NZ735761B2 - Pyrazole compounds and method for making and using the compounds - Google Patents

Abstract

Disclosed embodiments of the formula below concern novel interleukin receptor associated kinases (IRAK) inhibitors and compositions comprising such inhibitors. Also disclosed are methods of making and using the compounds and compositions. The disclosed compounds and/or compositions may be used to treat or prevent an IRAK-associated disease or condition. eat or prevent an IRAK-associated disease or condition.

Description

PYRAZOLE COMPOUNDS AND METHOD FOR MAKING AND USING THE COMPOUNDS CROSS NCE TO RELATED APPLICATION This application claims the benefit of the earlier filing date of U.S. provisional patent application No. 62/151,274, filed April 22, 2015, which is incorporated herein by nce in its entirety.

FIELD This disclosure concerns pyrazole compounds, and embodiments of a method for making and using the compounds, such as for inhibiting interleukin receptor-associated kinase (IRAK), and for treating diseases and conditions related to IRAK.

BACKGROUND Interleukin-1 receptor-associated kinases (IRAKs) are ant mediators of signaling processes, such as toll-like receptors (TLR) and interleukin-1 receptor (IL-1R) signaling processes. IRAKs have been implicated in modulating signaling networks that control inflammation, apoptosis, and cellular differentiation. Four IRAK genes have been identified in the human genome (IRAK1, IRAK2, IRAK3 and IRAK4), and s have ed distinct, non-redundant biological roles. IRAK1 and IRAK4 have been shown to exhibit kinase activity.

SUMMARY Disclosed herein are pyrazole nds, and compositions comprising such compounds that are useful as, inter alia, kinase inhibitors, such as IRAK inhibitors.

In one aspect, the present invention provides a compound having a a or salt thereof, wherein: R2 is H, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted heterocycloaliphatic, substituted or unsubstituted aryl, amide, substituted or unsubstituted heterocyclyl or tuted or unsubstituted araliphatic; each R3 independently is H, substituted or unsubstituted aliphatic, halogen, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted -O-aliphatic, substituted or unsubstituted cyclyl, substituted or unsubstituted aryl, tuted or unsubstituted hatic, substituted or unsubstituted erocyclyl, hydroxyl, nitro, cyano, carboxyl, carboxyl ester, acyl, amide, amino, 17609606_1 (GHMatters) P106926.NZ sulfonyl, sulfonamide, sulfanyl, sulfinyl, haloalkyl, hosphate, or alkylphosphonate, wherein R3 is not pyridinyl; R4, R5, R6 and R7 are each independently H, substituted or unsubstituted aliphatic, halogen, haloalkyl, substituted or unsubstituted heteroaliphatic, alkoxy, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted –O-heterocyclyl; R8 and R9 are each independently H , n, haloalkyl, or substituted or unsubstituted alkyl; and R10 is H, substituted or unsubstituted aliphatic, substituted or unsubstituted -O-aliphatic, substituted or tituted heteroaliphatic, carboxyl ester, substituted or unsubstituted aryl, acyl, substituted or unsubstituted araliphatic, substituted or unsubstituted heterocyclyl, sulfonyl, amino, NO2, CN, OH, haloalkyl, alkyl phosphate or alkylphosphonate. y is from 1 to 6; and Het-1 is furyl, lyl or oxazolyl; wherein a substituent for substituting one or more hydrogen atoms on a saturated carbon atom in the specified group or moiety is -R60, halo, =O, -OR70, -SR70, -N(R80)2, haloalkyl, perhaloalkyl, -CN, -NO2, =N2, -N3, -SO2R70, -SO3–M+, -SO3R70, -OSO2R70, -OSO3– M+, -OSO3R70, -P(O)(O–)2(M+)2, -P(O)(O–)2M2+, -P(O)(OR70)O–M+, -P(O)(OR70) 70, -C(S)R70, 0)R70, -CO - 2, -C(O)R 2 M+, -CO2R70, -C(S)OR70, -C(O)N(R80)2, -C(NR70)(R80)2, -OC(O)R70, R70, -OCO2-M+, -OCO 70, -OC(S)OR70, -NR70C(O)R70, -NR70C(S)R70, -NR70CO – 2R 2 M+, -NR70CO2R70, -NR70C(S)OR70, -NR70C(O)N(R80)2, -NR70C(NR70)R70 and -NR70C(NR70)N(R80)2, where R60 is C1-6alkyl optionally tuted with 1, 2, or 3 OH; each R70 is independently for each occurrence hydrogen or R60; each R80 is independently for each occurrence R70 or alternatively, two R80 groups, taken together with the nitrogen atom to which they are bonded, form a 3- to 7-membered heteroalicyclyl which optionally includes from 1 to 4 of the same or different additional heteroatoms selected from O, N and S, of which N optionally has H or C1-C3alkyl substitution; and each M+ is a counter ion with a net single positive charge; a substituent for replacing a hydrogen atom on an unsaturated carbon atom in a group containing unsaturated carbons is -R60, halo, -O-M+, -OR70, -SR70, -S–M+, -N(R80)2, perhaloalkyl, -CN, -OCN, -SCN, -NO, -NO2, -N3, 0, -SO3–M+, -SO3R70, -OSO2R70, -OSO3– M+, 70, -PO3-2(M+)2, -PO3-2M2+, -P(O)(OR70)O– M+, OR70)2, 70, -C(S)R70, -C(NR70)R70, -CO2– M+, -CO2R70, -C(S)OR70, -C(O)NR80R80, -C(NR70)N(R80)2, R70, -OC(S)R70, -OCO2– M+, -OCO2R70, -OC(S)OR70, -NR70C(O)R70, -NR70C(S)R70, -NR70CO2– M+, -NR70CO2R70, -NR70C(S)OR70, -NR70C(O)N(R80)2, -NR70C(NR70)R70 or -NR70C(NR70)N(R80)2, 17609606_1 (GHMatters) P106926.NZ where R60, R70, R80 and M+ are as previously defined, provided that in each case of substituted alkene or alkyne, the substituents are not -OM+, -OR70, -SR70, or -S–M+; and a tuent group for replacing a hydrogen atom on a nitrogen atom in a group containing such nitrogen atom is -R60, -O-M+, -OR70, -SR70, -S-M+, -N(R80)2, perhaloalkyl, -CN, -NO, -NO2, - 70, -SO3-M+, -SO3R70, -OS(O)2R70, -OSO3-M+, -OSO3R70, -PO32-(M+)2, -PO32-M2+, - P(O)(OR70)O-M+, -P(O)(OR70)(OR70), -C(O)R70, -C(S)R70, -C(NR70)R70, -CO2R70, -C(S)OR70, - C(O)NR80R80, -C(NR70)NR80R80, -OC(O)R70, R70, 70, -OC(S)OR70, -NR70C(O)R70, - NR70C(S)R70, -NR70CO2R70, -NR70C(S)OR70, -NR70C(O)N(R80)2, -NR70C(NR70)R70 or - NR70C(NR70)N(R80)2, where R60, R70, R80 and M+ are as previously defined.

In another , the present invention provides a composition comprising a compound as defined herein, and a ceutically acceptable excipient.

In a r aspect, the present invention provides the use of a compound as defined herein, or a composition as defined herein, in the manufacture of a medicament for treating a disease or condition for which an IRAK inhibitor is indicated.

Certain disclosed embodiments concern le compounds having a a or salt, solvate, N-oxide or g thereof, wherein R is aliphatic, heteroaliphatic, heteroaryl, aryl, halo, amide or CN; R1 is H, aliphatic or heteroaliphatic; or R and R1, together with the atoms to which they are attached, form a cyclyl ring; R2 is H, aliphatic, heteroaliphatic, heterocycloaliphatic, aryl, amide, heterocyclyl or araliphatic; each R3 independently is H, aliphatic, halogen, heteroaliphatic, -O-aliphatic, heterocyclyl, aryl, araliphatic, –O-heterocyclyl, hydroxyl, nitro, cyano, carboxyl, carboxyl ester, acyl, amide, amino, sulfonyl, sulfonamide, sulfanyl, sulfinyl, haloalkyl, hosphate, or alkylphosphonate; y is from 1 to the number of possible substituents on the particular system in question; and Het-1 is heteroaryl. In some embodiments, R is alkyl, amide, heteroaryl, or CN.

In certain ments, the compound has a formula 17609606_1 (GHMatters) P106926.NZ wherein x is from 1 to the number of possible substituents on the particular system in question, and Het-2 is heteroaryl.

In some embodiments, Het-1 and Het-2, if present, independently is a 5- or 6-membered heteroaryl, and maybe selected from furan, thiophene, pyrazole, pyrrole, imidazole, oxazole, thiazole, isoxazole, isothiazole, 1,2,3-triazole, triazole, 1,3,4-triazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,5-thiadiazole, tetrazole, pyrimidine, pyridine, 1,2,3-triazine, 1,2,4-triazine, triazine, pyrazine, or pyridazine. In particular embodiments, Het-1 is furan, thiazole or oxazole. In other embodiments, Het-2 is pyridine, pyrimidine, pyrazine, oxadiazole or le.

In some ments, the compound has a formula where Het-3 is a heterocycle, and z is from 1 to the number of possible substituents on the particular system in question. Het -3 may be a 5- or 6-memebered heteroaryl, and in some embodiments Het-3 is selected from furan, thiophene, pyrazole, e, imidazole, oxazole, thiazole, isoxazole, isothiazole, 1,2,3-triazole, 1,2,4- le, 1,3,4-triazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,5-oxadiazole, 1,2,3- thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,5-thiadiazole or tetrazole. In particular embodiments, Het-3 is pyrazole.

The compound may have a formula ed from , , 17609606_1 (GHMatters) P106926.NZ , , or .

With respect to these as, R4, R5, R6 and R7 are each independently H, aliphatic, heteroaliphatic, alkoxy, heterocyclyl, aryl, araliphatic, –O-heterocyclyl, hydroxyl, haloalkyl, n, nitro, cyano, carboxyl, carboxyl ester, acyl, amide, amino, sulfonyl, sulfonamide, sulfanyl or sulfinyl. I n some examples the compound has a formula In certain embodiments, the compound has a formula selected from or 17609606_1 (GHMatters) P106926.NZ With respect to these formulas, R8, R9 and R10 are each independently H, tic, heteroaliphatic, aryl, -O- aliphatic, araliphatic, heterocyclyl, sulfonyl, nitro, OH, halogen, haloalkyl, carboxyl ester, cyano, acyl, amino, alkyl phosphate or alkylphosphonate, and R11, R12, R13 and R14 are each ndently H, aliphatic, heteroaliphatic, aryl, heterocyclyl, sulfonyl, nitro, carboxyl ester, cyano or amino.

In particular embodiments, the compound has a formula selected from , , , , , , , , , , , 17609606_1 (GHMatters) P106926.NZ , , , , , , , or ; where Het-3 is heteroaryl, and in some embodiments, is .

In particular embodiments of the above formulas, R8, R9, R11, R12, R13 and R14 are each independently H or alkyl, and R10 is H, alkyl, carboxyl ester, acyl, alkyl phosphate, alkyl phosphonate, heterocycloalkyl or aralkyl.

In any of the above formulas, R4, R5, R6 and R7 may be each independently H, halogen, haloalkyl, aliphatic, heteroaliphatic, alkoxy, heterocyclyl or –O-heterocyclyl. In n es, R5 is H, halogen, haloaklyl, alkoxy, -O-heterocyclyl or heterocyclyl, and in particular examples, R5 is H, F, CF3, methoxy, morpholinyl, 1-methylpiperidinyl, -O-CH2C(CH3)2OH, or –O-(oxetanyl). In certain examples, each of R4, R6 and R7 independently is H, CF3, F.

R2 may be H, amide, alkyl, particularly lower alkyl, cycloalkyl, aliphatic, alicyclyl or haloalkyl, and/or may comprise cyclobutyl, inyl, morpholinyl, 4-methylpiperazinyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl. In certain embodiments, R2 is H, methyl, difluoromethyl, trifluoroethyl, isopropyl, tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, N-tert-butyloxycarbonyl azetidin yl, 3-methyoxy cyclobutyl, 3-benzyloxycyclobutyl, 3-ethyloxy cyclobutyl, 3-isopropyl utyl, 3- 17609606_1 (GHMatters) P106926.NZ hydroxy cyclobutyl, 4-ethoxy cyclohexyl, 4-hydroxy exyl, 4-((2,2-difluoroethyl)amino)cyclohexyl, 3- ethyloxy cyclopentyl, or 3-hydroxy cyclopentyl. And in some examples, R10 is H, alkyl, carboxyl ester, acyl, alkyl phosphate, alkyl phosphonate or aralkyl. In certain embodiments R1 is Ra, a)m-ORa , -(CH2)m-O-Ra, -(CRaRa)m-O-(CRaRa)m-O-Ra or -(CH2)m-O-(CH2)m-O-Ra; each m independently is 1, 2 or 3; R2 is Ra, Rb, Ra substituted with 1, 2 or 3 Rb, Ra substituted with Rb and Rc, Ra substituted with Rc, – (CRaRa)n-Ra, -(CH2)n-Ra, -(CRaRa)n-Rb or -(CH2)n-Rb; each of R4, R5, R6 and R7independently is Ra, Rb, Ra substituted with Rc, -ORa, -O-(CRaRa)p-Rb; R10 is Ra, Rb, Ra substituted with –OP(O)(Rf)2, Ra substituted with 1, 2 or 3 Rb, Ra substituted with Rc, Ra substituted with –P(O)(Rf)2, aralkyl, -(CRaRa)n-Ra, -(CH2)n-Ra or -C(O)C(Ra)2NRaRb; n is 1, 2 or 3; p is 1, 2, or 3; Ra is independently for each ence H, D, C1-6alkyl, C3-6cycloalkyl, C3-6cycloalkenyl, or C3-6heteroalicyclyl; Rb is independently for each occurrence -OH, -CF3, - ORc, -NRdRd, -C(O)OH, -C(O)Rc, -C(O)ORc, -C(O)NRdRd or halogen; Rc is independently for each occurrence C1-6alkyl, cloalkyl, C3-6heteroalicyclyl, aralkyl, C1-6alkyl substituted with 1, 2 or 3 Re, C3- e, or C e; Rd is 6cycloalkyl substituted with 1, 2 or 3 R 3-6heteroalicyclyl substituted with 1, 2 or 3 R independently for each occurrence H, C1-6alkyl optionally substituted with 1, 2 or 3 Re, C3-6cycloalkyl optionally substituted with 1, 2 or 3 Re, or two Rd groups together with the nitrogen bound thereto form a C3- 6heteroalicyclyl moiety optionally substituted with kyl, such as morpholinyl, dinyl, N- methylpiperidinyl or pyrrolidinyl; Re is independently for each occurrence halogen, C1-6alkyl, C3-6cycloalkyl, C3-6heteroalicyclyl, C1-6alkyl-OH, -ORa, -OC(O)Ra or -O-aralkyl; Rf is independently for each occurrence - ORa, -O-M+ or –O-[M2+]0.5; each M+ ndently is an alkali metal ion or an ammonium ion; and M2+ is an alkaline metal earth ion.

In particular embodiments, R2 is CH3OCH2CH2-, CH3OCH2CH2OCH2CH2-, CH3CH2OCH2CH2-, methyl, nyl, F, CF3, or H, R3 is H, and/or R4, R5, R6 and R7 independently are H, F, or CF3.

In any of the above embodiments, the compound may be a salt, such as a pharmaceutically able acid on salt or a pharmaceutically able base addition salt. In certain examples, the compound is a hydrochloride, formic acid or trifluoroacetic acid salt. In other examples, the compound is a sodium, calcium, ammonium, trimethylamine, tris(hydroxymethyl)aminomethane, lysine, arginine, or potassium salt.

Also disclosed herein are embodiments of a composition comprising a sed nd and a ceutically able excipient. The composition may also comprise an additional therapeutic agent.

Alternatively, the pyrazole compounds, or compositions comprising the pyrazole nds, may be administered as a combination with a second therapeutic(s).

Embodiments of a method for administering a pyrazole compound or composition comprising a pyrazole compound(s) are also disclosed. For example, disclosed herein are embodiments of a method for treating different classes of diseases, such as by ting an enzyme, such as a kinase, for example an IRAK protein sing contacting the IRAK protein with an effective amount of a pyrazole compound.

In some embodiments the method comprises contacting the protein in vitro. In other embodiments, the IRAK protein may be in a subject. Exemplary compounds may have an EC50 of from greater than 0 to 5 17609606_1 (GHMatters) P106926.NZ µM, such as from greater than 0 to 1 µM. In certain embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a pyrazole compound or composition comprising the pyrazole compound. The method may be a method of treating a disease or condition for which an IRAK modulator or inhibitor is indicated.

The ing and other objects, features, and advantages of the invention will become more apparent from the following detailed ption.

DETAILED DESCRIPTION I. Definitions The following ations of terms and methods are provided to better describe the t disclosure and to guide those of ordinary skill in the art in the practice of the present disclosure. The singular forms "a," "an," and "the" refer to one or more than one, unless the context clearly dictates otherwise. The term "or" refers to a single element of stated alternative elements or a combination of two or more elements, unless the t clearly indicates otherwise. As used herein, "comprises" means "includes." Thus, "comprising A or B," means "including A, B, or A and B," t excluding additional elements. All references, including patents and patent applications cited , are incorporated by reference.

Unless otherwise indicated, all numbers expressing quantities of components, molecular s, percentages, temperatures, times, and so forth, as used in the specification or claims are to be understood as being modified by the term "about." Accordingly, unless otherwise indicated, implicitly or explicitly, the numerical parameters set forth are approximations that may depend on the desired properties sought and/or limits of detection under standard test conditions/methods. When directly and explicitly distinguishing embodiments from sed prior art, the embodiment numbers are not approximates unless the word "about" is recited.

Unless explained otherwise, all technical and ific terms used herein have the same meaning as commonly understood to 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 the present disclosure, suitable methods and materials are described below. The als, methods, and examples are rative only and not intended to be limiting.

When chemical structures are depicted or described, unless explicitly stated otherwise, all carbons are assumed to include hydrogen so that each carbon ms to a valence of four. For example, in the structure on the left-hand side of the schematic below there are nine hydrogen atoms implied. The nine hydrogen atoms are ed in the right-hand ure. 17609606_1 (GHMatters) P106926.NZ mes a particular atom in a structure is described in textual formula as having a en or hydrogen atoms, for example -CH2CH2-. It will be tood by a person of ordinary skill in the art that the aforementioned descriptive techniques are common in the chemical arts to provide brevity and simplicity to description of organic structures.

A person of ordinary skill in the art will appreciate that the definitions may be combined to further describe a particular compound. For example, hydroxyaliphatic refers to an aliphatic group substituted with an hydroxy (-OH) group, and haloalkylaryl refers to an aryl group substituted with an alkyl group, where the alkyl group too is substituted with a halogen, and where the point of attachment to the parent structure is via the aryl moiety since aryl is the base name of the substituent.

As used herein, the term ituted" refers to all subsequent modifiers in a term, for example in the term "substituted arylC1-8alkyl," substitution may occur on the "C1-8alkyl" portion, the "aryl" n or both portions of the arylC1-8alkyl group. Also by way of e, alkyl es tuted cycloalkyl groups.

"Substituted," when used to modify a specified group or moiety, means that at least one, and s two or more, hydrogen atoms of the specified group or moiety is independently replaced with the same or different substituent groups as defined below. In a particular ment, a group, moiety or substituent may be substituted or unsubstituted, unless expressly defined as either "unsubstituted" or "substituted." Accordingly, any of the groups specified herein may be unsubstituted or substituted. In particular embodiments, the substituent may or may not be expressly defined as substituted, but is still plated to be optionally substituted. For example, an "alkyl" substituent may be unsubstituted or substituted, but an "unsubstituted alkyl" may not be substituted.

"Substituents" or "substituent groups" for substituting for one or more hydrogen atoms on saturated carbon atoms in the specified group or moiety are, unless otherwise specified, -R60, halo, =O, -OR70, -SR70, -N(R80)2, kyl, perhaloalkyl, -CN, -NO2, =N2, -N3, -SO2R70, -SO3– M+, -SO3R70, -OSO2R70, -OSO3–M+, -OSO3R70, -P(O)(O–)2(M+)2, -P(O)(O–)2M2+, -P(O)(OR70)O– M+, -P(O)(OR70) 2, -C(O)R70, -C(S)R70, -C(NR70)R70, -CO2– M+, -CO2R70, -C(S)OR70, -C(O)N(R80)2, -C(NR70)(R80)2, -OC(O)R70, -OC(S)R70, -OCO2-M+, -OCO2R70, -OC (S)OR70, -NR70C(O)R70, -NR70C(S)R70, -NR70CO2– M+, O2R70, -NR70C(S)OR70, -NR70C(O)N(R80)2, -NR70C(NR70)R70 and -NR70C(NR70)N(R80)2, where R60 is C1-6alkyl optionally tuted with 1, 2, or 3 OH; each R70 is independently for each ence hydrogen or R60; each R80 is independently for each occurrence R70 or alternatively, two R80 groups, taken together with the en atom to which they are bonded, form a 3- to 7-membered heteroalicyclyl which optionally includes from 1 to 4 of the same or ent additional heteroatoms selected from O, N and S, of which N optionally has H or C1-C3alkyl substitution; and each M+ is a counter ion with a net single positive charge. Each M+ is independently for each ence, for example, an alkali metal ion, such as K+, Na+, Li+; an ammonium ion, such as +N(R60)4; a protonated amino acid ion, such as a lysine ion , or an arginine ion; or an alkaline metal earth ion, such as [Ca2+]0.5, [Mg2+]0.5, or [Ba2+]0.5 (a subscript "0.5" means, for 17609606_1 (GHMatters) P106926.NZ example, that one of the counter ions for such divalent alkali earth ions can be an ionized form of a compound of the invention and the other a typical counter ion such as chloride, or two ionized compounds can serve as counter ions for such divalent alkali earth ions, or a doubly d compound can serve as the counter ion for such divalent alkali earth ions). As specific examples, -N(R80)2 includes -NH2, -NH-alkyl, -NH-pyrrolidinyl, N-pyrrolidinyl, N-piperazinyl, 4N-methyl-piperazinyl, N- morpholinyl and the like. Any two hydrogen atoms on a single carbon can be replaced with =O, =NR70, =NOR70 , =N2 or =S.

Substituent groups for replacing hydrogen atoms on unsaturated carbon atoms in groups containing unsaturated s are, unless otherwise specified, -R60, halo, -O-M+, -OR70, -SR70, -S–M+, -N(R80)2, oalkyl, -CN, -OCN, -SCN, -NO, -NO2, -N3, -SO2R70, -SO3–M+, -SO3R70, -OSO2R70, -OSO3–M+, -OSO3R70, -PO3-2(M+)2, M2+, -P(O)(OR70)O–M+, -P(O)(OR70)2, 70, -C(S)R70, -C(NR70)R70, -CO2–M+, 0, -C(S)OR70, -C(O)NR80R80, -C(NR70)N(R80)2, -OC(O)R70, -OC(S)R70, -OCO2–M+, -OCO2R70, OR70, -NR70C(O)R70, (S)R70, -NR70CO2–M+, -NR70CO2R70, -NR70C(S)OR70, -NR70C(O)N(R80)2, (NR70)R70 and (NR70)N(R80)2, where R60, R70, R80 and M+ are as usly defined, provided that in case of substituted alkene or alkyne, the substituents are not -O-M+, -OR70, -SR70, or -S–M+.

Substituent groups for ing hydrogen atoms on nitrogen atoms in groups containing such nitrogen atoms are, unless otherwise specified, -R60, -O-M+, -OR70, -SR70, -S-M+, -N(R80)2, perhaloalkyl, -CN, -NO, -NO2, -S(O)2R70, -SO3-M+, -SO3R70, -OS(O)2R70, -OSO3-M+, -OSO3R70, -PO32- (M+)2, -PO32- M2+, -P(O)(OR70)O-M+, -P(O)(OR70)(OR70), -C(O)R70, -C(S)R70, -C(NR70)R70, -CO2R70, R70, -C(O)N R80R80, -C(NR70)NR80R80, R70, -OC(S)R70, -OCO2R70, -OC(S)OR70, -NR70C(O)R70, -NR70C(S)R70, -N R70CO2R70, -NR70C(S)OR70, -NR70C(O)N(R80)2, -NR70C(NR70)R70 and -NR70C(NR70)N(R80)2, where R60, R70, R80 and M+ are as usly defined.

In one embodiment, a group that is substituted has 1 substituent, 2 substituents, substituents, or 4 substituents.

Additionally, in embodiments where a group or moiety is substituted with a substituted substituent, the nesting of such substituted substituents is limited to three, thereby preventing the formation of polymers.

Thus, in a group or moiety comprising a first group that is a substituent on a second group that is itself a substituent on a third group, which is attached to the parent structure, the first (outermost) group can only be substituted with unsubstituted substituents. For example, in a group comprising -(aryl-1)-(aryl-2)-(aryl-3), aryl-3 can only be substituted with substituents that are not themselves substituted.

"Acyl" refers to the group –C(O)R, where R is H, aliphatic, heteroaliphatic, heterocyclic or aryl.

Exemplary acyl moieties include, but are not limited to, -C(O)H, -C(O)alkyl, -C(O)C1-C6alkyl, - C(O)C1-C6haloalkyl-C(O)cycloalkyl, -C(O)alkenyl, -C(O)cycloalkenyl, ryl, -C(O)heteroaryl, or - C(O)heterocyclyl. Specific examples include, -C(O)H, -C(O)Me, -C(O)Et, or -C(O)cyclopropyl. 17609606_1 (GHMatters) P106926.NZ "Aliphatic" refers to a substantially hydrocarbon-based group or moiety, including alkyl, alkenyl, alkynyl groups, cyclic versions thereof, such as cycloalkyl, cycloalkenyl or cycloalkynyl, and further including straight- and branched-chain arrangements, and all stereo and position isomers as well. Unless expressly stated otherwise, an tic group contains from one to twenty-five carbon atoms; for e, from one to n, from one to ten, from one to six, or from one to four carbon atoms.

"Lower aliphatic" refers to an aliphatic group containing from one to ten carbon atoms. An aliphatic group may be substituted or unsubstituted, unless expressly referred to as an "unsubstituted aliphatic" or a "substituted aliphatic." An aliphatic group can be substituted with one or more substituents (up to two substituents for each methylene carbon in an aliphatic chain, or up to one substituent for each carbon of a -C=C- double bond in an aliphatic chain, or up to one substituent for a carbon of a terminal methine group). Exemplary substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, alkylthio, acyl, aldehyde, amide, amino, aminoalkyl, aryl, arylalkyl, carboxyl, cyano, cycloalkyl, dialkylamino, halo, iphatic, heteroaliphatic, heteroaryl, cycloaliphatic, hydroxyl, oxo, sulfonamide, sulfhydryl, thioalkoxy, phosphate, or other functionality.

"Alkoxy" refers to the group –OR, where R is a substituted or unsubstituted alkyl group. In certain examples R is a C1-6 alkyl group. Methoxy (-OCH3) and ethoxy (-OCH2CH3) are exemplary alkoxy groups.

In a substituted alkoxy, R is substituted alkyl, examples of which useful in the presently disclosed compounds include haloalkoxy groups, such as –OCF2H.

"Alkoxyalkyl" refers to the group –alkyl-OR, where R is a tuted or unsubstituted alkyl group.

–CH2CH2-O-CH2CH3 is an exemplary alkoxyalkyl group.

"Alkyl" refers to a saturated aliphatic hydrocarbyl group having from 1 to 25 carbon atoms, typically 1 to 10 carbon atoms such as 1 to 6 carbon atoms alkyl). An alkyl moiety may be substituted or unsubstituted. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH3), ethyl (-CH2CH3), yl H2CH3), isopropyl (-CH(CH3)2), l (-CH2- CH2CH2CH3), isobutyl (-CH2CH2(CH3)2), sec-butyl (-CH(CH3)(CH2CH3), l (-C(CH3)3), n-pentyl (- CH2CH2CH3), and neopentyl (-CH2C(CH3)3).

"Amino" refers to the group -NH2, -NHR, or -NRR, where each R independently is ed from H, aliphatic, heteroaliphatic, aryl or heterocyclic, or two R groups er with the nitrogen attached thereto form a heterocyclic ring. Examples of such heterocyclic rings include those wherein two R groups together with the nitrogen to which they are attached form a –(CH2)2-5– ring optionally interrupted by one or two N O heteratom groups, such as –O– or –N(Rg) such as in the groups and wherein Rg is R70, -C(O)R70, -C(O)OR60 or -C(O)N(R80)2.

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

"Aryl" or tic" refers to an ic group of, unless specified otherwise, from 5 to 15 ring atoms having a single ring (e.g., phenyl) or multiple fused rings in which at least one ring is aromatic (e.g., naphthyl). For groups having multiple rings, at least one of which is aromatic and one is not, such groups 17609606_1 (GHMatters) P106926.NZ are nevertheless referred to as "aryl" provided that the point of attachment to the remainder of the nd is through an atom of an aromatic portion of the aryl group. Aryl groups may be monocyclic, bicyclic, tricyclic or tetracyclic. Unless otherwise stated, an aryl group may be substituted or unsubstituted.

"Araliphatic" refers to an aryl group attached to the parent via an aliphatic moiety. Araliphatic includes aralkyl or kyl groups such as benzyl and phenylethyl.

"Carboxyl," "carboxy" or "carboxylate" refers to -CO2H, -C(O)O- or salts f. xyl ester" or "carboxy ester" refers to the group –C(O)OR, where R is aliphatic, heteroaliphatic, , and heterocyclic, including aryl and heteroaryl.

"Cyano" refers to the group -CN. aliphatic" 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, provided that the point of attachment is through an atom of an aliphatic region of the cycloaliphatic group.

Cycloaliphatic includes saturated and unsaturated systems, including lkyl, cycloalkenyl and lkynyl. Exemplary cycloaliphatic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, eptyl, cyclopentenyl, or cyclohexenyl.

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

"Haloalkyl" refers to an alkyl moiety substituted with one or more halogens. An exemplary haloalkyl moiety is CF3.

"Heteroaliphatic" refers to an aliphatic compound or group having at least one heteroatom, i.e., one or more carbon atoms has been replaced with an atom having at least one lone pair of electrons, typically nitrogen, oxygen, phosphorus, silicon, or sulfur. Heteroaliphatic compounds or groups may be substituted or unsubstituted, branched or unbranched, acyclic or cyclic, such as a heteroalicyclyl group, chiral or achiral, and may include heterocycle, heterocyclyl, heterocycloaliphatic, or heterocyclic groups.

"Heteroaryl" refers to an aryl group where one or more carbon atoms, such as methine (-CH=) or vinylene (-CH=CH-) groups, have been replaced by ent or divalent heteroatoms, respectively, in such a way as to maintain aromaticity, such as determined by the continuous, delocalized π-electron system characteristic of the aromatic group, and the number of out of plane π-electrons corresponding to the Hückel rule (4n + 2).

"Heterocycloalkyl" and ocyclylalkyl" refer to a heterocyclyl moiety ed to the parent structure via an alkyl moiety, for example, (tetrahydropyranyl)methyl, (pyridineyl)methyl, morpholinoethyl or piperazinylethyl.

"Heterocyclyl," "heterocyclo" and "heterocycle" refer to aromatic and non-aromatic ring systems, and more specifically refer to a stable three- to fifteen-membered ring moiety comprising carbon atoms and at least one, such as from one to five atoms. The cyclyl moiety may be a monocyclic moiety, or may comprise multiple rings, such as in a bicyclic or tricyclic ring system, provided that at least one of the rings contains a heteroatom. Such a multiple ring moiety can include fused or bridged ring s as well as spirocyclic systems; and the nitrogen, phosphorus, carbon, silicon or sulfur atoms in the heterocyclyl 17609606_1 (GHMatters) P106926.NZ moiety can be optionally oxidized to various oxidation states. For convenience, nitrogens, particularly but not exclusively, those defined as annular aromatic nitrogens, are meant to include their corresponding N- oxide form, although not itly defined as such in a ular example. Thus, for a compound having, for example, a pyridyl ring; the corresponding pyridyl-N-oxide is included as another compound of the ion, unless expressly excluded by context. In addition, annular en atoms can be optionally quaternized. Heterocycle includes heteroaryl moieties, and heteroalicyclyl or heterocycloaliphatic moieties, which are heterocyclyl rings which are lly or fully saturated. Thus a term such as "heterocyclylalkyl" es heteroalicyclylalkyls and heteroarylalkyls. Examples of cyclyl groups include, but are not limited to, azetidinyl, oxetanyl, acridinyl, benzodioxolyl, benzodioxanyl, uranyl, carbazoyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl, tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, ridonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolinyl, lidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, droindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, droisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, diazabicycloheptane, diazapane, diazepine, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothieliyl, rpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyl, and oxadiazolyl.

"Hydroxyl" refers to the group –OH.

"Nitro" refers to the group –NO2. hate" refers to the group –O-P(O)(OR’)2, where each -OR’ independently is -OH, -O- aliphatic, such as –O-alkyl, l, or –O-aralkyl, or -OR’ is –O-M+, where M+ is a counter ion with a single positive . Each M+ may be an alkali ion, such as K+, Na+, Li+; an ammonium ion, such as +N(R") 2+] 2+] 4 where R" is H, aliphatic, heterocyclyl or aryl; or an alkaline earth ion, such as [Ca 0.5, [Mg 0.5, or [Ba2+]0.5. Alkyl phosphate refers to the group –alkyl-phosphate, such as, for example, -CH2OP(O)(OH)2, or a salt f, such as -CH2OP(O)(O-Na+)2.

"Phosphonate" refers to the group –P(O)(OR’)2, where each -OR’ independently is -OH, -O- aliphatic such as –O-alkyl, -O-aryl, or –O-aralkyl, or where -OR’ is –O-M+, and M+ is a counter ion with a single positive charge. Each M+ may be an alkali metal ion, such as K+, Na+, Li+; an ammonium ion, such as +N(R") 2+] 4 where R" is H, tic, heterocyclyl or aryl; or an alkaline earth metal ion, such as [Ca 0.5, [Mg2+]0.5, or [Ba2+]0.5. Alkyl phosphonate refers to the group –alkyl-phosphonate, such as, for example, -CH2P(O)(OH)2, or -CH2P(O)(O-Na+)2.

"Patient" or "Subject" refers to mammals and other animals, particularly . Thus disclosed methods are applicable to both human y and veterinary applications. 17609606_1 (GHMatters) P106926.NZ aceutically 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 particles of a pharmaceutical composition, or it may be physically mixed with particles of a pharmaceutical composition. An excipient can be used, for example, to dilute an active agent and/or to modify properties of a pharmaceutical composition. Excipients can include, but are not limited to, antiadherents, s, coatings, c coatings, disintegrants, flavorings, sweeteners, colorants, lubricants, ts, sorbents, preservatives, adjuvants, rs or vehicles. Excipients may be starches and modified starches, ose and cellulose derivatives, saccharides and their derivatives such as disaccharides, polysaccharides and sugar alcohols, protein, synthetic polymers, inked polymers, antioxidants, amino acids or vatives. Exemplary excipients include, but are not limited to, magnesium stearate, stearic acid, ble stearin, sucrose, lactose, starches, hydroxypropyl ose, hydroxypropyl methylcellulose, xylitol, sorbitol, maltitol, gelatin, polyvinylpyrrolidone (PVP), polyethyleneglycol (PEG), tocopheryl polyethylene glycol 1000 succinate (also known as vitamin E TPGS, or TPGS), carboxy methyl cellulose, dipalmitoyl phosphatidyl choline (DPPC), vitamin A, vitamin E, vitamin C, retinyl palmitate, selenium, cysteine, methionine, citric acid, sodium citrate, methyl paraben, propyl paraben, sugar, silica, talc, magnesium carbonate, sodium starch glycolate, tartrazine, aspartame, benzalkonium chloride, sesame oil, propyl gallate, sodium metabisulphite or lanolin.

An ant" is an excipient that modifies the effect of other agents, lly the active ingredient. Adjuvants are often cological and/or immunological agents. An adjuvant may modify the effect of an active ient by increasing an immune response. An adjuvant may also act as a stabilizing agent for a formulation. Exemplary adjuvants include, but are not limited to, aluminum hydroxide, alum, aluminum phosphate, killed bacteria, squalene, detergents, cytokines, paraffin oil, and ation adjuvants, such as freund’s complete adjuvant or ’s lete adjuvant.

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

In general, the nature of the r will depend on the particular mode of administration being employed. For instance, parenteral formulations usually se able fluids that include pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle. In some examples, the pharmaceutically acceptable carrier may be sterile to be suitable for administration to a subject (for example, by parenteral, intramuscular, or subcutaneous injection). In addition to ically-neutral carriers, pharmaceutical compositions to be administered can contain minor amounts of non-toxic auxiliary substances, such as 17609606_1 (GHMatters) P106926.NZ wetting or emulsifying agents, preservatives, and pH buffering agents and the like, for example sodium acetate or sorbitan monolaurate.

"Pharmaceutically acceptable salt" refers to ceutically acceptable salts of a compound that are derived from a variety of organic and inorganic counter ions as will be known to a person of ry skill in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of c or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, and the like. aceutically acceptable acid addition salts" are a subset of "pharmaceutically acceptable salts" that retain the biological effectiveness of the free bases while formed by acid partners. In particular, the sed compounds form salts with a variety of pharmaceutically acceptable acids, including, without limitation, nic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, as well as organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, ic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, benzene sulfonic acid, isethionic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, xinafoic acid and the like. aceutically acceptable base addition salts" are a subset of "pharmaceutically acceptable salts" that are derived from inorganic bases such as sodium, potassium, lithium, um, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Exemplary salts are the ammonium, potassium, sodium, m, 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 ing substituted amines, cyclic amines and basic ion ge resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, tris(hydroxymethyl)aminomethane (Tris), lamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Exemplary organic bases are isopropylamine, diethylamine, tris(hydroxymethyl)aminomethane (Tris), ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. (See, for example, S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66:1-19 which is incorporated herein by reference.) In particular disclosed embodiments, the pyrazole nd may be a formate or sodium salt.

"Pharmaceutically effective amount" and "therapeutically effective " refer to an amount of a compound sufficient to treat a specified disorder or disease, or to ameliorate or eradicate one or more of its symptoms and/or to prevent the occurrence of the disease or disorder. The amount of a compound which tutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the age of the patient to be treated, and the like. The therapeutically ive amount can be determined by a person of ordinary skill in the art.

"Prodrug" refers to compounds that are transformed in vivo to yield a biologically active compound, particularly the parent compound, for example, by ysis in the gut or enzymatic conversion. 06_1 (GHMatters) P106926.NZ Common es of prodrug moieties e, but are not d to, ester and amide forms of a compound having an active form bearing a carboxylic acid moiety. Examples of pharmaceutically acceptable esters of the compounds of this invention include, but are not limited to, esters of ate groups and carboxylic acids, such as aliphatic esters, particularly alkyl esters (for example kyl esters ). Other prodrug moieties include phosphate esters, such as -P(O)(OR')2 or a salt thereof, wherein R' is H or C1-6alkyl.

Acceptable esters also include cycloalkyl esters and arylalkyl esters such as, but not limited to benzyl.

Examples of pharmaceutically acceptable amides of the compounds of this invention include, but are not limited to, primary , and secondary and tertiary alkyl amides (for example with between about one and about six carbons). Amides and esters of sed ary embodiments of compounds according to the t invention can be prepared according to conventional s. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference for all es.

"Solvate" refers to a complex formed by combination of solvent molecules with molecules or ions of the solute. The t can be an organic compound, an inorganic compound, or a mixture of both. Some examples of solvents include, but are not limited to, methanol, N,N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and water. The compounds bed herein can exist in un-solvated as well as solvated forms when combined with solvents, pharmaceutically acceptable or not, such as water, ethanol, and the like. Solvated forms of the presently disclosed compounds are within the scope of the embodiments disclosed herein.

"Sulfonamide" refers to the group or moiety –SO2amino, or –N(Rc)sulfonyl, where Rc is H, aliphatic, heteroaliphatic, cyclic, and heterocyclic, including aryl and heteroaryl.

"Sulfanyl" refers to the group or –SH, –S-aliphatic, –S-heteroaliphatic, -S-cyclic, –S-heterocyclyl, including –S-aryl and –S-heteroaryl .

"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. nyl" refers to the group: –SO2H, –SO2aliphatic, teroaliphatic, -SO2cyclic, – SO2heterocyclyl, including –SO2aryl and –SO2heteroaryl.

"Treating" or "treatment" as used herein ns treatment of a disease or condition of interest in a patient or subject, particularly a human having the disease or condition of interest, and includes by way of example, and without limitation: (i) preventing the disease or condition from occurring in a patient or subject, in particular, when such patient or subject is predisposed to the condition but has not yet been diagnosed as having it; (ii) inhibiting the disease or condition, for example, arresting or slowing its development; (iii) relieving the disease or condition, for example, g regression of the disease or condition or a symptom thereof; or 17609606_1 (GHMatters) P106926.NZ (iv) stabilizing the disease or condition.

As used herein, the terms "disease" and "condition" can be used interchangeably or can be different in that the particular malady or ion may not have a known causative agent (so that etiology has not yet been determined) and it is therefore not yet recognized as a disease but only as an undesirable condition or syndrome, where a more or less specific set of symptoms have been identified by clinicians.

The above definitions and the following general formulas are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluoro groups). Such impermissible substitution ns are easily recognized by a person having ordinary skill in the art.

Any of the groups referred to herein may be optionally substituted by at least one, possibly two or more, substituents as defined herein. That is, a substituted group has at least one, possible two or more, substitutable hydrogens replaced by a substituent or substitutents as defined herein, unless the context indicates otherwise or a ular structural formula precludes substitution.

A person of ordinary skill in the art will appreciate that compounds may exhibit the phenomena of tautomerism, conformational isomerism, geometric isomerism, and/or optical isomerism. For e, certain disclosed nds can include one or more chiral centers and/or double bonds and as a uence can exist as stereoisomers, such as -bond isomers (i.e., geometric isomers), enantiomers, diasteromers, and es thereof, such as c mixtures. As another example, certain disclosed compounds can exist in several tautomeric forms, including the enol form, the keto form, and mixtures f. As the various compound names, formulae and compound gs within the specification and claims can represent only one of the possible tautomeric, conformational isomeric, optical isomeric, or ric isomeric forms, it would be understood that the disclosed compounds encompass any tautomeric, conformational ic, l ic, and/or geometric isomeric forms of the compounds described herein, as well as mixtures of these various different isomeric forms. In cases of limited rotation, e.g. around the amide bond or between two directly attached rings such as the pyrazole and pryidyl rings, atropisomers are also possible and are also specifically included in the compounds of the invention.

In any embodiments, any or all hydrogens present in the compound, or in a particular group or moiety within the compound, may be replaced by a ium or a tritium. Thus, a recitation of alkyl includes deuterated alkyl, where from one to the maximum number of ens present may be replaced by deuterium. For example, ethyl may be C2H5 or C2H5 where from 1 to 5 ens are replaced by deuterium.

II. IRAK-active Compounds and Compositions Comprising IRAK-active Compounds A. Pyrazoles Disclosed herein are pyrazole compounds, methods of making the compounds, and methods of using the compounds. In one embodiment the disclosed nds are tyrosine kinase inhibitors. In a particular ment the compounds useful in blocking one or more cytokine signaling pathways, such as the IL-17 signaling pathway. For certain embodiments, the pyrazole compounds are useful for treating conditions in 17609606_1 (GHMatters) P106926.NZ which inhibition of an eukin-1 receptor-associated kinase (IRAK) pathway is therapeutically . In some embodiments, the nds directly inhibit an IRAK protein, such as IRAK1, IRAK2, IRAK3 or IRAK4.

Exemplary pyrazole compounds within the scope of the present invention have a general formula 1 or salts, prodrugs, es or solvates thereof, wherein the compounds are not a compound disclosed in aryl; CN; halo; or amide. In some embodiments, R is alkyl, particularly CF3, heteroaryl, amide or CN. R1 is H, aliphatic or heteroaliphatic. Alternatively, R and R1, together with the atoms to which they are attached, form a ring, such as a heterocyclyl ring, having 3, 4, 5, 6, 7, 8 or more ring atoms, particularly 5, 6, or 7 ring atoms. Het-1 is heteroaryl, and may comprise a single ring or multiple rings, such as in a fused ring system.

R2 is H; aliphatic, including alkyl, alkenyl, alkynyl, cycloalkyl, and lkenyl; heteroaliphatic; heterocyclyl, including heteroaryl and cycloaliphatic; amide; aryl; or araliphatic. y is from 1 to the number of possible substituents on the particular system in question, such as from 1 to 2, 3, 4, 5, or at least 6. Each R3 independently is H; aliphatic, ing alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl; halogen; heteroaliphatic; -O-aliphatic, such as ; heterocyclyl, including heteroaryl and heterocycloaliphatic; aryl; araliphatic; erocyclyl; hydroxyl; nitro; cyano; carboxyl; carboxyl ester; acyl; amide; amino; sulfonyl; sulfonamide; yl; sulfinyl; haloalkyl; alkylphosphate; or alkylphosphonate. Het-1 can be unsubstituted (if R3 is H for all occurrences on that particular moiety) or substituted. In some embodiments of formula I, R3 is not pyridinyl. In other embodiments, R 3 is not pyridinyl, thiophenyl, furyl, pyrazinyl, quinolinyl, or pyrrolopyridinyl.

For certain embodiments of formula 1, Het-1 may be a 5- or ered heteroaryl. In some embodiments, Het-1 is a 5-membered heteroaryl ring. In particular examples, Het-1 is furan; thiophene; le; pyrrole; imidazole; e; thiazole; isoxazole; isothiazole; triazole, such as 1,2,3-triazole, 1,2,4- triazole, or 1,3,4-triazole; oxadiazole, such as 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, or 1,2,5- oxadiazole; thiadiazole, such as 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, or 1,2,5-thiadiazole; or tetrazole. In particular examples, Het-1 is furan, thiazole or oxazole, such as furanyl, furanyl, thiazolyl, thiazolyl, lyl, oxazolyl, oxazolyl or oxazolyl.

In some embodiments of formula 1, R2 is H, alkyl, cycloaliphatic, typically cycloalkyl, such as cyclopropyl, cyclobutyl, entyl or cyclohexyl, heteroaliphatic, or heterocycloaliphatic. In some examples, R2 may be substituted with a hydroxyl group. 17609606_1 ters) P106926.NZ In some embodiments, R1 is Ra, -(CRaRa)m-O-Ra, -(CH2)m-O-Ra, -(CRaRa)m-O-(CRaRa)m-O-Ra, - [(CH2)m-O-]n-Ra or -(CH2)m-O-(CH2)m-O-Ra wherein each m and n independently are 1, 2 or 3; R2 is Ra, Rb, Ra substituted with 1, 2, or 3 Rb, Ra substituted with Rb and Rc, Ra substituted with Rc, – (CRaRa)n-Ra, -(CH2)n-Ra, -(CRaRa)n-Rb, -(CH2)n-Rb, -[(CH2)m-O-]n-Ra, -[(CH2)m-O-]n-[Ra substituted with 1, 2 or 3 Rb], or -(CH2)m-O-(CH2)m-O-Ra n each m and n ndently are 1, 2 or 3; Ra is independently for each occurrence H, D, C1-6alkyl, C3-6cycloalkyl, C3-6cycloalkenyl or C3- 6heteroalicyclyl; Rb is independently for each occurrence -OH, -CF3, -ORc, -NRdRd, -C(O)OH, -C(O)Rc, -C(O)ORc, - C(O)NRdRd or halogen; Rc is independently for each occurrence C1-6alkyl, C3-6cycloalkyl, C3-6heteroalicyclyl, aralkyl, C1- e, C e, or C 6alkyl substituted with 1, 2 or 3 R 3-6cycloalkyl substituted with 1, 2 or 3 R 3-6heteroalicyclyl tuted with 1, 2 or 3 Re; Rd is independently for each occurrence H, C1-6alkyl optionally substituted with 1, 2 or 3 Re, C3- e, or two Rd groups together with the nitrogen bound 6cycloalkyl optionally substituted with 1, 2 or 3 R thereto form a C3-6heteroalicyclyl moiety optionally substituted with C1-6alkyl and optionally interrupted with one or two –O– or –N(Rg) wherein Rg is R70, -C(O)R70, -C(O)OR60 or -C(O)N(R80)2,; and Re is independently for each occurrence halogen, C1-6alkyl, cloalkyl, C3-6heteroalicyclyl, C1- a, -OC(O)Ra or -O-aralkyl. 6alkyl-OH, -OR With respect to formula 1, Het-1 may be: 1A) a 5-membered aryl; 1B) a 6-membered aryl; 1C) selected from furan, thiazole, or oxazole; 1D) furan; 1E) oxazole; 1F) le; 1G) furan yl; 1H) 2-yl substituted at least at the 5-position; 1I) furanyl substituted at least at the 5-position with a heteroaryl moiety; 1J) oxazolyl; 1K) oxazolyl substituted at least at the 2-position; 1L) oxazol- 4-yl substituted at least at the 2-position with a heteroaryl moiety; 1M) 2-(pyrazolyl)oxazolyl; 1N) 2- ((1-cyclopropylmethyl)pyrazolyl)oxazolyl; 1O) thiazolyl; 1P) thiazolyl substituted at least at the 2-position; or 1Q) lyl substituted at least at the 2-position with a heteroaryl moiety.

With respect to Het-1 embodiments 1A to 1Q, R may be, in combination with 1A to 1Q: 2A) heteroaryl; 2B) aliphatic; 2C) a 5-membered heteroaryl; 2D) a 6-membered heteroaryl; 2E) an alkyl; 2F) amide; 2G) -CF3; 2G) -CN; 2H) -C(O)NH2; 2I) selected from ne, thiazole, oxadiazole, pyrazine, or pyrimidine; 2J) thiazolyl; 2K) dinyl; 2L) pyridinyl; 2M) pyrazineyl; 2N) zolyl; 2O) 5-morpholinylpyridinyl; 2P) 5-(N-methylpiperidinyl)pyridineyl; 2Q) ydroxy methylpropoxy)pyridinyl; 2R) 5-(oxetanyloxy)pyridinyl; 2S) oxypyridinyl; 2T) 3- fluoropyridyl; 2U) 1,3,4-oxadiazolyl; 2V) 5-trifluoromethylpyridinyl; 2W) 3- trifluoromethylpyridinyl; 2X) 6-trifluoromethylpyridinyl; 2Y) 5-fluoropyridyl; 2Z) 4-fluoropyrid yl; or 2AA) 6-fluoropyridyl; 3,6-difluoropyridinyl.

A person of ordinary skill in the art will understand that any of 2A to 2AA may be combined with any of 1A to 1Q, to form any and all combinations between such substituents. 17609606_1 (GHMatters) P106926.NZ With respect to the Het-1 embodiments 1A to 1Q and the R embodiments 2A to 2AB, R1 is, in combination with 1A to 1Q and 2A to 2AA: 3A) aliphatic; 3B) heteroaliphatic; 3C) H; or 3D) - CH2CH2OCH2CH2OCH3.

Alternatively, with respect to the Het-1 ments 1A to 1Q, R and R1 together form combined embodiment 3E) a 6-membered heterocyclyl ring that comprises the atoms to which R and R1 are attached.

A person of ordinary skill in the art will understand that any of 3A to 3E may be combined with any of 1A to 1Q, and any of 2A to 2AA, where appropriate, to form any and all combinations between such tuents.

With respect to the Het-1 embodiments 1A to 1Q, the R embodiments 2A to 2AA and the R1 embodiments 3A to 3D, or the combined R and R1 embodiment 3E, R2 may be, in any combination with 1A to 1Q, and 2A to 2AA and 3A to 3D, or 3E: 4A) H, tic, heteroaliphatic, heterocyclyl, aryl , amide or araliphatic; 4B) H, alkyl, cycloalkyl, cycloalkenyl or heterocycloaliphatic; 4C) heterocycloaliphatic; 4D) alkyl; 4E) cycloalkyl substituted with O-alkyl, l)2, OH, halogen, cyclyl, or a combination thereof; 4F) tetrahydropyran, oxetane, tetrahydrofuran or azetidine; 4G) cyclobutyl, cyclopentyl, cyclohexyl, or utenyl; 4H) –C1-6alkyl-O-C1-6alkyl or –C1-6alkyl-O-C1-6alkyl-O-C1-6alkyl; 4I) - CH2CH2OCH2CH2OCH3; 4J) -CH2CH2OCH2CH3; 4K) -CH2CH2OCH2CH2F; 4L) -CH2CH2OCH2CHF2; 4M) -CH2CH2OCH2CF3; 4N) H; 4O) CH2C(CH3)2OH; 4P) CH2CH2OCH3; 4Q) CH2CH2OH; 4R) -CH2CF3; 4S) – CHF2; 4T) –CH2CH(OH)CF3; 4U) –CH2(OH)(CF3)2; 4V) -C(O)N(CH3)2; 4W) –C(O)N(Et)2; 4X) –C(O)- morpholine; 4Y) benzyl; 4Z) 3-fluorocyclobutenyl; 4AA) 3,3-difluorocyclobutyl; 4AB) tetrahydropyranyl; 4AC) yl; 4AD) (1r, 3r)ethoxycyclobutyl; 4AE) (1s, 3s) ethoxycyclobutyl; 4AF) (1s, 3s)hydroxycyclobutyl; 4AG) (1r, 3r)hydroxycyclobutyl; 4AH) (1s, 3s) dimethylaminocyclobutyl; 4AI) (1r, 3r)dimethylaminocyclobutyl; 4AJ) (3-methyloxetanyl)methyl; 4AK) methyl; 4AL) 1-(tert-butoxycarbonyl)azetidinyl; 4AM) 3-methoxycyclobutyl; 4AN) (1r, 3r) methoxycyclobutyl; 4AO) (1s, 3s)methoxycyclobutyl; 4AP) 3-benzyloxycyclobutyl; 4AQ) azetidinyl; 4AR) 1-acetoxyazetidinyl; 4AS) 1-(tert-butylcarbamoyl)azetidinyl; 4AT) 1- (propylcarbamoyl)azetidinyl; 4AU) 1-(cyclopropylcarbamoyl)azetidinyl; 4AV) 1- propanecarbonyl)azetidinyl; 4AW) 1-(tert-butylcarbonyl)azetidinyl; 4AX) 1-(pyrrolidine carbonyl)azetidinyl; 4AY) propanecarbonyl)azetidinyl; 4AZ) 1-(2,2,2-trifluoroethyl)azetidin yl; 4BA) ylazetidinyl; 4BB) 1-(2,2-difluorocyclopropanecarbonyl)azetidinyl; 4BC) isopropyl; 4BD) 2-morpholinoethyl; 4BE) (4-methylpiperazinyl)ethyl; 4BF) tetrahydropyranyl; 4BG) (tetrahydropyranyl)methyl; 4BH) (3-(hydroxymethyl)oxetanyl)methyl; 4BI) 2-(diethylamino)ethyl; 4BJ) 2-fluoroethyl; 4BK) (1R, 3R)hydroxycyclopentyl; 4BL) (1R, 3S)hydroxycyclopentyl; 4BM) (1S, 3R)hydroxycyclopentyl; 4BN) (1S, 3S)hydroxycyclopentyl; 4BO) 1,4-dioxaspiro[4,5]decanyl; 4BP) (1s, 3s)(2-fluoroethoxy)cyclobutyl; 4BQ) (1r, 3r)(2-fluoroethoxy)cyclobutyl; 4BR) (1s, 3s)(2- trifloroethoxy)cyclobutyl; 4BS) (1r, 3r)(2-trifloroethoxy)cyclobutyl; 4BT) (1s, 3s) poxycyclobutyl; 4BU) (1r, 3r)isopropoxycyclobutyl; 4BV) (1r, 3r)hydroxymethylcyclobutyl; 4BW) (1s, 3s)hydroxymethylcyclobutyl; 4BX) (1s, ethoxy-d5)cyclobutyl; 4BY) (1r, 3r) 17609606_1 (GHMatters) P106926.NZ ethoxy-d5)cyclobutyl; 4BZ) (1R, 3R)ethoxycyclopentyl; 4CA) (1R, ethoxycyclopentyl; 4CB) (1S, 3R)ethoxycyclopentyl; 4CC) (1S, 3S)ethoxycyclopentyl; 4CD) (1R, 3R)hydroxycyclohexyl; 4CE) (1S, 3S)hydroxycyclohexyl; 4CF) (1R, 3R)ethoxycyclohexyl; 4CG) (1S, ethoxycyclohexyl; 4CH) (1R, 3S)ethoxyfluorocyclobutyl; 4CI) (1S, 3S)ethoxyfluorocyclobutyl; 4CJ) (1R, 3R) ethoxyfluorocyclobutyl; 4CK) (1S, 3R)ethoxyfluorocyclobutyl; or 4CL) tetrahydrofuranyl.

