WO2025072384A1 - 5/6-5/6-bisaryl compounds as tak1 inhibitors - Google Patents

Abstract

5/6-5/6 bisaryl compounds that inhibit transforming growth factor-β activated kinase (TAK1); compositions comprising same; and their use for treating cancers and inflammatory diseases.

Description

  5/6-5/6-BISARYL COMPOUNDS AS TAK1 INHIBITORS CROSS-REFERENCE TO RELATED APPLICATION [0001] This application claims priority to U.S. provisional patent application no. 63/541,050, which was filed September 28, 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 inhibitors of transforming growth factor-β activated kinase (TAK1), 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] Cancer is a condition where cell growth regulators do not function properly. As a result, cell growth exceeds cell death. Recent studies have shown that the transforming growth factor-β activated kinase (TAK1) is upregulated and overexpressed in several cancers, for example, multiple myeloma (MM). TAK1 also plays a vital role in various inflammatory diseases. TAK1 is a serine/threonine kinase important for cell growth, differentiation, and apoptosis. Various extracellular signals trigger TAK1 activation, including cytokines, growth factors, and toll-like receptor ligands. In the classical TAK1 signaling pathways, TAK1 is activated by receptor- associated proteins, such as TGF-β receptors or interleukin-1 receptors. Activation of these receptors recruits adapter proteins TAB1, TAB2, and TAB3 to TAK1. TAK1 then phosphorylates downstream signaling molecules, including MAP kinases and various transcription factors. TAK1 is involved in numerous cellular processes, including the regulation of immune responses, inflammation, cell survival, and differentiation. Dysregulation of TAK1 has been implicated in various diseases, including cancer, autoimmune disorders, and inflammatory diseases. Therefore, TAK1 has emerged as a potential target for therapeutic intervention in these diseases. [0005] It has been found that inhibition of TAK1 leads to the suppression of NF-κB, p38MAPK, ERK, and STAT3 signaling pathways, which consequently inhibits the expression of key regulators involved in the growth and survival of MM, such as PIM2, MYC, Mcl1, IRF4, and Sp1. It was also found that TAK1 inhibition significantly reduces the levels of the angiogenic factor   VEGF in MM cells. Harada et al. Cancers, 2021, 13, 4441, discloses that the dysregulation of the TAK1-PIM2 pathway is a key factor in promoting tumor growth and bone destruction in MM and that targeting the TAK1 pathway could be a therapeutic strategy for effectively addressing MM and its associated complications. Overall, these findings suggest that TAK1 can be a promising therapeutic target for the treatment of multiple myeloma. [0006] 5/6 bi-cyclic hinge binders, such as pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-a]pyridine, imidazo[1,2-b][1,2,4]triazine, imidazo[1,2-b]pyridazine, and imidazo[1,2-a]pyridine, are privileged drug moieties that are found in many approved drugs, for example, ponatinib, capmatinib and larotrectinib, and experimental drugs. It has been reported that, while the imidazo[1,2-b] pyridazine moiety binds to the hinge region of kinases, substitutions at positions 2, 3, 6, 7, and 8 dictate kinase selectivity and potency (e.g., Eur. J. Med. Chem., 2021, 226, 113867). Considering that there are over 500 kinases in the human kinome and the indazole- imidazo[1,2-b]pyridazine moiety (referred to as a 5/6-5/6- system) has eight different positions to place a substituent, it is currently not obvious how different substitutions could impact kinase selectivity and affect drug-like properties. Additionally, for the successful translation of a compound into the drug, the compound should ideally have good oral bioavailability and be tolerated by animals. TAK1 inhibitors, such as OTS964, NG-25, LX2343, 5Z-7-oxozeaenol, ponatinib, and takinib, have been described in the art (FIG. 1), but the reported GI50 values for these compounds against TAK1-overexpressing cancers, such as MM, are in the micromolar range and, hence, it would be difficult to achieve effective concentrations in blood without encountering dose-limiting toxicities. [0007] Therefore, there is an unmet need for a compound that potently inhibits TAK1 inhibitors and has good oral bioavailability. 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-cyclic aryl moiety represented by a structure: wherein each X i dently N, S, O, CO, 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, alkoxy, alkyl, trifluoroalkyl, haloalkyl, dihaloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heteroalkyl, aminoalkyl, cyanoalkyl, dialkylaminoalkyl, morpholinylalkyl, piperazinylalkyl, dialkylaminocarbonyl, dialkylaminosulfonyl, hydroxyaryl, alkoxyaryl, carboxylic acid, ester, OR_d, and NR_dR_d, wherein each Rd is independently selected from hydrogen, alkyl, heteroalkyl and heteroaryl; wherein alkyl is optionally substituted with alkyl or heteroalkyl; The bond between X-X or X-C in a 5-membered ring can be a single bond or a 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 is independent

