5-6-5 / 6-bisaryl compounds as FLT3 inhibitors

Abstract

5-6-5 / 6-bisaryl compounds that are selective inhibitors of FMS-related tyrosine kinase 3 (FLT3); compositions comprising the same; and their use for inhibiting FLT3 in a patient, such as a patient with cancer or an inflammatory disease or a patient with pain.

Description

70378-02   5-6-5 / 6-BISARYL COMPOUNDS AS FLT3 INHIBITORS CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to U.S. provisional patent application no.63 / 542,619, which was filed October 5, 2023, and which is hereby incorporated by reference in its entirety TECHNICAL FIELD

[0002] The present disclosure relates to 5-6-5 / 6-bisaryl compounds that are selective inhibitors of Fms-related tyrosine kinase 3 (FLT3), pharmaceutical compositions comprising the same, and their use in treating cancer and inflammatory diseases. BACKGROUND

[0003] This section introduces aspects that may help facilitate a better understanding of the disclosure. Accordingly, these statements are to be read in this light and are not to be construed as admissions about what is or is not prior art.

[0004] Kinase inhibitors are increasingly being used for diverse therapeutic interventions. One of the factors that accounts for dose-limiting toxicities of current kinase inhibitors, such as Fms- related tyrosine kinase 3 (FLT3) inhibitors, is target promiscuity, especially targets critical for essential functions. For example, the FLT3 receptor is similar to essential receptor tyrosine kinases (RTKs), such as kinase insert domain receptor (KDR, also known as VEGFR2), fibroblast growth receptor (FGFR), platelet-derived growth factor receptor (PDGFR), proto-oncogene receptor tyrosine kinase (c-KIT), and rearranged during transfection (RET). It has been challenging to develop an inhibitor that selectively inhibits FLT3 without co-inhibiting these related kinases. It is well known that targeting cardiovascular (KDR, FGFR1 / 2, and PDGFR ^ / ^) and / or kidney (RET) related kinases can result in low compound tolerability and increased side effects. Additionally, because both FLT3 and c-KIT are important for myeloid cells, the co- inhibition of FLT3 and c-KIT is synthetically lethal and has been shown to result in myelosuppression.

[0005] FLT3 activation can also lead to a block in myeloid differentiation or apoptosis. FLT3 is overexpressed in over 90% of acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) patients (Blood, 1993, 82, 1110-119). In addition to overexpression of wild-type FLT3 in hematologic malignancies, about 30% of AML patients harbor mutated FLT3 (activating kinase domain mutation or internal tandem duplication, ITD, in the juxtamembrane domain), and these 1   70378-02   patients typically have a poorer prognosis than those harboring wild-type FLT3. Many FLT3 kinase mutations that are insensitive to one or more of clinically trialed FLT3 inhibitors have been observed in AML patients, including FLT3-D835Y / V / H (type II inhibitor, such as quizartinib, resistant), gatekeeper mutation F691I / L (gilteritinib resistant), and K429E (crenolanib resistant) (Cancer Discovery, 2019, 9, 1050–1063; Blood Adv. 2022, 6, 2144–2155; Biomedicines, 2020, 8, 245). Some of these FLT3 inhibitors have been moderately successful in increasing survival rates of patients with AML, but often, dose-limiting toxicities hinder efficacy, especially in elderly patients, vide supra (CA Cancer J. Clin., 2022, 72, 7-33).

[0006] In addition to the need for a new FLT3 inhibitor that could overcome on-target drug resistance (such as FLT3-ITD-F691L, which is resistant to standard-of-care gilteritinib), there is also a need for a selective FLT3 inhibitor that avoids critical anti-targets, such as KDR, FGFR1 / 2, PDGFR ^ / ^, c-KIT, and RET. Such selective FLT3 inhibitors could find applications in maintenance therapy, which requires chronic dosing, and / or extend FLT3 inhibitor therapy to elderly patients with cardiovascular or renal co-morbidities.

[0007] Therefore, there is an unmet need for a potent and selective FLT3 inhibitor compound which avoids inhibition of anti-targets, such as c-KIT, KDR, FGFR1 / 2, PDGFR ^ / ^, and RET. It is an object of the present disclosure to provide such a compound. This and other objects and advantages, as well as inventive features, will be apparent from the detailed description. SUMMARY

[0008] Provided is a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof:     (I) wherein the compound of formula (I) comprises: (i) B, a 5-6 bi-aryl moiety represented by a structure:2   70378-02   wherein each X is independently N, O, NRa, or CRb, wherein Ra is selected from H, alkyl, cycloalkyl, heteroalkyl, alkylcarbonyl, arylcarbonyl, heteroalkylcarbonyl, amide, and sulfonamide; and Rb is selected from H, cyano, halo, alkyl, trifluoroalkyl, haloalkyl, dihaloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heteroalkyl, aminoalkyl, cyanoalkyl, dialkylaminoalkyl, morpholinylalkyl, piperazinylalkyl, dialkylaminocarbonyl, dialkylaminosulfonyl, hydroxyaryl, alkoyxaryl, carboxylic acid, and ester; wherein alkyl is optionally substituted with alkyl or heteroalkyl; and a bond between any two X is a single or double bond; and each E is independently N or CRc, wherein Rc is H or halogen; (ii) P, a 5 / 6 bi-cyclic aryl moiety represented by a structure: wherein each A iseach G is independently CH or N; W is N or CRb, wherein Rb is selected from H, cyano, halo, alkyl, trifluoroalkyl, haloalkyl, dihaloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heteroalkyl, aminoalkyl, cyanoalkyl, dialkylaminoalkyl, morpholinylalkyl, piperazinylalkyl, dialkylaminocarbonyl, dialkylaminosulfonyl, hydroxyaryl, alkoyxaryl, carboxylic acid, and ester; wherein alkyl is optionally substituted with alkyl or heteroalkyl; and B is as defined above; (iii) Y is H or a 4- to 12-membered monocyclic ring or bi-cyclic ring, wherein the bi-cyclic ring is a fused bi-cyclic ring, a bridged bi-cyclic ring, or a spiro bi-cyclic ring, substituted with one or more groups selected from R1-R8 based on the ring size and represented by a structure: wherein T is sp3- carbon,3   70378-02   each R1, R2, R3, R4, R5, R6, R7, and R8 is independently selected from H, halo, nitro, cyano, alkyl, aminoalkyl, hydroxyalkyl, alkoxyalkyl, alkylcarbonyl, alkylsulfonyl, cycloalkyl, heteroalkyl, aryl, and heteroaryl; or any two R groups from R1-R8, together with the carbon atom to which they are attached, form a 3- to 8-membered cyclic ring; and Q is O, S, S=O, SO2, NRaor CRbRb, wherein Rais as defined above and each Rbis independently as defined above or the two Rb, together with the carbon atom to which they are attached, form a 3- to 6- membered cyclic ring optionally containing one or more heteroatoms, wherein each heteroatom is independently N, S or O.

[0009] In some embodiments, the P, 5 / 6 bi-cyclic aryl moiety is:and heteroaryl.

[0010] In some embodiments of the compound of formula (I), the X is N, NH, N-alkyl, O, or CH. In some embodiments of the compound of formula (I), the E is N or CH.

[0011] Provided is a compound of formula (IA), or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof:   4   70378-02   HN N 5 R9R10Ywherein each R9 and R10 is from hydrogen, deuterium, alkyl, and heteroalkyl;each E is independently N or CRc, wherein Rc is H or halogen; and Y is H or a 4- to 12-membered monocyclic ring or bi-cyclic ring, wherein the bi-cyclic ring is a fused bi-cyclic ring, a bridged bi-cyclic ring, or a spiro bi-cyclic ring, substituted with one or more groups selected from R1-R8based on the ring size and represented by a structure: wherein T is sp3- carbon,each R1, R2, R3, R4, R5, R6, R7, and R8is independently selected from H, halo, nitro, cyano, alkyl, aminoalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heteroalkyl, aryl, and heteroaryl; or any two R groups from R1-R8, together with the carbon atom to which they are attached, form a 3- to 8-membered cyclic ring; and Q is O, S, S=O, SO2, NRaor CRbRb, wherein Rais as defined above and each Rbis independently as defined above or the two Rb, together with the carbon atom to which they are attached, form a 3- to 6- membered cyclic ring optionally containing one or more heteroatoms, wherein each heteroatom is independently N, S or O.

[0012] In some embodiments, the Y is: 5   70378-02   N N N N N N N O ..

[0014] In some embodiments, the Y is: XXXX X XXX X XXX  70378-02        .             7   70378-02    (IA), or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer of either of the foregoing, and a pharmaceutically acceptable carrier, excipient, or diluent.

[0018] Provided is a method of inhibiting Fms-related tyrosine kinase 3 (FLT3) in a patient, which method comprises administering to the patient (i) a therapeutically effective amount of the compound of formula (I) or (IA), (ii) a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer of (i), or (iii) a pharmaceutical composition comprising (i) or (ii) and a pharmaceutically acceptable carrier, excipient, or diluent, whereupon FLT3 in the patient is inhibited. 8   70378-02

[0019] In some embodiments, the patient has cancer or an inflammatory disease. The compound is administered orally, intravenously, intramuscularly, dermally, rectally, nasally, otically, or ocularly.

[0020] Provided is a method of treating or inhibiting cancer in a patient, wherein the method comprises administering to the patient (i) a therapeutically effective amount of a compound of formula (I) or (IA), (ii) a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer of (i), or (iii) a pharmaceutical composition comprising (i) or (ii) and a pharmaceutically acceptable carrier, excipient, or diluent, whereupon the cancer in the patient is treated or inhibited.

[0021] In some embodiments, the cancer is leukemia, multiple myeloma, lung cancer, liver cancer, thyroid cancer, colon cancer, pancreatic cancer, lymphoma, ovarian cancer, breast cancer, throat cancer, head and neck cancer, prostate cancer, brain cancer, stomach cancer, anal cancer, and melanoma. In some embodiments, the inflammatory disease is arthritis or pain.

[0022] Provided is a method of treating or inhibiting pain in a patient, wherein the method comprises administering to the patient (i) a therapeutically effective amount of a compound of formula (I) or (IA), (ii) a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer of (i), or (iii) a pharmaceutical composition comprising (i) or (ii) and a pharmaceutically acceptable carrier, excipient, or diluent, whereupon the pain in the patient is treated or inhibited. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] The present disclosure will be more readily understood from the detailed description of embodiments presented below considered in conjunction with the attached drawings of which:

[0024] Fig.1 shows compounds known as Fms-related tyrosine kinase 3 (FLT3) inhibitors.

[0025] Fig. 2 shows FLT3 inhibition. Preliminary compounds were screened at a concentration of 100 nM against FLT3 enzyme using an ADP Glo kinase assay. Values reported are means of triplicates and error bars represent standard deviation.

[0026] Fig.3 shows enzyme inhibition data. Compounds were screened against enzymes, such as FLT3, proto-oncogene receptor tyrosine kinase (c-KIT), and kinase insert domain receptor (KDR) at a compound concentration of 100 nM using an ADP Glo Kinase Assay (Promega®) with ATP concentration of 10 µM and kinase concentration of 0.1 µg / µL. Results shown are means of triplicates, and error bars represent standard deviation.

[0027] Fig.4A shows enzyme inhibition data for compound 17 and positive control, gilteritinib. Compounds were tested against enzyme FLT3 internal tandem duplication (FLT3-ITD) in 10- dose IC50duplicate mode with a 3-fold serial dilution starting at 10 μM. All data was fitted to a non-linear regression equation using GraphPad Prism 9.0 software. 9   70378-02

[0028] Fig. 4B shows enzyme inhibition data for compound 17 and positive control, gilteritinib. Compounds were tested against enzyme c-KIT in 10-dose IC50duplicate mode with a 3-fold serial dilution starting at 10 μM. All data was fitted to a non-linear regression equation using GraphPad Prism 9.0 software.

[0029] Fig. 4C shows enzyme inhibition data for compound 17 and positive control, gilteritinib. Compounds were tested against enzyme rearranged during transfection (RET) in 10-dose IC50duplicate mode with a 3-fold serial dilution starting at 10 μM. All data was fitted to a non-linear regression equation using GraphPad Prism 9.0 software.

[0030] Fig. 4D shows enzyme inhibition data for compound 17 and positive control, gilteritinib. Compounds were tested against enzyme KDR in 10-dose IC50duplicate mode with a 3-fold serial dilution starting at 10 μM. All data was fitted to a non-linear regression equation using GraphPad Prism 9.0 software.

[0031] Fig. 4E shows enzyme inhibition data for compound 17 and positive control, gilteritinib. Compounds were tested against enzyme fibroblast growth factor receptor 1 (FGFR1) in 10-dose IC50 duplicate mode with a 3-fold serial dilution starting at 10 μM. All data was fitted to a non- linear regression equation using GraphPad Prism 9.0 software.

[0032] Fig. 4F shows enzyme inhibition data for compound 17 and positive control, gilteritinib. Compounds were tested against enzyme fibroblast growth factor receptor 2 (FGFR2) in 10-dose IC50duplicate mode with a 3-fold serial dilution starting at 10 μM. All data was fitted to a non- linear regression equation using GraphPad Prism 9.0 software.

[0033] Fig.4G shows enzyme inhibition data for compound 17 and positive control, gilteritinib. Compounds were tested against enzyme platelet-derived growth factor receptor alpha (PDGFRα) in 10-dose IC50duplicate mode with a 3-fold serial dilution starting at 10 μM. All data was fitted to a non-linear regression equation using GraphPad Prism 9.0 software.