A person of ordinary skill in the art will understand that any of 4A to 4CL may be combined in Formula 1 with any of 1A to 1Q, any of 2A to 2K and any of 3A to 3D, or 3E, to form any and all combinations between such substituents.

In some embodiments, R is heteroaryl, g to compounds having a 2 With t to formula 2, Het-2 is a heteroaryl, and may comprise a single ring or multiple rings, such as in a fused ring system. x is from 1 to the number of possible substituents on the particular system in question, such as from 1 to 2, 3, 4, 5, or at least 6, and each R3 independently is as previously defined for formula 1. Het -2 can be unsubstituted (if R3 is H for all occurrences on that particular moiety) or substituted. In particular embodiments of formula 2, Het-2 is not tetrazolyl or oxadiazolyl.

Het-2 may be a 5- or 6-membered heteroaryl. In some examples, Het-2 is furan; thiophene; pyrazole; pyrrole; imidazole; oxazole; thiazole; isoxazole; isothiazole; le, such as 1,2,3-triazole, 1,2,4- triazole, or 1,3,4-triazole; oxadiazole, such as oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole or 1,2,5- oxadiazole; thiadiazole, such as 1,2,3-thiadiazole, 1,2,4-thiadiazole, thiadiazole or 1,2,5-thiadiazole; tetrazole; pyrimidine; pyridine; triazine, such as 1,2,3-triazine, 1,2,4-triazine or 1,3,5-triazine; pyrazine; or pyridazine. In particular examples, Het-2 is: pyridine, such as pyridyl, pyridyl or pyridyl; pyrimidine, such as dinyl; pyramidinyl or pyramidinyl; pyrazine, such as pyrazineyl; or thiazole, such as thiazolyl, thiazolyl or thiazolyl.

In some embodiments of a 2, Het-1 is a substituted heteroaryl. In some embodiments, Het-1 is tuted with at least a heterocycle moiety, leading to compounds having formula 3 17609606_1 (GHMatters) P106926.NZ With reference to formula 3, Het-1, R, Het-2, R2, R3, x and y are as defined above for formulas 1 and 2.

Het-3 is a cycle, and may be unsubstituted (if R3 is H for all occurrences on Het-3) or substituted. z is from 1 to the number of possible substituents on the particular system in question, such as from 1 to 2, 3, 4, , or at least 6.

In some embodiments of formula 3, Het-3 is a 5- or 6-membered cycle, such as a 5- or 6- membered heteroaryl or heteroalicyclyl moiety. In some embodiments, Het-3 is furan; thiophene; pyrazole, such as pyrazolyl, or pyrazolyl; pyrrole; imidazole; oxazole; thiazole; isoxazole; isothiazole; triazole, such as 1,2,3-triazole, 1,2,4-triazole, or 1,3,4-triazole; oxadiazole, such as 1,2,3-oxadiazole, 1,2,4- oxadiazole, 1,3,4-oxadiazole or 1,2,5-oxadiazole; thiadiazole, such as 1,2,3-thiadiazole, 1,2,4-thiadiazole, thiadiazole or 1,2,5-thiadiazole; tetrazole; pyrimidine; pyridine; ne, such as 1,2,3-triazine, 1,2,4- triazine or 1,3,5-triazine; pyrazine; or pyridazine. In some embodiments, Het-3 is not pyridinyl. In certain embodiments, Het-3 is not pyridinyl, thiophenyl, furyl, pyrazinyl, quinolinyl, or pyrrolopyridinyl. In particular embodiments, Het-3 is pyrazole, and may be lyl. Each of R3 independently may be H, aliphatic, alkoxy, heteroaliphatic, yl ester, araliphatic, such as aralkyl, NO2, CN, OH, haloalkyl, such as CF3, alkyl phosphate or alkylphosphonate.

With respect to formula 3 and any of the Het-1 embodiments 1A to 1Q, any of the R embodiments 2A to 2AB, any of the R1 embodiments 3A to 3D, or the combined R and R1 embodiment 3E, and any of the R2 embodiments 4A to 4CL, Het-3 may be, in any combination with 1A to 1Q, 2A to 2AB, 3A to 3D, or 3E, and 4A to 4CL: 5A) a 5-membered heteroaryl; 5B) a 6-membered heteroaryl; 5C) pyrazole; 5D) pyrrole; 5E) pyrazolyl; 5F) pyrrolyl; 5G) opyrrolyl; 5H) 1-methylpyrazolyl; 5I) 1-(tertbutoxycarbonyl )pyrazolyl; 5J) 3-methylpyrazolyl; 5K) 1-(((di-tertbutoxyphosphoryl ethyl)pyrazolyl; 5L) 1-(((tert-butoxy(hydroxy)phosphoryl)oxy)methyl)pyrazol- 4-yl; 5M) 1-((phosphonooxy)methyl)pyrazolyl; 5N) 3-trifluoromethylpyrazolyl; 5O) 1-((1- (isobutyryloxy)ethoxy)carbonyl)pyrazolyl; 5P) 1-((tert-butoxycarbonyl)-D-valyl)pyrazolyl; 5Q) 1-((1- cyclopropoxy)carbonyl)pyrazolyl; 5R) 1-(((1-((4-methoxybenzyl)oxy)methylpropan yl)oxy)carbonyl)pyrazolyl; 5S) 1-((phosphonooxy)methyl)pyrazolyl sodium salt; 5T) 1-ethylpyrazol- 4-yl; 5U) 1-isopentylpyrazolyl; 5V) 1-((3-methyloxetanyl)methyl)pyrazolyl; 5W) 1-(2-(2- methoxyethoxy)ethyl)pyrazolyl; 5X) 3,5-dimethylpyrazolyl; 5Y) methyloxo-1,3-dioxol yl)methyl)pyrazolyl; 5Z) 1-((diethoxyphosphoryl)methyl)pyrazolyl; 5AA) 1- honomethyl)pyrazolyl; 5AB) 1-(phosphonomethyl)pyrazolyl sodium salt; 5AC) 1- ((phosphonooxy)methyl)pyrazolyl potassium salt; 5AD) 1-(4-methoxybenzyl)pyrazolyl; 5AE) pyrazol- 3-yl; 5AF) 1-(cyclobutyl)pyrazolyl; 5AG) 5-fluoro((2-(trimethyl-λ4-sulfanyl)ethoxy)methyl)-pyrazol- 4-yl; 5AH) 5-fluoropyrazolyl; 5AI) osphonooxy)methyl)pyrazolyl calcium salt; 5AJ) 1- ((phosphonooxy)methyl)pyrazolyl ammonium salt; 5AK) 1-((phosphonooxy)methyl)pyrazolyl lysine salt; 5AL) 1-((phosphonooxy)methyl)pyrazolyl arginine salt; 5AM) 1-((phosphonooxy)methyl)pyrazol yl tris(hydroxymethyl)aminomethane salt; 5AN) osphonooxy)methyl)pyrazolyl triethylamine salt; 5AO) 1-(2,2,2-trifluoroethyl)pyrazolyl; or 5AP) 1-difluoromethylpyrazolyl. 17609606_1 (GHMatters) P106926.NZ A person of ordinary skill in the art will understand that any of 5A to 5AP may be combined with any of 1A to 1Q, any of 2A to 2AB and any of 3A to 3D, or 3E, and any of 4A to 4CL, to form any and all combinations n such substituents.

In some embodiments of formula 3, Het-2 is pyridine, leading to compounds having formula 4 In certain embodiments of formula 4, the pyridine ring is 2-pyridyl, leading to compounds having formula 5 5.

With reference to formula 4 and a 5, R4-R7 are each ndently H, aliphatic, heteroaliphatic, alkoxy, heterocyclyl, aryl, araliphatic, –O-heterocyclyl, hydroxyl, haloalkyl, halogen, nitro, cyano, carboxyl, carboxyl ester, acyl, amide, amino, sulfonyl, sulfonamide, sulfanyl or sulfinyl. In some embodiments, R4-R7 are each independently H, aliphatic, halogen, haloalkyl, heteroaliphatic, alkoxy, cyclyl, or –O- heterocyclyl. In particular embodiments, R4-R7 may be independently H, halogen, haloalkyl, alkyl, heterocyclyl, alkoxy, or –O-heterocyclyl. In one embodiment of the compounds according to formulas 4 and , at least one of R4-R7 is not H, for example, in one ment R4 is not H.

In certain embodiments, each of R4, R5, R6, and R7 independently is Ra, Rb, Ra substituted with Rc, - ORa, -O-(CRaRa)p-Rb n p is 1, 2 or 3, and Ra, Rb and Rc are as previously defined. In specific examples, R5 is H, F, CF3, methoxy, morpholinyl, 1-methylpiperidinyl, -O-CH2C(CH3)2OH, or –O- (oxetanyl), and/or R4, R6 and R7 are H, F or CF3.

In some embodiments of formula 4, Het-3 is a pyrazole, g to compounds having a general formula 6 17609606_1 (GHMatters) P106926.NZ Certain embodiments of formula 6 further satisfy formula 7 7.

With reference to formula 6 and formula 7, R2-R7 and Het-1 are as previously defined for formula 5; R8, R9 and R10 are each independently H, aliphatic, aliphatic, aryl, -O-aliphatic, such as alkoxy, araliphatic, such as aralkyl, heterocyclyl, sulfonyl, nitro, OH, haloalkyl, carboxyl ester, cyano, acyl, amino, alkyl phosphate or alkylphosphonate. R10 may be H, aliphatic, -O-aliphatic, such as alkoxy, heteroaliphatic, carboxyl ester, acyl, araliphatic, such as l, NO2, CN, OH, haloalkyl, such as CF3, alkyl phosphate or alkylphosphonate. In particular examples, R10 is H, alkyl, carboxyl ester, acyl, alkyl phosphate, alkyl phosphonate, heterocycloalkyl or l. In n examples, R8 and R9 are each independently, H, alkyl or haloalkyl, such as trifluoromethyl. In certain embodiments, Het-1 is furan, thiazole or oxazole, and in particular embodiments, R8 and R9 are both H, one of R8 and R9 is H and the other is lower alkyl, such as methyl, or trifluoromethyl, or both of R8 and R9 are lower alkyl.

In some embodiments of formulas 6-7, R10 is Ra, Rb, Ra substituted with –OP(O)(Rf)2, Ra substituted with 1, 2 or 3 Rb, Ra tuted with Rc, Ra substituted with –P(O)(Rf)2, aralkyl, -(CRaRa)n-Ra, -(CH2)n-Ra or -C(O)C(Ra)2NRaRb, wherein n, Ra, Rb and Rc are as usly defined, and Rf is independently for each occurrence -ORa, -O-M+ where each M+ independently is an alkali metal ion, such as K+, Na+, Li+ or an ammonium ion, such as +NH +N(Ra) -[M2+] 2+ is an ne metal earth ion, such as 4 or 4, or –O 0.5 where M Mg2+, Ca2+ or Ba2+. In certain examples of the compounds of formulas 6-7, R10 is -CH2OP(O)(OH)2, or a salt thereof.

In other embodiments of formula 5, Het-1 is furan, thiazole or e, such as furanyl, 3- yl, thiazolyl, thiazolyl, thiazolyl, oxazolyl, oxazolyl or oxazolyl. In certain embodiments, the compound has a general a selected from 17609606_1 (GHMatters) P106926.NZ With reference to formulas 8, 9 and 10, R2-R7, Het-3 and z are as previously defined for formula 5; and R11- R14 are each independently H, aliphatic, heteroaliphatic, aryl, heterocyclyl, sulfonyl, nitro, carboxyl ester, cyano or amino. In certain embodiments, the compound has a a selected from , , or 17609606_1 (GHMatters) P106926.NZ With reference to formulas 11, 12 and 13, R2-R7, z and Het-3 are as previously defined for formula 5; R11- R14 may be each independently H, C1-6alkyl, CF3, acyl, CN, or OH. In certain examples, R11, R12, R13 and R14 are each independently H or alkyl, and in particular examples, R11, R12, R13 and R14 are H.

In some embodiments of formulas 8-13, Het-3 is a pyrazole, such as a pyrazolyl, pyrazolyl, pyrazolyl or pyrazolyl. In particular ments, the compound has a formula selected from , , or where R2-R10 are as defined with respect to a 7.

In certain embodiments of formula 1, R and R1 together with the atoms to which they are attached, form a heterocylyl ring. In certain embodiment of formula 1, compounds have a formula selected from , , , or wherein Het-3 is heteroaryl.

In other embodiments of formula 1, R is aliphatic, such as alkyl, particularly CF3; CN; or amide. In certain ments of formula 1, compound may have a a ed from 17609606_1 (GHMatters) P106926.NZ , , , , , , , , , , , or , n Het-3 is heteroaryl. With respect to formulas 20 and 30-32, each of R15 and R16 independently is H; aliphatic, such as alkyl, particularly methyl; aryl; heteroaryl; or together with the nitrogen to which they are attached, form a heterocyclyl ring, such as morpholine, piperidine, or piperazine.

In some embodiments of formulas 17-32, Het-3 is pyrazole, and in certain ments the moiety is , where R8, R9 and R10 are as previously defined. 17609606_1 (GHMatters) P106926.NZ In certain embodiments of any of the above formulas, R4, R6, R7 are H, halogen, or haloalkyl; R5 is H, halogen, haloalkyl, alkoxy or N(RdRd) where each Rd independently is as previously d; R11, R12, R13 and R14 are H; and R8 and R9 are both H, or one of R8 and R9 is H and the other is methyl or trifluoromethyl, or both of R8 and R9 are methyl. In some embodiment, each of R4, R5, R6, and R7 independently is H, F or CF3.

Some ary compounds according to formula 1 include: I-1 I-2 I-3 I-4 I-5 I-6 I-7 I-8 I-9 17609606_1 (GHMatters) P106926.NZ I-10 I-11 I-12 I-13 I-14 I-15 I-16 I-17 I-18 I-19 I-20 I-21 06_1 (GHMatters) P106926.NZ I-22 I-23 I-24 I-25 I-26 I-27 I-28 I-29 I-30 I-31 I-32 I-33 I-34 I-35 06_1 (GHMatters) P106926.NZ I-37 I-38 I-39 I-40 I-41 I-42 I-43 I-44 I-45 I-47 I-48 I-49 I-50 I-51 06_1 (GHMatters) P106926.NZ I-52 I-53 I-54 I-55 I-56 I-57 I-58 I-59 I-60 I-61 I-62 I-63 I-64 I-65 I-66 17609606_1 ters) P106926.NZ I-67 I-68 I-69 I-70 I-71 I-72 I-73 I-74 I-75 I-76 I-77 I-78 I-79 I-80 I-81 17609606_1 ters) P106926.NZ I-82 I-83 I-84 I-85 I-86 I-87 I-88 I-89 I-90 I-91 I-92 I-93 17609606_1 ters) P106926.NZ I-94 I-95 I-96 I-97 I-98 I-99 I-100 I-101 I-102 I-103 I-104 I-105 06_1 (GHMatters) P106926.NZ I-106 I-107 I-108 I-109 I-110 I-111 I-112 I-113 I-114 I-115 I-116 I-117 06_1 (GHMatters) P106926.NZ I-118 I-119 I-120 I-121 I-122 I-123 I-124 I-125 I-126 I-127 I-128 I-129 I-130 I-131 I-132 06_1 (GHMatters) P106926.NZ I-133 I-134 I-135 I-136 I-137 I-138 I-139 I-140 I-141 I-142 I-143 I-144 I-145 I-146 I-147 06_1 (GHMatters) P106926.NZ I-148 I-149 I-150 I-151 I-152 I-153 I-154 I-155 I-156 In other embodiments, the compound according to formula 1 is selected from II-1 II-2 II-3 II-4 II-5 II-6 06_1 (GHMatters) P106926.NZ II-7 II-8 II-9 II-10 II-11 II-12 II-13 II-14 II-15 II-16 II-17 II-18 II-19 II-20 II-21 17609606_1 ters) P106926.NZ II-22 II-23 II-24 II-25 II-26 II-27 II-28 II-29 II-30 II-31 II-32 II-33 II-34 II-35 II-36 II-37 II-38 II-39 17609606_1 ters) P106926.NZ II-40 II-41 II-42 II-43 II-44 II-45 II-46 II-47 II-48 II-49 II-50 II-51 II-52 II-53 II-54 06_1 (GHMatters) P106926.NZ II-55 II-56 II-57 II-58 II-59 II-60 II-61 II-62 II-63 II-64 II-65 II-66 17609606_1 ters) P106926.NZ II-67 II-68 II-69 II-70 II-71 II-72 II-73 II-74 II-75 II-76 II-77 II-78 17609606_1 ters) P106926.NZ II-79 II-80 II-81 II-82 II-83 II-84 II-85 II-86 II-87 II-88 II-89 II-90 17609606_1 ters) P106926.NZ II-91 II-92 II-93 II-94 II-95 II-96 II-97 II-98 II-99 II-100 II-101 II-102 II-103 II-104 II-105 06_1 (GHMatters) P106926.NZ II-106 II-107 II-108 II-109 II-110 II-111 II-112 II-113 II-114 II-115 II-116 II-117 II-118 II-119 II-120 06_1 (GHMatters) P106926.NZ II-121 II-122 II-123 II-124 II-125 II-126 II-127 II-128 II-129 II-130 II-131 II-132 II-133 II-134 II-135 06_1 (GHMatters) P106926.NZ II-136 II-137 II-138 II-139 II-140 II-141 II-142 II-143 II-144 II-145 II-146 II-147 II-148 II-149 II-150 17609606_1 ters) P106926.NZ II-151 II-152 II-153 II-154 II-155 II-156 II-157 II-158 II-159 II-160 II-161 II-162 II-163 II-164 II-165 II-166 II-167 II-168 17609606_1 ters) P106926.NZ II-169 II-170 II-171 II-172 II-173 II-174 II-175 II-176 II-177 II-178 II-179 II-180 In other embodiments, the compound according to formula 1 is ed from III-1 III-2 III-3 17609606_1 (GHMatters) P106926.NZ III-4 III-5 III-6 III-7 III-8 Exemplary compounds according to formula 1 include: I-1: N-(1-(2-hydroxymethylpropyl)(pyridinyl)-1H-pyrazolyl)(1-methyl-1H-pyrazol- urancarboxamide 2,2,2-trifluoroacetate; I-2: N-(1-(2-hydroxymethylpropyl)(pyridinyl)-1H-pyrazolyl)(1-methyl-1H-pyrazol- 4-yl)furancarboxamide; I-3: N-(1-(2-hydroxymethylpropyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)furan- 2-carboxamide; I-4: tert-butyl 4-(5-((1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)carbamoyl)furanyl)-1H- pyrazolecarboxylate; I-5: N-(1-(2-methoxyethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)furan carboxamide; I-6: N-(1-(2-methoxyethyl)(pyridinyl)-1H-pyrazolyl)(3-methyl-1H-pyrazolyl)furan- 2-carboxamide formic acid; I-7: N-(1-(2-methoxyethyl)(pyrimidinyl)-1H-pyrazolyl)(1H-pyrazolyl)furan carboxamide; I-8: N-(1-(2-methoxyethyl)(pyrimidinyl)-1H-pyrazolyl)(3-methyl-1H-pyrazol yl)furancarboxamide; I-9: 2-methoxyethyl)(pyridinyl)-1H-pyrazolyl)(3-methyl-1H-pyrazolyl)furan- 2-carboxamide; I-10: di-tert-butyl ((4-(5-((1-(2-methoxyethyl)(pyridinyl)-1H-pyrazolyl)carbamoyl)furan- 2-yl)-1H-pyrazolyl)methyl) phosphate; 17609606_1 (GHMatters) P106926.NZ I-11: tert-butyl ((4-(5-((1-(2-methoxyethyl)(pyridinyl)-1H-pyrazolyl)carbamoyl)furan yl)-1H-pyrazolyl)methyl) hydrogen phosphate; I-12: (4-(5-((1-(2-methoxyethyl)(pyridinyl)-1H-pyrazolyl)carbamoyl)furanyl)-1H- pyrazolyl)methyl dihydrogen phosphate; I-13: N-(1-(2-methoxyethyl)(pyridinyl)-1H-pyrazolyl)(3-(trifluoromethyl)-1H-pyrazol- 4-yl)furancarboxamide; I-14: sodium (4-(5-((1-(2-methoxyethyl)(pyridinyl)-1H-pyrazolyl)carbamoyl)furanyl)- 1H-pyrazolyl)methyl ate; I-15: N-(1-(2-hydroxyethyl)(pyrimidinyl)-1H-pyrazolyl)(1H-pyrazolyl)furan carboxamide; I-16: N-(1-(2-(2-methoxyethoxy)ethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide; I-17: N-(1-(2-(2-methoxyethoxy)ethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide hydrochloride salt; I-18: N-(1-(2-(2-methoxyethoxy)ethyl)(pyridinyl)-1H-pyrazolyl)(3-methyl-1H-pyrazol- 4-yl)furancarboxamide; I-19: butyryloxy)ethyl 4-(5-((1-(2-methoxyethyl)(pyridinyl)-1H-pyrazol yl)carbamoyl)furanyl)-1H-pyrazolecarboxylate; I-20: tert-butyl (S)-(1-(4-(5-((1-(2-methoxyethyl)(pyridinyl)-1H-pyrazol yl)carbamoyl)furanyl)-1H-pyrazolyl)methyloxobutanyl)carbamate; I-21: 1-methylcyclopropyl (1-(2-methoxyethyl)(pyridinyl)-1H-pyrazol yl)carbamoyl)furanyl)-1H-pyrazolecarboxylate; I-22: methoxybenzyl)oxy)methylpropanyl 4-(5-((1-(2-methoxyethyl)(pyridinyl)- 1H-pyrazolyl)carbamoyl)furanyl)-1H-pyrazolecarboxylate; I-23: 5-(1H-pyrazolyl)-N-(3-(pyridinyl)(tetrahydro-2H-pyranyl)-1H-pyrazolyl)furan- 2-carboxamide; I-24: 5-(5-nitro-1H-pyrrolyl)-N-(1-(propoxymethyl)(pyridinyl)-1H-pyrazolyl)furan carboxamide; I-25: oxetanyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)furan carboxamide; I-26: 5-(1-methyl-1H-pyrazolyl)-N-(1-(oxetanyl)(pyridinyl)-1H-pyrazolyl)furan carboxamide; I-27: N-(1-((1,3-trans)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide; I-28: N-(1-((1,3-cis)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide; I-29: N-(1-((1,3-cis)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(3-methyl-1H- pyrazolyl)furancarboxamide; 17609606_1 (GHMatters) P106926.NZ I-30: 5-(3-methyl-1H-pyrazolyl)-N-(1-(oxetanyl)(pyridinyl)-1H-pyrazolyl)furan carboxamide; I-31: N-(1-((1,3-cis)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(1-methyl-1H- pyrazolyl)furancarboxamide; I-32: (1,3-cis)hydroxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide; I-33: N-(1-((1s,3s)(dimethylamino)cyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol- 4-yl)furancarboxamide; I-34: N-(1-((1s,3s)(dimethylamino)cyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol- 4-yl)furancarboxamide e; I-35: (4-(5-((1-((1,3-cis)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)carbamoyl)furan yl)-1H-pyrazolyl)methyl phosphate bis-sodium salt; I-36: (4-(5-((1-((1s,3s)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)carbamoyl)furan yl)-1H-pyrazolyl)methyl dihydrogen phosphate; I-37: N -(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)furan carboxamide formate; I-38: N -ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)furan carboxamide; I-39: N -(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(1-ethyl-1H-pyrazolyl)furan amide formate; I-40: 2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(1-ethyl-1H-pyrazolyl)furan carboxamide; I-41: N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(3-(trifluoromethyl)-1H-pyrazol yl)furancarboxamide formate; I-42: N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(3-(trifluoromethyl)-1H-pyrazol yl)furancarboxamide; I-43: N -(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(1-isopentyl-1H-pyrazolyl)furan- 2-carboxamide formate; I-44: N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(1-isopentyl-1H-pyrazolyl)furan- 2-carboxamide; I-45: N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(1-methyl-1H-pyrazolyl)furan carboxamide formate; I-46: N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(1-methyl-1H-pyrazolyl)furan carboxamide; I-47: 5-(1H-pyrazolyl)-N-(3-(pyridinyl)-1H-pyrazolyl)furancarboxamide; I-48: 5-(1-((3-methyloxetanyl)methyl)-1H-pyrazolyl)-N-(1-((3-methyloxetanyl)methyl) (pyridinyl)-1H-pyrazolyl)furancarboxamide formate; 17609606_1 (GHMatters) P106926.NZ I-49: 5-(1-((3-methyloxetanyl)methyl)-1H-pyrazolyl)-N-(1-((3-methyloxetanyl)methyl) (pyridinyl)-1H-pyrazolyl)furancarboxamide; I-50: N -(2-(2-methoxyethoxy)ethyl)(1-(2-(2-methoxyethoxy)ethyl)-1H-pyrazolyl)-N-(1-(2-(2- methoxyethoxy)ethyl)(pyridinyl)-1H-pyrazolyl)furancarboxamide formate; I-51: N-(2-(2-methoxyethoxy)ethyl)(1-(2-(2-methoxyethoxy)ethyl)-1H-pyrazolyl)-N-(1-(2-(2- methoxyethoxy)ethyl)(pyridinyl)-1H-pyrazolyl)furancarboxamide; I-52: 5 -(1-(2-(2-methoxyethoxy)ethyl)-1H-pyrazolyl)-N-(1-(2-(2-methoxyethoxy)ethyl) (pyridinyl)-1H-pyrazolyl)furancarboxamide formate; I-53: 5-(1-(2-(2-methoxyethoxy)ethyl)-1H-pyrazolyl)-N-(1-(2-(2-methoxyethoxy)ethyl) (pyridinyl)-1H-pyrazolyl)furancarboxamide; I-54: (4 -(5-((1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)carbamoyl)furanyl)-1H- lyl)methyl ogen phosphate; I-55: sodium (4 -(5-((1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)carbamoyl)furanyl)-1H- pyrazolyl)methyl phosphate; I-56: N -(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(3-methyl-1H-pyrazolyl)furan carboxamide formate; I-57: N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(3-methyl-1H-pyrazolyl)furan carboxamide; I-58: 5 -(3,5-dimethyl-1H-pyrazolyl)-N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazol yl)furancarboxamide formate; I-59: 5-(3,5-dimethyl-1H-pyrazolyl)-N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazol yl)furancarboxamide; I-60: 5 -(1H-pyrazolyl)-N-(1-(tetrahydro-2H-pyranyl)(thiazolyl)-1H-pyrazolyl)furan- 2-carboxamide formate; I-61: 5-(1H-pyrazolyl)-N-(1-(tetrahydro-2H-pyranyl)(thiazolyl)-1H-pyrazolyl)furan- 2-carboxamide; I-62: N 1s,3s)ethoxycyclobutyl)(thiazolyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide formate; I-63: N-(1-((1s,3s)ethoxycyclobutyl)(thiazolyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide; I-64: N-(1-(2-(2-methoxyethoxy)ethyl)(thiazolyl)-1H-pyrazolyl)(1H-pyrazolyl)furan- 2-carboxamide; I-65: 5 -(1H-pyrazolyl)-N-(1-(tetrahydro-2H-pyranyl)(thiazolyl)-1H-pyrazolyl)furan- 2-carboxamide; I-66: 5-(1H-pyrazolyl)-N-(1-(tetrahydro-2H-pyranyl)(thiazolyl)-1H-pyrazolyl)furan- 2-carboxamide; I-67: ethyl(pyridineyl)-1H-pyrazolyl}(1H-pyrazolyl)furancarboxamide, formate salt; 06_1 (GHMatters) P106926.NZ I-68: 5-(1-Methyl-1H-pyrazolyl)-N-{1-methyl(pyridineyl)-1H-pyrazolyl}furan amide; I-69: 5-(1-Methyl-1H-pyrazolyl)-N-{1-methyl(pyridineyl)-1H-pyrazolyl}furan carboxamide, formate salt; I-70: tert-Butyl[4-{5-(1H-pyrazoleyl)furancarboxamido}(pyridineyl)-1H-pyrazol yl]azetidinecarboxylate, formate salt; I-71: N-{1-(3-Methoxycyclobutyl)(pyridineyl)-1H-pyrazolyl}(1H-pyrazolyl)furan carboxamide, formate salt, Cis isomer; I-72: N-{1-(3-Methoxycyclobutyl)(pyridineyl)-1H-pyrazolyl}(1H-pyrazolyl)furan carboxamide, Cis isomer; I-73: N-{1-(3-Benzyloxy)cyclobutyl)(pyridineyl)-1H-pyrazolyl}(1H-pyrazol ancarboxamide, Trans ; I-74: tert-Butyl[4-{5-(1H-pyrazoleyl)furancarboxamido}(pyridineyl)-1H-pyrazol yl]azetidinecarboxylate; I-75: N-(1-((1s,3s)methoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide formate; I-76: N-(1-((1s,3s)methoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide; I-77: N-{1-Methyl(pyridineyl)-1H-pyrazolyl}(1H-pyrazolyl)furancarboxamide, free base; I-78: N-{1-(Azetidinyl)(pyridineyl)-1H-pyrazolyl}(1H-pyrazolyl)furan carboxamide, TFA salt; I-79: N-{1-(Azetidinyl)(pyridineyl)-1H-pyrazolyl}(1H-pyrazolyl)furan carboxamide; I-80: Di-tert-butyl-[[4-{4-(5-((1-methyl(pyridineyl)-1H-pyrazolyl)carbamoyl)furanyl)- 1H-pyrazolyl}methyl] phosphate; I-81: [4-{5-((1-Methyl(pyridineyl)-1H-pyrazolyl)carbamoyl)furan-2yl}-1H-pyrazol yl]methyl dihydrogen phosphate; I-82: Sodium [4-{5-((1-Methyl(pyridineyl)-1H-pyrazolyl)carbamoyl)furanyl}-1H- pyrazolyl]methyl phosphate; I-83: N-{1-(1-Acetylazetidinyl)(pyridineyl)-1H-pyrazolyl}(1H-pyrazolyl)furan carboxamide, free base; I-84: 5-(1H-Pyrazolyl)furancarboxamido}(pyridineyl)-1H-pyrazolyl]-N-(tertbutyl )azetidinecarboxamide, free base; I-85: 3-[4-{5-(1H-Pyrazolyl)furancarboxamido}(pyridineyl)-1H-pyrazolyl]-N- isopropylazetidinecarboxamide, free base; I-86: 3-[4-{5-(1H-Pyrazolyl)furancarboxamido}(pyridineyl)-1H-pyrazolyl]-N- azetidinecarboxamide, free base. 17609606_1 (GHMatters) P106926.NZ I-87: 3-[4-{5-(1H-Pyrazolyl)furancarboxamido}(pyridineyl)-1H-pyrazolyl]-N- cyclopropylazetidinecarboxamide, formate salt; I-88: 3-[4-{5-(1H-Pyrazolyl)furancarboxamido}(pyridineyl)-1H-pyrazolyl]-N- cyclopropylazetidinecarboxamide; I-89: N-[1-{1-(Cyclopropanecarbonyl)azetidinyl}(pyridineyl)-1H-pyrazolyl](1H- pyrazolyl)furancarboxamide, formate salt; I-90: N-[1-{1-(Cyclopropanecarbonyl)azetidinyl}(pyridineyl)-1H-pyrazolyl](1H- pyrazolyl)furancarboxamide; I-91: N-[1-{1-Pivaloylazetidinyl}(pyridineyl)-1H-pyrazolyl](1H-pyrazolyl)furan- 2-carboxamide, formate salt; I-92: N-[1-{1-Pivaloylazetidinyl}(pyridineyl)-1H-pyrazolyl](1H-pyrazolyl)furan- 2-carboxamide; I-93: 5-(1H-Pyrazolyl)-N-{3-(pyridineyl)(pyrrolidinecarbonyl)azetidinyl}-1H- pyrazolyl)furancarboxamide, formate salt; I-94: 5-(1H-Pyrazolyl)-N-{3-(pyridineyl)(pyrrolidinecarbonyl)azetidinyl}-1H- pyrazolyl)furancarboxamide; I-95: N-[1-{1-Isobutyrylazetidinyl}(pyridineyl)-1H-pyrazolyl](1H-pyrazol yl)furancarboxamide, formate salt; I-96: N-[1-{1-Isobutyrylazetidinyl}(pyridineyl)-1H-pyrazolyl](1H-pyrazol yl)furancarboxamide; I-97: N-(1H-Pyrazolyl)-N-{3-(pyridineyl){1-(2,2,2-trifluoroethyl)azetidinyl}-1H- pyrazolyl}furancarboxamide, TFA salt; I-98: N-(1H-Pyrazolyl)-N-{3-(pyridineyl){1-(2,2,2-trifluoroethyl)azetidinyl}-1H- lyl}furancarboxamide; I-99: 1-Butyrylazetidinyl}(pyridineyl)-1H-pyrazolyl](1H-pyrazolyl)furan- 2-carboxamide, formate salt; I-100: N-[1-{1-Butyrylazetidinyl}(pyridineyl)-1H-pyrazolyl](1H-pyrazolyl)furan- 2-carboxamide; I-101: N-{1-(1-Methylazetidinyl)(pyridineyl)-1H-pyrazolyl}(1H-pyrazolyl)furan- 2-carboxamide, formate salt; I-102: N-{1-(1-Methylazetidinyl)(pyridineyl)-1H-pyrazolyl}(1H-pyrazolyl)furan- 2-carboxamide; I-103: N-[1-{1-(2,2-difluorocyclopropanecarbonyl)azetidinyl}(pyridineyl)-1H-pyrazol- 4-yl](1H-pyrazolyl)furancarboxamide, formate salt; I-104: N-[1-{1-(2,2-difluorocyclopropanecarbonyl)azetidinyl}(pyridineyl)-1H-pyrazol- 4-yl](1H-pyrazolyl)furancarboxamide; I-105: ethyl(5-morpholinopyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)furan carboxamide; 06_1 (GHMatters) P106926.NZ I-106: ethyl(5-(4-methylpiperazinyl)pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide; I-107: N-(3-(5-(2-hydroxymethylpropoxy)pyridinyl)methyl-1H-pyrazolyl)(1H- pyrazolyl)furancarboxamide; I-108: N-(1-methyl(5-(oxetanyloxy)pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)furan- 2-carboxamide; I-109: N-(3-(5-methoxypyridinyl)methyl-1H-pyrazolyl)(1H-pyrazolyl)furan carboxamide; I-110: N-(1-isopropyl(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)furancarboxamide; I-111: N-(1-(2-morpholinoethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)furan carboxamide; I-112: N-(1-(2-(4-methylpiperazinyl)ethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide; I-113: 5-(1H-pyrazolyl)-N-(3-(pyridinyl)(2-(2,2,2-trifluoroethoxy)ethyl)-1H-pyrazol yl)furancarboxamide; I-114: N-(1-((1s,3s)isopropoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide; I-115: N-(1-(difluoromethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)furan carboxamide; I-116: N-(1-((1s,3s)ethoxycyclobutyl)(6-(trifluoromethyl)pyridinyl)-1H-pyrazolyl) (1H-pyrazolyl)furancarboxamide; I-117: 5-(1H-pyrazolyl)-N-(3-(pyridinyl)(2,2,2-trifluoroethyl)-1H-pyrazolyl)furan carboxamide; I-118: N-(1-(2-ethoxyethyl)(thiazolyl)-1H-pyrazolyl)(1H-pyrazolyl)furan carboxamide formate; I-119: N-(1-(2-ethoxyethyl)(thiazolyl)-1H-pyrazolyl)(1H-pyrazolyl)furan carboxamide; I-120: 5-(1H-pyrazolyl)-N-(1-(tetrahydrofuranyl)(thiazolyl)-1H-pyrazolyl)furan carboxamide formate; I-121: pyrazolyl)-N-(1-(tetrahydrofuranyl)(thiazolyl)-1H-pyrazolyl)furan carboxamide; I-122: 5-(1-cyclobutyl-1H-pyrazolyl)-N-(1-cyclobutyl(pyridinyl)-1H-pyrazolyl)furan carboxamide 2,2,2-trifluoroacetate; I-123: 5-(1-cyclobutyl-1H-pyrazolyl)-N-(1-cyclobutyl(pyridinyl)-1H-pyrazolyl)furan amide; I-124: N-(1-((1s,4s)hydroxycyclohexyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide formate; 17609606_1 ters) P106926.NZ I-125: N-(1-((1s,4s)hydroxycyclohexyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide; I-126: N-(1-((1r,4r)hydroxycyclohexyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide formate; I-127: N-(1-((1r,4r)hydroxycyclohexyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide; I-128: 5-(1H-pyrazolyl)-N-(3-(pyridinyl)(3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol- 4-yl)furancarboxamide formate; I-129: 5-(1H-pyrazolyl)-N-(3-(pyridinyl)(3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol- 4-yl)furancarboxamide; I-130: (1r,4r)ethoxycyclohexyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide formate; I-131: N-(1-((1r,4r)ethoxycyclohexyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide; I-132: N-(1-((1S,3R)ethoxycyclopentyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol ancarboxamide formate; I-133: N-(1-((1S,3R)ethoxycyclopentyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide; I-134: N-(1-((1S,3R)hydroxycyclopentyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide formate; I-135: N-(1-((1S,3R)hydroxycyclopentyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide; I-136: N-(1-((1S,3S)hydroxycyclopentyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide formate; I-137: N-(1-((1S,3S)hydroxycyclopentyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide; I-138: N-(1-((1s,3s)ethoxycyclobutyl)(5-fluoropyridinyl)-1H-pyrazolyl)(1H-pyrazol- 4-yl)furancarboxamide formate; I-139: N-(1-((1s,3s)ethoxycyclobutyl)(5-fluoropyridinyl)-1H-pyrazolyl)(1H-pyrazol- 4-yl)furancarboxamide; I-140: N-(1-((1S,3R)ethoxyfluorocyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H- pyrazolyl)furancarboxamide e; I-141: N-(1-((1S,3R)ethoxyfluorocyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H- lyl)furancarboxamide; I-142: N-(1-((1s,3s)ethoxycyclobutyl)(3-fluoropyridinyl)-1H-pyrazolyl)(1H-pyrazol- urancarboxamide formate; I-143: N-(1-((1s,3s)ethoxycyclobutyl)(3-fluoropyridinyl)-1H-pyrazolyl)(1H-pyrazol- 4-yl)furancarboxamide; 17609606_1 (GHMatters) P106926.NZ I-144: N-(1-((1s,3s)ethoxycyclobutyl)(6-fluoropyridinyl)-1H-pyrazolyl)(1H-pyrazol- 4-yl)furancarboxamide formate; I-145: N-(1-((1s,3s)ethoxycyclobutyl)(6-fluoropyridinyl)-1H-pyrazolyl)(1H-pyrazol- 4-yl)furancarboxamide; I-146: pyrazolyl)-N-(3-(pyridinyl)((1s,3s)(2,2,2-trifluoroethoxy)cyclobutyl)-1H- pyrazolyl)furancarboxamide formate; I-147: 5-(1H-pyrazolyl)-N-(3-(pyridinyl)((1s,3s)(2,2,2-trifluoroethoxy)cyclobutyl)-1H- pyrazolyl)furancarboxamide; I-148: N-(1-((1s,3s)ethoxycyclobutyl)(4-fluoropyridinyl)-1H-pyrazolyl)(1H-pyrazol- 4-yl)furancarboxamide formate; I-149: N-(1-((1s,3s)ethoxycyclobutyl)(4-fluoropyridinyl)-1H-pyrazolyl)(1H-pyrazol- 4-yl)furancarboxamide; I-150: 6-fluoropyridinyl)((1s,3s)(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol yl)(1H-pyrazolyl)furancarboxamide formate; I-151: N-(3-(6-fluoropyridinyl)((1s,3s)(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol yl)(1H-pyrazolyl)furancarboxamide; I-152: N-(3-(3-fluoropyridinyl)((1s,3s)(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol yl)(1H-pyrazolyl)furancarboxamide formate; I-153: N-(3-(3-fluoropyridinyl)((1s,3s)(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol (1H-pyrazolyl)furancarboxamide; I-154: N-(1-((1r,4r)ethoxycyclohexyl)(3-fluoropyridinyl)-1H-pyrazolyl)(1H-pyrazol- 4-yl)furancarboxamide formate; I-155: N-(1-((1r,4r)ethoxycyclohexyl)(3-fluoropyridinyl)-1H-pyrazolyl)(1H-pyrazol- 4-yl)furancarboxamide; or I-156: N-(3-(3,6-difluoropyridinyl)((1s,3s)ethoxycyclobutyl)-1H-pyrazolyl)(1H- pyrazolyl)furancarboxamide.

Exemplary embodiments of a compound ing to formula 1 also include: II-1: N-(1-(2-hydroxymethylpropyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide; II-2: 1-(isobutyryloxy)ethyl 4-(4-((1-methyl(pyridinyl)-1H-pyrazolyl)carbamoyl)thiazol yl)-1H-pyrazolecarboxylate; II-3: tert-butyl (R)-(3-methyl(4-(4-((1-methyl(pyridinyl)-1H-pyrazol yl)carbamoyl)thiazolyl)-1H-pyrazolyl)oxobutanyl)carbamate; II-4: 2-(1-((5-methyloxo-1,3-dioxolyl)methyl)-1H-pyrazolyl)-N-(1-methyl(pyridin yl)-1H-pyrazolyl)thiazolecarboxamide; II-5: 1-methylcyclopropyl 4-(4-((1-methyl(pyridinyl)-1H-pyrazolyl)carbamoyl)thiazol yl)-1H-pyrazolecarboxylate; 17609606_1 ters) P106926.NZ II-6: 1-((4-methoxybenzyl)oxy)methylpropanyl 4-(4-((1-methyl(pyridinyl)-1H-pyrazol- arbamoyl)thiazolyl)-1H-pyrazolecarboxylate; II-7: l ((4-(4-((1-methyl(pyridinyl)-1H-pyrazolyl)carbamoyl)thiazolyl)-1H- pyrazolyl)methyl)phosphonate; II-8: sodium ((4-(4-((1-methyl(pyridinyl)-1H-pyrazolyl)carbamoyl)thiazolyl)-1H- lyl)methyl)phosphonate; II-9: ((4-(4-((1-methyl(pyridinyl)-1H-pyrazolyl)carbamoyl)thiazolyl)-1H-pyrazol yl)methyl)phosphonic acid; II-10: 2 -(1H-pyrazolyl)-N-(3-(pyridinyl)(tetrahydro-2H-pyranyl)-1H-pyrazol yl)thiazolecarboxamide; II-11: N-(1-((1,3-cis)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide; II-12: N-(1-((1,3-trans)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide; II-13: N-(1-((1,3-cis)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(1-methyl-1H- pyrazolyl)thiazolecarboxamide; II-14: N-(1-((1,3-cis)hydroxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide; II-15: N-(1-((1s,3s)(dimethylamino)cyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H- pyrazolyl)thiazolecarboxamide; II-16: (4-(4-((1-((1,3-cis)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)carbamoyl)thiazol- 2-yl)-1H-pyrazolyl)methyl phosphate bis-sodium salt; II-17: (4-(4-((1-((1s,3s)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)carbamoyl)thiazol yl)-1H-pyrazolyl)methyl dihydrogen phosphate; II-18: N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole carboxamide, formic acid salt; II-19: N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(5-(trifluoromethyl)-1H-pyrazol azolecarboxamide, formic acid salt; II-20: N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(5-(trifluoromethyl)-1H-pyrazol yl)thiazolecarboxamide; II-21: N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(3-methyl-1H-pyrazol yl)thiazolecarboxamide, formic acid salt; II-22: N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(3-methyl-1H-pyrazol yl)thiazolecarboxamide; II-23: 2-(3,5-dimethyl-1H-pyrazolyl)-N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazol yl)thiazolecarboxamide, formic acid salt; II-24: 2-(3,5-dimethyl-1H-pyrazolyl)-N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazol yl)thiazolecarboxamide; 17609606_1 (GHMatters) P106926.NZ II-25: N -(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole carboxamide; II-26: N-(1-methyl(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazolecarboxamide; II-27: 2-(3-methyl-1H-pyrazolyl)-N-(1-methyl(pyridinyl)-1H-pyrazolyl)thiazole amide; II-28: N-(1-(2-methoxyethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole carboxamide; II-29: N-(1-(2-methoxyethyl)(pyridinyl)-1H-pyrazolyl)(3-methyl-1H-pyrazol yl)thiazolecarboxamide, formic acid salt; II-30: N-(1-(2-methoxyethyl)(pyridinyl)-1H-pyrazolyl)(3-methyl-1H-pyrazol yl)thiazolecarboxamide; II-31: N -(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(3-methyl-1H-pyrazol yl)thiazolecarboxamide; II-32: 2 yrazolyl)-N-(3-(pyridinyl)-1H-pyrazolyl)thiazolecarboxamide e; II-33: 2-(1H-pyrazolyl)-N-(3-(pyridinyl)-1H-pyrazolyl)thiazolecarboxamide; II-34: N-(1-(oxetanyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole carboxamide; II-35: (4 -(4-((1-methyl(pyridinyl)-1H-pyrazolyl)carbamoyl)thiazolyl)-1H-pyrazol yl)methyl dihydrogen phosphate; II-36: Sodium (4-(4-((1-methyl(pyridinyl)-1H-pyrazolyl)carbamoyl)thiazolyl)-1H- pyrazolyl)methyl phosphate; II-37: N-(1-(2-(2-methoxyethoxy)ethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide; II-38: potassium (4 -(4-((1-methyl(pyridinyl)-1H-pyrazolyl)carbamoyl)thiazolyl)-1H- pyrazolyl)methyl phosphate; II-39: N -(1-(2-(2-methoxyethoxy)ethyl)(pyridinyl)-1H-pyrazolyl)(3-methyl-1H-pyrazol- 4-yl)thiazolecarboxamide e; II-40: N-(1-(2-(2-methoxyethoxy)ethyl)(pyridinyl)-1H-pyrazolyl)(3-methyl-1H-pyrazol- 4-yl)thiazolecarboxamide; II-41: 2-(3-methyl-1H-pyrazolyl)-N-(1-(oxetanyl)(pyridinyl)-1H-pyrazolyl)thiazole- 4-carboxamide, formic acid salt; II-42: 2-(3-methyl-1H-pyrazolyl)-N-(1-(oxetanyl)(pyridinyl)-1H-pyrazolyl)thiazole- 4-carboxamide; II-43: 2 -(1H-pyrazolyl)-N-(3-(pyridinyl)(tetrahydrofuranyl)-1H-pyrazolyl)thiazole carboxamide formate; II-44: 2-(1H-pyrazolyl)-N-(3-(pyridinyl)(tetrahydrofuranyl)-1H-pyrazolyl)thiazole carboxamide; 17609606_1 (GHMatters) P106926.NZ II-45: 2 -(3-methyl-1H-pyrazolyl)-N-(3-(pyridinyl)((tetrahydro-2H-pyranyl)methyl)-1H- pyrazolyl)thiazolecarboxamide formate; II-46: 2-(3-methyl-1H-pyrazolyl)-N-(3-(pyridinyl)((tetrahydro-2H-pyranyl)methyl)-1H- pyrazolyl)thiazolecarboxamide; II-47: N-(1-((3-(hydroxymethyl)oxetanyl)methyl)(pyridinyl)-1H-pyrazolyl)(3- methyl-1H-pyrazolyl)thiazolecarboxamide e; II-48: N-(1-((3-(hydroxymethyl)oxetanyl)methyl)(pyridinyl)-1H-pyrazolyl)(3- methyl-1H-pyrazolyl)thiazolecarboxamide; II-49: N-(1-(2-(diethylamino)ethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole- 4-carboxamide, formic acid salt; II-50: 2-(diethylamino)ethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole- 4-carboxamide; II-51: 2 -(1-(4-methoxybenzyl)-1H-pyrazolyl)-N-(1-(3-methoxycyclobutyl)(pyridinyl)-1H- pyrazolyl)thiazolecarboxamide; II-52: N -fluoroethyl)(pyridinyl)-1H-pyrazolyl)(1-(4-methoxybenzyl)-1H-pyrazol- 4-yl)thiazolecarboxamide; II-53: 2 -methoxybenzyl)-1H-pyrazolyl)-N-(3-(pyridinyl)-1H-pyrazolyl)thiazole carboxamide; II-54: tert-Butyl[4-{2-(1H-pyrazoleyl)thiazolecarboxamido}(pyridineyl)-1H-pyrazol- 1-yl]azetidinecarboxylate, free base; II-55: N-{1-(Azetidinyl)(pyridineyl)-1H-pyrazolyl}(1H-pyrazolyl)thiazole carboxamide, TFA salt; II-56: N-{1-(Azetidinyl)(pyridineyl)-1H-pyrazolyl}(1H-pyrazolyl)thiazole carboxamide; II-57: N-{1-(3-Methoxycyclobutyl)(pyridineyl)-1H-pyrazolyl}(1H-pyrazol yl)thiazolecarboxamide, free base, Cis isomer; II-58: N-(3-(5-methoxypyridinyl)methyl-1H-pyrazolyl)(1H-pyrazolyl)thiazole carboxamide; II-59: N-(1-isopropyl(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole carboxamide; II-60: N-(1-(2-morpholinoethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole carboxamide; II-61: N-(1-(2-(4-methylpiperazinyl)ethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide; II-62: N-(1-((1s,3s)ethoxycyclobutyl)(trifluoromethyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide; II-63: N-(1-methyl(trifluoromethyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole carboxamide 2,2,2-trifluoroacetate; 17609606_1 (GHMatters) P106926.NZ II-64: N-(1-methyl(trifluoromethyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole carboxamide; II-65: N-(3-(3-fluoropyridinyl)((1s,3s)hydroxycyclobutyl)-1H-pyrazolyl)(1H- pyrazolyl)thiazolecarboxamide; II-66: 2-(1H-pyrazolyl)-N-(3-(pyridinyl)(2-(2,2,2-trifluoroethoxy)ethyl)-1H-pyrazol yl)thiazolecarboxamide; II-67: (2-(1H-pyrazolyl)thiazolyl)(2-((1s,3s)ethoxycyclobutyl)-2,5,6,7-tetrahydro-4H- pyrazolo[4,3-b]pyridinyl)methanone; II-68: (2-(1H-pyrazolyl)thiazolyl)(2-((1s,3s)ethoxycyclobutyl)-2,5,6,7-tetrahydro-4H- lo[4,3-b]pyridinyl)methanone 2,2,2-trifluoroacetate; II-69: (2-(1H-pyrazolyl)thiazolyl)(1-(3-ethoxycyclobutyl)-1,5,6,7-tetrahydro-4H- pyrazolo[4,3-b]pyridinyl)methanone trifluoroacetate; II-70: N-(3-carbamoyl((1s,3s)ethoxycyclobutyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide; II-71: N-(1-((1s,3s)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(5-fluoro((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazolyl)thiazolecarboxamide; II-72: N-(1-((1s,3s)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(5-fluoro-1H-pyrazol- 4-yl)thiazolecarboxamide; II-73: N-(1-((1s,3s)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(5-fluoro-1H-pyrazol- 4-yl)thiazolecarboxamide formate; II-74: N-(1-((1s,3s)ethoxycyclobutyl)(1,3,4-oxadiazolyl)-1H-pyrazolyl)(1H-pyrazol- 4-yl)thiazolecarboxamide; II-75: N-(3-(1,3,4-oxadiazolyl)(tetrahydro-2H-pyranyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide; II-76: N-(1-((1s,3s)isopropoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol azolecarboxamide; II-77: potassium (4-(4-((1-((1s,3s)ethoxycyclobutyl)(pyridinyl)-1H-pyrazol yl)carbamoyl)thiazolyl)-1H-pyrazolyl)methyl phosphate; II-78: calcium (4-(4-((1-((1s,3s)ethoxycyclobutyl)(pyridinyl)-1H-pyrazol yl)carbamoyl)thiazolyl)-1H-pyrazolyl)methyl phosphate; II-79: N-(1-((1r,3r)hydroxymethylcyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H- pyrazolyl)thiazolecarboxamide; II-80: ammonium (4-(4-((1-((1s,3s)ethoxycyclobutyl)(pyridinyl)-1H-pyrazol bamoyl)thiazolyl)-1H-pyrazolyl)methyl phosphate; II-81: 5-aminocarboxypentanaminium (4-(4-((1-((1s,3s)ethoxycyclobutyl)(pyridin yl)-1H-pyrazolyl)carbamoyl)thiazolyl)-1H-pyrazolyl)methyl phosphate; II-82: 1-(4-aminocarboxybutyl)guanidinium (4-(4-((1-((1s,3s)ethoxycyclobutyl)(pyridin yl)-1H-pyrazolyl)carbamoyl)thiazolyl)-1H-pyrazolyl)methyl ate; 17609606_1 (GHMatters) P106926.NZ II-83: (4-(4-((1-((1s,3s)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)carbamoyl)thiazol -pyrazolyl)methyl dihydrogen phosphate; II-84: 1,3-dihydroxy(hydroxymethyl)propanaminium (4-(4-((1-((1s,3s)ethoxycyclobutyl)- idinyl)-1H-pyrazolyl)carbamoyl)thiazolyl)-1H-pyrazolyl)methyl hydrogen phosphate; II-85: ylammonium (4-(4-((1-((1s,3s)ethoxycyclobutyl)(pyridinyl)-1H-pyrazol yl)carbamoyl)thiazolyl)-1H-pyrazolyl)methyl hydrogen phosphate; II-86: N-(1-((1s,3s)ethoxycyclobutyl)(5-(trifluoromethyl)pyridinyl)-1H-pyrazolyl) (1H-pyrazolyl)thiazolecarboxamide; II-87: N-(1-(3-hydroxymethylcyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide; II-88: N-(1-(difluoromethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole carboxamide; II-89: N-(1-((1s,3s)ethoxycyclobutyl)(3-(trifluoromethyl)pyridinyl)-1H-pyrazolyl) (1H-pyrazolyl)thiazolecarboxamide; II-90: N-(1-((1s,3s)ethoxycyclobutyl)(6-(trifluoromethyl)pyridinyl)-1H-pyrazolyl) (1H-pyrazolyl)thiazolecarboxamide; II-91: N-(1-((1s,3s)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(3-(trifluoromethyl)- 1H-pyrazolyl)thiazolecarboxamide; II-92: N-(1-((1s,3s)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(3-methyl-1H- pyrazolyl)thiazolecarboxamide; II-93: 2-(3,5-dimethyl-1H-pyrazolyl)-N-(1-((1s,3s)ethoxycyclobutyl)(pyridinyl)-1H- lyl)thiazolecarboxamide; II-94: 2-(1H-pyrazolyl)-N-(3-(pyridinyl)(2,2,2-trifluoroethyl)-1H-pyrazolyl)thiazole carboxamide; II-95: N-(1-(difluoromethyl)(pyridinyl)-1H-pyrazolyl)(3-(trifluoromethyl)-1H-pyrazol- 4-yl)thiazolecarboxamide; II-96: N-(1-(difluoromethyl)(pyridinyl)-1H-pyrazolyl)(3-methyl-1H-pyrazol yl)thiazolecarboxamide; II-97: N-(1-(difluoromethyl)(pyridinyl)-1H-pyrazolyl)(1-(2,2,2-trifluoroethyl)-1H- pyrazolyl)thiazolecarboxamide; II-98: 2-(1-(difluoromethyl)-1H-pyrazolyl)-N-(1-(difluoromethyl)(pyridinyl)-1H-pyrazol- 4-yl)thiazolecarboxamide; II-99: N-(1-((1s,3s)ethoxycyclobutyl)(6-(trifluoromethyl)pyridinyl)-1H-pyrazolyl)(3- -1H-pyrazolyl)thiazolecarboxamide; II-100: 2-(3-methyl-1H-pyrazolyl)-N-(3-(pyridinyl)(2,2,2-trifluoroethyl)-1H-pyrazol yl)thiazolecarboxamide; II-101: N-(1-((1s,3s)hydroxycyclobutyl)(pyrazinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide; 17609606_1 (GHMatters) P106926.NZ II-102: N-(1-((1s,3s)ethoxycyclobutyl)(pyrimidinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide; II-103: 2-(1-(4-methoxybenzyl)-1H-pyrazolyl)-N-(3-(pyridinyl)(3,3,3-trifluoro hydroxypropyl)-1H-pyrazolyl)thiazolecarboxamide formate; II-104: 2-(1-(4-methoxybenzyl)-1H-pyrazolyl)-N-(3-(pyridinyl)(3,3,3-trifluoro hydroxypropyl)-1H-pyrazolyl)thiazolecarboxamide; II-105: N-(1-(dimethylcarbamoyl)(pyridinyl)-1H-pyrazolyl)(1-(4-methoxybenzyl)-1H- lyl)thiazolecarboxamide formate; II-106: N-(1-(dimethylcarbamoyl)(pyridinyl)-1H-pyrazolyl)(1-(4-methoxybenzyl)-1H- pyrazolyl)thiazolecarboxamide; II-107: 2-(1-(4-methoxybenzyl)-1H-pyrazolyl)-N-(3-(pyridinyl)(3,3,3-trifluorohydroxy- 2-(trifluoromethyl)propyl)-1H-pyrazolyl)thiazolecarboxamide formate; II-108: 2-(1-(4-methoxybenzyl)-1H-pyrazolyl)-N-(3-(pyridinyl)(3,3,3-trifluorohydroxy- 2-(trifluoromethyl)propyl)-1H-pyrazolyl)thiazolecarboxamide; II-109: N-(1-(2-ethoxyethyl)(thiazolyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole carboxamide formate; : N-(1-(2-ethoxyethyl)(thiazolyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole amide; II-111: 2-(1H-pyrazolyl)-N-(1-(tetrahydro-2H-pyranyl)(thiazolyl)-1H-pyrazol yl)thiazolecarboxamide formate; II-112: 2-(1H-pyrazolyl)-N-(1-(tetrahydro-2H-pyranyl)(thiazolyl)-1H-pyrazol yl)thiazolecarboxamide; II-113: N-(1-(2-(2-methoxyethoxy)ethyl)(thiazolyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide formate; II-114: N-(1-(2-(2-methoxyethoxy)ethyl)(thiazolyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide; II-115: 2-(1H-pyrazolyl)-N-(1-(tetrahydrofuranyl)(thiazolyl)-1H-pyrazolyl)thiazole- 4-carboxamide formate; II-116: 2-(1H-pyrazolyl)-N-(1-(tetrahydrofuranyl)(thiazolyl)-1H-pyrazolyl)thiazole- 4-carboxamide; II-117: N-(1-(2-(diethylamino)ethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide; II-118: N-(1-(2-(2-fluoroethoxy)ethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol azolecarboxamide formate; : N-(1-(2-(2-fluoroethoxy)ethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide; II-120: N-(1-benzyl(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazolecarboxamide; 17609606_1 (GHMatters) P106926.NZ II-121: N clobutyl(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole carboxamide; II-122: N-(1-(2-(2,2-difluoroethoxy)ethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide; II-123: ((1r,3r)hydroxycyclobutyl)methyl)(pyridinyl)-1H-pyrazolyl)(1H- pyrazolyl)thiazolecarboxamide formate; II-124: N-(1-(((1r,3r)hydroxycyclobutyl)methyl)(pyridinyl)-1H-pyrazolyl)(1H- lyl)thiazolecarboxamide; II-125: N-(1-(dimethylcarbamoyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole- 4-carboxamide formate; II-126: N-(1-(dimethylcarbamoyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole- 4-carboxamide; II-127: N-(1-((1s,3s)(ethoxy-d5)cyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide; II-128: N-(1-(diethylcarbamoyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole carboxamide; II-129: N-(1-(morpholinecarbonyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide; II-130: N-(1-((1s,3s)(2-fluoroethoxy)cyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H- lyl)thiazolecarboxamide; II-131: N-(1-(morpholinecarbonyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide formate; II-132: 3-fluorocyclobutenyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide; II-133: N-(1-(3-fluorocyclobutenyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide formate; II-134: N-(1-(3,3-difluorocyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide formate; II-135: N-(1-(3,3-difluorocyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide; : N-(3-cyano((1s,3s)hydroxycyclobutyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole- 4-carboxamide; II-137: N-(3-cyanomethyl-1H-pyrazolyl)(1H-pyrazolyl)thiazolecarboxamide; II-138: N-(3-cyano((1s,3s)ethoxycyclobutyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole carboxamide; II-139: N-(3-cyano((1s,3s)ethoxycyclobutyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole carboxamide formate; 17609606_1 (GHMatters) P106926.NZ II-140: N-(3-(3-fluoropyridinyl)(1,4-dioxaspiro[4.5]decanyl)-1H-pyrazolyl)(1H- pyrazolyl)thiazolecarboxamide; II-141: 2-(1H-pyrazolyl)-N-(3-(pyridinyl)((1r,3r)(2,2,2-trifluoroethoxy)cyclobutyl)-1H- lyl)thiazolecarboxamide formate; II-142: 2-(1H-pyrazolyl)-N-(3-(pyridinyl)((1r,3r)(2,2,2-trifluoroethoxy)cyclobutyl)-1H- lyl)thiazolecarboxamide; II-143: N-(1-((1r,4r)hydroxycyclohexyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide formate; II-144: N-(1-((1r,4r)hydroxycyclohexyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide; II-145: N-(1-((1r,4r)ethoxycyclohexyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide formate; II-146: N-(1-((1r,4r)ethoxycyclohexyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide; : N-(1-((1S,3R)ethoxycyclopentyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide formate; II-148: N-(1-((1S,3R)ethoxycyclopentyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide; II-149: N-(1-((1S,3R)hydroxycyclopentyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide formate; II-150: N-(1-((1S,3R)hydroxycyclopentyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide; II-151: N-(1-((1S,3S)hydroxycyclopentyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide formate; II-152: N-(1-((1S,3S)hydroxycyclopentyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide; II-153: (1s,3s)ethoxycyclobutyl)(5-fluoropyridinyl)-1H-pyrazolyl)(1H- pyrazolyl)thiazolecarboxamide formate; II-154: (1s,3s)ethoxycyclobutyl)(5-fluoropyridinyl)-1H-pyrazolyl)(1H- pyrazolyl)thiazolecarboxamide; : N-(1-((1S,3R)ethoxyfluorocyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H- pyrazolyl)thiazolecarboxamide formate; II-156: N-(1-((1S,3R)ethoxyfluorocyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H- pyrazolyl)thiazolecarboxamide; II-157: N-(1-((1s,3s)ethoxycyclobutyl)(3-fluoropyridinyl)-1H-pyrazolyl)(1H- pyrazolyl)thiazolecarboxamide; II-158: N-(1-((1s,3s)ethoxycyclobutyl)(4-fluoropyridinyl)-1H-pyrazolyl)(1H- pyrazolyl)thiazolecarboxamide formate; 17609606_1 (GHMatters) P106926.NZ II-159: N-(1-((1s,3s)ethoxycyclobutyl)(4-fluoropyridinyl)-1H-pyrazolyl)(1H- pyrazolyl)thiazolecarboxamide; II-160: N-(1-((1s,3s)ethoxycyclobutyl)(6-fluoropyridinyl)-1H-pyrazolyl)(1H- pyrazolyl)thiazolecarboxamide; II-161: 2-(1H-pyrazolyl)-N-(3-(pyridinyl)((1s,3s)(2,2,2-trifluoroethoxy)cyclobutyl)-1H- pyrazolyl)thiazolecarboxamide formate; : 2-(1H-pyrazolyl)-N-(3-(pyridinyl)((1s,3s)(2,2,2-trifluoroethoxy)cyclobutyl)-1H- pyrazolyl)thiazolecarboxamide; II-163: (4-(4-((1-((1s,3s)ethoxycyclobutyl)(3-fluoropyridinyl)-1H-pyrazol yl)carbamoyl)thiazolyl)-1H-pyrazolyl)methyl dihydrogen phosphate;\ II-164: sodium (4-(4-((1-((1s,3s)ethoxycyclobutyl)(3-fluoropyridinyl)-1H-pyrazol yl)carbamoyl)thiazolyl)-1H-pyrazolyl)methyl phosphate; II-165: N-(3-(3-fluoropyridinyl)((1s,3s)(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol yl)(1H-pyrazolyl)thiazolecarboxamide formate; II-166: N-(3-(3-fluoropyridinyl)((1s,3s)(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol yl)(1H-pyrazolyl)thiazolecarboxamide; : N-(3-(3-fluoropyridinyl)((1r,3r)(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol (1H-pyrazolyl)thiazolecarboxamide formate; II-168: N-(3-(3-fluoropyridinyl)((1r,3r)(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol yl)(1H-pyrazolyl)thiazolecarboxamide; II-169: N-(1-((1r,4r)ethoxycyclohexyl)(3-fluoropyridinyl)-1H-pyrazolyl)(1H- pyrazolyl)thiazolecarboxamide; II-170: N-(3-(6-fluoropyridinyl)((1s,3s)(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol yl)(1H-pyrazolyl)thiazolecarboxamide formate; : N-(3-(6-fluoropyridinyl)((1s,3s)(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol yl)(1H-pyrazolyl)thiazolecarboxamide; II-172: N-(3-(6-fluoropyridinyl)((1s,3s)hydroxycyclobutyl)-1H-pyrazolyl)(1H- pyrazolyl)thiazolecarboxamide; II-173: (4-(4-((1-((1s,3s)ethoxycyclobutyl)(6-fluoropyridinyl)-1H-pyrazol yl)carbamoyl)thiazolyl)-1H-pyrazolyl)methyl dihydrogen phosphate; II-174: N-(3-(3,6-difluoropyridinyl)((1s,3s)ethoxycyclobutyl)-1H-pyrazolyl)(1H- pyrazolyl)thiazolecarboxamide; II-175: N-(1-((1s,4s)ethoxycyclohexyl)(3-fluoropyridinyl)-1H-pyrazolyl)(1H- pyrazolyl)thiazolecarboxamide; : N-(3-(3,6-difluoropyridinyl)((1r,4r)ethoxycyclohexyl)-1H-pyrazolyl)(1H- pyrazolyl)thiazolecarboxamide; : N-(3-(3,6-difluoropyridinyl)((1s,4s)ethoxycyclohexyl)-1H-pyrazolyl)(1H- pyrazolyl)thiazolecarboxamide; 17609606_1 (GHMatters) P106926.NZ : N-(1-((1r,4r)ethoxycyclohexyl)(1,3,4-oxadiazolyl)-1H-pyrazolyl)(1H-pyrazol- 4-yl)thiazolecarboxamide; II-179: (1r,4r)((2,2-difluoroethyl)amino)cyclohexyl)(pyrimidinyl)-1H-pyrazolyl)- 2-(1H-pyrazolyl)thiazolecarboxamide; or II-180: N-(3-(3,5-difluoropyridinyl)((1r,4r)ethoxycyclohexyl)-1H-pyrazolyl)(1H- pyrazolyl)thiazolecarboxamide.