each G is independently N or CR’_c, wherein R’_c is H, halogen, or C₁-C₆ alkyl; W is N or CRb, wherein Rb is selected from H, cyano, halo, alkoxy, alkyl, trifluoroalkyl, haloalkyl, dihaloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heteroalkyl, aminoalkyl, cyanoalkyl, dialkylaminoalkyl, morpholinylalkyl, piperazinylalkyl, dialkylaminocarbonyl, dialkylaminosulfonyl, hydroxyaryl, alkoxyaryl, carboxylic acid, ester, OR_d, and NR_dR_d, wherein each Rd is independently selected from hydrogen, alkyl, heteroalkyl and heteroaryl; wherein alkyl is optionally substituted with alkyl or heteroalkyl; and B is as defined above;   (iii) Y, a 4- to 12-membered mono 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 R₈ is independently selected from H, halo, nitro, cyano, alkyl, aminoalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, and heteroalkyl; 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, NR_a or CR_bR_b, wherein R_a is as defined above and each R_b 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, which optionally contains one or more heteroatoms, wherein each heteroatom is independently N, S or O. [0009] In some embodiments, the B, 5/6 bi-cyclic aryl moiety is:  

   

 

 

wherein: R is H, cyano, halo, alkyl, trifluoroalkyl, haloalkyl, dihaloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heteroalkyl, aminoalkyl, cyanoalkyl, dialkylaminoalkyl, morpholinylalkyl, piperazinylalkyl, dialkylaminocarbonyl, dialkylaminosulfonyl, hydroxyaryl, alkoxyaryl, carboxylic acid, or ester; wherein alkyl group is optionally substituted with alkyl or heteroalkyl;  with the proviso that B and Y are not (a) 3-unsubsituted indazole and unsubstituted morpholine, respectively, at the same time, (b) 3-unsubsituted indazole and unsubstituted piperazine, respectively, at the same time, or (c) 3-unsubsituted indazole and methyl piperazine, respectively, at the same time.  [0010] In some embodiments, the P is:

         wh nd heteroaryl.

[0011] Provided is a compound of formula (IA), or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof: wherein each X is independently N, CR_b, wherein R_a is selected from H, alkyl,

cycloalkyl, heteroalkyl, alkylcarbonyl, arylcarbonyl, heteroalkylcarbonyl, amide, and sulfonamide; and R_b is selected from H, cyano, halo, alkoxy, alkyl, trifluoroalkyl, haloalkyl, dihaloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heteroalkyl, aminoalkyl, cyanoalkyl, dialkylaminoalkyl, morpholinylalkyl, piperazinylalkyl, dialkylaminocarbonyl, dialkylaminosulfonyl, hydroxyaryl, alkoxyaryl, carboxylic acid, ester, ORd, and NRdRd, wherein each R_d is independently selected from hydrogen, alkyl, heteroalkyl and heteroaryl; wherein alkyl is optionally substituted with alkyl or heteroalkyl; The bond between X-X or X-C in a 5-membered ring can be a single bond or a double bond; and Y is a 4- to 12-membered mono 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-carbo

each R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈ is independently selected from H, halo, nitro, cyano, alkyl, aminoalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, and heteroalkyl; 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 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, which optionally contains one or more heteroatoms, wherein each heteroatom is independently N, S or O. [0012] In some embodiments of the compound of formula (IA), each X is independently N, S, O, CO, NR_a or CR_b, wherein R_a is H or alkyl; and R_b is a group selected from H, cyano, halo, alkoxy, alkyl, trifluoroalkyl and cycloalkyl; wherein alkyl is optionally substituted with alkyl or heteroalkyl. [0013] In some embodiments, the Y is:

  O O O O O H H O O ^S _H O H H H i .

_ne . [0015] In some embodiments, the Y is:    

  wh [001

6] In some embodiments, each X is independently selected from CH₂, O, S, S=O, SO₂, NH, N-alkyl, N-heteroalkyl, amide, sulfonamide, urea and carbamate. [0017] In some embodiments, the Y is: . 

  [0018] In some embodiments, the Y is: .

[0019] In some embodiments of the compound of formula (IA), the Y is:   N OMe N N N N N O N O O O O O .

