FMS-like tyrosine kinase 3 (FLT3) inhibitors for treating cell proliferative diseases or conditions

Abstract

The compounds of formula (I) and methods of making and using compounds are described herein where R1, R2, and X are defined according to the present disclosure. The compounds can have FLT3 inhibitory, BCR::ABL1 inhibitory, and / or antiproliferative activity and may be used in methods for treating subjects a cell proliferative disease or condition.

Description

[0001] FMS-LIKE TYROSINE KINASE 3 (FLT3) INHIBITORS FOR TREATING CELL PROLIFERATIVE DISEASES OR CONDITIONS CROSS-REFERENCE TO RELATED APPLICATIONS This application claims benefit of priority to U.S. Application Serial No. 63 / 519,117, filed August 11, 2023, the content of which is incorporated by reference in its entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH This invention was made with government support under R01 CA249282, R01 CA194094, and K00 CA212480 awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND OF THE INVENTION Acute myeloid leukemia (AML) is a hematologic cancer characterized by proliferative, clonal, abnormally differentiated, and poorly differentiated cells. Activating mutations in FMS- like tyrosine kinase 3 (FLT3) are the most frequent genetic alteration in AML, found in 30% of newly diagnosed cases. FLT3 activating mutations have two subtypes: internal tandem duplication at the juxtamembrane domain (FLT3-ITD), and point mutations in the tyrosine kinase domain (FLT3-TKD). Recently, the BCR::ABL1 gene fusion has emerged as a cause of off-target secondary clinical resistance in AML after FLT3 inhibitor treatment. As a result, there is a need for inhibitors for FLT3, including inhibitors with dual FLT3 / BCR::ABL1 inhibition, for the treatment of cell proliferative diseases and conditions, such as AML. BRIEF SUMMARY OF THE INVENTION Disclosed herein are compounds, and pharmaceutically acceptable salts thereof, having FLT3 inhibitory, BCR::ABL1 inhibitory, and antiproliferative activity. The compounds disclosed herein may have a formula of , where R1, R2, and X are defined as N, CH, or CR2. R1may be selected from Page 1 of 82 QB\169852.00141\91596905.1 O S . R2may be NRARBor halo. comprises NRARB, RAis hydrogen and RBis an said alkoxyl optionally substituted with a heterocycle or a halo, an alkyl, said alkyl optionally substituted with a halo, an amino or an ester, an alkenyl, a sulfonyl, a nitro, a cyano, a halo, or C(O)ORCwherein RCis an alkyl; a heteroaryl optionally substituted with an alkyl, or an aryl, said aryl optionally substituted with an alkyl or a halo; a heterocyclyl optionally substituted with Boc; or and n is 1 or 2; or an alkyl optionally aryl, said aryl optionally substituted with a halo. In other embodiments where the compound comprises NRARB, RAand RBtogether form a heterocycyl optionally substituted with an alkyl or a protecting group, such as Boc. Another aspect of the technology provides for pharmaceutical compositions comprising one or more of the compounds described herein. Another aspect of the technology provides for a method for treating a subject for a cell proliferative disease or condition by administering the subject one or more of the compounds described herein. Suitably, the cell proliferative disease or condition is hematological cancer, such as leukemia. The leukemia may be acute myeloid leukemia or chronic myelogenous leukemia. In some instances, the cell proliferative disease or condition is characterized by an FLT3 activating mutation. Additionally or alternatively, the cell proliferative disease or condition is characterized by a BCR::ABL1 gene fusion. Another aspect of the technology provides for a method for inhibiting the growth or proliferation of a cancer cell. BRIEF DESCRIPTION OF THE DRAWINGS Non-limiting embodiments of the present invention will be described by way of example with reference to the accompanying figures, which are schematic and are not intended to be drawn to scale. In the figures, each identical or nearly identical component illustrated is typically represented by a single numeral. For purposes of clarity, not every component is labeled in every figure, nor is every component of each embodiment of the invention shown Page 2 of 82 QB\169852.00141\91596905.1 where illustration is not necessary to allow those of ordinary skill in the art to understand the invention. Figure 1A illustrates the reference compounds Gilteritinib, Quizartinib, and Vandetanib. Figure 1B illustrates the structure of compound A. Figure 1C illustrates FLT3 inhibitor MZH29 previously reported with high anti leukemic cellular effects. Figure 2 illustrates the dose-response MV4-11 activity curve for compound A and Giltertinib. Figure 3A illustrates the western blot analysis of MV4-11 cells treated with quizartinib. DMSO diluent was used as control in each experiment, and GAPDH as a loading control. Figure 3B illustrates the western blot analysis of MV4-11 cells treated with compound A. DMSO diluent was used as control in each experiment, and GAPDH as a loading control. Figure 3C illustrates the dose-response quantification of p-ERK signal versus vehicle (DMSO) treatment. Figure 4 illustrates the Lineweaver–Burk plot of FLT3 inhibition kinetic studies co- incubated with various concentrations of compound A. Figure 5 illustrates the apoptosis analysis of compound A on MV4-11 cell line. Figure 6 illustrates the kinase selectivity profiling of compound A. Figure 7 demonstrates that compound A’s effects may have biphasic characteristics. Figure 8 illustrates the structure of compound A and compound B. Figure 9 illustrates the cell-based viability curve of Gilteritinib and compound 24. Figure 10A illustrates the western blot analysis of MOLM14, MOLM14-D835Y, and MOLM14-F691L cells treated with compound 24. DMSO diluent was used as control in each experiment, and GAPDH as a loading control. Figure 10B illustrates the western blot analysis of MOLM14, MOLM14-D835Y, and MOLM14-F691L cells treated with Gilteritinib. DMSO diluent was used as control in each experiment, and GAPDH as a loading control. Figure 11 illustrates the cell-based viability curves of compound C with multiple cell lines. Figure 12 illustrates the chemical structures of compounds C and B. Figure 13A illustrates the western blot of compound C on MOLM14. Figure 13B illustrates the western blot of compound C on MOLM14-D835Y. Page 3 of 82 QB\169852.00141\91596905.1 Figure 13C illustrates the western blot of compound C on MOLM14-F691L. Figure 13D illustrates the western blot of compound C on K562 (D). Figure 14 illustrates the apoptosis assays of MOL14 cells treated with 1 nM and 10 nM of compound C for 24h, 48h, or 72h, respectively. DMSO was used as control. DETAILED DESCRIPTION OF THE INVENTION Disclosed herein are compounds having FLT3 inhibitory, BCR::ABL1 inhibitory, and antiproliferative activity. Diseases and disorders treated by the disclosed compounds, pharmaceutical compositions, and methods may include, but are not limited to, cell proliferative diseases and disorders such as cancer, including acute myeloid leukemia, acute lymphoblastic leukemia, and chronic myeloid leukemia. Several small molecule compounds have shown high potency toward various cancer related cell lines. In previous studies, inhibitors with high potency at mid- to high-picomolar levels against leukemic cell lines were discovered, and were usually associated with strong FLT3 inhibition. However, the Examples demonstrated a compound with IC50as low as ~2 pM against MV4-11 cells. Moreover, the FLT3 inhibition of may be in the nanomolar range, rather than the picomolar range observed against MV4-11 cells, indicating that there may be another antiproliferative molecular mechanism distinct from FLT3 inhibition that is responsible for its high anti-MV4-11 potency. The examples also demonstrated a compound with dual FLT3 / BCR::ABL1 inhibition. Definitions The disclosed subject matter may be further described using definitions and terminology as follows. The definitions and terminology used herein are for the purpose of describing particular embodiments only and are not intended to be limiting. As used in this specification and the claims, the singular forms “a,” “an,” and “the” include plural forms unless the context clearly dictates otherwise. For example, the term “a substituent” should be interpreted to mean “one or more substituents,” unless the context clearly dictates otherwise. As used herein, “about”, “approximately,” “substantially,” and “significantly” will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which they are used. If there are uses of the term which are not clear to persons of ordinary skill in the art given the context in which it is used, “about” and “approximately” will mean up to plus or minus 10% of the particular term and “substantially” and “significantly” will mean more than plus or minus 10% of the particular term. Page 4 of 82 QB\169852.00141\91596905.1 As used herein, the terms “include” and “including” have the same meaning as the terms “comprise” and “comprising.” The terms “comprise” and “comprising” should be interpreted as being “open” transitional terms that permit the inclusion of additional components further to those components recited in the claims. The terms “consist” and “consisting of” should be interpreted as being “closed” transitional terms that do not permit the inclusion of additional components other than the components recited in the claims. The term “consisting essentially of” should be interpreted to be partially closed and allowing the inclusion only of additional components that do not fundamentally alter the nature of the claimed subject matter. The phrase “such as” should be interpreted as “for example, including.” Moreover, the use of any and all exemplary language, including but not limited to “such as”, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. Furthermore, in those instances where a convention analogous to “at least one of A, B and C, etc.” is used, in general such a construction is intended in the sense of one having ordinary skill in the art would understand the convention (e.g., “a system having at least one of A, B and C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together.). It will be further understood by those within the art that virtually any disjunctive word and / or phrase presenting two or more alternative terms, whether in the description or figures, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms. For example, the phrase “A or B” will be understood to include the possibilities of “A” or ‘B or “A and B.” All language such as “up to,” “at least,” “greater than,” “less than,” and the like, include the number recited and refer to ranges which can subsequently be broken down into ranges and subranges. A range includes each individual member. Thus, for example, a group having 1-3 members refers to groups having 1, 2, or 3 members. Similarly, a group having 6 members refers to groups having 1, 2, 3, 4, or 6 members, and so forth. The modal verb “may” refers to the preferred use or selection of one or more options or choices among the several described embodiments or features contained within the same. Where no options or choices are disclosed regarding a particular embodiment or feature contained in the same, the modal verb “may” refers to an affirmative act regarding how to make or use and aspect of a described embodiment or feature contained in the same, or a definitive decision to use a specific skill regarding a described embodiment or feature contained in the Page 5 of 82 QB\169852.00141\91596905.1 same. In this latter context, the modal verb “may” has the same meaning and connotation as the auxiliary verb “can.” Chemical Entities The term "alkyl" refers to a straight-chain or branched alkyl radical in all of its isomeric forms, such as a straight or branched group of 1-12, 1-10, or 1-6 carbon atoms, referred to herein as C1-C12-alkyl, C1-C10-alkyl, and C1-C6-alkyl, respectively. The term "alkylene" refers to a diradical of straight-chain or branched alkyl group (e.g., a diradical of straight-chain or branched C1-C12alkyl group). Exemplary alkylene groups include, but are not limited to -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)CH2-, - CH2CH(CH3)CH2-, -CH(CH2CH3)CH2-, and the like. The term "alkenyl" refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched group of 2-12, 2-10, or 2- 6 carbon atoms, referred to herein as C2-C12-alkenyl, C2-C10-alkenyl, and C2-C6-alkenyl, respectively. The terms "alkoxy" or "alkoxyl" refers to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxy groups include methoxy, ethoxy, tert- butoxy and the like. The term "cycloalkyl" refers to a monovalent saturated or partially saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as "C4-8-cycloalkyl," derived from a cycloalkane. Unless specified otherwise, the cycloalkyl group is not substituted, i.e., it is unsubstituted. The term “heterocycle”, or "heterocycloalkyl" (or "heterocyclyl") refers to a monovalent saturated or partially saturated cyclic, bicyclic, or bridged cyclic hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons in which at least one carbon of the cycloalkane is replaced with a heteroatom such as, for example, N, O, and / or S. The terms “amine” and “amino” refer to both unsubstituted and substituted amines, wherein substituents may include, for example, alkyl, cycloalkyl, heterocyclyl, alkenyl, and aryl. The term "halo" refers to a halogen atom or halogen radical (e.g., -F, -Cl, -Br, or -I). The term "haloalkyl" refers to an alkyl group that is substituted with at least one halogen. For example, -CH2F, -CHF2, -CF3, -CH2CF3, -CF2CF3, and the like. The term "aryl" refers to a carbocyclic aromatic group. The term "aryl" includes monocyclic ring systems, and polycyclic ring systems having two or more carbocyclic rings in Page 6 of 82 QB\169852.00141\91596905.1 which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic and, e.g., the other ring(s) may be cycloalkyls, cycloalkenyls, cycloalkynyls, and / or aryls. Unless specified otherwise, the aryl ring is unsubstituted. In certain embodiments, the aryl group is a 6-10 membered ring structure. Representative aryl groups include phenyl, naphthyl, anthracenyl, 1,3-benzodioxolyl, 1,4- benzodioxanyl and the like. The substituents on the aryl (e.g., phenyl) rings in the compounds of the disclosure may be at ortho-, meta-, or para- positions. The term "heteroaryl" refers to an aromatic 5- to 10-membered ring structure, alternatively 6- to 10-membered rings, whose ring structures include one to four heteroatoms, such as nitrogen, oxygen, and sulfur. The number of ring atoms in the heteroaryl group can be specified using Cx-Cx nomenclature where x is an integer specifying the number of ring atoms. For example, a C3-C7 heteroaryl group refers to an aromatic 3- to 7-membered ring structure containing one to four heteroatoms, such as nitrogen, oxygen, and sulfur. The term "heteroaryl" includes monocyclic ring systems, and polycyclic ring systems having two or more heterocyclic rings in which two or more carbon or heteroatom are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is a heterocyclic aromatic group and, e.g., the other ring(s) may be cycloalkyls, cycloalkenyls, cycloalkynyls, and / or aryls. Representative heteroaryl groups include pyridinyl, quinolinyl, furanyl, thionyl, indolyl, and the like. The term “Boc” refers to tert-butyloxycarbonyl. The term “optionally substituted” refers to one or more carbon atoms in the group being independently substituted with one or more functional groups described herein. The compounds of the disclosure may contain one or more chiral centers and / or double bonds and, therefore, exist as stereoisomers, such as geometric isomers, enantiomers or diastereomers. The term "stereoisomers" when used herein consist of all geometric isomers, enantiomers or diastereomers. These compounds may be designated by the symbols "R" or "S," or "+" or "-" depending on the configuration of substituents around the stereogenic carbon atom and or the optical rotation observed. The present invention encompasses various stereo isomers of these compounds and mixtures thereof. Stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers may be designated (±)" in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. It is understood that graphical depictions of chemical structures, e.g., generic Page 7 of 82 QB\169852.00141\91596905.1 chemical structures, encompass all stereoisomeric forms of the specified compounds, unless indicated otherwise. Also contemplated herein are compositions comprising, consisting essentially of, or consisting of an enantiopure compound, which composition may comprise, consist essentially of, or consist of at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of a single enantiomer of a given compound (e.g., at least about 99% of an R enantiomer of a given compound). As used herein, "salt" refers to acid addition salts and basic addition salts. It may also refer to those salts that may be prepared in situ during the final isolation and purification of the compounds of the invention. Examples of acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isothionate), lactate, malate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides such as, but not limited to, methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as, but not limited to, decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained. Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid and such organic acids as acetic acid, fumaric acid, maleic acid, 4-methylbenzenesulfonic acid, succinic acid, and citric acid. Basic addition salts may be prepared in situ during the final isolation and purification of compounds of this invention by reacting a carboxylic acid-containing moiety with a suitable base such as, but not limited to, the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as, but not limited to, lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylamine, Page 8 of 82 QB\169852.00141\91596905.1 dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine and the like. Other examples of organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like. Compounds described herein may exist in unsolvated as well as solvated forms, including hydrated forms, such as hemi-hydrates. In general, the solvated forms, with pharmaceutically acceptable solvents such as water and ethanol among others are equivalent to the unsolvated forms for the purposes of the invention. Compounds Disclosed herein includes a compound of Formula I (Formula I), or a pharmaceutically acceptable X may be selected from N, CH, or CR2. In some embodiments, X is N. In other embodiments, X is CH. In yet other embodiments, X is CR2.O R1may be selected from . In some embodiments, . optionally substituted with an alkoxyl, said alkoxyl optionally substituted with a heterocycle or a halo, an alkyl, said alkyl optionally substituted with a halo, an amino or an ester, an amide, an alkenyl, a sulfonyl, a nitro, a cyano, a halo, or C(O)ORCwhere RCis an alkyl; or RBis a heteroaryl optionally substituted with an alkyl, or an aryl, said aryl optionally substituted with an alkyl or a halo; or RBis a heterocyclyl optionally substituted with Boc; or RBand n is 1 or 2; or RBis an alkyl optionally substituted with aryl, said aryl with a halo; orbR2may be NRARBwhere RAand RBtogether form a heterocycyl optionally substituted with an alkyl or Boc; or R2may be a halo. Page 9 of 82 QB\169852.00141\91596905.1 In some embodiments, R2is NRARBand RAis hydrogen and RBis an aryl optionally substituted with an alkoxyl, said alkoxyl optionally substituted with a heterocycle or a halo, an alkyl, said alkyl optionally substituted with a halo, an amino or an ester, an alkenyl, a sulfonyl, a nitro, a cyano, a halo, or C(O)ORCwherein RCis an alkyl. In some embodiments, R2is NRARBand RAis hydrogen and RBis an aryl optionally substituted with an alkoxyl, said alkoxyl optionally substituted with a heterocycle or a halo, an alkyl, said alkyl optionally substituted with a halo, an amino or an ester, or a sulfonyl. In some embodiments, R2is NRARBand RAis hydrogen and RBis an aryl optionally substituted with an alkoxyl, said alkoxyl optionally substituted with a heterocycle, an alkyl, said alkyl optionally substituted with an amino, or a sulfonyl. In some embodiments, R2is NRARBand RAis hydrogen and RBis a heteroaryl optionally substituted with an alkyl, or an aryl, said aryl optionally substituted with an alkyl or a halo. In some embodiments, R2is NRARBand RAis hydrogen and RBis a heterocyclyl optionally substituted with Boc. In some embodiments, R2is NRARBand RAis hydrogen and wherein n is 1 or 2. In some embodiments, R2is NRARBand RAand RBtogether form a heterocycyl optionally substituted with an alkyl or Boc. In some embodiments, R2is halo. In some embodiments, the compound is N-(2,4-dimethoxyphenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3- yl)pyridin-2-amine, N-(4-methoxyphenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3- yl)pyridin-2-amine, 3-(2-chlorophenyl)-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine. 3-(3-chlorophenyl)-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine, 3-(4-chlorophenyl)-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine, 4-(6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2- yl)piperazine-1-carboxylate, tert-butyl 2-methyl-4-(6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3- yl)pyridin-2-yl)piperazine-1-carboxylate, Page 10 of 82 QB\169852.00141\91596905.1 tert-butyl 4-((6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2- yl)amino)piperidine-1-carboxylate, 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(4-(2-(piperidin-1- yl)ethoxy)phenyl)pyridin-2-amine, 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(4-(2- morpholinoethoxy)phenyl)pyridin-2-amine, 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(4- morpholinophenyl)pyridin-2-amine, 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(4-(2-(pyrrolidin-1- yl)ethoxy)phenyl)pyridin-2-amine, N-(4-(2-(diethylamino)ethoxy)phenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2- a]pyridin-3-yl)pyridin-2-amine, 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(p-tolyl)pyridin-2- amine, 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(4- vinylphenyl)pyridin-2-amine, N-(4-ethylphenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3- yl)pyridin-2-amine, N-(4-isopropylphenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3- yl)pyridin-2-amine, N-(4-(tert-butyl)phenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3- yl)pyridin-2-amine, N-(3-(tert-butyl)phenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3- yl)pyridin-2-amine, N-(2-methoxyphenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3- yl)pyridin-2-amine, N-(3,4-dimethoxyphenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3- yl)pyridin-2-amine, 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(3,4,5- trimethoxyphenyl)pyridin-2-amine, N-(benzo[d][1,3]dioxol-5-yl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin- 3-yl)pyridin-2-amine, Page 11 of 82 QB\169852.00141\91596905.1 N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-(7-(1-methyl-1H-pyrazol-4- yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-amine, 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(4- (methylsulfonyl)phenyl)pyridin-2-amine, 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(2- (trifluoromethyl)phenyl)pyridin-2-amine, 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(3- (trifluoromethyl)phenyl)pyridin-2-amine, 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(4- (trifluoromethyl)phenyl)pyridin-2-amine, 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(4- (trifluoromethoxy)phenyl)pyridin-2-amine, 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(4- nitrophenyl)pyridin-2-amine, N-(6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-yl)pyrazin- 2-amine, 4-((6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2- yl)amino)benzonitrile, N-(4-chlorophenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3- yl)pyridin-2-amine, N-(2,6-difluorobenzyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3- yl)pyridin-2-amine, methyl 4-methyl-3-((6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3- yl)pyridin-2-yl)amino)benzoate, tert-butyl 4-((6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2- yl)amino)benzoate, ethyl 2-(4-((6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2- yl)amino)phenyl)acetate, N-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)-6-(7-(1-methyl-1H-pyrazol-4- yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-amine, N-(3-(tert-butyl)-1-(4-fluorophenyl)-1H-pyrazol-5-yl)-6-(7-(1-methyl-1H-pyrazol-4- yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-amine, Page 12 of 82 QB\169852.00141\91596905.1 N-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-6-(7-(1-methyl-1H-pyrazol-4- yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-amine, N-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)-6-(7-(4- (methylsulfonyl)phenyl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-amine, N-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-6-(7-(4- (methylsulfonyl)phenyl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-amine, 6-(7-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridin-3-yl)-N-(3,4,5- trimethoxyphenyl)pyridin-2-amine, N-(4-(tert-butyl)phenyl)-6-(7-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridin-3- yl)pyridin-2-amine, or N-(3-methoxyphenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3- yl)pyridin-2-amine. In some embodiments, the compound is N-(2,4-dimethoxyphenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3- yl)pyridin-2-amine, N-(4-methoxyphenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3- yl)pyridin-2-amine, 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(4-(2-(piperidin-1- yl)ethoxy)phenyl)pyridin-2-amine (compound 8), 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(4-(2- morpholinoethoxy)phenyl)pyridin-2-amine (compound 9), 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(4-(2-(pyrrolidin-1- yl)ethoxy)phenyl)pyridin-2-amine (compound 11), N-(4-(2-(diethylamino)ethoxy)phenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2- a]pyridin-3-yl)pyridin-2-amine (compound 12), 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(p-tolyl)pyridin-2- amine (compound 13), N-(2-methoxyphenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3- yl)pyridin-2-amine (compound 19), N-(3,4-dimethoxyphenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3- yl)pyridin-2-amine (compound 20), N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-(7-(1-methyl-1H-pyrazol-4- yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-amine (compound 23), Page 13 of 82 QB\169852.00141\91596905.1 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(4- (methylsulfonyl)phenyl)pyridin-2-amine (compound 24), 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(3- (trifluoromethyl)phenyl)pyridin-2-amine (compound 26), N-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)-6-(7-(1-methyl-1H-pyrazol-4- yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-amine (compound 37), N-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)-6-(7-(4- (methylsulfonyl)phenyl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-amine (compound 40), 6-(7-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridin-3-yl)-N-(3,4,5- trimethoxyphenyl)pyridin-2-amine (compound 42), or N-(3-methoxyphenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3- yl)pyridin-2-amine. The disclosed compounds may be formulated as pharmaceutical compositions. In some embodiments, pharmaceutical compositions as contemplated herein include a compound as disclosed herein, for example, in an effective amount for treating a disease or disorder, and a suitable pharmaceutical carrier, excipient, or diluent. The disclosed compounds, and / or pharmaceutical compositions comprising the disclosed compound may be administered to subjects in need