IRAK inhibitors for treating cytokine release-associated conditions associated with respiratory viral infections

Abstract

Disclosed herein are methods for treating and / or preventing a cytokine release-associated condition associated with infection by a respiratory virus, e.g., COVID-19 or influenza. In certain embodiments, the method may include administering a compound that inhibits interleukin receptor-associated kinase (IRAK) to a subject experiencing or at risk of developing said condition. In some embodiments, the compound may have a structure according to Formula IV or VII, or a salt, solvate, N-oxide, and / or prodrug thereof.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 241,973, filed September 8, 2021, which application is incorporated by reference in its entirety for all purposes. [Background technology]

[0002] background Initial reports suggest that COVID-19 is associated with severe illness requiring intensive care in approximately 5% of cases. The most documented reason for requiring intensive care is respiratory support. Approximately two-thirds of patients requiring intensive care have acute respiratory distress syndrome (ARDS), and a relatively high percentage of patients with ARDS (e.g., 35–50% of patients) die. ARDS appears to be the most common cause of death among patients infected with COVID-19 (see, e.g., Wang et al., JAMA. 2020:1585). Emerging evidence also suggests that acute kidney injury can be a serious complication of COVID-19 infection. Acute kidney injury has been reported in up to 25% of critically ill patients (Gabarre et al., Intensive Care Med. 2020, 46(7):1339–1348). In addition, COVID-19 patients have been reported to be at increased risk of thrombosis (Khan et al. J. Vasc. Surg. 2020, S0741-5214(20)31157-5 (Non-Patent Document 3)). Similar problems exist with other respiratory viruses.

[0003] High levels of proinflammatory cytokines have been reported in response to infections with several respiratory viruses. These cytokines, including interferons, interleukins, chemokines, colony-stimulating factors, and tumor necrosis factors, contribute to the symptoms of coronavirus infection. Excessive production of proinflammatory cytokines can lead to a "cytokine storm," during which inflammation spreads throughout the body via the circulation. One consequence of a cytokine storm is acute lung injury, which can progress to a more severe form called acute respiratory distress syndrome. Another consequence of a cytokine storm is the failure of multiple organs, including heart failure and acute kidney injury. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Wang et al. JAMA.2020:1585 [Non-patent document 2] Gabarre et al.Intensive Care Med.2020,46(7):1339-1348 [Non-patent document 3] Khan et al.J.Vasc.Surg.2020,S0741-5214(20)31157-5 Summary of the Invention

[0005] overview Disclosed herein are methods for treating and / or preventing cytokine release-associated conditions associated with respiratory viral infections. In some embodiments, the methods can include administering to a subject an effective amount of a compound that inhibits interleukin receptor-associated kinase (IRAK), e.g., a compound of Formulas IV-VII, or a salt, solvate, N-oxide, and / or prodrug thereof. Without wishing to be bound by any particular theory, the compounds are believed to quell the cytokine storm associated with some viral infections, thereby treating those patients. In any embodiment, the patient can have or be expected to develop acute respiratory distress syndrome (ARDS), pneumonia, or acute damage to one or more organs.

[0006] Although the present method is exemplified by influenza and COVID-19, the method can also be used to treat other influenza-related diseases, such as pneumonia, because some of the symptoms of pneumonia infections (e.g., bacterial pneumonia caused by Streptococcus pneumoniae) share the same underlying cause (e.g., cytokine storm in the lungs and / or kidneys). Additionally, the present method can also be used to treat other viral infections, including, but not limited to, Ebola virus (i.e., Zaire ebolavirus), dengue virus, human rhinovirus, respiratory syncytial virus, parainfluenza virus, adenovirus, paramyxovirus (i.e., the virus that causes measles), enterovirus, parechovirus, and the like, because some of the symptoms of respiratory viral infections share the same underlying cause (e.g., cytokine storm in the lungs and / or kidneys). In certain embodiments, patients can be infected with coronavirus, MERS, SARS, or other similar conditions. The method can also be used to treat ventilator-induced ARDS.

[0007] In some embodiments, the compound is a pyrazole compound and can have Formula IV, or a salt, prodrug, solvate, and / or N-oxide thereof. TIFF2024534919000002.tif42128 With respect to Formula IV, Het-1 is a 5-membered heteroaryl such as thiazolyl or furanyl, y is 1-2, and R C2 is H, aliphatic, heteroaliphatic, heterocycloaliphatic, aryl, amido, heterocyclyl, or araliphatic, and H can be alkyl, haloalkyl, or cycloalkyl, e.g., H or alkyl; each R C3 are independently H or aliphatic, and R C4 , R C5 , R C6 , and R C7 are each independently H, aliphatic, heteroaliphatic, alkoxy, heterocyclyl, aryl, araliphatic, -O-heterocyclyl, hydroxyl, haloalkyl, halogen, nitro, cyano, carboxyl, carboxyl ester, acyl, amido, amino, sulfonyl, sulfonamido, sulfanyl, or sulfinyl; R C8 and R C9 are each independently H, aliphatic, heteroaliphatic, aryl, heterocyclyl, sulfonyl, nitro, halogen, haloalkyl, carboxylic ester, cyano, or amino, e.g., H, halogen, haloalkyl, or alkyl; R C10 is H, aliphatic, alkoxy, heteroaliphatic, carboxylic ester, araliphatic, NO, CN, OH, haloalkyl, acyl, alkyl phosphate, or alkyl phosphonate, e.g., H, alkyl, alkyl phosphate, or alkyl phosphonate. In some embodiments, R C4 , R C6 , and R C7 Each of R is independently H, halo, alkyl, or haloalkyl, and may be H or F. Also, in certain embodiments, R C5 is H, halo, aliphatic, alkoxy, heterocyclyl, or -O-heterocyclyl, and R C5 can be H, F, CF, methoxy, —O—CHC(CHOH), morpholin-4-yl, 1-methylpiperidin-4-yl, or —O-(oxetan-3-yl).

[0008] In some embodiments, the compound has a structure according to Formula V or VI, or a salt, prodrug, solvate, and / or N-oxide thereof. TIFF2024534919000003.tif42128 Regarding Formulas V and VI, R C11 , R C12 , and R C14 Each of is independently H or aliphatic.

[0009] In an alternative embodiment, the compound is a pyrazole compound according to Formula VII, or a salt, prodrug, solvate, and / or N-oxide thereof. TIFF2024534919000004.tif55128 With respect to Formula VII, R can be H, aliphatic, acyl, heterocyclyl, carboxylic ester, amide, alkyl phosphoramidate, or alkyl phosphate. In some embodiments, R is not H, or alternatively, R is H, and the compound is a salt. In other embodiments, R is alkyl, acyl, carboxylic ester, amide, non-aromatic heterocyclyl, alkyl phosphoramidate, or alkyl phosphate. One of skill in the art will appreciate that a compound in which R is not H can act, for example, as a prodrug of a compound in which R is H when administered to a subject.

[0010] In any embodiment of the method, the subject may be infected with a respiratory virus but does not exhibit a cytokine release-associated state associated with infection by a respiratory virus, hi such embodiments, administering the compound substantially prevents the onset of the cytokine release-associated state.

[0011] In other embodiments, the subject is infected with a virus and exhibits at least one sign or symptom of a cytokine release-associated condition. The compound may be administered within 24 hours of the onset of the sign or symptom, and / or administering the compound may ameliorate the sign or symptom of the infection compared to the severity of the sign or symptom before administration of the compound, such as reducing the grade of the infection. Alternatively, the symptoms are substantially alleviated such that the subject no longer experiences symptoms associated with the infection. In some embodiments, the sign or symptom is fever, and may be a fever of 40°C or higher.

[0012] High levels of proinflammatory cytokines have been reported for several respiratory viruses, including COVID-19 and influenza. These cytokines, including interferons, interleukins, chemokines, colony-stimulating factors, and tumor necrosis factors, contribute to the symptoms of coronavirus infection. One consequence of the cytokine storm associated with COVID-19 and influenza infections is acute organ damage, which, in the case of lung damage, can progress to a more severe form called acute respiratory distress syndrome. Therefore, the present compounds can be administered to patients infected with COVID-19, influenza, and other respiratory viruses to block, ameliorate, or treat inflammation associated with the condition and its treatment.

[0013] In some embodiments, the compounds may be administered in combination with one or more other therapeutic agents that may target any of the symptoms of SARS-CoV-2 or COVID-19 infection. These agents include (a) inhibitors of SARS-CoV-2 cell entry, (b) inhibitors of SARS-CoV-2 replication, membrane fusion, and assembly, (c) immunosuppressive / immunomodulatory agents such as steroids, and (d) phytochemicals and natural products that target coronaviruses. If a patient has influenza, the compounds may be administered in combination with one or more other therapeutic agents that target influenza infection. This therapy may optionally be combined with plasma therapy.

[0014] In some instances, the methods may result in increased survival rates for virally infected patients, such as those with ARDS, acute kidney injury, or thrombosis.

[0015] The foregoing and other objects, features, and advantages of the present invention will become more apparent from the following detailed description. [Brief explanation of the drawings]

[0016] Certain aspects of some embodiments of the present invention can be best understood from the following detailed description when read in conjunction with the accompanying drawings. It is emphasized that, according to common practice, the various features of the drawings are not to scale. On the other hand, the dimensions of the various features have been arbitrarily increased or reduced for clarity. The following figures are included in the drawings:

[0017] [Figure 1] Tamoxifen-induced Shp1 deletion in hematopoietic cells results in ARDS-like disease in mice. An ARDS-like disease model was generated by crossing Shp1fl / fl with Shp1fl / fl RosaERT2-CRE / + mice. RosaERT2-CRE / + is expressed under a tamoxifen-inducible promoter. Administration of tamoxifen to Shp1fl / fl RosaERT2-CRE / + mice activates CRE recombinase, resulting in the deletion of Shp1 in hematopoietic cells. [Figure 2]The dose of Compound VII-49 (0.5 g / kg diet) was based on a previous dietary pharmacokinetic (PK) study. A) Mice were fed an AIN-76A rodent diet supplemented with Compound VII-49 (0.5 g / kg diet) for 5 days. The accumulation of Compound VII-1 (the active metabolite of Compound VII-49) (ng / mL) was measured from plasma harvests after dietary supplementation with Compound VII-49. B) Measurement of Compound VII-1 concentrations (area under the curve = AUC and Cmax) in plasma collected from mice fed Compound VII-49 at doses of 0.12 g / kg, 0.3 g / kg, and 0.6 g / kg. C) Body weight change over time in NZB / W F1 mice fed diets supplemented with vehicle, Compound VII-49 at 0.12 g / kg, or R509-Tris at 0.6 g / kg. Compound VII-1 is the active metabolite of the prodrug compound VII-49. [Figure 3] Evaluation of Compound VII-49 administered via diet in a Shp1fl / fl RosaERT2-Cre / + mouse model of pulmonary inflammation study design. Tamoxifen is administered on day 1. Tamoxifen is administered twice daily at 200 mg / kg / bid (400 mg / kg / day) for a total of 4 days. After 7.5 days of control diet, mice are fed a diet supplemented with Compound VII-49 at 0.5 g / kg diet for approximately 13 days. On day 21, mice were euthanized. [Figure 4] Treatment with compound VII-49 rescues Shp1fl / fl RosaERT2-Cre / + from lung inflammation, as seen in body weight change. Daily body weight change in Shp1fl / fl or Shp1fl / fl ERT2-cre mice fed either control diet or IRAKi diet (IRAKi diet contains an IRAK inhibitor). [Figure 5]Compound VII-49 treatment rescues Shp1fl / fl RosaERT2-Cre / + mice from lung inflammation, as measured by total cell counts, total white blood cell counts, % alveolar macrophages, and total myeloid cell counts. Changes in the numbers of cells, white blood cells, alveolar macrophages, and myeloid cells were measured in bronchoalveolar lavage in Shp1fl / fl or Shp1fl / fl ERT2-cre mice fed either a standard diet or an IRAKi diet. [Figure 6] Inhibition of IRAK1 / 4 by compound VII-49 rescues the development of "motheaten" lung disease. Changes in the number of cells, alveolar macrophages, and myeloid cells were measured in bronchoalveolar lavage in Shp1fl / fl or Shp1fl / fl ERT2-cre mice fed either control or test diets. Lungs from the mice are shown on the left. DETAILED DESCRIPTION OF THE INVENTION

[0018] Detailed Description I. Definition The following explanations of terms and methods are provided to better describe the present disclosure and to guide those skilled in the art in practicing the disclosure. The singular forms "a," "an," and "the" refer to one or more, unless the context clearly dictates otherwise. The term "or" refers to a single element of the stated alternative elements or a combination of two or more elements, unless the context clearly dictates otherwise. As used herein, "comprises" means "includes." Thus, "including A or B" means "including A, B, or A and B," without excluding any additional elements. All references cited herein, including patents and patent applications, are incorporated by reference.

[0019] Unless otherwise indicated, all numerical values ​​expressing properties such as amounts, molecular weights, proportions of ingredients, temperatures, times, and the like used in the specification or claims should be understood as being modified by the term "about." Thus, unless otherwise indicated, numerical parameters, implicitly or explicitly stated, are approximations that may depend on the desired properties and / or limits of detection sought under standard testing conditions / methods. Where directly and explicitly distinguishing an embodiment from the prior art discussed, the numerical values ​​of the embodiments are not approximations unless the word "about" is recited.

[0020] Unless otherwise explained, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below. The materials, methods, and examples are illustrative only and are not intended to be limiting.

[0021] When chemical structures are depicted or described, unless expressly stated otherwise, all carbons are considered to contain hydrogen, and therefore each carbon corresponds to a valence of 4. For example, in the structure on the left of the schematic below, there are 9 implied hydrogen atoms. The 9 hydrogen atoms are depicted in the structure on the right. TIFF2024534919000005.tif22128

[0022] In some cases, certain atoms within a structure are described in textual form as having a hydrogen or hydrogen atom, e.g., -CHCH-. It will be appreciated by those skilled in the art that the foregoing descriptive technique is common in the chemical arts to provide brevity and simplicity in describing organic structures.

[0023] When the group R is depicted as "floating" in the ring system, for example, the group In TIFF2024534919000006.tif14128, unless otherwise defined, the substituent R may be present on any atom of the fused bicyclic ring system so long as a stable structure is formed that complies with standard valence conditions, as understood by one of ordinary skill in the art. In the depicted example, the R group may be present on any atom of the 5- or 6-membered ring of the indolyl ring system, including heteroatoms, by replacing hydrogens that are explicitly recited, but Atoms carrying bonds with the symbol TIFF2024534919000007.tif5128 and bridging carbon atoms are excluded.

[0024] When there is more than one such depicted "floating" group, for example, In TIFF2024534919000008.tif18128, where two groups, i.e., R and a bond indicating attachment to the parent structure, are present, unless otherwise defined, it is assumed that each "floating" group may reside on any atom of the ring system and each may replace a drawn, implied, or explicitly defined hydrogen on the ring system, and that chemically stable compounds may be formed by such arrangements.

[0025] When the group R is depicted as being in a ring system containing saturated carbons, for example, In TIFF2024534919000009.tif11128, in this example, y can be two or more, and it is assumed that each R replaces a hydrogen currently depicted, implied, or explicitly defined on the ring, and two R can be present on the same carbon unless otherwise defined. A simple example is when R is a methyl group. The depicted structure can exist as a pair of dimethyls on the depicted ring carbons ("annular" carbons). In another example, two Rs on the same carbon containing the same carbon can form a ring, thus creating a spirocyclic ring ("spirocyclyl" group) structure. For example, the two Rs shown below can form a piperidine ring in a spirocyclic arrangement with cyclohexane as follows: TIFF2024534919000010.tif11128

[0026] Those skilled in the art will understand that definitions can be combined to further describe a particular compound. For example, hydroxyaliphatic refers to an aliphatic group substituted with a hydroxy (—OH) group, haloalkylaryl refers to an aryl group substituted with an alkyl group, where the alkyl group is also substituted with a halogen, and aryl is the base name of the substituent, so that the point of attachment to the parent structure is through the aryl moiety.

[0027] As used herein, for example, "substituted aryl C 1~8 The term "substituted" in the term "alkyl" refers to all subsequent modifiers, and substitution is 1~8 The alkyl group, "C 1~8 It may occur in the "alkyl" portion, the "aryl" portion, or both portions. Also by way of example, alkyl includes substituted cycloalkyl groups.

[0028] "Substituted," when used to modify a specified group or moiety, means that at least one, and possibly more than one, hydrogen atom of the specified group or moiety is independently replaced with the same or different substituent(s) as defined below. In certain embodiments, a group, moiety, or substituent may be substituted or unsubstituted unless expressly defined as either "unsubstituted" or "substituted." Thus, any of the groups specified herein may be unsubstituted or substituted. In certain embodiments, a substituent may or may not be expressly defined as substituted, but is still intended to be optionally substituted. For example, an "alkyl" or "pyrazolyl" moiety may be unsubstituted or substituted, but an "unsubstituted alkyl" or an "unsubstituted pyrazolyl" is not substituted.

[0029] "Substituents" or "substituent groups" to replace one or more hydrogen atoms on a saturated carbon atom of a specified group or moiety are defined as -R unless otherwise specified. 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 ), -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 , or -NR 70 C(NR 70 )N(R 80)2, where R 60 But C 1~10 Aliphatic, heteroaliphatic, or alicyclic, typically C 1~6 Aliphatic, more typically C 1~6 alkyl, and R 60 may be optionally substituted, and each R 70 independently at each occurrence, hydrogen or R 60 and each R 80 But for each occurrence, R 70 or alternatively, two R 80 groups, together with the nitrogen atom to which they are attached, optionally form a 3- to 7-membered heterocycloaliphatic ring system containing 1 to 4 of the same or different additional heteroatoms selected from O, N, and S, wherein N is optionally H or an R group such as a C1-C3 alkyl substituted group; 70 substitutions, and each M + is a counterion with a net single positive charge. + is calculated independently for each occurrence, e.g., K + , Na + , Li + Alkali metal ions such as + N(R 70 ) 4, protonated amino acid ions such as lysine ion or arginine ion, 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 divalent alkaline earth ions may be the ionized form of an inventive compound, and that other typical counterions, such as chloride, or a two-ionized compound may serve as the counterion of such divalent alkaline earth ion, or alternatively, a two-ionized compound may serve as the counterion of such divalent alkaline earth ion.) Specific examples include -N(R 80)2 includes -NH2, -NH-alkyl, -NH-pyrrolidin-3-yl, N-pyrrolidinyl, N-piperazinyl, N-methyl-piperazin-1-yl, N-morpholinyl, etc. Any two hydrogen atoms on a single carbon can also be substituted, for example, with =O, =NR 70 , =N-OR 70 , =N2, or =S.

[0030] Substituents for replacing hydrogen atoms on unsaturated carbon atoms in groups containing unsaturated carbon atoms are -R unless otherwise specified. 60 , halo, -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 or -NR 70 C(NR 70 )N(R 80 ) 2、 where R 60 , R 70 , R 80 , and M + is as previously defined, except that in the case of a substituted alkene or alkyne, the substituent is -O - M + , -OR 70 , -SR 70 , or -S - M + The condition is that it is not.

[0031] Substituents for replacing a hydrogen atom on a nitrogen atom in such nitrogen-containing groups 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 , or -NR 70 C(NR 70 )N(R 80 )2, where R 60 , R 70 , R 80 , and M + is as previously defined.

[0032] In one embodiment, a substituted group has one substituent, two substituents, a substituent, or four substituents.

[0033] Additionally, in embodiments in which groups or moieties are substituted with substituted substituents, the nesting of such substituted substituents is limited to three, thereby preventing the formation of polymers. Thus, in a group or moiety containing a first group that is a substituent of a second group attached to a parent structure, which is itself a substituent of a third group, the first (outermost) group can only be substituted with unsubstituted substituents. For example, in a group containing -(aryl-1)-(aryl-2)-(aryl-3), aryl-3 can only be substituted with substituents that are themselves unsubstituted.

[0034] The term "acute respiratory distress syndrome" or "ARDS" refers to a syndrome characterized by severe shortness of breath, forced and abnormally rapid breathing, hypotension, confusion, and extreme fatigue. This syndrome can be diagnosed based on a PaO2 / FiO2 ratio of less than 300 mmHg despite PEEP of more than 5 cm H2O (Fan et al. JAMA. 319:698-71).

[0035] ARDS occurs when fluid accumulates in the alveoli. This fluid prevents the lungs from filling with enough air, limiting the amount of oxygen reaching the bloodstream and depriving organs of the oxygen they need to function. ARDS symptoms can vary in intensity depending on the cause and severity. The severe shortness of breath that characterizes ARDS typically develops within hours to days of COVID-19 infection. Many people who develop ARDS do not survive, and the risk of death increases with age and the severity of the disease. Some patients who survive ARDS recover fully, while others suffer permanent lung damage.

[0036] "Acyl" refers to the group -C(O)R, where R is H, aliphatic, heteroaliphatic, heterocyclic, or aromatic. Exemplary acyl moieties include -C(O)H, -C(O)alkyl, -C(O)C 1~ C6 alkyl, -C(O)C 1~Examples include, but are not limited to, 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.

[0037] "Aliphatic" refers to a substantially hydrocarbon-based group or moiety. Aliphatic groups or moieties can be acyclic, including alkyl, alkenyl, or alkynyl groups, cyclic versions thereof, such as alicyclic groups or moieties, including cycloalkyl, cycloalkenyl, or cycloalkynyl, including straight-chain and branched-chain configurations, and all stereoisomers and positional isomers as well. Unless expressly stated otherwise, aliphatic groups are groups having 1 to 25 carbon atoms (C 1~25 ), for example, 1 to 15 (C 1~15 ), 1 to 10 (C 1~10 ), 1~6(C 1~6 ), or 1 to 4 carbon atoms (C 1~4 ), 2 to 25 carbon atoms (C 2~25 ), for example, 2 to 15 (C 2~15 ), 2~10(C 2~10 ), 2~6(C 2~6 ), or 2 to 4 carbon atoms (C 2~4 ), or 3 to 15 (C 3~15 ), 3~10(C 3~10 ), 3~6(C 3~6 ), or 3 to 4 (C 3~4 ) carbon atoms. An aliphatic group can be substituted or unsubstituted, unless specifically referred to as "unsubstituted aliphatic" or "substituted aliphatic." An aliphatic group can be substituted with one or more substituents (up to two substituents for each methylene carbon of the aliphatic chain, or up to one substituent for each carbon of the -C=C- double bond of the aliphatic chain, or up to one substituent for the carbon of the terminal methine group).

[0038] "Alkoxy" refers to the group -OR, where R is a substituted or unsubstituted alkyl, or a substituted or unsubstituted cycloalkyl group. In certain instances, R is C 1~6 Alkyl group or C 3~6 is a cycloalkyl group. Methoxy (-OCH3) and ethoxy (-OCH2CH3) are exemplary alkoxy groups. In substituted alkoxy, R is a substituted alkyl or substituted cycloalkyl, examples of which include haloalkoxy groups such as -OCF2H or -OCF3.

[0039] "Alkyl" is a group consisting of 1 to 25 (C 1~25 ) or more carbon atoms, more typically 1 to 8 (C 1~8 ) carbon atoms, 1 to 6 (C 1~6 ) or 1 to 4 carbon atoms (C 1~4 ) carbon atoms, such as 1 to 10 (C 1~10 ) carbon atoms. The alkyl portion can be substituted or unsubstituted. By way of example, the term includes straight-chain and branched hydrocarbyl groups such as methyl (CH), ethyl (-CHCH), n-propyl (-CHCHCH), isopropyl (-CH(CH)), n-butyl (-CHCHCHCH), isobutyl (-CHCH(CH)), sec-butyl (-CH(CH)(CHCH), t-butyl (-C(CH)), n-pentyl (-CHCHCHCHCHCH), and neopentyl (-CHC(CH)). As used herein, "lower alkyl" refers to a saturated aliphatic hydrocarbyl group having (C 1~ C8) alkyl.

[0040] "Amino" refers to the groups -NH, -NHR, or -NRR, where each R is independently selected from aliphatic, heteroaliphatic, aromatic, including both aryl and heteroaryl, or heterocycloaliphatic, or where two R groups, together with the nitrogen to which they are attached, form a heterocyclic ring. Examples of such heterocyclic rings include two R groups, together with the nitrogen to which they are attached, forming the group O, S, or N (R) g ) may be interrupted by one or two heteroatom groups such as -(CH2) 2-5- Forms a ring, R g But R 70 , -C(O)R 70 , -C(O)OR 60 , or -C(O)N(R 80 )2.

[0041] An "amide" or "carboxamide" is an amide where R is hydrogen, heteroaliphatic, aromatic, or alkyl, especially C 1~6 It refers to the group -N(R) acyl, or -C(O) amino, which is aliphatic such as alkyl.

[0042] "Aromatic," unless otherwise specified, refers to a cyclic conjugated group or moiety of 5 to 15 ring atoms having a single ring (e.g., phenyl, pyridinyl, or pyrazolyl) or multiple fused rings (e.g., naphthyl, indolyl, or pyrazolopyridinyl) in which at least one ring is aromatic, i.e., at least one ring, and optionally multiple fused rings, have a contiguous delocalized π-electron system. Typically, the number of out-of-plane π-electrons corresponds to Hückel's rule (4n+2). The point of attachment to the parent structure is typically through the aromatic portion of the fused ring system. For example, TIFF2024534919000012.tif13128. However, in certain instances, the context or explicit disclosure may indicate that the point of attachment is through the non-aromatic portion of the fused ring system. For example: TIFF2024534919000013.tif15128. An aromatic group or moiety can contain only carbon atoms in the ring, such as an aryl group or moiety, or it can contain one or more ring carbon atoms and one or more ring heteroatoms (e.g., S, O, N, P, or Si) containing lone electron pairs, such as a heteroaryl group or moiety. Unless otherwise stated, an aromatic group can be substituted or unsubstituted.

[0043] "Aryl," unless otherwise specified, refers to an aromatic carbocyclic group of 6 to 15 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings in which at least one ring is aromatic (e.g., 1,2,3,4-tetrahydroquinoline, benzodioxole, etc.), provided that the point of attachment is through the aromatic portion of the ring system. If any aromatic ring moiety contains a heteroatom, the group is heteroaryl and not aryl. Aryl groups can be, for example, monocyclic, bicyclic, tricyclic, or tetracyclic. Unless otherwise specified, aryl groups can be substituted or unsubstituted.

[0044] "Aliphatic" refers to an aryl group attached to the parent through an aliphatic moiety. Aliphatic groups include aralkyl or arylalkyl groups such as benzyl and phenylethyl.

[0045] "Carboxyl" or "carboxylic acid" refers to -CO2H, "Carboxylate" is -C(O)O - Or its salt.

[0046] "Carboxyl ester" or "carboxylate ester" refers to the group --C(O)OR, where R is aliphatic, heteroaliphatic, or aromatic (including both aryl and heteroaryl).

[0047] A "combination" refers to 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. The combination, or its components, may be a composition. In some embodiments, the effective periods of all administered components overlap with each other. In an exemplary embodiment of a combination comprising 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 independently overlap with each other. In another exemplary embodiment of a combination comprising three components, the effective period of the first administered component overlaps with the effective period of the second component but does not overlap with the effective period of the third component, and the effective period of the second component overlaps with the effective periods of the first and third components. The combination may be a composition comprising the components, a composition comprising one or more components and another separate component(s) or composition(s) comprising the remaining component(s), or the combination may be two or more individual components. In some embodiments, 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.

[0048] "Cyano" refers to the group --CN.

[0049] "Alicyclic" refers to a cyclic aliphatic group having a single ring (e.g., cyclohexyl) or multiple rings, such as in a fused, bridged, or spirocyclic system, at least one of which is aliphatic. Typically, the point of attachment to the parent structure is through the aliphatic portion of the multiple ring system. Alicyclics include saturated and unsaturated systems, including cycloalkyl, cycloalkenyl, and cycloalkynyl. Alicyclic groups can contain 3 to 25 carbon atoms, e.g., 3 to 15, 3 to 10, or 3 to 6 carbon atoms. Unless otherwise stated, alicyclic groups can be substituted or unsubstituted. Exemplary alicyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, or cyclohexenyl. As used herein, lower cycloalkyl refers to C 3~8 Refers to cycloalkyl.

[0050] "Halo," "halide," or "halogen" refers to fluoro, chloro, bromo, or iodo.

[0051] "Haloalkyl" refers to an alkyl moiety, as defined herein, that is substituted with one or more halogens. Exemplary haloalkyl moieties include -CHF, -CHF, and -CF.

[0052] "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 with an atom having at least one lone pair of electrons, typically nitrogen, oxygen, phosphorus, silicon, or sulfur. For example, a heteroalkyl moiety is a heteroaliphatic moiety in which the aliphatic moiety of the base is alkyl, as defined herein. Heteroaliphatic compounds or groups, such as heteroalicyclic groups, can be substituted or unsubstituted, branched or unbranched, chiral or achiral, and / or acyclic or cyclic.

[0053] "Heteroaryl" refers to an aromatic group or moiety of 5 to 15 ring atoms, containing at least one carbon atom and at least one heteroatom such as N, S, O, P, or Si, unless otherwise specified. A heteroaryl group or moiety can contain a single ring (e.g., pyridinyl, pyrimidinyl, or pyrazolyl) or multiple condensed rings (e.g., indolyl, benzopyrazolyl, or pyrazolopyridinyl). A heteroaryl group or moiety can be, for example, monocyclic, bicyclic, tricyclic, or tetracyclic. Unless otherwise specified, a heteroaryl group or moiety can be substituted or unsubstituted.

[0054] "Heterocyclyl," "heterocyclo," and "heterocycle" refer to both aromatic and non-aromatic ring systems, and more specifically to stable 3- to 15-membered ring moieties containing at least one carbon atom, typically multiple carbon atoms, and at least one heteroatom, such as 1 to 5. The heteroatom(s) can be nitrogen, phosphorus, oxygen, silicon, or sulfur atom(s). A heterocyclyl moiety can be a monocyclic moiety or can contain multiple rings, such as in a bicyclic or tricyclic ring system, provided that at least one of the rings contains a heteroatom. Such polycyclic moieties can include fused or bridged ring systems, as well as spirocyclic systems, and any nitrogen, phosphorus, carbon, silicon, or sulfur atom of the heterocyclyl moiety can be optionally oxidized to various oxidation states. For convenience, nitrogens, particularly, but not limited to, those defined as cyclic aromatic nitrogens, are meant to include their corresponding N-oxide forms, even if not expressly defined as such in specific instances. Thus, for example, for a compound having a pyridinyl ring, the corresponding pyridinyl-N-oxide is included as another compound of the invention unless expressly excluded or excluded by context. In addition, the ring nitrogen atom may optionally be quaternized. Heterocycles include heteroaryl moieties where the heterosilyl moiety is aromatic, and heterocycloaliphatic moieties such as heterocycloalkyl, heterocycloalkenyl, or heterocycloalkynyl, which are partially or fully saturated heterocyclyl rings.Examples of heterocyclyl groups include azetidinyl, oxetanyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazoyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, naphthalazinyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetracyclyl, and the like. Zoyl, tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, Examples include, but are not limited to, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, diazebicycloheptane, diazapane, diazepine, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothieyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphosphoranyl, and oxadiazolyl.

[0055] "Hydroxyl" refers to the group --OH.

[0056] "Nitro" refers to the group -NO2.

[0057] "Oxo" refers to the group =O (double bond O).

[0058] A "phosphate" is a group in which each -OR' is independently -OH; -O-aliphatic such as -O-alkyl or -O-cycloalkyl; -O-aromatic, including both -O-aryl and -O-heteroaryl; -O-aralkyl; or -OR' is M + is a single positively charged counterion -O - M + Each M + is K + , Na + , Li + Alkaline ions such as + an ammonium ion such as N(R")4 (where each R" is independently H, aliphatic, heterocyclyl, or aryl), or [Ca 2+ ] 0.5 , [Mg 2+ ] 0.5 , or [Ba 2+ ] 0.5 The phosphonooxyalkyl may be, for example, —CH2OP(O)(O - Na + (((dialkoxyphosphoryl)oxy)alkyl) refers to a dialkyl ester of a phosphonooxyalkyl group such as, for example, —CH2OP(O)(O-tert-butyl)2.

[0059] A "phosphonate" is a group in which each -OR' is independently -OH; -O-aliphatic, such as -O-alkyl or -O-cycloalkyl; -O-aromatic, including both -O-aryl and -O-heteroaryl; or -O-aralkyl; or -OR' is -O - M + and M + refers to the group -P(O)(OR')2, a counterion with a single positive charge. + is a positively charged counterion, e.g., K + , Na + , Li + Alkali metal ions such as +an ammonium ion such as N(R")4 (where each R" is independently H, aliphatic, heterocyclyl, or aryl), or [Ca 2+ ] 0.5 , [Mg 2+ ] 0.5 , or [Ba 2+ ] 0.5 The phosphonoalkyl may be, for example, —CHP(O)(OH) or —CHP(O)(O - Na + (((dialkoxyphosphoryl)alkyl) refers to a dialkyl ester of a phosphonoalkyl group such as, for example, —CH 2 P(O)(O-tert-butyl) 2 .

[0060] "Phosphoramidates" are compounds in which each R' is independently an aliphatic group such as H, alkyl, aryl, or aralkyl, or -OR' is -O - M + and M + refers to the group -OP(O)(OR')(N(R')2), which is a counterion with a single positive charge. + is K + , Na + , Li + Alkaline ions such as + ammonium ions such as N(R")4 (where each R" is independently H, aliphatic, e.g., alkyl, hydroxyalkyl, or combinations thereof, heterocyclyl, or aryl), or [Ca 2+ ] 0.5 , [Mg 2+ ] 0.5 , or [Ba 2+ ] 0.5 The alkyl phosphoramidate may be, for example, an alkaline earth ion such as -CH2OP(O)(O-phenyl)[NHC(CH3)CO2isopropyl], or -CH2OP(O)(OH)(N(H)alkyl), such as -CH2O-P(O)(OR')(N(R'2)) or -CH2(CH3)OP(O)(OR')(N(R'2)), or -CH2OP(O)(O - Na +)(N(H) alkyl-phosphoramidates, such as their salts.

[0061] "Patient" or "subject" refers to mammals and other animals, particularly humans. Accordingly, the disclosed methods are applicable to both human therapy and veterinary uses.