[0034] Fig.4H shows enzyme inhibition data for compound 17 and positive control, gilteritinib. Compounds were tested against enzyme platelet-derived growth factor receptor beta (PDGFRβ) in 10-dose IC50duplicate mode with a 3-fold serial dilution starting at 10 μM. All data was fitted to a non-linear regression equation using GraphPad Prism 9.0 software.

[0035] Fig. 5 shows dose-response curves. FLT3-driven AML cells were treated with varying concentrations of compound 17 for 72 hours. Data was fitted to a non-linear regression equation using GraphPad Prism 9.0 software. Each data point represents the mean, and error bars represent the SEM of triplicates. 10   70378-02

[0036] Fig.6 shows the molecular docking of gilteritinib and compound 17 to FLT3 in “DFG-in” homology model. A) shows compound 17 docked to FLT3 “DFG-in” homology model. B) shows gilteritinib docked to FLT3 DFG-in homology model.

[0037] Fig. 7A shows western blot analysis. Molm-14 cells were treated with compound 17 (5 or 100 nM) or control for 2 hours. Gilteritinib at 5 nM was used as a positive control. Bands were quantified relative to actin loading control.

[0038] Fig.7B shows western blot analysis. Molm-14 cells were treated with compound 17 (5 or 100 nM) or control for 2 hours. Gilteritinib at 5 nM was used as a positive control. Values are reported as means of duplicates, and error bars represent standard deviation. (p > 0.05: NS, p < 0.05: *, p < 0.01: **, p < 0.001: ***, p < 0.0001: ****).

[0039] Fig.8 shows FLT3 percentage inhibition at 20 nM for compounds 32-41 using the ADP- GLO Kinase Assay.

[0040] Fig.9 shows the pk graph of total plasma concentration vs. time profile for compound 17 after administering 2 mg / kg intravenous dose (IV) and 20 mg / kg oral dose (PO) in male CD1 mice. DETAILED DESCRIPTION

[0041] For the purposes of promoting an understanding of the principles of the present disclosure, reference will now be made to the embodiments illustrated in the drawings, and specific language will be used to describe the same. It will nevertheless be understood that no limitation of the scope of the claimed invention is thereby intended.

[0042] The term "FLT3 inhibitors" refers to a compound that inhibits Fms-related tyrosine kinase 3 (FLT3, also called Fms-related receptor tyrosine kinase 3; Fms-like tyrosine kinase 3; Receptor- Type Tyrosine-Protein Kinase FLT3; Stem Cell Tyrosine Kinase 1; FL Cytokine Receptor; CD135; CD135 Antigen; STK1; FLK2; FLK-2; EC 2.7.10.1; Growth Factor Receptor Tyrosine Kinase Type III; Fetal Liver Kinase 2; Fetal Liver Kinase-2).

[0043] The present disclosure is predicated, at least in part, on the discovery that the imidazo[1,2- b] pyridazine moiety, found in many approved and experimental drugs, binds to the hinge region of kinases. Substitutions at positions 2, 3, 6, 7, and 8 dictate kinase selectivity and potency (Eur. J. Med. Chem., 2021, 226, 113867). It is reported that fusing kinase hinge binders, such as isoquinolines, napthyridines, and imidazo[1,2-b]pyridazine, with alkynyl pyridines, are highly potent FLT3 inhibitors. But, these compounds and FDA-approved FLT3 inhibitors, such as 11   70378-02   gilteritinib, quizartinib, and midostauri, kinase inhibitors, such as sorafenib (KDR inhibitor) or ponatinib (ABL1 inhibitor) which are also FLT3 inhibitors, and other FLT3 inhibitors, such as crenolanib, tandutinib, FF-10101, and tuspetinib (see Fig.1) also potently inhibit anti-targets such as KDR, c-KIT, FGFR1 / 2, PDGFR ^ / ^, and RET. FLT3 has also been reported as a potential target for chronic pain, and for non-oncology applications, a high therapeutic ratio is usually required.

[0044] In view of the above, the present disclosure provides 5-6-5 / 6-bisaryl compounds  comprising substituted imidazo[1,2-b] pyridazine core that are selective FLT3 inhibitors. The compounds can be substituted at the C6 position with a moiety such as a substituted morpholine or a substituted piperidine to obtain potent and selective FLT3 inhibition with low off-target activity.

[0045] Thus, provided is a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof: (I) wherein the compound of formula (I) comprises: (i) B, a 5-6 bi-aryl moiety represented by a structure:   wherein each X is independentlyor CRb, wherein Rais selected from H, C1-C6alkyl, C3-C8 cycloalkyl, hetero C2-C6 alkyl, C1-C6 alkylcarbonyl, arylcarbonyl, hetero C2-C6 alkylcarbonyl, amide, and sulfonamide; and Rbis selected from H, cyano, halo, C1-C6alkyl, trifluoro C1-C6 alkyl, halo C1-C6 alkyl, dihalo C1-C6 alkyl, hydroxy C1-C6 alkyl, alkoxy C1-C6 alkyl, C3-C8cycloalkyl, hetero C2-C6alkyl, amino C1-C6alkyl, hydroxy C1-C6alkyl, alkoyx C1- C6 alkyl, cyano C1-C6 alkyl, C1-C6 dialkylamino C1-C6 alkyl, morpholinyl C1-C6 alkyl, piperazinyl C1-C6alkyl, C1-C6dialkylaminocarbonyl, C1-C6dialkylaminosulfonyl, carboxylic acid, and ester; wherein alkyl is optionally substituted with C1-C6 alkyl or hetero C1-C6 alkyl; and a bond between any two X is a single or double bond; and 12   70378-02   each E is independently N or CRc, wherein Rc is H or halogen; (ii) P, a 5 / 6 bi-cyclic aryl moiety represented by a structure:               wherein each A iseach G is independently CH or N; W is N or CRb, wherein Rb is selected from H, cyano, halo, C1-C6 alkyl, trifluoro C1-C6 alkyl, halo C1-C6alkyl, dihalo C1-C6alkyl, hydroxy C1-C6alkyl, alkoxy C1-C6alkyl, C3-C8cycloalkyl, hetero C2-C6 alkyl, amino C1-C6 alkyl, cyano C1-C6 alkyl, C1-C6 dialkylamino C1-C6 alkyl, morpholinyl C1-C6alkyl, piperazinyl C1-C6alkyl, C1-C6dialkylaminocarbonyl, C1-C6dialkylaminosulfonyl, hydroxyaryl, alkoyxaryl, carboxylic acid, and ester; wherein alkyl is optionally substituted with C1-C6alkyl or hetero C2-C6alkyl; and            B is as defined above;            (iii) Y is H or a 4- to 12-membered monocyclic ring or bi-cyclic ring, wherein the bi-cyclic ring is a fused bi-cyclic ring, a bridged bi-cyclic ring, or a spiro bi-cyclic ring, substituted with one or more groups selected from R1-R8 based on the ring size and represented by a structure:   wherein T is sp3- carbon,each R1, R2, R3, R4, R5, R6, R7,and R8is independently selected from H, halo, nitro, cyano, C1-C6 alkyl, amino C1-C6 alkyl, hydroxy C1-C6 alkyl, alkoxy C1-C6 alkyl, C1-C6 alkylcarbonyl, C1-C6alkylsulfonyl, C3-C8cycloalkyl, hetero C2-C6alkyl, aryl, and heteroaryl; or any two R groups from R1-R8, together with the carbon atom to which they are attached, form a 3- to 8-membered cyclic ring; and           Q is O, S, S=O, SO2, NRa or CRbRb, wherein Ra is as defined above and each Rb is independently as defined above or the two Rb, together with the carbon atom to which they are 13   70378-02   attached, form a 3- to 6- membered cyclic ring optionally containing one or more heteroatoms, wherein each heteroatom is independently N, S or O.

[0046] In some embodiments of the compound of formula (I), X is N, NH, N-alkyl, O, or CH.

[0047] In some embodiments of the compound of formula (I), E is N or CH.

[0048] In some embodiments, provided is a compound of formula (IA), or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof: HN N 5 Y   wherein each R9 and R10 isfrom hydrogen, deuterium, C1-C6 alkyl, and hetero C2-C6alkyl; each E is independently N or CRc, wherein Rcis H or halogen; and Y is H or a 4- to 12-membered monocyclic ring or bi-cyclic ring, wherein the bi-cyclic ring is a fused bi-cyclic ring, a bridged bi-cyclic ring, or a spiro bi-cyclic ring, substituted with one or more groups selected from R1-R8based on the ring size and represented by a structure: wherein T is sp3- carbon,each R1, R2, R3, R4, R5, R6, R7, and R8is independently selected from H, halo, nitro, cyano, C1-C6 alkyl, amino C1-C6 alkyl, hydroxy C1-C6 alkyl, alkoxy C1-C6 alkyl, C3-C8 cycloalkyl, hetero C2-C6alkyl, aryl, and heteroaryl; or any two R groups from R1-R8, together, with the carbon atom to which they are attached, form a 3- to 8-membered cyclic ring; and 14   70378-02   Q is O, S, S=O, SO2, NRa or CRbRb, wherein Ra is as defined above and each Rb is independently as defined above or the two Rbtogether, with the carbon atom to which they are attached, form a 3- to 6- membered cyclic ring optionally containing one or more heteroatoms, wherein each heteroatom is independently N, S or O.

[0049] In some embodiments, the Y is: N N N N N N N   .

[0051] In some embodiments, the Y is: 15   70378-02   .

[0052] In some embodiments, the Y is:  70378-02   .

[0053] In some embodiments, the Y is:    70378-02   .S  . hetero C2-C6 alkyl, and heteroaryl. 18   70378-02

[0056] In some embodiments, each X in the structures 7a-7u is independently CH2, O, S, S=O, SO2, NH, N-alkyl, N-heteroalkyl, amide, sulfonamide, urea, or carbamate.

[0057] In some embodiments, the compound of formula (I) or (IA) is:70378-02   HNN.

[0058] In some embodiments, the compounds of formula (I) and (IA) are selective FLT3 inhibitors. The compounds can inhibit FLT3 at nanomolar concentrations. The compounds do not inhibit other commonly targeted kinases and exhibit very low activity against immune or cardiovascular anti-targets, such as c-KIT, KDR, FGFR1 / 2, PDGFR ^ / ^, and RET. Thus, compounds avoid co-inhibition of FLT3 with other targeted kinases, including c-KIT and KDR, which are particularly problematic as this leads to synthetic lethality.

[0059] In some embodiments, the compound of formula (I) and (IA) inhibit FLT3 with IC50 value between about 0.01 nM to about 30 nM, such as about 0.01 nM to 30 nM or 0.01 nM to about 30 nM or 0.01 nM to 30 nM.

[0060] In some embodiments, the compound of formula (I) or (IA) has low activity against anti- targets KDR, c-KIT, FGFR1 / 2, PDGFR ^ / ^, and / or RET. The compound of formula (I) or (IA) inhibits said anti-targets with an IC50 value greater than 300 nM, which is at least ten times higher than the IC50value for FLT3.

[0061] In some embodiments, the compound of formula (I) and (IA), for example, compound 17 inhibits FLT3-ITD mutant with IC50 of about 1 nM (Fig.4A). It shows low inhibition for KIT and RET with IC50 values about 912 ± 67 nM and 18400 ± 9100 nM (Figs. 4B-4C) and very low activity against cardiovascular kinases FGFR1 / 2 and PDGFR ^ / ^, with IC50 values >2690 nM 20   70378-02   (Figs.4E-4H). Compound 17 can be FLT3 type I inhibitor. It shows IC50 of about 0.41±0.12 nM and about 1 nM against mutants FLT3-D835 and FLT3-D835Y, which are similar to known FLT3 type I inhibitors e.g., gliteritinib (0.19±0.06 nM and 1 NM).

[0062] Thus, the compounds of the disclosure evade the inhibition of these critical anti-targets while targeting FLT3, which can allow for inhibition of the oncogenic pathway associated with FLT3 mutations without interfering with the normal physiological functions of essential receptors, such as c-KIT, KDR, and RET.

[0063] Provided is a pharmaceutical composition comprising a compound of formula (I) or (IA) or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer of either of the foregoing, and a pharmaceutically acceptable carrier, excipient, or diluent. The carrier, excipient, or diluent can vary based on the particular route of administration (see, e.g., Remington’s The Science and Practice of Pharmacy, 23rded. (2020))

[0064] Provided is a method of inhibiting a FLT3 in a patient, which method comprises administering to the patient (i) a therapeutically effective amount of compound of formula (I) or (IA), (ii) a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer of (i), or (iii) a pharmaceutical composition comprising (i) or (ii) and a pharmaceutically acceptable carrier, excipient, or diluent, whereupon FLT3 in the patient is inhibited.

[0065] In some embodiments, the patient has a disease or condition such as cancer. In some embodiments, the patient has an inflammatory disease such as arthritis or pain.

[0066] Provided is a method of treating or inhibiting cancer in a patient comprising administering to the patient (i) a therapeutically effective amount of a compound of formula (I) or (IA), (ii) a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer of (i), or (iii) a pharmaceutical composition comprising (i) or (ii) and a pharmaceutically acceptable carrier, excipient, or diluent. The method comprises inhibition of FLT3.

[0067] Examples of cancers include, but are not limited to, leukemia, multiple myeloma, lung cancer, liver cancer, thyroid cancer, colon cancer, pancreatic cancer, lymphoma, ovarian cancer, breast cancer, throat cancer, head and neck cancer, prostate cancer, brain cancer, stomach cancer, anal cancer, and melanoma. In some embodiments, the cancer can be leukemia. In some embodiments, the cancer can be acute myeloid leukemia.