thereof, for example, to treat and / or prevent a disease or disorder. Suitable diseases or disorders may include cell proliferative diseases or disorders such as cancer. Suitable cancers treated and / or prevented in the disclosed methods may include, but are not limited to, acute myeloid leukemia and chronic myelogenous leukemia. The disclosed compounds may exhibit one or more biological activities. In some embodiments, the disclosed compounds modulate the activity of a cancer cell, such as MV4- 11, expressing FLT3-ITD mutation; activity of the AML cancer cell line MOLM. In some embodiments, the cancer cell is MOLM14, including MOLM14-D835Y and MOLM14-F691L sublines; or K562, expressing BCR::ABL1 mutation. In some embodiments, the disclosed compounds inhibit cell activity by at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% at a concentration of less than 1000 nM, 100 nM, 50 nM, 10 nM, 1 nM, 0.1 nM, 0.01 nM or less. In some embodiments, the disclosed compounds modulate the activity of the AML cancer cell line MOLM. In some embodiments, the cancer cell is MOLM14, including MOLM14-D835Y and MOLM14-F691L sublines. In some embodiments, the disclosed Page 14 of 82 QB\169852.00141\91596905.1 compounds inhibit cell activity by at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% at a concentration of less than 1000 nM, 100 nM, 50 nM, 10 nM, 1 nM, 0.1 nM, or less. In some embodiments, the disclosed compounds modulate the activity of the CML cancer cell line K562. In some embodiments, the disclosed compounds inhibit cell activity by at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% at a concentration of less than 1000 nM, 100 nM, 50 nM, 10 nM, 1 nM, 0.1 nM, or less. In some embodiments, the disclosed compounds modulate the activity of FMS-like tyrosine kinase 3 (FLT3). In some embodiments, the disclosed compounds inhibit the activity of FLT3 by at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% at a concentration of less than 1000 nM, 100 nM, 50 nM, 10 nM, 1 nM, 0.1 nM, or less. In some embodiments, the disclosed compounds modulate the activity of FMS-like tyrosine kinase 3 (FLT3) with internal tandem duplication at the juxtamembrane domain (FLT3-ITD mutation). In some embodiments, the disclosed compounds inhibit the activity of FLT3 by at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% at a concentration of less than 1000 nM, 100 nM, 50 nM, 10 nM, 1 nM, 0.1 nM, or less. In some embodiments, the disclosed compounds modulate the activity of the BCR::ABL1 pathway. Off-target activation of such pathway may cause resistance to the treatment of FLT3 mutated AML. In some embodiments, the disclosed compounds inhibit BCR::ABL1 pathway by at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% at a concentration of less than 1000 nM, 100 nM, 50 nM, 10 nM, 1 nM, 0.1 nM, or less. Cell proliferation and inhibition thereof by the disclosed compounds may be assessed by cell viability methods disclosed in the art. In some embodiments, the disclosed compounds have an IC50from greater than 1 pM to 1000 nM, from greater than 1 pM to 500 nM, from greater than 1 pM to 100 nM, from greater than 1 pM to 50 nM, from greater than 1 pM to 40 nM, from greater than 1 pM to 30 nM, from greater than 1 pM to 20 nM, from greater than 1 pM to 10 nM, from greater than 1 pM to 5 nM, from greater than 1 pM to 1 nM, from greater than 1 pM to 500 pM, from greater than 1 pM to 100 pM, or from greater than 1 pM to less than 10 pM. Kinase inhibition thereof by the disclosed compounds may be assessed by FLT3 kinase activity assay including ADP-Glo kinase assay, FLT3 inhibition kinetic study, and western blot disclosed in the art. In some embodiments, the disclosed compounds have an IC50from greater than 1 pM to 1000 nM, from greater than 1 pM to 500 nM, from greater than 1 pM to 100 nM, from greater than 1 pM to 50 nM, from greater than 1 pM to 40 nM, from greater than 1 pM to Page 15 of 82 QB\169852.00141\91596905.1 30 nM, from greater than 1 pM to 20 nM, from greater than 1 pM to 10 nM, from greater than 1 pM to 5 nM, from greater than 1 pM to 1 nM, from greater than 1 pM to 500 pM, or from greater than 1 pM to 100 pM. Pharmaceutical Compositions The compounds employed in the compositions and methods disclosed herein may be administered as pharmaceutical compositions and, therefore, pharmaceutical compositions incorporating the compounds are considered to be embodiments of the compositions disclosed herein. Such compositions may take any physical form which is pharmaceutically acceptable; illustratively, they can be orally administered pharmaceutical compositions. Such pharmaceutical compositions contain an effective amount of a disclosed compound, which effective amount is related to the daily dose of the compound to be administered. Each dosage unit may contain the daily dose of a given compound or each dosage unit may contain a fraction of the daily dose, such as one-half or one-third of the dose. The amount of each compound to be contained in each dosage unit can depend, in part, on the identity of the particular compound chosen for the therapy and other factors, such as the indication for which it is given. The pharmaceutical compositions disclosed herein may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing well known procedures. In some embodiments, the compounds disclosed herein may be formulated as pharmaceutical compositions that include: (a) a therapeutically effective amount of one or more compounds as disclosed herein; and (b) one or more pharmaceutically acceptable carriers, excipients, or diluents. The pharmaceutical composition may include the compound in a range of about 0.1 to 2000 mg (preferably about 0.5 to 500 mg, and more preferably about 1 to 100 mg). The pharmaceutical composition may be administered to provide the compound at a daily dose of about 0.1 to about 1000 mg / kg body weight (preferably about 0.5 to about 500 mg / kg body weight, more preferably about 50 to about 100 mg / kg body weight). In some embodiments, after the pharmaceutical composition is administered to a subject (e.g., after about 1, 2, 3, 4, 5, or 6 hours post-administration), the concentration of the compound at the site of action may be within a concentration range bounded by end-points selected from 0.001 µM, 0.005 µM, 0.01 µM, 0.5 µM, 0.1 µM, 1.0 µM, 10 µM, and 100 µM (e.g., 0.1 µM - 1.0 µM). It is understood by those skilled in the art that dosage amount will vary with the activity of a particular inhibitor compound, disease state, route of administration, duration of treatment, Page 16 of 82 QB\169852.00141\91596905.1 and like factors well-known in the medical and pharmaceutical arts. In general, a suitable dose will be an amount which is the lowest dose effective to produce a therapeutic or prophylactic effect. If desired, an effective dose of such a compound, pharmaceutically acceptable salt thereof, or related composition may be administered in two or more sub-doses, administered separately over an appropriate period of time. In some embodiments, a pharmaceutical composition comprising the compound of as disclosed herein and a pharmaceutically suitable carrier, diluent, or excipient is provided. The pharmaceutical composition may include the compound in a range of about 0.1 to 2000 mg. In some embodiments, the pharmaceutical composition may include the compound in a range of from about 0.5 to 500 mg. In some embodiments, the pharmaceutical composition may include the compound in a range of from about 1 to 100 mg. The pharmaceutical composition may be administered to provide the compound at a daily dose of about 0.1 to about 1000 mg / kg body weight. In some embodiments, the pharmaceutical composition may be administered to provide the compound at a daily dose of about 0.5 to about 500 mg / kg body weight. In some embodiments, the pharmaceutical composition may be administered to provide the compound at a daily dose of about 50 to about 100 mg / kg body weight. In some embodiments, after the pharmaceutical composition is administered to a subject (e.g., after about 1, 2, 3, 4, 5, or 6 hours post-administration), the concentration of the compound at the site of action may be within a concentration range bounded by end-points selected from 0.001 µM, 0.005 µM, 0.01 µM, 0.5 µM, 0.1 µM, 1.0 µM, 10 µM, and 100 µM (e.g., 0.1 µM - 1.0 µM). The compounds utilized in the methods disclosed herein may be formulated as a pharmaceutical composition that includes a carrier. For example, the carrier may be selected from the group consisting of proteins, carbohydrates, sugar, talc, magnesium stearate, cellulose, calcium carbonate, and starch-gelatin paste. The compounds utilized in the methods disclosed herein may be formulated as a pharmaceutical composition that includes one or more binding agents, filling agents, lubricating agents, suspending agents, sweeteners, flavoring agents, preservatives, buffers, wetting agents, disintegrants, and effervescent agents. Filling agents may include lactose monohydrate, lactose anhydrous, and various starches; examples of binding agents are various celluloses and cross-linked polyvinylpyrrolidone, microcrystalline cellulose, such as Avicel® PH101 and Avicel® PH102, microcrystalline cellulose, and silicified microcrystalline cellulose (ProSolv SMCC™). Suitable lubricants, including agents that act on the flowability Page 17 of 82 QB\169852.00141\91596905.1 of the powder to be compressed, may include colloidal silicon dioxide, such as Aerosil®200, talc, stearic acid, magnesium stearate, calcium stearate, and silica gel. Examples of sweeteners may include any natural or artificial sweetener, such as sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and acsulfame. Examples of flavoring agents are Magnasweet® (trademark of MAFCO), bubble gum flavor, and fruit flavors, and the like. Examples of preservatives may include potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl or benzyl alcohol, phenolic compounds such as phenol, or quaternary compounds such as benzalkonium chloride. Suitable diluents may include pharmaceutically acceptable inert fillers, such as microcrystalline cellulose, lactose, dibasic calcium phosphate, saccharides, and mixtures of any of the foregoing. Examples of diluents include microcrystalline cellulose, such as Avicel® PH101 and Avicel® PH102; lactose such as lactose monohydrate, lactose anhydrous, and Pharmatose® DCL21; dibasic calcium phosphate such as Emcompress®; mannitol; starch; sorbitol; sucrose; and glucose. Suitable disintegrants include lightly crosslinked polyvinyl pyrrolidone, corn starch, potato starch, maize starch, and modified starches, croscarmellose sodium, cross-povidone, sodium starch glycolate, and mixtures thereof. Examples of effervescent agents are effervescent couples such as an organic acid and a carbonate or bicarbonate. Suitable organic acids include, for example, citric, tartaric, malic, fumaric, adipic, succinic, and alginic acids and anhydrides and acid salts. Suitable carbonates and bicarbonates include, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, sodium glycine carbonate, L-lysine carbonate, and arginine carbonate. Alternatively, only the sodium bicarbonate component of the effervescent couple may be present. The compounds utilized in the methods disclosed herein may be administered in conventional dosage forms prepared by combining the active ingredient with standard pharmaceutical carriers or diluents according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation. Pharmaceutical compositions comprising the compounds may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or Page 18 of 82 QB\169852.00141\91596905.1 parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route. Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s). Pharmaceutical compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions. Pharmaceutical compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. For example, the active ingredient may be delivered from the patch by iontophoresis. Pharmaceutical compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, impregnated dressings, sprays, aerosols or oils and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams. For applications to the eye or other external tissues, for example the mouth and skin, the pharmaceutical compositions are in some embodiments applied as a topical ointment or cream. When formulated in an ointment, the compound may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the compound may be formulated in a cream with an oil-in-water cream base or a water-in-oil base. Pharmaceutical compositions adapted for topical administration to the eye include eye drops where the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent. Pharmaceutical compositions adapted for topical administration in the mouth include lozenges, pastilles and mouth washes. Pharmaceutical compositions adapted for rectal administration may be presented as suppositories or enemas. Pharmaceutical compositions adapted for nasal administration where the carrier is a solid include a coarse powder having a particle size (e.g., in the range 20 to 500 microns) which is administered in the manner in which snuff is taken (i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose). Suitable formulations where the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient. Page 19 of 82 QB\169852.00141\91596905.1 Pharmaceutical compositions adapted for administration by inhalation include fine particle dusts or mists which may be generated by means of various types of metered dose pressurized aerosols, nebulizers or insufflators. Pharmaceutical compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations. Pharmaceutical compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets. Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tableting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavoring or coloring agents. Optionally, the disclosed compounds or pharmaceutical compositions comprising the disclosed compounds may be administered with additional therapeutic agents, optionally in combination, in order to treat cell proliferative diseases and disorders. In some embodiments Page 20 of 82 QB\169852.00141\91596905.1 of the disclosed methods, one or more additional therapeutic agents are administered with the disclosed compounds or with pharmaceutical compositions comprising the disclosed compounds, where the additional therapeutic agent is administered prior to, concurrently with, or after administering the disclosed compounds or the pharmaceutical compositions comprising the disclosed compounds. In some embodiments, the disclosed pharmaceutical composition is formulated to comprise the disclosed compounds and further to comprise one or more additional therapeutic agents, for example, one or more additional therapeutic agents for treating cell proliferative diseases and disorders. Methods of preparing pharmaceutical formulations or compositions include the step of bringing an inhibitor compound into association with a carrier and, optionally, one or more additional adjuvants or ingredients. For example, standard pharmaceutical formulation techniques can be employed, such as those described in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. Regardless of composition or formulation, those skilled in the art will recognize various avenues for medicament administration, together with corresponding factors and parameters to be considered in rendering such a medicament suitable for administration. Methods of Treatment The disclosed compounds and pharmaceutical compositions comprising the disclosed compounds may be administered in methods of treating a subject in need thereof. For example, in the methods of treatment a subject in need thereof may include a subject having a cell proliferative disease, disorder, or condition such as cancer. As used herein, the terms “treating” or “to treat” each mean to alleviate symptoms, eliminate the causation of resultant symptoms either on a temporary or permanent basis, and / or to prevent or slow the appearance or to reverse the progression or severity of resultant symptoms of the named disease or disorder. As such, the methods disclosed herein encompass both therapeutic and prophylactic administration. A “subject in need thereof” as utilized herein refers to a subject in need of treatment for a disease or disorder associated with FMS-like tyrosine kinase 3 (FLT3) activity. The term “subject” may be used interchangeably with the terms “individual” and “patient” and includes human and non-human mammalian subjects. In some embodiments, the treated subject may be a mammalian subject. Although the methods disclosed herein are particularly intended for the treatment of proliferative disorders in humans, other mammals are included. By way of non- Page 21 of 82 QB\169852.00141\91596905.1 limiting examples, mammalian subjects include monkeys, equines, cattle, canines, felines, mice, rats and pigs. As used herein, the term "disorder" refers to a condition in which there is a disturbance of normal functioning. A "disease" is any abnormal condition of the body or mind that causes discomfort, dysfunction, or distress to the person affected or those in contact with the person. Sometimes the term is used broadly to include injuries, disabilities, syndromes, symptoms, deviant behaviors, and atypical variations of structure and function, while in other contexts these may be considered distinguishable categories. It should be noted that the terms "disease", "disorder", "condition" and "illness", are equally used herein. Diseases and disorders associated with FLT3 activity may include, but are not limited to, cell proliferative diseases and disorders such as cancer. Cancers may include, but are not limited to, Acute Myeloid Leukemia (AML), Chronic Myeloid Leukemia (CML), Cutaneous Melanoma, Colon Adenocarcinoma, Endometrial Endometrioid Adenocarcinoma, Breast Invasive Ductal Carcinoma, Myelodysplastic Syndromes, Prostate Adenocarcinoma, Conventional Glioblastoma Multiforme, Skin Squamous Cell Carcinoma, Pancreatic Adenocarcinoma, Rectal Adenocarcinoma, High Grade Ovarian Serous Adenocarcinoma, Endometrial Carcinoma, Acute Lymphoblastic Leukemia, Malignant Solid Tumor, Multiple Myeloma, Non-Hodgkin Lymphoma, Hodgkin Lymphoma, Acute Leukemia, Melanoma, Secondary Acute Myeloid Leukemia, Non-Small Cell Lung Carcinoma, Bladder Carcinoma, Colorectal Carcinoma, Diffuse Large B-Cell Lymphoma, Ovarian Carcinoma, Head And Neck Carcinoma, Breast Carcinoma, Pancreatic Carcinoma, Acute Biphenotypic Leukemia, Mantle Cell Lymphoma, Therapy-Related Myelodysplastic Syndrome, Acute Promyelocytic Leukemia, T-Cell Lymphoblastic Leukemia / Lymphoma, Mixed Phenotype Acute Leukemia, Therapy-Related Acute Myeloid Leukemia, Malignant Uterine Neoplasm, Myeloproliferative Neoplasm, Anaplastic Large Cell Lymphoma, Lung Carcinoma, Glioblastoma, Lymphoma, Esophageal Squamous Cell Carcinoma, Cervical Carcinoma, Anaplastic Astrocytoma, Marginal Zone Lymphoma, Gallbladder Carcinoma, Prostate Carcinoma, Bile Duct Carcinoma, Sarcoma, B-Cell Non-Hodgkin Lymphoma, Soft Tissue Sarcoma, Gastric Adenocarcinoma, Adenocarcinoma Of The Gastroesophageal Junction, Follicular Lymphoma, Acute Erythroid Leukemia, Acute Megakaryoblastic Leukimia, Acute Undifferentiated Leukemia, Aplastic Anemia, B-Cell Acute Lymphoblastic Leukemia, B-Cell Prolymphocytic Leukemia, Bronchogenic Carcinoma, Burkitt Leukemia, Burkitt Lymphoma, Chronic Lymphocytic Leukemia, Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, Page 22 of 82 QB\169852.00141\91596905.1 Lymphoblastic Lymphoma, Myelodysplastic / Myeloproliferative Neoplasm, T-Cell Acute Lymphoblastic Leukemia, T-Cell Prolymphocytic Leukemia, or Therapy-Related Chronic Myelomonocytic Leukemia. In some embodiments, the cell proliferative disease or condition is a hematological cancer, such as leukemia. In some embodiments, the cell proliferative disease or condition is Acute Myeloid Leukemia (AML) In some embodiments, the cell proliferative disease or condition is Chronic Myeloid Leukemia (CML). In some embodiments, the cell proliferative disease or condition is characterized by an FLT3 activating mutation. In some embodiments, the cell proliferative disease or condition is characterized by a BCR::ABL1 gene fusion. The compounds for use according to the methods disclosed herein may be administered as a single compound or a combination of compounds. For example, a compound that modulates FLT3 activity may be administered as a single compound or in combination with another compound that modulates FLT3 activity or that has a different pharmacological activity. In some embodiments of the disclosed treatment methods, the subject may be administered a dose of a compound as low as 1.25 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 32.5 mg, 35 mg, 37.5 mg, 40 mg, 42.5 mg, 45 mg, 47.5 mg, 50 mg, 52.5 mg, 55 mg, 57.5 mg, 60 mg, 62.5 mg, 65 mg, 67.5 mg, 70 mg, 72.5 mg, 75 mg, 77.5 mg, 80 mg, 82.5 mg, 85 mg, 87.5 mg, 90 mg, 100 mg, 200 mg, 500 mg, 1000 mg, or 2000 mg once daily, twice daily, three times daily, four times daily, once weekly, twice weekly, or three times per week in order to treat the disease or disorder in the subject. In some embodiments, the subject may be administered a dose of a compound as high as 1.25 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 32.5 mg, 35 mg, 37.5 mg, 40 mg, 42.5 mg, 45 mg, 47.5 mg, 50 mg, 52.5 mg, 55 mg, 57.5 mg, 60 mg, 62.5 mg, 65 mg, 67.5 mg, 70 mg, 72.5 mg, 75 mg, 77.5 mg, 80 mg, 82.5 mg, 85 mg, 87.5 mg, 90 mg, 100 mg, 200 mg, 500 mg, 1000 mg, or 2000 mg, once daily, twice daily, three times daily, four times daily, once weekly, twice weekly, or three times per week in order to treat the disease or disorder in the subject. Minimal and / or maximal doses of the compounds may include doses falling within dose ranges having as end-points any of these disclosed doses (e.g., 2.5 mg – 200 mg). In some embodiments of the disclosed treatment methods, a minimal dose level of a compound for achieving therapy in the disclosed methods of treatment may be at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, Page 23 of 82 QB\169852.00141\91596905.1 700, 750, 800, 850, 900, 950, 1000, 1200, 1400, 1600, 1800, 1900, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 15000, or 20000 ng / kg body weight of the subject. In some embodiments, a maximal dose level of a compound for achieving therapy in the disclosed methods of treatment may not exceed about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1200, 1400, 1600, 1800, 1900, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 15000, or 20000 ng / kg body weight of the subject. Minimal and / or maximal dose levels of the compounds for achieving therapy in the disclosed methods of treatment may include dose levels falling within ranges having as endpoints any of these disclosed dose levels (e.g., 500 – 2000 ng / kg body weight of the subject). As used herein the term “effective amount” refers to the amount or dose of the compound, upon single or multiple dose administration to the subject, which provides the desired effect in the subject under diagnosis or treatment. The disclosed methods may include administering an effective amount of the disclosed compounds (e.g., as present in a pharmaceutical composition) for treating a disease or disorder associated with FLT3 activity. An effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances. In determining the effective amount or dose of compound administered, a number of factors can be considered by the attending diagnostician, such as: the species of the subject; its size, age, and general health; the degree of involvement or the severity of the disease or disorder involved; the response of the individual subject; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances. A typical daily dose may contain from about 0.01 mg / kg to about 100 mg / kg (such as from about 0.05 mg / kg to about 50 mg / kg and / or from about 0.1 mg / kg to about 25 mg / kg) of each compound used in the present method of treatment. Compositions can be formulated in a unit dosage form, each dosage containing from about 1 to about 500 mg of each compound individually or in a single unit dosage form, such as from about 5 to about 300 mg, from about 10 to about 100 mg, and / or about 25 mg. The term “unit dosage form” refers to a physically discrete unit suitable as unitary dosages for a patient, each unit containing a predetermined quantity of active material calculated to produce Page 24 of 82 QB\169852.00141\91596905.1 the desired therapeutic effect, in association with a suitable pharmaceutical carrier, diluent, or excipient. Oral administration is an illustrative route of administering the compounds employed in the compositions and methods disclosed herein. Other illustrative routes of administration include transdermal, percutaneous, intravenous, intramuscular, intranasal, buccal, intrathecal, intracerebral, or intrarectal routes. The route of administration may be varied in any way, limited by the physical properties of the compounds being employed and the convenience of the subject and the caregiver. The compounds and compositions disclosed herein may be administered in methods of treatment as known in the art. Accordingly, various such compounds and compositions can be administered in conjunction with such a method in any suitable way. For example, administration may comprise oral, intravenous, intraarterial, intramuscular, subcutaneous, intraperitoneal, parenteral, transdermal, intravaginal, intranasal, mucosal, sublingual, topical, rectal or subcutaneous administration, or any combination thereof. The disclosed compounds and pharmaceutical compositions comprising the disclosed compounds may also be administered in methods of inhibiting the growth or proliferation of a cancer cell. For example, the methods of inhibiting the growth or proliferation of a cancer cell may include contacting the cell with the compounds or pharmaceutical compositions disclosed herein. In some embodiments, the cancer cell is a hematological cancer cell, such as a leukemia cancer cell. In some embodiments, the cancer cell is an acute myeloid leukemia cancer cell. In some embodiments, the cancer cell is a chronic myelogenous leukemia cancer cell. In some embodiments, the cancer cell expresses a FLT3 activating mutation. In some embodiments, the cancer cell expresses a BCR::ABL1 fusion gene. In some embodiments, the cancer cell is MV4-11, MOLM, or K562 cancer cell. In some embodiments, the cancer cell is contacted with the compound in vitro or ex vivo. In some embodiments, the cancer cell is contacted with the compound in vivo. Miscellaneous All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise Page 25 of 82 QB\169852.00141\91596905.1 claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention. All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein. Preferred aspects of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred aspects may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect a person having ordinary skill in the art to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context. EXAMPLES Example 1 1. Introduction Acute myeloid leukemia (AML) is a hematologic cancer characterized by proliferative, clonal, abnormally differentiated, and poorly differentiated cells [1]. Activating mutations in FMS-like tyrosine kinase 3 (FLT3) are the most frequent genetic alteration in AML, found in 30% of newly diagnosed cases. FLT3 activating mutations have two subtypes: internal tandem duplication at the juxtamembrane domain (FLT3-ITD) [2], and point mutations in the tyrosine kinase domain (FLT3-TKD) [3, 4]. MV4-11 is an AML cell line that carries a FLT3-ITD mutation and is often used to co-incubate with kinase inhibitors to test their anti-FLT3 potency. We screened the imidazo[1,2-a]pyridine derivatives within our chemical library against the MV4-11 cell line. FLT3 inhibitors gilteritinib [7] and quizartinib [8, 9], and multi-kinase inhibitor vandetanib