[0062] A "pharmaceutically acceptable excipient" refers to a substance, other than the active ingredient, that is included in a formulation of the active ingredient. As used herein, an excipient may be incorporated within or physically mixed with particles of a pharmaceutical composition. An excipient may be used, for example, to dilute the active ingredient and / or modify the properties of a pharmaceutical composition. Excipients may include, but are not limited to, anti-adherents, binders, coatings, enteric coatings, disintegrants, flavors, sweeteners, colorants, lubricants, glidants, adsorbents, preservatives, adjuvants, carriers, or vehicles. Excipients may be starches and modified starches, cellulose and cellulose derivatives, sugars and sugar 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, hydroxypropylmethylcellulose, xylitol, sorbitol, maltitol, gelatin, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), tocopheryl polyethylene glycol 1000 succinate (also known as vitamin E TPGS, or TPGS), carboxymethylcellulose, dipalmitoylphosphatidylcholine (DPPC), vitamin A, vitamin E, vitamin C, retinyl palmitate, selenium, cysteine, methionine, citric acid, sodium citrate, methylparaben, propylparaben, sugar, silica, talc, magnesium carbonate, sodium starch glycolate, tartrazine, aspartame, benzalkonium chloride, sesame oil, propyl gallate, sodium metabisulfite, or lanolin.

[0063] An "adjuvant" is an excipient that modifies the effect of another agent, typically an active ingredient. Adjuvants are often pharmacological and / or immunological agents. Adjuvants can modify the effect of an active ingredient by increasing the immune response. Adjuvants can also act as stabilizers for the formulation. Exemplary adjuvants include, but are not limited to, aluminum hydroxide, alum, aluminum phosphate, killed bacteria, squalene, detergents, cytokines, paraffin oil, and combination adjuvants such as Freund's complete or incomplete adjuvant.

[0064] "Pharmaceutically acceptable carrier" refers to an excipient that is a carrier or vehicle, such as a suspending aid, solubilizing aid, or aerosolizing aid. Pharmaceutically acceptable carriers are conventional. Remington: The Science and Practice of Pharmacy, The University of the Sciences in Philadelphia, Editor, Lippincott, Williams, & Wilkins, Philadelphia, PA, 21 st Edition (2005) describes compositions and formulations suitable for the pharmaceutical delivery of one or more therapeutic compositions and additional pharmaceutical agents.

[0065] Generally, the nature of the carrier will depend on the particular mode of administration used. For example, parenteral formulations usually contain an injectable fluid containing pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solution, aqueous dextrose, glycerol, or the like as a vehicle. In some instances, the pharmaceutically acceptable carrier may be sterilized so as to be suitable for administration to a subject (e.g., by parenteral, intramuscular, or subcutaneous injection). In addition to biologically neutral carriers, the administered pharmaceutical composition may contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives, and pH buffering agents, for example, sodium acetate or sorbitan monolaurate.

[0066] "Pharmaceutically acceptable salts," as would be known to one of ordinary skill in the art, refer to pharmaceutically acceptable salts of compounds derived from a variety of organic and inorganic counterions, including, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc., and, where the molecule contains a basic functional group, salts of organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc. "Pharmaceutically acceptable acid addition salts" are a subset of "pharmaceutically acceptable salts" that are formed with acid partners while retaining the biological effectiveness of the free base. Specifically, the disclosed compounds are capable of reacting with inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, as well as with formic acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, benzenesulfonic acid, isethionic acid, salicylic acid, xinafoic acid, and the like. It forms salts with a variety of pharmaceutically acceptable acids, including organic acids such as p-toluenesulfonic acid, salicylic acid, stearic acid, muconic acid, p-toluenesulfonic acid, salicylic acid, and muconic acid.Pharmaceutically acceptable salts also include salts formed when an acidic proton present in the parent compound is either replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth metal ion, or an aluminum ion), or coordinates with an organic base (e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, piperidine, dimethylamine, diethylamine, triethylamine, ammonia, etc.).

[0067] "Pharmaceutically acceptable base addition salts" are a subset of "pharmaceutically acceptable salts" derived from inorganic bases, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, etc. Exemplary salts are ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, tris(hydroxymethyl)aminomethane (Tris), ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Exemplary organic bases are isopropylamine, diethylamine, tris(hydroxymethyl)aminomethane (Tris), ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. (See, e.g., S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977;66:1-19, incorporated herein by reference).

[0068] An "effective amount," such as a therapeutically effective amount, refers to an amount of a compound sufficient to achieve a desired result, e.g., to treat a specified disorder or disease, or to ameliorate or eradicate one or more of its symptoms, and / or to prevent the onset of a disease or disorder. The amount of a compound that constitutes an "effective amount" will vary depending on the compound, the condition and its severity, the age of the patient being treated, and the like. An effective amount can be determined by one of ordinary skill in the art. An appropriate "effective" amount in any individual case can be determined using any suitable technique, such as a dose escalation study.

[0069] "Prodrug" refers to a compound that is converted in vivo to yield a biologically active compound, particularly the parent compound, for example, by hydrolysis in the intestine or enzymatic conversion. Common examples of prodrug moieties include, but are not limited to, ester and amide forms of a compound having an active form bearing a carboxylic acid moiety. Examples of pharmaceutically acceptable esters suitable for use in the disclosed compounds include aliphatic esters, particularly alkyl esters (e.g., C 1~6 Other prodrug moieties include, but are not limited to, phosphate ester groups and carboxylic acid esters, such as alkyl esters (e.g., alkyl esters). Other prodrug moieties include those where R' is H or C 1~6and alkyl phosphate esters, such as -CH2-OP(O)(OR')2, or salts thereof. Acceptable esters also include, but are not limited to, cycloalkyl esters and arylalkyl esters, such as benzyl. Examples of pharmaceutically acceptable amides of the disclosed compounds include, but are not limited to, primary amides and secondary and tertiary alkyl amides (e.g., having about 1 to about 6 carbons). The amides and esters of the disclosed compounds can be prepared according to conventional methods. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, "Prodrugs 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 of which are incorporated by reference for all purposes.

[0070] The term "protecting group" refers to a group of atoms that, when attached to a reactive functional group in a molecule, masks, reduces, or prevents the reactivity of the functional group. Typically, a protecting group can be selectively removed as desired during the course of a synthesis. Examples of protecting groups are found in Greene and Wuts, Protective Groups in Organic Chemistry, 3 rdEd., 1999, John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8, 1971-1996, John Wiley & Sons, NY Representative amino-protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilyl-ethanesulfonyl ("TES"), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl ("FMOC"), nitroveratryloxycarbonyl ("NVOC"), and the like. Representative hydroxyl protecting groups include, but are not limited to, those in which the hydroxyl group is either acylated or alkylated, such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPPS groups), and allyl ethers.

[0071] A "spray-dried dispersion" refers to a single-phase dispersion of one or more compounds in a polymer matrix. Typically, the one or more compounds are amorphous.

[0072] "Solvate" refers to a complex formed by the combination of solvent molecules with molecules or ions of the solute. The solvent can be an organic compound, an inorganic compound, or a mixture of both. Some examples of solvents include, but are not limited to, methanol, ethanol, isopropanol, ethyl acetate, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, and water. The compounds described herein can exist in unsolvated and solvated forms when combined with pharmaceutically acceptable or non-acceptable solvents, such as water, ethanol, etc. Solvated and unsolvated forms of the disclosed compounds are within the scope of the embodiments disclosed herein.

[0073] "Subject" refers to human and non-human subjects.

[0074] "Sulfanyl" refers to the group or -SH, -S-aliphatic, -S-heteroaliphatic, -S-cyclic, -S-heterocyclyl (including -S-aryl and -S-heteroaryl).

[0075] "Sulfinyl" refers to the group or moiety -S(O)H, -S(O)aliphatic, -S(O)heteroaliphatic, -S(O)cyclic, -S(O)heterocyclyl (including -S(O)aryl and -S(O)heteroaryl).

[0076] "Sulfonyl" refers to the groups: -SO2H, -SO2aliphatic, -SO2heteroaliphatic, -SO2cyclic, -SO2heterocyclyl (including -SO2aryl and -SO2heteroaryl).

[0077] "Sulfonamide" is R c is H, aliphatic, heteroaliphatic, cyclic, and heterocyclic (including aryl and heteroaryl), the group or moiety -SO2amino, or -N(R c ) refers to sulfonyl.

[0078] As used herein, "treating" or "treatment" relates to the treatment of COVID-19 in a patient or subject, particularly a human experiencing COVID-19, including, by way of example and not limitation, the following: (i) inhibiting COVID-19, e.g., preventing or delaying its onset; (ii) mitigating COVID-19, for example, causing regression of COVID-19 or its symptoms; or (iii) stabilizing COVID-19, for example, by preventing an increase in the grade and / or severity of COVID-19;

[0079] For example, in the case of COVID-19-associated cytokine elevation leading to ARDS, successful treatment may include reduced shortness of breath, reduced forced breathing or respiratory rate, higher blood pressure, reduced confusion, and / or reduced fatigue. Treatment may be administered prophylactically, i.e., before the onset of ARDS. Prophylactic treatment prevents ARDS and can be administered to patients who have or are suspected of having a COVID-19 infection but do not have severe symptoms of ARDS. For example, prophylactic treatment can be administered to patients who have a cough without other symptoms of ARDS.

[0080] "Preventing" as used herein specifically relates to reducing cytokine levels or their inflammatory effects to prevent COVID-19 from occurring in a patient or subject, where such patient or subject is at risk of developing COVID-19 but has not yet been diagnosed with COVID-19.

[0081] As used herein, the terms "disease" and "condition" may be used interchangeably or may differ in that a particular disease or condition may not have a known causative agent (and thus the etiology has not yet been determined) and therefore is not yet recognized as a disease, but is recognized only as an undesirable state or syndrome in which a more or less specific set of symptoms has been identified by clinicians.

[0082] The above definitions and the following general formula are not intended to include impermissible substitution patterns (e.g., methyl substituted with five fluoro groups), which would be readily recognized by one of ordinary skill in the art.

[0083] Any of the groups mentioned herein can be optionally substituted with at least one, two or more of the possible substituents, as defined herein, i.e., a substituent has at least one, two or more of the possible substitutable hydrogens replaced by one or more substituents, as defined herein, unless the context indicates otherwise or a particular structural formula precludes substitution.

[0084] Those skilled in the art will understand that compounds may exhibit the 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 and, as a result, may exist as stereoisomers, such as double bond isomers (i.e., geometric isomers), enantiomers, diastereomers, and mixtures thereof, such as racemic mixtures. Thus, the compounds and compositions may be provided as individual pure enantiomers or diastereomers, or as stereoisomeric mixtures, including racemic mixtures. In certain embodiments, the compounds disclosed herein are synthesized in or purified to a substantially enantiomerically pure form, such as 85% enantiomeric excess (ee), 90% enantiomeric excess, 95% enantiomeric excess, 97% enantiomeric excess, 98% enantiomeric excess, 99% enantiomeric excess, or even greater than 99% enantiomeric excess. Those skilled in the art will understand that in compounds containing one or more asymmetric centers, unless a specific enantiomer or diastereomer is shown or described, one or both enantiomers or diastereomers are intended.

[0085] As another example, certain disclosed compounds may exist in several tautomeric forms, including enol forms, keto forms, and mixtures thereof. Because the various compound names, formulas, and compound diagrams in the specification and claims may represent only one of the possible tautomeric, conformational, optical, or geometric isomeric forms, those skilled in the art will understand that the disclosed compounds encompass any tautomeric, conformational, optical, and / or geometric isomeric form of the compounds described herein, as well as mixtures of these various different isomeric forms. In cases of restricted rotation, such as around an amide bond or between two directly bonded rings such as a pyridinyl ring or a biphenyl group, atropisomers are also possible and are also specifically included in the compounds of the present invention.

[0086] In any embodiment, any or all hydrogens present in the compound, or in a particular group or moiety within the compound, can be replaced with deuterium or tritium. Thus, the recitation of alkyl includes deuterated alkyls where from one to a maximum number of hydrogens present can be replaced with deuterium. For example, C2D x H 5-x If one to five hydrogens in, etc. are replaced with deuterium, ethyl can be C2H5 or C2H5.

[0087] The term "acute respiratory distress syndrome" or "ARDS" refers to a syndrome characterized by severe shortness of breath, forced and abnormally rapid breathing, hypotension, confusion, and extreme fatigue. This syndrome can be diagnosed based on a PaO2 / FiO2 ratio of less than 300 mmHg despite PEEP of more than 5 cm H2O (Fan et al. JAMA. 319:698-71).

[0088] ARDS occurs when fluid accumulates in the alveoli. This fluid prevents the lungs from filling with enough air, limiting the amount of oxygen reaching the bloodstream and depriving organs of the oxygen they need to function. ARDS symptoms can vary in intensity depending on the cause and severity. The severe shortness of breath that characterizes ARDS typically develops within hours to days after infection with some respiratory viruses, such as COVID-19 and influenza. Many people who develop ARDS do not survive, and the risk of death increases with age and the severity of the illness. Some patients who survive ARDS recover completely, while others suffer permanent lung damage. ARDS may be referred to as acute lung injury (ALI) in some publications.

[0089] As used herein, the terms "acute kidney injury" or "AKI" or "acute kidney injury" or "ARI" or "acute renal failure" or "ARF" refer in their conventional sense to a syndrome characterized by a sudden decline in renal function, including, for example, the ability to excrete waste products from a patient's blood. AKI is characterized by a decrease in glomerular filtration rate, urine output, or both. This decrease in filtration capacity results in the retention of nitrogenous (urea and creatinine) and non-nitrogenous waste products normally excreted by the kidney, a decrease in urine output, or both. AKI can be classified in causation as prerenal, intrinsic renal, or postrenal. Intrinsic renal disease can be further divided into glomerular, tubular, interstitial, and vascular abnormalities. AKI is accompanied by an inflammatory response, which, if unchecked, can lead to renal fibrosis and chronic renal failure. AKI usually develops over a period of hours or days and is potentially reversible. AKI can be characterized as an abrupt (e.g., within 14 days, 7 days, 72 hours, or 48 hours) decline in renal function identified by an absolute increase in serum creatinine of 0.3 mg / dl or more (26.4 μmol / l or more), a percentage increase in serum creatinine of 50% or more (1.5-fold from baseline), or a decline in urine output (documented oliguria of less than 0.5 ml / kg per hour for at least 6 hours). Risk factors include, for example, subjects undergoing or having major vascular surgery, coronary artery bypass, or other cardiac surgery, subjects with pre-existing congestive heart failure, pre-eclampsia, eclampsia, diabetes, hypertension, coronary artery disease, proteinuria, renal failure, glomerular filtration below the normal range, liver cirrhosis, serum creatinine above the normal range, or sepsis, or subjects exposed to NSAIDs, cyclosporine, tacrolimus, aminoglycosides, foscarnet, ethylene glycol, hemoglobin, myoglobin, ifosfamide, heavy metals, methotrexate, radiopaque contrast agents, or streptozotocin. This list is not limiting.

[0090] As used herein, the term "renal insufficiency" is intended to include kidney damage, kidney disease, kidney failure, kidney cancer, the accidental absence, surgical removal or genetic disorder of at least one kidney, or other conditions in which one or both kidneys are not functioning properly. The term renal insufficiency can include acute kidney injury.

[0091] The term "thrombosis" as used herein refers in its conventional sense to a clotting disorder in which excess platelets contribute. Thrombosis can refer to the formation of a thrombus (blood clot) in a blood vessel. The term encompasses arterial and venous thrombosis, including, but not limited to, deep vein thrombosis, portal vein thrombosis, jugular vein thrombosis, renal vein thrombosis, stroke, myocardial infarction, Budd-Chiari syndrome, Paget-Schroetter disease, and cerebral venous sinus thrombosis. In some embodiments, the patient is at increased risk (e.g., as measured by recognized risk factors) for a thrombotic event compared to the general population. In some embodiments, the patient has one or more risk factors that place the patient at increased risk for developing thrombosis compared to the general population. Risk factors for thrombosis include, for example, classic cardiovascular disease risk factors: dyslipidemia, smoking, diabetes, hypertension, and abdominal obesity; strong classic venous thromboembolism risk factors: trauma or fracture, major orthopedic surgery, and oncological surgery; moderate classic venous thromboembolism risk factors: non-oncological surgery, oral contraceptives and hormone replacement therapy, pregnancy and the postpartum period, hypercoagulability, and previous venous thromboembolism; and weak classic venous thromboembolism risk factors: age, bed rest (>3 days), prolonged travel, and metabolic syndrome. Additional risk factors include, for example, hereditary: antithrombin deficiency, protein C deficiency, protein S deficiency, factor V Leiden, and prothrombin G20210A; acquired: antiphospholipid syndrome; and mixed: hereditary, acquired, and mixed coagulation or metabolic risk factors for thrombosis, such as hyperhomocysteinemia, elevated fibrinogen levels, elevated factor VIII levels, and elevated factor IX levels. In some cases, the use of heparin may increase the risk of thrombosis, including, for example, heparin-induced thrombocytopenia (HIT).Diseases and conditions associated with thrombosis include, but are not limited to, acute venous thrombosis, pulmonary embolism, thrombosis in pregnancy, hemorrhagic dermonecrosis, acute or chronic disseminated intravascular coagulation (DIC), sepsis-induced coagulopathy (SIC), clot formation from surgery, prolonged bed rest, prolonged immobilization, venous thrombosis, fulminant meningococcemia, acute thrombotic stroke, acute coronary artery occlusion, acute peripheral arterial occlusion, massive pulmonary embolism, axillary vein thrombosis, iliofemoral vein thrombosis, massive iliomedullary vein thrombosis, obstructed arterial cannula, obstructed venous cannula, obstructed venous cannula, cardiomyopathy, veno-occlusive disease of the liver, hypotension, decreased cardiac output, decreased vascular resistance, pulmonary hypertension, decreased lung compliance, leukopenia, microcytopenia (e.g., immune microcytopenia), and immune microcytic clearance. For subjects at risk of thrombosis, methods for maintaining hemostasis in patients at risk of thrombosis can be used to monitor the subject. Examples of methods for monitoring patients at risk of thrombosis include, but are not limited to, digital subtraction angiography, in vitro assays, or non-invasive methods. Examples of in vitro assays useful for identifying and monitoring subjects at risk of thrombosis and treating them using the present method include, but are not limited to, functional assays and antibody detection assays.

[0092] The term "thrombotic event" includes thrombotic disorders such as, but not limited to, myocardial infarction, unstable angina, stroke, pulmonary embolism, transient ischemic attack, deep vein thrombosis, thrombotic reocclusion, and peripheral vascular thrombosis. Thrombotic events also include thrombotic reocclusion occurring after coronary interventional procedures or thrombolytic therapy. The term "thrombotic event" refers to any disorder involving occlusion or partial occlusion of an artery or vein with thrombosis.

[0093] The term "COVID-19" refers to the disease caused by infection with SARS-CoV-2 (formerly known as 2019-nCoV), which first emerged in Wuhan, China.

[0094] The term "COVID-19-associated ARDS" refers to ARDS caused by infection with SARS-CoV-2. Patients with COVID-19-associated ARDS may have been diagnosed with COVID-19, may have been exposed to another person with COVID-19, or may be suspected of having COVID-19 based on their symptoms.

[0095] The term "COVID-19-associated AKI" refers to AKI caused by SARS-CoV-2 infection. Patients with COVID-19-associated AKI may have been diagnosed with COVID-19, may have been exposed to another person with COVID-19, or may be suspected of having COVID-19 based on their symptoms. In some cases, COVID-19-associated AKI includes symptomatic AKI, such as those described in Batlle et al. J.AM.SOC.NEPHROL. 2020, 31(7):1380-1383 and Gabarre et al. Intensive Care Med. 2020, 46(7):1339-1348 (the disclosures of which are incorporated herein by reference in their entireties).

[0096] The term "COVID-19-associated thrombosis" refers to thrombosis caused by infection with SARS-CoV-2. Patients with COVID-19-associated thrombosis may have been diagnosed with COVID-19, may have been exposed to another person with COVID-19, or may be suspected of having COVID-19 based on their symptoms. In some cases, COVID-19-associated thrombosis includes any of the symptoms described, for example, in Connors et al. Blood 2020, 135(23):2033-2040 and Bikdeli et al. J. Am. Coll. Cardiol. 2020, 75(23):2950-73 (the disclosures of which are incorporated herein by reference in their entireties).

[0097] The term "COVID-19 associated" refers to symptoms or indications that typically occur within 28 days of hospitalization due to / signs of COVID-19.

[0098] The term "treatment" refers to a reduction in symptoms. For COVID-19-associated ARDS, successful treatment may include a reduction in shortness of breath, a decrease in forced breathing or respiratory rate, an increase in blood pressure, a reduction in confusion, and / or a reduction in fatigue. Treatment may be administered prophylactically, i.e., before the onset of ARDS. Prophylactic treatment prevents ARDS and can be administered to patients who have or are suspected of having COVID-19 infection but do not have severe symptoms of ARDS. For example, prophylactic treatment can be administered to patients who have a cough without other symptoms of ARDS.

[0099] For COVID-19-associated AKI, successful treatment may include an increase in renal function. Renal function may be assessed by measuring serum creatinine levels, serum creatinine clearance, or blood urea nitrogen levels. In some cases, successful treatment may include a reduction in metabolic acidosis, hyperkalemia, oliguria or anuria, azotemia, restoration of fluid balance, and improved effects on other organ systems. Treatment may be administered prophylactically, i.e., before the onset of AKI. Prophylactic treatment prevents AKI and can be administered to patients who have or are suspected of having COVID-19 infection but do not have severe symptoms of AKI. For example, prophylactic treatment can be administered to patients who have one or more of the following symptoms without other symptoms of AKI: increased serum or urinary creatinine, hematuria, hypoproteinemia, decreased antithrombin III levels, hypoalbuminemia, leucozyturia, or proteinuria.

[0100] For COVID-19-associated thrombosis, successful treatment may include improving a subject's coagulation profile or preventing, slowing, delaying, or preventing a worsening of a coagulation profile for which the subject is at risk. The coagulation profile may be assessed by measuring one or more coagulation parameters, including, for example, serum levels of one or more of D-dimer, factor II, factor V (e.g., factor V Leiden), factor VII, factor VIII, factor IX, factor XI, factor XII, factor XIII, F / fibrin degradation products, thrombin-antithrombin 111 complex, fibrinogen, plasminogen, prothrombin, and von Willebrand factor. Additional coagulation parameters that may be measured for the coagulation profile include, for example, prothrombin time, thromboplastin time, activated partial thrombosis time (aPTT), antithrombin activity, platelet count, protein C level, and protein S level. Additionally, C-reactive protein levels may also be assessed in patients prior to treatment, and if elevated, may be used as a further indicator of an increased risk of thrombosis in the patient.

[0101] The term "sepsis" refers to a clinical syndrome of life-threatening organ dysfunction caused by a dysregulated immune response to infection. A severe form of sepsis, "septic shock," is characterized by a critical reduction in tissue perfusion and acute failure of multiple organs, including the lungs, kidneys, and liver. Common causes in immunocompetent patients include many different species of gram-positive and gram-negative bacteria. Immunocompromised patients may have unusual bacterial or fungal species as the cause. Symptoms include fever, hypotension, oliguria, and confusion. Diagnosis is primarily a clinical combination with culture results indicating infection, and early detection and treatment are critical. Treatment involves aggressive fluid resuscitation, antibiotics, surgical removal and drainage of infected or necrotic tissue, and supportive care.

[0102] The term "influenza" refers to the disease commonly known as "flu." Influenza is caused by a group of viruses that can be divided into four distinct groups: influenza A, influenza B, influenza C, and influenza D, which are separated based on their nucleoproteins and matrix proteins. Influenza causes a viral respiratory infection, resulting in fever, head cold, cough, headache, and malaise. Influenza A, B, and C can all infect humans, although no cases of human influenza D infection have been documented. Influenza C, on the other hand, does not cause the typical flu illness seen in individuals infected with influenza A, B, or C.

[0103] Influenza A strains are further classified based on two surface proteins, hemagglutinin (H) and neuraminidase (N). There are 18 different hemagglutinin subtypes and 11 different neuraminidase subtypes (H1-H18 and N1-N11, respectively). There are potentially 198 different influenza A subtype combinations, but in practice, only 131 subtypes have been detected. Current subtypes of influenza A viruses circulating routinely in humans include A(H1N1) and A(H3N2).

[0104] The term "influenza-associated cytokine release-associated condition" refers to any condition associated with influenza that results in high levels of cytokine release in the lungs and / or kidneys, including, but not limited to, influenza-associated ARDS, influenza-associated AKI, influenza-associated thrombosis, influenza-associated sepsis, influenza-associated septic shock, etc.

[0105] The term "influenza-associated ARDS" refers to ARDS caused by influenza infection. A patient with influenza-associated ARDS may have been diagnosed with influenza infection, may have been exposed to another person with influenza infection, or may be suspected of having influenza infection based on their symptoms.

[0106] The term "influenza-associated AKI" refers to AKI caused by influenza infection. Patients with influenza-associated AKI may have been diagnosed with influenza infection, may have been exposed to another person with influenza infection, or may be suspected of having influenza infection based on their symptoms. In some cases, influenza-associated AKI includes symptomatic AKI, such as those described in Batlle et al. J.AM.SOC.NEPHROL. 2020, 31(7):1380-1383 and Gabarre et al. Intensive Care Med. 2020, 46(7):1339-1348 (the disclosures of which are incorporated herein by reference in their entireties).

[0107] The term "influenza-associated thrombosis" refers to thrombosis caused by influenza infection. A patient with influenza-associated thrombosis may have been diagnosed with influenza infection, may have been exposed to another person with influenza infection, or may be suspected of having influenza infection based on their symptoms. In some cases, influenza-associated thrombosis includes any of the symptoms described, for example, in Connors et al. Blood 2020, 135(23):2033-2040 and Bikdeli et al. J. Am. Coll. Cardiol. 2020, 75(23):2950-73 (the disclosures of which are incorporated herein by reference in their entireties).

[0108] The term "influenza-associated sepsis" refers to sepsis caused by influenza infection. A patient with influenza-associated sepsis may have been diagnosed with influenza infection, may have been exposed to another person with influenza infection, or may be suspected of having influenza infection based on their symptoms. In some cases, influenza-associated thrombosis includes any of the symptoms described, for example, in Florescu et al. Virulence. 2014 Jan 1;5(1):137-142 and Gu et al. Eur Respir Rev. 2020 Jul 21;29(157):200038 (the disclosures of which are incorporated herein by reference in their entireties).

[0109] The term "influenza-associated" refers to symptoms or indications that develop within 28 days of hospitalization / onset of influenza infection.

[0110] The term "treatment" refers to the reduction of symptoms. For influenza-associated ARDS, successful treatment may include a reduction in shortness of breath, a reduction in forced breathing or respiratory rate, an increase in blood pressure, a reduction in mental confusion, and / or a reduction in fatigue. Treatment may be administered prophylactically, i.e., before the onset of ARDS. Prophylactic treatment prevents ARDS and can be administered to patients who have or are suspected of having an influenza infection but do not have severe symptoms of ARDS. For example, prophylactic treatment can be administered to patients who have a cough without other symptoms of ARDS.

[0111] For influenza-associated AKI, successful treatment may include an increase in renal function. Renal function may be assessed by measuring serum creatinine levels, serum creatinine clearance, or blood urea nitrogen levels. In some cases, successful treatment may include a reduction in metabolic acidosis, hyperkalemia, oliguria or anuria, azotemia, restoration of fluid balance, and improved effects on other organ systems. Treatment may be administered prophylactically, i.e., before the onset of AKI. Prophylactic treatment prevents AKI and can be administered to patients who have or are suspected of having an influenza infection but do not have severe symptoms of AKI. For example, prophylactic treatment can be administered to patients who have one or more of the following: increased serum or urinary creatinine, hematuria, hypoproteinemia, decreased antithrombin III levels, hypoalbuminemia, leukocytosis, or proteinuria, without other symptoms of AKI.

[0112] For influenza-associated thrombosis, successful treatment may include improving a subject's coagulation profile or preventing, slowing, delaying, or preventing a worsening of the coagulation profile for which the subject is at risk. The coagulation profile may be assessed by measuring one or more coagulation parameters, including, for example, the subject's serum levels of one or more of D-dimer, factor II, factor V (e.g., factor V Leiden), factor VII, factor VIII, factor IX, factor XI, factor XII, factor XIII, F / fibrin degradation products, thrombin-antithrombin 111 complex, fibrinogen, plasminogen, prothrombin, and von Willebrand factor. Additional coagulation parameters that may be measured for the coagulation profile include, for example, prothrombin time, thromboplastin time, activated partial thrombosis time (aPTT), antithrombin activity, platelet count, protein C level, and protein S level. Additionally, C-reactive protein levels may also be assessed in patients prior to treatment, and if elevated, may be used as a further indicator of an increased risk of thrombosis in the patient.

[0113] For influenza-associated sepsis or septic shock, successful treatment may include a reduction in fever, a reduction in high or moderately high heart rate (e.g., tachycardia), a reduction in sweating (i.e., diaphoresis), a reduction in confusion and / or fatigue, and / or a reduction in shortness of breath, reduced forced breathing, or a reduction in respiratory rate. Treatment may be administered prophylactically, i.e., prior to the onset of sepsis or septic shock. Prophylactic treatment prevents sepsis or septic shock and can be administered to patients who have or are suspected of having an influenza infection but do not have severe symptoms of sepsis or septic shock. For example, prophylactic treatment can be administered to patients who have a cough that is not accompanied by other symptoms of sepsis or septic shock.

[0114] II. Compounds Disclosed herein are compounds, prodrugs, corresponding salts and / or solvate forms, and methods of using these compounds, prodrugs, and salt / solvate forms for treating and / or preventing cytokine release-associated conditions associated with respiratory viral infections. The compounds may modulate the interleukin receptor-associated kinase (IRAK) pathway, specifically by inhibiting IRAK1, and optionally IRAK4 (and / or IRAK2 and IRAK3).

[0115] In some embodiments, the compound is a pyrazole compound. The compound has formula IV: TIFF2024534919000014.tif42128, or a salt, prodrug, solvate, and / or N-oxide thereof. With respect to Formula IV, Het-1 is a 5-membered heteroaryl such as thiazolyl or furanyl; y is 1 to 2, R C2 is H, aliphatic, heteroaliphatic, heterocycloaliphatic, aryl, amido, heterocyclyl, or araliphatic such as H alkyl, haloalkyl, or cycloalkyl, and in some embodiments, R C2is alkyl, haloacyl, or cycloalkyl; Each R C3 are independently H or aliphatic such as H or alkyl; R C4 , R C5 , R C6 , and R C7 are each independently H, aliphatic, heteroaliphatic, alkoxy, heterocyclyl, aryl, araliphatic, -O-heterocyclyl, hydroxyl, haloalkyl, halogen, nitro, cyano, carboxyl, carboxyl ester, acyl, amido, amino, sulfonyl, sulfonamido, sulfanyl, or sulfinyl; R C8 and R C9 are each independently H, aliphatic, heteroaliphatic, aryl, heterocyclyl, sulfonyl, nitro, halogen, haloalkyl, carboxylic ester, cyano, or amino, such as H, halogen, haloalkyl, or alkyl, and in some embodiments, R C8 and R C9 is each independently H or aliphatic, such as H, alkyl, or haloalkyl. R C10 is an aliphatic such as H, aliphatic, alkoxy, heteroaliphatic, carboxyl ester, araliphatic, NO, CN, OH, haloalkyl, acyl, alkyl phosphate, or alkyl phosphonate such as H, alkyl, carboxyl ester, acyl, alkyl phosphate, alkyl phosphonate, or aralkyl, and in some embodiments, R C10 is H, alkyl, alkyl phosphate, or alkyl phosphonate.

[0116] In some embodiments, R C4 , R C6 , and R C7 each independently represents H, halo such as F, or aliphatic such as alkyl or haloalkyl, preferably CF, and / or R C5is H, halo such as F, aliphatic such as alkyl or haloalkyl, preferably CF, alkoxy such as methoxy or —O—CHC(CH)OH, heterocyclyl such as morpholin-4-yl or 1-methylpiperidin-4-yl, or —O-heterocyclyl such as —O-(oxetan-3-yl). C4 , R C5 , R C6 , and R C7 Each of R is independently H or F. Also, in certain embodiments, R C4 , R C5 , R C6 , and R C7 At least one of them is not H.

[0117] In some embodiments, the compound has Formula V or VI TIFF2024534919000015.tif42132, or a salt, prodrug, solvate, and / or N-oxide thereof. For Formula V and Formula VI, the variables are as previously defined for Formula IV, and R C11 , R C12 , and R C14 Each of is independently H or an aliphatic such as H or alkyl.

[0118] Exemplary compounds according to Formula IV include, but are not limited to, those listed below in Schedule 2.