In other embodiments, the compound according to formula 1 is III-1: 2-(1-(cyclopropylmethyl)-1H-pyrazolyl)-N-(1-methyl(pyridinyl)-1H-pyrazol yl)oxazolecarboxamide; III-2: 2-(1H-pyrazolyl)-N-(3-(pyridinyl)(tetrahydro-2H-pyranyl)-1H-pyrazol yl)oxazolecarboxamide; III-3: 2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)oxazole carboxamide; III-4: N-(1-((1s,3s)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)oxazolecarboxamide; III-5: N-(1-cyclobutyl(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)oxazole carboxamide; III-6: N-(1-(2-(2-methoxyethoxy)ethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)oxazolecarboxamide; III-7: N-(1-(2-(2,2-difluoroethoxy)ethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)oxazolecarboxamide; or III-8: N-(1-(2-(2,2-difluoroethoxy)ethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)oxazolecarboxamide.

B. Synthesis Disclosed pyrazole compounds can be prepared as exemplified below, and as will be understood by a person of ordinary skill in the art in organic synthesis. An ary synthesis may include the following 1st reaction step according to Scheme 1: Scheme 1 17609606_1 (GHMatters) P106926.NZ Acetyl nd 2 is reacted with dimethylformamide dimethylacetal 4 to form ediate compound 6, at a temperature suitable to tate a reaction. A suitable temperature is lly from 85 °C to 130 °C. ediate compound 6 is then reacted with hydrazine e 8 to form the le compound 10. The on is performed in a suitable solvent, for example, an alcohol such as ethanol, methanol or isopropanol, and is typically heated, such as to reflux.

A 2nd on step in the exemplary synthesis is provided below according to Scheme 2: Scheme 2 Compound 10 is nitrated using a suitable ing 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 the nitric acid are added slowly, one to the other. Cooling, such as by an ice bath, may be used to maintain the reaction temperature within a suitable range, such as from about 0 °C to less than 50 °C, from 0 °C to 20 °C, or from 0 °C to 10 °C. After the addition is complete the reaction is allowed to proceed until the reaction is substantially complete, and may be allowed to warm to room temperature to facilitate the reaction. Optionally, additional nitrating reagent, or mixture of nitrating reagents, may be added to facilitate the reaction proceeding to completion.

The reaction is then quenched, such as by addition to water and/or ice, and the product is separated or ted from the aqueous and purified if required. Purification techniques suitable for purifying a product from any reaction disclosed herein include, but are not limited to, llization, distillation and/or chromatography.

With continued reference to Scheme 2, compound 14 is then reacted with compound 16 to form compound 18. nd 16 comprises a desired R1 moiety and a le leaving group, LG. Suitable leaving groups include any group that will act as a g group to facilitate the addition of the R1 moiety to compound 14. Suitable leaving groups include, but are not limited to, halogens, typically bromo, chloro or iodo, and te or mesylate groups. Compound 14 is reacted with compound 16 in a suitable solvent and typically in the ce 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-methyl pyrrolidone, or combinations thereof. Suitable bases include any base that will facilitate the reactions, such as a hydride, typically sodium hydride, or a carbonate, such as potassium carbonate, sodium carbonate, or cesium carbonate. The reaction may be heated, such as to 50 °C, 100 °C or higher, as required , or the reaction may 17609606_1 (GHMatters) P106926.NZ proceed at room temperature. Compound 18 is then isolated from the on mixture and purified if required.

Compound 18 is then reacted with a reducing agent 20 suitable 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; a borohydride, such as sodium borohydride, optionally in the presence of a st, 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 a palladium on carbon catalyst, and in a suitable solvent, such as ethyl acetate or ol. In some embodiments, a combination of reducing agents and/or techniques are used. For example, reduction may be initially med using a first method comprising a first ng agent and/or technique, but result in a mixture of products. The first method may be repeated, and/or a second method may be performed, comprising a second reducing agent and/or technique. Once the reaction is complete, as indicated by an analytical technique such as LC-MS, TLC or HPLC, the product compound 22 is ed and purified if necessary.

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

Compound 26 is then coupled with compound 28 to form compound 30 using any coupling reaction suitable to form a bond between two rings. In the example above, a boronic acid coupling is shown, where the leaving group LG on compound 26 is typically bromo or iodo. Other suitable coupling functional groups include trialkyl tin or boronic esters. The ng reaction typically proceeds in the presence of a suitable catalyst. For a boronic acid ng, the catalyst typically is a palladium catalyst, such as PdCl2(dppf)2, Pd[P(Ph)3]2Cl2, palladium acetate and triphenyl phosphine, or tetrakis(triphenylphosphine)palladium(0).

The reaction is performed in the presence of a base, such as sodium, potassium or cesium carbonate, and is performed in a suitable solvent or solvent mixture, such as dioxane, dioxane/water or DME/ethanol/water.

The reaction may be heated at a suitable temperature, such as from 50 °C to 125 °C, typically about 100 °C, and/or agitated for a suitable period of time, such as from 1 hour to 3 days, from 6 hours to 24 hours, or from 17609606_1 (GHMatters) P106926.NZ 12 hours to 18 hours, to facilitate the reaction proceeding to completion. Compound 30 is then isolated from the on mixture and purified by a suitable technique.

An ative exemplary synthesis may include the following 1st reaction step according to Scheme Scheme 4 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, ally in the presence of sulfuric acid. Typically, nd 32 and the nitric acid are added slowly, one to the other. Cooling, such as by an ice bath, may be used to maintain the reaction temperature within a suitable range, such as from about 0 °C to less than 50 °C, from 0 °C to 20 °C, or from 0 °C to 10 °C. After the addition is te the reaction is allowed to proceed until the reaction is substantially complete, and may be allowed to warm to room temperature to facilitate the reaction. Optionally, additional nitrating reagent, or mixture of ing reagents, may be added to facilitate the reaction proceeding to completion.

The reaction is then quenched, such as by addition to water and/or ice, and the product is separated or ted from the aqueous and purified if required. Purification techniques suitable for purifying a product from any reaction disclosed herein include, but are not limited to, crystallization, distillation and/or chromatography.

With continued reference to Scheme 4, compound 36 is then reacted with compound 38 to form compound 40. Compound 38 comprises a d ring, such as a utyl, cyclopentyl, or cyclohexyl ring, and a le g group, LG. Suitable leaving groups include any group that will act as a leaving group to facilitate the addition of the ring to compound 36. Suitable leaving groups include, but are not limited to, halogens, typically bromo, chloro or iodo, and tosylate or mesylate groups. Compound 36 is reacted with compound 38 in a suitable solvent and typically in the presence of a base. Suitable solvents include any solvent that facilitates the on, such as aprotic solvents. Suitable solvents include, but are not limited to, DMF, THF, DMSO, acetonitrile, chlorinated solvents such as dichloromethane and chloroform, DMA, e, yl pyrrolidone, or combinations thereof. Suitable bases include any base that will facilitate the reactions, such as a hydride, typically sodium hydride, or a carbonate, such as potassium carbonate, sodium carbonate, or cesium carbonate. The reaction may be heated, such as to 50 °C, 100 °C or higher, as ed, or the reaction may proceed at room temperature. Compound 40 is then isolated from the reaction mixture and purified if required. 17609606_1 (GHMatters) P106926.NZ Compound 40 is then reacted with a reducing agent 42 le to reduce the carbonyl moiety to a hydroxyl. Suitable reducing agents include, but are not limited to, sodium borohydride, di-isobutyl aluminum hydride, or m aluminum hydride. The reaction is performed in a solvent suitable to facilitate the on, such as an alcohol, particularly methanol or ethanol; THF; or diethyl ether. The reaction may be heated, such as to 50 °C, 100 °C or higher, as required, cooled, such as to below 20 °C, below 10 °C, below 0 °C or lower, or the reaction may proceed at room temperature. Once the reaction is complete, as indicated by an analytical technique such as LC-MS, TLC or HPLC, the product compound 44 is isolated and purified if necessary, by a le que, such as column chromatography.

Optionally, nd 44 may be reacted with compound 46 to form compound 48. Compound 46 comprises a desired Rx moiety and a suitable leaving group, LG. Suitable leaving groups e any group that will act as a leaving group to facilitate the addition of the Rx moiety to compound 44. Suitable leaving groups include, but are not limited to, halogens, typically bromo, chloro or iodo, and tosylate or mesylate . Compound 44 is reacted with compound 46 in a le t and typically in the presence of a base or other reagent or reagents that facilitate the on. 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 romethane and chloroform, DMA, dioxane, N- methyl pyrrolidone, or combinations thereof. Suitable bases or reagents that facilitate the reaction include, but are not limited to, silver triflate, -t-butylpyridine, sodium hydride, or combinations thereof.

Typically, compound 46 is slowly combined with the reaction. Cooling, such as by an ice bath, may be used to maintain the on temperature within a suitable range, such as from about 0 °C to less than 50 °C, from 0 °C to 20 °C, or from 0 °C to 10 °C. After the addition is complete the reaction is allowed to proceed until the reaction is substantially te, and may be d to warm to room temperature, or the reaction may be heated, such as to 50 °C, 100 °C or higher, to facilitate the reaction. Once the reaction is complete, as indicated by an analytical technique 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.

Alternatively, compound 40 may be prepared by an exemplary synthetic route according to Scheme Scheme 5 With respect to Scheme 5, compound 36 is reacted with compound 50 to form nd 52. Compound 50 comprises a desired ring, such as a cyclobutyl, cyclopentyl, or cyclohexyl ring, a suitable leaving group, LG, and a protected yl moiety, such as an acetal or a ketal. In the example above a cyclic ketal moiety is 17609606_1 (GHMatters) P106926.NZ shown. Suitable leaving groups include any group that will act as a leaving group to facilitate the addition of the ring to nd 36, and include, but are not d to, halogens, typically bromo, chloro or iodo, and tosylate or mesylate groups. Compound 36 is reacted with compound 50 in a suitable solvent and lly in the presence of a base. le ts include any solvent that facilitates the on, such as c solvents. Suitable solvents include, but are not d to, DMF, THF, DMSO, acetonitrile, chlorinated solvents such as dichloromethane and chloroform, DMA, dioxane, N-methyl pyrrolidone, or combinations thereof. Suitable bases include any base that will facilitate the reactions, such as a hydride, typically sodium e, or a carbonate, such as potassium carbonate, sodium carbonate, or cesium carbonate. The on may be heated, such as to 50 °C, 100 °C or higher, as required, or the reaction may proceed at room temperature. nd 52 is then isolated from the on mixture and purified if required by a suitable technique, such as column chromatography.

Compound 52 is then reacted with a suitable reagent 54 to form compound 40. Reagent 54 may be any reagent le to remove the protecting group and/or form the carbonyl moiety. In the exemplary synthesis shown in Scheme 5, the protecting group is a cyclic ketal, and suitable ts 54 include, but are not limited to, pyridinium tosylate (PPTS), para-toluene sulfonic acid, hydrochloric acid, or acetic acid. The reaction is performed in a solvent or mixture of solvents suitable to facilitate the reaction, such as e, THF, acetic acid, water, or a combination thereof. The reaction may be heated, such as to 50 °C, 100 °C or higher, or at reflux, as required, or the reaction may proceed at room temperature. Compound 40 is then isolated from the reaction mixture and purified if required by a suitable technique, such as column chromatography.

A 2nd step of the exemplary reaction sequence is provided below according to Scheme 6: Scheme 6 Compound 48 is then reacted with a reducing agent 56 suitable to reduce the nitro moiety to an amine. In certain embodiments where the desired product compound comprises a hydroxyl moiety, compound 44 may 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; a borohydride, such as sodium borohydride, optionally in the presence of a st, 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 a palladium on carbon catalyst, and in a suitable solvent, such as ethyl acetate or methanol. In some embodiments, a combination of reducing agents and/or techniques are used. For example, reduction may be initially performed using a first method sing a first reducing agent and/or technique, but result in a 17609606_1 (GHMatters) P106926.NZ e of products. The first method may be repeated, and/or a second method may be performed, comprising a second reducing agent and/or technique. Once the reaction is complete, as indicated by an analytical technique such as LC-MS, TLC or HPLC, the product compound 58 is isolated and purified if necessary.

Compound 58 is reacted with a carboxylic acid 60 to form compound 62. The carboxylic acid 60 is ted by any le method and then reacted with the amine on compound 58. Suitable activation methods e, but are not limited to: forming the acid chloride by treatment with thionyl chloride; by treatment with 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid uorophosphate (HATU) and a base such as diisopropylethylamine (DIPEA); by treatment with carbonyldiimidazole (CDI); or by treatment with a carbodiimide, such as dicyclohexylcarbodiimide (DCC) or 1-Ethyl(3-dimethylaminopropyl)carbodiimide (EDC).

Compound 62 is then coupled with compound 64 to form compound 66 using any coupling reaction suitable to form a bond between two rings. In the example above, a boronic ester ng is shown, where the leaving group LG on compound 62 is typically bromo or iodo. Other suitable coupling functional groups include trialkyl tin or boronic acids. The coupling reaction typically proceeds in the presence of a suitable catalyst. For a boronic ester or boronic acid coupling, the catalyst typically is a ium catalyst, such as PdCl2(dppf)2, Pd[P(Ph)3]2Cl2, palladium acetate and triphenyl phosphine, or tetrakis(triphenylphosphine)palladium(0). The reaction is med in the presence of a base, such as sodium, potassium or cesium ate, and is performed in a suitable t or solvent mixture, such as dioxane, dioxane/water or DME/ethanol/water. The reaction may be heated at a suitable temperature, such as from 50 °C to 125 °C, typically about 100 °C, and/or agitated for a suitable period of time, such as from 1 hour to 3 days, from 6 hours to 24 hours, or from 12 hours to 18 hours, to facilitate the on proceeding to completion. nd 66 is then isolated from the reaction mixture and purified by a suitable technique.

Certain embodiments may comprise a phosphate moiety. Scheme 7 provides an exemplary synthesis of certain such embodiments: 17609606_1 ters) P106926.NZ Scheme 7 nd 68 is reacted with compound 70 to form compound 72. Compound 70 comprises desired Ry moieties and a suitable leaving group, LG. Typical Ry moieties e, but are not limited to aliphatic, such as alkyl, typically methyl, ethyl, , isopropyl or t-butyl; aryl; heteroaliphatic; or heterocyclic. The two Ry moieties may be the same or different. Suitable leaving groups include, but are not limited to, halogens, typically bromo, chloro or iodo, and te or mesylate groups. Compound 68 is reacted with compound 70 in a suitable solvent and 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- methyl pyrrolidone, or ations thereof. le bases include any base that will facilitate the reactions, such as a hydride, typically sodium hydride, or a carbonate, such as potassium carbonate, sodium carbonate, or cesium carbonate. The reaction may be heated, such as to 50 °C, 100 °C or higher, as required , or the reaction may proceed at room temperature. Compound 72 is then isolated from the reaction mixture and purified if required.

Compound 72 is then reacted with compound 74 to form compound 76. Compound 74 may be any compound suitable to form the acid moieties in compound 76. Comp ound 74 may be an acidic reagent, such as trifluoroacetic acid, hloride acid, or hydrobromic acid, or it may 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 may be heated, such as to 50 °C, 100 °C or higher, as required, cooled, such as to below 20 °C, below 10 °C, below 0 °C or lower, or the reaction may proceed at room temperature. Once the reaction is complete, as ted by an ical technique such as LC-MS, TLC or HPLC, the product nd 76 is isolated and purified if necessary, by a suitable technique, such as by ing, such as by stirring or tion, in a suitable solvent or solvent . Suitable solvents or solvent systems include, but are not limited to, acetone/water, e, diethyl ether, or l/water.

Compound 76 is then reacted with compound 78 to form the salt compound 80. Compound 78 can be any compound that will e a suitable counterion CA for the salt nd 80, such as m hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonia, trimethylamine, tris(hydroxymethyl)aminomethane, or an amino acid such as lysine or arginine. A person of ry skill in the art will appreciate that if counter ion CA has a single ve charge, as in Na+, K+, Li+, or NH4+, then compound 80 will comprise two CA ions, whereas if counter ion CA has two ve charges, as in CA2+ compound 80 will comprise one CA ion.

C. Combinations of Therapeutic Agents The pyrazole compounds of the present invention may be used alone, in combination with one another, or as an adjunct to, or in combination with, other established therapies. In another aspect, the compounds of the present invention may be used in combination with other therapeutic agents useful for the 17609606_1 (GHMatters) P106926.NZ disorder or condition being treated. These compounds may be stered simultaneously, sequentially in any order, by the same route of stration, or by a different route.

In some embodiments, the second eutic agent is an analgesic, an antibiotic, an anticoagulant, an antibody, an anti-inflammatory agent, an immunosuppressant, a guanylate cyclase-C t, an intestinal secretagogue, an ral, anticancer, antifungal, or a combination thereof. The anti-inflammatory agent may be a steroid or a nonsteroidal anti-inflammatory agent. In certain embodiments, the nonsteroidal antiinflammatory agent is selected from aminosalicylates, cyclooxygenase inhibitors, enac, etodolac, famotidine, fenoprofen, flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin, meclofenamate, mefenamic acid, meloxicam, nambumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin, or a combination thereof. In some embodiments, the immunosuppressant is mercaptopurine, a corticosteroid, an alkylating agent, a calcineurin inhibitor, an inosine monophosphate dehydrogenase inhibitor, antilymphocyte globulin, antithymocyte in, an anti-T-cell antibody, or a combination thereof. In one embodiment, the antibody is infliximab.

In some ments, the present compounds may be used with other anti-cancer or cytotoxic agents. Various classes of anti-cancer and anti-neoplastic compounds include, but are not d to, alkylating agents, antimetabolites, BCL-2 inhibitors, vinca alkyloids, taxanes, antibiotics, enzymes, cytokines, platinum coordination complexes, proteasome inhibitors, substituted ureas, kinase inhibitors, hormones and hormone antagonists, and hypomethylating agents, for e DNMT inhibitors, suchas azacitidine and decitabine. Exemplary alkylating agents include, t limitation, mechlorothamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, ethyleneimines, methylmelamines, alkyl ates (e.g., an), and carmustine. Exemplary antimetabolites include, by way of example and not tion, folic acid analog methotrexate; pyrmidine analog fluorouracil, cytosine arbinoside; purine analogs mercaptopurine, thioguanine, and azathioprine. Exemplary vinca alkyloids include, by way of example and not limitation, vinblastine, stine, paclitaxel, and colchicine. Exemplary antibiotics include, by way of example and not limitation, actinomycin D, daunorubicin, and bleomycin. An exemplary enzyme effective as an anti-neoplastic agent includes L-asparaginase. Exemplary coordination compounds include, by way of example and not limitation, cisplatin and carboplatin. Exemplary hormones and hormone related compounds include, by way of example and not tion, adrenocorticosteroids prednisone and dexamethasone; aromatase inhibitors amino glutethimide, formestane, and anastrozole; progestin nds hydroxyprogesterone te, medroxyprogesterone; and anti-estrogen compound tamoxifen.

These and other useful anti-cancer compounds are described in Merck Index, 13th Ed. (O'Neil M. J. et al., ed.) Merck Publishing Group (2001) and n and ’s The Pharmacological Basis of Therapeutics, 12th Edition, Brunton L.L. ed., Chapters 60-63, McGraw Hill, (2011), both of which are incorporated by reference herein.

Among the CTLA 4 antibodies that can be used in combination with the presently disclosed inhbitors is ipilimumab, marketed as YERVOY® by Bristol-Myers Squibb.

Other chemotherapeutic agents for combination include immunooncology agents, such as oint y inhibitors, for example, PD-1 inhibitors, such as nivolumab and lambrolizumab, and 17609606_1 ters) P106926.NZ PD-L1 inhibitors, such as pembrolizumab, MEDI-4736 and MPDL3280A/RG7446. Additional checkpoint inhibitors for combination with the compounds disclosed herein include, Anti-LAG-3 agents, such as BMS- 986016 (MDX-1408).

Further chemotherapeutic agents for combination with the presently disclosed tors include Anti-SLAMF7 agents, such as the humanized monoclonal antibody elotuzumab (BMS-901608), anti-KIR agents, such as the anti-KIR monoclonal antibody lirilumab (BMS-986015), and anti-CD137 agents, such as the fully human monoclonal antibody ab (BMS-663513).

Additional anti-proliferative compounds useful in combination with the nds of the present invention include, by way of example and not limitation, antibodies directed against growth factor receptors (e.g., anti-Her2); and cytokines such as interferon-α and interferon-γ, interleukin-2, and GM-CSF.

Additional chemotherapeutic agents useful in ation with the present le nds e proteasome inhibitors, such as bortezomib, carfilzomib, mib and the like.

Examples of kinase inhibitors that are useful in combination with the presently disclosed compounds, ularly in treating malignancies e, Btk inhibitors, such as ibrutinib, CDK inhibitors, such as palbociclib, EGFR inhibitors, such as afatinib, nib, gefitinib, lapatinib, tinib and vandetinib, Mek inhibitors, such as trametinib, Raf inhibitors, such as dabrafenib, sorafenib and fenib, VEGFR inhibitors, such as axitinib, lenvatinib, nintedanib, pazopanib, BCR-Abl inhibitors, such as bosutinib, dasatinib, imatinib and nilotinib, Syk inhibitors, such as fostamatinib, and JAK inhibitors, such as ruxolitinib, In other embodiments, the second therapeutic agent may be ed from any of the following: analgesics-morphine, fentanyl, hydromorphone, oxycodone, codeine, acetaminophen, hydrocodone, buprenorphine, tramadol, axine, flupirtine, meperidine, pentazocine, dextromoramide, dipipanone; antibiotics-aminoglycosides (e.g., amikacin, gentamicin, kanamycin, neomycin, netilmicin, tobramycin, and paromycin), carbapenems (e.g., ertapenem, doripenem, imipenem, cilastatin, and meropenem), cephalosporins (e.g., cefadroxil, cefazolin, cefalotin, exin, cefaclor, cefamandole, tin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, and cefobiprole), glycopeptides (e.g., teicoplanin, vancomycin, and telavancin), lincosamides (e.g., mycin and incomysin), lipopeptides) e.g., daptomycin), macrolides romycin, clarithromycin, dirithromycin, omycin, roxithromycin, troleandomycin, telithromycin, and spectinomycin), monobactams (e.g., aztreonam), nitrofurans (e.g., furazolidone and nitrofurantoin), penicilllins (e.g., amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, acillin, flucloxacillin, mezlocillin, methicillin, nafcillin, oxacillin, penicillin G, llin V, piperacillin, temocillin, and ticarcillin), penicillin combinations (e.g., amoxicillin/clavulanate, ampicillin/sulbactam, piperacillin/tazobactam, and ticarcillin/clavulanate), polypeptides (e.g., bacitracin, colistin, and polymyxin B), quinolones (e.g., ciprofloxacin, enoxacin, gatifloxacin, oxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin, and temafloxacin), amides (e.g., mafenide, sulfonamidochrysoidine, sulfacetamide, sulfadiazine, silver sulfadiazine, sulfamethizole, sulfamethoxazole, sulfanilimide, sulfasalazine, 17609606_1 (GHMatters) P106926.NZ oxazole, trimethoprim, and trimethoprim-sulfamethoxaxzole), yclines (e.g., demeclocycline, doxycycline, minocycline, oxytetracycline, and tetracycline), antimycobacterial compounds (e.g., clofazimine, dapsone, capreomycin, cycloserine, ethambutol, ethionamide, isoniazid, pyrazinamide, rifampicin (rifampin), rifabutin, rifapentine, and streptomycin), and others, such as arsphenamine, chloramphenicol, fosfomycin, fusidic acid, linezolid, metronidazole, mupirocin, platensimycin, quinuprisin/dalfopristin, rifaximin, thiamphenicol, tigecycline, and timidazole; antibodies-anti-TNF-α antibodies, e.g., infliximab (RemicadeTM), adalimumab, mab, certolizumab; anti-B cell antibodies, e.g., rituximab; anti-IL-6 dies, e.g., tocilizumab; anti-IL-1 antibodies, e.g., anakinra; anti PD-1 and/or anti-PD-L1 antibodies, e.g. nivolumab, pembrolizumab, pidilizumab, BMS-936559, MPDL3280A, AMP-224, MEDI4736; ixekizumab, brodalumab, ofatumumab, sirukumab, clenoliximab, clazakiumab, fezakinumab, fletikumab, mavrilimumab, ocrelizumab, sarilumab, secukinumab, toralizumab, zanolimumab; anticoagulants-warfarin dinTM), acenocoumarol, phenprocoumon, atromentin, phenindione, n, fondaparinux, rinux, rivaroxaban, apixaban, n, lepirudin, bivalirudin, argatrobam, dabigatran, ximelagatran, batroxobin, hementin; anti-inflammatory agents-steroids, e.g., budesonide, nonsteroidal anti-inflammatory agents, e.g., aminosalicylates (e.g., sulfasalazine, mesalamine, olsalazine, and balsalazide), cyclooxygenase inhibitors (COX-2 inhibitors, such as rofecoxib, celecoxib), enac, etodolac, famotidine, ofen, flurbiprofen, ketoprofen, ketorolac, fen, thacin, meclofenamate, mefenamic acid, meloxicam, nambumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, in; immunosuppressants-mercaptopurine, corticosteroids such as dexamethasone, hydrocortisone, prednisone, methylprednisolone and prednisolone, ting agents such as cyclophosphamide, calcineurin inhibitors such as cyclosporine, sirolimus and tacrolimus, inhibitors of inosine monophosphate dehydrogenase (IMPDH) such as mycophenolate, mycophenolate mofetil and azathioprine, and agents designed to suppress cellular immunity while leaving the recipient's humoral logic response intact, including various antibodies (for example, antilymphocyte in (ALG), ymocyte globulin (ATG), monoclonal anti-T-cell antibodies (OKT3)) and irradiation. Azathioprine is currently available from Salix Pharmaceuticals, Inc. under the brand name Azasan; mercaptopurine is currently available from Gate Pharmaceuticals, Inc. under the brand name Purinethol; prednisone and solone are currently available from Roxane Laboratories, Inc.; Methyl prednisolone is currently available from Pfizer; sirolimus (rapamycin) is currently available from Wyeth-Ayerst under the brand name Rapamune; tacrolimus is tly available from Fujisawa under the brand name Prograf; cyclosporine is current available from Novartis under the brand name mune and Abbott under the brand name Gengraf; IMPDH tors such as mycophenolate mofetil and mycophenolic acid are currently available from Roche under the brand name Cellcept and Novartis under the brand name Myfortic; oprine is currently available from Glaxo Smith Kline under the brand name Imuran; and antibodies are currently available from Ortho Biotech under the brand name Orthoclone, Novartis under the brand name Simulect (basiliximab) and Roche under the brand name Zenapax (daclizumab); and 17609606_1 ters) P106926.NZ Guanylate cyclase-C receptor agonists or intestinal secretagogues--for example linaclotide, sold under the name Linzess.

These various agents can be used in accordance with their standard or common dosages, as specified in the prescribing information accompanying commercially available forms of the drugs (see also, the ibing information in the 2006 Edition of The Physician's Desk Reference), the disclosures of which are incorporated herein by reference.

D. Compositions Comprising Pyrazole nds The disclosed pyrazole nds may be used alone, in any combination, and in combination with, or adjunctive to, at least one second eutic agent, and r the pyrazole compounds, and the at least one second therapeutic, may be used in combination with any suitable additive useful for forming compositions for stration to a subject. Additives can be included in pharmaceutical compositions for a variety of purposes, such as to dilute a composition for delivery to a subject, to facilitate processing of the formulation, to e advantageous material properties to the formulation, to facilitate dispersion from a delivery device, to stabilize the formulation (e.g., antioxidants or buffers), to provide a pleasant or palatable taste or tency to the formulation, or the like. Typical additives include, by way of example and without limitation: pharmaceutically acceptable excipients; pharmaceutically acceptable carriers; and/or adjuvants, such as mono-, di-, and polysaccharides, sugar ls and other polyols, such as, e, glucose, raffinose, tose, lactitol, maltitol, trehalose, sucrose, mannitol, starch, or combinations thereof; surfactants, such as sorbitols, diphosphatidyl choline, and lecithin; bulking agents; buffers, such as phosphate and citrate buffers; anti-adherents, such as magnesium stearate; binders, such as saccharides (including disaccharides, such as sucrose and lactose,), polysaccharides (such as starches, cellulose, rystalline cellulose, cellulose ethers (such as hydroxypropyl cellulose), gelatin, tic polymers (such as polyvinylpyrrolidone, polyalkylene gylcols); coatings (such as cellulose ethers, including hydroxypropylmethyl cellulose, shellac, corn protein zein, and gelatin); e aids (such as enteric coatings); disintegrants (such as crospovidone, crosslinked sodium ymethyl cellulose, and sodium starch glycolate); fillers (such as dibasic calcium phosphate, vegetable fats and oils, e, sucrose, glucose, mannitol, sorbitol, calcium carbonate, and magnesium stearate); flavors and sweeteners (such as mint, cherry, anise, peach, apricot or ce, raspberry, and vanilla; lubricants (such as minerals, exemplified by talc or silica, fats, exemplified by vegetable stearin, magnesium stearate or c acid); 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 methyl paraben and propyl paraben); nts; compression aids; fying agents; encapsulation agents; gums; granulation agents; and combinations thereof.

III. Methods of Use A. Diseases/Disorders 17609606_1 (GHMatters) P106926.NZ The disclosed pyrazole compounds, as well as combinations and/or compositions thereof, may be used to rate, treat or prevent a variety of diseases and/or disorders. In particular embodiments, the pyrazole nd, ations of pyrazole compounds, or compositions f, may be used to treat or prevent auto-immune diseases, inflammatory disorders, cardiovascular diseases, nerve disorders, neurodegenerative ers, allergic disorders, asthma, pancreatitis, organ failure, kidney diseases, platelet aggregation, cancer, lantation, sperm motility, erythrocyte deficiency, graft rejection, lung injuries, respiratory diseases, ischemic conditions, and bacterial and viral infections.

In some embodiments, the pyrazole compound, combinations of pyrazole compounds, or compositions thereof, may be used to treat or t allergic diseases, amyotrophic lateral sclerosis (ALS), systemic lupus erythematosus, rheumatoid arthritis, type I diabetes mellitus, inflammatory bowel disease, y cirrhosis, uveitis, multiple sclerosis, Crohn's disease, ulcerative colitis, s pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, r's granulomatosis, ichthyosis, Graves ophthalmopathy or asthma.

The pyrazole compound, combinations of le compounds, or compositions thereof, may also be useful for ameliorating, treating or preventing immune regulatory disorders related to bone marrow or organ transplant rejection or graft-versus-host disease. Examples of inflammatory and immune regulatory disorders that can be treated with the present nds include, but are not limited to, transplantation of organs or tissue, graft-versus-host diseases t about by transplantation, autoimmune syndromes including rheumatoid arthritis, systemic lupus erythematosus, oto's thyroiditis, multiple sclerosis, ic sclerosis, enia gravis, type I diabetes, uveitis, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, fectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis, inflammatory and hyperproliferative skin diseases, psoriasis, atopic dermatitis, contact dermatitis, eczematous itis, seborrhoeic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedemas, vasculitis, erythema, cutaneous eosinophilia, lupus erythematosus, acne, alopecia areata, keratoconjunctivitis, vernal conjunctivitis, uveitis associated with 's disease, keratitis, herpetic keratitis, l cornea, dystrophia epithelialis corneae, corneal leukoma, ocular pemphigus, Mooren's ulcer, scleritis, Graves' opthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, pollen allergies, reversible obstructive airway disease, bronchial asthma, ic asthma, intrinsic asthma, extrinsic asthma, dust asthma, chronic or inveterate asthma, late asthma and airway hyper-responsiveness, bronchitis, gastric ulcers, vascular damage caused by ischemic diseases and osis, ic bowel diseases, inflammatory bowel diseases, necrotizing enterocolitis, intestinal lesions associated with thermal burns, celiac diseases, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative s, migraine, rhinitis, eczema, interstitial nephritis, Goodpasture's syndrome, hemolytic-uremic syndrome, diabetic nephropathy, multiple myositis, Guillain-Barre syndrome, Meniere's disease, polyneuritis, multiple neuritis, mononeuritis, radiculopathy, hyperthyroidism, Basedow's disease, pure red cell aplasia, ic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, anerythroplasia, orosis, sarcoidosis, fibroid lung, idiopathic interstitial pneumonia, dermatomyositis, leukoderma 17609606_1 ters) P106926.NZ vulgaris, ichthyosis vulgaris, photoallergic sensitivity, cutaneous T cell lymphoma, chronic lymphocytic leukemia, osclerosis, atherosclerosis, is syndrome, polyarteritis nodosa, myocardosis, scleroderma, Wegener's granuloma, Sjögren's syndrome, adiposis, eosinophilic fascitis, lesions of gingiva, periodontium, alveolar bone, substantia ossea dentis, glomerulonephritis, male pattern alopecia or alopecia s by preventing epilation or providing hair germination and/or promoting hair generation and hair growth, muscular dystrophy, pyoderma and Sezary's syndrome, Addison's disease, ischemia-reperfusion injury of organs which occurs upon preservation, transplantation or ischemic disease, endotoxin-shock, pseudomembranous colitis, colitis caused by drug or radiation, ischemic acute renal insufficiency, chronic renal insufficiency, toxinosis caused by lung-oxygen or drugs, lung , pulmonary emphysema, cataracta, siderosis, tis pigmentosa, senile macular degeneration, l scarring, corneal alkali burn, dermatitis erythema multiforme, linear IgA ballous itis and cement dermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental ion, aging, carcinogenesis, metastasis of oma and hypobaropathy, disease caused by histamine or riene-C4 release, 's e, autoimmune hepatitis, primary y cirrhosis, sclerosing cholangitis, partial liver resection, acute liver necrosis, necrosis caused by toxin, viral hepatitis, shock, or anoxia, B-virus hepatitis, non-A/non-B hepatitis, sis, alcoholic liver disease, including alcoholic cirrhosis, non-alcoholic steatohepatitis (NASH), hepatic failure, fulminant hepatic failure, late-onset hepatic failure, "acute-on-chronic" liver failure, augmentation of chemotherapeutic effect, cytomegalovirus infection, HCMV infection, AIDS, cancer, senile dementia, Parkinson’s disease, trauma, or chronic bacterial infection.

In certain embodiments the present compounds are useful for treating nerve pain, including athic pain and inflammation d pain.

In n embodiments, the le compound, combinations of pyrazole compounds, or compositions thereof, are useful for treating and/or preventing rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis, osteoporosis, systemic sclerosis, multiple sclerosis, psoriasis, in particular pustular psoriasis, type I diabetes, type II diabetes, inflammatory bowel e (Cronh's disease and ulcerative colitis), hyperimmunoglobulinemia d and periodic fever syndrome, cryopyrin-associated periodic syndromes, Schnitzler's syndrome, systemic le thic arthritis, s onset Still's disease, gout, gout flares, pseudogout, sapho syndrome, Castleman's disease, sepsis, stroke, atherosclerosis, celiac disease, DIRA (deficiency of Il-1 receptor antagonist), Alzheimer's disease, Parkinson's disease.

Proliferative diseases that may be treated by the le compound, combinations of pyrazole compounds, or itions thereof, include benign or malignant , solid tumor, carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas, multiple myeloma, gastrointestinal cancer, especially colon oma or colorectal adenoma, a tumor of the neck and head, an epidermal hyperproliferation, psoriasis, te hyperplasia, a sia, a neoplasia of epithelial character, adenoma, arcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small-cell lung carcinoma, lymphomas, Hodgkins and 17609606_1 (GHMatters) P106926.NZ Non-Hodgkins, a mammary carcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, IL-1 driven disorders, a MyD88 driven disorder (such as ABC diffuse large B-cell lymphoma ), ström's macroglobulinemia, Hodgkin's lymphoma, primary cutaneous T-cell lymphoma or chronic lymphocytic leukemia),smoldering or nt multiple a, or hematological malignancies ding leukemia, acute d leukemia (AML), DLBCL, ABC DLBCL, chronic lymphocytic leukemia (CLL), chronic cytic ma, primary effusion lymphoma, Burkitt lymphoma/leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic ma, myelodysplastic syndromes (MDS), myelofibrosis, polycythemia vera, Kaposi’s sarcoma, Waldenström's macroglobulinemia (WM), splenic al zone lymphoma, multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma). In particular, the presently disclosed compounds are useful in treating drug resistant malignancies, such as those resistant to JAK inhibitors ibrutinib resistant malignancies, including ibrutinib resistant hematological malignancies, such as ibrutinib resistant CLL and ibrutinib resistant Waldenström's macroglobulinemia.

Examples of allergic disorders that may be treated using the pyrazole compound, combinations of le compounds, or itions thereof, e, but are not limited to, asthma (e.g. atopic asthma, allergic asthma, atopic bronchial IgE-mediated , non-atopic asthma, bronchial asthma, non-allergic asthma, essential asthma, true asthma, intrinsic asthma caused by pathophysiologic disturbances, essential asthma of unknown or unapparent cause, emphysematous asthma, exercise-induced asthma, emotioninduced asthma, extrinsic asthma caused by environmental factors, cold air induced asthma, occupational asthma, infective asthma caused by or associated with bacterial, , protozoal, or viral infection, incipient , wheezy infant syndrome, bronchiolitis, cough variant asthma or drug-induced asthma), allergic bronchopulmonary aspergillosis (ABPA), allergic rhinitis, perennial allergic rhinitis, perennial rhinitis, vasomotor rhinitis, post-nasal drip, purulent or non-purulent sinusitis, acute or chronic sinusitis, and ethmoid, frontal, maxillary, or sphenoid sinusitis.

As another example, rheumatoid arthritis (RA) typically results in swelling, pain, loss of motion and tenderness of target joints throughout the body. RA is characterized by chronically inflamed synovium that is densely crowded with lymphocytes. The synovial membrane, which is typically one cell layer thick, becomes intensely cellular and assumes a form r to lymphoid tissue, including dendritic cells, T-, B- and NK cells, macrophages and clusters of plasma cells. This process, as well as a plethora of immunopathological mechanisms including the formation of antigen-immunoglobulin complexes, eventually result in destruction of the integrity of the joint, resulting in deformity, permanent loss of function and/or bone erosion at or near the joint. The pyrazole compound, combinations of pyrazole compounds, or compositions thereof, may be used to treat, ameliorate or prevent any one, several or all of these symptoms of RA. Thus, in the t of RA, the compounds are considered to e therapeutic benefit when a reduction or amelioration of any of the symptoms commonly ated with RA is achieved, less of whether the treatment results in a concomitant treatment of the underlying RA and/or a reduction in the amount of circulating rheumatoid factor ("RF"). 06_1 (GHMatters) P106926.NZ The American College of Rheumatology (ACR) has developed criteria for defining improvement and clinical remission in RA. Once such parameter, the ACR20 (ACR criteria for 20% clinical improvement), requires a 20% improvement in the tender and swollen joint count, as well as a 20% improvement in 3 of the following 5 parameters: patient's global assessment, physician's global assessment, patient's assessment of pain, degree of disability, and level of acute phase reactant. These criteria have been expanded for 50% and 70% improvement in ACR50 and ACR70, respectively. Other criteria include Paulu's criteria and radiographic progression (e.g. Sharp score).

In some ments, therapeutic benefit in patients suffering from RA is achieved when the patient exhibits an ACR20. In specific embodiments, ACR improvements of ACRC50 or even ACR70 may be achieved.

B. Formulations and Administration Pharmaceutical compositions comprising the active nds of the ion (or prodrugs thereof) may be manufactured by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilization processes. The compositions may be formulated in conventional manner using one or more physiologically acceptable excipients, diluents, carriers, adjuvants or aries to provide preparations which can be used ceutically.

The active compound or prodrug may be formulated in the pharmaceutical compositions per se, or in the form of a hydrate, solvate, N-oxide or pharmaceutically acceptable salt. Typically, such salts are more soluble in s solutions than the corresponding free acids and bases, but salts having lower solubility than the corresponding free acids and bases may also be formed.

Pharmaceutical compositions of the ion may take a form suitable for virtually any mode of administration, including, for example, topical, ocular, oral, , ic, nasal, injection, such as i.v. or i.p., ermal, rectal, vaginal, etc., or a form suitable for administration by inhalation or insufflation.

For topical administration, the active compound(s), hydrate, solvate, N-oxide or pharmaceutically acceptable salt or prodrug(s) may be formulated as solutions, gels, ointments, creams, suspensions, etc. as are nown in the art.

Systemic formulations include those designed for administration by injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for ermal, ucosal oral or pulmonary stration.

Useful injectable preparations include sterile suspensions, solutions or emulsions of the active compound(s) in aqueous or oily vehicles. The compositions may also n formulating agents, such as suspending, stabilizing and/or dispersing agent. The formulations for injection may be presented in unit dosage form, e.g., in ampules or in multidose containers, and may contain added preservatives.

Alternatively, the injectable formulation may be provided in powder form for reconstitution with a suitable e, ing but not limited to sterile, pyrogen-free water, buffer, dextrose solution, etc., before use. To this end, the active compound(s) maybe dried by any art-known technique, such as lyophilization, and reconstituted prior to use. 17609606_1 (GHMatters) P106926.NZ For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are known in the art.

For oral administration, the pharmaceutical compositions may take the form of, for example, lozenges, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients, such as: binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl cellulose); fillers (e.g., lactose, microcrystalline cellulose or m 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). The tablets may be coated by methods well known in the art with, for example, sugars, films or enteric gs.

Liquid preparations for oral administration may take the form of, for example, elixirs, solutions, syrups or suspensions, or they may be ted as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with ceutically 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, cremophoreTM. or fractionated vegetable oils); and preservatives (e.g., methyl or -phydroxybenzoates or sorbic acid). The preparations may also n buffer salts, vatives, flavoring, coloring and sweetening agents as appropriate.

Preparations for oral administration may be suitably formulated to give controlled release of the active compound or prodrug, as is well known.

For buccal administration, the compositions may take the form of s or lozenges formulated in conventional manner.

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

For nasal administration or administration by inhalation or insufflation, the active compound(s), e, solvate, e, pharmaceutically acceptable salt or g(s) can be conveniently delivered in the form of an aerosol spray from pressurized packs or a zer with the use of a suitable propellant, e.g.,) dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a d amount. Capsules and cartridges for use in an inhaler or insufflator (for e capsules and cartridges comprised of gelatin) may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

A specific example of an aqueous suspension formulation suitable for nasal administration using commercially-available nasal spray devices includes the following ients: 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); carboxymethylcellulose sodium or microcrystalline cellulose (1 15 mg/ml); phenylethanol (1 4 mg/ml); and dextrose (20 50 mg/ml). The pH of the final suspension can be adjusted to range from about pH 5 to pH 7, with a pH of about pH 5.5 being typical. 17609606_1 ters) P106926.NZ Another specific example of an aqueous suspension suitable for administration of the compounds via inhalation contains 20 mg/mL Compound or prodrug, 1% (v/v) Polysorbate 80 (TWEEN® 80), 50 mM citrate and/or 0.9% sodium chloride.