[0010] were used as reference compounds (Figure 1A). Through screening, we identified N-(2,4-dimethoxyphenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2- a]pyridin-3-yl)pyridin-2-amine (compound A) (Figure 1B) with surprisingly low IC50 against MV4-11 cells, at 2.13±0.29 pM. In previous studies, inhibitors with high potency at mid- to high-picomolar levels against leukemic cell lines were discovered, and were usually associated with strong FLT3 Page 26 of 82 QB\169852.00141\91596905.1 inhibition

[0011] . For example, FLT3 inhibitor MZH29 has high potency toward MV4-11 cells, with IC50of 0.14 nM

[0012] (Figure 1C). However, a compound with IC50as low as ~2 pM is unprecedented. The FLT3 inhibition of compound A is relatively low (IC50= 16.26±1.40 nM) but not in the picomolar range, indicating that there may be another antiproliferative molecular mechanism distinct from FLT3 inhibition that is responsible for its high anti-MV4-11 potency. 2. Results and Discussion 2.1 Compound A’s high potency on MV4-11 cells is verified with dose-response curve In order to further verify the surprisingly high potency of compound A against MV4- 11 cells initially observed, we tested nine concentrations to establish a dose-response curve. In order to further investigate its antiproliferative mechanism, we compared its cellular dose- response curve to gilteritinib. We noted that the effect of compound A against MV4-11 cells is very gradual. Gilteritinib has >90% inhibition on MV4-11 cell growth at 20 nM but has <20% inhibition at 0.2 nM; however, compound A has >90% inhibition at 20 nM while maintaining ~50% inhibition at 2 pM (Figure 2). The dose-response curve indicates that compound A’s effects may have biphasic characteristics (Figure 7). 2.2 Compound A’s FLT3 inhibition The effects of FLT3 inhibitors against MV4-11 cells are usually associated with FLT3 kinase inhibitory effects. We compared the FLT3 kinase inhibition of compound A generated from ADP-Glo method with those of gilteritinib and quizartinib. The IC50s of these three compounds are comparable (Table 1). In addition, FLT3-ITD causes FLT3 autophosphorylation, leading to subsequent phosphorylation of downstream targets such as ERK, STAT5, AKT, etc. In order to further evaluate the FLT3 inhibitory effects on cellular basis, we examined the status of signaling downstream of FLT3 in MV4-11 cells treated with compound A or quizartinib by western blot. DMSO diluent was used as control in each experiment, and GAPDH as a loading control. Both quizartinib and compound A begin showing reduction of FLT3 autophosphorylation and downstream phosphorylation of ERK at ~1 nM (Figures 3A and 3B). The experiment was performed in triplicate, and the FLT3 IC50 was calculated with p-ERK as an indicator (Table 1). The cell-based FLT3 inhibitory effects of compound A and quizartinib are comparable (Figure 3C). Although the in vitro kinase inhibitory effects appear to be similar, inhibitors with different binding mechanisms may work differently in cells [13, 14]. Therefore, it is possible Page 27 of 82 QB\169852.00141\91596905.1 that compound A’s high potency toward MV4-11 cells is associated with a new FLT3 inhibitory mechanism. We therefore conducted additional inhibition kinetics studies with compound A (Figure 4). We found that compound A has ATP-competitive characteristics, and can therefore be classified as a type-I FLT3 inhibitor, similar to gilteritinib. Both ADP-Glo method and western blot show comparable FLT3 inhibition of compound A, gilteritinib and quizartinib, but compound A has much better anti-MV4-11 effects, indicating that compound A may have another molecular mechanism for antiproliferative effects other than FLT3 inhibition. Table 1: Anti kinase activities and antiproliferative activities (IC50s) of compounds of interest (nM). Compound Gilteritinib Quizartinib Vandetanib A FLT3 (ADP-Glo)a10.59±1.42 11.35±2.97 >1000 16.26±1.40 FLT3 (Western Blot)bN.T.d0.66±0.24 N.T. 0.80±0.23 MV4-11c1.07 ± 0.08 0.177±0.033 1195 ±203 0.0021±0.0003 Molm14 5.47 ±0.25 N.T. 1108 ±84 1.42 ±0.23 K562 13100±2532 N.T. 1535±150 1583±313 Ba / F3 968±32 N.T. 5663±254 8467±499aIC50for ADP-Glo, compound concentration required to inhibit the luminescent signal by 50%, referring the ADP that is produced in the enzymatic reaction;bIC50 for western blot, compound concentration required to inhibit the p-ERK signal relative to untreated MV4-11 cells by 50%;cIC50 on cells, compound concentration required to inhibit tumor cell proliferation by 50%. Data are expressed as the mean ± SD from the dose−response curves of at least three independent experiments.dNT, not tested. 2.3 Mechanism investigation for Compound A’s high potency on MV4-11 cells Both the dose-response curve of compound A on MV4-11 cells and the comparison of anti-MV4-11 effects with anti FLT3 kinase effects indicate that compound A may have a distinct molecular mechanism for its high anti-MV4-11 potency. In order to unravel the cellular mechanism responsible for this observation, MV4-11 cells were centrifuged twice after 72 Page 28 of 82 QB\169852.00141\91596905.1 hours treatment with compound A and subjected to apoptosis assays (Figure 5). The result shows that in the low concentration treatments (1pM to 1nM), early apoptotic cells very gradually accumulate as the concentration rises; in comparison, with the higher concentration treatment (10nM), both early apoptotic cells and late apoptotic cells have notably higher percentage. Compound A treated cells do not reach a substantial apoptotic percentage until nanomolar concentrations, indicating that the potency of compound A against MV4-11 cells are uncoupled from proapoptotic effects. Simultaneous inhibition of FLT3 and other kinase targets, such as CDK9 [15, 16], BCL- 2

[0017] , PI3K

[0018] , PDGFR

[0019] , KIT

[0020] , etc., has been shown to enhance antitumor effects by inducing apoptosis

[0021] . In order to investigate if the high anti-MV4-11 potency of compound A is associated with co-inhibition of other kinases, we performed kinase selectivity profiling. From the results of the site-directed competition binding assay of compound A on 96 kinases, 3 interactions (>50% wash-off) and 8 interactions (>50% wash-off) were mapped for 1 nM and for 10 nM, respectively (Figure 6). However, aside from FLT3, none of the kinases tested were mapped with >90% wash-off in either concentration. The results of kinase selectivity profiling shows that out of 96 kinases tested, no kinase other than FLT3 is strongly bound by compound A, which suggests that its high potency is unlikely due to the effect of co- inhibition of FLT3 and any other kinases. 2.4 Compound A’s high potency with MV4-11 cells Besides MV4-11 cells, we tested the antiproliferative effects of the compounds of interest on other cells (Table 1). Compound A has good antiproliferative effects on Molm14, another FLT3-ITD expressing cell line, though not as potent as in MV4-11 cells. In comparison, compound A’s inhibitory effects on Molm14 more closely correspond with FLT3 inhibition. Compound A has much less inhibitory effects on other cell lines lacking FLT3 activating mutations (K562 and Ba / F3 cells). Interestingly, compound A and its close analogue compound B (Figure 8) work very similarly on all other cells tested except MV4-11 cells (Table 2). The results of cell based anti-proliferative assays indicate that the high potency of compound A is at least partly associated with its inhibitory effects to FLT3 kinase. However, among all the cells tested, Compound A’s high potency at low picomolar level is uniquely observed with MV4-11 cells. The future investigation of MV4-11 genome and transcriptome may provide more clues on the molecular mechanism of compound A’s anti-MV4-11 effects. MV4-11 was established Page 29 of 82 QB\169852.00141\91596905.1 from blasts cells of a 10-year-old male with biphenotypic B-myelomonocytic leukemia (AML FAB M5) that carries a FLT3-ITD mutation

[0022] . In addition, it is also reported that the chromosome translocation t(4;11)(q21;q23) carried on MV4-11 contributes to AML’s poor prognosis

[0023] . This translocation leads to KMT2A-AFF1 gene fusion, causing to the loss of the methyltransferase domain of KMT2A in the KMT2A fusion protein, which influences gene expression. Additionally, AFF1 binds to multiple key transcription factors including P-TEFb

[0024] , RUNX1

[0025] , and MYC

[0026] ; therefore the KMT2A-AFF1 fusion protein controls a wide gene network. Other gene mutations with MV4-11 cell line were found on CCLE database and appended as a supplementary material (Table 3). 3. Conclusion We identified compound A with potent anti-MV4-11 effects. Further research showed that it is a type-I FLT3 inhibitor. Surprisingly, although it achieves FLT3 inhibition with comparable potency as gilteritinib and quizartinib, it is much more effective at inhibiting the growth of MV4-11 cells, suggesting a possible novel antiproliferative mechanism. Our studies showed that the picomolar concentration range anti-MV4-11 effects of compound A are not associated with proapoptotic effects and appear unlikely to be due to synergism of co-inhibition of FLT3 and any other kinases. The molecular mechanism of its high anti-MV4-11 effects is unknown. Here, we report this unique phenomenon, and preliminary investigations into its mechanism. Further investigations are ongoing. Compound A’s high potency is uniquely toward MV4-11 cells. Although there have been previous reports of several potent anti-leukemic inhibitors [11, 12], an inhibitor with an IC50 of 2 pM in a cell-based assay is unprecedented to the best of our knowledge. 4. Experimental section 4.1. Chemistry All the starting materials were obtained from commercial suppliers and used without further purification. Thermo Finnigan LCQ Deca with Thermo Surveyor LCMS System at variable wavelengths of 254 nm and 214 nm was used to monitor the reaction and test the purity of the compounds. The purity of all the final compounds is >95%. The water-methanol gradient buffered with 0.1% formic acid was used as the mobile phase for the HPLC system. NMR spectra was completed on a Varian 400 MHz instrument. The1H NMR spectra and13C spectra were recorded at 400 MHz and 101 MHz, respectively. All final compounds were purified using Silica gel (0.035e0.070 mm, 60 Å) flash chromatography, unless otherwise noted. Page 30 of 82 QB\169852.00141\91596905.1 Microwave assisted reactions were completed in sealed vessels using a Biotage Initiator microwave synthesizer (Biotage, Uppsala, Sweden). 4.1.1. The overall synthetic scheme Scheme 1 depicts the synthesis of compound A. Synthesis of imidazopyridine derivatives began with the condensation reaction of 4-chloro-2-amino pyridine and 2- chloroacetaldehyde in n-Butanol as a solvent at 130 ºC for 12 h gives the 7-chloroimidazo[1,2- a]pyridine (I) in 90% yield. The resulted imidazopyridine (I) further reacting with 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole under the Suzuki reaction conditions produced the pyrazole attached imidazopyridine derivative (II) in 40% yield. Which is further transformed into III by palladium catalyzed Heck type coupling with 2, 6-dichloro pyridine in 30% of reaction yield. Further derivatization of III followed by the Buchwald- Hartwig cross coupling reaction with 4-methoxyaniline and 2,4-dimethoxyaniline afforded compound A in 30-40% yields, respectively. (a) 2- chloroacetaldehyde, n-Butanol, 130 °C, 12 h; (b) 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole, Pd2(dba)3, PCy3, CH3COOK, DMF / H2O (4:1), 130 °C, 1 h, M / W; (c) 2,6-dichloropyridine, Pd (PPh3)4, Pd (OAc)2, K2CO3, 1,4-Dioxane / H2O (10:1), 100 °C, 14 h; (d) 2,4-dimethoxyaniline, Pd(PPh3)4, Cs2CO3, 1,4-Dioxane, 100 °C, 14h. Page 31 of 82 QB\169852.00141\91596905.1 4.1.2. Synthesis of compound 7-chloroimidazo[1,2-a]pyridine, I. 4-chloro-2-amino pyridine (10.00 g, 77.78 mmol) and 2-chloroacetaldehyde (18.3 mL, 116.7 mmol) were dissolved in 100 mL n-Butanol. The resulting mixture was stirred at 130 °C for 12 h (sealed bottle). After completion of reaction, the reaction mixture was concentrated in vacuo. The resulting solid was washed with Hexane and dried under decreased pressure yielded crude product compound I as brown solid (14.9 g, 125%). MS m / z [M + 1] 153.3. 4.1.3. Synthesis of 7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine, II. 7-chloroimidazo[1,2-a]pyridine (I) (10.00 g, 65.54 mmol), 1-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (20.45 g, 98.31 mmol), potassium acetate (19.30 g, 196.62 mmol) were dissolved into 100 mL mixed solvent (DMF:H2O = 4:1). The resulting reaction mixture was degassed with nitrogen for 5-10 min. After that, Pd2(dba)3 (1.80 g, 1.97 mmol) and trycyclohexyl phosphine (1.65 g, 5.90 mmol) were added. The resulting mixture was stirred at 130 °C under N2atmosphere overnight (sealed bottle). After completion of reaction, the reaction mixture was filtered and concentrated in vacuo. Flash chromatography (MeOH / DCM 0−7%) yielded II as a black solid (5.91 g, 45.49%). MS m / z [M + 1] 199.2.1H NMR (400 MHz, dmso) δ 8.51 (d, J = 7.1 Hz, 1H), 8.29 (s, 1H), 8.02 (s, 1H), 7.85 (d, J = 0.7 Hz, 1H), 7.75 (d, J = 0.8 Hz, 1H), 7.51 (s, 1H), 7.14 (d, J = 7.1 Hz, 1H), 3.87 (s, 3H). 4.1.4. Synthesis of 3-(6-chloropyridin-2-yl)-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2- a]pyridine, III. Compound II (5.00 g, 25.22 mmol), 2,6-dichloro pyridine (7.47 g, 50.45 mmol), potassium carbonate (6.97 g, 50.45 mmol) were dissolved into 50 mL mixed solvent (Dioxane:H2O = 10:1). The resulting reaction mixture was degassed with nitrogen for 5-10 min. After that, Pd(PPh3)4(2.91 g, 2.52 mmol) and Pd(OAc)2(283.14 mg, 1.26 mmol) were added. The resulting mixture was stirred at 100 °C under N2 atmosphere overnight (sealed bottle). After completion of reaction, the reaction mixture was filtered and concentrated in vacuo. Flash chromatography (MeOH / DCM 0−7%) yielded III as a yellow solid (2.79 g, 35.71%). MS m / z [M + 1] 310.2.1H NMR (400 MHz, dmso) δ 9.67 (dd, J = 7.4, 0.9 Hz, 1H), 8.46 (s, 1H), 8.37 (s, 1H), 8.11 (d, J = 0.7 Hz, 1H), 8.01 (dd, J = 8.0, 0.7 Hz, 1H), 7.95 (dd, J = 1.9, 0.9 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.47 (dd, J = 7.4, 1.9 Hz, 1H), 7.37 (dd, J = 7.7, 0.7 Hz, 1H), 3.90 (s, 3H). Page 32 of 82 QB\169852.00141\91596905.1 4.1.5. Synthesis of N-(2,4-dimethoxyphenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2- a]pyridin-3-yl)pyridin-2-amine, compound A. 3-(6-chloropyridin-2-yl)-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine (III) (100 mg, 322.83 umol), 2,4-dimethoxyaniline (98.9 mg, 645.67 umol), cesium carbonate (157.78 mg, 434.25 umol) were dissolved into 5 mL Dioxane. The resulting reaction mixture was degassed with nitrogen for 5-10 min. After that, Pd(PPh3)4(37.31 mg, 32.28 umol) was added. The resulting mixture was stirred at 100 °C under N2 atmosphere overnight (sealed bottle). After completion of reaction, the reaction mixture was filtered and concentrated in vacuo. Flash chromatography (MeOH / DCM 0−7%) followed by preparation TLC yielded wanted compound A (purity > 95%). MS m / z [M + 1] 427.2.1H NMR (400 MHz, dmso) δ 9.67 (dd, J = 7.4, 0.9 Hz, 1H), 8.46 (s, 1H), 8.37 (s, 1H), 8.11 (d, J = 0.7 Hz, 1H), 8.01 (dd, J = 8.0, 0.7 Hz, 1H), 7.95 (dd, J = 1.9, 0.9 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.47 (dd, J = 7.4, 1.9 Hz, 1H), 7.37 (dd, J = 7.7, 0.7 Hz, 1H), 3.90 (s, 3H).13C NMR (101 MHz, dmso) δ 157.04, 156.94, 153.84, 147.68, 147.03, 137.76, 136.61, 134.99, 129.53, 128.73, 128.29, 126.13, 123.23, 122.17, 120.06, 110.74, 110.46, 109.08, 105.68, 104.29, 99.27, 55.52, 55.42, 38.79. HRMS (ESI): m / z [M + H]+calcd for C24H23N6O2+, 427.1877; found, 427.1863. 4.2. Cell cultures and viability assay MV4-11 cells were obtained from the laboratory of Dr. Farrar in Arkansas Children’s Hospital and cultured in IMDM (Gibco, USA) contained 10% fetal bovine serum (FBS) (Gibco, USA). All media contained 100 units / mL penicillin (Gibco, USA), and 100 μg / mL streptomycin (Gibco, USA). Other cell lines were obtained from the laboratory of Dr. Shah in University of California San Francisco and cultured in appropriate media according to provider’s instructions. Cells were incubated at 37 °C in a humidified atmosphere of 5% CO2. For the viability assays, cells in logarithmic phase were seeded into 96-well culture plates at densities of (5000) cells per well. Then, after 24h of incubation, cells were treated in triplicate with various concentrations of compounds for 72 h in final volumes of 200 μL. Upon end point, 20 μL Resazurin solution (Biotium, USA) was added to each well, and the cells were incubated for an additional 4-6 h. Fluorescence values at a wavelength of 590 nM were taken on a spectrophotometer (BioTek, USA). GI50values were calculated using percentage of growth versus vehicle (DMSO) treated control. The data were finally fitted in GraphPad Prism V9.0 software to obtain IC50 (half-life) values using [inhibitor] vs. normalized response (variable slope) model. Each compound was tested at least three times. Page 33 of 82 QB\169852.00141\91596905.1 4.3. FLT3 kinase activity assay Kinase assays was conducted using the bioluminescent ADP-Glo™ kinase assay (Promega, USA), following the manufacturer's instructions. Assay was performed with the test compounds at 8-point half log dilutions (1 uM to 0.316 nM). Luminescence signal was measured on a spectrophotometer (BioTek, USA), and IC50 values reported are based on the dose-response curve fitted in GraphPad Prism V9.0 using [inhibitor] vs. normalized response model. Each compound was tested at least three times. 4.4. FLT3 inhibition kinetic study Compound A was diluted in indicated concentrations in the same kinase buffer as FLT3 inhibition assay. The same kinase reaction as the kinase activity assay was conducted with various concentrations of initial ATP, respectively. The reaction time was recorded. In order for the calculation of reaction speed (v), various ADP dilutions were parallelly prepared in the same kinase buffer, and a standard curve was generated against the luminescence signal. The Lineweaver-Burk plot of 1 / v against 1 / [ATP] was generated by GraphPad Prisim V9.0. 4.5. Western Blot MV4-11 cells, at 5x105cells / ml, were exposed to Quizartinib or compound A for 2 hours at 37 degrees at the indicated doses. Total cell lysates were resolved by SDS- polyacrylamide gel electrophoresis and transferred to nitrocellulose membranes. The membranes were then probed with primary antibodies purchased from Cell Signaling (Danvers, MA, USA) [pFLT3 Y969 (#3463), FLT3 (#3462), pERK (#4370), ERK (#9107) and GAPDH (#5174)] followed by secondary antibodies purchased from Licor (Lincoln, NE, USA). Immunoblots were then visualized by a Biorad ChemiDoc MP Imagine System (Hercules, CA, USA). 4.6. Apoptosis assay MV4-11 cell line was cultured in 2 ml of growth medium in 6-well plate for 24 h. Then the cells were treated with DMSO or various concentrations of compound A. After 72 h exposure to the compound, the cells were collected and centrifuged for 5 min at 1200 rpm. Then the cells were re-suspended in PBS and counted using Countess II Automated Cell Counter (Applied Biosystems, Foster City, USA). After that, the cells were centrifuged again and the PBS removed. Further, the cells were washed with cold PBS twice and resuspended in binding buffer (BD Bioscience, San Jose, USA) to a concentration of 1 × 106cells / ml. Then, transferred 100 ul of the cell suspension solution to FACS tubes, followed by adding 5 ul of FITC Annexin V (BD Bioscience, San Jose, USA) and 5 ul PI (BD Bioscience, San Jose, USA) Page 34 of 82 QB\169852.00141\91596905.1 as the manufacture's instruction stated.400 ul of binding buffer was added to each sample after 15 min incubation at room temperature in the dark. Lastly, all the samples were analyzed by flow cytometry using BD Accuri C6 Plus flow cytometer (BD Bioscience, San Jose, USA). 4.7. Kinase selectivity profiling Compound A was dissolved in DMSO to 1 nM and 10 nM concentrations and sent to Eurofins DiscoverX Corporation located in San Diego, CA USA for KINOMEscan™ Profiling Service. The TREEspot™ Interaction Maps was generated online based on the testing results. Table 2: Antiproliferative effects (IC50a) of compound A and compound B on cells (nM). Compound A B MV4-11 0.0021±0.0003 0.114 ±0.029 Molm14 1.42 ±0.23 3.20 ±0.13 Molm14-FLT3-ITD-D835Y 0.86±0.25 2.45±0.27 Molm-FLT3-ITD-F691L 17.74±3.80 19.82±4.38 K562 1583±313 7786±2727aIC50, compound concentration required to inhibit tumor cell line proliferation by 50%; data are expressed as the mean ± SD from the dose−response curves of at least three independent experiments. Table 3: Gene mutations in MV4-11 cell line in comparison with MOLM13a. gene name MV4-11 MOLM13 AAK1 Wildtype Mutated ACOXL Wildtype Mutated ADAM28 Mutated Mutated ADAMTSL3 Wildtype Mutated ADCK2 Wildtype Mutated ADGRG4 Mutated Wildtype AFF3 Wildtype Mutated AIFM1 Wildtype Mutated AKAP12 Mutated Mutated AKAP9 Wildtype Mutated ALPK3 Wildtype Mutated AURKC Wildtype Mutated BIRC6 Wildtype Mutated BMP2K Mutated Wildtype BRCA2 Wildtype Mutated Page 35 of 82 QB\169852.00141\91596905.1 BRD2 Mutated Wildtype CACNB2 Mutated Mutated CBL Wildtype Mutated CD160 Mutated Wildtype CD40 Wildtype Mutated CDK11B Mutated Wildtype CHD1 Mutated Wildtype CLTCL1 Mutated Mutated COL18A1 Mutated Wildtype CREB3L2 Wildtype Mutated CUBN Mutated Wildtype CXCL12 Mutated Wildtype CYP27B1 Mutated Wildtype DACH1 Mutated Mutated DYRK1A Mutated Wildtype EDN1 Mutated Wildtype EGF Wildtype Mutated EPHA6 Mutated Mutated EPHA7 Wildtype Mutated ESR2 Wildtype Mutated ETV1 Mutated Mutated FBXO43 Wildtype Mutated FGFR1OP Wildtype Mutated FGFR3 Wildtype Mutated FLI1 Mutated Mutated FMN2 Mutated Mutated FN1 Mutated Mutated FSCB Wildtype Mutated GLYAT Mutated Wildtype GRIA3 Mutated Mutated GRIK1 Wildtype Mutated GUCY2C Mutated Mutated HDAC2 Wildtype Mutated HERC2 Wildtype Mutated HNF1A Mutated Wildtype HSP90B1 Wildtype Mutated ILK Mutated Mutated INPP5D Wildtype Mutated ITPR2 Mutated Mutated KMT2A Mutated Mutated LATS2 Wildtype Mutated LMTK2 Wildtype Mutated MAF Mutated Wildtype MAML2 Wildtype Mutated MAML3 Mutated Mutated MAP3K1 Mutated Mutated MAP3K14 Mutated Mutated MAPKAPK3 Mutated Wildtype Page 36 of 82 QB\169852.00141\91596905.1 MECOM Mutated Mutated MLLT6 Mutated Wildtype Wildtype Mutated Wildtype Mutated Mutated Mutated Wildtype Mutated Wildtype Mutated Wildtype Mutated Mutated Wildtype Mutated Wildtype Mutated Mutated Mutated Mutated Mutated Wildtype Wildtype Mutated Mutated Wildtype Wildtype Mutated Mutated Wildtype Wildtype Mutated Wildtype Mutated Mutated Wildtype Mutated Mutated Mutated Mutated Wildtype Mutated Wildtype Mutated Mutated Mutated Mutated Mutated Mutated Wildtype Mutated Mutated Wildtype Mutated Wildtype Mutated Mutated Wildtype Mutated Mutated Wildtype Mutated Mutated Wildtype Mutated Wildtype Mutated Wildtype Mutated Wildtype Mutated Wildtype Wildtype Mutated Mutated Wildtype Mutated Wildtype Mutated Mutated Wildtype Mutated Wildtype Mutated Mutated Wildtype Mutated Wildtype Mutated Wildtype Wildtype Mutated Page 37 of 82 QB\169852.00141\91596905.1 TRIM33 Mutated Wildtype TRPM6 Wildtype Mutated TTN Wildtype Mutated UNC13C Mutated Mutated VEGFC Mutated Mutated VPS13B Mutated Wildtype WNK2 Wildtype Mutated ZNF521 Mutated Wildtype ZNF608 Wildtype MutatedaMOLM13 and MOLM14 are sister cell lines established from the peripheral blood of the same patient with acute monocytic leukemia. References [1] T.J. Ley, C. Miller, L. Ding, B.J. Raphael, A.J. Mungall, A. Robertson, K. Hoadley, T.J. Triche, Jr., P.W. Laird, J.D. Baty, L.L. Fulton, R. Fulton, S.E. Heath, J. Kalicki-Veizer, C. Kandoth, J.M. Klco, D.C. Koboldt, K.L. Kanchi, S. Kulkarni, T.L. Lamprecht, D.E. Larson, L. Lin, C. Lu, M.D. McLellan, J.F. McMichael, J. Payton, H. Schmidt, D.H. Spencer, M.H. Tomasson, J.W. Wallis, L.D. Wartman, M.A. Watson, J. Welch, M.C. Wendl, A. Ally, M. Balasundaram, I. Birol, Y. Butterfield, R. Chiu, A. Chu, E. Chuah, H.J. Chun, R. Corbett, N. Dhalla, R. Guin, A. He, C. Hirst, M. Hirst, R.A. Holt, S. Jones, A. Karsan, D. Lee, H.I. Li, M.A. Marra, M. Mayo, R.A. Moore, K. Mungall, J. Parker, E. Pleasance, P. Plettner, J. Schein, D. Stoll, L. Swanson, A. Tam, N. Thiessen, R. Varhol, N. Wye, Y. Zhao, S. Gabriel, G. Getz, C. Sougnez, L. Zou, M.D. Leiserson, F. Vandin, H.T. Wu, F. Applebaum, S.B. Baylin, R. Akbani, B.M. Broom, K. Chen, T.C. Motter, K. Nguyen, J.N. Weinstein, N. Zhang, M.L. Ferguson, C. Adams, A. Black, J. Bowen, J. Gastier-Foster, T. Grossman, T. Lichtenberg, L. Wise, T. Davidsen, J.A. Demchok, K.R. Shaw, M. Sheth, H.J. Sofia, L. Yang, J.R. Downing, G. Eley, Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia, N Engl J Med, 368 (2013) 2059-2074. [2] C.C. Smith, Q. Wang, C.S. Chin, S. Salerno, L.E. Damon, M.J. Levis, A.E. Perl, K.J. Travers, S. Wang, J.P. Hunt, P.P. Zarrinkar, E.E. Schadt, A. Kasarskis, J. Kuriyan, N.P. Shah, Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia, Nature, 485 (2012) 260-263. [3] C.C. Smith, C. Zhang, K.C. Lin, E.A. Lasater, Y. Zhang, E. Massi, L.E. Damon, M. Pendleton, A. Bashir, R. Sebra, A. Perl, A. Kasarskis, R. Shellooe, G. Tsang, H. Carias, B. Powell, E.A. Burton, B. Matusow, J. Zhang, W. Spevak, P.N. Ibrahim, M.H. Le, H.H. Hsu, G. Habets, B.L. West, G. Bollag, N.P. Shah, Characterizing and Overriding the Structural Page 38 of 82 QB\169852.00141\91596905.1 Mechanism of the Quizartinib-Resistant FLT3 "Gatekeeper" F691L Mutation with PLX3397, Cancer Discov, 5 (2015) 668-679. [4] C.C. Smith, K. Lin, A. Stecula, A. Sali, N.P. Shah, FLT3 D835 mutations confer differential resistance to type II FLT3 inhibitors, Leukemia, 29 (2015) 2390-2392. [5] B. Frett, N. McConnell, C.C. Smith, Y. Wang, N.P. Shah, H.Y. Li, Computer aided drug discovery of highly ligand efficient, low molecular weight imidazopyridine analogs as FLT3 inhibitors, Eur J Med Chem, 94 (2015) 123-131. [6] L. Zhang, N.R. Lakkaniga, J.B. Bharate, N. McConnell, X. Wang, A. Kharbanda, Y.K. Leung, B. Frett, N.P. Shah, H.Y. Li, Discovery of imidazo[1,2-a]pyridine-thiophene derivatives as FLT3 and FLT3 mutants inhibitors for acute myeloid leukemia through structure-based optimization of an NEK2 inhibitor, Eur J Med Chem, 225 (2021) 113776. [7] M. Mori, N. Kaneko, Y. Ueno, M. Yamada, R. Tanaka, R. Saito, I. Shimada, K. Mori, S. Kuromitsu, Gilteritinib, a FLT3 / AXL inhibitor, shows antileukemic activity in mouse models of FLT3 mutated acute myeloid leukemia, Invest New Drugs, 35 (2017) 556-565. [8] P.P. Zarrinkar, R.N. Gunawardane, M.D. Cramer, M.F. Gardner, D. Brigham, B. Belli, M.W. Karaman, K.W. Pratz, G. Pallares, Q. Chao, K.G. Sprankle, H.K. Patel, M. Levis, R.C. Armstrong, J. James, S.S. Bhagwat, AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML), Blood, 114 (2009) 2984-2992. [9] J. Cortes, A.E. Perl, H. Döhner, H. Kantarjian, G. Martinelli, T. Kovacsovics, P. Rousselot, B. Steffen, H. Dombret, E. Estey, S. Strickland, J.K. Altman, C.D. Baldus, A. Burnett, A. Krämer, N. Russell, N.P. Shah, C.C. Smith, E.S. Wang, N. Ifrah, G. Gammon, D. Trone, D. Lazzaretto, M. Levis, Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial, The Lancet Oncology, 19 (2018) 889-903.