[0119] SCHEDULE 1: EXEMPLARY COMPOUNDS ACCORDING TO FORMULA IV V-1: N-(1-(2-hydroxy-2-methylpropyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-methyl-1H-pyrazol-4-yl)furan-2-carboxamide 2,2,2-trifluoroacetic acid salt, V-2: N-(1-(2-hydroxy-2-methylpropyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-methyl-1H-pyrazol-4-yl)furan-2-carboxamide, V-3: N-(1-(2-hydroxy-2-methylpropyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-4: tert-butyl 4-(5-((1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazole-1-carboxylate, V-5: N-(1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-6: N-(1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-methyl-1H-pyrazol-4-yl)furan-2-carboxamide formic acid, V-9: N-(1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-methyl-1H-pyrazol-4-yl)furan-2-carboxamide, V-10: di-tert-butyl((4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)methyl)phosphate, V-11: tert-butyl((4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)methyl) hydrogen phosphate, V-12: (4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate, V-13: N-(1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)furan-2-carboxamide, V-14: sodium (4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)methyl phosphate, V-16: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-17: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide hydrochloride, V-18: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-methyl-1H-pyrazol-4-yl)furan-2-carboxamide, V-19: 1-(isobutyryloxy)ethyl 4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazole-1-carboxylate, V-20: tert-butyl (S)-(1-(4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate, V-21: 1-methylcyclopropyl 4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazole-1-carboxylate, V-22: 1-((4-methoxybenzyl)oxy)-2-methylpropan-2-yl 4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazole-1-carboxylate, V-23: 5-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)furan-2-carboxamide, V-24: 5-(5-nitro-1H-pyrrol-3-yl)-N-(1-(propoxymethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide, V-25: N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-26: 5-(1-methyl-1H-pyrazol-4-yl)-N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide, V-27: N-(1-((1,3-trans)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-28: N-(1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-29: N-(1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-methyl-1H-pyrazol-4-yl)furan-2-carboxamide, V-30: 5-(3-methyl-1H-pyrazol-4-yl)-N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide, V-31: N-(1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-methyl-1H-pyrazol-4-yl)furan-2-carboxamide, V-32: N-(1-((1,3-cis)-3-hydroxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-33: N-(1-((1s,3s)-3-(dimethylamino)cyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-34: N-(1-((1s,3s)-3-(dimethylamino)cyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate, V-35: (4-(5-((1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)methyl phosphate bis-sodium salt, V-36: (4-(5-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate, V-37: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate, V-38: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-39: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-ethyl-1H-pyrazol-4-yl)furan-2-carboxamide formate, V-40: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-ethyl-1H-pyrazol-4-yl)furan-2-carboxamide, V-41: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)furan-2-carboxamide formate, V-42: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)furan-2-carboxamide, V-43: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-isopentyl-1H-pyrazol-4-yl)furan-2-carboxamide formate, V-44: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-isopentyl-1H-pyrazol-4-yl)furan-2-carboxamide, V-45: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-methyl-1H-pyrazol-4-yl)furan-2-carboxamide formate, V-46: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-methyl-1H-pyrazol-4-yl)furan-2-carboxamide, V-47: 5-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide, V-48: 5-(1-((3-methyloxetan-3-yl)methyl)-1H-pyrazol-4-yl)-N-(1-((3-methyloxetan-3-yl)methyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide formate, V-49: 5-(1-((3-methyloxetan-3-yl)methyl)-1H-pyrazol-4-yl)-N-(1-((3-methyloxetan-3-yl)methyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide, V-52: 5-(1-(2-(2-methoxyethoxy)ethyl)-1H-pyrazol-4-yl)-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide formate, V-53: 5-(1-(2-(2-methoxyethoxy)ethyl)-1H-pyrazol-4-yl)-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide, V-54: (4-(5-((1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate, V-55: sodium (4-(5-((1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)methyl phosphate, V-56: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-methyl-1H-pyrazol-4-yl)furan-2-carboxamide formate, V-57: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-methyl-1H-pyrazol-4-yl)furan-2-carboxamide, V-58: 5-(3,5-dimethyl-1H-pyrazol-4-yl)-N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide formate, V-59: 5-(3,5-dimethyl-1H-pyrazol-4-yl)-N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide, V-67: N-{1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate, V-68: 5-(1-methyl-1H-pyrazol-4-yl)-N-{1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl}furan-2-carboxamide, V-69: 5-(1-methyl-1H-pyrazol-4-yl)-N-{1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl}furan-2-carboxamide formate, V-70: tert-butyl-3-[4-{5-(1H-pyrazol-4-yl)furan-2-carboxamido}-3-(pyridin-2-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate formate, V-71: N-{1-(3-methoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate, cis isomer, V-72: N-{1-(3-methoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide, cis isomer, V-73: N-{1-(3-benzyloxy)cyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide, trans isomer, V-74: tert-butyl-3-[4-{5-(1H-pyrazol-4-yl)furan-2-carboxamido}-3-(pyridin-2-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate, V-75: N-(1-((1s,3s)-3-methoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, formate, V-76: N-(1-((1s,3s)-3-methoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-77: N-{1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide, free base, V-78: N-{1-(azetidin-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide, TFA salt, V-79: N-{1-(azetidin-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-80: di-tert-butyl-[[4-{4-(5-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl}methyl]phosphate, V-81: [4-{5-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2yl}-1H-pyrazol-1-yl]methyl dihydrogen phosphate, V-82: sodium [4-{5-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl}-1H-pyrazol-1-yl]methyl phosphate, V-83: N-{1-(1-acetylazetidin-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide, free base, V-84: 3-[4-{5-(1H-pyrazol-4-yl)furan-2-carboxamido}-3-(pyridin-2-yl)-1H-pyrazol-1-yl]-N-(tert-butyl)azetidine-1-carboxamide, free base. V-85: 3-[4-{5-(1H-pyrazol-4-yl)furan-2-carboxamido}-3-(pyridin-2-yl)-1H-pyrazol-1-yl]-N-isopropylazetidine-1-carboxamide, free base. V-86: 3-[4-{5-(1H-pyrazol-4-yl)furan-2-carboxamido}-3-(pyridin-2-yl)-1H-pyrazol-1-yl]-N-propylazetidine-1-carboxamide, free base. V-87: 3-[4-{5-(1H-pyrazol-4-yl)furan-2-carboxamido}-3-(pyridin-2-yl)-1H-pyrazol-1-yl]-N-cyclopropylazetidine-1-carboxamide, formate, V-88: 3-[4-{5-(1H-pyrazol-4-yl)furan-2-carboxamide}-3-(pyridin-2-yl)-1H-pyrazol-1-yl]-N-cyclopropylazetidine-1-carboxamide, V-89: N-[1-{1-(cyclopropanecarbonyl)azetidin-3-yl}-3-(pyridin-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazol-4-yl)furan-2-carboxamide, formate, V-90: N-[1-{1-(cyclopropanecarbonyl)azetidin-3-yl}-3-(pyridin-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-91: N-[1-{1-pivaloylazetidin-3-yl}-3-(pyridin-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazol-4-yl)furan-2-carboxamide, formate, V-92: N-[1-{1-pivaloylazetidin-3-yl}-3-(pyridin-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-93: 5-(1H-pyrazol-4-yl)-N-{3-(pyridin-2-yl)-1-(pyrrolidine-1-carbonyl)azetidin-3-yl}-1H-pyrazol-4-yl)furan-2-carboxamide, formate, V-94: 5-(1H-pyrazol-4-yl)-N-{3-(pyridin-2-yl)-1-(pyrrolidine-1-carbonyl)azetidin-3-yl}-1H-pyrazol-4-yl)furan-2-carboxamide, V-95: N-[1-{1-isobutylazetidin-3-yl}-3-(pyridin-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazol-4-yl)furan-2-carboxamide, formate, V-96: N-[1-{1-isobutylazetidin-3-yl}-3-(pyridin-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-97: N-(1H-pyrazol-4-yl)-N-{3-(pyridin-2-yl)-1-{1-(2,2,2-trifluoroethyl)azetidin-3-yl}-1H-pyrazol-4-yl}furan-2-carboxamide, TFA salt, V-98: N-(1H-pyrazol-4-yl)-N-{3-(pyridin-2-yl)-1-{1-(2,2,2-trifluoroethyl)azetidin-3-yl}-1H-pyrazol-4-yl}furan-2-carboxamide, V-99: N-[1-{1-butyrylazetidin-3-yl}-3-(pyridin-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazol-4-yl)furan-2-carboxamide, formate, V-100: N-[1-{1-butylazetidin-3-yl}-3-(pyridin-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-101: N-[1-{1-methylazetidin-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide, formate, V-102: N-[1-{1-methylazetidin-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-103: N-[1-{1-(2,2-difluorocyclopropane-1-carbonyl)azetidin-3-yl}-3-(pyridin-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazol-4-yl)furan-2-carboxamide, formate, V-104: N-[1-{1-(2,2-difluorocyclopropane-1-carbonyl)azetidin-3-yl}-3-(pyridin-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-105: N-(1-methyl-3-(5-morpholinopyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-106: N-(1-methyl-3-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-107: N-(3-(5-(2-hydroxy-2-methylpropoxy)pyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-108: N-(1-methyl-3-(5-(oxetan-3-yloxy)pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-109: N-(3-(5-methoxypyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-110: N-(1-isopropyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-111: N-(1-(2-morpholinoethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-112: N-(1-(2-(4-methylpiperazin-1-yl)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-113: 5-(1H-pyrazol-3-yl)-N-(3-(pyridin-2-yl)-1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-pyrazol-4-yl)furan-2-carboxamide, V-114: N-(1-((1s,3s)-3-isopropoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-115: N-(1-(difluoromethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-116: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-117: 5-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)furan-2-carboxamide, V-122: 5-(1-cyclobutyl-1H-pyrazol-4-yl)-N-(1-cyclobutyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide 2,2,2-trifluoroacetic acid salt, V-123: 5-(1-cyclobutyl-1H-pyrazol-4-yl)-N-(1-cyclobutyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide, V-124: N-(1-((1s,4s)-4-hydroxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate, V-125: N-(1-((1s,4s)-4-hydroxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-126: N-(1-((1r,4r)-4-hydroxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate, V-127: N-(1-((1r,4r)-4-hydroxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-128: 5-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)furan-2-carboxamide formate, V-129: 5-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)furan-2-carboxamide, V-130: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate, V-131: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-132: N-(1-((1S,3R)-3-ethoxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate, V-133: N-(1-((1S,3R)-3-ethoxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-134: N-(1-((1S,3R)-3-hydroxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate, V-135: N-(1-((1S,3R)-3-hydroxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-136: N-(1-((1S,3S)-3-hydroxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate, V-137: N-(1-((1S,3S)-3-hydroxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-138: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(5-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate, V-139: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(5-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-140: N-(1-((1S,3R)-3-ethoxy-2-fluorocyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate, V-141: N-(1-((1S,3R)-3-ethoxy-2-fluorocyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-142: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate, V-143: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-144: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(6-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate, V-145: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(6-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-146: 5-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)furan-2-carboxamide formate, V-147: 5-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)furan-2-carboxamide, V-148: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(4-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate, V-149: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(4-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-150: N-(3-(6-fluoropyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate, V-151: N-(3-(6-fluoropyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-152: N-(3-(3-fluoropyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate, V-153: N-(3-(3-fluoropyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-154: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate, V-155: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-156: N-(3-(3,6-difluoropyridin-2-yl)-1-((1s,3s)-3-ethoxycyclobutyl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, VI-1: N-(1-(2-hydroxy-2-methylpropyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-2: 1-(isobutyryloxy)ethyl 4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate, VI-3: tert-butyl (R)-(3-methyl-1-(4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)-1-oxobutan-2-yl)carbamate, VI-4: 2-(1-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)-1H-pyrazol-4-yl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-5: 1-methylcyclopropyl 4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate, VI-6: 1-((4-methoxybenzyl)oxy)-2-methylpropan-2-yl 4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate, VI-7: diethyl ((4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)phosphonate, VI-8: sodium ((4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)phosphonate, VI-9: ((4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)phosphonic acid, VI-10: 2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-11: N-(1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-12: N-(1-((1,3-trans)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-13: N-(1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-14: N-(1-((1,3-cis)-3-hydroxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-15: N-(1-((1s,3s)-3-(dimethylamino)cyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-16: (4-(4-((1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate bis-sodium salt, VI-17: (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate, VI-18: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, formate, VI-19: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(5-(trifluoromethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, formate, VI-20: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(5-(trifluoromethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-21: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide, formate, VI-22: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-23: 2-(3,5-dimethyl-1H-pyrazol-4-yl)-N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, formate, VI-24: 2-(3,5-dimethyl-1H-pyrazol-4-yl)-N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-25: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-26: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-27: 2-(3-methyl-1H-pyrazol-4-yl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-28: N-(1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-29: N-(1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide, formate, VI-30: N-(1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-31: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-32: 2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-33: 2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-34: N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-35: (4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate, VI-36: sodium (4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate, VI-37: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-38: potassium (4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate, VI-39: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-40: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-41: 2-(3-methyl-1H-pyrazol-4-yl)-N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, formate, VI-42: 2-(3-methyl-1H-pyrazol-4-yl)-N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-43: 2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-44: 2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-45: 2-(3-methyl-1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-46: 2-(3-methyl-1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-47: N-(1-((3-(hydroxymethyl)oxetan-3-yl)methyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-48: N-(1-((3-(hydroxymethyl)oxetan-3-yl)methyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-49: N-(1-(2-(diethylamino)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, formate, VI-50: N-(1-(2-(diethylamino)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-51: 2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-N-(1-(3-methoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-52: N-(1-(2-fluoroethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-53: 2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-54: tert-butyl-3-[4-{2-(1H-pyrazol-4-yl)thiazole-2-carboxamido}-3-(pyridin-2-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate, free base, VI-55: N-{1-(azetidin-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, TFA salt, VI-56: N-{1-(azetidin-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-57: N-{1-(3-methoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, free base, cis isomer, VI-58: N-(3-(5-methoxypyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-59: N-(1-isopropyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-60: N-(1-(2-morpholinoethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-61: N-(1-(2-(4-methylpiperazin-1-yl)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-65: N-(3-(3-fluoropyridin-2-yl)-1-((1s,3s)-3-hydroxycyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-66: 2-(1H-pyrazol-3-yl)-N-(3-(pyridin-2-yl)-1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-71: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(5-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-72: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(5-fluoro-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-73: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(5-fluoro-1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-76: N-(1-((1s,3s)-3-isopropoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-77: potassium (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate, VI-78: calcium (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate, VI-79: N-(1-((1r,3r)-3-hydroxy-3-methylcyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-80: ammonium (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate, VI-81: 5-amino-5-carboxypentan-1-aminium (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate, VI-82: 1-(4-amino-4-carboxybutyl)guanidinium (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate, VI-83: ​​(4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate, VI-84: 1,3-dihydroxy-2-(hydroxymethyl)propan-2-aminium (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate, VI-85: triethylammonium (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl hydrogen phosphate, VI-86: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-87: N-(1-(3-hydroxy-3-methylcyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-88: N-(1-(difluoromethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-89: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(3-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-90: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-91: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-92: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-93: 2-(3,5-dimethyl-1H-pyrazol-4-yl)-N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-94: 2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-95: N-(1-(difluoromethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-96: N-(1-(difluoromethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-97: N-(1-(difluoromethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-98: 2-(1-(difluoromethyl)-1H-pyrazol-4-yl)-N-(1-(difluoromethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-99: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-100: 2-(3-methyl-1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-103: 2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(3,3,3-trifluoro-2-hydroxypropyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-104: 2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(3,3,3-trifluoro-2-hydroxypropyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-105: N-(1-(dimethylcarbamoyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-106: N-(1-(dimethylcarbamoyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-107: 2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(3,3,3-trifluoro-2-hydroxy-2-(trifluoromethyl)propyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-108: 2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(3,3,3-trifluoro-2-hydroxy-2-(trifluoromethyl)propyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-117: N-(1-(2-(diethylamino)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-118: N-(1-(2-(2-fluoroethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-119: N-(1-(2-(2-fluoroethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-120: N-(1-benzyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-121: N-(1-cyclobutyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-122: N-(1-(2-(2,2-difluoroethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-123: N-(1-(((1r,3r)-3-hydroxycyclobutyl)methyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-124: N-(1-(((1r,3r)-3-hydroxycyclobutyl)methyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-125: N-(1-(dimethylcarbamoyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-126: N-(1-(dimethylcarbamoyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-127: N-(1-((1s,3s)-3-(ethoxy-d5)cyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-128: N-(1-(diethylcarbamoyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-129: N-(1-(morpholine-4-carbonyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-130: N-(1-((1s,3s)-3-(2-fluoroethoxy)cyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-131: N-(1-(morpholine-4-carbonyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-132: N-(1-(3-fluorocyclobut-2-en-1-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-133: N-(1-(3-fluorocyclobut-2-en-1-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-134: N-(1-(3,3-difluorocyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-135: N-(1-(3,3-difluorocyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-140: N-(3-(3-fluoropyridin-2-yl)-1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-141: 2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-((1r,3r)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-142: 2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-((1r,3r)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-143: N-(1-((1r,4r)-4-hydroxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-144: N-(1-((1r,4r)-4-hydroxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-145: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-146: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-147: N-(1-((1S,3R)-3-ethoxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-148: N-(1-((1S,3R)-3-ethoxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-149: N-(1-((1S,3R)-3-hydroxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-150: N-(1-((1S,3R)-3-hydroxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-151: N-(1-((1S,3S)-3-hydroxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-152: N-(1-((1S,3S)-3-hydroxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-153: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(5-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-154: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(5-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-155: N-(1-((1S,3R)-3-ethoxy-2-fluorocyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-156: N-(1-((1S,3R)-3-ethoxy-2-fluorocyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-157: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-158: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(4-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-159: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(4-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-160: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(6-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-161: 2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-162: 2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-163: (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate, VI-164: sodium (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate, VI-165: N-(3-(3-fluoropyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-166: N-(3-(3-fluoropyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-167: N-(3-(3-fluoropyridin-2-yl)-1-((1r,3r)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-168: N-(3-(3-fluoropyridin-2-yl)-1-((1r,3r)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-169: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-170: N-(3-(6-fluoropyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-171: N-(3-(6-fluoropyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-172: N-(3-(6-fluoropyridin-2-yl)-1-((1s,3s)-3-hydroxycyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-173: (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(6-fluoropyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate, VI-174: N-(3-(3,6-difluoropyridin-2-yl)-1-((1s,3s)-3-ethoxycyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-175: N-(1-((1s,4s)-4-ethoxycyclohexyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-176: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-177: N-(3-(3,6-difluoropyridin-2-yl)-1-((1s,4s)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, or VI-180: N-(3-(3,5-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide.

[0120] In certain embodiments, the compound is TIFF2024534919000016.tif86154, or a pharmaceutically acceptable salt thereof.

[0121] Additional information regarding pyrazole compounds, such as compounds according to Formula IV, can be found in US Pat. No. 9,982,000, which is incorporated herein by reference in its entirety.

[0122] In an alternative embodiment, the pyrazole compound has the general formula VII TIFF2024534919000017.tif55128, or a salt, solvate, or N-oxide thereof, wherein R is selected from H, aliphatic, acyl, heterocyclyl, carboxylic ester, amide, alkyl phosphoramidate, and alkyl phosphate.

[0123] In some embodiments, R is H and the pyrazole compound is a salt of Formula (VII).

[0124] In some embodiments, R is selected from aliphatic, acyl, heterocyclyl, carboxylic ester, amide, alkyl phosphoramidate, and alkyl phosphate. For example, R can be selected from alkyl, acyl, carboxylic ester, amide, non-aromatic heterocyclyl, alkyl phosphoramidate, and alkyl phosphate. In these embodiments, R is selected from H, C 1~4 Alkyl phosphate, C 1~4 Alkyl phosphoramidate, C 1~6 Alkyl, C 1~6 Acyl, -C(O)OC 1~6 Aliphatic, -C(O)N(R b ) 2, and 5- or 6-membered non-aromatic heterocyclyl, and each R b are 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 one or two -O- or -N(R g ) may be inserted. 3~6 forming a non-aromatic heterocyclyl moiety, and each R g are independently H or C 1~4 R is, for example, C 1~6 It can be alkyl.

[0125] In some embodiments, R is a 5- or 6-membered non-aromatic heterocyclyl, OH, —OC(O)—R a , -N(R b )2, -OC(O)-R c , carboxyl, or a combination thereof; 1~6 alkyl, and each R a are independently a 5-membered non-aromatic heterocyclyl, -CHN(R b ) 2-substituted aryl, carboxyl-substituted C 3~6 Cycloalkyl, C 1~6 Alkoxy, unsubstituted C 1~6 alkyl, or one or more N(R b )2 substituted C 1~6 Alkyl, carboxyl, carboxyl ester, -OC 1~6 Acyl, -NHC(O)(NH2)C 1~6 Alkyl, and -(OCH2CH2) 1-8 N(R b )2, and each R b are 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 one or two -O- or -N(R g ) may be inserted. 3~6 forming a non-aromatic heterocyclyl moiety, wherein each R g are independently H or C 1~4 alkyl, and each R c are independently -N(R b )2, and -N(R b )2 each R b can be the same or different nitrogen-containing non-aromatic heterocyclyl.

[0126] In some embodiments, R is —OC(O)—R c C replaced with 1~6 R may be alkyl;c can be a 5- or 6-membered unsaturated non-aromatic nitrogen-containing heterocyclyl, which can be pyrrolidinyl. c is -N(R b )2 and -N(R b )2 is -OC(O)-R c is selected to be the acid moiety of an amino acid, and optionally the acid moiety of an amino acid is the acid moiety of a naturally occurring 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, their enantiomers, and their diastereomers. In some embodiments, the naturally occurring amino acid may be an L-amino acid.

[0127] In some embodiments, -OC(O)-R c is -OC(O)CH(NH2)R d , TIFF2024534919000018.tif15128, or -OC(O)-(CH2) 1-2 C(NH2)CO2H, R d represents the amino acid side chain, H, -CH3, isopropyl, -CH2CH(CH3)2, -CH(CH3)Et, -CH2CH2SCH3, TIFF2024534919000019.tif22128, -CH2OH, -CH(OH)CH3, -CH2C(O)NH2, -CH2CH2C(O)NH2, -CH2SH, -CH2CH2CH2NHC(O)(NH)NH2, TIFF2024534919000020.tif11128, -CH2CH2CH2CH2NH2, -CH2CO2H, and CH2CH2CO2H.

[0128] In some embodiments, R is C 1~6In these embodiments, 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 substituted with alkyl, or a combination thereof 1~6 R can be acyl a , R b , and R c are each independently selected from H, aliphatic, acyl, heterocyclyl, carboxylic ester, amide, alkyl phosphoramidate, and alkyl phosphate; a are independently a 5-membered non-aromatic heterocyclyl, -CHN(R b ) 2-substituted aryl, carboxyl-substituted C 3~6 Cycloalkyl, C 1~6 Alkoxy, unsubstituted C 1~6 alkyl, or one or more N(R b )2 substituted C 1~6 Alkyl, carboxyl, carboxyl ester, -OC 1~6 Acyl, -NHC(O)(NH2)C 1~6 Alkyl, and -(OCH2CH2) 1~8 N(R b )2, and each R b are 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 one or two -O- or -N(R g ) may be inserted. 3~6 forming a non-aromatic heterocyclyl moiety, wherein each R g are independently H or C 1~4 alkyl, and each R c are independently -N(R b) 2, or 5- or 6-membered unsaturated nitrogen-containing heterocyclyl, for example, nitrogen-containing non-aromatic heterocyclyl such as pyrrolidinyl.

[0129] In any embodiment, R is a 5- or 6-membered oxygen-containing heterocyclyl, a 5- or 6-membered oxygen-containing heterocyclyl substituted with hydroxyl, hydroxymethyl, or a combination thereof, —C(O)OC 1~6 Aliphatic, OC(O)C 1~4 Alkyl, or N(R b )2 substituted with -C(O)OC 1~6 may be aliphatic or -C(O)OC 1~6 Aliphatic is C 1~4 -C(O)OC optionally substituted with alkyl 3~6 cycloalkyl, and each R b is independently selected from H, aliphatic, acyl, heterocyclyl, carboxylic ester, amide, alkyl phosphoramidate, and alkyl phosphate.

[0130] In any embodiment, the compound may be a salt, such as a pharmaceutically acceptable salt, as defined herein, and in some embodiments, the salt is hydrochloride, citrate, hemicitrate, hemitartrate, tartrate, benzenesulfonate, mesylate, sodium, hemisuccinate, or succinate.

[0131] Some exemplary compounds according to Formula VII include: TIFF2024534919000021.tif221145TIFF2024534919000022.tif208145TIFF2024534919000023.tif201145TIFF2024534919000024.tif22114 5TIFF2024534919000025.tif219145TIFF2024534919000026.tif197145TIFF2024534919000027.tif212145TIFF2024534919000028.tif52145

[0132] SCHEME 2: Exemplary compounds according to Formula VII include: VII-1: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VII-2: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate, VII-3: di-tert-butyl((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)phosphate, VII-4: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate disodium salt, VII-5: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide, VII-6: 2-(1-(acetyl-L-leucyl)-1H-pyrazol-4-yl)-N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VII-7: 1-methylcyclopropyl 4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate, VII-8: 1-(Isobutyryloxy)ethyl 4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate, VII-9: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VII-10: 2-morpholinoethyl 4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate, VII-11: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide hemi-tartrate, VII-12: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-(morpholine-4-carbonyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VII-13: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-((3-morpholinopropyl)carbamoyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VII-14: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-((3-(dimethylamino)propyl)carbamoyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VII-15: 3-morpholinopropyl 4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate, VII-16: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl L-valinate hydrochloride, VII-17: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl L-prolinate hydrochloride, VII-18: 1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethyl dihydrogen phosphate, VII-19: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl glycinate hydrochloride, VII-20: 1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethyl phosphate disodium salt, VII-21: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl (S)-2-amino-3,3-dimethylbutanoate hydrochloride, VII-22: 2-(1-acetyl-1H-pyrazol-4-yl)-N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VII-23: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl 2-amino-2-methylpropanoate hydrochloride, VII-24: 4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic acid, VII-25: methyl 4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)-4-oxobutanoate, VII-26: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-(2-morpholinoacetyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VII-27: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-(2-hydroxy-3-morpholinopropyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VII-28: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl 2-morpholinoacetate, VII-29: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl L-valinate, VII-30: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl L-valinate benzenesulfonate, VII-31: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl L-valinate mesylate, VII-32: 2-(4-methylpiperazin-1-yl)ethyl 4-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)-4-oxobutanoate, VII-33: 1-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)4-methyl L-aspartate hydrochloride, VII-34: methyl N-(2-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)-2-oxoethyl)-N-methylglycinate, VII-35: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl (S)-2-amino-3,3-dimethylbutanoate, VII-36: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl (S)-2-amino-3,3-dimethylbutanoate benzenesulfonate, VII-37: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl 4-(morpholinomethyl)benzoate, VII-38: 4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)1-methyl L-aspartate hydrochloride, VII-39: (1R,2R)-2-(((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)carbonyl)cyclohexane-1-carboxylic acid, VII-40: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl (S)-2-amino-3,3-dimethylbutanoate mesylate, VII-41: (S)-2-amino-4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic acid hydrochloride, VII-42: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4S)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-((2S,3S,4R,5R,6S)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VII-43: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4R)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-((2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VII-44: tert-butyl(1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethyl)phosphate hydrogen acetate sodium salt, VII-45: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl isopropyl carbonate, VII-46: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl di(((isopropoxycarbonyl)oxy)methyl)phosphate, VII-47: 1-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)4-methyl L-aspartate, VII-48: 1-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl) 4-methyl L-aspartic acid benzenesulfonate, VII-49: 1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethyl dihydrogen phosphate tris salt, VII-50: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl glycinate benzenesulfonate, VII-51: 2-(4-methylpiperazin-1-yl)ethyl 4-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)-4-oxobutanoate benzenesulfonate, VII-52: 2-(4-methylpiperazin-1-yl)ethyl 4-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)-4-oxobutanoate succinate, VII-53: (2R,3R)-2,3-diacetoxy-4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic acid, VII-54: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl acetate, VII-55: 4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl) 1-methyl L-aspartic acid benzenesulfonate, VII-56: 4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic acid tris salt, VII-57: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl 4-((S)-2-amino-3-methylbutanamido)butanoate hydrochloride, VII-58: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VII-59: 2-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)acetic acid, VII-60: ((((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)(hydroxy)phosphoryl)oxy)methyl isopropyl carbonate, VII-61: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl 1-amino-3,6,9,12,15,18-hexaoxahenicosan-21-oate hydrochloride, VII-62: isopropyl(((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate, VII-63: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate tris salt, VII-64: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide hydrochloride, VII-65: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide benzenesulfonate, VII-66: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide tartrate, VII-67: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide sodium salt, VII-68: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide hemicitrate, VII-69: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate ditris salt, VII-70: benzyl ((S)-1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)-4-methyl-1-oxopentan-2-yl)carbamate, VII-71: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl L-prolinate, VII-72: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl glycinate, VII-73: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl (R)-2-amino-3,3-dimethylbutanoate, VII-74: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl 2-amino-2-methylpropanoate, VII-75: (4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)1-methyl L-aspartate, VII-76: (S)-2-amino-4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic acid, VII-77: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl 4-((S)-2-amino-3-methylbutanamido)butanoate, VII-78: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl 1-amino-3,6,9,12,15,18-hexaoxahenicosan-21-oate, VII-79: 2-(1-(acetyl-D-leucyl)-1H-pyrazol-4-yl)-N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VII-80: 2-(1-(acetylleucyl)-1H-pyrazol-4-yl)-N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VII-81: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl D-valinate, VII-82: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methylvalinate, VII-83: ​​(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl D-prolinate, VII-84: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl prolinate, VII-85: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl 2-amino-3,3-dimethylbutanoate, VII-86: (1S,2S)-2-(((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)carbonyl)cyclohexane-1-carboxylic acid, VII-87: (1R,2S)-2-(((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)carbonyl)cyclohexane-1-carboxylic acid, VII-88: (1S,2R)-2-(((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)carbonyl)cyclohexane-1-carboxylic acid, VII-89: 2-(((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)carbonyl)cyclohexane-1-carboxylic acid, VII-90: (R)-2-amino-4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic acid, VII-91: 2-amino-4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic acid, VII-92: 4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)1-methyl D-aspartate, VII-93: 4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)1-methylaspartate, VII-94: 1-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)4-methyl D-aspartate, VII-95: 1-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)4-methylaspartate, VII-96: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl 4-((R)-2-amino-3-methylbutanamido)butanoate, VII-97: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl 4-(2-amino-3-methylbutanamido)butanoate, VII-98: isopropyl(((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)(phenoxy)phosphoryl)-D-alaninate, VII-99: isopropyl(((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)(phenoxy)phosphoryl)alaninate, VII-100: (2R,3S)-2,3-diacetoxy-4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic acid, VII-101: (2S,3R)-2,3-diacetoxy-4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic acid, VII-102: (2S,3S)-2,3-diacetoxy-4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic acid, VII-103: 2,3-diacetoxy-4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic acid, VII-104: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide phosphate, VII-105: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide gentisate, or VII-106: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide succinate.

[0133] III.Synthesis Synthesis of pyrazole compounds The disclosed pyrazole compounds can be prepared as exemplified below and as would be understood by one skilled in organic synthesis. An exemplary synthesis can include the following first reaction step according to Scheme VIII: TIFF2024534919000029.tif42128 Acetyl compound 2 is reacted with dimethylformamide dimethyl acetal 4 to form intermediate compound 6 at a suitable temperature to promote the reaction. Suitable temperatures are typically between 85°C and 130°C. Intermediate compound 6 is then reacted with hydrazine hydrate 8 to form pyrazole compound 10. The reaction is carried out in a suitable solvent, for example, an alcohol such as ethanol, methanol, or isopropanol, and is typically heated to reflux.

[0134] The second reaction step in an exemplary synthesis is provided below according to Scheme IX. Compound 10 is nitrated using a suitable nitrating reagent or mixture of reagents 12 to form compound 14. Suitable nitrating conditions include reacting compound 10 with nitric acid, such as fuming nitric acid, optionally in the presence of sulfuric acid. Typically, compound 10 and nitric acid are added slowly to each other. Cooling, such as with an ice bath, can be used to maintain the reaction temperature within a suitable range, such as between about 0°C and less than 50°C, between 0°C and 20°C, or between 0°C and 10°C. After the addition is complete, the reaction can be allowed to proceed until substantially complete and can be warmed to room temperature to facilitate the reaction. Optionally, additional nitrating reagent or a mixture of nitrating reagents can be added to facilitate the reaction going to completion. The reaction is then quenched, such as by addition to water and / or ice, and the product is isolated or extracted from the aqueous solution and purified as needed. Suitable purification techniques for purifying the products from any of the reactions disclosed herein include, but are not limited to, crystallization, distillation, and / or chromatography.

[0135] Continuing with Scheme IX, compound 14 is reacted with compound 16 to form compound 18. Compound 16 is then reacted with the desired R 1 The moiety includes a suitable leaving group, LG. Suitable leaving groups include R 1The leaving group may be any group that acts as a leaving group to facilitate the addition of the moiety. Suitable leaving groups include, but are not limited to, halogens, typically bromo, chloro, or iodo, as well as tosylate or mesylate groups. Compound 14 is reacted with compound 16 in a suitable solvent, typically in the presence of a base. Suitable solvents include any solvent that facilitates the reaction, such as an aprotic solvent. Suitable solvents include, but are not limited to, DMF, THF, DMSO, acetonitrile, chlorinated solvents such as dichloromethane and chloroform, DMA, dioxane, N-methylpyrrolidone, or combinations thereof. Suitable bases include any base that will facilitate the reaction of a hydride, typically sodium hydride, or a carbonate, such as potassium carbonate, sodium carbonate, or cesium carbonate. The reaction can be heated, if necessary, to 50° C., 100° C., or higher, or the reaction can proceed at room temperature. Compound 18 is then isolated from the reaction mixture and purified as needed.

[0136] Compound 18 is then reacted with a suitable reducing agent 20 to reduce the nitro moiety to an amine. Suitable reducing agents include, but are not limited to, hydrogen gas in the presence of a catalyst such as a palladium catalyst; borohydride such as sodium borohydride, optionally in the presence of a catalyst such as a nickel catalyst; zinc metal in acetic acid; or iron powder in water or water and acid. In certain embodiments, hydrogen gas is used in the presence of palladium on a carbon catalyst and in a suitable solvent such as ethyl acetate or methanol. In some embodiments, a combination of reducing agents and / or techniques is used. For example, the reduction can be first carried out using a first method involving a first reducing agent and / or technique, but results in a mixture of products. The first method can be repeated, and / or a second method involving a second reducing agent and / or technique can be carried out. Upon completion of the reaction, as indicated by analytical techniques such as LC-MS, TLC, or HPLC, the product compound 22 is isolated and purified as necessary.

[0137] The third step of an exemplary reaction sequence is provided below according to Scheme X. Compound 22 is reacted with carboxylic acid 24 to form compound 26. Carboxylic acid 24 is activated by any suitable method and then reacted with the amine on compound 22. Suitable activation methods include, but are not limited to, forming the acid chloride by treatment with thionyl chloride, by treatment with a base such as 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) and diisopropylethylamine (DIPEA), by treatment with carbonyldiimidazole (CDI), or by treatment with a carbodiimide such as dicyclohexylcarbodiimide (DCC) or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC).

[0138] Compound 26 is then coupled with compound 28 to form compound 30 using any suitable coupling reaction for forming a bond between two rings. In the above example, a boronic acid coupling is shown, and the leaving group LG on compound 26 is typically bromo or iodo. Other suitable coupling functional groups include trialkyltin or boronic acid esters. The coupling reaction typically proceeds in the presence of a suitable catalyst. For boronic acid coupling, the catalyst is typically a palladium catalyst such as PdCl(dppf), Pd[P(Ph)]Cl, palladium acetate and triphenylphosphine, or tetrakis(triphenylphosphine)palladium(0). The reaction is carried out in the presence of a base such as sodium, potassium, or cesium carbonate and in a suitable solvent or solvent mixture such as dioxane, dioxane / water, or DME / ethanol / water. The reaction can be heated to a suitable temperature, e.g., 50°C to 125°C, typically about 100°C, and / or stirred for a suitable time, e.g., 1 hour to 3 days, 6 hours to 24 hours, or 12 hours to 18 hours, to facilitate completion of the reaction. Compound 30 is then isolated from the reaction mixture and purified by suitable techniques.

