Certain chemical entities, compositions, and methods

Abstract

This disclosure provides compounds of Formula (I) and Formula (II), pharmaceutical compositions comprising the foregoing, and methods of using the same, including uses in treating c-Kit-mediated diseases, disorders, and / or conditions.

Description

[0001] Agent Ref: 16738.0002-00304

[0002] CERTAIN CHEMICAL ENTITIES, COMPOSITIONS, AND METHODS RELATED APPLICATIONS

[0003] [1] This application claims the benefit of U. S. Provisional Patent Application No.

[0004] 63 / 744,049, filed on January 10, 2025, U. S. Provisional Patent Application No. 63 / 744,158, filed on January 10, 2025, and U. S. Provisional Patent Application No. 63 / 939,536, filed on December 12, 2025, each of which is hereby incorporated by reference in its entirety.

[0005] BACKGROUND OF THE DISCLOSURE

[0006] [2] There are at least 400 enzymes identified as protein kinases. These enzymes catalyze the phosphorylation of target protein substrates. The phosphorylation is usually a transfer reaction of a phosphate group from ATP to the protein substrate. The specific structure in the target substrate to which the phosphate is transferred is a tyrosine, serine, or threonine residue. Since these amino acid residues are the target structures for the phosphoryl transfer, these protein kinase enzymes are commonly referred to as tyrosine kinases or serine / threonine kinases.

[0007] [3] The phosphorylation reactions, and counteracting phosphatase reactions, at the tyrosine, serine and threonine residues are involved in countless cellular processes that underlie responses to diverse intracellular signals (typically mediated through cellular receptors), regulation of cellular functions, and activation or deactivation of cellular processes. A cascade of protein kinases often participate in intracellular signal transduction and are necessary for the realization of these cellular processes. Because of their ubiquity in these processes, protein kinases can be found as an integral part of the plasma membrane or as cytoplasmic enzymes or localized in the nucleus, often as components of enzyme complexes. In many instances, these protein kinases are an essential element of the enzyme and structural protein complexes that determine where and when a cellular process occurs within a cell.

[0008] [4] One example of such kinases is c-Kit, which is a type III receptor tyrosine kinase (RTK) and a proto-oncogene in a region on the long arm of chromosome 4 (4q11-4q13) that encodes the stem cell factor (SCF) (Babaei et al., Drug Des Devel Ther. 2016;10:2443-2459). c-Kit is involved in intracellular signalling and participates in the development of melanocytes, mast, germ, and hematopoietic cells. c-Kit plays critical roles in immune and inflammatory responses, and inhibition thereof has been shown to be useful for treating a variety of diseases with abnormal cellular response. c-Kit also plays a crucial role in cellAgent Ref: 16738.0002-00304

[0009] proliferation, survival, and migration, and is implicated in several physiological processes (e.g., pigmentation, hematopoiesis, and gut movement) and in the occurrence of cell proliferative disorders (e.g, leukemia, unilateral ovarian dysgerminoma, melanoma, colorectal carcinoma, breast carcinoma, small-cell lung carcinoma, neuroblastoma, and gynecological tumor), fibrotic disorders (e.g., pulmonary fibrosis), and metabolic disorders (e.g., diabetes). Accumulating evidence has also shown that dysregulated c-Kit function, caused by overexpression or mutations in c-Kit, promotes tumor development and progression in various human cancers.

[0010] [5] A few research groups have studied Kit and Kit-related diseases. For example, Bibi et al. studied molecular defects in mastocytosis related to Kit and Kit mutation (Bibi etal., Immunol Allergy Clin North Am. 2014, 34(2), 239-262). Gilreath et al. studied novel approaches to treating advanced systemic mastocytosis related to Kit (Gilreath et al., Clinical Pharmacology: Advances and Applications 2019:11 77-92). Babaei et al. studied receptor tyrosine kinase (c-Kit) inhibitors as potential therapeutic targets in cancer cells (Babaei et al., Drug Design, Development and Therapy 2016: 102443-2459). Bauer et al. studied early and next-generation KIT / PDGFRA kinase inhibitors and the future of treatment for advanced gastrointestinal stromal tumor (Bauer et al., Front. Oncol. 2021, 11:672500).

[0011] [6] Because inhibition of aberrant expression and / or activation of c-Kit and / or a mutant form(s) of c-Kit has been linked to treating diseases or disorders related to unregulated kinase signal transduction, such as cell proliferative disorders, fibrotic disorders, and metabolic disorders, there is an ongoing need for effective and safe protein kinase inhibitors.

[0012] SUMMARY OF THE DISCLOSURE

[0013] [7] In one aspect, the present disclosure provides compounds of Formula I:

[0014]

[0015] or a pharmaceutically acceptable salt thereof, wherein

[0016] (i) R1is hydrogen, optionally substituted lower alkyl, or optionally substituted cycloalkyl; (ii) R2and R3are each independently hydrogen, cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, sulfonyl, optionally substituted alkoxy, optionally substitutedAgent Ref: 16738.0002-00304

[0017] cycloalkyloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, or optionally substituted carbamimidoyl; or

[0018] R2and R3may be joined together with any intervening atoms to form an optionally substituted heteroaryl ring;

[0019] (iii) R4is hydrogen, optionally substituted lower alkyl, or optionally substituted cycloalkyl; and

[0020]

[0021] Xi, X2, X3, X4, Xs, Xe, X7, Xs, X9, and X10 are each independently CR5or N, and R5is independently hydrogen, cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, sulfonyl, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, or optionally substituted carbamimidoyl,

[0022] with the proviso that at least two of Xi, X2, Xs, and X4 are independently CR5, and at least two of X5, Xe, X7, and Xs are independently CR5.

[0023] [8] In one aspect, the present disclosure provides compounds of Formula II:

[0024]

[0025] Formula II,

[0026] or a pharmaceutically acceptable salt thereof, whereinAgent Ref: 16738.0002-00304

[0027] (i) R1is hydrogen, optionally substituted lower alkyl, or optionally substituted cycloalkyl; (ii) R2and R3are each independently hydrogen, cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, sulfonyl, optionally substituted alkoxy, optionally substituted cycloalkydoxy, optionally substituted heterocycloalkydoxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxy carbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, or optionally substituted carbamimidoyl; or

[0028] R2and R3may be joined together with any intervening atoms to form an optionally substituted heteroaryl ring;

[0029] (iii) R4is hydrogen, optionally substituted lower alkyd, or optionally substituted cycloalkyl;

[0030]

[0031] Xi, X2, X3, X4, X5, Xe, X7, Xs, X9, and X10 are each independently CR5or N, and R5is independently hydrogen, cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, sulfonyl, optionally substituted alkoxy, optionally substituted cycloalkydoxy, optionally substituted heterocycloalkyloxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, or optionally substituted carbamimidoyl,

[0032] with the proviso that at least two of Xi, X2, X3, and X4 are independently CR5, and at least two of X5, Xe, X7, and Xs are independently CR5;

[0033] (v) each R6is independently hydrogen, cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, sulfonyl, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted ary l, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionallyAgent Ref: 16738.0002-00304

[0034] substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, or optionally substituted carbamimidoyl;

[0035] (vi) ring B is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, or optionally substituted cycloalkyl; and

[0036] (vii) n is 0, 1, 2, 3, 4 or 5.

[0037] [9] In another aspect, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound or pharmaceutically acceptable salt of any of the compounds described herein. The pharmaceutical composition may be formulated in a form which is a tablet, capsule, powder, liquid, suspension, suppository, or aerosol. The pharmaceutical composition may be packaged with instructions for using the composition to treat a subject suffering from a c-Kit-mediated disorder, disease, or condition.

[0038]

[0010] In another aspect, the present disclosure provides a method of inhibiting wild-type c-Kit or a c-Kit mutant thereof in a biological sample, which comprises contacting the sample with a compound or pharmaceutically acceptable salt of any of the compounds described herein, or with a pharmaceutical composition of any one of the compounds described herein. The present disclosure also provides a method of inhibiting wild-type c-Kit or a c-Kit mutant thereof in a subject in need thereof, which comprises administering to the subject a therapeutically effective amount of a compound or pharmaceutically acceptable salt of any of the compounds described herein, or a pharmaceutical composition of any one of the compounds described herein.

[0039]

[0011] In another aspect, the present disclosure provides a method of treating a c-Kit-mediated disorder, disease, or condition, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutically acceptable salt or pharmaceutical composition of any one of the compounds described herein. In some embodiments, the c-Kit-mediated disorder, disease, or condition is a mast-cell associated disease, a respiratory disease, an inflammatory disorder, an autoimmune disorder, a metabolic disease, a fibrotic disease, a dermatological disease, an allergic disease, a cardiovascular disease, or a neurological disorder. In some embodiments, the c-Kit-mediated disorder, disease, or condition is mediated by wild-type c-Kit kinase. In some embodiments, the c-Kit-mediated disorder, disease, or condition is mediated by a c-Kit mutant.Agent Ref: 16738.0002-00304

[0040] INCORPORATION BY REFERENCE

[0041]

[0012] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference in their entireties to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0042] DETAILED DESCRIPTION OF THE DISCLOSURE

[0043]

[0013] As used herein, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0044]

[0014] The following abbreviations and terms have the indicated meanings throughout:

[0045] ACN Acetonitrile

[0046] AIBN Azobisisobutyronitrile

[0047] Boc ter / -butoxy carbonyl

[0048] c- Cyclo

[0049] Cbz Benzyloxycarbonyl

[0050] Cmpd Compound

[0051] DCE 1,2-di chloroethane

[0052] DCM Dichloromethane

[0053] D1EA N, N-diisopropylethylamine

[0054] DMA Dimethylacetamide

[0055] DMAP 4-dimethylaminopyridine

[0056] DMEDA N. N’-dimethylethane-l,2-diamine

[0057] DMF Dimethylformamide

[0058] DMP Dess-Martin periodinane

[0059] DMSO dimethyl sulfoxide

[0060] eq equivalent(s)

[0061] Et Ethyl

[0062] EtOAc or EA ethyl acetate

[0063] EtOH Ethanol

[0064] g Gram

[0065] h Hour

[0066] HATU l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5- b]pyridinium 3-oxide hexafluorophosphateAgent Ref.: 16738.0002-00304

[0067] HPLC high pressure liquid chromatography

[0068] i- Iso

[0069] kg Kilogram

[0070] L or 1 Liter

[0071] LANCE lanthanide chelate excite

[0072] LC / MS LCMS = liquid chromatography -mass spectrometry

[0073] LRMS low resolution mass spectrometry

[0074] m / z mass-to-charge ratio

[0075] Me Methyl

[0076] MeOH Methanol

[0077] mg Milligram

[0078] min Minute

[0079] mL Milliliter

[0080] mmol Millimole

[0081] MPa Megapascal

[0082] n- Normal

[0083] NBS N-bromosuccinimide

[0084] NIS N-iodosuccinimide

[0085] NMI 1 -methyl-lH-imidazole

[0086] NaOAc sodium acetate

[0087] PE petroleum ether

[0088] PMB p-methoxybenzyl

[0089] Ph Phenyl

[0090] Prep Preparative

[0091] PyBOP (benzotriazol-l-yloxy)tripyrrolidinophosphonium hexafluorophosphate

[0092] quant. Quantitative

[0093] rt, r.t, or RT room temperature

[0094] s- sec- (secondary)

[0095] t- tert- (tertiary)

[0096] TEA Triethylamine

[0097] TFA trifluoroacetic acid

[0098] TFAA trifluoroacetic anhydrideAgent Ref: 16738.0002-00304

[0099] TfOH triflic acid

[0100] THF Tetrahydrofuran

[0101] TR-FRET time-resolved fluorescence resonance energy transfer

[0102] UV ultraviolet

[0103]

[0015] As used herein, when any variable occurs more than one time in a chemical formula, its definition on each occurrence is independent of its definition at every other occurrence.

[0104]

[0016] As used herein, a dash

[0105]

[0106] that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH2 is attached through the carbon atom.

[0107]

[0017] As used herein, "optional" or "optionally" is meant that the subsequently described event or circumstance may or may not occur, and that the description includes instances wherein the event or circumstance occurs and instances in which it does not. For example, "optionally substituted alkyl" encompasses both "alkyl" and "substituted alkyl" as defined below. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non-feasible, and / or inherently unstable.

[0108]

[0018] As used herein, "alkyl" refers to straight chain and branched chain having the indicated number of carbon atoms, usually from 1 to 20 carbon atoms, for example 1 to 8 carbon atoms, such as 1 to 6 carbon atoms. For example Ci-Ce alkyl encompasses both straight and branched chain alkyl of from 1 to 6 carbon atoms. When an alkyl residue having a specific number of carbons is named, all branched and straight chain versions having that number of carbons are intended to be encompassed; thus, for example, "butyl" is meant to include n-butyl, sec-butyl, isobutyl and t-butyl; "propyl" includes n-propyl and isopropyl. " Lower alkyl" refers to alkyl groups having one to six carbons. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopenty l, neopenty l, hexyl, 2 -hexyl, 3-hexyl, 3-methylpentyl, and the like. Alkylene is a subset of alkyd, referring to the same residues as alkyl, but having two points of attachment. Alkylene groups will usually have from 2 to 20 carbon atoms, for example 2 to 8 carbon atoms, such as from 2 to 6 carbon atoms. For example, Co alkylene indicates a covalent bond and Ci alky lene is a methylene group.

[0109]

[0019] As used herein, "alkenyl" refers to an unsaturated branched or straight-chain alkyl group having at least one carbon-carbon double bond derived by the removal of one molecule of hydrogen from adjacent carbon atoms of the parent alkyl. The group may be in either theAgent Ref: 16738.0002-00304

[0110] cis or trans configuration about the double bond(s). Typical alkenyl groups include, but are not limited to, ethenyl: propenyls such as prop-l-en-l-yl, prop-l-en-2-yl. prop-2-en- 1 -yl (allyl), prop-2-en-2-yl; butenyls such as but-l-en-l-yl, but-l-en-2-yl, 2-methyl-prop-l-en-l-yl, but-2-en-l-yl, but-2-en-l-yl, but-2-en-2-yl, buta-l,3-dien-l-yl, buta-l,3-dien-2-yl; and the like. In certain embodiments, an alkenyl group has from 2 to 20 carbon atoms and in other embodiments, from 2 to 6 carbon atoms. " Lower alkenyl" refers to alkenyl groups having two to six carbons.

[0111]

[0020] As used herein, "alkynyl" refers to an unsaturated branched or straight-chain alkyl group having at least one carbon-carbon triple bond derived by the removal of two molecules of hydrogen from adjacent carbon atoms of the parent alkyl. Typical alkynyl groups include, but are not limited to, ethynyl: propynyls such as prop-l-yn-l-yl, prop-2-yn-l-yl; butynyls such as but-l-yn-l-yl, but-l-yn-3-yl, but-3-yn-l-yl; and the like. In certain embodiments, an alkynyl group has from 2 to 20 carbon atoms and in other embodiments, from 3 to 6 carbon atoms. " Lower alky nyl" refers to alkynyl groups having two to six carbons.

[0112]

[0021] As used herein, "cycloalkyl" refers to a non-aromatic carbocyclic ring, usually having from 3 to 7 ring carbon atoms. The ring may be saturated or have one or more carbon-carbon double or triple bonds. Examples of cycloalkyd groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl, as well as bridged and caged ring groups such as norbomane.

[0113]

[0022] As used herein, "alkoxy" refers to an alkyl group of the indicated number of carbon atoms attached through an oxygen bridge such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentyloxy, 2-pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, 2-hexyloxy, 3-hexyloxy, 3-methylpentyloxy, and the like. Alkoxy groups will usually have from 1 to 7 carbon atoms attached through the oxygen bridge.

[0114] " Lower alkoxy" refers to alkoxy groups having one to six carbons.

[0115]

[0023] As used herein, "acyl" refers to the groups H-C(O)-; (alkyl)-C(O)-; (cycloalkyl)-C(O)-; (aryl)-C(O)-; (heteroaryl)-C(O)-; and (heterocycloalkyl)-C(O)-, wherein the group is attached to the parent structure through the carbonyl functionality and wherein alkyl, cycloalkyd, aryl, heteroaryl, and heterocycloalkyl are as described herein. Acyl groups have the indicated number of carbon atoms, with the carbon of the keto group being included in the numbered carbon atoms. For example a C2 acyl group is an acetyl group having the formula CH3(C=O)-.

[0116]

[0024] As used herein, "formyl" refers to the group -C(O)H.Agent Ref: 16738.0002-00304

[0117]

[0025] As used herein, "alkoxy carbonyl" refers to a group of the formula (alkoxy )(C=O)-attached through the carbonyl carbon wherein the alkoxy group has the indicated number of carbon atoms. Thus a Ci-Ce alkoxy carbonyl group is an alkoxy group having from 1 to 6 carbon atoms attached through its oxygen to a carbonyl linker.

[0118]

[0026] As used herein, "azido" refers to the group -N3.

[0119]

[0027] As used herein, "amino" refers to the group -NH2.

[0120]

[0028] As used herein, "mono- and di-(alkyl)amino" refers to secondary and tertiary alkyl amino groups, wherein the alkyl groups are as defined above and have the indicated number of carbon atoms. The point of attachment of the alkylamino group is on the nitrogen.

[0121] Examples of mono- and di-alkylamino groups include ethylamino, dimethylamino, and methyl-propyl-amino.

[0122]

[0029] As used herein, "aminocarbonyl" refers to the group -CONRbRc, where

[0123] Rbis H, optionally substituted Ci-Ce alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted alkoxy; and

[0124] Rcis hydrogen or optionally substituted C1-C4 alkyl; or

[0125] Rband Rctaken together with the nitrogen to which they are bound, form an optionally substituted 4- to 8-membered nitrogen-containing hcterocycloalk l which optionally includes 1 or 2 additional heteroatoms chosen from O, N, and S in the heterocycloalkyl ring;

[0126] where each substituted group is independently substituted with one or more substituents independently C1-C4 alkyl, aryl, heteroaryl, ary l-Ci-Cu alkyd-, heteroaryl-Ci-C4 alkyl-, C1-C4 haloalkyl, -OC1-C4 alkyl, -OC1-C4 alkylphenyl, -C1-C4 alkyl-OH, -OC1-C4 haloalkyl, halo, -OH, -NH2, -C1-C4 alkyl-NH2, -N(CI-C4 alkyl)(Ci-C4alkyl), -NH(CI-C4alkyl), -N(CI-C4 alk 1)(CI-C4 alkylphenyl), -NH(CI-C4 alkylphenyl), cyano, nitro, oxo (as a substituent for cycloalkyl, heterocycloalkyl, or heteroaryl), -CO2H, -C(O)OCi-C4 alkyl, -CON(CI-C4alkyl)(Ci-C4 alkyl), -CONH(CI-C4alkyl), -CONH2, -NHC(O)(CI-C4alkyl), -NHC(O)(phenyl), -N(CI-C4alkyl)C(O)(Ci-C4 alkyl). -N(CI-C4alkyl)C(O)(phenyl), -C(O)Ci-C4 alkyl, -C(O)Ci-C4alkylphenyl, -C(O)Ci-C4haloalkyl, -OC(O)Ci-C4alkyl, -SO2(Ci-C4alkyl), -SO2(phenyl), -SO2(Ci-C4 haloalkyl), -SO2NH2, -SO2NH(CI-C4alky l), -SO2NH(phenyl), -NHSO2(CI-C4 alkyl), -NHSO2(phenyl), or -NHSO2(CI-C4 haloalkyl).

[0127]

[0030] As used herein, "aryl" refers to: 6-membered carbocyclic aromatic rings, for example, benzene; bicyclic ring systems wherein at least one ring is carbocyclic and aromatic, forAgent Ref: 16738.0002-00304

[0128] example, naphthalene, indane, and tetralin; and tricyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, fluorene.

[0129]

[0031] For example, aryl includes 6-membered carbocyclic aromatic rings fused to a 4- to 8-membered non-aromatic ring containing 1 or more heteroatoms chosen from N, O, and S. For such fused, bicyclic ring systems wherein only one of the rings is a carbocyclic aromatic ring, the point of attachment may be at the carbocyclic aromatic ring or the non-aromatic ring. And, however, does not encompass or overlap in any way with heteroaryl, separately defined below. Hence, if one or more carbocyclic aromatic rings is fused with an aromatic ring containing 1 or more heteroatoms chosen from N, O, and S, the resulting ring system is heteroaryl, not aryl, as defined herein.

[0130]

[0032] As used herein, "aryloxy" refers to the group -O-aryl.

[0131]

[0033] As used herein, "aralkyl" refers to the group -alkyl-aryl.

[0132]

[0034] As used herein, "carbamimidoyl" refers to the group -C(=NH)-NH2.

[0133]

[0035] As used herein, "substituted carbamimidoyl" refers to the group -C(=NRe)-NRfRgwhere

[0134] Reis hydrogen, cyano, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyd; and

[0135] Rfand R8are independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted ary l, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl,

[0136] provided that at least one of Re, Rf, and Rgis not hydrogen and wherein substituted alkyl, cycloalkyd, aryl, heterocycloalkyd, and heteroaryl refer respectively to alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl wherein one or more (such as up to 5, for example, up to 3) hydrogen atoms are replaced by a substituent independently -Ra, -ORb, optionally substituted amino (including -NRcCORb, -NRcCO2Ra, -NRcCONRbRc, -NRbC(NRc)NRbRc, -NRbC(NCN)NRbRc, and -NRcS02Ra), halo, cyano, nitro, oxo (as a substituent for cycloalkyl, heterocycloalkyl, and heteroaryl), optionally substituted acyl (such as -CORb), optionally substituted alkoxy carbonyl (such as -C02Rb), aminocarbonyl (such as -CONRbRc), -OCORb, -OCO2Ra, -OCONRbRc, -OP(O)(ORb)ORc, sulfanyl (such as SRb), sulfinyl (such as -SORa), or sulfonyl (such as -SChRaand -SO2NRbRc),

[0137] where Rais optionally substituted Ci-Ce alkyl, optionally substituted ary l, or optionally substituted heteroaryl;Agent Ref: 16738.0002-00304

[0138] Rbis H. optionally substituted Ci-Ce alky l, optionally substituted aryl, or optionally substituted heteroaryl; and

[0139] Rcis hydrogen or optionally substituted C1-C4 alkyl; or

[0140] Rband Rc, and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group; and

[0141] where each optionally substituted group is unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently C1-C4 alkyl, aryl, heteroaryl, aryl-Ci-C4 alky l-, heteroaryl-Ci-C4 alkyl-, C1-C4 haloalkyl, -OC1-C4 alkyl, -OC1-C4 alkylphenyl, -C1-C4 alkyl-OH, -OC1-C4 haloalkyl, halo, -OH, -NH2, -C1-C4 alkyl-NH2, -N(CI-C4alkyl)(Ci-C4alkyl), -NH(CI-C4 alkyl), -N(CI-C4alkyl)(Ci-C4alkylphenyl). -NH(CI-C4 alkylphenyl), cyano, nitro, oxo (as a substituent for cycloalkyl, heterocycloalkyl, or heteroaryl), -CO2H, -C(O)OCi-C4 alkyl, -CON(CI-C4 alkyl)(Ci-C4 alkyl), -CONH(CI-C4alkyl), -CONH2, -NHC(O)(CI-C4alkyl), -NHC(O)(phenyl), -N(CI-C4alkyl)C(O)(Ci-C4alkyl), -N(CI-C4alkyl)C(O)(phenyl), -C(O)Ci-C4alkyl, -C(O)Ci-C4phenyl. -C(O)Ci-C4haloalkyl, -OC(O)Ci-C4 alkyl, -SO2(Ci-C4alkyl), -SO2(phenyl), -SO2(Ci-C4haloalkyl), -SO2NH2, -SO2NH(Ci-C4 alkyl), -SO2 NH(phenyl), -NHSO2(CI-C4alkyl), -NHSO2(phenyl), or -NHSO2(CI-C4haloalkyl).

[0142]

[0036] As used herein, "carboxy" refers to the group -C(O)OH.

[0143]

[0037] As used herein, "cycloalkyloxy" refers to a cycloalkyl as defined above having one of the ring carbon atoms attached through an oxygen bridge. Examples of cycloalkyloxy include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentyloxy and cyclohexyloxy. " Substituted cycloalkyloxy" refers to a substituted cycloalkyl as defined above having one of the ring carbon atoms attached through an oxygen bridge, wherein the substituents are as defined for “substituted alkyl.”

[0144]

[0038] As used herein, "halo" refers to fluoro, chloro, bromo, and iodo, and the term "halogen" includes fluorine, chlorine, bromine, and iodine.

[0145]

[0039] As used herein, "haloalkyl" refers to alky l as defined above having the specified number of carbon atoms, substituted with one or more halogen atoms, up to the maximum allowable number of halogen atoms. Examples of haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, 2-fluoroethyl, and penta-fluoroethyl.

[0146]

[0040] As used herein, "heteroaryl" refers to:

[0147] 5- to 7-membered aromatic, monocyclic rings containing one or more, for example, from 1 to 4, or in certain embodiments, from 1 to 3. heteroatoms chosen from N, O, and S. with the remaining ring atoms being carbon;Agent Ref: 16738.0002-00304

[0148] bicyclic rings containing one or more, for example, from 1 to 4, or in certain embodiments, from 1 to 3, heteroatoms chosen from N, O, and S. with the remaining ring atoms being carbon and wherein at least one heteroatom is present in an aromatic ring; and tricyclic rings containing one or more, for example, from 1 to 5, or in certain embodiments, from 1 to 4, heteroatoms chosen from N, O, and S, with the remaining ring atoms being carbon and wherein at least one heteroatom is present in an aromatic ring.

[0149] In certain embodiments, a heteroaryl contrains one or more oxo groups attached to one or more ring caron atoms.

[0150] Polycyclic heteroaryls include bicyclic heteroaryls and tricyclic heteroaryls. As used herein, the term "heteroaryl" refers to a group containing one or more points of attachment. For example, the term "heteroaryl" may refer to a group containing one point of attachment or two points of attachment (i.e., heteroarylene).

[0151]

[0041] For example, heteroaryl includes a 5- to 7-membered aromatic ring fused to a 4- to 8-membered cycloalkyl or heterocycloalkyl ring. For such fused, bicy clic heteroaryl ring systems wherein only one of the rings contains one or more heteroatoms, the point of attachment may be at either ring. When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another. In certain embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2. In certain embodiments, the total number of S and O atoms in the aromatic heterocycle is not more than 1. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothiophenyl, furanyl, pyrrolyl, benzofuranyl, benzoimidazolyl, indolyl, pyridazinyl, triazolyl, quinolinyl, quinoxalinyl, quinazolinyl, 2-pyridonyl, pyrimidin-2(lH)-onyl, and 5,6,7,8-tetrahydroisoquinolinyl. Heteroaryl does not encompass or overlap with aryl, cycloalkyl, or heterocycloalkyl, as defined herein.

[0152]

[0042] Substituted heteroaryl also includes ring systems substituted with one or more oxide (-O') substituents, such as pyridinyl N-oxides.

[0153]

[0043] As used herein, "heterocycloalkyl" refers to a single, non-aromatic ring, usually with 3 to 8 ring atoms, containing at least 2 carbon atoms in addition to 1-3 heteroatoms independently chosen from oxygen, sulfur, and nitrogen, as well as combinations comprising at least one of the foregoing heteroatoms. The ring may be saturated or have one or more carbon-carbon double bonds, or carbon-carbon triple bonds. Suitable heterocycloalkyl groups include but are not limited to, for example, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, azetidinyl, diazepanyl, diazocanyl, pyrrolidinyl, morpholinyl, piperidinyl,Agent Ref: 16738.0002-00304

[0154] piperazinyl, imidazolidinyl, pyrazolidinyl, dihydrofuranyl, and tetrahydrofuranyl. Substituted heterocycloalkyl can also include ring systems substituted with one or more oxo (=0) or oxide (-O') substituents, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-l-thiomorpholinyl and 1,1-dioxo-l-thiomorpholinyl.

[0155]

[0044] " Heterocycloalkyl" also includes bicyclic, or bridged, or spirocyclic ring systems wherein one non-aromatic ring, usually with 3 to 7 ring atoms, contains at least 2 carbon atoms in addition to 1-3 heteroatoms independently chosen from oxygen, sulfur, and nitrogen, as well as combinations comprising at least one of the foregoing heteroatoms; and the other ring, usually with 3 to 7 ring atoms, optionally contains 1-3 heteratoms independently chosen from oxygen, sulfur, and nitrogen and is not aromatic. For example, 8-azabicyclo[3.2.1]octanyl is a bridged heterocyclic ring system.

[0156]

[0045] As used herein, "heterocycloalkyloxy" refers to a heterocycloalkyl as defined above having one of the ring carbon atoms attached through an oxygen bridge. For example, pyrrolidin-3-yloxy is a heterocycloalkyloxy. " Substituted heterocycloalkyloxy" refers to a substituted heterocycloalky 1 as defined above having one of the ring carbon atoms attached through an oxygen bridge, wherein the substituents are as defined for “substituted alkyl.’7

[0046] As used herein, "sulfanyl" refers to the groups: -S-(optionally substituted (Ci-Ce)alkyl), -S-(optionally substituted cycloalkyl), -S-(optionally substituted aryl), -S-(optionally substituted heteroaryl), and -S-(optionally substituted heterocycloalkyl). Hence, sulfanyl includes the group Ci-Ce alkylsulfanyl.

[0157]

[0047] As used herein, "sulfinyl" refers to the groups: -S(O)-(optionally substituted (Ci-Ce)alky 1), -S(O)-(optionally substituted cycloalkyd), -S(O)-(optionally substituted ary l), -S(O)-optionally substituted heteroaryl). -S(O)-(optionally substituted heterocycloalky 1); and -S(O)-(optionally substituted amino).

[0158]

[0048] As used herein, "sulfonyl" refers to the groups: -S(O2)-(optionally substituted (Ci-Ce)alky 1), -S(O2)-(optionally substituted cycloalkyl), -S(O2)-(optionally substituted aryl), -S(O2)-(optionally substituted heteroaryl), -S(O2)-(optionally substituted heterocycloalkyl), and -S(O2)-(optionally substituted amino).

[0159]

[0049] As used herein, "aminosulfonyl" refers to the groups: -S(O2)NH2-, S(O2)NH(optionally substituted (Ci-Ce)alkyl), S(C>2)N(optionally substituted (Ci-Ce)alkyl)2, -S(O2)NH-(optionally substituted cycloalkyd), -S(O2)N-(optionally substituted cycloalkyl)2,-S(O2)NH-(optionally substituted aryl), S(O2)N-(optionally substituted ary 4)2, -S(02)NH-(optionally substituted heteroaryl). -S(02)N-(optionally substituted heteroaryl)2, -S(02)N-(optionally substituted heterocycloalkyl)2, and -S(O2)NH-(optionally substitutedAgent Ref: 16738.0002-00304

[0160] heterocycloalkyl). As used herein, "substituted" refers to any one or more hydrogens on the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded. When a substituent is oxo (i.e. =0) then 2 hydrogens on the atom are replaced. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation from a reaction mixture, and subsequent formulation as an agent having at least practical utility. Unless otherwise specified, substituents are named into the core structure. For example, it is to be understood that when (cycloalky I (alky I is listed as a possible substituent, the point of attachment of this substituent to the core structure is in the alkyl portion. For functional groups that are composed of a functional group for which optional substituents are provided herein, the definition of these optional substituents shall apply to such functional group as well. For instance, “alkoxy” is defined herein as “an alkyl group of the indicated number of carbon atoms attached through an oxygen bridge.” Thus, “substituted alkoxy” is “a substituted alkyl group of the indicated number of carbon atoms attached through an oxygen bridge,” wherein the optional substituents are as defined for “substituted alkyl.”

[0161]

[0050] In some embodiments, substituents (such as in situations where a group is optionally substituted with one or more substituents) or “optional substituents” are independently selected from halogen. -R'. -OR', =0, =NR'. =N-0R', -NR'R", -SR'. -SiR'R" R'", -OC(=O)R’, -C(=O)R', -CO2R', -C(=0)NR'R", -OC(=O)NR'R", -NR" C(=0)R', -NR'-C(=0)NR" R'", -NR'-S02NR" R"', -NR" C02R', -NH-C(NH2)=NH, -NR’C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -SO2R', -S02NR'R", -NR" SO2R', -CN, -N02, -N3, -CH(Ph)2, -(CH2)x0H (wherein x is an integer selected from 1 to 20), perfluoro(Ci-C4)alkoxy, and perfluoro(Ci-C4)alkyl. R1, R", and R'" each independently refer to hydrogen, cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, sulfonyl, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted cycloalkenyl, optionally substituted cycloalkynyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, or optionally substituted carbamimidoyl.Agent Ref: 16738.0002-00304

[0162]

[0051] As used herein, the terms "substituted" alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, unless otherwise expressly defined, refer respectively to alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl wherein one or more (such as up to 5, for example, up to 3) hydrogen atoms are replaced by a substituent independently -Ra, -ORb, optionally substituted amino (including -NRcCORb, -NRcCO2Ra, -NR°CONRbRc, -NRbC(NRc)NRbRc. -NRbC(NCN)NRbRc, and -NRcSO2Ra), halo, cyano, azido, nitro, oxo (as a substituent for cycloalkyl or heterocycloalkyl), optionally substituted acyl (such as -CORb), optionally substituted alkoxy carbonyl (such as -CO2Rb), aminocarbonyl (such as -CONRbRc), -OCORb, -OCO2Ra, -OCONRbRc, -OP(O)(ORb)ORc’ sulfanyl (such as SRb), sulfinyl (such as -SORa), or sulfonyl (such as -SO2Raand -SO2NRbRc).

[0163] where Rais optionally substituted Ci-Ce alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyd, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, or optionally substituted heteroaryl; Rbis hydrogen, optionally substituted Ci-Ce alkyd, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and Rcis hydrogen or optionally substituted C1-C4 alkyl; or

[0164] RbandRc, and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group; and

[0165] where each optionally substituted group is unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently C1-C4 alkyd, aryl, heteroaryl, aryl-Ci-C4 alkyd-, heteroaryl-Ci-C alkyd-, C1-C4 haloalky 1, -OC1-C4 alkyl, -OC1-C4 alkylphenyl, -C1-C4 alkyl-OH, -OC1-C4 haloalkyl, halo, -OH, -NH2, -C1-C4 alkyl-NH2, -N(CI-C4alkyl)(Ci-C4alkyd), -NH(CI-C4alkyl). -N(CI-C4alkyl)(Ci-C4alkylphenyl), -NH(Ci-C4 alkylphenyd), cyano, nitro, oxo (as a substituent for cycloalkyd or heterocycloalkyl), -CO2H, -C(O)OCi-C4alkyl, -CON(CI-C4alkyd)(Ci-C4alkyl), -CONH(CI-C4alkyl), -CONH2, -NHC(O)(CI-C4alkyd), -NHC(O)(phenyl), -N(CI-C4alkyl)C(O)(Ci-C4 alkyl), -N(CI-C4alkyl)C(O)(phenyl), -C(O)Ci-C4alkyl, -C(O)Ci-C4alkylphenyl, -C(O)Ci-C4haloalkyl, -OC(O)Ci-C4alkyl. -SO2(Ci-C4alkyl). -SO2(phenyl), -SO2(Ci-C4haloalkyl), -SO2NH2, -SO2NH(CI-C4alkyl), -SO2NH(phenyl), -NHSO2(CI-C4alkyd), -NHSO2(phenyl), or -NHSO2(CI-C4haloalkyl).

[0166]

[0052] As used herein, "substituted acyl" refers to the groups (substituted alkyl)-C(O)-; (substituted cycloalkyl)-C(O)-; (substituted aryl)-C(O)-; (substituted heteroaryl)-C(O)-; and (substituted heterocycloalkyl)-C(O)-, wherein the group is attached to the parent structureAgent Ref: 16738.0002-00304

[0167] through the carbonyl functionality and wherein substituted alkyl, cycloalkyl, aryl, heteroar l, and heterocycloalkyl, refer respectively to alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl wherein one or more (such as up to 5, for example, up to 3) hydrogen atoms are replaced by a substituent independently -Ra, -ORb, optionally substituted amino (including -NRcCORb, -NRcCO2Ra, -NRcCONRbRc, -NRbC(NRc)NRbRc, -NRbC(NCN)NRbRc, and -NRcS02Ra), halo, cyano, nitro, oxo (as a substituent for cycloalkyl or heterocycloalkyl), optionally substituted acyl (such as -CORh), optionally substituted alkoxycarbonyl (such as -CC>2Rb), aminocarbonyl (such as -CONRbRc), -OCORb, -OCChR3, -OCONRbRc, -OP(O)(ORb)ORc, sulfanyl (such as SRb), sulfinyl (such as -SORa), or sulfonyl (such as -SO2Raand -S02NRbRc),

[0168] where Rais optionally substituted Ci-Ce alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0169] Rbis H, optionally substituted Ci-Ce alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and

[0170] Rcis hydrogen or optionally substituted C1-C4 alkyl; or

[0171] RbandRc, and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group; and

[0172] where each optionally substituted group is unsubstituted or independently substituted with one or more, such as one. two, or three, substituents independently C1-C4 alkyl, aryl, heteroaryl, aryl-Ci-C4 alkyl-, heteroaryl -C1-C4 alkyl-, C1-C4 haloalkyl, -OC1-C4 alkyl, -OC1-C4 alkylphenyl, -C1-C4 alkyl-OH, -OC1-C4 haloalkyl, halo, -OH, -NH2, -C1-C4 alkyl-NH2, -N(CI-C4alkyl)(Ci-C4alkyl), -NH(CI-C alkyl), -N(CI-C4alkyl)(Ci-C4alkylphenyl). -NH(CI-C4 alkylphenyl), cyano, nitro, oxo (as a substituent for cycloalkyl or heterocycloalkyl), -CO2H, -C(O)OCi-C4alkyl, -CON(CI-C4 alkyl)(Ci-C4alkyl), -CONH(CI-C4alkyl), -CONH2, -NHC(O)(CI-C4alkyl), -NHC(O)(phenyl), -N(CI-C4alkyl)C(O)(Ci-C4alkyl), -N(CI-C4alkyl)C(O)(phenyl), -C(O)Ci-C4alkyl, -C(O)Ci-C4alkylphenyl, -C(O)Ci-C4haloalkyl, -OC(O)Ci-C4alkyl, -SO2(Ci-C4 alkyl). -SO2(phenyl), -SO2(Ci-C4haloalkyl), -SO2NH2. -SO2NH(Ci-C4 alkyl). -SO2NH(phenyl), -NHSO2(CI-C4 alkyl), -NHSO2(phenyl), or -NHSO2(CI-C4 haloalkyl).

[0173]

[0053] As used herein, "substituted alkoxy" refers to alkoxy wherein the alky l constituent is substituted (i.e. -©-(substituted alkyl)) wherein "substituted alkyl" refers to alkyl wherein one or more (such as up to 5. for example, up to 3) hydrogen atoms are replaced by a substituent independently -Ra, -ORb, optionally substituted amino (including -NRcCORb, -NRcCO2Ra,Agent Ref: 16738.0002-00304

[0174] -NRcCONRbRc, -NRbC(NRc)NRbRc, -NRbC(NCN)NRbRc, and -NRcSO2Ra), halo, cyano, nitro, oxo (as a substituent for cycloalkyl or heterocycloalkyl), optionally substituted acyl (such as -C0Rb), optionally substituted alkoxycarbonyl (such as -C02Rb), aminocarbonyl (such as -C0NRbRc), -0C0Rb, -OCO2Ra, -0C0NRbRc, -0P(0)(0Rb)0Rc, sulfanyl (such as SRb), sulfinyl (such as -SORa), and sulfonyl (such as -SO2Raand -S02NRbRc),

[0175] where Rais optionally substituted Ci-Ce alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0176] Rbis H, optionally substituted Ci-Ce alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyd, optionally substituted ary l, or optionally substituted heteroaryl; and

[0177] Rcis hydrogen or optionally substituted C1-C4 alkyl; or

[0178] RbandRc, and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group; and

[0179] where each optionally substituted group is unsubstituted or independently substituted with one or more, such as one. two, or three, substituents independently C1-C4 alkyl, aryl, heteroaryl, aryl-Ci-C4 alkyl-, heteroaryl-Ci-C4 alkyl-, C1-C4 haloalkyl, -OC1-C4 alkyl, -OC1-C4 alky Iphenyl, -C1-C4 alkyl-OH, -OC1-C4 haloalky 1, halo, -OH, -NH2, -C1-C4 alkyl-NH2, -N(CI-C4alkyd)(Ci-C4alky l), -NH(CI-C4alkyl), -N(CI-C4alkyl)(Ci-C4alky lphenyl). -NH(CI-C4 alkylphenyl), cyano, nitro, oxo (as a substituent for cycloalkyl or heterocycloalkyl), -COdd, -C(O)OCi-C4alkyl, -CON(CI-C4 alkyl)(Ci-C4alkyl), -C0NH(CI-C4alkyl), -CONH2, -NHC(0)(CI-C4alkyl), -NHC(O)(phenyl), -N(CI-C4alkyl)C(O)(Ci-C4alkyl), -N(CI-C4alkyl)C(O)(phenyl), -C(0)Ci-C4 alkyd, -C(O)Ci-C4alkydphenyl, -C(O)Ci-C4haloalkyl, -OC(O)Ci-C4alkyd, -SO2(Ci-C4 alkyl), -SO2(phenyl), -SO2(C1-C4 haloalkyl), -SO2NH2. -SQ2NH(Ci-C4 alkyl), -SO2NH(phenyl), -NHSQ2(CI-C4 alkyl), -NHSO2(phenyl), or-NHSO2(Ci-C4 haloalkyl).