[0068] In some embodiments, the compound of formula (I) or (IA), or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer of either of the foregoing, can be administered orally intravenously, intramuscularly, dermally, rectally, nasally, optically or ocularly. 21   70378-02

[0069] The compounds can be administered in unit dosage forms and / or compositions containing one or more pharmaceutically acceptable carriers, adjuvants, diluents, excipients, and / or vehicles, and combinations thereof. As used herein, the term "administering" and its formatives generally refer to any and all means of introducing compounds to the patient including, but not limited to, by oral, intravenous, intratumoral, intramuscular, subcutaneous, transdermal, topically, and like routes of administration.

[0070] For oral administration, the compounds can be formulated readily by combining the active compound(s) with pharmaceutically acceptable carriers, excipients, or diluents well-known in the art. Such carriers, excipients, or diluents enable the compounds to be formulated as tablets, pills, powders, dragees, capsules, liquids, gels, syrups, slurries, suspensions, solutions, and the like for oral ingestion by a subject to be treated.

[0071] Useful dosages of the compounds can be determined by comparing their in vitro activity with their in vivo activity in animal models. Methods of the extrapolation of effective dosages in mice and other animals to human subjects are known in the art. Indeed, the dosage of the compounds can vary significantly depending on the condition of the subject, the age of the subject, the type of disease the subject is experiencing or at risk of experiencing, the particular compounds used, how advanced the pathology is, the route of administration of the compounds and the possibility of co-usage of other therapeutic treatments or additional drugs in combination therapies. The amount of the composition required for use in treatment (e.g., the therapeutically effective amount or dose) will vary not only with the particular application, but also with the salt selected (if applicable) and the characteristics of the subject (such as, for example, age, condition, sex, the subject’s body surface area and / or mass, tolerance to drugs) and will ultimately be at the discretion of the attendant physician, clinician, or otherwise.

[0072] The compositions comprising the compound (s) can be formulated in a unit dosage form, each dosage containing from about 1 mg to about 1,000 mg (1 g), more usually about 100 mg to about 500 mg, of the active ingredient.

[0073] In some embodiments, the compositions provided herein contain from about 1 mg to about 50 mg of the active ingredient. One having ordinary skill in the art will appreciate that this embodies compounds or compositions containing about 1 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, or about 45 mg to about 50 mg of the active ingredient.

[0074] In some embodiments, the compositions provided herein contain from about 50 mg to about 500 mg of the active ingredient. One having ordinary skill in the art will appreciate that this 22   70378-02   embodies compounds or compositions containing about 50 mg to about 100 mg, about 100 mg to about 150 mg, about 150 mg to about 200 mg, about 200 mg to about 250 mg, about 250 mg to about 300 mg, about 350 mg to about 400 mg, or about 450 mg to about 500 mg of the active ingredient.

[0075] In some embodiments, the compositions provided herein contain from about 500 mg to about 1,000 mg of the active ingredient. One having ordinary skill in the art will appreciate that this embodies compounds or compositions containing about 500 mg to about 550 mg, about 550 mg to about 600 mg, about 600 mg to about 650 mg, about 650 mg to about 700 mg, about 700 mg to about 750 mg, about 750 mg to about 800 mg, about 800 mg to about 850 mg, about 850 mg to about 900 mg, about 900 mg to about 950 mg, or about 950 mg to about 1,000 mg of the active ingredient.

[0076] The active compound may be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0077] In some embodiments, the compound can be administered in an amount ranging from about 1 mg / kg to about 100 mg / kg. In some embodiments, the compound can be administered in an amount of about 1 mg / kg to about 20 mg / kg, about 5 mg / kg to about 50 mg / kg, about 10 mg / kg to about 40 mg / kg, about 15 mg / kg to about 45 mg / kg, about 20 mg / kg to about 60 mg / kg, or about 40 mg / kg to about 70 mg / kg. For example, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, about 60 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, about 95 mg / kg, or about 100 mg / kg. In some embodiments, such administration can be once-daily or twice-daily (BID) administration.

[0078] The compounds of the present disclosure can also be used in combination with other compounds or known drugs that are used to treat cancer. Examples of the known drugs that can be used to treat lung cancer, thyroid cancer, pancreatic cancer, and breast cancer include, but are not limited to carboplatin, cisplatin, paclitaxel, capecitabine, gemcitabine, fluorouracil, everlolimus, doxorubicin, alectinib, afatinib, brigatinib, gefitinib, ceritinib, crizotinib, entrectinib, imatinib, lorlatinib, osimertinib, sorafenib, vandetanib, cabozantinib, erlotinib, sunitinib, alectinib, lenvatinib, trametinib, selpercatinib and pralsetinib. 23   70378-02

[0079] Provided is a pharmaceutical combination for treating cancer in a patient in need thereof, which comprises (i) a compound of formula (I) or (IA) or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof, (ii) an additional therapeutic agent, and (iii) optionally at least one pharmaceutically acceptable carrier, excipient, or diluent.

[0080] The term "pharmaceutical combination", refers to a pharmaceutical therapy resulting from the mixing or combining of more than one active ingredient. For a combination, the compound of formula (I) or (IA) or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof and at least one additional therapeutic agent can be administered to a patient simultaneously or sequentially by the same or different route of administration in a single composition or two separate compositions to achieve the desired effect. The therapeutic agent can be administered in an amount to provide its desired therapeutic effect. The effective dosage range for each therapeutic agent is well known in the art, and the therapeutic agent is administered to a patient in need thereof within such established ranges.

[0081] The term "substituted" refers to a functional group in which one or more hydrogen atoms contained therein are replaced by one or more non-hydrogen atoms. The term "functional group" or "substituent" refers to a group that can be or is substituted onto a molecule. Examples of substituents or functional groups include, but are not limited to, a halo (e.g., F, Cl, Br, and I); an oxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxyl groups including carboxylic acids, carboxylates, and carboxylate esters; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atom in groups such as amines, azides, hydroxylamines, cyano, nitro groups, N-oxides, hydrazides, and enamines; and other heteroatoms in various other groups.

[0082] Non-limiting examples of substituents, which can be bonded to a substituted carbon atom (or other atom, such as nitrogen) include F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO, NO2, ONO2, azido, CF3, OCF3, R, O (oxo), S (thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, (CH2)0-2P(O)OR2, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH2)0-2N(R)C(O)R, (CH2)0-2N(R)C(O)OR, (CH2)0-2N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, and C(=NOR)R wherein R can be hydrogen or a carbon-based moiety, and wherein the carbon-based moiety can itself be further substituted; for example, where R can be hydrogen, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl, any alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, 24   70378-02   heteroaryl, or heteroarylalkyl or R can be independently mono- or multi-substituted; or when two R groups bonded to a nitrogen atom or to adjacent nitrogen atoms can, together with the nitrogen atom or atoms to which they are bonded, form a heterocyclyl, the heterocycle can be mono- or independently multi-substituted.

[0083] The term " alkyl" refers to substituted or unsubstituted straight-chain and branched alkyl groups and cycloalkyl groups having from 1 to about 20 carbon atoms (e.g., C1-C20), 1 to 12 carbons (e.g., C1-C12), 1 to 8 carbon atoms (e.g., C1-C8), or, in some embodiments, from 1 to 6 carbon atoms (e.g., C1-C6). Examples of straight-chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. The term "alkyl" encompasses n-alkyl, isoalkyl, and anteisoalkyl groups as well as other branched chain forms of alkyl. Representative substituted alkyl groups can be substituted one or more times with any of the groups listed herein, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, carbonyl, and halogen groups.

[0084] The term "alkenyl" refers to substituted or unsubstituted straight-chain and branched divalent alkenyl and cycloalkenyl groups having from 2 to 20 carbon atoms(e.g., C2-C20), 2 to 12 carbons (e.g., C2-C12), 2 to 8 carbon atoms (e.g., C2-C8) or, in some embodiments, from 2 to 4 carbon atoms (e.g., C2-C4) and at least one carbon-carbon double bond. Examples of straight-chain alkenyl groups include those with from 2 to 8 carbon atoms such as -CH=CH-, -CH=CHCH2-, and the like. Examples of branched alkenyl groups include, but are not limited to, -CH=C(CH3)- and the like.

[0085] The term "alkynyl" refers to an unsaturated monovalent chain of carbon atoms, including at least one triple bond, which may be optionally branched. In various embodiments that include alkynyl, illustrative examples include lower alkynyl, such as C2-C6,C2-C4alkynyl, and the like.

[0086] The term "hydroxyalkyl" refers to alkyl groups substituted with at least one hydroxyl (- OH) group.

[0087] The term "cycloalkyl" refers to substituted or unsubstituted cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group can have 3 to about 8-12 ring members, whereas in other embodiments, the number of ring carbon atoms ranges from 3 to 4, 5, 6, or 7. In some embodiments, cycloalkyl groups can have 3 to 6 carbon atoms (e.g., C3-C6). Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, 25   70378-02   adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like.

[0088] The term "acyl" refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom. The carbonyl carbon atom is also bonded to another carbon atom, which can be part of a substituted or unsubstituted alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl group or the like. In the special case wherein the carbonyl carbon atom is bonded to a hydrogen, the group is a "formyl" group, an acyl group as the term is defined herein. An acyl group can include 0 to about 12-40, 6- 10, 1-5 or 2-5 additional carbon atoms bonded to the carbonyl group. An acryloyl group is an example of an acyl group. An acyl group can also include heteroatoms within the meaning herein. A nicotinoyl group (pyridyl-3-carbonyl) is an example of an acyl group within the meaning herein. Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and cryloyl groups and the like. When the group containing the carbon atom that is bonded to the carbonyl carbon atom contains a halogen, the group is termed a "haloacyl" group. An example is a trifluoroacetyl group.

[0089] The term "aryl" refers to substituted or unsubstituted cyclic aromatic hydrocarbons that do not contain heteroatoms in the ring. Thus, aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, aryl groups contain about 6 to about 14 carbons (e.g., C6-C14) or from 6 to 10 carbon atoms (e.g., C6-C10) in the ring portions of the groups. Aryl groups can be unsubstituted or substituted, as defined herein. Representative substituted aryl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or 2-8 substituted naphthyl groups, which can be substituted with carbon or non-carbon groups such as those listed herein.

[0090] The term "heteroaryl" represents aromatic ring comprising at least one hetero atom such as N, S, O, or Se. Heteroaryl in the present disclosure may be any hetero aryl. Heteroaryl includes, but is not limited to, pyrrolidinyl, azetidinyl, piperidynyl, piperazinyl, morpholinyl, chromanyl, indolinonyl, isoindolinonyl, furanyl, pyrrolidinyl, pyridinyl, pyrazinyl, pyrimidinyl, triazinyl, thiophenyl, tetrahydrofuranyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl, triazyolyl, tetrazolyl, benzoxazolinyl, benzthiazolinyl, benzimidazolinyl groups, or any combination thereof.

[0091] The term "halo" is used to describe chemical compounds which contain one or more halogen atoms, such as fluorine, chlorine, bromine, and iodine. 26   70378-02

[0092] The term "heterocycloalkyl" refers to a non-aromatic heterocycle where one or more of the ring-forming atoms is / are a heteroatom, such as an O, N, or S atom. Heterocycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems as well as spirocycles. Example heterocycloalkyl groups include morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-1,4- dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, and the like. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the nonaromatic heterocyclic ring, for example phthalimidyl, naphthalimidyl, and benzo derivatives of heterocycles. A heterocycloalkyl group having one or more fused aromatic rings can be attached though either the aromatic or non-aromatic portion. Also included in the definition of hetero-cycloalkyl are moieties where one or more ring-forming atoms are substituted by 1 or 2 oxo or sulfido groups. In some embodiments, the heterocycloalkyl group has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms. In some embodiments, the heterocycloalkyl group contains 3 to about 20, 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In some embodiments, the heterocycloalkyl group contains O to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 triple bonds.

[0093] It is understood that each of alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkylene, and heterocycle may be optionally substituted with independently selected groups such as alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, carboxylic acid and derivatives thereof, including esters, amides, and nitrites, hydroxy, alkoxy, acyloxy, amino, alky and dialky-lamino, acylamino, thio, and the like, and combinations thereof.

[0094] The terms "optionally substituted" and "optional substituents" indicate that the groups in question are either unsubstituted or substituted with one or more of the substituents specified. When the groups in question are substituted with more than one substituent, the substituents may be the same or different. When used with the terms "independently", "independently are," and "independently selected from," the groups in question may be the same or different. Certain of the herein defined terms may occur more than once in the structure and, upon such occurrence, each term shall be defined independently of the other.

[0095] The term "amine" refers to primary, secondary, and tertiary amines having, e.g., the formula N(group)3 wherein each group can independently be H or non-H, such as alkyl, aryl, and the like. Amines include, but are not limited to, R-NH2, for example, alkylamines, arylamines, alkylarylamines; R2NH, wherein each R is independently selected, such as dialkylamines, 27   70378-02   diarylamines, aralkylamines, heterocyclylamines and the like; and R3N, wherein each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, and the like. The term "amine" also includes ammonium ions.

[0096] The term "amino group" refers to a substituent of the form -NH2, -NHR, -NR2, -NR3+, wherein each R is independently selected, and protonated forms of each, except for -NR3+, which cannot be protonated. Accordingly, any compound substituted with an amino group can be viewed as an amine. An "amino group" can be a primary, secondary, tertiary, or quaternary amino group. An "alkylamino" group includes a monoalkylamino, a dialkylamino, and a trialkylamino group.