[0139] An alternative exemplary synthesis may involve the following first reaction step according to Scheme XI: Compound 32 is nitrated using a suitable nitrating reagent or mixture of reagents 34 to form compound 36. Suitable nitrating conditions include reacting compound 32 with nitric acid, such as fuming nitric acid, optionally in the presence of sulfuric acid. Typically, compound 32 and nitric acid are added slowly to each other. Cooling, such as with an ice bath, can be used to maintain the reaction temperature within a suitable range, such as about 0°C to less than 50°C, 0°C to 20°C, or 0°C to 10°C. After the addition is complete, the reaction can be allowed to proceed until substantially complete and can be warmed to room temperature to promote the reaction. Optionally, additional nitrating reagent or mixture of nitrating reagents can be added to promote the reaction to completion. The reaction is then quenched, such as by addition to water and / or ice, and the product is isolated or extracted from the aqueous solution and purified as needed. Suitable purification techniques for purifying the products from any of the reactions disclosed herein include, but are not limited to, crystallization, distillation, and / or chromatography.

[0140] Continuing with Scheme XI, compound 36 is reacted with compound 38 to form compound 40. Compound 38 contains a desired ring, such as a cyclobutyl, cyclopentyl, or cyclohexyl ring, and a suitable leaving group LG. Suitable leaving groups include any group that serves as a leaving group to facilitate the addition of a ring to compound 36. Suitable releasing groups include, but are not limited to, halogens, typically bromo, chloro, or iodine, and tosylate or mesylate groups. Compound 36 is reacted with compound 38 in a suitable solvent, typically in the presence of a base. Suitable solvents include any solvent that promotes the reaction, such as an aprotic solvent. Suitable solvents include, but are not limited to, DMF, THF, DMSO, acetonitrile, chlorinated solvents such as dichloromethane and chloroform, DMA, dioxane, N-methylpyrrolidone, or a combination thereof. Suitable bases include any base that will promote the reaction of a hydride, typically sodium hydride, or a carbonate, such as potassium carbonate, sodium carbonate, or cesium carbonate. The reaction can be heated to 50° C., 100° C. or higher, if necessary, or the reaction can proceed at room temperature. Compound 40 is then isolated from the reaction mixture and purified as needed.

[0141] Compound 40 is then reacted with a suitable reducing agent 42 to reduce the carbonyl moiety to a hydroxyl. Suitable reducing agents include, but are not limited to, sodium borohydride, diisobutylaluminum hydride, or lithium aluminum hydride. The reaction is carried out in a suitable solvent to promote the reaction, such as an alcohol, especially methanol or ethanol, THF, or diethyl ether. The reaction can be heated, as needed, to 50° C., 100° C. or higher, or cooled to below 20° C., below 10° C., below 0° C., or the reaction can proceed at room temperature. Upon completion of the reaction, as indicated by analytical techniques such as LC-MS, TLC, or HPLC, the product compound 44 is optionally isolated and purified by a suitable technique, such as column chromatography.

[0142] Optionally, compound 44 can be reacted with compound 46 to form compound 48. Compound 46 can be prepared by reacting the desired R x The moiety includes a suitable leaving group, LG. Suitable leaving groups include R x The leaving group may be any group that serves as a leaving group to facilitate the addition of a moiety. Suitable leaving groups include, but are not limited to, halogens, typically bromo, chloro, or iodo, as well as tosylate or mesylate groups. Compound 44 is reacted with compound 46 in a suitable solvent, typically in the presence of a base or other reagent(s) that facilitates the reaction. Suitable solvents include any solvent that facilitates the reaction, such as an aprotic solvent. Suitable solvents include, but are not limited to, DMF, THF, DMSO, acetonitrile, chlorinated solvents such as dichloromethane and chloroform, DMA, dioxane, N-methylpyrrolidone, or combinations thereof. Suitable bases or reagents that facilitate the reaction include, but are not limited to, silver triflate, 2,6-di-t-butylpyridine, sodium hydride, or combinations thereof. Typically, compound 46 is slowly combined with the reactants. Cooling, such as with an ice bath, may be used to maintain the reaction temperature within a suitable range, such as between about 0°C and less than 50°C, between 0°C and 20°C, or between 0°C and 10°C. After the addition is complete, the reaction can be allowed to proceed until substantially complete, or to facilitate the reaction, the reaction can be allowed to warm to room temperature or can be heated, for example, to 50° C., 100° C. or higher. Upon completion of the reaction, as indicated by analytical techniques such as LC-MS, TLC, or HPLC, the product, compound 48, is isolated and purified, if necessary, by a suitable technique, such as column chromatography.

[0143] Alternatively, compound 40 can be prepared by the exemplary synthetic route according to Scheme XII. Referring to Scheme XII, compound 36 is reacted with compound 50 to form compound 52. Compound 50 contains a desired ring, such as a cyclobutyl, cyclopentyl, or cyclohexyl ring, a suitable leaving group, LG, and a protected carbonyl moiety, such as an acetal or ketal. In the example above, a cyclic ketal moiety is shown. Suitable leaving groups include any group that serves as a leaving group to facilitate the addition of a ring to compound 36, including, but not limited to, halogens, typically bromo, chloro, or iodo, and tosylate or mesylate groups. Compound 36 is reacted with compound 50 in a suitable solvent, typically in the presence of a base. Suitable solvents include any solvent that facilitates the reaction, such as aprotic solvents. Suitable solvents include, but are not limited to, DMF, THF, DMSO, acetonitrile, chlorinated solvents such as dichloromethane and chloroform, DMA, dioxane, N-methylpyrrolidone, or combinations thereof. Suitable bases include any base that will promote the reaction of a hydride, typically sodium hydride, or a carbonate, such as potassium carbonate, sodium carbonate, or cesium carbonate. The reaction can be heated to 50° C., 100° C., or higher, if necessary, or the reaction can proceed at room temperature. Compound 52 is then isolated from the reaction mixture and purified, if necessary, by a suitable technique, such as column chromatography.

[0144] Compound 52 is then reacted with a suitable reagent 54 to form compound 40. Reagent 54 can be any reagent suitable for removing a protecting group and / or forming a carbonyl moiety. In the exemplary synthesis shown in Scheme 5, the protecting group is a cyclic ketal, and suitable reagents 54 include, but are not limited to, pyridinium tosylate (PPTS), para-toluenesulfonic acid, hydrochloric acid, or acetic acid. The reaction is carried out in a solvent or mixture of solvents suitable for promoting the reaction, such as acetone, THF, acetic acid, water, or a combination thereof. The reaction can be heated, for example, to 50° C., 100° C. or higher, or at reflux, if desired, or the reaction can proceed at room temperature. Compound 40 is then isolated from the reaction mixture and optionally purified by a suitable technique, such as column chromatography.

[0145] The second step of an exemplary reaction sequence is provided below according to Scheme XIII. Compound 48 is then reacted with a suitable reducing agent 56 to reduce the nitro moiety to an amine. In certain embodiments where the desired product compound contains a hydroxyl moiety, compound 44 can be used in place of compound 48. Suitable reducing agents include, but are not limited to, hydrogen gas in the presence of a catalyst such as a palladium catalyst, borohydride such as sodium borohydride, optionally in the presence of a catalyst such as a nickel catalyst, zinc metal in acetic acid, or iron powder in water or water and acid. In certain embodiments, hydrogen gas is used in the presence of palladium on a carbon catalyst and in a suitable solvent such as ethyl acetate or methanol. In some embodiments, a combination of reducing agents and / or techniques is used. For example, reduction can be first performed using a first method involving a first reducing agent and / or technique, resulting in a mixture of products. The first method can be repeated, and / or a second method involving a second reducing agent and / or technique can be performed. Upon completion of the reaction, as indicated by analytical techniques such as LC-MS, TLC, or HPLC, the product, compound 58, is isolated and purified as necessary.

[0146] Compound 58 is reacted with carboxylic acid 60 to form compound 62. Carboxylic acid 60 is activated by any suitable method and then reacted with the amine on compound 58. Suitable activation methods include, but are not limited to, forming the acid chloride by treatment with thionyl chloride, by treatment with a base such as 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) and diisopropylethylamine (DIPEA), by treatment with carbonyldiimidazole (CDI), or by treatment with a carbodiimide such as dicyclohexylcarbodiimide (DCC) or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC).

[0147] Compound 62 is then coupled with compound 64 to form compound 66 using any suitable coupling reaction for forming a bond between two rings. In the above example, a boronic acid coupling is shown, and the leaving group LG on compound 62 is typically bromo or iodo. Other suitable coupling functional groups include trialkyltin or boronic acid. The coupling reaction typically proceeds in the presence of a suitable catalyst. For boronic ester or boronic acid coupling, the catalyst is typically a palladium catalyst such as PdCl(dppf), Pd[P(Ph)]Cl, palladium acetate and triphenylphosphine, or tetrakis(triphenylphosphine)palladium(0). The reaction is carried out in the presence of a base such as sodium, potassium, or cesium carbonate and in a suitable solvent or solvent mixture such as dioxane, dioxane / water, or DME / ethanol / water. The reaction can be heated to a suitable temperature, for example, 50°C to 125°C, typically about 100°C, and / or stirred for a suitable time, for example, 1 hour to 3 days, 6 hours to 24 hours, or 12 hours to 18 hours, to facilitate completion of the reaction. Compound 66 is then isolated from the reaction mixture and purified by suitable techniques.

[0148] Certain embodiments may include a phosphate moiety. Scheme XIV provides an exemplary synthesis of certain such embodiments. TIFF2024534919000035.tif80141 Compound 68 is reacted with compound 70 to form compound 72. Compound 70 can be used to obtain the desired R y Exemplary R groups include the aryl group and a suitable leaving group, LG. y The moieties include, but are not limited to, alkyl, aliphatic, typically methyl, ethyl, propyl, isopropyl, or t-butyl, aryl, heteroaliphatic, or heterocyclic. y The moieties can be the same or different. Suitable leaving groups include, but are not limited to, halogens, typically bromo, chloro, or iodo, and tosylate or mesylate groups. Compound 68 is reacted with compound 70 in a suitable solvent, typically in the presence of a base. Suitable solvents include any solvent that promotes the reaction, such as an aprotic solvent. Suitable solvents include, but are not limited to, DMF, THF, DMSO, acetonitrile, chlorinated solvents such as dichloromethane and chloroform, DMA, dioxane, N-methylpyrrolidone, or combinations thereof. Suitable bases include any base that will promote the reaction of a hydride, typically sodium hydride, or a carbonate, such as potassium carbonate, sodium carbonate, or cesium carbonate. The reaction can be heated, if necessary, to 50° C., 100° C. or higher, or the reaction can proceed at room temperature. Compound 72 is then isolated from the reaction mixture and purified as needed.

[0149] Compound 72 is then reacted with compound 74 to form compound 76. Compound 74 can be any compound suitable for forming the acid moiety in compound 76. Compound 74 can be an acidic reagent such as trifluoroacetic acid, hydrochloric acid, or hydrobromic acid, or it can be a basic reagent such as sodium hydroxide, lithium hydroxide, or potassium hydroxide. Suitable solvents include, but are not limited to, chlorinated solvents such as dichloromethane and chloroform, alcohols such as methanol and ethanol, water, or combinations thereof. The reaction can be heated, as needed, to 50° C., 100° C. or higher, or cooled to below 20° C., below 10° C., below 0° C., or the reaction can proceed at room temperature. Upon completion of the reaction, as indicated by analytical techniques such as LC-MS, TLC, or HPLC, the product compound 76 is optionally isolated and purified by suitable techniques, such as by agitation, such as by stirring or sonication, in a suitable solvent or solvent system. Suitable solvents or solvent systems include, but are not limited to, acetone / water, acetone, diethyl ether, or alcohol / water.

[0150] Compound 76 is then reacted with compound 78 to form salt compound 80. Compound 78 can be any compound that provides a suitable counterion CA to salt compound 80, such as calcium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonia, trimethylamine, tris(hydroxymethyl)aminomethane, or an amino acid such as lysine or arginine. + , K. + , Li + , or NH4 + When compound 80 contains two CA ions, the counterion CA is 2+ Those skilled in the art will understand that when compound 80 has two positive charges, such as in the formula: , compound 80 contains one CA ion.

[0151] IV. Compositions Comprising the Compounds Disclosed Herein The disclosed compounds can be used alone or in combination, and / or in combination with or adjunctively with at least one second therapeutic agent, and further, the compound(s), and, if present, the at least one second therapeutic agent, can be used in combination with any suitable additive useful in forming a composition for administration to a subject. Additives can be included in pharmaceutical compositions for a variety of purposes, such as diluting the composition for delivery to a subject, facilitating processing of the formulation, providing advantageous material properties to the formulation, facilitating dispersion from a delivery device, stabilizing the formulation (e.g., antioxidants or buffers), or providing a pleasant or palatable taste or consistency to the formulation.Typical excipients include, by way of example and without limitation, mono-, di-, and polysaccharides, sugar alcohols, and other polyols such as lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol, starch, or combinations thereof; surfactants such as sorbitol, diphosphatidylcholine, and lecithin; bulking agents; buffers such as phosphate and citrate buffers; anti-adherents such as magnesium stearate; binders such as sugars (including disaccharides such as sucrose and lactose), polysaccharides (such as starch, cellulose, microcrystalline cellulose, cellulose ethers (such as hydroxypropyl cellulose)), gelatin, synthetic polymers (such as polyvinylpyrrolidone, polyalkylene glycols (gylcol)); coatings (such as hydroxypropyl methylcellulose, shellac, corn protein zein, and cellulose ethers including gelatin); release aids (such as enteric coatings); disintegrants (such as dibasic calcium phosphate, vegetable fats and oils, lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, and magnesium stearate); fillers (such as mint, cherry, anise, peach, apricot or licorice, raspberry, and vanilla); flavors and sweeteners (such as minerals exemplified by talc or silica, vegetable stearin, magnesium stearate, or stearic acid); lubricants (such as fats and oils exemplified by phosphates); preservatives (such as 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); colorants; compression aids; emulsifiers; encapsulating agents; gums; pharmaceutically acceptable excipients including carriers and / or adjuvants such as granulating agents; and combinations thereof.

[0152] V. Therapeutic Combinations The disclosed compounds can be used alone, in combination with other disclosed compounds, and / or as an adjunct to or in combination with other established therapies. In another aspect, the compounds can be used in combination with other therapeutic agents useful for treating infectious diseases and / or other diseases or conditions. The compounds and / or other agents can be administered simultaneously, sequentially in any order, by the same route of administration or by different routes.

[0153] In some embodiments, 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 secretagogue, an antiviral agent, an anticancer agent, an antifungal agent, or a combination thereof. In certain embodiments, the second therapeutic agent may be an anti-inflammatory agent, an immunosuppressant, and / or a steroid. In certain conditions, the patient is also treated with an antiviral agent, such as remdesivir or GS-441524, in combination with the compound.

[0154] The anti-inflammatory agent can be a steroid, such as budesonide, dexamethasone, or prednisone, or a non-steroidal anti-inflammatory agent. In certain embodiments, the non-steroidal anti-inflammatory agent is selected from aminosalicylates (e.g., sulfasalazine, mesalamine, olsalazine, and balsalazide), cyclooxygenase inhibitors (COX-2 inhibitors, such as rofecoxib and celecoxib), diclofenac, etodolac, famotidine, fenoprofen, flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin, meclofenamate, mefenamic acid, meloxicam, nambumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin, or a combination thereof.

[0155] In some embodiments, the immunosuppressant is a drug designed to inhibit cellular immunity while leaving the recipient's humoral immune response intact, including corticosteroids such as mercaptopurine, dexamethasone, hydrocortisone, prednisone, methylprednisolone, and prednisone; alkylating agents such as cyclophosphamide; calcineurin inhibitors such as cyclosporine, sirolimus, and tacrolimus; inhibitors of inosine monophosphate dehydrogenase (IMPDH) such as mycophenolic acid, mycophenolate mofetil, and azathioprine; and various antibodies (e.g., antilymphocyte globulin (ALG), antithymocyte globulin (ATG), monoclonal anti-T cell antibody (OKT3)), radiation, or a combination thereof. In one embodiment, the antibody is infliximab. Azathioprine is currently available from Salix Pharmaceuticals, Inc. under the trade name Azasan; mercaptopurine is currently available from Gate Pharmaceuticals, Inc. under the trade name Purinethol; prednisone and prednisolone are currently available from Roxane Laboratories, Inc.; methylprednisolone is currently available from Pfizer; sirolimus (rapamycin) is currently available from Wyeth-Ayerst under the trade name Rapamune; tacrolimus is currently available from Fujisawa under the trade name Prograf; cyclosporine is currently available from Novartis under the trade name Sandimmune and from Abbott under the trade name Gengraf; IMPDH inhibitors such as mycophenolate mofetil and mycophenolic acid are currently available from Roche under the trade name Cellcept and from Novartis under the trade name Myfortic; azathioprine is currently available from GlaxoSmithKline under the trade name Imuran; and antibodies are currently available from Ortho It is available from Biotech under the trade name Orthoclone, from Novartis under the trade name Simulect (basiliximab), and from Roche under the trade name Zenapax (daclizumab).

[0156] In certain embodiments, the second therapeutic agent is or includes a steroid, such as a corticosteroid, including, but not limited to, a glucocorticoid and / or a mineralocorticoid. Steroids suitable for use in combination with the disclosed compounds include synthetic and non-synthetic glucocorticoids. Exemplary steroids, such as glucocorticoids, suitable for use in the disclosed methods include, but are not limited to, alclometasone, algestone, beclomethasone (e.g., beclomethasone dipropionate), betamethasone (e.g., betamethasone 17-valerate, betamethasone sodium acetate, betamethasone sodium phosphate, betamethasone valerate), budesonide, clobetasol (e.g., clobetasol propionate), clobetasone, clocortolone (e.g., clocortolone pivalate), cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone (e.g., dexamethasone 21-phosphate, dexamethasone acetate, dexamethasone sodium phosphate), diflorasone (e.g., diflorasone diacetate), diflucortolone, difluprednate, enoxolone, fluazacort, flucloronide, flu Drocortisone (e.g., fludrocortisone acetate), flumethasone (e.g., flumethasone pivalate), flunisolide, fluocinolone (e.g., fluocinolone acetonide), fluocinonide, fluocortin, fluocortolone, fluorometholone (e.g., fluorometholone acetate), fluperolone (e.g., fluperolone acetate), fluprednidene, fluprednisolone, flurandrenolide, fluticasone (e.g., fluticasone propionate), formocol Tar, halcinonide, halobetasol, halometasone, halopredone, hydrocortamate, hydrocortisone (e.g., hydrocortisone 21-butyrate, hydrocortisone aceponate, hydrocortisone acetate, hydrocortisone buteprate, hydrocortisone butyrate, hydrocortisone cypionate, hydrocortisone hemisuccinate, hydrocortisone probutate, hydrocortisone sodium phosphate, hydrocortisone sodium succinate,hydrocortisone valerate), loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone (methylprednisolone aceponate, methylprednisolone acetate, methylprednisolone hemisuccinate, methylprednisolone sodium succinate), mometasone (e.g., mometasone furoate), paramethasone (e.g., paramethasone acetate), prednicarb, prednisolone (e.g., prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisolone 21-hemisuccinate, prednisolone acetate; prednisolone farnesylate prednisolone, prednisolone hemisuccinate, prednisolone-21 (beta-D-glucuronide), prednisolone metasulfobenzoate, prednisolone stearate, prednisolone tebutate, prednisolone tetrahydrophthalate), prednisone, prednivar, prednylidene, rimexolone, tixocortol, triamcinolone (e.g., triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, triamcinolone acetonide 21-palmitate, triamcinolone diacetate), or any combination thereof. Further information regarding steroids and their salts can be found, for example, in Remington's Pharmaceutical Sciences, A. Osol, ed., Mack Pub. Co., Easton, Pa. (16th ed. 1980).

[0157] In some instances, the steroid is a glucocorticoid and may be selected from cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, or a combination thereof. In particular instances, the steroid is or includes prednisone. In another particular instance, the steroid is or includes dexamethasone.

[0158] In some embodiments, the compounds may be administered in combination with one or more other therapeutic agents that may target either SARS-CoV-2 or the symptoms of COVID-19 infection. These agents include: (a) inhibitors of SARS-CoV-2 cell entry; (b) inhibitors of SARS-CoV-2 replication, membrane fusion, and assembly; and (c) phytochemicals and natural products that target coronaviruses. The therapy may optionally be combined with plasma therapy.

[0159] Inhibitors of SARS-CoV-2 cell entry Inhibitors of SARS-CoV-2 entry into cells include inhibitors of the TMPRSS2 serine protease and inhibitors of angiotensin-converting enzyme 2 (ACE2).

[0160] Inhibitors of TMPRSS2 serine protease include, but are not limited to:

[0161] Camostat mesylate (Foipan™) Camostat (FOY-305), [N,N-dimethylcarbamoylmethyl 4-(4-guanidinobenzoyloxy)-phenylacetate]methanesulfate, and camostat mesylate (Foipan™), alternatively known as camostat mesylate (NI-03), (CAS number: 59721-28-7).

[0162] Nafamostat mesylate (Buipel™) Nafamostat mesylate (Buipel™), (6-amidino-2-naphthyl-4-guanidinobenzoic acid-dimethanesulfonate) (FUT-175), (CAS number: 81525-10-2).

[0163] ACE2 inhibitors and antimalarials / parasitics include, but are not limited to:

[0164] Chloroquine phosphate and hydroxychloroquine Chloroquine phosphate (Resochin™) and its derivatives hydroxychloroquine (Quensyl™, Plaquenil™, Hydroquin™, Dolquine™, Quinoric™), which have been used for decades to prevent and treat malaria, have recently been demonstrated as potential broad-spectrum antiviral drugs.

[0165] Cepharanthine / Selamectin / Mefloquine Hydrochloride Cepharanthine (an anti-inflammatory alkaloid from Stephania cepharantha Hayata) (CAS number: 48,104,902), selamectin (an avermectin isolated from Streptomyces avermitilis and used as an antihelminthic and parasitic agent in veterinary medicine) (CAS number: 220119-17-5), and mefloquine hydrochloride (Lariam™, used for the prevention and treatment of malaria) have been shown to inhibit infection of monkey Vero E6 cells by pengolin coronavirus GX_P2V / 2017 / Guangxi (GX_P2V).

[0166] Experimental inhibitors of ACE2 In addition to the above, peptide inhibitors (e.g., K of 2.8 nM) i and an IC of 10.1 μM 50 Many experimental inhibitors of ACE2 exist, including DX600 (Huang et al., J. Biol. Chem. 2003;278:15532-15540), a dipeptide and tripeptide with ACE2 activity, and small molecules (e.g., MLN-4760 (CAS No.: 305335-31-3), N-(2-aminoethyl)-1-aziridine-ethanamine, and the TNF-α converting enzyme (TACE) small molecule inhibitor TAPI-2). In addition, the phytochemical nicotianamine (CAS No.: 34441-14-0), a metal chelator ubiquitously present in higher plants, has an IC of 84 nM. 50 It can be used because it is a potent inhibitor of human ACE2 having

[0167] Casirivimab (REGN10933) Casirivimab is a monoclonal antibody specifically designed to block SARS-CoV-2 infectivity. It has been granted Emergency Use Authorization (EUA) by the FDA for use in combination with imdevimab. The two potent virus-neutralizing antibodies that form the cocktail bind non-competitively to the critical receptor-binding domain of the viral spike protein, which reduces the ability of mutated viruses to evade treatment and protects against spike variants that have emerged in the human population.

[0168] Imdevimab (REGEN10987) Imdevimab is a monoclonal antibody specifically designed to block SARS-CoV-2 infectivity. It has been granted EUA by the FDA for use in combination with casirivimab. The two potent virus-neutralizing antibodies that form the cocktail bind non-competitively to the critical receptor-binding domain of the viral spike protein, which reduces the ability of mutated viruses to evade treatment and protects against spike variants that have emerged in the human population.

[0169] Casirivimab and imdevimab can be administered together, for example, separately or as a mixture, this combination also known as the Regeneron Antibody Cocktail.

[0170] Bamlanivimab (LY-CoV555) Bamlanivimab is a recombinant neutralizing human IgG1k monoclonal antibody that binds to the receptor-binding domain of the SARS-CoV-2 spike protein and prevents the spike protein from binding to the human ACE2 receptor. Bamlanivimab has been granted EUA by the FDA for use in combination with etesevimab in non-hospitalized adult and adolescent patients with mild to moderate symptoms of COVID-19 and in patients who are at high risk of developing severe COVID-19 symptoms or who are likely to require hospitalization.

[0171] Etesevimab (LY-CoV016) Etesevimab (LY-CoV016, also known as JS016) is a recombinant, fully human, monoclonal neutralizing antibody that binds with high affinity and specificity to the SARS-CoV-2 surface spike protein receptor-binding domain and can block viral binding to the ACE2 host cell surface receptor. Etesevimab has been granted EUA by the FDA for use in combination with bamlanivimab in non-hospitalized adult and adolescent patients with mild to moderate symptoms of COVID-19 and in patients at high risk of developing severe COVID-19 symptoms or requiring hospitalization.

[0172] Bamlanivimab and etezevimab can be administered together, for example, separately, or as a mixture, this combination also known as the Lilly antibody cocktail.

[0173] Inhibitors of SARS-CoV-2 replication, membrane fusion, and assembly These agents include ribonucleoside analogs, protease inhibitors, membrane fusion inhibitors, guanine analogs, and other compounds, examples of which are described below.

[0174] Remdesivir (VeKlury) Remdesivir (GS-5734) (CAS number: 1809249-37-3) is a small molecule adenine nucleotide analogue antiviral drug that has demonstrated efficacy against Ebola virus in rhesus monkeys. The drug can be administered daily by intravenously administering 10 mg kg(-1) of remdesivir for several days. Remdesivir is a prodrug that is metabolized to the active form GS-441524, an adenine nucleotide analogue that interferes with the activity of viral RNA-dependent RNA polymerase (RdRp), promoting evasion of viral exoribonuclease proofreading and resulting in inhibition of viral RNA synthesis. The drug's prophylactic and therapeutic activity are well documented. Remdesivir has been approved by the FDA for the treatment of COVID-19 requiring hospitalization.

[0175] N 4 -Hydroxycytidine N4-hydroxycytidine, or EIDD-1931, is a ribonucleoside analog that induces mutations in RNA virions. N4-hydroxycytidine has been shown to inhibit SARS-CoV-2 and other human and bat coronaviruses in mouse and human airway epithelial cells. Sheahan et al. Sci. Transl. Med. 2020 12 541. N4-hydroxycytidine or a prodrug (e.g., EIDD-2801) can be used. The N4-hydroxycytidine prodrug, EIDD-2801, is also being investigated for broad-spectrum activity against the coronavirus family of viruses. 3

[0176] Lopinavir / ritonavir (Kaletra™) Lopinavir (ABT-378) is a highly potent inhibitor of the human immunodeficiency virus (HIV) protease, which is essential for intracellular HIV assembly. The combination of lopinavir and ritonavir (Kaletra™) has been established as an effective oral medication for treating patients infected with coronavirus. Patients can be treated, for example, with a lopinavir (400 mg) / ritonavir (100 mg) combination every 12 hours for 14 days.

[0177] Umifenovir (Arbidol™) Umifenovir (Arbidol™), (ethyl-6-bromo-4-[(dimethylamino)methyl]-5-hydroxy-1-methyl-2[(phenylthio)methyl]-indole-3-carboxylate hydrochloride monohydrate) (CAS number: 131707-25-0), is a small indole derivative molecule that blocks viral host cell entry by inhibiting membrane fusion between the viral envelope and the host cytoplasmic membrane through the inhibition of clathrin-mediated endocytosis.

[0178] Favipiravir (Avigan™) Favipiravir (Avigan™), (T-705), (6-fluoro-3-hydroxy-2-pyrazinecarboxamide) (CAS number: 259793-96-9) is an oral pyrazinecarboxamide derivative and guanine analog that selectively and potently inhibits the RNA-dependent RNA polymerase (RdRp) of RNA viruses, inducing lethal RNA transversion mutations and thereby producing a nonviable viral phenotype. Favipiravir inhibits the replication of numerous RNA viruses, including influenza A virus, flaviviruses, alphaviruses, filoviruses, bunyaviruses, arenaviruses, and noroviruses, as well as West Nile virus, yellow fever virus, foot-and-mouth disease virus, Ebola virus, and Lassa virus.

[0179] This treatment may be combined with, for example, a monoclonal antibody against the human interleukin-6 receptor, tocilizumab, or chloroquine phosphate.

[0180] SARS-CoV-2 3Clpro protease inhibitor 3Cl (also called M) constitutes the main protease of betacoronaviruses, essential for processing the polyprotein translated from viral RNA. Inhibitors of 3Cl, called N3, have been identified through computer-aided drug design. Michael receptor inhibitors that can inhibit N3, SARS-CoV, and MERS-CoV 3Cls, can also be used.

[0181] Oseltamivir (Tamiflu) Oseltamivir (GS-4104) is a neuraminidase inhibitor, a competitive inhibitor of the influenza neuraminidase enzyme. This enzyme cleaves sialic acid found on glycoproteins on the surface of human cells, helping new virions leave the cell. Oseltamivir therefore prevents new virus particles from being released.

[0182] immunomodulator Dexamethasone Dexamethasone is a corticosteroid and immunomodulator / immunosuppressant used to treat various inflammatory conditions, including, but not limited to, rheumatoid arthritis, bronchospasm, and lupus. Dexamethasone is an agonist of the glucocorticoid receptor, which, upon binding, activates glucocorticoid signaling, leading to suppression of the immune response. Dexamethasone has been granted Emergency Use Authorization (EUA) by the FDA for the treatment of severe COVID-19 cases requiring hospitalization and supplemental oxygen. The randomized evaluation of the COVID-19 Therapy (Recovery) trial found that dexamethasone treatment reduced COVID-19 mortality compared with standard care. Dexamethasone has also been granted EUA for use in combination with remdesivir when patients require increased amounts of oxygen.

[0183] Prednisone Prednisone is a corticosteroid and immunomodulator / immunosuppressant used to treat various inflammatory conditions, including but not limited to asthma, chronic obstructive pulmonary disease, and rheumatoid arthritis. Prednisone is an agonist of the glucocorticoid receptor, and upon binding, activates glucocorticoid signaling, which leads to suppression of the immune response. Prednisone has been granted EUA by the FDA as an alternative to dexamethasone for the treatment of severe COVID-19 cases requiring hospitalization and supplemental oxygen.

[0184] Methylprednisone Methylprednisone is a synthetic glucocorticoid primarily used for anti-inflammatory and immunosuppressive purposes. Methylprednisone is an agonist of the glucocorticoid receptor, and upon binding, activates glucocorticoid signaling, which leads to suppression of the immune response. Methylprednisone has been granted EUA by the FDA as an alternative to dexamethasone for the treatment of severe COVID-19 cases requiring hospitalization and supplemental oxygen.

[0185] Hydrocortisone Hydrocortisone is a glucocorticoid, a pharmaceutical form of the hormone cortisol. It is used to treat autoimmune disorders and immunosuppression. Hydrocortisone is an agonist of the glucocorticoid receptor, and upon binding, it activates glucocorticoid signaling, which leads to suppression of the immune response. Hydrocortisone has been granted EUA by the FDA as an alternative to dexamethasone for the treatment of severe COVID-19 cases requiring hospitalization and supplemental oxygen. A meta-analysis study published by the World Health Organization, titled Rapid Evidence Appraisal for COVID-19 Therapies (REACT), found that hydrocortisone is effective in reducing mortality in severe COVID-19 patients compared with standard treatment.

[0186] Baricitinib (Olumiant) Baricitinib is a Janus kinase (JAK) inhibitor often used to treat rheumatoid arthritis, in addition to other autoimmune diseases. Baricitinib has been granted EUA by the FDA only for use in combination with remdesivir in rare circumstances where corticosteroids may be used. Baricitinib has been shown to specifically inhibit the activity of Janus kinases 1 and 2.

[0187] others Other immunomodulatory agents include osilizumab and sarilumab, monoclonal antibodies that target cytokines or their receptors, and other JAK inhibitors (such as tofacitinib, upadacitinib, and ruxolitinib).

[0188] This therapy may also be used in conjunction with plasma therapy and / or invermectin.

[0189] In influenza embodiments, the compounds of the invention may be administered in combination with one or more other therapeutic agents that may target either the influenza virus or the symptoms of influenza infection. The agents include (a) inhibitors of influenza virus cell entry, (b) inhibitors of influenza virus replication, assembly, and release, and (c) immunomodulators. This therapy may optionally be combined with plasma therapy.

[0190] Inhibitors of influenza virus entry into cells Inhibitors of influenza virus entry into cells include inhibitors of influenza HA-induced membrane fusion.

[0191] Inhibitors of influenza HA-induced membrane fusion include, but are not limited to:

[0192] C20-Jp-Hp C20-Jp-Hp is a preclinical drug that is the result of hybridization of two short peptides. C20-Jp-Hp may inhibit early viral infection by interacting with the fusion domain of the HA2 subunit. This process involves blocking conformational rearrangement of HA2, thereby preventing viral membrane fusion with targeted host cells. C20-Jp-Hp was described by Lin et al. Sci Rep. 2016 Mar 8;6:22790.

[0193] MBX2329 and MBX2546 MBX2329 and MBX2546 are preclinical drugs with aminoalkylphenol ether and aminoacetamidosulfonamide scaffolds, respectively, that potently (IC50s of 0.47-5.8 μM) and selectively (CC50s of >100 μM) inhibit multiple influenza A viruses, including the 2009 pandemic influenza A / H1N1 virus, highly pathogenic avian influenza (HPAI) A / H5N1 virus, and oseltamivir-resistant A / H1N1 strains, in vitro. Mechanistic studies have shown that these compounds bind to a conserved epitope within the HA stem region, which is involved in the HA-mediated membrane fusion process. MBX2329 and MBX2546 are described in Basu et al. J Virol. 2014 Feb;88(3):1447-1460.