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

For prolonged delivery, the active compound(s) or prodrug(s) can be formulated as a depot ation for administration by implantation or intramuscular injection. The active ingredient maybe formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly e derivatives, e.g., as a sparingly soluble salt. atively, ermal delivery systems manufactured as an adhesive disc or patch which slowly releases the active compound(s) for percutaneous absorption may be used. To this end, permeation enhancers may be used to facilitate transdermal penetration of the active compound(s). Suitable transdermal patches are described in for example, 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; ,163,899; 5,088,977; 240; 110; and 4,921,475, which are incorporated herein by reference. atively, other pharmaceutical delivery systems may be employed. Liposomes and emulsions are nown examples of delivery vehicles that may be used to deliver active compound(s) or g(s).

Certain c solvents, such as dimethylsulfoxide (DMSO), may also be employed, although y at the cost of greater ty.

The ceutical 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, se metal or plastic foil, such as a blister pack. The pack or dispenser device may be anied by instructions for administration.

C. Dosages The pyrazole compound or ations of pyrazole compounds will generally be used in an amount effective to achieve the intended result, for example, in an amount effective to treat or prevent a particular condition. The pyrazole compound(s), or compositions thereof, can be stered therapeutically to achieve therapeutic benefit or prophylactically to achieve prophylactic benefit.

Therapeutic benefit means eradication or amelioration of the underlying disorder being d and/or eradication or amelioration of one or more of the symptoms associated with the underlying disorder such that the patient reports an improvement in feeling or condition, notwithstanding that the t may still be afflicted with the underlying disorder. For example, administration of a compound to a patient suffering from an allergy provides therapeutic benefit not only when the underlying allergic se is eradicated or ameliorated, but also when the patient reports a decrease in the severity or duration of the symptoms associated with the allergy following exposure to the allergen. As another example, therapeutic benefit in 17609606_1 (GHMatters) P106926.NZ the context of asthma includes an improvement in respiration following the onset of an asthmatic attack or a reduction in the frequency or severity of asthmatic episodes. Therapeutic benefit also includes halting or slowing the ssion of the disease, regardless of whether improvement is realized.

As known by those of ordinary skill in the art, the red dosage of le compounds will also depend on various factors, including the age, weight, general health, and severity of the ion of the patient or subject being d. Dosage may also need to be tailored to the sex of the individual and/or the lung capacity of the dual, when administered by tion. Dosage may also be tailored to individuals suffering from more than one condition or those individuals who have additional conditions that affect lung ty and the ability to breathe normally, for e, emphysema, bronchitis, pneumonia, and respiratory infections. Dosage, and frequency of administration of the pyrazole compound(s) or compositions thereof, will also depend on whether the pyrazole compound(s) are formulated for treatment of acute episodes of a condition or for the prophylactic treatment of a er. A person or ordinary skill in the art will be able to determine the optimal dose for a particular individual.

For lactic administration, the pyrazole compound, combinations of pyrazole nds, or compositions thereof, can be administered to a t or subject at risk of developing one of the previously described conditions. For example, if it is unknown whether a patient or subject is allergic to a particular drug, the pyrazole compound, combinations of pyrazole compounds, or compositions thereof, can be administered prior to administration of the drug to avoid or ameliorate an allergic response to the drug.

Alternatively, prophylactic stration can be used to avoid or ameliorate the onset of symptoms in a patient diagnosed with the underlying disorder. For example, a pyrazole compound(s), or composition thereof, can be administered to an allergy sufferer prior to expected exposure to the allergen. A pyrazole nd, combinations of le compounds, or compositions thereof, can also be administered prophylactically to healthy individuals who are repeatedly exposed to agents known to one of the abovedescribed maladies to t the onset of the disorder. For e, a pyrazole compound, combinations of pyrazole compounds, or compositions thereof, can be administered to a healthy individual who is repeatedly exposed to an allergen known to induce allergies, such as latex, in an effort to prevent the individual from developing an y. Alternatively, a pyrazole compound, combinations of pyrazole compounds, or compositions thereof, can be administered to a patient suffering from asthma prior to partaking in activities which trigger asthma s to lessen the severity of, or avoid altogether, an asthmatic episode.

Effective dosages can be estimated initially from in vitro assays. For example, an initial dosage for use in subjects can be formulated to achieve a circulating blood or serum concentration of active compound that is at or above an IC50 or EC50 of the particular compound as measured in an in vitro assay. Dosages can be calculated to e such circulating blood or serum concentrations taking into account the bioavailability of the 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 nces cited n, provide additional guidance concerning effective dosages. 17609606_1 (GHMatters) P106926.NZ In some embodiments, the disclosed compounds have an EC50 from greater than 0 to 20 µM, such as from greater than 0 to 10 µM, from greater than 0 to 5 µM, from greater than 0 to 1 µM, from greater than 0 to 0.5 µM, or from greater than 0 to 0.1 µM.

Initial dosages can also be estimated from in vivo data, such as animal models. Animal models useful for testing the efficacy of compounds to treat or prevent the various diseases bed above are well-known in the art. Suitable animal models of ensitivity or allergic reactions are described in Foster, (1995) Allergy 50(21Suppl):6-9, discussion 34-38 and Tumas et al., (2001), J. Allergy Clin.

Immunol. 107(6):1025-1033. Suitable animal models of ic rhinitis are described in Szelenyi et al., (2000), Arzneimittelforschung 50(11):1037-42; Kawaguchi et al., (1994), Clin. Exp. Allergy 24(3):238-244 and Sugimoto et al., (2000), Immunopharmacology 48(1):1-7. Persons of ordinary skill in the art can adapt such information to determine dosages suitable for human administration.

Dosage amounts of disclosed pyrazole compounds will typically be in the range of from about greater than 0 mg/kg/day, such as 0.0001 mg/kg/day or 0.001 mg/kg/day or 0.01 mg/kg/day, up to at least about 100 day. More typically, the dosage (or effective amount) may range from about 0.0025 mg/kg to about 1 mg/kg administered at least once per day, such as from 0.01 mg/kg to about 0.5 mg/kg or from about 0.05 mg/kg to about 0.15 mg/kg. The total daily dosage lly ranges from about 0.1 mg/kg to about 5 mg/kg 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 per day to about 2.5 mg/kg/day. Dosage amounts can be higher or lower depending upon, among other factors, the activity of the pyrazole compound, its bioavailability, the mode of stration, and various factors discussed above.

Dosage amount and dosage interval can be adjusted for individuals to provide plasma levels of the pyrazole compound that are sufficient to maintain therapeutic or lactic effect. For example, the nds can be stered once per day, multiple times per day, once per week, multiple times per week (e.g., every other day), one per month, multiple times per month, or once per year, depending upon, amongst other things, the mode of administration, the specific indication being treated, and the judgment of the prescribing physician. Persons of ordinary skill in the art will be able to optimize effective local dosages without undue experimentation. itions comprising one or more of the disclosed pyrazole compounds typically comprise from greater than 0 up to 99% of the le compound, or compounds, and/or other therapeutic agent by total weight percent. More lly, compositions comprising one or more of the disclosed pyrazole compounds comprise from about 1 to about 20 total weight percent of the le compound and other therapeutic agent, and from about 80 to about 99 weight percent of a pharmaceutically able additive.

Preferably, the pyrazole compound, ations of pyrazole compounds, or compositions thereof, will provide therapeutic or prophylactic t without causing substantial ty. Toxicity of the pyrazole compound can be determined using standard pharmaceutical procedures. The dose ratio n toxic and therapeutic (or prophylactic) effect is the therapeutic index. Pyrazole compounds that exhibit high therapeutic indices are preferred. 17609606_1 (GHMatters) P106926.NZ IV. Examples Example 1 Preparation of Amine 106: 2-(1H-Pyrazolyl)pyridine (10 g) was suspended in concentrated sulfonic acid (30 mL), then fuming nitric acid (6.5 mL, 2 eq.) was added to the solution dropwise while stirring. The reaction e was stirred ght at room temperature. It was quenched by pouring into ice-water (500 mL). The aqueous solution was neutralized by adding solid sodium carbonate, until pH reached around 8. White precipitate was collected by filtration, washed with water and dried to give 2-(4-nitro-1H-pyrazol yl)pyridine 102 (13 g, 99% yield). 2-(4-nitro-1H-pyrazolyl)pyridine 102 (2 g), and 1-bromoethoxycyclobutane (90% trans isomer, 2 g) were suspended in THF (20 mL) and DMF (10 mL). Sodium hydride (60% in oil, 670 mg, 1.5 eq.) was added to the reaction. The reaction solution was heated at 100 °C for 3 days and then was evaporated. The residue was ed by combiflash chromatography (EtOAc in hexanes = 10 – 100%) to give product 104. nd 104 was dissolved in EtOAc (100 mL) and charged with 10% Pd-C catalyst (200 mg).

The reaction e was shaken under 40 psi hydrogen for 1 hour. LC-MS indicated fully reduction of nitro group. The catalyst was filtered off through celite and washed with EtOAc (5 x 20 mL). The filtrate was concentrated to give amine 106 (1.4 g, 52% yield in two steps). 06_1 (GHMatters) P106926.NZ Example 2 Exemplary synthesis of I-28: N-(1-((1,3-cis)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl) (1H-pyrazolyl)furancarboxamide.

Compound 106 (700 mg), 5-bromofuroic acid (622 mg, 1.2 eq.), and 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) (1.54 g, 1.5 eq.) were dissolved in THF (30 mL) and diisopropylethylamine ) (0.7 mL, 1.5 eq.) was added to the solution. The reaction mixture was d at room temperature overnight and evaporated. The residue was purified by combiflash tography (EtOAc in hexanes = 10 – 100%) to give product 108 (1 g, 87% yield).

Compound 108 (1g), pyrazoleboronic acid (780 mg, 3 eq.), Na2CO3 (2.45 g, 10 eq.) and PdCl2 (dppf)2 (250 mg) were stirred in dioxane (15 mL) and water (15 mL). The reaction mixture was heated at 100 °C overnight. LC-MS indicated fully conversion to the product. The reaction mixture was evaporated and ed by combiflash tography (2.0 M NH3/MeOH in DCM = 0 – 20%) to give desired product I-28 (750 mg, 77% yield). 1H NMR (300 MHz, 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+). 17609606_1 (GHMatters) P106926.NZ Example 3 Preparation of 2-methyl(4-nitro(pyridinyl)-1H-pyrazolyl)propanol (110).

Sodium hydride (1.657 g, 41.4 mmol) was weighed out and added to a dry reaction tube with magnetic stir bar and cooled to 0 ºC. This was carefully suspended in 86 mL THF and the system was purged with nitrogen. 2-(4-Nitro-1H-pyrazolyl)pyridine (3.928 g, 20.7 mmol) was added in 40 mL dimethylformamide followed by 7 mL dimethylformamide washings. This was stirred 30 minutes at 0 ºC ed by 30 s at room temperature. It was then cooled back to 0 ºC and isobutylene oxide (5.5 mL, 61.9 mmol) was added. The reaction was d warming to room temperature, heated 3 hours at 100 ºC and stirred overnight at room temperature. The reaction was recharged with sodium hydride (0.445 g, 11.2 mmol) and isobutylene oxide (1.8 mL, 20.3 mmol) and heated 2 hours more at 100 ºC. The reaction was quenched with water and concentrated to dryness; the residue was partitioned n saturated s sodium bicarbonate and ethyl acetate. The aqueous layer was extracted three times more with ethyl acetate and the combined organic layer was washed with brine and dried over sodium sulfate. Product solution was filtered, concentrated onto silica and purified by column chromatography. After drying, 1.92 g of the title compound 110 was obtained in two batches (35% yield). 1H NMR (300 MHz, DMSO-d 6) 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)+.

Example 4 ation of 1-(4-amino(pyridinyl)-1H-pyrazolyl)methylpropanol 112. 17609606_1 (GHMatters) P106926.NZ 2-Methyl(4-nitro(pyridinyl)-1H-pyrazolyl)propanol 110 (0.994 g, 3.8 mmol) was added to a Parr reaction bottle in 100 mL ethyl acetate. This was put under nitrogen and charged with (wet) % Pd on carbon (0.404 g, 0.2 mmol). This was run at 60 psi hydrogen overnight on the Parr hydrogenator. The reaction was filtered through Celite with methanol washings, concentrated onto silica and purified by column chromatography. 0.723 g of the title compound 112 was obtained after drying on high vacuum (82% . 1H NMR (300 MHz, DMSO-d 6) 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)+.

Example 5 ation of 5-bromo-N-(1-(2-hydroxymethylpropyl)(pyridinyl)-1H-pyrazolyl)furan carboxamide 114. 5-Bromofurancarboxylic acid (0.148 g, 0.77 mmol) was weighed out and added to a flask with ic stir bar. This was dissolved in 33 mL dichloromethane and diisopropylethylamine (0.20 mL, 1.2 mmol) was added followed by HATU (0.381 g, 1.0 mmol). This is stirred 30 minutes at room temperature and 1-(4-amino(pyridinyl)-1H-pyrazolyl)methylpropanol 112 (0.214 g, 0.92 mmol) was added in 13 mL dichloromethane solution. The reaction was stirred overnight at room temperature. This was trated directly onto silica and ed by column chromatography. After drying, 0.358 g of the title compound 114 was obtained. (96% mass balance based on the aminopyrazole; hydroybutyl-related byproducts remained in the purified product. This was used ly.) 1H NMR (300 MHz, DMSO-d 6) 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 isotopes). 17609606_1 (GHMatters) P106926.NZ Example 6 Preparation of I-1: N-(1-(2-hydroxymethylpropyl)(pyridinyl)-1H-pyrazolyl)(1-methyl- 1H-pyrazolyl)furancarboxamide. bromo-N-(1-(2-hydroxymethylpropyl)(pyridinyl)-1H-pyrazolyl)furancarboxamide 114 (49 mg, 0.12 mmol) in 1.7 mL premixed 7/3 dimethoxyethane/ethanol solution was added to a microwave reaction vial with magnetic stir bar. (1-Methyl-1H-pyrazolyl)boronic acid (99 mg, 0.78 mmol) was weighed out and added to the vial. 2M aqueous sodium carbonate solution (0.41 mL, 0.82 mmol) was added and the on was subjected to vigorous subsurface en sparge. Pd[P(Ph)3]2Cl2 (16 mg, 0.02 mmol) was added, the tube was sealed under nitrogen and then heated 30 minutes in the microwave at 130º C. The reaction was worked up in the tube, first diluting with ethyl acetate. This was washed in succession with brine, 1M s sodium hydroxide solution, and brine, pipetting the aqueous layer off the bottom of the tube. The s was back-extracted twice with ethyl acetate and the combined organic layer was dried in a vial over sodium sulfate. The product solution was filtered into another vial, evaporated, and ed by preparative HPLC. After drying, 6 mg of the title compound I-1 was obtained as the TFA salt (10% yield; an additional 12 mg less pure product was recovered). 1H NMR (300 MHz, DMSO-d 6) 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)+. 17609606_1 (GHMatters) P106926.NZ Example 7 ation of I-3: N-(1-(2-hydroxymethylpropyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol- 4-yl)furancarboxamide. bromo-N-(1-(2-hydroxymethylpropyl)(pyridinyl)-1H-pyrazolyl)furancarboxamide 114 (0.289 g, 0.71 mmol) was weighed out and added to a microwave reaction tube with magnetic stir bar. le 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 water and added to the reaction. This was subjected to us sub-surface nitrogen . Pd[P(Ph)3]2Cl2 (60 mg, 0.09 mmol) was added, the tube was sealed under nitrogen and then heated 30 minutes in the microwave at 130º C.

The solution was diluted into ethyl acetate and washed first with brine, then 1M aqueous sodium hydroxide, and again with brine before drying over sodium sulfate. (The base wash was analyzed for desired product to monitor potential loss to the aqueous layer.) Product solution was filtered, concentrated onto silica and purified by column chromatography. 0.180 g of the title compound I-3 was obtained after drying (64% yield). 1H NMR (300 MHz, DMSO-d 6) 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 .

Example 8 Preparation of I-4: tert-butyl 4-(5-((1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazol yl)carbamoyl)furanyl)-1H-pyrazolecarboxylate. -bromo-N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)furancarboxamide (2.435 g, 6.0 mmol) was weighed out and added to a reaction tube with magnetic stir bar. 1-Boc-pyrazoleboronic acid pinacol ester (3.535 g, 12.0 mmol) was added and these were dissolved in 60 mL dimethylformamide. 17609606_1 (GHMatters) P106926.NZ Cesium carbonate (3.916 g, 12.0 mmol) was d out and added and the reaction was subjected to us sub-surface nitrogen sparge. Pd(dppf)Cl2•CH2Cl2 (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 a 0.64 mmol pilot reaction run under the same conditions and ed through Celite with ethyl acetate washings. The filtrate was concentrated to dryness and partitioned between ethyl acetate and water. The aqueous layer is extracted three times more with ethyl acetate and the combined organic layer is washed with brine and dried over sodium sulfate. Product solution is filtered, concentrated onto silica and purified by column chromatography. Pure fractions are combined, concentrated and dried on high vacuum to give 2.2 g of the title compound I-4 (69% yield total). 1H NMR (300 MHz, 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)+.

Example 9 Preparation of 2-bromo-N-(1-(2-hydroxymethylpropyl)(pyridinyl)-1H-pyrazolyl)thiazole carboxamide 116. 2-Bromothiazolecarboxylic acid (0.257 g, 1.2 mmol) was weighed out and added to a flask with a magnetic stir bar and taken up in 53 mL 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(pyridinyl)-1H-pyrazolyl)methylpropanol 112 (0.344 g, 1.5 mmol) was added in 21 mL romethane solution and the on was stirred overnight at room temperature. This was trated ly onto silica and purified by column chromatography. Product containing fractions were all found to contain hydroxyazabenzotriazole as a inant. These were concentrated and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was washed with ethyl acetate until product was completely ted. The combined organic layer was washed with brine and dried over sodium sulfate. Filtration, concentration and drying on high vacuum afforded 0.429 g of the pure title compound 114 (82% yield). 1H NMR (300 MHz, DMSO-d 6) 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 isotopes). 06_1 (GHMatters) P106926.NZ Example 10 Preparation of II-1: N-(1-(2-hydroxymethylpropyl)(pyridinyl)-1H-pyrazolyl)(1H- pyrazolyl)thiazolecarboxamide. 2-Bromo-N-(1-(2-hydroxymethylpropyl)(pyridinyl)-1H-pyrazolyl)thiazole carboxamide 116 (0.212 g, 0.50 mmol) was d out and added to a microwave reaction vial with magnetic stir bar. 1-Boc-pyrazoleboronic acid pinacol ester (0.944 g, 3.2 mmol) was added followed by 4.9 mL dimethoxyethane and 2.1 mL ethanol. Sodium carbonate (0.362 g, 3.4 mmol) was dissolved in 1.7 mL water and added to the reaction. The solution was subjected to vigorous sub-surface nitrogen sparge and Pd[P(Ph)3]2Cl2 (60 mg, 0.09 mmol) was added. The tube was sealed under nitrogen and heated 30 minutes in the ave at 130º C.

The solution was diluted into ethyl acetate and washed with saturated aqueous sodium onate and brine.

The emulsified layer was back-extracted three times with ethyl acetate and the combined organic layer was dried over sodium sulfate. This was filtered, concentrated and purified by column chromatography to give 0.160 g of the title compound II-1 after drying (78% yield). 1H NMR (300 MHz, DMSO-d 6) 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)+. 17609606_1 (GHMatters) P106926.NZ Example 11 Preparation of II-11: N-(1-((1,3-cis)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H- pyrazolyl)thiazolecarboxamide.

Compound 106 (680 mg), 2-bromothiazolecarboxylic acid (658 mg, 1.2 eq.), and HATU (1.5 g, 1.5 eq.) were dissolved in THF (30 mL) and DIPEA (0.7 mL, 1.5 eq.) was added to the solution. The reaction mixture was stirred at room temperature overnight and evaporated. The residue was purified by combiflash chromatography (EtOAc in hexanes = 10 – 100%) to give t 118 (980 mg, 83% yield). nd 118 (1g), pyrazoleboronic acid (750 mg, 3 eq.), Na2CO3 (2.37 g, 10 eq.) and PdCl2(dppf)2 (200 mg) were stirred in dioxane (15 mL) and water (15 mL). The reaction mixture was heated at 100 °C overnight. LC-MS indicated fully conversion to the t. The on mixture was evaporated and purified by combiflash chromatography (2.0 M NH3/MeOH in DCM = 0 – 20%) to give desired product II-11 (700 mg, 72% yield). 1H 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+). 17609606_1 (GHMatters) P106926.NZ Example 12 Preparation of 4-nitro(trifluoromethyl)-1H-pyrazole 120. 72 mL concentrated sulfuric acid was added to a flask with magnetic stir bar and cooled to 0oC. 3- (trifluoromethyl)-pyrazole (12.070 g, 88.70 mmol) was weighed out and added gradually. An addition funnel was attached and charged with 90% fuming nitric acid (36 mL, 766 mmol). This was added in dropwise at 0 oC, and the reaction was d warming to room temperature overnight. The reaction was then recharged with the same nitric acid described above (19 mL, 404 mmol) at room temperature and then red. Stirring at room temperature continued overnight.

The on was poured over ice and neutalized by slow addition of 200 g sodium carbonate. The pH was adjusted to 6 with 1M hydrochloric acid and the solution was ted six times with ethyl acetate.

The combined organic layer was dried over sodium sulfate, filtered, and trated to an oil. This crystallized, and the solid was washed with minimal dichloromethane to give 3.250 g of the title nd 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. 1H NMR (300 MHz, DMSO-d 6) δ 9.16 (s, 1H). m/z = 180 (M-H)-.

Example 13 Preparation of 3-(4-nitro(trifluoromethyl)-1H-pyrazolyl)cyclobutanone 122.

Compound 120 (1.2356 g, 6.82 mmol) was dried in the tared on flask and weighed. This was taken up in 22 mL tetrahydrofuran, and a magnetic stir bar was added. 3-Bromocyclobutanone (1.3837 g, 9.29 mmol) was weighed into a tared vial and added to the reaction in 11 mL ydrofuran solution.

Potassium carbonate (1.417 g, 10.25 mmol) was weighed out and added, and the reaction was stirred overnight at room temperature. 17609606_1 (GHMatters) P106926.NZ The reaction was next recharged with ocyclobutanone (1.232 g, 8.27 mmol) in 5 mL tetrahydrofuran and stirred ght at room temperature. The mixture was then concentrated to remove THF, and partitioned between ethyl acetate and water. The aqueous was extracted three times more with ethyl acetate and the combined organic layer was washed with brine and dried over sodium sulfate. This was filtered and concentrated and it spontaneously crystallized. The solid was collected, washed with a minimal volume of dichloromethane and dried on high vacuum to give 677.2 mg of the title compound 122.

A second crop isolated after crystallizing from the filtrate gave 432.2 mg more product 122 (65% yield). A 1D NOE experiment confirmed the N1 assignment of the pyrazole alkylation. 1H NMR (300 MHz, DMSO-d 6) δ 9.44 (s, 1H), 5.34 (p, J = 6.9 Hz, 1H), 3.67 (d, J = 6.7 Hz, 4H). Parent ion not observed.

Example 14 Preparation of (1s,3s)(4-nitro(trifluoromethyl)-1H-pyrazolyl)cyclobutanol 124.

Compound 122 (601.0 mg, 2.41 mmol) was dried in the tared reaction flask and weighed. This was dissolved in 12 mL methanol, a magnetic stir bar was added, and the solution was cooled to 0 oC. Sodium borohydride (137.9 mg, 3.64 mmol) was weighed out and added. The reaction was stirred 2 hours at room ature. After HPLC showed completion, this was concentrated onto silica and purified by column tography. After drying, 536.2 mg was ed of the title nd 124 (88% yield). 1H NMR (300 MHz, DMSO-d 6) 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)+.

Example 15 Preparation of 1-((1s,3s)ethoxycyclobutyl)nitro(trifluoromethyl)-1H-pyrazole 126. 17609606_1 (GHMatters) P106926.NZ Compound 124 (189.6 mg, 0.76 mmol) was transferred to a reaction tube with magnetic stir bar in 5 mL dichloromethane. Silver triflate (586.2 mg, 2.28 mmol) was weighed out and added, and -tbutylpyridine was added (0.58 mL, 2.62 mmol). The reaction was cooled to 0 oC and ethyl iodide was added (0.20 mL, 2.50 mmol). The cooling bath was then removed, and it was stirred overnight at room temperature. This reaction was combined with another (46.0 mg, 0.18 mmol) run under the same conditions and filtered through Celite with dichloromethane washings. The filtrate was concentrated onto silica and ed by column chromatography. After drying, 172.8 mg was obtained of the pure title nd 126 (66% yield). 1H NMR (300 MHz, 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)+.

Example 16 Preparation of 1-((1s,3s)ethoxycyclobutyl)(trifluoromethyl)-1H-pyrazolamine 128.

Compound 126 (231.4 mg, 0.83 mmol) was added to a Parr reaction bottle in 30 mL ethyl acetate.

This was put under nitrogen and charged with (wet) 10% Pd on carbon (90.1 mg, 0.04 mmol). This was run at 50 psi hydrogen for 5 hours on the Parr hydrogenator. The reaction was filtered through Celite with ol washings and concentrated to dryness. HPLC showed a complex mixture. 110.6 mg of this residue was dissolved in 10 mL ol. NiCl2• x hydrate (400.1 mg, 1.68 mmol as the hexahydrate) was weighed out and added, and the mixture was cooled to 0 oC. Sodium borohydride (127.4 mg, 3.4 mmol) was weighed out and added slowly, portionwise. The reaction was allowed to stir overnight, warming to room temperature. This was ed h Celite with methanol gs, concentrated onto silica and purified by column chromatography. After drying, 76.2 mg was obtained of the title compound as an oil. (The remainder of the residue recovered from the hydrogenation was reduced using similar conditions and an additional 46.1 mg of the title nd 128 was obtained- 59% yield). 1H NMR (300 MHz, 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)+. 17609606_1 (GHMatters) P106926.NZ Example 17 Preparation of 2-bromo-N-(1-((1s,3s)ethoxycyclobutyl)(trifluoromethyl)-1H-pyrazol yl)thiazolecarboxamide 130. 2-Bromothiazolecarboxylic acid (61.4 mg, 0.30 mmol) was weighed out and added to a flask with a magnetic stir bar and taken up in 12 mL dichloromethane. ropylethylamine (0.077 mL, 0.44 mmol) was added ed 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 in 5 mL dichloromethane solution and the reaction was stirred overnight at room temperature. This was concentrated ly onto silica and purified by column chromatography. trating, then drying the pure fractions on high vacuum afforded 71.0 mg of the title compound 130 (55% yield). 1H NMR (300 MHz, 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, .2, 2.6 Hz, 2H), 1.23 (t, J = 7.0 Hz, 3H). m/z = 439/441 (M+H)+ (bromine isotopes).

Example 18 Preparation of II-62: N-(1-((1s,3s)ethoxycyclobutyl)(trifluoromethyl)-1H-pyrazolyl)(1H- pyrazolyl)thiazolecarboxamide.

Compound 130 (67.7 mg, 0.15 mmol) was transferred to a microwave reaction tube with magnetic stir bar in solution (4.2 mL dimethoxyethane and 3.0 mL ethanol). 1-Boc-pyrazoleboronic acid pinacol ester (290.6 mg, 1.0 mmol) was weighed out and added. Sodium carbonate (109.0 mg, 1.0 mmol) was 06_1 (GHMatters) P106926.NZ weighed into a tared vial, ved in 1.0 mL water, and added to the reaction. The solution was subjected to vigorous sub-surface nitrogen sparge. Pd[P(Ph)3]2Cl2 (18.4 mg, 0.03 mmol) was weighed out and added and the tube was sealed under nitrogen. This was heated 30 minutes at 100 oC in the microwave. 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 layer was washed with brine and dried over sodium sulfate. This was filtered, concentrated and subjected to column chromatography. The purest fractions were concentrated to give a solid which was triturated with acetonitrile and dried on high vacuum to give 8.0 mg of the title compound II-62. (Additional less pure material was recovered.) 1H NMR (300 MHz, 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)+.

Example 19 Preparation of 2-bromo-N-(1-methyl(trifluoromethyl)-1H-pyrazolyl)thiazolecarboxamide 132.

Bromothiazolecarboxylic acid (416.2 mg, 2.00 mmol) was d out and added to a flask with a magnetic stir bar and taken up in 40 mL romethane. 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(trifluoromethyl)-1H-pyrazolamine (329.4 mg, 2.00 mmol) was added in 10 mL dichloromethane solution and the reaction was stirred overnight at room ature. This was concentrated directly onto silica and purified by column tography. After drying, 471.6 mg was obtained of the title compound 132 (66% yield- additional less pure material was recovered). 1H NMR (300 MHz, form-d) δ 9.12 (s, 1H), 8.29 (s, 1H), 8.13 (s, 1H), 3.96 (s, 3H). m/z = 355/357 (M+H)+ ne isotopes). 17609606_1 (GHMatters) P106926.NZ Example 20 Preparation of II-63: N-(1-methyl(trifluoromethyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole carboxamide trifluoroacetate salt.

Compound 132 (100.0 mg, 0.28 mmol) and 1-Boc-pyrazoleboronic acid pinacol ester (531.4 mg, 1.80 mmol) were weighed out and added to a microwave reaction tube with ic stir bar. 7.7 mL dimethoxyethane and 5.5 mL ethanol were added. Sodium carbonate (200.2 mg, 1.89 mmol) was weighed into a tared vial, dissolved in 2.0 mL water, and added to the reaction. The solution was ted to vigorous sub-surface nitrogen sparge. Pd[P(Ph)3]2Cl2 (34.4 mg, 0.05 mmol) was weighed out and added and the tube was sealed under nitrogen. This was heated 30 minutes at 100 oC in the microwave. This was concentrated to remove dimethoxyethane and ethanol and extracted four times with ethyl e. The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. This was ed by preparative HPLC to give compound II-64. After drying, 54.3 mg was obtained of the title compound II-63 as a trifluoroacetic acid salt. 1H NMR (300 MHz, DMSO-d 6) δ 9.61 (s, 1H), 8.32 (s, 1H), 8.25 (s, 2H), 3.95 (s, 3H). m/z = 343 (M+H)+.

Example 21 Preparation of (1s,3s)(4-amino(3-fluoropyridinyl)-1H-pyrazolyl)cyclobutanol 134. (1s,3s)(3-(3-fluoropyridinyl)nitro-1H-pyrazolyl)cyclobutanol (1.070 g, 3.85 mmol) was weighed out and added to a flask with magnetic stir bar, and dissolved in 98 mL ethyl e. This was put under nitrogen and charged with (wet) 10% Pd on carbon (117.8 mg, 0.014 mmol). After thoroughly purging with nitrogen, this was stirred for 3 hours under a balloon of en. The reaction was then filtered through Celite with excess ethyl acetate washings. The te was concentrated and dried to give quantitative recovery of the title compound 134 as a foam. This was used in the next reaction without further purification. 17609606_1 (GHMatters) P106926.NZ 1H NMR (300 MHz, DMSO-d 6) 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)+.

Example 22 Preparation of 2-bromo-N-(3-(3-fluoropyridinyl)((1s,3s)hydroxycyclobutyl)-1H-pyrazol yl)thiazolecarboxamide 136.

Compound 134 (0.96 g, 3.85 mmol) was dried in the tared reaction flask and weighed. This was dissolved in 30 mL dichloromethane, and 10 mL dimethylformamide was added along with a magnetic stir 2-Bromothiazolecarboxylic acid (800.6 mg, 3.85 mmol) was weighed out and added.

Diisopropylethylamine (1.0 mL, 5.7 mmol) was added ed by HATU (1.901 g, 5.00 mmol) and the reaction was stirred at room temperature overnight. This was concentrated directly onto silica and purified by column chromatography. Concentrating, then drying the pure fractions on high vacuum ed 1.158 g of the title nd 136 (69% yield). 1H NMR (300 MHz, DMSO-d 6) 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 isotopes). 17609606_1 (GHMatters) P106926.NZ Example 23 Preparation of II-65: N-(3-(3-fluoropyridinyl)((1s,3s)hydroxycyclobutyl)-1H-pyrazolyl) (1H-pyrazolyl)thiazolecarboxamide.

Compound 136 (0.497 g, 1.13 mmol) was transferred to a microwave reaction tube with magnetic stir bar in solution (13 mL dimethoxyethane and 5.5 mL ethanol). 1-Boc-pyrazoleboronic acid pinacol ester (1.334 g, 4.53 mmol) was weighed out and added. Sodium carbonate (0.480 g, 4.53 mmol) was weighed into a tared vial, dissolved in 4.5 mL water, and added to the reaction. The solution was subjected to vigorous sub-surface en sparge. Pd[P(Ph)3]2Cl2 (79.6 mg, 0.11 mmol) was weighed out and added and the tube was sealed under nitrogen. This was heated 90 minutes at 100 oC in the microwave. This was concentrated to remove dimethoxyethane and ethanol and extracted four times with ethyl acetate. However, there was substantial undissolved solid. This was ted and washed repeatedly with methanol. After drying, this gave 174.0 mg of the title compound at 90% purity.

The combined organic layer from the tion was washed with brine, dried over sodium sulfate, filtered, and combined with the methanol washings of the precipitated solid. The solution was concentrated onto silica and purified by column chromatography. tration of pure fractions gave a solid which was triturated with l dichloromethane. After drying, 169.2 mg was obtained of the pure title nd II-65. 1H NMR (300 MHz, DMSO-d 6) 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)+. 17609606_1 (GHMatters) P106926.NZ Preparation of 2-(4-nitro(1,4-dioxaspiro[4.5]decanyl)-1H-pyrazolyl)pyridine 138.

A stirring suspension of 2-(4-nitro-1H-pyrazolyl)pyridine (950 mg, 5.00 mmol), 1,4- dioxaspiro[4.5]decanyl ylbenzenesulfonate (1.69 g, 5.41 mmol) and Cs2CO3 (2.44 g, 7.50 mmol) in anhydrous THF:DMF (15 mL, 4:1, v/v) was heated to 100 oC and stirred for 16 hours. The on mixture was diluted in water (50 mL), extracted with EtOAc (3 x 50 mL), the organic layer was washed with brine (50 mL), dried over MgSO4, concentrated and column chromatography (0-100 % EtOAc in hexane, gradient) gave compound 138 as a light brown semisolid (910 mg, 55.14 %). MS (m/e): 330.34 (MH+).

Example 25 Preparation of 4-(4-nitro(pyridinyl)-1H-pyrazolyl)cyclohexanone 140.

To a stirring solution of compound 138 (910 mg, 2.75 mmol) in acetone:H2O (20 mL, 1:1, v/v) was added pyridinium p-tolulene sulfonate (1.38 g, 5.50 mmol) and the reaction mixture was heated to 80 oC and d for 16 hours. Acetone was evaporated in vacuo, the aqueous layer was quenched with NaOH to pH = 8, extracted with EtOAc (3 x 50 mL), the organic layer was washed with brine (50 mL), dried over MgSO4, concentrated and column chromatography (0-100 % MeOH in DCM, gradient) gave compound 140 as a dark brown oil (600 mg, 76.08 %). MS (m/e): 286.29 (MH+). 17609606_1 (GHMatters) P106926.NZ Example 26 Preparation of (trans)(4-nitro(pyridinyl)-1H-pyrazolyl)cyclohexanol 142.

NaBH4 (20 mg, 0.524 mmol) was added to a stirring solution of 2 (600 mg, 2.10 mmol) in MeOH (10 mL) at 0 oC, stirred for 0.5 hours, concentrated and column chromatography (0-100 % MeOH (1M NH3 solution) in DCM, gradient) afforded the product 142 as a viscous oil (362 mg, 60 %). 1H 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+).

Example 27 Preparation of 2-(1-((trans)ethoxycyclohexyl)nitro-1H-pyrazolyl)pyridine 146.

NaH (60 % dispersion in mineral oil, 60 mg, 1.50 mmol) was added to a stirring solution of compound 142 (360 mg, 1.25 mmol) and iodoethane (200 L, 2.50 mmol) in anhydrous DMF (8 mL) at -20 oC. The on mixture was allowed to warm to room temperature for 2 hours. The reaction mixture was diluted in water (40 mL), extracted with EtOAc (3 x 50 mL), the organic layer was washed with brine (30 mL), dried over MgSO4, concentrated, and column chromatography (0-100 % EtOAc in hexane, nt) afforded the product 146 as s oil (296 mg, 74.93 %). MS (m/e): 316.36 (MH+). 06_1 (GHMatters) P106926.NZ Example 28 Preparation of ans)ethoxycyclohexyl)(pyridinyl)-1H-pyrazolamine 148.

A solution of compound 146 (290 g, 0.917 mmol) in EtOAc (10 mL) with Pd/C (10 % wt, 50 mg) was hydrogenated under 50 psi H2 (g) for 12 hours, filtered through celite and trated to give compound 148 as a viscous oil (230 mg, 87.61 %). MS (m/e): 286.38 (MH+).

Example 29 Preparation of 2-bromo-N-(1-((trans)ethoxycyclohexyl)(pyridinyl)-1H-pyrazolyl)thiazole carboxamide 150.

HATU (458 mg, 1.20 mmol) was added to a stirring solution of 2-bromothiazole carboxylic acid (184 mg, 0.883 mmol) and DIPEA (280 L, 1.61 mmol) in anhydrous THF (4 mL) at room temperature for 10 minutes, followed by addition of a solution of compound 148 (230 mg, 0.803 mmol) in anhydrous THF (4 mL). After 1 hour, the reaction mixture was d in water (10 mL), extracted with EtOAc (3 x 20 mL), the organic layer was washed with brine (20 mL), dried over MgSO4, concentrated, and column tography (0-100 % EtOAc in hexane, gradient) afforded the product 150 as a semisolid, which was used without further purification. Assumed quantitative yield. MS (m/e): 476.39 (MH+). 17609606_1 (GHMatters) P106926.NZ Example 30 Preparation of II-145: N-(1-((trans)ethoxycyclohexyl)(pyridinyl)-1H-pyrazolyl)(1H- pyrazolyl)thiazolecarboxamide.

A mixture of crude compound 150 (0.803 mmol), 1H-pyrazoleboronic 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 oC and stirred for 16 hours. The reaction mixture was cooled to room temperature, diluted in water (20 mL), extracted with EtOAc (3 x 30 mL), the c layer was washed with brine (20 mL), dried over MgSO4, concentrated, and column tography (0-100 % EtOAc in hexane, gradient) gave a semisolid, which was submitted for analytical cation, followed by lization to afford the title compound II-145 as a white fluffy solid (75 mg, 20.15 %). 1H NMR (300 MHz, DMSO-d 6) 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+).

The following exemplary compounds were prepared using the methods of Examples 1-23.

Characterization data for these additional compounds are provided below.

I-5: N-(1-(2-methoxyethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)furancarboxamide. 1H NMR (DMSO d 6, 300MHz): δ 11.66 (s, 1H), 8.75-8.73 (m, IH), 8.38 (s, IH), 8.12-7.92 (m, 4H), 7.45- 7.41 (m, 1H), 7.29-7.27 (m, IH), 6.79-6.78 (m, IH), 4.37 (t, J = 6.7Hz, 2H), 3.75 (t, J = 6.7Hz, 2H), 3.27 (s, 3H); LCMS (m/z): 379.52 (MH+). 17609606_1 (GHMatters) P106926.NZ I-6: 2-methoxyethyl)(pyridinyl)-1H-pyrazolyl)(3-methyl-1H-pyrazolyl)furan carboxamide Formic Acid.

LCMS (m/z): 393.49 (MH+).

I-7: N-(1-(2-methoxyethyl)(pyrimidinyl)-1H-pyrazolyl)(1H-pyrazolyl)furan carboxamide.

LCMS (m/z): 380.54 (MH+).

I-8: N -(1-(2-methoxyethyl)(pyrimidinyl)-1H-pyrazolyl)(3-methyl-1H-pyrazolyl)furan carboxamide. 1H NMR (DMSO d 6, 300MHz): δ 11.09 (s, 1H), 8.93 (d, J = 3.3Hz, 2H), 8.46 (s, IH), 7.49 (t, J = 6.7Hz, 1H), 7.33 (d, J = 3.3Hz, 1H), 6.70 (d, J = 3.3Hz, 1H), 4.40 (t, J = 6.7Hz, 2H), 3.76 (t, J = 6.7Hz, 2H), 3.27 (s, 3H), 2.50 (s, 3H); LCMS (m/z): 394.45 (MH+). 17609606_1 (GHMatters) P106926.NZ I-9: N-(1-(2-methoxyethyl)(pyridinyl)-1H-pyrazolyl)(3-methyl-1H-pyrazolyl)furan carboxamide. 1H NMR (DMSO d 6, 300MHz): δ 11.43 (s, 1H), 8.67-8.64 (m, 1H), 8.41 (s, IH), 8.05-7.91 (m, 3H), 7.43- 7.29 (m, 1H), 7.30 (d, J = 3.3Hz, 1H), 6.69 (d, J = 3.3Hz, 1H), 4.37 (t, J = 6.7Hz, 2H), 3.75 (t, J = 6.7Hz, 2H), 3.27 (s, 3H), 2.53 (s, 3H); LCMS (m/z): 393.53 (MH+).

I-10: di-tert-butyl ((4-(5-((1-(2-methoxyethyl)(pyridinyl)-1H-pyrazolyl)carbamoyl)furanyl)- 1H-pyrazolyl)methyl) phosphate. 1H NMR (CDCl 3, 300MHz): δ 11.86 (s, 1H), 8.77-8.75 (m, 1H), 8.41 (s, IH), .07 (m, 2H), 7.98 (s, 1H), 7.80-7.74 (m, 1H), 7.23 (d, J = 6.7Hz, 1H), 6.52 (d, J = 3.3Hz, 1H), 5.94 (d, J = 13.3Hz, 2H), 4.34 (t, J = 6.7Hz, 2H), 3.83 (t, J = 6.7Hz, 2H), 3.37 (s, 3H), 1.44 (s, 18H); LCMS (m/z): 601.70 (MH+). 17609606_1 (GHMatters) P106926.NZ I-11: tert-butyl ((4-(5-((1-(2-methoxyethyl)(pyridinyl)-1H-pyrazolyl)carbamoyl)furanyl)- 1H-pyrazolyl)methyl) hydrogen phosphate. 1H NMR (CDCl 3, 300MHz): δ 11.61 (s, 1H), 8.51-8.49 (m, 1H), 8.26 (s, IH), 8.00-7.93 (m, 2H), 7.77 (s, 1H), 7.66-7.58 (m, 2H), 7.14-7.10 (m, 1H), 7.03 (d, J = 3.3Hz, 1H), 6.37 (d, J = 3.3Hz, 1H), 5.79-5.70 (m, 2H), 4.26 (t, J = 6.7Hz, 2H), 3.78 (t, J = 6.7Hz, 2H), 3.34 (s, 3H), 1.27 (s, 9H); LCMS (m/z): 545.74 (MH+).

I-12: (4-(5-((1-(2-methoxyethyl)(pyridinyl)-1H-pyrazolyl)carbamoyl)furanyl)-1H-pyrazol- 1-yl)methyl dihydrogen phosphate. 1H NMR (DMSO d 6, 300MHz): δ 11.71 (s, 1H), 8.86-8.84 (m, 1H), .37 (m, 2H), 8.06-7.92 (m, 3H), 7.43-7.39 (m, 1H), 7.30 (d, J = 3.3Hz, 1H), 6.88 (d, J = 3.3Hz, 1H) 5.92 (d, J = , 2H), 4.38 (t, J = 6.7Hz, 2H), 3.75 (t, J = 6.7Hz, 2H), 3.27 (s, 3H); LCMS (m/z): 489.51 (MH+). 17609606_1 (GHMatters) P106926.NZ I-13: N -(1-(2-methoxyethyl)(pyridinyl)-1H-pyrazolyl)(3-(trifluoromethyl)-1H-pyrazol yl)furancarboxamide.

LCMS (m/z): 447.67 (MH+).

I-14: sodium ((1-(2-methoxyethyl)(pyridinyl)-1H-pyrazolyl)carbamoyl)furanyl)-1H- pyrazolyl)methyl phosphate. 1H NMR (D 2O, 300MHz): δ 7.90-7.86 (m, 2H), 7.48 (s,1H), 7.45 (t, J = 10.0Hz, 1H), 7.28-7.23 (m, 2H), 6.96-6.92 (m, 1H), 6.65 (d, J = 3.3Hz, 1H), 6.23 (d, J = 3.3Hz, 1H), ), 5.64 (d, J = 3.3Hz, 2H), 4.02 (t, J = 6.7Hz, 2H), 3.75 (t, J = 6.7Hz, 2H), 3.35 (s, 3H); LCMS (m/z): 489.24 (MH+). 17609606_1 (GHMatters) P106926.NZ I-15: N-(1-(2-hydroxyethyl)(pyrimidinyl)-1H-pyrazolyl)(1H-pyrazolyl)furan carboxamide. 1H NMR (DMSO d 6, 300MHz): δ 11.31 (s, 1H), 8.98 (d, J = 3.3Hz, 2H), 8.43 (s, 1H), 7.50 (t, J = 6.7Hz, 1H), 7.31 (d, J = 3.3Hz, 1H), 6.79 (d, J = 6.7Hz, 1H), 4.98 (t, J = 6.7Hz, 1H), 4.27 (t, J = 6.7Hz, 2H), 3.84- 3.78 (m, 1H); LCMS (m/z): 366.55 (MH+).

I-16: N-(1-(2-(2-methoxyethoxy)ethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)furan carboxamide.

LCMS (m/z): 423.60 (MH+). 06_1 (GHMatters) P106926.NZ I-17: N-(1-(2-(2-methoxyethoxy)ethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)furan carboxamide hloride salt. 1H NMR (DMSO d 6, 300MHz): δ 11.65 (s, 1H), 8.75-8.73 (m, 1H), 8.40 (s, 1H), 8.12 (s, 2H), 8.04-7.93 (m, 2H), 7.29 (d, J = 3.3Hz, 1H), 6.79 (d, J = 6.7Hz, 1H), 4.37 (t, J = 6.7Hz, 1H), 3.84 (t, J = 6.7Hz, 2H), 3.56- 3.53 (m, 2H), 3.44-3.41 (m, 2H), 3.22 (s, 3H); LCMS (m/z): 423.62 (MH+).

I-18: N-(1-(2-(2-methoxyethoxy)ethyl)(pyridinyl)-1H-pyrazolyl)(3-methyl-1H-pyrazol yl)furancarboxamide. 1H NMR (DMSO d 6, 300MHz): δ 11.40 (s, 1H), 8.63-8.61 (m, 1H), 8.40 (s, 1H), 8.02-7.89 (m, 3H), 7.40- 7.36 (m, 1H), 7.27 (d, J = 3.3Hz, 1H), 6.66 (d, J = 3.3Hz, 1H), 4.34 (t, J = 6.7Hz, 1H), 3.81 (t, J = 6.7Hz, 2H), 3.53-3.50 (m, 2H), 3.41-3.37 (m, 2H), 3.18 (s, 3H), 2.47 (s, 3H); LCMS (m/z): 437.66 (MH+). 17609606_1 (GHMatters) P106926.NZ I-19: 1-(isobutyryloxy)ethyl 4-(5-((1-(2-methoxyethyl)(pyridinyl)-1H-pyrazol yl)carbamoyl)furanyl)-1H-pyrazolecarboxylate. 1H NMR (DMSO d 6, 300MHz): δ 11.72 (s, 1H), 8.80 (s, 1H), 8.75-8.73 (m, 1H), 8.38 (d, J = 3.3Hz, 2H), 8.05-7.94 (m, 2H), 7.44-7.40 (m, 1H), 7.34 (d, J = 3.3Hz, 1H), 7.10 (d, J = 3.3Hz, 1H), 7.05-7.00 (m, 1H), 4.38 (t, J = 6.7Hz, 1H), 3.76 (t, J = 6.7Hz, 2H), 3.27 (s, 3H), 2.63 (s, J = 3.3Hz, 1H), 1.66 (d, J = 6.7Hz, 3H), 1.11 (d, J = 6.7Hz, 6H); LCMS (m/z): 537.68 (MH+).

I-20: tert-butyl (S)-(1-(4-(5-((1-(2-methoxyethyl)(pyridinyl)-1H-pyrazolyl)carbamoyl)furan yl)-1H-pyrazolyl)methyloxobutanyl)carbamate. 1H NMR (DMSO d 6, ): δ 11.71 (s, 1H), 8.92 (s, 1H), 8.76-8.74 (m, 1H), 8.40 (s, 2H), 8.05-7.93 (m, 2H), 7.50-7.41 (m, 2H), 7.36 (d, J = 3.3Hz, 1H), 7.12 (d, J = 3.3Hz, 1H), 5.25-5.20 (m, 1H), 4.38 (t, J = 6.7Hz, 1H), 3.76 (t, J = 6.7Hz, 2H), 3.27 (s, 3H), 1.84 (s, 1H), 1.39 (s, 9H), 0.93 (s, J = 6.7Hz, 6H); LCMS (m/z): 578.76 (MH+). 17609606_1 (GHMatters) P106926.NZ I-21: 1-methylcyclopropyl 4-(5-((1-(2-methoxyethyl)(pyridinyl)-1H-pyrazol bamoyl)furanyl)-1H-pyrazolecarboxylate. 1H NMR (DMSO d 6, 300MHz): δ 11.71 (s, 1H), 8.75-8.72 (m, 2H), 8.39 (s, 1H), 8.31 (s, 1H), 8.05-7.94 (m, 2H), 7.45-7.41 (m, 1H), 7.33 (d, J = 3.3Hz, 1H), 7.06 (d, J = 6.7Hz, 1H), 4.38 (t, J = 6.7Hz, 1H), 3.76 (t, J = 6.7Hz, 2H), 3.27 (s, 3H), 1.69 (s, 3H), 1.16 (t, J = 6.7Hz, 1H), 0.86 (t, J = 6.7Hz, 2H); LCMS (m/z): 477.66 (MH+).

I-22: 1-((4-methoxybenzyl)oxy)methylpropanyl 4-(5-((1-(2-methoxyethyl)(pyridinyl)-1H- pyrazolyl)carbamoyl)furanyl)-1H-pyrazolecarboxylate. 1H NMR (DMSO d 6, 300MHz): δ 11.73 (s, 1H), 8.71-8.70 (m, 1H), 8.64 (s, 1H), 8.39 (s, 1H), 8.30 (s, 1H), 8.04-7.92 (m, 2H), 7.40-7.33 (m, 1H), 7.21 (d, J = 6.7Hz, 1H), 7.07 (d, J = 3.3Hz, 1H), 6.83 (d, J = 6.7Hz, 1H), 4.47 (s, 2H), 4.38 (t, J = 6.7Hz, 1H), 3.75 (t, J = 6.7Hz, 2H), 3.67 (s, 3H), 3.27 (s, 3H), 1.61 (s, 6H); LCMS (m/z): 615.79 (MH+). 17609606_1 (GHMatters) P106926.NZ I-23: 5-(1H-pyrazolyl)-N-(3-(pyridinyl)(tetrahydro-2H-pyranyl)-1H-pyrazolyl)furan carboxamide. 1H NMR (DMSO d 6, 300MHz): δ 13.27 (s, 1H), 11.67 (s, 1H), 8.75-8.73 (m, 1H), 8.42 (s, 1H), 8.26 (s, 1H), 8.06-7.95 (m, 3H), 7.45-7.43 (m, 1H), 7.28 (d, J = 3.3Hz, 1H), 6.79 (d, J = 3.3Hz, 1H), 4.53 (s, br, 1H), 4.02-3.98 (m, 2H), 3.53-3.45 (m, 2H), 2.04 (s, br, 4H); LCMS (m/z): 405.56 (MH+).

I-24: 5-(5-nitro-1H-pyrrolyl)-N-(1-(propoxymethyl)(pyridinyl)-1H-pyrazolyl)furan carboxamide.

LCMS (m/z): 437.54 (MH+).

I-25: N-(1-(oxetanyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)furancarboxamide. 1H NMR (300 MHz, DMSO-d6) δ 13.20 (br, 1H), 11.61 (s, 1H), 8.70 (d, J = 6.6 Hz, 1H), 8.44 (s, 1H), 8.20 (s, 1H), 8.8.07 (d, J = 9.0 Hz, 1H), 7.96 -7.90 (m, 2H), 7.42 – 7.38 (m, 1H), 7.23 (d, J = 3.6 Hz, 1H), 6.72 (d, J = 3.6 Hz, 1H), 5.66 (p, J = 6.6 Hz, 1H), 4.94 – 4.87 (m, 4H); LCMS: : 100%; MS (m/e): 377.47 (MH+). 17609606_1 (GHMatters) P106926.NZ I-26: 5-(1-methyl-1H-pyrazolyl)-N-(1-(oxetanyl)(pyridinyl)-1H-pyrazolyl)furan carboxamide. 1H NMR (300 MHz, DMSO-d6) δ 11.64 (s, 1H), 8.76 (d, J = 7.8 Hz, 1H), 8.48 (s, 1H), 8.18 (s, 1H), 8.11 (d, J = 10.2 Hz, 1H), 7.97 (dt, J = 7.5, 1.8 Hz, 1H), 7.89 (s, 1H), 7.45 (ddd, J = 7.5, 4.8, 1.2 Hz, 1H), 7.28 (d, J = 3.6 Hz, 1H), 6.75 (d, J = 3.6 Hz, 1H), 5.71 (p, J = 6.9 Hz, 1H), 4.97 – 4.94 (m, 4H), 3.94 (s, 3H); LCMS: purity: 100%; MS (m/e): 391.48 (MH+).

I-27: N-(1-((1,3-trans)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide. 1H NMR (300 MHz, 6) δ 13.25 (s, 1H), 11.64 (s, 1H), 8.73 (d, J = 4.8 Hz, 1H), 8.40 (s, 1H), 8.25 (s, 1H), 8.06 (d, J = 7.8 Hz, 1H), 7.98 – 7.92 (m, 2H), 7.42 (m, 1H), 7.26 (d, J = 3.6 Hz, 1H), 6.77 (d, J = 3.9 Hz, 1H), 5.06 (p, J = 6.0 Hz, 1H), 4.28 (m, 1H), 3.40 (q, J = 6.9 Hz, 2H), 2.74 – 2.66 (m, 2H), 1.14 (t, J = 6.9 Hz, 3H); LCMS: purity: 91.98%; MS (m/e): 419.60 (MH+).

I-29: N-(1-((1,3-cis)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(3-methyl-1H-pyrazol yl)furancarboxamide. 17609606_1 (GHMatters) P106926.NZ 1H NMR (300 MHz, DMSO-d6) δ 11.40 (s, 1H), 8.64 (d, J = 4.8 Hz, 1H), 8.41 (s, 1H), 8.07 (d, J = 7.8 Hz, 1H), 7.93 (m, 1H), 7.39 (m, 1H), 7.28 (d, J = 3.6 Hz, 1H), 6.67 (d, J = 3.6 Hz, 1H), 4.60 (p, J = 6.9 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 = 7.2 Hz, 3H); LCMS: purity: 91.56%; MS (m/e): 433.52 (MH+).

I-30: 5-(3-methyl-1H-pyrazolyl)-N-(1-(oxetanyl)(pyridinyl)-1H-pyrazolyl)furan carboxamide. 1H NMR (300 MHz, DMSO-d6) δ 12.99 (br, 1H), 11.43 (s, 1H), 8.67 (d, 1H), 8.51 (s, 1H), 8.12 (d, J = 7.8 Hz, 1H), 7.97 (t, J = 8.4 Hz, 1H), 7.85 (s, 1H), 7.43 (d, J = 5.7 Hz, 1H), 7.30 (d, J = 3.6 Hz, 1H), 6.67 (d, J = 3.9 Hz, 1H), 5.70 (p, J = 6.9 Hz, 1H), 4.96 – 4.92 (m, 4H), 2.54 (s, 3H); LCMS: purity: 88.90%; MS (m/e): 391.51 (MH+).