[0097] The term "compound" as used herein, is meant to include all stereoisomers, geometric isomers, and tautomers of the structures depicted.

[0098] The compounds desribed herein as "optical isomers" may contain one or more chiral centers or may otherwise be capable of existing as multiple stereoisomers. In various embodiments, the compounds are not limited to any particular stereochemical requirement, and the compounds, and compositions, methods, uses, and medicaments that include them, may be optically pure or any of a variety of stereoisomeric mixtures, including racemic and other mixtures of enantiomers, other mixtures of diastereomers, and the like. Such mixtures of stereoisomers may include a single stereochemical configuration at one or more chiral centers, while including mixtures of stereochemical configuration at one or more other chiral centers.

[0099] Similarly, the compounds described herein may include geometric centers, such as cis, trans, E, and Z double bonds. In various embodiments, the compounds are not limited to any particular geometric isomer requirement, and the compounds, and compositions, methods, uses, and medicaments that include them, may be pure or any of a variety of geometric isomer mixtures. Such mixtures of geometric isomers may include a single configuration at one or more double bonds, while including mixtures of geometry at one or more other double bonds.

[0100] The term "SP3carbon" refers to a tetravalent carbon that forms single covalent bonds (sigma bonds) with atoms. The bonds formed are of equal strength and at an angle of 109.5odue to which the central carbon atom is tetrahedral in shape. The steric number of carbon is 4.

[0101] The term "SP2carbon" refers to a carbon that forms two single bonds and one double bond between three atoms and has trigonal planer geometry. The steric number of carbon is 3.

[0102] The terms “treat,” “treating,” “treated,” or “treatment” (with respect to a disease or condition) is an approach for obtaining beneficial or desired results including and preferably clinical results and includes, but is not limited to, one or more of the following: improving a condition associated with a disease, curing a disease, lessening severity of a disease, delaying progression of a disease, alleviating one or more symptoms associated with a disease, increasing 28   70378-02   the quality of life of one suffering from a disease, prolonging survival and / or prophylactic or preventative treatment.

[0103] The term "pharmaceutical composition" includes a therapeutically effective amount of one or more compounds for treating a patient with a disease or condition such as cancer or inflammatory diseases. The composition may include other components and / or ingredients, including, but not limited to, other therapeutically active compounds and / or one or more pharmaceutically acceptable carriers, diluents, excipients, and the like.

[0104] The term "therapeutic effect" refers to a beneficial local or systemic effect in animals, particularly mammals and, more particularly, humans, caused by the administration of a compound.

[0105] The term "therapeutically effective amount" means the amount of a compound that is effective to treat a disease or a disorder, such as cancer or inflammatory disease, at a reasonable benefit / risk ratio. The therapeutically effective amount of such compound will vary depending upon the patient and the disease or disorder being treated, the weight and age of the patient, the severity of the disease or disorder, the manner of administration, and the like, which can readily be determined by one of skill in the art. EXAMPLES The following examples serve to illustrate the present disclosure. The examples are not intended to limit the scope of the claimed invention in any way.

[0106] A new kinase inhibitor library, which consisted of compounds composed of known hinge binders (see compounds 1-10 below) connected to a pyrazole, was designed. Additionally, some compounds within the library contained various cyclic heterocycles, such as morpholine, piperazine, and tetrahydrofuran (for example, compounds 4-10). These heterocycles are also considered privileged moieties, as they could impact a compound’s aqueous solubility, as well as engage in hydrogen-bonding interactions with different protein residues, including the backbone amide. 29   70378-02   HN N HN NHNNHNNQ

[0107] Compoundsreactions (Scheme 1). Final compounds with substitutions at the C6 position, denoted “Q”, were formed via a two- step synthesis (see Scheme 1, steps A and B). Intermediates were synthesized by reacting various amine / alcohol substituents with 3-bromo-6-chloroimidazo[1,2-b]pyridazine. Subsequent Suzuki cross-coupling between the pyrazolo boronic acid and the bromide afforded the final compounds.  70378-02   Scheme 1: Synthesis of analogs via two-step synthesis. (A) synthesis of the intermediate by addition of amine / alcohol to aryl chloride to afford “Q” substituted pyrazolopyrimidine derivatives. (B) formation of final compounds via Suzuki coupling.

[0108] After synthesis of the initial pyrazole-containing compounds (1-10 above), the compounds were screened at concentration of 100 nM against FLT3 via an ADP Glo Kinase Assay (Fig. 2). Among the various hinge binders, the imidazo[1,2-b]pyridazine seemed to perform the best, when substituted at the 6-position (denoted Q) with 6-membered and not 5-membered heterocycles. For example, compound 3, the unsubstituted imidazo[1,2-b]pyridazine showed 0% inhibition of FLT3, and analogs 1 and 2, which have alternate hinge binders, only inhibited FLT3 at 11.8 ± 7.4% and 8.3 ± 2.2%, respectively. In terms of Q, FLT3 inhibition was lower with 5-membered heterocycles, as compounds 4 and 5 showed inhibitory activities of 9.6 ± 0.8% and 8.7 ± 2.5%, respectively. On the contrary, 6-membered heterocycles substituted at the 6-position (Q) appeared to have significant inhibitory activity against FLT3, as seen with compounds 6-10. The morpholine substituent (6) showed 30.2 ± 6.5% inhibition of FLT3, but this was improved with a trans-dimethyl substitution, as seen in compound 7 (46.2 ± 4.9%), and inhibition increased even further with the cis-dimethyl substitution in compound 8 (61.6 ± 0.7%). Additionally, two substituted piperazine analogs (9 and 10) were evaluated but showed less inhibitory activity against FLT3 (33.4 ± 4.2% and 29.8 ± 6.7%, respectively) compared to the dimethylmorpholines.

[0109] After the preliminary FLT3 screening, analog 8, containing the trans-2,6- dimethylmorpholine, emerged as the most potent inhibitor (Fig.2). The optimization of analog 8 were carried out to probe selectivity for FLT3 over the aforementioned KDR and c-KIT anti- targets. In addition to being the most potent FLT3 inhibitor, analog 8 had a higher fraction of sp3- hybridized carbon atoms and thus was deemed more drug-like than the other preliminary compounds, such as 1, 2, and 6. A structure-activity relationship (SAR) study was carried out to explore how modifications affected FLT3 and off-target inhibition. The new pyrazolo-based compounds (11-20) that are potent, yet selective, FLT3 inhibitors were identified. 31   70378-02   NC HNNNNNO  The above compounds (11-20) were screened against FLT3 and primary anti-targets c-KIT and KDR (Fig. 3). Different substitutions in the pyrazole ring were explored. Compound 11, which contains the 1H-pyrazol-3-yl as opposed to the 1H-pyrazol-4-yl in lead compound 8, showed a significant decrease in FLT3 inhibition (28.3 ± 0.8%). The -NEt substitution (13) showed similar inhibitory activity against FLT3 (59.1 ± 2.9%) compared to compound 8, but less selectivity over c-KIT and KDR. Other modifications to the pyrazole, including the addition of a nitrile moiety (12) and a morpholine ring (14), also resulted in loss of FLT3 inhibition. When substituting with a phenyl ring, as in 15, increased inhibitory activity was found against FLT3 but not the selectivity over the c-KIT and KDR anti-targets. Placing a phenyl linker between the imidazo[1,2- b]pyridazine and the pyrazole (17) increased FLT3 inhibition (95.6 ± 0.6%), while significantly decreasing inhibitory activity against c-KIT (27.2 ± 2.9%) and KDR (9.9 ± 1.8%). Under similar conditions, compound 17 showed better selectivity against these off-target enzymes than ponatinib, which has been approved for CML and trialed for AML, and gilteritinib (Fig. 3). 32   70378-02   Substituting the pyrazole moiety in compound 17 with a methyl group (18) resulted in reduced FLT3 inhibition (43.4 ± 2.7%).

[0111] IC50 values for FLT3 and the anti-targets c-KIT, KDR, (see Fig. 5), RET, FGFR1 / 2, and PDGFR ^ / ^ were determined. While compound 17 and gilteritinib inhibited FLT3-ITD with similar IC50values (~1 nM), compound 17 had very little activity against the anti-targets (see Figs. 4A-4H), whereas gilteritinib potently inhibited c-KIT and RET with IC50 values of 59.7 ± 4.4 nM and 16.7 ± 1.2 nM, respectively (compared to 912 ± 67 nM and 18400 ± 9100 nM, respectively, for compound 17). Additionally, compound 17 showed very limited activity against cardiovascular kinases FGFR1 / 2 and PDGFR ^ / ^, with IC50 values >2690 nM. Avoiding the inhibition of these critical anti-targets while targeting FLT3 could allow for inhibition of the oncogenic pathway associated with FLT3 mutations without interfering with the normal physiological functions of essential receptors, such as c-KIT, KDR, and RET.

[0112] Kinase inhibitor type and cellular activity The reported FLT3 inhibitors are either type I (for example gilteritinib or midostaurin) or type II (for example quizartinib or ponatinib). The FLT3-D835 mutation generally leads to induced “DFG-in” conformation, which favors type I inhibitor binding. On the contrary, most FLT3-D835 mutants are resistant to type II inhibitors. The IC50values for gilteritinib (a type I inhibitor) and compound 17 against mutated FLT3-D835Y are very similar (0.19 ± 0.06 nM and 0.41 ± 0.12 nM, respectively). Under similar experimental conditions, both compounds inhibited FLT3- D835Y with IC50values of approximately 1 nM, so it appears that the D to Y mutation, which favors the DFG-in conformation, did not affect the activity of compound 17; therefore, compound 17 could be a type I inhibitor. Docking studies of 17 (Fig.6) to the active conformer of FLT3 (the “DFG-in” homology model) were performed. In the docked model, the imidazo[1,2-b]pyridazine moiety in compound 17 (a known hinge-binding moiety) interacts with the FLT3 Cys-694 residue. Similarly, the hinge binding moiety pyrazine-2-carboxamide found in gilteritinib interacts with the hinge Cys-694.

[0113] The antiproliferative activities of compound 17 against FLT3-driven AML cell line Molm- 14 as well as the Molm-14 FLT3-D835Y and FLT3-F691L mutant cell lines were also examined. As expected for a potential type I inhibitor, compound 17 inhibited mutated Molm-14 FLT3-ITD- D835Y better (GI50= 9.58 ± 1.33 nM) than the mutated Molm-14-FLT3-ITD-F691L (GI50= 23.1 ± 6.8 nM), (Fig. 8). Immunoblotting confirmed that compound 17 could reduce the levels of phosphorylated FLT3 in Molm-14 at similar levels to gilteritinib (Figs.7A-7B).   33   70378-02

[0114] Kinase Assay The ADP-Glo Kinase Assay Kit (Promega®) was utilized for determination of FLT3, c-KIT, and KDR inhibition. Kinase Buffer (25 mM MOPS, pH 7.2, 12.5 mM β -glycerol-phosphate, 25 mM MgCl2, 2 mM EDTA) was supplemented with DTT (0.2 mM) and BSA (40 µg / mL) immediately prior to use. Reaction volumes of 5 µL containing enzyme, inhibitor, 10 µM ATP, and the appropriate peptide substrate (20 µM) were incubated for 3 hours, and then quenched with 5 µL of GLO reagent. After 40 min, 10 µL DET reagent was added and incubated for 1 hour before visualization on a Cytation™ 5 Cell Imaging Multi-Mode Reader (BioTek).

[0115] Docking Gilteritinib and compound 17 structures were converted to mol2 files, uploaded to Maestro, and prepared using LigPrep protocol. PDB: 6JQR was used for the FLT3 inactive conformation. FLT3 homology model was used for the FLT3 active conformation. Protein structures were prepared for docking using the Protein Preparation Wizard. Compounds were docked to each proteins structure using the Induced Fit Docking protocol. Docking conformations were examined Visual representations were generated using The PyMol Molecular Graphics System, Version 2.0. Ligands were extracted from the docking poses and crystal structure in Maestro. The function use_neutral_scaffold was utilized to ignore multiple bonds patterns and ionization states.

[0116] Cell Cultures Molm-14, Molm-14 (D835Y), and Molm-14 (F691L) cell lines. Cells were cultured to confluence in RPMI supplemented with 10% fetal bovine serum and 1X Penicillin-Streptomycin (Gibco™). Cells were plated at 5000 cells / well in 96 well plates. After 24-hour incubation at 37 °C in a 5% CO2 incubator, compounds diluted in the same media were added to the indicated final concentration and allowed to incubate at 37 °C in a 5% CO2incubator for 72 hours. Viability was determined using CellTiter-Blue® Cell Viability Assay (Promega) with absorbance readings at 570 nm performed on a Cytation™ 5 Cell Imaging Multi-Mode Reader (BioTek) 3 hours after addition.

[0117] Immunoblotting Molm-14 cells were treated with 17 or control for 2 hours. Cells were collected and lysed, and protein concentrations were quantified relative to BSA standards. After protein denaturation, proteins were separated via SDS-PAGE electrophoresis and transferred to NC membranes. After blocking, overnight incubation with specific primary antibodies, and room temperature incubation for 2 hours with peroxidase-conjugated secondary antibodies, peroxidase activity was detected with SuperSignal West Pico reagents using a CCD camera LAS-4000. Bands were normalized 34   70378-02   relative to loading control. Values reported represent the means of triplicates and error bars represent SD. All specific antibodies were purchased from Cell Signaling.

