. (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl) Preparation of Azole-2-yl)-1H-pyrazole-1-yl)methyl L-valinate hydrochloride, I-16 [ka] To a solution / suspension of Boc-protected valine methylene ester (1.73 g, 2.38 mmol, 1.0 equivalent) in ethyl acetate (25 mL), 5.94 mL (23.76 mmol, 10.0 equivalent) of 4 M dioxane hydrogen chloride solution was added. The reaction mixture was stirred at room temperature for 18 hours. A further 3.0 mL (11.88 mmol, 5.0 equivalent) of 4 M dioxane hydrogen chloride solution was added, and the reaction mixture was stirred for a further 8 hours, after which it was concentrated under reduced pressure. The residue was concentrated from RINKAN (2 × 30 mL) and dried under vacuum to give the marked compound (1.50 g, quantitatively) as a white solid; 1H nmr (400MHz, D6-DMSO)δ 8.66 (1H,s, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 8.51 (1H,s, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 8.35 (1H,s, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 8.22 (1H,s, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 8.07 (1H,td,J 9.0,6.0Hz, pyridine H-4 or H-5), 7.25 (1H,ddd,J 8.5, 3.0, 2.5 Hz, pyridine H-4 or H-5), 6.2x, 6.2x (2d, AB system, J Hz, NCH2OCO), 4.32 (1H, tt, J 11.5, 3.0 Hz, cyclohexane H-1 or H-4), 3.90 (1H, d, J 4.0 Hz, COCHNH2), 3.45 (2H, q, J 7.0 Hz, OCH2CH3), 3.30 (1H, tt, J 11.0, 4.0 Hz, cyclohexane H-1 or H-4), 2.12-2.00 (5H, m, 4H of cyclohexane H-2, H-3, H-5, H-6, CH(CH3)2), 1.88-1.80 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.38-1.29 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.08 (3H, t, J 7.0 Hz, OCH2CH3), 0.87 (3H, d, J 7.0 Hz, 3H of CH(CH3)2), 0.83 (3H, d, J 7.0 Hz, 3H of CH(CH3)2); 19 F nmr(380MHz,D6-DMSO)δ -73.0(d,J 28.5Hz),-124.1(dd,J 27.0,9.5Hz);m / z:629[M+H] + (Measured value [M+H]) + ,629.2477,C 29 H 34 F2N8O4S is [M+H] + (Requires 629.2465).

[0165] Those skilled in the art will understand that this method is generally applicable to all amino acids, particularly naturally occurring amino acids, as disclosed herein.

[0166] Example 13 Synthesis of 1-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)ethyl dihydrogen phosphate (I-18) [ka] I. Preparation of chloroethyl chlorosulfate [ka] Chlorosulfonic acid (4.90 mL, 73.7 mmol, 1.46 equivalents) was added dropwise to chloroethyl chloroformate (5.44 mL, 50.4 mmol, 1.0 equivalent) at 0°C over 20 minutes. The reaction mixture was stirred at 0°C for 2 hours, then at room temperature for 10 minutes (during which time the solution temperature rose to 5°C). Dichloromethane (50 mL) was added, followed by careful addition of ice (2 g), and the mixture was quickly stirred to ensure mixing. Some bubbling was observed, and the yellow solution turned blackish-green. The mixture was washed with NaHCO3 (2 × 40 mL) to ensure that the organic solution was not acidic. The organic solution was washed with brine (40 mL) and dried (Na2SO4) to obtain a clear solution, which was concentrated under reduced pressure to obtain the marked compound (4.72 g, 52%) as a blackish-brown oil; 1 H nmr(400MHz, CDCl3)δ 6.46(1H,q,J 6.0Hz,ClCH(CH3)O),1.97(3H,d,J 5.5Hz,CHCH3).

[0167] II. Synthesis of 1-chloroethyldi-tert-butyl phosphate [ka] Potassium di-tert-butyl phosphate (5.44g, 21.97mmol, 1. 0 equivalents of the organic compound were dissolved in dichloromethane-water (200 mL, 1:1) and cooled to 0°C. Sodium bicarbonate (7.37 g, 87.74 mmol, 4.0 equivalents) and tetrabutylammonium hydrogen phosphate (0.74 g, 2.19 mmol, 0.1 equivalents) were added, and the reaction mixture was stirred at 0°C for 10 minutes. Then, chloroethyl chlorosulfate (4.72 g, 26.37 mmol, 1.2 equivalents as a solution in 20 mL of dichloromethane) was added dropwise over 30 minutes at 0°C. The resulting mixture was rapidly stirred at room temperature for 18 hours and then partitioned. The organic solution was washed with water (3 × 100 mL) and brine (100 mL), dried, and concentrated under reduced pressure to obtain the marked compound (2.35 g, 39%) as a light brown oil; 1 H nmr(400MHz,CDCl3)δ 6.19(1H,dq,J 8.5,5.5Hz,ClCH(CH3)O),1.79(3H,dd,J 5.5,1.0Hz,CHCH3),1.49(9H,s,1×OC(CH3)3),1.48(9H,s,1×OC(CH3)3); 32 P nmr(380MHz, CDCl3)δ -13.0.

[0168] III. Preparation of di-tert-butyl(1-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)ethyl)phosphate [ka] To a suspension of I-1 (2.00 g, 4.01 mmol, 1.0 equivalent) in degassed dimethylformamide (15 mL), potassium iodide (0.07 g, 0.40 mmol, 0.1 equivalent) and potassium hydroxide (0.90 g, 16.03 mmol, 4.0 equivalent) as small flakes were added. Chloroethyl di-tert-butyl phosphate (1.64 g, 6.01 mmol, 1.5 equivalent as a solution in 5 mL of dimethylformamide) was added dropwise over 10 minutes. The resulting mixture was heated at 50°C for 14 hours, then cooled and diluted with SiO2 (50 mL). The reaction product was partitioned between SiO2 (100 mL) and water (150 mL). The organic solution was washed with brine (100 mL), water (150 mL), and brine (100 mL), dried, and concentrated under reduced pressure in (Na2SO4). Column chromatography (silica, 50 → 100% siRNA-hexane) yielded the marked compound as a white solid; 1 H nmr(400MHz,CDCl3)δ 11.73(1H,s,NH),8.51(1H,s,pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5),8.33(1H,s,pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5),8.16(1H,s,pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5),8.05(1H,s pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5),7.65(1H,td,J 9.0,6.5Hz,pyridine H-4 or H-5),6.88(1H,ddd,J 8.0,3.0,2.5Hz,pyridine H-4 or H-5),6.39(1H,dq,J 7.5,6.5Hz,NCH(CH3)O),4.27(1H,tt,J 11.5,3.5Hz,cyclohexane H-1 or H-4),3.56(2H,q,J 7.0Hz,OCH2CH3),3.37(1H,tt,J 10.5,4.5Hz,cyclohexane H-1 or H-4),2.32-2.26(2H,m,2H of cyclohexane H-2,H-3,H-5,H-6),2.26-1.90(2H,m,2H of cyclohexane H-2,H-3,H-5,H-6) ), 1.94(3H,d,J 6.5Hz,NCH(CH3)O), 1.93-1.84(2H,m,2H of cyclohexane H-2,H-3,H-5,H-6), 1.52-1.42(11H,m,2H of cyclohexane H-2,H-3,H-5,H-6,1×C(CH3)3), 1.37(9H,s,1×C(CH3)3), 1.23(3H,t,J 7.0Hz,OCH2CH3); 19 F nmr(380MHz,CDCl3)δ -72.3,-124.5; 32 P nmr(380MHz,CDCl3)δ -11.9;m / z:758[M+Na] + .

[0169] Alternative synthesis of di-tert-butyl(1-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)ethyl)phosphate Dioxane (48 mL) was added to a mixture of I-1 (7.00 g, 14.0 mmol, 1.0 equivalent) and potassium iodide (0.23 g, 1.4 mmol, 0.1 equivalent), followed by cesium carbonate (9.15 g, 28.1 mmol, 2.0 equivalent). The resulting suspension was stirred at room temperature, and chloroethyl di-tert-butyl phosphate (4.20 g, 15.4 mmol, 1.1 equivalent as a solution in 8 mL of dioxane) was added. The reaction mixture was heated at 70°C for 30 hours, then cooled and partitioned between SiO2 (100 mL) and NH4Cl-water (1:1, 100 mL). The organic solution was dried (Na2SO4) and concentrated under reduced pressure. Upon standing in a refrigerator, a solid formed along with some liquid, presumably water. The liquid contained no product and was decanted. à (7.5 mL) was added, the solid was isolated by filtration, and washed with à (7.5 mL and 5 mL). The solid was dried under vacuum to obtain the marked compound (5.20 g, 50%) as a grayish-white solid. 1H nmr(400MHz,CDCl3)δ 11.73(1H,s,NH),8.51(1H,s,pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5),8.33(1H,s,pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5),8.16(1H,s,pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5),8.05(1H,s pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5),7.65(1H,td,J 9.0,6.5Hz,pyridine H-4 or H-5),6.88(1H,ddd,J 8.0,3.0,2.5Hz,pyridine H-4 or H-5),6.39(1H,dq,J 7.5,6.5Hz,NCH(CH3)O),4.27(1H,tt,J 11.5,3.5Hz,CyclohexaneH-1 or H-4),3.56(2H,q,J 7.0Hz,OCH2CH3),3.37(1H,tt,J 10.5,4.5Hz,CyclohexaneH-1 or H-4),2.32-2.26(2H,m,2H of CyclohexaneH-2,H-3,H-5,H-6),2.26-1.90(2H,m,2H of CyclohexaneH-2,H-3,H-5,H-6),1.94(3H,d,J 6.5Hz, NCH(CH3)O), 1.93-1.84 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.52-1.42 (11H, m, 2H of cyclohexane H-2, H-3, H-5, H-6, 1×C(CH3)3), 1.37 (9H, s, 1×C(CH3)3), 1.23 (3H, t, J 7.0Hz, OCH2CH3); 19 F nmr(380MHz,CDCl3)δ -72.3,-124.5; 32 P nmr(162MHz,CDCl3)δ -11.9;m / z:758[M+Na] + The filtrate contains further products.

[0170] IV. Preparation of 1-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)ethyl dihydrogen phosphate [ka] A solution of di-tert-butyl phosphate (0.202 g, 0.275 mmol) in dichloromethane (3 mL) was cooled to 0°C, and phosphoric acid (85%, 9 mL) was added. The reaction mixture was stirred at room temperature for 3 minutes, then added to water (60 mL). The organic solution was extracted with siRNA (3 × 40 mL). The combined organic solution was dried and concentrated to approximately 7 mL under reduced pressure using (Na₂SO₄). A precipitate formed, which was isolated by filtration to obtain the marked compound (0.082 g, 48%) as a pink solid. 1 H nmr (400MHz, D6-DMSO) δ 11.45 (1H,s,NH), 8.55 (1H,s,pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 8.50 (1H,s,pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 8.30 (1H,s,pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 8.13 (1H,s pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 8.06 (1H,td,J 9.5,6.5Hz, pyridine H-4 or H-5), 7.24 (1H,dt,J 9.0, 2.5 Hz, pyridine H-4 or H-5), 6.28-6.21 (1H, m, NCH(CH3)O), 4.31 (1H, br t, J 11.5 Hz, cyclohexane H-1 or H-4), 3.46 (2H, q, J 7.0 Hz, OCH2CH3), 3.30 (1H, br t, J 10.5 Hz, cyclohexane H-1 or H-4), 2.10-2.03 (4H, m, 4H of cyclohexane H-2, H-3, H-5, H-6), 1.88-1.78 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.77 (3H, d, J 6.0Hz, NCH(CH3)O), 1.38-1.29 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.08 (3H, t, J 7.0Hz, OCH2CH3); 19 F nmr(380MHz,D6-DMSO)δ -72.8,-124.2; 32 P nmr(380MHz,D6-DMSO)δ -3.3;m / z:624[M+H] +(Measured value [M+H]) + ,624.1610,C 25 H 28 F2N7O6PS is [M+H] + (Requires 624.1600).

[0171] To a suspension of di-tert-butyl phosphate (0.100 g, 0.136 mmol, 1.0 equivalent) in tetrahydrofuran (0.8 mL), water (0.8 mL, distilled, deionized, 18 MΩ) was added, and sodium acetate (0.008 g, 0.010 mmol, 0.75 equivalents) was added. The reaction mixture was sealed and stirred at 70°C for 5.5 hours, then cooled, and acetone (20 mL) was added. A precipitate formed, which was isolated by filtration to obtain the marked compound (0.055 g, 65%) as a white solid; the data are consistent with those described above.

[0172] V. Preparation of sodium 1-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)ethyl phosphate (I-20) [ka] A suspension of phosphate (I-18) (2.34 g, 3.75 mmol, 1.0 equivalent) in acetonitrile (15 mL) and water (20 mL) was cooled to 0°C, and sodium hydroxide (0.27 g, 6.76 mmol, 1.8 equivalents in 5 mL of water) was added dropwise over 30 minutes (approximately 4 mL of solution was added, resulting in a reaction mixture pH of approximately 9). The reaction mixture was stirred at 0°C for a further 15 minutes, after which water (10 mL) was added. The mixture was stirred at 0°C for 15 minutes and then filtered (on filter paper). The filtrate was frozen and dried by freeze-drying to obtain the marked compound (2.40 g, 96%) as a white powder; 1H nmr(400MHz,D2O)δ 8.05 (1H,s,pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 7.86 (1H,s,pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 7.55 (1H,s,pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 7.52 (1H,s pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 7.37 (1H,m,pyridine H-4 or H-5), 6.59 (1H,m,pyridine H-4 or H-5), 6.00 (1H,t,J 7.5Hz,NCH(CH3)O), 3.94 (1H,m,cyclohexane H-1 or H-4), 3.56 (2H,q,J 7.0Hz, OCH2CH3), 3.43 (1H, m, cyclohexane H-1 or H-4), 2.16-2.08 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 2.07-2.00 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.69 (3H, d, J 6.0Hz, NCH(CH3)O), 1.68-1.60 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.36-1.25 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.10 (3H, t, J 7.0Hz, OCH2CH3); 13 C nmr(100MHz,D2O)δ 160.4,157.9,156.8(d,J 237Hz),152.4(d,J 256.5Hz),147.5,137.2(d,J 10.5Hz),135.9(t,J 14.5Hz),132.0(d,J 9.0Hz),130.2(dd,J 25.0,8.5Hz),128.0,122.7,120.4,119.2,116.0,108.6(d,J 41.0Hz),82.1,76.7,63.8,60.7,30.5,30.2,22.1,14.5; 19 F nmr(380MHz,D2O)δ -72.8,-124.8; 32 P nmr(162MHz,D2O)δ 1.2; m / z:624[M+H] + .