[0180]

[0054] In some embodiments, a substituted alkoxy group is "polyalkoxy" or -O-(optionally substituted alky dene)-(optionally substituted alkoxy), and includes groups such as -OCH2CH2OCH3. and residues of glycol ethers such as polyethyleneglycol, and -O(CH2CH2O)XCH?, where x is an integer of 2-20, such as 2-10, and for example, 2-5.

[0181] Another substituted alkoxy group is hydroxyalkoxy or -OCH2(CH2)yOH, where y is an integer of 1-10, such as 1-4.

[0182]

[0055] As used herein, "substituted alkoxy carbonyl" refers to the group (substituted alkyl)-O-C(O)- wherein the group is attached to the parent structure through the carbonyl functionality and wherein substituted refers to alkyl wherein one or more (such as up to 5, for example, upAgent Ref: 16738.0002-00304

[0183] to 3) hydrogen atoms are replaced by a substituent independently -Ra, -ORb, optionally substituted amino (including -NRcCORb, -NRcC02Ra. -NRcCONRbRc, -NRbC(NR°)NRbRc, -NRbC(NCN)NRbRc, and -NRcSO2Ra), halo, cyano, nitro, oxo (as a substituent for cycloalkyl or heterocycloalkyl), optionally substituted acyl (such as -CORb), optionally substituted alkoxycarbony l (such as -CO2Rb), aminocarbonyl (such as -CONRbRc), -OCORb, -OCO2R1. -OCONRhR°, -OP(O)(ORb)ORc, sulfanyl (such as SRb). sulfinyl (such as -SORa), and sulfonyl (such as -SChR3and -SO2NRbRc),

[0184] where Rais optionally substituted Ci-Ce alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0185] Rbis H, optionally substituted Ci-Ce alky l, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and

[0186] Rcis hydrogen or optionally substituted C1-C4 alkyl; or

[0187] RbandRc, and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group; and

[0188] where each optionally substituted group is unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently C1-C4 alky 1, aryl, heteroary l, aryl-Ci-C4 alky l-, heteroary I-C1-C4 alkyl-, C1-C4 haloalky 1, -OC1-C4 alkyl, -OC1-C4 alkylphenyl, -C1-C4 alkyl-OH, -OC1-C4 haloalkyl, halo, -OH, -NH2, -C1-C4 alkyl-NH2. -N(CI-C4alkyl)(Ci-C4alky 1), -NH(CI-C4alkyl). -N(CI-C4alkyl)(Ci-C4alkylphenyl), -NH(Ci-C4 alkylpheny l), cyano, nitro, oxo (as a substituent for cycloalky l or heterocycloalkyd), -CO2H, -C(O)OCi-C4alkyl, -CON(CI-C4alkyl)(Ci-C4alkyd), -CONH(CI-C4alkyl), -CONH2, -NHC(O)(CI-C4alkyl), -NHC(O)(phenyl), -N(CI-C4alkyl)C(O)(Ci-C4 alkyl). -N(CI-C4alkyl)C(O)(phenyl), -C(O)Ci-C4alkyl, -C(O)Ci-C4alkylphenyl, -C(O)Ci-C4haloalkyl, -OC(O)Ci-C4alkyl, -SO2(Ci-C4 alkyl), -SO2(phenyl), -SO2(Ci-C4haloalkyl), -SO2NH2, -SO2NH(CI-C4 alkyl), -SO2NH(phenyl), -NHSO2(CI-C4alkyl), -NHSO2(phenyd), or -NHSO2(CI-C4 haloalkyl).

[0189]

[0056] As used herein, "substituted amino" refers to the group -NHRdor -NRdRewherein Rdis hydroxyl, formyl, optionally substituted alkoxy, optionally substituted alkyd, optionally substituted cycloalkyd, optionally substituted acyl, optionally substituted carbamimidoyl, aminocarbonyl, optionally substituted aryl, optionally substituted heteroary 1, optionally substituted heterocycloalkyd, optionally substituted alkoxy carbonyl, sulfinyl and sulfonyl, and wherein Reis chosen from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substitutedAgent Ref: 16738.0002-00304

[0190] heterocycloalkyl, and wherein substituted alky l, cycloalkyl, aryl, heterocycloalk l, and heteroaryl refer respectively to alkyl, cycloalkyl, ary l, heterocycloalkyl, and heteroaryl wherein one or more (such as up to 5, for example, up to 3) hydrogen atoms are replaced by a substituent independently -Ra, -ORb, optionally substituted amino (including -NRcCORb, -NRcCO2Ra, -NRcCONRbRc, -NRbC(NRc)NRbRc, -NRbC(NCN)NRbRc, and -NRcSO2Ra), halo, cyano, nitro, oxo (as a substituent for cycloalkyl or heterocycloalkyl), optionally substituted acyl (such as -CORb), optionally substituted alkoxy carbonyl (such as -CO2Rb). aminocarbonyl (such as -CONRbRc), -OCORb, -OCO2Ra, -OCONRbRc, -OP(O)(ORb)ORc, sulfanyl (such as SRb), sulfinyl (such as -SORa), or sulfonyl (such as -SO2Raand -SO2NRbRc),

[0191] wherein Rais optionally substituted Ci-Ce alkyl, optionally substituted alkeny l, optionally substituted alkyny 1, optionally substituted aryl, or optionally substituted heteroaryl;

[0192] Rbis H, optionally substituted Ci-Ce alky l, optionally substituted cycloalky l, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and

[0193] Rcis hydrogen or optionally substituted C1-C4 alkyl; or Rband Rc, and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group; and wherein each optionally substituted group is unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently chosen from C1-C4 alkyl, aryl, heteroaryl, aryl-Ci-C4 alkyd-, heteroaryl -C1-C4 alkyl-, C1-C4 haloalkyl, -OC1-C4 alkyl, -OC1-C4 alky lphenyl, -C1-C4 alkyl-OH, -OC1-C4 haloalky l, halo, -OH, -NH2, -C1-C4 alkyl-NH2, -N(CI-C4alky l)(Ci-C4alky 1), -NH(CI-C alkyl), -N(CI-C4alkyl)(Ci-C4alkylphenyl). -NH(Ci-C4 alkylphenyl), cyano, nitro, oxo (as a substituent for cycloalkyl or heterocycloalkyl), -CO2H, -C(O)OCi-C4alkyl, -CON(CI-C4 alkyl)(Ci-C4alkyl), -CONH(CI-C4alkyl), -CONH2, -NHC(O)(CI-C4alkyl), -NHC(O)(phenyl), -N(CI-C4alkyl)C(O)(Ci-C4 alky l), -N(CI-C4alky l)C(O)(phenyl), -C(O)Ci-C4alkyl, -C(O)Ci-C4alkylphenyl, -C(O)Ci-C4haloalkyl, -OC(O)Ci-C4alkyd. -SO2(Ci-C4 alkyl). -SO2(phenyl), -SO2(Ci-C4haloalkyl), -SO2NH2. -SO2NH(CI-C4alkyl). -SO2NH(phenyl), -NHSO2(CI-C4alkyl), -NHSO2(phenyl), or -NHSO2(CI-C4 haloalkyl); and

[0194] wherein optionally substituted acyl, optionally substituted alkoxy carbonyl, sulfinyl and sulfonyl are as defined herein.

[0195]

[0057] The term "substituted amino" also refers to N-oxides of the groups -NHRd, and NRdRdeach as described above. N-oxides can be prepared by treatment of the corresponding aminoAgent Ref: 16738.0002-00304

[0196] group with, for example, hydrogen peroxide or m-chloroperoxybenzoic acid. The person skilled in the art is familiar with reaction conditions for carrying out the N-oxidation.

[0197]

[0058] Combinations of chemical components (such as substituents, ring structures, or heteroatoms) as disclosed herein are those that result in the formation of stable or chemically feasible compounds. For abbreviation or according to common practice, certain hydrogen atoms attached to a certain atom (e.g., a carbon atom C or a nitrogen atom N) are not specifically spelled out in a chemical structure, formula, or notation; hydrogen atoms are deemed to be present to the extent the valences of the certain atom (e g., C or N) are completed.

[0198]

[0059] Compounds described herein include, but are not limited to, their optical isomers, racemates, and other mixtures thereof. In those situations, the single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral high-pressure liquid chromatography (HPLC) column. In addition, compounds include Z- and E- forms (or cis- and trans- forms) of compounds with carbon-carbon double bonds. Where compounds described herein exist in various tautomeric forms, the term “compound’' is intended to include all tautomeric forms of the compound.

[0199]

[0060] Compounds of Formula I and Formula II also include crystalline and amorphous forms of those compounds, including, for example, polymorphs, pseudopolymorphs, solvates (including hydrates), unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.

[0200] " Crystalline form," "polymorph." and "novel form" may be used interchangeably herein, and are meant to include all crystalline and amorphous forms of the compound, including, for example, polymorphs, pseudopolymorphs, solvates (including hydrates), unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, as well as mixtures thereof, unless a particular crystalline or amorphous form is referred to. Similarly, “pharmaceutically acceptable forms” of compounds of Formula I and Formula II also include crystalline and amorphous forms of those compounds, including, for example, polymorphs, pseudopolymorphs, solvates (including hydrates), unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the pharmaceutically acceptable salts, as well as mixtures thereof.Agent Ref: 16738.0002-00304

[0201]

[0061] A “solvate” is formed by the interaction of a solvent and a compound. The term “compound” is intended to include solvates of compounds. Similarly, “pharmaceutically acceptable salts” includes solvates of pharmaceutically acceptable salts. Suitable solvates are pharmaceutically acceptable solvates, such as hydrates, including monohydrates and hemihydrates.

[0202]

[0062] Compounds of Formula I and Formula II also include other pharmaceutically acceptable forms of the recited compounds, including chelates, non-covalent complexes, prodrugs, and mixtures thereof.

[0203]

[0063] A “chelate” is formed by the coordination of a compound to a metal ion at two (or more) points. The term “compound” is intended to include chelates of compounds. Similarly, “pharmaceutically acceptable salts” includes chelates of pharmaceutically acceptable salts.

[0204]

[0064] A “non-covalent complex” is formed by the interaction of a compound and another molecule wherein a covalent bond is not formed between the compound and the molecule. For example, complexation can occur through van der Waals interactions, hydrogen bonding, and electrostatic interactions (also called ionic bonding). Such non-covalent complexes are included in the term "compound”. Similarly, pharmaceutically acceptable salts include “non-covalent complexes” of pharmaceutically acceptable salts.

[0205]

[0065] The term "hydrogen bond" refers to a form of association between an electronegative atom (also known as a hydrogen bond acceptor) and a hydrogen atom attached to a second, relatively electronegative atom (also known as a hydrogen bond donor). Suitable hydrogen bond donor and acceptors are well understood in medicinal chemistry.

[0206]

[0066] “Hydrogen bond acceptor” refers to a group comprising an oxygen or nitrogen, such as an oxygen or nitrogen that is sp2-hybridized, an ether oxygen, or the oxygen of a sulfoxide or N-oxide.

[0207]

[0067] The term "hydrogen bond donor" refers to an oxygen, nitrogen, or heteroaromatic carbon that bears a hydrogen. group containing a ring nitrogen or a heteroaryl group containing a ring nitrogen.

[0208]

[0068] The compounds disclosed herein can be used in different enriched isotopic forms, e.g., enriched in the content of2H,3H,11C,13C and / or14C. In one particular embodiment, the compound is deuterated at least one position. Such deuterated forms can be made by the procedure described in U. S. Patent Nos. 5,846,514 and 6,334,997. As described in U. S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the efficacy and increase the duration of action of drugs.Agent Ref: 16738.0002-00304

[0209]

[0069] Deuterium substituted compounds can be synthesized using various methods such as described in: Dean, Dennis C.: Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0210]

[0070] “Pharmaceutically acceptable salts” include, but are not limited to salts with inorganic acids, such as hydrochlorate, phosphate, diphosphate, hydrobromate, sulfate, sulfinate, nitrate, and like salts; as well as salts with an organic acid, such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate. 2-hydroxy ethylsulfonate, benzoate, salicylate, stearate, and alkanoate such as acetate, HOOC-(CH2)n-COOH where n is 0-4, and like salts. Similarly, pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium, and ammonium.

[0211]

[0071] In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare non-toxic pharmaceutically acceptable addition salts.

[0212]

[0072] “Prodrugs” described herein include any compound that becomes a compound of Formula I or Formula II when administered to a subject, e.g., upon metabolic processing of the prodrug. Similarly, “pharmaceutically acceptable salts” includes “prodrugs” of pharmaceutically acceptable salts. Examples of prodrugs include derivatives of functional groups, such as an amine group or a carboxylic acid group, in the compounds of Formula I and Formula II. Exemplary prodrugs of an amine group include, but are not limited to, amides, N-acyloxyalkoxy carbonyls, N-acyloxyalkylesters, P-aminoketones, P-aminoesters, imines (Schiff bases), N-Mannich bases, enamines, enaminones, and lactones (Simplicio et al., Molecules. 2008 Mar; 13(3): 519-547; Bundgaard H., Methods in Enzymology, Academic Press, 112, 1985, Pages 347-359, ISSN 0076-6879, ISBN 9780121820121).Agent Ref: 16738.0002-00304

[0213] Exemplary prodrugs of a carboxylic acid carboxylic acid esters such as alkyl esters, hydroxyalkyl esters, arylalkyd esters, and aryloxyalkyl esters. Other exemplary prodrugs include lower alkyl esters such as ethyl ester, acyloxyalkyl esters such as pivaloyloxymethyl (POM), glycosides, and ascorbic acid derivatives.

[0214]

[0073] Other exemplary prodrugs include amides of carboxylic acids. Exemplary' amide prodrugs include metabolically labile amides that are formed, for example, with an amine and a carboxylic acid. Exemplary amines include NEE, primary, and secondary amines such as NHRX, and NRxRy, wherein Rxis hydrogen, (Ci-Cis)-alky 1, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(Ci-C4)-alkyl-, (Ce-Ci4)-aryd which is unsubstituted or substituted by a residue (Ci-C2)-alkyl, (Ci-C2)-alkoxy, fluoro, or chloro; heteroaryl-, (C6-Ci4)-aryl-(Ci-C4)-alkyl-where aryl is unsubstituted or substituted by a residue (Ci-C2)-alkyl, (Ci-C2)-alkoxy. fluoro, or chloro; or heteroaryl-(Ci-C4)-alkyl- and in which Ryhas the meanings indicated for Rxwith the exception of hydrogen or wherein Rxand Ry, together with the nitrogen to which they are bound, form an optionally substituted 4- to 7-membered heterocycloalkyl ring which optionally includes one or two additional heteroatoms chosen from nitrogen, oxygen, and sulfur. A 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, in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.

[0215]

[0074] As used herein, the terms "group", "radical" or "fragment" are synonymous and are intended to indicate functional groups or fragments of molecules attachable to a bond or other fragments of molecules.

[0216]

[0075] As used herein, the term “leaving group'’ refers to the meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or group displaceable under nucleophilic displacement conditions. Examples of leaving groups include, but are not limited to, dimethylhydroxylamino (e.g., Weinreb amide), halogen, alkane- or arylsulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy, thiomethyl, benzenesulfonyloxy, tosyloxy. and thienyloxy, dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy, acyloxy, and the like.

[0217]

[0076] As used herein, the term “protective group” or “protecting group” refers to a group which selectively blocks one reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry. Certain processes of this disclosure rely upon the protective groups to block certain reactive sites present in the reactants.Agent Ref: 16738.0002-00304

[0218] Examples of protecting groups can be found in Wuts et al., Green ’s Protective Groups in Organic Synthesis. (J. Wiley, 4th ed. 2006).

[0219]

[0077] As used herein, the term '‘deprotection” or “deprotecting” refers to a process by which a protective group is removed after a selective reaction is completed. Certain protective groups may be preferred over others due to their convenience or relative ease of removal. Without being limiting, deprotecting reagents for protected amino or anilino group include strong acid such as trifluoroacetic acid (TFA), concentrated HC1, H2SO4, or HBr. and the like.

[0220]

[0078] As used herein, "modulation" refers to a change in activity as a direct or indirect response to the presence of a chemical entity as described herein, relative to the activity of in the absence of the chemical entity. The change may be an increase in activity or a decrease in activity, and may be due to the direct interaction of the compound with the a target or due to the interaction of the compound with one or more other factors that in turn affect the target's activity. For example, the presence of the chemical entity may, for example, increase or decrease the target activity by directly binding to the target, by causing (directly or indirectly) another factor to increase or decrease the target activity, or by (directly or indirectly) increasing or decreasing the amount of target present in the cell or organism.

[0221]

[0079] As used herein, "active agent" is used to indicate a chemical entity which has biological activity. In certain embodiments, an "active agent" is a compound having pharmaceutical utility. For example an active agent may be an anti-cancer therapeutic.

[0222]

[0080] As used herein, "significant" refers to any detectable change that is statistically significant in a standard parametric test of statistical significance such as Student's T-test, where p < 0.05.

[0223]

[0081] As used herein, a "pharmaceutically acceptable" component is one that is suitable for use with humans and / or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit / risk ratio.

[0224]

[0082] As used herein, "therapeutically effective amount" of a chemical entity described herein refers to an amount effective, when administered to a human or non-human subject, to provide a therapeutic benefit such as amelioration of symptoms, slowing of disease progression, or prevention of disease.

[0225]

[0083] " Treating" or “treatment” encompasses administration of at least one compound of Formula I, Formula II, or a pharmaceutically acceptable salt of any of the foregoing, to a subject, particularly a human subject, in need of such an administration and includes (i) arresting the development of clinical symptoms of the disease, such as cancer, (ii) bringingAgent Ref: 16738.0002-00304

[0226] about a regression in the clinical symptoms of the disease, such as cancer, and / or (iii) prophylactic treatment for preventing the onset of the disease, such as cancer.

[0227]

[0084] As used herein, "cancer" refers to all types of cancer or neoplasm or malignant tumors found in mammals, including carcinomas and sarcomas. Examples of cancer are cancer of the brain, breast, cervix, colon, head & neck, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus and Medulloblastoma.

[0228]

[0085] As used herein, "subject" refers to an animal, e.g., a mammal, that has been or will be the object of treatment, observation or experiment. The methods described herein can be useful in both human therapy and veterinary applications. In some embodiments, the subject is a human.

[0229]

[0086] The term "mammal" is intended to have its standard meaning, and encompasses humans, dogs, cats, sheep, and cows, for example.

[0230]

[0087] As used herein, the term “c-Kit” is used to refer to a membrane receptor protein tyrosine kinase which is preferably activated upon binding Stem Cell Factor (SCF) to its extracellular domatin. C-Kit is also known as KIT, CD 117, and stem cell factor receptor, and may be used to refer to the gene or protein product of the gene.

[0231]

[0088] As used herein, the term "c-Kit-mediated disorder, disease, or condition" refers to a disorder, disease, or condition mediated by wild-type c-Kit kinase and / or a c-Kit mutant.

[0232]

[0089] As used herein, the term “c-Kit mutant” is used to refer to Kit having one or more of the mutations including, but are not limited to, D816F, D816H. D816N, D816Y, D816V, K642E, Y823D, Del 550-558, Del 557-561, N822K, V654A, N822H, Del 550-558+V654A, Del 557-561+V654A, Ins503AY, V560G, 558NP, Del 557-558, Del W559-560, F522C, Del 579, R634W, K642E, T801I, C809G, D820Y, N822K, N822H, Y823D, Y823C and T670I.

[0233] A. Compounds

[0234]

[0090] In some embodiments, provided is a compound of Formula I:

[0235]

[0236] Formula 1,

[0237] or a pharmaceutically acceptable salt thereof, wherein

[0238] (i) R1is hydrogen, optionally substituted lower alky l, or optionally substituted cycloalkyl;Agent Ref: 16738.0002-00304

[0239] (ii) R2and R3are each independently hydrogen, cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, sulfonyl, optionally substituted alkoxy, optionally substituted cycloalkydoxy, optionally substituted heterocycloalkyloxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted ary l, optionally substituted heteroary l, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxy carbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, or optionally substituted carbamimidoyl; or

[0240] R2and R3may be joined together with any intervening atoms to form an optionally substituted heteroaryl ring;

[0241] (iii) R4is hydrogen, optionally substituted lower alkyl, or optionally substituted cycloalkyl; and

[0242]

[0243] Xi, X2, X3, X4, X5, Xe, X7, Xs, X9, and X10 are each independently CR5or N, and R3is independently hydrogen, cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, sulfonyl, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, or optionally substituted carbamimidoyl,

[0244] with the proviso that at least two of Xi, X2, X3, and X4 are independently CR5and at least two of X5, Xe, X7, and Xs are independently CR3.

[0245]

[0091] In some embodiments, provided is a compound of Formula II:

[0246]

[0247] Agent Ref: 16738.0002-00304

[0248] Formula II,

[0249] or a pharmaceutically acceptable salt thereof, wherein

[0250] (i) R1is hydrogen, optionally substituted lower alkyl, or optionally substituted cycloalkyl; (ii) R2and R3are each independently hydrogen, cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, sulfonyl, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, or optionally substituted carbamimidoyl; or

[0251] R2and R3may be joined together with any intervening atoms to form an optionally substituted heteroaryl ring;

[0252] (iii) R4is hydrogen, optionally substituted lower alkyl, or optionally substituted cycloalkyl;

[0253] (iv) ring A

[0254]

[0255] is wherein

[0256] Xi, X2, X3, X4, Xs, Xe, X7, Xs, X9, and X10 are each independently CR5or N, and R5is independently hydrogen, cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, sulfonyl, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, or optionally substituted carbamimidoyl,

[0257] with the proviso that at least two of Xi, X2, X3, and X4 are independently CR5, and at least two of X5, Xe, X7, and Xs are independently CR5;

[0258] (v) each R6is independently hydrogen, cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, sulfonyl, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted heterocycloalk loxy. optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substitutedAgent Ref: 16738.0002-00304

[0259] heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxy carbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, or optionally substituted carbamimidoyl;

[0260] (vi) ring B is optionally substituted ary l, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, or optionally substituted cycloalkyl; and

[0261] (vii) n is 0, 1, 2, 3. 4 or 5.

[0262]

[0092] In some embodiments, R1is hydrogen or optionally substituted lower alkyl. In some embodiments, R1is hydrogen or optionally substituted C1-C3 alkyl. In some embodiments, R1is hydrogen or methyl. In some embodiments, R1is hydrogen. In some embodiments, R1is methyl.

[0263]

[0093] In some embodiments, R2and R3are each independently hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl. In some embodiments, R2and R3are independently hydrogen or optionally substituted lower alkyl.

[0264]

[0094] In some embodiments, R2and R3are each independently hydrogen, lower alkyl optionally substituted with 1-3 substituents independently selected from hydroxy and halo, or optionally substituted C3-C6 cycloalkyl. In some embodiments, R2and R3are each independently hydrogen, C1-C3 alkyl, C1-C3 alkyl substituted with one hydroxy or one halo, or C3-C6 cycloalkyl. In some embodiments, R2and R3are each independently hydrogen, methyl optionally substituted with 1-3 substituents selected from hydroxy and fluoro, or cyclopropyl. In some embodiments, R2and R3are each independently hydrogen, methyl, hydroxymethyl, fluoromethyl, or cyclopropyl.

[0265]

[0095] In some embodiments, R2and R3are lower alkyl. In some embodiments, R2is lower alkyl and R3is hydrogen. In some embodiments, R2is hydrogen and R3is lower alkyl. In some embodiments, R2is lower alkyl optionally substituted with 1-3 substituents independently selected from hydroxy and halo, and R3is lower alkyl. In some embodiments, R2is lower alkyl and R3is lower alkyl optionally substituted with 1-3 substituents independently selected from hydroxy and halo.

[0266]

[0096] In some embodiments, R2and R3are methyl. In some embodiments, R2is methyl and R3is hydrogen. In some embodiments, R2is hydrogen and R3is methyl. In some embodiments, R2is cyclopropyl and R3is methyl. In some embodiments, R2is hydroxymethyl and R3is methyl. In some embodiments, R2is methyl and R3is hydroxymethyl. In some embodiments, R2is monofluoromethyl and R3is methyl.

[0267]

[0097] In some embodiments, R2and R3may be joined together with any intervening atoms to form an optionally substituted heteroaryl ring.Agent Ref: 16738.0002-00304

[0268]

[0098] In some embodiments, R2and R3may be joined together with any intervening atoms to form an optionally substituted indazolyl, an optionally substituted 4, 5,6,7-tetrahydroindazolyl, an optionally substituted azaindazolyl, an optionally substituted IH-pyrazolo[3,4-c]pyridyl, an optionally substituted 177-pyrazolo[4,3-c]pyridyl, or an optionally substituted IT / -pyrazolo|4.3-b|pyridyl.

[0269]

[0099] In some embodiments, R2and R3, together with the pyrazole ring to which they are

[0270] attached, form an optionally substituted ring structure

[0271]

[0272] R1

[0273]

[0100] In some embodiments, R4is hydrogen or optionally substituted lower alkyl.

[0274]

[0101] In some embodiments, R4is hydrogen.

[0275]

[0102] In some embodiments, R5is independently hydrogen, cyano, halo, hydroxy, carboxy, sulfonyl, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, or optionally substituted aminosulfonyl. In some embodiments, R5is independently hydrogen, cyano, halo, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted ary l. optionally substituted heteroaryl, or optionally substituted heterocycloalkyl. In some embodiments, R5is independently hydrogen, optionally substituted aryl, or optionally substituted heteroaryl.

[0276]

[0103] In some embodiments, R5is independently hydrogen, optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted pyrazolyl, or optionally substituted oxazolyl.

[0277]

[0104] In some embodiments, R5is independently hydrogen; phenyl optionally substituted with 1-3 substituents independently selected from optionally substituted heterocycloalkyl, halo, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted haloalkyl, optionally substituted alkoxy, optionally substituted aryl, cyano, and optionally substituted heteroaryl; pyridinyl optionally substituted with 1-3 substituents independently selected from optionally substituted heterocycloalkyl and optionally substituted heteroaryl; pyrazolyl optionally substituted with 1-3 substituents independently selected from optionally substituted heterocycloalkyl, optionally substituted lower alkyl,Agent Ref: 16738.0002-00304

[0278] optionally substituted cycloalkyl, and optionally substituted aryl; or oxazolyl optionally substituted with optionally substituted lower alkyl.

[0279]

[0105] In some embodiments, R5is hydrogen.

[0280]

[0106] In some embodiments, R3is phenyl optionally substituted with 1-3 substituents independently selected from optionally substituted heterocycloalkyl, halo, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted haloalkyl, optionally substituted alkoxy, optionally substituted aryl, cyano, and optionally substituted heteroaryl.

[0281]

[0107] In some embodiments, R3is phenyl optionally substituted with 1-3 substituents independently selected from morpholinyl, fluoro, chloro, morpholin-3-onyl, methyl, cyclopropyl, trifluoromethyl, methoxy, chlorobenzenyl. cyano, 2-pyridonyl, and pyrimidin-2(lH)-onyl.

[0282]

[0108] In some embodiments, R3is pyridinyl optionally substituted with 1-4 substituents independently selected from optionally substituted morpholinyl and optionally substituted 2-pyridonyl. In some embodiments, R5is pyridinyl optionally substituted with 1-4 substituents independently selected from morpholinyl and 2-pyridonyl.

[0283]

[0109] In some embodiments, R3is pyrazolyl optionally substituted with 1-2 substituents independently selected from optionally substituted cyclopropyl, optionally substituted methyl, optionally substituted isopropyl, optionally substituted isobutyl, optionally substituted tetrahydropyranyl, optionally substituted pyrrolidinyl. optionally substituted piperidinyl, optionally substituted 8 -azabi cyclo [3.2. l]octanyl, optionally substituted oxetanyl, optionally substituted cyclobutyl, optionally substituted azetidinyl, and optionally substituted phenyl.

[0284]

[0110] In some embodiments, R5is pyrazolyl optionally substituted with 1-3 substituents independently selected from cyclopropyl, methyl, isopropyl optionally substituted with 1-6 fluoro, isobulyl optionally substituted with 1-3 hydroxy, tetrahydropyranyl, pyrrolidinyl optionally substituted with 1 -3 substituents independently selected from methyl, fluoro, acetyl, and methoxy carbonyl, piperidinyl optionally substituted with 1-3 substituents independently selected from methyl, fluoro, acetyl, and methoxy carbonyl, 8-azabicyclo[3.2.1]octanyl optionally substituted with 1-3 substituents independently selected from acetyl, methoxy carbonyl, and methyl, oxetanyl, cyclobutyl optionally substituted with 1-3 substituents independently selected from methyl and hydroxy, azetidinyl optionally substituted with 1-3 substituents independently selected from methyl, acetyl, and methoxy carbonyl, and phenyl optionally substituted with cyano.Agent Ref.: 16738.0002-00304

[0285]

[0111] In some embodiments, R5is oxazolyl optionally substituted with optionally substituted lower alkyl. In some embodiments, R5is oxazolyl optionally substituted with optionally substituted isopropyl.

[0286]

[0112] In some embodiments, R5is independently hydrogen,

[0287]

[0288]

[0289] Agent Ref: 16738.0002-00304

[0290]

[0291]

[0113] In some embodiments of Formula I, Xi, X2, X3, X4, and X9 are each independently CR5; X5, Xs, X7, Xs, and X10 are each independently CR5: Xi is N, andX2, X3, X4, and X9 are each independently CR5; X2 is N, andXi, X3, X4, and X9 are each independently CR5; X3 is N, andXi, X2, X4, and X9 are each independently CR3; X4is N, andXi, X2, Xs, and X9 are eachAgent Ref: 16738.0002-00304

[0292] independently CR5; Xs is N, and Xe, X7, Xs, and X10 are each independently CR5; Xe is N, and Xs. X7. Xs. and X10 are each independently CR5; or X7 is N, and Xs, Xe, Xs, and X10 are each independently CR5.

[0293] if. X,X3~Y

[0114] In some embodiments of Formula I, ring A

[0294]

[0295] isA2and Xi, X2, X3, X4, and X9 are each independently CR5.

[0296] X7-v

[0115] In some embodiments of Formula I, ring A

[0297]

[0298] is6and Xs. Xe. X7. Xs. and X10 are each independently CR5.

[0299]

[0116] In some embodiments of Formula II, one of Xi, X2, X3, X4, and X9 is attached to ring B and the rest of Xi, X2, X3, X4, and X9 are each independently CR5; one of Xs, Xe, X7, Xs, and X10 is attached to ring B and the rest of Xs, Xe, X7, Xs, and X10 are each independently CR5; Xi is N. one of X2, X3, X4, and X9 is attached to ring B, and the rest of X2, X3, X4, and X9 are each independently CR5; X2is N, one of Xi, X3, X4, and X9 is attached to ring B, and the rest of Xi, X3, X4, and X9 are each independently CR5; X3 is N, one of Xi, X2, X4, and X9 is attached to ring B, and the rest of Xi, X2, X4, and X9 are each independently CR5; X4is N, one of Xi, X2, X3, and X9 is attached to ring B, and the rest of Xi. X2. X3. and X9 are each independently CR5; Xs is N, one of Xe, X7, Xs, and X10 is attached to ring B, and the rest of Xe, X7, Xs, and X10 are each independently CR5; Xe is N, one of Xs, X7, Xs, and X10 is attached to ring B, and the rest of Xs, X7, Xs, and X10 are each independently CR5; or X7 is N, one of Xs, Xe, Xs, and X10 is attached to ring B, and the rest of Xs, Xe, Xs, and X10 are each independently CR5.

[0300] ir

[0301]

[0117] In some embodiments of Formula II. ring

[0302]

[0303] A isA2and one of Xi, X2, X3, X4, and X9 is attached to ring B, and the rest of Xi, X2, Xs, X4, and X9 are each independently CR5.Agent Ref: 16738.0002-00304

[0304] z N

[0305]

[0118] In some embodiments of Formula II, ring A

[0306]

[0307] is7*6oneof Xs, Xe, X7, Xs, and X10 is attached to ring B, and the rest of Xs, Xe, X7, Xs, and X10 are each independently CR5.

[0308]

[0119] In some embodiments, ring B is optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl. In some embodiments, ring B is optionally substituted aryl or optionally substituted heteroaryl.

[0309]

[0120] In some embodiments, ring B is phenyl, pyridyl, pyrazinyl, pyridazinlyl, pyrimidinyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, triazolyl, oxadiazolyl. or tetrazolyl. In some embodiments, ring B is phenyl, pyridyl, pyrazinyl, pyridazinlyl, or pyrimidinyl. In some embodiments, ring B is pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, triazolyl, or oxadiazolyl.

[0310]

[0121] In some embodiments, ring B is optionally substituted phenyl, optionally substituted pyrazolyl, optionally substituted pyridinyl, or optionally substituted oxazolyl.

[0311]

[0312]

[0123] In some embodiments, R6is independently hydrogen, cyano, halo, optionally substituted alkoxy, optionally substituted alkyd, optionally substituted haloalkyl, optionally substituted cycloalky 1, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl.

[0313]

[0124] In some embodiments, each R6is independently hydrogen, cyano, halo, hydroxy, carboxy, sulfonyl, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted heterocycloalky doxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted ary l, optionally substituted heteroaryl, optionally substituted heterocycloalkyd, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, or optionally substituted aminosulfonyl.Agent Ref: 16738.0002-00304

[0314]

[0125] In some embodiments, each R6is independently hydrogen, cyano, halo, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl.

[0315]

[0126] In some embodiments, each R6is independently hydrogen, optionally substituted alkyl, optionally substituted cycloalky l, or optionally substituted heterocycloalky l.

[0316]

[0127] In some embodiments, R6is independently hydrogen, cyano, fluoro, chloro, optionally substituted methyl, optionally substituted isopropyl, optionally substituted isobutyl, optionally substituted tert-butyl, optionally substituted methoxy, optionally substituted cyclopropyl, optionally substituted bicyclo[l.l.l]pentanyl, optionally substituted phenyl, optionally substituted morpholin-3-onyl, optionally substituted tetrahydropyranyl, optionally substituted pyrrolidinyl, optionally substituted piperidinyl. optionally substituted 2-pyridonyl, optionally substituted pyrimidin-2(lH)-onyl, optionally substituted 8-azabicyclo[3.2.1]octanyl, optionally substituted oxetanyl, optionally substituted cyclobutyl, optionally substituted azetidinyl, or optionally substituted morpholinyl.

[0317]

[0128] In some embodiments, R6is independently hydrogen, cyano, fluoro, chloro, methyl optionally substituted with 1-3 fluoro, isopropyl optionally substituted with 1-6 fluoro, isobutyl optionally substituted with 1-3 hydroxy, methoxy, cyclopropyl optionally substituted with 1-5 substituents independently selected from fuoro and hydroxy, cyclobutyl optionally substituted with 1-7 substituents independently selected from fuoro and hydroxy. bicyclo[l.l.l]pentanyl optionally substituted with 1-9 substituents independently selected from fuoro and hydroxy, phenyl optionally substituted with 1 -5 substituents independently selected from cyano and chloro, morpholin-3-onyl, tetrahydropyranyl, pyrrolidinyl optionally substituted with 1 -3 substituents independently selected from methyl, fluoro, acetyl, and methoxy carbonyl, piperidinyl optionally substituted with 1-3 substituents independently selected from methyl, fluoro, acetyl, and smethoxy carbonyl, 2-pyridonyl, pyrimidin-2(lH)-onyl, 8-azabicyclo[3.2.1]octanyl optionally substituted with 1-3 substituents independently selected from acety l, methoxycarbonyl, and methyl, oxetanyl, cyclobuty l optionally substituted with 1-3 substituents independently selected from methyl and hydroxy, azetidinyl optionally substituted with 1-3 substituents independently selected from methyl, acetyl, and methoxy carbonyl, or morpholinyl.

[0318]

[0129] In some embodiments, R6is independently hydrogen, fluoro, chloro, methyl,

[0319]

[0320] isopropyl, cyclobutyl, bicyclo[l.l.l]pentanyl, cyano, methoxy, phenyl, -CF3,CF3,CF3Agent Ref: 16738.0002-00304

[0321]

[0322]

[0130] In some embodiments, n is 0, 1, 2, 3, 4, or 5. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5.