[0020] Provided is a pharmaceutical composition comprising a compound of formula (I) or (IA), or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.   [0021] Further provided is a method of inhibiting transforming growth factor-β activated kinase (TAK1) in a patient in need thereof, which the 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) or a pharmaceutical composition comprising (i) or (ii) and a pharmaceutically acceptable carrier, excipient, or diluent, whereupon TAK1 in the patient is inhibited. In some embodiments, the patient has cancer or an inflammatory disease. The compound can be administered orally, intravenously, intramuscularly, dermally, rectally, nasally, otically, or ocularly. [0022] Further 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 the (i) or (ii) and a pharmaceutically acceptable carrier, excipient, or diluent, whereupon the cancer in the patient is treated or inhibited. [0023] In some embodiments, the cancer can be multiple myeloma. The compound can be administered orally, intravenously, intramuscularly, dermally, rectally, nasally, otically, or ocularly. BRIEF DESCRIPTION OF THE DRAWINGS [0024] The above and other objects, features, and advantages of the present disclosure will be apparent when the description is read in conjunction with the drawings. [0025] FIG. 1 shows reported small molecules that are transforming growth factor-β activated kinase (TAK1) inhibitors. [0026] FIG.2A shows the comparative analysis of the binding modes of takinib and the docking model of compound 3 within the binding pocket of TAK1 (PDB: 5V5N). It illustrates the polar interactions between takinib (left) and compound 3 (right) and the active site of TAK1. Each ligand forms hydrogen bonds with the conserved lysine Lys-63 and with Ala-107 within the hinge region. Takinib makes an additional interaction with DFG residue Asp-175. [0027] FIG.2B shows the comparative analysis of the binding modes of takinib and the docking model of compound 3 within the binding pocket of TAK1 (PDB: 5V5N). It illustrates the surface models of each ligand surrounded by representative hydrophobic residues within the binding pocket. Slight conformational shifts to residues Lys-63, Gly-45, and Cys-174 from the bound   structure of takinib to the docked structure of compound 3 indicate a possible induction of entropically favored hydrophobic interactions. [0028] FIG. 3A shows the histograms of TAK1 inhibition at compound concentrations of 500 nM. Compounds were screened against TAK1 using the ADP Glo kinase assay (Promega®). The dashed line denotes 50% enzyme inhibition, and compounds performing above the line were assessed at the next concentration. [0029] FIG.3B shows the histograms of TAK1 inhibition at compound concentrations of 100 nM and 20 nM. Compounds were screened against TAK1 using the ADP Glo kinase assay (Promega®). The dashed line denotes 50% enzyme inhibition, and compounds performing above the line were assessed at the next concentration. [0030] FIG. 4 shows TAK1 inhibition and IC50 values of compounds 3, 25-26, and 29-35. Data were fitted to a non-linear regression equation using GraphPad Prism 9.0 software. Each data point represents the mean, and error bars represent the SD of duplicates. [0031] FIG. 5 shows the performance of compounds 1-35 in cell culture at concentrations 1 µM and 0.2 µM. Each data point represents the mean, and error bars represent the SD of triplicates. [0032] FIG. 6A shows the dose-response curves. Multiple melanoma (MM) cell H929, a human plasma cell line, was treated with varying concentrations of compounds 3, 25-26, and 29-34 for 72 hours. Data were 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. [0033] FIG.6B shows the dose-response curves. MM cell MPC-11, a murine plasmacytoma cell line, was treated with varying concentrations of compounds 3, 25, 26, 29-34 for 72 hours. Data were 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. [0034] FIG. 7A shows the western blot analysis. MPC-11 cells were treated with compound 26 or compound 3 at 0.1 or 0.5 µM, respectively, or dimethyl sulfoxide (DMSO) control for 48 hours. Bands were quantified relative to actin loading control. Values are reported as means of duplicates, and error bars represent standard deviation. [0035] FIG. 7B shows the western blot analysis. MPC-11 cells were treated with compound 26 or compound 3 at 0.1 or 0.5 µM, respectively, or DMSO control for 48 hours. Bands were quantified relative to actin loading control. Values are reported as means of duplicates, and error bars represent standard deviation. [0036] FIG. 8 shows the antitumor activity of compound 33 against RPMI-8226 subcutaneous xenograft model in B-NDG Mice. Mice were dosed at 15 mg/Kg (oral dosing, QD) of compound 33 and compared to vehicle (10% DMA/20% PG/40% PEG-400/30% PBS).   [0037] FIG.9 shows the in-house kinase screening using ADP-GLO kinase assay. [0038] FIG. 10 shows the screening of compounds for cell growth inhibition against MPC-11 at 200 nM. [0039] FIG. 11 shows the in vivo efficacy of compound 26 against multiple myeloma cancer (RPMI-8226). [0040] FIG. 12 shows the in vivo efficacy of compound 107 against multiple myeloma cancer (RPMI-8226). [0041] FIG. 13 shows the in vivo efficacy of compound 111 against multiple myeloma cancer (RPMI-8226). [0042] FIG. 14 shows the in vivo efficacy of compound 125 against multiple myeloma cancer (RPMI-8226). [0043] FIG. 15 shows the TNF-α expression levels of compound 107 and TNF-α and IL-6 expression levels of compound 154 against Tak1 Inhibitors. DETAILED DESCRIPTION [0044] 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. [0045] The present disclosure is predicated, at least in part, on the discovery that the imidazo[1,2- b] pyridazine moiety, which is 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. The imidazo[1,2-b]pyridazine scaffold has been explored to inhibit various kinases. For example, it has been reported that C3- and C6-substituted imidazo[1,2-b]pyridazine compounds inhibit adaptor-associated kinase 1 (AAK1), and that these compounds could have utility for treating brain disorders, such as schizophrenia, bipolar disorder, Parkinson’s disease, and Alzheimer’s disease (Int’l Pat. App. Pub. No. WO 2013/134219). In other studies, Huertas et al. (Oncogene 2012 31, 1408–1418) and Elie at al. (J. Enzyme Inhib. Med. Chem. 2020, 35, 1840–1853) demonstrated that imidazo[1,2-b]pyridazine core compounds inhibit Haspin, PIM1, GSK3 ^/ ^, DYRK1A, CDK2, CDK5 and CDK9. [0046] In view of the above, the present disclosure provides 5/6-5/6-bisaryl compounds  comprising imidazo[1,2-b] pyridazine core that are transforming growth factor-β activated kinase   (TAK1) inhibitors. The compounds can be substituted at the C6 position with a moiety such as a morpholine or a piperidine to obtain TAK 1 inhibition. [0047] 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-cyclic aryl moiety represented by a structure: wherein each X ndently N, S, O, CO, NRa or CRb, wherein Ra