[0173] VI. Preparation of sodium 1-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)ethyl hydrogen phosphate (I-107) [ka] A suspension of di-tert-butyl phosphate (1.81 g, 2.47 mmol, 1.0 equivalent) in tetrahydrofuran (14.5 mL) was mixed with sodium acetate (0.15 g, 1.85 mmol, 0.75 equivalents). Water (14.5 mL, distilled, deionized, 18 MΩ) was added, and the reaction mixture was stirred at 70°C for 8 hours. The reaction mixture was analyzed every hour from 4 hours, and heating was continued until the profile showed approximately 10% monophosphate and 70% product. (Prolonged heating may cause product decomposition). The reaction mixture was cooled and added to acetone (75 mL), which formed a precipitate. This precipitate was isolated by filtration, and the marked compound (1.04 g, 67%) was obtained as a white solid; IR ν max (Film) 3427, 2935, 2869, 1660, 1593, 1556, 1490, 1372, 1333, 1229, 1103, 1092, 1022, 963, 823, 784, 713, 665, 647cm -1 ; 1H nmr (400MHz, D6-DMSO) δ 11.43 (1H,s,NH), 8.42 (1H,s,1H of pyrazole H-5, thiazole H-5, pyrazole H-3,H-5), 8.47 (1H,s,1H of pyrazole H-5, thiazole H-5, pyrazole H-3,H-5), 8.23 ​​(1H,s,1H of pyrazole H-5, thiazole H-5, pyrazole H-3,H-5), 8.04 (1H,dt,J 9.5,6.5Hz, pyridine H-4 or H-5), 8.03 (1H,s,1H of pyrazole H-5, thiazole H-5, pyrazole H-3,H-5), 7.27 (1H,dt,J 8.5, 2.5 Hz, 1H of pyridine H-4 or H-5), 6.11 (1H, dq, J 3.5, 6.0 Hz, NCH(CH3)O), 4.31 (1H, tt, J 11.5, 3.5 Hz, cyclohexane H-1 or H-4), 3.47 (2H, q, J 7.0 Hz, OCH2CH3), 3.35 (1H, tt, J 10.5, 3.5 Hz, cyclohexane H-1 or H-4), 2.12-2.05 (4H, m, 4H of cyclohexane H-2, H-3, H-5, H-6), 1.90-1.80 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.63 (3H, d, J 6.0Hz, CHCH3), 1.41-1.30 (2H, m, cyclohexane H-2, H-3, H-5, H-6 2H), 1.10 (3H, t, J 7.0Hz, OCH2CH3); m / z: 624 [M+H] + .

[0174] VII. Preparation of potassium 1-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)ethyl hydrogen phosphate [ka] Except for using potassium acetate instead of sodium acetate, a procedure similar to the one given above was used for the sodium salt, but the reaction may take longer to complete. 1H nmr (400MHz, D6-DMSO)δ 11.43 (1H,s,NH), 8.47 (1H,s,1H of pyrazole H-5, thiazole H-5, pyrazole H-3,H-5), 8.46 (1H,s,1H of pyrazole H-5, thiazole H-5, pyrazole H-3,H-5), 8.22 (1H,s,1H of pyrazole H-5, thiazole H-5, pyrazole H-3,H-5), 8.07-8.00 (1H,m,pyridine H-4 or H-5), 8.02 (1H,s,1H of pyrazole H-5, thiazole H-5, pyrazole H-3,H-5), 7.25 (1H,d,J 8.5Hz,1H of pyridine H-4 or H-5), 6.10 (1H,dq,J 9.0,6.0Hz,NCH(CH3)O),4.30(1H,br t,J 11.5Hz,cyclohexane H-1 or H-4),3.47(2H,q,J 7.0Hz,OCH2CH3),3.34(1H,br t,J 10.5Hz,cyclohexane H-1 or H-4),2.12-2.03(4H,m,4H of cyclohexane H-2,H-3,H-5,H-6),2.00-1.78(2H,m,2H of cyclohexane H-2,H-3,H-5,H-6),1.63(3H,d,J 6.0Hz,CHCH3),1.39-1.29(2H,m,2H of cyclohexane H-2,H-3,H-5,H-6),1.09(3H,t,J 7.0Hz, OCH2CH3); 32 P nmr(162MHz,D6-DMSO)δ -2.0; 19 F nmr(380MHz,D6-DMSO)δ-72.5(d,J 27.5Hz),-124.4(dd,J 30.5,11.0Hz);m / z:624[M+H] + .

[0175] VIII. Preparation of 2-amino-2-(hydroxymethyl)propane-1,3-diol 1-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)ethylhydrogen phosphate (I-49) [ka] Except for using tris(hydroxymethyl)aminomethane, a procedure similar to the one given above was used for the sodium salt. 1 H nmr(400MHz, D6-DMS) O)δ 11.45 (1H,s,NH), 8.49 (1H,s,pyrazole H-5, thiazole H-5, pyrazole H-3,H-5 1H), 8.47 (1H,s,pyrazole H-5, thiazole H-5, pyrazole H-3,H-5 1H), 8.25 (1H,s,pyrazole H-5, thiazole H-5, pyrazole H-3,H-5 1H), 8.08-8.02 (1H,mHz,pyridine H-4 or H-5), 8.05 (1H,s,pyrazole H-5, thiazole H-5, pyrazole H-3,H-5 1H), 7.27 (1H,br d,J 8.5Hz, pyridine H-4 or H-5 (1H), 6.11(1H, dq,J 9.0,6.0Hz,NCH(CH3)O),4.31(1H,br t,J 11.5Hz,cyclohexane H-1 or H-4),3.46(2H,q,J 7.0Hz,OCH2CH3),3.40(6H,s,NH2C(CH2OH)3),3.34(1H,br t,J 10.0Hz,cyclohexane H-1 or H-4),2.12-2.04(4H,m,4H of cyclohexane H-2, H-3, H-5, H-6),1.89-1.79(2H,m,2H of cyclohexane H-2, H-3, H-5, H-6),1.65(3H,d,J 6.0Hz, CHCH3), 1.39-1.29 (2H, m, cyclohexane H-2, H-3, H-5, H-6 2H), 1.09 (3H, t, J 7.0Hz, OCH2CH3); 32 P nmr(162MHz,D6-DMSO)δ -1.7; 19 F nmr(380MHz,D6-DMSO)δ -72.5(d,J 27.5Hz),-124.4(dd,J 30.5,11.0Hz);m / z:624[M+H] + .

[0176] Example 14 Synthesis of (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methylisopropyl carbonate (I-45) [ka] N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1H-pyrazole-4-yl)thiazole-4-carboxamide (50 mg, 0.1 mmol) and chloromethylisopropyl carbonate (20 mg, 0.13 mmol) were dissolved in anhydrous DMF (1 mL) and cesium carbonate (40 mg, 0.12 mmol) was added. Next, the resulting reaction mixture was stirred overnight at ambient temperature, then diluted with water (50 mL), filtered, and dried to obtain (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methylisopropyl carbonate as a white solid, weighing 49 mg (80%). 1 H NMR(400MHz,CD3OD)δ 11.73(s,1H),8.55-8.47(m,2H),8.26-8.15(m,2H),7.88(ddd,J=9.7,8.8,6.2Hz,1H),7.14-7.06(m,1H),6.11(d,J=4.3Hz,2H),4.96-4 .88(m,1H),4.36-4.25(m,1H),3.60(qd,J=7.0,1.4Hz,2H),3.52-3.42(m,1H),2.31-2.18(m,4H),1.97(q,J=11.5Hz,2H),1.54-1.41(m, 2H),1.29(d,J=6.3Hz,6H),1.21(t,J=7.0Hz,3H).MS m / e: Calculated value 615.21; Actual value 616.2(M+H) + .

[0177] Example 15 Synthesis of (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl4-((S)-2-amino-3-methylbutanamide)butanoate hydrochloride (I-57) [ka] I. Synthesis of methyl(S)-4-(2-((tert-butoxycarbonyl)amino)-3-methylbutanamide)butanoate (3) Diisopropylethylamine (568 mg, 0.76 mL, 4.4 mmol) was added to a solution of methyl 4-aminobutanoate hydrochloride 1 (306 mg, 2.0 mmol) and (tert-butoxycarbonyl)-L-valine 2 (433 mg, 2.0 mmol) in anhydrous DMF (5 mL). The mixture was then cooled to 0°C, HATU (835 mg, 2.2 mmol) was added, and the resulting solution was warmed to ambient temperature and stirred for 17 hours. Water (50 mL) and ethyl acetate (100 mL) were then added to separate the organic layer, washed with water (3 × 30 mL) and brine (30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by chromatography using a gradient of 0-100% ethyl acetate in hexane to obtain methyl(S)-4-(2-((tert-butoxycarbonyl)amino)-3-methylbutanamide)butanoate 3 (591 mg, 94%) as a pale, viscous oil. MS m / e: Calculated value 316.20; Measured value 261.1[M- t [AD+H] + .

[0178] II.(S)-4-(2-((tert-butoxycarbonyl)amino)-3-methylbutoxycarbonyl Synthesis of tanamide butanoic acid (4) A solution of methyl(S)-4-(2-((tert-butoxycarbonyl)amino)-3-methylbutanamide)butanoate 3 (583 mg, 1.85 mmol) in a mixture of THF (4 mL) and MeOH (1 mL) was mixed with an aqueous solution of NaOH (1 mL, 4 N, 4 mmol). The resulting solution was stirred at ambient temperature for 15 hours. Most of the solvent mixture was removed under reduced pressure, and water (50 mL) was added to the resulting residue. The aqueous layer was then washed with ethyl ether (50 mL), acidified to pH 4 with aqueous HCl (5 mL, 1 N), and extracted with ethyl acetate (3 × 40 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give (S)-4-(2-((tert-butoxycarbonyl)amino)-3-methylbutanamide)butanoic acid 4 (480 mg, 86%) as a white solid. MS m / e: Calculated value 302.18; Measured value 247.2[M- t Bu+H]+.

[0179] III. Synthesis of chloromethyl(S)-4-(2-((tert-butoxycarbonyl)amino)-3-methylbutanamide)butanoate (6) To a solution of (S)-4-(2-((tert-butoxycarbonyl)amino)-3-methylbutanamide)butanoic acid 4 (370 mg, 1.23 mmol) in a mixture of dichloromethane (7 mL) and water (7 mL), sodium bicarbonate (412 mg, 4.90 mmol) and tetrabutylammonium bisulfate (42 mg, 0.123 mmol) were added, followed by chloromethyl chlorosulfate 5 (233 mg, 143 μL, 1.41 mmol). The resulting solution was stirred at ambient temperature for 2 days, and dichloromethane (80 mL) and water (30 mL) were added. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (30 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was further purified by chromatography using a gradient of 0-100% ethyl acetate in hexane to obtain chloromethyl(S)-4-(2-((tert-butoxycarbonyl)amino)-3-methylbutanamide)butanoate 6 (369 mg, 86%) as a colorless oil. MS m / e: Calculated value 350.16; Measured value 251.1[M-Boc+H] + .

[0180] IV. Synthesis of (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl4-((S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanamide)butanoate (8) To a solution of chloromethyl(S)-4-(2-((tert-butoxycarbonyl)amino)-3-methylbutanamide)butanoate 6 (45 mg, 0.128 mmol) in anhydrous DMF (1 mL), diisopropylethylamine (33.2 mg, 45 μL, 0.128 mmol) was added, followed by N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1H-pyrazole-4-yl)thiazole-4-carboxamide 7 (64 mg, 0.128 mmol). The resulting solution was stirred at ambient temperature for 2 days, then water (20 mL) was added, and the aqueous solution was extracted with ethyl acetate (2 × 40 mL). The combined organic layers were then washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by reverse-phase HPLC (40-100% acetonitrile in water buffered with 0.1% formic acid). The desired fractions were combined and freeze-dried to obtain (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl4-((S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanamide)butanoate 8 (26 mg, 25%) as a white foam. MS m / e: Calculated value 813.34; measured value Value 814.3 [M+H] + .

[0181] V. Synthesis of (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl4-((S)-2-amino-3-methylbutanamide)butanoate hydrochloride (I-57) A suspension of (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl4-((S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanamide)butanoate 8 (26 mg, 0.032 mmol) in ethyl acetate was mixed with HCl (0.31 mL, 4 M in dioxane). The resulting solution was stirred at ambient temperature for 19 hours. A turbid solution was obtained, filtered, and the resulting solid was washed with ethyl acetate and hexane and dried under high vacuum to give (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl4-((S)-2-amino-3-methylbutanamide)butanoate hydrogen chloride (21.4 mg, 89%) as a white solid. 1 H NMR(400MHz,CD3OD)δ 8.51-8.48(m,2H),8.22(d,J=0.7Hz,1H),8.20(s,1H),7.89(td,J=9.2,6.2Hz,1H),7.09(ddd,J=8.8,3.4,2.6Hz ,1H),6.15(s,2H),4.31(ddd,J=11.7,8.4,3.7Hz,1H),3.61(q,J=7.0Hz,2H),3.53(d,J=5.9Hz,1H),3.50-3.40(m ,1H),3.27(dt,J=6.9,3.4Hz,2H),2.48(t,J=7.4Hz,2H),2.30-2.17(m,4H),2.11(dq,J=13.4,6.4Hz,1H),2.05- 1.91(m,2H),1.86(p,J=7.2Hz,2H),1.47(q,J=11.8Hz,2H),1.21(t,J=7.0Hz,3H),1.01(dd,J=6.9,5.4Hz,6H).MS m / e: Calculated value 713.29; Actual value 714.3 [M+H] +

[0182] Example 16 Synthesis of (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl1-amino-3,6,9,12,15,18-hexaoxahenicosan-21-oate hydrochloride (I-61) [ka] I. Synthesis of chloromethyl 2,2-dimethyl-4-oxo-3,8,11,14,17,20,23-heptaoxa-5-azahexacosan-26-oate (11) To a solution of 2,2-dimethyl-4-oxo-3,8,11,14,17,20,23-heptaoxa-5-azahexacosan-26-acid (250 mg, 0.551 mmol) in a mixture of dichloromethane (5.2 mL) and water (5.2 mL), sodium bicarbonate (185 mg, 2.21 mmol) and tetrabutylammonium bisulfate (18.7 mg, 0.0551 mmol) were added. Then, chloromethyl chlorosulfate 5 (105 mg, 64 μL, 0.634 mmol) was added, and the resulting solution was stirred at ambient temperature for 18 hours. Next, water (10 mL) was added, and the resulting aqueous solution was extracted with dichloromethane (3 × 30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product of chloromethyl 2,2-dimethyl-4-oxo-3,8,11,14,17,20,23-heptaoxa-5-azahexacosan-26-oate 11 (303 mg, 100%) with a purity of 91%. The crude product was used directly in the next step without further purification. MS m / e: Calculated value 501.23; Measured value 402.1 [M-Boc+H] + .