[0010] L. Koch, Pharmacotherapy: vandetanib-a new therapeutic option in advanced medullary thyroid cancer, Nat Rev Endocrinol, 8 (2011) 1.

[0011] Z. Wang, J. Cai, J. Cheng, W. Yang, Y. Zhu, H. Li, T. Lu, Y. Chen, S. Lu, FLT3 Inhibitors in Acute Myeloid Leukemia: Challenges and Recent Developments in Overcoming Resistance, J Med Chem, (2021).

[0012] B. Xu, Y. Zhao, X. Wang, P. Gong, W. Ge, MZH29 is a novel potent inhibitor that overcomes drug resistance FLT3 mutations in acute myeloid leukemia, Leukemia, 31 (2017) 913-921. Page 39 of 82 QB\169852.00141\91596905.1

[0013] A.S. Alotaibi, M. Yilmaz, R. Kanagal-Shamanna, S. Loghavi, T.M. Kadia, C.D. DiNardo, G. Borthakur, M. Konopleva, S.A. Pierce, S.A. Wang, G. Tang, V. Guerra, B. Samra, N. Pemmaraju, E. Jabbour, N.J. Short, G.C. Issa, M. Ohanian, G. Garcia-Manero, K.N. Bhalla, K.P. Patel, K. Takahashi, M. Andreeff, J.E. Cortes, H.M. Kantarjian, F. Ravandi, N. Daver, Patterns of Resistance Differ in Patients with Acute Myeloid Leukemia Treated with Type I versus Type II FLT3 Inhibitors, Blood Cancer Discovery, 2 (2021) 125- 134.

[0014] R. Roskoski, Jr., Classification of small molecule protein kinase inhibitors based upon the structures of their drug-enzyme complexes, Pharmacol Res, 103 (2016) 26-48.

[0015] E. Reznickova, S. Krajcovicova, M. Perina, M. Kovalova, M. Soural, V. Krystof, Modulation of FLT3-ITD and CDK9 in acute myeloid leukaemia cells by novel proteolysis targeting chimera (PROTAC), Eur J Med Chem, 243 (2022) 114792.

[0016] A.T. Anshabo, L. Bantie, S. Diab, J. Lenjisa, A. Kebede, Y. Long, G. Heinemann, J. Karanjia, B. Noll, S.K.C. Basnet, M. Li, R. Milne, H. Albrecht, S. Wang, An Orally Bioavailable and Highly Efficacious Inhibitor of CDK9 / FLT3 for the Treatment of Acute Myeloid Leukemia, Cancers (Basel), 14 (2022).

[0017] R. Zhu, L. Li, B. Nguyen, J. Seo, M. Wu, T. Seale, M. Levis, A. Duffield, Y. Hu, D. Small, FLT3 tyrosine kinase inhibitors synergize with BCL-2 inhibition to eliminate FLT3 / ITD acute leukemia cells through BIM activation, Signal Transduct Target Ther, 6 (2021) 186.

[0018] S. Darici, M. Zavatti, L. Braglia, B. Accordi, V. Serafin, G.A. Horne, L. Manzoli, C. Palumbo, X. Huang, H.G. Jorgensen, S. Marmiroli, Synergistic cytotoxicity of dual PI3K / mTOR and FLT3 inhibition in FLT3-ITD AML cells, Adv Biol Regul, 82 (2021) 100830.

[0019] C.C. Smith, E.A. Lasater, K.C. Lin, Q. Wang, M.Q. McCreery, W.K. Stewart, L.E. Damon, A.E. Perl, G.R. Jeschke, M. Sugita, M. Carroll, S.C. Kogan, J. Kuriyan, N.P. Shah, Crenolanib is a selective type I pan-FLT3 inhibitor, Proc Natl Acad Sci U S A, 111 (2014) 5319-5324.

[0020] A.A. Warkentin, M.S. Lopez, E.A. Lasater, K. Lin, B.L. He, A.Y. Leung, C.C. Smith, N.P. Shah, K.M. Shokat, Overcoming myelosuppression due to synthetic lethal toxicity for FLT3-targeted acute myeloid leukemia therapy, Elife, 3 (2014).

[0021] F.W. Peng, J. Xuan, T.T. Wu, J.Y. Xue, Z.W. Ren, D.K. Liu, X.Q. Wang, X.H. Chen, J.W. Zhang, Y.G. Xu, L. Shi, Design, synthesis and biological evaluation of N- Page 40 of 82 QB\169852.00141\91596905.1 phenylquinazolin-4-amine hybrids as dual inhibitors of VEGFR-2 and HDAC, Eur J Med Chem, 109 (2016) 1-12.

[0022] M.J.S. Asmaa, H.A. Al-Jamal, A.R. Hussein, B.H. Yahaya, R. Hassan, F.A. Hussain, S. Shamsuddin, M.F. Johan, Transcriptomic Profiles of MV4-11 and Kasumi 1 Acute Myeloid Leukemia Cell Lines Modulated by Epigenetic Modifiers Trichostatin A and 5-Azacytidine, Int J Hematol Oncol Stem Cell Res, 14 (2020) 72-92.

[0023] A. Piciocchi, M. Messina, L. Elia, A. Vitale, S. Soddu, A.M. Testi, S. Chiaretti, M. Mancini, G. Specchia, A. Spadano, M. Krampera, R. Cairoli, F. Di Raimondo, F. Ferrara, G. Cimino, R. Bassan, P. Fazi, M. Vignetti, Prognostic Impact of t(4;11)(q21;q23) / KMT2A- AFF1-Positivity in 926 BCR::ABL11-Negative B-Lineage Acute Lymphoblastic Leukemia Patients Treated in Gimema Clinical Trials Since 1996, Blood, 134 (2019) 1469-1469.

[0024] H. Lu, Z. Li, Y. Xue, U. Schulze-Gahmen, J.R. Johnson, N.J. Krogan, T. Alber, Q. Zhou, AFF1 is a ubiquitous P-TEFb partner to enable Tat extraction of P-TEFb from 7SK snRNP and formation of SECs for HIV transactivation, Proc Natl Acad Sci U S A, 111 (2014) E15-24.

[0025] A.C. Wilkinson, E. Ballabio, H. Geng, P. North, M. Tapia, J. Kerry, D. Biswas, R.G. Roeder, C.D. Allis, A. Melnick, M.F. de Bruijn, T.A. Milne, RUNX1 is a key target in t(4;11) leukemias that contributes to gene activation through an AF4-MLL complex interaction, Cell Rep, 3 (2013) 116-127.

[0026] J.R. Harman, R. Thorne, M. Jamilly, M. Tapia, N.T. Crump, S. Rice, R. Beveridge, E. Morrissey, M. de Bruijn, I. Roberts, A. Roy, T.A. Fulga, T.A. Milne, A KMT2A-AFF1 gene regulatory network highlights the role of core transcription factors and reveals the regulatory logic of key downstream target genes, Genome Res, 31 (2021) 1159-1173. Example 2 Structure-activity relationship study: Table 4 demonstrates the structure-activity relationship of exemplary compounds. IC50 values were determined by the method described in Section 4.2 of Example 1. Table 4: Structure-activity study of the six-member aromatic ring. N QB\169852.00141\91596905.1NO. ArMOLM14MOLM14-D835Y MOLM14-F691L K562 IC50(nM)IC50(nM) IC50(nM) IC50(nM) ) 2 7 17.18±1.2 618.18±2.48 97.46±31.20 >10008 0.19±0.08 0.77±0.44 9.80±1.88 >1000 9 1.00±0.22 1.83±0.49 7.10±1.61 >1000 10 3.25±0.23 1.41±0.32 238.5±43.8 >1000 11 0.77±0.10 2.21±0.57 12.47±1.66 >1000 Page 42 of 82 QB\169852.00141\91596905.1 12 0.51±0.10 0.87±0.19 7.42±3.56 924±109 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 QB\169852.00141\91596905.1 29 6.82±1.00 5.19±0.96 314.5±61.3 923±245 30 31 32 33 34 35 36 37 38 39 40 Page 44 of 82 QB\169852.00141\91596905.1 41 278.4±52. 613.2±147. Table 6: FLT3 kinase inhibition of selected compounds. NO. FLT3 IC50(nM) Figure 9 shows the cell-based viability curve of Gilteritinib and Compound 24. Figures 10A-10B show the western blot analysis results of compound 24 and Gilteritinib. The general synthetic scheme and structural characterization Scheme 2 depicts the general synthetic route of compounds 1-43. The synthesis of intermediate I, II and compound 1 (i.e., intermediate III of Example 1) was described in Example 1, section 4.1. 4-chloro-2-amino pyridine and 2-chloroacetaldehyde were subjected to condensation, a Suzuki reaction, and a palladium catalyzed Heck type coupling to yield compound 1. Further Buchwald-Hartwig cross coupling reactions of compound 1 with respective nonaromatic-amines or aromatic-amines afforded compound 5-39 in 30-40% yields, respectively. Compounds 2-4 were synthesized from II by the same palladium catalyzed Heck type coupling as 1 with a higher temperature and longer reaction time, because of lower reactivity of the benzene ring than pyridine. Compounds 40-43 were afforded from III by the same Buchwald-Hartwig cross coupling as reaction d. Page 45 of 82 QB\169852.00141\91596905.1