I-31: N-(1-((1,3-cis)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(1-methyl-1H-pyrazol yl)furancarboxamide. 1H NMR (300 MHz, DMSO-d6) δ 11.62 (s, 1H), 8.74 (d, J = 5.4 Hz, 1H), 8.39 (s, 1H), 8.18 (s, 1H), 8.06 (d, J = 8.1 Hz, 1H), 7.94 (td, J = 7.8, 1.8 Hz, 1H), 7.88 (s, 1H), 7.43 (ddd, J = 7.5, 5.0, 1.3 Hz, 1H), 7.26 (d, J = 3.6 Hz, 1H), 6.75 (d, J = 3.6 Hz, 1H), 4.60 (p, J = 8.4 Hz, 1H), 3.94 (s, 3H), 3.83 (p, J = 6.6 Hz, 1H), 3.40 (q, J = 6.9 Hz, 2H), 2.84 – 2.75 (m, 2H), 2.46 – 2.36 (m, 2H), 1.13 (t, J = 6.9 Hz, 3H); LCMS: purity: 91.65%; MS (m/e): 433.57 (MH+). 17609606_1 ters) P106926.NZ I-32: N-(1-((1,3-cis)hydroxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)furan- 2-carboxamide. 1H NMR (300 MHz, DMSO-d6) δ 13.23 (br, 1H), 11.64 (s, 1H), 8.72 (d, J = 5.1 Hz, 1H), 8.41 (s, 1H), 8.25 (br, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.98 – 7.92 (m, 2H), 7.40 (m, 1H), 7.27 (d, J = 3.6 Hz, 1H), 6.77 (d, J = 3.3 Hz, 1H), 5.31 (d, J = 6.6 Hz, 1H), 4.42 (m, 1H), 3.96 (q, J = 7.2 Hz, 1H), 2.79 (m, 2H), 2.40 (m, 2H); LCMS: purity: 92.77%; MS (m/e): 391.56 (MH+).

I-34: N-(1-((1,3-cis)(dimethylamino)cyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide.

LCMS: purity: 94.57%; MS (m/e): 418.59 (MH+).

I-35: ((1-((1,3-cis)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)carbamoyl)furanyl)- 1H-pyrazolyl)methyl phosphate bis-sodium salt. 1H NMR (300 MHz, Deuterium Oxide) δ 7.77 (d, 1H), 7.50 (m, 3H), 7.16 (m, 2H), 6.94 (m, 1H), 6.50 (d, 1H), 6.03 (d, J = 3.3 Hz, 1H), 5.50 (d, J = 9.9 Hz, 2H), 4.07 (t, J = 8.1 Hz, 1H), 3.86 (t, J = 6.9 Hz, 17609606_1 (GHMatters) P106926.NZ 1H), 3.44 (q, J = 6.9 Hz, 2H), 2.73 (m, 2H), 2.10 (q, J = 9.3 Hz, 2H), 1.10 (t, J = 7.2 Hz, 3H); LCMS: purity: 98.27%; MS (m/e): 529.62 (MH+).

I-37: N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)furancarboxamide formic acid salt.

MS (ESI) (m/z): 393 [M+H]+ I-38: N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)furancarboxamide. 1H NMR (300 MHz, DMSO-d 6) δ 11.65 (s, 1H), 8.74 (d, J = 4.9 Hz, 1H), 8.39 (s, 1H), 8.11 (s, 2H), 8.02 (d, J = 7.9 Hz, 1H), 7.94 (td, J = 7.8, 1.8 Hz, 1H), 7.42 (t, J = 6.1 Hz, 1H), 7.28 (d, J = 3.6 Hz, 1H), 6.78 (d, J = 3.6 Hz, 1H), 4.36 (t, J = 5.3 Hz, 2H), 3.79 (t, J = 5.3 Hz, 2H), 3.45 (q, J = 7.1 Hz, 3H), 1.08 (t, J = 7.0 Hz, 3H); MS (ESI) (m/z): 393 [M+H]+.

I-39: N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)furancarboxamide, formic acid salt. 1H NMR (300 MHz, DMSO-d 6) δ 11.64 (s, 1H), 8.77 – 8.71 (m, 1H), 8.39 (s, 1H), 8.24 (d, J = 0.7 Hz, 1H), 8.02 (dt, J = 8.1, 1.2 Hz, 1H), 7.98 – 7.91 (m, 1H), 7.91 (d, J = 0.8 Hz, 1H), 7.42 (ddd, J = 7.3, 5.0, 1.4 Hz, 1H), 7.27 (d, J = 3.6 Hz, 1H), 6.76 (d, J = 3.5 Hz, 1H), 4.36 (t, J = 5.3 Hz, 2H), 4.24 (q, J = 7.3 Hz, 2H), 3.79 (t, J = 5.3 Hz, 2H), 3.45 (q, J = 7.0 Hz, 2H), 1.45 (t, J = 7.3 Hz, 3H), 1.08 (t, J = 7.0 Hz, 3H); MS (ESI) (m/z): 421 [M+H]+. 17609606_1 ters) P106926.NZ I-41: N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(3-(trifluoromethyl)-1H-pyrazol yl)furancarboxamide, formic acid salt. 1H NMR (300 MHz, DMSO-d 6) δ 11.47 (s, 1H), 8.63 (ddd, J = 5.1, 1.8, 1.0 Hz, 1H), 8.50 (d, J = 1.2 Hz, 1H), 8.43 (s, 1H), 8.01 (dt, J = 8.0, 1.1 Hz, 1H), 7.92 (td, J = 7.7, 1.7 Hz, 1H), 7.38 (ddd, J = 7.3, 5.0, 1.4 Hz, 1H), 7.34 (dd, J = 3.6, 0.6 Hz, 1H), 6.80 (d, J = 3.6 Hz, 1H), 4.36 (t, J = 5.3 Hz, 2H), 3.79 (t, J = 5.3 Hz, 2H), 3.45 (q, J = 7.0 Hz, 2H), 1.08 (t, J = 7.0 Hz, 3H); MS (ESI) (m/z): 461 [M+H]+.

I-43: N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(1-isopentyl-1H-pyrazolyl)furan carboxamide, formic acid salt. 1H NMR (300 MHz, DMSO-d 6) δ 11.64 (s, 1H), 8.73 (ddd, J = 5.0, 1.7, 1.0 Hz, 1H), 8.39 (s, 1H), 8.25 (d, J = 0.7 Hz, 1H), 8.02 (dt, J = 8.0, 1.2 Hz, 1H), 7.98 – 7.93 (m, 1H), 7.93 – 7.89 (m, 1H), 7.40 (ddd, J = 7.3, 5.0, 1.4 Hz, 1H), 7.27 (d, J = 3.6 Hz, 1H), 6.75 (d, J = 3.5 Hz, 1H), 4.35 (t, J = 5.3 Hz, 2H), 4.23 (t, J = 7.2 Hz, 2H), 3.78 (t, J = 5.3 Hz, 2H), 3.45 (q, J = 7.0 Hz, 2H), 1.74 (q, J = 6.9 Hz, 2H), 1.51 (dp, J = 13.4, 6.7 Hz, 1H), 1.08 (t, J = 7.0 Hz, 3H), 0.93 (d, J = 6.6 Hz, 6H); MS (ESI) (m/z): 463 [M+H]+.

I-45: N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(1-methyl-1H-pyrazolyl)furan carboxamide, formic acid salt. 1H NMR (300 MHz, DMSO-d 6) δ 11.64 (s, 1H), 8.39 (s, 1H), 8.19 (d, J = 0.7 Hz, 1H), 8.02 (dt, J = 8.1, 1.2 Hz, 1H), 7.94 (ddd, J = 8.0, 7.3, 1.7 Hz, 1H), 7.90 (s, 1H), 7.70 – 7.47 (m, 1H), 7.43 (ddd, J = 7.3, 17609606_1 ters) P106926.NZ 4.9, 1.4 Hz, 1H), 7.28 (dd, J = 3.6, 0.5 Hz, 1H), 6.83 – 6.70 (m, 1H), 4.36 (t, J = 5.3 Hz, 2H), 3.95 (s, 3H), 3.79 (t, J = 5.3 Hz, 2H), 3.45 (q, J = 7.0 Hz, 2H), 1.08 (t, J = 7.0 Hz, 3H); MS (ESI) (m/z): 407 [M+H]+.

I-47: 5-(1H-pyrazolyl)-N-(3-(pyridinyl)-1H-pyrazolyl)furancarboxamide. 1H NMR (300 MHz, DMSO-d 6) δ 13.40 – 12.84 (m, 1H), 11.67 (s, 1H), 8.75 (dt, J = 5.0, 1.3 Hz, 1H), 8.34 (s, 1H), 8.26 (s, 1H), 8.16 – 7.81 (m, 3H), 7.42 (ddd, J = 7.5, 5.0, 1.3 Hz, 1H), 7.27 (d, J = 3.6 Hz, 1H), 6.78 (d, J = 3.5 Hz, 1H); MS (ESI) (m/z): 321 [M+H]+.

I-48: 5-(1-((3-methyloxetanyl)methyl)-1H-pyrazolyl)-N-(1-((3-methyloxetanyl)methyl) (pyridinyl)-1H-pyrazolyl)furancarboxamide formic acid salt.

MS (ESI) (m/z): 489 .

I-50: N-(2-(2-methoxyethoxy)ethyl)(1-(2-(2-methoxyethoxy)ethyl)-1H-pyrazolyl)-N-(1-(2-(2- methoxyethoxy)ethyl)(pyridinyl)-1H-pyrazolyl)furancarboxamide formic acid salt.

MS (ESI) (m/z): 627 [M+H]+. 17609606_1 (GHMatters) P106926.NZ I-52: 5-(1-(2-(2-methoxyethoxy)ethyl)-1H-pyrazolyl)-N-(1-(2-(2-methoxyethoxy)ethyl)(pyridin yl)-1H-pyrazolyl)furancarboxamide formic acid salt.

MS (ESI) (m/z): 525 [M+H]+.

I-54: (4-(5-((1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)carbamoyl)furanyl)-1H-pyrazol yl)methyl dihydrogen phosphate. 1H NMR (300 MHz, DMSO-d 6) δ 11.70 (s, 1H), 8.83 (dt, J = 5.0, 1.3 Hz, 1H), 8.36 (d, J = 8.6 Hz, 2H), 8.09 – 7.86 (m, 3H), 7.49 – 7.33 (m, 1H), 7.28 (d, J = 3.6 Hz, 1H), 6.86 (d, J = 3.6 Hz, 1H), 5.88 (d, J = .9 Hz, 2H), 4.35 (t, J = 5.3 Hz, 2H), 3.78 (t, J = 5.3 Hz, 2H), 3.45 (dd, J = 14.0, 7.0 Hz, 2H), 1.08 (t, J = 7.0 Hz, 3H); MS (ESI) (m/z): 503 [M+H]+.

I-56: N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(3-methyl-1H-pyrazolyl)furan carboxamide.

MS (ESI) (m/z): 407 [M+H]+. 17609606_1 ters) P106926.NZ I-58: 5-(3,5-dimethyl-1H-pyrazolyl)-N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)furan carboxamide.

MS (ESI) (m/z): 421 [M+H]+.

I-60: 5-(1H-pyrazolyl)-N-(1-(tetrahydro-2H-pyranyl)(thiazolyl)-1H-pyrazolyl)furan carboxamide formic acid salt.

MS (ESI) (m/z): 411 [M+H]+.

I-62: N-(1-((1s,3s)ethoxycyclobutyl)(thiazolyl)-1H-pyrazolyl)(1H-pyrazolyl)furan amide, formic acid salt. 1H NMR (300 MHz, DMSO-d 6) δ 10.83 (s, 1H), 8.38 (s, 1H), 8.11 (s, 1H), 8.09 (d, J = 3.3 Hz, 1H), 7.82 (d, J = 3.3 Hz, 1H), 7.29 (d, J = 3.6 Hz, 1H), 6.78 (d, J = 3.6 Hz, 1H), 4.61 (tt, J = 8.9, 7.3 Hz, 1H), 3.82 (qd, J = 7.6, 6.4 Hz, 1H), 3.40 (q, J = 7.0 Hz, 2H), 2.80 (dddd, J = 11.5, 7.1, 5.9, 2.6 Hz, 2H), 2.46 – 2.31 (m, 2H), 1.14 (t, J = 7.1 Hz, 3H) MS (ESI) (m/z): 425 [M+H]+. 17609606_1 (GHMatters) P106926.NZ I-64: N-(1-(2-(2-methoxyethoxy)ethyl)(thiazolyl)-1H-pyrazolyl)(1H-pyrazolyl)furan amide. 1H NMR (300 MHz, DMSO-d 6) δ 13.25 (s, 1H), 10.82 (s, 1H), 8.38 (s, 1H), 8.26 (s, 1H), 8.09 (d, J = 3.3 Hz, 1H), 7.98 (s, 1H), 7.80 (d, J = 3.3 Hz, 1H), 7.30 (dd, J = 3.6, 0.5 Hz, 1H), 6.79 (d, J = 3.5 Hz, 1H), 4.37 (t, J = 5.2 Hz, 2H), 3.82 (t, J = 5.2 Hz, 2H), 3.58 – 3.50 (m, 2H), 3.45 – 3.38 (m, 2H), 3.21 (d, J = 0.5 Hz, 3H); MS (ESI) (m/z): 429 [M+H]+.

I-65: 5-(1H-pyrazolyl)-N-(1-(tetrahydro-2H-pyranyl)(thiazolyl)-1H-pyrazolyl)furan carboxamide. 1H NMR (300 MHz, DMSO-d 6) δ 10.83 (s, 1H), 8.40 (d, J = 1.0 Hz, 1H), 8.09 (dd, J = 3.4, 1.0 Hz, 2H), 7.81 (dd, J = 3.2, 1.2 Hz, 1H), 7.70 – 7.50 (m, 3H), 7.30 (dd, J = 3.6, 1.2 Hz, 1H), 6.79 (dd, J = 3.6, 1.1 Hz, 1H), 4.56 (tt, J = 10.6, 6.0 Hz, 1H), 3.99 (dt, J = 11.5, 3.3 Hz, 2H), 3.48 (td, J = 11.2, 4.1 Hz, 2H), 2.09 – 1.95 (m, 4H); MS (ESI) (m/z): 411 [M+H]+.

I-67: N-{1-Methyl(pyridineyl)-1H-pyrazolyl}(1H-pyrazolyl)furancarboxamide, formate salt. 1H NMR (300 MHz, DMSO-d 6) δ 8.72 (d, J=4.8Hz, 1H), 8.34 (s, 1H), 8.25 (bs, 1H), 8.01-7.9 (m, 3H), 7.43- 7.38 (m, 1H), 7.26 (d, J=3.3Hz, 1H), 6.76 (d, J=3.3Hz, 1H), 3.93 (s, 3H); MS (m/e) 335.16 MH+. 17609606_1 (GHMatters) P106926.NZ I-69: 5-(1-Methyl-1H-pyrazolyl)-N-{1-methyl(pyridineyl)-1H-pyrazolyl}furan carboxamide, formate salt. 1H NMR (300 MHz, DMSO-d 6) δ 8.73 (d, J=4.8Hz, 1H), 8.34 (s, 1H), 8.17 (s, 1H), 8.00-7.9 (m, 3H), 7.43- 7.39 (m, 1H), 7.26 (d, J=3.3Hz, 1H), 6.74 (d, J=3.6Hz, 1H), 3.9 (s, 3H); MS (m/e) 349.12 MH+.

I-70: tert-Butyl[4-{5-(1H-pyrazoleyl)furancarboxamido}(pyridineyl)-1H-pyrazol yl]azetidinecarboxylate, formate salt.

MS (m/e) 476.51 MH+ I-71: N-{1-(3-Methoxycyclobutyl)(pyridineyl)-1H-pyrazolyl}(1H-pyrazolyl)furan carboxamide, formate salt, Cis isomer. 1H NMR (300 MHz, DMSO-d 6) δ 8.73 (d, J=4.2Hz, 1H), 8.39 (s, 1H), 8.25 (bs, 1H), .05 (m, 1H), 7.98-7.92 (m, 2H), 7.45-7.4 (m, 1H), 7.27 (d, J=3.6Hz, 1H), 6.77 (d, J=3.9Hz, 1H), 4.64-4.58 (m, 1H), 3.78- 3.73 (m, 1H), 3.2 (s, 3H), 2.84-2.78 (m, 2H), 2.45-2.39 (m, 2H); MS (m/e) 405.4 MH+. 17609606_1 (GHMatters) P106926.NZ I-72: N-{1-(3-Methoxycyclobutyl)(pyridineyl)-1H-pyrazolyl}(1H-pyrazolyl)furan carboxamide, Cis isomer. 1H NMR (300 MHz, DMSO-d 6) δ 8.73 (d, J=4.2Hz, 1H), 8.39 (s, 1H), 8.25 (bs, 1H), 8.07-8.04 (m, 1H), 7.97-7.92 (m, 2H), 7.44-7.4 (m, 1H), 7.27 (d, J=3.6Hz, 1H), 6.77 (d, J=3.9Hz, 1H), .58 (m, 1H), 3.78- 3.73 (m, 1H), 3.2 (s, 3H), 2.84-2.78 (m, 2H), 2.45-2.39 (m, 2H); MS (m/e) 405.5 MH+.

I-73: N-{1-(3-Benzyloxy)cyclobutyl)(pyridineyl)-1H-pyrazolyl}(1H-pyrazolyl)furan carboxamide, Trans isomer. 1H NMR (300 MHz, DMSO-d 6) δ 8.73 (d, J=5.7Hz, 1H), 8.41 (s, 1H), 8.25 (bs, 1H), .04 (m, 1H), 7.98-7.92 (m, 2H), 7.44-7.4 (m, 1H), 7.37-7.36 (m, 4H), 7.33-7.28 (m, 1H), 7.26 (d, J=3.3Hz, 1H), 6.76 (d, J=3.6Hz, 1H), 5.15-5.1 (m, 1H), 4.45 (s, 2H), 4.43-4.38 (m, 1H), 2.77-2.59 (m, 2H), 2.58-2.52 (m, 2H); MS (m/e) 481.53 MH+.

I-74: tert-Butyl[4-{5-(1H-pyrazoleyl)furancarboxamido}(pyridineyl)-1H-pyrazol yl]azetidinecarboxylate. 17609606_1 ters) P106926.NZ 1H NMR (300 MHz, DMSO-d 6) δ 8.75 (d, J=4.2Hz, 1H), 8.45 (s, 1H), 8.24 (m, 1H), 8.09-8.06 (m, 1H), 7.99-7.95 (m, 1H), 7.46-7.42 (m, 1H), 6.77 (d, J=3.6Hz, 1H), 5.34-5.32 (m, 1H), 4.32 (t, J=8.4Hz, 2H), 4.2 (m, 2H), 1.42 (s, 9H); MS (m/e) 476.78 MH+.

I-75: N-{1-(3-Methoxycyclobutyl)(pyridineyl)-1H-pyrazolyl}(1H-pyrazolyl)furan carboxamide, Trans isomer. 1H NMR (300 MHz, DMSO-d 6) δ 8.73 (d, J=4.2Hz, 1H), 8.4 (s, 1H), 8.25 (bs, 1H), 8.07-8.05 (m, 1H), 7.98- 7.92 (m, 2H), 7.44-7.4 (m, 1H), 7.27 (d, J=3.6Hz, 1H), 6.77 (d, J=3.9Hz, 1H), 5.08-5.03 (m, 1H), 4.21-4.17 (m, 1H), 3.2 (s, 3H), 2.73-2.64 (m, 2H); MS (m/e) 405.51 MH+.

I-77: N-{1-Methyl(pyridineyl)-1H-pyrazolyl}(1H-pyrazolyl)furancarboxamide, free base. 1H NMR (300 MHz, DMSO-d 6) δ 8.72 (d, z, 1H), 8.34 (s, 1H), 8.25 (bs, 1H), 8.01-7.9 (m, 3H), 7.43- 7.38 (m, 1H), 7.26 (d, J=3.3Hz, 1H), 6.76 (d, J=3.3Hz, 1H), 3.93 (s, 3H); MS (m/e) 335.16 MH+.

I-78: N-{1-(Azetidinyl)(pyridineyl)-1H-pyrazolyl}(1H-pyrazolyl)furan carboxamide, TFA salt. 1H NMR (300 MHz, DMSO-d 6) δ 8.78-8.76 (m, 1H), 8.58 (s, 1H), .99 (m, 4H), .46 (m, 1H), 7.29 (d, J=3.3Hz, 1H), 6.78 (d, J=3.3Hz, 1H), 5.56-5.51 (m, 1H), 4.46-4.39 (m, 4H); MS (m/e) 376.45 MH+. 17609606_1 (GHMatters) P106926.NZ I-80: Di-tert-butyl-[[4-{4-(5-((1-methyl(pyridineyl)-1H-pyrazolyl)carbamoyl)furanyl)-1H- pyrazolyl}methyl] phosphate. 1H NMR (300 MHz, DMSO-d 6) δ 8.84 (d, J=5.1Hz, 1H), 8.37 (s, 1H), 8.35 (s, 1H), 8.08 (bs, 1H), 8.01-7.9 (m, 2H), 7.39-7.35 (m, 1H), 7.29 (d, J=3.3Hz, 1H), 6.87 (d, J=3.6Hz, 1H), 5.97 (s, 1H), 5.93 (s, 1H), 3.93 (s, 3H), 1.37 (s, 18H); MS (m/e) 557.69 MH+.

I-81: ((1-Methyl(pyridineyl)-1H-pyrazolyl)carbamoyl)furan-2yl}-1H-pyrazol yl]methyl dihydrogen phosphate. 1H NMR (300 MHz, DMSO-d 6) δ 8.82 (d, J=4.8Hz, 1H), 8.35 (s, 1H), 8.34 (bs, 1H), 8.04 (s, 1H), 7.99-7.92 (m, 2H), 7.41-7.37 (m, 1H), 7.28 (d, z, 1H), 6.86 (d, J=3.6Hz, 1H), 5.88 (d, Hz, 2H), 3.93 (s, 3H); MS (m/e) 445.53 MH+.

I-82: Sodium [4-{5-((1-Methyl(pyridineyl)-1H-pyrazolyl)carbamoyl)furanyl}-1H-pyrazol yl]methyl phosphate. 1H NMR (300 MHz, D 2O) δ 8.11 (bs, 1H), 7.95 (s, 1H), 7.71 (s, 1H), 7.56 (t, J=8.4Hz, 1H), 7.49 (s, 1H), 7.37-7.34 (m, 1H), 7.07 (t, J=7.5Hz, 1H), 6.78 (d, J=3.9Hz, 1H), 6.36 (d, J=3.6Hz, 1H), 5.6 (d, J=6.6Hz, 2H), 3.6 (s, 3H); MS (m/e) 445.53 MH+. 17609606_1 (GHMatters) P106926.NZ I-83: N-{1-(1-Acetylazetidinyl)(pyridineyl)-1H-pyrazolyl}(1H-pyrazolyl)furan carboxamide, free base. 1H NMR (300 MHz, DMSO-d 6) δ 8.75 (d, J=4.2Hz, 1H), 8.53 (s, 1H), 8.1-8.08 (m, 1H), 7.99-7.94 (m, 1H), .43 (m, 1H), 7.28 (d, J=3.3Hz, 1H), 6.77 (d, J=3.6Hz, 1H), 5.43-5.34 (m, 1H), 4.58 (t, J=8.7Hz, 1H), 4.5-4.46 (m, 1H), 4.31 (t, J=9.6Hz, 1H), 4.2-4.16 (m, 1H), 1.84 (s, 3H); MS (m/e) 418.61 MH+.

I-84: 3-[4-{5-(1H-Pyrazolyl)furancarboxamido}(pyridineyl)-1H-pyrazolyl]-N-(tert- butyl)azetidinecarboxamide, free base. 1H NMR (300 MHz, DMSO-d 6) δ 8.75 (d, z, 1H), 8.47 (s, 1H), 8.07-8.05 (m, 1H), 7.99-7.93 (m, 1H), 7.47-7.42 (m, 1H), 7.28 (d, J=3.3Hz, 1H), 6.77 (d, J=3.3Hz, 1H), 5.87 (s, 1H), 5.3-5.25 (m, 1H), 4.24 (t, J=8.4Hz, 2H), 4.14-4.09 (m, 2H), 1.26 (s, 9H); MS (m/e) 475.65 MH+. 17609606_1 (GHMatters) P106926.NZ I-85: 3-[4-{5-(1H-Pyrazolyl)furancarboxamido}(pyridineyl)-1H-pyrazolyl]-N- isopropylazetidinecarboxamide, free base. 1H NMR (300 MHz, DMSO-d 6) δ 8.73 (m, 1H), 8.47 (s, 1H), 8.25 (bs, 1H), 8.08-8.05 (m, 1H), 7.99-7.96 (m, 2H), 7.47-7.42 (m, 1H), 7.29-7.28 (m, 1H), .76 (m, 1H), 6.25 (d, J=8.1Hz, 1H), 5.31 (m, 1H), 4.24 (t, J=8.4Hz, 2H), 4.14-4.09 (m, 2H), 3.76-3.69 (m, 1H), 1.07 (s, 3H), 1.05 (s, 3H); MS (m/e) 461.58 MH+.

I-86: 3-[4-{5-(1H-Pyrazolyl)furancarboxamido}(pyridineyl)-1H-pyrazolyl]-N- propylazetidinecarboxamide, free base. 1H NMR (300 MHz, DMSO-d 6) δ 8.75-8.74 (m, 1H), 8.47 (s, 1H), 8.25 (bs, 1H), 8.08-8.05 (m, 1H), 7.99- 7.93 (m, 2H), .42 (d, J=3.3Hz, 1H), 7.29-7.28 (d, J=3.6Hz, 1H), 6.49 (m, 1H), 6.25 (d, J=8.1Hz, 1H), .32 (m, 1H), 4.25 (t, J=8.4Hz, 2H), 4.16-4.12 (m, 2H), 3.0-2.94 (m, 2H), 1.45-1.38 (m, 2H), 0.84 (t, J=7.5Hz, 3H); MS (m/e) 461.58 MH+. 17609606_1 (GHMatters) P106926.NZ I-87: 3-[4-{5-(1H-Pyrazolyl)furancarboxamido}(pyridineyl)-1H-pyrazolyl]-N- cyclopropylazetidinecarboxamide, formate salt. 1H NMR (300 MHz, DMSO-d 6) δ 8.75 (bs, 1H), 8.47 (bs, 1H), 8.14-8.04 (bs, 2H), 8.08-7.94 (m, 1H), 7.47- 7.42 (m, 1H), 7.29-7.27 (m, 1H), 6.76 (m, 1H), 5.31 (m, 1H), 4.24-4.21 (m, 2H), 4.18-4.12 (m, 2H), 0.55 (m, 2H), 0.4 (m, 2H); MS (m/e) 459.57 MH+.

I-89: N-[1-{1-(Cyclopropanecarbonyl)azetidinyl}(pyridineyl)-1H-pyrazolyl](1H-pyrazol- 4-yl)furancarboxamide, formate salt. 1H NMR (300 MHz, DMSO-d 6) δ 8.75 (d, J=5.1Hz, 1H), 8.52 (s, 1H), 8.5 (s, 1H), 8.1-8.08 (m, 1H), 7.99- 7.94 (m, 1H), 7.47-7.43 (m, 1H), 7.28 (d, J=3.3Hz, 1H), 6.77 (d, J=3.9Hz, 1H), 5.47-5.43 (m, 1H), 4.73 (t, J=8.4Hz, 1H), 4.6 (m 1H), 4.37-4.3 (m, 1H), 4.2-4.16 (m, 1H), 1.66-1.59 (m, 1H), 0.76 (s, 2H), 0.74 (s, 2H); MS (m/e) 444.61 MH+. 06_1 ters) P106926.NZ I-91: 1-Pivaloylazetidinyl}(pyridineyl)-1H-pyrazolyl](1H-pyrazolyl)furan amide, formate salt. 1H NMR (300 MHz, DMSO-d 6) δ 8.75 (d, J=4.5Hz, 1H), 8.51 (s, 1H), 8.3-8.2 (ms, 1H), 8.08-8.05 (m, 1H), 7.99-7.94 (m, 2H), 7.47-7.43 (m, 1H), 7.29-7.27 (m, 1H), 6.78-6.76 (m, 1H), 5.37 (m, 1H), 1.16 (s, 9H); MS (m/e) 460.61 MH+.

I-93: 5-(1H-Pyrazolyl)-N-{3-(pyridineyl)(pyrrolidinecarbonyl)azetidinyl}-1H-pyrazol yl)furancarboxamide, formate salt. 1H NMR (300 MHz, DMSO-d 6) δ 8.74 (m, 1H), 8.49 b(s, 1H), 8.25-8.2 (bs, 1H), 8.06 (m, 1H), 7.96 (m, 2H), 7.44 (m, 1H), 7.28 (m, 1H), 6.77 (m, 1H), 5.34 (m, 1H), 4.32-4.25 (m, 4H), 1.77 (bs, 4H); MS (m/e) 473.6 MH+.

I-95: N-[1-{1-Isobutyrylazetidinyl}(pyridineyl)-1H-pyrazolyl](1H-pyrazolyl)furan carboxamide, formate salt.

MS (m/e) 446.55 MH+. 17609606_1 (GHMatters) P106926.NZ I-97: N-(1H-Pyrazolyl)-N-{3-(pyridineyl){1-(2,2,2-trifluoroethyl)azetidinyl}-1H-pyrazol yl}furancarboxamide, TFA salt. 1H NMR (300 MHz, DMSO-d 6) δ 8.74 (d, J=4.5Hz, 1H), 8.54 (s, 1H), 8.09-8.07 (m, 1H), 7.99-7.94 (m, 1H), 7.46-7.42 (m, 1H), 7.28 (d, J=3.6Hz, 1H), 6.77 (d, z, 1H), 5.21-5.16 (m, 1H), 3.89 (t, J=7.8Hz, 2H), 3.74 (t, J=7.2Hz, 2H), 3.38 (q, J=9.9Hz, 2H); MS (m/e) 458.55 MH+. 17609606_1 (GHMatters) P106926.NZ I-75: 1-Butyrylazetidinyl}(pyridineyl)-1H-pyrazolyl](1H-pyrazolyl)furan carboxamide, e salt. 1H NMR (300 MHz, DMSO-d 6) δ 8.75-8.74 (m, 1H), 8.52 (s, 1H), 8.09-8.06 (m, 1H), 7.99-7.94 (m, 2H), 7.47-7.43 (m, 1H), 7.29-7.27 (m, 1H), 6.78-6.77 (m, 1H), 5.39 (m, 1H), 4.59 (t, J=8.7Hz, 1H), 4.5-4.45 (m, 1H), 4.32 (t, J=9.9Hz, 1H), 4.2-4.16 (m, 1H), 2.1 (t, J=7.5Hz, 2H), 1.53 (q, J=7.5Hz, 2H), 0.9 (t, J=7.2Hz, 9H); MS (m/e) 446.58 MH+.

I-101: N-{1-(1-Methylazetidinyl)(pyridineyl)-1H-pyrazolyl}(1H-pyrazolyl)furan carboxamide, formate salt. 1H NMR (300 MHz, DMSO-d 6) δ 8.29 (d, J=5.7Hz, 1H), 8.07 (s, 1H), 7.8 (s, 1H), 7.63-7.61 (m, 1H), 7.55- 7.49 (m, 1H), 7.01-6.97 (m, 1H), 6.83 (d, J=3.6Hz, 1H), 6.33 (d, J=3.6Hz, 1H), 4.64-4.59 (m, 1H), 3.26 (t, J=8.1Hz, 2H), m (t, 2H); MS (m/e) 390.55 MH+. 17609606_1 (GHMatters) P106926.NZ I-103: N-[1-{1-(2,2-difluorocyclopropanecarbonyl)azetidinyl}(pyridineyl)-1H-pyrazolyl]- -(1H-pyrazolyl)furancarboxamide, formate salt. 1H NMR (300 MHz, DMSO-d 6) δ 8.76 (m, 1H), 8.55 (s, 1H), 8.53 (s, 1H), 8.25 (m, 1H), .08 (m, 1H), 7.99-7.94 (m, 2H), 7.47-7.43 (m, 1H), 7.29 (d, J=3.6Hz, 1H), 6.77 (d, J=3.3Hz, 1H), 5.46 (m, 1H), 4.8 (m, 1H), 4.69 (m, 1H), 4.57 (m, 1H), 4.4 (m, 1H), 4.3 (m, 1H), 2.79 (m, 1H), 1.9 (m, 2H); MS (m/e) 480.49 I-105: N-(1-methyl(5-morpholinopyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)furan carboxamide. 1H NMR (300 MHz, DMSO-d 6) δ 11.66 (s, 1H), 8.38 (d, J = 2.9 Hz, 1H), 8.28 (s, 1H), 8.10 (s, 2H), 7.85 (d, J = 8.9 Hz, 1H), 7.56 (dd, J = 8.9, 2.9 Hz, 1H), 7.25 (d, J = 3.6 Hz, 1H), 6.74 (d, J = 3.6 Hz, 1H), 3.91 (s, 3H), 3.80 (t, J = 4.9 Hz, 4H), 3.27 (t, J = 4.9 Hz, 4H).

LCMS (m/z): 420.55 (MH+). 17609606_1 (GHMatters) P106926.NZ I-106: N-(1-methyl(5-(4-methylpiperazinyl)pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide. 1H NMR (300 MHz, DMSO-d 6) δ 13.31 (s, 1H), 11.69 (s, 1H), 8.37 (d, J = 2.9 Hz, 1H), 8.27 (m, 8.27 – 8.23, 2H), 7.98 (s, 1H), 7.83 (d, J = 8.9 Hz, 1H), 7.55 (dd, J = 8.9, 2.9 Hz, 1H), 7.26 (d, J = 3.6 Hz, 1H), 6.77 (d, J = 3.6 Hz, 1H), 3.90 (s, 3H), 3.32 (t, J = 6.4 Hz, 4H), 2.51 (t, J = 6.4 Hz, 4H), 2.26 (s, 3H).

LCMS (m/z): 433.72 (MH+).

I-107: N-(3-(5-(2-hydroxymethylpropoxy)pyridinyl)methyl-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide. 1H NMR (300 MHz, DMSO-d 6) δ 13.30 (s, 1H), 11.46 (s, 1H), 8.43 (s, 1H), 8.32 (s, 1H), 8.27 (s, 1H), 8.01 – 7.91 (m, 2H), 7.60 (dd, J = 8.9, 2.9 Hz, 1H), 7.28 (d, J = 3.6 Hz, 1H), 6.78 (d, J = 3.6 Hz, 1H), 4.72 (s, 1H), 3.92 (s, 3H), 3.90 (s, 3H), 1.25 (s, 6H).

LCMS (m/z): 423.60 (MH+). 17609606_1 ters) P106926.NZ I-108: ethyl(5-(oxetanyloxy)pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)furan carboxamide. 1H NMR (300 MHz, DMSO-d 6) δ 13.34 (s, 1H), 11.45 (s, 1H), 8.32 (s, 1H), 8.25 (d, J = 2.6 Hz, 1H), 7.94 (d, J = 9.2 Hz, 1H), 7.45 (dd, J = 8.9, 2.9 Hz, 1H), 7.28 (d, J = 3.6 Hz, 1H), 6.78 (d, J = 3.6 Hz, 1H), 6.62 (s, 1H), 5.48 (p, J = 5.4, 5.0 Hz, 1H), 5.00 (t, J = 6.9 Hz, 2H), 4.70 – 4.63 (m, 2H), 3.92 (s, 3H).

LCMS (m/z): 407.35 (MH+).

I-109: N-(3-(5-methoxypyridinyl)methyl-1H-pyrazolyl)(1H-pyrazolyl)furan carboxamide. 1H NMR (300 MHz, DMSO-d 6) δ 13.33 (s, 1H), 11.55 (s, 1H), 8.44 (d, J = 2.9 Hz, 1H), 8.35 (s, 1H), 8.30 (s, 1H), 8.00 – 7.97 (m, 2H), 7.62 (dd, J = 8.9, 3.0 Hz, 1H), 7.31 (d, J = 3.5 Hz, 1H), 6.81 (d, J = 3.5 Hz, 1H), 3.96 (s, 3H), 3.96 (s, 3H); LRMS (M+H) m/z 365.57. 17609606_1 (GHMatters) P106926.NZ I-110: N-(1-isopropyl(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)furancarboxamide. 1H NMR (300 MHz, DMSO-d 6) δ 13.31 (s, 1H), 11.70 (s, 1H), 8.78 (ddd, J = 5.0, 1.6, 1.0 Hz, 1H), 8.42 (s, 1H), 8.31 – 8.30 (m, 1H), 8.08 (ddd, J = 8.1, 1.1, 1.1 Hz, 1H), 8.02 – 7.96 (m, 2H), 7.46 (ddd, J = 7.3, 5.0, 1.3 Hz, 1H), 7.31 (d, J = 3.5 Hz, 1H), 6.82 (d, J = 3.5 Hz, 1H), 4.67 (hept, J = 6.7 Hz, 1H), 1.53 (d, J = 6.7 Hz, 6H); LRMS (M+H) m/z 363.67.

I-111: N-(1-(2-morpholinoethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)furan carboxamide. 1H NMR (300 MHz, form-d) δ 11.82 (s, 1H), 10.31 (v br s, 1H), 8.67 (ddd, J = 5.0, 1.7, 1.0 Hz, 1H), 8.41 (s, 1H), 8.09 (ddd, J = 8.1, 1.1, 1.1 Hz, 1H), 7.99 (s, 2H), 7.78 (ddd, J = 8.0, 7.6, 1.8 Hz, 1H), 7.26 – 7.21 (m, 2H, partially overlapped with CHCl3), 6.53 (d, J = 3.5 Hz, 1H), 4.30 (t, J = 6.7 Hz, 2H), 3.73 – 3.70 (m, 4H), 2.90 (t, J = 6.7 Hz, 2H), 2.54 – 2.51 (m, 4H); LRMS (M+H) m/z 434.84. 17609606_1 (GHMatters) P106926.NZ I-112: 2-(4-methylpiperazinyl)ethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide. 1H NMR (300 MHz, DMSO-d 6) δ 13.33 (br s, 1H), 11.69 (s, 1H), 8.77 (ddd, J = 5.0, 1.6, 1.0 Hz, 1H), 8.46 (s, 1H), 8.15 (br s, 2H), 8.06 (ddd, J = 8.1, 1.2 Hz, 1H), 7.98 (ddd, J = 7.7, 7.7, 1.7 Hz, 1H), 7.46 (ddd, J = 7.3, 5.0, 1.4 Hz, 1H), 7.32 (d, J = 3.6 Hz, 1H), 6.82 (d, J = 3.6 Hz, 1H), 4.35 (t, J = 6.5 Hz, 2H), 3.41 (br s, 2H), 2.80 (t, J = 6.5 Hz, 3H), 2.50 (br s, partially overlapped with DMSO, 2H), 2.34 (br s, 4H), 2.17 (s, 3H); LRMS (M+H) m/z 447.76.

I-113: 5-(1H-pyrazolyl)-N-(3-(pyridinyl)(2-(2,2,2-trifluoroethoxy)ethyl)-1H-pyrazol yl)furancarboxamide. 1HNMR (300 MHz, DMSO-d6) δ 11.66 (s, 1H), 8.74 (d, J = 6.7 Hz, 1H), 8.42 (s, 1H), 8.27 (s, 1H), 8.05 – 7.93 (m, 3H), 7.46 – 7.42 (m, 1H), 7.28 (d, J = 3.3 Hz, 1H), 6.79 (d, J = 3.3 Hz, 1H), 4.43 (t, J = 6.7 Hz, 2H), 4.16 – 4.01 (m, 4H); LCMS (m/z): 447.13 (MH+). 17609606_1 (GHMatters) P106926.NZ I-114: N-(1-((1,3-cis)isopropoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide. 1H NMR (300 MHz, 6) δ 11.63 (s, 1H), 8.73 (d, J = 4.8 Hz, 1H), 8.38 (s, 1H), 8.06 (d, J = 7.8 Hz, 1H), 7.97 (t, J = 7.8 Hz, 1H), 7.42 (t, d = 6.3 Hz, 1H), 7.26 (d, J = 3.6 Hz, 1H), 6.77 (d, J = 3.6 Hz, 1H), 4.58 (m, 1H), 3.89 (p, J = 6.6 Hz, 1H), 3.62 (p, J = 6.3 Hz, 1H), 2.78 (m, 2H), 2.41 (m, 2H), 1.10 (d, J = 6.3 Hz, 6H); LCMS: purity: 91.77%; MS (m/e): 433.22 (MH+).

I-115: N-(1-(difluoromethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)furan carboxamide. 1H NMR (300 MHz, DMSO-d6) δ 13.27 (s, 1H), 11.69 (s, 1H), 8.81 (d, J = 7.5 Hz, 1H), 8.76 (s, 1H), 8.27 (s, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.03 (t, J = 8.1 Hz, 1H), 7.96 (s, 1H), 7.92 (t, J = 58.5 Hz, 1H), 7.55 (dd, J = 7.4, 5.0 Hz, 1H), 7.34 (d, J = 3.6 Hz, 1H), 6.79 (d, J = 3.6 Hz, 1H); LCMS: purity: 100%; MS (m/e): 371.18 (MH+). 17609606_1 (GHMatters) P106926.NZ I-116: N-(1-((1,3-cis)ethoxycyclobutyl)(6-(trifluoromethyl)pyridinyl)-1H-pyrazolyl)(1H- pyrazolyl)furancarboxamide. 1H NMR (300 MHz, DMSO-d6) δ 13.22 (s, 1H), 10.43 (s, 1H), 8.50 (s, 1H), 8.33 (d, J = 8.1 Hz, 1H), 8.20 (t, J = 8.1 Hz, 1H), 8.15 (s, 1H), 7.88 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 3.6 Hz, 1H), 6.78 (d, J = 3.6 Hz, 1H), 4.64 (p, J = 7.9 Hz, 1H), 3.84 (p, J = 6.9 Hz, 1H), 3.41 (q, J = 6.9 Hz, 2H), 2.85 – 2.77 (m, 2H), 2.44 – 2.37 (m, 2H), 1.13 (t, J = 7.0 Hz, 3H); LCMS: purity: 100%; MS (m/e): 487.25 (MH+).

I-117: 5-(1H-pyrazolyl)-N-(3-(pyridinyl)(2,2,2-trifluoroethyl)-1H-pyrazolyl)furan amide. 1H NMR (300 MHz, DMSO-d6) δ 13.26 (s, 1H), 11.67 (s, 1H), 8.76 (d, J = 5.1 Hz, 1H), 8.54 (s, 1H), 8.26 (s, 1H), 8.05 – 7.95 (m, 3H), 7.47 (t, J = 5.1 Hz, 1H), 7.29 (d, J = 3.6 Hz, 1H), 6.78 (d, J = 3.3 Hz, 1H), 5.28 (q, J = 9.1 Hz, 2H); LCMS: purity: 100%; MS (m/e): 403.18 (MH+); LCMS: purity: 100%; MS (m/e): 403.18 (MH+). 17609606_1 (GHMatters) P106926.NZ I-119: 2-ethoxyethyl)(thiazolyl)-1H-pyrazolyl)(1H-pyrazolyl)furancarboxamide. 1H NMR (400 MHz, DMSO-d 6) δ 8.36 (s, 1H), 8.11 (s, 2H), 8.07 (d, J = 3.3 Hz, 1H), 7.78 (d, J = 3.2 Hz, 1H), 7.28 (d, J = 3.6 Hz, 1H), 6.77 (d, J = 3.5 Hz, 1H), 4.34 (t, J = 5.3 Hz, 2H), 3.81 – 3.71 (m, 2H), 3.43 (q, J = 7.0 Hz, 2H), 1.06 (t, J = 7.0 Hz, 3H).

MS (ESI) (m/z): 399 [M+H]+ I-120: 5-(1H-pyrazolyl)-N-(1-(tetrahydrofuranyl)(thiazolyl)-1H-pyrazolyl)furan carboxamide. 1H NMR (300 MHz, DMSO-d 6) δ 13.20 (s, 1H), 10.78 (s, 1H), 8.32 (s, 1H), 8.20 (s, 1H), 8.03 (d, J = 3.3 Hz, 1H), 7.91 (s, 1H), 7.76 (d, J = 3.3 Hz, 1H), 7.24 (d, J = 3.6 Hz, 1H), 6.73 (d, J = 3.6 Hz, 1H), 5.11 (dq, J = 8.5, 4.1 Hz, 1H), 4.03 – 3.88 (m, 3H), 3.76 (td, J = 8.3, 5.8 Hz, 1H), 2.42 – 2.31 (m, 1H), 2.30 – 2.17 (m, 1H).

MS (ESI) (m/z): 397 [M+H]+ 17609606_1 (GHMatters) P106926.NZ I-122: 5-(1-cyclobutyl-1H-pyrazolyl)-N-(1-cyclobutyl(pyridinyl)-1H-pyrazolyl)furan carboxamide MS (ESI) (m/z): 429 [M+H]+ I-124: N-(1-((cis)hydroxycyclohexyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)furan carboxamide 1H NMR (300 MHz, DMSO-d 6) δ 13.23 (s, 1H), 11.64 (s, 1H), 8.72 (d, J = 3.0 Hz, 1H), 8.34 (s, 1H), 7.98 (m, 3H), 7.39 (m, 1H), 7.26 (d, J = 3.6 Hz, 1H), 6.77 (d, J = 3.6 Hz, 1H), 6.49 (s, 1H), 4.58 (m, 1H), 4.27 (m, 1H), 3.85 (m, 1H), 2.21 (m, 2H), 1.88 (m, 4H), 1.58 (m, 2H). LCMS: purity: 81.36 %. MS (m/e): 418.46 (MH+). 17609606_1 ters) P106926.NZ I-126: N-(1-((trans)hydroxycyclohexyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)furan- oxamide 1H NMR (300 MHz, DMSO-d 6) δ 13.26 (s, 1H), 11.64 (s, 1H), 8.71 (d, J = 5.1 Hz, 1H), 8.35 (s, 1H), 8.24 (m, 1H), 7.95 (m, 3H), 7.40 (t, J = 6.9 Hz, 1H), 7.25 (d, J = 3.6 Hz, 1H), 6.77 (d, J = 3.6 Hz, 1H), 4.66 (m, 1H), 4.25 (m, 1H), 4.27 (m, 1H), 3.52 (m, 1H), 1.95 (m, 6H), 1.38 (m, 2H). LCMS: purity: 89.15 %. MS (m/e): 418.46 (MH+).

I-128: 5-(1H-pyrazolyl)-N-(3-(pyridinyl)((trans)(2,2,2-trifluoroethoxy)cyclobutyl)-1H- pyrazolyl)furancarboxamide 1H NMR (300 MHz, DMSO-d 6) δ 13.25 (s, 1H), 11.64 (s, 1H), 8.73 (d, J = 4.8 Hz, 1H), 8.42 (s, 1H), 8.25 (s, 1H), 8.07 (d, J = 7.8 Hz, 1H), 7.96 (t, J = 7.8 Hz, 1H), 7.43 (t, J = 6.0 Hz, 1H),7.26 (d, J = 3.6 Hz, 1H), 6.77 (d, J =3.6 Hz, 1H), 5.08 (m, 1H), 4.54 (m, 1H), 4.06 (m, 2H), 2.74 (m, 2H), 2.58 (m, 2H).

LCMS: purity: 92.43 %. MS (m/e): 472.43 (MH+). 17609606_1 (GHMatters) P106926.NZ I-130: N-(1-((trans)ethoxycyclohexyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)furan carboxamide 1H NMR (300 MHz, DMSO-d 6) δ 13.20 (s, 1H), 11.59 (s, 1H), 8.67 (d, J = 4.2 Hz, 1H), 8.30 (s, 1H), 8.19 (s, 1H), 7.92 (m, 2H), 7.35 (m, 2H), 7.21 (d, J = 3.3 Hz, 1H), 4.77 (m, 1H), 3.93 (m, 1H), 3.40 (m, 2H), 2.04 (m, 4H), 1.81 (m, 2H), 1.73 (t, J = 6.9 Hz, 3H) . LCMS: purity: 93.93 %. MS (m/e): 446.51 (MH+).

I-132: N-(1-((cis)ethoxycyclopentyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)furan amide 1H NMR (300 MHz, DMSO-d 6) δ 13.20 (s, 1H), 11.59 (s, 1H), 8.67 (d, J = 4.8 Hz, 1H), 8.38 (s, 1H), 8.20 (s, 1H), 7.92 (m, 2H), 7.35 (m, 1H), 7.21 (d, J = 3.3 Hz, 1H),6.71 (d, J = 3.6 Hz, 1H), 4.24 (m, 1H), 3.44 (m, 2H), 2.01 (m, 4H), 1.81 (m, 2H), 1.32 (m, 2H), 1.05 (t, J = 6.9 Hz, 3H). LCMS: purity: 98.04 %. MS (m/e): 432.48 (MH+). 17609606_1 (GHMatters) P106926.NZ I-134: N-(1-((cis)hydroxycyclopentyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)furan carboxamide 1H NMR (300 MHz, DMSO-d 6) δ 11.64 (s, 1H), 8.72 (d, J = 4.8 Hz, 1H), 8.43 (d, J = 14.7 Hz, 1H), 8.10 (s, 1H), 7.94 (m, 2H), 7.41 (m, 1H), 7.27 (m, 1H), 6.77 (d, J = 3.6 Hz, 1H), 4.79 (m, 1H), 4.20 (m, 1H), 2.39 (m, 2H), 2.06 (m, 2H), 1.80 (m, 2H). LCMS: purity: 93.14 %. MS (m/e): 404.43 (MH+).

I-136: N-(1-((trans)hydroxycyclopentyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide 1H NMR (300 MHz, DMSO-d 6) δ 11.63 (s, 1H), 8.71 (d, J = 3.9 Hz, 1H), 8.43 (d, J = 6.3 Hz, 1H), 8.37 (s, 1H), 8.09 (m, 1H), 7.93 (m, 3H), 7.40 (m, 1H), 7.27 (m, 1H), 7.76 (d, J = 3.6 Hz, 1H), 4.97 (m, 1H), 4.37 (m, 1H), 2.33 (m, 2H), 2.07 (m, 2H), 1.93 (m, 2H). LCMS: purity: 90.43 %. MS (m/e): 404.43 (MH+). 17609606_1 ters) P106926.NZ I-138: N-(1-((cis)ethoxycyclobutyl)(5-fluoropyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide 1H NMR (300 MHz, DMSO-d 6) δ 13.24 (s, 1H), 11.20 (s, 1H0, 8.71 (d, J = 3.0 Hz, 1H), 8.40 (s, 1H), 8.26 (s, 1H), 8.12 (m, 1H), 7.88 (m, 2H), 7.27 (m, 1H), 6.76 (m, 1H), 4.60 (m, 1H), 3.82 (m, 1H), 3.36 (m, 2H), 2.77 (m, 2H), 2.42 (m, 2H), 1.21 (t, J = 7.2 Hz, 3H). LCMS: : 100 %. MS (m/e): 436.45 (MH+).

I-140: N-(1-((cis)ethoxyfluorocyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide 1H NMR (300 MHz, CDCl 3) δ 11.81 (s, 1H), 8.66 (d, J = 3.3 Hz, 1H), 8.42 (s, 1H), 8.14 (m, 1H), 7.79 (m, 1H), 7.48 (m, 2H), 7.25 (m, 2H), 6.53 (m, 1H), 5.29 (m, 1H), 4.42 (m, 1H), 3.97 (m, 1H), 3.64 (m, 1H), 2.75 (m, 1H), 2.17 (m, 1H), 1.59 (m, 1H), 1.29 (t, J = 7.5 Hz, 3H). LCMS: purity: 94.28 %. MS (m/e): 436.45 (MH+). 17609606_1 (GHMatters) P106926.NZ I-142: N-(1-((cis)ethoxycyclobutyl)(3-fluoropyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide 1H NMR (300 MHz, DMSO-d 6) δ 13.25 (s, 1H), 11.44 (s, 1H), 8.62 (m, 1H), 8.45 (s, 1H), 8.09 (s, 2H),7.91 (m, 1H), 7.54 (m, 1H), 7.27 (m, 1H), 6.76 (d, J = 3.6 Hz, 1H), 4.62 (m, 1H), 3.81 (m, 1H), 3.39 (m, 2H), 2.79 (m, 2H), 2.41 (m, 2H), 1.13 (t, J = 7.2 Hz, 3H). LCMS: purity: 100 %. MS (m/e): 436.45 (MH+).

I-144: N-(1-((cis)ethoxycyclobutyl)(6-fluoropyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide 1H NMR (300 MHz, DMSO-d 6) δ 13.28 (s, 1H), 10.90 (s, 1H), 8.44 (s, 1H), 8.23 (s, 1H), 8.12 (m, 1H), 7.98 (m, 1H), 7.50 (m, 2H), 7.27 (m, 1H), 6.78 (d, J = 3.6 Hz, 1H), 4.62 (m, 1H), 3.83 (m, 1H), 3.37 (m, 2H), 2.80 (m, 2H), 2.48 (m, 2H, 1.15 (t, J = 6.9 Hz, 3H). LCMS: purity: 100 %. MS (m/e): 436.45 (MH+). 17609606_1 ters) P106926.NZ I-146: 5-(1H-pyrazolyl)-N-(3-(pyridinyl)((cis)(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol- urancarboxamide 1H NMR (300 MHz, DMSO-d 6) δ 11.63 (s, 1H), 8.74 (t, J = 4.8 Hz, 1H), 8.42 (s, 1H), 8.09 (s, 1H), 8.05 (s, 1H), 7.93 (m, 2H), 7.42 (m, 1H), 7.26 (d, J = 3.9 Hz, 1H), 6.76 (d, J = 3.6 Hz, 1H), 5.08 (m, 1H), 4.54 (m, 1H), 4.06 (m, 2H), 2.75 (m, 2H), 2.54 (m, 2H). LCMS: purity: 95.52 %. MS (m/e): 472.43 (MH+).

I-148: N-(1-((cis)ethoxycyclobutyl)(4-fluoropyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide 1H NMR (300 MHz, DMSO-d 6) δ 13.41 (s, 1H), 12.02 (s, 1H), 8.81 (m, 1H), 8.50 (m, 2H), 8.29 (s, 1H), 7.80 (s, 1H), 7.76 (m, 1H), 7.34 (m, 2H), 4.56 (m, 1H), 3.84 (m, 1H), 3.43 (m, 2H), 2.80 (m, 2H), 2.42 (m, 2H), 1.16 (t, J = 6.9 Hz, 3H). LCMS: purity: 100 %. MS (m/e): 436.45 (MH+). 17609606_1 (GHMatters) P106926.NZ I-150: N-(3-(6-fluoropyridinyl)((cis)(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazolyl)(1H- pyrazolyl)furancarboxamide 1H NMR (300 MHz, DMSO-d 6) δ 13.24 (s, 1H), 11.45 (s, 1H), 8.62 (d, J = 4.5 Hz, 1H), 8.48 (s, 1H), 8.25 (s, 1H), 7.91 (m, 2H), 7.52 (m, 1H), 7.27 (d, J = 3.3 Hz, 1H), 6.76 (d, J = 3.6 Hz, 1H), 5.10 (m, 1H), 4.51 (m, 1H), 4.03 (m, 2H), 2.72 (m, 2H), 2.54 (m, 2H). LCMS: : 97.7 %. MS (m/e): 490.42 (MH+).