[0118] Pharmacokinetics (PK)

[0119] Compound was formulated in 10% DMA, 20% PG, 40% PEG400 and 30% PBS. CD1 Mice were used, and each animal (n = 3 / group) was dosed at 20 mg / Kg for PO and 2 mg / Kg for IV. The following timepoints were used for sampling: 0.083 hours, 0.25 hours, 0.5 hours, 1hour, 2 hours, 4 hours, 8 hours, and 24 hours. Approximately 0.03 mL blood was collected at each time point. The samples were centrifuged at 4000 g for 5 minutes in a 4°C centrifuge. The plasma samples were stored in a freezer prior to analysis. PK samples analyses: Concentrations of compound in the plasma samples were analyzed using a LC-MS / MS method. Pk Table PK Parameter Unit IV Dose (2 PO Dose (20 mg / kg) mean mg / kg) mean

[0120] Compound 17 was administered to the CD1 mouse. Fig.9 shows the pk graph of total plasma concentration vs. time profile for 0 - 24 hours for compound 17 after administering 2 mg / kg intravenous dose (IV) and 20 mg / kg oral dose (PO) in male CD1 mice. Experimental

[0121] General Synthesis Information Unless noted otherwise, all reagents and solvents were purchased from commercial suppliers and used as received. All reactions were performed in a screw- cap 20 mL microwave vial. The1H and13C NMR spectra were obtained in Chloroform-d, Methanol-d4,or DMSO-d6as solvent using a 500 MHz spectrometer with tetramethylsilane as an internal standard. Coupling constants (J values) reported in Hz. Purification was performed by flash or column chromatography using silica gel (230−400 mesh). All compounds were characterized by1H and13C NMR and HRMS 35   70378-02   data. Electron spray ionization (ESI) and TOF mass analyzer technique have been used to record the High-resolution mass spectra (HRMS).

[0122] General Procedure for the Suzuki Coupling:

[0123] Condition a: A solution of imidazo[1,2-b] pyridazine substrate (1 equiv), boronic acid or substrate (1.1 equiv), Pd(dppf)Cl2, DCM (10 mol%), Cs2CO3 (1.5 equiv), K3PO4 (1.5 equiv) and 0.5 mL water in degassed dioxane (5 mL) was stirred at 130 °C in a sealed microwave vial for 18 hours. After completion of the reaction, ethyl acetate and water were added. The organic layer was collected and washed with brine, followed by concentration under reduced pressure and purification by silica gel column chromatography.

[0124] Condition b: A solution of imidazo[1,2-b] pyridazine substrate, 1H-pyrazol-4-yl) boronic acid (145.46 mg, 1.3 mmol), Pd(dppf)Cl2 (5 mol%), K3PO4 (1.5eq) in a 3:1 mixture of acetonitrile / water (4 ml) as the solvent, were sealed microwave vial. The reaction mixture was degassed under argon. The reaction was then carried out in a microwave for 30 minutes at 160 °C. After completion, ethyl acetate and water were added. The organic layer was collected and washed with brine, then dried over Na2SO4 followed by concentration under reduced pressure and purification by silica gel column chromatography.

[0125] Example 1: 5-(1H-pyrazol-4-yl)pyrimidin-2-amine (1) Compound 1 was prepared using1yellow solid (22.5 mg, 14.0%). H NMR (500 MHz, Methanol-d4) δ 8.51 (s, 2H), 7.93 (s, 2H).13C NMR (201 MHz, Methanol-d4) δ 161.8, 155.0, 135.4, 124.6, 116.6, 115.9. HRMS (ESI) m / z calcd for C7H7N5[M + H]+162.0779, found 162.0776.

[0126] Example 2: 5-(1H-pyrazol-4-yl)-1,7-naphthyridin-8-amine (2) 36   70378-02   Compound 2 was prepared using solid (28.3 mg, 13.4%).1H NMR (500 MHz, Methanol-d4) δ 8.82 (dd, J = 4.2, , 8.30 (dd, J = 8.5, 1.6 Hz, 1H), 7.82 (d, J = 11.6 Hz, 3H), 7.71 (dd, J = 8.5, 4.2 Hz, 1H), 1.9 (s, 2H).13C NMR (201 MHz, DMSO-d6) δ 172.4, 157.2, 148.7, 142.0, 132.9, 132.9, 130.1, 126.0, 116.0, 112.9. HRMS (ESI) m / z calcd for C11H9N5[M + H]+212.0936 found 212.0936.

[0127] Example 3: 3-(1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine (3) Compound 3 was prepared using solid (55 mg, 30%).1H NMR (500 MHz,Methanol-d4) δ 8.52 (dd, J = 4.5, 1.6 Hz, 1H), 8.47 (s, 1H), 8.2 (s, 1H), 8.05 – 7.95 (m, 2H), 7.24 (dd, J = 9.2, 4.4 Hz, 1H);13C NMR (126 MHz, Methanol-d4) δ 143.7, 138.9, 136.5, 129.0, 126.0, 124.5, 122.6, 116.5, 109.1. HRMS (ESI) m / z calcd for C9H8N5[M + H]+186.0779, found 186.0779.

[0128] Example 4: Synthesis of (R)-3-Bromo-6-((tetrahydrofuran-3-yl)oxy)imidazo[1,2-b]pyridazine (Substrate (S)1) Reaction mixture of 3-bromo-pyridazine (500 mg) and (R)- tetrahydrofuran-3-ol (2.3 equiv) in dry THF (20 mL) cooled to 0 °C followed by addition of NaH (2 equiv). The reaction mixture was stirred at room temperature overnight. After completion, the reaction was extracted with ethyl acetate and washed with brine. Organic layer was collected and dried over sodium sulfate and concentrated under reduced pressure to get the desired products. 37   70378-02   Pale yellow solid (471 mg, 77%).1H NMR (500 MHz, Chloroform-d) δ 7.74 (d, J = 9.6 Hz, 1H), 7.57 (s, 1H), 6.69 (d, J = 9.6 Hz, 1H), 5.58 – 5.51 (m, 1H), 4.13 – 4.06 (m, 1H), 4.03 – 3.92 (m, 2H), 3.92 – 3.82 (m, 1H), 2.34 (dtd, J = 14.5, 8.0, 6.5 Hz, 1H), 2.23 – 2.14 (m, 1H);13C NMR (126 MHz, Chloroform-d) δ 159.4, 137.7, 132.7, 127.7, 112.1, 100.8, 78.0, 73.1, 67.1, 32.8. HRMS (ESI) m / z calcd for C10H11BrN3O2 [M + H]+284.0034, found 284.0031.

[0129] Example 5: (R)-3-(1H-pyrazol-4-yl)-6-(tetrahydrofuran-3-yl) imidazo[1,2-b]pyridazine (4) Synthesized using substrate S11solid (73 mg, 27%). H NMR (500 MHz, DMSO-d6) δ 8.42 (s, 1H), 8.13 (s, 1H), 8.02 (d, J = 9.6 Hz, 1H), 7.94 (s, 1H), 6.81 (d, J = 9.6 Hz, 1H), 5.60 (ddt, J = 6.5, 4.3, 1.9 Hz, 1H), 4.03 – 3.94 (m, 2H), 3.81 (q, J = 7.8 Hz, 1H), 3.72 (td, J = 8.3, 4.8 Hz, 1H), 2.41 – 2.24 (m, 1H), 2.14 – 2.10 (m, 1H);13C NMR (126 MHz, DMSO-d6) δ 159.3, 137.0, 136.7, 129.6, 128.3, 125.9, 123.0, 110.6, 109.3, 78.1, 72.8, 66.9, 32.9. HRMS (ESI) m / z calcd for C13H14N5O2 [M + H]+272.1147, found 272.1147.

[0130] Example 6: Synthesis of (S)-3-Bromo-6-((tetrahydrofuran-3-yl)oxy)imidazo[1,2-b]pyridazine (S2) Reaction mixture of 3-pyridazine (500 mg) and (S)- tetrahydrofuran-3-ol (2.3 equiv.) in dry THF (20 mL) cooled to 0 °C followed by addition of NaH (2 equiv.). The reaction mixture was stirred at room temperature overnight. After completion, the reaction was extracted with ethyl acetate and washed with brine. Organic layer was collected and dried over sodium sulfate and concentrated under reduced pressure to get the desired product. Brown-yellow solid (512 mg, 84%).1H NMR (500 MHz, DMSO-d6) δ 8.03 (d, J = 9.7 Hz, 1H), 7.72 (s, 1H), 6.93 (d, J = 9.6 Hz, 1H), 5.49 (td, J = 4.6, 2.3 Hz, 1H), 4.00 – 3.93 (m, 1H), 3.91 – 3.82 (m, 2H), 3.80 – 3.71 (m, 1H), 2.31 (dtd, J = 14.5, 8.0, 6.6 Hz, 1H), 2.15 – 2.05 (m, 1H); 13C NMR (126 MHz, DMSO-d6) δ 159.9, 137.9, 132.8, 128.6, 112.9, 100.6, 78.3, 72.6, 66.8, 32.8. HRMS (ESI) m / z calcd for C10H11BrN3O2[M + H]+284.0034, found 284.0034. 38   70378-02

[0131] Example 7: (S)-3-(1H-pyrazol-4-yl)-6-(tetrahydrofuran-3-yl)imidazo[1,2-b]pyridazine (5) Synthesized using substrate S2 soli1d (79 mg, 29%). H NMR (500 MHz, DMSO-d6) δ 8.42 (s, 1H), 8.13 (s, 1H), 8.04 (dd, J = 9.7, 2.4 Hz, 1H), 7.91 (d, J = 2.5 Hz, 1H), 6.80 (dd, J = 9.7, 2.4 Hz, 1H), 5.71 – 5.54 (m, 1H), 4.03 – 3.91 (m, 2H), 3.83 (qd, J = 7.8, 2.3 Hz, 1H), 3.79 – 3.71 (m, 1H), 2.40 – 2.24 (m, 1H), 2.19 – 2.11 (m, 1H).13C NMR (126 MHz, DMSO-d6) δ 159.3, 137.0, 136.7, 129.6, 128.3, 125.9, 123.0, 110.6, 109.3, 78.1, 72.8, 66.9, 32.9; HRMS (ESI) m / z calcd for C13H14N5O2[M + H]+272.1147, found 272.1147.

[0132] Example 8: General procedure for the synthesis of substituted imidazo[1,2-b] pyridazine substrates: (S3, S4, S5, S6, and S7): In a sealed tube 3-Bromo-6-chloroimidazo[1,2-b] pyridazine (500 mg) and appropriate amine (4 equiv.) in n-propanol (1 mL) or amine as solvent, refluxed at 150 °C overnight. After completion, the reaction was extracted with ethyl acetate and washed with brine. Organic layer collected, dried over sodium sulfate, and concentrated under reduced pressure. The crude was purified via silica gel column chromatography to yield the desired product.

[0133] Example 9: 4-(3-bromoimidazo[1,2-b]pyridazin-6-yl)morpholine (S3) Off-white solid (169 mg, 31%)d4) δ 7.72 (d, J = 10.0 Hz, 1H), 7.50 (s, 1H), 7.15 (d, J = 10.0 Hz, 1H), 3.85 – 3.79 (m, 4H), 3.59 – 3.53 (m, 4H).13C NMR (126 MHz, Methanol-d4) δ 155.7, 136.9, 130.8, 124.9, 110.8, 100.2, 66.1, 45.9. HRMS (ESI) m / z calcd for C13H14N6O [M + H]+284.1311, found 284.1311.

[0134] Example 10: 4-(3-(1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine (6) 39   70378-02   Synthesized using substrate S3. solid (141 mg, 42%).1H NMR (500 MHz, Methanol-d4) δ 8.19 (s,, – , (d, J = 9.9 Hz, 1H), 3.82 (t, J = 4.9 Hz, 4H), 3.53 (d, J = 4.9 Hz, 4H).13C NMR (201 MHz, DMSO-d6) δ 155.7, 136.6, 136.3, 129.0, 126.3, 125.6, 122.4, 109.7, 109.1, 66.2, 46.5. HRMS (ESI) m / z calcd for C13H14N6O [M + H]+271.1307, found 271.1308.

[0135] Example 11: (2S,6S)-4-(3-Bromoimidazo[1,2-b] pyridazin-6-yl)-2,6-dimethylmorpholine (S4) Off-white solid (236 mg, 35%) d) δ 7.68 (d, J = 9.9 Hz, 1H),7.53 (s, 1H), 6.79 (d, J = 9.9 Hz, 1H), 4.27 – 4.06 (m, 2H), 3.65 (dd, J = 12.8, 3.4 Hz, 2H), 3.27 (dd, J = 12.8, 6.3 Hz, 2H), 1.30 (d, J = 6.4 Hz, 6H);13C NMR (125 MHz, Chloroform-d) δ 155.4, 136.8, 132.0, 126.0, 109.4, 100.3, 66.0, 50.7, 17.9. HRMS (ESI) m / z calcd for C12H16BrN4O [M + H]+311.0507, found 311.0507.

[0136] Example 12: (2S,6S)-4-(3-(1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)-2,6-dimethylmorpholine (7) Synthesized using substrate S4solid (86 mg, 29%).1H NMR (500 MHz, Methanol-d4) δ 8.3 (s, 2H), 7.8 – 7.6 (m, 2H), 7.1 (t, J = 10.1 Hz, 1H), 4.2 (qd, J = 6.3, 5.8, 3.5 Hz, 2H), 3.7 (dt, J = 12.5, 4.0 Hz, 2H), 3.4 – 3.3 (m, 2H), 1.3 (dd, J = 6.6, 3.2 Hz, 6H);13C NMR (126 MHz, Methanol-d4) δ 155.8, 143.0, 136.7, 136.1, 127.1, 125.6, 124.7, 122.3, 109.6, 66.0, 50.7, 16.7. HRMS (ESI) m / z calcd for C15H19N6O [M + H]+299.1620, found 299.1620.