[0323]

[0131] In some embodiments, the present disclosure provides a compound chosen from the group consisting of:

[0324] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(lH-pyrazol-5-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0325] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-phenylimidazo[l,2-a]pyridine-3-carboxamide; N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(3-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0326] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide;Agent Ref.: 16738.0002-00304

[0327] N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(2-isopropyloxazol-4-yl)pyrazolo[l,5-a]pyridine-3 -carboxamide;

[0328] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(6-morpholinopyridin-2-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0329] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(5-morpholinopyridin-2-yl)imidazo[l,2-a] pyridine-3-carboxamide;

[0330] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(3-fluoro-4-morpholinophenyl)imidazo[L2-a]pyridine-3-carboxamide;

[0331] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(6-morpholinopyridin-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0332] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(2-fluoro-4-morpholinophenyl)imidazo[1.2-a]pyridine-3-carboxamide;

[0333] 7-(2,3-difluoro-4-morpholinophenyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0334] 7-(3-chloro-4-morpholinophenyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[1.2-a]pyridine-3-carboxamide;

[0335] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-(3-oxomorpholino)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0336] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(3-methyl-4-morpholinophenyl)imidazo[l,2-a|pyridme-3-carboxamide;

[0337] N-(5-methyl-lH-pyrazol-3-yl)-7-(4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0338] N-(4-methyl-lH-pyrazol-3-yl)-7-(4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0339] 7-(3-cyclopropyl-4-morpholinophenyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0340] N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-(4-morpholino-3-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridine-3-carboxamide;

[0341] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(3-methoxy-4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0342] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(3-fluorophenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0343] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(3-methoxyphenyl)imidazo[l,2-a]pyridine-3-carboxamide;Agent Ref.: 16738.0002-00304

[0344] 7-(3-cyclopropylphenyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0345] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0346] 7-(4-chlorophenyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0347] 7 -(4'-chloro- [ 1.1 '-biphenyl] -4-yl)-N -(4,5-dimethyl- 1 H-py razol-3 -y l)imidazo [1.2-a]pyridine-3-carboxamide;

[0348] N-(5-cyclopropyl-4-methyl-lH-pyrazol-3-yl)-7-(4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0349] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-isocyanophenyl)imidazo[L2-a]pyridine-3-carboxamide;

[0350] 7-(3-chlorophenyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0351] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(2-oxo-2H-[l,2'-bipyridin]-5'-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0352] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(3-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0353] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-fluorophenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0354] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-methoxyphenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0355] 7-(4-cyclopropylphenyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0356] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-(2-oxopyridin-l(2H)-yl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0357] 7-(3-cyanophenyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0358] N-(5-(hydroxymethyl)-4-methyl-lH-pyrazol-3-yl)-7-(4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0359] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-(2-oxopyrimidin-l(2H)-yl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;

[0360] N-(4-(hydroxymethyl)-5-methyl-lH-pyrazol-3-yl)-7-(4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide;Agent Ref.: 16738.0002-00304

[0361] N-(5-(fluoromethyl)-4-methyl-lH-pyrazol-3-yl)-7-(4-morpholinophenyl)imidazo[l,2-a] pyridine-3-carboxamide;

[0362] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l,3-dimethyl-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0363] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-methyl-lH-pyrazol-4-yl)imidazo[l,2-a] pyridine-3-carboxamide;

[0364] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(2-hydroxy-2-methylpropyl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0365] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(2-hydroxy-2-methylpropyl)-3-methyl-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0366] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(2-hydroxy-2-methylpropyl)-5-methyl-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0367] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0368] 7-(l-cyclopropyl-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0369] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-isopropyl-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0370] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-phenyl-lH-pyrazol-4-yl)imidazo[1.2-a|pyridine-3-carboxamide;

[0371] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(pyrrolidin-3-yl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3 -carboxamide;

[0372] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)imidazo[l,2-a] pyridine-3-carboxamide;

[0373] 7-(l-(4-cyanophenyl)-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0374] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(l-methylpiperidin-4-yl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide:

[0375] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(l-methylpyrrolidin-3-yl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0376] 7-(l-cyclopropyl-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0377] 7-(l-isopropyl-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;Agent Ref.: 16738.0002-00304

[0378] N-(lH-indazol-3-yl)-7-(l-isopropyl-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0379] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-((3R,4R)-4-fluoropyrrolidin-3-yl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0380] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-((3R,4R)-4-fluoro-l-methylpyrrolidin-3-yl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0381] N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(lH-pyrazol-5-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0382] N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-phenylpyrazolo[l,5-a]pyridine-3-carboxamide; N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(4-morpholinophenyl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0383] N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(3-fluoro-4-morpholinophenyl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0384] N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(6-morpholinopyridin-3-yl)pyrazolo[l,5-a] pyridine-3-carboxamide;

[0385] N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(2-fluoro-4-morpholinophenyl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0386] 6-(2,3-difluoro-4-morpholinophenyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0387] N-(4.5-dimethyl-lH-pyrazol-3-yl)-6-(5-morpholinopyridin-2-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0388] N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l,3-dimethyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0389] N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0390] N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(2-hydroxy-2-methylpropyl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0391] 6-(l-cyclopropyl-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)pyrazolo[1.5-a]pyridine-3-carboxamide;

[0392] N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-isopropyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0393] 6-(l-isopropyl-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;Agent Ref.: 16738.0002-00304

[0394] 6-(l-cyclopropyl-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[1.5-a] pyridine-3-carboxamide;

[0395] 6-(l-isopropyl-lH-pyrazol-4-yl)-N-(5-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0396] 6-(l-cyclopropyl-lH-pyrazol-4-yl)-N-(5-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a] pyridine-3-carboxamide;

[0397] 7-(l-isopropyl-lH-pyrazol-4-yl)-N-(1,4,5-trimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0398] 6-(l-isopropyl-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0399] 5-(l-isopropyl-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0400] N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0401] N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(l-methylpiperidin-4-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyndine-3-carboxamide;

[0402] methyl 4-(4-(3-((4,5-dimethyl-lH-pyrazol-3-yl)carbamoyl)pyrazolo[l,5-a]pyridin-6-y 1)- 1 H-pyrazol- 1 -y l)piperidine- 1 -carboxylate;

[0403] N-(4-methyl-lH-pyrazol-3-yl)-6-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a|pyridine-3-carboxamide;

[0404] N-(4-methyl-lH-pyrazol-3-yl)-6-(l-(l-methylpiperidin-4-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0405] 6-(l-(l-acetylpiperidin-4-yl)-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0406] N-(4-methyl-lH-pyrazol-3-yl)-6-(l-(l,l,l-trifluoropropan-2-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0407] N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(l,l,l-trifluoropropan-2-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0408] 6-(l-(l-acetylpiperidin-4-yl)-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0409] methyl 4-(4-(3-((4-methyl-lH-pyrazol-3-yl)carbamoyl)pyrazolo[l,5-a]pyridin-6-yl)- 1 H-pyrazol- 1 -y l)piperidine- 1 -carboxylate;

[0410] (S)-N-(4-methyl-lH-pyrazol-3-yl)-6-(l-(pyrrolidin-3-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;Agent Ref.: 16738.0002-00304

[0411] (S)-N-(4-methyl-lH-pyrazol-3-yl)-6-(l-(l-methylpyrrolidin-3-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0412] methyl (R)-3-(4-(3-((4,5-dimethyl- lH-pyrazol-3-yl)carbamoyl)pyrazolo[ 1,5-a]pyridin-6-yl)-lH-pyrazol-l-yl)pyrrolidine-l -carboxylate;

[0413] methyl (S)-3-(4-(3-((4-methyl-lH-pyrazol-3-yl)carbamoyl)pyrazolo[l,5-a]pyridin-6-yl)- 1 H-pyrazol- 1 -yl)pyrrolidine- 1 -carboxy late;

[0414] (S)-6-(l-(l-acetylpyrrolidin-3-yl)-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0415] (R)-6-(l-(l-acetylpyrrolidin-3-yl)-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0416] (S)-N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(l-methylpyrrolidin-3-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0417] methyl (R)-3-(4-(3-((4-methyl-lH-pyrazol-3-yl)carbamoyl)pyrazolo[l,5-a]pyridin-6-y 1)- 1 H-pyrazol- 1 -y l)pyrrolidine- 1 -carboxylate;

[0418] (R)-6-(l-(l-acetylpyrrolidin-3-yl)-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyndine-3-carboxamide;

[0419] (S)-N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(pyrrolidin-3-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0420] (S)-6-(l-(l-acetylpyrrolidin-3-yl)-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0421] methyl (S)-3-(4-(3-((4,5-dimethyl-lH-pyrazol-3-yl)carbamoyl)pyrazolo[l,5-a] py ridin-6-y 1)- 1 H-pyrazol- 1 -yl)pyrrolidine- 1 -carboxylate;

[0422] (R)-N-(4-methyl-lH-pyrazol-3-yl)-6-(l-(pyrrolidin-3-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0423] (R)-N-(4-methyl-lH-pyrazol-3-yl)-6-(l-(l-methylpyrrolidin-3-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0424] N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(l,l,l-trifluoro-2-methylpropan-2-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0425] 6-(3-cyclopropyl-l-isopropyl-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0426] 6-(l-isopropyl-3-methyl-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0427] 6-( 1 -isopropyl-5-methyl-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;Agent Ref: 16738.0002-00304

[0428] 6-(l-isopropyl-3,5-dimethyl-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0429] 7-(l-(l,3-difluoropropan-2-yl)-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0430] 7-(l-(l,3-difluoropropan-2-yl)-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide:

[0431] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(l,l,l-trifluoropropan-2-yl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0432] N-(4-methyl-lH-pyrazol-3-yl)-7-(l-(l,l,l-trifluoro-2-methylpropan-2-yl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0433] N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-(1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide;

[0434] N-(4-methyl-lH-pyrazol-3-yl)-7-(l-(l,l,l-trifluoropropan-2-yl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0435] (R)-N-(4.5-dimethyl-lH-pyrazol-3-yl)-6-(l -(1,1,1 -trifluoropropan-2-yl)- IH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0436] (R)-N-(4-methyl-lH-pyrazol-3-yl)-6-(l -(1,1, 1 -trifluoropropan-2-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0437] (S)-N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(l,l,l-triHuoropropan-2-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0438] (S)-N-(4-methyl-lH-pyrazol-3-yl)-6-(l -(1,1,1 -tri fluoropropan-2-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0439] N-(5-(l-isopropyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridin-3-yl)-4,5-dimethyl-lH-pyrazole-3-carboxamide;

[0440] N-(4-methyl-lH-pyrazol-3-yl)-6-(l-(l,l,l-trifluoro-2-methylpropan-2-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0441] 6-(l-(l,3-difluoropropan-2-yl)-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0442] 6-(l-(l,3-difluoropropan-2-yl)-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0443] 7-(l-(tert-butyl)-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0444] 7-(l -cyclobutyl- lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)imidazo[ 1.2-a]pyridine-3-carboxamide;Agent Ref.: 16738.0002-00304

[0445] 7-(l-cyclobutyl-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a] pyridine-3-carboxamide;

[0446] 7-(l-(tert-butyl)-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0447] N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-((lS,2R)-2-fluorocyclopropyl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0448] 7-(l-(bicyclo[l.l.l]pentan-l-yl)-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0449] 7-(l-(bicyclo[l.l.l]pentan-l-yl)-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide:

[0450] 7-(2-cyclopropyl-2H-l,2,3-triazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0451] 7-(2-cyclopropyl-2H-l,2,3-triazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0452] 1-(4-(3-((4-methyl-lH-pyrazol-3-yl)carbamoyl)imidazo[l,2-a]pyridin-7-yl)-lH-pyrazol- 1 -y l)cy clopropane- 1 -carboxylic acid;

[0453] 2-methyl-2-(4-(3-((4-methyl-lH-pyrazol-3-yl)carbamoyl)imidazo[l,2-a]pyridin-7-yl)-IH-pyrazol-l -yl)propanoic acid;

[0454] methyl 2-methyl-2-(4-(3-((4-methyl-lH-pyrazol-3-yl)carbamoyl)imidazo[l,2-a]pyridin-7-yl)-lH-pyrazol-l-yl)propanoate;

[0455] methyl l-(4-(3-((4-methyl-lH-pyrazol-3-yl)carbamoyl)imidazo[l,2-a]pyridin-7-yl)- 1 H-pyrazol- 1 -yl)cy clopropane- 1 -carboxylate;

[0456] 7-(l-(l-(hydroxymethyl)cyclopropyl)-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide:

[0457] 7-(l -( 1 -hydroxy -2-methylpropan-2 -yl)-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0458] 6-(l-(bicyclo[l.l.l]pentan-l-yl)-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0459] 6-(l-(bicyclo[l.l.l]pentan-l-yl)-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0460] 7-(l-isopropyl-lH-l,2,3-triazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0461] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(3-fluorobicyclo[l.l.l]pentan-l-yl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide;Agent Ref.: 16738.0002-00304

[0462] 7-(2-isopropyl-2H-l,2,3-triazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)imidazo[l,2-a] pyridine-3-carboxamide:

[0463] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(r-methyl-l'H-[l,4'-bipyrazol]-4-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0464] 7-(1'-cyclopropyl-1'H-[1,4'-bipyrazol]-4-yl)-N-(4,5-dimethyl-1H-pyrazol-3-yl)imidazo[1,2-a]pyridine-3-carboxamide:

[0465] N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(r-isopropyl-rH-[l,4'-bipyrazol]-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0466] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(r-isopropyl-l'H-[l,4'-bipyrazol]-4-yl)imidazo[l,2-a]pyridine-3-carboxamide:

[0467] 7-( 1'H- [ 1, 4 ' -bipy razol] -4-y l)-N-(4.5 -dimethyl- 1 H-pyrazol-3-y l)imidazo[ 1,2-a]pyridine-3-carboxamide;

[0468] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0469] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(isoxazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0470] 7-(l '-methyl- 1 'H- [ 1,4' -bipy razol] -4-yl)-N-(4-methyl- 1 H-pyrazol-3 -y l)imidazo [1,2-a]pyridine-3-carboxamide;

[0471] 7-(r-cyclopropyl-l'H-[l,4'-bipyrazol]-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3 -carboxamide:

[0472] 7-(l '-isopropyl-1 'H-[ 1,4'-bipyrazol]-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0473] 7-(rH-[l,4'-bipyrazol]-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0474] 7-(l-(3,3-difluorocyclobutyl)-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0475] 6-(l-(8-acetyl-8-azabicyclo[3.2.1]octan-3-yl)-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0476] methyl 3-(4-(3-((4,5-dimethyl-lH-pyrazol-3-yl)carbamoyl)pyrazolo[l,5-a]pyridin-6-yl)-lH-pyrazol-l-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate;

[0477] N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0478] 6-(l-(8-acetyl-8-azabicyclo[3.2. l]octan-3-yl)-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;Agent Ref.: 16738.0002-00304

[0479] N-(4-methyl-lH-pyrazol-3-yl)-6-(l-(8-methyl-8-azabicyclo[3.2. l]octan-3-yl)-lH-pyrazol-4-yl)pyrazolo[1.5-a]pyridine-3-carboxamide;

[0480] methyl 3-(4-(3-((4-methyl-lH-pyrazol-3-yl)carbamoyl)pyrazolo[l,5-a]pyridin-6-yl)-lH-pyrazol-l-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate;

[0481] methyl 3-(4-(3-((4,5-dimethyl-lH-pyrazol-3-yl)carbamoyl)pyrazolo[l,5-a]pyridin-6-yl)- 1 H-pyrazol- 1 -yl)pyrrolidine- 1 -carboxy late;

[0482] 6-(l -( 1 -acetylpyrrolidin-3-yl)- lH-pyrazol-4-yl)-N-(4,5-dimethyl- lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0483] N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(l-methylpyrrolidin-3-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0484] N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(pyrrolidin-3-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0485] (R)-methyl 3-(4-(3-((4,5-dimethyl-lH-pyrazol-3-yl)carbamoyl)pyrazolo[l,5-a] py ridin-6-y 1)- 1 H-pyrazol- 1 -yl)pyrrolidine- 1 -carboxylate;

[0486] (S)-methyl 3-(4-(3-((4,5-dimethyl-lH-pyrazol-3-yl)carbamoyl)pyrazolo[l,5-a]pyridin-6-yl)-lH-pyrazol-l-yl)pyrrolidine-l -carboxylate;

[0487] methyl 3-(4-(3-((4-methyl-lH-pyrazol-3-yl)carbamoyl)pyrazolo[l,5-a]pyridin-6-yl)-1 H-pyrazol- 1 -y l)pyrrolidine- 1 -carboxylate;

[0488] 6-(l-(l-acetylpyrrolidin-3-yl)-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0489] N-(4-methyl-lH-pyrazol-3-yl)-6-(l-(l-methylpyrrolidin-3-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0490] N-(4-methyl-lH-pyrazol-3-yl)-6-(l-(pyrrolidin-3-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a] pyridine-3-carboxamide;

[0491] (R)-methyl 3-(4-(3-((4-methyl-lH-pyrazol-3-yl)carbamoyl)pyrazolo[l,5-a]pyridin-6-yl)-lH-pyrazol-l-yl)pyrrolidine-l-carboxylate;

[0492] (S)-methyl 3-(4-(3-((4-methyl-lH-pyrazol-3-yl)carbamoyl)pyrazolo[l,5-a]pyridin-6-yl)- 1 H-pyrazol- 1 -yl)pyrrolidine- 1 -carboxy late;

[0493] N-(4-methy 1- lH-pyrazol-3-y 1 )-6-( 1 -(oxetan-3-yl)- lH-pyrazol-4-yl)pyrazolo[ 1,5-a]pyridine-3-carboxamide;

[0494] N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(oxetan-3-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0495] N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(3-hydroxy-3-methylcyclobutyl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;Agent Ref.: 16738.0002-00304

[0496] N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-((ls.3s)-3-hydroxy-3-methylcyclobutyl)-lH-pyrazol-4-yl)pyrazolo[1.5-a]pyridine-3-carboxamide;

[0497] 6-(l-(3-hydroxy-3-methylcyclobutyl)-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0498] 6-(l-((ls,3s)-3-hydroxy-3-methylcyclobutyl)-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0499] 7 -( 1 -(3 -fluorobicy cl o [ 1.1.1] pentan- 1 -y 1)- 1 H-pyrazol-4-y l)-N-(4-methyl- 1 H-py razol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0500] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(3-hydroxybicyclo[l.l.l]pentan-l-yl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0501] 7 -( 1 -(3-hydroxybicy clo[ 1.1.1 ]pentan- 1 -yl)- lH-pyrazol-4-yl)-N-(4-methy 1- 1H-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;

[0502] N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(3-fluorobicyclo[l.l.l]pentan-l-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0503] 6-(l-(3-fluorobicyclo[l.l.l]pentan-l-yl)-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0504] N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(3-hydroxybicyclo[l.l.l]pentan-l-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0505] 6-(l -(3-hydroxybicy clofl.l. l]pentan-l -yl)-lH-pyrazol-4-yl)-N-(4-methyl- 1H-pyrazol-3-yl)pyrazolo[1.5-a]pyridine-3-carboxamide;

[0506] methyl 3-(4-(3-((4,5-dimethyl-lH-pyrazol-3-yl)carbamoyl)pyrazolo[l,5-a]pyridin-6-y 1)- 1 H-pyrazol- 1 -y l)azetidine- 1 -carboxylate;

[0507] 6-(l-(l-acetylazetidin-3-yl)-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0508] N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(l-methylazetidin-3-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0509] 6-(l-(azetidin-3-yl)-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)pyrazolo[l,5-a] pyridine-3-carboxamide;

[0510] N-(4,5-dimethyl- lH-pyrazol-3-y l)-6-( 1 -(4-fluoro- 1 -methylpyrrolidin-3-yl)- 1H-pyrazol-4-yl)pyrazolo[ 1,5-a]pyridine-3-carboxamide;

[0511] N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(4-fluoropyrrolidin-3-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0512] 6-(l -(4-fluoro- l-methylpyrrolidin-3-yl)-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;Agent Ref: 16738.0002-00304

[0513] 6-(l-(4-fluoropyrrolidin-3-yl)-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0514] N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(3-fluoro-l-methylpiperidin-4-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0515] N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(3-fluoropiperidin-4-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0516] 6-(l-(3-fluoro-l-methylpiperidin-4-yl)-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0517] 6-(l-(3-fluoropiperidin-4-yl)-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0518] N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-((3R)-3-fluoro-l-methylpiperidin-4-yl)-lH-pyrazol-4-yl)pyrazolo[ 1,5-a]pyridine-3-carboxamide;

[0519] N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-((3S)-3-fluoro-l-methylpiperidin-4-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;

[0520] 6-(l-((3R)-3-fluoro-l-methylpiperidin-4-yl)-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazololL5-aJpyridine-3-carboxamide; and

[0521] 6-(l-((3S)-3-fluoro-l-methylpiperidin-4-yl)-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide; and

[0522] pharmaceutically acceptable salts thereof.

[0523] |132| In another aspect, the present disclosure provides a compound chosen from the compounds set forth in Table 1 below and pharmaceutically acceptable salts thereof.

[0524] Table 1. Illustrative Compounds of the Present Disclosure Compound

[0525] Chemical Name

[0526] No.

[0527] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(lH-pyrazol-5-yl)imidazo[l,2- C001

[0528] a]pyridine-3-carboxamide

[0529] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-phenylimidazo[l,2-a]pyridine-3- C002

[0530] carboxamide

[0531] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(3-morpholinophenyl)imidazo[l,2- C003

[0532] a]pyridine-3-carboxamide

[0533] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-morpholinophenyl)imidazo[l,2- C004

[0534] a]pyridine-3-carboxamide

[0535] N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(2-isopropyloxazol-4- C005

[0536] yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0537] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(6-morpholinopyridin-2- C006

[0538]

[0539] yl)imidazo[l,2-a]pyridine-3-carboxamideAgent Ref.: 16738.0002-00304

[0540] N-(4.5-dimethyl-lH-pyrazol-3-yl)-7-(5-morpholinopyridin-2- C007

[0541] yl)imidazo[l,2-a]pyridine-3-carboxamide

[0542] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(3-fluoro-4- C008

[0543] morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide

[0544] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(6-morpholinopyridin-3- C009

[0545] yl)imidazo[l,2-a]pyridine-3-carboxamide

[0546] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(2-fluoro-4- C010

[0547] morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide

[0548] 7-(2,3-difluoro-4-morpholinophenyl)-N-(4,5-dimethyl-lH-pyrazol-3- con

[0549] yl)imidazo[l,2-a]pyridine-3-carboxamide

[0550] 7-(3-chloro-4-morpholinophenyl)-N-(4.5-dimethyl-lH-pyrazol-3- C012

[0551] yl)imidazo[l,2-a]pyridine-3-carboxamide

[0552] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-(3- C013

[0553] oxomorpholino)phenyl)imidazo[l,2-a]pyridine-3-carboxamide N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(3-methyl-4- C014

[0554] morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide

[0555] N-(5-methyl-lH-pyrazol-3-yl)-7-(4-morpholinophenyl)imidazo[l,2- C015

[0556] a]pyridine-3-carboxamide

[0557] N-(4-methyl-lH-pyrazol-3-yl)-7-(4-morpholinophenyl)imidazo[l,2- C016

[0558] a]pyridine-3-carboxamide

[0559] 7-(3-cyclopropyl-4-morpholinophenyl)-N-(4,5-dimethyl-lH-pyrazol-3- C017

[0560] yl)imidazo[l,2-a]pyridine-3-carboxamide

[0561] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-morpholino-3- C018

[0562] (trifluoromethyl)phenyl)imidazo[ 1,2-a]pyridine-3-carboxamide N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(3-methoxy-4- C019

[0563] morpholinophenyl)imidazo[1,2-a]pyridine-3-carboxamide

[0564] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(3-fluorophenyl)imidazo[l,2- C020

[0565] a]pyridine-3-carboxamide

[0566] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(3-methoxyphenyl)imidazo[l,2- C021

[0567] a]pyridine-3-carboxamide

[0568] 7-(3-cyclopropylphenyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2- C022

[0569] a]pyridine-3-carboxamide

[0570] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4- C023

[0571] (trifluoromethyl)phenyl)imidazo[ 1,2-a]pyridine-3-carboxamide 7-(4-chlorophenyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2- C024

[0572] a]pyridine-3-carboxamide

[0573] 7-(4'-chloro-[l,r-biphenyl]-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3- C025

[0574] yl)imidazo[l,2-a]pyridine-3-carboxamide

[0575] N-(5-cyclopropyl-4-methyl-lH-pyrazol-3-yl)-7-(4- C026

[0576] morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide

[0577] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-isocyanophenyl)imidazo[1,2- C027

[0578]

[0579] a]pyridine-3-carboxamideAgent Ref.: 16738.0002-00304

[0580] 7-(3-chlorophenyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2- C028

[0581] a]pyridine-3-carboxamide

[0582] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(2-oxo-2H-[l,2'-bipyridin]-5'- C029

[0583] yl)imidazo[l,2-a]pyridine-3-carboxamide

[0584] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(3- C030

[0585] (trifluoromethyl)phenyl)imidazo[ 1,2-a]pyridine-3-carboxamide N-(4,5-dirnethyl-lH-pyrazol-3-yl)-7-(4-fluorophenyl)imidazo[l,2- C031

[0586] a]pyridine-3-carboxamide

[0587] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-methoxyphenyl)imidazo[l,2- C032

[0588] a]pyridine-3-carboxamide

[0589] 7-(4-cyclopropylphenyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[1.2- C033

[0590] a]pyridine-3-carboxamide

[0591] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-(2-oxopyridin-l(2H)- C034

[0592] yl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide

[0593] 7-(3-cyanophenyl)-N-(4.5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2- C035

[0594] a]pyridine-3-carboxamide

[0595] N-(5-(hydroxymethyl)-4-methyl-lH-pyrazol-3-yl)-7-(4- C036

[0596] morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide

[0597] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-(2-oxopyrimidin-l(2H)- C037

[0598] yl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide

[0599] N-(4-(hydroxymethyl)-5-methyl-lH-pyrazol-3-yl)-7-(4- C038

[0600] morpholinophenyl)imidazo[L2-a]pyridine-3-carboxamide

[0601] N-(5-(fluoromethyl)-4-methyl-lH-pyrazol-3-yl)-7-(4- C039

[0602] morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide

[0603] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l,3-dimethyl-lH-pyrazol-4- C040

[0604] yl)imidazo[ 1,2-a]pyridine-3-carboxamide

[0605] N-(4.5-dimethyl-lH-pyrazol-3-yl)-7-(l-methyl-lH-pyrazol-4- C041

[0606] yl)imidazo[l,2-a]pyridine-3-carboxamide

[0607] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(2-hydroxy-2-methylpropyl)-lH- C042

[0608] pyrazol-4-yl)imidazo[ 1,2-a]pyridine-3 -carboxamide

[0609] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(2-hydroxy-2-methylpropyl)-3- C043

[0610] methyl-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(2-hydroxy-2-methylpropyl)-5- C044

[0611] methyl-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(tetrahydro-2H-pyran-4-yl)-lH- C045

[0612] pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide

[0613] 7-(l-cyclopropyl-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3- C046

[0614] yl)imidazo[l,2-a]pyridine-3-carboxamide

[0615] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-isopropyl-lH-pyrazol-4- C047

[0616] yl)imidazo[l,2-a]pyridine-3-carboxamide

[0617] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-phenyl-lH-pyrazol-4- C048

[0618]

[0619] yl)imidazo[l,2-a]pyridine-3-carboxamideAgent Ref.: 16738.0002-00304

[0620] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(pyrrolidin-3-yl)-lH-pyrazol-4- C049

[0621] yl)imidazo[l,2-a]pyridine-3-carboxamide

[0622] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(piperidin-4-yl)-lH-pyrazol-4- C050

[0623] yl)imidazo[l,2-a]pyridine-3-carboxamide

[0624] 7-(l-(4-cy anophenyl)- lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3- C051

[0625] yl)imidazo[l,2-a]pyridine-3-carboxamide

[0626] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(l-methylpiperidin-4-yl)-lH- C052

[0627] pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide

[0628] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(l-methylpyrrolidin-3-yl)-lH- C053

[0629] pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide

[0630] 7-(l-cyclopropyl-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3- C054

[0631] yl)imidazo[l,2-a]pyridine-3-carboxamide

[0632] 7-(l-isopropyl-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3- C055

[0633] y l)imi dazo [ 1,2-a] py ri dine-3 -carbox ami de

[0634] N-(lH-indazol-3-yl)-7-(l-isopropyl-lH-pyrazol-4-yl)imidazo[l,2- C056

[0635] a]pyridine-3-carboxamide

[0636] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-((3R,4R)-4-fluoropyrrolidin-3-yl)- C057

[0637] 1 H-pyrazol-4-yl)imidazo [ 1,2-a] py ridine-3 -carboxamide

[0638] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-((3R.4R)-4-fluoro-l- C058 methylpyrrolidin-3-yl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3- carboxamide

[0639] N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(lH-pyrazol-5-yl)pyrazolo[l,5- C059

[0640] a]pyridine-3-carboxamide

[0641] N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-phenylpyrazolo[l,5-a]pyridine-3- C060

[0642] carboxamide

[0643] N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(4-morpholinophenyl)pyrazolo[1.5- C061

[0644] a]pyridine-3-carboxamide

[0645] N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(3-fluoro-4- C062

[0646] morpholinophenyl)pyrazolo[ 1,5-a]pyridine-3-carboxamide

[0647] N-(4.5-dimethyl-lH-pyrazol-3-yl)-6-(6-morpholinopyridin-3- C063

[0648] yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0649] N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(2-fluoro-4- C064

[0650] morpholinophenyl)pyrazolo[ 1,5-a]pyridine-3-carboxamide

[0651] 6-(2,3-difluoro-4-morpholinophenyl)-N-(4,5-dimethyl-lH-pyrazol-3- C065

[0652] yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0653] N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(5-morpholinopyridin-2- C066

[0654] yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0655] N-(4.5-dimethyl-lH-pyrazol-3-yl)-6-(l,3-dimethyl-lH-pyrazol-4- C067

[0656] yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0657] N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l -methyl- lH-pyrazol-4- C068

[0658] yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0659] N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(2-hydroxy-2-methylpropyl)-lH- C069

[0660]

[0661] pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamideAgent Ref.: 16738.0002-00304

[0662] 6-(l-cyclopropyl-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3- C070

[0663] yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0664] N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-isopropyl-lH-pyrazol-4- C071

[0665] yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0666] 6-(l-isopropyl-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3- C072

[0667] yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0668] 6-(l-cyclopropyl-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3- C073

[0669] yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0670] 6-(l-isopropyl-lH-pyrazol-4-yl)-N-(5-methyl-lH-pyrazol-3- C074

[0671] yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0672] 6-(l-cyclopropyl-lH-pyrazol-4-yl)-N-(5-methyl-lH-pyrazol-3- C075

[0673] yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0674] 7-(l-isopropyl-lH-pyrazol-4-yl)-N-(l,4,5-trimethyl-lH-pyrazol-3- C076

[0675] y l)imi dazo [ 1,2-a] py ri dine-3 -carbox ami de

[0676] 6-(l-isopropyl-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3- C077

[0677] yl)imidazo[l,2-a]pyridine-3-carboxamide

[0678] 5-(l-isopropyl-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3- C078

[0679] yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0680] N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(piperidin-4-yl)-lH-pyrazol-4- C079

[0681] yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0682] N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(l-methylpiperidin-4-yl)-lH- C080

[0683] pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide methyl 4-(4-(3-((4,5-dimethyl-lH-pyrazol-3-yl)carbamoyl)pyrazolo[1.5- C081

[0684] a]pyridin-6-yl)-lH-pyrazol-l-yl)piperidine-l -carboxylate

[0685] N-(4-methyl-lH-pyrazol-3-yl)-6-(l-(piperidin-4-yl)-lH-pyrazol-4- C082

[0686] yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0687] N-(4-methyl-lH-pyrazol-3-yl)-6-(l-(l-methylpiperidin-4-yl)-lH-pyrazol- C083

[0688] 4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0689] 6-(l-(l-acetylpiperidin-4-yl)-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH- C084

[0690] pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0691] N-(4-methyl-lH-pyrazol-3-yl)-6-(l-(l,l,l-trifluoropropan-2-yl)-lH- C085

[0692] pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0693] N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(l,l,l-trifluoropropan-2-yl)-lH- C086

[0694] pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0695] 6-(l-(l-acetylpiperidin-4-yl)-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol- C087

[0696] 3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0697] methyl 4-(4-(3-((4-methyl-lH-pyrazol-3-yl)carbamoyl)pyrazolo[l,5- C088

[0698] a] py ridin-6-yl)-lH-pyrazol-l-yl)piperi dine- 1 -carboxy late

[0699] (S)-N-(4-methyl-lH-pyrazol-3-yl)-6-(l-(pyrrolidin-3-yl)-lH-pyrazol-4- C089

[0700] yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0701] (S)-N-(4-methyl-lH-pyrazol-3-yl)-6-(l-(l-methylpyrrolidin-3-yl)-lH- C090

[0702]

[0703] pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamideAgent Ref.: 16738.0002-00304

[0704] methyl (R)-3-(4-(3-((4,5-dimethyl-lH-pyrazol-3- C091 y l)carbamoyl)pyrazolo[ 1,5 -a]pyridin-6-yl)- 1 H-pyrazol- 1 -yl)py rrolidine- 1 - carboxylate

[0705] methyl (S)-3-(4-(3-((4-methyl-lH-pyrazol-3-yl)carbamoyl)pyrazolo[1.5- C092

[0706] a] py ridin-6-yl)- IH-py razol- 1 -yl)pyrrolidine- 1 -carboxylate

[0707] (S)-6-(l-(l-acetylpyrrolidin-3-yl)-lH-pyrazol-4-yl)-N-(4-methyl-lH- C093

[0708] pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0709] (R)-6-(l-(l-acetylpyrrolidin-3-yl)-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH- C094

[0710] pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0711] (S)-N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(l-methylpyrrolidin-3-yl)-lH- C095

[0712] pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide methyl (R)-3-(4-(3-((4-methyl-lH-pyrazol-3-yl)carbamoyl)pyrazolo[1.5- C096

[0713] a]pyridin-6-yl)- IH-pyrazol- 1 -yl)pyrrolidine- 1 -carboxylate

[0714] (R)-6-( 1 -( 1 -acety lpyrrolidin-3 -yl)- 1 H-py razol-4-y l)-N-(4-methyl- 1 H- C097

[0715] pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0716] (S)-N-(4.5-dimethyl-lH-pyrazol-3-yl)-6-(l-(pyrrolidin-3-yl)-lH-pyrazol- C098

[0717] 4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0718] (S)-6-(l-(l-acetylpyrrolidin-3-yl)-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH- C099

[0719] pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide methyl (S)-3-(4-(3-((4,5-dimethyl-lH-pyrazol-3- C100 y l)carbamoyl)pyrazolo[ 1,5 -a]pyridin-6-yl)- 1 H-pyrazol- 1 -yl)py rrolidine- 1 - carboxylate

[0720] (R)-N-(4-methyl-lH-pyrazol-3-yl)-6-(l-(pyrrolidin-3-yl)-lH-pyrazol-4- C101

[0721] yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0722] (R)-N-(4-methyl-lH-pyrazol-3-yl)-6-(l-(l-methylpyrrolidin-3-yl)-lH- C102

[0723] pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0724] N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(l,l,l-trifluoro-2-methylpropan- C103

[0725] 2-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide 6-(3-cyclopropyl-l -isopropyl- lH-pyrazol-4-yl)-N-(4-methyl- IH-pyrazol- Cl 04

[0726] 3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0727] 6-(l-isopropyl-3-methyl-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3- C105

[0728] yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0729] 6-(l-isopropyl-5-methyl-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3- C106

[0730] yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0731] 6-(l-isopropyl-3,5-dimethyl-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3- C107

[0732] yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0733] 7-( 1 -( h3-difluoropropan-2-y 1)- 1 H-pyrazol-4-yl)-N-(4,5-dimethyl-lH- C108

[0734] pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide

[0735] 7-(l-(l,3-difluoropropan-2-yl)-lH-pyrazol-4-yl)-N-(4-methyl-lH- C109

[0736] pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide

[0737] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(l,l,l-trifluoropropan-2-yl)-lH- C110

[0738]

[0739] pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamideAgent Ref.: 16738.0002-00304

[0740] N-(4-methyl-lH-pyrazol-3-yl)-7-(l-(l,l,l-trifluoro-2-methylpropan-2-yl)- C111 1 H-pyrazol-4-yl)imidazo [ 1,2-a] pyridine-3 -carboxamide

[0741] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(l,l,l-trifluoro-2-methylpropan- C112

[0742] 2-yl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide N-(4-methyl-lH-pyrazol-3-yl)-7-(l-(l,l,l-trifluoropropan-2-yl)-lH- C113

[0743] pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide

[0744] (R)-N-(4,5-dimethyl- lH-pyrazol-3-yl)-6-(l -( 1,1,1 -trifluoropropan-2-yl)- C114

[0745] lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0746] (R)-N-(4-methy 1- lH-pyrazol-3-yl)-6-( 1 -(1,1,1 -trifluoropropan-2-yl)- 1H- C115

[0747] pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0748] (S)-N-(4,5-dimethyl- lH-pyrazol-3-yl)-6-(l -( 1, 1, 1 -trifluoropropan-2-yl)- C116

[0749] lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0750] (S)-N-(4-methyl- 1 H-pyrazol-3-y l)-6-( 1 -( 1, 1, 1 -trifluoropropan-2-y 1)- 1 H- C117

[0751] pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0752] N-(5-(l-isopropyl-lH-pyrazol-4-yl)pyrazolo[1.5-a]pyridin-3-yl)-4.5- C118

[0753] dimethyl-lH-pyrazole-3-carboxamide

[0754] N-(4-methyl-lH-pyrazol-3-yl)-6-(l-(l,l,l-trifluoro-2-methylpropan-2-yl)- C119

[0755] lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0756] 6-(l-(l,3-difluoropropan-2-yl)-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH- C120

[0757] pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0758] 6-(l-(l,3-difluoropropan-2-yl)-lH-pyrazol-4-yl)-N-(4-methyl-lH- C121

[0759] pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0760] 7-(l-(tert-butyl)-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3- C122

[0761] yl)imidazo[l,2-a]pyridine-3-carboxamide

[0762] 7-( 1 -cyclobutyl- 1 H-pyrazol-4-y l)-N-(4-methyl- 1 H-pyrazol-3 - C123

[0763] y l)imidazo[ 1,2-a]pyridine-3-carboxamide

[0764] 7-(l-cyclobutyl-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3- C124

[0765] yl)imidazo[l,2-a]pyridine-3-carboxamide

[0766] 7-(l-(tert-butyl)-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3- C125

[0767] yl)imidazo[ 1,2-a]pyridine-3-carboxamide

[0768] N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-((lS.2R)-2-fluorocyclopropyl)- C126

[0769] lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0770] 7-(l-(bicyclo[l.l.l]pentan-l-yl)-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH- C127

[0771] pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide

[0772] 7-( 1 -(bicy clo [ 1.1.1 ] pentan- 1 -y 1)- lH-pyrazol-4-y l)-N-(4-methy 1- 1 H- C128

[0773] pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide

[0774] 7-(2-cyclopropyl-2H-l,2,3-triazol-4-yl)-N-(4-methyl-lH-pyrazol-3- C129

[0775] yl)imidazo[l,2-a]pyridine-3-carboxamide

[0776] 7-(2-cyclopropyl-2H-l,2,3-triazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3- C130

[0777] yl)imidazo[l,2-a]pyridine-3-carboxamide

[0778] l-(4-(3-((4-methyl-lH-pyrazol-3-yl)carbamoyl)imidazo[l,2-a]pyridin-7- C131

[0779]

[0780] yl)-lH-pyrazol-l-yl)cyclopropane-l-carboxylic acidAgent Ref.: 16738.0002-00304

[0781] 2-methyl-2-(4-(3-((4-methyl-lH-pyrazol-3-yl)carbamoyl)imidazo[l,2- C132

[0782] a]pyridin-7-yl)-lH-pyrazol-l-yl)propanoic acid

[0783] methyl 2-methyl-2-(4-(3-((4-methyl- lH-pyrazol-3- C133

[0784] yl)carbamoyl)imidazo[l,2-a]pyridin-7-yl)-lH-pyrazol-l-yl)propanoate methyl 1 -(4-(3-((4-methyl- lH-pyrazol-3-yl)carbamoyl)imidazo[ 1,2- C134

[0785] a]pyridin-7-yl)-lH-pyrazol-l-yl)cyclopropane-l-carboxylate 7-(l-(l-(hydroxymethyl)cyclopropyl)-lH-pyrazol-4-yl)-N-(4-methyl-lH- C135

[0786] pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide

[0787] 7-( 1 -( 1 -hydroxy-2-methylpropan-2-yl)-lH-pyrazol-4-yl)-N-(4-methyl- C136

[0788] 1 H-pyrazol-3 -yl)imidazo [ 1,2-a] pyridine-3 -carboxamide

[0789] 6-(l-(bicyclo[l.l.l]pentan-l-yl)-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH- C137

[0790] pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0791] 6-(l-(bicyclo[l.l.l]pentan-l-yl)-lH-pyrazol-4-yl)-N-(4-methyl-lH- C138

[0792] pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0793] 7-(l -isopropyl- 1H-1, 2, 3-triazol-4-yl)-N-(4-methyl-lH-pyrazol-3- C139

[0794] yl)imidazo[l,2-a]pyridine-3-carboxamide

[0795] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(3-fluorobicyclo[l.l.l]pentan-l- C140

[0796] yl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide 7-(2-isopropyl-2H-l,2,3-triazol-4-yl)-N-(4-methyl-lH-pyrazol-3- C141

[0797] yl)imidazo[l,2-a]pyridine-3-carboxamide

[0798] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l'-methyl-l'H-[l,4'-bipyrazol]-4- C142

[0799] yl)imidazo[l,2-a]pyridine-3-carboxamide

[0800] 7-(r-cyclopropyl-l'H-[l,4'-bipyrazol]-4-yl)-N-(4,5-dimethyl-lH-pyrazol- C143

[0801] 3-yl)imidazo[l,2-a]pyridine-3-carboxamide

[0802] N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l'-isopropyl-rH-[l,4'-bipyrazol]-4- C144

[0803] yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0804] N-(4.5-dimethyl-lH-pyrazol-3-yl)-7-(r-isopropyl-l'H-[l,4'-bipyrazol]-4- C145

[0805] yl)imidazo[l,2-a]pyridine-3-carboxamide

[0806] 7-(l'H-[l,4'-bipyrazol]-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3- C146

[0807] yl)imidazo[ 1,2-a]pyridine-3-carboxamide

[0808] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(lH-pyrazol-4-yl)imidazo[l,2- C147

[0809] a]pyridine-3-carboxamide

[0810] N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(isoxazol-4-yl)imidazo[l,2- C148

[0811] a]pyridine-3-carboxamide

[0812] 7-(r-methyl-l'H-[l,4'-bipyrazol]-4-yl)-N-(4-methyl-lH-pyrazol-3- C149

[0813] yl)imidazo[l,2-a]pyridine-3-carboxamide

[0814] 7-(l'-cyclopropyl-l'H-[l,4'-bipyrazol]-4-yl)-N-(4-methyl-lH-pyrazol-3- C150

[0815] yl)imidazo[l,2-a]pyridine-3-carboxamide

[0816] 7 -( 1 '-isopropyl- l'H-[ 1,4'-bipy razol] -4-y l)-N-(4-methy 1- 1 H-pyrazol-3 - C151

[0817] yl)imidazo[l,2-a]pyridine-3-carboxamide

[0818] 7-(1'H-[1,4'-bipyrazol]-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)imidazo[1,2- C152

[0819]

[0820] a]pyridine-3-carboxamideAgent Ref: 16738.0002-00304

[0821] 7-(l-(3,3-difluorocyclobutyl)-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH-

[0822]

[0823] pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide

[0824] B. Methods of Making

[0825]

[0133] Compounds disclosed herein may be prepared according to standard chemical practices and as illustrated by the routes described below in Examples 1-76. Materials used herein are either commercially available or prepared by synthetic methods generally known in the art. These schemes as illustrated in Examples 1-76 are not limited to the compounds listed or by any particular substituents, which are employed for illustrative purposes.