[0183] II. Synthesis of (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl2,2-dimethyl-4-oxo-3,8,11,14,17,20,23-heptaoxa-5-azahexacosan-26-oate (12) Chloromethyl 2,2-dimethyl-4-oxo-3,8,11,14,17,20,23-heptaoxa-5-azahexacosan-26-oate-11 (51.8 mg, 0.10 To a solution of 3 mmol) and N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1H-pyrazole-4-yl)thiazole-4-carboxamide 7 (51.5 mg, 0.103 mmol) in anhydrous DMF (1 mL), anhydrous cesium carbonate (37 mg, 0.113 mmol) was added. The resulting reaction mixture was stirred at ambient temperature for 16 hours. Then, water (20 mL) and ethyl acetate (100 mL) were added, the organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by reverse-phase HPLC (30-100% acetonitrile in water buffered with 0.1% formic acid). The desired fractions were combined and freeze-dried to give (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl2,2-dimethyl-4-oxo-3,8,11,14,17,20,23-heptaoxa-5-azahexacosan-26-oate 12 (57.4 mg, 58%) as a colorless viscous oil. MS m / e: Calculated value 964.42; Measured value 865.3 [M-Boc+H] + .

[0184] III. Synthesis of (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl1-amino-3,6,9,12,15,18-hexaoxahenicosan-21-oate hydrochloride (I-61) (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl2,2-dimethyl-4-oxo-3,8,11,14,17,20,23-heptaoxa-5-azahexacosan-26-oate 12 (57.4 mg, 0.0595 mmol) was dissolved in ethyl acetate (5 mL) and HCl (2.4 mL, 1 M in ethyl ether, 2.4 mmol) was added. The resulting solution was stirred at ambient temperature for 2 days. The entire solvent was removed under reduced pressure, and the obtained residue was purified by reverse-phase HPLC (0-70% acetonitrile in water buffered with 0.1% formic acid). The desired fractions were combined, HCl solution (65 μL, 1N) was added, and the mixture was freeze-dried to obtain (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl1-amino-3,6,9,12,15,18-hexaoxahenicosan-21-oate hydrochloride (19 mg, 35%) as a sticky pale yellow solid. 1H NMR(400MHz,CD3OD)δ 11.71(s,1H),8.50(s,2H),8.28-8.16(m,2H),7.90(td,J=9.2,6.1Hz,1H),7.21-7.00( m,1H),6.17(s,2H),4.31(ddd,J=11.8,8.3,3.7Hz,1H),3.76(t,J=5.9Hz,2H),3.72-3.4 8(m,24H),3.06(t,J=5.1Hz,2H),2.70(t,J=5.9Hz,2H),2.66(s,1H),2.30-2.17(m,4H), 1.97(dt,J=13.7,11.2Hz,2H),1.56-1.41(m,2H),1.29(s,3H),1.21(t,J=7.0Hz,3H).MS m / e: Calculated value 864.37; Actual value 865.3 [M+H] + .

[0185] Example 17 Synthesis of isopropyl(((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (I-62) [ka] Synthesis of IN-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1-(hydroxymethyl)-1H-pyrazole-4-yl)thiazole-4-carboxamide (14) To a solution of N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1H-pyrazole-4-yl)thiazole-4-carboxamide 7 (501 mg, 1 mmol) in anhydrous ethanol (3 mL), formaldehyde aqueous solution (162 mg, 0.15 mL, 37 wt%, 2 mmol) was added. The resulting solution was heated at 50°C for 18 hours, and the resulting turbid reaction mixture was filtered and washed with anhydrous ethanol and hexane. When the obtained white solid was placed under high vacuum, N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1-(hydroxymethyl)-1H-pyrazole-4-yl)thiazole-4-carboxamide 14 (385 mg, 73%) was obtained. 1 H NMR(400MHz,DMSO-d6)δ 11.47(s,1H),8.52(d,J=8.5Hz,2H),8.31(s,1H),8.10(d,J=15.2Hz,2H),7.28(s,1H),6.99(s,1H),5.43(d,J=7.7Hz,2H),4.33 (s,1H),3.47(d,J=7.4Hz,2H),2.08(d,J=11.9Hz,4H),1.86(d,J=13.4Hz,2H),1.35(d,J=12.3Hz,2H),1.10(t,J=7.0Hz,3H).MS m / e: Calculated value 529.17; Actual value 530.1 [M+H] + .

[0186] II. Synthesis of Isopropyl(((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (I-62) N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1-(hydroxymethyl)-1H-pyrazole-4-yl)thiazole-4-carboxamide 14 (57.3 mg, 0.108 mmol) in anhydrous dichloromethane (2 mL) with diisopropyl ethoxymethyl Luamine (28 mg, 38 μL, 0.217 mmol) was added, followed by isopropyl(chloro(phenoxy)phosphoryl)-L-alaninate 15 (36.4 mg, 30 μL, 0.119 mmol). The resulting solution was stirred at ambient temperature for 2 days and then concentrated under reduced pressure. The obtained residue was purified by reverse-phase HPLC (50-100% acetonitrile in water buffered with 0.1% formic acid), the desired fractions were combined, and lyophilized to give isopropyl(((4-(((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (16 mg, 19%) as a white solid. 1 H NMR(400MHz,CD3OD)δ 8.51(s,1H),8.48(d,J=14.4Hz,1H),8.24(d,J=4.5Hz,1H),8.22(s,1H),7.87(ddd,J=9.7,8.8,6.2Hz,1H),7 .33-7.25(m,2H),7.21-7.01(m,4H),6.11(d,J=11.8Hz,1H),6.06(dd,J=11.6,2.3Hz,1H),4.95(pd,J=6.3,5. 3Hz,1H),4.38-4.25(m,1H),3.99-3.81(m,1H),3.60(q,J=7.0Hz,2H),3.51-3.39(m,1H),2.32-2.14(m,4H), 1.98(q,J=12.1,11.6Hz,2H),1.47(q,J=12.1Hz,2H),1.32(ddd,J=8.8,7.2,1.2Hz,3H),1.26-1.09(m,9H).MS m / e: Calculated value 798.25; Actual value 799.2 [M+H] +

[0187] Example 18 Synthesis of ((((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methoxy)(hydroxy)phosphoryl)oxy)methylisopropyl carbonate (I-60) [ka] (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl dihydrogen phosphate (1.00 g, 1.64 mmol, 1.0 equivalent) was dissolved in dimethyl sulfoxide (10 mL) and chloromethyl isopropyl carbonate (2.17 mL, 16.4 mmol, 10 equivalents) and diisopropylethylamine (2.71 mL, 16.4 mmol, 10 equivalents) were added. The solution was stirred at room temperature for 2 days. The reaction mixture was purified by reverse-phase HPLC (C-18, water / acetonitrile 0.1% formic acid) to obtain the marked compound (309 mg, 26%) as a white solid. 1 H NMR(400MHz,CDCl3)δ 11.6(s,1H),8.37(s,1H),8.25(s,1H),8.03(s,1H),7.95(s,1H),7.57-7 .51(m,1H),6.81-6.79(m,1H),5.97(d,J=10.8Hz,2H),5.65(d,J=10.8Hz, 2H),4.93-4.87(m,1H),4.27-4.21(m,1H),3.57(q,J=7.2,6.8Hz,2H),3.41-3.35(m ,1H),2.32-2.22(m,4H),1.93-1.84(m,2H),1.52-1.43(m,2H),1.33-1.24(m,9H).MS m / e: Calculated value 725.18; Actual value 726.2 (M+H) + .

[0188] The following exemplary compounds were prepared using the methods of Examples 4-18. Characterization data for these additional compounds are given below.

[0189] I-6:2-(1-(acetyl-L-leucyl)-1H-pyrazole-4-yl)-N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)thiazole-4-carboxamide [ka] 1 H nmr(400MHz,CDCl3)δ 8.78(1H,s,pyrazole H-3 or H-5), 8.50(1H,s,thiazole H-5 or pyrazole H-5), 8.36(1H,s,pyrazole H-3 or H-5), 8.14(1H,s,thiazole H-5 or pyrazole H-5), 7.65(1H,td,J 9.0,6.0Hz,pyridine H-4 or H-5), 6.91(1H,ddd,J 9.0,3.5,2.5Hz,pyridine H-4 or H-5), 6.11(1H,d,J 9.0Hz,NHCOCH3), 5.88(1H,m,COCHNHCO), 4.27(1H,tt,J 11.5, 4.0 Hz, cyclohexane H-1 or H-4), 3.56 (2H, q, J 7.0 Hz, OCH2CH3), 3.37 (1H, tt, J 10.5, 4.0 Hz, cyclohexane H-1 or H-4), 2.30 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 2.22 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 2.08 (3H, s, COCH3), 1.89 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.86-1.76 (2H, m, 2H of CHCH2CH(CH3)2), 1.65 (1H, m, 1H of CHCH2CH(CH3)2), 1.33 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.22 (3H, t, J 7.0 Hz, OCH2CH3), 1.07 (3H, d, J 6.0Hz, CH(CH3)2 (1×CH3), 0.97(3H,d,J 6.5Hz, CH(CH3)2 (1×CH3); m / z: 677[M+Na]+ ,655[M+H] + (Measured value [M+H]) + ,655.2623,C 31 H 36 F2N8O4S is [M+H] + (Requires 655.2621).

[0190] I-7: 1-Methylcyclopropyl 4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate [ka] 1H nmr(400MHz,CDCl3)δ 8.73 (1H,s, thiazole H-5, pyrazole H-5 or pyrazole H-3,H-5 1H), 8.50 (1H,s, thiazole H-5, pyrazole H-5 or pyrazole H-3,H-5 1H), 8.33 (1H,s, thiazole H-5, pyrazole H-5 or pyrazole H-3,H-5 1H), 8.13 (1H,s, thiazole H-5, pyrazole H-5 or pyrazole H-3,H-5 1H), 7.66 (1H,td,J 9.0,6.0Hz, pyridine H-4 or H-5), 6.88 (1H,ddd,J 9.0,3.5,2.5Hz, pyridine H-4 or H-5), 4.28 (1H,tt,J 11.5, 4.0 Hz, cyclohexane H-1 or H-4), 3.56 (2H, q, J 7.0 Hz, OCH2CH3), 3.37 (1H, tt, J 10.5, 4.0 Hz, cyclohexane H-1 or H-4), 2.30 (2H, br t, J 11.5Hz, cyclohexane H-2, H-3, H-5, H-6 (2H), 2.22(2H,m, cyclohexane H-2, H-3, H-5, H-6 (2H)), 1.89(2H,m, cyclohexane H-2, H-3, H-5, H-6 (2H)), 1.76(3H,s,CH3), 1.47(2H,m, cyclohexane H-2, H-3, H-5, H-6 (2H)), 1.24(2H,m,cPrH-2, H-3 (2H)), 1.23(3H,t,J 7.0Hz,OCH2CH3), 0.86(2H,m,cPrH-2, H-3 (2H)); 19 F nmr(380MHz,CDCl3)δ -72.6,-124.3;m / z:598[M+H] + (Measured value [M+H]) + ,598.2035,C 28 H 29 F2N7O4S is [M+H] + (Requires 598.2043).

[0191] I-8: 1-(isobutyryloxy)ethyl 4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate [ka] 1 H nmr (400MHz, CDCl3)δ 8.76 (1H,s, 1H of thiazole H-5, pyrazole H-5, pyrazole H-3, H-5), 8.51 (1H,s, 1H of thiazole H-5, pyrazole H-5, pyrazole H-3, H-5), 8.38 (1H,s, 1H of thiazole H-5, pyrazole H-5, pyrazole H-3, H-5), 8. 14(1H,s, thiazole H-5, pyrazole H-5, pyrazole H-3, H-5 of 1H), 7.66(1H,td,J 9.0,6.0Hz, pyridine H-4 or H-5), 7.15(1H,q,J 5.5Hz, OCH(CH3)O), 6.87(1H,ddd,J 9.0,3.5,2.5Hz, pyridine H-4 or H-5), 4.28(1H,tt,J 11.5,4.0Hz, cyclohexane H-1 or H-4), 3.57(2H,q,J 7.0Hz, OCH2CH3), 3.37(1H,tt,J 10.5,4.0Hz, cyclohexane H-1 or H-4), 2.63(1H,heptet,J 7.0Hz, COCH(CH3)2), 2.30 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 2.22 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.90 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.74 (3H, d, J 5.5Hz, OCH(CH3)O), 1.47 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.23 (3H, t, J 7.0Hz, OCH2CH3), 1.21 (3H, d, J 7.0Hz, (1×CH3 of CH(CH3)2), 1.21 (3H, d, J 6.5Hz, 1×CH3 of CH(CH3)2); 19 F nmr(380MHz,CDCl3)δ -72.6(ddd,J 27.0,5.5,4.0Hz),-124.3(ddd,27.0,9.5,2.5Hz);m / z:658[M+H] + (Measured value [M+H]) + ,658.2553,C 30 H 33 F2N7O6S is [M+H]+ (Requires 658.2254).

[0192] I-9:N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)-1H-pyrazole-4-yl)thiazole-4-carboxamide [ka] 1 H nmr (400MHz, CDCl3)δ 8.50 (1H,s, 1H of thiazole H-5, pyrazole H-5, pyrazole H-3, H-5), 8.49 (1H,s, 1H of thiazole H-5, pyrazole H-5, pyrazole H-3, H-5), 8.11 (1H,s, 1H of thiazole H-5, pyrazole H-5, pyrazole H-3, H-5), 8.09 (1H,s, 1H of thiazole H-5, pyrazole H-5, pyrazole H-3, H-5), 7.67 (1H,td,J 9.0,6.5Hz, pyridine H-4 or H-5), 6.92 (1H,dt,J 9.0,3.0Hz, pyridine H-4 or H-5), 5.19 (1H,d,J 4.5Hz, NCH2C (1H), 4.73 (1H, d, J 4.5Hz, NCH2C (1H), 4.28 (1H, tt, J 11.5, 4.0Hz, cyclohexane H-1 or H-4), 3.57 (2H, q, J 7.0Hz, OCH2CH3), 3.38 (1H, tt, J 10.5, 4.0 Hz, cyclohexane H-1 or H-4), 2.36 (3H, s, CCH3), 2.30 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 2.23 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.90 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.48 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.23 (3H, t, J 7.0 Hz, OCH2CH3); 19 F nmr (380MHz,CDCl3)δ -73.5,-124.1(ddd,27.0,9.5,3.0Hz);m / z:612[M+H] + (Measured value [M+H]) + ,612.1835,C 28 H 27 F2N7O5S is [M+H] + (Requires 612.1857).