[0137] Example 13: 40   70378-02   (2S,6R)-4-(3-Bromoimidazo[1,2-b] pyridazin-6-yl)-2,6-dimethylmorpholine (S5) Pale yellow solid (640 mg, 95%)d) δ 7.66 (d, J = 9.9 Hz, 1H), 7.52 (s, 1H), 6.80 (d, J = 9.9 Hz, 1H), 4.01 – 3.89 (m, 2H), 3.81 – 3.65 (m, 2H), 2.65 (dd, J = 12.8, 10.6 Hz, 2H), 1.28 (d, J = 6.3 Hz, 6H).13C NMR (125 MHz, Chloroform-d) δ 154.8, 136.9, 132.1, 126.0, 109.4, 100.3, 71.3, 51.3, 18.9. HRMS (ESI) m / z calcd for C12H16BrN4O [M + H]+311.0507, found 311.0507.

[0138] Example 14: (2S,6R)-4-(3-(1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)-2,6-dimethylmorpholine (8) Synthesized using substrate S5 solid (122 mg, 41%).1H NMR (500MHz, DMSO-d6) δ 8.3 (s, 1H), 8.2 (s, 1H), 7.9 (d, J = 9.9 Hz, 1H), 7.8 (s, 1H), 7.2 (d, J = 9.9 Hz, 1H), 4.1 – 3.9 (m, 2H), 3.8 – 3.6 (m, 2H), 2.6 – 2.5 (m, 2H), 1.2 (d, J = 6.2 Hz, 6H).13C NMR (126 MHz, DMSO-d6) δ 155.3, 136.6, 136.3, 131.9, 128.9, 126.3, 122.4, 109.8, 109.4, 71.2, 51.7, 19.2; HRMS (ESI) m / z calcd for C15H19N6O [M + H]+299.1620, found 299.1620.

[0139] Example 15: 3-Bromo-6-((3S,5R)-3,4,5-trimethylpiperazin-1-yl) imidazo[1,2-b] pyridazine (S6) Off-white solid (596 mg, 85%).1Hd) δ 7.66 (d, J = 9.8 Hz, 1H), 7.52 (s, 1H), 6.82 (dd, J = 9.9, 2.6 Hz, 1H), 4.14 – 3.84 (m, 2H), 2.84 (t, J = 11.9 Hz, 2H), 2.35 (d, J = 13.4 Hz, 5H), 1.22 (d, J = 6.3 Hz, 6H).13C NMR (125 MHz, Chloroform-d) δ 154.5, 136.8, 132.1, 126.0, 109.5, 100.3, 57.4, 52.6, 37.6, 17.9. HRMS (ESI) m / z calcd for C13H19BrN5[M + H]+324.0823, found 324.0822.

[0140] Example 16: 41   70378-02   3-(1H-pyrazol-4-yl)-6-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)imidazo[1,2-b]pyridazine (9) Synthesized using substrate S6 solid (112 mg, 36%).1H NMR (500 MHz, DMSO-d ) δ 8.4 (s,6 1H), , 1H), 7.8 (s, 1H), 7.2 (d, J = 9.9 Hz, 1H), 4.1 – 3.9 (m, 2H), 2.7 – 2.6 (m, 2H), 2.3 – 2.2 (m, 2H), 2.2 (s, 3H), 1.1 (d, J = 6.2 Hz, 6H).13C NMR (126 MHz, DMSO-d6) δ 155.0, 136.6, 136.2, 128.8, 126.2, 125.6, 122.3, 109.8, 109.5, 57.1, 53.1, 37.9, 18.3. HRMS (ESI) m / z calcd for C16H22N7 [M + H]+312.1936, found 312.1936.

[0141] Example 17: 3-Bromo-6-(4-(2-methoxyethyl)piperazin-1-yl)imidazo[1,2-b]pyridazine (S7) Off-white solid (583 mg, 79%)d4) δ 7.66 (d, J = 9.9 Hz, 1H), 7.47 (s, 1H), 7.10 (d, J = 10.0 Hz, 1H), 3.61 – 3.51 (m, 6H), 3.34 (s, 3H), 2.66 – 2.58 (m, 6H).;13C NMR (125 MHz, Methanol-d4) δ 155.3, 136.7, 130.6, 124.8, 110.9, 100.1, 69.6, 57.6, 57.2, 52.6, 45.1. HRMS (ESI) m / z calcd for C13H19BrN5O [M + H]+340.0773, found 340.0770.

[0142] Example 18: 6-(4-(2-methoxyethyl)piperazin-1-yl)-3-(1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine (10) Compound 10 was prepared(108 mg, 33%).1H NMR (500 MHz, DMSO-d6) δ 8.4 (s, 1H), 8.1 (s, 1H), 7.8 (d, J = 9.9 Hz, 1H), 7.8 (s, 1H), 7.1 (d, J = 9.9 Hz, 1H), 3.5 – 3.4 (m, 4H), 3.4 (t, J = 5.7 Hz, 2H), 3.2 (s, 3H), 2.6 – 2.5 (m, 4H), 2.5 (d, J = 5.6 Hz, 2H).13C NMR (126 MHz, DMSO-d6) δ 155.6, 136.7, 136.2, 128.9, 126.2, 125.6, 122.3, 109.8, 109.4, 70.4, 58.5, 57.4, 53.1, 46.3. HRMS (ESI) m / z calcd for C16H22N7O [M + H]+328.1885, found 328.1885.

[0143] Example 19: (2S,6R)-4-(3-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-6-yl)-2,6-dimethylmorpholine (11) 42   70378-02   Compound 11 was prepared(29 mg, 11%).1H NMR (500 MHz, Methanol-d4) δ 7.91 (s, 1H), 7.77 (d, J = 9.9 Hz, 2H), 7.17 (d, J = 9.4 Hz, 2H), 4.12 – 4.02 (m, 2H), 3.78 (dqd, J = 12.5, 6.2, 2.3 Hz, 2H), 2.64 (dd, J = 12.8, 10.6 Hz, 2H), 1.26 (d, J = 6.2 Hz, 6H).13C NMR (126 MHz, Methanol-d4) δ 155.2, 136.7, 128.5, 124.8, 110.5, 103.3, 71.3, 51.3, 17.7. HRMS (ESI) m / z calcd for C15H18N6O [M + H]+299.1620, found 299.1621.

[0144] Example 20: General procedure for the synthesis of compounds 12, 13, and 14. A solution of compound 8 (1 equiv.) in tetrahydrofuran (2 mL) was cooled to 0 °C, followed by the addition of sodium hydride (10.46 mg, 0.44 mmol, 1.3 equiv.). The resulting mixture was stirred at 0 °C for 30 minutes before slowly adding their bromo alkane substrates (100 μL, 1.1 mmol, 3 equiv.). The reaction was allowed to proceed with stirring at 20 °C for 6-8 hours. The reaction mixture was then subjected to extraction with two portions of ethyl acetate, and the organic layer was washed with brine, dried with NaSO4, and concentrated under vacuum. The resulting residue was subjected to purification by column chromatography on silica gel using a hexanes / ethyl acetate mixture.

[0145] Example 21: 2-(4-(6-((2S,6R)-2,6-dimethylmorpholino)imidazo[1,2-b]pyridazin-3-yl)-1H-pyrazol-1- yl)acetonitrile (12) Brown solid (49 mg, 43%).1Hd4) δ 8.44 (s, 1H), 8.19 (d, J = 0.7 Hz, 1H), 7.77 (s, 1H), 7.75 (d, J = 9.9 Hz, 1H), 7.14 (d, J = 9.9 Hz, 1H), 5.43 (s, 2H), 4.06 – 4.02 (m, 2H), 3.79 (ddd, J = 10.6, 6.3, 2.4 Hz, 2H), 2.65 (dd, J = 12.8, 10.6 Hz, 2H), 1.28 (d, J = 6.2 Hz, 7H).13C NMR (126 MHz, Methanol-d4) δ 155.4, 138.2, 136.5, 127.6, 127.5, 124.8, 121.5, 114.4, 111.9, 110.1, 71.4, 51.5, 38.9, 17.7. HRMS (ESI) m / z calcd for C17H19N7O [M + H]+338.1723, found 338.1731. 43   70378-02

[0146] Example 22: (2S,6R)-4-(3-(1-ethyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)-2,6- dimethylmorpholine (13) Yellow solid (47 mg, 43%).1H d4) δ 8.31 (s, 1H), 8.13 (d, J = 0.7 Hz,1H), 7.74 (d, J = 10.0 Hz, 2H), = , 4.27 (q, J = 7.3 Hz, 2H), 4.07 – 4.01 (m,2H), 3.80 (dqd, J = 10.3, 2.3 Hz, 2H), 2.65 (dd, J = 12.8, 10.6 Hz, 2H), 1.53 (t, J = 7.3 Hz, 3H), 1.27 (d, J = 6.2 Hz, 6H).13C NMR (126 MHz, Methanol-d4) δ 155.4, 136.2, 127.1, 126.5, 124.8, 122.2, 110.3, 109.9, 71.3, 51.6, 46.6, 17.7, 14.4. HRMS (ESI) m / z calcd for C17H22N6O [M + H]+327.1927, found 327.1933.

[0147] Example 23: (2S,6R)-2,6-dimethyl-4-(3-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)imidazo[1,2- b]pyridazin-6-yl)morpholine (14) Pale yellow solid (18 mg, 17%)d4) δ 8.32 (d, J = 0.7 Hz, 1H), 8.15 (d, J = 0.7 Hz, 1H), 7.75 (d, J = 9.6 Hz, 2H), 7.13 (d, J = 9.9 Hz, 1H), 4.37 (t, J = 6.6 Hz, 2H), 4.09 – 4.01 (m, 2H), 3.80 (dqd, J = 12.4, 6.2, 2.4 Hz, 2H), 3.70 – 3.61 (m, 4H), 2.86 (t, J = 6.6 Hz, 2H), 2.65 (dd, J = 12.8, 10.6 Hz, 2H), 2.54 – 2.46 (m, 4H), 1.27 (d, J = 6.2 Hz, 7H).13C NMR (126 MHz, Methanol-d4) δ 155.4, 136.5, 127.7, 127.2, 110.4, 109.9, 71.3, 66.5, 57.8, 53.4, 51.6, 49.1, 17.9. HRMS (ESI) m / z calcd for C21H29N7O2 [M + H]+412.2455, found 412.2464.

[0148] Example 24: (2S,6R)-2,6-dimethyl-4-(3-(1-phenyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-6- yl)morpholine (15)   44   70378-02     Compound 15 was prepared using solid (287 mg, 79%).1H NMR (500 MHz, Methanol-d4) δ 8.72 (d, J =, , 7.73 (s, 1H), 7.71 – 7.66 (m, 2H), 7.64 (d, J = 9.9 Hz, 1H), 7.44 (dd, J = 8.5, 7.3 Hz, 2H), 7.33 – 7.27 (m, 1H), 7.01 (d, J = 9.9 Hz, 1H), 3.95 – 3.87 (m, 2H), 3.75 (dqd, J = 14.8, 6.2, 2.4 Hz, 2H), 2.56 (dd, J = 12.5, 10.6 Hz, 2H), 1.24 (d, J = 6.3 Hz, 6H).13C NMR (126 MHz, Methanol-d4) δ 155.2, 139.6, 138.2, 136.3, 129.2, 127.5, 126.5, 124.7, 123.9, 121.4, 118.4, 112.4, 109.8, 71.2, 51.4, 17.8. HRMS (ESI) m / z calcd for C21H22N6O [M + H]+375.19278, found 375.1941.

[0149] Example 25:

[0150] Synthesis of (2S,6R)-2,6-dimethyl-4-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-pyrazol- 4-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine(16) Cesium carbonate (218.42 mg 0.68Cu(OAc)2 (0.2 equiv.) were added to a stirred solution of compound 8 (100 mg, 0.34 mmol) and 1-iodo-4-(trifluoromethoxy)benzene (111.62 mg, 0.5 mmol, 1.20 equiv.) in DMF (2.0 mL) at room temperature under argon atmosphere. The reaction was stirred at 110 °C for 24 hours and cooled to room temperature. The reaction was extracted with water as the aqueous layer with two portions of ethyl acetate. The ethyl acetate layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel with hexanes / ethyl acetate mixture. Yellow powder (110 mg, 87%).1H NMR (500 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.45 (s, 1H), 8.03 – 7.96 (m, 2H), 7.92 (d, J = 10.0 Hz, 2H), 7.57 – 7.51 (m, 2H), 7.22 (d, J = 9.8 Hz, 1H), 4.13 – 4.05 (m, 2H), 3.72 (ddt, J = 12.5, 6.4, 3.2 Hz, 2H), 2.59 (dd, J = 12.7, 10.6 Hz, 2H), 1.20 (d, J = 6.2 Hz, 6H).13C NMR (126 MHz, Methanol-d4) δ 155.3, 147.2, 138.7, 138.5, 127.7, 124.8, 124.1, 122.0, 119.8, 112.9, 110.0, 71.2, 51.4, 17.8 (d, J = 3.4 Hz). HRMS (ESI) m / z calcd for C22H22F3N6O2[M + H]+459.1756, found 459.1754. 45   70378-02

[0151] Example 26: S(2S,6R)-4-(3-(4-(1H-pyrazol-4-yl)phenyl)imidazo[1,2-b]pyridazin-6-yl)-2,6- dimethylmorpholine (17) Compound 17 was prepared using powder (271mg, 20%). H NMR (500 MHz, Methanol-d4) δ 8.11 – 8.06 (m, 2H), 8.02 (s, 2H), 7.84 (s, 1H), 7.76 (d, J = 9.9 Hz, 1H), 7.71 – 7.65 (m, 2H), 7.15 (d, J = 10.0 Hz, 1H), 4.07 – 4.00 (m, 2H), 3.77 (dqd, J = 10.6, 6.2, 2.4 Hz, 2H), 2.62 (dd, J = 12.9, 10.6 Hz, 2H), 1.25 (d, J = 6.2 Hz, 6H).13C NMR (126 MHz, Methanol- d4) δ 154.9, 137.2, 132.0, 129.2, 128.2, 126.8, 126.6, 125.1, 124.9, 121.8, 110.4, 71.3, 51.5, 17.7. HRMS (ESI) m / z calcd for C21H22N6O [M + H]+375.1927, found 375.1938.