[0826] Although various steps are described and depicted in the schemes, the steps in some cases may be performed in a different order than the order shown in the schemes. Various modifications to these synthetic reaction schemes may be made and will be suggested to one skilled in the art having referred to the disclosure contained in this Application. Numbering does not necessarily correspond to that of claims or other tables.

[0827] C. Pharmaceutical Compositions and Formulations

[0828]

[0134] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. In specific embodiments, pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable techniques, carriers, and excipients are used as suitable to formulate the pharmaceutical compositions described herein: Remington: The Science and Practice of Pharmacy. Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N. Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999).

[0829]

[0135] Provided herein are pharmaceutical compositions comprising a compound of Formula I or Formula II, and a pharmaceutically acceptable diluent(s), excipient(s), or carrier(s). In certain embodiments, the compounds described are administered as pharmaceutical compositions in which compounds of Formula I or Formula II, are mixed with other active ingredients, as in combination therapy. Encompassed herein are all combinations of activesAgent Ref: 16738.0002-00304

[0830] set forth in the combination therapies section below and throughout this disclosure. In specific embodiments, the pharmaceutical compositions include one or more compounds of Formula I and / or Formula II.

[0831]

[0136] A pharmaceutical composition, as used herein, refers to a mixture of a compound of Formula I or Formula II with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and / or excipients. In certain embodiments, the pharmaceutical composition facilitates administration of the compound to an organism. In some embodiments, practicing the methods of treatment or use provided herein, therapeutically effective amounts of compounds of Formula I or Formula II, provided herein are administered in a pharmaceutical composition to a mammal having a disease or condition to be treated. In specific embodiments, the mammal is a human. In certain embodiments, therapeutically effective amounts vary depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. The compounds described herein are used singly or in combination with one or more therapeutic agents as components of mixtures.

[0832]

[0137] In one embodiment, one or more compounds of Formula I or Formula II, is formulated in an aqueous solution. In specific embodiments, the aqueous solution is selected from, by way of example only, a physiologically compatible buffer, such as Hank’s solution, Ringer's solution, or physiological saline buffer. In other embodiments, one or more compound of Formula I or Formula II, is formulated for transmucosal administration. In specific embodiments, transmucosal formulations include penetrants that are appropriate to the barrier to be permeated. In still other embodiments wherein the compounds described herein are formulated for other parenteral injections, appropriate formulations include aqueous or nonaqueous solutions. In specific embodiments, such solutions include physiologically compatible buffers and / or excipients.

[0833]

[0138] In another embodiment, compounds described herein are formulated for oral administration. Compounds described herein, including compounds of Formula I or Formula II, are formulated by combining the active compounds with, e.g., pharmaceutically acceptable carriers or excipients. In various embodiments, the compounds described herein are formulated in oral dosage forms that include, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions and the like.

[0834]

[0139] In certain embodiments, pharmaceutical preparations for oral use are obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after addingAgent Ref: 16738.0002-00304

[0835] suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as: for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In specific embodiments, disintegrating agents are optionally added. Disintegrating agents include, by way of example only, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[0836]

[0140] In one embodiment, dosage forms, such as dragee cores and tablets, are provided with one or more suitable coating. In specific embodiments, concentrated sugar solutions are used for coating the dosage form. The sugar solutions, optionally contain additional components, such as by way of example only, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs and / or pigments are also optionally added to the coatings for identification purposes. Additionally, the dyestuffs and / or pigments are optionally utilized to characterize different combinations of active compound doses.

[0837]

[0141] In certain embodiments, therapeutically effective amounts of at least one of the compounds described herein are formulated into other oral dosage forms. Oral dosage forms include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In specific embodiments, push-fit capsules contain the active ingredients in admixture with one or more filler. Fillers include, by way of example only, lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In other embodiments, soft capsules, contain one or more active compound that is dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oil, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers are optionally added.

[0838]

[0142] In other embodiments, therapeutically effective amounts of at least one of the compounds described herein are formulated for buccal or sublingual administration.

[0839] Formulations suitable for buccal or sublingual administration include, by way of example only, tablets, lozenges, or gels. In still other embodiments, the compounds described herein are formulated for parental injection, including formulations suitable for bolus injection or continuous infusion. In specific embodiments, formulations for injection are presented in unit dosage form (e.g., in ampoules) or in multi-dose containers. Preservatives are, optionally.Agent Ref: 16738.0002-00304

[0840] added to the injection formulations. In still other embodiments, the pharmaceutical composition of a compound of Formula I and / or Formula II is formulated in a form suitable for parenteral injection as sterile suspension, solution or emulsion in oily or aqueous vehicles. Parenteral injection formulations optionally contain formulatory agents such as suspending, stabilizing and / or dispersing agents. In specific embodiments, pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. In additional embodiments, suspensions of the active compounds are prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. In certain specific embodiments, aqueous injection suspensions contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension contains suitable stabilizers or agents which increase the solubility7of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, in other embodiments, the active ingredient is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0841]

[0143] In still other embodiments, the compounds of Formula I or Formula II are administered topically. The compounds described herein are formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams or ointments. Such pharmaceutical compositions optionally contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.

[0842]

[0144] In yet other embodiments, the compounds of Formula I or Formula II are formulated for transdermal administration. In specific embodiments, transdermal formulations employ transdermal delivery devices and transdermal delivery patches and can be lipophilic emulsions or buffered, aqueous solutions, dissolved and / or dispersed in a polymer or an adhesive. In various embodiments, such patches are constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. In additional embodiments, the transdermal delivery of the compounds of Formula I or Formula II, is accomplished by means of iontophoretic patches and the like. In certain embodiments, transdermal patches provide controlled delivery7of the compounds of Formula I or Formula II. In specific embodiments, the rate of absorption is slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel. In alternative embodiments, absorption enhancers are used to increase absorption. Absorption enhancers or carriers include absorbableAgent Ref: 16738.0002-00304

[0843] pharmaceutically acceptable solvents that assist passage through the skin. For example, in one embodiment, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.

[0844]

[0145] In other embodiments, the compounds of Formula I or Formula II are formulated for administration by inhalation. Various forms suitable for administration by inhalation include, but are not limited to, aerosols, mists or powders. Pharmaceutical compositions of Formula I or Formula II, are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser. with the use of a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas). In specific embodiments, the dosage unit of a pressurized aerosol is determined by providing a valve to deliver a metered amount. In certain embodiments, capsules and cartridges of, such as, by way of example only, gelatin for use in an inhaler or insufflator are formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[0845]

[0146] In still other embodiments, the compounds of Formula I or Formula II, are formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like. In suppository forms of the compositions, a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter is first melted.

[0846]

[0147] In certain embodiments, pharmaceutical compositions are formulated in any conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable techniques, carriers, and excipients are optionally used as suitable. Pharmaceutical compositions comprising a compound of Formula I or Formula II, are manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, drageemaking, levigating, emulsifying, encapsulating, entrapping or compression processes.Agent Ref: 16738.0002-00304

[0847]

[0148] Pharmaceutical compositions include at least one pharmaceutically acceptable carrier, diluent or excipient and at least one compound of Formula I or Formula II, described herein as an active ingredient. The active ingredient is in free-acid or free-base form, or in a pharmaceutically acceptable salt form. In addition, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), as well as active metabolites of these compounds having the same type of activity. All tautomers of the compounds described herein are included within the scope of the compounds presented herein. Additionally, the compounds described herein encompass unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated fonns of the compounds presented herein are also considered to be disclosed herein. In addition, the pharmaceutical compositions optionally include other medicinal or pharmaceutical agents, carriers, adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, buffers, and / or other therapeutically valuable substances.

[0848]

[0149] Methods for the preparation of compositions comprising the compounds described herein include formulating the compounds with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid or liquid. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein. Semi-solid compositions include, but are not limited to, gels, suspensions and creams. The form of the pharmaceutical compositions described herein include liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions also optionally contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and so forth.

[0849]

[0150] In some embodiments, a pharmaceutical composition comprising at least one compound of Formula I or Formula II. illustratively takes the form of a liquid where the agents are present in solution, in suspension or both. Typically when the composition is administered as a solution or suspension a first portion of the agent is present in solution and a second portion of the agent is present in particulate form, in suspension in a liquid matrix. In some embodiments, a liquid composition includes a gel formulation. In other embodiments, the liquid composition is aqueous.Agent Ref: 16738.0002-00304

[0850]

[0151] In certain embodiments, useful aqueous suspension contain one or more polymers as suspending agents. Useful polymers include water-soluble polymers such as cellulosic polymers, e.g., hydroxypropyl methylcellulose, and water-insoluble polymers such as crosslinked carboxyl-containing polymers. Certain pharmaceutical compositions described herein comprise a mucoadhesive polymer, selected for example from carboxymethylcellulose, carbomer (acrylic acid polymer), poly (methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate and dextran.

[0851]

[0152] Useful pharmaceutical compositions also, optionally, include solubilizing agents to aid in the solubility of a compound of Formula I or Formula II. The term “solubilizing agent” generally includes agents that result in formation of a micellar solution or a true solution of the agent. Certain acceptable nonionic surfactants, for example polysorbate 80. are useful as solubilizing agents, as can ophthalmically acceptable glycols, poly glycols, e.g., polyethylene glycol 400, and glycol ethers.

[0852]

[0153] Furthermore, useful pharmaceutical compositions optionally include one or more pH adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and trishy droxymethylaminomethane; and buffers such as citrate / dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range.

[0853]

[0154] Additionally, useful compositions also, optionally, include one or more salts in an amount required to bring osmolality of the composition into an acceptable range. Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.

[0854]

[0155] Other useful pharmaceutical compositions optionally include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury -containing substances such as merfен and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.

[0855]

[0156] Still other useful compositions include one or more surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fattyAgent Ref: 16738.0002-00304

[0856] acid glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkylethers and alkylphenyl ethers, e.g, octoxynol 10. octoxynol 40.

[0857]

[0157] Still other useful compositions include one or more antioxidants to enhance chemical stability where required. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.

[0858]

[0158] In certain embodiments, aqueous suspension compositions are packaged in singledose non-reclosable containers. Alternatively, multiple-dose reclosable containers are used, in which case it is typical to include a preservative in the composition.

[0859]

[0159] In alternative embodiments, other delivery systems for hydrophobic pharmaceutical compounds are employed. Liposomes and emulsions are examples of delivery vehicles or earners useful herein. In certain embodiments, organic solvents such as / V-methylpyrrolidone are also employed. In additional embodiments, the compounds described herein are delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials are useful herein. In some embodiments, sustained-release capsules release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization are employed.

[0860]

[0160] In certain embodiments, the formulations described herein comprise one or more antioxidants, metal chelating agents, thiol containing compounds and / or other general stabilizing agents. Examples of such stabilizing agents, include, but are not limited to: (a) about 0.5% to about 2% w / v glycerol, (b) about 0.1 % to about 1% w / v methionine, (c) about 0.1% to about 2% w / v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w / v ascorbic acid, (f) 0.003% to about 0.02% w / v polysorbate 80, (g) 0.001% to about 0.05% w / v. polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (1) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof.

[0861] D. Routes of Administration

[0862]

[0161] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.Agent Ref: 16738.0002-00304

[0863]

[0162] In certain embodiments, a compound as described herein is administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation. In specific embodiments, long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with organ-specific antibody. In such embodiments, the liposomes are targeted to and taken up selectively by the organ. In yet other embodiments, the compound as described herein is provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation. In yet other embodiments, the compound described herein is administered topically.

[0864] E. Kits / Articles of Manufacture

[0865]

[0163] For use in the therapeutic applications described herein, kits and articles of manufacture are also provided. In some embodiments, such kits comprise a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers are formed from a variety of materials such as glass or plastic.

[0866]

[0164] The articles of manufacture provided herein contain packaging materials. Packaging materials for use in packaging pharmaceutical products include those found in, e.g., U. S. Pat. Nos. 5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment. For example, the container(s) includes one or more compounds described herein, optionally in a composition or in combination with another agent as disclosed herein. The container(s) optionally have a sterile access port (for example the container is an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). Such kits optionally comprising a compound with an identifying description or label or instructions relating to its use in the methods described herein.

[0867]

[0165] For example, a kit typically includes one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and / or devices) desirable from a commercial and user standpoint for use of a compound describedAgent Ref: 16738.0002-00304

[0868] herein. Non-limiting examples of such materials include, but not limited to, buffers, diluents, filters, needles, syringes; carrier, package, container, vial and / or tube labels listing contents and / or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included. A label is optionally on or associated with the container. For example, a label is on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself, a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g, as a package insert. In addition, a label is used to indicate that the contents are to be used for a specific therapeutic application. In addition, the label indicates directions for use of the contents, such as in the methods described herein. In certain embodiments, the pharmaceutical compositions is presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein. The pack for example contains metal or plastic foil, such as a blister pack. Or, the pack or dispenser device is accompanied by instructions for administration. Or, the pack or dispenser is accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, is the labeling approved by the U. S. Food and Drug Administration for prescription drugs, or the approved product insert. In some embodiments, compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier are prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0869] F. Methods of Use

[0870]

[0166] The chemical entities described herein are useful in the treatment, or in the preparation of a medicament for the treatment of various disorders. For example, compounds of Formula I and Formula II, or pharmaceutically acceptable salt of compounds of Formula I and Formula II, are useful as inhibitors of protein kinases. In some embodiments, the chemical entities described herein inhibit activity of one or more protein kinases. In some embodiments, the compounds of Formula I and Formula II, or pharmaceutically acceptable salt of compounds of Formula I and Formula II, are inhibitors of wild-type c-Kit or a c-Kit mutant. In some embodiments, the compounds of Formula I and Formula II, or pharmaceutically acceptable salt of compounds of Formula I and Formula II, are inhibitors of wild-type c-Kit. In some embodiments, the compounds of Formula I and Formula II, orAgent Ref: 16738.0002-00304

[0871] pharmaceutically acceptable salt of compounds of Formula I and Formula II, are inhibitors of a c-Kit mutant. In some embodiments, the compounds of Formula I and Formula II, or pharmaceutically acceptable salt of compounds of Formula I and Formula II, are inhibitors of c-Kit D816 mutant. In some embodiments, the compounds of Formula I and Formula II, or pharmaceutically acceptable salt of compounds of Formula I and Formula II, are inhibitors of c-Kit D816V mutant.

[0872]

[0167] Without wishing to be bound by any particular theory, the compounds of Formula I and Formula II are particularly useful for treating or lessening the severity of a disease, condition, or disorder where activation of one or more kinases, such as c-Kit, is implicated in the disease, condition, or disorder. c-Kit has been implicated in a wide range of diseases (Lipson et al., US 2004 / 0002534 Al). As described in more detail below, the compounds of Formula I and Formula II are particularly useful for treating or lessening the severity of a mast-cell associated disease, a respiratory disease, an inflammatory disorder, an autoimmune disorder, a metabolic disease, a fibrotic disease, a dermatological disease, an allergic disease, a cardiovascular disease, or a neurological disorder.

[0873]

[0168] When activation of c-Kit is implicated in a particular disease, condition, or disorder (e.g., the biological function of wild-type c-Kit and / or mutant c-Kit affects the development and / or course of the disease or condition, and / or in which modulation of wild-type c-Kit and / or mutant c-Kit alters the development, course, and / or symptoms), the disease, condition, or disorder may also be referred to as “c-Kit-mediated disease” or disease symptom.

[0874] Accordingly, in another aspect, the present disclosure provides a method for treating or lessening the severity of a disease, condition, or disorder where activation of c-Kit is implicated in the disease state.

[0875]

[0169] c-Kit. a proto-oncogene in a region on the long arm of chromosome 4 (4q11-4q13), encodes the Stem Cell Factor (SCF) receptor (CD 117). c-Kit is the cellular equivalent of the v-kit oncogene, a transforming feline retrovirus, and a 145 kDa transmembrane glycoprotein, which belongs to class III of the receptor tyrosine kinase (RTK) family. Similar to other members of class III of the RTK family, structurally, c-Kit consists of three domains: a hydrophobic transmembrane, an extracellular ligand-binding domain, and a cytoplasmic domain with tyrosine kinase activity. c-Kit participates in the signal transduction through different intracellular pathways, including Ras / Erk signal transduction pathway, PI3K pathway, JAK / STAT pathway, PLC-y signaling transduction pathway, Src family kinase pathway, and MAPK pathway. c-Kit signaling plays a very important role in regulation of the red blood cell production, lymphocyte proliferation, mast cell development and function,Agent Ref: 16738.0002-00304

[0876] melanin formation, and gamete formation. Specific binding of SCF can induce homologous dimerization, and drives downstream signal transduction pathway. It subsequently regulates gene expression and cell growth, proliferation and differentiation. (Pathania et al., BBA - Reviews on Cancer, 1876 (2021) 188631; Babaei et al., Drug Des Devel Ther. 2016;10:2443-2459; Liang etal., Int. J. Biol. Sci. 2013, Vol. 9, 435-442).

[0877]

[0170] The inhibition of kinases may be assayed in vitro, in vivo or in a cell line.

[0878] Specifically, activity of one or more of the compounds of the instant disclosure as an inhibitor of wild-type c-Kit or a c-Kit mutant may be determined through assays such as in vitro assays or in vivo assays. In vitro assays include assays that determine inhibition of either the phosphorylation activity or ATPase activity of activated kinase. Alternate in vitro assays quantitate the ability of the inhibitor to bind to kinase. Inhibitor binding may be measured by radiolabelling the inhibitor prior to binding, isolating the inhibitor, complex and determining the amount of radiolabel bound. Alternatively, inhibitor binding may be determined by running a competition experiment where new inhibitors are incubated with kinase bound to known radioligands. At 1 pM concentration, one or more compounds of the present disclosure exhibits at least about 50%, 60%, 70, 80%, 90% or even higher inhibition of kinases including c-Kit. Non-limiting examples of in vitro and in vivo assays useful in assaying a c-Kit inhibitory activity include those described and disclosed in one or more of the references above, each of which is herein incorporated by reference in its entirety.

[0879]

[0171] In some embodiments, the compounds described herein are inhibitors of wild-type c-Kit or a c-Kit mutant. In some embodiments, the compounds described herein are inhibitors of c-Kit that are useful for treating one or more disorders associated with wild-type c-Kit activity or activity of mutants of c-Kit.

[0880]

[0172] In some embodiments, the present disclosure provides a method for inhibiting wildtype c-Kit or a c-Kit mutant thereof in a biological sample. The method comprises contacting the sample with the compounds of Formula I or Formula II, or pharmaceutically acceptable salt of compounds of Formula I or Formula II, or pharmaceutical composition of any of the foregoing.

[0881]

[0173] In some embodiments, the present disclosure provides a method for inhibiting wildtype c-Kit or a c-Kit mutant thereof in a subject in need thereof. The method comprises administering to the subject a therapeutically effective amount of the compounds of Formula I or Formula II, or pharmaceutically acceptable salt of compounds of Formula I or Formula II, or the pharmaceutical composition of any of the foregoing.Agent Ref: 16738.0002-00304

[0882]

[0174] In some embodiments, the present disclosure provides a method for treating a c-Kit-mediated disorder comprising a step of administering to a patient in need thereof a therapeutically effective amount of one or more compounds of the present disclosure, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods for treating or lessening the severity of one or more diseases in which wildtype c-Kit, or a c-Kit mutant thereof, is known to play a role. Such c-Kit-mediated disorders include but are not limited to mast-cell associated diseases, respiratory diseases, inflammatory disorders, autoimmune disorders, metabolic diseases, fibrotic diseases, dermatological diseases, allergic diseases, cardiovascular diseases, or neurological disorders.

[0883]

[0175] In some embodiments, the diseases or conditions treatable with the compounds of the present disclosure include, but are not limited to,

[0884]

[0176] In some embodiments, the disclosure provides methods for treating any c-Kit protein kinase mediated disease or condition, including any wild-type c-Kit or c-Kit mutant kinase mediated disease or condition in an animal subject in need thereof, wherein the method involves administering to the subject an effective amount of any one or more compound(s) as described herein.

[0885]

[0177] In some embodiments, the disclosure provides methods for treating a disorder, disease, or condition mediated by wild-type c-Kit kinase.

[0886]

[0178] In some embodiments, the disorder, disease, or condition mediated by wild-type c-Kit kinase is selected from urticaria, dermatosis, idiopathic anaphylaxis, asthma, hereditary alpha tryptasemia (HAT), neurofibromatosis, idiopathic pulmonary fibrosis, bullous pemphigoid, prurigo nodularis, age-related macular degeneration, allergic conjunctivitis, allergic rhinitis, alpha-I antitrypsin deficiency, Alzheimer's disease, amyotrophic lateral sclerosis (AML), bronchiectasis. Celiac disease, chronic graft verse host disease, chronic rhinosinusitis with nasal polyps, colorectal cancer, dermatitis herpetiformis, irritable bowel syndrome (IBS), fibromyalgia, fibrosis, food allergies, insulin-dependent diabetes mellitus, mast cell leukemia, migraine, multiple sclerosis, Parkinson's disease, psoriasis, rheumatoid arthritis, pulmonary' arterial hypertension (PAH), inflammatory’ bowel disease (IBD), scleroderma, dermatosis, dermatitis herpetiformis, melanoma, gastrointestinal stromal tumor, mast cell tumor, anaphylactic syndrome, idiopathic anaphylaxis, eosinophilic esophagitis, and mastocytosis.

[0887]

[0179] In some embodiments, the c-Kit-mediated disorder, disease, or condition is selected from asthma, chronic urticaria, rheumatoid arthritis, psoriasis, atopic dermatitis, neurofibromatosis, multiple sclerosis, and idiopathic pulmonary’ fibrosis.Agent Ref: 16738.0002-00304

[0888]

[0180] In some embodiments, the disorder, disease, or condition is mediated by a c-Kit mutant. In some embodiments, the disorder, disease, or condition is mediated by D816 (such as D816F, D816H, D816N, D816Y or D816V) mutant. In some embodiments, the disorder, disease, or condition is mediated by a D816V mutant.

[0889]

[0181] In some embodiments, the c-Kit-mutant-mediated disorder, disease, or condition is selected from piebaldism, gastrointestinal stromal tumors (GIST), melanoma, systemic mastocytosis, mast cell disease, leukemia (acute myelogenous, core-factor binding, and mast cell), sinonasal natural killer / T-cell lymphoma (NKTCL), seminoma, lung adenocarcinoma, colon adenocarcinoma, conventional glioblastoma multiforme, intracranial dysgerminoma, and ovarian dysgerminoma.

[0890]

[0182] In some embodiments, the c-Kit-mutant-mediated disorder, disease, or condition is selected from GIST and systemic mastocytosis.

[0891]

[0183] The chemical entities described herein may be prepared in substantially pure form, typically by standard chromatographic methods, prior to formulation in a pharmaceutically acceptable form. The chemical entities described herein may be used in treating a variety of diseases, disorders, or conditions.

[0892]

[0184] In certain embodiments, the compound of Formula I and Formula II is administered in combination with one or more additional therapeutic agents. This additional therapeutic agent, which may ordinarily be administered to treat or prevent a disease, disorder, or condition, may be administered in combination with the compounds of Formula I and Formula II.

[0893]

[0185] In some embodiments, the chemical entities described herein may be administered in combination with one or more of a monoclonal antibody and an siRNA therapeutic.

[0894]

[0186] In some embodiments, the additional agents may be administered separately from a provided combination therapy, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with one or more compounds of the present disclosure in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another.

[0895]

[0187] In some embodiments, the amount of additional therapeutic agent present in a compositions comprising one or more compounds of the present disclosure will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent.Agent Ref: 16738.0002-00304

[0896]

[0188] In some embodiments, the present disclosure provides compositions comprising one or more compounds of Formula I and / or Formula II and one or more additional therapeutic agents. The therapeutic agent may be administered together with a compound of Formula I and / or Formula II or may be administered before or after administration of a compound of Formula I and / or Formula II. Suitable therapeutic agents are described in further detail below. In certain embodiments, a compound of Formula I and / or Formula II may be administered up to 5 min, 10 min. 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h, 12 h, 13 h, 14 h, 15 h, 16 h, 17 h, or 18 h before the therapeutic agent. In some embodiments, a compound of Formula I and / or Formula II may be administered up to 5 min, 10 min, 15 min, 30 mm, 1 h, 2 h, 3 h, 4 h, 5, h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h, 12 h, 13 h, 14 h, 15 h, 16 h, 17 h, or 18 h following the therapeutic agent.

[0897]

[0189] In some embodiments, the present disclosure provides methods of treating an inflammatory disease, disorder or condition by administering to a patient in need thereof a compound of Formula I and / or Formula II and one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are selected from an alkylating agent, an antibiotic, an antimetabolite, an antibody therapy, a taxane, a retinoid, an alkaloid, an antiangiogenic agent, a topoisomerase inhibitor, a kinase inhibitor, a targeted signal transduction inhibitor, a biological response modifier, and other chemotherapeutics.

[0898]

[0190] When a chemical entity described herein is administered into a human subject, the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual subject, as well as the severity of the subject’s symptoms.

[0899]

[0191] In some embodiments, a suitable amount of at least one chemical entity of the present disclosure is administered to a patient in need thereof for treating one or more of the various diseases and disorders described herein. Administration typically occurs in an amount of between about 0.01 mg / kg of body weight to about 100 mg / kg of body weight per day (administered in single or divided doses), such as at least about 0.1 mg / kg of body weight per day. A particular therapeutic dosage can include, e.g, from about 0.01 mg to about 1000 mg of the chemical entity, such as including, e.g., from about 1 mg to about 1000 mg. The quantity of the at least one chemical entity' in a unit dose of preparation may be varied or adjusted from about 0.1 mg to 1000 mg, such as from about 1 mg to 300 mg, for example 10 mg to 200 mg, according to the particular application. The amount administered will vary' depending on the particular IC50 value of the at least one chemical entity used and the judgment of the attending clinician taking into consideration factors such as health, weight.Agent Ref: 16738.0002-00304

[0900] and age. In combinational applications in which the at least one chemical entity described herein is not the sole active ingredient, it may be possible to administer lesser amounts of the at least one chemical entity and still have therapeutic or prophylactic effect.

[0901]

[0192] In some embodiments, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.

[0902]

[0193] The actual dosage employed may be varied depending upon the requirements of the subject and the severity of the condition being treated. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the at least one chemical entity. Thereafter, the dosage is increased by small amounts until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.

[0903]

[0194] The amount and frequency of administration of the at least one chemical entities described herein, and if applicable other additional therapeutic agents, will be regulated according to the judgment of the attending clinician (physician) considering such factors as age, condition and size of the subject as w ell as severity of the disease being treated.

[0904]

[0195] Also, in general, the at least one chemical entities described herein need not be administered in the same pharmaceutical composition as other additional therapeutic agent, and may. because of different physical and chemical characteristics, be administered by a different route. For example, the chemical entities / compositions may be administered orally to generate and maintain good blood levels thereof, while the additional therapeutic agent may be administered intravenously. The determination of the mode of administration and the advisability’ of administration, where possible, in the same pharmaceutical composition, is w ell within the know ledge of the skilled clinician. The initial administration can be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician.

[0905]

[0196] The particular choice of chemical entity (and where appropriate, additional therapeutic agent) will depend upon the diagnosis of the attending physicians and their judgment of the condition of the subject and the appropriate treatment protocol.

[0906]

[0197] The chemical entities described herein (and where appropriate additional therapeutic agent) may be administered concurrently (e.g., simultaneously, essentially simultaneously or within the same treatment protocol) or sequentially, depending upon the nature of theAgent Ref: 16738.0002-00304

[0907] proliferative disease, the condition of the subject, and the actual choice of chemotherapeutic agent and / or radiation to be administered in conjunction (i.e., within a single treatment protocol) with the chemical entity / composition.

[0908]

[0198] In combinational applications and uses, the chemical entity / composition and the additional therapeutic agent need not be administered simultaneously or essentially simultaneously, and the initial order of administration of the chemical entity / composition, and the additional therapeutic agent, may not be important. Thus, the at least one chemical entity described herein may be administered first followed by the administration of the additional agent; or the additional therapeutic agent may be administered first followed by the administration of the at least one chemical entity described herein. This alternate administration may be repeated during a single treatment protocol. The determination of the order of administration, and the number of repetitions of administration of each therapeutic agent during a treatment protocol, is well within the knowledge of the skilled physician after evaluation of the disease being treated and the condition of the subject. For example, the additional therapeutic agent may be administered first, and then the treatment continued with the administration of the at least one chemical entity described herein followed, where determined advantageous, by the administration of the additional therapeutic agent, and so on until the treatment protocol is complete.

[0909]

[0199] Thus, in accordance with experience and knowledge, the practicing physician can modify each protocol for the administration of a chemical entity / composition for treatment according to the individual subject 's needs, as the treatment proceeds.

[0910]

[0200] The attending clinician, in judging whether treatment is effective at the dosage administered, will consider the general well-being of the subject as well as more definite signs such as relief of disease-related symptoms. Relief of disease-related symptoms such as pain, and improvement in overall condition can also be used to help judge effectiveness of treatment.

[0911] EXAMPLES

[0912]

[0201] The following examples serve to more fully describe the manner of using the subject matter of the present diclosure. These examples are presented for illustrative purposes and should not serve to limit the true scope of the present disclosure.

[0913]

[0202] In carrying out the procedures of the methods described herein, it is of course to be understood that reference to particular buffers, media, reagents, cells, culture conditions and the like are not intended to be limiting, but are to be read so as to include all related materialsAgent Ref: 16738.0002-00304

[0914] that one of ordinary skill in the art would recognize as being of interest or value in the particular context in which that discussion is presented. For example, it is often possible to substitute one buffer system or culture medium for another and still achieve similar, if not identical, results. Those of skill in the art will have sufficient knowledge of such systems and methodologies so as to be able, without undue experimentation, to make such substitutions as will optimally serve their purposes in using the methods and procedures disclosed herein.

[0915]

[0203] I. Chemical Synthesis

[0916] Example 1: Preparation of N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(lH-pyrazol-5-yl)imidazo[l,2-a]pyridine-3 -carboxamide

[0917]

[0918]

[0204] A solution of ethyl 7-bromoimidazo[l,2-a]pyridine-3-carboxylate (500.0 mg. 1.90 mmol, 1.0 eq), (lH-pyrazol-3-yl)boronic acid (416.1 mg, 3.80 mmol, 2.0 eq), Cs₂CO₃ (1.8 g, 5.70 mmol, 3.0 eq) and Pd(PPh₃)₄ (215.3 mg, 0.19 mmol, 0.1 eq) in dioxane / H₂O (5 mL / 0.5 mL) was stirred at 130 °C for 4 h under N2. The mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography on silica gel (DCM / MeOH = 20 / 1, v / v) to afford ethyl 7-(lH-pyrazol-5-yl)imidazo[l,2-a]pyridine-3-carboxylate (100.2 mg, 20.0%) as a white solid. LCMS (M+H+) m / z calculated 257.1, found 257.2.

[0919]

[0920]

[0205] To a solution of ethyl 7-(lH-pyrazol-5-yl)imidazo[l,2-a]pyridine-3-carboxylate (100.2 mg, 0.39 mmol, 1.0 eq) in MeOH / THF / H₂O (5 ml / 5 mL / 3 mL) was added NaOH (47.1 mg, 1.2 mmol, 3.0 eq). The mixture was stirred at rt for 15 h. The solvent was partially removed under vacuum, and the solution was acidified to pH 5 with cone. HC1. The precipitate was collected by filtration and dried under vacuum to afford 7-(lH-pyrazol-5-yl)imidazo[l,2-a]pyridine-3-carboxylic acid (95.3 mg, quant.). LCMS (M+H+) m / z calculated 229.1, found 229.2.

[0921]

[0922] Agent Ref: 16738.0002-00304

[0923]

[0206] To a solution of 7-(lH-pyrazol-5-yl)imidazo[l,2-a]pyridine-3-carboxylic acid (89.0 mg, 0.39 mmol, 1.0 eq), 4,5-dimethyl-lH-pyrazol-3-amine (52.6 mg, 0.47 mmol. 1.2 eq) and pyridine (0.31 mL, 3.9 mmol, 10.0 eq) in DCM (20 mL) was added POCl₃ (0.2 mL, 2.0 mmol, 5.0 eq) at 0 °C. The reaction mixture was stirred at rt for 5 h. The reaction mixture was diluted with water (50 mL) and extracted with DCM (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by Prep-HPLC to afford N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(lH-pyrazol-5-yl)imidazo[l,2-a]pyridine-3-carboxamide as a white solid (3.3 mg, 2.6%). LCMS (M+H+) m / z calculated 322.1, found 322.1. ’H NMR (DMSO-d₆, 400 MHz) 5 13.14 (s, 1 H), 12.15 (s, 1 H), 10.09 (s, 1 H), 9.43 (d.

[0924] 1 H). 8.53 (s, 1 H). 8.12 (s, 1 H), 7.87 (s, 1 H), 7.68 (d, 1 H), 7.00 (s, 1 H), 2.17 (s, 3 H), 1.84 (s, 3 H).

[0925] Example 2: Preparation of N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-phenylimidazo[l,2-a]pyridine-3-carboxamide

[0926] Pd(PPh3)4, K2CO3

[0927] Dioxane / H2O, 75 °C, 2 h

[0928]

[0929]

[0207] To a solution of ethyl 7-bromoimidazo[l,2-a]pyndine-3-carboxylate (2.0 g,7.5 mmol, 1.0 eq) in dioxane / H₂O (30 mL / 10 mL) were added phenylboronic acid (1.4 g, 11.25 mmol, 1.5 eq), Pd(PPh₃)₄ (866 mg, 0.75mmol, 0.1 eq), and K2CO3 (3.1 g, 22.5 mmol, 3.0 eq) under N2. The mixture was stirred at 75 °C for 2 h. The reaction mixture was diluted with water (50 mL). extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (PE / EtOAc = 1 / 1, v / v) to afford the ethyl 7-phenylimidazo[l,2-a]pyridine-3-carboxylate (1.5 g, 75%) as a grey solid. LCMS (M+H+) m / z calculated 267.1, found 267.3.

[0930] NaOH, EtOH, H2O

[0931]

[0932] Agent Ref: 16738.0002-00304

[0933]

[0208] To a solution of ethyl 7-phenylimidazo[l,2-a]pyridine-3 -carboxy late (1.0 g, 3.8 mmol, 1.0 eq) in EtOH / H₂O (15 / 5 mL) was added NaOH (0.3 g,7.6 mmol. 2.0 eq). The mixture was stirred at rt for 2 h. The solvent was partially removed under vacuum, and the solution was acidified to pH=5 with cone. HC1. The precipitate was collected by filtration and dried under vacuum to afford 7-phenylimidazo[l,2-a]pyridine-3-carboxylic acid (700 mg, 78%) as a white solid. LCMS (M+H+) m / z calculated 239.1, found 239.3.

[0934]

[0935]

[0209] To a solution of 7-phenylimidazo[l,2-a]pyridine-3-carboxylic acid (100.1 mg, 0.42 mmol, 1.0 eq) in DCM (15mL) were added 4,5-dimethyl-lH-pyrazol-3-amine (47.0 mg, 0.42 mmol, 1.0 eq), pyridine (270.0 mg, 3.4 mmol, 8.0 eq) and POCh (260.2 mg, 1.7 mmol. 4.0 eq) at 0 °C for 2 h. The reaction mixture was diluted with water (30 mL), and extracted with DCM (30 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by Prep-HPLC to afford the N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-phenylimidazo[l,2-a]pyridine-3-carboxamide (16.1 mg, 11%) as a white solid. LCMS (M+H⁺) m / z calculated 332.1, found 332.4. 'H NMR (DMSO-d₆, 400 MHz) 5 12.16 (s, 1 H), 10.12 (s, 1 H), 9.49 (d, 1 H), 8.57 (s, 1 H), 8.08 (s, 1 H), 7.89 (d, 2 H), 7.52-7.58 (m, 3 H), 7.46 (t, 1 H), 2.17 (s, 3 H), 1.84 (s, 3 H).

[0936] Example 3: Preparation of N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(3-morpholinophenyl)imidazo[l,2-aJpyridine-3-carboxamide

[0937]

[0938]

[0210] To a solution of ethyl 7-bromoimidazo[l,2-a]pyridine-3-carboxylate (0.5 g. 1.9 mmol, 1.0 eq) in dioxane / H₂O (15 mL / 5 mL) were added (3-morpholinophenyl)boronic acid (0.6 g.

[0939] 2.9 mmol, 1.5 eq), Pd(PPh3)4 (220.2 mg, 0.19 mmol, 0.1 eq), and Cs₂CO₃ (1.8 g, 5.7 mmol, 3.0 eq) under N2. The mixture was stirred at 100 °C for 2 h. The reaction mixture was diluted with water (50 mL), and extracted with EtOAc (30 mL x 2). The combined organic layersAgent Ref: 16738.0002-00304

[0940] were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (PE / EtOAc = 1 / 1, v / v) to afford the ethyl 7-(3-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxylate (600.0 mg, 92%) as a grey solid. LCMS (M+H+) m / z calculated 352.2, found 352.4.

[0941]

[0942]

[0211] To a solution of ethyl 7-(3-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxylate (0.6 g, 1.7 mmol, 1.0 eq) in EtOH / H₂O (15 mL / 5 mL) was added NaOH (0.14 g, 3.4 mmol, 2.0 eq). The mixture was stirred at 50 °C for 2 h. The solvent was partially removed under vacuum, and the solution was acidified to pH 5 with cone. HC1. The precipitate was collected by filtration and dried under vacuum to afford 7-(3-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxylic acid (260.2 mg, 47%) as a white solid. LCMS (M+H+) m / z calculated 324.1, found 324.3.