[0193] I-10: 2-Morpholinoethyl 4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate [ka] 1H nmr(400MHz,CDCl3)δ 8.75 (1H,s, 1H of thiazole H-5, pyrazole H-5, pyrazole H-3, H-5), 8.49 (1H,s, 1H of thiazole H-5, pyrazole H-5, pyrazole H-3, H-5), 8.35 (1H,s, 1H of thiazole H-5, pyrazole H-5, pyrazole H-3, H-5), 8.13 (1H,s, 1H of thiazole H-5, pyrazole H-5, pyrazole H-3, H-5), 7.64 (1H,td,J 9.0,6.0Hz, pyridine H-4 or H-5), 6.86 (1H,dt,J 8.5,3.5,2.5Hz, pyridine H-4 or H-5), 4.63 (2H,t,J 6.0Hz, COOCH2CH2N), 4.26 (1H, tt, J 11.5, 4.0Hz, cyclohexane H-1 or H-4), 3.70, 3.68 (4H, 2d AB system, J 4.5Hz, morpholine 4H), 3.55 (2H, q, J 7.0Hz, OCH2CH3), 3.36 (1H, tt, J 10.5, 4.0Hz, cyclohexane H-1 or H-4), 2.84 (2H, t, J 6.0Hz, COOCH2CH2N), 2.58, 2.57 (4H, 2d AB system, J 4.5Hz, morpholine (4H), 2.28(2H,m, cyclohexane H-2, H-3, H-5, H-6 (2H)), 2.20(2H,m, cyclohexane H-2, H-3, H-5, H-6 (2H)), 1.88(2H,m, cyclohexane H-2, H-3, H-5, H-6 (2H)), 1.45(2H,m, cyclohexane H-2, H-3, H-5, H-6 (2H)), 1.21(3H,t,J 7.0Hz, OCH2CH3); 19 F nmr(380MHz,CDCl3)δ -72.7(ddd,J 27.0,5.5,4.0Hz),-124.3(ddd,27.0,11.0,9.5Hz);m / z:657[M+H] + .

[0194] I-12:N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1-(morpholine-4-carbonyl)-1H-pyrazole-4-yl)thiazole-4-carboxamide [ka] 1 H nmr (400MHz, CDCl3)δ 8.71 (1H,s, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 8.50 (1H,s, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 8.26 (1H,d,J 0.5Hz,),8.10(1H,s,pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5),7.64(1H,td,J 9.0,6.0Hz,pyridine H-4 or H-5),6.90(1H,ddd,J 9.0,3.5,2.5Hz,pyridine H-4 or H-5),4.27(1H,tt,J 11.5,4.0 3.83,3.82(4H,2d AB system,J 4.0Hz, morpholine 4H),3.56(2H,q,J 7.0Hz,OCH2CH3),3.36(1H,tt,J 11.0,4.0Hz,cyclohexane H-1 or H-4),Hz,cyclohexane H-1 or H-4),3.94(4H,br s, morpholine (4H), 2.33-2.25 (2H, m, cyclohexane H-2, H-3, H-5, H-6 (2H)), 2.55-1.90 (2H, m, cyclohexane H-2, H-3, H-5, H-6 (2H)), 1.94-1.84 (2H, m, cyclohexane H-2, H-3, H-5, H-6 (2H)), 1.52-1.41 (2H, m, cyclohexane H-2, H-3, H-5, H-6 (2H)), 1.22 (3H, t, J 7.0Hz, OCH2CH3); 19 F nmr(380MHz,CDCl3)δ -72.5,-124.4;m / z:613[M+H] + (Measured value [M+H]) + ,613.2163,C 28 H 30 F2N8O4S is [M+H] + (Requires 613.2152).

[0195] I-13:N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1-((3-morpholinopropyl)carbamoyl)-1H-pyrazole-4-yl)thiazol-4-carboxamide [ka] 1 H nmr (400MHz, CDCl3)δ 8.85 (1H,t,J 5.0Hz, CONHCH2), 8.79 (1H,s, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 8.49 (1H,s, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 8.25 (1H,s, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 8.08 (1H,s, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 7.36 (1H,td,J 9.0,6 0Hz, pyridine H-4 or H-5), 6.90 (1H, ddd, J 9.0, 3.5, 2.5Hz, pyridine H-4 or H-5), 4.26 (1H, tt, J 12.0, 4.0Hz, cyclohexane H-1 or H-4), 3.85, 3.84 (4H, 2d AB system, J 4.5Hz, morpholine 4H), 3.60-3.56 (2H, m, CONHCH2CH2CH2N), 3.55 (2H, q, J 7.0Hz, OCH2CH3), 3.36 (1H, tt, J 10.5, 4.0Hz, cyclohexane H-1 or H-4), 2.57-2.54 (2H, m, CONHCH2CH2CH2N), 2.51 (4H, br s, morpholine (4H), 2.30-2.26 (2H, m, cyclohexane H-2, H-3, H-5, H-6 (2H)), 2.23-2.18 (2H, m, cyclohexane H-2, H-3, H-5, H-6 (2H)), 1.93-1.84 (2H, m, cyclohexane H-2, H-3, H-5, H-6 (2H)), 1.84-1.78 (2H, m, CONHCH2CH2CH2N), 1.51-1.41 (2H, m, cyclohexane H-2, H-3, H-5, H-6 (2H)), 1.21 (3H, t, J 7.0Hz, OCH2CH3);19 F nmr(380MHz,CDCl3)δ -72.6(ddd,J 27.0,5.5,4.0Hz),-124.5(ddd,J 27.0,9.5,2.5Hz);m / z:670[M+H] + .

[0196] I-14:N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1-((3-(dimethylamino)propyl)carbamoyl)-1H-pyrazole-4-yl)thiazole-4-carboxamide [ka] 1 H nmr (400MHz, CDCl3)δ 8.80 (1H,s, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 8.49 (1H,s pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 8.36 (1H,t,J 5.5Hz, pyrazole CONH), 8.20 (1H,d,J 0.5Hz, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 8.08 (1H,s, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 7.63 (1H,td,J 9.0,6.0Hz, pyridine H-4 or H-5), 6.89 (1H,ddd,J 9.0,3.5,2.5Hz, pyridine H-4 or H-5), 4.26 (1H,tt,J 11.5,4.0Hz, cyclohexane H-1 or H-4), 3.58-3.52 (4H,m,OCH2CH3, pyrazole CONHCH2), 3.36 (1H,tt,J 10.5, 4.0 Hz, cyclohexane H-1 or H-4), 2.44 (2H, t, J 6.5 Hz, CH2N(CH3)2), 2.26 (6H, s, N(CH3)2), 2.30-2.18 (4H, m, 4H of cyclohexane H-2, H-3, H-5, H-6), 1.93-1.83 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.79 (2H, penet, J 6.5 Hz, NCH2CH2CH2N(CH3)2), 1.51-1.41 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.21 (3H, t, J 7.0 Hz, OCH2CH3); 19 F nmr(380MHz,CDCl3)δ -72.6,-124.5;m / z:628[M+H] + (Measured value [M+H]) + ,628.2628,C 29 H 35 F2N9O3S is [M +H] + (Requires 628.2624).

[0197] I-15:3-Morpholinopropyl 4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate [ka] 1H nmr (400MHz, CDCl3)δ 8.75 (1H,s, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 8.49 (1H,s, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 8.34 (1H,s, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 8.12 (1H,s, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 7.64 (1H,td,J 9.0,6.0Hz, pyridine H-4 or H-5), 6.87 (1H,ddd,J 9.0, 3.5, 2.5 Hz, pyridine H-4 or H-5), 4.61 (2H, 6.5 Hz, 2H of OCH2CH2CH2N), 4.26 (1H, tt, J 11.5, 4.0 Hz, cyclohexane H-1 or H-4), 3.66, 3.65 (4H, 2d AB system, J 4.5Hz, 4H of morpholine), 3.55 (2H, q, J 7.0Hz, OCH2CH3), 3.35 (1H, tt, J 10.5, 4.0Hz, cyclohexane H-1 or H-4), 2.52 (2H, J 7.0Hz, 2H of OCH2CH2CH2N), 2.44 (4H, m, 4H of morpholine), 2.30-2.24 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 2.24-2.17 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 2.05 (2H, penet, J 6.5Hz, OCH2CH2CH2N), 1.93-1.83 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.51-1.41 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.21 (3H, t, J 7.0Hz, OCH2CH3); 19 F nmr(380MHz,CDCl3)δ -72.7(ddd,J 28.5,5.5,4.0Hz),-124.3(ddd,J 28.0,9.5,2.5Hz);m / z:671[M+H] + (Measured value [M+H]) + ,671.2560,C 31 H 36 F2N8O5S is [M+H] + (Requires 671.2570).

[0198] I-16: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl L-valinate hydrogen chloride [ka] 1 H nmr (400MHz, D6-DMSO)δ 8.66 (1H,s, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 8.51 (1H,s, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 8.35 (1H,s, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 8.22 (1H,s, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 8.07 (1H,td,J 9.0,6.0Hz, pyridine H-4 or H-5), 7.25 (1H,ddd,J 8.5, 3.0, 2.5 Hz, pyridine H-4 or H-5), 6.2x, 6.2x (2d, AB system, J Hz, NCH2OCO), 4.32 (1H, tt, J 11.5, 3.0 Hz, cyclohexane H-1 or H-4), 3.90 (1H, d, J 4.0 Hz, COCHNH2), 3.45 (2H, q, J 7.0 Hz, OCH2CH3), 3.30 (1H, tt, J 11.0, 4.0 Hz, cyclohexane H-1 or H-4), 2.12-2.00 (5H, m, 4H of cyclohexane H-2, H-3, H-5, H-6, CH(CH3)2), 1.88-1.80 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.38-1.29 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.08 (3H, t, J 7.0 Hz, OCH2CH3), 0.87 (3H, d, J 7.0 Hz, 3H of CH(CH3)2), 0.83 (3H, d, J 7.0 Hz, 3H of CH(CH3)2); 13C nmr(100MHz,D6-DMSO)δ 168.8,160.2,157.6,157.5(d,J 236.0Hz),153.5(dd,J 259.0,4.5Hz),149.4,139.5(d,6.5Hz),138.2(t,J 14.5Hz),132.6(d,8.5Hz),132.3,131.9(dd,22.5,9.5Hz),124.4,121.4,120.3,117.8,109.2(br d,J 34.0Hz),76.0,73.6,63.0,60.8,57.4,30.9(2C),29.8,18.6,17.7,16.1; 19 F nmr(380MHz,D6-DMSO)δ -73.0(d,J 28.5Hz),-124.1(dd,J 27.0,9.5Hz);m / z:629[M+H] + (Measured value [M+H]) + ,629.2477,C 29 H 34 F2N8O4S is [M+H] + (Requires 629.2465).

[0199] I-17: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl L-proline hydrogen chloride [ka] 1 H nmr (400MHz, D6-DMSO) δ 11.48 (1H, s, 1×NH), 9.32 (1H, br s, 1×NH), 8.66 (1H, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 8.51 (1H, s, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 8.35 (1H, s, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 8.22 (1H, s, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 8.07 (1H, td, J 9.5, 6.5Hz, pyridine H-4 or H-5), 7.26 (1H, dt, J 8.5, 2.5 Hz, pyridine H-4 or H-5), 6.24 (2H, s, NCH2OCOCHN), 4, 42 (1H, tt, J 8.5, 3.5 Hz, cyclohexane H-1 or H-4), 3.45 (2H, q, J 7.0 Hz, OCH2CH3), 3.33 (1H, tt, J 10.0, 4.0 Hz, cyclohexane H-1 or H-4), 3.23-3.11 (2H, m, COCH(NH)CH2), 2.27-2.19 (1H, m, 1H of COCH(NH)CH2), 2.10-2.04 (4H, m, 4H of cyclohexane H-2, H-3, H-5, H-6), 1.98-1.80 (5H, m, 2H of cyclohexane H-2, H-3, H-5, H-6, 3H of COCH(NH)CH2CH2), 1.38-1.29 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.08 (3H, t, J 7.0 Hz, OCH2CH3); 19 F nmr(380MHz,D6-DMSO)δ -73.0(d,J 27.5Hz),-124.1(dd,J 27.0,9.5Hz);m / z:627[M+H] + .

[0200] I-18:1-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-yl)ethyldihydrogenphosphate [ka] 1 H nmr (400MHz, D6-DMSO) δ 11.45 (1H,s,NH), 8.55 (1H,s,pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 8.50 (1H,s,pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 8.30 (1H,s,pyrazole H-5, thiazole H-5, pyrazole H -3 or H-5), 8.13 (1H,s Pyrazole H-5, Thiazole H-5, Pyrazole H-3 or H-5), 8.06 (1H,td,J 9.5,6.5Hz, Pyridine H-4 or H-5), 7.24 (1H,dt,J 9.0,2.5Hz, Pyridine H-4 or H-5), 6.28-6.21 (1H,m,NCH(CH3)O), 4.31 (1H,br t,J 11.5Hz, Cyclohexane H-1 or H-4), 3.46 (2H,q,J 7.0Hz, OCH2CH3), 3.30 (1H,br t,J 10.5Hz, cyclohexane H-1 or H-4), 2.10-2.03 (4H, m, 4H of cyclohexane H-2, H-3, H-5, H-6), 1.88-1.78 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.77 (3H, d, J 6.0Hz, NCH(CH3)O), 1.38-1.29 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.08 (3H, t, J 7.0Hz, OCH2CH3); 19 F nmr(380MHz,D6-DMSO)δ -72.8,-124.2; 32 P nmr(380MHz,D6-DMSO)δ -3.3;m / z:624[M+H] + (Measured value [M+H]) + ,624.1610,C 25 H 28 F2N7O6PS is [M+H] + (Requires 624.1600).