[0002] QB\169852.00141\91596905.1 Scheme 2: A general synthetic scheme. Reagents and conditions: (a) 2- chloroacetaldehyde, n-Butanol, 130 °C, 12 h; (b) 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole, Pd2(dba)3, PCy3, CH3COOK, DMF / H2O (4:1), 130 °C, 1 h, M / W; (c) 2,6-dichloropyridine, Pd(PPh3)4, Pd(OAc)2, K2CO3, 1,4-Dioxane / H2O (10:1), 100 °C, 14 h; (d) respective amines, Pd(PPh3)4, Cs2CO3, 1,4-Dioxane, 100 °C, 14h; (e) respective dichlorobenzene, Pd(PPh3)4, Pd(OAc)2, K2CO3, 1,4-Dioxane / H2O (10:1), 120 °C, 24 h; (f) respective amines, Pd(PPh3)4, Cs2CO3, 1,4-Dioxane, 100 °C, 14h. Synthesis of 3-(2-chlorophenyl)-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine, 2. Compound II (1.50 g, 7.57 mmol), 1,2-dichlorobenzene (3.34 g, 22.70 mmol), potassium carbonate (2.61 g, 18.92 mmol) were dissolved into 20 mL mixed solvent (Dioxane:H2O = 10:1). The resulting reaction mixture was degassed with nitrogen for 5-10 min. After that, Pd(PPh3)4 (0.87 g, 757 umol) and Pd(OAc)2 (85 mg, 378 umol) were added. The resulting mixture was stirred at 120 °C under N2atmosphere for 24h (sealed bottle). After completion of reaction, the reaction mixture was filtered and concentrated in vacuo. Flash chromatography (MeOH / DCM 0−7%) yielded compound 2 as a yellow solid (0.71 g, 30.39%). MS m / z [M + 1] 309.2.1H NMR (400 MHz, cdcl3) δ 7.83 (d, J = 0.7 Hz, 1H), 7.81 (dd, J = 7.2, 0.8 Hz, 1H), 7.73 (dd, J = 1.7, 0.9 Hz, 1H), 7.71 (s, 1H), 7.68 (s, 1H), 7.60 – 7.55 (m, 1H), 7.50 – 7.46 (m, 1H), 7.43 – 7.39 (m, 2H), 6.94 (dd, J = 7.2, 1.7 Hz, 1H), 3.98 (s, 3H).13C NMR (101 MHz, cdcl3) δ 146.58, 137.05, 134.70, 134.33, 132.85, 130.39, 130.37, 129.54, 128.28, 127.52, 127.38, 124.63, 122.88, 121.40, 112.23, 111.39, 39.43. Synthesis of 3-(3-chlorophenyl)-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine, 3. Compound II (1.00 g, 5.04 mmol), 1,3-dichlorobenzene (2.22 g, 15.13 mmol), potassium carbonate (1.39 g, 10.09 mmol) were dissolved into 15 mL mixed solvent (Dioxane:H2O = 10:1). The resulting reaction mixture was degassed with nitrogen for 5-10 min. After that, Pd(PPh3)4 (0.58 g, 504 umol) and Pd(OAc)2 (57 mg, 252 umol) were added. The resulting mixture was stirred at 120 °C under N2atmosphere for 24h (sealed bottle). After completion of reaction, the reaction mixture was filtered and concentrated in vacuo. Flash chromatography (MeOH / DCM 0−7%) yielded compound 3 as a yellow solid (0.52 g, 33.38%). MS m / z [M + 1] 309.2.1H NMR (400 MHz, cdcl3) δ 8.34 – 8.27 (m, 1H), 7.83 (d, J = 1.8 Hz, 1H), 7.71 (d, J = 2.0 Hz, 2H), 7.67 (q, J = 2.3 Hz, 1H), 7.57 – 7.55 (m, 1H), 7.49 – 7.43 (m, 2H), 7.42 – 7.36 (m, 1H), 7.01 – 6.90 (m, 1H), 3.98 (s, 3H).13C NMR (101 MHz, cdcl3) δ Page 47 of 82 QB\169852.00141\91596905.1 147.13, 137.02, 133.62, 132.17, 130.69, 129.40, 128.57, 128.21, 128.01, 127.72, 127.56, 125.91, 123.43, 121.18, 112.43, 112.08, 39.44. Synthesis of 3-(4-chlorophenyl)-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine, 4. Compound II (1.50 g, 7.57 mmol), 1,4-dichlorobenzene (3.34 g, 22.70 mmol), potassium carbonate (2.61 g, 18.92 mmol) were dissolved into 20 mL mixed solvent (Dioxane:H2O = 10:1). The resulting reaction mixture was degassed with nitrogen for 5-10 min. After that, Pd(PPh3)4 (0.87 g, 757 umol) and Pd(OAc)2 (85 mg, 378 umol) were added. The resulting mixture was stirred at 120 °C under N2atmosphere for 24h (sealed bottle). After completion of reaction, the reaction mixture was filtered and concentrated in vacuo. Flash chromatography (MeOH / DCM 0−7%) yielded compound 4 as a yellow solid (0.73 g, 31.24%). MS m / z [M + 1] 309.2.1H NMR (400 MHz, cdcl3) δ 8.34 – 8.22 (m, 1H), 7.83 (s, 1H), 7.71 (s, 2H), 7.66 (d, J = 4.4 Hz, 1H), 7.59 – 7.51 (m, 2H), 7.49 (s, 2H), 6.95 (td, J = 7.5, 1.8 Hz, 1H), 3.98 (s, 3H).13C NMR (101 MHz, cdcl3) δ 147.01, 137.00, 134.12, 134.06, 133.34, 129.67 (2C), 129.40 (2C), 129.17, 128.23, 128.01, 127.52, 127.49, 123.35, 121.22, 112.44, 111.98, 39.44. Synthesis of tert-butyl 4-(6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3- yl)pyridin-2-yl)piperazine-1-carboxylate, compound 5. Compound 1 (100 mg, 322.83 umol), the respective amine (645.67 umol, 2 equiv), cesium carbonate (157.78 mg, 434.25 umol) were dissolved into 5 mL Dioxane. The resulting reaction mixture was degassed with nitrogen for 5-10 min. After that, Pd(PPh3)4 (37.31 mg, 32.28 umol) was added. The resulting mixture was stirred at 100 °C under N2atmosphere overnight (sealed bottle). After completion of reaction, the reaction mixture was filtered and concentrated in vacuo. Silica flash chromatography (MeOH / DCM 0−7%) followed by C18flash chromatography (MeOH / H2O 10−80%) yielded compound 5 as a yellow solid (54 mg, 36.40%). MS m / z [M + 1] 460.1.1H NMR (400 MHz, dmso) δ 9.65 (d, J = 7.4 Hz, 1H), 8.35 (s, 1H), 8.21 (s, 1H), 8.08 (s, 1H), 7.88 (s, 1H), 7.65 (t, J = 8.0 Hz, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H), 6.76 (d, J = 8.5 Hz, 1H), 3.89 (s, 3H), 3.65 – 3.55 (m, 4H), 3.55 – 3.45 (m, 4H), 1.44 (s, 9H).13C NMR (101 MHz, cdcl3) δ 158.84, 154.86, 148.57, 147.80, 138.42, 137.10, 135.22, 129.86, 127.64, 127.38, 124.31, 121.31, 111.93, 111.60, 110.64, 104.81, 80.15 (2C), 45.55 (2C), 39.25, 28.51 (3C). Synthesis of tert-butyl 2-methyl-4-(6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2- a]pyridin-3-yl)pyridin-2-yl)piperazine-1-carboxylate, compound 6. Page 48 of 82 QB\169852.00141\91596905.1 Compound 6 was synthesized according to the same procedure of compound 5 and was isolated as a yellow compound. MS m / z [M + 1] 474.1.1H NMR (400 MHz, dmso) δ 9.67 (d, J = 7.4 Hz, 1H), 8.36 (s, 1H), 8.21 (s, 1H), 8.08 (s, 1H), 7.88 (s, 1H), 7.65 – 7.61 (m, 1H), 7.40 (d, J = 7.5 Hz, 1H), 7.22 (d, J = 7.5 Hz, 1H), 6.73 (d, J = 8.6 Hz, 1H), 4.27 (s, 1H), 4.18 – 4.07 (m, 2H), 3.89 (s, 3H), 3.84 (s, 1H), 3.23 (d, J = 10.4 Hz, 2H), 3.06 – 2.98 (m, 1H), 1.44 (s, 9H), 1.18 (d, J = 6.7 Hz, 3H).13C NMR (101 MHz, cdcl3) δ 159.14, 154.89, 148.61, 147.85, 138.36, 137.09, 135.17, 132.27, 132.17, 129.88, 128.69, 128.57, 127.57, 127.52, 124.44, 121.41, 111.96, 111.57, 110.17, 104.25, 80.06, 49.45, 45.36, 39.41, 28.62 (3C), 16.53. Synthesis of tert-butyl 4-((6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3- yl)pyridin-2-yl)amino)piperidine-1-carboxylate, compound 7. Compound 7 was synthesized according to the same procedure of compound 5 and was isolated as a white compound. MS m / z [M + 1] 474.1.1H NMR (400 MHz, cdcl3) δ 9.77 (dd, J = 7.3, 0.8 Hz, 1H), 8.03 (s, 1H), 7.85 (d, J = 0.7 Hz, 1H), 7.74 (s, 1H), 7.71 (d, J = 1.0 Hz, 1H), 7.49 – 7.43 (m, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.98 (dd, J = 7.3, 1.8 Hz, 1H), 6.27 (d, J = 8.3 Hz, 1H), 4.51 (d, J = 7.6 Hz, 1H), 4.17 (dd, J = 33.6, 8.2 Hz, 2H), 3.97 (s, 3H), 3.91 (ddd, J = 14.0, 10.5, 5.5 Hz, 1H), 2.99 (t, J = 11.8 Hz, 2H), 2.13 (d, J = 10.7 Hz, 2H), 1.47 (s, 9H).13C NMR (101 MHz, cdcl3) δ 157.05, 154.96, 148.81, 147.65, 138.09, 137.07, 134.71, 130.02, 127.75, 124.10, 121.29, 111.78, 111.43, 109.63, 104.94, 79.90, 50.85, 49.13 (2C), 39.39, 32.54 (2C), 29.82, 28.58 (3C). Synthesis of 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(4-(2- (piperidin-1-yl)ethoxy)phenyl)pyridin-2-amine, compound 8. Compound 8 was synthesized according to the same procedure of compound 5 and was isolated as a white compound. MS m / z [M + 1] 494.3.1H NMR (400 MHz, dmso) δ 9.71 (d, J = 7.3 Hz, 1H), 8.88 (s, 1H), 8.36 (s, 1H), 8.22 (s, 1H), 8.08 (s, 1H), 7.86 (s, 1H), 7.59 (t, J = 7.9 Hz, 1H), 7.41 (d, J = 8.9 Hz, 2H), 7.26 (d, J = 7.5 Hz, 1H), 7.14 (dd, J = 7.3, 1.7 Hz, 1H), 6.97 (d, J = 8.9 Hz, 2H), 6.61 (d, J = 8.3 Hz, 1H), 4.08 (t, J = 6.1 Hz, 2H), 3.89 (s, 3H), 2.66 (t, J = 6.0 Hz, 2H), 2.48 – 2.37 (m, 4H), 1.49 (dt, J = 10.9, 5.5 Hz, 4H), 1.38 (dd, J = 10.9, 5.5 Hz, 2H).13C NMR (101 MHz, dmso) δ 155.90, 153.84, 147.69, 147.13, 138.04, 136.69, 135.22, 134.07, 129.69, 128.83, 128.01, 123.36, 122.10 (2C), 120.07, 114.80 (2C), 110.99, 110.55, 109.86, 106.28, 65.84, 57.51, 54.45 (2C), 38.79, 25.58 (2C), 23.94. Synthesis of 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(4-(2- morpholinoethoxy)phenyl)pyridin-2-amine, compound 9. Page 49 of 82 QB\169852.00141\91596905.1 Compound 9 was synthesized according to the same procedure of compound 5 and was isolated as a white compound. MS m / z [M + 1] 496.3.1H NMR (400 MHz, dmso) δ 9.71 (d, J = 7.3 Hz, 1H), 8.89 (s, 1H), 8.36 (s, 1H), 8.22 (s, 1H), 8.08 (s, 1H), 7.86 (s, 1H), 7.59 (t, J = 7.9 Hz, 1H), 7.42 (d, J = 8.9 Hz, 2H), 7.26 (d, J = 7.6 Hz, 1H), 7.14 (dd, J = 7.3, 1.6 Hz, 1H), 6.98 (d, J = 8.9 Hz, 2H), 6.62 (d, J = 8.3 Hz, 1H), 4.10 (dd, J = 10.8, 5.4 Hz, 2H), 3.89 (s, 3H), 3.65 – 3.50 (m, 4H), 2.71 (t, J = 5.8 Hz, 2H).13C NMR (101 MHz, dmso) δ 155.89, 153.77, 147.68, 147.13, 138.03, 136.68, 135.21, 134.14, 129.67, 128.80, 128.00, 123.36, 122.09 (2C), 120.07, 114.81 (2C), 110.98, 110.55, 109.87, 106.28, 66.16 (2C), 65.59, 57.14, 53.66 (2C), 38.78. Synthesis of 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(4- morpholinophenyl)pyridin-2-amine, compound 10. Compound 10 was synthesized according to the same procedure of compound 5 and was isolated as a yellow compound. MS m / z [M + 1] 452.3.1H NMR (400 MHz, cdcl3) δ 9.70 (d, J = 7.3 Hz, 1H), 8.06 (s, 1H), 7.83 (s, 1H), 7.69 (s, 2H), 7.50 (t, J = 7.9 Hz, 1H), 7.34 – 7.27 (m, 2H), 7.13 (d, J = 7.6 Hz, 1H), 6.99 – 6.93 (m, 2H), 6.90 (dd, J = 7.3, 1.7 Hz, 1H), 6.55 (d, J = 8.2 Hz, 1H), 6.50 (s, 1H), 3.97 (s, 3H), 3.93 – 3.87 (m, 4H), 3.21 – 3.14 (m, 4H).13C NMR (101 MHz, cdcl3) δ 156.57, 149.01, 148.22, 147.92, 138.33, 137.06, 135.17, 132.96, 129.93, 128.37, 127.55, 124.22 (2C), 123.90, 121.46, 116.80 (2C), 111.77, 111.40, 111.02, 104.81, 67.09 (2C), 50.03 (2C), 39.40, 29.83. Synthesis of 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(4-(2- (pyrrolidin-1-yl)ethoxy)phenyl)pyridin-2-amine, compound 11. Compound 11 was synthesized according to the same procedure of compound 5 and was isolated as a white compound. MS m / z [M + 1] 480.2.1H NMR (400 MHz, cdcl3) δ 9.70 (dd, J = 7.3, 0.8 Hz, 1H), 8.07 (s, 1H), 7.84 (d, J = 0.7 Hz, 1H), 7.72 (s, 1H), 7.70 (dd, J = 1.8, 0.8 Hz, 1H), 7.54 – 7.48 (m, 1H), 7.34 – 7.27 (m, 2H), 7.14 (d, J = 7.6 Hz, 1H), 6.99 – 6.93 (m, 2H), 6.91 (dd, J = 7.3, 1.9 Hz, 1H), 6.53 (d, J = 8.2 Hz, 1H), 6.43 (s, 1H), 4.15 (t, J = 5.9 Hz, 2H), 3.98 (s, 3H), 2.95 (t, J = 5.9 Hz, 2H), 2.72 – 2.61 (m, 4H), 1.89 – 1.78 (m, 4H).13C NMR (101 MHz, cdcl3) δ 156.54, 155.77, 149.03, 147.98, 138.35, 137.10, 135.27, 133.42, 129.98, 128.39, 127.63, 124.55 (2C), 123.89, 121.47, 116.54, 115.45 (2C), 111.82, 111.44, 111.06, 104.87, 67.56, 55.31, 54.90 (2C), 39.40, 29.85, 23.66 (2C). Synthesis of N-(4-(2-(diethylamino)ethoxy)phenyl)-6-(7-(1-methyl-1H-pyrazol-4- yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-amine, compound 12. Page 50 of 82 QB\169852.00141\91596905.1 Compound 12 was synthesized according to the same procedure of compound 5 and was isolated as a yellow compound. MS m / z [M + 1] 482.2.1H NMR (400 MHz, dmso) δ 9.71 (d, J = 7.3 Hz, 1H), 8.88 (s, 1H), 8.35 (s, 1H), 8.22 (s, 1H), 8.07 (s, 1H), 7.86 (s, 1H), 7.62 – 7.57 (m, 1H), 7.41 (d, J = 8.9 Hz, 2H), 7.26 (d, J = 7.6 Hz, 1H), 7.13 (dd, J = 7.4, 1.8 Hz, 1H), 6.96 (d, J = 8.9 Hz, 2H), 6.61 (d, J = 8.2 Hz, 1H), 4.03 (t, J = 6.2 Hz, 2H), 3.89 (s, 3H), 2.79 (t, J = 6.2 Hz, 2H), 2.56 (q, J = 7.1 Hz, 4H), 0.98 (t, J = 7.1 Hz, 6H).13C NMR (101 MHz, cdcl3) δ 156.53, 155.69, 148.91, 147.87, 138.25, 137.01, 135.12, 133.35, 129.89, 128.35, 127.55, 124.40 (2C), 123.86, 121.36, 115.27 (2C), 111.68, 111.33, 110.89, 104.83, 67.08, 51.96, 47.96 (2C), 39.31, 11.96 (2C). Synthesis of 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(p- tolyl)pyridin-2-amine, compound 13. Compound 13 was synthesized according to the same procedure of compound 5 and was isolated as a green compound. MS m / z [M + 1] 381.3.1H NMR (400 MHz, cdcl3) δ 9.73 (d, J = 7.3 Hz, 1H), 8.08 (s, 1H), 7.85 (s, 1H), 7.72 (s, 1H), 7.70 (d, J = 0.9 Hz, 1H), 7.54 (t, J = 7.9 Hz, 1H), 7.29 (d, J = 8.3 Hz, 2H), 7.23 – 7.15 (m, 3H), 6.93 (dd, J = 7.3, 1.8 Hz, 1H), 6.65 (d, J = 8.2 Hz, 1H), 6.52 (s, 1H), 3.98 (s, 3H), 2.38 (s, 3H).13C NMR (101 MHz, cdcl3) δ 155.83, 149.04, 138.38, 137.77, 137.11, 135.30, 133.12, 129.97, 129.94 (2C), 128.37, 127.58, 121.83 (2C), 121.46, 111.83, 111.43, 105.29, 39.44, 21.05. Synthesis of 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(4- vinylphenyl)pyridin-2-amine, compound 14. Compound 14 was synthesized according to the same procedure of compound 5 and was isolated as a yellow compound. MS m / z [M + 1] 393.2.1H NMR (400 MHz, cdcl3) δ 9.70 (d, J = 7.3 Hz, 1H), 8.09 (s, 1H), 7.85 (s, 1H), 7.71 (s, 2H), 7.57 (t, J = 7.9 Hz, 1H), 7.40 (dd, J = 20.7, 8.5 Hz, 4H), 7.21 (d, J = 7.7 Hz, 1H), 6.92 (d, J = 7.3 Hz, 1H), 6.78 – 6.68 (m, 2H), 6.65 (s, 1H), 5.71 (d, J = 17.6 Hz, 1H), 5.21 (d, J = 10.8 Hz, 1H), 3.98 (s, 3H).13C NMR (101 MHz, cdcl3) δ 155.04, 149.00, 148.04, 140.14, 138.45, 137.11, 136.38, 135.37, 132.50, 130.07, 128.37, 127.61, 127.22 (2C), 123.84, 121.39, 120.76 (2C), 112.47, 111.93, 111.79, 111.50, 106.07, 39.44. Synthesis of N-(4-ethylphenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3- yl)pyridin-2-amine, compound 15. Compound 15 was synthesized according to the same procedure of compound 5 and was isolated as a grey compound. MS m / z [M + 1] 395.3.1H NMR (400 MHz, cdcl3) δ 9.73 (dd, J = 7.3, 0.9 Hz, 1H), 8.08 (s, 1H), 7.85 (d, J = 0.7 Hz, 1H), 7.72 (s, 1H), 7.71 (dd, J = 1.8, Page 51 of 82 QB\169852.00141\91596905.1 0.9 Hz, 1H), 7.57 – 7.52 (m, 1H), 7.33 – 7.28 (m, 2H), 7.22 (d, J = 8.8 Hz, 1H), 7.18 (dd, J = 7.6, 0.6 Hz, 1H), 6.93 (dd, J = 7.3, 1.9 Hz, 1H), 6.66 (d, J = 8.2 Hz, 1H), 6.46 (s, 1H), 3.99 (s, 3H), 2.68 (q, J = 7.5 Hz, 2H), 1.29 (t, J = 7.6 Hz, 3H).13C NMR (101 MHz, cdcl3) δ 158.02, 155.84, 149.06, 148.00, 139.68, 138.40, 137.94, 137.11, 135.32, 129.97, 128.76 (2C), 128.43, 127.57, 122.02 (2C), 121.48, 111.84, 111.44, 110.17, 105.31, 39.46, 28.49, 16.00. Synthesis of N-(4-isopropylphenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2- a]pyridin-3-yl)pyridin-2-amine, compound 16. Compound 16 was synthesized according to the same procedure of compound 5 and was isolated as a white compound. MS m / z [M + 1] 409.3.1H NMR (400 MHz, dmso) δ 9.75 – 9.70 (m, 1H), 9.01 (s, 1H), 8.34 (s, 1H), 8.23 (s, 1H), 8.06 (d, J = 0.6 Hz, 1H), 7.87 (d, J = 0.9 Hz, 1H), 7.63 (d, J = 7.7 Hz, 1H), 7.43 (d, J = 8.5 Hz, 2H), 7.29 (d, J = 7.5 Hz, 1H), 7.24 (d, J = 8.5 Hz, 2H), 7.11 (dd, J = 7.3, 1.9 Hz, 1H), 6.70 (d, J = 8.2 Hz, 1H), 3.90 (s, 3H), 2.91 (dt, J = 13.8, 7.0 Hz, 1H), 1.24 (d, J = 6.9 Hz, 6H).13C NMR (101 MHz, dmso) δ 155.56, 147.69, 147.16, 141.77, 138.80, 138.14, 136.65, 135.28, 131.52, 131.42, 129.69, 128.81, 128.77, 128.69, 128.07, 126.54 (2C), 123.38, 120.18 (2C), 120.07, 110.93, 110.59, 110.30, 106.69, 38.83, 32.83, 24.12 (2C). Synthesis of N-(4-(tert-butyl)phenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2- a]pyridin-3-yl)pyridin-2-amine, compound 17. Compound 17 was synthesized according to the same procedure of compound 5 and was isolated as a orange compound. MS m / z [M + 1] 423.3.1H NMR (400 MHz, dmso) δ 9.74 (d, J = 7.3 Hz, 1H), 9.01 (s, 1H), 8.32 (s, 1H), 8.23 (s, 1H), 8.04 (s, 1H), 7.87 (s, 1H), 7.62 (t, J = 7.9 Hz, 1H), 7.40 (dd, J = 20.2, 8.7 Hz, 4H), 7.30 (d, J = 7.6 Hz, 1H), 7.09 (dd, J = 7.3, 1.6 Hz, 1H), 6.70 (d, J = 8.3 Hz, 1H), 3.90 (s, 3H), 1.32 (s, 9H).13C NMR (101 MHz, dmso) δ 155.56, 147.70, 147.14, 144.04, 138.44, 138.14, 136.58, 135.26, 129.65, 128.69, 128.10, 125.41 (2C), 123.36, 120.07, 119.95 (2C), 110.88, 110.60, 110.29, 106.59, 33.98, 31.33 (3C). Synthesis of N-(3-(tert-butyl)phenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2- a]pyridin-3-yl)pyridin-2-amine, compound 18. Compound 18 was synthesized according to the same procedure of compound 5 and was isolated as a white compound. MS m / z [M + 1] 423.3.1H NMR (400 MHz, cdcl3) δ 9.73 (dd, J = 7.3, 0.7 Hz, 1H), 8.08 (s, 1H), 7.83 (s, 1H), 7.71 – 7.69 (m, 1H), 7.69 (s, 1H), 7.55 (t, J = 7.9 Hz, 1H), 7.33 – 7.28 (m, 3H), 7.18 (d, J = 7.6 Hz, 1H), 7.16 – 7.13 (m, 1H), 6.91 (dd, J = 7.3, 1.8 Hz, 1H), 6.74 – 6.68 (m, 2H), 3.96 (s, 3H), 1.33 (s, 9H).13C NMR (101 MHz, cdcl3) δ 155.67, 152.76, 149.10, 147.96, 140.16, 138.40, 137.08, 135.22, 130.02, 128.98, 128.34, Page 52 of 82 QB\169852.00141\91596905.1 127.57, 123.88, 121.43, 120.52, 118.52, 111.78, 111.60, 111.53, 105.46, 39.39, 34.90, 31.47 (3C), 29.83. Synthesis of N-(2-methoxyphenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2- a]pyridin-3-yl)pyridin-2-amine, compound 19. Compound 19 was synthesized according to the same procedure of compound 5 and was isolated as a grey compound. MS m / z [M + 1] 397.2.1H NMR (400 MHz, cdcl3) δ 9.71 (d, J = 7.3 Hz, 1H), 8.04 (s, 1H), 8.00 (d, J = 7.5 Hz, 1H), 7.83 (s, 1H), 7.68 (s, 2H), 7.53 (t, J = 7.9 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 7.05 – 6.92 (m, 4H), 6.89 (d, J = 7.3 Hz, 1H), 6.67 (d, J = 8.2 Hz, 1H), 3.94 (s, 3H), 3.91 (s, 3H).13C NMR (101 MHz, cdcl3) δ 154.98, 149.15, 148.55, 138.26, 137.13, 135.08, 130.03, 129.98, 128.45, 127.72, 127.43, 124.08, 122.15, 121.34, 120.71, 119.77, 111.81, 111.47, 111.37, 110.55, 107.15, 55.86, 39.39. Synthesis of N-(3,4-dimethoxyphenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2- a]pyridin-3-yl)pyridin-2-amine, compound 20. Compound 20 was synthesized according to the same procedure of compound 5 and was isolated as a brown compound. MS m / z [M + 1] 427.2.1H NMR (400 MHz, dmso) δ 9.73 (d, J = 7.4 Hz, 1H), 8.92 (s, 1H), 8.35 (s, 1H), 8.22 (s, 1H), 8.08 (s, 1H), 7.87 (s, 1H), 7.60 (t, J = 7.9 Hz, 1H), 7.27 (d, J = 7.5 Hz, 1H), 7.12 (dd, J = 5.2, 2.0 Hz, 2H), 7.04 (dd, J = 8.6, 2.3 Hz, 1H), 6.96 (d, J = 8.6 Hz, 1H), 6.65 (d, J = 8.2 Hz, 1H), 3.89 (s, 3H), 3.77 (s, 3H), 3.68 (s, 3H).13C NMR (101 MHz, dmso) δ 155.76, 149.01, 147.69, 147.15, 144.11, 138.21, 136.75, 135.24, 134.66, 129.67, 128.79, 127.98, 123.41, 120.04, 112.57, 112.26, 110.91, 110.45, 110.15, 106.52, 105.61, 56.06, 55.45, 39.52, 38.68. Synthesis of 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(3,4,5- trimethoxyphenyl)pyridin-2-amine, compound 21. Compound 21 was synthesized according to the same procedure of compound 5 and was isolated as a yellow compound. MS m / z [M + 1] 457.2.1H NMR (400 MHz, dmso) δ 9.70 (d, J = 7.4 Hz, 1H), 9.06 (s, 1H), 8.34 (s, 1H), 8.23 (s, 1H), 8.07 (s, 1H), 7.88 (s, 1H), 7.65 (t, J = 8.0 Hz, 1H), 7.31 (d, J = 7.5 Hz, 1H), 7.14 (dd, J = 7.3, 1.6 Hz, 1H), 6.85 (s, 2H), 6.73 (d, J = 8.2 Hz, 1H), 3.89 (s, 3H), 3.68 (s, 6H), 3.66 (s, 3H).13C NMR (101 MHz, cdcl3) δ 155.66, 153.49 (2C), 148.47, 147.62, 138.14, 136.85, 136.73, 134.66, 133.74, 132.04, 131.94, 129.99, 128.59, 128.47, 128.30, 127.58, 123.84, 120.92, 111.30, 111.13, 106.16, 98.98 (2C), 61.02, 56.04 (2C), 39.10. Synthesis of N-(benzo[d][1,3]dioxol-5-yl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2- a]pyridin-3-yl)pyridin-2-amine, compound 22. Page 53 of 82 QB\169852.00141\91596905.1 Compound 22 was synthesized according to the same procedure of compound 5 and was isolated as a yellow compound. MS m / z [M + 1] 411.2.1H NMR (400 MHz, cdcl3) δ 9.83 (d, J = 7.3 Hz, 1H), 8.02 (s, 1H), 7.85 (s, 1H), 7.72 (s, 1H), 7.71 – 7.67 (m, 1H), 7.50 – 7.45 (m, 1H), 7.29 – 7.21 (m, 1H), 7.06 (d, J = 7.6 Hz, 1H), 7.02 (dd, J = 7.3, 1.5 Hz, 1H), 6.92 (t, J = 7.8 Hz, 2H), 6.38 (d, J = 8.2 Hz, 1H), 4.92 (t, J = 6.2 Hz, 1H), 4.75 (d, J = 6.2 Hz, 2H), 3.97 (s, 3H).13C NMR (101 MHz, cdcl3) δ 162.99, 160.53, 157.50, 148.92, 147.86, 138.17, 137.10, 135.08, 129.89, 129.51, 128.15, 127.56, 124.12, 121.53, 111.77, 111.52, 111.41, 110.29, 104.55, 50.88, 39.38, 34.32, 29.84. Synthesis of N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-(7-(1-methyl-1H-pyrazol-4- yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-amine, compound 23. Compound 23 was synthesized according to the same procedure of compound 5 and was isolated as a white compound. MS m / z [M + 1] 425.2.1H NMR (400 MHz, dmso) δ 9.76 (d, J = 7.3 Hz, 1H), 8.90 (s, 1H), 8.36 (s, 1H), 8.23 (s, 1H), 8.09 (s, 1H), 7.87 (d, J = 0.8 Hz, 1H), 7.60 (t, J = 7.9 Hz, 1H), 7.28 (d, J = 7.6 Hz, 1H), 7.15 (dd, J = 7.4, 1.4 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 6.95 (dd, J = 8.5, 2.3 Hz, 1H), 6.86 (d, J = 8.6 Hz, 1H), 6.62 (d, J = 8.3 Hz, 1H), 4.27 (dd, J = 10.5, 5.2 Hz, 4H), 3.90 (s, 3H).13C NMR (101 MHz, dmso) δ 155.55, 147.60, 147.13, 143.26, 138.41, 138.07, 136.69, 135.19, 134.68, 129.76, 128.81, 128.02, 123.37, 120.05, 116.87, 113.47, 111.07, 110.48, 110.06, 109.26, 106.61, 64.21, 63.98, 38.81. Synthesis of 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(4- (methylsulfonyl)phenyl)pyridin-2-amine, compound 24. Compound 24 was synthesized according to the same procedure of compound 5 and was isolated as a yellow compound. MS m / z [M + 1] 445.2.1H NMR (400 MHz, dmso) δ 9.77 (s, 1H), 9.57 (d, J = 7.3 Hz, 1H), 8.36 (s, 1H), 8.27 (s, 1H), 8.10 (s, 1H), 7.92 (s, 1H), 7.86 – 7.75 (m, 4H), 7.48 (d, J = 7.7 Hz, 1H), 7.24 (d, J = 6.5 Hz, 1H), 6.87 (d, J = 8.1 Hz, 1H), 3.90 (s, 3H), 3.19 (s, 3H).13C NMR (101 MHz, dmso) δ 153.96, 147.62, 147.36, 146.09, 138.71, 136.74, 135.70, 131.58, 130.00, 128.85, 128.34 (2C), 127.41, 123.30, 120.00, 117.47 (2C), 112.75, 111.32, 110.66, 108.88, 44.06, 38.81. Synthesis of 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(2- (trifluoromethyl)phenyl)pyridin-2-amine, compound 25. Compound 25 was synthesized according to the same procedure of compound 5 and was isolated as a black compound. MS m / z [M + 1] 435.1.1H NMR (400 MHz, cdcl3) δ 9.62 (dd, J = 7.3, 0.8 Hz, 1H), 8.11 (s, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.85 (d, J = 0.7 Hz, 1H), 7.75 – 7.67 (m, 3H), 7.61 (t, J = 7.9 Hz, 1H), 7.55 (t, J = 7.3 Hz, 1H), 7.30 (dd, J = 7.7, 0.5 Hz, 1H), Page 54 of 82 QB\169852.00141\91596905.1 7.21 (t, J = 7.7 Hz, 1H), 6.90 (dd, J = 7.3, 1.8 Hz, 1H), 6.71 (s, 1H), 6.68 (d, J = 8.1 Hz, 1H), 3.99 (s, 3H).13C NMR (101 MHz, cdcl3) δ 154.64, 149.11, 148.15, 138.65, 137.12, 135.63, 132.56, 130.16, 128.35, 127.62, 126.94, 123.97, 122.99, 121.38, 112.70, 111.86, 111.57, 106.69, 104.50, 39.45. Synthesis of 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(3- (trifluoromethyl)phenyl)pyridin-2-amine, compound 26. Compound 26 was synthesized according to the same procedure of compound 5 and was isolated as a yellow compound. MS m / z [M + 1] 435.2.1H NMR (400 MHz, dmso) δ 9.54 (d, J = 7.0 Hz, 2H), 8.35 (s, 1H), 8.25 (s, 1H), 8.07 (s, 1H), 8.00 (s, 1H), 7.90 (s, 1H), 7.82 (d, J = 7.7 Hz, 1H), 7.73 (t, J = 7.7 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.28 (d, J = 8.2 Hz, 1H), 7.14 (d, J = 7.4 Hz, 1H), 6.78 (d, J = 8.2 Hz, 1H), 3.89 (s, 3H).13C NMR (101 MHz, dmso) δ 154.47, 147.45, 147.29, 142.08, 138.57, 136.64, 135.53, 129.91, 129.85, 128.79, 127.30, 123.37, 122.19, 120.01, 117.02, 116.98, 114.31, 114.27, 111.92, 111.23, 110.58, 108.27, 38.78. Synthesis of 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(4- (trifluoromethyl)phenyl)pyridin-2-amine, compound 27. Compound 27 was synthesized according to the same procedure of compound 5 and was isolated as a grey compound. MS m / z [M + 1] 435.2.1H NMR (400 MHz, cdcl3) δ 9.63 (dd, J = 7.3, 0.5 Hz, 1H), 8.11 (s, 1H), 7.86 (s, 1H), 7.76 – 7.71 (m, 2H), 7.64 (t, J = 8.0 Hz, 1H), 7.60 (d, J = 8.7 Hz, 2H), 7.54 (d, J = 8.6 Hz, 2H), 7.30 (d, J = 7.6 Hz, 1H), 6.93 (dd, J = 7.3, 1.8 Hz, 1H), 6.78 – 6.70 (m, 2H), 3.99 (s, 3H).13C NMR (101 MHz, cdcl3) δ 154.02, 149.02, 143.82, 138.70, 137.12, 135.67, 130.29, 128.15, 127.65, 126.60, 126.56, 121.29, 119.22 (2C), 113.01, 111.90, 111.62, 107.06, 39.46. Synthesis of 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(4- (trifluoromethoxy)phenyl)pyridin-2-amine, compound 28. Compound 28 was synthesized according to the same procedure of compound 5 and was isolated as a white compound. MS m / z [M + 1] 451.3.1H NMR (400 MHz, cdcl3) δ 9.63 (d, J = 7.3 Hz, 1H), 8.08 (s, 1H), 7.84 (s, 1H), 7.72 (s, 1H), 7.70 (s, 1H), 7.58 (t, J = 7.9 Hz, 1H), 7.45 (d, J = 8.8 Hz, 2H), 7.23 (d, J = 7.7 Hz, 2H), 6.88 (d, J = 7.3 Hz, 1H), 6.73 (s, 1H), 6.65 (d, J = 8.2 Hz, 1H), 3.98 (s, 3H).13C NMR (101 MHz, dmso) δ 154.79, 151.31, 147.53, 142.11, 140.53, 138.43, 136.66, 135.38, 129.89, 128.82, 127.66, 123.35, 121.79, 120.27, 120.02, 111.39, 111.08, 110.59, 107.65, 38.80. Page 55 of 82 QB\169852.00141\91596905.1 Synthesis of 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(4- nitrophenyl)pyridin-2-amine, compound 29. Compound 29 was synthesized according to the same procedure of compound 5 and was isolated as a orange compound. MS m / z [M + 1] 412.1.1H NMR (400 MHz, cdcl3) δ 9.59 (d, J = 7.3 Hz, 1H), 8.22 (d, J = 9.2 Hz, 2H), 8.12 (s, 1H), 7.86 (s, 1H), 7.74 (s, 2H), 7.69 (t, J = 7.9 Hz, 1H), 7.58 (d, J = 9.2 Hz, 2H), 7.38 (d, J = 7.7 Hz, 1H), 7.03 – 6.94 (m, 2H), 6.77 (d, J = 8.1 Hz, 1H), 3.98 (s, 3H).13C NMR (101 MHz, dmso) δ 153.34, 148.04, 147.73, 147.49, 139.63, 138.95, 136.82, 135.93, 130.18, 128.99, 127.37, 125.52 (2C), 123.19, 120.01, 116.80 (2C), 113.60, 111.51, 110.63, 109.62, 38.83. Synthesis of N-(6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2- yl)pyrazin-2-amine, compound 30. Compound 30 was synthesized according to the same procedure of compound 5 and was isolated as a yellow compound. MS m / z [M + 1] 369.3.1H NMR (400 MHz, dmso) δ 10.17 (s, 1H), 10.02 (d, J = 7.3 Hz, 1H), 8.71 (s, 1H), 8.40 (s, 1H), 8.33 (s, 1H), 8.32 (dd, J = 2.3, 1.1 Hz, 1H), 8.15 – 8.09 (m, 2H), 7.91 (s, 1H), 7.84 – 7.75 (m, 2H), 7.56 (d, J = 7.3 Hz, 1H), 7.30 (dd, J = 7.3, 1.6 Hz, 1H), 3.91 (s, 3H).13C NMR (101 MHz, dmso) δ 152.43, 150.97, 148.14, 147.42, 141.44, 138.69, 136.77, 135.72, 135.62, 135.41, 130.14, 128.93, 128.39, 122.81, 120.02, 113.26, 111.39, 110.48, 108.66, 38.82. Synthesis of 4-((6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2- yl)amino)benzonitrile, compound 31. Compound 31 was synthesized according to the same procedure of compound 5 and was isolated as a yellow compound. MS m / z [M + 1] 392.3.1H NMR (400 MHz, dmso) δ 9.96 (s, 1H), 9.69 (d, J = 7.4 Hz, 1H), 8.71 (s, 1H), 8.59 (s, 1H), 8.27 (s, 1H), 8.06 (s, 1H), 7.92 – 7.84 (m, 1H), 7.76 (s, 3H), 7.71 (dd, J = 7.4, 1.4 Hz, 1H), 7.55 (d, J = 7.5 Hz, 1H), 7.00 (d, J = 8.3 Hz, 1H), 3.93 (s, 3H).13C NMR (101 MHz, dmso) δ 172.06, 154.01, 145.37, 145.19, 139.25, 137.76, 133.41 (2C), 130.53, 128.91, 124.35, 119.71, 118.70, 117.92 (2C), 114.37, 114.11, 111.30, 106.02, 102.00, 39.02. Synthesis of N-(4-chlorophenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin- 3-yl)pyridin-2-amine, compound 32. Compound 32 was synthesized according to the same procedure of compound 5 and was isolated as a white compound. MS m / z [M + 1] 401.3.1H NMR (400 MHz, cdcl3) δ 9.64 (d, J = 7.3 Hz, 1H), 8.10 (d, J = 4.6 Hz, 1H), 7.86 (s, 1H), 7.73 (d, J = 3.2 Hz, 2H), 7.58 (t, J = 7.9 Hz, 1H), 7.40 – 7.31 (m, 3H), 7.23 (d, J = 7.7 Hz, 1H), 6.93 (dd, J = 7.3, 1.6 Hz, 1H), 6.64 Page 56 of 82 QB\169852.00141\91596905.1 (d, J = 8.2 Hz, 1H), 6.53 (s, 1H), 3.99 (s, 3H).13C NMR (101 MHz, dmso) δ 154.74, 147.55, 147.24, 140.24, 138.36, 136.75, 135.45, 129.88, 128.89, 128.64 (2C), 127.55, 124.43, 123.37, 120.32 (2C), 120.02, 111.33, 111.20, 110.60, 107.76, 38.78. Synthesis of N-(2,6-difluorobenzyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2- a]pyridin-3-yl)pyridin-2-amine, compound 33. Compound 33 was synthesized according to the same procedure of compound 5 and was isolated as a white compound. MS m / z [M + 1] 417.2.1H NMR (400 MHz, dmso) δ 9.73 (d, J = 7.5 Hz, 1H), 8.96 (s, 1H), 8.36 (s, 1H), 8.23 (s, 1H), 8.09 (s, 1H), 7.87 (s, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.29 (d, J = 7.3 Hz, 1H), 7.16 (s, 1H), 7.14 (s, 1H), 6.94 (s, 2H), 6.63 (d, J = 8.3 Hz, 1H), 6.04 (s, 2H), 3.90 (s, 3H).13C NMR (101 MHz, dmso) δ 155.60, 147.60, 147.37, 147.17, 142.10, 138.11, 136.69, 135.42, 135.28, 129.71, 128.82, 127.95, 123.33, 120.02, 112.96, 110.99, 110.53, 110.13, 108.14, 106.61, 102.72, 100.89, 38.78. Synthesis of methyl 4-methyl-3-((6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin- 3-yl)pyridin-2-yl)amino)benzoate, compound 34. Compound 34 was synthesized according to the same procedure of compound 5 and was isolated as a yellow compound. MS m / z [M + 1] 439.2.1H NMR (400 MHz, dmso) δ 9.40 (d, J = 7.3 Hz, 1H), 8.59 (s, 1H), 8.29 (d, J = 7.9 Hz, 2H), 8.17 (d, J = 1.5 Hz, 1H), 8.02 (s, 1H), 7.83 (s, 1H), 7.73 (dd, J = 7.9, 1.6 Hz, 1H), 7.65 (t, J = 7.9 Hz, 1H), 7.48 (d, J = 7.9 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 6.80 (dd, J = 7.4, 1.6 Hz, 1H), 6.71 (d, J = 8.2 Hz, 1H), 3.89 (s, 3H), 3.72 (s, 3H), 2.34 (s, 3H).13C NMR (101 MHz, cdcl3) δ 174.77, 167.05, 155.79, 147.20, 138.90, 138.44, 137.28, 136.90, 133.75, 132.08, 131.05, 128.81, 128.32, 127.75, 125.43, 124.82, 123.59, 120.96, 111.43, 110.87, 106.02, 52.10, 39.23, 21.61, 18.53. Synthesis of tert-butyl 4-((6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3- yl)pyridin-2-yl)amino)benzoate, compound 35. Compound 35 was synthesized according to the same procedure of compound 5 and was isolated as a yellow compound. MS m / z [M + 1] 467.0.1H NMR (400 MHz, cdcl3) δ 9.69 (dd, J = 7.3, 0.6 Hz, 1H), 8.11 (s, 1H), 7.99 (d, J = 8.7 Hz, 2H), 7.86 (d, J = 0.7 Hz, 1H), 7.74 (s, 1H), 7.73 (d, J = 0.9 Hz, 1H), 7.63 (t, J = 7.9 Hz, 1H), 7.46 (d, J = 8.8 Hz, 2H), 7.30 (d, J = 7.4 Hz, 1H), 6.98 (dd, J = 7.3, 1.8 Hz, 1H), 6.80 (s, 1H), 6.77 (d, J = 8.1 Hz, 1H), 3.99 (s, 3H), 1.61 (s, 9H).13C NMR (101 MHz, cdcl3) δ 165.72, 153.93, 149.09, 148.18, 144.57, 138.62, 137.12, 135.64, 131.08 (2C), 130.28, 128.19, 127.70, 125.50, 123.73, 121.33, 118.15 (2C), 113.00, 111.88, 111.73, 107.20, 80.81, 39.44, 28.46 (3C). Page 57 of 82 QB\169852.00141\91596905.1 Synthesis of ethyl 2-(4-((6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3- yl)pyridin-2-yl)amino)phenyl)acetate, compound 36. Compound 36 was synthesized according to the same procedure of compound 5 and was isolated as a white compound. MS m / z [M + 1] 453.2.1H NMR (400 MHz, cdcl3) δ 9.68 (dd, J = 7.3, 0.8 Hz, 1H), 8.08 (s, 1H), 7.88 (d, J = 0.7 Hz, 1H), 7.76 (s, 1H), 7.69 (dd, J = 1.8, 0.8 Hz, 1H), 7.57 – 7.52 (m, 1H), 7.39 – 7.27 (m, 4H), 7.19 (dd, J = 7.6, 0.5 Hz, 1H), 6.97 (dd, J = 7.3, 1.9 Hz, 1H), 6.68 (s, 1H), 6.64 (d, J = 7.8 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.96 (s, 3H), 3.63 (s, 2H), 1.28 (t, J = 7.1 Hz, 3H).13C NMR (101 MHz, cdcl3) δ 172.02, 155.41, 148.93, 148.00, 139.46, 138.37, 137.15, 135.18, 130.17 (2C), 128.97, 128.59, 127.76, 123.79, 121.80 (2C), 121.43, 111.54, 105.86, 61.04, 40.89, 39.35, 29.83, 14.38. Synthesis of N-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)-6-(7-(1-methyl-1H-pyrazol-4- yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-amine, compound 37. Compound 37 was synthesized according to the same procedure of compound 5 and was isolated as a white compound. MS m / z [M + 1] 427.2.1H NMR (400 MHz, cdcl3) δ 9.41 (dd, J = 7.3, 0.8 Hz, 1H), 8.09 (d, J = 2.0 Hz, 1H), 7.82 (d, J = 0.7 Hz, 1H), 7.71 – 7.65 (m, 2H), 7.56 (t, J = 7.9 Hz, 1H), 7.22 (dd, J = 7.7, 0.5 Hz, 1H), 6.93 (dd, J = 7.3, 1.9 Hz, 1H), 6.45 – 6.40 (m, 1H), 6.29 (s, 1H), 6.04 (s, 1H), 3.96 (s, 3H), 3.73 (s, 3H), 1.36 (s, 9H).13C NMR (101 MHz, cdcl3) δ 161.15, 156.04, 149.22, 148.12, 138.74, 138.47, 137.08, 135.37, 130.23, 128.27, 127.56, 123.33, 121.33, 111.84, 111.64, 111.58, 104.70, 97.34, 39.40, 35.33, 32.48, 30.75 (3C). Synthesis of N-(3-(tert-butyl)-1-(4-fluorophenyl)-1H-pyrazol-5-yl)-6-(7-(1-methyl-1H- pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-amine, compound 38. Compound 38 was synthesized according to the same procedure of compound 5 and was isolated as a yellow compound. MS m / z [M + 1] 507.3.1H NMR (400 MHz, cdcl3) δ 9.58 (d, J = 7.3 Hz, 1H), 8.09 (s, 1H), 7.83 (s, 1H), 7.75 (s, 1H), 7.72 (s, 1H), 7.62 – 7.53 (m, 3H), 7.13 – 7.06 (m, 2H), 7.01 – 6.97 (m, 1H), 6.56 (d, J = 8.1 Hz, 1H), 6.31 (s, 1H), 6.13 (s, 1H), 3.98 (s, 3H), 1.40 (s, 9H).13C NMR (101 MHz, cdcl3) δ 162.72, 162.48, 160.26, 155.27, 149.02, 147.92, 138.80, 138.60, 136.91, 135.18, 130.12, 128.27, 127.47, 126.07, 125.98, 123.41, 121.16, 116.14, 115.92, 111.85, 111.65, 111.48, 105.32, 97.64, 39.28, 32.63, 30.53 (3C). Synthesis of N-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-6-(7-(1-methyl-1H-pyrazol-4- yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-amine, compound 39. Compound 39 was synthesized according to the same procedure of compound 5 and was isolated as a white compound. MS m / z [M + 1] 503.3.1H NMR (400 MHz, cdcl3) δ 9.61 Page 58 of 82 QB\169852.00141\91596905.1 (d, J = 7.3 Hz, 1H), 8.07 (s, 1H), 7.81 (s, 1H), 7.69 (s, 1H), 7.67 (s, 1H), 7.57 (t, J = 7.9 Hz, 1H), 7.47 (s, 1H), 7.45 (s, 1H), 7.25 – 7.18 (m, 3H), 6.94 (dd, J = 7.3, 0.9 Hz, 1H), 6.57 (d, J = 8.2 Hz, 1H), 6.34 (s, 1H), 6.32 (s, 1H), 3.97 (s, 3H), 2.35 (s, 3H), 1.40 (s, 9H).13C NMR (101 MHz, cdcl3) δ 162.26, 154.91, 149.17, 148.09, 138.67, 138.45, 137.42, 137.07 (2C), 136.42, 135.45, 130.17, 130.02, 128.32, 127.53, 124.39 (2C), 123.57, 121.38, 112.16, 111.77, 111.74, 105.44, 96.51, 39.42, 32.68, 30.63 (3C), 21.21. Synthesis of N-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)-6-(7-(4- (methylsulfonyl)phenyl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-amine, compound 40. Compound III (124 mg, 322.83 umol), 3-(tert-butyl)-1-methyl-1H-pyrazol-5-amine (645.67 umol, 2 equiv), cesium carbonate (157.78 mg, 434.25 umol) were dissolved into 5 mL Dioxane. The resulting reaction mixture was degassed with nitrogen for 5-10 min. After that, Pd(PPh3)4(37.31 mg, 32.28 umol) was added. The resulting mixture was stirred at 100 °C under N2 atmosphere overnight (sealed bottle). After completion of reaction, the reaction mixture was filtered and concentrated in vacuo. Silica flash chromatography (MeOH / DCM 0−7%) followed by C18 flash chromatography (MeOH / H2O 10−80%) yielded compound 40 as a green solid (62 mg, 38.36%) MS m / z [M + 1] 501.2.1H NMR (400 MHz, cdcl3) δ 9.54 (d, J = 7.4 Hz, 1H), 8.19 (s, 1H), 8.08 – 8.01 (m, 2H), 7.90 (d, J = 1.9 Hz, 1H), 7.83 (dq, J = 8.3, 2.1 Hz, 2H), 7.60 (t, J = 7.9 Hz, 1H), 7.30 – 7.25 (m, 1H), 7.08 (dt, J = 7.0, 1.8 Hz, 1H), 6.48 (d, J = 8.2 Hz, 1H), 6.26 (s, 1H), 6.05 (s, 1H), 3.73 (s, 3H), 3.11 (s, 3H), 1.36 (s, 9H).13C NMR (101 MHz, cdcl3) δ 161.19, 156.11, 148.84, 147.53, 144.14, 140.08, 138.90, 138.33, 136.06, 135.67, 128.62, 128.37 (2C), 127.71 (2C), 123.80, 115.46, 112.16, 111.91, 105.33, 97.43, 44.73, 35.37, 32.50, 30.77 (3C). Synthesis of N-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-6-(7-(4- (methylsulfonyl)phenyl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-amine, compound 41. Compound 41 was synthesized according to the same procedure of compound 40 and was isolated as a green compound. MS m / z [M + 1] 577.3.1H NMR (400 MHz, cdcl3) δ 9.75 (dd, J = 7.3, 0.5 Hz, 1H), 8.18 (s, 1H), 8.08 – 8.00 (m, 2H), 7.92 (d, J = 1.1 Hz, 1H), 7.87 – 7.81 (m, 2H), 7.61 (t, J = 7.9 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 7.6 Hz, 1H), 7.21 (d, J = 8.1 Hz, 2H), 7.11 (dd, J = 7.4, 2.0 Hz, 1H), 6.61 (d, J = 8.2 Hz, 1H), 6.33 (s, 1H), 6.29 (s, 1H), 3.11 (s, 3H), 2.35 (s, 3H), 1.40 (s, 9H).13C NMR (101 MHz, cdcl3) δ 162.29, 155.02, 148.81, 147.52, 144.20, 140.14, 138.84, 138.29, 137.49, 136.41, 136.16, 135.66, 130.05 (2C), 128.66, 128.41 (2C), 127.72 (2C), 124.36 (2C), 115.58, 112.51, 112.11, 106.03, 96.68, 44.74, 32.71, 30.65 (3C), 21.22. Page 59 of 82 QB\169852.00141\91596905.1 Synthesis of 6-(7-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridin-3-yl)-N-(3,4,5- trimethoxyphenyl)pyridin-2-amine, compound 42. Compound 42 was synthesized according to the same procedure of compound 40 and was isolated as a yellow compound. MS m / z [M + 1] 531.1.1H NMR (400 MHz, cdcl3) δ 9.86 (d, J = 7.4 Hz, 1H), 8.18 (s, 1H), 8.03 (dd, J = 8.5, 1.7 Hz, 2H), 7.91 (d, J = 1.1 Hz, 1H), 7.82 (dd, J = 8.5, 1.8 Hz, 2H), 7.59 (t, J = 7.9 Hz, 1H), 7.24 (dd, J = 10.9, 4.3 Hz, 1H), 7.07 (dd, J = 7.4, 1.9 Hz, 1H), 6.74 – 6.58 (m, 4H), 3.87 (s, 3H), 3.81 (s, 6H), 3.10 (s, 3H).13C NMR (101 MHz, cdcl3) δ 155.86, 153.82 (2C), 148.60, 147.38, 144.11, 140.09, 138.62, 136.36, 135.95, 135.61, 134.58, 128.71, 128.36 (2C), 127.76 (2C), 124.30, 115.58, 111.84, 106.32, 99.85 (2C), 61.21, 56.30 (2C), 44.74, 29.82. Synthesis of N-(4-(tert-butyl)phenyl)-6-(7-(4-(methylsulfonyl)phenyl)imidazo[1,2- a]pyridin-3-yl)pyridin-2-amine, compound 43. Compound 43 was synthesized according to the same procedure of compound 40 and was isolated as a yellow compound. MS m / z [M + 1] 497.2.1H NMR (400 MHz, cdcl3) δ 9.85 (dd, J = 7.4, 0.8 Hz, 1H), 8.17 (s, 1H), 8.08 – 8.02 (m, 2H), 7.92 (dd, J = 1.9, 0.8 Hz, 1H), 7.87 – 7.80 (m, 2H), 7.59 – 7.54 (m, 1H), 7.45 – 7.38 (m, 2H), 7.37 – 7.30 (m, 2H), 7.21 (d, J = 7.2 Hz, 1H), 7.04 (dd, J = 7.4, 2.0 Hz, 1H), 6.71 (d, J = 8.1 Hz, 1H), 6.63 (s, 1H), 3.11 (s, 3H), 1.37 (s, 9H).13C NMR (101 MHz, cdcl3) δ 155.96, 148.60, 147.35, 146.70, 144.28, 140.04, 138.49, 137.63, 135.89, 135.45, 128.84, 128.37 (2C), 127.70 (2C), 126.20 (2C), 124.37, 121.77 (2C), 115.52, 111.69, 111.67, 105.99, 44.73, 34.56, 31.62 (3C). Example 3 1. Introduction Activating mutations in FLT3 are detected in about 30% of all acute myeloid leukemia (AML) cases [1, 2], most commonly consisting of internal tandem duplication (FLT3-ITD) mutations in the juxtamembrane region (25%) [3]. To date, two generations of FLT3 kinase inhibitors have been developed and assessed in clinical trials, with three inhibitors clinically approved. Midostaurin, a first generation FLT3 kinase inhibitor, is able to inhibit FLT3 autophosphorylation, but its lack of selectivity limits its clinical use [4-6]. Therefore, midostaurin was only approved by the USFDA for use in combination with other chemotherapy agents. Second generation FLT3 kinase inhibitors such as quizartinib [7-13] and gilteritinib [14, 15] were improved in potency and selectivity, and were approved for single agent therapy of FLT3-ITD mutated AML. However, the clinical efficacy of quizartinib and gilteritinib is Page 60 of 82 QB\169852.00141\91596905.1 short-lived due to the emergence of drug-resistant secondary mutations within FLT3 after 3-4 months of treatment. The most clinically important resistance mutations are FLT3-ITD / D835Y and FLT3-ITD / F691L [16-18]. FLT3-ITD / D835Y is resistant to quizartinib [19, 20] while FLT3-ITD / F691L is resistant to both quizartinib and gilteritinib