[0943] N H POCI3, Pyridine

[0944] DCM, 0 °C to rt, 2 h

[0945]

[0946]

[0212] To a solution of 7-phenylimidazo[l,2-a]pyridine-3-carboxylic acid (100 mg, 0.31 mmol, 1.0 eq) in DCM (15 mL) were added 4,5-dimethyl-lH-pyrazol-3-amine (34 mg, 0.31 mmol, 1.0 eq), pyrdine (196 mg, 2.48 mmol, 8.0 eq) and POCl₃ (190 mg, 1.24 mmol, 4.0 eq) at 0 °C for 2h. The reaction mixture was diluted wi th water (30 mL), and extracted with DCM (30 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by Prep-HPLC to afford N-(4, 5-dimethyl-lH-pyrazol-3-yl)-7-(3-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide(21.2 mg, 16%) as a white solid. LCMS (M+H+) m / z calculated 417.2, found 417.5. ’H NMR (DMSO-d₆, 400 MHz) 5 12.17 (s, 1 H), 10.13 (s, 1 H), 9.47 (d, 1 H), 8.57 (s, 1 H), 8.10 (s, 1 H), 7.57 (d. 1 H). 7.32-7.42 (m, 2 H), 7.29 (d, 1 H), 7.04 (d, 1 H), 3.60-3.90 (m. 4 H), 3.14-3.25 (m. 4 H), 2.17 (s, 3 H), 1.84 (s, 3 H).Agent Ref.: 16738.0002-00304

[0947] Example 4: Preparation of N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(lH-pyrazol-5-yl)imidazo[l,2-a]pyridine-3-carboxamide

[0948]

[0949]

[0213] A solution of 7-bromo-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide (200 mg, 0.60 mmol, 1.0 eq), (4-morpholinophenyl)boronic acid (247.8 mg, 1.20 mmol, 2.0 eq), Cs₂CO₃ (584.9 mg, 1.80 mmol, 3.0 eq) and Pd(PPh₃)₄ (69.3 mg, 0.06 mmol, 0.1 eq) in dioxane / H₂O (20 mL / 2 mL) was stirred at 100 °C for 2 h under N2. The mixture was concentrated under reduced pressure and the resulting residue was purified by Prep-HPLC to afford N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide (65.9 mg, 26.4%) as a white solid. LCMS (M+H+) m / z calculated 417.2, found 417.3. 'H NMR (400 MHz, DMSO-t / e) 5 12.17 (s, 1 H), 10.08 (s, 1 H), 9.42 (d, 1 H), 8.53 (s, 1 H). 7.98 (s, 1 H), 7.79 (d, 2 H), 7.54 (d, 1 H), 7.07 (d. 2 H). 3.76 (m, 4 H), 3.21 (m, 4 H), 2.17 (s, 3 H), 1.84 (s, 3 H).

[0950] Example 5: Preparation of N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(2-isopropyloxazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0951]

[0952]

[0214] A solution of ethyl 6-bromopyrazolo[l,5-a]pyridine-3-carboxylate (5 g. 18.7 mmol, 1.0 eq), tributyl(l -ethoxy vinyl)stannane (8.7 g, 24 mmol, 1.3 eq), Pd(dppf)Cl₂ (2 g, 2.73 mmol, 0.15 eq) in dioxane (100 mL) was stirred at 120 °C for 5 h under N2. HCl (1N, 50 mL) was added and stirred at rt for 4 h under N2. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, by column chromatography on silica gel (PE / EA = 20 / 1, v / v) to afford ethyl 6-acetylpyrazolo[l,5-a]pyridine-3-carboxylate (4 g, 80.0%) as a white solid. LCMS (M+H+) m / z calculated 233.1, found 233.2.Agent Ref: 16738.0002-00304

[0953]

[0954]

[0215] To a solution of ethyl 6-acetylpyrazolo[l,5-a]pyridine-3-carboxylate (1.5 g, 6.4 mmol, 1.0 eq) in AcOH (30 mL) was added HBr (1.02 mL, 19.2 mmol, 3.0 eq) and Br₂ (0.3 ml, 6.4 mmol, 1.0 eq). The mixture was stirred at rt for 15 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, by column chromatography on silica gel (PE / EA = 20 / 1. v / v) to afford ethyl 6-(2-bromoacetyl)pyrazolo[ 1,5-a]pyridine-3-carboxylate as a white solid (1 g, 45%). LCMS (M+H+) m / z calculated 311.0, found 311.2.

[0955]

[0956]

[0216] To a solution of ethyl 6-(2-bromoacetyl)pyrazolo[l,5-a]pyridine-3-carboxylate (1.0 g, 3.2 mmol, 1.0 eq) in EtOAc (20 mL) were added isobutyramide (280 mg, 6.4 mmol, 2.0 eq) and Ag(SO₃CF₃) (410 mg. 3.2 mmol, 1.0 eq). The mixture was stirred at 80 °C for 15 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (PE / EA = 4 / 1, v / v) to afford ethyl 6-(2-isopropyloxazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxylate as a white solid (500 mg, 45%.). LCMS (M+H+) m / z calculated 300.1, found 300.2.

[0957]

[0958]

[0217] A solution of ethyl 6-(2-isopropyloxazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (100 mg, 0.33 mmol, 1.0 eq), 4,5-dimethyl-lH-pyrazol-3-amine (40 mg, 0.36 mmol, 1.1 eq), in toluene (3 mL) was added Al(Me)₃ (2 M in Toluene, 0.99 mL, 1.98 mmol, 6.0 eq) at 0 °C. The reaction was stirred at 80 °C for 3 h under N2. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by Prep-HPLC to afford N-(4,5-Agent Ref: 16738.0002-00304

[0959] dimethyl-lH-pyrazol-3-yl)-6-(2-isopropyloxazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide (8 mg, 6.6%) as a white solid. LCMS (M+H+) m / z calculated 365.2, found 365.4. ¹H NMR (DMSO-d₆, 400 MHz) 8 12.11 (s, 1 H), 9.87 (s, 1 H), 9.07 (s, 1 H), 8.71 (s, 1 H), 8.64 (s, 1 H), 8.26 (d, 1 H), 7.87 (d, 1 H), 3.11-3.22 (m, 1 H), 2.15 (s, 3 H), 1.82 (s, 3 H), 1.34 (d, 6H).

[0960] Example 6: Preparation of N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(6-morpholinopyridin-2-yl)imidazo[l,2-a]pyridine-3-carboxamide

[0961]

[0962]

[0218] 7-Bromoimidazo[l,2-a]pyridine-3-carboxylic acid was converted to 7-bromo-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide as described for N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(lH-pyrazol-5-yl)imidazo[l,2-a]pyridine-3-carboxamide. LCMS (M+H+) m / z calculated 334.0, found 334.2.

[0963]

[0964]

[0219] A solution of 7-bromo-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide (100 mg, 0.30 mmol, 1.0 eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (98.9 mg, 0.39 mmol, 1.3 eq), KOAc (88.0 mg, 0.90 mmol. 3.0 eq) and Pd(dppf)Cl₂ (21.7 mg, 0.03 mmol, 0.1 eq) in dioxane (5 mL) was stirred at 90 °C for 14 h under N2. The mixture was concentrated under reduced pressure to afford the crude product (3-((4,5-dimethyl-lH-pyrazol-3-yl)carbamoyl)imidazo[l,2-a]pyridin-7-yl)boronic acid (382.3 mg, quant) as a black solid. LCMS (M+H+) m / z calculated 300.1, found 300.3.

[0965]

[0966]

[0220] (3-((4,5-Dimethyl-lH-pyrazol-3-yl)carbamoyl)imidazo[l,2-a]pyridin-7-yl)boronic acid was converted to N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(6-morpholinopyridin-2-Agent Ref: 16738.0002-00304

[0967] yl)imidazo[l,2-a]pyridine-3-carboxamide as described for ethyl 7-(lH-pyrazol-5-yl)imidazo[l,2-a]pyridine-3-carboxylate. LCMS (M+H+) m / z calculated 418.2, found 418.3. 'H NMR (DMSO-d6, 400 MHz) 8 12.16 (brs, 1 H), 10.13 (s, 1 H), 9.47 (d, 1 H), 8.58 (brs, 1 H), 8.41 (s, 1 H), 7.88 (dd, 1 H), 7.70-7.74 (m, 1 H), 7.51 (d,l H), 6.91 (d,l H), 3.74-3.78 (m, 4 H), 3.56-3.60 (m, 4 H), 2.17 (s, 3 H), 1.84 (s, 3 H).

[0968] Example 7: Preparation of N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(5-morpholinopyridin-2-yl)imidazo[l,2-a]pyridine-3-carboxamide

[0969]

[0970]

[0221] N-(4,5-Dimethyl-lH-pyrazol-3-yl)-7-(5-morpholinopyridin-2-yl)imidazo[l,2-a]pyridine-3-carboxamide was prepared as described forN-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(6-morpholinopyridin-2-yl)imidazo[l,2-a]pyridine-3-carboxamide. LCMS (M+H+) m / z calculated 418.2. found 418.3. 'H NMR (DMSO-d6, 400 MHz) 8 12.15 (brs, 1 H), 10.10 (s, 1 H), 9.45 (d, 1 H), 8.55 (brs, 1 H), 8.46 (d, 1 H), 8.32 (s, 1 H), 8.09 (d, 1 H), 7.89 (dd, 1 H), 7.45 (dd, 1 H), 3.75-3.80 (m, 4 H), 3.27-3.31 (m, 4 H), 2.17 (s, 3 H), 1.84 (s, 3 H).

[0971] Example 8: Preparation of N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(3-fluoro-4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide

[0972]

[0973]

[0222] N-(4,5-Dimethyl-lH-pyrazol-3-yl)-7-(3-fluoro-4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide was prepared as described for N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide. LCMS (M+H+) m / z calculated 435.2, found 435.3.1H NMR (400 MHz, DMSO-d6 8 12.16 (s, 1 H), 10.11 (s, 1 H), 9.44 (d, 1 H), 8.55 (s, 1 H), 8.08 (s, 1 H), 7.75 (d, 1 H), 7.71 (d, 1 H), 7.68 (d, 1 H), 7.13 (t, 1 H), 3.77 (m, 4 H), 3.08-3.11 (m, 4 H), 2.17 (s, 3 H), 1.83 (s, 3 H).Agent Ref: 16738.0002-00304

[0974] Example 9: Preparation of N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(6-morpholinopyridin-3-yl)imidazo[l,2-a]pyridine-3-carboxamide

[0975] 01

[0976] L -N

[0977]

[0978]

[0223] N-(4,5-Dimethyl-lH-pyrazol-3-yl)-7-(6-morpholinopyridin-3-yl)imidazo[l,2-a]pyridine-3-carboxamide was prepared as described for N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide. LCMS (M+H+) m / z calculated 418.2, found 418.3. 'H NMR (400 MHz, DMSO-d6) 5 12.16 (s, 1 H), 10.08 (s, 1 H), 9.43 (d, 1 H), 8.70 (s, 1 H), 8.53 (s, 1 H), 8.11 (t, 1 H), 8.04 (s, 1 H), 7.55 (d, 1 H), 6.97 (d, 1 H), 3.70-3.74 (m, 4 H), 3.54-3.57 (m, 4 H), 2.17 (s, 3 H), 1.84 (s, 3H).

[0979] Example 10: Preparation of N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(2-fluoro-4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide

[0980]

[0981]

[0224] A solution of 4-bromo-3-fluoroaniline (2.0 g, 10.6 mmol, 1.0 eq), l-bromo-2-(2-bromoethoxy)ethane (3.6 g, 15.9 mmol, 1.5 eq) and DIEA (4.1 g, 31.8 mmol, 3.0 eq) in toluene (20 mL) was stirred at 110 °C in a sealed tube for 12 h. The reaction was quenched with H2O (50 mL). The reaction mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (PE / EtOAc = 2 / 1, v / v) to afford 4-(4-bromo-3-fluorophenyl)morpholine as a light yellow solid (1.0 g, 37%). LCMS (M+H+) m / z calculated 260.0, found 260.1.

[0982]

[0983] IAgent Ref: 16738.0002-00304

[0984]

[0225] A solution of 4-(4-bromo-3-fluorophenyl)morpholine (1.0 g, 3.8 mmol, 1.0 eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (1.5 g, 5.8 mmol. 1.5 eq), Pd(dppf)Cl2 (277.8 mg, 0.38 mmol, 0.1 eq) and KOAc (744.8 mg, 7.6 mmol, 2.0 eq) in dioxane (20.0 mL) was stirred at 110 °C for 4 h under N2. The reaction was quenched with H2O (50 mL). The reaction mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100.0 mL) and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (PE / EtOAc = 3 / 1, v / v) to afford 4-(3-fluoro-4-(4, 4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)morpholine as a light yellow solid (600 mg, 51%). LCMS (M+H+) m / z calculated 308.2, found 308.2.

[0985]

[0986]

[0226] A solution of 4-(3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)morpholine (120 mg, 0.39 mmol, 1.0 eq), 7-bromo-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide (129.8 mg, 0.39 mmol, 1.0 eq), Pd(PPh3)4 (45.1 mg, 0.039 mmol. 0.1 eq) and Cs2CO3(254.3 mg, 0.78 mmol, 2.0 eq) in dioxane / H2O (4 mL / 1 mL) was stirred at 100 °C for 4 h under N2. The reaction was quenched with H2O (50 mL). The reaction mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by Prep-HPLC to afford N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(2-fluoro-4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide as a white solid (14.3 mg, 8.4%). LCMS (M+H+) m / z calculated 435.2, found 435.2. 'H NMR (DMSO-d6, 400 MHz) 5 12.16 (s, 1 H), 10.10 (s, 1 H), 9.45 (d, 1 H), 8.55 (s. 1 H). 7.84 (s, 1 H), 7.61 (t, 1 H), 7.37 (d, 1 H), 6.90-6.93 (m. 2 H). 3.73-3.76 (m. 4 H). 3.23-3.25 (m, 3 H), 2.16 (s, 3 H), 1.83 (s, 3 H).

[0987] Example 11: Preparation of 7-(2,3-difluoro-4-morpholinophenyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide

[0988] o I

[0989] Br^O' L. N

[0990] K2CO3, DMF, 150 °C, 20 h

[0991]

[0992] Agent Ref: 16738.0002-00304

[0993]

[0227] To a solution of 4-bromo-2,3-difluoroaniline (2.0 g, 9.7 mmol, 1.0 eq) in DMF (20 mL) were added l-bromo-2-(2-bromoethoxy)ethane (8.9 g, 38.8 mmol. 4.0 eq) and K2CO3 (5.3 g, 38.8 mmol, 4.0 eq). The mixture was stirred at 150 °C for 20 h. The reaction mixture was diluted with water (30 mL), and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (PE / EtOAc = 2 / 1, v / v) to afford 4-(4-bromo-2,3-difluorophenyl)morpholine (2.1 g, 77%) as a yellow solid. LCMS (M+H+) m / z calculated 278.0, found 278.5.

[0994] Pd(dppf)CI2, KOAc

[0995] Dioxane 100 °C, 4 h

[0996]

[0997]

[0228] To a solution of 4-(4-bromo-2,3-difluorophenyl)morpholine (1.0 g, 3.6 mmol, 1.0 eq) in dioxane (10 mL) were added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (1.4 g,5.4 mmmol, 1.5 eq), Pd(dppf)Cl2(263.0 mg, 0.36 mmol, 0.1 eq) and KOAc (1.01 g, 10.8 mmol, 3.0 eq). The mixture was stirred at 100 °C for 4 h under N2. The reaction mixture was diluted with water (30 mL), and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (PE / EtOAc = 2 / 1, v / v) to afford 4-(2, 3-difluoro-4-(4, 4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)morpholine (880mg, 64%) as a grey solid.

[0998] LCMS (M+H+) m / z calculated 326.2, found 326.5.

[0999] Pd(dppf)Cl2. Cs2CO3

[1000] Dioxane / H2O 100°C, 4 h

[1001]

[1002]

[0229] To a solution of 7-bromo-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide (127.0 mg, 0.38 mmol, 1.0 eq) in dioxane / H2O (3 mL / 1 mL) were added 4-(2,3-difluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)morpholine (150.0 mg, 0.46 mmol, 1.2 eq), Pd(dppf)Cl2 (28.0 mg, 0.038 mmol, 0.1 eq), and Cs2CO3(370.0 mg, 1.14Agent Ref: 16738.0002-00304

[1003] mmol, 3.0 eq) under N2. The mixture was stirred at 100 °C for 4 h. The reaction mixture was diluted with water (10 mL), and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by Prep-HPLC to afford 7-(2,3-difluoro-4-morpholinophenyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide (37.5 mg, 22%) as a white solid. LCMS (M+H+) m / z calculated 453.2, found 453.5. 'H NMR (400 MHz, DMSO-d6) 5 12.16 (s. 1 H), 10.15 (s, 1 H), 9.49 (d.

[1004] 1 H), 8.59 (s, 1 H), 7.92 (s, 1 H), 7.48 (t, 1 H), 7.39 (d, 1 H), 7.00 (t, 1 H), 3.73-3.82 (m, 4 H), 3.18-3.09 (m, 4 H), 2.17 (s, 3 H), 1.84 (s, 3 H).

[1005] Example 12: Preparation of 7-(3-chloro-4-morpholinophenyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide

[1006] Pd(PPh3)4. Cs2CO3Dioxane / H20, 100 °C, 2 h

[1007]

[1008]

[0230] To a solution of 7-bromo-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide (0.3 g, 0.9 mmol, 1.0 eq) in dioxane / H2O (10 mL / 3 mL) were added 4-(2-chloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)morpholine (436.0 mg, 1.35 mmol, 1.5 eq), Pd(PPh3)4( 104.0 mg, 0.09 mmol, 0.1 eq) and Cs2CO3(0.88 g, 2.7 mmol, 3.0 eq) under N2. The mixture was stirred at 100 °C for 2 h. The reaction mixture was diluted with water (30 mL), and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by Prep-HPLC to afford 7-(3-chloro-4-morpholinophenyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide (82 mg, 20%) as a white solid. LCMS (M+H+) m / z calculated 451.2, found 451.5. ’H NMR (DMSO-d6, 400 MHz) 6 12.17 (s. 1 H), 10.13 (s, 1 H), 9.46 (d.

[1009] 1 H), 8.57 (s, 1 H), 8.10 (s, 1 H), 7.97 (d, 1 H), 7.86 (dd, 1 H), 7.57 (dd, 1 H), 7.28 (d, 1 H), 3.76-3.87 (m, 4 H), 2.95-3.15 (m, 4 H), 2.17 (s, 3 H), 1.84 (s, 3 H).

[1010] Example 13: Preparation of N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-(3-oxomorpholino)phenyl)imidazo[1.2-a]pyridine-3-carboxamideAgent Ref: 16738.0002-00304

[1011]

[1012]

[0231] N-(4,5-Dimethyl-lH-pyrazol-3-yl)-7-(4-(3-oxomorpholino)phenyl)imidazo[l,2-a]pyridine-3-carboxamide was prepared as described forN-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide. LCMS (M+H+) m / z calculated 431.2, found 431.4. 'H NMR (400 MHz, DMSO-d6) 5 12.16 (s, 1 H), 10.13 (s, 1 H). 9.49 (d, 1 H), 8.58 (s, 1 H), 8.11 (s, 1 H), 7.93 (d, 2 H), 7.56-7.60 (m. 3 H). 4.24 (s, 2 H), 3.99-4.03 (m, 2 H), 3.80-3.83 (m, 2 H), 2.17 (s, 3 H), 1.84 (s, 3 H).

[1013] Example 14: Preparation of N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(3-methyl-4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide

[1014]

[1015]

[0232] N-(4,5-Dimethyl-lH-pyrazol-3-yl)-7-(3-methyl-4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide was prepared as described forN-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide. LCMS (M+H+) m / z calculated 431.2, found 431.4. 'H NMR (400 MHz, DMSO-d6) 512.17 (s, 1 H), 10.10 (s, 1 H), 9.45 (d, 1 H), 8.55 (s, 1 H), 8.00 (s, 1 H), 7.67-7.73 (m, 2 H), 7.54 (dd, 1 H), 7.14 (d, 1 H), 3.75-3.78 (m, 4 H), 2.89-2.92 (m, 4 H), 2.36 (s, 3 H), 2.17 (s, 3 H), 1.84 (s. 3 H).

[1016] Example 15: Preparation of N-(5-methyl-lH-pyrazol-3-yl)-7-(4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide

[1017]

[1018] Agent Ref: 16738.0002-00304

[1019]

[0233] A solution of ethyl ethyl 7-bromoimidazo[l,2-a]pyridine-3-carboxylate (2.0 g, 7.43 mmol, 1.0 eq), (4-morpholinophenyl)boronic acid (769.0 mg, 3.71 mmol, 1.5 eq), Cs2CO3(4.8 g, 14.9 mmol, 2.0 eq) and Pd(PPh3)4 (854.7 mg, 0.74 mmol, 0.1 eq) in dioxane / IHhO (25 mL / 5 mL) was stirred at 100 °C for 4 h under N2. The mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography on silica gel (DCM / MeOH = 20 / 1, v / v) to afford ethyl 7-(4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxylate (1.2 g, 31.2%) as a white solid. LCMS (M+H+) m / z calculated 352.2, found 352.5.

[1020]

[1021]

[0234] A solution of ethyl 7-(4-morpholinophenyl)imidazo[l,2-a]pyridine-3 -carboxylate (1.2 g, 3.42 mmol, 1.0 eq) and NaOH (273.6 mg, 6.84 mmol, 2 eq) in EtOH / H2O (15 mL / 5 mL) was stirred at 50 °C for 12 h. The solvent was partially removed under vacuum, and the solution was acidified to pH 5 with cone. HC1. The precipitate was collected by filtration and dried under vacuum to afford 7-(4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxylic acid as a yellow solid (800 mg, 72.4%). LCMS (M+H+) m / z calculated 324.1, found 324.2.

[1022]

[1023]

[0235] To a stirred solution of 7-(4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxylic acid (100.0 mg, 0.31 mmol, 1.2 eq), 5-methyl-lH-pyrazol-3-amine (25.2 mg, 0.26 mmol, 1.0 eq) and pyridine (162.7 mg, 2.06 mmol, 8.0 eq) in DCM (10 mL) was added POCh (157.5 mg, 1.03 mmol, 4.0 eq) at 0 °C. The reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with water (50 mL). The aqueous layer was extracted with DCM (50.0 mL x 3) and the combined organic layers were washed with brine (50 mL) and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to afford N-(5-methyl-lH-pyrazol-3-yl)-7-(4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide as a white solid (30.0 mg, 33.2%). LCMS (M+H+) m / z calculated 403.2, found 403.5. 'H NMR (DMSO-d6, 400 MHz) 5 12.12 (s, 1 H), 10.73 (s, 1 H), 9.48 (d, 1 H), 8.64 (s, 1 H), 7.96 (s, 1 H), 7.79 (d,Agent Ref: 16738.0002-00304

[1024] 2 H), 7.53 (d, 1 H). 7.07 (d, 2 H), 6.42 (s, 1 H), 3.75-3.77 (m, 4 H), 3.20-3.22 (m, 4 H), 2.24 (s, 3 H).

[1025] Example 16: Preparation of N-(5-methyl-lH-pyrazol-3-yl)-7-(4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide

[1026]

[1027]

[0236] To a stirred solution of 7-(4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxylic acid (100.0 mg, 0.31 mmol, 1.2 eq), 4-methyl-lH-pyrazol-3-amine (25.2 mg. 0.26 mmol, 1.0 eq) and pyridine (162.7 mg, 2.06 mmol, 8.0 eq) in DCM (10 mL) were added POCI3 (157.5 mg, 1.03 mmol, 4.0 eq) at 0 °C. The mixture was stirred at rt for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (50 mL) and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to afford N-(5-methyl-lH-pyrazol-3-yl)-7-(4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide as a white solid (30.0 mg, 33.2%). LCMS (M+H+) m / z calculated 403.2, found 403.5. 'H NMR (DMSO-d₆, 400 MHz) 5 12.36 (s, 1 H), 10.13 (s, 1 H), 9.43 (d, 1 H), 8.51 (s, 1 H), 7.98 (s, 1 H), 7.79 (d. 2 H). 7.51-7.55 (m, 2 H), 7.07 (d, 2 H), 3.75-3.77 (m, 4 H), 3.20-3.22 (m, 4 H), 1.94 (s, 3 H)

[1028] Example 17: Preparation of 7-(3-cyclopropyl-4-morpholinophenyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide

[1029] OH B

[1030] Pd(PPh3)4, Cs2CO3

[1031]

[1032] Dioxane / H2O, 100 °C. 16 h

[1033]

[0237] To a solution of 4-bromo-2-iodoaniline (2.0 g, 6.7 mmol, 1.0 eq) in dioxane / H2O (20 mL / 5 mL) were added cyclopropylboronic acid (86.0 mg, 10.0 mmol, 1.5 eq), Pd(PPh3)4 (774.0 mg, 0.67mmol, 0.1 eq) and Cs2CO3(6.4 g, 20 mmol, 3.0 eq) under N2. The mixture was stirred at 100 °C for 16 h. The reaction mixture was diluted with water (30 mL), and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (PE / EtOAc = 3 / 1,Agent Ref: 16738.0002-00304

[1034] v / v) to afford the 4-bromo-2-cyclopropylaniline (1.2 g, 85%) as a white solid. LCMS (M+H ) m / z calculated 212.0, found 212.5.

[1035] DIEA, toluene, 140 °C, 16.h

[1036]

[1037]

[0238] To a solution of 4-bromo-2-cyclopropylaniline (1.2 g, 5.7 mmol, 1.0 eq) in toluene (15 mL) were added l-bromo-2-(2-bromoethoxy)ethane (5.2 g, 22.8 mmol. 4.0 eq) and DIEA (2.9 g, 22.8 mmol, 4.0 eq). The mixture was stirred at 140 °C for 16 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (PE / EtOAc = 2 / 1. v / v) to afford 4-(4-bromo-2-cyclopropylphenyl)morpholine (740.0 mg, 46%) as a yellow solid. LCMS (M+H+) m / z calculated 282.0, found 282.5.

[1038] Pd(dppf)CI2, KOAc

[1039] Br Dioxane, 100 °C, 4 h

[1040]

[1041]

[0239] To a solution of 4-(4-bromo-2-cyclopropylphenyl)morpholine (740.0 mg, 2.6 mmol, 1.0 eq) in dioxane (10 mL) were added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (990.0 mg, 3.9 mmol, 1.5 eq), Pd(dppf)Cl2 (190.0 mg, 0.26mmol, 0.1 eq) and KOAc (620 mg, 7.8mmol. 3.0 eq) under N2. The mixture was stirred at 100 °C for 4 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (PE / EtOAc = 2 / 1, v / v) to afford 4-(2-cyclopropyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)morpholine (740.0 mg, 85%) as a grey solid. LCMS (M+H+) m / z calculated 330.2, found 330.5.

[1042]

[1043] Agent Ref: 16738.0002-00304

[1044]

[0240] To a solution of 7-bromo-N-(4,5-dimethyl-1H-pyrazol-3-yl)imidazo[1,2-a]pyridine-3-carboxamide (0.33 g, 1.0 mmol, 1.0 eq) in dioxane / H2O (3 mL / 1 mL) were added 4-(2-cyclopropyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)morpholine (400 mg, 1.2 mmol, 1.2 eq), Pd(PPh3)4 (112 mg, 0.1 mmol, 0.1 eq) and Cs2CO3(1.0 g, 3.0 mmol, 3.0 eq) under N2. The mixture was stirred at 100 °C for 2 h. The reaction mixture was diluted with water (10 mL), and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by Prep-HPLC to afford 7-(3-cyclopropyl-4-morpholinophenyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide (100.0 mg, 22%) as a white solid. LCMS (M+H+) m / z calculated 457.2, found 457.5. 'H NMR (400 MHz, DMSO-d6) 5 12.15 (s. 1 H). 10.09 (s. 1 H). 9.43 (d, 1 H), 8.54 (s, 1 H), 8.02 (s, 1 H), 7.63 (dd, 1 H), 7.52 (d, 1 H), 7.22 (s, 1 H), 7.14 (d, 1 H), 3.64-4.04 (m, 4 H), 2.86-3.08 (m, 4 H), 2.32-2.18 (m, 1 H), 2.17 (s, 3 H), 1.83 (s, 3 H), 1.02 (dd, 2 H), 0.91 (d, 2 H).

[1045] Example 18: Preparation of N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-(4-morpholino-3-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridine-3-carboxamide

[1046] K2CO3, DMSO, 120 °C, 16 h

[1047]

[1048]

[0241] To a solution of 4-bromo-l-fluoro-2-(trifluoromethyl)benzene (3.0 g, 12 mmol, 1.0 eq) in DMSO (30 mL) were added morpholine (4.2 g, 48 mmol, 4.0 eq) and K2CO3 (6.6 g, 48 mmol, 4.0 eq). The mixture was stirred at 120 °C for 16 h. The reaction mixture was diluted with water (50 mL), and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (PE / EtOAc = 2 / 1, v / v) to afford 4-(4-bromo-2- (trifluoromethyl)phenyl)morpholine (600.0 mg, 16%) as a yellow solid. LCMS (M+H+) m / z calculated 310.0, found 310.5.

[1049] Pd(dppf)CI2, KOAc

[1050] Dioxane, 100 °C, 4 h

[1051]

[1052] Agent Ref: 16738.0002-00304

[1053]

[0242] To a solution of 4-(4-bromo-2-(trifluoromethyl)phenyl)morpholine (600.0 mg, 2.0 mmol, 1.0 eq) in dioxane (10 mL) were added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (760.0 mg, 3.0 mmmol, 1.5 eq), Pd(dppf)Cl2 (146.0 mg, 0.2 mmol, 0.1 eq) and KO Ac (590.0 mg, 6 mmol, 3.0 eq) under N2. The mixture was stirred at 100 °C for 4 h. The reaction mixture was diluted with water (30 mL), and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (PE / EtOAc = 2 / 1, v / v) to afford 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenyl)morpholine (500.0 mg, 70%) as a grey solid. LCMS (M+H+) m / z calculated 358.2, found 358.5.

[1054] Pd(PPh3)4, Cs2CO3, Dioxane / H2O,100 °C, 2 h

[1055]

[1056]

[0243] To a solution of 7-bromo-N-(4,5-dimethyl-1H-pyrazol-3-yl)imidazo[1,2-a]pyridine-3-carboxamide (0.33 g, 1.0 mmol, 1.0 eq) in dioxane / H2O (3.0 mL / 1.0 mL) were added 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenyl)morpholine (400 mg, 1.1 mmoLl.l eq). Pd(PPh3)4 (112 mg, 0.1 mmol. 0.1 eq) and Cs2CO?(1.0 g, 3.0 mmol, 3.0 eq) under N2. The mixture was stirred at 100 °C for 2 h. The reaction mixture was diluted with water (10 mL), and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by Prep-HPLC to afford N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-(4-morpholino-3-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridine-3-carboxamide (89.8 mg, 18%) as a white solid. LCMS (M+H+) m / z calculated 485.2, found 485.5.

[1057]

[1058] NMR (400 MHz, DMSO-d₆) δ 12.16 (s, 1 H), 10.15 (s, 1 H), 9.50 (d, 1 H), 8.59 (s, 1 H), 8.17-8.18 (m, 2 H), 8.10 (d, 1 H), 7.70 (d, 1 H), 7.61 (dd, 1 H), 3.61-3.81 (m, 4 H), 2.85-3.00 (m, 4 H), 2.17 (s, 3 H), 1.84 (s, 3 H).

[1059] Example 19: Preparation of N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(3-methoxy-4-morpholinophenyl)imidazo[l,2-a]pyridine-3 -carboxamideAgent Ref: 16738.0002-00304

[1060] H

[1061] /

[1062]

[1063] V-(4,5-dimethyl-1H-pyrazol-3-yl)-7-(3-methoxy-4-morpholinophenyl)imidazo[1,2-a]pyridine-3-carboxamide

[1064]

[0244] N-(4,5-Dimethyl-1H-pyrazol-3-yl)-7-(3-methoxy-4-morpholinophenyl)imidazo[1,2-a]pyridine-3-carboxamide was prepared as described for N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-(4-morpholinophenyl)imidazo[1,2-a]pyridine-3-carboxamide. LCMS (M+H+) m / z calculated 447.2, found 447.3. ¹H NMR (400 MHz, DMSO-d₆) δ 12.16 (s, 1 H), 10.09 (s, 1 H), 9.44 (d, 1 H), 8.55 (s, 1 H), 8.09 (s, 1 H), 7.57 (d, 1 H), 7.41-7.43 (m, 2 H), 7.00 (d, 1 H), 2.93 (s, 3 H), 3.74-3.76 (m, 4 H), 3.02-3.04 (m, 4 H), 2.17 (s, 3 H), 1.84 (s, 3 H).

[1065] Example 20: Preparation of N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(3-fluorophenyl)imidazo[ 1.2-a]pyridine-3 -carboxamide

[1066] Pd(PPh3)4, Cs2CO3

[1067] dioxane / H₂O, 100 °C, 4 h

[1068]

[1069]

[0245] To a solution of 7-bromo-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide (150 mg, 0.45 mmol, 1.0 eq) in dioxane / H2O (3 mL / 1 mL) were added ((3-fluorophenyl)boronic acid (95 mg, 0.68 mmol, 1.5 eq), Pd(PPh3)4(52 mg, 0.045mmol, 0.1 eq) and Cs2CO3(0.44 g, 1.35 mmol, 3.0 eq) under N2. The mixture was stirred at 100 °C for 4 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by Prep-HPLC to afford N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(3-fluorophenyl)imidazo[l, 2-a]pyridine-3-carboxamide (25.6 mg, 16%) as a white solid. LCMS (M+H+) m / z calculated 350.1, found 350.5. ¹H NMR (400 MHz, DMSO-d₆) δ 12.17 (s, 1 H), 10.16 (s, 1 H), 9.50 (d, 1 H), 8.60 (s, 1 H), 8.18 (d, 1 H), 7.75-7.80 (m, 2 H), 7.51-7.66 (m, 2 H), 7.27-7.32 (m, 1 H), 2.17 (s, 3 H), 1.84 (s, 3 H).

[1070] Example 21: Preparation of N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(3-methoxyphenyl)imidazo[l,2-a]pyridine-3-carboxamideAgent Ref.: 16738.0002-00304

[1071] Pd(PPh3)4, Cs2CO3

[1072] Dioxane / H₂O, 100 °C, 4 h

[1073]

[1074]

[0246] To a solution of 7-bromo-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide (150 mg, 0.45 mmol, 1.0 eq) in dioxane / H2O (3 mL / 1 mL) were added (3-methoxyphenyl)boronic acid (104 mg, 0.68 mmol, 1.5 eq), Pd(PPh3)4(52 mg, 0.045 mmol, 0.1 eq) and Cs2CO3(0.44 g, 1.35 mmol, 3.0 eq) under N2. The mixture was stirred at 100 °C for 4 h. The reaction mixture was diluted with water (20 mL). and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by Prep-HPLC to afford N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(3-methoxyphenyl)imidazo[l,2-a]pyridine-3-carboxamide (20.5 mg. 13%) as a white solid. LCMS (M+H ) m / z calculated 362.2, found 362.5. 'H NMR (400 MHz, DMSO-d6) 5 12.16 (s, 1 H), 10.13 (s, 1 H), 9.48 (d, 1 H), 8.58 (s, 1 H), 8.11 (s, 1 H), 7.57 (dd, 1 H), 7.42-7.45 (m, 3 H), 7.01-7.04 (m, 1 H), 3.87 (s, 3 H), 2.17 (s, 3 H), 1.84 (s, 3 H).

[1075] Example 22: Preparation of 7-(3-cyclopropylphenyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide

[1076] Pd(PPh3)4, Cs2CO3

[1077] Dioxane / H2O, 100 °C, 4 h

[1078]

[1079]

[0247] To a solution of 7-bromo-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide (150 mg, 0.45 mmol, 1.0 eq) in dioxane / H₂O (3 mL / 1 mL) were added (3-cyclopropylphenyl)boronic acid (110 mg, 0.68 mmol, 1.5 eq), Pd(PPh₃)₄ (52 mg, 0.045 mmol, 0.1 eq) and Cs₂CO₃ (0.44 g, 1.35 mmol, 3.0 eq) under N2. The mixture was stirred at 100 °C for 4 h. The reaction mixture was diluted with w ater (20 mL). and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by Prep-HPLC to afford 7-(3-cyclopropylphenyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide (31.3 mg, 19%) as a white solid. LCMS (M+H⁺) m / z calculated 372.2, found 372.5. ¹H NMR (400 MHz, DMSO-d₆) δ 12.15 (s, 1 H),Agent Ref: 16738.0002-00304

[1080] 10.12 (s, 1 H), 9.48 (d, 1 H), 8.57 (s, 1 H), 8.08 (s, 1 H), 7.62 (d, 1 H), 7.56 (dt, 2 H). 7.39 (t, 1 H), 7.15 (d, 1 H). 2.17 (s, 3 H), 1.95-2.08 (m, 1 H), 1.84 (s, 3 H), 0.94-1.06 (m. 2 H). 0.72-0.89 (m, 2 H).

[1081] Example 23: Preparation of N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide

[1082]

[1083]

[0248] A solution of ethyl 7-bromo-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide (100 mg, 0.30 mmol, 1.0 eq), (4-(trifluoromethyl)phenyl)boronic acid (114.1 mg, 0.60 mmol, 2.0 eq), Cs2CO3(294.8 mg, 0.90 mmol, 3.0 eq) and Pd(dppf)C12 (22.3 mg, 0.03 mmol, 0.1 eq) in dioxane / H₂O (5 mL / 0.5 mL) was stirred at 100 °C for 5 h under N₂. The mixture was concentrated under reduced pressure and the resulting residue was purified Prep-HPLC to afford N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide (34.8 mg, 29.2%) as a white solid. LCMS (M+H+) m / z calculated 400.1, found 400.2.

[1084]

[1085] NMR (DMSO-d₆, 400 MHz) δ 12.18 (s, 1 H), 10.18 (s, 1 H), 9.53 (d, 1 H), 8.62 (brs, 1 H), 8.21 (d, 1 H), 8.12 (d, 2 H), 7.88 (d, 2 H), 7.62 (dd, 1 H), 2.17 (s, 3 H), 1.85 (s, 3 H).

[1086] Examples 24 and 25: Preparation of 7-(4-chlorophenyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide and 7-(4'-chloro-[l,l'-biphenyl]-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide

[1087]

[1088]

[0249] 7-Bromo-N-(4.5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide was converted to 7-(4-chlorophenyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide and 7-(4'-chloro-[l,l'-biphenyl]-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide as described for N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide. 7-(4-chlorophenyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide:Agent Ref: 16738.0002-00304

[1089] LCMS (M+H+) m / z calculated 366.1, found 366.1. NMR (DMSO-d6, 400 MHz) 5 12.16 (s, 1 H), 10.14 (s, 1 H), 9.49 (d, 1 H), 8.58 (brs, 1 H), 8.11 (s, 1 H), 7.93 (d, 2 H). 7.55-7.60 (m, 3 H), 2.17 (s, 3 H), 1.84 (s, 3 H); 7-(4'-chloro-[l,r-biphenyl]-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide: LCMS (M+H+) m / z calculated 442.1, found 442.2.JH NMR (DMSO-d6, 400 MHz) 5 12.17 (s, 1 H), 10.14 (s, 1 H), 9.50 (d, 1 H), 8.58 (brs, 1 H). 8.16 (s, 1 H), 8.01 (d, 2 H), 7.79-7.86 (m, 4 H), 7.63 (dd, 1 H), 7.55 (d. 2 H).

[1090] 2.17 (s. 3 H). 1.85 (s, 3 H).

[1091] Example 26: Preparation of N-(5-cyclopropyl-4-methyl-lH-pyrazol-3-yl)-7-(4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide

[1092] NBS, DMF

[1093] rt, 15 h

[1094]

[1095]

[0250] A solution of 4-methyl-3-nitro-lH-pyrazole (5.0 g, 39.4 mmol, 1.0 eq) and NBS (14.0 g, 78.8 mmol, 2.0 eq) in DMF (200.0 mL) was stirred at rt for 15 h. The reaction was quenched with H2O (2000 mL). The reaction mixture was extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine (500 mL). dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (PE / EtOAc = 2 / 1, v / v) to afford 5-bromo-4-methyl-3-nitro-lH-pyrazole as a light yellow solid (6.0 g, 75%).

[1096] 02N O2N

[1097] K / SEMCI, NaH

[1098] N T - N J

[1099] N^BrTHF, rt, 2 h,NAr

[1100]

[1101] SEM

[1102]

[0251] To a stirred solution of 5-bromo-4-methyl-3-nitro-lH-pyrazole (1.0 g, 4.9 mmol. 1.0 eq) in THF (10.0 mL) was added NaH (392 mg, 9.8 mmol, 2.0 eq). The mixture was stirred at 0 °C for 1 h. SEMCI (1.6 g, 9.8 mmol, 2.0 eq) was added to the above mixture and the resulting mixture was stirred at rt for 2 h. The reaction was quenched with H2O (10 mL). The reaction mixture was extracted by with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL) and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (PE / EtOAc = 3 / 1, v / v) to afford 5-bromo-4-methyl-3-nitro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazole as a light yellow solid (1.0 g. 61%).