[0201] I-19: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methylglycinate hydrogen chloride [ka] 1H nmr (400MHz, D6-DMSO)δ 11.47 (1H,s,NH), 8.67 (1H,s,1H of pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 8.52 (1H,s,1H of pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 8.37 (1H,s,1H of pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 8.34 (2H,br s,NH2), 8.23 ​​(1H,s,1H of pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 8.09 (1H,td,J 9.5,6.5Hz, pyridine H-4 or H-5), 7.27 (1H,dt,J 8.5, 2.5 Hz, pyridine H-4 or H-5), 6.25 (2H, s, NCH2O or COCH2NH2), 4.33 (1H, tt, J 11.5, 3.5 Hz, cyclohexane H-1 or H-4), 3.89 (2H, s, NCH2O or COCH2NH2), 3.47 (2H, q, J 7.0 Hz, OCH2CH3), 3.34 (1H, tt, J 11.0, 3.5 Hz, cyclohexane H-1 or H-4), 2.12-2.04 (4H, m, 4H of cyclohexane H-2, H-3, H-5, H-6), 1.91-1.80 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.41-1.29 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.10 (3H, t, J 7.0 Hz, OCH2CH3); 19 F nmr(380MHz,D6-DMSO)δ -72.9,-124.1;m / z:587[M+H] + (Measured value [M+H]) + ,587.1996,C 26 H 28 F2N8O4S is [M+H] + (Requires 587.1995).

[0202] I-20: Sodium 1-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)ethyl phosphate [ka] 1 H nmr(400MHz,D2O)δ 8.05 (1H,s,pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 7.86 (1H,s,pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 7.55 (1H,s,pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 7.52 (1H,s pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 7.37 (1H,m,pyridine H-4 or H-5), 6.59 (1H,m,pyridine H-4 or H-5), 6.00 (1H,t,J 7.5Hz,NCH(CH3)O), 3.94 (1H,m,cyclohexane H-1 or H-4), 3.56 (2H,q,J 7.0Hz, OCH2CH3), 3.43 (1H, m, cyclohexane H-1 or H-4), 2.16-2.08 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 2.07-2.00 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.69 (3H, d, J 6.0Hz, NCH(CH3)O), 1.68-1.60 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.36-1.25 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.10 (3H, t, J 7.0Hz, OCH2CH3); 19 F nmr(380MHz,D2O)δ -72.8,-124.8; 32 P nmr(380MHz,D2O)δ 1.2;m / z:624[M+H] + .

[0203] I-21: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl(S)-2-amino-3,3-dimethylbutanoate hydrogen chloride [ka] 1H nmr (400MHz, D6-DMSO)δ 11.47 (1H,s,NH), 8.68 (1H,s, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5 1H), 8.52 (1H,s, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5 1H), 8.43 (2H,br s,NH2), 8.37 (1H,s, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5 1H), 8.24 (1H,s, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5 1H), 8.09 (1H,td,J 9.5,6.5Hz, pyridine H-4 or H-5), 7.26 (1H,br d,J 8.5Hz, pyridine H-4 or H-5), 6.34, 6.24 (2H, 2d AB system, J 11.0Hz, NCH2O), 4.33 (1H, br t,J 11.5,Hz,Cyclohexane H-1 or H-4), 3.86(1H,s,COCH(tBu)NH2), 3.47(2H,q,J 7.0Hz,OCH2CH3), 3.38-3.30(1H,m,Cyclohexane H-1 or H-4), 2.12-2.05(4H,m,4H of cyclohexane H-2, H-3, H-5, H-6), 1.91-1.81(2H,m,2H of cyclohexane H-2, H-3, H-5, H-6), 1.40-1.30(2H,m,2H of cyclohexane H-2, H-3, H-5, H-6), 1.10(3H,t,J 7.0Hz,OCH2CH3), 0.93(9H,s,C(CH3)3); 19 F nmr(380MHz,D6-DMSO)δ -72.9,-124.1;m / z:643[M+H] + (Measured value [M+H]) + ,643.2607,C 30 H 36 F2N8O4S is [M+H] + (Requires 643.2621).

[0204] I-23: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl 2-amino-2-methylpropanoate hydrogen chloride [ka] 1 H nmr (400MHz, D6-DMSO) δ 8.68 (1H,s, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5 1H), 8.52 (2H,br s, 2×NH), 8.52 (1H,s, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5 1H), 8.37 (1H,s, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5 1H), 8.24 (1H, s, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5 1H), 8.09 (1H, td, J 9.0,6.5Hz, pyridine H-4 or H-5), 7.26(1H,dt,J 9.0,3.0Hz, pyridine H-4 or H-5), 6.26(2H,s,NCH2O), 4.33(1H,br t,J 12.0Hz, cyclohexane H-1 or H-4), 3.47(2H,q,J 7.0Hz, OCH2CH3), 3.34(1H,tt,J 10.5, 3.5 Hz, cyclohexane H-1 or H-4), 2.11-2.04 (4H, m, 4H of cyclohexane H-2, H-3, H-5, H-6), 1.91-1.80 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.43 (6H, s, C(CH3)2), 1.41-1.30 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.10 (3H, t, J 7.0 Hz, OCH2CH3); 19 F nmr(380MHz,D6-DMSO)δ -72.9,-124.1;m / z:615[M+H] + (Measured value [M+H]) + ,615.2343,C 28 H 32 F2N8O4S is [M+H] +(Requires 615.2309).

[0205] I-24:4-((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-yl)methoxy)-4-oxobutanoic acid [ka] 1 H nmr (400MHz, CDCl3)δ 11.71 (1H,s,NH), 8.48 (1H,s,pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5 1H), 8.29 (1H,s,pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5 1H), 8.14 (1H,s,pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5 1H), 8.06 (1H,s,pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5 1H), 7.63 (1H,td,J 9.0,6.5Hz,pyridine H-4 or H-5), 6.88 (1H,ddd,J 8.5, 3.5, 2.5 Hz, pyridine H-4 or H-5), 6.11 (2H, s, OCH2O), 4.26 (1H, tt, J 11.5, 4.0 Hz, cyclohexane H-1 or H-4), 3.56 (2H, q, J 7.0 Hz, OCH2CH3), 3.37 (1H, tt, J 10.5, 4.0 Hz, cyclohexane H-1 or H-4), 2.69 (4H, br s,COCH2CH2CO),2.32-2.2.18(4H,m,4H of cyclohexane H-2,H-3,H-5,H-6),1.94-1.83(2H,m,2H of cyclohexane H-2,H-3,H-5,H-6),1.52-1.42(2H,m,2H of cyclohexane H-2,H-3,H-5,H-6),1.22(3H,t,J 7.0Hz,OCH2CH3); 13C nmr(100MHz,CDCl3)δ 175.8,171.6,159.8,158.2,157.5(d,J 237.5Hz),153.4(dd,J 260.5,4.5Hz),150.1,139.7(d,J 5.0Hz),138.7(t,J 14.5Hz),133.0(d,J 8.5Hz),130.4(d,J 5.0Hz),129.9(dd,J 22.5,9.0Hz),122.0,121.8,119.4,118.6,107.6(dd,J 40.5,5.5Hz ),76.4,72.4,63.7,61.5,31.0,30.9,28.7,28.5,15.7; 19 F nmr(380MHz,CDCl3)δ -72.5 dd,J 27.5,9.5Hz),-124.4(ddd,J 28.5,9.5,2.5Hz);m / z:630[M+H] + (Measured value [M+H]) + ,630.1927,C 28 H 29 F2N7O6S is [M+H] + (Requires 630.1941).

[0206] I-28: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl 2-morpholinoacetate [ka] 1H nmr (400MHz, CDCl3)δ 8.50 (1H,s, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5 1H), 8.31 (1H,s, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5 1H), 8.17 (1H,s, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5 1H), 8.06 (1H,s, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5 1H), 7.65 (1H,td,J 9.0,6.0Hz, pyridine H-4 or H-5), 6.89 (1H,ddd,J 8.5, 3.0, 2.5 Hz, pyridine H-4 or H-5), 6.13 (2H, s, NCH2O), 4.27 (1H, tt, J 11.5, 3.5 Hz, cyclohexane H-1 or H-4), 3.73, 3.72 (4H, 2d AB system, J 4.5 Hz, morpholine 4H), 3.56 (2H, q, J 7.0 Hz, OCH2CH3), 3.37 (1H, tt, J 10.5, 4.0 Hz, cyclohexane H-1 or H-4), 3.29 (2H, s, COCH2N), 2.57, 2.56 (4H, 2d AB system, JHz, morpholine (4H), 2.32-2.26 (2H, m, cyclohexane H-2, H-3, H-5, H-6 (2H)), 2.26-2.18 (2H, m, cyclohexane H-2, H-3, H-5, H-6 (2H)), 1.94-1.84 (2H, m, cyclohexane H-2, H-3, H-5, H-6 (2H)), 1.52-1.42 (2H, m, cyclohexane H-2, H-3, H-5, H-6 (2H)), 1.22 (3H, t, J 7.0Hz, OCH2CH3); 19 F nmr(380MHz,CDCl3)δ -72.6(ddd,J 27.0,7.0,2.5Hz),-124.4((ddd,J 27.0,9.5,2.5Hz);m / z:657[M+H] + (Measured value [M+H]) + ,657.2432,C 30 H 34 F2N8O5S is [M+H] + (Requires 657.2414).

[0207] I-29: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl L-valinate [ka] 1 H nmr (400MHz, CDCl3)δ 11.72 (1H,s,NH), 8.49 (1H,s,1H of pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 8.31 (1H,s,1H of pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 8.16 (1H,s,1H of pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 8.05 (1H,s,1H of pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5), 7.65 (1H,td,J 9.0,6.5Hz,pyridine H-4 or H-5), 6.88 (1H,dt,J 8.5, 3.0 Hz, pyridine H-4 or H-5), 6.14, 6.10 (2H, 2d AB system, J 10.5 Hz, NCH2O), 4.26 (1H, tt, J 11.5, 4.0 Hz, cyclohexane H-1 or H-4), 3.45 (2H, q, J 7.0Hz, OCH2CH3), 3.40-3.32 (2H, m, cyclohexane H-1 or H-4, COCHNH2), 2.33-2.25 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 2.23-2.17 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 2.05-2.01 (1H, m, CHCH(CH3)2), 1.94-1.83 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.51-1.41 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.22 (3H, t, J 7.0Hz, OCH2CH3), 0.91 (3H, d, J 7.0Hz, CH(CH3)2 (1×CH3), 0.82(3H,d,J 6.5Hz, CH(CH3)2 (1×CH3); 19 F nmr(380MHz,CDCl3)δ -72.7,-124.4;m / z:629[M+H] +(Measured value [M+H]) + ,629.2474,C 29 H 34 F2N8O4S is [M+H] + (Requires 629.2465).

[0208] I-30: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl L-valinatebenzenesulfonic acid [ka] 1 H nmr (400MHz, D6-DMSO) δ 11.47 (1H,s,NH), 8.68 (1H,s,pyrazole H-5, thiazole H-5, pyrazole H-3 or H- 5(1H), 8.53(1H,s,pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5(1H)), 8.37(1H,s,pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5(1H)), 8.27(2H,br s,NH2), 8.24(1H,s,pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5(1H)), 8.09(1H,td,J 9.5,6.5Hz,pyridine H-4 or H-5), 7.69-7.56(2H,m,C6H5SO3H(2H)), 7.32-7.24(4H,m,C6H5SO3H(3H)(pyridine H-4 or H-5)), 6.34,6.25(2H,2d AB system,J 11.0Hz, NCH2O), 4.33 (1H, tt, J 11.5, 3.5Hz, cyclohexane H-1 or H-4), 4.03 (1H, d, J 4.5Hz, COCHNH2), 3.47 (2H, q, J 7.0Hz, OCH2CH3), 3.34 (1H, tt, J 10.5, 4.0 Hz, cyclohexane H-1 or H-4), 2.14-2.06 (5H, m, CHCH(CH3)2, 4H of cyclohexane H-2, H-3, H-5, H-6), 1.90-1.80 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.41-1.30 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.10 (3H, t, J 7.0 Hz, OCH2CH3), 0.89 (3H, d, J 6.5 Hz, 1×CH3 of CH(CH3)2), 0.86 (3H, d, J 7.0 Hz, 1×CH3 of CH(CH3)2); 19 F nmr(380MHz,D6-DMSO)δ -72.6,-124.5;m / z:629[M+H] + .

[0209] I-31: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl L-valinate methanesulfonate [ka] 1H nmr (400MHz, D6-DMSO)δ 8.68 (1H,s, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5 1H), 8.53 (1H,s, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5 1H), 8.37 (1H,s, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5 1H), 8.34 (2H,br s, NH2), 8.24 (1H,s, pyrazole H-5, thiazole H-5, pyrazole H-3 or H-5 1H), 8.09 (1H,dt,J 9.0,6.5Hz, pyridine H-4 or H-5), 7.26 (1H,ddd,J 9.0,3.0,2.5Hz, pyridine H-4 or H-5), 6.34,6.25 (2H,2d AB system,J 11.0Hz, NCH2O), 4.33 (1H,tt,J 11.5,3.0Hz, cyclohexane H-1 or H-4), 4.04 (1H,t,J 5.0Hz, COCHNH2), 3.47 (2H,q,J 7.0Hz, OCH2CH3), 3.38-3.30 (1H, m, cyclohexane H-1 or H-4), 2.31 (3H, s, CH3SO3H), 2.16-2.04 (5H, m, 4H of cyclohexane H-2, H-3, H-5, H-6, CHCH(CH3)2), 1.91-1.80 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.40-1.30 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.10 (3H, t, J 7.0 Hz,OCH2CH3),0.90(3H,d,J 7.0Hz,1×CH3 of CH(CH3)2),0.86(3H,d,J 7.0Hz,1×CH3 of CH(CH3)2); 19 F nmr(380MHz,D6-DMSO)δ -73.0,-124.1;m / z:629[M+H] + .

[0210] I-35: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl(S)-2-amino-3,3-dimethylbutanoate [ka] 1 H nmr (400MHz, CDCl3)δ 11.70 (1H,s,NH), 8.48 (1H,s,pyrazole H-5, thiazole H-5, pyrazole H-3, H-5 1H), 8.29 (1H,s,pyrazole H-5, thiazole H-5, pyrazole H-3, H-5 1H), 8.15 (1H,s,pyrazole H-5, thiazole H-5, pyrazole H-3, H-5 1H), 8.04 (1H,s,pyrazole H-5, thiazole H-5, pyrazole H-3, H-5 1H), 7.63 (1H,td,J 9.0,6.5Hz,pyridine H-4 or H-5), 6.86 (1H,ddd,J 9.0, 3.0, 2.5 Hz, pyridine H-4 or H-5), 6.13, 6.08 (2H, 2d AB system, J 10.5 Hz, NCH2CO), 4.25 (1H, tt, J 11.5, 4.0 Hz, cyclohexane H-1 or H-4), 3.54 (2H, q, J 7.0 Hz, OCH2CH3), 3.35 (1H, tt, J 11.0, 4.0 Hz, cyclohexane H-1 or H-4), 3.20 (1H, s, COCH(C(CH3)3)NH2), 2.32-2.24 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 2.24-2.16 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.93-1.82 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.50-1.40 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.20 (3H, t, J 7.0 Hz, OCH2CH3), 0.89 (9H, s, C(CH3)3); 19 F nmr(380MHz,CDCl3)δ -72.6,-124.4;m / z:643[M+H] + (Measured value [M+H]) + ,643.2595,C 30 H 37 F2N8O4S is [M+H] + (Requires 643.2621).