[0194] Inhibitors of influenza virus replication, assembly, and release These agents include produgs, neuraminidase inhibitors, endonuclease inhibitors, M2 protein proton channel inhibitors, and other compounds, examples of which are described below.

[0195] Adamantane Adamantane, amantadine, and rimantadine have been used previously, but these drugs are no longer recommended for treatment because over 99% of current and recently circulating influenza A viruses are resistant to adamantane. Adamantane blocks the M2 ion channel, preventing the virus from uncoating inside the cell.

[0196] Baloxavir marboxil (Xofluza) Baloxavir marboxil was developed as a prodrug strategy whose metabolism releases the active agent, baloxavir acid (BXA). BXA then functions as an enzyme inhibitor targeting the cap-dependent endonuclease activity of influenza viruses, which is used by the viral polymerase complex in "cap snatching," a process essential to its life cycle. Baloxavir interferes with viral replication by blocking viral RNA transcription.

[0197] Peramivir (Rapivab) Peramivir is a neuraminidase inhibitor that functions as a transition-state analogue inhibitor of influenza neuraminidase, thereby preventing new virus from emerging from infected cells.

[0198] zanamivir (Relenza) Zanamivir works by binding to the active site of the neuraminidase protein, preventing the influenza virus from escaping its host cell and infecting others. This enzyme cleaves sialic acid found on glycoproteins on the surface of human cells, helping new virions to leave the cell. Zanamivir therefore prevents new virus particles from being released.

[0199] Oseltamivir (Tamiflu) Oseltamivir (GS-4104) is a neuraminidase inhibitor, a competitive inhibitor of the influenza neuraminidase enzyme. This enzyme cleaves sialic acid found on glycoproteins on the surface of human cells, helping new virions leave the cell. Oseltamivir therefore prevents new virus particles from being released.

[0200] Additionally, any of the immunomodulatory agents listed hereinabove, such as dexamethasone, prednisone, etc., may be administered to the patient.

[0201] V. Formulation and Administration Pharmaceutical compositions containing one or more of the disclosed compounds (including salts, solvates, N-oxides, and / or prodrugs thereof) can be manufactured by conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, entrapping, or lyophilizing processes. The compositions can be formulated in a conventional manner using one or more physiologically acceptable excipients, diluents, carriers, adjuvants, or auxiliaries to provide preparations that can be used pharmaceutically. A wide variety of suitable pharmaceutical compositions are known in the art. See, for example, Remington: The Science and Practice of Pharmacy, volume I and volume II. (22 nd Ed., University of the Sciences, Philadelphia).

[0202] The disclosed compounds (s) or prodrugs thereof can be formulated in pharmaceutical compositions per se or in the form of a solvate, N-oxide, or pharmaceutically acceptable salt. Typically, such salts are more soluble in aqueous solution than the corresponding free acids and bases, although salts having lower solubility than the corresponding free acids and bases can also be formed.

[0203] Pharmaceutical compositions comprising one or more of the disclosed compounds can be in a form suitable for virtually any mode of administration, including, for example, topical, ophthalmic, oral, buccal, systemic, nasal, injection such as iv or ip, transdermal, rectal, vaginal, sublingual, urethral (e.g., urethral suppository), etc., or in a form suitable for administration by inhalation or insufflation. In certain embodiments, the mode of administration is oral or injection.

[0204] Systemic formulations include those designed for administration by injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection, as well as those designed for transdermal, transmucosal oral, or pulmonary administration.

[0205] Useful injectable preparations include sterile suspensions, solutions, or emulsions of active compound(s) in aqueous or oily vehicles. The compositions may also contain formulating agents such as suspending agents, stabilizers, and / or dispersing agents. The formulations for injection may be presented in unit dosage form, for example, in ampoules or multi-dose containers, and may contain added preservatives.

[0206] Alternatively, injectable formulations may be provided in powder form for reconstitution with a suitable vehicle, including, but not limited to, sterile pyrogen-free water, buffer, dextrose solution, etc., before use. To this end, the disclosed compound(s) may be dried by any art-known technique, such as lyophilization, and reconstituted prior to use.

[0207] For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

[0208] For oral administration, the pharmaceutical compositions can take the form of lozenges, tablets, or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropylmethylcellulose); 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). Tablets can be coated, for example, with sugars, films, or enteric coatings by methods well known in the art.

[0209] Additionally, pharmaceutical compositions containing the disclosed compound(s) or their solvates, N-oxides, pharmaceutically acceptable salts, or prodrug(s) as an active ingredient in a form suitable for oral use may also include, for example, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient (including prodrugs) in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients can be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium or sodium phosphate, granulating and disintegrating agents (e.g., corn starch or alginic acid), binders (e.g., starch, gelatin, or acacia), and lubricating agents (e.g., magnesium stearate, stearic acid, or talc). Tablets can be uncoated or coated by known techniques, including microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate can be used. They can also be coated by the techniques described in U.S. Pat. Nos. 4,256,108, 4,166,452, and 4,265,874 to form osmotic therapeutic tablets for controlled release. The pharmaceutical compositions of the present invention can also be in the form of oil-in-water emulsions. Tablets may also be film coated, where the film coating may include one or more of polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, talc, iron oxide yellow, and iron oxide red.

[0210] Liquid preparations for oral administration may take the form of, for example, elixirs, solutions, syrups, or suspensions, or they may be provided as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible fats), emulsifying agents (e.g., lecithin or acacia), non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, cremophore™, or fractionated vegetable oils), and preservatives (e.g., methyl or propyl-p-hydroxybenzoate or sorbic acid). The preparations may also contain buffer salts, preservatives, flavoring agents, coloring agents, and sweeteners, as needed.

[0211] Preparations for oral administration can be suitably formulated to give controlled release of the disclosed compounds, as is well known.

[0212] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0213] For topical administration, the disclosed compound(s) (including solvates, N-oxides, or pharmaceutically acceptable salts, and / or prodrug(s) thereof) may be formulated as solutions, gels, ointments, creams, suspensions, etc., as known in the art.

[0214] For rectal and vaginal routes of administration, the active compound(s) may be formulated as solutions (for retention enemas) suppositories or ointments containing conventional suppository bases such as cocoa butter or other glycerides.

[0215] For nasal administration or administration by inhalation or insufflation, the disclosed compound(s), solvates, N-oxides, pharmaceutically acceptable salts, or prodrug(s) can be conveniently delivered in the form of an aerosol spray from pressurized packs or nebulizers using a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, fluorocarbons, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges (e.g., composed of gelatin) for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base, such as lactose or starch.

[0216] The pharmaceutical composition may be in the form of a sterile injectable aqueous or oily suspension. This suspension may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents as described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution.

[0217] In accordance with the present invention, the disclosed compound(s), their solvates, N-oxides, pharmaceutically acceptable salts, or prodrug(s) forms may also be used in the preparation of pharmaceutical compositions and compositions disclosed in, for example, U.S. Pat. No. 6,241,969, U.S. Pat. No. 6,060,069, U.S. Pat. No. 6,238,647, U.S. Pat. No. 6,335,316, U.S. Pat. No. 5,364,838, U.S. Pat. No. 5,672,581, WO96 / 32149, WO95 / 24183, U.S. Pat. No. 5,654,007, U.S. Pat. No. 5,404,871, U.S. Pat. No. 5,672,581, U.S. Pat. No. 5,743,250, U.S. Pat. No. 5,419,315, U.S. Pat. No. 5,558,085, WO98 / 33480, U.S. Pat. The compositions may also be delivered by any of a variety of inhalation devices known in the art, including U.S. Pat. No. 833, U.S. Pat. No. 5,320,094, U.S. Pat. No. 5,780,014, U.S. Pat. No. 5,658,878, U.S. Pat. No. 5,518,998, U.S. Pat. No. 5,506,203, U.S. Pat. No. 5,661,130, U.S. Pat. No. 5,655,523, U.S. Pat. No. 5,645,051, U.S. Pat. No. 5,622,166, U.S. Pat. No. 5,577,497, U.S. Pat. No. 5,492,112, U.S. Pat. No. 5,327,883, U.S. Pat. No. 5,277,195, U.S. Patent Publication No. 20010041190, U.S. Patent Publication No. 20020006901, and U.S. Patent Publication No. 20020034477.

[0218] Among the devices that can be used to administer forms of the active compound(s) are those well known in the art, such as metered dose inhalers, liquid nebulizers, dry powder inhalers, atomizers, thermal vaporizers, etc. Other suitable techniques for administering certain 2,4-pyrimidinediamine compounds include electrohydrodynamic aerosolizers.

[0219] In addition, the inhalation device is preferably practical in the sense that it is easy to use, small enough to be conveniently carried, capable of providing multiple doses, and durable. Some specific examples of commercially available inhalation devices are Turbohaler (Astra, Wilmington, DE), Rotahaler (Glaxo, Research Triangle Park, NC), Diskus (Glaxo, Research Triangle Park, NC), Ultravent nebulizer (Mallinckrodt), Acorn II nebulizer (Marquest Medical Products, Totowa, NJ), Ventolin metered-dose inhaler (Glaxo, Research Triangle Park, NC), etc. In one embodiment, the disclosed compound(s), their solvates, N-oxides, pharmaceutically acceptable salts, or prodrug(s) can be delivered by a dry powder inhaler or nebulizer.

[0220] As those skilled in the art will recognize, the formulation of the disclosed compound(s), their solvates, N-oxides, pharmaceutically acceptable salts, or prodrug(s), the amount of the formulation delivered, and the duration of administration of a single dose depend on the type of inhalation device used and other factors. In some aerosol delivery systems, such as nebulizers, the frequency and length of time the system is activated depend primarily on the concentration of the disclosed compound(s) in the aerosol. For example, a shorter administration period can be used with a higher concentration of the disclosed compound(s) in the nebulizer solution. Devices such as metered-dose inhalers can generate higher aerosol concentrations and, in some embodiments, can be operated for a shorter period to deliver a desired amount of active compound. Devices such as dry powder inhalers deliver active agent until a predetermined amount of agent is expelled from the device. In this type of inhaler, the amount of the disclosed compound(s), their solvates, N-oxides, pharmaceutically acceptable salts, or prodrug(s) in a given amount of powder determines the dose delivered in a single administration. The formulation of the disclosed compound(s) is selected to obtain the desired particle size in the selected inhalation device.

[0221] Formulations of the disclosed compounds for administration from a dry powder inhaler will typically include a finely divided dry powder containing the disclosed compound(s), although the powder may also include bulking agents, buffers, carriers, excipients, other additives, etc. Additives may be included in the dry powder formulation to, for example, dilute the powder as needed for delivery from a particular powder inhaler, facilitate processing of the formulation, provide advantageous powder properties to the formulation, facilitate dispersion of the powder from the inhalation device, stabilize the formulation (e.g., antioxidants or buffers), provide taste to the formulation, etc. Typical additives include mono-, di-, and polysaccharides; sugar alcohols and other polyols, such as lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol, starch, or combinations thereof; surfactants, such as sorbitol, diphosphatidylcholine, or lecithin.

[0222] The methods of the present invention can be embodied in pharmaceutical compositions comprising the disclosed compound(s) suitable for administration by inhalation. For example, dry powder formulations can be prepared in several ways using conventional techniques, such as those described in any of the publications listed above and expressly incorporated herein by reference; see, for example, U.S. Patent No. 5,700,904 to Baker et al., the entire disclosure of which is expressly incorporated herein by reference. Particles in a size range suitable for maximum deposition in the lower respiratory tract can be produced by micronization, milling, etc. Liquid formulations can also be prepared by dissolving the compound in a suitable solvent, such as water, at an appropriate pH with a buffer or other excipients.

[0223] A specific example of an aqueous suspension formulation suitable for nasal administration using a commercially available nasal spray device contains the following ingredients: 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); sodium carboxymethylcellulose or microcrystalline cellulose (1-15 mg / ml); phenylethanol (14 mg / ml); and dextrose (20-50 mg / ml). The pH of the final suspension can be adjusted to a range of about pH 5 to pH 7, with a pH of about pH 5.5 being typical.

[0224] Another specific example of an aqueous suspension suitable for administering a compound via inhalation contains 20 mg / mL of the compound or prodrug, 1% (v / v) polysorbate 80 (TWEEN® 80), 50 mM citrate, and / or 0.9% sodium chloride.

[0225] For ophthalmic administration, the active compound(s) or prodrug(s) can be formulated as a solution, emulsion, suspension, etc. suitable for administration to the eye. Various vehicles suitable for administering compounds to the eye are known in the art. Specific non-limiting examples are described in U.S. Patent Nos. 6,261,547, 6,197,934, 6,056,950, 5,800,807, 5,776,445, 5,698,219, 5,521,222, 5,403,841, 5,077,033, 4,882,150, and 4,738,851, which are incorporated herein by reference.

[0226] For long-term delivery, the disclosed compound(s) can be formulated as a depot preparation for administration by implantation or intramuscular injection. The active ingredient can be formulated with a suitable polymer or hydrophobic material (e.g., as an emulsion in an acceptable oil), or an ion exchange resin, or can be formulated as a sparingly soluble derivative, for example, as a sparingly soluble salt. Alternatively, a transdermal delivery system can be used, manufactured as an adhesive disk or patch that slowly releases the disclosed compound(s) for percutaneous absorption. For this purpose, a penetration enhancer can be used to promote percutaneous penetration of the active compound(s). Suitable transdermal patches are described, for example, in U.S. Pat. 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.

[0227] Alternatively, other pharmaceutical delivery systems can be used. Liposomes and emulsions are well-known examples of delivery vehicles that can be used to deliver active compound(s) or prodrug(s). Certain organic solvents, such as dimethyl sulfoxide (DMSO), can also be used, but usually at the cost of higher toxicity. In some embodiments, the disclosed compound(s) or their solvates, N-oxides, pharmaceutically acceptable salts, or prodrug(s) are orally administered in tablet form.

[0228] The pharmaceutical compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active compound(s). The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration.

[0229] I. Spray-dried formulation Disclosed herein are spray-dried formulation embodiments comprising one or more disclosed compounds, such as one or more compounds according to Formula VII. The spray-dried formulation may be a carrier, such as a polymer matrix, or a dispersion, such as a spray-dried dispersion, of the compound(s) according to Formula VII in a matrix. Typically, the spray-dried formulation comprises a single-phase, amorphous dispersion of the disclosed compound(s) in a carrier, such as a polymer matrix.

[0230]

[0013] Embodiments of the spray-dried formulation comprise, consist essentially of, or consist of an effective amount of one or more compounds, e.g., one or more compounds according to Formula VII, and a sufficient amount of carrier to form a spray-dried formulation. While one of skill in the art will appreciate that the effective amount of compound(s) can vary, typically, an effective amount is 0.1% to 50% (w / w of carrier) or more, e.g., 1% to 50%, 5% to 40%, 10% to 35%, 15% to 30%, or 15% to 25%. In certain embodiments, the spray-dried formulation comprises, consists essentially of, or consists of 20% w / w of the disclosed compound(s) and 80% w / w of a carrier, such as a polymer matrix.

[0231] In some embodiments, the carrier is a polymer, such as a polymer suitable for forming a spray-dried formulation with the disclosed compound(s). Suitable polymers include, but are not limited to, cellulose derivatives such as hydroxypropyl methylcellulose acetate succinate (hypromellose acetate; HPMCAS), hydroxypropyl methylcellulose phthalate (hypromellose phthalate; HPMCP), or hydroxypropyl methylcellulose (HPMC), vinyl polymers such as poly(vinylpyrrolidone) (PVP) or poly(vinylpyrrolidone-vinyl acetate) (PVPVA), lactide polymers such as polylactide (PLA) or polylactide-glycolide (PLGA), sugars such as sucrose or trehalose, or any combination thereof. In certain embodiments, the carrier is HPMCAS. Polymers such as HPMCAS can be any grade suitable for forming a spray-dried formulation, for example, grade L, grade M, or grade H. In certain embodiments, grade M is used. Additionally, the HPMCAS can be fine (F) or granular (G) in certain embodiments, the fine size is used, and in certain working embodiments, the carrier is HPMCAS-MF.

[0232] In some embodiments, the spray-dried formulation has a suitable glass transition temperature, which can be below 100°C to above 120°C, such as 105°C to 110°C or 107°C to 110°C. In certain working embodiments, the glass transition temperature is 108°C to 109°C.

[0233] In some embodiments, the formulation may include additional components that may be included in the pharmaceutical composition for a variety of purposes, such as diluting the composition for delivery to a subject, facilitating processing of the formulation, providing advantageous material properties to the formulation, facilitating dispersion from a delivery device, stabilizing the formulation (e.g., antioxidants or buffers), or providing a pleasant or palatable taste or consistency to the formulation.Typical additional components include, by way of example and without limitation, mono-, di-, and polysaccharides, sugar alcohols, and other polyols such as lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol, starch, or combinations thereof; surfactants such as sorbitol, diphosphatidylcholine, and lecithin; bulking agents; buffers such as phosphate and citrate buffers; anti-adherents such as magnesium stearate; binders such as sugars (including disaccharides such as sucrose and lactose), polysaccharides (such as starch, cellulose, microcrystalline cellulose, cellulose ethers (such as hydroxypropyl cellulose), gelatin, synthetic polymers (such as polyvinylpyrrolidone, polyalkylene glycols (gylcol)); coatings (such as hydroxypropyl methylcellulose, shellac, corn protein zein, and cellulose ethers including gelatin); release aids (such as enteric coatings); disintegrants (such as dibasic calcium phosphate, vegetable fats and oils, lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, and magnesium stearate); fillers (such as mint, cherry, anise, peach, apricot or licorice, raspberry, and vanilla); flavors and sweeteners (such as minerals exemplified by talc or silica, vegetable stearin, magnesium stearate, or stearic acid). lubricants (such as oils and fats exemplified by vitamin A, vitamin E, vitamin C, antioxidants exemplified by retinyl palmitate, and selenium, amino acids exemplified by cysteine ​​and methionine, citric acid and sodium citrate, parabens exemplified by methylparaben and propylparaben); colorants; pharmaceutically acceptable excipients such as compression aids; emulsifiers; encapsulating agents; gums; granulating agents; pharmaceutically acceptable carriers; and / or adjuvants, and combinations thereof.

[0234] II. Methods of Making Spray-Dried Formulations Also disclosed herein are methods for preparing spray-dried formulations. In some embodiments, one or more compounds, such as one or more compounds according to Formula VII, and a polymer are dissolved in a suitable solvent or mixture of solvents and then spray-dried. Suitable solvent(s) include any solvent or mixture of solvents that dissolves the disclosed compound(s) and carrier 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 some embodiments, the disclosed compound(s) are dissolved in a solvent or mixture of solvents, and the polymer is added to the mixture. However, in other embodiments, the polymer is dissolved first, and the compound(s) are added later, or the compound(s) and polymer are mixed with the solvent or solvent mixture substantially simultaneously. Regardless of the order of addition, the mixture is typically mixed until the disclosed compound(s) and polymer are dissolved and / or the mixture has a uniform appearance. In some embodiments, the resulting mixture is stored at low temperatures, 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., typically about 5° C. The solution may also be protected from light, i.e., stored in a dark environment.

[0235] 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 feed temperature, inlet temperature, target outlet temperature, and suction, are set to values ​​suitable for the disclosed compound(s) and polymer, as will be understood by those skilled in the art. In certain embodiments, the feed temperature is 15°C or lower to 35°C or higher, e.g., 20°C to 25°C. The inlet temperature can be 40°C or lower to 60°C or higher, e.g., 45°C to 55°C. The target outlet temperature can be 30°C or lower to 45°C or higher, e.g., 32°C to 42°C, or 34°C to 40°C. And / or the aspirator can be 50% or higher to 100%, such as 70% to 100% or 80% to 100%.

[0236] The resulting spray-dried solid can be further dried at a temperature suitable to remove at least a portion, and potentially substantially all, of any residual solvent without substantially degrading the disclosed compound(s) and / or carrier. In some embodiments, 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 can be dried until substantially all of the residual solvent is removed and / or until no further weight loss is achieved. Drying can continue for 1 hour to 48 hours or more, such as 6 hours to 36 hours, 12 hours to 32 hours, or 18 hours to 24 hours. The resulting solid formulation can be stored at a lower temperature, such as below 25°C, or between 25°C and below 0°C, between 15°C and 0°C, between 10°C and 0°C, or between 7°C and 3°C, typically about 5°C. The solution can also be protected from light, i.e., stored in a dark environment, and / or stored under dry conditions, such as in the presence of a desiccant and / or in a dry atmosphere.

[0237] VI. Dosage The disclosed compound(s) or compositions thereof will generally be used in an amount effective to achieve the desired result, e.g., an amount effective to treat or prevent a symptom. The compound(s) or compositions thereof may be administered therapeutically to achieve a therapeutic benefit and / or prophylactically to achieve a prophylactic benefit. Therapeutic benefit refers to eradication or amelioration of the underlying infection during treatment and / or eradication or amelioration of one or more symptoms such that the patient reports a feeling or state of improvement, even though the patient may still be suffering from the infection. In some embodiments, an indication of therapeutic improvement and / or successful treatment may include the subject becoming free of one or more symptoms with an associated score on a rating scale. Additionally or alternatively, an indication of therapeutic improvement and / or successful treatment may be a change in the rating or severity on a rating scale. A prophylactic benefit may be achieved by substantially preventing the onset of the infection, such as preventing the onset of any symptom or preventing the progression of one or more symptoms. As known by those skilled in the art, the preferred dosage of the disclosed compound(s) also depends on various factors, including age, weight, general health, and the severity of the condition of the patient or subject being treated. The dosage may also need to be adjusted for the individual's gender and / or lung capacity when administered by inhalation. The dosage may also be adjusted for individuals suffering from more than one condition, or for individuals with additional conditions that affect lung capacity and normal breathing ability, such as emphysema, bronchitis, pneumonia, and respiratory infections. The dosage and frequency of administration of the disclosed compound(s) or compositions thereof will also depend on whether the compound(s) are formulated for the treatment of an acute episode or for prophylactic treatment. Those skilled in the art will be able to determine the optimal dose for a particular individual.

[0238] In another embodiment, the disclosed compound(s) or compositions thereof can be administered during the course of treatment. In another embodiment, the disclosed compound(s) or compositions thereof can be administered either after completion of treatment, immediately or shortly thereafter (e.g., within 24, 48, 72, or 96 hours, or within one week of completion of treatment). In another embodiment, the disclosed compound(s) or compositions thereof can be administered during two or more of the periods consisting of before, during, or after treatment.

[0239] In prophylactic administration, the disclosed compound(s) or compositions thereof can be administered to a patient or subject at risk of developing a condition. For example, the compound(s) or compositions thereof can be administered to a subject before or immediately after exposure to a virus.

[0240] An effective dose can be estimated initially from in vitro assays. For example, an initial dose for use in a subject may be determined based on the IC 50 or EC 50 The active compound may be formulated to achieve a circulating blood or serum concentration equal to or greater than 100 mg / kg of the active compound. The dosage to achieve such a circulating blood or serum concentration can be calculated taking into account the bioavailability of a particular 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, provide additional guidance regarding effective dosages.

[0241] In some embodiments, the disclosed compounds have an EC50 of greater than 0 to 20 μM, e.g., greater than 0 to 10 μM, greater than 0 to 5 μM, greater than 0 to 1 μM, greater than 0 to 0.5 μM, greater than 0 to 0.1 μM. 50 It has.

[0242] Initial dosages can also be estimated from in vivo data, such as from animal models, including mouse and non-human primate models. Suitable animal models are known to those skilled in the art, and additional information can be found in Norelli, M., Camisa, B., Barbiera, G. et al. Monocyte-derived IL-1 and IL-6 are differentially required for cytokine release syndrome and CAR T cell-induced neurotoxicity. Nat Med. 2018;24:739-748, and Giavridis, T., van der Stegen, SJC, Eyquem, J., Hamieh, M., Piersigilli, A., and Sadelain, M. CAR T cell-induced cytokine release syndrome is mediated by macrophages and is alleviated by IL-1 blockade. Nat Med. 2018;24:731-738.

[0243] Dosages of the disclosed compounds typically range from 0.0001 mg / kg / day or 0.001 mg / kg / day, or greater than about 0 mg / kg / day, such as 0.01 mg / kg / day, to at least about 1000 mg / kg / day, such as 100 mg / kg / day, but can be higher or lower depending on, among other factors, the activity of the compound, its bioavailability, the mode of administration, and various factors discussed herein. More typically, dosages (or effective amounts) can range from about 0.0025 mg / kg to about 1 mg / kg, such as 0.01 mg / kg to about 0.5 mg / kg, or from about 0.05 mg / kg to about 0.15 mg / kg, per at least one daily administration. Total daily dosages typically range from about 0.1 mg / kg to about 5 mg / kg per day, or to about 20 mg / kg per day, such as from 0.5 mg / kg to about 10 mg / kg per day, or from about 0.7 mg / kg to about 2.5 mg / kg per day. Dosages may be higher or lower depending on, among other factors, the activity of the compound, its bioavailability, the mode of administration, and the various factors discussed above.

[0244] Dosage amounts and dosing intervals can be tailored to the individual to provide plasma levels of the compound(s) sufficient to achieve and / or maintain the desired therapeutic or prophylactic effect. For example, the compound can be administered once daily, multiple times daily, once weekly, multiple times weekly (e.g., every other day), once monthly, multiple times monthly, or once yearly, depending on, among other things, the mode of administration, the specific indication being treated, and the judgment of the prescribing physician. Those skilled in the art will be able to optimize an effective local dosage without undue experimentation. In some embodiments, the amount of the disclosed compound in the administered composition or the amount of the compound administered in the methods disclosed herein is a suboptimal dose. As used herein, a suboptimal dose is a dose typically used in a single administration to a patient in monotherapy or in combination with standard therapy.

[0245] Compositions comprising one or more of the disclosed compounds typically contain from greater than 0 up to 99% total weight percent of the compound or compounds and / or other therapeutic agents. More typically, compositions comprising one or more of the disclosed compounds contain from about 1 to about 20 total weight percent of the compound(s) and other therapeutic agents, and from about 80 to about 99 weight percent of pharmaceutically acceptable excipients.

[0246] Preferably, the compound(s) or compositions thereof will provide therapeutic or prophylactic benefit without causing substantial toxicity. The toxicity of a compound can be determined using standard pharmaceutical procedures. The dose ratio between toxic effects and therapeutic (or prophylactic) effect is the therapeutic index. Compounds that exhibit high therapeutic indices are preferred.

[0247] VII. Treatment Methods In some embodiments, the method may include administering a compound described herein to a patient having or suspected of having a respiratory virus, e.g., COVID-19 or influenza infection. In some embodiments, the method may include administering a compound described herein to an infected patient having, suspected of having, or expected to develop acute respiratory distress syndrome. In some embodiments, the method may include administering a compound described herein to a patient having, suspected of having, or expected to develop a symptom associated with a cytokine response. In some embodiments, the symptom is associated with virus-associated acute respiratory distress syndrome, AKI, and / or sepsis, etc. In some embodiments, the method may include administering a compound described herein to a patient having, suspected of having, or expected to develop acute kidney injury. In some embodiments, the method may include administering a compound described herein to a patient having, suspected of having, or expected to develop thrombosis.

[0248] As described above, various methods involving administering a compound described herein to a patient are provided herein. Also provided are methods for identifying a patient with renal dysfunction, e.g., acute kidney injury, and / or thrombosis (e.g., detecting renal dysfunction and / or thrombosis in a patient) and administering a compound described herein to the patient. The method can include, for example, step (a) of testing the patient for renal dysfunction (e.g., acute kidney injury) and / or thrombosis before any treatment including a compound described herein is administered. The method can then include step (b) of administering a compound described herein to the patient according to any of the embodiments described herein.

[0249] In addition, the present methods can be used to treat ventilator-induced ARDS, a mechanical lung injury that triggers a wide range of biological responses, including the activation of inflammatory and damaging cytokine cascades, referred to as biotrauma. In these embodiments, the present methods can include administering to a patient who has or is expected to develop ventilator-induced ARDS an effective amount of a compound that inhibits interleukin receptor-associated kinase (IRAK). These patients may or may not be infected with a virus.

[0250] In some embodiments, the patient may have an influenza A infection, and in some cases, may be one of the following: H1N1, H1N2, H1N3, H1N4, H1N5, H1N6, H1N7, H1N8, H1N9, H1N10, H1N11, H2N1, H2N2, H2N3, H2N4, H2N5, H2N6, H2N7, H2N8, H2N9, H2N10, H2N11, H3N1, H3N2, H3N3, H3N4, H3N5, H3N6, H3N7, H3N8, H3N9, H3N10, H3N11, H4N1, H4N2, H4N3, H4N4, H4N5, H4N6, H4N7, H 4N8, H4N9, H4N10, H4N11, H5N1, H5N2, H5N3, H5N4, H5N5, H5N6, H5N7, H5N8, H 5N9, H5N10, H5N11, H6N1, H6N2, H6N3, H6N4, H6N5, H6N6, H6N7, H6N8, H6N9, H6 N10, H6N11, H7N1, H7N2, H7N3, H7N4, H7N5, H7N6, H7N7, H7N8, H7N9, H7N10, H 7N11, H8N1, H8N2, H8N3, H8N4, H8N5, H8N6, H8N7, H8N8, H8N9, H8N10, H8N11, H 9N1, H9N2, H9N3, H9N4, H9N5, H9N6, H9N7, H9N8, H9N9, H9N10, H9N11, H10N1, H10N2, H10N3, H10N4, H10N5, H10N6, H10N7, H10N8, H10N9, H10N10, H10N11, H 11N1, H11N2, H11N3, H11N4, H11N5, H11N6, H11N7, H11N8, H11N9, H11N10, H1 1N11, H12N1, H12N2, H12N3, H12N4, H12N5, H12N6, H12N7, H12N8, H12N9, H12N 10, H12N11, H13N1, H13N2, H13N3, H13N4, H13N5, H13N6, H13N7, H13N8, H13N 9, H13N10, H13N11, H14N1, H14N2, H14N3, H14N4, H14N5, H14N6, H14N7, H14N8 , H14N9, H14N10, H14N11, H15N1, H15N2, H15N3, H15N4, H15N5, H15N6, H15N7 , H15N8, H15N9, H15N10, H15N11, H16N1, H16N2, H16N3, H16N4, H16N5, H16N6,The person may be infected by an influenza A subtype selected from H16N7, H16N8, H16N9, H16N10, H16N11, H17N1, H17N2, H17N3, H17N4, H17N5, H17N6, H17N7, H17N8, H17N9, H17N10, H17N11, H18N1, H18N2, H18N3, H18N4, H18N5, H18N6, H18N7, H18N8, H18N9, H18N10, or H18N11.

[0251] As summarized above, aspects of the method may include identifying a patient with renal insufficiency and / or thrombosis (e.g., detecting renal insufficiency and / or thrombosis in the patient) and administering a compound described herein to the patient. The method may include step (a) of testing the patient for renal insufficiency and / or thrombosis. The testing may be performed before any treatment, including a compound described herein, is administered. Exemplary tests for identifying a patient with renal insufficiency include urinalysis and blood tests (e.g., to test creatinine levels and ACR (albumin-to-creatinine ratio) and estimate GFR (glomerular filtration rate)), blood urea nitrogen (BUN) tests, kidney tissue biopsy, and kidney imaging tests (e.g., ultrasound scan, MRI scan, CT scan). Exemplary tests for identifying patients with thrombosis include imaging tests (e.g., ultrasound scan, MRI scan, CT scan, duplex ultrasound), blood tests (e.g., D-dimer test), venography, computed tomographic pulmonary angiography, ventilation / perfusion (V / Q) scan, and pulmonary angiography. In some embodiments, step (a) may generate or provide one or more test results indicating that the patient has, is suspected of having, or is predicted to develop renal dysfunction and / or thrombosis. Optionally, the method may include determining whether the patient has, is suspected of having, or is predicted to develop acute kidney injury and / or thrombosis based on one or more results from step (a). Optionally, the results of step (a) or step (a) indicate that the patient has, is suspected of having, or is predicted to develop acute kidney injury and / or thrombosis. The method may then include step (b) of administering a compound described herein to a patient identified as having renal insufficiency and / or thrombosis based on the results of step (a). The administration may be performed according to any of the embodiments described herein.

[0252] In any embodiment, the patient may have or be expected to have or develop acute respiratory distress syndrome. In some cases, however, the patient may have signs of respiratory distress, such as a cough, but not have acute respiratory distress syndrome. In these embodiments, the patient may not be in intensive care.

[0253] In some embodiments, the patient may have or be expected to develop acute kidney injury. In some cases, the patient may have signs of renal damage or impairment, including, for example, proteinuria, hematuria, kaliuria, albuminuria, oliguria, increased blood urea nitrogen, and / or increased serum creatinine. However, in some cases, the patient may have signs of reduced renal function or renal insufficiency, such as, for example, proteinuria, hematuria, changes (e.g., increases) in serum creatinine (sCr) and / or blood urea nitrogen, decreased urine output, etc. However, in some cases, the patient may have signs of reduced renal function or renal insufficiency but not acute kidney injury. In these embodiments, the patient may not be in intensive care.

[0254] In some embodiments, the patient may have, or be expected to have, or develop, thrombosis. In some cases, the patient may have symptoms of thrombosis, including, for example, pain and swelling, warm skin, red or dark skin, cyanosis, dilated veins, shortness of breath, arrhythmia, chest pain, lightheadedness, sweating, cough (e.g., a cough that produces blood), and / or low blood pressure. In some cases, the patient may have a prothrombotic coagulation profile but not thrombosis. In some cases, the patient may have a prothrombotic coagulation profile and have, or be expected to have, thrombosis. A prothrombotic coagulation profile may include, for example, a worsening, e.g., increased or decreased level or activity, of any one or more of the coagulation parameters described herein, e.g., compared to a control. For example, in some cases, a prothrombotic coagulation profile may include an increased level of D-dimer. The control may be, for example, the coagulation profile of an asymptomatic individual with a viral infection, an individual with a mild infection, or a healthy individual. In these embodiments, the patient may not be in intensive care.

[0255] In any embodiment, the patient may be at least 60 years old, at least 70 years old, or at least 80 years old. The patient may have or have had one or more other pulmonary diseases in the past. For example, in some cases, the patient has or has a history of asthma, airway thorax, atelectasis, bronchitis, chronic obstructive pulmonary disease, lung cancer, or pneumonia.