is selected from H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, hetero C₂-C₆ alkyl, C₁-C₆ alkylcarbonyl, arylcarbonyl, hetero C₂- C6 alkylcarbonyl, amide, and sulfonamide; and Rb is selected from H, cyano, halo, alkoxy, C1-C6 alkyl, trifluoro C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ dihaloalkyl, hydroxy C₁-C₆ alkyl, alkoxy C₁- C6 alkyl, C3-C8 cycloalkyl, hetero C2-C6 alkyl, amino C1-C6 alkyl, cyano C1-C6 alkyl, C1-C6 dialkylamino C₁-C₆ alkyl, morpholinyl C₁-C₆ alkyl, piperazinyl C₁-C₆ alkyl, C₁-C₆ dialkylaminocarbonyl, C1-C6 dialkylaminosulfonyl, hydroxyaryl, alkoxyaryl, carboxylic acid, ester, OR_d, and NR_dR_d, wherein each R_d is independently selected from hydrogen, C₁-C₆ alkyl, hetero C2-C6 alkyl and heteroaryl; wherein alkyl is optionally substituted with C1-C6 alkyl or hetero C2-C6 alkyl; The bond between X-X or X-C in a 5-membered ring can be a single bond or a double bond; and each E is independently N or CR_c, wherein R_c is H or halogen; (ii) P, a 5/6 bi-cyclic aryl moiety represented by a structure:   wherein each A is independently

each G is independently N or CR’_c, wherein R’_c is H, halogen, or C₁-C₆ alkyl; W is N or CRb, wherein Rb is selected from H, cyano, halo, alkoxy, C1-C6 alkyl, trifluoro C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ dihaloalkyl, hydroxy C₁-C₆ alkyl, alkoxy C₁-C₆ alkyl, cyclo C3-C8 alkyl, hetero C2-C6 alkyl, amino C1-C6 alkyl, cyano C1-C6 alkyl, C1-C6 dialkylamino C1-C6 alkyl, morpholinyl C₁-C₆ alkyl, piperazinyl C₁-C₆ alkyl, C₁-C₆ dialkylaminocarbonyl, C₁-C₆ dialkylaminosulfonyl, hydroxyaryl, alkoxyaryl, carboxylic acid, ester, ORd, and NRdRd, wherein each R_d is independently selected from hydrogen, C₁-C₆ alkyl, hetero C₂-C₆ alkyl and heteroaryl; wherein alkyl is optionally substituted with C1-C6 alkyl or hetero C2-C6 alkyl; and B is as defined above; (iii) Y, a 4- to 12-membered mono 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 R8 is 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, aryl, heteroaryl, and hetero C2-C6 alkyl; 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, NR_a or CR_bR_b, wherein each R_b 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, which optionally contains one or more heteroatoms, wherein each heteroatom is independently N, S or O.   [0048] In some embodiments, the 5/6 bi-cyclic aryl moiety B is:    