[0211] I-36: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl(S)-2-amino-3,3-dimethylbutanoatebenzenesulfonic acid [ka] 1 H nmr (400MHz, D6-DMSO) δ 11.74 (1H,s,NH), 8.68 (1H,s,pyrazole H-5, thiazole H-5, pyrazole H-3,H-5 of 1H), 8.53 (1H,s,pyrazole H-5, thiazole H-5, pyrazole H-3,H-5 of 1H), 8.37 (1H,s,pyrazole H-5, thiazole H-5, pyrazole H-3,H-5 of 1H), 8.29 (2H,m,2×NH2), 8.25 (1H,s,pyrazole H-5, thiazole H-5, pyrazole H-3,H-5 of 1H), 8.09 (1H,dt,J 9.5,6.5Hz, pyridine H-4 or H-5), 7.59-7.56 (2H,m,C6H5SO3H), 7.32-7.23 (4H,m,C6H5SO3H), pyridine H-4 or H-5), 6.34,6.26 (2H,2d AB system, J 11.0Hz, NCH2CO), 4.33 (tt,J 11.5,3.5Hz, cyclohexane H-1 or H-4), 3.91 (1H,br s,COCH(C(CH3)3)NH2), 3.47 (2H,q,J 7.0Hz, OCH2CH3), 3.34 (1H,tt,J 10.5, 3.5 Hz, cyclohexane H-1 or H-4), 2.12-2.05 (4H, m, 4H of cyclohexane H-2, H-3, H-5, H-6), 1.92-1.80 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.41-1.30 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.10 (3H, t, J 7.0 Hz, OCH2CH3), 0.93 (9H, s, C(CH3)3); 13 C nmr(100MHz,D6-DMSO)δ 168.5,160.2,157.5(d,J 234.0Hz),157.5,153.5(d,J 258.0Hz),149.4,148.9,139.6(d,J 7.5Hz),138.1(d,J 14.5Hz),132.6(d,J 9.0Hz),132.4(d,J 3.0Hz),128.7,128.0,125.9,124.4,121.4,120.3,117.9,76.0,73.7,63.0,60.8,33.7,30.9(2C),26.4,16.1; 19 F nmr(380MHz,D6-DMSO)δ -72.9,-124.1;m / z:643[M+H] + .

[0212] I-37: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl4-(morpholinomethyl)benzoate [ka] 1H nmr (400MHz, CDCl3)δ 11.73 (1H,s,NH), 8.50 (1H,s,1H of pyrazole H-5, thiazole H-5, pyrazole H-3,H-5), 8.42 (1H,s,1H of pyrazole H-5, thiazole H-5, pyrazole H-3,H-5), 8.18 (1H,s,1H of pyrazole H-5, thiazole H-5, pyrazole H-3,H-5), 8.06 (1H,1H of pyrazole H-5, thiazole H-5, pyrazole H-3,H-5), 8.02 (2H,d,J 8.0Hz,2H of C6H4), 7.64 (1H,dt,J 9.0,6.5Hz,pyridine H-4 or H-5), 7.42 (1H,d,J 8.0Hz, C6H4 (2H), 6.85 (1H, m, pyridine H-4 or H-5), 6.34 (2H, s, NCH2CO), 4.27 (1H, tdd, J 11.5, 4.0, 3.5Hz, cyclohexane H-1 or H-4), 3.70, 3.69 (4H, 2d AB system, J 4.5Hz, morpholine (4H)), 3.56 (2H, q, J 7.0Hz, OCH2CH3), 3.54 (2H, s, C6H4CH2N), 3.37 (1H, tt, J 10.5, 4.0Hz, cyclohexane H-1 or H-4), 2.42 (4H, br s, morpholine (4H), 2.32-2.26 (2H, m, cyclohexane H-2, H-3, H-5, H-6 (2H)), 2.26-2.18 (2H, m, cyclohexane H-2, H-3, H-5, H-6 (2H)), 1.94-1.84 (2H, m, cyclohexane H-2, H-3, H-5, H-6 (2H)), 1.52-1.42 (2H, m, cyclohexane H-2, H-3, H-5, H-6 (2H)), 1.22 (3H, t, J 7.0Hz, OCH2CH3); 19 F nmr(380MHz,CDCl3)δ -72.5,-124.4;m / z:733[M+H] + .

[0213] I-39:(1R,2R)-2-(((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methoxy)carbonyl)cyclohexane-1-carboxylic acid [ka] 1 H nmr (400MHz, D6-DMSO)δ 12.25 (1H, br s, OH), 11.47 (1H, s, NH), 8.57 (1H, s, pyrazole H-5, thiazole H-5, pyrazole H-3, H-5 of 1H), 8.52 (1H, s, pyrazole H-5, thiazole H-5, pyrazole H-3, H-5 of 1H), 8.34 (1H, pyrazole H-5, thiazole H-5, pyrazole H-3, H-5 of 1H), 8.19 (1H, s, pyrazole H-5, thiazole H-5, pyrazole H-3, H-5 of 1H), 8.08 (1H, dt, J 9.0, 6.5Hz, pyridine H-4 or H-5), 7.27 (1H, dt, J 8.5, 2.5 Hz, pyridine H-4 or H-5), 6.13, 6.05 (2H, 2d AB system, J 11.0 Hz, NCH2O), 4.33 (1H, tt, J 11.5, 3.5 Hz, cyclohexane H-1 or H-4), 3.47 (2H, q, J 7.0 Hz, OCH2CH3), 3.35 (1H, tt, J 11.0,3.5Hz, cyclohexane H-1 or H-4), 2.78-2.40 (1H,m, cyclohexanedicarboxylic acid H-1 or H-2), 2.12-2.04 (4H,m, 4H of cyclohexane H-2, H-3, H-5, H-6), 1.97-1.82 (1H,m, 1H of cyclohexanedicarboxylic acid H-1 or H-2), 1.90-1.81 (4H,m, cyclohexane H- 2H of 2,H-3,H-5,H-6, cyclohexanedicarboxylic acid H-3,H-4,H-5,H-6), 1.65(2H,br s, cyclohexanedicarboxylic acid H-3,H-4,H-5,H-6), 1.39-1.30(2H,m, cyclohexane H-2,H-3,H-5,H-6), 1.27-1.17(4H,m, cyclohexanedicarboxylic acid H-3,H-4,H-5,H-6), 1.10(3H,t,J 7.0Hz,OCH2CH3); 19 F nmr(380MHz,D6-DMSO)δ -72.8,-124.2;m / z:684[M+H] + (Measured value [M+H]) +,684.2416,C 32 H 35 F2N7O6S is [M+H] + (Requires 684.2410).

[0214] I-40: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl(S)-2-amino-3,3-dimethylbutanoate methanesulfonate [ka] 1 H nmr (400MHz, D6-DMSO)δ 12.47 (1H, br s, NH), 8.68 (1H, s, pyrazole H-5, thiazole H-5, pyrazole H-3, H-5 1H), 8.53 (1H, s, pyrazole H-5, thiazole H-5, pyrazole H-3, H-5 1H), 8.37 (1H, pyrazole H-5, thiazole H-5, pyrazole H-3, H-5 1H), 8.30 (2H, br s, NH2), 8.25 (1H, s, pyrazole H-5, thiazole H-5, pyrazole H-3, H-5 1H), 8.09 (1H, dt, J 9.5, 6.5Hz, pyridine H-4 or H-5), 7.27 (1H, dt, J 8.5, 2.5 Hz, pyridine H-4 or H-5), 6.34, 6.26 (2H, 2d AB system, J 11.0 Hz, NCH2O), 4.33 (1H, tt, J 11.5, 3.5 Hz, cyclohexane H-1 or H-4 1H), 3.90 (1H, d, J 4.5 Hz, COCH(C(CH3)3)NH2), 3.47 (2H, q, J 7.0Hz, OCH2CH3), 3.39-3.31 (1H, m, cyclohexane H-1 or H-4), 2.30 (3H, s, CH3SO3H), 2.12-2.04 (4H, m, 4H of cyclohexane H-2, H-3, H-5, H-6), 1.90-1.80 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.40-1.30 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.10 (3H, t, J 7.0Hz, OCH2CH3), 0.93 (9H, s, C(CH3)3); 13 C nmr(100MHz,D6-DMSO)δ 168.5,160.2,157.6,157.5(d,J 236.0Hz),155.7(dd,J 260.0,4.5Hz),149.4,139.5(d,J 6.5Hz),138.2(t,J 14.0Hz),132.6(d,J 8.5Hz),132.4,124.4,121.4,120.3,117.9,76.0,73.7,65.4,63.0,60.8,33.7,30.9(2C),26.4,16.1; 19 F nmr(380MHz,D6-DMSO)δ -72.9,-124.0;m / z:643[M+H] + .

[0215] I-42:N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4S)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1-((2 S,3S,4R,5R,6S)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-yl)thiazole-4-carboxamide [ka] 1H nmr (400MHz, D6-DMSO) δ 11.47 (1H,s,NH), 8.66 (1H,s,1H of pyrazole H-5, thiazole H-5, pyrazole H-3,H-5), 8.53 (1H,s,1H of pyrazole H-5, thiazole H-5, pyrazole H-3,H-5), 8.32 (1H,s,1H of pyrazole H-5, thiazole H-5, pyrazole H-3,H-5), 8.14 (1H,s,1H of pyrazole H-5, thiazole H-5, pyrazole H-3,H-5), 8.08 (1H,td,J 9.5,6.5Hz, pyridine H-4 or H-5), 7.26 (1H,dt,J 8.5,2.5Hz, pyridine H-4 or H-5), 5.30 (1H,d,J 6.0Hz,OH-2),5.23-5.21(2H,m,H-1,OH-3),5.09(1H,d,J 5.5Hz,OH-4),4.61(1H,t,J 5.5Hz,OH-6),4.33(1H,br t,J 11.5Hz,cHexH-1 or H-4),3.79(1H,td,J 9.0,6.0Hz,H-2),3.70(1H,dd,J 11.0,5.5Hz,1×H-6),3.47(2H,q,J 7.0Hz, OCH2CH3), 3.45-3.32 (3H, m, cHexH-1 or H-4, H-3, 1×H-6), 3.24-3.21 (1H, m, H-4), 2.12-2.04 (4H of 4H, m, cHexH-2, H-3, H-5, H-6), 1.91-1.81 (2H of 1H, m, cHexH-2, H-3, H-5, H-6), 1.40-1.31 (2H of 2H, m, cHexH-2, H-3, H-5, H-6), 1.10 (3H, t, J 7.0Hz, OCH2CH3); 19 F nmr(380MHz,D6-DMSO)δ -72.8,-124.2;m / z:662[M+H] + (Measured value [M+H]) + ,662.2219,C 29 H 33 F2N7O7S is [M+H] + (Requires 662.2203).

[0216] I-43:N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4R)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1-((2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-yl)thiazole-4-carboxamide [ka] 1 H nmr (400MHz, D6-DMSO)δ 11.49 (1H,s,NH), 8.59 (1H,s, pyrazole H-5, thiazole H-5, pyrazole H-3,H-5 1H), 8.53 (1H,s, pyrazole H-5, thiazole H-5, pyrazole H-3,H-5 1H), 8.33 (1H,s, pyrazole H-5, thiazole H-5, pyrazole H-3,H-5 1H), 8.17 (1H,s, pyrazole H-5, thiazole H-5, pyrazole H-3,H-5 1H), 8.09 (1H,td,J 9.5,6.0Hz, pyridine H-4 or H-5), 7.28 (1H,dt,J 8.5,2.5Hz, pyridine H-4 or H-5), 5.70 (1H,d,J 4.0Hz,H-1),5.15(1H,br s,1×OH),4.93(2H,br m,2×OH),4.54(1H,br s,1×OH),4.39(1H,t,J 3.5Hz,H-2),4.33(1H,br t,J 11.5Hz,cHexH-1 or H-4),3.91(1H,dd,J 7.0,3.0Hz,H-3),3.63(1H,d,J 10.0Hz,1×H-6),3.58-3.52(2H,m,H-4,1×H-6),3.47(2H,q,J 7.0Hz, OCH2CH3), 3.45-3.42 (1H, m, H-5), 3.35 (1H, m, cHexH-1 or H-4), 2.12-2.04 (4H of 4H, m, cHexH-2, H-3, H-5, H-6), 1.92-1.81 (2H of 2H, m, cHexH-2, H-3, H-5, H-6), 1.40-1.31 (2H of 2H, m, cHexH-2, H-3, H-5, H-6), 1.10 (3H, t, J 7.0Hz, OCH2CH3); 19F nmr(380MHz,D6-DMSO)δ -72.7,-124.2;m / z:662[M+H] + (Measured value [M+H]) + ,662.2195,C 29 H 33 F2N7O7S is [M+H] + (Requires 662.2203).

[0217] I-49:1-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)ethylhydrogenphosphate tris salt [ka] 1 H nmr (400MHz, D6-DMSO) δ 11.46 (1H,s,NH), 8.51 (1H,s,pyrazole H-5,thiazole H-5,pyrazole H-3,H-5 of 1H), 8.49 (1H,s,pyrazole H-5,thiazole H-5,pyrazole H- 3,H-5 (1H), 8.28 (1H,s,pyrazole H-5, thiazole H-5, pyrazole H-3,H-5 (1H)), 8.07 (1H,s,pyrazole H-5, thiazole H-5, pyrazole H-3,H-5 (1H)), 8.06 (1H,dt,J 10.0,6.5Hz,pyridine H-4 or H-5), 7.28 (1H,dt,J 8.5,2.5Hz,pyridine H-4 or H-5), 6.12 (1H,dq,J 9.0,6.0Hz,NCH(CH3)OP), 4.32 (1H,br t,J 11.5Hz,cyclohexane H-1 or H-4), 3.47 (2H,q,J 7.0Hz, OCH2CH3), 3.44(6H,s,C(CH2OH)3), 3.35(1H,tt,J 10.5,3.5Hz,cyclohexane H-1 or H-4), 2.12-2.05(4H,m,4H of cyclohexane H-2, H-3, H-5, H-6), 1.91-1.81(2H,m,2H of cyclohexane H-2, H-3, H-5, H-6), 1.66(3H,d,J 6.0Hz,NCH(CH3)OP), 1.40-1.30(2H,m,2H of cyclohexane H-2, H-3, H-5, H-6), 1.10(3H,t,J 7.0Hz, OCH2CH3); 32 P nmr(380MHz,D6-DMSO)δ 0.2; 19 F nmr(380MHz,D6-DMSO)δ -72.6,-124.4;m / z:624[M+H] + .