[1103] OH

[1104] °2N 0, N

[1105] OH N I - Pd(dppf)Cl2, Cs2CO3

[1106] S

[1107]

[1108] EM Dioxane / H2O, 140 °C, 12 h SE ■M0Agent Ref: 16738.0002-00304

[1109]

[0252] A solution of 5-bromo-4-methyl-3-nitro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazole (2.0 g, 5.9 mmol, 1.0 eq), cyclopropylboronic acid (761.1 mg. 8.8 mmol, 1.5 eq), Pd(dppf)Cl2 (431.3 mg, 0.59 mmol, 0.1 eq) and Cs2CO3(3.8 g, 11.8 mmol, 2.0 eq) in dioxane / H2O (40mL / 10 mL) was stirred at 140 °C for 12 h under N2. The reaction was quenched with H2O (50 mL). The reaction mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL) and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (PE / EtOAc = 3 / 1, v / v) to afford 5-cyclopropyl-4-methyl-3-nitro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazole as a white solid (1.0 g, 56%).

[1110] Fe, NH4CI

[1111] EtOH, 80°C, 12 h

[1112]

[1113]

[0253] A solution of 5-cyclopropyl-4-methyl-3-nitro-l-((2-(trimethylsilyl)ethoxy)methyl)-IH-pyrazole (1.0 g, 3.3 mmol, 1.0 eq) and ferric powder (369.6 mg, 6.6 mmol, 2.0 eq) in ethanol (10.0 mL) and saturated NH₄Cl aqueous (10 mL) was stirred at 80 °C for 12 h. The mixture was filtrated to remove ferric powder, and the filtrate was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (PE / EtOAc = 1 / 1, v / v) to afford 5-cyclopropyl-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-amine as a yellow oil (400.1 mg, 44%). LCMS (M+H+) m / z calculated 268.2, found 268.2.

[1114]

[1115]

[0254] To a stirred solution of 5-cyclopropyl-4-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-3-amine (400 mg, 1.5 mmol, 1.0 eq), 7-(4-morpholinophenyl)imidazo[1,2-a]pyridine-3-carboxylic acid (483.9 mg, 1.5 mmol, 1.0 eq) and pyridine (592.5 mg, 7.5 mmol, 5.0 eq) in DCM (10.0 mL) was added POCI3 (688.5 mg, 4.5 mmol, 3.0 eq) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was diluted with water (50 mL). The aqueous layer was extracted with DCM / MeOH (10 / 1. 50 mL x 3) and the combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate,Agent Ref: 16738.0002-00304

[1116] filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (DCM / MeOH = 10 / 1. v / v) to afford N-(5-cyclopropyl-4-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-3-yl)-7-(4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide as a light yellow solid (200.2 mg, 24%). LCMS (M+H⁺) m / z calculated 573.3, found 573.3.

[1117]

[1118]

[0255] A solution of N-(5-cyclopropyl-4-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-3-yl)-7-(4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide (200 mg, 0.35 mmol, 1.0 eq) in TFA (4.0 mL) was stirred at rt for 4 h. The mixture was concentrated under reduced pressure. The resulting residue was dissolved in methanol (4.0 mL) and ammonium hydroxide was added. The mixture was stirred at rt for 2 h and the mixture was concentrated under reduced pressure. The resulting residue was purified by Prep-HPLC to afford N-(5-cyclopropyl-4-methyl-lH-pyrazol-3-yl)-7-(4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide as a white solid (39 mg, 25.3%). LCMS (M+H+) m / z calculated 443.2, found 443.2. ¹H NMR (DMSO-d₆, 400 MHz) δ 12.00 (brs, 1 H), 10.05 (s, 1 H), 9.42 (d, 1 H), 8.52 (brs, 1 H), 7.97 (s, 1 H), 7.77-7.80 (d, 2 H), 7.53 (dd, 1 H), 7.07 (d, 2 H), 3.75-3.77 (m, 4 H), 3.20-3.22 (m, 4 H), 1.91 (s, 3 H), 1.81-1.86 (m, 1 H), 0.88-0.90 (m, 2 H), 0.73-0.77 (m, 2 H).

[1119] Example 27: Preparation of N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-isocyanophenyl)imidazo[l,2-a]pyridine-3-carboxamide

[1120]

[1121]

[0256] A solution of 7-bromo-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide (150 mg, 0.45 mmol, 1.0 eq), (4-isocyanophenyl)boronic acid (99.2 mg, 0.68 mmol, 1.5 eq), Pd(dppf)Cl2 (32.8 mg, 0.045 mmol, 0.1 eq) and Cs2CO3(293.4 mg, 0.9 mmol, 2.0 eq) in dioxane / H₂O (4 mL / 1 mL) was stirred at 110 °C for 4 h under N₂. The reaction was quenched with H2O (10 mL). The reaction mixture was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purifiedAgent Ref: 16738.0002-00304

[1122] by Prep-HPLC to afford N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-isocyanophenyl)imidazo[l,2-a]pyridine-3-carboxamide as a white solid (1.3 mg, 0.8%). LCMS (M+H⁺) m / z calculated 357.1, found 357.1. ¹H NMR (DMSO-d₆, 400 MHz) δ 12.17 (s, 1 H), 10.18 (s, 1 H), 9.52 (d, 1 H), 8.62 (brs, 1 H), 8.24 (s, 1 H), 7.98-8.12 (m, 4 H), 7.63 (d, 1 H), 2.17 (s, 3 H), 1.84 (s, 3 H).

[1123] Example 28: Preparation of 7-(3-chlorophenyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide

[1124] Pd(dppf)Cl2, Cs2CO3,

[1125] Dioxane / H2O, 110 °C, 4 h

[1126]

[1127]

[0257] A solution of 7-bromo-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide (150 mg, 0.45 mmol. 1.0 eq), (3-chlorophenyl)boronic acid (106.1 mg, 0.68 mmol, 1.5 eq), Pd(dppf)Cl2 (32.8 mg, 0.045 mmol, 0.1 eq) and Cs2CO3(293.4 mg, 0.9 mmol, 2.0 eq) in dioxane / H2O (4 mL / 1 mL) was stirred at 110 °C for 4 h under N2. The reaction was quenched with H2O (10 mL). The reaction mixture was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by Prep-HPLC to afford 7-(3-chlorophenyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide as a white solid (11.7 mg, 7.1%). LCMS (M+H+) m / z calculated 366.1, found 366.1. 'H NMR (DMSO-d6, 400 MHz) 5 12.16 (brs, 1 H), 10.15 (s, 1 H), 9.49 (d, 1 H), 8.59 (brs, 1 H), 8.16 (s. 1 H), 7.97 (s. 1 H). 7.87 (d, 1 H), 7.50-7.61 (m. 3 H). 2.17 (s, 3 H), 1.84 (s, 3 H).

[1128] Example 29: Preparation of N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(2-oxo-2H-[l,2'-bipyridin]-5'-yl)imidazo[l,2-a]pyridine-3-carboxamide

[1129]

[1130]

[0258] To a solution of pyridin-2(lH)-one (4.0 g, 42.1 mmol, 1.0 eq) in DMSO (50 mL) was added 5-bromo-2-chloropyridine (8.1 g, 42.1 mmol, 1.0 eq) at 25 °C. The reaction mixture was stirred at 100 °C for 4 h. The reaction mixture was diluted with water (50 mL). The aqueous layer was extracted with EtOAc (50 mL x 3) and the combined organic layers wereAgent Ref: 16738.0002-00304

[1131] washed with brine (50 mL) and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to afford 5'-bromo-2H-[l,2'-bipyridin] -2-one (3.2 g, 32.4%) as a white solid. LCMS (M+H+) m / z calculated 332.1, found 332.4. LCMS (M+H+) m / z calculated 251.0, found 251.1

[1132]

[1133]

[0259] A solution of 5'-bromo-2H-[l,2'-bipyridin]-2-one (251.0 mg, 1.0 mmol, 1.0 eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (381.0 mg, 1.5 mmol, 1.5 eq), KOAc (294.0 mg, 3.0 mmol, 3.0 eq) and Pd(dppf)Cl2 (73.1 mg. 0.1 mmol, 0.1 eq) in dioxane (10 mL) was stirred at 100 °C for 4 h under N2. The mixture was concentrated under reduced pressure to afford 5'-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2H-[l,2'-bipyridin]-2-one (320.0 mg, quant.) as a black solid. LCMS (M+H+) m / z calculated 299.2, found 299.1.

[1134]

[1135]

[0260] A solution of 7-bromo-N-(4.5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide (50.0 mg, 0.15 mmol, 1.0 eq), 5'-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2H-[l,2'-bipyridin]-2-one (66.9 mg, 0.22 mmol, 1.5 eq), Cs2CO3(146.2 mg, 0.45 mmol, 3.0 eq) and Pd(PPh3)4 (17.3 mg, 0.015 mmol, 0.1 eq) in dioxane / H₂O (5 mL / 0.5 mL) was stirred at 100 °C for 2 h under N₂. The mixture was concentrated under reduced pressure, and the resulting residue was purified by Prep-HPLC to afford N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(2-oxo-2H-[l,2'-bipyridin]-5'-yl)imidazo[l,2-a]pyridine-3-carboxamide (17.5 mg, 26.7%) as a white solid. LCMS (M+H+) m / z calculated 426.2, found 426.2.

[1136]

[1137] NMR (DMSO-d6, 400 MHz) 5 12.20 (brs. 1 H). 10.20 (s, 1 H), 9.55 (d, 1 H), 9.14 (s, 1 H), 8.62 (s, 1 H), 8.50 (d, 1 H), 8.32 (s, 1 H), 7.94-7.98 (m, 2 H), 7.69 (d, 1 H), 7.56 (t, 1 H), 6.55 (d. 1 H), 6.40-6.43 (m, 1 H), 2.18 (s, 3 H), 1.85 (s, 3 H).

[1138] Example 30: Preparation of N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(3- (trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamideAgent Ref: 16738.0002-00304

[1139] Pd(PPh3)4, Cs2CO3

[1140] dioxane / H2O, 100 °C, 4 h

[1141]

[1142]

[0261] A solution of 7-bromo-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide (150.0 mg, 0.45 mmol, 1.0 eq), (3-(trifluoromethyl)phenyl)boronic acid (111.0 mg, 0.58 mmol, 1.3 eq), Cs2CO3(438.2 mg, 1.35 mmol, 3.0 eq) and Pd(PPh3)4 (52.0 mg, 0.045 mmol, 0.1 eq) in dioxane / H2O (10 mL / 2 mL) was stirred at 100 °C for 4 h under N2. The mixture was concentrated under reduced pressure and the resulting residue was purified by Prep-HPLC to afford N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(3-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide (13.5 mg, 7.2%) as a white solid. LCMS (M+H+) m / z calculated 400.1, found 400.3. 'H NMR (DMSO-d6, 400 MHz) 5 12.17 (brs, 1 H), 10.17 (s, 1 H), 9.52 (d. 1 H), 8.60 (brs. 1 H). 8.22-8.25 (m, 2 H), 8.12-8.15 (m, 1 H), 7.77-7.81 (m, 2 H), 7.57-7.65 (m, 1 H), 2.17 (s, 3 H), 1.84 (s, 3 H).

[1143] Example 31: Preparation of N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-fluorophenyl)imidazo[l,2-a]pyridine-3-carboxamide

[1144] A / -(45-dimethyl-1 / / -pyrazol-3-yl)-7-(4-fluorophenyl)imidazo[1,2-

[1145]

[1146] a]pyridine-3-carboxamide

[1147]

[0262] N-(4,5-Dimethyl-lH-pyrazol-3-yl)-7-(4-fluorophenyl)imidazo[l,2-a]pyridine-3-carboxamide was prepared as described for N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-(4-morpholinophenyl)imidazo[1,2-a]pyridine-3-carboxamide. LCMS (M+H+) m / z calculated 350.1, found 350.2. ’H NMR (400 MHz, DMSO-d6) 5 12.19 (brs, 1 H), 10.14 (s, 1 H), 9.50 (d, 1 H), 8.55 (s, 1 H), 8.07 (s, 1 H), 7.93-7.97 (m, 2 H), 7.55 (d, 1 H), 7.37 (t, 2 H), 2.16 (s, 3 H), 1.84 (s. 3 H).

[1148] Example 32: Preparation of N-(4.5-dimethyl-lH-pyrazol-3-yl)-7-(4-methoxyphenyl)imidazo[l,2-a]pyridine-3-carboxamideAgent Ref: 16738.0002-00304

[1149]

[1150]

[0263] N-(4,5-Dimethyl-lH-pyrazol-3-yl)-7-(4-methoxyphenyl)imidazo[l,2-a]pyridine-3-carboxamide was prepared as described forN-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide. LCMS (M+H+) m / z calculated 362.2, found 362.4. 'H NMR (400 MHz, DMSO-d6) 5 12.04 (brs. 1 H). 10.10 (s. 1 H). 9.45 (d, 1 H), 8.55 (s, 1 H), 8.00 (s, 1 H), 7.84-7.86 (m, 2 H), 7.53 (d, 1 H), 7.07-7.10 (m, 2 H), 3.82 (s, 3 H), 2.16 (s, 3 H), 1.84 (s, 3 H).

[1151] Example 33: Preparation of 7-(4-cyclopropylphenyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide

[1152]

[1153]

[0264] 7-(4-Cyclopropylphenyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide was prepared as described for N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide. LCMS (M+H+) m / z calculated 372.2, found 372.3. 'H NMR (400 MHz, DMSO-^) 8 11.98 (brs, 1 H), 10.11 (s, 1 H), 9.46 (d, 1 H), 8.56 (s, 1 H), 8.02 (s, 1 H), 7.76-7.80 (m, 2 H), 7.53 (d, 1 H), 7.21-7.32 (m, 2 H), 2.16 (s, 3 H), 1.97-2.01 (m, 1 H), 1.84 (s, 3 H), 0.98-1.03 (m, 2 H), 0.73-0.76 (m, 2 H).

[1154] Example 34: Preparation of N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-(2-oxopyridin-l(2H)-yl)phenyl)imidazo[l,2-a]pyridine-3-carboxamideAgent Ref.: 16738.0002-00304

[1155] H

[1156] / V-(4,5-dimethyl-1H-pyrazol-3-yl)-7-(4-(2- oxopyridin-1 (2H)-yl)phenyl)imidazo[1 2-

[1157]

[1158] a]pyridine-3-carboxamide

[1159]

[0265] N-(4,5-Dimethyl-lH-pyrazol-3-yl)-7-(4-(2-oxopyridin-l(2H)-yl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide was prepared as described forN-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide. LCMS (M+H+) m / z calculated 425.2, found 425.3. 'H NMR (400 MHz, DMSO-d6) 5 12.17 (s, 1 H), 10.16 (s, 1 H), 9.52 (d, 1 H), 8.60 (s, 1 H), 8.17 (s, 1 H), 8.02-8.04 (m, 2 H), 7.52-7.86 (m, 5 H), 6.51 (d, 1 H), 6.36 (t, 1 H), 2.17 (s. 3 H), 1.85 (s, 3 H).

[1160] Example 35: Preparation of 7-(3-cyanophenyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide

[1161] Pd(PPh3)4, Cs2CO3

[1162] Dioxane / H2O, 100 °C, 4 h

[1163]

[1164]

[0266] A solution of 7-bromo-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide (150.0 mg, 0.45 mmol, 1.0 eq), (3-cyanophenyl)boronic acid (85.2 mg, 0.58 mmol, 1.3 eq), Cs2CO3(438.2 mg, 1.35 mmol, 3.0 eq) and Pd(PPh3)4 (52.0 mg, 0.045 mmol, 0.1 eq) in dioxane / H2O (10 mL / 2 mL) was stirred at 100 °C for 4 h under N2. The mixture was concentrated under reduced pressure, and the resulting residue was purified by Prep-HPLC to afford N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(3-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide (13.5 mg, 7.2%) as a white solid. LCMS (M+H+) m / z calculated 357.1, found 357.4. *HNMR (DMSO-d6, 400 MHz) 5 12.16 (brs, 1 H), 10.16 (brs, 1 H), 9.52 (d, 1 H), 8.51 (s, 1 H), 8.42 (s, 1 H), 8.24-8.26 (m, 2 H), 7.91-7.93 (m, 1 H), 7.73 (t, 1 H), 7.63-7.65 (m, 1 H), 2.17 (s, 3 H), 1.85 (s, 3 H).

[1165] Example 36: Preparation of N-(5-(hydroxymethyl)-4-methyl-lH-pyrazol-3-yl)-7-(4-morpholinophenyl) imidazo [l,2-a]pyridine-3-carboxamideAgent Ref: 16738.0002-00304

[1166] 0, N

[1167] Pd(PPh3)4, Cs2CO3

[1168]

[1169] SEM Dioxane / H2O, 100 " C, 12 h

[1170]

[0267] To a solution of 5-bromo-4-methyl-3-nitro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazole (1.5 g, 4.5 mmol, 1.0 eq) in Dioxane / H2O (20 mL / 5 mL) were added potassium (tert-butoxymethyl)trifluoroborate (1.3 g, 6.8 mmol, 1.5 eq), Pd(PPh3)4 (520.0 mg, 0.45 mmol, 0.1 eq) and Cs2CO3(4.4 g, 1.35 mmol, 3.0 eq). The mixture was stirred at 100 °C for 12 h. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (PE / EtOAc = 2 / 1, v / v) to afford 5-(tert-butoxymethyl)-4-methyl-3-nitro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazole (1.2 g, 85%) as a white solid. LCMS (M+H+) m / z calculated 344.2, found 344.5.

[1171] Fe, NH4CI / EtOH 80 °C, 5 h

[1172]

[1173]

[0268] To a solution of 5-(tert-butoxymethyl)-4-methyl-3-nitro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrazole (1.5 g, 4.4 mmol, 1.0 eq) in EtOH (10 mL) and sat. NH4Cl solution (10 mL)were added Fe (740.0 mg. 13.2 mmol, 3.0 eq). The mixture was stirred at 80 °C for 5 h. The reaction mixture was diluted with water (50 mL), and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (PE / EtOAc = 1 / 1, v / v) to afford 5-(tert-butoxymethyl)-4-methyl-l -((2-(trimethylsilyl)ethoxy )methyl)- lH-pyrazol-3-amine (700 mg, 50%) as ayellow oil. LCMS (M+H+) m / z calculated 314.2, found 314.5.

[1174]

[1175]

[0269] To a solution of 5-(tert-butoxymethyl)-4-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-3 -amine (200 mg, 0.65 mmol, 1.0 eq) in DMF (5 mL) were added 7-(4-Agent Ref: 16738.0002-00304

[1176] morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxylic acid (189.0 mg, 0.59 mmol, 0.9 eq), HATU (370.0 mg, 0.98 mmol. 1.5 eq) and DIEA (253.0 mg, 1.96 mmol, 3.0 eq). The mixture was stirred at 80 °C for 2 h. The reaction mixture was diluted with water (30 mL), filtered to afford the filter cake. The filter cake was dried over vacuum to afford N-(5-(tert-butoxymethyl)-4-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-3-yl)-7-(4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide (180.0 mg, 45%) as ayellow solid. LCMS (M+H+) m / z calculated 619.3, found 619.5.

[1177]

[1178]

[0270] To a solution ofN-(5-(tert-butoxymethyl)-4-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-3-yl)-7-(4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide (200.0 mg, 0.3 mmol, 1.0 eq) in DCM (1.5 mL) was added TFA (3 mL). The mixture was stirred at rt for 1 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by Prep-HPLC to afford N-(5-(hydroxymethyl)-4-methyl-lH-pyrazol-3-yl)-7-(4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide (9.1 mg, 4.1%) as a white solid. LCMS (M+H+) m / z calculated 433.2, found 433.5. NMR (400 MHz, DMSO-cL) 5 12.38 (s, 1 H), 10.11 (s, 1 H), 9.43 (d, 1 H), 8.54 (brs, 1 H), 7.98 (s, 1 H), 7.78-7.80 (m, 2 H), 7.54 (dd, 1 H), 7.06-7.08 (m, 2 H), 5.19 (brs, 1 H). 4.43-4.45 (m, 2 H), 3.72-3.83 (m, 4 H), 3.16-3.25 (m. 4 H), 1.90 (s. 3 H).

[1179] Example 37: Preparation ofN-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-(2-oxopyrimidin-l(2H)-yl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide

[1180] H?N

[1181] L JI TFA, 70°C, 4 h L JI

[1182]

[1183] — Br — Br

[1184]

[0271] The mixture of 1 -(4-bromophenyl)urea (10.0 g, 46.7 mmol, 1.0 eq) and 1, 1,3,3-tetramethoxypropane (7.6 g, 46.7 mmol. 1.0 eq) in TFA (40.0 mL) was stirred at 70 °C for 4 h. The mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (DCM / MeOH = 10 / 1, v / v) to afford l-(4-bromophenyl)pyrimidin-2(lH)-one as a white solid (2.0 g, 17.2%). LCMS (M+H+) m / z calculated 251.0, found 251.1.Agent Ref: 16738.0002-00304

[1185]

[1186]

[0272] A mixture of l-(4-bromophenyl)pyrimidin-2(lH)-one (2.0 g, 8.0 mmol. 1.0 eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (3.0 g, 12.0 mmol, 1.5 eq), Pd(dppf)Cl2 (584.8 mg, 0.8 mmol, 0.1 eq) and KO Ac (1.5 g, 16 mmol, 2.0 eq) in dioxane (20 mL) was stirred at 100 °C for 4 h under N2. The reaction was quenched with H2O (50 mL). The reaction mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL) and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (DCM / MeOH = 10 / 1, v / v) to afford l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2(lH)-one as a light yellow solid (1.0 g, 42%). LCMS (M+H+) m / z calculated 299.2, found 299.2.

[1187]

[1188]

[0273] A mixture of l-(4-(4.4.5.5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2(lH)-one (300 mg, 1.0 mmol, 1.0 eq), 7-bromo-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide (333.0 mg, 1.0 mmol, 1.0 eq), Pd(dppf)C12 (73.1 mg, 0.1 mmol, 0.1 eq) and Cs2CO3(652 mg, 2.0 mmol, 2.0 eq) in dioxane (10.0 mL) and H2O (2.0 mL) was stirred at 100 °C for 2 h under N2. The reaction was quenched with H2O (50 mL). The reaction mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50.0 mL) and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by Prep-HPLC to afford N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-(2-oxopyrimidin-l(2H)-yl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide as a light yellow solid (1.7 mg. 0.4%). LCMS (M+H ) m / z calculated 426.2, found 426.2. 'H NMR (DMSO-d6, 400 MHz) 6 12.17 (brs, 1 H), 10.16 (s, 1 H), 9.52 (d, 1 H), 8.69-8.71 (m, 1 H), 8.60 (brs, 1 H), 8.26-8.28 (m, 1 H), 8.19 (d, 1 H), 8.04-8.06 (m, 2 H), 7.61-7.65 (m, 3 H), 6.56-6.59 (m, 1 H), 2.17 (s, 3 H), 1.84 (s. 3 H).Agent Ref: 16738.0002-00304

[1189] Example 38: Preparation of N-(4-(hydroxymethyl)-5-methyl-lH-pyrazol-3-yl)-7-(4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide

[1190]

[1191]

[0274] N-(4-(Hydroxymethyl)-5-methyl-lH-pyrazol-3-yl)-7-(4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide was prepared as described for N-(5-(hydroxymethyl)-4-methyl-lH-pyrazol-3-yl)-7-(4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide. LCMS (M+H+) m / z calculated 433.2, found 433.3.rH NMR (400 MHz, DMSO-d6) 5 12.33 (brs. 1 H). 10.21 (brs, 1 H), 9.40 (d, 1 H). 8.54 (s, 1 H), 7.98 (s, 1 H), 7.78-7.80 (m, 2 H), 7.54 (dd, 1 H), 7.06-7.08 (m, 2 H), 4.45 (brs, 1 H), 4.28 (d, 2 H), 3.75-3.78 (m, 4 H), 3.20-3.23 (m, 4 H), 2.25 (s, 3 H).

[1192] Example 39: Preparation of N-(5-(fluoromethyl)-4-methyl-lH-pyrazol-3-yl)-7-(4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide

[1193]

[1194]

[0275] To a solution of N-(5-(hydroxymethyl)-4-methyl-lH-pyrazol-3-yl)-7-(4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide (20.0 mg, 0.04 mmol, 1.0 eq) in DCM (6 mL) was added DAST (6 drops) at 0 °C for 2 h under N2. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by Prep-HPLC to afford N-(5-(fluoromethyl)-4-methyl-lH-pyrazol-3-yl)-7-(4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide (2.0 mg, 10%) as a white solid. LCMS (M+H+) m / z calculated 435.2, found 435.5. 'H NMR (400 MHz, DMSO-d6) 5 10.25 (brs. 1 H). 9.42 (d, 1 H), 8.55 (s, 1 H), 8.46 (s, 1 H), 7.99 (s, 1 H), 7.80 (d, 2 H), 7.56 (d, 1 H), 7.07 (d. 2 H). 5.44 (s, 1 H), 5.31 (s, 1 H), 3.74-3.81 (m, 4 H), 3.20-3.23 (m, 4 H), 1.98 (s, 3 H).Agent Ref.: 16738.0002-00304

[1195] Example 40: Preparation of N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l,3-dimethyl-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide

[1196]

[1197]

[0276] 7-Bromo-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide was converted to N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l,3-dimethyl-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide as described for N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide. LCMS (M+H+) m / z calculated 350.2, found 350.3. 'H NMR (DMSO-tfc 400 MHz) 512.15 (s, 1 H), 10.06 (s, 1 H), 9.40 (d, 1 H), 8.50 (brs, 1 H), 8.18 (s, 1 H), 7.69 (s, 1 H), 7.29 (dd, 1 H), 3.82 (s, 3 H), 2.41 (s, 3 H). 2.16 (s, 3 H), 1.83 (s, 3 H).

[1198] Example 41: Preparation of N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-methyl-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide

[1199]

[1200]

[0277] 7-Bromo-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide was converted to N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-methyl-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide as described for N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-(trifluoromethyl)phenyl)imidazo[1.2-a]pyridine-3-carboxamide. LCMS (M+H+) m / z calculated 336.2. found 336.2. 'H NMR (DMSO-t / e, 400 MHz) 5 12.14 (s, 1 H), 10.05 (s, 1 H), 9.37 (d, 1 H), 8.49 (brs, 1 H), 8.38 (s, 1 H), 8.10 (s, 1 H), 7.95 (s, 1 H), 7.41 (dd, 1 H), 3.89 (s, 3 H), 2.16 (s, 3 H), 1.83 (s, 3 H).

[1201] Example 42: Preparation of N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(2-hydroxy-2-methylpropyl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide

[1202]

[1203] Agent Ref: 16738.0002-00304

[1204]

[0278] 7-Bromo-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide was converted to N-(4.5-dimethyl-lH-pyrazol-3-yl)-7-(l-(2-hydroxy-2-methylpropyl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide as described for N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide. LCMS (M+H+) m / z calculated 394.2, found 394.3. ‘HNMR (DMSO- 400 MHz) 5 12.14 (s, 1 H), 10.05 (s, 1 H), 9.37 (d, 1 H), 8.49 (brs, 1 H), 8.33 (s, 1 H), 8.13 (s, 1 H), 7.97 (s, 1 H), 7.44 (dd, 1 H), 4.77 (s, 1 H), 4.06 (s, 2H), 2.16 (s, 3 H), 1.83 (s. 3 H), 1.10 (s. 6 H).

[1205] Examples 43 and 44: Preparation of N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(2-hydroxy-2-methylpropyl)-3-methyl-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide and N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(2-hydroxy-2-methylpropyl)-5-methyl-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide

[1206]

[1207]

[0279] A solution of 4-(4,4,5,5-tetramethyl-1.3.2-dioxaborolan-2-yl)-lH-pyrazole (7.0 g, 33.6 mmol, 1.0 eq), 2,2-dimethyloxirane (2.90 g, 40.3 mmol, 1.2 eq) and Cs2CO3(10.9 g, 33.6 mmol, 1.0 eq) in DMF (lOOmL) was stirred at 100 °C for 3 h under N2. The mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography on silica gel (DCM / MeOH = 20 / 1, v / v) to afford a mixture of 2-methyl-l-(5-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl)propan-2-ol and 2-methyl-l-(3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l -yl)propan-2-ol (7.0 g, 80.0%) as a yellow oil. LCMS (M+H+) m / z calculated 281.2, found 281.2.

[1208]

[1209]

[0280] 7-Bromo-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide was converted to a mixture ofN-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(2-hydroxy-2-methylpropyl)-3-methyl-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide and N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(2-hydroxy-2-methylpropyl)-5-methyl-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide as described for N-(4,5-dimethyl-lH-pyrazol-3-yl)-Agent Ref: 16738.0002-00304

[1210] 7 -( 1 -(2-hydroxy-2-methylpropyl)- lH-pyrazol-4-yl)imidazo[ 1,2-a]pyridine-3 -carboxamide. A mixture ofN-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(2-hydroxy-2-methylpropyl)-3-methyl-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide and N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(2-hydroxy-2-methylpropyl)-5-methyl-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide was separated by chiral column chromatography (Column: CHIRALPAK IK, mobile phase: hexane / EtOH / DEA = 50 / 50 / 0.1(V / V / V)) to affordN-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(2-hydroxy-2-methylpropyl)-3-methyl-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide and N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(2-hydroxy-2-methylpropyl)-5-methyl-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide. N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(2-hydroxy-2-methylpropyl)-3-methyl-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide: LCMS (M+H+) m / z calculated 408.2, found 408.4. 'H NMR (DMSO- 400 MHz) 5 12.16 (s, 1 H), 10.06 (s, 1 H), 9.39 (d, 1 H), 8.51 (brs, 1 H), 8.14 (s, 1 H), 7.71 (s, 1 H), 7.32 (dd, 1 H), 4.75 (s, 1 H), 3.98 (s, 2 H), 2.43 (s, 3 H), 2.17 (s, 3 H), 1.83 (s, 3 H), 1.11 (s, 6 H); N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(2-hydroxy-2-methylpropyl)-5-methyl-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide: LCMS (M+H ) m / z calculated 408.2, found 408.4. ‘HNMR (DMSO-rfc 400 MHz) 5 12.16 (s, 1 H), 10.06 (s, 1 H), 9.41 (d, 1 H), 8.51 (brs, 1 H), 7.87 (s, 1 H), 7.70 (s, 1 H), 7.32 (dd, 1 H), 4.70 (s, 1 H), 4.05 (s, 2 H), 2.49 (s, 3 H), 2.17 (s, 3 H), 1.83 (s, 3 H), 1.15 (s, 6 H).

[1211] Example 45: Preparation ofN-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide

[1212]

[1213]

[0281] 7-Bromo-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide was converted to N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide as described for N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide. LCMS (M+H+) m / z calculated 406.2, found 406.4. ‘HNMR (DMSO-d6, 400 MHz) 5 12.16 (s, 1 H), 10.06 (s, 1 H), 9.37 (d, 1 H), 8.54 (s, 1 H), 8.49 (brs, 1 H), 8.15 (s, 1 H), 7.99 (s, 1 H), 7.44 (dd, 1 H), 4.41-4.46 (m, 1 H), 3.97-4.01 (m, 2 H), 3.46-3.53 (m, 2 H), 2.17 (s, 3 H), 1.96-2.03 (m. 4H). 1.84 (s. 3 H).Agent Ref: 16738.0002-00304

[1214] Example 46: Preparation of7-(l-cyclopropyl-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide

[1215]

[1216]

[0282] 7-Bromo-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide was converted to 7-(l-cyclopropyl-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide as described for N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide. LCMS (M+H+) m / z calculated 362.2, found 362.3. 'H NMR (DMSO-d6, 400 MHz) 512.15 (s, 1 H), 10.05 (s, 1 H), 9.37 (d, 1 H), 8.49 (s, 2 H), 8.10 (s, 1 H), 7.97 (s, 1 H), 7.44 (dd, 1 H), 3.75-3.79 (m, 1 H), 2.16 (s, 3 H), 1.84 (s, 3 H), 0.99-1.12 (m, 4 H).

[1217] Example 47: Preparation of N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-isopropyl-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide

[1218]

[1219]

[0283] 7-Bromo-N-(4.5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide was converted to N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-isopropyl-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide as described for N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide. LCMS (M+H+) m / z calculated 364.2. found 364.3. 'H NMR (DMSO-tfe, 400 MHz) 5 12.15 (s, 1 H), 10.05 (s, 1 H). 9.37 (d, 1 H), 8.49 (s, 2 H), 8.10 (s, 1 H), 7.97 (s. 1 H). 7.44 (dd, 1 H), 4.51-4.55 (m. 1 H).

[1220] 2.16 (s, 3 H), 1.84 (s, 3 H), 1.47 (d, 6 H).

[1221] Example 48: Preparation of N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-phenyl-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide

[1222]

[1223] Agent Ref: 16738.0002-00304

[1224]

[0284] 7-Bromo-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide was converted to N-(4.5-dimethyl-lH-pyrazol-3-yl)-7-(l-phenyl-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide as described for N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide. LCMS (M+H+) m / z calculated 398.2, found 398.3. 'H NMR (DMSO-d6, 400 MHz) 512.15 (brs, 1 H), 10.10 (s, 1 H), 9.43 (d, 1 H), 9.27 (s, 1 H), 8.53 (brs, 1 H), 8.47 (s, 1 H), 8.15 (s, 1 H), 7.91 (d. 2H). 7.54-7.59 (m, 3 H), 7.37 (t, 1 H), 2.17 (s, 3 H), 1.84 (s, 3 H).

[1225] Example 49: Preparation of N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(pyrrolidin-3-yl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide

[1226]

[1227]

[0285] 7-Bromo-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide was converted to tert-butyl 3-(4-(3-((4,5-dimethyl-lH-pyrazol-3-yl)carbamoyl)imidazo[ 1,2-a]pyridin-7-yl)-lH-pyrazol-l-yl)pyrrolidine-l-carboxylate as described for N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide.

[1228] LCMS (M+H+) m / z calculated 491.2, found 491.3.

[1229]

[1230]

[0286] To a stirred solution of tert-butyl 3-(4-(3-((4,5-dimethyl-lH-pyrazol-3-yl)carbamoyl)imidazo[l,2-a]pyridin-7-yl)-lH-pyrazol-l-yl)pyrrolidine-l-carboxylate (100.2 mg, 0.20 mmol, 1.0 eq) in MeOH (10 mL) was added HC1 in Dioxane (4 M, 5 mb). The reaction was stirred at rt for 2 h. The mixture was concentrated under reduced pressure and the resulting residue was purified by Prep-HPLC to afford N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(pyrrolidin-3-yl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide as a white solid (75.0 mg, quant.). LCMS (M+H+) m / z calculated 391.2, found 391.3. 'H NMR (DMSO-d6, 400 MHz) 5 10.07 (s. 1 H). 9.37 (d, 1 H), 8.50 (s, 2 H), 8.13 (s, 1 H), 7.98 (s, 1 H), 7.44 (dd, 1 H), 4.81-4.86 (m, 1 H), 3.14-3.20 (m, 1 H), 2.98-3.10 (m, 2 H), 2.83-2.90 (m, 1 H), 2.19-2.25 (m, 1 H), 2.16 (s, 3 H), 2.04-2.11 (m, 1 H), 1.84 (s, 3 H).

[1231] IllAgent Ref: 16738.0002-00304

[1232] Example 50: Preparation of N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide

[1233]

[1234]

[0287] N-(4,5-Dimethyl-lH-pyrazol-3-yl)-7-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide was prepared as described forN-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(pyrrolidin-3-yl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide. LCMS (M+H ) m / z calculated 405.2, found 405.3. 'H NMR (DMSO- 400 MHz) 5 10.71 (s, 1 H), 9.54 (d, 1 H), 9.28 (d, 1 H), 9.12 (d, 1 H), 8.96 (s, 1 H), 8.75 (s, 1 H), 8.33 (s, 1 H), 8.19 (s, 1 H), 7.89 (dd, 1 H), 4.55-4.63 (m, 1 H), 3.38-3.42 (m, 2 H), 3.06-3.15 (m, 2H), 2.22-2.30 (m, 4 H), 2.19 (s, 3 H), 1.87 (s, 3 H).

[1235] Example 51: Preparation of 7-(l-(4-cyanophenyl)-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide

[1236]

[1237]

[0288] 7-Bromo-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide was converted to 7-(l-(4-cyanophenyl)-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide as described for N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide. LCMS (M+H+) m / z calculated 423.2, found 423.4. 'H NMR (DMSO-tfc, 400 MHz) 512.16 (brs, 1 H), 10.11 (s, 1 H), 9.44 (d, 1 H), 9.43 (s, 1 H), 8.59 (s, 1 H), 8.54 (brs, 1 H), 8.04-8.18 (m, 5 H), 7.55 (dd, 1 H), 2.17 (s. 3 H). 1.84 (s, 3 H).

[1238] Example 52: Preparation of N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(l-methylpiperidin-4-yl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide

[1239]

[1240] Agent Ref: 16738.0002-00304

[1241]

[0289] 7-Bromo-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide was converted to N-(4.5-dimethyl-lH-pyrazol-3-yl)-7-(l-(l-methylpiperidin-4-yl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide as described for N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide. LCMS (M+H+) m / z calculated 419.2, found 419.3. 'H NMR (DMSO- 400 MHz) 5 10.05 (s, 1 H), 9.37 (d, 1 H), 8.51 (s, 1 H), 8.49 (brs, 1 H), 8.19 (s, 1 H), 8.14 (s, 1 H), 7.98 (s. 1 H). 7.44 (dd.

[1242] 1 H). 4.14-4.19 (m, 1 H), 2.90-2.94 (m, 2 H), 2.26 (s, 3 H), 2.12-2.19 (m. 5 H). 1.98-2.08 (m, 4H), 1.83 (s, 3 H).

[1243] Example 53: Preparation of N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(l-methylpyrrolidin-3-yl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide

[1244]

[1245]

[0290] To a solution of N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(pyrrolidin-3-yl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide (40.0 mg. 0.10 mmol, 1.0 eq) in DCM / MeOH (10 mL / 10 mL) were added HCHO (1 mL, 37% in water), NaBH(OAc)s (108.7 mg, 0.5 mmol, 5.0 eq) and HOAc (61.5 mg, 1.0 mmol, 10.0 eq). The mixture was stirred at rt for 15 h. The reaction mixture was diluted with water (100 mL), and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by Prep-HPLC to afford N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(l-methylpyrrolidin-3-yl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide (33.3 mg, 80.5%) as a yellow solid. LCMS (M+H+) m / z calculated 405.2, found 405.3. 'H NMR (DMSO-d6, 400 MHz) 512.07 (brs, 1 H), 10.05 (s, 1 H), 9.44 (brs, 1 H), 8.50 (brs, 2 H), 8.12 (s, 1 H), 7.97 (s, 1 H), 7.44 (dd, 1 H), 4.88-4.95 (m, 1 H), 2.75-2.90 (m, 3 H), 2.34-2.54 (m, 2 H), 2.31 (s, 3 H), 2.15 (brs, 4 H), 1.84 (s, 3 H).

[1246] Example 54: Preparation of 7-(l-cyclopropyl-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide

[1247]

[1248] Agent Ref.: 16738.0002-00304

[1249]

[0291] To a stirred solution of ethyl 7-bromoimidazo[l,2-a]pyridine-3-carboxylate (1.0 g, 3.7 mmol, 1.0 eq) and 4-methyl-lH-pyrazol-3-amine (360.6 mg, 3.7 mmol. 1.0 eq) in tolune (30 mL) was added Al(Me)? (2 M in tolune, 5.6 mL, 11.2 mmol, 3.0 eq) at 0 °C under N2. The reaction mixture was stirred at 80 °C for 15 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography on silica gel (PE / EA = 1 / 1, v / v) to afford 7-bromo-N-(4-methyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide as ayellow solid (1.0 g, 84.0%). LCMS (M+H+) m / z calculated 320.0, found 320.1.