I-152: N-(3-(3-fluoropyridinyl)((cis)(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazolyl)(1H- pyrazolyl)furancarboxamide 1H NMR (300 MHz, DMSO-d 6) δ 13.24 (s, 1H), 11.44 (s, 1H), 8.62 (d, J = 4.5 Hz, 1H), 8.46 (s, 1H), 8.24 (s, 1H), 7.91 (m, 2H), 7.54 (m, 1H), 7.27 (d, J = 3.3 Hz, 1H), 6.76 (d, J = 3.6 Hz, 1H), 4.64 (m, 1H), 4.06 (m, 2H), 3.58 (m, 1H), 2.83 (m, 2H), 2.54 (m, 2H). LCMS: purity: 94.59 %. MS (m/e): 490.42 (MH+). 17609606_1 (GHMatters) P106926.NZ I-154: N-(1-((trans)ethoxycyclohexyl)(3-fluoropyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide 1H NMR (300 MHz, DMSO-d 6) δ 13.26 (s, 1H), 11.47 (s, 1H), 8.62 (d, J = 4.2 Hz, 1H), 8.50 (s, 2H), 8.41 (s, 1H), 7.90 (m, 2H), 7.50 (m, 1H), 7.26 (d, J = 3.6 Hz, 1H), 6.76 (d, J = 3.6 Hz, 1H), 4.31 (m, 1H), 3.46 (m, 2H), 3.36 (m, 1H), 2.05 (m, 4H), 1.82 (m, 2H), 1.35 (m, 2H), 1.12 (t, J = 7.2 Hz, 3H). LCMS: purity: 100 %. MS (m/e): 464.50 (MH+).

I-156: N-(3-(3,6-difluoropyridinyl)((cis)ethoxycyclobutyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide 1H NMR (300 MHz, DMSO-d 6) δ 13.26 (s, 1H), 10.75 (s, 1H), 8.48 (s, 1H), 8.21 (s, 1H), 8.13 (m, 1H), 7.98 (s, 1H), 7.29 (m, 2H), 6.78 (d, J = 3.6 Hz, 1H), 4.63 (m, 1H), 3.83 (m, 1H), 3.42 (m, 2H), 2.78 (m, 2H), 2.41 (m, 2H), 1.13 (t, J = 7.2 Hz, 3H). LCMS: : 100 %. MS (m/e): 454.44 (MH+). 17609606_1 (GHMatters) P106926.NZ II-2: 1-(isobutyryloxy)ethyl 4-(4-((1-methyl(pyridinyl)-1H-pyrazolyl)carbamoyl)thiazolyl)- 1H-pyrazolecarboxylate. 1H NMR (DMSO d 6, 300MHz): δ 12.23 (s, 1H), 9.12 (s, 1H), 8.75-8.73 (m, IH), 8.48-8.43 (m, 3H), 8.02- 7.91 (m, 2H), 7.42-7.38 (m, 1H), .00 (m, IH), 3.96 (s, 3H), 2.63 (septet, J = 6.7Hz, IH), 1.66 (d, J = 6.7Hz, 3H), 1.14-1.11 (m, 6H); LCMS (m/z): 422.60 (MH+).

II-3: tert-butyl (S)-(3-methyl(4-(4-((1-methyl(pyridinyl)-1H-pyrazolyl)carbamoyl)thiazol yl)-1H-pyrazolyl)oxobutanyl)carbamate. 1H NMR (DMSO d 6, 300MHz): δ 12.22 (s, 1H), 9.21 (s, 1H), 8.79-8.76 (m, IH), 8.51-8.44 (m, 3H), 8.02- 7.91 (m, 2H), .40 (m, 2H), 5.26-5.24 (m, IH), 3.96 (s, 3H), 1.40 (s, 9H), 1.23-1.18 (m, 1H), 0.95 (d, J = 6.7Hz, 6H), 0.86-0.80 (m, 1H); LCMS (m/z): 551.72 (MH+). 17609606_1 (GHMatters) P106926.NZ II-4: 2-(1-((5-methyloxo-1,3-dioxolyl)methyl)-1H-pyrazolyl)-N-(1-methyl(pyridinyl)-1H- pyrazolyl)thiazolecarboxamide. 1H NMR (300 MHz, DMSO-d 6) δ 12.23 (s, 1H), 8.95 (s, 1H), 8.77 (d, J = 6.2 Hz, 1H), 8.44 (s, 1H), 8.40 (s, 1H), 8.34 (s, 1H), 8.05 – 7.87 (m, 2H), 7.42 (t, J = 6.6 Hz, 1H), 3.96 (s, 3H), 2.45 (s, 3H); LCMS (m/z): 464.61 (MH+).

II-5: ylcyclopropyl 4-(4-((1-methyl(pyridinyl)-1H-pyrazolyl)carbamoyl)thiazolyl)- 1H-pyrazolecarboxylate. 1H NMR (300 MHz, DMSO-d6) δ 12.23 (s, 1H), 9.02 (t, J = 0.6 Hz, 1H), 8.73 (ddd, J = 5.0, 1.7, 0.9 Hz, 1H), 8.58 – 8.27 (m, 3H), 8.15 – 7.77 (m, 3H), 7.41 (ddd, J = 7.1, 4.9, 1.5 Hz, 1H), 3.96 (d, J = 0.6 Hz, 3H), 1.69 (s, 3H), 1.33 – 1.04 (m, 2H), 1.03 – 0.70 (m, 2H); LCMS (m/z): 450.60 (MH+).

II-6: 1-((4-methoxybenzyl)oxy)methylpropanyl 4-(4-((1-methyl(pyridinyl)-1H-pyrazol yl)carbamoyl)thiazolyl)-1H-pyrazolecarboxylate. 17609606_1 (GHMatters) P106926.NZ 1H NMR (300 MHz, DMSO-d6) δ 12.34 – 12.12 (m, 1H), 9.07 – 8.85 (m, 1H), 8.83 – 8.61 (m, 1H), 8.54 – 8.34 (m, 2H), 7.96 (dtd, J = 16.9, 8.0, 1.4 Hz, 2H), 7.38 (ddd, J = 7.3, 4.8, 1.3 Hz, 1H), 7.34 – 7.11 (m, 2H), 6.94 – 6.70 (m, 2H), 4.49 (s, 2H), 3.96 (d, J = 1.1 Hz, 3H), 3.81 – 3.60 (m, 5H), 1.80 – 1.47 (m, 6H); LCMS (m/z): 588.74 (MH+).

II-7: diethyl ((4-(4-((1-methyl(pyridinyl)-1H-pyrazolyl)carbamoyl)thiazolyl)-1H-pyrazol yl)methyl)phosphonate.

LCMS (m/z): 502.52 (MH+).

II-8: sodium ((4-(4-((1-methyl(pyridinyl)-1H-pyrazolyl)carbamoyl)thiazolyl)-1H-pyrazol- 1-yl)methyl)phosphonate. 1H NMR (300 MHz, Deuterium Oxide) δ 8.14 (t, J = 6.0 Hz, 2H), 7.94 – 7.69 (m, 1H), 7.71 – 7.45 (m, 3H), 7.31 (t, J = 9.7 Hz, 1H), 7.25 – 7.01 (m, 1H), 4.29 (d, J = 13.3 Hz, 2H), 3.67 (s, 3H); LCMS (m/z): 446.50 (MH+).

II-10: pyrazolyl)-N-(3-(pyridinyl)(tetrahydro-2H-pyranyl)-1H-pyrazolyl)thiazole- 4-carboxamide. 17609606_1 (GHMatters) P106926.NZ 1H NMR (300 MHz, DMSO-d6) δ 13.42 (s, 1H), 12.21 (s, 1H), 8.96 – 8.67 (m, 1H), 8.48 (d, J = 2.8 Hz, 2H), 8.42 – 8.22 (m, 1H), 8.25 – 7.80 (m, 3H), 7.59 – 7.19 (m, 1H), 4.56 (s, 1H), 4.00 (dd, J = 10.8, 3.7 Hz, 2H), 3.73 – 3.39 (m, 2H), 2.19 – 1.82 (m, 4H); LCMS (m/z): 422.52 (MH+).

II-12: N-(1-((1,3-trans)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide. 1H NMR (300 MHz, DMSO-d6) δ 13.41 (s, 1H), 12.18 (s, 1H), 8.75 (d, J = 4.2 Hz, 1H), 8.47 (m, 2H), 8.27 (s, 1H), 8.09 (s, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.93 (t, J = 7.2 Hz, 1H), 7.42 (dd, J = 5.1 Hz, 1H), .06 (p, J = 6.9 Hz, 1H), 4.28 (p, J = 6.6 Hz, 1H), 3.40 (q, J = 6.9 Hz, 2H), 2.71 (m, 2H), 1.14 (t, J = 6.9 Hz, 3H); LCMS: purity: 86.42%; MS (m/e): 436.50 (MH+).

II-13: N-(1-((1,3-cis)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(1-methyl-1H-pyrazol yl)thiazolecarboxamide. 1H NMR (300 MHz, DMSO-d6) δ 12.15 (s, 1H), 8.77 (d, J = 4.5 Hz, 1H), 8.46 (s, 1H), 8.43 (s, 1H), 8.27 (s, 1H), 8.04 (m, 2H), 7.93 (t, J = 8.7 Hz, 1H), 7.42 (dd, J = 6.0 Hz, 1H), 4.61 (p, J = 7.5 Hz, 1H), 3.95 (s, 3H), 3.83 (p, J = 6.6 Hz, 1H), 3.41 (q, J = 6.9 Hz, 2H), 2.80 (m, 2H), 2.41 (m, 2H), 1.14 (t, J = 6.9 Hz, 3H); LCMS: purity: 96.61%; MS (m/e): 450.77 (MH+). 17609606_1 ters) P106926.NZ II-14: N-(1-((1,3-cis)hydroxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide. 1H NMR (300 MHz, DMSO-d6) δ 13.41 (s, 1H), 12.19 (s, 1H), 8.75 (d, J = 4.5 Hz, 1H), 8.48 (s, 2H), 8.28 (s, 1H), 8.10 (s, 1H), 8.03 (d, J = 7.8 Hz, 1H), 7.93 (t, J = 8.4 Hz, 1H), 7.41 (ddd, J = 7.4, 4.9, 1.3 Hz, 1H), 5.32 (d, J = 6.6 Hz, 1H), 4.48 (p, J = 6.6 Hz, 1H), 3.96 (q, J = 6.6 Hz, 1H), 2.82 – 2.74 (m, 2H), 2.41 – 2.34 (m, 2H); LCMS: purity: 97.58%; MS (m/e): 408.53 (MH+).

II-15: N-(1-((1s,3s)(dimethylamino)cyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide. 1H NMR (300 MHz, 6) δ 13.40 (br, 1H), 12.19 (s, 1H), 8.76 (d, J = 4.5 Hz, 1H), 8.52 (d, J = 8.7 Hz, 2H), 8.28 (s, 1H), 8.12 (s, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.94 (td, J = 7.8, 1.8 Hz, 1H), 7.42 (dd, J = 6.6 Hz, 1H), 4.73 (p, J = 8.1 Hz, 1H), 2.71 (m, 2H), 2.40 (s, 6H); LCMS: purity: 100%; MS (m/e): 435.57 (MH+).

II-16: (4-(4-((1-((1,3-cis)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)carbamoyl)thiazol yl)-1H-pyrazolyl)methyl phosphate bis-sodium salt. 17609606_1 (GHMatters) P106926.NZ 1H NMR (300 MHz, Deuterium Oxide) δ 7.77 (s, 1H), 7.67 (s, 1H), 7.50 (s, 1H), 7.45 (s, 1H), 7.31 (s, 1H), 7.08 (m, 2H), 6.95 (s, 1H), 5.50 (d, J = 9.3 Hz, 2H), 4.10 (t, J = 7.5 Hz, 1H), 3.87 (t, J = 7.5 Hz, 1H), 3.46 (q, J = 6.9 Hz, 2H), 2.78 (m, 2H), 2.14 (m, 2H), 1.12 (t, J = 6.9 Hz, 3H); LCMS: purity: 100%; MS (m/e): 546.57 (MH+).

II-18: N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole carboxamide, formic acid salt. 1H NMR (300 MHz, DMSO-d 6) δ 12.20 (s, 1H), 8.76 (ddd, J = 4.9, 1.7, 1.0 Hz, 1H), 8.46 (s, 1H), 8.29 (d, J = 0.5 Hz, 1H), 8.06 – 7.87 (m, 2H), 7.42 (ddd, J = 7.3, 4.9, 1.4 Hz, 1H), 4.36 (t, J = 5.3 Hz, 2H), 3.80 (t, J = 5.3 Hz, 2H), 3.50 – 3.42 (m, 2H), 1.17 – 1.00 (m, 3H); MS (ESI) (m/z): 410 [M+H]+.

II-19: N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(5-(trifluoromethyl)-1H-pyrazol yl)thiazolecarboxamide, formic acid salt. 1H NMR (300 MHz, DMSO-d 6) δ 11.82 (s, 1H), 8.70 (d, J = 1.1 Hz, 1H), 8.60 (dt, J = 5.0, 1.4 Hz, 1H), 8.51 (s, 1H), 8.48 (s, 1H), 8.00 (dt, J = 8.1, 1.2 Hz, 1H), 7.90 (td, J = 7.7, 1.8 Hz, 1H), 7.36 (ddd, J = 7.4, 5.0, 1.3 Hz, 1H), 4.36 (t, J = 5.3 Hz, 2H), 3.79 (t, J = 5.3 Hz, 2H), 3.46 (dd, J = 14.0, 7.0 Hz, 2H), 1.09 (t, J = 7.0 Hz, 3H); MS (ESI) (m/z): 478 [M+H]+.

II-21: N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(3-methyl-1H-pyrazolyl)thiazole carboxamide, formic acid salt. 17609606_1 ters) P106926.NZ 1H NMR (300 MHz, DMSO-d 6) δ 8.64 (ddd, J = 5.0, 1.7, 0.9 Hz, 1H), 8.51 (s, 1H), 8.31 (d, J = 0.6 Hz, 1H), 8.05 – 7.98 (m, 1H), 7.92 (td, J = 7.7, 1.8 Hz, 1H), 7.67 – 7.50 (m, 3H), 7.44 – 7.35 (m, 1H), 4.36 (t, J = 5.3 Hz, 2H), 3.84 – 3.75 (m, 2H), 3.46 (q, J = 6.9 Hz, 2H), 2.70 (s, 3H), 1.15 – 1.02 (m, 3H); MS (ESI) (m/z): 424 .

II-23: 2-(3,5-dimethyl-1H-pyrazolyl)-N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazol yl)thiazolecarboxamide, formic acid salt. 1H NMR (300 MHz, DMSO-d 6) δ 11.64 (s, 1H), 8.58 (dd, J = 3.9, 2.7 Hz, 1H), 8.53 (s, 1H), 8.35 (d, J = 0.3 Hz, 1H), 8.07 – 7.97 (m, 1H), 7.91 (td, J = 7.7, 1.8 Hz, 1H), 7.38 (ddd, J = 7.5, 5.0, 1.3 Hz, 1H), 4.36 (t, J = 5.3 Hz, 2H), 3.84 – 3.74 (m, 2H), 3.50 – 3.41 (m, 2H), 2.63 (s, 3H), 2.57 (s, 3H), 1.09 (t, J = 7.0 Hz, 3H); MS (ESI) (m/z): 438 [M+H]+.

II-26: N-(1-methyl(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazolecarboxamide. 1H NMR (300 MHz, DMSO-d 6) δ 12.20 (s, 1H), 8.76 (d, J = 4.8 Hz, 0H), 8.59 – 8.45 (s br, 1H), 8.43 (s, 1H), 8.30 (d, J = 0.4 Hz, 1H), 8.13 (s br, 1H), 8.02 – 7.89 (m, 2H), 7.41 (ddd, J = 7.2, 4.9, 1.5 Hz, 1H), 3.96 (s, 3H); MS (ESI) (m/z): 352 [M+H]+.

II-27: 2-(3-methyl-1H-pyrazolyl)-N-(1-methyl(pyridinyl)-1H-pyrazolyl)thiazole carboxamide. 1H NMR (300 MHz, DMSO-d 6) δ 11.82 (s, 1H), 8.62 (ddd, J = 5.1, 1.7, 0.9 Hz, 1H), 8.45 (s, 1H), 8.27 (s, 1H), 8.05 – 7.95 (m, 1H), 7.89 (td, J = 7.8, 1.8 Hz, 1H), 7.83 – 7.65 (m, 1H), 7.36 (ddd, J = 7.4, 5.0, 1.3 Hz, 1H), 3.94 (s, 3H), 2.68 (s, 3H); MS (ESI) (m/z): 366 [M+H]+. 17609606_1 (GHMatters) P106926.NZ II-28: N-(1-(2-methoxyethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole carboxamide. 1H NMR (300 MHz, DMSO-d 6) δ 12.21 (s, 1H), 8.82 – 8.73 (m, 1H), 8.46 (d, J = 0.8 Hz, 1H), 8.36 – 8.27 (m, 3H), 8.06 – 7.87 (m, 2H), 7.46 – 7.37 (m, 1H), 4.38 (t, J = 5.4 Hz, 2H), 3.81 – 3.72 (m, 2H), 3.27 (s, 3H); MS (ESI) (m/z): 395 [M+H]+.

II-29: N-(1-(2-methoxyethyl)(pyridinyl)-1H-pyrazolyl)(3-methyl-1H-pyrazolyl)thiazole- 4-carboxamide, formic acid salt. 1H NMR (300 MHz, DMSO-d 6) δ 11.85 (s, 1H), 8.67 – 8.61 (m, 1H), 8.49 (s, 1H), 8.30 (s, 1H), 8.15 (s, 1H), 8.05 – 7.99 (m, 1H), 7.92 (td, J = 7.7, 1.8 Hz, 1H), 7.39 (ddd, J = 7.4, 5.0, 1.3 Hz, 1H), 4.38 (t, J = .2 Hz, 2H), 3.76 (t, J = 5.2 Hz, 2H), 3.27 (s, 3H), 2.69 (s, 3H); MS (ESI) (m/z): 410 .

II-31: N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(3-methyl-1H-pyrazolyl)thiazole carboxamide.

MS (ESI) (m/z): 424 [M+H]+. 17609606_1 (GHMatters) P106926.NZ II-32: pyrazolyl)-N-(3-(pyridinyl)-1H-pyrazolyl)thiazolecarboxamide formic acid salt.

MS (ESI) (m/z): 338 [M+H]+.

II-34: N-(1-(oxetanyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazolecarboxamide. 1H NMR (300 MHz, DMSO-d 6) δ 13.43 (s, 1H), 12.22 (s, 1H), 8.78 (ddd, J = 5.0, 1.8, 0.9 Hz, 1H), 8.56 (s, 1H), 8.50 (d, J = 3.5 Hz, 0H), 8.29 (s, 1H), 8.10 (dt, J = 8.0, 1.1 Hz, 1H), 7.96 (td, J = 7.8, 1.8 Hz, 1H), 7.45 (ddd, J = 7.5, 4.9, 1.3 Hz, 1H), 5.72 (tt, J = 7.4, 6.5 Hz, 1H), 4.98 (dd, J = 6.9, 2.0 Hz, 4H); MS (ESI) (m/z): 394 [M+H]+.

II-36: Sodium (4-(4-((1-methyl(pyridinyl)-1H-pyrazolyl)carbamoyl)thiazolyl)-1H-pyrazol- 1-yl)methyl phosphate. 1H NMR (300 MHz, DMSO-d 6) δ 12.21 (s, 1H), 8.86 (dt, J = 4.8, 1.3 Hz, 1H), 4.68 – 4.35 (m, 2H), 8.63 (d, J = 0.8 Hz, 1H), 8.38 (s, 1H), 8.23 (s, 1H), 8.02 (d, J = 0.8 Hz, 1H), 7.96 – 7.81 (m, 2H), 7.42 (ddd, J = 6.9, 4.9, 1.5 Hz, 1H), 5.72 (d, J = 10.9 Hz, 2H), 3.94 (s, 3H); MS (ESI) (m/z): 462 [M+H]+. 17609606_1 (GHMatters) P106926.NZ II-37: N-(1-(2-(2-methoxyethoxy)ethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole- 4-carboxamide. 1H NMR (300 MHz, Acetone-d 6) δ 11.75 (d, J = 2.6 Hz, 1H), 8.31 (dt, J = 3.0, 1.4 Hz, 1H), 8.09 – 7.94 (m, 1H), 7.95 – 7.78 (m, 2H), 7.63 – 7.41 (m, 2H), 6.96 (dddd, J = 7.4, 4.9, 2.3, 1.2 Hz, 1H), 3.98 – 3.85 (m, 2H), 3.45 – 3.34 (m, 2H), 3.16 – 3.05 (m, 2H), 2.97 (dt, J = 3.0, 1.8 Hz, 2H), 2.76 (s, 3H); MS (ESI) (m/z): 440 [M+H]+.

II-38: Potassium (4-(4-((1-methyl(pyridinyl)-1H-pyrazolyl)carbamoyl)thiazolyl)-1H- pyrazolyl)methyl ate.

MS (ESI) (m/z): 462 [M+H]+.

II-39: N-(1-(2-(2-methoxyethoxy)ethyl)(pyridinyl)-1H-pyrazolyl)(3-methyl-1H-pyrazol yl)thiazolecarboxamide.

MS (ESI) (m/z): 454 [M+H]+. 17609606_1 (GHMatters) P106926.NZ II-41: 2-(3-methyl-1H-pyrazolyl)-N-(1-(oxetanyl)(pyridinyl)-1H-pyrazolyl)thiazole amide, formic acid salt. 1H NMR (300 MHz, DMSO-d 6) δ 11.87 (s, 1H), 8.67 (ddd, J = 5.0, 1.8, 1.0 Hz, 1H), 8.62 (s, 1H), 8.52 (s, 1H), 8.32 (s, 1H), 8.17 – 8.09 (m, 1H), 7.96 (td, J = 7.8, 1.8 Hz, 1H), 7.44 (ddd, J = 7.6, 5.0, 1.3 Hz, 1H), 5.80 – 5.66 (m, 1H), 4.98 (dd, J = 6.9, 1.7 Hz, 4H), 2.69 (s, 3H); MS (ESI) (m/z): 408 [M+H]+.

II-43: 2-(1H-pyrazolyl)-N-(3-(pyridinyl)(tetrahydrofuranyl)-1H-pyrazolyl)thiazole carboxamide formic acid salt.

MS (ESI) (m/z): 408 [M+H]+.

II-45: 2-(1H-pyrazolyl)-N-(3-(pyridinyl)((tetrahydro-2H-pyranyl)methyl)-1H-pyrazol yl)thiazolecarboxamide formic acid salt.

MS (ESI) (m/z): 436 [M+H]+. 17609606_1 (GHMatters) P106926.NZ II-47: N-(1-((3-(hydroxymethyl)oxetanyl)methyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol- 4-yl)thiazolecarboxamide formic acid salt.

MS (ESI) (m/z): 438 [M+H]+.

II-49: N-(1-(2-(diethylamino)ethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole carboxamide, formic acid salt. 1H NMR (300 MHz, DMSO-d 6) δ 12.19 (s, 1H), 8.76 (dt, J = 4.9, 1.4 Hz, 1H), 8.48 (s, 1H), 8.37 – 8.30 (m, 2H), 8.29 (s, 1H), 8.04 – 7.98 (m, 1H), 7.93 (td, J = 7.7, 1.8 Hz, 1H), 7.41 (ddd, J = 7.3, 4.9, 1.4 Hz, 1H), 4.25 (t, J = 6.4 Hz, 2H), 3.60 – 3.44 (m, 4H), 2.85 (t, J = 6.4 Hz, 2H), 0.93 (t, J = 7.1 Hz, 6H); MS (ESI) (m/z): 437 [M+H]+.

II-54: tert-Butyl[4-{2-(1H-pyrazoleyl)thiazolecarboxamido}(pyridineyl)-1H-pyrazol yl]azetidinecarboxylate, free base. 1H NMR (300 MHz, DMSO-d 6) δ 8.76 (d, J=5.1Hz, 1H), 8.55 (s, 1H), 8.5 (bs, 1H), 8.29 (s, 1H), 8.11-8.05 (m, 2H), .92 (m, 1H), 7.46-7.42 (m, 1H), 5.38-5.33 (m, 1H), 4.33 (t, J=8.7Hz, 2H), 4.23- 3.36 (m, 2H), 1.42 (s, 9H); MS (m/e) 493.62 MH+. 17609606_1 (GHMatters) P106926.NZ II-55: N-{1-(Azetidinyl)(pyridineyl)-1H-pyrazolyl}(1H-pyrazolyl)thiazole carboxamide, TFA salt. 1H NMR (300 MHz, DMSO-d 6) δ 8.8 (d, J=5.1Hz, 1H), 8.66 (s, 1H), 8.3 (s, 2H), 8.13-8.1 (m, 1H), 8.03-7.98 (m, 1H), 7.5-7.46 (m, 1H), 5.57-5.52 (m, 1H), 4.45-4.41 (m, 4H); MS (m/e) 393.54 MH+.

II-57: N-{1-(3-Methoxycyclobutyl)(pyridineyl)-1H-pyrazolyl}(1H-pyrazolyl)thiazole carboxamide, free base, Cis isomer. 1H NMR (300 MHz, DMSO-d 6) δ 8.75 (d, J=4.8Hz, 1H), 8.49 (bs, 1H), 8.46 (s, 1H), 8.26 (bs, 1H), 8.1 (bs, 1H), 8.05-8.03 (m, 1H), 7.96-7.91 (m, 1H), 4.64-4.59 (m, 1H), .74 (m, 1H), 2.83-2.78 (m, 2H), 2.43-2.39 (m, 2H); MS (m/e) 422.58 MH+.

II-58: 5-methoxypyridinyl)methyl-1H-pyrazolyl)(1H-pyrazolyl)thiazole carboxamide. 1H NMR (300 MHz, DMSO-d 6) δ 13.48 (s, 1H), 12.11 (s, 1H), 8.55 (s, 1H), 8.45 (dd, J = 3.0, 0.6 Hz, 1H), 8.42 (s, 1H), 8.32 (s, 1H), 8.16 (br s, 1H), 7.99 (dd, J = 8.9, 0.6 Hz, 1H), 7.62 (dd, J = 8.9, 3.0 Hz, 1H), 3.97 (s, 6H); LRMS (M+H) m/z 382.66. 17609606_1 (GHMatters) P106926.NZ II-59: N-(1-isopropyl(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazolecarboxamide. 1H NMR (300 MHz, DMSO-d 6) δ 13.47 (s, 1H), 12.25 (s, 1H), 8.80 (ddd, J = 4.9, 1.7, 1.0 Hz, 1H), 8.55 – 8.54 (m, 1H), 8.49 (s, 1H), 8.32 (s, 1H), 8.16 (d, J = 1.5 Hz, 1H), 8.06 (ddd, J = 8.1, 1.2, 1.2 Hz, 1H), 7.97 (ddd, J = 7.7, 7.7, 1.8 Hz, 1H), 7.45 (ddd, J = 7.4, 4.9, 1.3 Hz, 1H), 4.67 (hept, J = 6.7 Hz, 1H), 1.54 (d, J = 6.7 Hz, 6H); LRMS (M+H) m/z 380.65.

II-60: 2-morpholinoethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole carboxamide. 1H NMR (300 MHz, Chloroform-d) δ 12.40 (s, 1H), 10.38 (br s, 1H), 8.72 (ddd, J = 4.9, 1.8, 1.0 Hz, 1H), 8.46 (s, 1H), 8.17 (s, 2H), 8.09 – 8.06 (m, 2H), 7.77 (ddd, J = 8.0, 7.5, 1.8 Hz, 1H), 7.26 – 7.21 (m, 1H, partially overlapped with CHCl3), 4.31 (t, J = 6.7 Hz, 2H), 3.74 – 3.70 (m, 4H), 2.91 (t, J = 6.7 Hz, 2H), 2.55 – 2.52 (m, 4H); LRMS (M+H) m/z 451.75 II-61: N-(1-(2-(4-methylpiperazinyl)ethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide. 1H NMR (300 MHz, DMSO-d 6) δ 13.49 (br s, 1H), 12.24 (s, 1H), 8.80 (br d, J = 4.9 Hz, 1H), 8.53 (s, 1H), 8.35 (v br s, 2H), 8.34 (s, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.97 (ddd, J = 7.5, 7.5, 1.7 Hz, 1H), 7.45 (ddd, J = 7.2, 5.0, 1.4 Hz, 1H), 4.36 (t, J = 6.5 Hz, 2H), 3.40 (br s, 2H), 2.81 (t, J = 6.5 Hz, 2H), 2.51 (s, partially overlapped with DMSO, 2H), 2.35 (br s, 4H), 2.18 (s, 3H); LRMS (M+H) m/z 464.74. 17609606_1 (GHMatters) P106926.NZ II-66: 2-(1H-pyrazolyl)-N-(3-(pyridinyl)(2-(2,2,2-trifluoroethoxy)ethyl)-1H-pyrazol yl)thiazolecarboxamide. 1HNMR (300 MHz, DMSO-d6) δ 13.41 (s, 1H), 12.21 (s, 1H), 8.78 – 8.76 (m, 1H), 8.49 (s, 2H), 8.30 (s, 1H), 8.12 (s, br, 1H), 8.03 – 7.92 (m, 2H), 7.46 – 7.41 (m, 1H), 4.44 (t, J = 6.7 Hz, 2H), 4.13 (q, J = .8 Hz, 2H), 4.04 (t, J = 6.7 Hz, 2H); LCMS (m/z): 464.11 (MH+).

II-67: -pyrazolyl)thiazolyl)(2-((1s,3s)ethoxycyclobutyl)-2,5,6,7-tetrahydro-4H- pyrazolo[4,3-b]pyridinyl)methanone. 1HNMR (300 MHz, MeOD-d4) δ 8.28 (s, 1H), 8.17 (s, 1H), 7.92 (m, 1H), 4.48 - 4.37 (m, 1H), 4.06 - 4.02 (m, 2H), 3.95 - 3.87 (m, 1H), 2.87 - 2.78 (m, 4H), 2.48 - 2.39 (m, 2H), 2.10 - 2.04 (m, 2H), 1.21 (t, J = 6.7 Hz, 3H); LCMS (m/z): 399.21 (MH+).

II-68: R927583 (2-(1H-pyrazolyl)thiazolyl)(2-((1s,3s)ethoxycyclobutyl)-2,5,6,7-tetrahydro-4H- pyrazolo[4,3-b]pyridinyl)methanone as TFA salt. 17609606_1 (GHMatters) P106926.NZ 1HNMR (300 MHz, MeOD-d4) δ 8.17 (s, br, 3H), 7.92 (s, 1H), 4.44 – 4.37 (m, 1H), 4.02 – 3.89 (m, 4H), 3.49 (q, J = 6.7 Hz, 2H), 2.83 – 2.53 (m, 6H), 2.07 (s, br, 2H), 1.21 (t, J = 6.7 Hz, 3H), 4.13 (q, J = 10.8 Hz, 2H).

II-69: R927597: (2-(1H-pyrazolyl)thiazolyl)(1-(3-ethoxycyclobutyl)-1,5,6,7-tetrahydro-4H- pyrazolo[4,3-b]pyridinyl)methanone as TFA salt. 63:37 mixture of somers with R927583 (II-68, above).

II-70: N-(3-carbamoyl((1s,3s)ethoxycyclobutyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole carboxamide. 1HNMR (300 MHz, DMSO-d6) δ 13.41 (s, 1H), 11.25 (s, 1H), 8.40 (s, 1H), 8.39 (s, 1H), 8.29 (s, 1H), 8.00 (s, 1H), 7.73 (s, 1H), 7.55 (s, 1H), 4.65 – 4.54 (m, 1H), 3.87 – 3.78 (m, 1H), 3.40 (q, J = 6.7 Hz, 2H), 2.83 – 2.74 (m, 2H), 2.47 – 2.37 (m, 2H), 1.13 (t, J = 6.7 Hz, 2H); LCMS (m/z): 402.20 (MH+).

II-71: N-(1-((1s,3s)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(5-fluoro((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazolyl)thiazolecarboxamide.

LCMS (m/z): 584.33 (MH+). 17609606_1 (GHMatters) P106926.NZ II-72: N-(1-((1s,3s)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(5-fluoro-1H-pyrazol yl)thiazolecarboxamide. 1HNMR (300 MHz, DMSO-d6) δ 12.17 (s, 1H), 8.75 – 8.73 (m, 1H), 8.49 -8.46 (m, 2H), 8.36 (s, 1H), 8.07 – 8.04 (m, 1H), 7.97 – 7.91 (m, 1H), 7.44 – 7.39 (m, 1H), 4.68 – 4.57 (m, 1H), 3.90 – 3.80 (m, 1H), 3.42 (q, J = 6.7 Hz, 2H), 2.85 – 2.73 (m, 2H), 2.45 – 2.42 (m, 2H), 1.15 (t, J = 6.7 Hz, 2H); LCMS (m/z): 454.22 (MH+).

II-73: N-(1-((1s,3s)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(5-fluoro-1H-pyrazol azolecarboxamide as formate salt.

LCMS (m/z): 454.15 (MH+).

II-74: N-(1-((1s,3s)ethoxycyclobutyl)(1,3,4-oxadiazolyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide. 17609606_1 (GHMatters) P106926.NZ 1HNMR (300 MHz, DMSO-d6) δ 10.88 (s, 1H), 9.43 (s, 1H), 8.55 (s, 1H), 8.36 (s, 1H), 8.29 (s, 1H), 4.77 – 4.66 (m, 1H), 3.91 – 3.81 (m, 1H), 3.42 (q, J = 6.7 Hz, 2H), 2.88 – 2.79 (m, 2H), 2.47 – 2.37 (m, 2H), 1.15 (t, J = 6.7 Hz, 2H); LCMS (m/z): 427.24 (MH+).

II-75: 1,3,4-oxadiazolyl)(tetrahydro-2H-pyranyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide. 1HNMR (300 MHz, DMSO-d6) δ 10.89 (s, 1H), 9.41 (s, 1H), 8.56 (s, 1H), 8.36 (s, 1H), 4.71 – 4.59 (m, 1H), 4.02 – 3.92 (m, 2H), 3.53 – 3.44 (m, 2H), 2.07 – 2.03 (m, 4H); LCMS (m/z): 413.13 (MH+).

II-76: N-(1-((1,3-cis)isopropoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide. 1H NMR (300 MHz, DMSO-d6) δ 13.41 (s, 1H), 12.18 (s, 1H), 8.75 (d, J = 5.1 Hz, 1H), 8.49 (s, 1H), 8.45 (s, 1H), 8.28 (s, 1H), 8.10 (s, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.93 (t, J = 8.7 Hz, 1H), 7.42 (t, J = 6.6 Hz, 1H), 4.58 (p, J = 7.8 Hz, 1H), 3.89 (p, J = 7.5 Hz, 1H), 3.63 (p, J = 6.0 Hz, 1H), 2.85 – 2.76 (m, 2H), 2.43 -2.36 (m, 2H), 1.10 (d, J = 6.0 Hz, 6H); LCMS: purity: 100%; MS (m/e): 450.19 (MH+). 17609606_1 (GHMatters) P106926.NZ II-77: ((1-((1,3-cis)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)carbamoyl)thiazol yl)-1H-pyrazolyl)methyl phosphate tassium salt.

To a mixture of (4-(4-((1-((1,3-cis)ethoxycyclobutyl)(pyridinyl)-1H-pyrazol yl)carbamoyl)thiazolyl)-1H-pyrazolyl)methyl phosphate (300 mg) in acetonitrile (2 mL) and water (1 mL), was added 1.0 N potassium hydroxide aqueous on (1.1 mL, 2 eq.) After sonicating for five 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 five minutes until a clear solution formed.

The solution was cooled to room temperature. The resulting precipitate was collected through filtration, washed with isopropanol (3 x 1 mL) and dried under high vacuum at room temperature for 24 hours to give potassium salt as a white solid (280 mg). 1H NMR (300 MHz, 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: : 100%; MS (m/e): 546.23 (MH+).

II-78: (4-(4-((1-((1,3-cis)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)carbamoyl)thiazol yl)-1H-pyrazolyl)methyl phosphate calcium salt.

To a e of (4-(4-((1-((1,3-cis)ethoxycyclobutyl)(pyridinyl)-1H-pyrazol yl)carbamoyl)thiazolyl)-1H-pyrazolyl)methyl ate (309 mg) in acetonitrile (2 mL) and water (1 mL), was added calcium hydroxide (42 mg, 1 eq.). After sonicating for five 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 five minutes and then cooled to room temperature. The resulting 17609606_1 (GHMatters) P106926.NZ precipitate was collected through filtration, washed with isopropanol (3 x 1 mL) and dried under high vacuum at room temperature for 24 hours to give m salt as a white solid (300 mg).

LCMS: purity: 95.41%; MS (m/e): 546.22 (MH+).

II-79: N-(1-((1r,3r)hydroxymethylcyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide. 1H NMR (300 MHz, DMSO-d6) δ 13.41 (s, 1H), 12.17 (s, 1H), 8.74 (d, J = 5.1 Hz, 1H), 8.49 (s, 1H), 8.46 (s, 1H), 8.27 (s, 1H), 8.10 (s, 1H), 8.03 (d, J = 7.8 Hz, 1H), 7.93 (t, J = 8.4 Hz, 1H), 7.40 (t, J = 6.6 Hz, 1H), 5.06 (s, 1H), 5.04 (p, J = 7.8 Hz, 1H), 1.37 (s, 3H); LCMS: purity: 100%; MS (m/e): 422.22 (MH+).

II-80: (4-(4-((1-((1,3-cis)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)carbamoyl)thiazol yl)-1H-pyrazolyl)methyl phosphate bis-ammonium salt.

To a mixture of (4-(4-((1-((1,3-cis)ethoxycyclobutyl)(pyridinyl)-1H-pyrazol yl)carbamoyl)thiazolyl)-1H-pyrazolyl)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 eq.). After ting for five minutes, the solution was lyophilized for 24 hours. The resulting powder was suspended in water (0.5 mL) and isopropanol (3 mL). The ing precipitate was collected through filtration, washed with isopropanol (3 x 1 mL) and dried under high vacuum at room temperature for 24 hours to give ammonium salt (180 mg) as a white solid. 1H NMR (300 MHz, ium 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+). 17609606_1 (GHMatters) P106926.NZ II-81: ((1-((1,3-cis)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)carbamoyl)thiazol yl)-1H-pyrazolyl)methyl phosphate bis-lysine salt.

To a mixture of (4-(4-((1-((1,3-cis)ethoxycyclobutyl)(pyridinyl)-1H-pyrazol bamoyl)thiazolyl)-1H-pyrazolyl)methyl phosphate (200 mg) in acetonitrile (1 mL) and water (1 mL), was added ne (107 mg, 2 eq.). After sonicating for five minutes, the solution was lyophilized for 24 hours. The ing powder was suspended in water (0.5 mL) and isopropanol (3 mL). The resulting precipitate was collected through filtration, washed with isopropanol (3 x 1 mL) and dried under high vacuum at room temperature for 24 hours to give bis-lysine salt (200 mg) as a white solid. 1H NMR (300 MHz, 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+).

II-82: (4-(4-((1-((1,3-cis)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)carbamoyl)thiazol yl)-1H-pyrazolyl)methyl phosphate bis-arginine salt.

To a mixture of (4-(4-((1-((1,3-cis)ethoxycyclobutyl)(pyridinyl)-1H-pyrazol yl)carbamoyl)thiazolyl)-1H-pyrazolyl)methyl phosphate (200 mg) in acetonitrile (1 mL) and water (1 mL), was added L-arginine (128 mg, 2 eq.). After sonicating for five minutes, the solution was lyophilized for 24 hours. The resulting powder was suspended in water (0.5 mL) and isopropanol (3 mL). The resulting 17609606_1 (GHMatters) P106926.NZ precipitate was collected h filtration, washed with isopropanol (3 x 1 mL) and dried under high vacuum at room temperature for 24 hours to give 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 through filtration, washed with acetone and dried under high vacuum at room temperature for 24 hours to give bis-arginine salt (120 mg) as a white solid. 1H NMR (300 MHz, 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+).

II-83: (4-(4-((1-((1,3-cis)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)carbamoyl)thiazol -pyrazolyl)methyl dihydrogen phosphate.

N-(1-((1,3-Cis)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole- 4-carboxamide (59 g) and cesium carbonate (88 g, 2eq.) were suspended in dimethylformamide (500 mL), di-tert-butyl (chloromethyl) phosphate (53 g, 1.5 eq.) was added to the reaction and the mixture allowed to stir at room temperature for 16-20 hours. The on e was diluted with water (1 L) and extracted with ethyl acetate (2 x 800 mL). The combined organic layers were evaporated at room temperature and purified using the Torrent Combiflash®Rf column chromatography (ethyl e in s, 20 to 100%) to give the prodrug ester as a colorless oil (85 g, 95% yield). LCMS: purity: 100%; MS (m/e): 658.38 (MH+).

Di-tert-butyl((4-(4-((1-((1,3-cis)ethoxycyclobutyl)(pyridinyl)-1H-pyrazol yl)carbamoyl)thiazolyl)-1H-pyrazolyl)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 drop-wise. The reaction mixture was stirred at 0 °C for 6 hours, when LC-MS analysis showed full conversion to the acid, the on was evaporated on a rotary evaporator at room temperature. The residue was dried further under high vacuum at room ature for 24 hours to give a light yellow semi-solid as the acid and used subsequently to form salts. (4-(4-((1-((1,3-cis)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)carbamoyl)thiazolyl)- 1H-pyrazolyl)methyl dihydrogen phosphate (100 mg) was d overnight at 50 °C in acetone (10 mL) 17609606_1 (GHMatters) P106926.NZ and water (0.5 mL). 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 ature for 24 hours (90 mg). 1H 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+).

II-84: (4-(4-((1-((1,3-cis)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)carbamoyl)thiazol yl)-1H-pyrazolyl)methyl phosphate Tris salt.

To a mixture of (4-(4-((1-((1,3-cis)ethoxycyclobutyl)(pyridinyl)-1H-pyrazol bamoyl)thiazolyl)-1H-pyrazolyl)methyl phosphate (118 mg) in acetonitrile (1 mL) and water (1 mL), was added Tris(hydroxymethyl)aminomethane (52 mg, 2 eq.). After sonicating for five 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 one week at room ature, the ing precipitate was collected through filtration, washed with acetone (3 x 1 mL) and dried under high vacuum at room temperature for 24 hours to give mono-Tris salt (120 mg) as a white solid. 1H NMR (300 MHz, 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+). 17609606_1 (GHMatters) P106926.NZ II-85: ((1-((1,3-cis)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)carbamoyl)thiazol yl)-1H-pyrazolyl)methyl phosphate triethylamine salt. 1H NMR (300 MHz, Deuterium Oxide) δ 7.81 (d, 1H), 7.77 (s, 1H), 7.61 (s, 1H), 7.39 (s, 2H), 7.26 (s, 1H), 7.14 (d, J = 7.8 Hz, 1H), 6.87 (t, J = 6.6 Hz, 1H), 5.55 (d, J = 9.0 Hz, 2H), 4.11 (p, J = 8.4 Hz, 1H), 3.90 (p, J = 7.1 Hz, 1H), 3.48 (q, J = 7.1 Hz, 2H), 3.05 (q, J = 7.4 Hz, 6H), 2.80 (m, 2H), 2.15 (m, 2H), 1.13 (t, J = 7.3 Hz, 12H); LCMS: purity: 100%; MS (m/e): 546.15 (MH+).

II-86: N-(1-((1,3-cis)ethoxycyclobutyl)(5-(trifluoromethyl)pyridinyl)-1H-pyrazolyl)(1H- pyrazolyl)thiazolecarboxamide. 1H NMR (300 MHz, DMSO-d6) δ 13.45 (s, 1H), 11.84 (s, 1H), 9.04 (s, 1H), 8.53 (s, 2H), 8.32 – 8.30 (m, 2H), 8.23 (d, J = 8.1 Hz, 1H), 8.12 (s, 1H), 4.65 (p, J = 7.5 Hz, 1H), 3.84 (p, J = 6.6 Hz, 1H), 3.41 (q, J = 7.0 Hz, 2H), 2.82 (m, 2H), 2.42 (m, 2H), 1.13 (t, J = 7.0 Hz, 3H); ; LCMS: purity: 94.79%; MS (m/e): 502.27 (MH+). 17609606_1 (GHMatters) P106926.NZ II-87: N-(1-(3-hydroxymethylcyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide.

LCMS: purity: 91.70%; MS (m/e): 422.16 (MH+).

II-88: N-(1-(difluoromethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole carboxamide. 1H NMR (300 MHz, DMSO-d6) δ 13.42 (s, 1H), 12.26 (s, 1H), 8.85 – 8.82 (m, 2H), 8.51 (s, 1H), 8.35 (s, 1H), 8.13 – 8.10 (m, 2H), 8.02 (t, J = 8.7 Hz, 1H), 7.93 (t, J = 59.1 Hz, 1H), 7.55 (dd, J = 7.5, 4.9 Hz, 1 H); LCMS: purity: 100%; MS (m/e): 388.10 (MH+).

II-89: N-(1-((1,3-cis)ethoxycyclobutyl)(3-(trifluoromethyl)pyridinyl)-1H-pyrazolyl)(1H- pyrazolyl)thiazolecarboxamide. 1H NMR (300 MHz, 6) δ 13.43 (s, 1H), 11.68 (s, 1H), 9.05 (d, J = 4.8 Hz, 1H), 8.48 (m, 1H), 8.38 (d, J = 7.9 Hz, 1H), 8.28 (s, 3H), 7.66 (dd, J = 8.1, 4.9 Hz, 1H), 4.62 (p, J = 8.1 Hz, 1H), 3.83 (p, J = 7.2 Hz, 1H), 3.40 (q, J = 7.0 Hz, 2H), 2.82 – 2.73 (m, 2H), 2.45 – 2.38 (m, 2H), 1.12 (t, J = 7.0 Hz, 3H); LCMS: purity: 92.15%; MS (m/e): 504.22 (MH+). 17609606_1 (GHMatters) P106926.NZ II-90: N-(1-((1,3-cis)ethoxycyclobutyl)(6-(trifluoromethyl)pyridinyl)-1H-pyrazolyl)(1H- pyrazolyl)thiazolecarboxamide. 1H NMR (300 MHz, DMSO-d6) δ 13.40 (s, 1H), 10.93 (s, 1H), 8.60 (s, 1H), 8.38 – 8.33 (m, 3H), 8.19 (t, J = 7.9 Hz, 1H), 8.05 (s, 1H), 7.87 (d, J = 7.6 Hz, 1H), 4.64 (p, J = 8.4 Hz, 1H), 3.84 (p, J = 7.1 Hz, 1H), 3.41 (q, J = 7.0 Hz, 2H), 2.86 – 2.77 (m, 2H), 2.42 – 2.38 (m, 2H), 1.13 (t, J = 7.0 Hz, 3H); LCMS: purity: 100%; MS (m/e): 504.22 (MH+).

II-91: N-(1-((1,3-cis)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(3-(trifluoromethyl)-1H- pyrazolyl)thiazolecarboxamide. 1H NMR (300 MHz, DMSO-d6) δ 11.80 (s, 1H), 8.67 (s, 1H), 8.59 (d, J = 5.0 Hz, 1H), 8.51 (s, 1H), 8.44 (s, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.90 (td, J = 7.8, 1.8 Hz, 1H), 7.36 (dd, J = 4.8, 1.2 Hz, 1H), 4.61 (p, J = 7.5 Hz, 1H), 3.83 (p, J = 6.9 Hz, 1H), 3.41 (q, J = 7.0 Hz, 2H), 2.82 – 2.76 (m, 2H), 2.43 – 2.40 (m, 2H), 1.13 (t, J = 7.0 Hz, 3H); LCMS: purity: 100%; MS (m/e): 504.22 (MH+). 17609606_1 ters) P106926.NZ II-92: N-(1-((1,3-cis)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(3-methyl-1H-pyrazol yl)thiazolecarboxamide. 1H NMR (300 MHz, DMSO-d6) δ 13.19 (s, 1H), 11.83 (s, 1H), 8.63 (d, J = 5.1 Hz, 1H), 8.50 (s, 1H), 8.29 (s, 1H), 8.06 (d, J = 7.8 Hz, 1H), 7.99 (m, 1H), 7.92 (td, J = 7.5, 1.2 Hz, 1H), 7.39 (t, J = 6.0 Hz, 1H), 4.61 (p, J = 8.1 Hz, 1H), 3.83 (p, J = 6.9 Hz, 1H), 3.41 (q, J = 7.1 Hz, 2H), 2.85 – 2.76 (m, 2H), 2.68 (s, 3H), 2.43 – 2.37 (m, 2H), 1.13 (t, J = 6.9 Hz, 3H); LCMS: purity: 100%; MS (m/e): 450.25 (MH+).

II-93: 2-(3,5-dimethyl-1H-pyrazolyl)-N-(1-((1,3-cis)ethoxycyclobutyl)(pyridinyl)-1H- pyrazolyl)thiazolecarboxamide. 1H NMR (300 MHz, DMSO-d6) δ 12.79 (s, 1H), 11.61 (s, 1H), 8.57 (d, J = 4.8 Hz, 1H), 8.53 (s, 1H), 8.33 (s, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.91 (td, J = 7.7, 1.8 Hz, 1H), 7.37 (dd, J = 7.5, 1.2 Hz, 1H), 4.61 (p, J = 7.5 Hz, 1H), 3.83 (p, J = 6.9 Hz, 1H), 3.41 (q, J = 7.0 Hz, 2H), 2.85 – 2.76 (m, 2H), 2.56 (br, 6H), 2.43 – 2.37 (m, 2H), 1.13 (t, J = 7.0 Hz, 3H); LCMS: purity: 100%; MS (m/e): 464.23 (MH+).

II-94: 2-(1H-pyrazolyl)-N-(3-(pyridinyl)(2,2,2-trifluoroethyl)-1H-pyrazolyl)thiazole carboxamide. 06_1 (GHMatters) P106926.NZ 1H NMR (300 MHz, DMSO-d6) δ 13.41 (s, 1H), 12.22 (s, 1H), 8.79 (dd, J = 4.9, 1.5 Hz, 1H), 8.61 (s, 1H), 8.50 (s, 1H), 8.31 (s, 1H), 8.11 (s, 1H), 8.02 (d, J = 6.6 Hz, 1H), 7.96 (td, J = 8.1, 1.8 Hz, 1H), 7.47 (dd, J = 8.7, 1.5 Hz, 1H), 5.29 (q, J = 9.0 Hz, 2H); LCMS: purity: 100%; MS (m/e): 420.15 (MH+).

II-95: N-(1-(difluoromethyl)(pyridinyl)-1H-pyrazolyl)(3-(trifluoromethyl)-1H-pyrazol yl)thiazolecarboxamide. 1H NMR (300 MHz, DMSO-d6) δ 11.88 (s, 1H), 8.89 (s, 1H), 8.72 (s, 1H), 8.66 (d, J = 4.2 Hz, 1H), 8.54 (s, 1H), 8.14 – 8.10 (m, 2H), 7.99 (t, J = 8.1 Hz, 1H), 7.94 (t, J = 58.8 Hz, 1H), 7.50 (dd, J = 6.0, 1.2 Hz, 1H); LCMS: : 100%; MS (m/e): 456.10 (MH+).

II-96: N-(1-(difluoromethyl)(pyridinyl)-1H-pyrazolyl)(3-methyl-1H-pyrazolyl)thiazole carboxamide. 1H NMR (300 MHz, DMSO-d6) δ 13.20 (s, 1H), 11.93 (s, 1H), 8.88 (s, 1H), 8.72 (d, J = 5.4 Hz, 1H), 8.37 (s, 1H), 8.13 (d, J = 8.1 Hz, 1H), 8.01 (t, J = 7.5 Hz, 2H), 7.94 (t, J = 58.8 Hz, 1H), 7.54 (t, J = 6.3 Hz, 1H), 2.69 (s, 3H); LCMS: purity: 100%; MS (m/e): 402.14 (MH+).

II-97: N-(1-(difluoromethyl)(pyridinyl)-1H-pyrazolyl)(1-(2,2,2-trifluoroethyl)-1H-pyrazol- 4-yl)thiazolecarboxamide. 1H NMR (300 MHz, DMSO-d6) δ 12.26 (s, 1H), 8.84 (d, J = 3.7 Hz, 2H), 8.61 (s, 1H), 8.42 (s, 1H), 8.23 (s, 1H), 8.12 (d, J = 8.1 Hz, 1H), 8.01 (t, J = 8.1 Hz, 1H), 7.94 (t, J = 59.1 Hz, 1H), 7.54 (ddd, J = 7.5, 4.9, 1.3 Hz, 1H), 5.31 (q, J = 9.0 Hz, 2H); LCMS: purity: 100%; MS (m/e): 470.15 (MH+). 17609606_1 (GHMatters) P106926.NZ II-98: 2-(1-(difluoromethyl)-1H-pyrazolyl)-N-(1-(difluoromethyl)(pyridinyl)-1H-pyrazol yl)thiazolecarboxamide. 1H NMR (300 MHz, DMSO-d6) δ 12.27 (s, 1H), 9.02 (s, 1H), 8.84 (m, 2H), 8.48 (s, 1H), 8.41 (s, 1H), 8.12 (d, J = 9.0 Hz, 1H), 8.02 (t, J = 8.1 Hz, 1H), 7.94 (t, J = 58.5 Hz, 2H), 7.55 (ddd, J = 7.5, 4.9, 1.3 Hz, 1H); LCMS: purity: 100%; MS (m/e): 438.09 (MH+).

II-99: N-(1-((1,3-cis)ethoxycyclobutyl)(6-(trifluoromethyl)pyridinyl)-1H-pyrazolyl)(3- methyl-1H-pyrazolyl)thiazolecarboxamide. 1H NMR (300 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.59 (s, 1H), 8.36 – 8.32 (m, 2H), 8.18 (t, J = 7.9 Hz, 1H), 7.97 (s, 1H), 7.85 (d, J = 7.6 Hz, 1H), 4.65 (p, J = 8.1 Hz, 1H), 3.85 (p, J = 6.5 Hz, 1H), 3.41 (q, J = 7.0 Hz, 2H), 2.82 (m, 2H), 2.42 (m, 2H), 1.14 (t, J = 7.2 Hz, 3H); LCMS: purity: 94.50%; MS (m/e): 518.33 (MH+).

II-100: 2-(3-methyl-1H-pyrazolyl)-N-(3-(pyridinyl)(2,2,2-trifluoroethyl)-1H-pyrazol yl)thiazolecarboxamide. 1H NMR (300 MHz, DMSO-d6) δ 13.18 (s, 1H), 11.88 (s, 1H), 8.68 – 8.65 (m, 2H), 8.32 (s, 1H), 8.05 – 7.92 (m, 3H), 7.44 (t, J = 5.8 Hz, 1H), 5.29 (q, J = 9.1 Hz, 2H), 2.68 (s, 3H); LCMS: : 100%; MS (m/e): 434.26 (MH+). 17609606_1 (GHMatters) P106926.NZ II-101: (1,3-cis)hydroxycyclobutyl)(pyrazinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide. 1H NMR (300 MHz, DMSO-d6) δ 13.41 (s, 1H), 11.68 (s, 1H), 9.24 (d, J = 1.5 Hz, 1H), 8.80 (dd, J = 2.6, 1.6 Hz, 1H), 8.63 (d, J = 2.6 Hz, 1H), 8.54 (s, 1H), 8.51 (s, 1H), 8.30 (s, 1H), 8.11 (d, J = 1.7 Hz, 1H), .33 (d, J = 7.0 Hz, 1H), 4.52 (p, J = 7.2 Hz, 1H), 3.97 (h, J = 6.6 Hz, 1H), 2.84 – 2.75 (m, 2H), 2.43 – 2.39 (m, 2H); LCMS: purity: 96.50%; MS (m/e): 409.16 (MH+).