[0256] In some cases, the patient may have or have had one or more other kidney diseases in the past. In some embodiments, kidney diseases comprise acromegaly, acute renal failure (ARF) amyloidosis, autosomal dominant polycystic kidney disease, kidney stones, renal cysts, autosomal recessive polycystic kidney disease, chronic renal failure (CRF), chronic kidney disease, Coffin-Lowry syndrome, cor pulmonale, cryoglobulinemia, diabetic nephropathy, dyslipidemia, Gaucher disease, glomerulonephritis, Goodpasture syndrome, hemolytic uremic syndrome, hepatitis, kidney cancer, kidney stones, leukemia, lipoproteinemia, lupus, multiple myeloma, nephritis, multiple renal cysts, post-streptococcal glomerulonephritis, glomerulonephritis, kidney pain, preeclampsia, kidney tuberculosis, tuberculosis, pyelonephritis, renal tubular acidosis kidney disease, streptococcal toxic shock syndrome, thromboembolism, toxoplasmosis, urinary tract infection, vesicoureteral reflux, or viral syndrome. In one embodiment, the renal disease or disorder is acute, or in another embodiment, chronic. In one embodiment, the phrase "susceptible to a renal disease or disorder" with respect to a subject is synonymous with the phrase "subject at risk" and includes a subject at risk of acute or chronic renal failure or at risk of needing renal replacement therapy if the subject is reasonably expected to suffer a gradual loss of renal function associated with the gradual loss of functional nephron units. Whether a particular subject is at risk is a determination that can be routinely made by one skilled in the relevant medical or veterinary field. In some cases, the patient is undergoing or has a history of undergoing dialysis treatment. In some cases, the patient has undergone a kidney transplant.

[0257] In some cases, the patient may have or have had a previous thrombosis or thrombotic event. For example, in some cases, the patient has or has a history of any of the risk factors, diseases, or conditions associated with thrombosis described herein, including, for example, deep vein thrombosis, pulmonary embolism, etc. In some cases, the patient has one or more risk factors for developing thrombosis compared to the general population.

[0258] Administration can be by any convenient method. For example, administration can be systemic, e.g., oral (via injection of a tablet, pill, or liquid) or intravenous (e.g., via injection or infusion). In other embodiments, administration is by pulmonary administration, e.g., using an inhaler or nebulizer. [Example]

[0259] VIII. Working Examples Example 1 Synthesis of pyrazole compounds Preparation of amine 106: TIFF2024534919000036.tif36143 2-(1H-pyrazol-3-yl)pyridine (10 g) was suspended in concentrated sulfonic acid (30 mL), and then fuming nitric acid (6.5 mL, 2 equivalents) was added dropwise to the solution with stirring. The reaction mixture was stirred overnight at room temperature. It was quenched by pouring it into ice water (500 mL). The aqueous solution was neutralized by adding solid sodium carbonate until the pH reached approximately 8. The white precipitate was collected by filtration, washed with water, and dried to give 2-(4-nitro-1H-pyrazol-3-yl)pyridine 102 (13 g, 99% yield).

[0260] 2-(4-Nitro-1H-pyrazol-3-yl)pyridine 102 (2 g) and 1-bromo-3-ethoxycyclobutane (90% trans isomer, 2 g) were suspended in THF (20 mL) and DMF (10 mL). Sodium hydride (60% in oil, 670 mg, 1.5 equiv.) was added to the reaction. The reaction solution was heated at 100 °C for 3 days and then evaporated. The residue was purified by Combiflash chromatography (10 to 100% EtOAc in hexanes) to give product 104.

[0261] Compound 104 was dissolved in EtOAc (100 mL) and charged with 10% Pd-C catalyst (200 mg). The reaction mixture was shaken under 40 psi of hydrogen for 1 h. LC-MS showed complete reduction of the nitro group. The catalyst was filtered through Celite and washed with EtOAc (5 × 20 mL). The filtrate was concentrated to give amine 106 (1.4 g, 52% yield over two steps).

[0262] V-28: Exemplary Synthesis of N-(1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide TIFF2024534919000037.tif41154 Compound 106 (700 mg), 5-bromo-2-furoic acid (622 mg, 1.2 equiv.), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (1.54 g, 1.5 equiv.) were dissolved in THF (30 mL), and diisopropylethylamine (DIPEA) (0.7 mL, 1.5 equiv.) was added to the solution. The reaction mixture was stirred at room temperature overnight and evaporated. The residue was purified by Combiflash chromatography (10% to 100% EtOAc in hexanes) to give product 108 (1 g, 87% yield).

[0263] Compound 108 (1 g), pyrazole-4-boronic acid (780 mg, 3 equiv.), NaCO (2.45 g, 10 equiv.), and PdCl(dppf) (250 mg) were stirred in dioxane (15 mL) and water (15 mL). The reaction mixture was heated at 100 °C overnight. LC-MS showed complete conversion to the product. The reaction mixture was evaporated and purified by Combiflash chromatography (2.0 M NH / MeOH in DCM, 0-20%) to give the desired product V-28 (750 mg, 77% yield). 1H NMR(300MHz,DMSO)δ 13.25(br,1H),11.63(s,1H),8.72(dd,J=6.0 Hz,1H),8.39(s,1H),8.25(s,1H),8.06(d,J=6.9 Hz,1H),7.95(m,2H),7.42(m,1H),7.26(d,J=3.9 Hz,1H),6.77(d,J=3.3 Hz,1H),4.60(p,J=7.8 Hz,1H),3.83(p,J=7.5 Hz,1H),3.40(q,J=6.9 Hz,2H),2.79(m,2H),2.41(m,2H),1.13(t,J=6.9 Hz, 3H); LCMS: Purity: 100%; MS (m / e): 419.60 (MH+).

[0264] Preparation of 2-methyl-1-(4-nitro-3-(pyridin-2-yl)-1H-pyrazol-1-yl)propan-2-ol (110) Sodium hydride (1.657 g, 41.4 mmol) was weighed and added to a dry reaction tube equipped with a magnetic stir bar and cooled to 0 °C. This was carefully suspended in 86 mL of THF, and the system was purged with nitrogen. 2-(4-nitro-1H-pyrazol-3-yl)pyridine (3.928 g, 20.7 mmol) was added to 40 mL of dimethylformamide, followed by a 7 mL dimethylformamide wash. This was stirred at 0 °C for 30 minutes, followed by 30 minutes at room temperature. It was then cooled back to 0 °C, and isobutylene oxide (5.5 mL, 61.9 mmol) was added. The reaction was allowed to warm to room temperature and stir, heated at 100 °C for 3 hours, and stirred at room temperature overnight. The reaction was recharged with sodium hydride (0.445 g, 11.2 mmol) and isobutylene oxide (1.8 mL, 20.3 mmol) and heated at 100° C. for an additional 2 h. The reaction was quenched with water, concentrated to dryness, and the residue was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The aqueous layer was extracted three more times with ethyl acetate, and the combined organic layers were washed with brine and dried over sodium sulfate. The product solution was filtered, concentrated onto silica, and purified by column chromatography. After drying, two batches gave 1.92 g of the title compound 110 (35% yield). 1 H NMR(300 MHz,DMSO-d6)δ 8.73(s,1H),8.72-8.45(m,1H),7.95-7.88(m,1H),7.71-7.65(m,1H),7 .51-7.43(m,1H),4.89(s,1H),4.14(s,2H),1.14(s,6H).m / z=263(M+H) + .

[0265] Preparation of 1-(4-amino-3-(pyridin-2-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol 112 TIFF2024534919000039.tif37128 2-Methyl-1-(4-nitro-3-(pyridin-2-yl)-1H-pyrazol-1-yl)propan-2-ol 110 (0.994 g, 3.8 mmol) was added to a Parr reaction bottle in 100 mL of ethyl acetate. This was placed under nitrogen and charged with 10% (wet) Pd on carbon (0.404 g, 0.2 mmol). This was run overnight on a Parr hydrogenator at 60 psi of hydrogen. The reaction was filtered through Celite with a methanol wash, concentrated onto silica, and purified by column chromatography. After drying under high vacuum, 0.723 g of the title compound 112 (82% yield) was obtained. 1 H NMR(300 MHz,DMSO-d6)δ 8.51(ddt,J=5.0,1.9,0.9 Hz,1H),7.85-7.71(m,2H),7.23-7.11(m,2H),4.98(s,2H),4.68(s,1H),3.92(s,2H),1.08(s,6H).m / z=233(M+H) + .

[0266] Preparation of 5-bromo-N-(1-(2-hydroxy-2-methylpropyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide 114 TIFF2024534919000040.tif381285-Bromofuran-2-carboxylic acid (0.148 g, 0.77 mmol) was weighed and added to a flask equipped with a magnetic stir bar. This was dissolved in 33 mL of dichloromethane, and diisopropylethylamine (0.20 mL, 1.2 mmol) was added, followed by HATU (0.381 g, 1.0 mmol). This was stirred at room temperature for 30 minutes, and 1-(4-amino-3-(pyridin-2-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol 112 (0.214 g, 0.92 mmol) was added in 13 mL of dichloromethane. The reaction was stirred overnight at room temperature. This was directly concentrated onto silica gel and purified by column chromatography. After drying, 0.358 g of the title compound 114 was obtained. (96% mass balance based on aminopyrazole, hydrobutyl-related by-products remained in the purified product, which was used directly.) 1 H NMR(300MHz,DMSO-d6)δ 11.82(s,1H),8.65(ddd,J=5.0,1.8,1.0 Hz,1H),8.34(s,1H),8.02-7.90(m,2H),7.41(ddd,J=7.2,5.0,1.6 Hz,1H),7.27(d,J=3.6 Hz,1H),6.88(d,J=3.6 Hz,1H),4.77(s,1H),4.11(s,2H),1.12(s,6H).m / z=405 / 407(M+H) + (Bromine isotope).

[0267] V-1: Preparation of N-(1-(2-hydroxy-2-methylpropyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-methyl-1H-pyrazol-4-yl)furan-2-carboxamide 5-Bromo-N-(1-(2-hydroxy-2-methylpropyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide 114 (49 mg, 0.12 mmol) in 1.7 mL of a premixed 7 / 3 dimethoxyethane / ethanol solution was added to a microwave reaction vial equipped with a magnetic stir bar. (1-Methyl-1H-pyrazol-4-yl)boronic acid (99 mg, 0.78 mmol) was weighed and added to the vial. 2 M aqueous sodium carbonate (0.41 mL, 0.82 mmol) was added, and the reaction was subjected to vigorous subsurface nitrogen sparging. Pd[P(Ph)3]2Cl2 (16 mg, 0.02 mmol) was added, and the tube was sealed under nitrogen and then heated in a microwave at 130 °C for 30 min. The reaction was worked up in a tube and first diluted with ethyl acetate. It was washed successively with brine, 1 M aqueous sodium hydroxide, and brine, and the aqueous layer was pipetted from the bottom of the tube. The aqueous was back-extracted twice with ethyl acetate, and the combined organic layers were dried over sodium sulfate in a vial. The product solution was filtered into another vial, evaporated, and purified by preparative HPLC. After drying, 6 mg of the title compound V-1 (10% yield; an additional 12 mg of less pure product was recovered) was obtained as the TFA salt. 1 H NMR(300 MHz,DMSO-d6)δ 11.65(s,1H),8.75(ddd,J=5.0,1.8,0.9 Hz,1H),8.38(s,1H),8.19(s,1H),8.02(dt,J=8.2,1.2 Hz,1H),7.99-7.92(m,1H),7.90(d,J=0.7 Hz,1H),7.43(ddd,J=7.3,4.9,1.4 Hz,1H),7.27(d,J=3.6 Hz,1H),6.76(d,J=3.6 Hz,1H),4.78(s,1H),4.11(s,2H),3.95(s,3H),1.12(s,6H).m / z=407(M+H) + .

[0268] V-3: Preparation of N-(1-(2-hydroxy-2-methylpropyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide TIFF2024534919000042.tif40143 5-Bromo-N-(1-(2-hydroxy-2-methylpropyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide 114 (0.289 g, 0.71 mmol) was weighed and added to a microwave reaction tube equipped with a magnetic stir bar. Pyrazole-4-boronic acid (0.511 g, 4.6 mmol) was added, followed by 10 mL of a 7:3 dimethoxyethane / ethanol solution. Sodium carbonate (0.514 g, 4.8 mmol) was dissolved in 2.42 mL of water and added to the reaction, which was subjected to vigorous subsurface nitrogen sparging. Pd[P(Ph)3]2Cl2 (60 mg, 0.09 mmol) was added and the tube was sealed under nitrogen and then heated in a microwave at 130 °C for 30 min.

[0269] The solution was diluted with ethyl acetate, washed first with brine, then with 1 M aqueous sodium hydroxide, and again with brine before drying over sodium sulfate. (The base wash was analyzed for the desired product to monitor potential loss to the aqueous layer.) The product solution was filtered, concentrated onto silica, and purified by column chromatography. After drying, 0.180 g of the title compound V-3 (64% yield) was obtained. 1 H NMR(300 MHz,DMSO-d6)δ 13.27(s,1H),11.67(s,1H),8.74(ddd,J=5.0,1.8,0.9 Hz,1H),8.38(s,1H),8.26(s,1H),8.10-7.80(m,3H),7.43(ddd,J=7.3,5.0,1.4 Hz,1H),7.27(d,J=3.5 Hz,1H),6.78(d,J=3.5 Hz,1H),4.78(s,1H),4.11(s,2H),1.13(s,6H).m / z=393(M+H) + .

[0270] V-4: Preparation of tert-butyl 4-(5-((1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazole-1-carboxylate TIFF2024534919000043.tif391385-Bromo-N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide (2.435 g, 6.0 mmol) was weighed and added to a reaction tube equipped with a magnetic stir bar. 1-Boc-pyrazole-4-boronic acid pinacol ester (3.535 g, 12.0 mmol) was added and dissolved in 60 mL of dimethylformamide. Cesium carbonate (3.916 g, 12.0 mmol) was weighed and added, and the reaction was subjected to a vigorous subsurface nitrogen sparge. Pd(dppf)Cl2·CHCl2 (0.491 g, 0.60 mmol) was added, followed by Ag2O (1.391 g, 6.0 mmol). The tube was sealed under nitrogen and stirred overnight at room temperature. The reaction solution was then combined with 0.64 mmol of a pilot reaction run under the same conditions and filtered through Celite with an ethyl acetate wash. The filtrate was concentrated to dryness and partitioned between ethyl acetate and water. The aqueous layer was extracted three more times with ethyl acetate, and the combined organic layers were washed with brine and dried over sodium sulfate. The product solution was filtered, concentrated onto silica, and purified by column chromatography. Pure fractions were combined, concentrated, and dried under high vacuum to give 2.2 g of the title compound V-4 (69% combined yield). 1 H NMR(300MHz,chloroform-d)δ 11.83(s,1H),8.69(ddd,J=5.0,1.9,1.0 Hz,1H),8.60-8.33(m,2H),8.29-7.91(m,2H),7.79(ddd,J=8.1,7.5,1.7 Hz,1H),7.28-7.21(m,2H),6.62(d,J=3.6 Hz,1H),4.35(t,J=5.6 Hz,2H),3.86(t,J=5.6 Hz,2H),3.51(q,J=7.0 Hz,2H),1.72(s,9H),1.19(t,J=7.0 Hz,3H).m / z=493(M+H)+ .

[0271] Preparation of 2-bromo-N-(1-(2-hydroxy-2-methylpropyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide 116 TIFF2024534919000044.tif39128 2-Bromothiazole-4-carboxylic acid (0.257 g, 1.2 mmol) was weighed and added to a flask equipped with a magnetic stir bar and taken up in 53 mL of dichloromethane. Diisopropylethylamine (0.322 mL, 1.8 mmol) was added, followed by HATU (0.611 g, 1.6 mmol), and the reaction was stirred at room temperature for 60 minutes. 1-(4-amino-3-(pyridin-2-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol 112 (0.344 g, 1.5 mmol) was added to a solution of 21 mL of dichloromethane, and the reaction was stirred at room temperature overnight. This was concentrated directly onto silica and purified by column chromatography. All product-containing fractions were found to contain hydroxyazabenzotriazole as a contaminant. These were concentrated and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was washed with ethyl acetate until the product was completely extracted. The combined organic layers were washed with brine and dried over sodium sulfate. Filtration, concentration, and drying under high vacuum gave 0.429 g of pure title compound 114 (82% yield). 1 H NMR(300 MHz,DMSO-d6)δ 12.23(s,1H),8.70-8.57(m,1H),8.42(d,J=5.7 Hz,2H),8.06-7.87(m,2H),7.39(ddd,J=7.3,4.9,1.5 Hz,1H),4.78(s,1H),4.12(s,2H),1.12(s,6H).m / z=422 / 424(M+H) + (Bromine isotope).

[0272] VI-1: Preparation of N-(1-(2-hydroxy-2-methylpropyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide TIFF2024534919000045.tif37140 2-Bromo-N-(1-(2-hydroxy-2-methylpropyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide 116 (0.212 g, 0.50 mmol) was weighed and added to a microwave reaction vial equipped with a magnetic stir bar. 1-Boc-pyrazole-4-boronic acid pinacol ester (0.944 g, 3.2 mmol) was added, followed by 4.9 mL of dimethoxyethane and 2.1 mL of ethanol. Sodium carbonate (0.362 g, 3.4 mmol) was dissolved in 1.7 mL of water and added to the reaction. The solution was subjected to vigorous subsurface nitrogen sparging, and Pd[P(Ph)3]2Cl2 (60 mg, 0.09 mmol) was added. The tube was sealed under nitrogen and heated in a microwave at 130° C. for 30 minutes.

[0273] The solution was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine. The emulsified layer was back-extracted three times with ethyl acetate, and the combined organic layers were dried over sodium sulfate. It was filtered, concentrated, and purified by column chromatography to give 0.160 g of the title compound VI-1 (78% yield) after drying. 1 H NMR(300 MHz,DMSO-d6)δ 13.42(s,1H),12.21(s,1H),8.77(ddd,J=5.0,1.8,1.0 Hz,1H),8.45(s,1H),8.44-8.05(br s,2H),8.28(s,1H),8.03-7.90(m,2H),7.42(ddd,J=7.4,4.9,1.4 Hz,1H),4.79(s,1H),4.12(s,2H),1.13(s,6H).m / z=410(M+H) + .

[0274] VI-11: Preparation of N-(1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide TIFF2024534919000046.tif46161 Compound 106 (680 mg), 2-bromothiazole-4-carboxylic acid (658 mg, 1.2 equiv.), and HATU (1.5 g, 1.5 equiv.) were dissolved in THF (30 mL), and DIPEA (0.7 mL, 1.5 equiv.) was added to the solution. The reaction mixture was stirred at room temperature overnight and evaporated. The residue was purified by Combiflash chromatography (10% to 100% EtOAc in hexanes) to give product 118 (980 mg, 83% yield).

[0275] Compound 118 (1 g), pyrazole-4-boronic acid (750 mg, 3 equiv.), NaCO (2.37 g, 10 equiv.), and PdCl(dppf) (200 mg) were stirred in dioxane (15 mL) and water (15 mL). The resulting mixture was heated at 100 °C overnight. LC-MS showed complete conversion to the product. The reaction mixture was evaporated and purified by Combiflash chromatography (2.0 M NH / MeOH in DCM = 0-20%) to give the desired product VI-11 (700 mg, 72% yield). 1 H NMR(300 MHz,DMSO)δ 13.41(br,1H),12.18(s,1H),8.75(d,J=4.5 Hz,1H),8.46(m,2H),8.27(s,1H),8.06(m,2H),7.93(m,1H),7.42(m,1H),4.61(p,J=8.1 Hz,1H),3.84(p,J=6.9 Hz,1H),3.41(q,J=6.9 Hz,2H),2.80(m,2H),2.44(m,2H),1.13(t,J=6.9 Hz,3H); LCMS: Purity: 100%; MS(m / e): 436.56(MH+).

[0276] Preparation of 4-nitro-3-(trifluoromethyl)-1H-pyrazole 120 TIFF2024534919000047.tif221287 Two mL of concentrated sulfuric acid was added to a flask equipped with a magnetic stir bar and cooled to 0°C. 3-(Trifluoromethyl)-pyrazole (12.070 g, 88.70 mmol) was weighed and added slowly. An addition funnel was attached and charged with 90% fuming nitric acid (36 mL, 766 mmol). This was added dropwise at 0°C, and the reaction was allowed to warm to room temperature and stir overnight. The reaction was then recharged with the same nitric acid as above (19 mL, 404 mmol) at room temperature and then quenched. Stirring at room temperature was continued overnight.

[0277] The reaction was poured onto ice and neutralized by the slow addition of 200 g of sodium carbonate. The pH was adjusted to 6 with 1 M hydrochloric acid, and the solution was extracted six times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to an oil. This crystallized, and the solid was washed with a minimum of dichloromethane to give 3.250 g of the title compound 120 after drying. A second crop was isolated from the filtrate to give 1.752 g more product (31% yield). Additional product remained in the filtrate. 1 H NMR(300 MHz,DMSO-d6)δ 9.16(s,1H).m / z=180(MH) - .

[0278] Preparation of 3-(4-nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl)cyclobutan-1-one 122 TIFF2024534919000048.tif35128 Compound 120 (1.2356 g, 6.82 mmol) was dried and weighed into a tared reaction flask. This was taken up in 22 mL of tetrahydrofuran and a magnetic stir bar was added. 3-Bromocyclobutan-1-one (1.3837 g, 9.29 mmol) was placed in a tared vial and added to the reaction in 11 mL of tetrahydrofuran solution. Potassium carbonate (1.417 g, 10.25 mmol) was weighed and added, and the reaction was stirred at room temperature overnight.

[0279] The reaction was then recharged with 3-bromocyclobutan-1-one (1.232 g, 8.27 mmol) in 5 mL of tetrahydrofuran and stirred overnight at room temperature. The mixture was then concentrated to remove THF and partitioned between ethyl acetate and water. The aqueous solution was extracted three more times with ethyl acetate, and the combined organic layers were washed with brine and dried over sodium sulfate. It was filtered and concentrated, allowing it to spontaneously crystallize. The solid was collected, washed with a minimal volume of dichloromethane, and dried under high vacuum to give 677.2 mg of the title compound 122. A second crop isolated after crystallization from the filtrate gave 432.2 mg more of the product 122 (65% yield). A 1D NOE experiment confirmed the N1 assignment of the pyrazole alkylation. 1 H NMR (300 MHz, DMSO-d) δ 9.44 (s, 1H), 5.34 (p, J = 6.9 Hz, 1H), 3.67 (d, J = 6.7 Hz, 4H). No parent ion was observed.

[0280] Preparation of (1s,3s)-3-(4-nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl)cyclobutan-1-ol 124 TIFF2024534919000049.tif37128 Compound 122 (601.0 mg, 2.41 mmol) was dried and weighed into a tared reaction flask. This was dissolved in 12 mL of methanol, a magnetic stir bar was added, and the solution was cooled to 0 °C. Sodium borohydride (137.9 mg, 3.64 mmol) was weighed and added. The reaction was stirred at room temperature for 2 hours. After HPLC showed completion, it was concentrated onto silica and purified by column chromatography. After drying, 536.2 mg of the title compound 124 was obtained (88% yield). 1 H NMR(300 MHz,DMSO-d6)δ 9.23(s,1H),5.38(d,J=6.7 Hz,1H),4.63-4.46(m,1H),4.06-3.89(m,1H),2.83-2.70(m,2H),2.42-2.29(m,2H).m / z=252(M+H) + .

[0281] Preparation of 1-((1s,3s)-3-ethoxycyclobutyl)-4-nitro-3-(trifluoromethyl)-1H-pyrazole 126 TIFF2024534919000050.tif37128 Compound 124 (189.6 mg, 0.76 mmol) was transferred to a reaction tube equipped with a magnetic stir bar in 5 mL of dichloromethane. Silver triflate (586.2 mg, 2.28 mmol) was weighed and added, followed by 2,6-di-t-butylpyridine (0.58 mL, 2.62 mmol). The reaction was cooled to 0 °C, and ethyl iodide (0.20 mL, 2.50 mmol) was added. The cooling bath was then removed, and the mixture was stirred at room temperature overnight. This reaction was combined with another run under the same conditions (46.0 mg, 0.18 mmol) and filtered through Celite with a dichloromethane wash. The filtrate was concentrated onto silica and purified by column chromatography. After drying, 172.8 mg of pure title compound 126 (66% yield) was obtained. 1 H NMR(300MHz,chloroform-d)δ 8.33(s,1H),4.46(tt,J=9.0,7.5 Hz,1H),3.90(tt,J=7.5,6.4 Hz,1H),3.47(q,J=7.0 Hz,2H),3.03-2.91(m,2H),2.57-2.44(m,2H),1.23(t,J=7.0 Hz,3H).m / z=280(M+H) + .

[0282] Preparation of 1-((1s,3s)-3-ethoxycyclobutyl)-3-(trifluoromethyl)-1H-pyrazol-4-amine 128 TIFF2024534919000051.tif37128 Compound 126 (231.4 mg, 0.83 mmol) was added to a Parr reaction bottle in 30 mL of ethyl acetate. This was placed under nitrogen and charged with 10% (wet) Pd on carbon (90.1 mg, 0.04 mmol). This was run on a Parr hydrogenator at 50 psi of hydrogen for 5 hours. The reaction was filtered through Celite with a methanol wash and concentrated to dryness. HPLC showed a complex mixture. 110.6 mg of this residue was dissolved in 10 mL of methanol. NiCl₂·xhydrate (400.1 mg, 1.68 mmol as the hydrate) was weighed and added, and the mixture was cooled to 0 °C. Sodium borohydride (127.4 mg, 3.4 mmol) was weighed and added slowly in portions. The reaction was stirred overnight while warming to room temperature. It was filtered through Celite with a methanol wash, concentrated onto silica, and purified by column chromatography. After drying, 76.2 mg of the title compound was obtained as an oil. (The remainder of the residue recovered from the hydrogenation was reduced using similar conditions to give an additional 46.1 mg of the title compound 128, 59% yield.) 1 H NMR(300MHz,chloroform-d)δ 7.17(s,1H),4.31(tt,J=9.1,7.5 Hz,1H),3.82(tt,J=7.6,6.5 Hz,1H),3.44(q,J=7.0 Hz,2H),2.93-2.80(m,2H),2.45-2.32(m,2H),1.22(t,J=7.0 Hz,3H).m / z=250(M+H) + .

[0283] Preparation of 2-bromo-N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide 130 TIFF2024534919000052.tif43128 2-Bromothiazole-4-carboxylic acid (61.4 mg, 0.30 mmol) was weighed and added to a flask equipped with a magnetic stir bar and taken up in 12 mL of dichloromethane. Diisopropylethylamine (0.077 mL, 0.44 mmol) was added, followed by HATU (145.4 mg, 0.38 mmol), and the reaction was stirred at room temperature for 45 minutes. Compound 128 (73 mg, 0.29 mmol) was added to a 5 mL solution of dichloromethane, and the reaction was stirred at room temperature overnight. This was concentrated directly onto silica and purified by column chromatography. Concentration and subsequent drying of the pure fractions under high vacuum yielded 71.0 mg of the title compound 130 (55% yield). 1 H NMR(300MHz,chloroform-d)δ 9.12(s,1H),8.40(s,1H),8.13(s,1H),4.52-4.32(m,1H),3.86(tt,J=7.6,6.5 Hz,1H),3.46(q,J=7.0 Hz,2H),2.91(dddd,J=9.3,7.5,6.5,2.9 Hz,2H),2.52(qdd,J=9.9,5.2,2.6 Hz,2H),1.23(t,J=7.0 Hz,3H).m / z=439 / 441(M+H) + (Bromine isotope).

[0284] VI-62: Preparation of N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide TIFF2024534919000053.tif46148 Compound 130 (67.7 mg, 0.15 mmol) was transferred to a microwave reaction tube equipped with a magnetic stir bar in a solution (4.2 mL of dimethoxyethane and 3.0 mL of ethanol). 1-Boc-pyrazole-4-boronic acid pinacol ester (290.6 mg, 1.0 mmol) was weighed and added. Sodium carbonate (109.0 mg, 1.0 mmol) was weighed into a tared vial, dissolved in 1.0 mL of water, and added to the reaction. The solution was subjected to a vigorous subsurface nitrogen sparge. Pd[P(Ph)3]2Cl2 (18.4 mg, 0.03 mmol) was weighed and added, and the tube was sealed under nitrogen. This was heated in a microwave at 100 °C for 30 minutes. The solution was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was extracted three more times with ethyl acetate, and the combined organic layers were washed with brine and dried over sodium sulfate. It was filtered, concentrated, and subjected to column chromatography. The purest fractions were concentrated to give a solid, which was triturated with acetonitrile and dried under high vacuum to give 8.0 mg of the title compound VI-62. (Additional impure material was recovered.) 1 H NMR(300MHz,chloroform-d)δ 9.44(s,1H),8.45(s,1H),8.12(s,2H),8.08(s,1H),4.43(ddd,J=16.6,9.3,7.5 Hz,1H),3.87(tt,J=7.7,6.4 Hz,1H),3.47(q,J=7.0 Hz,2H),2.92(dddd,J=9.3,7.5,6.5,3.3 Hz,2H),2.54(tdd,J=9.3,7.7,2.9 Hz,2H),1.23(t,J=7.0 Hz,3H).m / z=427(M+H) + .

[0285] Preparation of 2-bromo-N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide 132 TIFF2024534919000054.tif29142 Bromothiazole-4-carboxylic acid (416.2 mg, 2.00 mmol) was weighed and added to a flask equipped with a magnetic stir bar and taken up in 40 mL of dichloromethane. Diisopropylethylamine (0.52 mL, 3.0 mmol) was added, followed by HATU (990.4 mg, 2.60 mmol), and the reaction was stirred at room temperature for 45 minutes. 1-Methyl-3-(trifluoromethyl)-1H-pyrazol-4-amine (329.4 mg, 2.00 mmol) was added to a 10 mL solution of dichloromethane, and the reaction was stirred at room temperature overnight. This was concentrated directly onto silica and purified by column chromatography. After drying, 471.6 mg of the title compound 132 was obtained (66% yield—additional less pure material was recovered). 1 H NMR (300 MHz, chloroform-d) δ 9.12 (s, 1H), 8.29 (s, 1H), 8.13 (s, 1H), 3.96 (s, 3H). m / z = 355 / 357 (M+H) + (Bromine isotope).

[0286] VI-63: Preparation of N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide trifluoroacetate TIFF2024534919000055.tif34149 Compound 132 (100.0 mg, 0.28 mmol) and 1-Boc-pyrazole-4-boronic acid pinacol ester (531.4 mg, 1.80 mmol) were weighed and added to a microwave reaction tube equipped with a magnetic stir bar. 7.7 mL of dimethoxyethane and 5.5 mL of ethanol were added. Sodium carbonate (200.2 mg, 1.89 mmol) was weighed into a tared vial, dissolved in 2.0 mL of water, and added to the reaction. The solution was subjected to a vigorous subsurface nitrogen sparge. Pd[P(Ph)3]2Cl2 (34.4 mg, 0.05 mmol) was weighed and added, and the tube was sealed under nitrogen. This was heated in a microwave at 100 °C for 30 minutes. This was concentrated to remove dimethoxyethane and ethanol, and extracted four times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. This was purified by preparative HPLC to give compound VI-64. After drying, 54.3 mg of the title compound VI-63 was obtained as a trifluoroacetic acid salt. 1 H NMR(300 MHz,DMSO-d6)δ 9.61(s,1H),8.32(s,1H),8.25(s,2H),3.95(s,3H).m / z=343(M+H) + .

[0287] Preparation of (1s,3s)-3-(4-amino-3-(3-fluoropyridin-2-yl)-1H-pyrazol-1-yl)cyclobutan-1-ol 134 TIFF2024534919000056.tif44128 (1s,3s)-3-(3-(3-fluoropyridin-2-yl)-4-nitro-1H-pyrazol-1-yl)cyclobutan-1-ol (1.070 g, 3.85 mmol) was weighed and added to a flask equipped with a magnetic stir bar and dissolved in 98 mL of ethyl acetate. This was placed under nitrogen and charged with 10% (wet) Pd on carbon (117.8 mg, 0.014 mmol). After purging thoroughly with nitrogen, this was stirred under a balloon of hydrogen for 3 hours. The reaction was then filtered through Celite with excess ethyl acetate washings. The filtrate was concentrated to dryness to quantitatively recover the title compound 134 as a foam, which was used in the next reaction without further purification. 1 H NMR(300 MHz,DMSO-d6)δ 8.47-8.31(m,1H),7.79-7.62(m,1H),7.35-7.22(m,2H),5.26(d,J=6.6 Hz,1H),4.94(s,2H),4.34-4.18(m,1H),3.93(td,J=7.4,6.0 Hz,1H),2.71(dtd,J=8.7,7.1,3.0 Hz,2H),2.27(qd,J=8.7,2.9 Hz,2H).m / z=249(M+H) + .

[0288] Preparation of 2-bromo-N-(3-(3-fluoropyridin-2-yl)-1-((1s,3s)-3-hydroxycyclobutyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide 136 Compound 134 (0.96 g, 3.85 mmol) was dried and weighed into a tared reaction flask and dissolved in 30 mL of dichloromethane, and 10 mL of dimethylformamide was added along with a magnetic stir bar.

[0289] 2-Bromothiazole-4-carboxylic acid (800.6 mg, 3.85 mmol) was weighed and added. Diisopropylethylamine (1.0 mL, 5.7 mmol) was added, followed by HATU (1.901 g, 5.00 mmol), and the reaction was stirred at room temperature overnight. It was concentrated directly onto silica and purified by column chromatography. Concentration and subsequent drying of the pure fractions under high vacuum gave 1.158 g of the title compound 136 (69% yield). 1 H NMR(300MHz,DMSO-d6)δ 12.14(s,1H),8.57-8.48(m,2H),8.44(s,1H),7.91(ddd,J=11.5,8.4,1.3 Hz,1H),7.52(ddd,J=8.4,4.6,3.8 Hz,1H),5.34(d,J=6.9 Hz,1H),4.52(tt,J=9.1,7.3 Hz,1H),4.05-3.91(m,1H),2.86-2.72(m,2H),2.39(qd,J=8.6,2.8 Hz,2H).m / z=438 / 440(M+H) + (Bromine isotope).