[0021] . Therefore, new FLT3 kinase inhibitors which retain inhibitory effects on both FLT3-ITD / D835Y and FLT3- ITD / F691L are needed

[0022] . Besides on-target FLT3 secondary mutations, off-target secondary clinical resistance was also observed in patients after treatment with FLT3 kinase inhibitors, mainly due to mutations that activate the PI3K / AKT and / or RAS / MAPK pathways [23, 24]. Recently, the BCR::ABL1 gene fusion has emerged as another cause of off-target secondary clinical resistance in AML after FLT3 inhibitor treatment. BCR::ABL1 arises as a consequence of a chromosomal translocation between chromosome 9 and 22 - t(9, 22), resulting in the fusion of the BCR and ABL genes [25, 26]. The BCR::ABL1 gene fusion causes unregulated ABL activity, and is found in >95% of chronic myelogenous leukemia (CML) [27, 28], 20–30% of acute lymphoblastic leukemia (ALL)

[0029] , and a minority of primary AML cases. Notably, AML with the BCR::ABL1 genetic abnormality is stratified as an “adverse risk” group in European LeukemiaNet (ELN) [30, 31]. FLT3-ITD / BCR::ABL1 was recently reported as a new secondary clinical resistant subtype emerges after gilteritinib treatment and is detected in 5% of relapsed FLT3 mutated patients [23, 32-34]. However, there is no FLT3- ITD / BCR::ABL1 dual inhibitor which also inhibits the problematic FLT3-ITD / D835Y and FLT3-ITD / F691L mutations. Therefore, there is an unmet clinical need for an inhibitor that simultaneously blocks FLT3-ITD and BCR::ABL1 pathways to treat relapsed AML patients with FLT3-ITD / BCR::ABL1 secondary resistance subtype. Imidazo[1,2-a]pyridine was previously identified as a promising scaffold for the development of FLT3 inhibitors [35, 36]. In this study, in order to discover an inhibitor that simultaneously blocks FLT3-ITD and BCR::ABL1 pathways, we screened a newly synthesized library of >60 imidazo[1,2-a]pyridine derived compounds. Through screenings, we identified N-(3-methoxyphenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2- amine (compound C) as an inhibitor of both the FLT3-ITD and BCR::ABL1 pathways; in addition, it also potently inhibits FLT3-ITD / D835Y and FLT3-ITD / F691L secondary mutants. Page 61 of 82 QB\169852.00141\91596905.1 2. Results and Discussion 2.1. Cell Antiproliferative Effects In order to discover a small molecule inhibitor to treat AML patients with secondary clinical resistant subtypes, we screened a FLT3 inhibitor compounds library synthesized in a previous study for their antiproliferative effects on a few selected clinically relevant cell lines. MOLM14 is a patient-derived AML cell line driven by a FLT3-ITD mutation. MOLM14- D835Y and MOLM14-F691L are sublines of MOLM14 that were derived after long-term selection in quizartinib and carry drug-resistant FLT3 secondary mutations - either FLT3- ITD / D835Y or FLT3-ITD / F691L, respectively. In order to verify the compounds’ inhibitory effects on the BCR::ABL1 pathway, we also screened the compounds on K562, a patient- derived CML cell line driven by the BCR::ABL1 gene fusion. The abovementioned cell lines were treated with various concentrations of compound C, as well as several other FLT3 inhibitors, to assess their inhibitory effects (Table 7). Compound C was observed to have slightly better antiproliferative effects on MOLM14 cells than gilteritinib, with an IC50of (3.65 ± 0.56) nM versus (5.47 ± 0.25) nM. Importantly, compound C also retains very comparable antiproliferation effects on MOLM14-D835Y and MOLM14-F691L cells, with very close IC50values in all three MOLM14 cell lines (Figure 11). In contrast, although gilteritinib has similar inhibitory effects on both MOLM14-D835Y and MOLM14 cells, MOLM14-F691L cells are relatively resistant. K562 cells, which harbor a BCR::ABL1 mutation, are also sensitive to compound C treatment, with an IC50 of (8.43 ± 2.75) nM (Table 7). In order to verify that the antiproliferative effects of compound C are specific, we also assessed its activity in MDA-MB-231, MDA-BM-468, and HCC1806 cells, which are all triple-negative breast cancer cell lines with no known FLT3 or ABL mutations. No antiproliferative effects were observed in MDA-MB-231 or MDA-BM-468 cells, although HCC1806 cells show some sensitivity at higher concentrations, which indicates that compound C is not generally toxic. We compared the antiproliferative effects of compound C with its close analogue compound B. The structural difference between compounds C and B is the location of their methoxy groups. The methoxy group in compound C is at the meta-position of the aniline, while the methoxy group in compound B is at the para-position (Figure 12). Compound C and B act similarly in FLT3 mutant cell lines such as MOLM14, MOLM14-D835Y, and MOLM14- F691L; but they act differently in the BCR::ABL1 driven K562 cell line (Table 7). Therefore, Page 62 of 82 QB\169852.00141\91596905.1 the 3-methoxy aniline at the end of compound C is structurally important for the target inhibition in K562 cells. Table 7. IC50s (nM) of compounds C and B on FLT3 kinaseaand multiple cell linesb, gilteritinib and vandetanib as control. IC50compound C compound B gilteritinib vandetanib MOLM14 3.65±0.56 3.20 ±0.13 5.47±0.25 1108±84 MOLM14-D835Y 2.08±0.49 2.45±0.27 7.83±0.03 2805±139 MOLM14-F691L 4.23±0.50 19.82±4.38 58.8±1.0 >10000 K562 8.43±2.75 7786±2727 13100±2532 1535±150 MDA-MB-231 >20000 - - - MDA-MB-468 >20000 - - - HCC1806 114.7±2.5 - - -aIC50 on FLT3 kinase, compound concentration required to inhibit 50% enzymatic activity of FLT3;bIC50on cells, compound concentration required to inhibit tumor cell proliferation by 50%. 2.2. Western Blots To determine the molecular effects of compound C on FLT3 signaling, we treated MOLM14, MOLM14-D835Y, and MOLM14-F691L cells with compound C and gilteritinib at 1 / 10X, 1X, 10X, and 100X of their IC50values in MOLM14 cells for 2 hours and looked at activation of FLT3 and its downstream mediator ERK by western blot analysis (Figures 13A- 13C). In MOLM14 cells, compound C starts reducing the phosphorylation of FLT3 and ERK at 1 X IC50, and causes complete inhibition at 10 X IC50. Compound C works very similarly in MOLM14-D835Y cells, although in MOLM14-F691L cells there is some residual signal at 10 X IC50 suggesting that MOLM14-F691L cells are slightly resistant to compound C. To determine the molecular effects of compound C on BCR::ABL1 signaling, we treated K562 cells with compound C and dasatinib, a second-generation ABL inhibitor, at 1 / 10X, 1X, 10X, and 100X of their IC50values in K562 cells for 2 hours and looked at activation of BCR::ABL1 and its downstream mediators STAT5 and ERK by western blot analysis (Figure 13D). Compound C is able to inhibit the phosphorylation of BCR::ABL1 and downstream targets, STAT5 and ERK. The reduction of phosphorylation signals of BCR::ABL1, STAT5, and ERK are observed starting at 100X, 10X, and 100X of IC50s treatment of compound C, respectively. Page 63 of 82 QB\169852.00141\91596905.1 2.3. Apoptosis Assay Both FLT3 gain-of-function mutations [43-45] and the BCR::ABL1 gene-fusion [46, 47] mediate anti-apoptotic effects through downstream cascades of phosphorylation reactions and their associated signaling pathways such as RAS / RAF / MEK / ERK, JAK / STAT5 and PI3K / AKT / mTOR. In order to verify that compound C’s anti-proliferative effects are mediated by apoptosis, we performed apoptosis assays in MOLM14 cells 24, 48 and 72 hours after treatment with compound C (Figure 14). In the representative figures, cells in the lower left quadrant (Q1-LL) are nonapoptotic cells while cells in the lower right quadrant (Q1-LR) and upper right quadrant (Q1-UR) are early and late apoptotic cells, respectively. No notable difference was observed between DMSO and 1nM compound C treatments at any time points, indicating that this low dose, which is below the IC50 value of 3.65nM, did not induce apoptosis. However, 10 nM treatment of compound C showed a substantial increase in both early and late apoptotic cells at all timepoints, when compared with the DMSO treatment. Specifically, after 24 hours of treatment with 10 nM compound C, early apoptotic cells make up 9.5% of cells, while late apoptotic cells make up of 6.1% of cells. After 48 hours, early apoptotic cells decreased to 4.7% while late apoptotic cells increased to 24.0%. Finally, after 72 hours, early apoptotic cells further decreased to 4.3% while late apoptotic cells continued to increase to 45.5% of cells. In conclusion, compound C induces proapoptotic effects in MOLM14 cells in a dose- and time-dependent manner. 3. Conclusion Compound C was discovered to be an inhibitor of the FLT3-ITD and BCR::ABL1 pathways in a library screen for FLT3 kinase inhibitors. It is observed to have potent antiproliferative effects on a variety of clinically relevant leukemia cell lines driven by FLT3- ITD, FLT3-ITD / D835Y, FLT3-ITD / F691L, or BCR::ABL1, which do not appear to be due to a general mechanism of toxicity. Its inhibitory effects on FLT3-ITD, FLT3-ITD / D835Y, FLT3-ITD / F691L, and their downstream targets, are verified by loss of phosphorylation on FLT3 and its downstream signaling molecules by western blot analysis in MOLM14, MOLM14-D835Y, MOLM14-F691L cells, respectively. From the western blots of K562 cells, compound C is also identified as an inhibitor of the BCR::ABL1 pathway, although its inhibitory effects are not as potent as dasatinib. In addition, compound C may have other possible targets. In summary, compound C inhibits cell proliferation by mediating proapoptotic effects on cells through inhibiting FLT3 and BCR::ABL1 pathways, and other possible targets. Page 64 of 82 QB\169852.00141\91596905.1 4. Materials and Methods 4.1. Chemistry The synthesis of 3-(6-chloropyridin-2-yl)-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2- a]pyridine was described in Example 1, section 4.1. The other chemical reagents were obtained from commercial suppliers and used without further purification. Thermo Finnigan LCQ Deca with Thermo Surveyor LCMS System at variable wavelengths of 254 nm and 214 nm was used to monitor the reaction and test the purity of the compounds. The purity of all the final compounds is >95%. The water-methanol gradient buffered with 0.1% formic acid was used as the mobile phase for the HPLC system. NMR spectra were completed on a Varian 400 MHz instrument. The1H NMR spectra and13C spectra were recorded at 400 MHz and 101 MHz, respectively. The final compound was purified using Silica gel (0.035e0.070 mm, 60 Å) flash chromatography. 4.1.1 Synthesis and Characterization of N-(3-methoxyphenyl)-6-(7-(1-methyl-1H- pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-amine, compound C. 3-(6-chloropyridin-2-yl)-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine (100 mg, 322.83 umol), 3-methoxyaniline (79.52 mg, 645.67 umol), cesium carbonate (157.78 mg, 434.25 umol) were dissolved into 5 mL Dioxane. The resulting reaction mixture was degassed with nitrogen for 5-10 min. After that, Pd(PPh3)4 (37.31 mg, 32.28 umol) was added. The resulting mixture was stirred at 100 °C under N2atmosphere overnight (sealed bottle). After completion of reaction, the reaction mixture was filtered and concentrated in vacuo. Silica flash chromatography (MeOH / DCM 0−7%) followed by C18 flash chromatography (MeOH / H2O 10−80%) yielded compound C as a black solid (47 mg, 36.72%). MS m / z [M + 1] 397.2.1H NMR (400 MHz, dmso) δ 9.74 (d, J = 7.3 Hz, 1H), 9.15 (s, 1H), 8.36 (s, 1H), 8.25 (s, 1H), 8.09 (s, 1H), 7.88 (d, J = 0.9 Hz, 1H), 7.66 (t, J = 7.9 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.26 (t, J = 8.1 Hz, 1H), 7.15 (dt, J = 12.9, 5.4 Hz, 3H), 6.74 (d, J = 8.2 Hz, 1H), 6.58 (dd, J = 8.1, 2.1 Hz, 1H), 3.89 (s, 3H), 3.72 (s, 3H).13C NMR (101 MHz, dmso) δ 159.86, 155.04, 147.61, 147.22, 142.38, 138.34, 136.75, 135.41, 129.76, 128.80, 127.88, 123.38, 120.03, 111.75, 111.00, 110.65, 110.43, 107.53, 107.39, 106.61, 104.94, 54.97, 38.68. Page 65 of 82 QB\169852.00141\91596905.1 4.1.2 Synthesis and Characterization of N-(4-methoxyphenyl)-6-(7-(1-methyl-1H- pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-amine, compound B. 3-(6-chloropyridin-2-yl)-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine (100 O S mg, 322.83 umol), 4-methoxyaniline (645.67 umol), m carbonate (157.78 mg, 434.25 umol) were dissolved into 5 mL mixture was degassed with nitrogen for 5-10 min. After that, Pd(PPh3)4(37.31 mg, 32.28 umol) was added. The resulting mixture was stirred at 100 °C under N2 atmosphere overnight (sealed bottle). After completion of reaction, the reaction mixture was filtered and concentrated in vacuo. Silica flash chromatography (MeOH / DCM 0−7%) followed by C18 flash chromatography (MeOH / H2O 10−80%) yielded compound B as a yellow solid. MS m / z [M + 1] 397.2.1H NMR (400 MHz, cdcl3) δ 9.70 (d, J = 7.4 Hz, 1H), 8.06 (s, 1H), 7.83 (d, J = 0.5 Hz, 1H), 7.70 (s, 2H), 7.53 – 7.48 (m, 1H), 7.34 – 7.29 (m, 2H), 7.13 (d, J = 7.6 Hz, 1H), 6.97 – 6.92 (m, 2H), 6.90 (dd, J = 7.3, 1.8 Hz, 1H), 6.53 (d, J = 8.2 Hz, 1H), 6.49 (s, 1H), 3.97 (s, 3H), 3.85 (s, 3H).13C NMR (101 MHz, cdcl3) δ 156.62, 156.54, 148.87, 138.37, 137.10, 134.76, 133.28, 130.20, 128.44, 127.65, 124.78 (2C), 121.36, 114.66 (2C), 111.60, 111.50, 111.03, 104.90, 55.73, 50.93, 39.41, 29.84. 4.2 Cell Culture MV4-11 cells were obtained from the laboratory of Dr. Farrar in Arkansas Children’s Hospital and cultured in IMDM (Gibco, USA) containing 10% fetal bovine serum (FBS) (Gibco, USA). MOLM14, MOLM14-D835Y, MOLM14-F691L cells were obtained from the laboratory of Dr. Shah in University of California San Francisco and cultured in RPMI (Gibco, USA) containing 10% fetal bovine serum (FBS) (Gibco, USA). K562 cells were obtained from the laboratory of Dr. Shah in University of California San Francisco and cultured in IMDM (Gibco, USA) containing 10% fetal bovine serum (FBS) (Gibco, USA). MDA-MB-231 cells were obtained from the laboratory of Dr. Qin in University of Arkansas for Medical Sciences and cultured in DMEM (Gibco, USA) containing 10% fetal bovine serum (FBS) (Gibco, USA). All media contained 100 units / mL penicillin (Gibco, USA), and 100 μg / mL streptomycin (Gibco, USA). Other cell lines were cultured in appropriate media according to provider’s instructions. Cells were incubated at 37 °C in a humidified atmosphere of 5% CO2. Page 66 of 82 QB\169852.00141\91596905.1 4.3 Cell Viability Assays Cells in logarithmic phase were seeded into 96-well culture plates at 5000 cells per well. Then, after 24 h of incubation, cells were treated in triplicate with various concentrations of compounds for 72 h in final volumes of 200 μL. Upon end point, 20 μL Resazurin solution (Biotium, USA) was added to each well, and the cells were incubated for an additional 4-6 h. Fluorescence values at a wavelength of 590 nM were taken on a spectrophotometer (BioTek, USA). IC50 values were calculated using percentage of growth versus vehicle (DMSO) treated control. The data were finally fitted in GraphPad Prism V9.0 software to obtain IC50values using [inhibitor] vs. normalized response (variable slope) model. Each compound was tested at least three times. 4.4 FLT3 Kinase Inhibition Assay Kinase assays were conducted using the bioluminescent ADP-Glo™ kinase assay (Promega, USA), following the manufacturer's instructions. Assay was performed with the test compounds at 8-point half log dilutions (1 uM to 0.316 nM). Luminescence signal was measured on a spectrophotometer (BioTek, USA), and IC50values reported are based on the dose-response curve fitted in GraphPad Prism V9.0 using [inhibitor] vs. normalized response model. Each compound was tested at least three times. 4.5 Western Blot MOLM14, MOLM14-D835Y and MOLM14-F691L cells, at 5 x105cells / ml, were exposed to compound C or gilteritinib for 2 hours at 37 degrees at 1 / 10X, 1X, 10X, and 100X of their IC50values in Molm14 cells (3.65nM and 5.47nM, respectively). K562 cells, at 5x105cells / ml, were exposed to compound C or dasatinib for 2 hours at 37 degrees at 1 / 10X, 1X, 10X, and 100X of their IC50values in K562 cells (8.43nM and 0.56nM, respectively). Total cell lysates were resolved by SDS-polyacrylamide gel electrophoresis and transferred to nitrocellulose membranes. The membranes were then probed with primary antibodies purchased from Cell Signaling (Danvers, MA, USA) [pFLT3 Y842 (#4577), FLT3 (#3462), pABL Y245 (#2861), pSTAT5 Y694 (#9351), STAT5 (#9363), pERK (#4370), ERK (#9107) and GAPDH (#5174)] and from BD Biosciences (San Jose, CA, USA) [ABL (#554148)] followed by secondary antibodies purchased from Licor (Lincoln, NE, USA). Immunoblots were then visualized by a Biorad ChemiDoc MP Imagine System (Hercules, CA, USA). 4.6 Apoptosis Assay MOLM14 cells were cultured in 2 ml of growth medium in 6-well plates for 24 h. Then the cells were treated with DMSO or various concentrations of compound C. After a 72 h Page 67 of 82 QB\169852.00141\91596905.1 exposure to the compound, the cells were collected and centrifuged for 5 min at 1200 rpm, re- suspended in PBS and counted using a Countess II Automated Cell Counter (Applied Biosystems, Foster City, USA). The cells were then washed with cold PBS two more times and resuspended in binding buffer (BD Bioscience, San Jose, USA) at a concentration of 1 × 106cells / ml. Then, 100 uL of the cell suspension was transferred to FACS tubes and 5 uL of FITC Annexin V (BD Bioscience, San Jose, USA) and 5 uL PI (BD Bioscience, San Jose, USA) was added as the manufacture's instruction stated. 400 uL of binding buffer was added to each sample after 15 min incubation at room temperature in the dark. Lastly, all the samples were analyzed by flow cytometry using a BD Accuri C6 Plus flow cytometer (BD Bioscience, San Jose, USA). References [1] N.J. Short, M.E. Rytting, J.E. Cortes, Acute myeloid leukaemia, The Lancet 392(10147) (2018) 593-606. [2] T.J. Ley, C. Miller, L. Ding, B.J. Raphael, A.J. Mungall, A. Robertson, K. Hoadley, T.J. Triche, Jr., P.W. Laird, J.D. Baty, L.L. Fulton, R. Fulton, S.E. Heath, J. Kalicki-Veizer, C. Kandoth, J.M. Klco, D.C. Koboldt, K.L. Kanchi, S. Kulkarni, T.L. Lamprecht, D.E. Larson, L. Lin, C. Lu, M.D. McLellan, J.F. McMichael, J. Payton, H. Schmidt, D.H. Spencer, M.H. Tomasson, J.W. Wallis, L.D. Wartman, M.A. Watson, J. Welch, M.C. Wendl, A. Ally, M. Balasundaram, I. Birol, Y. Butterfield, R. Chiu, A. Chu, E. Chuah, H.J. Chun, R. Corbett, N. Dhalla, R. Guin, A. He, C. Hirst, M. Hirst, R.A. Holt, S. Jones, A. Karsan, D. Lee, H.I. Li, M.A. Marra, M. Mayo, R.A. Moore, K. Mungall, J. Parker, E. Pleasance, P. Plettner, J. Schein, D. Stoll, L. Swanson, A. Tam, N. Thiessen, R. Varhol, N. Wye, Y. Zhao, S. Gabriel, G. Getz, C. Sougnez, L. Zou, M.D. Leiserson, F. Vandin, H.T. Wu, F. Applebaum, S.B. Baylin, R. Akbani, B.M. Broom, K. Chen, T.C. Motter, K. Nguyen, J.N. Weinstein, N. Zhang, M.L. Ferguson, C. Adams, A. Black, J. Bowen, J. Gastier-Foster, T. Grossman, T. Lichtenberg, L. Wise, T. Davidsen, J.A. Demchok, K.R. Shaw, M. Sheth, H.J. Sofia, L. Yang, J.R. Downing, G. Eley, Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia, N Engl J Med 368(22) (2013) 2059-74. [3] S.B. Liu, H.J. Dong, X.B. Bao, Q.C. Qiu, H.Z. Li, H.J. Shen, Z.X. Ding, C. Wang, X.L. Chu, J.Q. Yu, T. Tao, Z. Li, X.W. Tang, S.N. Chen, D.P. Wu, L. Li, S.L. Xue, Impact of FLT3-ITD length on prognosis of acute myeloid leukemia, Haematologica 104(1) (2019) e9- e12. Page 68 of 82 QB\169852.00141\91596905.1 [4] T. Fischer, R.M. Stone, D.J. Deangelo, I. Galinsky, E. Estey, C. Lanza, E. Fox, G. Ehninger, E.J. Feldman, G.J. Schiller, V.M. Klimek, S.D. Nimer, D.G. Gilliland, C. Dutreix, A. Huntsman-Labed, J. Virkus, F.J. Giles, Phase IIB trial of oral Midostaurin (PKC412), the FMS-like tyrosine kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wild-type or mutated FLT3, J Clin Oncol 28(28) (2010) 4339-45. [5] R.M. Stone, D.J. DeAngelo, V. Klimek, I. Galinsky, E. Estey, S.D. Nimer, W. Grandin, D. Lebwohl, Y. Wang, P. Cohen, E.A. Fox, D. Neuberg, J. Clark, D.G. Gilliland, J.D. Griffin, Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small- molecule FLT3 tyrosine kinase inhibitor, PKC412, Blood 105(1) (2005) 54-60. [6] E. Weisberg, C. Boulton, L.M. Kelly, P. Manley, D. Fabbro, T. Meyer, D.G. Gilliland, J.D. Griffin, Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412, Cancer Cell 1(5) (2002) 433-43. [7] P.P. Zarrinkar, R.N. Gunawardane, M.D. Cramer, M.F. Gardner, D. Brigham, B. Belli, M.W. Karaman, K.W. Pratz, G. Pallares, Q. Chao, K.G. Sprankle, H.K. Patel, M. Levis, R.C. Armstrong, J. James, S.S. Bhagwat, AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML), Blood 114(14) (2009) 2984-92. [8] Q. Chao, K.G. Sprankle, R.M. Grotzfeld, A.G. Lai, T.A. Carter, A.M. Velasco, R.N. Gunawardane, M.D. Cramer, M.F. Gardner, J. James, P.P. Zarrinkar, H.K. Patel, S.S. Bhagwat, Identification of N-(5-tert-butyl-isoxazol-3-yl)-N'-{4-[7-(2-morpholin-4-yl- ethoxy)imidazo[2,1-b][1 ,3]benzothiazol-2-yl]phenyl}urea dihydrochloride (AC220), a uniquely potent, selective, and efficacious FMS-like tyrosine kinase-3 (FLT3) inhibitor, J Med Chem 52(23) (2009) 7808-16. [9] J. Cortes, A.E. Perl, H. Döhner, H. Kantarjian, G. Martinelli, T. Kovacsovics, P. Rousselot, B. Steffen, H. Dombret, E. Estey, S. Strickland, J.K. Altman, C.D. Baldus, A. Burnett, A. Krämer, N. Russell, N.P. Shah, C.C. Smith, E.S. Wang, N. Ifrah, G. Gammon, D. Trone, D. Lazzaretto, M. Levis, Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial, The Lancet Oncology 19(7) (2018) 889-903.