II-102: N-(1-((1,3-cis)ethoxycyclobutyl)(pyrimidinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide. 1H NMR (300 MHz, DMSO-d6) δ 13.40 (s, 1H), 11.91 (s, 1H), 8.98 (d, J = 4.9 Hz, 2H), 8.51 (s, 2H), 8.30 (s, 1H), 8.10 (s, 1H), 7.49 (t, J = 4.9 Hz, 1H), 4.65 (p, J = 8.5 Hz, 1H), 3.85 (p, J = 7.3 Hz, 1H), 3.41 (q, J = 7.0 Hz, 2H), 2.85 – 2.76 (m, 2H), 2.43 (m, 2H), 1.14 (t, J = 7.0 Hz, 3H); LCMS: purity: 100%; MS (m/e): 437.19 (MH+). 17609606_1 (GHMatters) P106926.NZ II-103: 2-(1-(4-methoxybenzyl)-1H-pyrazolyl)-N-(3-(pyridinyl)(3,3,3-trifluoro hydroxypropyl)-1H-pyrazolyl)thiazolecarboxamide.

MS (ESI) (m/z): 570 [M+H]+ II-105: N-(1-(dimethylcarbamoyl)(pyridinyl)-1H-pyrazolyl)(1-(4-methoxybenzyl)-1H- pyrazolyl)thiazolecarboxamide.

MS (ESI) (m/z): 529 [M+H]+ II-107: 2-(1-(4-methoxybenzyl)-1H-pyrazolyl)-N-(3-(pyridinyl)(3,3,3-trifluorohydroxy uoromethyl)propyl)-1H-pyrazolyl)thiazolecarboxamide.

MS (ESI) (m/z): 638 [M+H]+ 17609606_1 (GHMatters) P106926.NZ II-109: 6 N-(1-(2-ethoxyethyl)(thiazolyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole carboxamide. 1H NMR (400 MHz, DMSO-d 6) δ 13.40 (s, 1H), 11.43 (s, 1H), 8.48 (s, 1H), 8.45 (s, 1H), 8.31 (s, 1H), 8.11 (d, J = 3.3 Hz, 1H), 7.78 (d, J = 3.3 Hz, 1H), 7.65 – 7.48 (m, 2H), 4.36 (t, J = 5.2 Hz, 2H), 3.77 (dd, J = 5.7, 4.9 Hz, 2H), 3.45 (q, J = 7.0 Hz, 2H), 1.07 (t, J = 7.0 Hz, 3H).

MS (ESI) (m/z): 416 [M+H]+ : 2-(1H-pyrazolyl)-N-(1-(tetrahydro-2H-pyranyl)(thiazolyl)-1H-pyrazolyl)thiazole- 4-carboxamide.

MS (ESI) (m/z): 428 [M+H]+ II-113: N-(1-(2-(2-methoxyethoxy)ethyl)(thiazolyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole- 4-carboxamide. 1H NMR (400 MHz, DMSO-d 6) δ 11.43 (s, 1H), 8.45 (s, 1H), 8.31 (s, 1H), 8.11 (d, J = 3.3 Hz, 1H), 7.78 (d, J = 3.3 Hz, 1H), 4.36 (t, J = 5.3 Hz, 2H), 3.82 (dd, J = 5.7, 4.9 Hz, 2H), 3.56 – 3.52 (m, 2H), 3.43 – 3.39 (m, 2H), 3.20 (s, 3H).

MS (ESI) (m/z): 446 [M+H]+ 17609606_1 (GHMatters) P106926.NZ II-115: 2-(1H-pyrazolyl)-N-(1-(tetrahydrofuranyl)(thiazolyl)-1H-pyrazolyl)thiazole carboxamide. 1H NMR (400 MHz, DMSO-d 6) δ 13.48 (s, 1H), 11.45 (s, 1H), 8.46 (s, 1H), 8.30 (s, 1H), 8.12 (d, J = 3.3 Hz, 1H), 7.79 (d, J = 3.3 Hz, 1H), 5.16 (dq, J = 8.5, 4.5 Hz, 1H), 4.08 – 3.99 (m, 1H), 3.98 (d, J = 4.9 Hz, 2H), 3.82 (td, J = 8.3, 5.8 Hz, 1H), 2.47 – 2.39 (m, 1H), 2.30 (dddd, J = 13.3, 7.7, 5.8, 3.7 Hz, 1H).

MS (ESI) (m/z): 414 [M+H]+ II-117: N-(1-(2-(diethylamino)ethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole carboxamide. 1H NMR (400 MHz, DMSO-d 6) δ 13.45 (s, 1H), 12.18 (s, 1H), 8.74 (ddd, J = 4.9, 1.8, 1.0 Hz, 1H), 8.46 (s, 1H), 8.30 (s, 2H), 8.27 (s, 1H), 7.99 (dt, J = 8.0, 1.2 Hz, 1H), 7.91 (ddd, J = 8.0, 7.4, 1.8 Hz, 1H), 7.39 (ddd, J = 7.4, 4.9, 1.3 Hz, 1H), 4.22 (t, J = 6.4 Hz, 2H), 2.83 (t, J = 6.4 Hz, 2H), 2.52 – 2.44 (m, 4H), 0.90 (t, J = 7.1 Hz, 6H).

MS (ESI) (m/z): 437 [M+H]+ II-118: N-(1-(2-(2-fluoroethoxy)ethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole carboxamide. 17609606_1 ters) P106926.NZ 1H NMR (400 MHz, DMSO-d 6) δ 12.19 (s, 1H), 8.75 (ddd, J = 4.9, 1.8, 1.0 Hz, 1H), 8.47 (s, 1H), 8.30 (s, 2H), 8.28 (s, 1H), 7.99 (dt, J = 8.0, 1.2 Hz, 1H), 7.91 (ddd, J = 8.0, 7.4, 1.8 Hz, 1H), 7.40 (ddd, J = 7.4, 5.0, 1.3 Hz, 1H), 4.58 – 4.54 (m, 1H), 4.45 – 4.42 (m, 1H), 4.38 (t, J = 5.3 Hz, 2H), 3.88 (t, J = 5.3 Hz, 2H), 3.73 – 3.68 (m, 1H), 3.65 – 3.60 (m, 1H).

MS (ESI) (m/z): 428 [M+H]+ II-120: N-(1-benzyl(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazolecarboxamide. 1H NMR (400 MHz, DMSO-d 6) δ 13.41 (s, 1H), 12.21 (s, 1H), 8.75 (ddd, J = 5.0, 1.8, 1.0 Hz, 1H), 8.52 (s, 1H), 8.49 (s, 1H), 8.26 (s, 1H), 8.10 (s, 1H), 7.99 (dt, J = 8.0, 1.1 Hz, 1H), 7.91 (ddd, J = 8.1, 7.5, 1.8 Hz, 1H), 7.47 – 7.25 (m, 6H), 5.44 (s, 2H).

MS (ESI) (m/z): 428 [M+H]+ : N-(1-cyclobutyl(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazolecarboxamide. 1H NMR (300 MHz, DMSO-d 6) δ 13.40 (s, 1H), 12.18 (s, 1H), 8.75 (ddt, J = 4.9, 1.7, 0.9 Hz, 1H), 8.47 (d, J = 0.7 Hz, 1H), 8.27 (d, J = 0.9 Hz, 1H), 8.04 (dd, J = 8.0, 1.0 Hz, 1H), 7.97 – 7.88 (m, 1H), 7.45 – 7.37 (m, 1H), 5.08 – 4.77 (m, 1H), 2.63 – 2.35 (m, 4H), 1.82 (dtd, J = 10.5, 7.2, 2.2 Hz, 2H).

MS (ESI) (m/z): 392 [M+H]+ 17609606_1 (GHMatters) P106926.NZ II-122: N-(1-(2-(2,2-difluoroethoxy)ethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide. 1H NMR (400 MHz, DMSO-d 6) δ 13.43 (s, 1H), 12.21 (s, 1H), 8.75 (ddd, J = 4.9, 1.8, 1.0 Hz, 1H), 8.48 (s, 2H), 8.27 (s, 1H), 8.13 (s, 1H), 7.99 (dt, J = 8.1, 1.1 Hz, 1H), 7.95 – 7.84 (m, 1H), 7.38 (ddd, J = 7.5, 4.9, 1.2 Hz, 1H), 6.11 (tt, J = 54.9, 3.7 Hz, 1H), 4.40 (t, J = 5.2 Hz, 2H), 3.96 (t, J = 5.3 Hz, 2H), 3.72 (td, J = 15.1, 3.8 Hz, 2H).

MS (ESI) (m/z): 446 [M+H]+ II-123: N-(1-(((1r,3r)hydroxycyclobutyl)methyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide.

MS (ESI) (m/z): 422 [M+H]+ II-125: N-(1-(dimethylcarbamoyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole carboxamide.

MS (ESI) (m/z): 409 [M+H]+ 17609606_1 ters) P106926.NZ II-127: N-(1-((1s,3s)(ethoxy-d5)cyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol azolecarboxamide. 1H NMR (400 MHz, DMSO-d 6) δ 13.42 (s, 1H), 12.19 (s, 1H), 8.75 (ddd, J = 5.0, 1.8, 1.0 Hz, 1H), 8.49 (s, 1H), 8.45 (s, 1H), 8.27 (s, 1H), 8.11 (s, 1H), 8.03 (dt, J = 8.1, 1.1 Hz, 1H), 7.91 (ddd, J = 8.0, 7.5, 1.8 Hz, 1H), 7.39 (ddd, J = 7.5, 4.9, 1.2 Hz, 1H), 4.57 (tt, J = 9.0, 7.4 Hz, 1H), 3.79 (tt, J = 7.7, 6.6 Hz, 1H), 2.78 (dddd, J = 9.9, 9.0, 4.8, 2.7 Hz, 2H), 2.41 (dddd, J = 10.6, 9.0, 6.7, 2.8 Hz, 2H).

MS (ESI) (m/z): 441 [M+H]+ II-128: N-(1-(diethylcarbamoyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole carboxamide. 1H NMR (400 MHz, DMSO-d 6) δ 13.42 (s, 1H), 12.20 (s, 1H), 8.81 (ddd, J = 5.0, 1.7, 1.0 Hz, 1H), 8.76 (s, 1H), 8.34 (s, 1H), 8.32 – 8.16 (m, 2H), 8.11 – 7.97 (m, 2H), 7.52 (ddd, J = 7.3, 4.9, 1.4 Hz, 1H), 3.55 (d, J = 8.8 Hz, 4H), 1.27 (t, J = 6.9 Hz, 6H).

MS (ESI) (m/z): 437 [M+H]+ 17609606_1 (GHMatters) P106926.NZ II-129: N-(1-(morpholinecarbonyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole carboxamide. 1H NMR (400 MHz, DMSO-d 6) δ 12.21 (s, 1H), 8.83 (ddd, J = 5.0, 1.8, 1.0 Hz, 1H), 8.77 (s, 1H), 8.35 (s, 1H), 8.33 – 8.23 (m, 2H), 8.11 (dt, J = 8.0, 1.1 Hz, 1H), 8.02 (td, J = 7.8, 1.8 Hz, 1H), 7.54 (ddd, J = 7.5, 4.9, 1.3 Hz, 1H), 3.81 (s, 4H), 3.72 (dd, J = 5.6, 3.6 Hz, 4H).

MS (ESI) (m/z): 451 [M+H]+ II-130: N-(1-((1s,3s)(2-fluoroethoxy)cyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide. 1H NMR (400 MHz, DMSO-d 6) δ 13.42 (s, 1H), 12.18 (s, 1H), 8.75 (ddd, J = 5.0, 1.8, 1.0 Hz, 1H), 8.53 – 8.47 (m, 1H), 8.46 (s, 1H), 8.27 (s, 1H), 8.11 (s, 1H), 8.04 (dt, J = 8.0, 1.1 Hz, 1H), 7.92 (ddd, J = 8.1, 7.5, 1.8 Hz, 1H), 7.41 (ddd, J = 7.5, 4.9, 1.2 Hz, 1H), 4.68 – 4.54 (m, 2H), 4.52 – 4.45 (m, 1H), 3.90 (tt, J = 7.7, 6.5 Hz, 1H), 3.68 – 3.63 (m, 1H), 3.60 – 3.54 (m, 1H), 2.82 (dddd, J = 11.6, 7.3, 6.0, 2.7 Hz, 2H), 2.53 – 2.39 (m, 2H).

MS (ESI) (m/z): 454 [M+H]+ 06_1 (GHMatters) P106926.NZ II-132: N-(1-(3-fluorocyclobutenyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide.

MS (ESI) (m/z): 408 [M+H]+ II-134: N-(1-(3,3-difluorocyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole amide. 1H NMR (400 MHz, DMSO-d 6) δ 12.19 (s, 1H), 8.77 (ddd, J = 5.0, 1.8, 1.0 Hz, 1H), 8.56 (s, 1H), 8.29 (s, 1H), 8.06 (dt, J = 8.0, 1.1 Hz, 1H), 7.95 (td, J = 7.7, 1.8 Hz, 1H), 7.44 (ddd, J = 7.5, 4.9, 1.3 Hz, 1H), 5.07 (qd, J = 8.4, 6.5 Hz, 1H), 3.28 – 3.14 (m, 4H).

MS (ESI) (m/z): 428 [M+H]+ II-136: N-(3-cyano((1s,3s)hydroxycyclobutyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole carboxamide. 1H NMR (400 MHz, DMSO-d 6) δ 13.37 (s, 1H), 10.30 (s, 1H), 8.32 (s, 1H), 8.23 (s, 1H), 5.34 (d, J = 7.0 Hz, 1H), 4.50 (tt, J = 9.1, 7.3 Hz, 1H), 3.95 (q, J = 7.0 Hz, 1H), 2.83 – 2.69 (m, 2H), 2.33 (dddd, J = .9, 9.1, 6.7, 2.7 Hz, 2H).

MS (ESI) (m/z): 356 [M+H]+ II-137: N-(3-cyanomethyl-1H-pyrazolyl)(1H-pyrazolyl)thiazolecarboxamide. 17609606_1 (GHMatters) P106926.NZ 1H NMR (400 MHz, DMSO-d 6) δ 8.32 (s, 1H), 8.25 (s, 2H), 8.15 (s, 1H), 3.94 (s, 3H).

MS (ESI) (m/z): 300 [M+H]+ : N-(3-cyano((1s,3s)ethoxycyclobutyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole carboxamide. 1H NMR (300 MHz, DMSO-d 6) δ 13.29 (s, 1H), 8.22 (s, 2H), 8.06 (s, 1H), 8.05 – 7.54 (m, 2H), 4.54 – 4.28 (m, 1H), 3.92 (q, J = 6.9 Hz, 1H), 3.84 – 3.68 (m, 2H), 2.67 (q, J = 8.6, 7.9 Hz, 2H), 2.34 – 2.17 (m, 2H), 1.15 (t, J = 7.1 Hz, 3H).

MS (ESI) (m/z): 384 [M+H]+ II-140: N-(3-(3-fluoropyridinyl)(1,4-dioxaspiro[4.5]decanyl)-1H-pyrazolyl)(1H-pyrazol- 4-yl)thiazolecarboxamide.

MS (ESI) (m/z): 496 [M+H]+ 17609606_1 (GHMatters) P106926.NZ II-141: 2-(1H-pyrazolyl)-N-(3-(pyridinyl)((trans)(2,2,2-trifluoroethoxy)cyclobutyl)-1H- pyrazolyl)thiazolecarboxamide 1H NMR (300 MHz, DMSO-d 6) δ 13.41 (s, 1H), 12.18 (s, 1H), 8.76 (d, J = 4.8 Hz, 1H), 8.49 (s, 2H), 8.28 (s, 1H), 8.10 (m, 2H), 7.94 (m, 1H), 7.42 (t, J = 6.6 Hz, 1H), 5.09 (m, 1H), 4.54 (m, 1H), 4.05 (m, 2H), 2.71 (m, 2H), 2.60 (m, 2H). LCMS: purity: 88.96 %. MS (m/e): 489.48 (MH+).

II-143: N-(1-((trans)hydroxycyclohexyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol azolecarboxamide 1H NMR (300 MHz, DMSO-d 6) δ 13.41 (s, 1H), 12.18 (s, 1H), 8.74 (d, J = 4.8 Hz, 1H), 8.49 (s, 1H), 8.42 (s, 1H), 8.27 (s, 1H), 8.10 (s, 1H), 7.98 (m, 1H), 7.91 (t, J = 7.8 Hz, 1H), 7.39 (t, J = 6.0 Hz, 1H), 4.66 (d, J = 4.2 Hz, 1H), 4.25 (t, J = 11.1 Hz, 1H), 3.53 (m, 1H), 2.02 (m, 2H), 1.90 (m, 4H), 1.37 (m, 2H).

LCMS: purity: 94.52 %. MS (m/e): 435.51(MH+). 17609606_1 (GHMatters) P106926.NZ II-147: N-(1-((cis)ethoxycyclopentyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole- 4-carboxamide 1H NMR (300 MHz, DMSO-d 6) δ 13.36 (s, 1H), 12.14 (s, 1H), 8.69 (d, J = 4.8 Hz, 1H), 8.45 (s, 1H), 8.22 (s, 1H), 8.05 (s, 1H), 7.89 (m, 2H), 7.45 (m, 2H), 7.35 (m, 1H), 4.77 (m, 1H), 3.93 (m, 2H), 3.41 (m, 2H), 2.12 (m, 2H), 1.98 (m, 2H), 1.80 (m, 2H), 1.50 (t, J = 8.4 Hz, 3H). LCMS: purity: 96.91 %. MS (m/e): 449.53 (MH+).

II-149: N-(1-((cis)hydroxycyclopentyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide 1H NMR (300 MHz, DMSO-d 6) δ 12.18 (s, 1H), 8.75 (t, J = 0.9 Hz, 1H), 8.50 (d, J = 15.6 Hz, 1H), 8.27 (m, 3H), 7.95 (m, 2H), 7.38 (m, 1H), 4.80 (m, 1H), 4.21 (m, 1H), 3.60 (m, 1H), 2.19 (m, 2H), 2.12 (m, 2H), 1.81 (m, 2H). LCMS: purity: 95.63 %. MS (m/e): 421.48 (MH+). 06_1 (GHMatters) P106926.NZ II-151: (trans)hydroxycyclopentyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide 1H NMR (300 MHz, DMSO-d 6) δ 12.17 (s, 1H), 8.73 (t, J = 1.8 Hz, 1H), 8.44 (s, 1H), 8.27 (m, 3H), 7.92 (m, 2H), 7.40 (m, 1H), 4.98 (m, 1H), 4.38 (m, 1H), 3.44 (m, 1H), 2.24 (m, 2H), 2.07 (m, 3H), 1.72 (m, 1H). LCMS: purity: 100 %. MS (m/e): 421.48 (MH+).

II-153: N-(1-((cis)ethoxycyclobutyl)(5-fluoropyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide 1H NMR (300 MHz, DMSO-d 6) δ 13.36 (s, 1H), 11.76 (s, 1H), 8.68 (d, J = 3.0 Hz, 1H), 8.47 (s, 1H), 8.42 (s, 1H), 8.23 (s, 1H), 8.06 (s, 1H), 7.85 (m, 1H), 7.50 (m, 1H), 4.54 (m, 1H), 3.75 (m, 1H), 3.40 (m, 2H), 2.74 (m, 2H), 2.42 (m, 2H), 1.08 (t, J = 7.2 Hz, 3H). LCMS: purity: 96.80 %. MS (m/e): 453.50 (MH+). 17609606_1 (GHMatters) P106926.NZ II-155: N-(1-((cis)ethoxyfluorocyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide 1H NMR (300 MHz, CDCl 3) δ 12.39 (s, 1H), 8.71 (d, J = 3.9 Hz, 1H), 8.47 (s, 1H), 8.13 (d, J = 8.1 Hz, 1H), 8.07 (s, 1H), 7.78 (t, J = 7.8 Hz, 1H), 7.56 (m, 2H), 7.25 (t, J = 3.9 Hz, 1H), 5.17 (m, 1H), 4.36 (m, 1H), 3.93 (m, 1H), 3.64 (m, 1H), 2.76 (t, J = 8.7 Hz, 1H), 2.18 (q, J = 18.6 Hz, 1H), 1.55 (s, 1H), 1.29 (t, J = 6.9 Hz, 3H). LCMS: purity: 96.40 %. MS (m/e): 453.50 (MH+).

II-157: N-(1-((cis)ethoxycyclobutyl)(3-fluoropyridinyl)-1H-pyrazolyl)(1H-pyrazol azolecarboxamide 1H NMR (300 MHz, DMSO-d 6) δ 13.41 (s, 1H), 12.05 (s, 1H), 8.56 (m, 1H), 8.52 (s, 1H), 8.49 (s, 1H), 8.28 (s, 1H), 8.09 (s, 1H), 7.90 (t, J = 9.9 Hz, 1H), 7.53 (m, 1H), 4.61 (m, 1H), 3.83 (m, 1H), 3.42 (m, 2H), 2.81 (m, 2H), 2.42 (m, 2H), 1.14 (t, J = 7.2 Hz, 3H). LCMS: purity: 100 %. MS (m/e): 453.50 (MH+). 17609606_1 (GHMatters) P106926.NZ II-158: N-(1-((cis)ethoxycyclobutyl)(4-fluoropyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide 1H NMR (300 MHz, DMSO-d 6) δ 13.25 (s, 1H), 11.43 (s, 1H), 8.78 (m, 1H), 8.45 (s, 1H), 8.26 (s, 1H), 7.95 (s, 1H), 7.79 (m, 1H), 7.36 (m, 1H), 7.28 (d, J = 3.6 Hz, 1H), 4.61 (m, 1H), 3.83 (m, 1H), 3.41 (m, 2H), 2.80 (m, 2H), 2.41 (m, 2H), (t, J = 6.9 Hz, 3H). LCMS: purity: 100 %. MS (m/e): 453.50 (MH+).

II-160: N-(1-((cis)ethoxycyclobutyl)(6-fluoropyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide 1H NMR (300 MHz, DMSO-d 6) δ 13.42 (s, 1H), 11.58 (s, 1H), 8.50 (s, 1H), 8.46 (s, 1H), 8.29 (s, 1H), 8.16 (s, 1H), 8.13 (m, 1H), 7.96 (d, J = 2.4 Hz, 1H), 7.20 (d, J = 7.8 Hz, 1H), 4.63 (m, 1H), 3.83 (m, 1H), 3.40 (m, 2H), 2.80 (m, 2H), 2.45 (m, 2H), 1.14 (t, J = 6.9 Hz, 3H). LCMS: purity: 100 %. MS (m/e): 453.50 (MH+). 17609606_1 ters) P106926.NZ II-161: 2-(1H-pyrazolyl)-N-(3-(pyridinyl)((cis)(2,2,2-trifluoroethoxy)cyclobutyl)-1H- pyrazolyl)thiazolecarboxamide 1H NMR (300 MHz, DMSO-d 6) δ 13.43 (s, 1H), 12.18 (s, 1H), 8.76 (t, J = 4.2 Hz, 1H), 8.48 (t, J = 3.0 Hz, 2H), 8.13 (s, 1H), 8.04 (d, J = 6.9 Hz, 1H), 7.96 (m, 2H), 7.43 (m, 1H), 5.07 (m, 1H), 4.54 (m, 1H), 4.08 (m, 2H), 2.74 (m, 2H), 2.61 (m, 2H). LCMS: purity: 97.81 %. MS (m/e): 489.48 (MH+).

II-163: (4-(4-((1-((cis)ethoxycyclobutyl)(3-fluoropyridinyl)-1H-pyrazol yl)carbamoyl)thiazolyl)-1H-pyrazolyl)methyl ogen phosphate 1H NMR (300 MHz, DMSO-d 6) δ 12.10 (s, 1H), 8.72 (m, 1H), 8.60 (s, 1H), 8.52 (s, 1H), 8.34 (s, 1H), 8.17 (s, 1H), 7.89 (m, 1H), 7.50 (m, 1H), 5.92 (s, 1H), 5.88 (s, 1H), 4.63 (m, 1H), 3.83 (m, 1H), 3.40 (m, 2H), 2.82 (m, 2H), 2.44 (m, 2H), 1.13 (t, J = 6.9 Hz, 3H). LCMS: purity: 95.89 %. MS (m/e): 563.50 (MH+). 17609606_1 (GHMatters) P106926.NZ II-164: (4-(4-((1-((cis)ethoxycyclobutyl)(3-fluoropyridinyl)-1H-pyrazol bamoyl)thiazolyl)-1H-pyrazolyl)methyl disodium phosphate 1H NMR (300 MHz, Deuterium Oxide) δ 8.11 (s, 1H), 8.04 (d, J = 4.2 Hz, 1H), 8.00 (s, 1H), 7.68 (s, 1H), 7.56 (s, 1H), 7.41 (t, J = 8.1 Hz, 1H), 7.16 (m, 1H), 5.62 (s, 1H), 5.59 (s, 1H), 4.30 (m, 1H), 3.93 (m, 1H), 3.50 (m, 2H), 2.85 (m, 2H), 2.26 (m, 2H), 1.12 (t, J = 6.9 Hz, 3H). LCMS: purity: 95.89 %. MS (m/e): 563.50 (MH+).

II-165: N-(3-(3-fluoropyridinyl)((cis)(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazolyl) (1H-pyrazolyl)thiazolecarboxamide 1H NMR (300 MHz, DMSO-d 6) δ 13.37 (s, 1H), 12.00 (s, 1H), 8.60 (d, J = 4.8 Hz, 1H), 8.48 (s, 1H), 8.40 (s, 1H), 8.24 (s, 1H), 8.18 (s, 1H), 7.83 (m, 1H), 7.46 (m, 1H), 4.58 (m, 1H), 3.98 (m, 2H), 3.54 (m, 1H), 2.78 (m, 2H), 2.44 (m, 2H). LCMS: purity: 96.48 %. MS (m/e): 507.47 (MH+). 17609606_1 (GHMatters) P106926.NZ II-167: N-(3-(3-fluoropyridinyl)((trans)(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazolyl) (1H-pyrazolyl)thiazolecarboxamide 1H NMR (300 MHz, DMSO-d 6) δ 13.41 (s, 1H), 12.06 (s, 1H), 8.66 (d, J = 4.5 Hz, 1H), 8.55 (s, 1H), 8.28 (m, 3H), 7.91 (m, 1H), 7.55 (m, 1H), 5.11 (m, 1H), 4.52 (m, 1H), 4.05 (m, 2H), 2.71 (m, 2H), 2.48 (m, 2H). LCMS: purity: 95.89 %. MS (m/e): 507.47 (MH+).

: N-(1-((trans)ethoxycyclohexyl)(3-fluoropyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide 1H NMR (300 MHz, DMSO-d 6) δ 13.42 (s, 1H), 12.07 (s, 1H), 8.64 (d, J = 3.3 Hz, 1H), 8.48 (s, 2H), 8.28 (s, 1H), 8.09 (s, 1H), 7.87 (m, 1H), 7.53 (m, 1H), 4.32 (m, 1H), 3.44 (m, 2H), 3.35 (m, 1H), 2.06 (m, 4H), 1.92 (m, 2H), 1.38 (m, 2H), 1.10 (t, J = 6.9 Hz, 3H). LCMS: purity: 97.81 %. MS (m/e): 481.55 (MH+). 17609606_1 (GHMatters) P106926.NZ II-170: 6-fluoropyridinyl)((cis)(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazolyl) (1H-pyrazolyl)thiazolecarboxamide 1H NMR (300 MHz, DMSO-d 6) δ 13.37 (s, 1H), 11.53 (s, 1H), 8.49 (d, J = 6.9 Hz, 1H), 8.24 (m, 4H), 8.08 (m, 1H), 7.93 (m, 1H), 7.16 (d, J = 7.5 Hz, 1H), 4.60 (m, 1H), 4.00 (m, 3H), 2.78 (m, 2H), 2.46 (m, 2H). LCMS: purity: 100 %. MS (m/e): 507.47 (MH+).

II-172: N-(3-(6-fluoropyridinyl)((cis)hydroxycyclobutyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide 1H NMR (300 MHz, DMSO-d 6) δ 13.44 (s, 1H), 11.58 (s, 1H), 8.53 (s, 1H), 8.50 (s, 1H), 8.41 (s, 1H), 8.28 (s, 1H), 8.10 (m, 1H), 7.95 (d, J = 7.5 Hz, 1H), 7.20 (d, J = 7.8 Hz, 1H), 5.32 (m, 1H), 4.50 (m, 1H), 3.96 (m, 1H), 2.79 (m, 2H), 2.40 (m, 2H). LCMS: purity: 100 %. MS (m/e): 425.45 (MH+). 17609606_1 (GHMatters) P106926.NZ II-173: (4-(4-((1-((cis)ethoxycyclobutyl)(6-fluoropyridinyl)-1H-pyrazol yl)carbamoyl)thiazolyl)-1H-pyrazolyl)methyl ogen phosphate 1H NMR (300 MHz, DMSO-d 6) δ 11.59 (s, 1H), 8.61 (s, 1H), 8.51 (s, 1H), 8.35 (s, 1H), 8.22 (s, 1H), 8.10 (m, 1H), 7.96 (m, 1H), 7.21 (d, J = 6.6 Hz, 1H), 5.86 (s, 1H), 5.82 (s, 1H), 4.63 (m, 1H), 3.84 (m, 1H), 3.40 (m, 2H), 2.81 (m, 2H), 2.43 (m, 2H), 1.14 (t, J = 7.2 Hz, 3H). LCMS: purity: 100 %. MS (m/e): 563.51 (MH+).

II-174: N-(3-(3,6-difluoropyridinyl)((cis)ethoxycyclobutyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide 1H NMR (300 MHz, DMSO-d 6) δ 13.41 (s, 1H), 11.46 (s, 1H), 8.56 (s, 1H), 8.44 (s, 1H), 8.30 (s, 1H), 8.14 (m, 2H), 7.32 (m, 1H), 4.62 (m, 1H), 3.83 (m, 1H), 3.39 (m, 2H), 2.80 (m, 2H), 2.40 (m, 2H), 1.15 (t, J = 7.5 Hz, 3H). LCMS: purity: 100 %. MS (m/e): 471.49 (MH+). 17609606_1 (GHMatters) P106926.NZ II-175: N-(1-((cis)ethoxycyclohexyl)(3-fluoropyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide 1H NMR (300 MHz, DMSO-d 6) δ 13.41 (s, 1H), 12.07 (s, 1H), 8.65 (d, J = 4.2 Hz, 1H), 8.49 (s, 1H), 8.45 (s, 1H), 8.28 (s, 1H), 8.08 (s, 1H), 7.85 (m, 1H), 7.50 (m, 1H), 4.33 (m, 1H), 3.55 (m, 1H), 3.43 (m, 2H), 2.05 (m, 2H), 1.91 (m, 4H), 1.59 (m, 2H), 1.14 (t, J = 6.6 Hz, 3H). LCMS: purity: 100 %. MS (m/e): 481.55 (MH+).

II-176: 3,6-difluoropyridinyl)((trans)ethoxycyclohexyl)-1H-pyrazolyl)(1H-pyrazol- 4-yl)thiazolecarboxamide 1H NMR (300 MHz, DMSO-d 6) δ 13.41 (s, 1H), 11.47 (s, 1H), 8.53 (s, 1H), 8.49 (s, 1H), 8.44 (s, 1H), 8.30 (s, 1H), 8.09 (s, 1H), 7.28 (m, 1H), 4.33 (m, 1H), 3.46 (m, 1H), 3.35 (m, 2H), 2.10 (m, 2H), 1.86 (m, 4H), 1.33 (m, 2H), 1.11 (t, J = 7.2 Hz, 3H). LCMS: purity: 97.57 %. MS (m/e): 499.54 (MH+). 17609606_1 (GHMatters) P106926.NZ II-177: N-(3-(3,6-difluoropyridinyl)((cis)ethoxycyclohexyl)-1H-pyrazolyl)(1H-pyrazol azolecarboxamide 1H NMR (300 MHz, DMSO-d 6) δ 13.41 (s, 1H), 11.47 (s, 1H), 8.53 (s, 1H), 8.49 (s, 1H), 8.44 (s, 1H), 8.29 (s, 1H), 8.09 (s, 1H), 7.28 (m, 1H), 4.36 (m, 1H), 3.55 (m, 1H), 3.43 (m, 2H), 2.05 (m, 2H), 1.90 (m, 4H), 1.59 (m, 2H), 1.14 (t, J = 7.2 Hz, 3H). LCMS: purity: 100 %. MS (m/e): 499.54 (MH+).

II-178: N-(1-((1r,4r)ethoxycyclohexyl)(1,3,4-oxadiazolyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide.

LCMS (m/z): 455.28 (MH+).

II-179: N-(1-((1r,4r)((2,2-difluoroethyl)amino)cyclohexyl)(pyrimidinyl)-1H-pyrazolyl) (1H-pyrazolyl)thiazolecarboxamide. 17609606_1 (GHMatters) P106926.NZ 1H NMR (DMSO d 6, 300MHz): δ 13.42 (s, 1H), 11.93 (s, 1H), 8.98 (d, J = 6.7Hz, 2H), 8.50 (s, br, 2H), 8.31 (s, IH), 8.12 (s, 1H),0 .47 (m, 1H), 6.16-5.78 (m, 1H), 4.35-4.27 (m, 1H), 3.00-2.88 (m, 2H), 2.12-1.82 (m, 6H), 1.29-1.17 (m, 2H); LCMS (m/z): 500.18 (MH+).

II-180: N-(3-(3,5-difluoropyridinyl)((1r,4r)ethoxycyclohexyl)-1H-pyrazolyl)(1H-pyrazol- 4-yl)thiazolecarboxamide. 1H NMR (300 MHz, DMSO-d 6) δ 11.67 (s, 1H), 8.68 (d, J = 2.4 Hz, 1H), 8.49 (s, 0H), 8.28 (s, 1H), 8.11 (ddd, J = 11.3, 9.1, 2.4 Hz, 1H), 4.31 (t, J = 11.6 Hz, 1H), 3.47 (q, J = 7.0 Hz, 2H), 2.08 (d, J = 11.5 Hz, 4H), 1.85 (q, J = 12.3, 11.9 Hz, 2H), 1.35 (q, J = 10.7 Hz, 2H), 1.10 (t, J = 7.0 Hz, 3H). LCMS (m/z): 500.44 (MH+).

III-1: 2-(1-(cyclopropylmethyl)-1H-pyrazolyl)-N-(1-methyl(pyridinyl)-1H-pyrazol yl)oxazolecarboxamide. 1H NMR (300 MHz, DMSO-d6) δ 11.99 (s, 1H), 8.82 (d, J = 4.8 Hz, 1H), 8.72 (s, 1H), 8.52 (s, 1H), 8.38 (s, 1H), 8.08 (s, 1H), 7.98 – 7.88 (m, 2H), 7.40 – 7.36 (m, 1H), 4.09 (d, J = 6.9 Hz, 2H), 3.93 (s, 3H), 1.32 (m, 1H), 0.59 – 0.53 (m, 2H), 0.45 – 0.40 (m, 2H); LCMS: purity: 100%; MS (m/e): 390.59 (MH+).

III-2: 2-(1H-pyrazolyl)-N-(3-(pyridinyl)(tetrahydro-2H-pyranyl)-1H-pyrazolyl)oxazole- 4-carboxamide. 17609606_1 (GHMatters) P106926.NZ 1H NMR (300 MHz, DMSO-d 6) δ 13.54 (s, 1H), 12.04 (s, 1H), 8.86 (ddd, J = 5.0, 1.7, 0.9 Hz, 1H), 8.74 (s, 1H), 8.61 – 8.49 (m, 1H), 8.46 (s, 1H), 8.26 – 8.08 (m, 1H), 8.04 – 7.98 (m, 1H), 7.93 (td, J = 7.7, 1.8 Hz, 1H), 7.44 – 7.34 (m, 1H), 4.67 – 4.42 (m, 1H), 4.06 – 3.95 (m, 2H), 3.55 – 3.42 (m, 2H), 2.04 (h, J = .0, 4.3 Hz, 4H); MS (ESI) (m/z): 406 [M+H]+.

III-3: N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)oxazole amide. 1HNMR (300 MHz, DMSO-d6) δ 12.02 (s, 1H), 8.86 (d, J = 6.7 Hz, 2H), 8.74 (s, 1H), 8.44 (s, 1H), 8.34 (s, 1H), 8.01 – 7.90 (m, 2H), 7.42 – 7.38 (m, 1H), 4.37 (t, J = 6.7 Hz, 2H), 3.79 (t, J = 6.7 Hz, 2H), 3.46 (q, J = 6.7 Hz, 2H), 1.09 (t, J = 6.7 Hz, 3H); LCMS (m/z): 394.21 (MH+).

III-4: N-(1-((1s,3s)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)oxazole- 4-carboxamide. 1HNMR (300 MHz, DMSO-d6) δ 12.01 (s, 1H), 8.86 (d, J = 6.7 Hz, 1H), 8.74 (s, 1H), 8.45 (s, 1H), 8.33 (s, 1H), 8.06 – 8.03 (m, 1H), 7.97 – 7.92 (m, 1H), 7.43 – 7.39 (m, 1H), 4.65 – 4.59 (m, 1H), 3.87 – 3.82 (m, 1H), 3.42 (q, J = 6.7 Hz, 2H), 2.86 – 2.77 (m, 2H), 2.45 – 2.41 (m, 1H), 1.15 (t, J = 6.7 Hz, 3H); LCMS (m/z): 420.21 (MH+). 17609606_1 (GHMatters) P106926.NZ III-5: N-(1-cyclobutyl(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)oxazolecarboxamide as formate salt.

LCMS (m/z): 376.20 (MH+).

III-6: N-(1-(2-(2-methoxyethoxy)ethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)oxazole- 4-carboxamide. 1HNMR (300 MHz, DMSO-d6) δ 12.02 (s, 1H), 8.86 (d, J = 6.7 Hz, 1H), 8.74 (s, 1H), 8.44 (s, 1H), 8.34 (s, 1H), 8.01 – 7.90 (m, 2H), 7.42 – 7.38 (m, 1H), 4.37 (t, J = 6.7 Hz, 2H), 3.84 (t, J = 6.7 Hz, 2H), 3.56 – 3.53 (m, 2H); 3.44 – 3.41 (m, 2H); 3.22 (s, 3H); LCMS (m/z): 424.24 (MH+).

III-7: 2-(1H-pyrazolyl)-N-(3-(pyridinyl)(2-(2,2,2-trifluoroethoxy)ethyl)-1H-pyrazol yl)oxazolecarboxamide. 1HNMR (300 MHz, DMSO-d6) δ 12.03 (s, 1H), 8.87 (d, J = 6.7 Hz, 1H), 8.74 (s, 1H), 8.46 (s, 1H), 8.01 – 7.94 (m, 2H), 7.43 – 7.39 (m, 1H), 4.44 (t, J = 6.7 Hz, 2H), 4.13 – 4.01 (m, 4H); LCMS (m/z): 448.17 (MH+). 06_1 (GHMatters) P106926.NZ III-8: N-(1-(2-(2,2-difluoroethoxy)ethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)oxazole- 4-carboxamide. 1H NMR (400 MHz, DMSO-d 6) δ 13.53 (s, 1H), 12.04 (s, 1H), 8.84 (ddd, J = 5.0, 1.8, 1.0 Hz, 1H), 8.71 (s, 1H), 8.46 (s, 1H), 7.98 (dt, J = 8.0, 1.1 Hz, 1H), 7.89 (ddd, J = 8.1, 7.4, 1.8 Hz, 1H), 7.36 (ddd, J = 7.4, 4.9, 1.3 Hz, 1H), 6.11 (tt, J = 54.9, 3.7 Hz, 1H), 4.40 (t, J = 5.2 Hz, 2H), 3.96 (t, J = 5.3 Hz, 2H), 3.72 (td, J = 15.2, 3.7 Hz, 2H).

MS (ESI) (m/z): 430 [M+H]+ Example 24 LPS induced IL23p19 in THP-1 cells (with IFNγ primed) Assay Materials and Equipment THP-1 Cells (ATCC, Cat# 2), Dimethyl Sulfoxide (DMSO) (Sigma-Aldrich, Cat# D2650), RPMI 1640 (Cellgro, Cat# 10CM), Fetal Bovine Serum (Sigma, Cat# F4135), Albumin From Bovine Serum (BSA) (Sigma-Aldrich, Cat#A7906), LPS (Serotype K-235, Sigma, Product Number L 2143), IFN (Peprotech, Cat# 300-02) e antibody: Human IL-23p19 ELISA (e-Bioscience, Cat. # 1485), Detection antibody: Primary Mouse Biotinylated anti-human p40/p70) (e-Bioscience, Cat. # 9-85), Secondary HRP- conjugated Streptavidin (R&D Systems, Cat#DY998), 1x PBST Washing Buffer (PBS-Tween tablet) (VWR International, Cat#80058-558), ELISA Blocking Buffer (PBS with 1% BSA), ELISA Dilution Buffer (PBS with 1% BSA), 384 Well ottom, rp Black Immuno Plates (Thermo Scientific, Cat# 12 346), 384 Well Flat-Bottom, White Tissue Culture Plates (Thermo Scientific, Cat# 12343), Super Signal ELISA Pico Chemiluminescent Substrate (Thermo Scientific, Cat#37070), Cell Titer Glo reagent (Promega, Cat#G7573), Positive control, IKK2VI inhibitor (Calbiochem, Cat#401483), AquaMax 4000 plate washer (Molecular Devices), Luminometer, Wallac 2 1420 Multilabel Counter.

Method THP-1 Cells Stimulation: On day 1, 50K/well THP-1 cells were seeded and primed with IFN (50ng/mL) in 384-well plates for about 18 hours in RPMI media with 10%FBS. On day 2, the compound was serially d in DMSO 17609606_1 (GHMatters) P106926.NZ from 5 mM in 3-fold dilutions, and then diluted 1:125 in RPMI media with 10%FBS. 50 L/well 2x compound was added to 50 l THP-1 cells (with IFNy primed) in duplicate in 384 well tissue culture plates. The cells were pre-incubated with compound for 1 hour at 37 C, 5 % CO2 before on of L/well 11x LPS to give a final concentration of 1 ug/mL LPS. Day 3, after ation for 18 hours at 37 C, 5 % CO2, the assay plate was centrifuged and 70 L/well supernatant was harvested. IL-23p19 protein in 70 L/well of atant was measured by sandwich ELISA, and 25 µl/well Cell Titer Glo reagent was added to the remaining cells to measure compound toxicity.

Human IL-23p19 Sandwich ELISA: Maxisorp immuno ELISA plates were pre-coated with 25 L/well of anti-IL-23p19 capture antibody (2.5ug/mL) in PBS overnight at room temperature. After washing with 1x PBST, the plates were blocked using 100µL/well of 1% BSA in PBS for 2 hours at room temperature. The plates were washed three times with 1x PBST and 70 L/well supernatant were added. The plates were incubated at room temperature for 2 hours with shaking and washed three times with 1x PBST. 25 L/well of biotin labeled anti-IL-12(p40/p70) detection antibody (100 ng/mL) in PBS with 1% BSA was added and the plates were incubated at room temperature for 2 hours with shaking. After g three times with 1x PBST, 25 L/well of streptavidin- HRP (1:200) in PBS with 1% BSA was added and the plates were incubated at room temperature for 20 minutes with shaking. The plates were washed three times with 1x PBST and 25 L/well of Super Signal ELISA Pico Chemiluminescent Substrate were added. The plates were read with a luminometer, and the chemiluminescence values were entered into Athena (Rigel) for curve fitting, EC50 calculation, and database storage. The s are shown in Table 1.

Example 25 Compound ing Using DC Cells Materials Human PBMC cells (All Cells, Cat No. PB002) RPMI growth media containing 10% FBS IFN (Peprotech, Cat No. 300-02) GMCSF tech, Cat No. 300-03) and IL4 (Peprotech Cat No. 200-04) White clear bottom 96 well plates (Fisher, Cat No. 07587, Corning #3903) LPS (Make 2.5 mg/ml Stock in PBS) from Sigma Aldrich (Cat No. L2018-5MG) Cell Titer Glo reagent (Promega, Cat No. G7573) Positive controls, IKK2VI inhibitor (Calbiochem, Cat No. 401483) Protocol I. Differentiation of PBMC’s to DC cells: Human PBMC cells (400 n) obtained from the vendor were erred into a T-175 flask containing 15 ml RPMI media (10% FBS) and incubate for 2 hours at 37 ˚C. After 2 hours, the media 17609606_1 (GHMatters) P106926.NZ including floating cells was aspirated out carefully and 12 ml of fresh RPMI media (10% FBS) containing GMCSF (100 ng/ml) and IL4 (20 ng/ml) was added, and the flask was kept in a 37 ˚C incubator for 7 days.

After 3 days, fresh GMCSF (100 ng/ml) and IL4 (20 ng/ml) were added to the flask and the incubation continued. After 7 days, the fully differentiated cells were harvested by spinning down (1200 rpm / 5 min) and aspirating the media. The cells were suspended in fresh RPMI media (10% FBS) ning 50ng/ml IFNγ (1000 U/ml) and then plated (50K/well in 100 µl) onto a white clear bottom 96 well plate and left in a 37 ˚C tor for 24 hours.

II. Addition of compounds: After 24 hours incubation, 100 µl of RPMI media was added ning 2X concentrated test compound per well to the above cell-culture media (final concentration becomes 1X) and the plates were pre-incubated for 1 hour at 37 ˚C before stimulating with LPS.

After 1 hour compound pre-incubation, 10 µl per well of 20X concentrated LPS on in RPMI media was added to give a final concentration of 1 µg/ml. The mixture was shaken and incubated the plates at 37 ˚C for an additional 18 hours. 155 µl of the supernatant was harvested from each well carefully (without the tip touching the bottom of the well) and to the remaining 50 µl / well of the cell culture plate was added 50 µl of Cell Titer Glo reagent. The mixture was incubated for 1-2 minutes on a shaker and the plate was read for luminescence intensity to determine the compound cytotoxicity. The cell e supernatant collected above was used to carry out IL23 ELISA (65 µl -Supernatant) and IL10 ELISA (90 µl – Supernatant) as described below.

Example 26 Human IL-23 (p19/p40) ELISA Protocol (e-Biosciences) Materials: 96-well high binding opaque white plates (from Pierce, Cat No. 15042); 1X PBS; 1X TBST washing buffer; Blocking Solution: 0.5% Casein in PBS (from BDH, Cat No. 440203H); Dilution Solution: 1% BSA in PBS (10% BSA from Fisher, Cat No. 37525); Capture antibody: Rat anti-human IL-23 (p19) (e-Biosciences, Cat. No. 1485); Detection antibody: Primary Mouse Biotinylated anti-human IL-12 (p40/p70) (e-biosciences, Cat No. 13- 7129-85); Secondary HRP-conjugated Streptavidin (R&D Systems, Cat No. ; -IL-23 (e-biosciences, Cat No. 9) (Suggested starting concentration = 5 ng/ml in RPMI cell culture media); Cell Culture Supernatant (65 µl from THP-1 cells primed with IFNγ (50 ng/ml – 1000 U/ml) and stimulated with 0.01% SAC); SuperSignal ELISA Pico uminescent substrate e, Cat No. 37069]. 17609606_1 (GHMatters) P106926.NZ Coating Plates: To 10.5 ml PBS add 50 µl of anti-IL23 (p19) was added capture antibody (2.5µg/ml). The mixture was mixed well and 100 µl of the coating solution was added to each well of the 96 well white plates from Pierce. The wells were covered and incubated overnight at 4 ˚C.

Blocking the plates: The anti-IL23 (p19)-antibody-coated plates were washed 2X using TBST (use plate washer) and blocked using 200 µl of 0.5% Casein for 1.5-2 hours at room ature with shaking.

Addition of atant and Detection: The plates were washed 2X using TBST and the supernatant was transferred (65 µl/well) to the above pre-blocked / IL23(p19)-antibody-coated 96 well plate, and incubated at room ature for 1.5 hours with g.

The plates were washed 4X using TBST (plate washer) and 100 µl/well detection antibody solution prepared from 2 µl of biotin labeled anti-IL-12 (p40/p70) antibody in 11 ml 1%BSA/PBS solution 0 dilution) was added. The plates were incubated for 1 hour with shaking at Room temperature.

Again, the plates were washed 4X with TBST and 100 µl of HRP labeled Streptavidin (R&D Systems) solution (10 µl /10 ml 1%BSA solution) was added, and the plates were incubated at room temperature for r 45 minutes with shaking.

After 45 s, the plates were washed with TBST 4X and 100 ul / well Super Signal ELISA Pico Chemiluminescent Substrate from Pierce (3.5 ml A + 3.5 ml B + 3.5 ml MQ water) was added. The plates were shaken for 1-2 minutes then read on a plate reader.

The EC50 results from the assays described in Examples 24 and 26 are shown in Tables 1-3.