[0152] Example 27: (2S,6R)-2,6-dimethyl-4-(3-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)imidazo[1,2-b]pyridazin-6- yl)morpholine (18) Compound 18 was prepared1solid (101 mg, 74%). H NMR (500 MHz, Methanol-d4) δ 8.02 (dd, J = 8.4, 2.2 Hz, 2H), 7.96 (d, J = 2.2 Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.80 (s, 1H), 7.71 (dd, J = 9.9, 2.0 Hz, 1H), 7.61 – 7.55 (m, 2H), 7.08 (dd, J = 9.9, 2.0 Hz, 1H), 3.99 – 3.94 (m, 2H), 3.92 (d, J = 2.1 Hz, 3H), 3.77 – 3.68 (m, 2H), 2.56 (dd, J = 12.8, 10.6 Hz, 2H), 1.22 (dd, J = 6.3, 2.0 Hz, 6H).13C NMR (126 MHz, Methanol-d4) δ 154.8, 137.1, 136.0, 131.6, 129.2, 128.0, 127.8, 126.7, 126.5, 124.9, 124.8, 122.7, 110.3, 71.3, 51.4, 37.6, 17.7. HRMS (ESI) m / z calcd for C22H24N6O [M + H]+389.20898, found 389.2087.

[0153] Example 28: (2S,6R)-4-(3-(3-cyclopropyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)-2,6- dimethylmorpholine (19) 46   70378-02   Compound 19 was prepared solid (122 mg, 36%).1H NMR (500 MHz, Methanol-d4) δ 8.31 (s,, , 9.9 Hz, 1H), 7.12 (d, J = 9.9 Hz, 1H), 4.01 (dd, J = 13.1, 2.2 Hz, 2H), 3.84 – 3.71 (m, 2H), 2.72 – 2.51 (m, 2H), 2.05 (tt, J = 8.4, 5.2 Hz, 1H), 1.24 (d, J = 6.3 Hz, 6H), 1.08 – 0.99 (m, 2H), 0.86 (dd, J = 5.2, 2.0 Hz, 2H);13C NMR (126 MHz, Methanol-d4) δ 155.1, 136.0, 130.7, 128.2, 124.7, 122.4, 116.7, 110.0, 108.0, 71.2, 51.5, 17.7, 5.9. HRMS (ESI) m / z calcd for C18H23N6O [M + H]+339.1933, found 339.1933.

[0154] Example 29: (2S,6R)-2,6-dimethyl-4-(3-(3-(trifluoromethyl)-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-6- yl)morpholine (20) Compound 20 was prepared(77 mg, 21%).1H NMR (500 MHz, Methanol-d4) δ 8.53 (s, 1H), 7.79 (d, J = 9.9 Hz, 1H), 7.66 (s, 1H), 7.20 (d, J = 9.9 Hz, 1H), 4.01 (dd, J = 13.3, 2.0 Hz, 2H), 3.81 – 3.69 (m, 2H), 2.67 – 2.56 (m, 2H), 1.24 (d, J = 6.1 Hz, 6H);13C NMR (126 MHz, Methanol-d4) δ 155.2, 136.7, 129.9, 129.6, 124.9, 123.0 (q, J = 267.1 Hz), 119.2, 111.2, 110.9, 107.2, 71.3, 51.3, 17.6. HRMS (ESI) m / z calcd for C16H18F3N6O [M + H]+367.1494, found 367.1494.

[0155] Example 30: (2S,6R)-4-(3-(4-(1H-pyrazol-3-yl)phenyl)imidazo[1,2-b]pyridazin-6-yl)-2,6- dimethylmorpholine (21)47   70378-02  1H NMR (500 MHz, DMSO) δ 8.19 (d, J = 7.4 Hz, 2H), 8.05 – 8.01 (m, 1H), 7.93 (d, J = 9.9 Hz, 2H), 7.90 (s, 1H), 7.23 (d, J = 10.0 Hz, 1H), 6.77 (d, J = 2.2 Hz, 1H), 4.08 – 4.03 (m, 2H), 3.70 (ddd, J = 8.1, 6.1, 3.1 Hz, 2H), 2.58 (dd, J = 12.8, 10.6 Hz, 2H), 1.18 (d, J = 6.2 Hz, 6H).

[0156] Example 31: 4-(6-((2S,6R)-2,6-dimethylmorpholino)imidazo[1,2-b]pyridazin-3-yl)benzamide (22)1H NMR (500 MHz, Methanol- – 7.92 (m, 3H), 7.77 (d, J = 10.0Hz, 1H), 7.19 (d, J = 10.0 Hz, , – , (dqd, J = 12.5, 6.2, 2.3 Hz, 2H), 2.62 (dd, J = 12.9, 10.6 Hz, 2H), 1.25 (d, J = 6.2 Hz, 6H).13C NMR (126 MHz, Methanol-d4) δ 170.4, 155.0, 137.7, 132.3, 132.0, 130.4, 127.6, 127.2, 125.7, 125.1, 111.1, 71.3, 51.4, 17.7.

[0157] Example 32: 4-(6-((2S,6R)-2,6-dimethylmorpholino)imidazo[1,2-b]pyridazin-3-yl)-N-methylbenzamide (23) Off-white solid (265 mg,d4) δ 8.20 (dt, J = 8.4, 2.3 Hz, 2H), 7.95 – 7.87 (m, 3H), 7.77 (dq, J = 10.1, 2.0 Hz, 1H), 7.19 (dq, J = 10.0, 2.0 Hz, 1H), 4.05 – 3.99 (m, 2H), 3.81 – 3.72 (m, 2H), 2.94 (dt, J = 3.1, 1.6 Hz, 3H), 2.62 (ddd, J = 15.1, 11.6, 3.4 Hz, 2H), 1.25 (d, J = 6.3 Hz, 6H).13C NMR (126 MHz, Methanol-d4) δ 168.7, 155.0, 137.7, 132.6, 132.0, 130.4, 127.2, 127.1, 125.7, 125.1, 111.0, 71.3, 51.4, 25.5, 17.7.

[0158] Example 33: 4-(1-(3-(4-(1H-pyrazol-4-yl)phenyl)imidazo[1,2-b]pyridazin-6-yl)piperidin-4-yl)morpholine (24) 48   70378-02   HNNO1H NMR (500 MHz, DMSO) δ 1H), 7.87 (d, J = 9.9 Hz, 1H), 7.74 – 7.68 (m, 2H), 7.21 (d, J = 10.0, Hz, 2H), 3.55 (s, 2H), 2.96 (td, J = 12.8, 2.5 Hz, 2H), 2.46 (t, J = 4.6 Hz, 6H), 2.43 – 2.36 (m, 1H), 1.92 – 1.86 (m, 2H), 1.48 (qd, J = 12.1, 3.8 Hz, 2H).

[0159] Example 34: 3-(6-((2S,6R)-2,6-dimethylmorpholino)imidazo[1,2-b]pyridazin-3-yl)benzamide (25)1H NMR (500 MHz, DMSO) δ(ddd, J = 7.9, 1.9, 1.1 Hz, 1H), 8.08 (s, 1H), 7.94 (d, J = 9.9 Hz, 1H), 7.82 – 7.77 (m, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.25 (d, J = 10.0 Hz, 1H), 4.16 – 4.09 (m, 2H), 3.69 (dqd, J = 12.1, 5.9, 2.1 Hz, 2H), 2.57 (dd, J = 12.9, 10.6 Hz, 2H), 1.18 (d, J = 6.2 Hz, 6H).13C NMR (126 MHz, DMSO) δ 168.4, 168.3, 154.9, 137.8, 135.2, 135.2, 131.7, 129.6, 129.0, 128.6, 126.7, 126.7, 126.4, 125.3, 110.5, 71.2, 51.5, 19.2.

[0160] Example 35: 3-(6-((2S,6R)-2,6-dimethylmorpholino)imidazo[1,2-b]pyridazin-3-yl)-N-methylbenzamide (26)1H NMR (500 MHz, MeOD) δ 8.76(dt, J = 8.0, 1.4 Hz, 1H), 7.94 (s, 1H), 7.82 – 7.73 (m, 2H), 7.55 (t, J = 7.8 Hz, 1H), 7.21 (d, J = 10.0 Hz, 1H), 4.12 – 4.06 (m, 2H), 3.78 (dqd, J = 12.6, 6.2, 2.3 Hz, 2H), 2.95 (s, 3H), 2.65 (dd, J = 12.9, 10.6 Hz, 2H), 1.26 (d, J = 6.2 Hz, 6H). 49   70378-02

[0161] Example 36: (2S,6R)-4-(3-(4-(1,2,3-oxadiazol-4-yl)phenyl)imidazo[1,2-b]pyridazin-6-yl)-2,6- dimethylmorpholine (27)1H NMR (500 MHz, DMSO) δ (m, 2H), 8.15 (s, 1H), 8.13 – 8.07 (m,2H), 7.96 (d, J = 9.9 Hz, 1H), 7.29 = , – 4.01 (m, 2H), 3.70 (dqd, J = 12.2, 6.1, 2.1 Hz, 2H), 2.58 (dd, J = 12.8, 10.6 Hz, 2H), 1.19 (d, J = 6.2 Hz, 6H).

[0162] Example 37: (2S,6R)-4-(3-(4-(1H-pyrazol-1-yl)phenyl)imidazo[1,2-b]pyridazin-6-yl)-2,6- dimethylmorpholine (28)1H NMR (500 MHz, DMSO) δ(d, J = 8.5 Hz, 2H), 8.05 (s, 1H), 7.95 (dd, J = 9.3, 5.7 Hz, 3H), 7.76 (s, 1H), 7.25 (d, J = 10.0 Hz, 1H), 6.58 – 6.54 (m, 1H), 4.06 (d, J = 12.6 Hz, 2H), 3.71 (t, J = 8.7 Hz, 2H), 2.58 (t, J = 11.7 Hz, 2H), 1.19 (d, J = 6.3 Hz, 6H).

[0163] Example 38: (2S,6R)-4-(3-(4-(1H-1,2,3-triazol-1-yl)phenyl)imidazo[1,2-b]pyridazin-6-yl)-2,6- dimethylmorpholine (29)50   70378-02  1H NMR (500 MHz, DMSO) δ 8.89 (d, J = 1.2 Hz, 1H), 8.40 – 8.34 (m, 2H), 8.11 (s, 1H), 8.05 – 8.00 (m, 2H), 7.98 (d, J = 1.2 Hz, 1H), 7.95 (d, J = 10.0 Hz, 1H), 7.27 (d, J = 10.0 Hz, 1H), 4.09 – 4.02 (m, 2H), 3.70 (ddt, J = 12.2, 8.4, 6.0 Hz, 2H), 2.58 (dd, J = 12.8, 10.6 Hz, 2H), 1.18 (d, J = 6.2 Hz, 6H).13C NMR (126 MHz, DMSO) δ 155.1, 138.0, 135.6, 134.9, 132.1, 129.7, 127.2, 126.8, 126.2, 123.5, 120.7, 110.9, 71.2, 51.5, 19.2.

[0164] Example 39: (2S,6R)-4-(3-(4-(1H-imidazol-1-yl)phenyl)imidazo[1,2-b]pyridazin-6-yl)-2,6- dimethylmorpholine (30)1H NMR (500 MHz, DMSO) δ (m, 2H), 8.06 (s, 1H), 7.94 (d, J = 9.9Hz, 1H), 7.82 (d, J = 1.5 Hz, 1H), 7.79 – 7.72 (m, 2H), 7.24 (d, J = 10.0 Hz, 1H), 7.12 (s, 1H), 4.10 – 4.01 (m, 2H), 3.69 (ddd, J = 10.4, 6.2, 2.3 Hz, 2H), 2.57 (dd, J = 12.8, 10.6 Hz, 2H), 1.18 (d, J = 6.2 Hz, 6H).13C NMR (126 MHz, DMSO) δ 155.0, 137.8, 136.0, 131.8, 130.4, 128.1, 127.3, 126.7, 126.5, 120.8, 118.4, 110.6, 71.1, 51.5, 19.2.

[0165] Example 40: (2S,6R)-4-(3-(4-(1H-imidazol-2-yl)phenyl)imidazo[1,2-b]pyridazin-6-yl)-2,6- dimethylmorpholine (31)1H NMR (500 MHz, DMSO) δ(s, 1H), 8.03 (d, J = 8.2 Hz, 2H), 7.93 (d, J = 9.8 Hz, 1H), 7.24 (d, J = 9.9 Hz, 2H), 7.05 (s, 1H), 4.08 – 4.03 (m, 2H), 3.75 – 3.65 (m, 2H), 3.15 (d, J = 4.9 Hz, 2H), 2.58 (dd, J = 12.8, 10.5 Hz, 2H), 1.18 (d, J = 6.2 Hz, 6H).