[0010] J.E. Cortes, S. Khaled, G. Martinelli, A.E. Perl, S. Ganguly, N. Russell, A. Krämer, H. Dombret, D. Hogge, B.A. Jonas, A.Y.-H. Leung, P. Mehta, P. Montesinos, M. Radsak, S. Sica, M. Arunachalam, M. Holmes, K. Kobayashi, R. Namuyinga, N. Ge, A. Yver, Y. Zhang, M.J. Levis, Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD Page 69 of 82 QB\169852.00141\91596905.1 acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial, The Lancet Oncology 20(7) (2019) 984-997.

[0011] J.E. Cortes, M.S. Tallman, G.J. Schiller, D. Trone, G. Gammon, S.L. Goldberg, A.E. Perl, J.P. Marie, G. Martinelli, H.M. Kantarjian, M.J. Levis, Phase 2b study of 2 dosing regimens of quizartinib monotherapy in FLT3-ITD-mutated, relapsed or refractory AML, Blood 132(6) (2018) 598-607.

[0012] M.J. Levis, A.E. Perl, H. Dombret, H. Döhner, B.r. Steffen, P. Rousselot, G. Martinelli, E.H. Estey, A.K. Burnett, G. Gammon, D. Trone, E. Leo, J.E. Cortes, Final Results of a Phase 2 Open-Label, Monotherapy Efficacy and Safety Study of Quizartinib (AC220) in Patients with FLT3-ITD Positive or Negative Relapsed / Refractory Acute Myeloid Leukemia After Second-Line Chemotherapy or Hematopoietic Stem Cell Transplantation, Blood 120(21) (2012) 673-673.

[0013] H.K. Patel, R.M. Grotzfeld, A.G. Lai, S.A. Mehta, Z.V. Milanov, Q. Chao, K.G. Sprankle, T.A. Carter, A.M. Velasco, M.A. Fabian, J. James, D.K. Treiber, D.J. Lockhart, P.P. Zarrinkar, S.S. Bhagwat, Arylcarboxyamino-substituted diaryl ureas as potent and selective FLT3 inhibitors, Bioorg Med Chem Lett 19(17) (2009) 5182-5.

[0014] A.E. Perl, G. Martinelli, J.E. Cortes, A. Neubauer, E. Berman, S. Paolini, P. Montesinos, M.R. Baer, R.A. Larson, C. Ustun, F. Fabbiano, H.P. Erba, A. Di Stasi, R. Stuart, R. Olin, M. Kasner, F. Ciceri, W.C. Chou, N. Podoltsev, C. Recher, H. Yokoyama, N. Hosono, S.S. Yoon, J.H. Lee, T. Pardee, A.T. Fathi, C. Liu, N. Hasabou, X. Liu, E. Bahceci, M.J. Levis, Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML, N Engl J Med 381(18) (2019) 1728-1740.

[0015] A.E. Perl, J.K. Altman, J. Cortes, C. Smith, M. Litzow, M.R. Baer, D. Claxton, H.P. Erba, S. Gill, S. Goldberg, J.G. Jurcic, R.A. Larson, C. Liu, E. Ritchie, G. Schiller, A.I. Spira, S.A. Strickland, R. Tibes, C. Ustun, E.S. Wang, R. Stuart, C. Röllig, A. Neubauer, G. Martinelli, E. Bahceci, M. Levis, Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1–2 study, The Lancet Oncology 18(8) (2017) 1061-1075.

[0016] C.C. Smith, Q. Wang, C.S. Chin, S. Salerno, L.E. Damon, M.J. Levis, A.E. Perl, K.J. Travers, S. Wang, J.P. Hunt, P.P. Zarrinkar, E.E. Schadt, A. Kasarskis, J. Kuriyan, N.P. Shah, Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia, Nature 485(7397) (2012) 260-3. Page 70 of 82 QB\169852.00141\91596905.1

[0017] N. Daver, J. Cortes, F. Ravandi, K.P. Patel, J.A. Burger, M. Konopleva, H. Kantarjian, Secondary mutations as mediators of resistance to targeted therapy in leukemia, Blood 125(21) (2015) 3236-45.

[0018] Z. Zhao, H. Wu, L. Wang, Y. Liu, S. Knapp, Q. Liu, N.S. Gray, Exploration of type II binding mode: A privileged approach for kinase inhibitor focused drug discovery?, ACS Chem Biol 9(6) (2014) 1230-41.

[0019] C.C. Smith, K. Lin, A. Stecula, A. Sali, N.P. Shah, FLT3 D835 mutations confer differential resistance to type II FLT3 inhibitors, Leukemia 29(12) (2015) 2390-2.

[0020] C.C. Smith, C. Zhang, K.C. Lin, E.A. Lasater, Y. Zhang, E. Massi, L.E. Damon, M. Pendleton, A. Bashir, R. Sebra, A. Perl, A. Kasarskis, R. Shellooe, G. Tsang, H. Carias, B. Powell, E.A. Burton, B. Matusow, J. Zhang, W. Spevak, P.N. Ibrahim, M.H. Le, H.H. Hsu, G. Habets, B.L. West, G. Bollag, N.P. Shah, Characterizing and Overriding the Structural Mechanism of the Quizartinib-Resistant FLT3 "Gatekeeper" F691L Mutation with PLX3397, Cancer Discov 5(6) (2015) 668-79.

[0021] S. Zhou, B. Yang, Y. Xu, A. Gu, J. Peng, J. Fu, Understanding gilteritinib resistance to FLT3-F691L mutation through an integrated computational strategy, J Mol Model 28(9) (2022) 247.

[0022] K. Fedorov, A. Maiti, M. Konopleva, Targeting FLT3 Mutation in Acute Myeloid Leukemia: Current Strategies and Future Directions, Cancers (Basel) 15(8) (2023).

[0023] C.M. McMahon, T. Ferng, J. Canaani, E.S. Wang, J.J.D. Morrissette, D.J. Eastburn, M. Pellegrino, R. Durruthy-Durruthy, C.D. Watt, S. Asthana, E.A. Lasater, R. DeFilippis, C.A.C. Peretz, L.H.F. McGary, S. Deihimi, A.C. Logan, S.M. Luger, N.P. Shah, M. Carroll, C.C. Smith, A.E. Perl, Clonal Selection with RAS Pathway Activation Mediates Secondary Clinical Resistance to Selective FLT3 Inhibition in Acute Myeloid Leukemia, Cancer Discov 9(8) (2019) 1050-1063.

[0024] O. Piloto, M. Wright, P. Brown, K.T. Kim, M. Levis, D. Small, Prolonged exposure to FLT3 inhibitors leads to resistance via activation of parallel signaling pathways, Blood 109(4) (2007) 1643-52.

[0025] J.D. Rowley, Letter: A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining, Nature 243(5405) (1973) 290-3.

[0026] N.P. Shah, C. Tran, F.Y. Lee, P. Chen, D. Norris, C.L. Sawyers, Overriding imatinib resistance with a novel ABL kinase inhibitor, Science 305(5682) (2004) 399-401. Page 71 of 82 QB\169852.00141\91596905.1

[0027] Y. Chen, C. Peng, D. Li, S. Li, Molecular and cellular bases of chronic myeloid leukemia, Protein Cell 1(2) (2010) 124-32.

[0028] A. Quintas-Cardama, J. Cortes, Molecular biology of BCR::ABL11-positive chronic myeloid leukemia, Blood 113(8) (2009) 1619-30.

[0029] T. Burmeister, S. Schwartz, C.R. Bartram, N. Gökbuget, D. Hoelzer, E. Thiel, Patients' age and BCR::ABL1 frequency in adult B-precursor ALL: a retrospective analysis from the GMALL study group, Blood 112(3) (2008) 918-9.

[0030] H. Dohner, E. Estey, D. Grimwade, S. Amadori, F.R. Appelbaum, T. Buchner, H. Dombret, B.L. Ebert, P. Fenaux, R.A. Larson, R.L. Levine, F. Lo-Coco, T. Naoe, D. Niederwieser, G.J. Ossenkoppele, M. Sanz, J. Sierra, M.S. Tallman, H.F. Tien, A.H. Wei, B. Lowenberg, C.D. Bloomfield, Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel, Blood 129(4) (2017) 424-447.

[0031] N. Daver, R.F. Schlenk, N.H. Russell, M.J. Levis, Targeting FLT3 mutations in AML: review of current knowledge and evidence, Leukemia 33(2) (2019) 299-312.

[0032] A.S. Alotaibi, M. Yilmaz, S. Loghavi, C. DiNardo, G. Borthakur, T.M. Kadia, B. Thakral, N. Pemmaraju, G.C. Issa, M. Konopleva, N.J. Short, K. Patel, G. Tang, F. Ravandi, N. Daver, Emergence of BCR::ABL11 Fusion in AML Post-FLT3 Inhibitor-Based Therapy: A Potentially Targetable Mechanism of Resistance - A Case Series, Front Oncol 10 (2020) 588876.

[0033] H. Kurt, L. Zheng, H.M. Kantarjian, G. Tang, F. Ravandi-Kashani, G. Garcia-Manero, Z. Gong, H.M. Amin, S.N. Konoplev, M.J. Routbort, X. Han, W. Wang, L.J. Medeiros, S. Hu, Secondary Philadelphia chromosome acquired during therapy of acute leukemia and myelodysplastic syndrome, Mod Pathol 31(7) (2018) 1141-1154.

[0034] P.M. Kasi, M.R. Litzow, M.M. Patnaik, S.K. Hashmi, N. Gangat, Clonal evolution of AML on novel FMS-like tyrosine kinase-3 (FLT3) inhibitor therapy with evolving actionable targets, Leuk Res Rep 5 (2016) 7-10.

[0035] B. Frett, N. McConnell, C.C. Smith, Y. Wang, N.P. Shah, H.Y. Li, Computer aided drug discovery of highly ligand efficient, low molecular weight imidazopyridine analogs as FLT3 inhibitors, Eur J Med Chem 94 (2015) 123-31.

[0036] L. Zhang, N.R. Lakkaniga, J.B. Bharate, N. McConnell, X. Wang, A. Kharbanda, Y.K. Leung, B. Frett, N.P. Shah, H.Y. Li, Discovery of imidazo[1,2-a]pyridine-thiophene derivatives as FLT3 and FLT3 mutants inhibitors for acute myeloid leukemia through structure-based optimization of an NEK2 inhibitor, Eur J Med Chem 225 (2021) 113776. Page 72 of 82 QB\169852.00141\91596905.1

[0037] F.W. Peng, J. Xuan, T.T. Wu, J.Y. Xue, Z.W. Ren, D.K. Liu, X.Q. Wang, X.H. Chen, J.W. Zhang, Y.G. Xu, L. Shi, Design, synthesis and biological evaluation of N- phenylquinazolin-4-amine hybrids as dual inhibitors of VEGFR-2 and HDAC, Eur J Med Chem 109 (2016) 1-12.

[0038] E. Reznickova, S. Krajcovicova, M. Perina, M. Kovalova, M. Soural, V. Krystof, Modulation of FLT3-ITD and CDK9 in acute myeloid leukaemia cells by novel proteolysis targeting chimera (PROTAC), Eur J Med Chem 243 (2022) 114792.

[0039] A.T. Anshabo, L. Bantie, S. Diab, J. Lenjisa, A. Kebede, Y. Long, G. Heinemann, J. Karanjia, B. Noll, S.K.C. Basnet, M. Li, R. Milne, H. Albrecht, S. Wang, An Orally Bioavailable and Highly Efficacious Inhibitor of CDK9 / FLT3 for the Treatment of Acute Myeloid Leukemia, Cancers (Basel) 14(5) (2022).

[0040] S. Darici, M. Zavatti, L. Braglia, B. Accordi, V. Serafin, G.A. Horne, L. Manzoli, C. Palumbo, X. Huang, H.G. Jorgensen, S. Marmiroli, Synergistic cytotoxicity of dual PI3K / mTOR and FLT3 inhibition in FLT3-ITD AML cells, Adv Biol Regul 82 (2021) 100830.

[0041] C.C. Smith, E.A. Lasater, K.C. Lin, Q. Wang, M.Q. McCreery, W.K. Stewart, L.E. Damon, A.E. Perl, G.R. Jeschke, M. Sugita, M. Carroll, S.C. Kogan, J. Kuriyan, N.P. Shah, Crenolanib is a selective type I pan-FLT3 inhibitor, Proc Natl Acad Sci U S A 111(14) (2014) 5319-24.

[0042] A.A. Warkentin, M.S. Lopez, E.A. Lasater, K. Lin, B.L. He, A.Y. Leung, C.C. Smith, N.P. Shah, K.M. Shokat, Overcoming myelosuppression due to synthetic lethal toxicity for FLT3-targeted acute myeloid leukemia therapy, Elife 3 (2014).

[0043] D.L. Stirewalt, J.P. Radich, The role of FLT3 in haematopoietic malignancies, Nat Rev Cancer 3(9) (2003) 650-65.

[0044] J.A. McCubrey, L.S. Steelman, S.L. Abrams, F.E. Bertrand, D.E. Ludwig, J. Basecke, M. Libra, F. Stivala, M. Milella, A. Tafuri, P. Lunghi, A. Bonati, A.M. Martelli, Targeting survival cascades induced by activation of Ras / Raf / MEK / ERK, PI3K / PTEN / Akt / mTOR and Jak / STAT pathways for effective leukemia therapy, Leukemia 22(4) (2008) 708-22.

[0045] T.L. Gu, J. Nardone, Y. Wang, M. Loriaux, J. Villen, S. Beausoleil, M. Tucker, J. Kornhauser, J. Ren, J. MacNeill, S.P. Gygi, B.J. Druker, M.C. Heinrich, J. Rush, R.D. Polakiewicz, Survey of activated FLT3 signaling in leukemia, PLoS One 6(4) (2011) e19169.

[0046] J.L. Fernandez-Luna, BCR::ABL1 and inhibition of apoptosis in chronic myelogenous leukemia cells, Apoptosis 5(4) (2000) 315-8. Page 73 of 82 QB\169852.00141\91596905.1

[0047] H. Zhang, T. Song, Z. Wang, U. Laura Bonnette, Y. Guo, H. Wang, Q. Gao, Z. Zhang, BCR::ABL1 drives the formation of Hsp70 / Bim PPI to stabilize oncogenic clients and prevent cells from undergoing apoptosis, Biochem Pharmacol 198 (2022) 114964. Page 74 of 82 QB\169852.00141\91596905.1

Claims

CLAIMS 1. A compound of formula acceptable salt thereof,CH, or CR2, O S(i) and is hydrogen and is (a) an aryl optionally substituted with an alkoxyl, said alkoxyl optionally substituted with a heterocycle or a halo, an alkyl, said alkyl optionally substituted with a halo, an amino or an ester, an alkenyl, a sulfonyl, a nitro, a cyano, a halo, or C(O)ORCwherein RCis an alkyl; (b) a heteroaryl optionally substituted with an alkyl, or an aryl, said aryl optionally substituted with an alkyl or a halo; (c) a heterocyclyl optionally substituted with Boc; or 2;with aryl, said aryl optionally substituted with a halo, or (ii) NRARBand RAand RBtogether form a heterocycyl optionally substituted with an alkyl or Boc; or (iii) a halo.

2. The compound of claim 1, wherein R1.

3. The compound of claim 1, wherein R1. PageQB\169852.00141\91596905.

14. The compound of any one of claims 1-3, wherein R2is NRARBand RAis hydrogen and RBis an aryl optionally substituted with an alkoxyl, said alkoxyl optionally substituted with a heterocycle or a halo, an alkyl, said alkyl optionally substituted with a halo, an amino or an ester, an alkenyl, a sulfonyl, a nitro, a cyano, a halo, or C(O)ORCwherein RCis an alkyl.

5. The compound of claim 4, wherein RBis an aryl optionally substituted with an alkoxy, an alkyl, or a sulfonyl.

6. The compound of any one of claims 1-3, wherein R2is NRARBand RAis hydrogen and RBis a heteroaryl optionally substituted with an alkyl, or an aryl, said aryl optionally substituted with an alkyl or a halo.

7. The compound of any one of claims 1-3, wherein R2is NRARBand RAis hydrogen and RBis a heterocyclyl optionally substituted with Boc.

8. The compound of any one of claims 1-3, wherein R2is NRARBand RAis hydrogen .

9. one of claims 1-3, wherein R2is NRARBand RAand RBtogether form a heterocycyl optionally substituted with an alkyl or Boc.

10. The compound of any one of claims 1-3, wherein R2is halo.

11. The compound of any one of claims 1-10, wherein X is N.

12. The compound of claim 1 selected from the group consisting of N-(3-methoxyphenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3- yl)pyridin-2-amine, N-(2,4-dimethoxyphenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3- yl)pyridin-2-amine, N-(4-methoxyphenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3- yl)pyridin-2-amine, 3-(2-chlorophenyl)-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine. 3-(3-chlorophenyl)-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine, 3-(4-chlorophenyl)-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine, 4-(6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2- yl)piperazine-1-carboxylate, tert-butyl 2-methyl-4-(6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3- yl)pyridin-2-yl)piperazine-1-carboxylate, Page 76 of 82 QB\169852.00141\91596905.1tert-butyl 4-((6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2- yl)amino)piperidine-1-carboxylate, 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(4-(2-(piperidin-1- yl)ethoxy)phenyl)pyridin-2-amine, 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(4-(2- morpholinoethoxy)phenyl)pyridin-2-amine, 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(4- morpholinophenyl)pyridin-2-amine, 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(4-(2-(pyrrolidin-1- yl)ethoxy)phenyl)pyridin-2-amine, N-(4-(2-(diethylamino)ethoxy)phenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2- a]pyridin-3-yl)pyridin-2-amine, 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(p-tolyl)pyridin-2- amine, 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(4- vinylphenyl)pyridin-2-amine, N-(4-ethylphenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3- yl)pyridin-2-amine, N-(4-isopropylphenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3- yl)pyridin-2-amine, N-(4-(tert-butyl)phenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3- yl)pyridin-2-amine, N-(3-(tert-butyl)phenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3- yl)pyridin-2-amine, N-(2-methoxyphenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3- yl)pyridin-2-amine, N-(3,4-dimethoxyphenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3- yl)pyridin-2-amine, 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(3,4,5- trimethoxyphenyl)pyridin-2-amine, N-(benzo[d][1,3]dioxol-5-yl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin- 3-yl)pyridin-2-amine, Page 77 of 82 QB\169852.00141\91596905.1N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-(7-(1-methyl-1H-pyrazol-4- yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-amine, 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(4- (methylsulfonyl)phenyl)pyridin-2-amine, 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(2- (trifluoromethyl)phenyl)pyridin-2-amine, 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(3- (trifluoromethyl)phenyl)pyridin-2-amine, 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(4- (trifluoromethyl)phenyl)pyridin-2-amine, 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(4- (trifluoromethoxy)phenyl)pyridin-2-amine, 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(4- nitrophenyl)pyridin-2-amine, N-(6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-yl)pyrazin- 2-amine, 4-((6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2- yl)amino)benzonitrile, N-(4-chlorophenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3- yl)pyridin-2-amine, N-(2,6-difluorobenzyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3- yl)pyridin-2-amine, methyl 4-methyl-3-((6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3- yl)pyridin-2-yl)amino)benzoate, tert-butyl 4-((6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2- yl)amino)benzoate, ethyl 2-(4-((6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2- yl)amino)phenyl)acetate, N-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)-6-(7-(1-methyl-1H-pyrazol-4- yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-amine, N-(3-(tert-butyl)-1-(4-fluorophenyl)-1H-pyrazol-5-yl)-6-(7-(1-methyl-1H-pyrazol-4- yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-amine, Page 78 of 82 QB\169852.00141\91596905.1N-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-6-(7-(1-methyl-1H-pyrazol-4- yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-amine, N-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)-6-(7-(4- (methylsulfonyl)phenyl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-amine, N-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-6-(7-(4- (methylsulfonyl)phenyl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-amine, 6-(7-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridin-3-yl)-N-(3,4,5- trimethoxyphenyl)pyridin-2-amine, and N-(4-(tert-butyl)phenyl)-6-(7-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridin-3- yl)pyridin-2-amine.

13. The compound of claim 1 selected from the group consisting of N-(3-methoxyphenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3- yl)pyridin-2-amine, N-(2,4-dimethoxyphenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3- yl)pyridin-2-amine, N-(4-methoxyphenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3- yl)pyridin-2-amine, 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(4-(2-(piperidin-1- yl)ethoxy)phenyl)pyridin-2-amine, 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(4-(2- morpholinoethoxy)phenyl)pyridin-2-amine, 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(4-(2-(pyrrolidin-1- yl)ethoxy)phenyl)pyridin-2-amine, N-(4-(2-(diethylamino)ethoxy)phenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2- a]pyridin-3-yl)pyridin-2-amine, 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(p-tolyl)pyridin-2- amine, N-(2-methoxyphenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3- yl)pyridin-2-amine, N-(3,4-dimethoxyphenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3- yl)pyridin-2-amine, N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-(7-(1-methyl-1H-pyrazol-4- yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-amine, Page 79 of 82 QB\169852.00141\91596905.16-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(4- (methylsulfonyl)phenyl)pyridin-2-amine, 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(3- (trifluoromethyl)phenyl)pyridin-2-amine, N-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)-6-(7-(1-methyl-1H-pyrazol-4- yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-amine, N-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)-6-(7-(4- (methylsulfonyl)phenyl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-amine, and 6-(7-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridin-3-yl)-N-(3,4,5- trimethoxyphenyl)pyridin-2-amine.

14. The compound of claim 1, wherein the compound is N-(3-methoxyphenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3- yl)pyridin-2-amine, N-(2,4-dimethoxyphenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3- yl)pyridin-2-amine, N-(4-methoxyphenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3- yl)pyridin-2-amine, 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(4-(2-(piperidin-1- yl)ethoxy)phenyl)pyridin-2-amine, 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(4-(2- morpholinoethoxy)phenyl)pyridin-2-amine, N-(4-(2-(diethylamino)ethoxy)phenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2- a]pyridin-3-yl)pyridin-2-amine, N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-(7-(1-methyl-1H-pyrazol-4- yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-amine, or 6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(4- (methylsulfonyl)phenyl)pyridin-2-amine.

15. A pharmaceutical composition comprising the compound according to any one of claims 1-14 and a pharmaceutically acceptable carrier, excipient, or diluent.

16. A method of treating a subject for a cell proliferative disease or condition comprising administering a compound according to any one of claims 1-14 to the subject.

17. The method of claim 16, wherein the cell proliferative disease or condition is hematological cancer. Page 80 of 82 QB\169852.00141\91596905.

118. The method of claim 17, wherein the cell proliferative disease or condition is leukemia.

19. The method of claim 18, wherein the cell proliferative disease or condition is acute myeloid leukemia.

20. The method of claim 18, wherein the cell proliferative disease or condition is chronic myelogenous leukemia.

21. The method of any one of claims 16-20, wherein the cell proliferative disease or condition is characterized by an FLT3 activating mutation.

22. The method of any one of claims 16-21, wherein the cell proliferative disease or condition is characterized by a BCR::ABL1 gene fusion.

23. A method for inhibiting the growth or proliferation of a cancer cell comprising contacting the cell with the compound according to any one of claims 1-14.

24. The method of claim 23, wherein the cancer cell is a hematological cancer cell.

25. The method of claim 24, wherein the cancer cell is a leukemia cancer cell.

26. The method of claim 25, wherein the cancer cell is an acute myeloid leukemia cancer cell.

27. The method of claim 25, wherein the cancer cell is a chronic myelogenous leukemia cancer cell.

28. The method of any one of claims 23-27, wherein the cancer cell expresses a FLT3 activating mutation.

29. The method of any one of claims 23-28, wherein the cancer cell expresses a BCR::ABL1 fusion gene.

30. The method of claim 23, wherein the cancer cell is MV4-11, MOLM, or K562 cancer cell.

31. The method of any one of claims 23-30, wherein the cancer cell is contacted with the compound in vitro or ex vivo.

32. The method of any one of claims 23-30, wherein the cancer cell is contacted with the compound in vivo. Page 81 of 82 QB\169852.00141\91596905.1

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