[0218] I-50: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methylglycinatebenzenesulfonate [ka] 1H nmr (400MHz, D6-DMSO)δ 11.47 (1H, s, NH), 8.67 (1H, s, pyrazole H-5, thiazole H-5, pyrazole H-3, H-5 of 1H), 8.53 (1H, s, pyrazole H-5, thiazole H-5, pyrazole H-3, H-5 of 1H), 8.37 (1H, s, pyrazole H-5, thiazole H-5, pyrazole H-3, H-5 of 1H), 8.24 (1H, s, pyrazole H-5, thiazole H-5, pyrazole H-3, H-5 of 1H), 8.23 ​​(2H, br s, NH2), 8.09 (1H, dt, J 9.5,6.5Hz, pyridine H-4 or H-5), 7.59-7.56 (2H,m,C6H5SO3H), 7.32-7.25 (3H,4H,m,C6H5SO3H, pyridine H-4 or H-5), 6.26 (2H,s,NCH2CO), 4.34 (1H,tt,J 11.5,3.5Hz, cyclohexane H-1 or H-4), 3.92 (2H,br s,COCH2NH2), 3.47 (2H,q,J 7.0Hz, OCH2CH3), 3.39-3.33 (1H, m, cyclohexane H-1 or H-4), 2.12-2.05 (4H, m, 4H of cyclohexane H-2, H-3, H-5, H-6), 1.91-1.80 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.41-1.30 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.10 (3H, t, J 7.0Hz, OCH2CH3); 19 F nmr(380MHz,D6-DMSO)δ -73.0,-124.1;m / z:587[M+H] + .

[0219] I-56:4-((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methoxy)-4-oxobutanoate tris salt [ka] 1H nmr (400MHz, D2O)δ 7.52 (1H, s, pyrazole H-5, thiazole H-5, pyrazole H-3, H-5 1H), 7.49 (1H, s, pyrazole H-5, thiazole H-5, pyrazole H-3, H-5 1H), 7.16 (1H, s, pyrazole H-5, thiazole H-5, pyrazole H-3, H-5 1H), 7.13 (1H, s, pyrazole H-5, thiazole H-5, pyrazole H-3, H-5 1H), 7.13-7.07 (1H, m, pyridine H-4 or H-5), 6.24 (1H, br d,J 8.0Hz, pyridine H-4 or H-5), 5.69 (2H,s, NCH2O), 7.39 (1H,br t,J 11.5Hz, cyclohexane H-1 or H-4), 3.59 (6H,s, 3×CCH2OH), 3.55 (2H,q,J 7.0Hz, OCH2CH3), 3.37 (1H,br t,J 10.5Hz, cyclohexane H-1 or H-4), 2.54 (2H,t,J 6.5Hz, 2H of COCH2CH2CO), 2.39 (2H,t,J 6.5Hz, COCH2CH2CO (2H), 2.12-2.04 (2H, m, cyclohexane H-2, H-3, H-5, H-6 (2H)), 2.15-1.98 (2H, m, cyclohexane H-2, H-3, H-5, H-6 (2H)), 1.55-1.44 (2H, m, cyclohexane H-2, H-3, H-5, H-6 (2H)), 1.32-1.21 (2H, m, cyclohexane H-2, H-3, H-5, H-6 (2H)), 1.10 (3H, t, J 7.0Hz, OCH2CH3); 19 F nmr(380MHz,D2O)δ -73.4,-124.7;m / z:630[M+H] + .

[0220] I-68:N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1H-pyrazole-4-yl)thiazole-4-carboxamide citrate cocrystal [ka] 1H nmr (400MHz, D6-DMSO) δ 8.53 (1H, s, thiazole) H-5 or pyrazole H-5), 8.29 (3H,s, pyrazole H-3, H-5, thiazole H-5 or pyrazole H-5), 8.08 (1H,td, J 9.0, 6.0Hz, pyridine H-4 or H-5), 7.29 (1H,ddd, J 9.0, 3.0, 2.5Hz, pyridine H-4 or H-5), 5.14 (0.5H,br s, COH), 4.33 (1H,tt, J 11.5, 3.5Hz, cyclohexane H-1 or H-4), 3.47 (2H,q, J 7.0Hz, OCH2CH3), 3.35 (1H,m, cyclohexane H-1 or H-4), 2.74, 2.64 (3H,2d AB system, J 15.5Hz, 3×0.5 CCH2CO2H), 2.08 (4H, m, 4H of cyclohexane H-2, H-3, H-5, H-6), 1.85 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.35 (2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.10 (3H, t, J 7.0Hz, OCH2CH3); 19 F nmr(380MHz,D6-DMSO)δ -73.0,-124.2;m / z:500[M+H] + .

[0221] I-69: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyldihydrogenphosphate bis(tris(hydroxymethyl)aminomethane) salt [ka] 1H nmr(400MHz,D2O)δ 7.89(1H,s,thiazole H-5 or pyrazole H-5), 7.80(1H,s,thiazole H-5 or pyrazole H-5), 7.45(1H,s,pyrazole H-3 or H-5), 7.44(1H,s,pyrazole H-3 or H-5), 7.33(1H,m,pyridine H-4 or H-5), 6.53(1H,d,J 9.0Hz,pyridine H-4 or H-5), 5.51(1H,d,J 6.5Hz,NCH2OP), 3.93(1H,tt,J 12.0,3.0Hz,cyclohexane H-1 or H-4), 3.58(2H,q,J 7.0Hz, OCH2CH3), 3.57(12H, s, 2×H2NC(CH2OH)3), 3.45(1H, m, cyclohexane H-1 or H-4), 2.14(2H, br d, J 10.5Hz, 2H of cyclohexane H-2, H-3, H-5, H-6), 2.03(2H, br d, J 12.0Hz, cyclohexane H-2, H-3, H-5, H-6), 1.63(2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.32(2H, m, 2H of cyclohexane H-2, H-3, H-5, H-6), 1.11(3H, t, J 7.0Hz, OCH2CH3); 31 P nmr(162MHz,D2O)δ 1.05; 19 F nmr(380MHz,D2O)δ -72.8(d,26.0Hz),-124.7(dd,J 27.0,9.5Hz);m / z:610[M+H] + (Measured value [M+H]) + ,610.1432,C 24 H 26 F2N7O6PS is [M+H] + (Requires 610.1444).

[0222] I-70: Benzyl((S)-1-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole (4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)-4-methyl-1-oxopentan-2-yl)carbamate [ka] 1 H nmr (400MHz, CDCl3)δ 8.78 (1H,s, 1H of pyrazole H-3, H-5), 8.50 (1H,s, thiazole H-5 or pyrazole H-5), 8.35 (1H,s, 1H of pyrazole H-3, H-5), 8.14 (1H,s, thiazole H-5 or pyrazole H-5), 7.65 (1H,td,J 9.0,6.0Hz, pyridine H-4 or H-5), 7.35-7.30 (5H,m, C6H5), 6.90 (1H,ddd,J 9.0,3.0,2.5Hz, pyridine H-4 or H-5), 5.66 (1H,m, NCHCO), 5.50 (1H,d,J 9.0Hz, NH), 5.14, 5.11 (2H,2d AB system,J 12.5Hz, OCH2C6H5), 4.27 (1H, tt, J 11.5, 4.0Hz, cyclohexane H-1 or H-4), 3.56 (2H, q, J 7.0Hz, OCH2CH3), 3.37 (1H, tt, J 10.5, 4.0Hz, cyclohexane H-1 or H-4), 2.29 (2H, br d, J 12.0Hz, cyclohexane H-2, H-3, H-5, H-6 (2H), 2.22(2H,m, cyclohexane H-2, H-3, H-5, H-6 (2H)), 1.89(2H,m, cyclohexane H-2, H-3, H-5, H-6 (2H)), 1.82(2H,m,CHCH2CH(CH3)2), 1.65(1H,m,CHCH2CH(CH3)2), 1.47(2H,m, cyclohexane H-2, H-3, H-5, H-6 (2H)), 1.22(3H,t,J 7.0Hz, OCH2CH3), 1.07(2H,br d,J 5.5Hz, 1×CH(CH3)2), 0.96(3H,d,J 6.0Hz, 1×CH(CH3)2); 19 F nmr(380MHz,CDCl3)δ -72.5(d,J 27.5Hz),-124.4(dd,J 27.0,9.5Hz);m / z:769[M+Na] + ,747[M+H] + (Measured value [M+H]) + ,747.2885,C 37 H 40 F2N8O5S is [M+H] +(Requires 747.2883).

[0223] Example 19 The project objective is to evaluate several salts of compound I-18. Salts were prepared using 10 different bases (two charge ratios for NaOH and KOH). Suitable solvents include, but are not limited to, methanol, DMSO / acetone (1:4 or 4:1), ethyl acetate, THF / water (9:1), or combinations thereof. The salts were isolated by centrifugation and dried under vacuum. Optionally, the salts can be heated to dry and / or remove at least some of the residual solvent.

[0224] 1) Disodium salt was obtained by mixing 1 equivalent of I-18 with 2 equivalents of NaOH in a solvent at room temperature. 2) Dipotassium salt was obtained by mixing 1 equivalent of I-18 with 2 equivalents of KOH in a solvent at room temperature. 3) A magnesium salt was obtained by mixing equimolar amounts of I-18 and magnesium hydroxide in a solvent at room temperature. 4) A calcium salt was obtained by mixing equimolar amounts of I-18 and calcium hydroxide in a solvent at room temperature. 5) Ammonium salts were obtained by mixing equimolar amounts of I-18 and ammonium hydroxide in a solvent at room temperature. 6) Arginine salts were obtained by mixing equimolar amounts of I-18 and arginine in a solvent at room temperature. 7) Lysine salts were obtained by mixing equimolar amounts of I-18 and lysine in a solvent at room temperature. 8) Choline salts were obtained by mixing equimolar amounts of I-18 and choline in a solvent at room temperature. 9) Tris salt was obtained by mixing equimolar amounts of I-18 and tromethamine in a solvent at room temperature. 10) Meglumine salt was obtained by mixing equimolar amounts of I-18 and meglumine in a solvent at room temperature. 11) Monopotassium salt was obtained by mixing equimolar amounts of I-18 and KOH in a solvent at room temperature. 12) Monosodium salt was obtained by mixing equimolar amounts of I-18 and NaOH in a solvent at room temperature.

[0225] Total salt hits were characterized by XRPD, TGA, and DSC. Stoichiometric ratios were determined by 1H NMR or HPLC / IC. The characterization results for salt hits and free forms are listed in Table 5.

[0226] [Table 5]

[0227] Based on the above, potassium salt, arginine salt, choline salt, and Tris salt were selected for further evaluation.

[0228] [Table 6]

[0229] Hygroscopic evaluation To investigate the morphological stability of solids as a function of humidity, DVS isotherm plots of potassium, arginine, choline, and Tris salts were collected at 25°C from 0 to 95% RH. The DVS plot for potassium salt is shown in Figure 20. Water uptake was 0.42% at 70% RH and dramatically increased to 16.5% at 95% RH. The DVS plot for arginine salt is shown in Figure 21. Water uptake of 1.43% was observed at 80% RH, indicating that the arginine salt was slightly hygroscopic. The DVS plot for choline salt is shown in Figure 22. Water uptake was 3.66% at 70% RH and dramatically increased to 32.4% at 95% RH. The DVS plot for Tris salt is shown in Figure 23. Water uptake was 6.06% at 70% RH and dramatically increased to 39.5% at 95% RH.

[0230] Physical and chemical stability The physical and chemical stability of potassium salts, arginine salts, choline salts, and Tris salts was evaluated for one week under conditions of 25°C / 60%RH and 40°C / 75%RH. Each sample was placed in a 3 mL glass vial, sealed with Parafilm with several perforations, and maintained under the test conditions. After one week, the samples were subjected to XRPD and HPLC purity tests. All characterization data is summarized in Table 7.

[0231] [Table 7]

[0232] XRPD patterns showed no morphological changes observed in the arginine, choline, and Tris salts after storage under two conditions. For the potassium salt, no morphological changes were observed at 25°C / 60%RH, but morphological changes were observed at 40°C / 75%RH. A slight decrease in purity was observed in both the potassium and arginine salts after one week under both conditions. For the choline and Tris salts, no HPLC purity decrease was observed at 25°C / 60%RH, but a decrease in purity was observed at 40°C / 75%RH. A summary of impurities in the total salt hits is shown in Tables 8-11. The peak with a relative retention time of 1.17 corresponds to I-1, the parent compound of I-18 formed by hydrolysis. The decrease in purity of the I-18 salt is typically due to... This correlates with a corresponding increase in I-1 parental impurity levels.

[0233] [Table 8]

[0234] [Table 9]

[0235] [Table 10]

[0236] [Table 11]

[0237] Considering the many possible embodiments to which the principles of the disclosed invention may be applied, it should be recognized that the exemplary embodiments are merely preferred examples of the invention and should not be construed as limiting the scope of the invention. Rather, the scope of the invention is defined by the following claims. Accordingly, the inventors assert that the invention is contained within all of these claims and spirit.

Claims

1. A compound, which is given by formula 1 【Chemistry 1】 (In the formula, R is an aliphatic, acyl, heterocyclyl, carboxyl ester, amide, alkylphosphoamide or alkyl phosphate; or R is H, and the compound is a salt. A compound having the following properties.

2. The compound according to claim 1, wherein R is an alkyl, acyl, carboxyl ester, amide, non-aromatic heterocyclyl, alkylphosphoamide, or alkyl phosphate.

3. R is C １～４ Alkyl phosphate, C １～４ Alkyl phosphoramide, C １～６ Alkyl, C １～６ Acyl, -C(O)O-C １～６ Aliphatic, -C(O)N(R ｂ ) ２ or a five-membered or six-membered non-aromatic heterocycline; and Each R ｂ is independently H, unsubstituted C １～６ alkyl, -N(R ｇ ), ２ substituted C １～６ alkyl, carboxyl ester or 5- or 6-membered non-aromatic heterocyclyl, or two R ｂ together with the nitrogen to which they are attached form a C ｇ non-aromatic heterocyclyl moiety optionally intervened by one or two -O- or -N(R ３～６ ), where R ｇ is H or C １～４ alkyl, the compound according to claim 1 or 2.