[0290] VI-65: Preparation of N-(3-(3-fluoropyridin-2-yl)-1-((1s,3s)-3-hydroxycyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide TIFF2024534919000058.tif41140 Compound 136 (0.497 g, 1.13 mmol) was transferred to a microwave reaction tube equipped with a magnetic stir bar in a solution (13 mL of dimethoxyethane and 5.5 mL of ethanol). 1-Boc-pyrazole-4-boronic acid pinacol ester (1.334 g, 4.53 mmol) was weighed and added. Sodium carbonate (0.480 g, 4.53 mmol) was weighed into a tared vial, dissolved in 4.5 mL of water, and added to the reaction. The solution was subjected to vigorous subsurface nitrogen sparging. Pd[P(Ph)3]2Cl2 (79.6 mg, 0.11 mmol) was weighed and added, and the tube was sealed under nitrogen. This was heated in a microwave at 100 °C for 90 minutes. This was concentrated to remove dimethoxyethane and ethanol, and extracted four times with ethyl acetate. However, there was substantial undissolved solid. This was collected and washed repeatedly with methanol. After drying, this gave 174.0 mg of the title compound with a purity of 90%.

[0291] The combined organic layers from the extraction were washed with brine, dried over sodium sulfate, filtered, and combined with the methanol washes of the precipitated solid. The solution was concentrated onto silica and purified by column chromatography. Concentration of the pure fractions yielded a solid, which was triturated with a minimum of dichloromethane. After drying, 169.2 mg of pure title compound VI-65 was obtained. 1 H NMR(300 MHz,DMSO-d6)δ 13.43(s,1H),12.09(s,1H),8.66(dt,J=4.6,1.4 Hz,1H),8.57(s,1H),8.50(s,1H),8.30(s,1H),8.11(s,1H),7.91(ddd,J=11.5,8.4,1.3 Hz,1H),7.54(ddd,J=8.4,4.6,3.8 Hz,1H),5.34(d,J=6.9 Hz,1H),4.61-4.42(m,1H),3.98(h,J=7.4 Hz,1H),2.80(dtd,J=9.6,6.9,2.8 Hz,2H),2.47-2.33(m,2H).m / z=426(M+H) + .

[0292] Preparation of 2-(4-nitro-1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazol-3-yl)pyridine 138 A stirred suspension of 2-(4-nitro-1H-pyrazol-3-yl)pyridine (950 mg, 5.00 mmol), 1,4-dioxaspiro[4.5]decan-8-yl 4-methylbenzenesulfonate (1.69 g, 5.41 mmol), and CsCO (2.44 g, 7.50 mmol) in anhydrous THF:DMF (15 mL, 4:1, v / v) was heated to 100 °C and stirred for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 50 mL). The organic layer was washed with brine (50 mL), dried over MgSO, concentrated, and purified by column chromatography (0–100% EtOAc in hexanes, gradient) to give compound 138 (910 mg, 55.14%) as a light brown semisolid. MS(m / e):330.34(MH+).

[0293] Preparation of 4-(4-nitro-3-(pyridin-2-yl)-1H-pyrazol-1-yl)cyclohexan-1-one 140 To a stirred solution of compound 138 (910 mg, 2.75 mmol) in acetone:HO (20 mL, 1:1, v / v), pyridinium p-toluene sulfonate (1.38 g, 5.50 mmol) was added, and the reaction mixture was heated to 80 °C and stirred for 16 h. The acetone was evaporated in vacuo, and the aqueous layer was quenched with NaOH to pH = 8 and extracted with EtOAc (3 × 50 mL). The organic layer was washed with brine (50 mL), dried over MgSO, concentrated, and purified by column chromatography (0–100% MeOH in DCM, gradient) to give compound 140 (600 mg, 76.08%) as a dark brown oil. MS (m / e): 286.29 (MH+).

[0294] Preparation of (trans)-4-(4-nitro-3-(pyridin-2-yl)-1H-pyrazol-1-yl)cyclohexan-1-ol 142 TIFF2024534919000061.tif42128NaBH4 (20 mg, 0.524 mmol) was added to a stirred solution of 2 (600 mg, 2.10 mmol) in MeOH (10 mL) at 0 °C, stirred for 0.5 h, concentrated, and subjected to column chromatography (0 to 100% MeOH (1 M NH3 solution) in DCM, gradient) to give product 142 (362 mg, 60%) as a viscous oil. 1 H NMR (300 MHz, chloroform-d) δ 8.77 (d, J = 4.8 Hz, 1H), 8.29 (s, 1H), 7.84 (m, 2H), 7.36 (m, 1H), 4.24 (m, 1H), 3.76 (m, 1H), 3.46 (s, 1H), 2.14 (m, 8H). LCMS: Purity: 87.43%. MS(m / e):288.31(MH+).

[0295] Preparation of 2-(1-((trans)-4-ethoxycyclohexyl)-4-nitro-1H-pyrazol-3-yl)pyridine 146 NaH (60% dispersion in mineral oil, 60 mg, 1.50 mmol) was added to a stirred solution of compound 142 (360 mg, 1.25 mmol) and iodoethane (200 μL, 2.50 mmol) in anhydrous DMF (8 mL) at −20° C. The reaction mixture was allowed to warm to room temperature for 2 h. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (3 × 50 mL). The organic layer was washed with brine (30 mL), dried over MgSO4, concentrated, and purified by column chromatography (0–100% EtOAc in hexanes, gradient) to give product 146 (296 mg, 74.93%) as a viscous oil. MS (m / e): 316.36 (MH+).

[0296] Preparation of 1-((trans)-4-ethoxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-amine 148 A solution of compound 146 (290 g, 0.917 mmol) and Pd / C (10 wt%, 50 mg) in 10 mL of EtOAc was hydrogenated under 50 psi of H(g) for 12 h, filtered through Celite, and concentrated to give compound 148 (230 mg, 87.61%) as a viscous oil. MS (m / e): 286.38 (MH).

[0297] Preparation of 2-bromo-N-(1-((trans)-4-ethoxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide 150 HATU (458 mg, 1.20 mmol) was added to a stirred solution of 2-bromothiazole-4-carboxylic acid (184 mg, 0.883 mmol) and DIPEA (280 μL, 1.61 mmol) in anhydrous THF (4 mL) at room temperature for 10 min, followed by the addition of a solution of compound 148 (230 mg, 0.803 mmol) in anhydrous THF (4 mL). After 1 h, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 20 mL). The organic layer was washed with brine (20 mL), dried over MgSO4, concentrated, and purified by column chromatography (0–100% EtOAc in hexanes, gradient) to give product 150 as a semisolid, which was used without further purification. Expected quantitative yield. MS (m / e): 476.39 (MH+).

[0298] VI-145: Preparation of N-(1-((trans)-4-ethoxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide TIFF2024534919000065.tif43128 A mixture of crude compound 150 (0.803 mmol), 1H-pyrazole-4-boronic acid (180 mg, 1.61 mmol), Pd(dppf)Cl2 (65.6 mg, 0.080 mmol), 2 M Na2CO3 (1.61 mL, 3.21 mmol) and anhydrous 1,4-dioxane (10 mL) was heated at 105 °C and stirred for 16 h. The reaction mixture was cooled to room temperature, diluted with water (20 mL), extracted with EtOAc (3 × 30 mL), and the organic layer was washed with brine (20 mL), dried over MgSO, concentrated, and purified by column chromatography (0–100% EtOAc in hexanes, gradient) to afford a semi-solid, which was subjected to analytical purification and subsequently lyophilized to afford the title compound VI-145 (75 mg, 20.15%) as a white fluffy solid. 1 H NMR(300 MHz,DMSO-d6)δ 13.40(s,1H),12.18(s,1H),8.74(d,J=4.8 Hz,1H),8.49(s,1H),8.35(s,1H),8.27(s,1H),8.10(s,1H),7.97(m,2H),7.39(t,J=6.9 Hz,1H),4.29(t,J=11.7 Hz,1H),3.47(td,J=7.1,5.8 Hz,2H),3.35(t,J=11.7 Hz,1H),2.09(d,J=11.6 Hz,4H),1.87(q,J=11.8 Hz,2H),1.35(q,J=11.2 Hz,2H),1.10(t,J=6.9 Hz,3H).LCMS: Purity: 100%. MS(m / e):463.56(MH+).

[0299] VI-77: (4-(4-((1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate bis-potassium salt TIFF2024534919000066.tif46128 To a mixture of (4-(4-((1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate (300 mg) in acetonitrile (2 mL) and water (1 mL) was added 1.0 N aqueous potassium hydroxide solution (1.1 mL, 2 equivalents). After sonication for 5 minutes, the solution was lyophilized for 24 hours. The resulting powder was suspended in water (1 mL) and isopropanol (5 mL). The mixture was stirred at 70° C. for 5 minutes until a clear solution was formed. The solution was cooled to room temperature. The resulting precipitate was collected by filtration, washed with isopropanol (3×1 mL), and dried under high vacuum at room temperature for 24 hours to give the potassium salt (280 mg) as a white solid. 1 H NMR (300MHz, deuterium oxide) δ 7.83(d,1H),7.80(s,1H),7.64(s,1H),7.42(s,1H),7.41(m,1H),7.29(s,1H),7.17(d,J=7.2 Hz,1H),6.89(m,1H),5.57(d,J=8.1 Hz,2H),4.13(m,1H),3.91(t,J=7.8 Hz,1H),3.49(q,J=7.2 Hz,2H),2.83(m,2H),2.19(m,2H),1.14(t,J=7.2 Hz,3H); LCMS: Purity: 100%; MS(m / e): 546.23(MH+).

[0300] VI-78: (4-(4-((1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate calcium salt TIFF2024534919000067.tif46128 To a mixture of (4-(4-((1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate (309 mg) in acetonitrile (2 mL) and water (1 mL) was added calcium hydroxide (42 mg, 1 equivalent). After sonication for 5 minutes, the reaction mixture was lyophilized for 24 hours. The resulting powder was suspended in water (1 mL) and isopropanol (5 mL). The mixture was stirred at 70° C. for 5 minutes and then cooled to room temperature. The resulting precipitate was collected by filtration, washed with isopropanol (3×1 mL), and dried under high vacuum at room temperature for 24 hours to give the calcium salt (300 mg) as a white solid. LCMS: Purity: 95.41%; MS (m / e): 546.22 (MH+).

[0301] VI-80: (4-(4-((1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate bis-ammonium salt To a mixture of (4-(4-((1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate (200 mg) in acetonitrile (1 mL) and water (1 mL) was added 2.0 N ammonia in methanol solution (0.37 mL, 2 equiv.). After sonication for 5 minutes, the solution was lyophilized for 24 hours. The resulting powder was suspended in water (0.5 mL) and isopropanol (3 mL). The resulting precipitate was collected by filtration, washed with isopropanol (3 × 1 mL), and dried under high vacuum at room temperature for 24 hours to give the ammonium salt (180 mg) as a white solid. 1H NMR (300MHz, deuterium oxide) δ 7.71(s,2H),7.56(s,1H),7.33(m,2H),7.19(s,1H),7.08(d,J=8.1 Hz,1H),6.82(t,J=5.7 Hz,1H),5.53(d,J=7.8 Hz,2H),4.08(p,J=7.8 Hz,1H),3.89(m,1H),3.48(q,J=7.2 Hz,2H),2.79(m,2H),2.13(m,2H),1.13(t,J=7.2 Hz, 3H); LCMS: Purity: 100%; MS (m / e): 546.15 (MH+).

[0302] VI-81: (4-(4-((1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate bis-lysine salt TIFF2024534919000069.tif46128 To a mixture of (4-(4-((1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate (200 mg) in acetonitrile (1 mL) and water (1 mL) was added L-lysine (107 mg, 2 equivalents). After sonication for 5 minutes, the solution was lyophilized for 24 hours. The resulting powder was suspended in water (0.5 mL) and isopropanol (3 mL). The resulting precipitate was collected by filtration, washed with isopropanol (3 × 1 mL), and dried under high vacuum at room temperature for 24 hours to give the bis-lysine salt (200 mg) as a white solid. 1H NMR (300MHz, deuterium oxide) δ 7.82(m,1H),7.79(s,1H),7.63(s,1H),7.41(s,1H),7.39(m,1H),7.28(s,1H),7.16(d,J=9.0 Hz,1H),6.88(m,1H),5.56(d,J=8.1 Hz,2H),4.12(m,1H),3.90(t,J=7.8 Hz,1H),3.61(t,J=5.7 Hz,2H),3.48(q,J=6.9 Hz,2H),2.88(t,J=7.5 Hz,4H),2.82(m,2H),2.16(m,2H),1.80-1.72(m,4H),1.63-1.53(m,4H),1.42-1.29(m,4H),1.13(t,J=7.2 Hz, 3H); LCMS: Purity: 100%; MS (m / e): 546.15 (MH+).

[0303] VI-82: (4-(4-((1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate bis-arginine salt TIFF2024534919000070.tif46128 To a mixture of (4-(4-((1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate (200 mg) in acetonitrile (1 mL) and water (1 mL) was added L-arginine (128 mg, 2 equivalents). After sonication for 5 minutes, the solution was lyophilized for 24 hours. The resulting powder was suspended in water (0.5 mL) and isopropanol (3 mL). The resulting precipitate was collected by filtration, washed with isopropanol (3 × 1 mL), and dried under high vacuum at room temperature for 24 hours to give the bis-arginine salt (200 mg) as a white solid. The salt was redissolved in water (0.5 mL) and acetone (8 mL). After heating at 50° C. for 10 minutes, the solution was cooled to room temperature. The resulting precipitate was collected by filtration, washed with acetone, and dried under high vacuum at room temperature for 24 hours to give the bis-arginine salt (120 mg) as a white solid. 1 H NMR (300MHz, deuterium oxide) δ 7.88(d,J=5.4 Hz,1H),7.84(s,1H),7.68(s,1H),7.46(s,1H),7.41(d,J=6.3 Hz,1H),7.33(s,1H),7.20(d,J=8.1 Hz,1H),6.92(m,1H),5.57(d,J=8.7 Hz,2H),4.15(t,J=8.7 Hz,1H),3.91(t,J=6.6 Hz,1H),3.62(t,J=6.0 Hz,2H),3.49(q,J=7.2 Hz,2H),3.08(t,J=6.9 Hz,4H),2.82(m,2H),2.11(m,2H),1.80-1.72(m,4H),1.63-1.44(m,4H),1.14(t,J=7.2 Hz,3H);LCMS: Purity: 100%;MS(m / e):546.15(MH+).

[0304] VI-83: ​​(4-(4-((1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate N-(1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide (59 g) and cesium carbonate (88 g, 2 equiv.) were suspended in dimethylformamide (500 mL). Di-tert-butyl(chloromethyl)phosphate (53 g, 1.5 equiv.) was added to the reaction, and the mixture was stirred at room temperature for 16–20 h. The reaction mixture was diluted with water (1 L) and extracted with ethyl acetate (2 × 800 mL). The combined organic layers were evaporated at room temperature and purified using Torrent Combiflash® Rf column chromatography (ethyl acetate in hexanes, 20-100%) to give the prodrug ester (85 g, 95% yield) as a colorless oil. LCMS: Purity: 100%; MS (m / e): 658.38 (MH+).

[0305] Di-tert-butyl ((4-(4-((1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)phosphate (85 g) was dissolved in anhydrous dichloromethane (700 mL), the resulting solution was cooled to 0° C., and trifluoroacetic acid (150 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 6 hours, and when LC-MS analysis showed complete conversion to the acid, the solution was evaporated on a rotary evaporator at room temperature. The residue was further dried under high vacuum at room temperature for 24 hours to give a pale yellow semi-solid as the acid, which was then used to form the salt.

[0306] (4-(4-((1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate (100 mg) was stirred in acetone (10 mL) and water (0.5 mL) at 50° C. overnight. The cloudy solution was cooled to room temperature. The white precipitate was collected by filtration, washed with acetone, and dried under high vacuum at room temperature for 24 hours (90 mg). 1 H NMR(300 MHz,DMSO-d6)δ 12.20(s,1H),8.83(d,J=4.8 Hz,1H),8.61(s,1H),8.46(s,1H),8.32(s,1H),8.18(s,1H),8.04(d,J=8.1 Hz,1H),7.93(t,J=6.9 Hz,1H),7.40(t,J=6.0 Hz,1H),5.90(d,J=11.1 Hz,2H),4.60(t,J=8.4 Hz,1H),3.83(t,J=6.6 Hz,1H),3.41(q,J=6.9 Hz,2H),2.80(m,2H),2.42(m,2H),1.13(t,J=6.9 Hz, 3H); LCMS: Purity: 100%; MS (m / e): 546.15 (MH+).

[0307] VI-84: (4-(4-((1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate tris salt TIFF2024534919000072.tif46128 To a mixture of (4-(4-((1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate (118 mg) in acetonitrile (1 mL) and water (1 mL) was added tris(hydroxymethyl)aminomethane (52 mg, 2 equivalents). After sonication for 5 minutes, the solution was lyophilized for 24 hours. The resulting powder was suspended in water (0.5 mL) and acetone (5 mL). The solution was stirred at 50° C. for 30 minutes and cooled to room temperature. After 1 week at room temperature, the resulting precipitate was collected via filtration, washed with acetone (3×1 mL), and dried under high vacuum at room temperature for 24 hours to give the mono-tris salt (120 mg) as a white solid. 1 H NMR (300MHz, deuterium oxide) δ 7.83(m,2H),7.65(s,1H),7.43(s,1H),7.40(d,J=7.5 Hz,1H),7.30(s,1H),7.17(d,J=8.1 Hz,1H),6.90(t,J=6.0 Hz,1H),5.57(d,J=8.1 Hz,2H),4.13(t,J=7.5 Hz,1H),3.91(t,J=6.9 Hz,1H),3.60(s,6H),3.49(q,J=6.9 Hz,2H),2.82(m,2H),2.18(m,2H),1.14(t,J=6.9 Hz, 3H); LCMS: Purity: 100%; MS (m / e): 546.16 (MH+).

[0308] Compounds V-1 through V-156 and VI-1 through VI-180 were made by methods described herein and / or methods similar to those known to those of skill in the art. Additional information regarding these compounds can be found in U.S. Patent No. 9,982,000, which is incorporated herein by reference in its entirety.

[0309] Example 2 Synthesis of pyrazole compounds according to formula VII Formation of N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamidobenzenesulfonate (VII-65) TIFF2024534919000073.tif36143 N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide (0.050 g, 0.100 mmol, 1.0 equiv.) was dissolved in chloroform (1.0 equiv.) to give a clear, colorless solution. Benzenesulfonic acid (0.019 g, 0.120 mmol, 1.2 equiv.) was added, and a precipitate formed over the next 15 minutes. The reaction was stirred at room temperature for 1 hour, and the precipitate was isolated by filtration to give the title compound (0.038 g) as a white solid; 1 H nmr (400 MHz, 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, 1H of pyrazole H-3, H-5), 8.29 (1H, s, thiazole H-5 or pyrazole H-5, 1H of pyrazole H-3, H-5), 8.28 (1H, s, thiazole H-5 or pyrazole H-5, 1H of pyrazole H-3, H-5), 8.08 (1H, dt, J 9.0, 6.5 Hz, pyridine H-4 or H-5), 7.59-7.56 (2H, m, 2H of CHSOH), 7.32-7.27 (4H, m, 3H of CHSOH, pyridine H-4 or H-5), 4.33 (1H, tt, J 11.5, 3.5 Hz, cyclohexane H-1 or H-4), 3.47 (2H, q, J 7.0 Hz, OC H2CH3), 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, and H-6), 1.85 (2H, m, cyclohexane H-2, H-3, H-5, and H-6), 1.35 (2H, m, 2H of cyclohexane H-2, H-3, H-5, and H-6), 1.10 (3H, t, J 7.0 Hz, OCH2C H 3); 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] + .

[0310] Formation of N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide sodium salt (VII-67) TIFF2024534919000074.tif36143 N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide (0.062 g, 0.124 mmol, 1.0 equiv) was dissolved in chloroform (2.0 mL) to give a clear solution. Sodium hydroxide (0.05 mL of a 3 M aqueous solution, 0.149 mmol, 1.2 equiv) was added and the reaction was stirred at room temperature for 3 days. No precipitate formed. The reaction was concentrated and further concentrated from acetonitrile (5 mL) to give the title compound as a white solid. 1H nmr (400 MHz, 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 or H-5), 8.08 (1H, dt, J 9.5, 6.5 Hz, pyridine H-4 or H-5), 7.28 (1H, ddd, J 9.0, 3.0, 2.5 Hz, pyridine H-4 or H-5), 4.33 (1H, tt, J 11.5, 3.0 Hz, cyclohexane H-1 or H-4), 3.47 (2H, q, J 7.0 Hz, OC) H 2CH3), 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, and H-6), 1.85 (2H, m, cyclohexane H-2, H-3, H-5, and H-6), 1.35 (2H, m, 2H of cyclohexane H-2, H-3, H-5, and H-6), 1.10 (3H, t, J 7.0 Hz, OCH2C H 3); m / z: 500 [M+H] + .

[0311] Formation of N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide tartaric acid cocrystal (VII-66) TIFF2024534919000075.tif37143 L-Tartaric acid (0.017 g, 0.110 mmol, 1.1 equiv) was added to a solution of N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide (0.050 g 0.100 mmol, 1.0 equiv) in chloroform (1.0 equiv). A white solid slowly precipitated. The reaction was stirred at room temperature for 18 hours, and the precipitate was isolated by filtration to give the title compound (0.055 g, 85%) as a white solid; 1H nmr (400 MHz, 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 or H-5), 8.08 (1H, dt, J 9.5, 6.5 Hz, pyridine H-4 or H-5), 7.28 (1H, dt, J 9.0, 3.0 Hz, pyridine H-4 or H-5), 5.05 (2H, br s, 2xOH), 4.33 (1H, tt, J 11.5, 3.5 Hz, cyclohexane H-1 or H-4), 4.29 (2H, s, COC H (OH)C H (OH)CO), 3.47 (2H, q, J 7.0 Hz, OC H 2CH3), 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, and H-6), 1.85 (2H, m, cyclohexane H-2, H-3, H-5, and H-6), 1.35 (2H, m, 2H of cyclohexane H-2, H-3, H-5, and H-6), 1.09 (3H, t, J 7.0 Hz, OCH2C H 3); 13 C nmr(100MHz,D6-DMSO)δ173.5,161.7,157.7,157.6(d,J 236.0Hz),153.5(dd,J 259.0,4.0 Hz),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; 19 F nmr(380MHz,D6-DMSO)δ-73.0,-124.2;m / z:500[M+H] + .

[0312] Formation of N-(3-(3,6-difluoropyridin-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide hemi((2R,3R)-2,3-dihydroxysuccinate) (VII-11) TIFF2024534919000076.tif45128 A solution of (L)-tartaric acid (750.5 mg, 5 mmol) in MeOH (1.3 mL) was dissolved in N-(3-(3,6-difluoropyridin-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide (5.0 g, 10 mmol) in CHCl 2- A solution of MeOH (60 mL - 5 mL) was added dropwise at 35°C, and further MeOH (5 mL) and CH2Cl2 (100 mL) were added after 15 min. The mixture was stirred at 35°C for another 20 h and then cooled to room temperature. The solid was collected by filtration, washed with CH2Cl2, and further dried in vacuo. The title 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=9.8,8.8,6.3 Hz,1H),7.27(ddd,J=8.8,2.9,2.9 Hz,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,J=10.7,3.6 Hz,1H),2.08-2.03(m,4H),1.88-1.78(m,2H),1.38-1.28(m,2H),1.08(t,J=7.0 Hz,3H); 19 F NMR(376 MHz,DMSO-d6)δ-72.97(ddd,J=28.1,6.8,3.8 Hz),-124.18(ddd,J=28.1,10.3,3.2 Hz);LRMS(M+H)m / z 500.2.

[0313] A second crop of the same compound (1.58 g, total yield: 88%) was obtained from the filtrate by removing the solvent in vacuo and then resuspending the solid in CH2Cl2-MeOH (25 mL-2 mL) at 35 °C overnight.

[0314] Preparation of N-(3-(3,6-difluoropyridin-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide (VII-1) - Method 1 TIFF2024534919000077.tif90130I.C2.Preparation of 2-bromo-N-(3-(3,6-difluoropyridin-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide C-3 from HCl TIFF2024534919000078.tif45128 Diisopropylethylamine (8.5 mL, 48.95 mmol, 3.5 equiv) was added to a mixture of aminopyrazole C-2.HCl (5.00 g, 13.99 mmol, 1.0 equiv) and bromothiazolecarboxylic acid (3.20 g, 15.38 mmol, 1.1 equiv) in dichloromethane (50 mL) at 0 °C. HATU (5.85 g, 15.38 mmol, 1.1 equiv) was added. The reaction was stirred at 0 °C for 10 min and then at room temperature for 4 h. The reaction was diluted with CHCl (100 mL). The organics were washed with NaHCO (150 mL), NHCl (150 mL), and brine (100 mL), dried (NaSO), and concentrated under reduced pressure. The residue was suspended in EtOAc-hexane (1:1, 50 mL) and the resulting solid was isolated by filtration. The solid was suspended in NaHCO (50 mL) for 1 h to remove residual coupling agent, then isolated by filtration and dried under vacuum to give C-3 (5.3 g, 74%) as an off-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, OC H 2CH3), 3.36 (1H, tt, J 10.5, 4.0 Hz, cyclohexane H-1 or H-4), 2.28 (2H, br d, J 13.0 Hz, 2H of cyclohexane H-2, H-3, H-5, and H-6), 2.21 (2H, m, 2H of cyclohexane H-2, H-3, H-5, and H-6), 1.91, 1.84 (2H, 2dd AB system, J 13.0, 3.5 Hz, 2H of cyclohexane H-2, H-3, H-5, and H-6), 1.46 (2H, m, 2H of cyclohexane H-2, H-3, H-5, and H-6), 1.22 (3H, t, J 7.0 Hz, OCH2C H 3); 13 C nmr(100MHz,CDCl3)δ157.6(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 from the initial trituration was purified by column chromatography (20→80% EtOAc-hexanes) to give additional C-3 (0.8 g, 9%) as a pink foam.

[0315] II. Preparation of N-(3-(3,6-difluoropyridin-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide (VII-1) Dioxane (400 mL) was added to a mixture of bromothiazole C-3 (25.0 g, 48.8 mmol, 1.0 equiv.) and pyrazole-4-boronic acid (8.2 g, 73.2 mmol, 1.5 equiv.), followed by aqueous sodium carbonate (73.3 mL of a 2 M solution, 146.5 mmol, 3.0 equiv.). The reaction mixture was degassed by bubbling argon through it for 5 minutes. Tetrakis(triphenylphosphine)palladium (1.4 g, 1.2 mmol, 0.025 equiv.) was added, and the reaction was further degassed before heating to 105 °C for 6 hours. The reaction was filtered hot through Celite®, eluting with EtOAc (200 mL). The filtrate was concentrated to approximately 150 mL, upon which a precipitate formed. The precipitate was isolated by filtration. The filtrate was concentrated to remove residual organics, filtered to remove more precipitate, diluted with water-brine (1:2, 300 mL), and extracted with EtOAc (3 x 200 mL). The combined organics were combined, dried (NaSO), and concentrated under reduced pressure. The combined precipitate and extract were loaded onto silica. Column chromatography (silica, 0->10% MeOH-CHCl) gave the title 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 (400 MHz, CDCl3) δ 8.52 (1H, s, thiazole H-5 or pyrazole H-5), 8.24 (2H, s, NH pyrazole H-3 or H-5), 8.07 (1H, s, thiazole H-5 or pyrazole H-5), 7.41 (1H, td, J 9.0, 6.0 Hz, pyridine H-4 or H-5), 6.86 (1H, ddd, J 9.0, 3.5, 2.5 Hz, pyridine H-4 or H-5), 4.28 (1H, tt, J 11.5, 4.0 Hz, cyclohexane H-1 or H-4), 3.57 (2H, q, J 7.0 Hz, OC H 2CH3), 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, and 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, and 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, and H-6), 1.23 (3H, t, J 7.0 Hz, OCH2C H 3); 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),6.4,63.7,61.5,31.1,30.9,15.7; 19 F nmr(380MHz,CDCl3)δ-72.7(dddd,J 27.0,9.5,5.5,4.0Hz),-124.3(ddd,J 27.5,9.5,3.0 Hz); m / z:500[M+H] + (Measured value [M+H] + ,500.1687,C 23 H 23 F2N7O2S is [M+H] + (Requires 500.1675).

[0316] Preparation of N-(3-(3,6-difluoropyridin-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide (VII-1) - Method 2 TIFF2024534919000080.tif62143I. Formation of 2-(1H-pyrazol-4-yl)thiazole-4-carboxylic acid A solution of 2-bromothiazole-4-carboxylic acid (2.08 g, 10 mmol, 1.0 equiv.), (1H-pyrazol-4-yl)boronic acid (3.36 g, 30 mmol, 3.0 equiv.), tetrakis(triphenylphosphine)palladium (0.23 g, 0.2 mmol, 0.02 equiv.), and sodium carbonate (3.18 g, 30 mmol, 3.0 equiv.) in 1,4-dioxane-HO (32 mL - 8 mL) was degassed and back-filled with nitrogen gas three times. The cloudy solution was heated at 60 °C for 2 h (starting material: product: 1.0 mmol) by LC-MS. TIFF2024534919000082.tif31281:1), then stirred at 100°C for an additional 3 hours until the reaction was complete, as monitored by LC-MS. After removing the organic solvent under reduced pressure, the crude mixture was diluted with water (100 mL) and mixed thoroughly. The aqueous solution was passed through a Celite® pad and washed with water. With stirring, the filtrate was acidified with 6 M aqueous HCl (approximately 11 mL) until pH = 1-2. The precipitate was collected by filtration, washed with water, and further dried in vacuo to give the title compound (1.79 g, 92% yield) as a light tan solid; 1 H nmr (400 MHz, 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] + .

[0317] II. Preparation of N-(3-(3,6-difluoropyridin-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide (VII-1) A mixture of C2.HCl aminopyrazole hydrochloride (1.00 g, 2.80 mmol, 1.0 equiv.) and 2-(1H-pyrazol-4-yl)thiazole-4-carboxylic acid (0.65 g, 3.36 mmol, 1.2 equiv.) in dimethylformamide (14 mL) was cooled to 0 °C, and diisopropylethylamine (1.22 mL, 6.99 mmol, 2.5 equiv.) was added. To the resulting solution was added HATU (1.17 g, 3.08 mmol, 1.1 equiv.). 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 which collapsed into a viscous material. The liquid was decanted, and any solid was isolated by filtration. The gum and solid were dissolved in EtOAc-MeOH (4:1, 100 mL), combined, and concentrated under reduced pressure. The resulting solid was triturated with 10% EtOH-EtOAc (4 mL) to give the title compound VII-1 (0.76 g, 55%) as an off-white solid. The filtrate was concentrated and loaded onto silica. Column chromatography (0 → 10% MeOH-CH2Cl2) gave a pale yellow solid, which was stirred with NaHCO3 (15 mL). The liquid was decanted, and the residue was triturated with 10% EtOH-EtOAc (4 mL) to give additional product (0.226 g, 16%) as an off-white solid. Total yield 0.99 g, 71%; data consistent with those described above.

[0318] Exemplary Synthesis of Alkyl Phosphate Compounds TIFF2024534919000084.tif97140I. Preparation of di-tert-butyl((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)phosphate (VII-3) Potassium carbonate (0.41 g, 3.01 mmol, 1.5 equiv.) was added to a suspension of VII-1 (1.00 g, 2.00 mmol, 1.0 equiv.) in dimethylformamide (14 mL). The reaction 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 equiv.) in dimethylformamide (2 mL) was added. The reaction was stirred at room temperature for 14 hours. Additional chloromethyl di-tert-butyl phosphate (0.52 g, 2.00 mmol, 1.0 equiv.) and potassium carbonate (0.21 g, 1.50 mmol, 0.75 equiv.) were added, and the reaction was stirred for an additional 24 hours. The reaction was cooled to 0° C. and water (25 mL) was added dropwise over 45 minutes. A sticky solid formed which was isolated by decanting the liquid. The liquid was added to water (40 mL) and stirred to give more 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, 666 cm -1 ; 1 H nmr (400 MHz, CDCl3) 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, 6.0 Hz, pyridine H-4 or H-5), 6.88 (1H, ddd, J 9.0, 3.0, 2.5 Hz, pyridine H-4 or H-5), 5.93 (2H, d, J 12.5 Hz, NCH2OP), 4.27 (1H, tt, J 12.0, 4.0 Hz, cyclohexane H-1 or H-4), 3.56 (2H, q, J 7.0 Hz, OC H2CH3), 3.37 (1H, tt, J 10.5, 4.0 Hz, cyclohexane H-1 or H-4), 2.29 (2H, br d, J 12.5 Hz, 2H of cyclohexane H-2, H-3, H-5, and H-6), 2.22 (2H, br d, J 11.0 Hz, 2H of cyclohexane H-2, H-3, H-5, and H-6), 1.89 (2H, m, 2H of cyclohexane H-2, H-3, H-5, and H-6), 1.50 (2H, m, 2H of cyclohexane H-2, H-3, H-5, and H-6), 1.45 (18H, s, 2 x OC(CH3)3), 1.22 (3H, t, J 7.0 Hz, OCH2C H 3); 13 C nmr(100 MHz,CDCl3)δ 160.0,158.2,157.5(d,J 236.5 Hz),153.5(dd,J 260.0,5.0 Hz),150.2,139.5(d,J 6.0 Hz),138.9(t,J 15.0 Hz),133.0(d,J 9.0 Hz),130.0(d,J 4.5 Hz),129.8(d,J 9.0 Hz),122.0,121.8,119.4,118.6,107.6(dd,J 40.5,5.0 Hz),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 (162 MHz, CDCl3) δ-11.1; 19 F nmr(380 MHz,CDCl3)δ-72.4(dt,J 27.0,5.5 Hz),-124.5(dd,J 27.5,9.5 Hz);m / z:744 [M+Na] + .