[1250]

[1251]

[0292] 7-Bromo-N-(4-methyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide was converted to 7-(l-cyclopropyl-lH-pyrazol-4-yl)-N-(4-methyl-lEI-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide as described for N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide. LCMS (M+H+) m / z calculated 348.2, found 348.3.JH NMR (DMSO-< A. 400 MHz) 5 12.37 (s, 1 H), 10.10 (s, 1 H), 9.37 (d, 1 H), 8.50 (s, 2 H), 8.11 (s, 1 H), 7.97 (s, 1 H), 7.52 (s, 1 H), 7.44 (dd, 1 H), 3.75-3.79 (m, 1 H), 1.94 (s, 3 H), 0.99-1.14 (m, 4 H).

[1252] Example 55: Preparation of 7-(l-isopropyl-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3 -carboxamide

[1253]

[1254]

[0293] 7-Bromoimidazo[l,2-a]pyridine-3-carboxylic acid was converted to 7-(l-isopropyl-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxylic acid as described for N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide.

[1255] LCMS (M+H+) m / z calculated 271.1, found 271.3.

[1256]

[1257] Agent Ref.: 16738.0002-00304

[1258]

[0294] 7-(l-Isopropyl-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxylic acid was converted to 7-(l-isopropyl-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide as described for N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(lH-pyrazol-5-yl)imidazo[l,2-a]pyridine-3-carboxamide. LCMS (M+H+) m / z calculated 350.2, found 350.3. *H NMR (DMSO-d6, 400 MHz) 5 12.37 (s, 1 H), 10.10 (s, 1 H), 9.37 (d, 1 H), 8.50 (s, 2H), 8.11 (s. 1 H), 7.97 (s, 1 H), 7.52 (s, 1 H), 7.44 (dd, 1 H), 4.51-4.55 (m, 1 H), 1.94 (s, 3 H). 1.47 (d, 6H).

[1259] Example 56: Preparation of N-(lH-indazol-3-yl)-7-(l-isopropyl-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3 -carboxamide

[1260]

[1261]

[0295] 7-(l-Isopropyl-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxylic acid was converted to N-(lH-indazol-3-yl)-7-(l-isopropyl-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide as described for N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(lH-pyrazol-5-yl)imidazo[l,2-a]pyridine-3-carboxamide. LCMS (M+H+) m / z calculated 386.2, found 386.3. 'H NMR (DMSO-d6, 400 MHz) 5 12.80 (s, 1 H), 10.82 (s, 1 H), 9.42 (d, 1 H), 8.65 (s, 1 H), 8.52 (s, 1 H), 8.14 (s, 1 H), 8.01 (s, 1 H), 7.81 (d, 1 H), 7.46-7.51 (m, 2H), 131 (t, 1 H), 7.09 (t, 1 H), 4.51-4.55 (m, 1 H), 1.47 (d, 6H).

[1262] Example 57: Preparation of N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-((3S,4R)-4-fluoropyrrolidin-3-yl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide

[1263]

[1264]

[0296] To a solution of tert-butyl (3R,4R)-3-fluoro-4-hydroxypyrrolidine-l -carboxylate (205.0 mg, 1.0 mmol, 1.0 eq) in dry DCM (5 mL) were added pyridine (237.0 mg, 3 mmol, 3.0 eq) and Tf2O (564.3 mg, 2.0 mmol, 2.0 eq) at 0 °C. The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with water (100 mL) and extracted with DCM (2 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford tert-butyl (3R,4R)-3-fluoro-4-(((trifluoromethyl)sulfonyl)oxy)pyrrolidine-l-carboxylate (250 mg, quant.).Agent Ref: 16738.0002-00304

[1265]

[1266]

[0297] To a solution of 7-bromo-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide (2.6 g, 7.8 mmol, 1.0 eq) in dry' THF (50 mL) was added NaH (474.0 mg, 9.36 mmol, 1.2 eq) at 0 °C. The reaction mixture was stirred at 25 °C for 0.5 h. Then was added SEMCI (474.0 mg, 9.36 mmol, 1.2 eq). The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (PE / EtOAc = 3 / 1, v / v) to afford 7-bromo-N-(4,5-dimethyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide (1.3 g, 54.2%).

[1267]

[1268]

[0298] A solution of 7-bromo-N-(4,5-dimethyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide (1.0 g. 2.15 mmol. 1.0 eq), 4-(4.4.5.5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (627.2 mg, 3.2 mmol, 1.5 eq), Cs2CO3(1.4 g, 4.3 mmol, 2.0 eq) and Pd(dppf)Cl2 (146.2 mg, 0.2 mmol, 0.1 eq) in dioxane (15 mL) and H2O (3 mL) was stirred at 100 °C for 5 h under N2. The mixture was concentrated under reduced pressure and the resulting residue was purified by column chromatography on silica gel (PE / EtOAc = 2 / 1, v / v) to afford N-(4,5-dimethyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-3-yl)-7-(lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide. LCMS (M+H+) m / z calculated 452.2, found 452.6.

[1269]

[1270]

[0299] A solution of N-(4.5-dimethyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-3-yl)-7-(lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide (100.0 mg, 0.2 mmol, 1.0 eq),Agent Ref: 16738.0002-00304

[1271] tert-butyl (3R,4S)-3-fluoro-4-(((trifluoromethyl)sulfonyl)oxy)pyrrolidine-l-carboxylate (134.8 mg, 0.4 mmol, 2.0 eq). Cs2CO3(130.0 mg, 0.4 mmol, 2.0 eq) in DMF (5 mL) and was stirred at 25 °C for 16 h under N2. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (PE / EtOAc = 1 / 1, v / v) to afford tert-butyl (3S,4R)-3-(4-(3-((4,5-dimethyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-3-yl)carbamoyl)imidazo[l,2-a]pyridin-7-yl)-lH-pyrazol-l-yl)-4-fluoropyrrolidine-l-carboxylate (63.2 mg, 80.0%) as a yellow solid. LCMS (M+H+) m / z calculated 639.3, found 639.7.

[1272]

[1273]

[0300] A solution of tert-butyl (3S,4R)-3-(4-(3-((4,5-dimethyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-3-yl)carbamoyl)imidazo[l,2-a]pyridin-7-yl)-lH-pyrazol-l-yl)-4-fluoropyrrolidine-l -carboxylate (100.0 mg, 0.16 mmol, 1.0 eq) in DCM (2 mL) was added TFA (2mL). The mixture was stirred at rt for 2 h. The solvent was partially concentrated under reduced pressure. The resulting residue was purified by Pre-HPLC to afford N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-((3S,4R)-4-fluoropyrrolidin-3-yl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide (15 mg, 14%). LCMS (M+H+) m / z calculated 409.2, found 409.0. 'H NMR (400 MHz, DMSO-cL) 5 10.06 (s, 1 H), 9.37 (d, 1 H), 8.53 (s, 1 H), 8.50 (s, 1 H). 8.18 (s, 1 H), 8.00 (s, 1 H), 7.46 (dd, 1 H), 5.17-5.34 (m, 1 H), 4.76-4.84 (m, 1 H), 3.64-3.89 (m, 1 H), 3.35-3.41 (m, 2 H), 3.24-3.27 (m. 1 H), 3.02-3.13 (m, 1 H), 2.16 (s, 3 H), 1.83 (s, 3 H).

[1274] Example 58: Preparation of N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-((3S,4R)-4-fluoro-l-methylpyrrolidin-3-yl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide

[1275]

[1276] Agent Ref: 16738.0002-00304

[1277]

[0301] N-(4,5-Dimethyl-lH-pyrazol-3-yl)-7-(l-((3S,4R)-4-fluoro-l-methylpyrrolidin-3-yl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide was prepared as described for N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(l-methylpyrrolidin-3-yl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide. LCMS (M+H+) m / z calculated 423.2, found 423.0.

[1278]

[1279] NMR (400 MHz, DMSO-cL) 6 10.07 (s, 1 H), 9.37 (d, 1 H), 8.52 (s, 1 H), 8.50 (s, 1 H), 8.17 (s, 1 H), 8.02 (s, 1 H). 7.46 (dd, 1 H), 5.20-5.36 (m, 1 H), 4.99-5.10 (m, 1 H), 3.20-3.27 (m, 1 H), 2.97-3.14 (m, 2 H), 2.77-2.89 (m, 1 H), 2.39 (s, 3 H), 2.16 (s. 3 H), 1.83 (s. 3 H).

[1280] Example 59: Preparation of N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(lH-pyrazol-5-yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[1281]

[1282]

[0302] To a solution of ethyl 6-bromopyrazolo[l,5-a]pyridine-3-carboxylate (5.0 g, 18.5 mmol, 1.0 eq) and 4,5-dimethyl-lH-pyrazol-3-amine ( 4.32 g, 39 mmol, 2.0 eq) in tolune (30 mL) was added Al Me? (18.5 mL, 2M in tolune, 2.0 eq) at 0 °C under N2. The reaction mixture was heated to 110 °C and stirred for 12 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (PE / EtOAc = 1 / 1, v / v) to afford ethyl 6-bromo-N-(4,5-dimethyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide (3.1 g, 50%) as a white solid. LCMS (M+H+) m / z calculated 334.0, found 335.1.

[1283] B'OH

[1284]

[1285]

[0303] A solution of ethyl 6-bromo-N-(4,5-dimethyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide (50.0 mg, 0.11 mmol, 1.0 eq), (lH-pyrazol-5-yl)boronic acid (12.9 mg, 0.22 mmol, 2.0 eq), K2CO3 (30.3 mg, 0.22 mmol, 2.0 eq) and RuPhos Pd G3 (8.4 mg, 0.01 mmol, 0.1 eq) in dioxane / FLO (5 rnL / 0.5 mL) was stirred at 100 °C for 5 h under N2. The mixture was concentrated under reduced pressure and the resulting residue was purified by Prep-HPLC to afford N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(4-Agent Ref: 16738.0002-00304

[1286] morpholinophenyl)pyrazolo[l,5-a]pyridine-3-carboxamide (6.0 mg, 16.9%) as a yellow solid. LCMS (M+H ) m / z calculated 322.1, found 322.3. 'H NMR (DMSO- 400 MHz) 5 13.05 (s.

[1287] 1 H), 12.07 (s, 1 H), 9.84 (s, 1 H), 9.21 (s, 1 H), 8.74 (s, 1 H), 8.24 (d, 1 H), 8.02 (dd, 1 H), 7.85 (s, 1 H), 6.94 (s, 1 H), 2.15 (s, 3 H), 1.83 (s, 3 H).

[1288] Example 60: Preparation of N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-phenylpyrazolo[l,5-a] pyridine-3-carboxamide

[1289]

[1290]

[0304] To a solution of ethyl (E)-N-((mesitylsulfonyl)oxy)acetimidate (45.0 g, 284.8 mmol, 1.0 eq) in dioxane (100 mL) was added HCIO4 (30 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 4 h. The reaction mixture was diluted with water (50 mL). The precipitate was dissolved in DCM (40 mL), and 3-bromopyridine (25.0 g, 158.2 mmol, 1.0 eq) was added at 0 °C. The reaction mixture was stirred at 25 °C for 2 h. Petroleum ether was added, and the precipitate was filitered to afford l-amino-3-bromopyridin-l-ium 2,4,6-trimethylbenzenesulfonate (25.0 g, 41.2%).

[1291]

[1292]

[0305] A solution of l-amino-3-bromopyridin-l-ium 2,4,6-trimethylbenzenesulfonate (25.0 g, 67.0 mmol, 1.0 eq), ethyl propiolate (13.1 g, 134.0 mmol, 2.0 eq) and TEA (13.5 g, 134.0 mmol, 2.0 eq) in DMF (60 mL) was stirred at 50 °C for 2 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (PE / EtOAc = 3 / 1, v / v) to afford ethyl 6-bromopyrazolo[l,5-a]pyridine-3-carboxylate as a yellow solid (4.1 g, 16.3%). LCMS (M+H+) m / z calculated 269.0, found 269.1

[1293]

[1294]

[0306] A solution of ethyl 6-bromopyrazolo[l,5-a]pyridine-3-carboxylate (450.0 mg, 1.7 mmol, 1.0 eq), phenylboronic acid (407.5 mg, 3.3 mmol, 2.0 eq), NaHCCh (354.0 mg, 3.34Agent Ref: 16738.0002-00304

[1295] mmol, 2.0 eq) and Pd(dppf)Cl2 (124.3 mg, 0.17 mmol, 0.1 eq) in dioxane / I LO (5 mL / 0.5 mL) was stirred at 100 °C for 12 h under N2. The mixture was concentrated under reduced pressure and the resulting residue was purified by column chromatography on silica gel (PE / EtOAc = 2 / 1, v / v) to afford ethyl 6-phenylpyrazolo[l,5-a]pyridine-3-carboxylate (63.2 mg, 80.0%) as a yellow oil. LCMS (M+H+) m / z calculated 267.1, found 267.1.

[1296]

[1297]

[1298]

[0307] A solution of ethyl 6-phenylpyrazolo[l,5-a]pyridine-3-carboxylate (320.0 mg, 1.2 mmol, 1.0 eq) and NaOH (96.0 mg, 2.4 mmol, 2 eq) in EtOH / EbO (6 mL / 2 mL) was stirred at 80 °C for 1 h. The solvent was partially removed under vacuum, and the solution was acidified to pH=5 with Cone. HC1. The precipitate was collected by filtration and dried under vacuum to afford 6-phenylpyrazolo[l,5-a]pyridine-3-carboxylic acid as a yellow solid (290 mg, 98%). LCMS (M+H+) m / z calculated 239.1, found 239.2.

[1299]

[1300]

[0308] To a stirred solution of 6-phenylpyrazolo[l,5-a]pyridine-3-carboxylic acid (60.1 mg, 0.25 mmol, 1.2 eq), tert-butyl 3-amino-4,5-dimethyl-lH-pyrazole-l-carboxylate (44.3 mg, 0.2 mmol, 1.0 eq) and pyridine (132.7 mg, 1.7 mmol, 8.0 eq) in DCM (10.0 mL) was added POCh (128.5 mg, 0.84 mmol, 4.0 eq) at 0 °C. The reaction mixture was stirred at rt for 6 h. The reaction mixture was diluted with water (50.0 mL). The aqueous layer was extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (50 mL) and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to afford terl-buty I 4,5-dimethyl-3-(6-phenylpyrazolo[l,5-a]pyridine-3-carboxamido)-lH-pyrazole-l -carboxylate as a white solid (30.0 mg, 33.2%). LCMS (M+H+) m / z calculated 432.2, found 432.5.

[1301]

[1302] Agent Ref: 16738.0002-00304

[1303]

[0309] To a solution of tert-butyl 4,5-dimethyl-3-(6-phenylpyrazolo[l,5-a]pyridine-3-carboxamido)-lH-pyrazole-l-carboxylate (30.0 mg. 0.07 mmol, 1.0 eq) in DCM (2 mL) was added HC1 (2 M solution in EtOAc, 5 mL) at 0 °C. The reaction mixture was stirred at rt for 1 h. The reaction mixture was concentrated under reduced pressure and The resulting residue was purified by Prep-HPLC to afford N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-phenylpyrazolo[l,5-a]pyridine-3-carboxamide (6.0 mg, 25.8%) as a white solid. LCMS (M+H⁺) m / z calculated 332.1, found 332.4. 'H NMR (DMSO-d6, 400 MHz) 6 12.10 (s, 1 H), 9.86 (s, 1 H), 9.16 (s, 1 H), 8.78 (s, 1 H), 8.28 (d, 1 H), 7.87 (d, 1 H), 7.80-7.83 (m, 2 H), 7.49-7.53 (m, 2 H), 7.41-7.45 (m, 1 H), 2.17 (s, 3 H), 1.84 (s, 3 H).

[1304] Example 61: Preparation of N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-phenylpyrazolo[l,5-a]pyridine-3-carboxamide

[1305]

[1306]

[0310] To a solution of ethyl 6-bromopyrazolo[l,5-a]pyridine-3-carboxylate (5.0 g, 18.5 mmol, 1.0 eq) in THF / H2O (5 mL / 1 mL) wad added NaOH (1.56 g, 39 mmol, 2.0 eq) at 0 °C. The reaction mixture was stirred at rt for 12 h. The reaction mixture was diluted with water (50 mL). The aqueous layer was extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to afford 6-bromopyrazolo[L5-a]pyridine-3-carboxylic acid (4.0 g, 90%). LCMS (M+H+) m / z calculated 241.0, found 241.1.

[1307]

[1308]

[0311] To a stirred solution of 6-phenylpyrazolo[l,5-a]pyridine-3-carboxylic acid (1.0 g, 4.15 mmol, 1.2 eq), tert-butyl 3-amino-4,5-dimethyl-lH-pyrazole-l-carboxylate (723 mg, 3.46 mmol, 1.0 eq) and pyridine (2.22 mL, 27.7 mmol, 8.0 eq) in DCM (10.0 mL) was added POCh (1.25 mL, 13.8 mmol, 4.0 eq) at 0 °C. The reaction mixture was stirred at rt for 12 h. The reaction mixture was diluted with water (50.0 mL). The aqueous layer was extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resultingAgent Ref: 16738.0002-00304

[1309] residue was purified by column chromatography on silica gel to afford tert- but l 3-(6-bromopyrazolo[l,5-a]pyridine-3-carboxamido)-4.5-dimethyl-lH-pyrazole-l-carboxylate (600 mg, 40%) as a white solid. LCMS (M+H+) m / z calculated 434.1, found 434.5.

[1310]

[1311]

[0312] A solution of ethyl 6-bromopyrazolo[l,5-a]pyridine-3-carboxylate (200.0 mg, 0.46 mmol, 1.0 eq), (4-morpholinophenyl)boronic acid (190.0 mg, 0.92 mmol, 2.0 eq), Cs2CO3(354.0 mg, 3.34 mmol, 2.0 eq) and PCy3 Pd G3 (29.9 mg, 0.04 mmol, 0.1 eq) in dioxane / H2O (5 mL / 0.5 mL) was stirred at 100 °C for 5 h under N2. The mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography on silica gel (PE / EtOAc = 2 / 1, v / v) to afford tert- butyl 4,5-dimethyl-3-(6-(4-morpholinophenyl)pyrazolo[l,5-a]pyridine-3-carboxamido)-lH-pyrazole-l-carboxylate (60.0 mg, 25.2%) as a yellow solid. LCMS (M+H+) m / z calculated 517.3, found 517.6.

[1312]

[1313]

[0313] To a solution of tert-butyl 4,5-dimethyl-3-(6-(4-morpholinophenyl)pyrazolo[l,5-a]pyridine-3-carboxamido)-lH-pyrazole-l-carboxylate (60.0 mg, 0.11 mmol, 1.0 eq) in DCM (2 mL) was added HO (2M solution in EtOAc, 5 mL) at 0 °C. The reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase column chromatography (MeCN / ELO = 4 / 1, v / v) to afford N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(4-morpholinophenyl)pyrazolo[L5-a]pyridine-3-carboxamide (8.0 mg, 17.4%) as a white solid. LCMS (M+H+) m / z calculated 417.2, found 417.4. 'H NMR (DMSO-d6, 400 MHz) 5 12.08 (s, 1 H), 9.82 (s, 1 H), 9.06 (s, 1 H), 8.74 (s, 1 H), 8.23 (d, 1 H), 7.84 (d, 2 H), 7.05-7.07 (m, 2 H), 3.75-3.77 (m, 4 H), 3.17-3.18 (m, 4 H), 2.16 (s, 3 H), 1.83 (s, 3 H).

[1314] Example 62: Preparation of N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(3-fluoro-4-morpholinophenyl)pyrazolo[l,5-a]pyridine-3-carboxamideAgent Ref: 16738.0002-00304

[1315]

[1316]

[0314] A solution of ethyl 7-bromo-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide (60.0 mg, 0.18 mmol, 1.0 eq), (3-fluoro-4-morpholinophenyl)boronic acid (81.0 mg. 0.36 mmol, 2.0 eq), Cs2CO3(175.5 mg, 0.54 mmol, 3.0 eq) and Pd(dppf)C12 (14.6 mg, 0.02 mmol, 0.1 eq) in dioxane / H2O (5 mL / 0.5 mL) was stirred at 100 °C for 3 h under N2. The mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography on silica gel (DCMZ MeOH = 20 / 1, v / v) and Prep-HPLC to afford N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(3-fluoro-4-morpholinophenyl)pyrazolo[1.5-a]pyridine-3-carboxamide (15.1 mg, 19.2%) as a white solid. LCMS (M+H+) m / z calculated 435.2, found 435.5. 'H NMR (DMSO-d₆, 400 MHz) 5 12.08 (s, 1 H), 9.84 (s, 1 H), 9.17 (s, 1 H), 8.76 (s, 1 H), 8.24 (d, 1 H), 7.84 (d, 1 H), 7.72 (dd, 1 H), 7.66 (d, 1 H), 7.14 (t, 1 H), 3.76-3.78 (m, 4 H), 3.06-3.08 (m, 4 H), 2.16 (s, 3 H), 1.83 (s. 3 H).

[1317] Example 63: Preparation of N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(6-morpholinopyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[1318]

[1319]

[0315] A solution of ethyl 7-bromo-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide (60.0 mg, 0.18 mmol, 1.0 eq), (6-morpholinopyridin-3-yl)boronic acid (74.9 mg, 0.36 mmol. 2.0 eq), Cs2CO3(175.5 mg, 0.54 mmol, 3.0 eq) and Pd(dppf)Cl2 (14.6 mg, 0.02 mmol, 0.1 eq) in dioxane / I-hO (5 mL / 0.5 mL) was stirred at 100 °C for 3 h under N2. The mixture was concentrated under reduced pressure, and the resulting residue was purified by Prep-HPLC to afford N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(6-morpholinopyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide (10.3 mg, 13.7%) as a white solid. LCMS (M+H ) m / z calculated 418.2, found 418.5. 'H NMR (DMSO-d₆, 400 MHz) 5 12.09 (s, 1 H), 9.83 (s, 1 H), 9.14 (s, 1 H), 8.75 (s, 1 H), 8.60 (d, 1 H), 8.24 (d, 1 H), 8.03 (dd,Agent Ref: 16738.0002-00304

[1320] 1 H) 7.85 (d, 1 H). 6.96 (d, 1 H), 3.71-3.73 (m, 4 H), 3.32-3.54 (m. 4 H), 2.16 (s, 3 H), 1.83 (s, 3 H)

[1321] Example 64: Preparation of N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(2-fluoro-4-morpholinophenyl)pyrazolo[l,5-a]pyridine-3-carboxamide

[1322]

[1323]

[0316] A solution of 4-(3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)morpholine (120 mg, 0.39 mmol, 1.0 eq), 6-bromo-N-(4,5-dimethyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide (129.8 mg. 0.39 mmol, 1.0 eq), Pd(dppl)Ch (28.5 mg, 0.039 mmol, 0.1 eq) and Cs2CO3(254.3 mg, 0.78 mmol, 2.0 eq) in dioxane / I-hO (4 rnL / 1 mL) was stirred at 110 °C for 4 h. The reaction was quenched with H2O (50 mL). The reaction mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL) and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was was purified by Prep-HPLC to afford N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(2-fluoro-4-morpholinophenyl)pyrazolo[L5-a]pyridine-3-carboxamide as a white solid (32.2 mg, 18.9%). LCMS (M+H+) m / z calculated 435.2, found 435.2. 'l l NMR (DMSO-Je, 400 MHz) 5 12.09 (s, 1 H), 9.84 (s, 1 H), 8.91 (s, 1 H), 8.76 (s, 1 H). 8.24 (d, 1 H), 7.68 (d, 1 H), 7.54 (t, 1 H), 6.89-6.95 (m, 2 H), 3.73-3.76 (m, 4 H), 3.21-3.23 (m, 4 H), 2.16 (s, 3 H), 1.82 (s, 3 H).

[1324] Example 65: Preparation of 6-(2,3-difluoro-4-morpholinophenyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[1325] Pd(dppf)Cl2, Cs2CO3

[1326] dioxane / H2O, 100°C, 4 h

[1327]

[1328]

[0317] To a solution of 6-bromo-N-(4,5-dimethyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide (100.0 mg, 0.3 mmol, 1.0 eq) in dioxane / H2O (3 rnL / 1 mL) were added 4-(2,3-difluoro-4-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2-yl)phenyl)morpholine (146.0 mg,Agent Ref: 16738.0002-00304

[1329] 0.45 mmol. 1.5 eq) Pd(dppf)C12(22.0 mg, 0.03 mmol, 0.1 eq) and Cs2CO3(0.3 g, 0.9 mmol, 3.0 eq). The mixture was stirred at 100 °C for 4 h under N2. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by Prep-HPLC to afford 6-(2,3-difluoro-4-morpholinophenyl)-N-(4.5-dimethyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide (8.8 mg, 6%) as a white solid. LCMS (M+H+) m / z calculated 453.2, found 453.5. 'H NMR (400 MHz, DMSO-d6) 8 12.10 (s, 1 H), 9.88 (s, 1 H), 9.01 (s, 1 H), 8.80 (s, 1 H), 8.28 (d, 1 H), 7.69 (d, 1 H), 7.44 (t, 1 H), 6.99 (t, 1 H), 3.69-3.83 (m, 4 H), 2.97-3.18 (m, 5 H), 2.16 (s, 3 H), 1.83 (s, 3 H).

[1330] Example 66: Preparation of N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(5-morpholinopyridin-2-y l)py razol 0 [ 1, 5 -a] py ri dine-3 -carboxami de

[1331]

[1332]

[0318] A solution of 6-bromo-N-(4,5-dimethyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide (100 mg, 0.30 mmol, 1.0 eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (98.9 mg, 0.39 mmol, 1.3 eq), KOAc (88.0 mg, 0.90 mmol, 3.0 eq) and Pd(dppf)Cl2 (21.7 mg, 0.03 mmol. 0.1 eq) in dioxane (10 mL) was stirred at 90 °C for 4 h under N2. The mixture was concentrated under reduced pressure to afford N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridine-3-carboxamide (352.3 mg, quant). LCMS (M+H+) m / z calculated 382.2, found 382.2.

[1333]

[1334]

[0319] A solution of 4-(6-bromopyridin-3-yl)morpholine (50.0 mg. 0.21 mmol, 1.0 eq), N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridine-3-carboxamide (157.8 mg, 0.42 mmol, 2.0 eq), Cs2CO3(204.7 mg, 0.63 mmol, 3.0 eq) and Pd(PPh3)4 (23.3 mg, 0.02 mmol, 0.1 eq) in dioxane / H2O (5 mL / 0.5 mL) was stirred at 100 °C for 4 h under N2. The mixture was concentrated under reduced pressure, and theAgent Ref: 16738.0002-00304

[1335] resulting residue was purified by Prep-HPLC to afford N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridine-3-carboxamide (12.5 mg, 14.9%) as a white solid. LCMS (M+H+) m / z calculated 418.2, found 418.5. 'H NMR (DMSO-cA 400 MHz) 512.08 (s, 1 H), 9.84 (s, 1 H), 9.35 (s, 1 H), 8.77 (s, 1 H), 8.43 (s, 1 H), 8.19-8.26 (m, 2 H), 7.76 (d, 1 H), 7.45-7.48 (m, 1 H), 3.77-3.79 (m, 4 H), 3.25-3.27 (m, 4 H), 2.16 (s. 3 H). 1.83 (s, 3 H).

[1336] Example 67: Preparation of N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l,3-dimethyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[1337]

[1338]

[0320] Ethyl 6-bromopyrazolo[l,5-a]pyridine-3-carboxylate was converted to 6-bromo-N-(4,5-dimethyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide as described for 7-bromo-N-(4-methyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide. LCMS (M+H+) m / z calculated 334.0, found 334.3.

[1339]

[1340]

[0321] 6-Bromo-N-(4,5-dimethyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide was converted to N-(4.5-dimethyl-lH-pyrazol-3-yl)-6-(l,3-dimethyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyndine-3-carboxamide as described for N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide. LCMS (M+H+) m / z calculated 350.2, found 350.3. 'H NMR (DMSO-d6, 400 MHz) 512.00 (brs, 1 H), 9.82 (s, 1 H), 8.77 (s, 1 H), 8.72 (s, 1 H), 8.21 (d, 1 H), 8.05 (s, 1 H), 7.60 (dd, 1 H), 3.77 (s, 3 H), 2.21 (s, 3 H), 2.15 (s, 3 H), 1.82 (s, 3 H).

[1341] Example 68: Preparation of N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[1342]

[1343] Agent Ref: 16738.0002-00304

[1344]

[0322] 6-Bromo-N-(4,5-dimethyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide was converted to N-(4.5-dimethyl-lH-pyrazol-3-yl)-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide as described for N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide. LCMS (M+H+) m / z calculated 336.2, found 336.3. 'H NMR (DMSO-d6, 400 MHz) 5 12.04 (brs, 1 H), 9.81 (s, 1 H), 9.11 (s, 1 H). 8.71 (s, 1 H), 8.29 (s, 1 H), 8.19 (d, 1 H), 8.04 (s, 1 H), 7.75 (dd, 1 H), 3.89 (s, 3 H), 2.15 (s, 3 H), 1.82 (s, 3 H).

[1345] Example 69: Preparation of N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(2-hydroxy-2-methylpropyl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[1346] Pd(dppf)CI2, K2CO3DMF / H2O,100 °C, 4 h

[1347]

[1348]

[0323] 6-Bromo-N-(4.5-dimethyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide was converted to N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(2-hydroxy-2-methylpropyl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide as described for N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide. LCMS (M+H ) m / z calculated 394.2, found 394.4. 'H NMR (DMSO-d6, 400 MHz) 5 12.08 (s, 1 H), 9.81 (s, 1 H), 9.13 (s, 1 H), 8.70 (s, 1 H), 8.26 (s, 1 H), 8.19 (d, 1 H), 8.06 (s, 1 H), 7.78 (dd, 1 H), 4.76 (s, 1 H), 4.05 (s, 2 H), 2.16 (s, 3 H), 1.82 (s, 3 H), 1.10 (s, 6 H).

[1349] Example 70: Preparation of 6-(l-cyclopropyl-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol- 3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[1350] Pd(dppf)CI2, K2CO3

[1351] DMF / H2O,100 °C, 4 h

[1352]

[1353]

[0324] To a solution of 6-bromo-N-(4,5-dimethyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide (100 mg, 0.3 mmol, 1.0 eq) in dioxane / H2O (3 mL / 1 mL) were added 1-cyclopropyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (105 mg, 0.45 mmol, 1.5 eq) Pd(dppf)C12 (22 mg, 0.03 mmol, 0.1 eq) and Cs2CO3(0.3 g, 0.9 mmol, 3.0 eq). The mixture was stirred at 100 °C for 4 h under N2. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentratedAgent Ref: 16738.0002-00304

[1354] under reduced pressure. The resulting residue was purified by Prep-HPLC to afford 6-(l-cyclopropyl-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide (33 mg, 31%) as a white solid. LCMS (M+H+) m / z calculated 362.2, found 362.3. *H NMR (DMSO-tfc, 400 MHz) 5 12.08 (s, 1 H), 9.81 (s, 1 H), 9.12 (s, 1 H), 8.70 (s, 1 H), 8.41 (s, 1 H), 8.19 (dd, 1 H), 8.04 (s, 1 H), 7.78 (dd, 1 H), 3.73-3.76 (m, 1 H), 2.15 (s, 3 H), 1.82 (s. 3 H). 0.97-1.11 (m, 4 H).

[1355] Example 71: Preparation of N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-isopropyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[1356]

[1357]

[0325] To a solution of 6-bromo-N-(4,5-dimethyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide (100 mg, 0.3 mmol, 1.0 eq) in dioxane / H2O (3 mL / 1 mL) were added 1-isopropyl-4-(4.4.5.5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (106 mg. 0.45 mmol, 1.5 eq) Pd(dppf)Cl2 (22 mg, 0.03 mmol, 0.1 eq) and Cs2CO3(0.3 g, 0.9 mmol, 3.0 eq). The mixture was stirred at 100 °C for 4 h under N2. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by Prep-HPLC to afford N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-isopropyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide (27 mg, 25%) as a white solid. LCMS (M+H+) m / z calculated 364.2, found 364.3. 'H NMR (DMSO- 400 MHz) 5 12.08 (s. 1 H). 9.81 (s, 1 H), 9.12 (s, 1 H), 8.70 (s, 1 H). 8.41 (s, 1 H). 8.19 (dd. 1 H). 8.04 (s, 1 H). 7.78 (dd. 1 H). 4.48-4.55 (m, 1 H), 2.15 (s, 3 H), 1.82 (s, 3 H), 1.46 (d, 6 H).

[1358] Example 72: Preparation of 6-(l-isopropyl-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[1359]

[1360] Agent Ref: 16738.0002-00304

[1361]

[0326] To a solution of 6-bromo-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide (96 mg, 0.3 mmol, 1.0 eq) in dioxane / FTO (3 mL / 1 mL) were added 1-isopropyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (106 mg, 0.45 mmol, 1.5 eq) Pd(dppf)Cl2 (22 mg, 0.03 mmol, 0.1 eq) and Cs2CO3(0.3 g, 0.9 mmol, 3.0 eq). The mixture was stirred at 100 °C for 4 h under N2. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by Prep-HPLC to afford 6-(l-isopropyl-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide (33 mg, 32%) as a white solid. LCMS (M+H+) m / z calculated 350.2, found 350.3. 'H NMR (DMSO-t / e, 400 MHz) 5 12.33 (s, 1 H), 9.87 (s, 1 H), 9.13 (s. 1 H), 8.71 (s. 1 H). 8.42 (s, 1 H), 8.19 (dd, 1 H), 8.05 (s, 1 H), 7.78 (dd, 1 H), 7.48 (s, 1 H), 4.48-4.55 (m, 1 H), 1.93 (s, 3 H), 1.46 (d, 6 H).

[1362] Example 73: Preparation of 6-(l-cyclopropyl-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[1363]

[1364]

[0327] To a solution of 6-bromo-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide (96 mg, 0.3 mmol, 1.0 eq) in dioxane / H2O (3 rnL / 1 mL) were added 1-cyclopropyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (105 mg, 0.45 mmol, 1.5 eq) Pd(dppf)C12 (22 mg, 0.03 mmol, 0.1 eq) and Cs2CO3(0.3 g, 0.9 mmol, 3.0 eq). The mixture was stirred at 100 °C for 4 h under N2. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by Prep-HPLC to afford 6-(l-cyclopropyl-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide (25 mg, 24%) as a white solid. LCMS (M+H+) m / z calculated 348.2, found 348.3. H NMR (DMSO- s, 400 MHz) 5 12.33 (s, 1 H), 9.87 (s, 1 H), 9.13 (s, 1 H), 8.71 (s, 1 H), 8.42 (s, 1 H), 8.19 (dd, 1 H), 8.05 (s, 1 H), 7.78 (dd, 1 H), 7.48 (s, 1 H), 3.73-3.79 (m, 1 H), 1.93 (s, 3 H), 0.97-1.11 (m, 4 H).Agent Ref: 16738.0002-00304

[1365] Example 74: Preparation of 6-(l-isopropyl-lH-pyrazol-4-yl)-N-(5-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[1366]

[1367]

[0328] To a solution of ethyl 6-bromopyrazolo[l,5-a]pyridine-3-carboxylate (5.0 g, 18.5 mmol, 1.0 eq) and 5-methyl-lH-pyrazol-3-amine ( 3.78 g, 39 mmol, 2.0 eq) in tolune (30 mL) was added AlMes (18.5 mL, 2M in tolune, 2.0 eq) at 0 °C under N2. The reaction mixture was heated to 110 °C and stirred for 12 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (PE / EtOAc = 1 / 1, v / v) to afford 6-bromo-N-(5-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyndine-3-carboxamide (2.96 g, 50%) as a white solid. LCMS (M+H+) m / z calculated 320.0, found 320.1.

[1368]

[1369] H

[1370]

[0329] A solution of 6-bromo-N-(5-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide (400 mg, 1.25 mmol, 1.0 eq), l-isopropyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (590 mg, 2.50 mmol. 2.0 eq), K2CO3 (518 mg, 3.75 mmol, 3.0 eq) and Pd(dppf)Cl2 (92.9 mg. 0.13 mmol. 0.1 eq) in Dioxane / H2O (20 mL / 2 mL) was stirred at 100 °C for 3 h under N2. The mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography on silica gel (DCM / MeOH = 20 / 1, v / v) and Prep-HPLC to afford 6-(l-isopropyl-lH-pyrazol-4-yl)-N-(5-methyl-lH-pyrazol-3-yl)pyrazolo[1.5-a]pyridine-3-carboxamide (82 mg, 18.8%) as a white solid. LCMS (M+H ) m / z calculated 350.2, found 350.3. 'H NMR (400 MHz, DMSO-de) 5 12.03 (s, 1 H), 10.47 (s, 1 H), 9.11 (s, 1 H), 8.82 (s, 1 H), 8.42 (s, 1 H), 8.25 (d, 1 H), 8.05 (s, 1 H), 7.80 (dd, 1 H), 6.41 (s, 1 H), 4.51 (dt, 1 H), 2.23 (s, 3 H), 1.46 (d, 6 H).

[1371] Example 75: Preparation of 6-(l-cyclopropyl-lH-pyrazol-4-yl)-N-(5-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyndine-3-carboxamideAgent Ref: 16738.0002-00304

[1372] 6-( 1 -cyclopropyl- 1 H-pyrazol-4-yl)-N-(5-methyl-1 H-pyrazol-3-

[1373]

[1374] yl)pyrazolo[1,5-a]pyridine-3-carboxamide

[1375]

[0330] 6-(l-Cyclopropyl-lH-pyrazol-4-yl)-N-(5-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide was prepared as described for 6-(l -isopropyl- lH-pyrazol-4-yl)-N-(5-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide. LCMS (M+H+) m / z calculated 348.2, found 348.3. 'H NMR (400 MHz, DMSO-d6) 5 12.03 (s, 1 H), 10.49 (s, 1 H). 9.12 (s, 1 H). 8.83 (s, 1 H), 8.42 (s, 1 H), 8.25 (d, 1 H), 8.04 (s, 1 H), 7.79 (d. 1 H). 6.41 (s, 1 H), 3.71-3.79 (m, 1 H), 2.23 (s, 3H), 1.06-1.12 (m, 2 H), 1.00 (q, 2 H).

[1376] Example 76: Preparation of 7-(l-isopropyl-lH-pyrazol-4-yl)-N-(l,4,5-trimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide

[1377] H2N H2N

[1378] Mel, NaH

[1379] N'MI - THF, 0“C to rt, 4 h ” w ||

[1380]

[1381] H I

[1382]

[0331] To a solution of 4,5-dimethyl-lH-pyrazol-3-amine (1.0 g, 9.0 mmol, 1.0 eq) in THF (50 mL) was added NaH (540.5 mg, 13.5 mmol, 1.5 eq) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h, and Mel (0.7 mL, 10.8 mmol. 1.2 eq) was added. The reaction mixture was stirred at rt for 4 h. The reaction mixture was diluted with water (50 mL), extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by Prep-HPLC to afford l,4,5-trimethyl-lH-pyrazol-3-amine (179 mg, 16.3%) as a pink solid. LCMS (M+H+) m / z calculated 126.1, found 126.2.

[1383]

[1384]

[0332] L4.5-Trimethyl-lH-pyrazol-3-amine was converted to 7-(l-isopropyl-lH-pyrazol-4-yl)-N-(l,4,5-trimethyl-lH-pyrazol-3-yl)imidazo[L2-a]pyridine-3-carboxamide as described for N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(lH-pyrazol-5-yl)imidazo[l,2-a]pyridine-3-carboxamide. LCMS (M+H+) m / z calculated 378.2, found 378.3. 'll NMR (DMSO-d6, 400Agent Ref: 16738.0002-00304

[1385] MHz) 6 10.03 (s, 1 H), 9.37 (dd, 1 H), 8.50 (s, 1 H), 8.48 (s, 1 H), 8.11 (s, 1 H), 7.97 (s, 1 H), 7.44 (dd, 1 H), 4.51-4.55 (m, 1 H), 3.68 (s, 3 H), 2.19 (s, 3 H), 1.83 (s, 3 H), 1.48 (s, 3 H), 1.46 (s, 3 H).