[0166] Example 41: 4-(3-(4-(1H-pyrazol-4-yl)phenyl)imidazo[1,2-b]pyridazin-6-yl)morpholine (32) 51   70378-02  1H NMR (500 MHz, DMSO) δ J = 6.1 Hz, 3H), 7.77 – 7.69 (m, 3H), 7.55 (d, J = 8.0 Hz, 1H), 7.21 (d,J = 4.9 Hz, 4H), 3.50 (t, J = 4.9 Hz, 4H).

[0167] Example 42 : (R)-4-(3-(4-(1H-pyrazol-4-yl)phenyl)imidazo[1,2-b]pyridazin-6-yl)-2-methylmorpholine (33)1H NMR (500 MHz, DMSO) δ 8.02 – 7.90 (m, 3H), 7.73 (dd, J = 16.9, 7.9 Hz, 3H), 7.55 (d, J = 7.7 Hz,, 1H), 4.04 (d, J = 12.6 Hz, 1H), 3.96 (t, J = 11.8 Hz, 2H), 3.69 – 3.58 (m, 2H), 2.97 (td, J = 12.5, 3.6 Hz, 1H), 2.65 (dd, J = 12.7, 10.3 Hz, 1H), 1.18 (d, J = 6.2 Hz, 3H).

[0168] Example 43: (S)-4-(3-(4-(1H-pyrazol-4-yl)phenyl)imidazo[1,2-b]pyridazin-6-yl)-2-methylmorpholine (34)1H NMR (500 MHz, DMSO) δ7.94 (d, J = 2.4 Hz, 3H), 7.77 – 7.70 (m, 3H), 7.55 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 10.0 Hz, 1H), 4.04 (d, J = 12.6 Hz, 1H), 3.97 (t, J = 12.6 Hz, 2H), 3.67 – 3.59 (m, 2H), 3.01 – 2.93 (m, 1H), 2.65 (dd, J = 12.7, 10.4 Hz, 1H), 1.18 (d, J = 6.2 Hz, 3H).

[0169] Example 44: 52   70378-02   4-(3-(4-(1H-pyrazol-4-yl) phenyl)imidazo[1,2-b]pyridazin-6-yl)-2,2-dimethylmorpholine (35)1H NMR (500 MHz, DMSO) δ , 8.00 – 7.89 (m, 3H), 7.73 (dd, J = 15.6, 7.7 Hz, 3H), 7.55 (d, J = 7.8 Hz,1H), 3.78 (t, J = 5.0 Hz, 2H), 3.50 (t, J = 5.0 Hz, 2H), 3.37 (s, 2H), 1.23 (s, 6H).

[0170] Example 45: (2R,6R)-4-(3-(4-(1H-pyrazol-4-yl) phenyl)imidazo[1,2-b]pyridazin-6-yl)-2,6- dimethylmorpholine (36) HNN1H NMR (500 MHz, DMSO) δ 8.00 – 7.89 (m, 3H), 7.73 (dd, J = 15.8,7.8 Hz, 3H), 7.55 (d, J = 7.7 Hz, , = 1H), 4.09 (td, J = 6.5, 3.5 Hz, 2H), 3.62 (dd, J = 12.8, 3.4 Hz, 2H), 3.30 – 3.20 (m, 5H), 1.20 (t, J = 6.7 Hz, 6H).

[0171] Example 46: 4-(3-(4-(1H-pyrazol-4-yl)phenyl)imidazo[1,2-b]pyridazin-6-yl)-2,2,6,6- tetramethylmorpholine (37)1H NMR (500 MHz, DMSO) δ– 7.89 (m, 3H), 7.74 (dd, J = 14.5, 8.0 Hz, 3H), 7.55 (d, J = 7.8 Hz, 1H), 7.17 (d, J = 9.9 Hz, 1H), 3.46 (s, 4H), 1.23 (s, 12H).

[0172] Example 47 53   70378-02   4-(3-(4-(1H-pyrazol-4-yl)phenyl)imidazo[1,2-b]pyridazin-6-yl)thiomorpholine (38)1H NMR (500 MHz, DMSO) δ – 7.88 (m, 3H), 7.73 (dd, J = 20.6,8.0 Hz, 3H), 7.55 (d, J = 7.7 Hz, , = 1H), 3.94 – 3.88 (m, 4H), 2.74 – 2.69 (m, 4H).

[0173] Example 48: 3-(4-(1H-pyrazol-4-yl)phenyl)-6-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)imidazo[1,2- b]pyridazine (39)1H NMR (500 MHz, DMSO) δ7.99 (s, 1H), 7.91 (d, J = 9.9 Hz, 1H), 7.71 (d, J = 8.1 Hz, 3H), 7.24 (d, J = 10.0 Hz, 1H), 4.07 (d, J = 12.8 Hz, 2H), 2.91-2.77 (m, 2H), 2.35-2.25 (m, 2H), 1.89 (s, 3H), 1.14 (d, 6H).

[0174] Example 49: 3-(4-(1H-pyrazol-4-yl)phenyl)-6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazine (40)1H NMR (500 MHz, DMSO) δ, 7.99 (d, J = 1.9 Hz, 1H), 7.90 (dd, J = 9.9, 1.8 Hz, 1H), 7.71 (dd, J = 8.4, 1.9 Hz, 3H), 7.21 (dd, J = 10.0, 1.8 Hz, 1H), 3.53 (t, J = 5.1 Hz, 4H), 2.53 – 2.48 (m, 3H), 2.25 (s, 4H), 1.20 (s, 3H).

[0175] Example 50: 54   70378-02   3-(4-(1H-pyrazol-4-yl)phenyl)imidazo[1,2-b]pyridazine (41)1H NMR (500 MHz, DMSO) δ 8.64 Hz, 1H), 8.26 (d, J = 6.9 Hz, 2H), 8.20 (dd,J = 9.1, 1.6 Hz, 1H), 8.14 (d, J = 8.1 , (s, 1H), 7.74 (d, J = 8.1 Hz, 2H), 7.27 (dd, J = 9.2, 4.4 Hz, 1H)

[0176] As used herein, the following terms and phrases shall have the meanings set forth below. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art.

[0177] The term "about" can allow for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or of a stated limit of a range.

[0178] The term "substantially" can allow for a degree of variability in a value or range, for example, within 90%, within 95%, or within 99% of a stated value or of a stated limit of a range.

[0179] The terms "a," "an," or "the" are used to include one or more than one unless the context clearly dictates otherwise. The term "or" is used to refer to a nonexclusive "or" unless otherwise indicated. In addition, the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. Any use of section headings is intended to aid reading of the document and is not to be interpreted as limiting. Further, information that is relevant to a section heading may occur within or outside of that particular section. The terms "including" and "having" are defined as comprising (i.e., open language).

[0180] It will be appreciated by persons skilled in the art that the present disclosure is not limited by what has been particularly shown and described herein above. Rather the scope of the present disclosure includes both combinations and sub-combinations of the various features described hereinabove as well as variations and modifications which would occur to persons skilled in the art upon reading the specification and which are not in the prior art. 55   70378-02

[0181] All patents, patent application publications, journal articles, textbooks, and other publications mentioned in the specification are indicative of the level of skill of those in the art to which the disclosure pertains. All such publications are incorporated herein by reference to the same extent as if each individual publication were specifically and individually indicated to be incorporated by reference. 56

Claims

70378-02   WE CLAIM 1. A compound of formula (I), or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof:     (I) wherein the compound of formula (I) comprises: (i) B, a 5-6 bi-aryl moiety represented by a structure: wherein each X is independently or CRb, wherein Rais selected from H, alkyl, cycloalkyl, heteroalkyl, alkylcarbonyl, arylcarbonyl, heteroalkylcarbonyl, amide, and sulfonamide; and Rb is selected from H, cyano, halo, alkyl, trifluoroalkyl, haloalkyl, dihaloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heteroalkyl, aminoalkyl, cyanoalkyl, dialkylaminoalkyl, morpholinylalkyl, piperazinylalkyl, dialkylaminocarbonyl, dialkylaminosulfonyl, hydroxyaryl, alkoyxaryl, carboxylic acid, and ester; wherein alkyl is optionally substituted with alkyl or heteroalkyl; and a bond between any two X is a single or double bond; and each E is independently N or CRc, wherein Rcis H or halogen; (ii) P, a 5 / 6 bi-cyclic aryl moiety represented by a structure: wherein each A iseach G is independently CH or N; W is N or CRb, wherein Rb is selected from H, cyano, halo, alkyl, trifluoroalkyl, haloalkyl, dihaloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heteroalkyl, aminoalkyl, cyanoalkyl, dialkylaminoalkyl, morpholinylalkyl, piperazinylalkyl, dialkylaminocarbonyl, 57   70378-02   dialkylaminosulfonyl, hydroxyaryl, alkoyxaryl, carboxylic acid, and ester; wherein alkyl is optionally substituted with alkyl or heteroalkyl; and B is as defined above; (iii) Y is H or a 4- to 12-membered monocyclic ring or bi-cyclic ring, wherein the bi-cyclic ring is a fused bi-cyclic ring, a bridged bi-cyclic ring, or a spiro bi-cyclic ring, substituted with one or more groups selected from R1-R8based on the ring size and represented by a structure: wherein T is sp3- carbon,each R1, R2, R3, R4, R5, R6, R7, and R8is independently selected from H, halo, nitro, cyano, alkyl, aminoalkyl, hydroxyalkyl, alkoxyalkyl, alkylcarbonyl, alkylsulfonyl, cycloalkyl, heteroalkyl, aryl, and heteroaryl; or any two R groups from R1-R8, together with the carbon atom to which they are attached, form a 3- to 8-membered cyclic ring; and Q is O, S, S=O, SO2, NRa or CRbRb, wherein Ra is as defined above and each Rb is independently defined as above or the two Rb, together with the carbon atom to which they are attached, form a 3- to 6- membered cyclic ring optionally contianing one or more heteroatoms, wherein each heteroatom is independently N, S or O.

2. The compound of claim 1, wherein the P is:  70378-02   heteroaryl.

3. A compound of formula (IA), or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof: wherein each R9 and R10 is from hydrogen, deuterium, alkyl, andheteroalkyl; and each E is independently N or CRc, wherein Rcis H or halogen; and Y is H or a 4- to 12-membered monocyclic ring or bi-cyclic ring, wherein the bi-cyclic ring is a fused bi-cyclic ring, a bridged bi-cyclic ring, or a spiro bi-cyclic ring, substituted with one or more groups selected from R1-R8 based on the ring size and represented by a structure:wherein T is sp3- carbon, sp2-each R1, R2, R3, R4, R5, R6, R7,and R8is independently selected from H, halo, nitro, cyano, alkyl, aminoalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heteroalkyl, aryl, and heteroaryl; or any two R groups from R1-R8, together with the carbon atom to which they are attached, form a 3- to 8-membered cyclic ring; and 59   70378-02   Q is O, S, S=O, SO2, NRa or CRbRb, wherein Ra is as defined above and each Rb is independently as defined above or the two Rb, together with the carbon atom to which they are attached, form a 3- to 6- membered cyclic ring optionally containing one or more heteroatoms, wherein each heteroatom is independently N, S or O.

4. The compound of claim 1, wherein the X is N, NH, N-alkyl, O or CH; and E is N or CH.

5. The compound of claim 1 or 3, wherein the Y is: N N N N N N N . . 60   70378-02   7. The compound of claim 1 or 3, wherein the Y is:

8. The compound of claim 1 or 3, wherein the Y is:  70378-02   O O O O O N N N N N O N N .

9. The compound of claim 1 or 3, wherein the Y is:    62   70378-02   OH OMe NH2N NH2O N O F F .

10. The compound of claim 1 or 3, wherein the Y is:  .

11. The compound of claim 1 or 3, wherein the compound is: 63   70378-02  64   70378-02   HNN.

12. A pharmaceutical composition comprising a compound of any one of claims 1-11 or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.

13. A method of inhibiting Fms-related tyrosine kinase 3 (FLT3) in a patient, which method comprises administering to the patient a therapeutically effective amount of the compound of any one of claims 1-11 or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof, or as a pharmaceutical composition comprising the same and a pharmaceutically acceptable carrier, excipient, or diluent, whereupon FLT3 in the patient is inhibited.

14. The method of claim 13, wherein the patient has cancer or an inflammatory disease.

15. The method of claim 14, wherein the inflammatory disease is arthritis or pain.

16. The method of any one of claims 13-15, wherein the compound is administered orally, intravenously, intramuscularly, dermally, rectally, nasally, otically, or ocularly.

17. A method of treating or inhibiting cancer in a patient, wherein the method comprises administering to the patient a therapeutically effective amount of (i) a compound of formula (I) or (IA) of any one of claims 1-11, (ii) a pharmaceutically acceptable salt, hydrate, tautomer, or optical 65   70378-02   isomer of (i), or (iii) a pharmaceutical composition comprising (i) or (ii) and a pharmaceutically acceptable carrier, excipient, or diluent, whereupon the cancer in the patient is treated or inhibited.

18. The method of claim 17, wherein the cancer is selected from the group consisting of multiple myeloma, lung cancer, liver cancer, thyroid cancer, colon cancer, pancreatic cancer, leukemia, lymphoma, ovarian cancer, breast cancer, throat cancer, head and neck cancer, prostate cancer, brain cancer, stomach cancer, anal cancer, and melanoma.

19. The method of claim 17, wherein the cancer is leukemia. 66

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