[0319] II. Preparation of (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-(trans-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate (VII-2) To a solution of VII-3 (1.58 g crude, 1.80 mmol, 1.0 equiv.) in dichloromethane (8.0 mL) was added trifluoroacetic acid (0.99 mL, 12.80 mmol, 7.1 equiv.). The reaction was stirred at room temperature for 20 h, during which time a precipitate formed. After 20 h, the precipitate was isolated by filtration. The solid was washed with CHCl (2 × 8 mL) to give a white solid. The solid was stirred with dioxane-water (10:1, 11 mL) for 5 h, filtered, and washed with dioxane-water (10:1, 11 mL) to give VII-2 (0.60 g, 55% over two steps) as a white solid. The filtrate was concentrated and stirred in dioxane-water (10:1, 11 mL) for 18 hours before being isolated by filtration. The solid was washed with dioxane-water (10:1, 2×5.5 mL) to give additional product (0.12 g, total 0.72 g, 66%) as a white solid; 1 H NMR (400 MHz, D6-DMSO) δ 8.59 (1H, s, 1H of pyrazole H-3 and H-5), 8.52 (1H, s, 1H of pyrazole H-3 and H-5), 8.34 (1H, s, 1H of pyrazole H-5 and thiazole H-5), 8.19 (1H, s, 1H of pyrazole H-5 and thiazole H-5), 8.08 (1H, td, J 9.5, 6.5 Hz, pyridine H-4 or H-5), 6.88 (1H, ddd, J 9.0, 3.0, 2.5 Hz, pyridine H-4 or H-5), 5.83 (2H, d, J 12.5 Hz, NCH2OP), 4.33 (1H, tt, J 12.0, 3.0 Hz, cyclohexane H-1 or H-4), 3.47 (2H, q, J 7.0 Hz, OC H 2CH3), 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, 4H of cyclohexane H-2, H-3, H-5, and H-6), 1.85 (2H, m, 2H of cyclohexane H-2, H-3, H-5, and H-6), 1.35 (2H, m, 2H of cyclohexane H-2, H-3, H-5, and H-6), 1.10 (3H, t, J 7.0 Hz, OCH2C H 3); 13C nmr(100MHz,CDCl3)δ160.6,157.6,157.6(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 (162 MHz, D6-DMSO) δ -2.7; 19 F nmr(380MHz,D6-DMSO)δ-72.8,-124.2(ddd,J 27.0,9.5,3.0 Hz);m / z:610[M+H] + (Measured value [M+H] + ,610.1451,C 24 H 26 F2N7O6PS is [M+H] + (Requires 610.1444).

[0320] Other phosphate compounds were prepared in a similar manner.

[0321] Exemplary syntheses of carbamates and ureas as potential IRAK prodrugs I. Formation of 2-morpholinoethyl (4-nitrophenyl) carbonate TIFF2024534919000087.tif12143 A solution of 4-nitrophenol chloroformate (0.500 g, 2.48 mmol, 1.0 equiv) in dichloromethane (20 mL) was cooled to −78° C. Diisopropylethylamine (0.65 mL, 3.72 mmol, 1.5 equiv) was added, followed by 4-(2-hydroxyethyl)morpholine (0.30 mL, 2.48 mmol, 1.0 equiv), and the reaction was stirred at −78° C. to room temperature for 16 hours. The reaction was diluted with dichloromethane (40 mL), washed with NaHCO (60 mL) and brine (60 mL), dried (NaSO), and concentrated under reduced pressure to provide the title compound as an orange oil. 1H nmr (400 MHz, CDCl) δ 8.27 (2H, d, J 9.5 Hz, CHNO 2H), 7.37 (2H, d, J 9.0 Hz, CHNO 2H), 4.39 (2H, t, J 5.5 Hz, COOCHCHN 2H), 3.72, 3.71 (4H, 2d AB system, J 4.5 Hz, morpholine 4H), 2.72 (2H, t, J 5.5 Hz, COCHCHN 2H), 2.54, 2.53 (4H, 2d AB system, J 4.5 Hz, morpholine 4H).

[0322] II. Formation of 3-morpholinopropyl(4-nitrophenyl) carbonate TIFF2024534919000088.tif17143 Diisopropylethylamine (0.65 mL, 3.72 mmol, 1.5 equiv) was added to a solution of 4-nitrophenyl chloroformate (0.500 g, 2.48 mmol, 1.0 equiv) in dichloromethane (20 mL) at -78 °C. 3-(Hydroxypropyl)morpholine (0.34 mL, 2.48 mmol, 1.0 equiv) was added dropwise, and the reaction was stirred at -78 °C for 30 minutes. The reaction was frozen and warmed to 0 °C. After stirring at 0 °C for 5 hours, the reaction was allowed to warm to room temperature over 16 hours. The reaction was diluted with dichloromethane (20 mL) and washed with NaHCO (3 x 40 mL). The organics were dried (NaSO) and concentrated under reduced pressure to give the title 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,OC H 2CH2CH2N), 3.70 3.69 (4H, 2d AB system, J 4.5Hz, 4H of morpholine), 2.49-2.43 (6H, m, 4H of mor...

Claims

1. A pharmaceutical composition for use in a method of treating a patient having or suspected of having a cytokine release-associated condition associated with infection by a respiratory virus, comprising a compound that inhibits interleukin receptor-associated kinase (IRAK), The method comprises administering to the patient an effective amount of the compound.

2. The pharmaceutical composition of claim 1 , wherein the compound inhibits IRAK1 and IRAK4.

3. The compound is represented by formula IV or a salt, solvate, and / or N-oxide thereof, During the ceremony, Het-1 is a 5-membered heteroaryl; y is 1 to 2; R Ｃ２ is H, aliphatic, heteroaliphatic, heterocycloaliphatic, aryl, amido, heterocyclyl, or araliphatic; Each R Ｃ３ is independently H or aliphatic; R Ｃ４ , R Ｃ５ , R Ｃ６ , and R Ｃ７ are each independently H, aliphatic, heteroaliphatic, alkoxy, heterocyclyl, aryl, araliphatic, -O-heterocyclyl, hydroxyl, haloalkyl, halogen, nitro, cyano, carboxyl, carboxyl ester, acyl, amido, amino, sulfonyl, sulfonamido, sulfanyl, or sulfinyl; R Ｃ８ and R Ｃ９ are each independently H, aliphatic, heteroaliphatic, aryl, heterocyclyl, sulfonyl, nitro, halogen, haloalkyl, carboxylic ester, cyano, or amino; and R Ｃ１０ H, aliphatic, alkoxy, heteroaliphatic, carboxyl ester, araliphatic, NO ２ , CN, OH, haloalkyl, acyl, alkyl phosphate, or alkyl phosphonate; 3. The pharmaceutical composition of claim 1 or 2.

4. Het-1 is thiazolyl or furanyl; R Ｃ１０ is H, alkyl, alkyl phosphate, or alkyl phosphonate; R Ｃ４ , R Ｃ６ , and R Ｃ７ each is independently H, halo, alkyl, or haloalkyl; or It is a combination of these, The pharmaceutical composition of claim 3.

5. R Ｃ４ , R Ｃ６ , and R Ｃ７ each is independently H or F; R Ｃ５ But H, F, CF ３ , methoxy, —O—CH ２ C(CH ３ ) ２ -OH, morpholin-4-yl, 1-methylpiperidin-4-yl, or -O-(oxetan-3-yl), or It is a combination of these, The pharmaceutical composition of claim 3.

6. The compound is represented by Formula V or Formula VI or a salt, solvate, and / or N-oxide thereof, During the ceremony, R Ｃ１１ and R Ｃ１２ each is independently H or aliphatic; R Ｃ１４ is H or aliphatic; The pharmaceutical composition of claim 3.

7. The pyrazole compound is 4. The pharmaceutical composition of claim 3, wherein the compound is:

8. The compound is represented by formula VII or a salt, solvate, or N-oxide thereof, wherein R is selected from H, aliphatic, acyl, heterocyclyl, carboxylic ester, amide, alkyl phosphoramidate, and alkyl phosphate; 3. The pharmaceutical composition of claim 1 or 2.

9. 9. The pharmaceutical composition of claim 8, wherein R is H and the pyrazole compound is a salt of formula (VII).

10. R is selected from aliphatic, acyl, heterocyclyl, carboxylic ester, amide, alkyl phosphoramidate, and alkyl phosphate; 9. The pharmaceutical composition of claim 8, wherein optionally R is selected from alkyl, acyl, carboxylic ester, amide, non-aromatic heterocyclyl, alkyl phosphoramidate, and alkyl phosphate.

11. R is H, C １～４ 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 and 5- or 6-membered non-aromatic heterocyclyl; Each R ｂ are independently H, unsubstituted C １～６ Alkyl, —N(R ｇ ) ２ C substituted with 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 one or two -O- or -N(R ｇ ) may be inserted. ３～６ forming a non-aromatic heterocyclyl moiety, and each R ｇ are independently H or C １～４ is alkyl, The pharmaceutical composition of claim 10.

12. The compound is selected from the group consisting of: V-1: N-(1-(2-hydroxy-2-methylpropyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-methyl-1H-pyrazol-4-yl)furan-2-carboxamide 2,2,2-trifluoroacetate, V-2: N-(1-(2-hydroxy-2-methylpropyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-methyl-1H-pyrazol-4-yl)furan-2-carboxamide, V-3: N-(1-(2-hydroxy-2-methylpropyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-4: tert-butyl 4-(5-((1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazole-1-carboxylate, V-5: N-(1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-6: N-(1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-methyl-1H-pyrazol-4-yl)furan-2-carboxamide formic acid, V-9: N-(1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-methyl-1H-pyrazol-4-yl)furan-2-carboxamide, V-10: di-tert-butyl((4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)methyl)phosphate, V-11: tert-butyl((4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)methyl)hydrogen phosphate, V-12: (4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate, V-13: N-(1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)furan-2-carboxamide, V-14: sodium (4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)methyl phosphate, V-16: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-17: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide hydrochloride, V-18: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-methyl-1H-pyrazol-4-yl)furan-2-carboxamide, V-19: 1-(isobutyryloxy)ethyl 4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazole-1-carboxylate, V-20: tert-butyl (S)-(1-(4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate, V-21: 1-methylcyclopropyl 4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazole-1-carboxylate, V-22: 1-((4-methoxybenzyl)oxy)-2-methylpropan-2-yl 4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazole-1-carboxylate, V-23: 5-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)furan-2-carboxamide, V-24: 5-(5-nitro-1H-pyrrol-3-yl)-N-(1-(propoxymethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide, V-25: N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-26: 5-(1-methyl-1H-pyrazol-4-yl)-N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide, V-27: N-(1-((1,3-trans)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-28: N-(1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-29: N-(1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-methyl-1H-pyrazol-4-yl)furan-2-carboxamide, V-30: 5-(3-methyl-1H-pyrazol-4-yl)-N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide, V-31: N-(1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-methyl-1H-pyrazol-4-yl)furan-2-carboxamide, V-32: N-(1-((1,3-cis)-3-hydroxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-33: N-(1-((1s,3s)-3-(dimethylamino)cyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-34: N-(1-((1s,3s)-3-(dimethylamino)cyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate, V-35: (4-(5-((1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)methyl phosphate bis-sodium salt, V-36: (4-(5-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate, V-37: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate, V-38: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-39: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-ethyl-1H-pyrazol-4-yl)furan-2-carboxamide formate, V-40: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-ethyl-1H-pyrazol-4-yl)furan-2-carboxamide, V-41: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)furan-2-carboxamide formate, V-42: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)furan-2-carboxamide, V-43: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-isopentyl-1H-pyrazol-4-yl)furan-2-carboxamide formate, V-44: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-isopentyl-1H-pyrazol-4-yl)furan-2-carboxamide, V-45: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-methyl-1H-pyrazol-4-yl)furan-2-carboxamide formate, V-46: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-methyl-1H-pyrazol-4-yl)furan-2-carboxamide, V-47: 5-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide, V-48: 5-(1-((3-methyloxetan-3-yl)methyl)-1H-pyrazol-4-yl)-N-(1-((3-methyloxetan-3-yl)methyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide formate, V-49: 5-(1-((3-methyloxetan-3-yl)methyl)-1H-pyrazol-4-yl)-N-(1-((3-methyloxetan-3-yl)methyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide, V-52: 5-(1-(2-(2-methoxyethoxy)ethyl)-1H-pyrazol-4-yl)-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide formate, V-53: 5-(1-(2-(2-methoxyethoxy)ethyl)-1H-pyrazol-4-yl)-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide, V-54: (4-(5-((1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate, V-55: sodium (4-(5-((1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)methyl phosphate, V-56: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-methyl-1H-pyrazol-4-yl)furan-2-carboxamide formate, V-57: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-methyl-1H-pyrazol-4-yl)furan-2-carboxamide, V-58: 5-(3,5-dimethyl-1H-pyrazol-4-yl)-N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide formate, V-59: 5-(3,5-dimethyl-1H-pyrazol-4-yl)-N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide, V-67: N-{1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate, V-68: 5-(1-methyl-1H-pyrazol-4-yl)-N-{1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl}furan-2-carboxamide, V-69: 5-(1-methyl-1H-pyrazol-4-yl)-N-{1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl}furan-2-carboxamide formate, V-70: tert-butyl-3-[4-{5-(1H-pyrazol-4-yl)furan-2-carboxamido}-3-(pyridin-2-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate formate, V-71: N-{1-(3-methoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate, cis isomer, V-72: N-{1-(3-methoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide, cis isomer, V-73: N-{1-(3-benzyloxy)cyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide, trans isomer, V-74: tert-butyl-3-[4-{5-(1H-pyrazol-4-yl)furan-2-carboxamido}-3-(pyridin-2-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate, V-75: N-(1-((1s,3s)-3-methoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, formate, V-76: N-(1-((1s,3s)-3-methoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-77: N-{1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide, free base, V-78: N-{1-(azetidin-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide, TFA salt, V-79: N-{1-(azetidin-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-80: di-tert-butyl-[[4-{4-(5-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl}methyl]phosphate, V-81: [4-{5-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2yl}-1H-pyrazol-1-yl]methyl dihydrogen phosphate, V-82: sodium [4-{5-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl}-1H-pyrazol-1-yl]methyl phosphate, V-83: N-{1-(1-acetylazetidin-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide, free base. V-84: 3-[4-{5-(1H-pyrazol-4-yl)furan-2-carboxamide}-3-(pyridin-2-yl)-1H-pyrazol-1-yl]-N-(tert-butyl)azetidine-1-carboxamide, free base. V-85: 3-[4-{5-(1H-pyrazol-4-yl)furan-2-carboxamide}-3-(pyridin-2-yl)-1H-pyrazol-1-yl]-N-isopropylazetidine-1-carboxamide, free base. V-86: 3-[4-{5-(1H-pyrazol-4-yl)furan-2-carboxamide}-3-(pyridin-2-yl)-1H-pyrazol-1-yl]-N-propylazetidine-1-carboxamide, free base. V-87: 3-[4-{5-(1H-pyrazol-4-yl)furan-2-carboxamide}-3-(pyridin-2-yl)-1H-pyrazol-1-yl]-N-cyclopropylazetidine-1-carboxamide, formate, V-88: 3-[4-{5-(1H-pyrazol-4-yl)furan-2-carboxamide}-3-(pyridin-2-yl)-1H-pyrazol-1-yl]-N-cyclopropylazetidine-1-carboxamide, V-89: N-[1-{1-(cyclopropanecarbonyl)azetidin-3-yl}-3-(pyridin-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazol-4-yl)furan-2-carboxamide, formate, V-90: N-[1-{1-(cyclopropanecarbonyl)azetidin-3-yl}-3-(pyridin-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-91: N-[1-{1-pivaloylazetidin-3-yl}-3-(pyridin-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazol-4-yl)furan-2-carboxamide, formate, V-92: N-[1-{1-pivaloylazetidin-3-yl}-3-(pyridin-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-93: 5-(1H-pyrazol-4-yl)-N-{3-(pyridin-2-yl)-1-(pyrrolidine-1-carbonyl)azetidin-3-yl}-1H-pyrazol-4-yl)furan-2-carboxamide, formate, V-94: 5-(1H-pyrazol-4-yl)-N-{3-(pyridin-2-yl)-1-(pyrrolidine-1-carbonyl)azetidin-3-yl}-1H-pyrazol-4-yl)furan-2-carboxamide, V-95: N-[1-{1-isobutylirazetidin-3-yl}-3-(pyridin-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazol-4-yl)furan-2-carboxamide, formate, V-96: N-[1-{1-isobutylazetidin-3-yl}-3-(pyridin-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-97: N-(1H-pyrazol-4-yl)-N-{3-(pyridin-2-yl)-1-{1-(2,2,2-trifluoroethyl)azetidin-3-yl}-1H-pyrazol-4-yl}furan-2-carboxamide, TFA salt, V-98: N-(1H-pyrazol-4-yl)-N-{3-(pyridin-2-yl)-1-{1-(2,2,2-trifluoroethyl)azetidin-3-yl}-1H-pyrazol-4-yl}furan-2-carboxamide, V-99: N-[1-{1-butyrylazetidin-3-yl}-3-(pyridin-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazol-4-yl)furan-2-carboxamide, formate, V-100: N-[1-{1-butylrazetidin-3-yl}-3-(pyridin-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-101: N-[1-{1-methylazetidin-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide, formate, V-102: N-[1-{1-methylazetidin-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-103: N-[1-{1-(2,2-difluorocyclopropane-1-carbonyl)azetidin-3-yl}-3-(pyridin-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazol-4-yl)furan-2-carboxamide, formate, V-104: N-[1-{1-(2,2-difluorocyclopropane-1-carbonyl)azetidin-3-yl}-3-(pyridin-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-105: N-(1-methyl-3-(5-morpholinopyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-106: N-(1-methyl-3-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-107: N-(3-(5-(2-hydroxy-2-methylpropoxy)pyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-108: N-(1-methyl-3-(5-(oxetan-3-yloxy)pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-109: N-(3-(5-methoxypyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-110: N-(1-isopropyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-111: N-(1-(2-morpholinoethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-112: N-(1-(2-(4-methylpiperazin-1-yl)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-113: 5-(1H-pyrazol-3-yl)-N-(3-(pyridin-2-yl)-1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-pyrazol-4-yl)furan-2-carboxamide, V-114: N-(1-((1s,3s)-3-isopropoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-115: N-(1-(difluoromethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-116: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-117: 5-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)furan-2-carboxamide, V-122: 5-(1-cyclobutyl-1H-pyrazol-4-yl)-N-(1-cyclobutyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide 2,2,2-trifluoroacetate, V-123: 5-(1-cyclobutyl-1H-pyrazol-4-yl)-N-(1-cyclobutyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide, V-124: N-(1-((1s,4s)-4-hydroxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate, V-125: N-(1-((1s,4s)-4-hydroxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-126: N-(1-((1r,4r)-4-hydroxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate, V-127: N-(1-((1r,4r)-4-hydroxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-128: 5-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)furan-2-carboxamide formate, V-129: 5-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)furan-2-carboxamide, V-130: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate, V-131: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-132: N-(1-((1S,3R)-3-ethoxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate, V-133: N-(1-((1S,3R)-3-ethoxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-134: N-(1-((1S,3R)-3-hydroxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate, V-135: N-(1-((1S,3R)-3-hydroxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-136: N-(1-((1S,3S)-3-hydroxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate, V-137: N-(1-((1S,3S)-3-hydroxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-138: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(5-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate, V-139: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(5-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-140: N-(1-((1S,3R)-3-ethoxy-2-fluorocyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate, V-141: N-(1-((1S,3R)-3-ethoxy-2-fluorocyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-142: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate, V-143: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-144: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(6-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate, V-145: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(6-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-146: 5-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)furan-2-carboxamide formate, V-147: 5-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)furan-2-carboxamide, V-148: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(4-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate, V-149: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(4-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-150: N-(3-(6-fluoropyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate, V-151: N-(3-(6-fluoropyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-152: N-(3-(3-fluoropyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate, V-153: N-(3-(3-fluoropyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-154: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate, V-155: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, V-156: N-(3-(3,6-difluoropyridin-2-yl)-1-((1s,3s)-3-ethoxycyclobutyl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide, VI-1: N-(1-(2-hydroxy-2-methylpropyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-2: 1-(isobutyryloxy)ethyl 4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate, VI-3: tert-butyl (R)-(3-methyl-1-(4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)-1-oxobutan-2-yl)carbamate, VI-4: 2-(1-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)-1H-pyrazol-4-yl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-5: 1-methylcyclopropyl 4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate, VI-6: 1-((4-methoxybenzyl)oxy)-2-methylpropan-2-yl 4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate, VI-7: diethyl ((4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)phosphonate, VI-8: sodium ((4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)phosphonate, VI-9: ((4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)phosphonic acid, VI-10: 2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-11: N-(1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-12: N-(1-((1,3-trans)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-13: N-(1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-14: N-(1-((1,3-cis)-3-hydroxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-15: N-(1-((1s,3s)-3-(dimethylamino)cyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-16: (4-(4-((1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate bis-sodium salt, VI-17: (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate, VI-18: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, formate, VI-19: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(5-(trifluoromethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, formate, VI-20: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(5-(trifluoromethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-21: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide, formate, VI-22: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-23: 2-(3,5-dimethyl-1H-pyrazol-4-yl)-N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, formate, VI-24: 2-(3,5-dimethyl-1H-pyrazol-4-yl)-N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-25: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-26: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-27: 2-(3-methyl-1H-pyrazol-4-yl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-28: N-(1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-29: N-(1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide, formate, VI-30: N-(1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-31: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-32: 2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-33: 2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-34: N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-35: (4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate, VI-36: sodium (4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate, VI-37: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-38: potassium (4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate, VI-39: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-40: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-41: 2-(3-methyl-1H-pyrazol-4-yl)-N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, formate, VI-42: 2-(3-methyl-1H-pyrazol-4-yl)-N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-43: 2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-44: 2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-45: 2-(3-methyl-1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-46: 2-(3-methyl-1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-47: N-(1-((3-(hydroxymethyl)oxetan-3-yl)methyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-48: N-(1-((3-(hydroxymethyl)oxetan-3-yl)methyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-49: N-(1-(2-(diethylamino)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, formate, VI-50: N-(1-(2-(diethylamino)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-51: 2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-N-(1-(3-methoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-52: N-(1-(2-fluoroethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-53: 2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-54: tert-butyl-3-[4-{2-(1H-pyrazol-4-yl)thiazole-2-carboxamido}-3-(pyridin-2-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate, free base. VI-55: N-{1-(azetidin-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, TFA salt, VI-56: N-{1-(azetidin-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-57: N-{1-(3-methoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, free base, cis isomer, VI-58: N-(3-(5-methoxypyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-59: N-(1-isopropyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-60: N-(1-(2-morpholinoethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-61: N-(1-(2-(4-methylpiperazin-1-yl)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-65: N-(3-(3-fluoropyridin-2-yl)-1-((1s,3s)-3-hydroxycyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-66: 2-(1H-pyrazol-3-yl)-N-(3-(pyridin-2-yl)-1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-71: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(5-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-72: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(5-fluoro-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-73: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(5-fluoro-1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-76: N-(1-((1s,3s)-3-isopropoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-77: potassium (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate, VI-78: calcium (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate, VI-79: N-(1-((1r,3r)-3-hydroxy-3-methylcyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-80: ammonium (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate, VI-81: 5-amino-5-carboxypentan-1-aminium (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate, VI-82: 1-(4-amino-4-carboxybutyl)guanidinium (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate, VI-83: ​​(4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate, VI-84: 1,3-dihydroxy-2-(hydroxymethyl)propan-2-aminium (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate, VI-85: triethylammonium (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl hydrogen phosphate, VI-86: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-87: N-(1-(3-hydroxy-3-methylcyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-88: N-(1-(difluoromethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-89: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(3-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-90: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-91: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-92: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-93: 2-(3,5-dimethyl-1H-pyrazol-4-yl)-N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-94: 2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-95: N-(1-(difluoromethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-96: N-(1-(difluoromethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-97: N-(1-(difluoromethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-98: 2-(1-(difluoromethyl)-1H-pyrazol-4-yl)-N-(1-(difluoromethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-99: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-100: 2-(3-methyl-1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-103: 2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(3,3,3-trifluoro-2-hydroxypropyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-104: 2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(3,3,3-trifluoro-2-hydroxypropyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-105: N-(1-(dimethylcarbamoyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-106: N-(1-(dimethylcarbamoyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-107: 2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(3,3,3-trifluoro-2-hydroxy-2-(trifluoromethyl)propyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-108: 2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(3,3,3-trifluoro-2-hydroxy-2-(trifluoromethyl)propyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-117: N-(1-(2-(diethylamino)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-118: N-(1-(2-(2-fluoroethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-119: N-(1-(2-(2-fluoroethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-120: N-(1-benzyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-121: N-(1-cyclobutyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-122: N-(1-(2-(2,2-difluoroethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-123: N-(1-(((1r,3r)-3-hydroxycyclobutyl)methyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-124: N-(1-(((1r,3r)-3-hydroxycyclobutyl)methyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-125: N-(1-(dimethylcarbamoyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-126: N-(1-(dimethylcarbamoyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-127: N-(1-((1s,3s)-3-(ethoxy-d5)cyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-128: N-(1-(diethylcarbamoyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-129: N-(1-(morpholine-4-carbonyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-130: N-(1-((1s,3s)-3-(2-fluoroethoxy)cyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-131: N-(1-(morpholine-4-carbonyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-132: N-(1-(3-fluorocyclobut-2-en-1-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-133: N-(1-(3-fluorocyclobut-2-en-1-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-134: N-(1-(3,3-difluorocyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-135: N-(1-(3,3-difluorocyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-140: N-(3-(3-fluoropyridin-2-yl)-1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-141: 2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-((1r,3r)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-142: 2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-((1r,3r)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-143: N-(1-((1r,4r)-4-hydroxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-144: N-(1-((1r,4r)-4-hydroxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-145: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-146: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-147: N-(1-((1S,3R)-3-ethoxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-148: N-(1-((1S,3R)-3-ethoxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-149: N-(1-((1S,3R)-3-hydroxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-150: N-(1-((1S,3R)-3-hydroxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-151: N-(1-((1S,3S)-3-hydroxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-152: N-(1-((1S,3S)-3-hydroxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-153: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(5-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-154: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(5-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-155: N-(1-((1S,3R)-3-ethoxy-2-fluorocyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-156: N-(1-((1S,3R)-3-ethoxy-2-fluorocyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-157: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-158: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(4-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-159: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(4-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-160: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(6-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-161: 2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-162: 2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-163: (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate, VI-164: sodium (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate, VI-165: N-(3-(3-fluoropyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-166: N-(3-(3-fluoropyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-167: N-(3-(3-fluoropyridin-2-yl)-1-((1r,3r)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-168: N-(3-(3-fluoropyridin-2-yl)-1-((1r,3r)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-169: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-170: N-(3-(6-fluoropyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate, VI-171: N-(3-(6-fluoropyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-172: N-(3-(6-fluoropyridin-2-yl)-1-((1s,3s)-3-hydroxycyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-173: (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(6-fluoropyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate, VI-174: N-(3-(3,6-difluoropyridin-2-yl)-1-((1s,3s)-3-ethoxycyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-175: N-(1-((1s,4s)-4-ethoxycyclohexyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-176: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-177: N-(3-(3,6-difluoropyridin-2-yl)-1-((1s,4s)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VI-180: N-(3-(3,5-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VII-1: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, VII-2: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate, VII-3: di-tert-butyl((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)phosphate, VII-4: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate disodium salt, VII-5: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide, VII-6: 2-(1-(acetyl-L-leucyl)-1H-pyrazol-4-yl)-N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VII-7: 1-methylcyclopropyl 4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate, VII-8: 1-(isobutyryloxy)ethyl 4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate, VII-9: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VII-10: 2-morpholinoethyl 4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate, VII-11: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide hemi-tartrate, VII-12: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-(morpholine-4-carbonyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VII-13: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-((3-morpholinopropyl)carbamoyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VII-14: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-((3-(dimethylamino)propyl)carbamoyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VII-15: 3-morpholinopropyl 4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate, VII-16: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl L-valinate hydrochloride, VII-17: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl L-prolinate hydrochloride, VII-18: 1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethyl dihydrogen phosphate, VII-19: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl glycinate hydrochloride, VII-20: 1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethyl phosphate disodium salt, VII-21: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl (S)-2-amino-3,3-dimethylbutanoate hydrochloride, VII-22: 2-(1-acetyl-1H-pyrazol-4-yl)-N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VII-23: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl 2-amino-2-methylpropanoate hydrochloride, VII-24: 4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic acid, VII-25: methyl 4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)-4-oxobutanoate, VII-26: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-(2-morpholinoacetyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VII-27: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-(2-hydroxy-3-morpholinopropyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VII-28: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl 2-morpholinoacetate, VII-29: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl L-valinate, VII-30: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl L-valinate benzenesulfonate, VII-31: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl L-valinate mesylate, VII-32: 2-(4-methylpiperazin-1-yl)ethyl 4-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)-4-oxobutanoate, VII-33: 1-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)4-methyl L-aspartate hydrochloride, VII-34: methyl N-(2-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)-2-oxoethyl)-N-methylglycinate, VII-35: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl (S)-2-amino-3,3-dimethylbutanoate, VII-36: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl (S)-2-amino-3,3-dimethylbutanoate benzenesulfonate, VII-37: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl 4-(morpholinomethyl)benzoate, VII-38: 4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)1-methyl L-aspartate hydrochloride, VII-39: (1R,2R)-2-(((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)carbonyl)cyclohexane-1-carboxylic acid, VII-40: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl (S)-2-amino-3,3-dimethylbutanoate mesylate, VII-41: (S)-2-amino-4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic acid hydrochloride, VII-42: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4S)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-((2S,3S,4R,5R,6S)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VII-43: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4R)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-((2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VII-44: tert-butyl(1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethyl)phosphate hydrogen acetate sodium salt, VII-45: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl isopropyl carbonate, VII-46: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl di(((isopropoxycarbonyl)oxy)methyl)phosphate, VII-47: 1-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)4-methyl L-aspartate, VII-48: 1-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)4-methyl L-aspartic acid benzenesulfonate, VII-49: 1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethyl dihydrogen phosphate tris salt, VII-50: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl glycinate benzenesulfonate, VII-51: 2-(4-methylpiperazin-1-yl)ethyl 4-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)-4-oxobutanoate benzenesulfonate, VII-52: 2-(4-methylpiperazin-1-yl)ethyl 4-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)-4-oxobutanoate succinate, VII-53: (2R,3R)-2,3-diacetoxy-4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic acid, VII-54: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl acetate, VII-55: 4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)1-methyl L-aspartic acid benzenesulfonate, VII-56: 4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic acid tris salt, VII-57: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl 4-((S)-2-amino-3-methylbutanamido)butanoate hydrochloride, VII-58: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VII-59: 2-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)acetic acid, VII-60: ((((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)(hydroxy)phosphoryl)oxy)methyl isopropyl carbonate, VII-61: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl 1-amino-3,6,9,12,15,18-hexaoxahenicosan-21-oate hydrochloride, VII-62: isopropyl(((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate, VII-63: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate tris salt, VII-64: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide hydrochloride, VII-65: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamidobenzenesulfonate, VII-66: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide tartrate, VII-67: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide sodium salt, VII-68: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide hemicitrate, VII-69: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate ditris salt, VII-70: benzyl ((S)-1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)-4-methyl-1-oxopentan-2-yl)carbamate, VII-71: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl L-prolinate, VII-72: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl glycinate, VII-73: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl (R)-2-amino-3,3-dimethylbutanoate, VII-74: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl 2-amino-2-methylpropanoate, VII-75: (4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)1-methyl L-aspartate, VII-76: (S)-2-amino-4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic acid, VII-77: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl 4-((S)-2-amino-3-methylbutanamido)butanoate, VII-78: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl 1-amino-3,6,9,12,15,18-hexaoxahenicosan-21-oate, VII-79: 2-(1-(acetyl-D-leucyl)-1H-pyrazol-4-yl)-N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VII-80: 2-(1-(acetylleucyl)-1H-pyrazol-4-yl)-N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, VII-81: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl D-valinate, VII-82: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methylvalinate, VII-83: ​​(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl D-prolinate, VII-84: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl prolinate, VII-85: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl 2-amino-3,3-dimethylbutanoate, VII-86: (1S,2S)-2-(((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)carbonyl)cyclohexane-1-carboxylic acid, VII-87: (1R,2S)-2-(((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)carbonyl)cyclohexane-1-carboxylic acid, VII-88: (1S,2R)-2-(((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)carbonyl)cyclohexane-1-carboxylic acid, VII-89: 2-(((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)carbonyl)cyclohexane-1-carboxylic acid, VII-90: (R)-2-amino-4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic acid, VII-91: 2-amino-4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic acid, VII-92: 4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)1-methyl D-aspartate, VII-93: 4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)1-methylaspartate, VII-94: 1-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)4-methyl D-aspartate, VII-95: 1-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)4-methylaspartate, VII-96: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl 4-((R)-2-amino-3-methylbutanamido)butanoate, VII-97: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl 4-(2-amino-3-methylbutanamido)butanoate, VII-98: isopropyl(((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)(phenoxy)phosphoryl)-D-alaninate, VII-99: isopropyl(((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)(phenoxy)phosphoryl)alaninate, VII-100: (2R,3S)-2,3-diacetoxy-4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic acid, VII-101: (2S,3R)-2,3-diacetoxy-4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic acid, VII-102: (2S,3S)-2,3-diacetoxy-4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic acid, VII-103: 2,3-diacetoxy-4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic acid, VII-104: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide phosphate, VII-105: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide gentisate, and VII-106: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide succinate The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is selected from: (a) the patient has or is expected to develop acute respiratory distress syndrome (ARDS), pneumonia, or acute damage to one or more organs; and / or (b) the patient has COVID-19 or influenza, and / or (c) the patient is over 60 years old and / or has one or more other lung diseases, preferably the patient has or has a history of asthma, pneumothorax, atelectasis, bronchitis, chronic obstructive pulmonary disease, lung cancer, or pneumonia; and / or (d) the patient has or is expected to develop acute kidney injury, or the patient has reduced renal function but does not have acute kidney injury; and / or (e) the patient is over 60 years of age and / or has one or more other renal diseases; and / or (f) the patient is undergoing or has a history of undergoing dialysis treatment and / or has undergone a kidney transplant; and / or (g) the patient has or is suspected of developing thrombosis, and / or (h) the patient has a prothrombotic coagulation profile but no thrombosis, and optionally the patient has increased levels of D-dimer; and / or (i) the patient is over 60 years old and / or has one or more risk factors for developing thrombosis, and / or (j) the patient has or has had a thrombotic event; 13. The pharmaceutical composition of claim 1 or 12.

14. the administration is systemic, optionally the administration is oral or intravenous; or or the administration is by pulmonary administration, optionally the administration is performed using an inhaler or nebulizer; 13. The pharmaceutical composition of claim 1 or 12.

15. 13. The pharmaceutical composition of claim 1 or 12, wherein the patient is in intensive care.

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