[1386] Example 77: Preparation of 6-(l-isopropyl-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide

[1387]

[1388]

[0333] 6-(l-Isopropyl-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide was prepared as described forN-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(3-(trifluoromethyl)phenyl)imidazo[1.2-a]pyridine-3-carboxamide. LCMS (M+H ) m / z calculated 350.2, found 350.3. ‘H NMR (DMSO-tfc, 400 MHz) 5 12.38 (s, 1 H), 10.15 (s, 1 H), 9.64 (s, 1 H), 8.51 (s, 1 H), 8.31 (s, 1 H), 7.86 (s, 1 H), 7.76-7.81 (m, 2 H), 7.54 (s, 1 H), 4.50-4.58 (m, 1 H), 1.95 (s, 3 H), 1.45 (d, 6 H).

[1389] Example 78: Preparation of 5-(l-isopropyl-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[1390]

[1391]

[0334] To a solution of ethyl 5-bromopyrazolo[l,5-a]pyridine-3-carboxylate (1.0 g, 3.7 mmol, l. O eq) and 4-methyl-lH-pyrazol-3-amine (398 mg, 4.1 mmol, 1.1 eq) in tolune (30 mL) was added Al(Me)s (1 M in Tolune, 25 mL, 24.6 mmol, 6.0 eq) at 25 °C. The reaction mixture was stirred at 90 °C for 15 h under N2, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (DCM / MeOH = 20 / 1, v / v) to afford 5-bromo-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide (280 mg, 23.3%) as a yellow solid. LCMS (M+H+) m / z calculated 320.0, found 320.2.

[1392]

[1393]

[0335] A solution of 5-bromo-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide (70 mg, 0.22 mmol, 1.0 eq), l-isopropyl-4-(4,4,5,5-tetramethyl-l,3,2-Agent Ref: 16738.0002-00304

[1394] dioxaborolan-2-yl)-lH-pyrazole (67.5 mg, 0.28 mmol, 1.3 eq), Pd(dppf)Cl2 (16.1 mg, 0.02 mmol, 0.1 eq) and K3PO4 (91.1 mg, 0.66 mmol. 3.0 eq) in dioxane and H2O (10 mL / 2 mL) was stirred at 80 °C for 3 h under N2. The reaction was quenched with H2O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhy drous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by Prep-HPLC to afford 5-(l-isopropyl-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide as a white solid (27.7 mg, 36.1%). LCMS (M+H+) m / z calculated 350.2, found 350.2. 'H NMR (DMSO- 400 MHz) 8 12.31 (brs, 1 H), 9.82 (s, 1 H), 8.79 (d, 1 H), 8.65 (s, 1 H), 8.47 (s, 1 H), 8.31 (d, 1 H), 8.01 (s, 1 H), 7.48 (s, 1 H), 7.37 (dd, 1 H), 4.51-4.58 (m, 1 H), 1.94 (s, 3 H), 1.48 (s, 3 H). 1.46 (s. 3 H).

[1395] Example 79: Preparation of N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[1396]

[1397]

[0336] 6-Bromo-N-(4,5-dimethyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide was converted to tert-butyl 4-(4-(3-((4,5-dimethyl-lH-pyrazol-3-yl)carbamoyl)pyrazolo[l,5-a]pyridin-6-yl)-lH-pyrazol-l-yl)piperidine-l-carboxylate as described for N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide.

[1398] LCMS (M+H+) m / z calculated 505.3, found 505.3.

[1399]

[1400] [337| tert-Butyl 4-(4-(3-((4,5-dimethyl-lH-pyrazol-3-yl)carbamoyl)pyrazolo[1.5-a]pyridin-6-yl)-lH-pyrazol-l-yl)piperidine-l-carboxylate was converted to N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide as described for N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-((3S,4R)-4-fluoropyrrolidin-3-yl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide. LCMS (M+H+) m / z calculated 405.2, found 405.3. 'H NMR (400 MHz, DMSO-de) 69.81 (s, 1 H), 9.13 (s, 1H), 8.71 (brs, 1Agent Ref: 16738.0002-00304

[1401] H), 8.41 (s, 1 H), 8.18 (d, 1 H), 8.06 (s, 1 H), 7.79 (d, 1 H), 4.19 (q, 1 H), 3.03-3.07 (m, 2 H), 2.57-2.63 (m, 2 H), 2.16 (s, 3 H), 1.98-2.01 (m, 2 H), 1.83 (s, 3 H), 1.78-1.82 (m, 2 H).

[1402] Example 80: Preparation of N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(l-methylpiperidin-4-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[1403]

[1404]

[0338] N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide was converted to N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(l-methylpiperidin-4-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide as described for N-(4.5-dimethyl-lH-pyrazol-3-yl)-7-(l-(l-methylpyrrolidin-3-yl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide. LCMS (M+H ) m / z calculated 419.2, found 419.3. ’H NMR (DMSO-d6, 400 MHz) 5 12.06 (brs, 1 H), 9.81 (s, 1 H), 9.13 (s, 1 H), 8.71 (brs, 1 H), 8.44 (s, 1 H), 8.17 (d, 1 H), 8.06 (s, 1 H), 7.79 (d, 1 H), 4.12-4.15 (m, 1 H), 2.86-2.90 (m, 2 H), 2.22 (s, 3 H), 2.15 (s, 3 H), 2.01-2.09 (m, 6 H), 1.82 (s, 3 H).

[1405] Example 81: Preparation of methyl 4-(4-(3-((4,5-dimethyl-lH-pyrazol-3-yl)carbamoyl)pyrazolo[l, 5-a]pyridin-6-yl)-lH-pyrazol-l-yl)piperi dine- 1 -carboxylate

[1406]

[1407]

[0339] To a solution of N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide (150.0 mg, 0.37 mmol, 1.0 eq) in THF / H2O (6 mL / 2 mL) were added methyl carbonochloridate (51.2 mg, 0.56 mmol, 1.5 eq) and NaHCOs(156.0 mg, 185 mmol, 5.0 eq) at 0 °C. The reaction mixture was stirred at 0 °C for Ih, quenched with H2O (50 mL), and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL). dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by Prep-HPLC to afford methyl 4-(4-(3-((4,5-dimethyl-lH-pyrazol-3-yl)carbamoyl)pyrazolo[l,5-a] pyridin-6-yl)-lH-pyrazol-l-yl)piperi dine- 1 -carboxy late (17.0 mg, 10%) as a white solid. LCMS (M+H ) m / z calculated 463.2, found 463.2. 'H NMR (400 MHz, DMSO-cL) 5 12.08 (s, 1 H), 9.81 (s, 1 H), 9.12 (s, 1 H), 8.71 (brs, 1 H), 8.46 (s, 1 H), 8.19 (d, 1 H), 8.08 (s, 1 H),Agent Ref: 16738.0002-00304

[1408] 7.78 (d, 1 H), 4.37-4.43 (m, 1 H), 4.07 (d, 2 H), 3.63 (s, 3 H), 3.02 (s, 2 H), 2.15 (s, 3 H), 2.06-2.09 (m, 2 H), 1.86-1.83 (m, 2 H), 1.82 (s, 3 H).

[1409] Example 82: Preparation of N-(4-methyl-lH-pyrazol-3-yl)-6-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[1410]

[1411]

[0340] N-(4-Methyl-lH-pyrazol-3-yl)-6-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide was prepared as described for N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide. LCMS (M+H+) m / z calculated 391.2, found 391.3. 'H NMR (400 MHz, DMSO-de) 5 12.32 (s, 1 H), 9.88 (s, 1 H), 9.18 (s, 1 H), 8.72 (brs, 1 H), 8.44 (s, 1 H), 8.22 (d, 1 H), 8.14 (s, 1 H), 7.81 (d, 1 H). 7.50 (s, 1 H). 4.49-4.53 (m, 1 H), 3.33-3.43 (m. 3 H). 3.07-3.12 (m, 2 H), 2.08-2.27 (m, 4H), 1.93 (s, 3 H).

[1412] Example 83: Preparation of N-(4-methyl-lH-pyrazol-3-yl)-6-(l-(l-methylpiperidin-4-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide

[1413]

[1414]

[0341] N-(4-Methyl-lH-pyrazol-3-yl)-6-(l-(l-methylpiperidin-4-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide was prepared as described for N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(l-methylpiperidin-4-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide. LCMS (M+H+) m / z calculated 405.2, found 405.3.1H NMR (DMSO-<7e. 400 MHz) 5 12.31 (brs. 1 H), 9.86 (s, 1 H), 9.13 (s, 1 H), 8.72 (brs, 1 H), 8.44 (s, 1 H), 8.19 (d. 1 H), 8.07 (s, 1 H), 7.79 (d, 1 H), 7.50 (s, 1 H), 4.12-4.15 (m, 1 H), 2.86-2.90 (m, 2 H), 2.21 (s, 3 H), 2.01-2.09 (m, 6 H), 1.93 (s, 3 H).

[1415] Example 84: Preparation of 6-(l-(l-acetylpiperidin-4-yl)-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)pyrazolo[ 1.5-a]pyridine-3-carboxamideAgent Ref: 16738.0002-00304

[1416]

[1417]

[0342] 6-( 1 -( 1 - ...

Claims

Agent Ref: 16738.0002-00304What is claimed is:

1. A compound of Formula I:(A) R4x. 2 / ," y-N R3° N, >~-R2N IKR1Formula I,or a pharmaceutically acceptable salt thereof, wherein(i) R1is hydrogen, optionally substituted lower alkyl, or optionally substituted cycloalkyl; (ii) R2and R3are each independently hydrogen, cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, sulfonyl, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkyl, optionally substituted cycloalkyd, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxy carbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, or optionally substituted carbamimidoyl; orR2and R3may be joined together with any intervening atoms to form an optionally substituted heteroaryl ring;(iii) R4is hydrogen, optionally substituted lower alkyl, or optionally substituted cycloalkyl; andA N'YNHj N-X\° jit(iv) ring Aisx2 or7 X<3, whereinXi, X2, X3, X4, X5, Xe, X7, Xs, X9, and X10 are each independently CR5or N; and R5is independently hydrogen, cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, sulfonyl, optionally substituted alkoxy, optionally substituted cycloalkyloxy. optionally substituted heterocycloalkyloxy. optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionallyAgent Ref: 16738.0002-00304substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, or optionally substituted carbamimidoyl,with the proviso that at least two of Xi, X2, X3, and X4 are independently CR5, and at least two of Xs, Xg, X7, and Xs are independently CR5.

2. The compound or pharmaceutically acceptable salt of claim 1, whereinXi, X2, X3, X4, and X9 are each independently CR5;Xs. Xg, X7, Xs, and X10 are each independently CR5;Xi is N, andX2, X3, X4, and X9 are each independently CR5;X2 is N, andXi, Xs, X4, and X9 are each independently CR5;X3 is N. andXi, X2, X4, and X9 are each independently CR5;X4 is N. andXi, X2, X3, and X9 are each independently CR5;X5 is N, and Xg, X7, Xs, and X10 are each independently CR5;Xg is N, and Xs, X7, Xs, and X10 are each independently CR5; orX7 is N, and Xs, Xg, Xs, and X10 are each independently CR5.

3. The compound or pharmaceutically acceptable salt of claim 1 or 2, wherein ring A isz ~N*4 XX3'X sA2 and Xi, X2, X3, X4, and X9 are each independently CR.

4. The compound or pharmaceutically acceptable salt of claim 1 or 2, wherein ring A is N -Xl° J' / / zNAzX5X? x6 and Xs, Xg, X7, Xs, and X10 are each independently CR5.

5. The compound of any one of claims 1-4. having Formula II:Formula II,or a pharmaceutically acceptable salt thereof, whereinAgent Ref: 16738.0002-00304each R6is independently hydrogen, cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, sulfonyl, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxy carbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, or optionally substituted carbamimidoyl;ring B is optionally substituted ary l, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, or optionally substituted cycloalkyl; andn is 0, 1, 2, 3. 4, or 5.

6. The compound or pharmaceutically acceptable salt of claim 5, whereinone of Xi, X2, Xs, X4, and X9 is attached to ring B and the rest of Xi, X2, X3, X4, and X9 are each independently CR5;one of Xs, Xe, X7, Xs, and X10 is attached to ring B and the rest of Xs. Xe. X7. Xs. and X10 are each independently CR5;Xi is N, one of X2, X3, X4, and X9 is attached to ring B, and the rest of X2, Xs, X4, and X9 are each independently CR5;X2 is N. one of Xi, X3, X4, and X9 is attached to ring B, and the rest of Xi, X3, X4, and X9 are each independently CR5;X3 is N, one of Xi, X2, X4, and X9 is attached to ring B, and the rest of Xi, X2, X4, and X9 are each independently CR5;X4 is N, one of Xi, X2, X3, and X9 is attached to ring B, and the rest of Xi, X2, X3, and X9 are each independently CR5;Xs is N, one of Xe, X7, Xs, and X10 is attached to ring B, and the rest of Xe, X7, Xs, and X10 are each independently CR5;Xe is N, one of Xs, X7, Xs, and X10 is attached to ring B, and the rest of Xs, X7, Xs, and X10 are each independently CR5; orX7 is N, one of Xs, Xe, Xs, and X10 is attached to ring B, and the rest of Xs, Xe, Xs, and X10 are each independently CR5.

7. The compound or pharmaceutically acceptable salt of claim 6, whereinAgent Ref: 16738.0002-00304X3'Zring AisA2, one of Xi, X2, X3, X4, and X9 is atached to ring B, and the rest of Xi, X2, X3, X4, and X9 are each independently CR3.

8. The compound or pharmaceutically acceptable salt of claim 6, wherein ring A is N1N'L -X? x6, one of X5, Xe, X7, Xs, and X10 is atached to ring B, and the rest of X5, Xe, X7, Xs, and X10 are each independently CR5.

9. The compound or pharmaceutically acceptable salt of any one of claims 5-8, wherein ring B is optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl.

10. The compound or pharmaceutically acceptable salt of any one of claims 5-9, wherein ring B is optionally substituted aryl or optionally substituted heteroaiyl.

11. The compound or pharmaceutically acceptable salt of any one of claims 5-10, wherein ring B is phenyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, triazolyl, oxadiazolyl, or tetrazolyl.

12. The compound or pharmaceutically acceptable salt of any one of claims 5-11, wherein ring B is phenyl, pyridyl, pyrazinyl, pyridazinyl, or pyrimidinyl.

13. The compound or pharmaceutically acceptable salt of any one of claims 5-11, wherein ring B is pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, triazolyl, or oxadiazolyl.

14. The compound or pharmaceutically acceptable salt of any one of claims 5-13, wherein each R6is independently hydrogen, cyano, halo, hydroxy, carboxy, sulfonyl, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, or optionally substituted aminosulfonyl.

15. The compound or pharmaceutically acceptable salt of any one of claims 5-14, wherein each R6is independently hydrogen, cyano, halo, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl.Agent Ref: 16738.0002-0030416. The compound or pharmaceutically acceptable salt of any one of claims 5-15, wherein each R6is independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl.

17. The compound or pharmaceutically acceptable salt of any one of claims 1-16, wherein R1is hydrogen or optionally substituted lower alkyl.

18. The compound or pharmaceutically acceptable salt of any one of claims 1-17, wherein R1is hydrogen.

19. The compound or pharmaceutically acceptable salt of any one of claims 1-18, wherein R2and R3are independently hydrogen, optionally substituted alky l, or optionally substituted cycloalkyl.

20. The compound or pharmaceutically acceptable salt of any one of claims 1-19, wherein R2and R3are independently hydrogen or optionally substituted lower alkyl.

21. The compound or pharmaceutically acceptable salt of any one of claims 1-18, wherein R2and R3may be joined together with any intervening atoms to form an optionally substituted heteroaryl ring.

22. The compound or pharmaceutically acceptable salt of any one of claims 1-18 and 21, wherein R2and R3may be joined together with any intervening atoms to form an optionally substituted indazolyl, an optionally substituted 4,5,6,7-tetrahydroindazolyl, an optionally substituted azaindazolyl, an optionally substituted 17 / -pyrazolo|3.4-c|pyndyl. an optionally substituted 1 7-pyrazolo[4.3-c|pyridyl, or an optionally substituted 177-pyrazolo[4.3-b]pyridyl.

23. The compound or pharmaceutically acceptable salt of any one of claims 1 -22, wherein R4is hydrogen or optionally substituted lower alkyl.

24. The compound or pharmaceutically acceptable salt of any one of claims 1-23, wherein R4is hydrogen.

25. The compound or pharmaceutically acceptable salt of any one of claims 1-24, wherein each R' is independently hydrogen, cyano, halo, hydroxy, carboxy, sulfonyl, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted heterocycloalkyloxy. optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, or optionally substituted aminosulfonyl.

26. The compound or pharmaceutically acceptable salt of any one of claims 1-25, wherein each R5is independently hydrogen, cyano, halo, optionally substituted alkoxy, optionallyAgent Ref: 16738.0002-00304substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl.Tl. The compound or pharmaceutically acceptable salt of any one of claims 1-26, wherein each R' is independently hydrogen, optionally substituted aryl, or optionally substituted heteroaryl.

28. A compound chosen from the group consisting of:N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(lH-pyrazol-5-yl)imidazo[l,2-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-phenylimidazo[l,2-a]pyridine-3-carboxamide; N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(3-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(2-isopropyloxazol-4-yl)pyrazolo[l,5-a]pyridine-3 -carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(6-morpholinopyridin-2-yl)imidazoll,2-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(5-morpholinopyridin-2-yl)imidazo[l,2-a]pyridine-3-carboxamide;N-(4.5-dimethyl-lH-pyrazol-3-yl)-7-(3-fluoro-4-morpholinophenyl)imidazo[1.2-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(6-morpholinopyridin-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(2-fluoro-4-morpholinophenyl)imidazo[1.2-a]pyridine-3-carboxamide;7-(2,3-difluoro-4-morpholinophenyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;7-(3-chloro-4-morpholinophenyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[1.2-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-(3-oxomorpholino)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(3-methyl-4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide;Agent Ref.: 16738.0002-00304N-(5-methyl-lH-pyrazol-3-yl)-7-(4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide;N-(4-methyl-lH-pyrazol-3-yl)-7-(4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide;7-(3 -cy clopropyl-4-morpholinophenyl)-N-(4,5 -dimethyl- 1 H-pyrazol-3 -yl)imidazo[l,2-a]pyridine-3-carboxamide;N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-(4-morpholino-3-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(3-methoxy-4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(3-fluorophenyl)imidazo[l,2-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(3-methoxyphenyl)imidazo[l,2-a]pyridine-3-carboxamide;7-(3-cyclopropylphenyl)-N-(4.5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;7-(4-chlorophenyl)-N-(4.5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;7-(4'-chloro-[l J'-biphenyl]-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;N-(5-cyclopropyl-4-methyl-lH-pyrazol-3-yl)-7-(4-morpholinophenyl)imidazo[l,2-a] pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-isocyanophenyl)imidazo[l,2-a]pyridine-3-carboxamide;7-(3-chlorophenyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(2-oxo-2H-[l,2'-bipyridin]-5'-yl)imidazo[l,2-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(3-(trifluoromethyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-fluorophenyl)imidazo[l,2-a]pyridine-3-carboxamide;Agent Ref.: 16738.0002-00304N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-methoxyphenyl)imidazo[l,2-a]pyridine-3-carboxamide;7-(4-cyclopropylphenyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-(2-oxopyridin-l(2H)-yl)phenyl)imidazo[l,2-a] pyridine-3-carboxamide;7-(3-cyanophenyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;N-(5-(hydroxymethyl)-4-methyl-lH-pyrazol-3-yl)-7-(4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(4-(2-oxopyrimidin-l(2H)-yl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide;N-(4-(hydroxymethyl)-5-methyl-lH-pyrazol-3-yl)-7-(4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide;N-(5-(fluoromethyl)-4-methyl-lH-pyrazol-3-yl)-7-(4-morpholinophenyl)imidazo[l,2-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l,3-dimethyl-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-melhyl-lH-pyrazol-4-yl)imidazo[l,2-a|pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(2-hydroxy-2-methylpropyl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3 -carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(2-hydroxy-2-methylpropyl)-3-methyl-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(2-hydroxy-2-methylpropyl)-5-methyl-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide:7-(l-cyclopropyl-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[1.2-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-isopropyl-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-phenyl-lH-pyrazol-4-yl)imidazo[1.2-a]pyridine-3-carboxamide;Agent Ref.: 16738.0002-00304N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(pyrrolidin-3-yl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide:N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide;7-(l-(4-cyanophenyl)-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide:N-(4,5-dirnethyl-lH-pyrazol-3-yl)-7-(l-(l-methylpiperidin-4-yl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(l-methylpyrrolidin-3-yl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide:7-(l-cyclopropyl-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;7-(l-isopropyl-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;N-(lH-indazol-3-yl)-7-(l-isopropyl-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-((3R,4R)-4-fluoropyrrolidin-3-yl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-((3R,4R)-4-fluoro-l-methylpyrrolidin-3-yl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(lH-pyrazol-5-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-phenylpyrazolo[l,5-a]pyridine-3-carboxamide; N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(4-morpholinophenyl)pyrazolo[l,5-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(3-fluoro-4-morpholinophenyl)pyrazolo[l,5-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(6-morpholinopyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(2-fluoro-4-morpholinophenyl)pyrazolo[l,5-a]pyridine-3-carboxamide;6-(2,3-difluoro-4-morpholinophenyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;Agent Ref.: 16738.0002-00304N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(5-morpholinopyridin-2-yl)pyrazolo[l,5-a] pyridine-3-carboxamide;N-(4,5-dirnethyl-lH-pyrazol-3-yl)-6-(l,3-dimethyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a] pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(2-hydroxy-2-methylpropyl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;6-(l-cyclopropyl-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l -isopropyl- lH-pyrazol-4-yl)pyrazolo[ 1,5-a]pyridine-3-carboxamide;6-(l-isopropyl-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;6-(l-cyclopropyl-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[1.5-a]pyridine-3-carboxamide;6-(l-isopropyl-lH-pyrazol-4-yl)-N-(5-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;6-(l-cyclopropyl-lH-pyrazol-4-yl)-N-(5-methyl-lH-pyrazol-3-yl)pyrazolo[1.5-a|pyridine-3-carboxamide;7-(l -isopropyl- lH-pyrazol-4-yl)-N-(l, 4, 5-trimethyl-lH-pyrazol-3-yl)imidazo[l, 2-a]pyridine-3-carboxamide;6-(l-isopropyl-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)imidazo[l,2-a] pyridine-3-carboxamide;5-(l-isopropyl-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(l-methylpiperidin-4-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;methyl 4-(4-(3-((4,5-dimethyl-lH-pyrazol-3-yl)carbamoyl)pyrazolo[l,5-a]pyridin-6-y 1)- IH-pyrazol- 1 -yl)piperidine- 1 -carboxylate;N-(4-methyl-lH-pyrazol-3-yl)-6-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)pyrazolo[1.5-a]pyridine-3-carboxamide;Agent Ref.: 16738.0002-00304N-(4-methyl-lH-pyrazol-3-yl)-6-(l-(l-methylpiperidin-4-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;6-(l-(l-acetylpiperidin-4-yl)-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;N-(4-methyl-lH-pyrazol-3-yl)-6-(l-(l,l,l-trifluoropropan-2-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(l,l,l-trifluoropropan-2-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;6-(l-(l-acetylpiperidin-4-yl)-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;methyl 4-(4-(3-((4-methyl-lH-pyrazol-3-yl)carbamoyl)pyrazolo[l,5-a]pyridin-6-yl)-1 H-pyrazol- 1 -y l)piperidine- 1 -carboxylate;(S)-N-(4-methyl-lH-pyrazol-3-yl)-6-(l-(pyrrolidin-3-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;(S)-N-(4-methyl-lH-pyrazol-3-yl)-6-(l-(l-methylpyrrolidin-3-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyndine-3-carboxamide;methyl (R)-3-(4-(3-((4,5-dimethyl-lH-pyrazol-3-yl)carbamoyl)pyrazolo[l,5-a] py ridin-6-y 1)- 1 H-pyrazol- 1 -yl)pyrrolidine- 1 -carboxylate;methyl (S)-3-(4-(3-((4-methyl-lH-pyrazol-3-yl)carbamoyl)pyrazolo[l,5-a]pyridin-6-yl)- IH-pyrazol- 1 -y l)pyrrolidine- 1 -carboxylate;(S)-6-(l-(l-acetylpyrrolidin-3-yl)-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;(R)-6-(l-(l-acetylpyrrolidin-3-yl)-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;(S)-N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(l-methylpyrrolidin-3-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;methyl (R)-3-(4-(3-((4-methyl-lH-pyrazol-3-yl)carbamoyl)pyrazolo[l,5-a]pyridin-6-yl)- 1 H-pyrazol- 1 -yl)pyrrolidine- 1 -carboxy late;(R)-6-(l-(l-acetylpyrrolidin-3-yl)-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;(S)-N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(pyrrolidin-3-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;(S)-6-(l-(l-acetylpyrrolidin-3-yl)-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;Agent Ref.: 16738.0002-00304methyl (S)-3-(4-(3-((4,5-dimethyl-lH-pyrazol-3-yl)carbamoyl)pyrazolo[l,5-a]pyridin-6-yl)-lH-pyrazol-l-yl)pyrrolidine-l -carboxylate;(R)-N-(4-methyl- lH-pyrazol-3-yl)-6-( 1 -(pyrrolidin-3-yl)- lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;(R)-N-(4-methyl-lH-pyrazol-3-yl)-6-(l-(l-methylpyrrolidin-3-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;N-(4,5-dimethyl- lH-pyrazol-3-y l)-6-( 1 -( 1, 1, 1 -trifluoro-2-methylpropan-2-yl)- 1H-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;6-(3-cyclopropyl-l-isopropyl-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;6-( 1 -isopropyl-3-methyl-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;6-(l-isopropyl-5-methyl-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;6-(l-isopropyl-3,5-dimethyl-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyndine-3-carboxamide;7-(l-(l,3-difluoropropan-2-yl)-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3 -carboxamide;7-(l-(1.3-difluoropropan-2-yl)-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)imidazo|d,2-a]pyridine-3 -carboxamide:N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(l,l,1 -trifluoropropan-2-yl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3 -carboxamide;N-(4-methy 1- 1 H-pyrazol-3-y l)-7-( 1 -( 1, 1, 1 - trifl uoro-2 -methylpropan-2-yl)- 1H-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(l,l,l-trifluoro-2-methylpropan-2-yl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide;N-(4-methyl-lH-pyrazol-3-yl)-7-(l-(l,l,l-trifluoropropan-2-yl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide:(R)-N-(4,5-dimethyl- lH-pyrazol-3-y l)-6-( 1 -( 1, 1, 1 -trifluoropropan-2-yl)- IH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;(R)-N-(4-methyl-lH-pyrazol-3-yl)-6-(l-(l,l,l-trifluoropropan-2-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;(S)-N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(l,l,l-trifluoropropan-2-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;Agent Ref.: 16738.0002-00304(S)-N-(4-methyl- 1 H-pyrazol-3-y l)-6-( 1 -( 1, 1, 1 - trifl uoropropan-2-y 1)- 1 H-py razol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;N-(5-(l-isopropyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridin-3-yl)-4,5-dimethyl-lH-pyrazole-3-carboxamide;N-(4-methyl-lH-pyrazol-3-yl)-6-(l-(l,l,l-trifluoro-2-methylpropan-2-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;6-(l-(L3-difluoropropan-2-yl)-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;6-(l-(l,3-difluoropropan-2-yl)-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;7-(l-(tert-butyl)-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;7-(l-cyclobutyl-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;7-(l-cyclobutyl-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[1.2-a]pyridine-3-carboxamide;7-(l-(tert-butyl)-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-((lS,2R)-2-fluorocyclopropyl)-lH-pyrazol-4-yl)pyrazolofl,5-a]pyridine-3-carboxamide;7-(l -(bicyclofl.1.1 ]pentan-l -yl)-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3 -carboxamide;7-(l -(bicyclofl. l.l]pentan-l -yl)-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide:7-(2-cyclopropyl-2H-l,2,3-triazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;7-(2-cyclopropyl-2H-l,2,3-triazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide:1 -(4-(3-((4-methyl- lH-pyrazol-3-yl)carbamoyl)imidazo[ 1,2-a]pyridin-7-yl)-lH-pyrazol- 1 -yl)cyclopropane- 1 -carboxylic acid;2-methyl-2-(4-(3-((4-methyl-lH-pyrazol-3-yl)carbamoyl)imidazo[l,2-a]pyridin-7-yl)-lH-pyrazol-l-yl)propanoic acid;methyl 2-methyl-2-(4-(3-((4-methyl- lH-pyrazol-3-yl)carbamoyl)imidazo[l,2-a]pyridin-7-yl)-lH-pyrazol-l-yl)propanoate;Agent Ref.: 16738.0002-00304methyl l-(4-(3-((4-methyl-lH-pyrazol-3-yl)carbamoyl)imidazo[l,2-a]pyridin-7-yl)-1 H-pyrazol- 1 -y l)cy clopropane- 1 -carboxylate;7-(l-(l-(hydroxymethyl)cyclopropyl)-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;7-(l-(l -hydroxy -2-methylpropan-2-yl)-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide:6-(l-(bicyclo[l.l.l]pentan-l-yl)-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;6-(l-(bicyclo[l.l.l]pentan-l-yl)-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;7 -( 1 -isopropy 1- 1H- 1.2.3 -triazol-4-yl)-N-(4-methy 1- 1 H-py razol-3 -y l)imidazo [1.2-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(3-fluorobicyclo[l.l.l]pentan-l-yl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide;7-(2-isopropyl-2H-l,2,3-triazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(r-methyl-l'H-[l,4'-bipyrazol]-4-yl)imidazo[l,2-a]pyridine-3 -carboxamide;7-(r-cyclopropyl-lH-[L4'-bipyrazol]-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3 -carboxamide:N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l'-isopropyl-l 'H-[l,4'-bipyrazol]-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l'-isopropyl-rH-[l,4'-bipyrazol]-4-yl)imidazo[l,2-a]pyridine-3-carboxamide:7-(rH-[l,4'-bipyrazol]-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(isoxazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide;7-(r-methyl-l'H-[l,4'-bipyrazol]-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;7-(l'-cyclopropyl-l'H-| l.4'-bipyrazol|-4-yl)-N-(4-methvl-l H-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;Agent Ref.: 16738.0002-003047-(l'-isopropyl-lH-[l,4'-bipyrazol]-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)imidazo[l,2-a] pyridine-3-carboxamide;7-(rH-[l,4'-bipyrazol]-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;7-(l-(3,3-difluorocyclobutyl)-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide:6-(l-(8-acetyl-8-azabicyclo[3.2.1]octan-3-yl)-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;methyl 3-(4-(3-((4,5-dimethyl-lH-pyrazol-3-yl)carbamoyl)pyrazolo[l,5-a]pyridin-6-yl)-lH-pyrazol-l-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate;N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(8-methyl-8-azabicyclo[3.

2. l]octan-3-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;6-(l-(8-acetjd-8-azabicyclo[3.2.1]octan-3-yl)-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;N-(4-methyl-lH-pyrazol-3-yl)-6-(l-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-lH-pyrazol-4-yl)pyrazololL5-aJpyridine-3-carboxamide;methyl 3-(4-(3-((4-methyl-lH-pyrazol-3-yl)carbamoyl)pyrazolo[l,5-a]pyridin-6-yl)-lH-pyrazol-l-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate;methyl 3-(4-(3-((4,5-dimethyl-lH-pyrazol-3-yl)carbamoyl)pyrazolo[l,5-a]pyridin-6-yl)- IH-pyrazol- 1 -y l)pyrrolidine- 1 -carboxylate;6-(l-(l-acetylpyrrolidin-3-yl)-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(l-methylpyrrolidin-3-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(pyrrolidin-3-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;(R)-methyl 3-(4-(3-((4,5-dimethyl-lH-pyrazol-3-yl)carbamoyl)pyrazolo[l,5-a]pyridin-6-yl)-lH-pyrazol-l-yl)pyrrolidine-l -carboxylate;(S)-methyl 3-(4-(3-((4,5-dimethyl-lH-pyrazol-3-yl)carbamoyl)pyrazolo[l,5-a]pyridin-6-yl)-lH-pyrazol-l-yl)pyrrolidine-l -carboxylate;methyl 3-(4-(3-((4-methyl-lH-pyrazol-3-yl)carbamoyl)pyrazolo[l,5-a]pyridin-6-yl)- 1 H-pyrazol- 1 -y l)pyrrolidine- 1 -carboxylate;6-(l-(l-acetylpyrrolidin-3-yl)-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;Agent Ref.: 16738.0002-00304N-(4-rnethyl-lH-pyrazol-3-yl)-6-(l-(l-methylpyrrolidin-3-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;N-(4-methyl-lH-pyrazol-3-yl)-6-(l-(pyrrolidin-3-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;(R)-methyl 3-(4-(3-((4-methyl-lH-pyrazol-3-yl)carbamoyl)pyrazolo[l,5-a]pyridin-6-yl)- 1 H-pyrazol- 1 -yl)pyrrolidine- 1 -carboxy late;(S)-methyl 3-(4-(3-((4-methyl-lH-pyrazol-3-yl)carbamoyl)pyrazolo[l,5-a]pyridin-6-yl)-lH-pyrazol-l-yl)pyrrolidine-l -carboxylate;N-(4-methyl-lH-pyrazol-3-yl)-6-(l-(oxetan-3-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(oxetan-3-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(3-hydroxy-3-methylcyclobutyl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-((ls.3s)-3-hydroxy-3-methylcyclobutyl)-lH-pyrazol-4-yl)pyrazololL5-aJpyridine-3-carboxamide;6-(l-(3-hydroxy-3-methylcyclobutyl)-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;6-(l-((ls,3s)-3-hydroxy-3-methylcyclobutyl)-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[1.5-a]pyridine-3-carboxamide;7-(l -(3-fluorobicyclo[l.1.1 ]pentan-l -yl)-l H-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(l-(3-hydroxybicyclo[l.l.l]pentan-l-yl)-lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3-carboxamide;7-(l-(3-hydroxybicyclo[l.l.l]pentan-l-yl)-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)imidazo[l,2-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(3-fluorobicyclo[l.l.l]pentan-l-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;6-( 1 -(3 -fluorobicy cl o [ 1.1.1] pentan- 1 -y 1)- 1 H-pyrazol-4-y l)-N-(4-methyl- 1 H-py razol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(3-hydroxybicyclo[l.l.l]pentan-l-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;6-( 1 -(3-hydroxybicy clo[ 1.1.1 ]pentan- 1 -yl)- lH-pyrazol-4-yl)-N-(4-methy 1- 1H-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;Agent Ref: 16738.0002-00304methyl 3-(4-(3-((4,5-dimethyl-lH-pyrazol-3-yl)carbamoyl)pyrazolo[l,5-a]pyridin-6-y 1)- 1 H-pyrazol- 1 -y l)azetidine- 1 -carboxylate;6-(l-(l-acetylazetidin-3-yl)-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(l-methylazetidin-3-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;6-(l-(azetidin-3-yl)-lH-pyrazol-4-yl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(4-fluoro-l-methylpyrrolidin-3-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(4-fluoropyrrolidin-3-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;6-(l-(4-fluoro-l-methylpyrrolidin-3-yl)-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;6-(l-(4-fluoropyrrolidin-3-yl)-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyndine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(3-fluoro-l-methylpiperidin-4-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-(3-fluoropiperidin-4-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;6-(l-(3-fluoro-l-methylpiperidin-4-yl)-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;6-(l-(3-fluoropiperidin-4-yl)-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-((3R)-3-fluoro-l-methylpiperidin-4-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;N-(4,5-dimethyl-lH-pyrazol-3-yl)-6-(l-((3S)-3-fluoro-l-methylpiperidin-4-yl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carboxamide;6-(l-((3R)-3-fluoro-l-methylpiperidin-4-yl)-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide; and6-(l-((3S)-3-fluoro-l-methylpiperidin-4-yl)-lH-pyrazol-4-yl)-N-(4-methyl-lH-pyrazol-3-yl)pyrazolo[l,5-a]pyridine-3-carboxamide; andpharmaceutically acceptable salts thereof.

29. A pharmaceutical composition comprising a pharmaceutically acceptable carrier andAgent Ref: 16738.0002-00304the compound or pharmaceutically acceptable salt of any one of claims 1-28.

30. The pharmaceutical composition of claim 29, wherein the pharmaceutical composition is formulated in a form of tablets, capsules, powders, liquids, suspensions, suppositories, or aerosols.

31. A packaged pharmaceutical composition comprising a pharmaceutical composition of claim 29 or 30 and instructions for using the composition to treat a subject suffering from a c-Kit-mediated disorder, disease, or condition.

32. A method of inhibiting wild -type c-Kit or a c-Kit mutant thereof in a biological sample comprising contacting the sample with the compound or pharmaceutically acceptable salt of any one of claims 1-28, or the pharmaceutical composition of any one of claims 29-31.

33. A method of inhibiting wild-type c-Kit or a c-Kit mutant thereof in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound or pharmaceutically acceptable salt of any one of claims 1-28 or the pharmaceutical composition of any one of claims 29-31.

34. A method of treating a c-Kit-mediated disorder, disease, or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound or pharmaceutically acceptable salt of any one of claims 1-28 or the pharmaceutical composition of any one of claims 29-31.

35. The method of claim 34, wherein the c-Kit-mediated disorder, disease, or condition is a mast-cell associated disease, a respiratory disease, an inflammatory disorder, an autoimmune disorder, a metabolic disease, a fibrotic disease, a dermatological disease, an allergic disease, a cardiovascular disease, or a neurological disorder.

36. The method of claim 34 or 35, wherein the c-Kit-mediated disorder, disease, or condition is mediated by wild-type c-Kit kinase.

37. The method of claim 36, wherein the disorder, disease, or condition mediated by wildtype c-Kit kinase is selected from urticaria, dermatosis, idiopathic anaphylaxis, asthma, hereditary' alpha tr ptascmia (HAT), neurofibromatosis, idiopathic pulmonary fibrosis, bullous pemphigoid, prurigo nodularis, age-related macular degeneration, allergic conjunctivitis, allergic rhinitis, alpha-I antitrypsin deficiency, Alzheimer's disease, amyotrophic lateral sclerosis (AML), bronchiectasis, Celiac disease, chronic graft verse host disease, chronic rhinosinusitis with nasal polyps, colorectal cancer, dermatitis herpetiformis, irritable bowel syndrome (IBS), fibromyalgia, fibrosis, food allergies, insulin-dependent diabetes mellitus, mast cell leukemia, migraine, multiple sclerosis, Parkinson's disease, psoriasis, rheumatoid arthritis, pulmonary arterial hypertension (PAH), inflammatory bowelAgent Ref: 16738.0002-00304disease (IBD), scleroderma, dermatosis, dermatitis herpetiformis, melanoma, gastrointestinal stromal tumor, mast cell tumor, anaphylactic syndrome, idiopathic anaphylaxis, eosinophilic esophagitis, and mastocytosis.

38. The method of any one of claims 34-37, wherein the c-Kit-mediated disorder, disease, or condition is selected from asthma, chronic urticaria, rheumatoid arthritis, psoriasis, atopic dermatitis, neurofibromatosis, multiple sclerosis, and idiopathic pulmonary fibrosis.

39. The method of claim 34 or 35, wherein the c-Kit-mediated disorder, disease, or condition is mediated by a c-Kit mutant.

40. The method of claim 39, wherein the c-Kit mutant is a c-Kit D816 mutant.

41. The method of claim 40, wherein the c-Kit D816 mutant is a D816V mutant.

42. The method of any one of claims 39-41, wherein the c-Kit-mutant-mediated disorder, disease, or condition is selected from piebaldism, gastrointestinal stromal tumors (GIST), melanoma, systemic mastocytosis, mast cell disease, leukemia (acute myelogenous, corefactor binding, and mast cell), sinonasal natural killer / T-cell lymphoma (NKTCL), seminoma, lung adenocarcinoma, colon adenocarcinoma, conventional glioblastoma multiforme, intracranial dysgerminoma, and ovarian dysgerminoma.

43. The method of any one of claims 39-42, wherein the c-Kit-mutant-mediated disorder, disease, or condition is selected from GIST and systemic mastocytosis.

Images