Table 1 IL23-p19 19 IL23-p19 IL23-p19 ELISA, ELISA, ELISA, ELISA, Compound Dendritic, THP1-IFNy, Compound Dendritic, THP1-IFNy, LPS, 10pt, LPS, 10pt LPS, 10pt LPS, 10pt EC50 (µM) EC50 (µM) EC50 (µM) EC50 (µM) I-1 3.731 5.662 I-73 0.4102 0.697 I-3 0.3619 0.4237 I-74 0.1311 0.1514 I-4 0.6189 0.7126 I-75 0.0195 0.1024 I-5 0.136 0.0826 I-77 0.041 0.0504 I-6 0.9932 0.2635 I-78 0.1051 0.0784 I-7 0.3991 0.4334 I-80 2.06 2.223 I-8 0.4294 0.88 I-81 0.9595 0.1529 I-9 0.3092 0.281 I-82 0.7802 0.2052 I-10 3.271 21.94 I-83 0.0932 0.0348 I-11 5.192 4.845 I-84 0.0977 0.0423 I-12 1.05 0.5925 I-85 0.0196 0.0767 17609606_1 (GHMatters) P106926.NZ I-13 11.01 136.5 I-86 0.0637 0.0614 I-14 0.5714 1.246 I-87 0.1051 0.0433 I-15 2.2 2.232 I-89 0.0231 0.0166 I-16 0.4029 0.1249 I-91 0.0106 0.0122 I-17 0.4244 0.285 I-93 0.008 0.0108 I-18 1.197 0.5139 I-95 0.0338 0.0678 I-19 0.3368 0.3 I-97 0.0329 0.0362 I-20 0.1945 0.1666 I-99 0.0156 0.018 I-21 0.4582 0.2013 I-101 0.0501 0.0143 I-22 1.552 0.2036 I-103 0.0554 0.031 I-23 0.0372 0.0217 I-105 0.0265 8888 I-24 7777 4.218 I-106 1.221 18.89 I-25 0.0441 0.0571 I-107 0.3054 0.8602 I-26 0.2755 1.323 I-108 0.7298 0.4911 I-27 0.0158 0.1594 I-109 0.0221 0.1041 I-28 0.0218 0.0497 I-110 0.3881 0.2792 I-29 0.0972 0.2064 I-111 0.0268 0.0291 I-30 0.0589 0.038 I-112 0.0407 0.0428 I-31 1.253 6.289 I-133 0.3865 0.0806 I-32 0.083 0.0288 I-114 0.0616 0.0493 I-34 0.0144 0.0138 I-115 0.3649 0.0913 I-35 0.5201 0.0633 I-116 0.2182 0.2265 I-37 0.0174 0.1439 I-117 0.0257 0.2837 I-38 0.0582 0.1721 I-118 0.1607 0.0681 I-39 4.317 1.953 I-119 0.4303 0.1535 I-41 3.945 2.568 I-120 0.0948 0.0528 I-43 9999 4464 I-122 9999 3.764 I-45 5.449 1.084 I-124 0.1012 0.0534 I-47 0.3271 0.3924 I-126 0.0215 0.0819 I-48 7.505 5.518 I-128 0.0604 0.1339 I-50 3.506 14.24 I-130 0.023 0.0483 I-52 9999 1.378 I-132 0.1028 0.0812 I-54 1.575 0.617 I-134 0.091 0.0296 I-55 0.8006 1.204 I-136 0.0878 0.0448 I-56 7.718 0.1562 I-138 0.6863 0.9263 I-58 27.53 2.812 I-140 0.224 0.7994 I-60 0.0338 0.1745 I-142 0.0262 0.0689 I-62 0.1148 0.0481 I-144 0.0343 0.078 I-64 0.3663 0.0777 I-146 0.3704 0.1494 I-65 0.1993 0.0543 I-148 0.11 0.1732 17609606_1 ters) P106926.NZ I-67 0.0041 0.0723 I-150 0.2258 0.0648 I-69 0.3249 1.249 I-152 0.0716 0.0319 I-70 0.0283 0.3662 I-154 1.392 0.0575 I-71 0.0225 0.0265 I-156 0.1052 0.0595 I-72 0.005 0.0568 Table 2 IL23-p19 IL23-p19 IL23-p19 IL23-p19 ELISA, ELISA, ELISA, ELISA, Compound Dendritic, THP1-IFNy, Compound Dendritic, THP1-IFNy, LPS, 10pt, LPS, 10pt LPS, 10pt LPS, 10pt EC50 (µM) EC50 (µM) EC50 (µM) EC50 (µM) II-1 0.7791 0.1288 II-85 0.2866 0.0499 II-2 0.2981 0.1962 II-86 5.782 0.1372 II-3 0.3707 0.1976 II-87 Not tested 0.6147 II-4 0.3066 0.0861 II-88 0.3898 0.0965 II-5 0.157 0.0902 II-89 1.127 0.5891 II-6 6.888 0.0874 II-90 0.2176 0.176 II-7 9999 6.087 II-91 9999 Not tested II-8 9999 9999 II-92 0.2583 Not tested II-10 0.0105 0.0226 II-93 9999 0.1087 II-11 0.0623 0.05 II-94 0.0333 0.3106 II-12 0.0616 0.1353 II-95 6.225 2.25 II-13 10.39 4.799 II-96 0.4566 0.0837 II-14 0.0057 0.0434 II-97 9999 8 II-15 0.0096 0.0064 II-98 9999 24.64 II-16 0.5254 0.121 II-99 0.9888 0.4203 II-18 0.0314 0.3009 II-100 0.2259 0.0561 II-19 3.508 4.006 II-101 0.0355 0.023 II-21 0.5689 0.3147 II-102 0.0554 0.0619 II-23 16.29 4.761 II-103 9999 8.08 II-25 0.1704 0.1465 II-105 7777 5.546 II-26 0.1125 0.0771 II-107 2.309 1.503 II-27 0.3314 0.0741 II-109 0.3273 0.1399 II-28 0.063 0.2757 II-111 0.0343 0.0651 II-29 0.2482 0.1349 II-113 0.2881 0.0844 II-31 0.7993 0.1701 II-115 0.1593 0.0438 II-32 0.191 0.3608 II-117 0.1065 0.0566 II-34 0.0557 0.0861 II-118 0.2115 0.1086 17609606_1 (GHMatters) P106926.NZ II-35 0.2922 0.2064 II-120 1.17 0.6641 II-36 0.2412 0.1649 II-121 0.0444 0.0986 II-37 0.1927 0.1293 II-122 0.3037 0.2131 II-38 0.7712 0.5055 II-123 0.1489 0.0271 II-39 0.1778 0.1672 II-125 27.27 1.241 II-41 0.0188 0.0413 II-127 0.081 0.0487 II-43 0.0502 0.0278 II-128 2.475 1.152 II-45 0.1292 0.1287 II-129 9999 0.377 II-47 3.207 1.166 II-130 0.0898 0.056 II-49 0.0812 0.238 II-131 9.359 0.3602 II-51 26.62 3.609 II-132 0.9242 0.2242 II-52 7777 6.158 II-133 1.521 0.313 II-53 7777 24.07 II-134 0.225 0.1021 II-54 0.1887 0.1706 II-136 10.67 1.216 II-55 0.0435 0.0749 II-137 9999 0.206 II-57 0.0854 0.0418 II-138 9999 9999 II-58 0.112 0.1303 II-139 9999 9999 II-59 0.2156 0.4225 II-140 0.0323 0.0308 II-60 0.0533 0.0473 II-141 0.0517 0.2509 II-61 0.0504 0.0225 II-143 0.0164 0.0308 II-62 Not tested 6.477 II-145 0.0784 0.066 II-63 5.447 20.76 II-147 0.0987 0.0574 II-65 0.0489 0.0373 II-149 0.0568 0.0343 II-66 0.2438 0.1057 II-151 0.0622 0.0649 II-67 9999 26.22 II-153 0.1411 0.7485 II-68 9999 5011 II-155 0.0612 0.3993 II-69 9999 5014 II-157 0.5641 0.0615 II-70 1.016 1.865 II-158 0.0921 0.1445 II-71 10.39 49.57 II-160 0.0385 0.0267 II-72 0.1399 1.139 II-161 0.4821 0.1124 II-73 0.3429 0.3691 II-163 0.3477 0.1087 II-74 0.4046 0.4006 II-164 0.9118 0.1106 II-75 0.5369 2.493 II-165 0.0454 0.0444 II-76 0.0475 0.0524 II-167 0.0962 0.0949 II-77 0.1457 0.1471 II-169 0.4098 0.042 II-78 0.0799 0.1651 II-170 0.0904 0.0491 II-79 0.0152 0.0758 II-172 0.0242 0.013 II-80 0.2467 0.0495 II-173 0.3137 0.0414 II-81 0.1707 0.019 II-174 0.0708 0.0821 II-82 0.176 0.0387 II-178 0.0373 0.1193 17609606_1 ters) P106926.NZ II-83 0.2411 0.0863 II-179 0.0748 0.0125 II-84 0.3039 0.085 II-180 0.2629 0.0802 Table 3 IL23-p19 IL23-p19 IL23-p19 IL23-p19 ELISA, ELISA, ELISA, ELISA, Compound Dendritic, THP1-IFNy, Compound Dendritic, FNy, LPS, 10pt, LPS, 10pt LPS, 10pt LPS, 10pt EC50 (µM) EC50 (µM) EC50 (µM) EC50 (µM) III-1 Not tested 20.34 III-5 0.071 0.2702 III-2 0.1347 0.0399 III-6 0.2171 0.2377 III-3 0.1704 0.2433 III-7 0.4512 0.0853 III-4 0.0369 0.0434 III-8 0.161 0.4003 In view of the many possible embodiments to which the principles of the disclosed invention may be applied, it should be recognized that the rated embodiments are only preferred examples of the invention and should not be taken as ng the scope of the invention. Rather, the scope of the invention is defined by the following claims. We therefore claim as our invention all that comes within the scope and spirit of these claims. 17609606_1 (GHMatters) P106926.NZ We

Claims (9)

claim:

1. A compound having a formula or salt thereof, wherein: 5 R2 is H, substituted or unsubstituted aliphatic, substituted or tituted heteroaliphatic, substituted or unsubstituted heterocycloaliphatic, substituted or unsubstituted aryl, amide, substituted or unsubstituted heterocyclyl or substituted or tituted araliphatic; each R3 independently is H, substituted or unsubstituted aliphatic, halogen, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted phatic, substituted or unsubstituted 10 heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted araliphatic, substituted or unsubstituted –O-heterocyclyl, hydroxyl, nitro, cyano, carboxyl, carboxyl ester, acyl, amide, amino, sulfonyl, amide, sulfanyl, sulfinyl, haloalkyl, alkylphosphate, or alkylphosphonate, wherein R3 is not pyridinyl; R4, R5, R6 and R7 are each independently H, substituted or unsubstituted aliphatic, halogen, 15 kyl, substituted or unsubstituted heteroaliphatic, , tuted or unsubstituted heterocyclyl, or substituted or unsubstituted –O-heterocyclyl; R8 and R9 are each independently H , halogen, haloalkyl, or substituted or unsubstituted alkyl; and R10 is H, substituted or unsubstituted aliphatic, substituted or unsubstituted -O-aliphatic, 20 substituted or unsubstituted heteroaliphatic, carboxyl ester, substituted or unsubstituted aryl, acyl, substituted or unsubstituted araliphatic, substituted or unsubstituted heterocyclyl, sulfonyl, amino, NO2, CN, OH, kyl, alkyl ate or alkylphosphonate. y is from 1 to 6; and Het-1 is furyl, thiazolyl or oxazolyl; 25 wherein a substituent for substituting one or more hydrogen atoms on a saturated carbon atom in the ied group or moiety is -R60, halo, =O, -OR70, -SR70, -N(R80)2, haloalkyl, perhaloalkyl, -CN, -NO2, =N2, -N3, -SO2R70, -SO3–M+, -SO3R70, -OSO2R70, -OSO3– M+, -OSO3R70, -P(O)(O–)2(M+)2, -P(O)(O– )2M2+, -P(O)(OR70)O–M+, -P(O)(OR70) 2, -C(O)R70, -C(S)R70, -C(NR70)R70, -CO2- M+, -CO2R70, -C(S)OR70, -C(O)N(R80)2, -C(NR70)(R80)2, -OC(O)R70, -OC(S)R70, -OCO2-M+, -OCO2R70, -OC( 30 S)OR70, -NR70C(O)R70, -NR70C(S)R70, -NR70CO2– M+, -NR70CO2R70, -NR70C(S)OR70, -NR70C(O)N(R80)2, -NR70C(NR70)R70 and -NR70C(NR70)N(R80)2, where R60 is C1-6alkyl ally substituted with 1, 2, or 3 OH; each R70 is independently for each occurrence en or R60; each R80 is independently for each occurrence R70 or 17609606_1 (GHMatters) P106926.NZ atively, two R80 groups, taken together with the nitrogen atom to which they are bonded, form a 3- to 7- ed alicyclyl which ally includes from 1 to 4 of the same or different additional heteroatoms selected from O, N and S, of which N optionally has H or C1-C3alkyl substitution; and each M+ is a counter ion with a net single positive charge; 5 a substituent for replacing a hydrogen atom on an unsaturated carbon atom in a group containing unsaturated carbons is -R60, halo, -O-M+, -OR70, -SR70, -S–M+, -N(R80)2, perhaloalkyl, -CN, -OCN, -SCN, -NO, -NO2, -N3, -SO2R70, -SO3–M+, -SO3R70, -OSO2R70, -OSO3– M+, -OSO3R70, -PO3-2(M+)2, -PO3-2M2+, -P(O)(OR70)O– M+, OR70)2, -C(O)R70, -C(S)R70, -C(NR70)R70, -CO2– 10 M+, -CO2R70, -C(S)OR70, -C(O)NR80R80, 0)N(R80)2, -OC(O)R70, R70, -OCO2– M+, -OCO2R70, -OC(S)OR70, -NR70C(O)R70, -NR70C(S)R70, -NR70CO2– M+, -NR70CO2R70, -NR70C(S)OR70, -NR70C(O)N(R80)2, -NR70C(NR70)R70 or -NR70C(NR70)N(R80)2, where R60, R70, R80 and M+ are as usly defined, provided that in each case of substituted alkene or alkyne, the substituents are not -OM+, -OR70, -SR70, or -S–M+; and 15 a substituent group for replacing a hydrogen atom on a nitrogen atom in a group containing such en atom is -R60, -O-M+, -OR70, -SR70, -S-M+, -N(R80)2, perhaloalkyl, -CN, -NO, -NO2, -S(O)2R70, - SO3-M+, -SO3R70, -OS(O)2R70, -OSO3-M+, -OSO3R70, -PO32-(M+)2, -PO32-M2+, -P(O)(OR70)O-M+, - P(O)(OR70)(OR70), -C(O)R70, -C(S)R70, -C(NR70)R70, 0, -C(S)OR70, -C(O)NR80R80, -C(NR70)NR80R80, -OC(O)R70, R70, -OCO2R70, OR70, -NR70C(O)R70, -NR70C(S)R70, -NR70CO2R70, - 20 NR70C(S)OR70, -NR70C(O)N(R80)2, -NR70C(NR70)R70 or -NR70C(NR70)N(R80)2, where R60, R70, R80 and M+ are as previously defined.

2. The compound of claim 1, wherein: R2 is Ra, Rb, Ra substituted with 1, 2 or 3 Rb, Ra substituted with Rb and Rc, Ra substituted with Rc, – 25 (CRaRa)n-Ra, -(CH2)n-Ra, -(CRaRa)n-Rb or -(CH2)n-Rb; each of R4, R5, R6, and R7 independently is Ra, Rb, Ra substituted with Rc, -ORa, aRa)p-Rb; R10 is Ra, Rb, Ra substituted with –OP(O)(Rf)2, Ra substituted with 1, 2 or 3 Rb, Ra tuted with Rc, Ra substituted with –P(O)(Rf)2, aralkyl, -(CRaRa)n-Ra, -(CH2)n-Ra or -C(O)C(Ra)2NRaRb n is 1, 2 or 3; 30 p is 1, 2, or 3; Ra is independently for each occurrence H, D, C1-6alkyl, C3-6cycloalkyl, C3-6cycloalkenyl or C3- 6heteroalicyclyl; Rb is independently for each occurrence -OH, -CF3, -ORc, -NRdRd, -C(O)OH, -C(O)Rc, -C(O)ORc, - C(O)NRdRd or halogen; 35 Rc is independently for each occurrence C1-6alkyl, C3-6cycloalkyl, C3-6heteroalicyclyl, aralkyl, C1- e, C e, or C 6alkyl substituted with 1, 2 or 3 R 3-6cycloalkyl substituted with 1, 2 or 3 R 3-6heteroalicyclyl substituted with 1, 2 or 3 Re; 17609606_1 (GHMatters) P106926.NZ Rd is independently for each occurrence H, C1-6alkyl, C1-6alkyl tuted with 1, 2 or 3 Re, C3- e, or two Rd groups together with the 6cycloalkyl, C3-6cycloalkyl optionally substituted with 1, 2 or 3 R nitrogen bound thereto form a C3-6heteroalicyclyl moiety optionally substituted with C1-6alkyl, such as morpholinyl, piperidinyl, N-methylpiperidinyl or pyrrolidinyl; 5 Re is independently for each ence halogen, C1-6alkyl, C3-6cycloalkyl, C3-6heteroalicyclyl, C1- a, -OC(O)Ra or -O-aralkyl; 6alkyl-OH, -OR Rf is independently for each occurrence -ORa, -O-M+ or –O-[M2+]0.5; each M+ independently is an alkali metal ion or an ammonium ion; and M2+ is an ne metal earth ion.

3. The compound of either one of claim 1 or claim 2, having a formula wherein: R10 is H, substituted or unsubstituted alkyl, carboxyl ester, acyl, alkyl phosphate, alkyl onate, 15 substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted l.

4. The compound of any one of claims 1-3, wherein: R5 is H, F, CF3, methoxy, morpholinyl, 1-methylpiperidinyl, -O-CH2C(CH3)2OH, or –O- (oxetanyl); 20 each of R4, R6 and R7 independently is H, F or CF3; or a combination thereof.

5. The compound of claim 4, wherein: R3 is H; 25 R2 is H, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted cycloaliphatic, substituted or unsubstituted heteroaliphatic, or substituted or tituted heterocycloaliphatic; and R10 is H, substituted or tituted alkyl, carboxyl ester, acyl, alkyl phosphate, alkyl phosphonate or substituted or unsubstituted aralkyl. 30

6. The compound of any one of claims 1-5, wherein the compound has a a selected from 17609606_1 (GHMatters) P106926.NZ , , or ; and each of R11, R12, R13, and R14 independently is H or substituted or unsubstituted alkyl. 5

7. The compound of any one of claims 1-6, wherein R2 comprises cyclobutyl, azetidinyl, linyl, 4-methylpiperazinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or a combination thereof.

8. The compound any one of claims 1-6, wherein R2 is H, methyl, difluoromethyl, trifluoroethyl, isopropyl, tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, N-tert-butyloxycarbonyl azetidin- 10 3-yl, yoxy cyclobutyl, 3-benzyloxycyclobutyl, loxy cyclobutyl, 3-isopropyl cyclobutyl, 3- hydroxy cyclobutyl, 4-ethoxy cyclohexyl, 4-hydroxy cyclohexyl, 4-((2,2-difluoroethyl)amino)cyclohexyl, 3- ethyloxy cyclopentyl, or oxy cyclopentyl.

9. The compound of claim 1, or a salt thereof, wherein the compound is selected from: 15 I-1: N-(1-(2-hydroxymethylpropyl)(pyridinyl)-1H-pyrazolyl)(1-methyl-1H-pyrazol- 4-yl)furancarboxamide 2,2,2-trifluoroacetate; I-2: N-(1-(2-hydroxymethylpropyl)(pyridinyl)-1H-pyrazolyl)(1-methyl-1H-pyrazol- 4-yl)furancarboxamide; I-3: N-(1-(2-hydroxymethylpropyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)furan- 20 2-carboxamide; I-4: tert-butyl (1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)carbamoyl)furanyl)-1H- pyrazolecarboxylate; I-5: N-(1-(2-methoxyethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)furan carboxamide; 25 I-6: 2-methoxyethyl)(pyridinyl)-1H-pyrazolyl)(3-methyl-1H-pyrazolyl)furan- 2-carboxamide formic acid; 17609606_1 (GHMatters) P106926.NZ I-9: N-(1-(2-methoxyethyl)(pyridinyl)-1H-pyrazolyl)(3-methyl-1H-pyrazolyl)furan- 2-carboxamide; I-10: di-tert-butyl ((4-(5-((1-(2-methoxyethyl)(pyridinyl)-1H-pyrazolyl)carbamoyl)furan- 2-yl)-1H-pyrazolyl)methyl) phosphate; 5 I-11: tert-butyl ((4-(5-((1-(2-methoxyethyl)(pyridinyl)-1H-pyrazolyl)carbamoyl)furan yl)-1H-pyrazolyl)methyl) hydrogen phosphate; I-12: (4-(5-((1-(2-methoxyethyl)(pyridinyl)-1H-pyrazolyl)carbamoyl)furanyl)-1H- pyrazolyl)methyl dihydrogen phosphate; I-13: N-(1-(2-methoxyethyl)(pyridinyl)-1H-pyrazolyl)(3-(trifluoromethyl)-1H-pyrazol- 10 4-yl)furancarboxamide; I-14: sodium ((1-(2-methoxyethyl)(pyridinyl)-1H-pyrazolyl)carbamoyl)furanyl)- 1H-pyrazolyl)methyl ate; I-16: N-(1-(2-(2-methoxyethoxy)ethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol ancarboxamide; 15 I-17: N-(1-(2-(2-methoxyethoxy)ethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide hydrochloride salt; I-18: N-(1-(2-(2-methoxyethoxy)ethyl)(pyridinyl)-1H-pyrazolyl)(3-methyl-1H-pyrazol- 4-yl)furancarboxamide; I-19: 1-(isobutyryloxy)ethyl 4-(5-((1-(2-methoxyethyl)(pyridinyl)-1H-pyrazol 20 bamoyl)furanyl)-1H-pyrazolecarboxylate; I-20: tert-butyl (S)-(1-(4-(5-((1-(2-methoxyethyl)(pyridinyl)-1H-pyrazol yl)carbamoyl)furanyl)-1H-pyrazolyl)methyloxobutanyl)carbamate; I-21: 1-methylcyclopropyl 4-(5-((1-(2-methoxyethyl)(pyridinyl)-1H-pyrazol yl)carbamoyl)furanyl)-1H-pyrazolecarboxylate; 25 I-22: 1-((4-methoxybenzyl)oxy)methylpropanyl 4-(5-((1-(2-methoxyethyl)(pyridinyl)- 1H-pyrazolyl)carbamoyl)furanyl)-1H-pyrazolecarboxylate; I-23: 5-(1H-pyrazolyl)-N-(3-(pyridinyl)(tetrahydro-2H-pyranyl)-1H-pyrazolyl)furan- 2-carboxamide; I-24: 5-(5-nitro-1H-pyrrolyl)-N-(1-(propoxymethyl)(pyridinyl)-1H-pyrazolyl)furan 30 carboxamide; I-25: N-(1-(oxetanyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)furan carboxamide; I-26: 5-(1-methyl-1H-pyrazolyl)-N-(1-(oxetanyl)(pyridinyl)-1H-pyrazolyl)furan carboxamide; 35 I-27: N-(1-((1,3-trans)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide; I-28: N-(1-((1,3-cis)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide; 17609606_1 (GHMatters) P106926.NZ I-29: N-(1-((1,3-cis)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(3-methyl-1H- pyrazolyl)furancarboxamide; I-30: 5-(3-methyl-1H-pyrazolyl)-N-(1-(oxetanyl)(pyridinyl)-1H-pyrazolyl)furan carboxamide; 5 I-31: N-(1-((1,3-cis)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(1-methyl-1H- pyrazolyl)furancarboxamide; I-32: N-(1-((1,3-cis)hydroxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol ancarboxamide; I-33: N-(1-((1s,3s)(dimethylamino)cyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol- 10 4-yl)furancarboxamide; I-34: N-(1-((1s,3s)(dimethylamino)cyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol- 4-yl)furancarboxamide formate; I-35: (4-(5-((1-((1,3-cis)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)carbamoyl)furan yl)-1H-pyrazolyl)methyl phosphate bis-sodium salt; 15 I-36: (4-(5-((1-((1s,3s)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)carbamoyl)furan yl)-1H-pyrazolyl)methyl ogen phosphate; I-37: 2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)furan carboxamide formate; I-38: N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)furan 20 carboxamide; I-39: N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(1-ethyl-1H-pyrazolyl)furan carboxamide formate; I-40: N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(1-ethyl-1H-pyrazolyl)furan amide; 25 I-41: N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(3-(trifluoromethyl)-1H-pyrazol yl)furancarboxamide formate; I-42: N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(3-(trifluoromethyl)-1H-pyrazol yl)furancarboxamide; I-43: 2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(1-isopentyl-1H-pyrazolyl)furan- 30 2-carboxamide formate; I-44: N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(1-isopentyl-1H-pyrazolyl)furan- 2-carboxamide; I-45: N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(1-methyl-1H-pyrazolyl)furan carboxamide formate; 35 I-46: N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(1-methyl-1H-pyrazolyl)furan carboxamide; I-47: 5-(1H-pyrazolyl)-N-(3-(pyridinyl)-1H-pyrazolyl)furancarboxamide; 17609606_1 (GHMatters) P106926.NZ I-48: 5-(1-((3-methyloxetanyl)methyl)-1H-pyrazolyl)-N-(1-((3-methyloxetanyl)methyl) (pyridinyl)-1H-pyrazolyl)furancarboxamide formate; I-49: 5-(1-((3-methyloxetanyl)methyl)-1H-pyrazolyl)-N-(1-((3-methyloxetanyl)methyl) (pyridinyl)-1H-pyrazolyl)furancarboxamide; 5 I-50: N-(2-(2-methoxyethoxy)ethyl)(1-(2-(2-methoxyethoxy)ethyl)-1H-pyrazolyl)-N-(1-(2-(2- methoxyethoxy)ethyl)(pyridinyl)-1H-pyrazolyl)furancarboxamide formate; I-51: 2-methoxyethoxy)ethyl)(1-(2-(2-methoxyethoxy)ethyl)-1H-pyrazolyl)-N-(1-(2-(2- methoxyethoxy)ethyl)(pyridinyl)-1H-pyrazolyl)furancarboxamide; I-52: 5-(1-(2-(2-methoxyethoxy)ethyl)-1H-pyrazolyl)-N-(1-(2-(2-methoxyethoxy)ethyl) 10 (pyridinyl)-1H-pyrazolyl)furancarboxamide formate; I-53: 5-(1-(2-(2-methoxyethoxy)ethyl)-1H-pyrazolyl)-N-(1-(2-(2-methoxyethoxy)ethyl) (pyridinyl)-1H-pyrazolyl)furancarboxamide; I-54: (4-(5-((1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)carbamoyl)furanyl)-1H- lyl)methyl dihydrogen phosphate; 15 I-55: sodium (4-(5-((1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)carbamoyl)furanyl)-1H- pyrazolyl)methyl phosphate; I-56: N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(3-methyl-1H-pyrazolyl)furan carboxamide formate; I-57: 2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(3-methyl-1H-pyrazolyl)furan 20 carboxamide; I-58: 5-(3,5-dimethyl-1H-pyrazolyl)-N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazol yl)furancarboxamide formate; I-59: 5-(3,5-dimethyl-1H-pyrazolyl)-N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazol yl)furancarboxamide; 25 I-67: N-{1-Methyl(pyridineyl)-1H-pyrazolyl}(1H-pyrazolyl)furancarboxamide, formate salt; I-68: 5-(1-Methyl-1H-pyrazolyl)-N-{1-methyl(pyridineyl)-1H-pyrazolyl}furan carboxamide; I-69: 5-(1-Methyl-1H-pyrazolyl)-N-{1-methyl(pyridineyl)-1H-pyrazolyl}furan 30 carboxamide, formate salt; I-70: tert-Butyl[4-{5-(1H-pyrazoleyl)furancarboxamido}(pyridineyl)-1H-pyrazol yl]azetidinecarboxylate, formate salt; I-71: N-{1-(3-Methoxycyclobutyl)(pyridineyl)-1H-pyrazolyl}(1H-pyrazolyl)furan carboxamide, formate salt, Cis isomer; 35 I-72: N-{1-(3-Methoxycyclobutyl)(pyridineyl)-1H-pyrazolyl}(1H-pyrazolyl)furan carboxamide, Cis ; I-73: N-{1-(3-Benzyloxy)cyclobutyl)(pyridineyl)-1H-pyrazolyl}(1H-pyrazol yl)furancarboxamide, Trans isomer; 17609606_1 (GHMatters) P106926.NZ I-74: tert-Butyl[4-{5-(1H-pyrazoleyl)furancarboxamido}(pyridineyl)-1H-pyrazol yl]azetidinecarboxylate; I-75: N-(1-((1s,3s)methoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide formate; 5 I-76: N-(1-((1s,3s)methoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol ancarboxamide; I-77: N-{1-Methyl(pyridineyl)-1H-pyrazolyl}(1H-pyrazolyl)furancarboxamide, free base; I-78: N-{1-(Azetidinyl)(pyridineyl)-1H-pyrazolyl}(1H-pyrazolyl)furan 10 carboxamide, TFA salt; I-79: N-{1-(Azetidinyl)(pyridineyl)-1H-pyrazolyl}(1H-pyrazolyl)furan carboxamide; I-80: Di-tert-butyl-[[4-{4-(5-((1-methyl(pyridineyl)-1H-pyrazolyl)carbamoyl)furanyl)- 1H-pyrazolyl}methyl] phosphate; 15 I-81: [4-{5-((1-Methyl(pyridineyl)-1H-pyrazolyl)carbamoyl)furan-2yl}-1H-pyrazol yl]methyl dihydrogen phosphate; I-82: Sodium [4-{5-((1-Methyl(pyridineyl)-1H-pyrazolyl)carbamoyl)furanyl}-1H- pyrazolyl]methyl phosphate; I-83: N-{1-(1-Acetylazetidinyl)(pyridineyl)-1H-pyrazolyl}(1H-pyrazolyl)furan 20 carboxamide, free base; I-84: 3-[4-{5-(1H-Pyrazolyl)furancarboxamido}(pyridineyl)-1H-pyrazolyl]-N-(tertbutyl )azetidinecarboxamide, free base; I-85: 5-(1H-Pyrazolyl)furancarboxamido}(pyridineyl)-1H-pyrazolyl]-N- isopropylazetidinecarboxamide, free base; 25 I-86: 3-[4-{5-(1H-Pyrazolyl)furancarboxamido}(pyridineyl)-1H-pyrazolyl]-N- propylazetidinecarboxamide, free base. I-87: 5-(1H-Pyrazolyl)furancarboxamido}(pyridineyl)-1H-pyrazolyl]-N- cyclopropylazetidinecarboxamide, formate salt; I-88: 3-[4-{5-(1H-Pyrazolyl)furancarboxamido}(pyridineyl)-1H-pyrazolyl]-N- 30 cyclopropylazetidinecarboxamide; I-89: N-[1-{1-(Cyclopropanecarbonyl)azetidinyl}(pyridineyl)-1H-pyrazolyl](1H- pyrazolyl)furancarboxamide, formate salt; I-90: N-[1-{1-(Cyclopropanecarbonyl)azetidinyl}(pyridineyl)-1H-pyrazolyl](1H- pyrazolyl)furancarboxamide; 35 I-91: N-[1-{1-Pivaloylazetidinyl}(pyridineyl)-1H-pyrazolyl](1H-pyrazolyl)furan- 2-carboxamide, formate salt; I-92: N-[1-{1-Pivaloylazetidinyl}(pyridineyl)-1H-pyrazolyl](1H-pyrazolyl)furan- 2-carboxamide; 17609606_1 (GHMatters) P106926.NZ I-93: 5-(1H-Pyrazolyl)-N-{3-(pyridineyl)(pyrrolidinecarbonyl)azetidinyl}-1H- pyrazolyl)furancarboxamide, formate salt; I-94: 5-(1H-Pyrazolyl)-N-{3-(pyridineyl)(pyrrolidinecarbonyl)azetidinyl}-1H- lyl)furancarboxamide; 5 I-95: N-[1-{1-Isobutyrylazetidinyl}(pyridineyl)-1H-pyrazolyl](1H-pyrazol yl)furancarboxamide, e salt; I-96: N-[1-{1-Isobutyrylazetidinyl}(pyridineyl)-1H-pyrazolyl](1H-pyrazol yl)furancarboxamide; I-97: N-(1H-Pyrazolyl)-N-{3-(pyridineyl){1-(2,2,2-trifluoroethyl)azetidinyl}-1H- 10 pyrazolyl}furancarboxamide, TFA salt; I-98: N-(1H-Pyrazolyl)-N-{3-(pyridineyl){1-(2,2,2-trifluoroethyl)azetidinyl}-1H- pyrazolyl}furancarboxamide; I-99: N-[1-{1-Butyrylazetidinyl}(pyridineyl)-1H-pyrazolyl](1H-pyrazolyl)furan- 2-carboxamide, formate salt; 15 I-100: N-[1-{1-Butyrylazetidinyl}(pyridineyl)-1H-pyrazolyl](1H-pyrazolyl)furan- 2-carboxamide; I-101: N-{1-(1-Methylazetidinyl)(pyridineyl)-1H-pyrazolyl}(1H-pyrazolyl)furan- oxamide, formate salt; I-102: N-{1-(1-Methylazetidinyl)(pyridineyl)-1H-pyrazolyl}(1H-pyrazolyl)furan- 20 2-carboxamide; I-103: N-[1-{1-(2,2-difluorocyclopropanecarbonyl)azetidinyl}(pyridineyl)-1H-pyrazol- 4-yl](1H-pyrazolyl)furancarboxamide, formate salt; I-104: N-[1-{1-(2,2-difluorocyclopropanecarbonyl)azetidinyl}(pyridineyl)-1H-pyrazol- 4-yl](1H-pyrazolyl)furancarboxamide; 25 I-105: N-(1-methyl(5-morpholinopyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)furan carboxamide; I-106: N-(1-methyl(5-(4-methylpiperazinyl)pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide; I-107: N-(3-(5-(2-hydroxymethylpropoxy)pyridinyl)methyl-1H-pyrazolyl)(1H- 30 pyrazolyl)furancarboxamide; I-108: N-(1-methyl(5-(oxetanyloxy)pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)furan- 2-carboxamide; I-109: N-(3-(5-methoxypyridinyl)methyl-1H-pyrazolyl)(1H-pyrazolyl)furan carboxamide; 35 I-110: N-(1-isopropyl(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)furancarboxamide; I-111: N-(1-(2-morpholinoethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)furan amide; 17609606_1 (GHMatters) P106926.NZ I-112: N-(1-(2-(4-methylpiperazinyl)ethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol ancarboxamide; I-113: 5-(1H-pyrazolyl)-N-(3-(pyridinyl)(2-(2,2,2-trifluoroethoxy)ethyl)-1H-pyrazol yl)furancarboxamide; 5 I-114: N-(1-((1s,3s)isopropoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide; I-115: N-(1-(difluoromethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)furan carboxamide; I-116: N-(1-((1s,3s)ethoxycyclobutyl)(6-(trifluoromethyl)pyridinyl)-1H-pyrazolyl) 10 (1H-pyrazolyl)furancarboxamide; I-117: 5-(1H-pyrazolyl)-N-(3-(pyridinyl)(2,2,2-trifluoroethyl)-1H-pyrazolyl)furan carboxamide; I-122: 5-(1-cyclobutyl-1H-pyrazolyl)-N-(1-cyclobutyl(pyridinyl)-1H-pyrazolyl)furan carboxamide 2,2,2-trifluoroacetate; 15 I-123: 5-(1-cyclobutyl-1H-pyrazolyl)-N-(1-cyclobutyl(pyridinyl)-1H-pyrazolyl)furan carboxamide; I-124: N-(1-((1s,4s)hydroxycyclohexyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide formate; I-125: N-(1-((1s,4s)hydroxycyclohexyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol 20 yl)furancarboxamide; I-126: N-(1-((1r,4r)hydroxycyclohexyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide e; I-127: N-(1-((1r,4r)hydroxycyclohexyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide; 25 I-128: 5-(1H-pyrazolyl)-N-(3-(pyridinyl)(3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol- 4-yl)furancarboxamide formate; I-129: 5-(1H-pyrazolyl)-N-(3-(pyridinyl)(3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol- 4-yl)furancarboxamide; I-130: N-(1-((1r,4r)ethoxycyclohexyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol 30 ancarboxamide formate; I-131: N-(1-((1r,4r)ethoxycyclohexyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide; I-132: N-(1-((1S,3R)ethoxycyclopentyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide formate; 35 I-133: N-(1-((1S,3R)ethoxycyclopentyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide; I-134: N-(1-((1S,3R)hydroxycyclopentyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide formate; 06_1 (GHMatters) P106926.NZ I-135: N-(1-((1S,3R)hydroxycyclopentyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide; I-136: N-(1-((1S,3S)hydroxycyclopentyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)furancarboxamide formate; 5 I-137: N-(1-((1S,3S)hydroxycyclopentyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol ancarboxamide; I-138: N-(1-((1s,3s)ethoxycyclobutyl)(5-fluoropyridinyl)-1H-pyrazolyl)(1H-pyrazol- 4-yl)furancarboxamide formate; I-139: N-(1-((1s,3s)ethoxycyclobutyl)(5-fluoropyridinyl)-1H-pyrazolyl)(1H-pyrazol- 10 urancarboxamide; I-140: N-(1-((1S,3R)ethoxyfluorocyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H- pyrazolyl)furancarboxamide formate; I-141: N-(1-((1S,3R)ethoxyfluorocyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H- pyrazolyl)furancarboxamide; 15 I-142: N-(1-((1s,3s)ethoxycyclobutyl)(3-fluoropyridinyl)-1H-pyrazolyl)(1H-pyrazol- 4-yl)furancarboxamide formate; I-143: N-(1-((1s,3s)ethoxycyclobutyl)(3-fluoropyridinyl)-1H-pyrazolyl)(1H-pyrazol- 4-yl)furancarboxamide; I-144: N-(1-((1s,3s)ethoxycyclobutyl)(6-fluoropyridinyl)-1H-pyrazolyl)(1H-pyrazol- 20 4-yl)furancarboxamide formate; I-145: N-(1-((1s,3s)ethoxycyclobutyl)(6-fluoropyridinyl)-1H-pyrazolyl)(1H-pyrazol- 4-yl)furancarboxamide; I-146: 5-(1H-pyrazolyl)-N-(3-(pyridinyl)((1s,3s)(2,2,2-trifluoroethoxy)cyclobutyl)-1H- pyrazolyl)furancarboxamide formate; 25 I-147: 5-(1H-pyrazolyl)-N-(3-(pyridinyl)((1s,3s)(2,2,2-trifluoroethoxy)cyclobutyl)-1H- pyrazolyl)furancarboxamide; I-148: N-(1-((1s,3s)ethoxycyclobutyl)(4-fluoropyridinyl)-1H-pyrazolyl)(1H-pyrazol- 4-yl)furancarboxamide formate; I-149: N-(1-((1s,3s)ethoxycyclobutyl)(4-fluoropyridinyl)-1H-pyrazolyl)(1H-pyrazol- 30 4-yl)furancarboxamide; I-150: N-(3-(6-fluoropyridinyl)((1s,3s)(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol yl)(1H-pyrazolyl)furancarboxamide formate; I-151: N-(3-(6-fluoropyridinyl)((1s,3s)(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol yl)(1H-pyrazolyl)furancarboxamide; 35 I-152: N-(3-(3-fluoropyridinyl)((1s,3s)(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol yl)(1H-pyrazolyl)furancarboxamide e; I-153: 3-fluoropyridinyl)((1s,3s)(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol yl)(1H-pyrazolyl)furancarboxamide; 17609606_1 (GHMatters) P106926.NZ I-154: N-(1-((1r,4r)ethoxycyclohexyl)(3-fluoropyridinyl)-1H-pyrazolyl)(1H-pyrazol- 4-yl)furancarboxamide formate; I-155: N-(1-((1r,4r)ethoxycyclohexyl)(3-fluoropyridinyl)-1H-pyrazolyl)(1H-pyrazol- 4-yl)furancarboxamide; 5 I-156: N-(3-(3,6-difluoropyridinyl)((1s,3s)ethoxycyclobutyl)-1H-pyrazolyl)(1H- pyrazolyl)furancarboxamide; II-1: N-(1-(2-hydroxymethylpropyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol azolecarboxamide; II-2: 1-(isobutyryloxy)ethyl 4-(4-((1-methyl(pyridinyl)-1H-pyrazolyl)carbamoyl)thiazol 10 yl)-1H-pyrazolecarboxylate; II-3: tert-butyl (R)-(3-methyl(4-(4-((1-methyl(pyridinyl)-1H-pyrazol yl)carbamoyl)thiazolyl)-1H-pyrazolyl)oxobutanyl)carbamate; II-4: 2-(1-((5-methyloxo-1,3-dioxolyl)methyl)-1H-pyrazolyl)-N-(1-methyl(pyridin yl)-1H-pyrazolyl)thiazolecarboxamide; 15 II-5: 1-methylcyclopropyl 4-(4-((1-methyl(pyridinyl)-1H-pyrazolyl)carbamoyl)thiazol -pyrazolecarboxylate; II-6: 1-((4-methoxybenzyl)oxy)methylpropanyl 4-(4-((1-methyl(pyridinyl)-1H-pyrazol- 4-yl)carbamoyl)thiazolyl)-1H-pyrazolecarboxylate; II-7: diethyl ((4-(4-((1-methyl(pyridinyl)-1H-pyrazolyl)carbamoyl)thiazolyl)-1H- 20 pyrazolyl)methyl)phosphonate; II-8: sodium ((4-(4-((1-methyl(pyridinyl)-1H-pyrazolyl)carbamoyl)thiazolyl)-1H- pyrazolyl)methyl)phosphonate; II-9: ((4-(4-((1-methyl(pyridinyl)-1H-pyrazolyl)carbamoyl)thiazolyl)-1H-pyrazol yl)methyl)phosphonic acid; 25 II-10: 2-(1H-pyrazolyl)-N-(3-(pyridinyl)(tetrahydro-2H-pyranyl)-1H-pyrazol yl)thiazolecarboxamide; II-11: N-(1-((1,3-cis)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol azolecarboxamide; II-12: N-(1-((1,3-trans)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol 30 yl)thiazolecarboxamide; II-13: N-(1-((1,3-cis)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(1-methyl-1H- pyrazolyl)thiazolecarboxamide; II-14: N-(1-((1,3-cis)hydroxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide; 35 II-15: N-(1-((1s,3s)(dimethylamino)cyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H- pyrazolyl)thiazolecarboxamide; II-16: ((1-((1,3-cis)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)carbamoyl)thiazol- 2-yl)-1H-pyrazolyl)methyl phosphate bis-sodium salt; 17609606_1 (GHMatters) P106926.NZ II-17: (4-(4-((1-((1s,3s)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)carbamoyl)thiazol yl)-1H-pyrazolyl)methyl dihydrogen phosphate; II-18: N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole carboxamide, formic acid salt; 5 II-19: N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(5-(trifluoromethyl)-1H-pyrazol yl)thiazolecarboxamide, formic acid salt; II-20: N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(5-(trifluoromethyl)-1H-pyrazol yl)thiazolecarboxamide; II-21: N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(3-methyl-1H-pyrazol 10 yl)thiazolecarboxamide, formic acid salt; II-22: N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(3-methyl-1H-pyrazol yl)thiazolecarboxamide; II-23: 2-(3,5-dimethyl-1H-pyrazolyl)-N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazol yl)thiazolecarboxamide, formic acid salt; 15 II-24: 2-(3,5-dimethyl-1H-pyrazolyl)-N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazol yl)thiazolecarboxamide; II-25: N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole carboxamide; II-26: N-(1-methyl(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazolecarboxamide; 20 II-27: 2-(3-methyl-1H-pyrazolyl)-N-(1-methyl(pyridinyl)-1H-pyrazolyl)thiazole carboxamide; II-28: N-(1-(2-methoxyethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole amide; II-29: N-(1-(2-methoxyethyl)(pyridinyl)-1H-pyrazolyl)(3-methyl-1H-pyrazol 25 azolecarboxamide, formic acid salt; II-30: N-(1-(2-methoxyethyl)(pyridinyl)-1H-pyrazolyl)(3-methyl-1H-pyrazol yl)thiazolecarboxamide; II-31: N-(1-(2-ethoxyethyl)(pyridinyl)-1H-pyrazolyl)(3-methyl-1H-pyrazol yl)thiazolecarboxamide; 30 II-32: 2-(1H-pyrazolyl)-N-(3-(pyridinyl)-1H-pyrazolyl)thiazolecarboxamide formate; II-33: 2-(1H-pyrazolyl)-N-(3-(pyridinyl)-1H-pyrazolyl)thiazolecarboxamide; II-34: N-(1-(oxetanyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole carboxamide; II-35: (4-(4-((1-methyl(pyridinyl)-1H-pyrazolyl)carbamoyl)thiazolyl)-1H-pyrazol 35 yl)methyl ogen phosphate; II-36: Sodium (4-(4-((1-methyl(pyridinyl)-1H-pyrazolyl)carbamoyl)thiazolyl)-1H- pyrazolyl)methyl ate; 17609606_1 (GHMatters) P106926.NZ II-37: N-(1-(2-(2-methoxyethoxy)ethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide; II-38: potassium (4-(4-((1-methyl(pyridinyl)-1H-pyrazolyl)carbamoyl)thiazolyl)-1H- pyrazolyl)methyl ate; 5 II-39: N-(1-(2-(2-methoxyethoxy)ethyl)(pyridinyl)-1H-pyrazolyl)(3-methyl-1H-pyrazol- 4-yl)thiazolecarboxamide formate; II-40: N-(1-(2-(2-methoxyethoxy)ethyl)(pyridinyl)-1H-pyrazolyl)(3-methyl-1H-pyrazol- 4-yl)thiazolecarboxamide; II-41: 2-(3-methyl-1H-pyrazolyl)-N-(1-(oxetanyl)(pyridinyl)-1H-pyrazolyl)thiazole- 10 4-carboxamide, formic acid salt; II-42: 2-(3-methyl-1H-pyrazolyl)-N-(1-(oxetanyl)(pyridinyl)-1H-pyrazolyl)thiazole- 4-carboxamide; II-43: 2-(1H-pyrazolyl)-N-(3-(pyridinyl)(tetrahydrofuranyl)-1H-pyrazolyl)thiazole carboxamide formate; 15 II-44: 2-(1H-pyrazolyl)-N-(3-(pyridinyl)(tetrahydrofuranyl)-1H-pyrazolyl)thiazole carboxamide; II-45: 2-(3-methyl-1H-pyrazolyl)-N-(3-(pyridinyl)((tetrahydro-2H-pyranyl)methyl)-1H- pyrazolyl)thiazolecarboxamide formate; II-46: 2-(3-methyl-1H-pyrazolyl)-N-(3-(pyridinyl)((tetrahydro-2H-pyranyl)methyl)-1H- 20 pyrazolyl)thiazolecarboxamide; II-47: N-(1-((3-(hydroxymethyl)oxetanyl)methyl)(pyridinyl)-1H-pyrazolyl)(3- methyl-1H-pyrazolyl)thiazolecarboxamide formate; II-48: (3-(hydroxymethyl)oxetanyl)methyl)(pyridinyl)-1H-pyrazolyl)(3- methyl-1H-pyrazolyl)thiazolecarboxamide; 25 II-49: N-(1-(2-(diethylamino)ethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole- oxamide, formic acid salt; II-50: N-(1-(2-(diethylamino)ethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole- 4-carboxamide; II-51: 2-(1-(4-methoxybenzyl)-1H-pyrazolyl)-N-(1-(3-methoxycyclobutyl)(pyridinyl)-1H- 30 pyrazolyl)thiazolecarboxamide; II-52: N-(1-(2-fluoroethyl)(pyridinyl)-1H-pyrazolyl)(1-(4-methoxybenzyl)-1H-pyrazol- 4-yl)thiazolecarboxamide; II-53: 2-(1-(4-methoxybenzyl)-1H-pyrazolyl)-N-(3-(pyridinyl)-1H-pyrazolyl)thiazole carboxamide; 35 II-54: tert-Butyl[4-{2-(1H-pyrazoleyl)thiazolecarboxamido}(pyridineyl)-1H-pyrazol- 1-yl]azetidinecarboxylate, free base; II-55: N-{1-(Azetidinyl)(pyridineyl)-1H-pyrazolyl}(1H-pyrazolyl)thiazole carboxamide, TFA salt; 17609606_1 ters) P106926.NZ II-56: N-{1-(Azetidinyl)(pyridineyl)-1H-pyrazolyl}(1H-pyrazolyl)thiazole carboxamide; II-57: N-{1-(3-Methoxycyclobutyl)(pyridineyl)-1H-pyrazolyl}(1H-pyrazol yl)thiazolecarboxamide, free base, Cis isomer; 5 II-58: N-(3-(5-methoxypyridinyl)methyl-1H-pyrazolyl)(1H-pyrazolyl)thiazole carboxamide; II-59: N-(1-isopropyl(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole carboxamide; II-60: N-(1-(2-morpholinoethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole 10 carboxamide; II-61: N-(1-(2-(4-methylpiperazinyl)ethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide; II-65: N-(3-(3-fluoropyridinyl)((1s,3s)hydroxycyclobutyl)-1H-pyrazolyl)(1H- pyrazolyl)thiazolecarboxamide; 15 II-66: 2-(1H-pyrazolyl)-N-(3-(pyridinyl)(2-(2,2,2-trifluoroethoxy)ethyl)-1H-pyrazol yl)thiazolecarboxamide; II-71: N-(1-((1s,3s)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(5-fluoro((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazolyl)thiazolecarboxamide; II-72: N-(1-((1s,3s)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(5-fluoro-1H-pyrazol- 20 hiazolecarboxamide; II-73: (1s,3s)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(5-fluoro-1H-pyrazol- hiazolecarboxamide formate; II-76: N-(1-((1s,3s)isopropoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide; 25 II-77: potassium (4-(4-((1-((1s,3s)ethoxycyclobutyl)(pyridinyl)-1H-pyrazol yl)carbamoyl)thiazolyl)-1H-pyrazolyl)methyl phosphate; II-78: calcium (4-(4-((1-((1s,3s)ethoxycyclobutyl)(pyridinyl)-1H-pyrazol yl)carbamoyl)thiazolyl)-1H-pyrazolyl)methyl phosphate; II-79: N-(1-((1r,3r)hydroxymethylcyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H- 30 pyrazolyl)thiazolecarboxamide; II-80: ammonium (4-(4-((1-((1s,3s)ethoxycyclobutyl)(pyridinyl)-1H-pyrazol bamoyl)thiazolyl)-1H-pyrazolyl)methyl phosphate; II-81: 5-aminocarboxypentanaminium (4-(4-((1-((1s,3s)ethoxycyclobutyl)(pyridin yl)-1H-pyrazolyl)carbamoyl)thiazolyl)-1H-pyrazolyl)methyl phosphate; 35 II-82: 1-(4-aminocarboxybutyl)guanidinium (4-(4-((1-((1s,3s)ethoxycyclobutyl)(pyridin yl)-1H-pyrazolyl)carbamoyl)thiazolyl)-1H-pyrazolyl)methyl phosphate; II-83: (4-(4-((1-((1s,3s)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)carbamoyl)thiazol yl)-1H-pyrazolyl)methyl dihydrogen phosphate; 17609606_1 (GHMatters) P106926.NZ II-84: 1,3-dihydroxy(hydroxymethyl)propanaminium (4-(4-((1-((1s,3s)ethoxycyclobutyl)- 3-(pyridinyl)-1H-pyrazolyl)carbamoyl)thiazolyl)-1H-pyrazolyl)methyl hydrogen phosphate; II-85: triethylammonium (4-(4-((1-((1s,3s)ethoxycyclobutyl)(pyridinyl)-1H-pyrazol yl)carbamoyl)thiazolyl)-1H-pyrazolyl)methyl en phosphate; 5 II-86: N-(1-((1s,3s)ethoxycyclobutyl)(5-(trifluoromethyl)pyridinyl)-1H-pyrazolyl) (1H-pyrazolyl)thiazolecarboxamide; II-87: N-(1-(3-hydroxymethylcyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide; II-88: difluoromethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole 10 carboxamide; II-89: N-(1-((1s,3s)ethoxycyclobutyl)(3-(trifluoromethyl)pyridinyl)-1H-pyrazolyl) (1H-pyrazolyl)thiazolecarboxamide; II-90: N-(1-((1s,3s)ethoxycyclobutyl)(6-(trifluoromethyl)pyridinyl)-1H-pyrazolyl) (1H-pyrazolyl)thiazolecarboxamide; 15 II-91: N-(1-((1s,3s)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(3-(trifluoromethyl)- 1H-pyrazolyl)thiazolecarboxamide; II-92: N-(1-((1s,3s)ethoxycyclobutyl)(pyridinyl)-1H-pyrazolyl)(3-methyl-1H- pyrazolyl)thiazolecarboxamide; II-93: 2-(3,5-dimethyl-1H-pyrazolyl)-N-(1-((1s,3s)ethoxycyclobutyl)(pyridinyl)-1H- 20 pyrazolyl)thiazolecarboxamide; II-94: 2-(1H-pyrazolyl)-N-(3-(pyridinyl)(2,2,2-trifluoroethyl)-1H-pyrazolyl)thiazole carboxamide; II-95: N-(1-(difluoromethyl)(pyridinyl)-1H-pyrazolyl)(3-(trifluoromethyl)-1H-pyrazol- 4-yl)thiazolecarboxamide; 25 II-96: N-(1-(difluoromethyl)(pyridinyl)-1H-pyrazolyl)(3-methyl-1H-pyrazol azolecarboxamide; II-97: N-(1-(difluoromethyl)(pyridinyl)-1H-pyrazolyl)(1-(2,2,2-trifluoroethyl)-1H- pyrazolyl)thiazolecarboxamide; II-98: 2-(1-(difluoromethyl)-1H-pyrazolyl)-N-(1-(difluoromethyl)(pyridinyl)-1H-pyrazol- 30 4-yl)thiazolecarboxamide; II-99: N-(1-((1s,3s)ethoxycyclobutyl)(6-(trifluoromethyl)pyridinyl)-1H-pyrazolyl)(3- methyl-1H-pyrazolyl)thiazolecarboxamide; II-100: ethyl-1H-pyrazolyl)-N-(3-(pyridinyl)(2,2,2-trifluoroethyl)-1H-pyrazol azolecarboxamide; 35 II-103: 2-(1-(4-methoxybenzyl)-1H-pyrazolyl)-N-(3-(pyridinyl)(3,3,3-trifluoro hydroxypropyl)-1H-pyrazolyl)thiazolecarboxamide formate; II-104: 2-(1-(4-methoxybenzyl)-1H-pyrazolyl)-N-(3-(pyridinyl)(3,3,3-trifluoro hydroxypropyl)-1H-pyrazolyl)thiazolecarboxamide; 17609606_1 (GHMatters) P106926.NZ II-105: N-(1-(dimethylcarbamoyl)(pyridinyl)-1H-pyrazolyl)(1-(4-methoxybenzyl)-1H- pyrazolyl)thiazolecarboxamide formate; : N-(1-(dimethylcarbamoyl)(pyridinyl)-1H-pyrazolyl)(1-(4-methoxybenzyl)-1H- pyrazolyl)thiazolecarboxamide; 5 : 2-(1-(4-methoxybenzyl)-1H-pyrazolyl)-N-(3-(pyridinyl)(3,3,3-trifluorohydroxy- 2-(trifluoromethyl)propyl)-1H-pyrazolyl)thiazolecarboxamide formate; II-108: 2-(1-(4-methoxybenzyl)-1H-pyrazolyl)-N-(3-(pyridinyl)(3,3,3-trifluorohydroxy- 2-(trifluoromethyl)propyl)-1H-pyrazolyl)thiazolecarboxamide; II-117: N-(1-(2-(diethylamino)ethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol 10 yl)thiazolecarboxamide; II-118: 2-(2-fluoroethoxy)ethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide formate; II-119: 2-(2-fluoroethoxy)ethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide; 15 II-120: N-(1-benzyl(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazolecarboxamide; II-121: N-(1-cyclobutyl(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole carboxamide; II-122: N-(1-(2-(2,2-difluoroethoxy)ethyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide; 20 II-123: N-(1-(((1r,3r)hydroxycyclobutyl)methyl)(pyridinyl)-1H-pyrazolyl)(1H- pyrazolyl)thiazolecarboxamide formate; II-124: N-(1-(((1r,3r)hydroxycyclobutyl)methyl)(pyridinyl)-1H-pyrazolyl)(1H- pyrazolyl)thiazolecarboxamide; II-125: N-(1-(dimethylcarbamoyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole- 25 4-carboxamide formate; II-126: N-(1-(dimethylcarbamoyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole- 4-carboxamide; II-127: N-(1-((1s,3s)(ethoxy-d5)cyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide; 30 II-128: N-(1-(diethylcarbamoyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazolyl)thiazole carboxamide; II-129: N-(1-(morpholinecarbonyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide; II-130: N-(1-((1s,3s)(2-fluoroethoxy)cyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H- 35 pyrazolyl)thiazolecarboxamide; II-131: morpholinecarbonyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide formate; 17609606_1 (GHMatters) P106926.NZ II-132: N-(1-(3-fluorocyclobutenyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide; II-133: N-(1-(3-fluorocyclobutenyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide formate; 5 II-134: N-(1-(3,3-difluorocyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide formate; II-135: N-(1-(3,3-difluorocyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide; II-140: N-(3-(3-fluoropyridinyl)(1,4-dioxaspiro[4.5]decanyl)-1H-pyrazolyl)(1H- 10 pyrazolyl)thiazolecarboxamide; II-141: 2-(1H-pyrazolyl)-N-(3-(pyridinyl)((1r,3r)(2,2,2-trifluoroethoxy)cyclobutyl)-1H- pyrazolyl)thiazolecarboxamide formate; II-142: 2-(1H-pyrazolyl)-N-(3-(pyridinyl)((1r,3r)(2,2,2-trifluoroethoxy)cyclobutyl)-1H- pyrazolyl)thiazolecarboxamide; 15 II-143: N-(1-((1r,4r)hydroxycyclohexyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide formate; II-144: (1r,4r)hydroxycyclohexyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide; II-145: (1r,4r)ethoxycyclohexyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol 20 yl)thiazolecarboxamide e; II-146: N-(1-((1r,4r)ethoxycyclohexyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol azolecarboxamide; II-147: N-(1-((1S,3R)ethoxycyclopentyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide formate; 25 II-148: N-(1-((1S,3R)ethoxycyclopentyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide; II-149: N-(1-((1S,3R)hydroxycyclopentyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol yl)thiazolecarboxamide formate; II-150: N-(1-((1S,3R)hydroxycyclopentyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol 30 yl)thiazolecarboxamide; II-151: N-(1-((1S,3S)hydroxycyclopentyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol azolecarboxamide formate; II-152: N-(1-((1S,3S)hydroxycyclopentyl)(pyridinyl)-1H-pyrazolyl)(1H-pyrazol azolecarboxamide; 35 II-153: N-(1-((1s,3s)ethoxycyclobutyl)(5-fluoropyridinyl)-1H-pyrazolyl)(1H- pyrazolyl)thiazolecarboxamide formate; II-154: N-(1-((1s,3s)ethoxycyclobutyl)(5-fluoropyridinyl)-1H-pyrazolyl)(1H- pyrazolyl)thiazolecarboxamide; 17609606_1 (GHMatters) P106926.NZ II-155: N-(1-((1S,3R)ethoxyfluorocyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H- pyrazolyl)thiazolecarboxamide formate; II-156: N-(1-((1S,3R)ethoxyfluorocyclobutyl)(pyridinyl)-1H-pyrazolyl)(1H- pyrazolyl)thiazolecarboxamide; 5 II-157: N-(1-((1s,3s)ethoxycyclobutyl)(3-fluoropyridinyl)-1H-pyrazolyl)(1H- pyrazolyl)thiazolecarboxamide; : N-(1-((1s,3s)ethoxycyclobutyl)(4-fluoropyridinyl)-1H-pyrazolyl)(1H- pyrazolyl)thiazolecarboxamide formate; II-159: N-(1-((1s,3s)ethoxycyclobutyl)(4-fluoropyridinyl)-1H-pyrazolyl)(1H- 10 pyrazolyl)thiazolecarboxamide; II-160: N -(1-((1s,3s)ethoxycyclobutyl)(6-fluoropyridinyl)-1H-pyrazolyl)(1H- pyrazolyl)thiazolecarboxamide; II-161: 2-(1H-pyrazolyl)-N-(3-(pyridinyl)((1s,3s)(2,2,2-trifluoroethoxy)cyclobutyl)-1H- pyrazolyl)thiazolecarboxamide formate; 15 II-162: 2-(1H-pyrazolyl)-N-(3-(pyridinyl)((1s,3s)(2,2,2-trifluoroethoxy)cyclobutyl)-1H- pyrazolyl)thiazolecarboxamide; II-163: (4-(4-((1-((1s,3s)ethoxycyclobutyl)(3-fluoropyridinyl)-1H-pyrazol yl)carbamoyl)thiazolyl)-1H-pyrazolyl)methyl dihydrogen phosphate;