4. R is a 5-membered or 6-membered non-aromatic heterocycline, OH, -OC(O)-R ａ , -N(R ｂ ) ２ , -OC(O)-R ｃ C, optionally substituted with carboxyl or a combination thereof １～６ It is alkyl; R ａ It is a 5-membered non-aromatic heterocycline, -CH ２ N(R) ｂ ) ２ aryl substituted with, carboxyl substituted with C ３～６ Cycloalkyl, C １～６ alkoxy, unsubstituted C １～６ Alkyl or N(R) ｂ ) ２ carboxyl, carboxyl ester, -OC １～６ Achil, -NHC(O)(NH ２ ) C １～６ Alkyl or -(OCH ２ CH ２ ) １～８ N(R) ｂ ) ２ C is replaced by one or more of the following. １～６ It is alkyl; and -OC(O)-R ｃ It is derived from amino acids, where -OC(O)-R ｃ The -OC(O)- portion corresponds to the acid portion of the amino acid, and R ｃ is -N(R ｂ ) ２ The compound according to claim 3, or comprising a nitrogen-containing non-aromatic heterocycline.

5. The compound according to claim 4, wherein the amino acid is a naturally occurring amino acid.

6. The aforementioned amino acids are glycine, valine, alanine, leucine, isoleucine, and methionine. The compound according to claim 4, selected from phenylalanine, tryptophan, tyrosine, serine, threonine, asparagine, glutamine, arginine, histidine, lysine, aspartic acid, glutamic acid, cysteine, or proline.

7. R is -C(O)O-C １～４ Alkyl, -C(O)O-C １～４ Alkyl-N(R) ｂ ) ２ , N(R ｂ ) ２ ,-NHC(O)C １～４ C is optionally substituted with alkyl or a combination thereof. １～６ Is it the acyl part? R is a five-membered or six-membered non-aromatic heterocycline moiety that is optionally substituted with hydroxyl, hydroxymethyl, or a combination thereof; R is -OC(OC)C １～４ Alkyl or N(R) ｂ ) ２ -C(O)O-C ​​is optionally substituted. １～６ It is alkyl; or R is C １～４ -C(O)O-C, optionally substituted with alkyl groups. ３～６ The compound according to claim 3, wherein it is a cycloalkyl compound.

8. The compound according to claim 1, wherein R is H, and the salt is a hydrochloride, citrate, hemicitrate, hemitartrate, tartrate, benzenesulfonate, mesylate, sodium salt, hemisuccinate, or succinate.

9. The compound according to claim 1, wherein R is an alkyl phosphate or a salt thereof.

10. The compound according to claim 9, which is an alkali metal salt, an alkaline earth metal salt, an ammonium salt, an amino acid salt, an amino sugar salt, or a Tris salt.

11. The compound according to claim 9 or 10, which is a monosal or disal.

12. The compound according to any one of claims 9 to 11, wherein the alkyl phosphate is a mono- or disodium salt, a mono- or dipotassium salt, a calcium salt, a magnesium salt, an arginine salt, a lysine salt, a mono- or nitris salt, an ammonium salt, a choline salt, or a meglumine salt.

13. I-2: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl dihydrogen phosphate; I-3: Di-tert-butyl((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl)phosphate; I-4: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methylphosphate disodium salt; I-5: N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1-methyl-1H-pyrazole-4-yl)thiazole-4-carboxamide; I-6: 2-(1-(acetyl-L-leucyl)-1H-pyrazole-4-yl)-N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)thiazole-4-carboxamide; I-7: 1-methylcyclopropyl 4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole (-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-carboxylate; I-8: 1-(isobutyryloxy)ethyl 4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-carboxylate; I-9: N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)-1H-pyrazole-4-yl)thiazole-4-carboxamide; I-10: 2-morpholinoethyl 4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-carboxylate; I-11: N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1H-pyrazole-4-yl)thiazole-4-carboxamide hemitartrate; I-12: N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1-(morpholine-4-carbonyl)-1H-pyrazole-4-yl)thiazole-4-carboxamide; I-13: N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1-((3-morpholinopropyl)carbamoyl)-1H-pyrazole-4-yl)thiazole-4-carboxamide; I-14: N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1-((3-(dimethylamino)propyl)carbamoyl)-1H-pyrazole-4-yl)thiazole-4-carboxamide; I-15: 3-morpholinopropyl 4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-carboxylate; I-16: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl L-valinate hydrochloride; I-17: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl L-proline hydrochloride; I-18: 1-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)ethyl dihydrogen phosphate; I-19: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methylglycinate hydrochloride; I-20: 1-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1- ((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)ethyl phosphate disodium salt; I-21: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl(S)-2-amino-3,3-dimethylbutanoate hydrochloride; I-22: 2-(1-acetyl-1H-pyrazole-4-yl)-N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)thiazole-4-carboxamide; I-23: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl 2-amino-2-methylpropanoate hydrochloride; I-24: 4-((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methoxy)-4-oxobutanoic acid; I-25: Methyl 4-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)-4-oxobutanoate; I-26: N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1-(2-morpholinoacetyl)-1H-pyrazole-4-yl)thiazole-4-carboxamide; I-27: N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1-(2-hydroxy-3-morpholinopropyl)-1H-pyrazole-4-yl)thiazole-4-carboxamide; I-28: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl 2-morpholinoacetate; I-29: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl L-valinate; I-30: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl L-valinate benzenesulfonate; I-31: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl L-valinate mesylate; I-32: 2-(4-methylpiperazine-1-yl)ethyl 4-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)-4-oxobutanoate; I-33:1-((4-(4-((3-(3,6-difluoropyridine-2-yl)-1 -((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl)4-methyl L-aspartate hydrochloride; I-34: Methyl N-(2-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)-2-oxoethyl)-N-methylglycinate; I-35: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl(S)-2-amino-3,3-dimethylbutanoate; I-36: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl(S)-2-amino-3,3-dimethylbutanoatebenzenesulfonate; I-37: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl-4-(morpholinomethyl)benzoate; I-38: 4-((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl)1-methyl L-aspartate hydrochloride; I-39: (1R,2R)-2-(((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methoxy)carbonyl)cyclohexane-1-carboxylic acid; I-40: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl(S)-2-amino-3,3-dimethylbutanoate mesylate; I-41: (S)-2-amino-4-((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methoxy)-4-oxobutanoate; I-42: N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4S)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1-((2S,3S,4R,5R,6S)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-yl)thiazole-4-carboxamide; I-43: N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4R)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1-((2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-yl)thiazole-4-carboxamide; I-44: tert-butyl(1-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)ethyl)hydrogen phosphate sodium acetate salt; I-45: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-(( 1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methylisopropyl carbonate; I-46: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyldi(((isopropoxycarbonyl)oxy)methyl)phosphate; I-47: 1-((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl)4-methyl L-aspartate; I-48: 1-((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl)4-methyl L-aspartate benzene sulfonate; I-49: 1-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)ethyl dihydrogen phosphate tris salt; I-50: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methylglycinate benzene sulfonate; I-51: 2-(4-methylpiperazine-1-yl)ethyl 4-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)-4-oxobutanoatebenzenesulfonate; I-52: 2-(4-methylpiperazine-1-yl)ethyl 4-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)-4-oxobutanoate succinate; I-53: (2R,3R)-2,3-diacetoxy-4-((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methoxy)-4-oxobutanoic acid; I-54: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methylacetate; I-55: 4-((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl)1-methyl L-aspartate benzene sulfonate; I-56: 4-((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methoxy)-4-oxobutanoate Tris salt; I-57: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl-4-((S)-2-amino-3-methylbutanamide)butanoate hydrochloride; I-58: N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1-(2-hydroxyethyl)-1H-pyrazole-4-yl)thiazole-4-carboxamide; I-59: 2-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)acetic acid; I-60: ((((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methoxy)(hydroxy)phosphoryl)oxy)methylisopropyl carbonate; I-61: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl-1-amino-3,6,9,12,15,18-hexaoxahenicosane-21-oate hydrochloride; I-62: Isopropyl(((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; I-63: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyldihydrogen phosphate tris salt; I-64: N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1H-pyrazole-4-yl)thiazole-4-carboxamide hydrochloride; I-65: N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1H-pyrazole-4-yl)thiazole-4-carboxamidebenzenesulfonate; I-66: N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1H-pyrazole-4-yl)thiazole-4-carboxamide tartrate; I-67: N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1H-pyrazole-4-yl)thiazole-4-carboxamide sodium salt; I-68: N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1H-pyrazole-4-yl)thiazole-4-carboxamide hemicitrate; I-69: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyldihydrogen phosphate ditris salt; I-70: Benzyl((S)-1-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)-4-methyl-1-oxopentan-2-yl)carbamate; I-71: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl L-prolineate; I-72: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-(( 1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methylglycinate; I-73: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl(R)-2-amino-3,3-dimethylbutanoate; I-74: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl 2-amino-2-methylpropanoate; I-75: 4-((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl)1-methyl L-aspartate; I-76: (S)-2-amino-4-((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methoxy)-4-oxobutanoic acid; I-77: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl-4-((S)-2-amino-3-methylbutanamide)butanoate; I-78: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl-1-amino-3,6,9,12,15,18-hexaoxahenicosane-21-oate; I-79: 2-(1-(acetyl-D-leucyl)-1H-pyrazole-4-yl)-N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)thiazole-4-carboxamide; I-80: 2-(1-(acetylleucyl)-1H-pyrazole-4-yl)-N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)thiazole-4-carboxamide; I-81: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl D-valinate; I-82: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methylvalinate; I-83: ​​(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl D-prolineate; I-84: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methylproline; I-85: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl 2-amino-3,3-dimethylbutanoate; I-86: (1S,2S)-2-(((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methoxy)carbonyl)cyclohexane-1-carboxylic acid; I-87: (1R,2S)-2-(((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methoxy)carbonyl)cyclohexane-1-carboxylic acid; I-88: (1S,2R)-2-(((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methoxy)carbonyl)cyclohexane-1-carboxylic acid; I-89: 2-(((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methoxy)carbonyl)cyclohexane-1-carboxylic acid; I-90: (R)-2-amino-4-((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methoxy)-4-oxobutanoic acid; I-91: 2-amino-4-((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methoxy)-4-oxobutanoic acid; I-92: 4-((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl)1-methyl D-aspartate; I-93: 4-((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl)1-methylaspartate; I-94: 1-((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl)4-methyl D-aspartate; I-95: 1-((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl)4-methylaspartate; I-96: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl-4-((R)-2-amino-3-methylbutanamide)butanoate; I-97: (4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methyl-4-(2-amino-3-methylbutanamide)butanoate; I-98: Isopropyl(((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4 -yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methoxy)(phenoxy)phosphoryl)-D-alaninate; I-99: Isopropyl (((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methoxy)(phenoxy)phosphoryl)alaninate; I-100: (2R,3S)-2,3-diacetoxy-4-((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methoxy)-4-oxobutanoic acid; I-101: (2S,3R)-2,3-diacetoxy-4-((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methoxy)-4-oxobutanoic acid; I-102: (2S,3S)-2,3-diacetoxy-4-((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methoxy)-4-oxobutanoic acid; I-103: 2,3-diacetoxy-4-((4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)methoxy)-4-oxobutanoic acid; I-104: N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1H-pyrazole-4-yl)thiazole-4-carboxamide phosphate; I-105: N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1H-pyrazole-4-yl)thiazole-4-carboxamide gentisinate; I-106: N-(3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)-2-(1H-pyrazole-4-yl)thiazole-4-carboxamide succinate; I-107: Sodium 1-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)ethyl hydrogen phosphate; I-108: Potassium 1-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)ethyl hydrogen phosphate; I-109: Potassium 1-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)ethyl phosphate; I-110: 1-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)ethyl dihydrogen phosphate arginine salt; I-111: 1-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)ethyldihydro Genphosphate choline salt; I-112: Ammonium 1-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)ethyl hydrogen phosphate; I-113: 1-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)ethyldihydrogenphosphate lysine salt; I-114: 1-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)ethyl dihydrogen phosphate meglumine salt; I-115: Magnesium 1-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)ethyl phosphate; or I-116: Calcium 1-(4-(4-((3-(3,6-difluoropyridine-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4-yl)carbamoyl)thiazole-2-yl)-1H-pyrazole-1-yl)ethyl phosphate A compound according to claim 1, selected from the following.

14. A composition comprising a compound according to any one of claims 1 to 13 and a pharmaceutically acceptable excipient.

15. Polymer carrier and formula I: 【Chemistry 2】 (In the formula, R is an aliphatic, acyl, heterocyclyl, carboxyl ester, amide, alkylphosphoamide, or alkyl phosphate.) A spray-drying composition containing a compound.

16. The spray-drying composition according to claim 15, comprising 1% to 50% w / w of the compound relative to the carrier.

17. The spray-drying composition according to claim 15 or 16, wherein the polymer is a cellulose derivative, a vinyl polymer, a lactide polymer, a sugar, or a combination thereof.

18. The spray-drying composition according to any one of claims 15 to 17, wherein it is amorphous.

19. A spray-drying composition according to any one of claims 15 to 18, having a glass transition temperature of 100°C to 120°C.

20. A method for producing a spray-dried composition, A carrier, a solvent, and Formula I 【Transformation 3】 (In the formula, R is an aliphatic, acyl, heterocyclyl, carboxyl ester, amide, alkylphosphoamide, or alkyl phosphate.) To form a mixture containing a compound by; The mixture is spray-dried to form a spray-dried formulation containing the compound and the carrier. A method that includes this.

21. A method comprising administering an effective amount of a compound according to any one of claims 1 to 13 or a composition according to any one of claims 14 to 19 to a subject in need thereof.

22. The method according to claim 21, which is a method for treating a disease or condition for which an IRAK inhibitor is indicated.

23. The method according to claim 22, wherein the disease is an autoimmune disease, an inflammatory disease, a cardiovascular disease, a neurodegenerative disease, an allergic disease, multiple organ failure, kidney disease, platelet aggregation, cancer, transplantation, sperm motility, red blood cell deficiency, graft rejection, lung injury, respiratory disease, ischemia, bacterial infection, viral infection, immunomodulatory disease, or a combination thereof.

24. The method according to claim 21, further comprising administering a second therapeutic agent.

25. The method according to claim 24, wherein the second therapeutic agent is an analgesic, an antibiotic, an anticoagulant, an antibody, an anti-inflammatory agent, an immunosuppressant, a guanylate cyclase-C agonist, an intestinal secretion promoter, an antiviral agent, an anticancer agent, an antifungal agent, or a combination thereof.

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