     

 

R is H, cyano, halo, C₁-C₆ alkyl, trifluoro C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ dihaloalkyl, hydroxy C1-C6 alkyl, alkoxy C1-C6 alkyl, C3-C8 cycloalkyl, hetero C2-C6 alkyl, amino C1-C6 alkyl, cyano C₁-C₆ alkyl, C₁-C₆ dialkylamino C₁-C₆ alkyl, morpholinyl C₁-C₆ alkyl, piperazinyl C₁-C₆ alkyl, C1-C6 dialkylaminocarbonyl, C1-C6 dialkylaminosulfonyl, hydroxyaryl, alkoxyaryl, carboxylic acid, or ester; wherein alkyl group is optionally substituted with C₁-C₆ alkyl or hetero C2-C6 alkyl;    with the proviso that B and Y are not (a) 3-unsubsituted indazole and unsubstituted morpholine, respectively, at the same time, (b) 3-unsubsituted indazole and unsubstituted piperazine, respectively, at the same time, or (c) 3-unsubsituted indazole and methyl piperazine, respectively, at the same time, For example, structures (i) to (vi) . 

[ ] n some emo mens, e s seece rom:  

  N N N N N N N N

wherein each R', R₉, and R₁₀ is independently selected from H, C₁-C₆ alkyl, hetero C₂-C₆ alkyl, and heteroaryl. [0050] In some embodiments of the compound of formula (I), each X is independently selected from N, S, O, CO, SO, NH, C1-C6 N-alkyl, N-hetero C2-C6 alkyl, N-arylcarbonyl, N-hetero C2-C6 alkylcarbonyl, CH, C₁-C₆ C-alkyl, C-hetero C₂-C₆ alkyl, C-amide, C-sulfonamide, C-cyano, C- carboxylic acid and C-ester.  [0051] In some embodiments of the compound of formula (I), the W is selected from N, CH, C- alkyl, C-cyclopropyl, ORc, NRcRc, wherein each Rc is independently selected from H, C1-C6 alkyl, hetero C₂-C₆ alkyl or heteroaryl.  [0052] In some embodiments, provided is a compound of formula (IA) or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof: wherein each X is independently N

CR_b, wherein R_a is selected from H, C₁-C₆ alkyl, C3-C8 cycloalkyl, hetero C2-C6 alkyl, C1-C6 alkylcarbonyl, arylcarbonyl, hetero C2-C6 alkylcarbonyl, amide, and sulfonamide and R_b is selected from H, cyano, halo, alkoxy, C₁-C₆ alkyl, trifluoro C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 dihaloalkyl, hydroxy C1-C6 alkyl, alkoxy C1- C₆ alkyl, cyclo C₃-C₈ alkyl, hetero C₂-C₆ alkyl, amino C₁-C₆ alkyl, cyano C₁-C₆ alkyl, C₁-C₆ dialkylamino C1-C6 alkyl, morpholinyl C1-C6 alkyl, piperazinyl C1-C6 alkyl, C1-C6 dialkylaminocarbonyl, C₁-C₆ dialkylaminosulfonyl, hydroxyaryl, alkoxyaryl, carboxylic acid, ester ORd, and NRdRd, wherein each Rd is independently selected from hydrogen, C1-C6 alkyl, hetero C₂-C₆ alkyl and heteroaryl; wherein alkyl is optionally substituted with C₁-C₆ alkyl or hetero C2-C6 alkyl;   The bond between X-X or X-C in a 5-membered ring can be a single bond or a double bond; and Y is a 4- to 12-membered mono 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-carb

each R₁, R₂, R₃, R₄, R₅, R₆, R₇ and R₈ is independently selected from H, halo, nitro, cyano, C₁-C₆ alkyl, amino C1-C6 alkyl, hydroxy C1-C6 alkyl, alkoxy C1-C6 alkyl, cyclo C3-C8 alkyl, aryl, heteroaryl, and hetero C2-C6 alkyl; 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, NR_a or CR_bR_b, wherein each R_b 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, which optionally contains one or more heteroatoms, wherein each heteroatom is independently N, S or O. [0053] In some embodiments of the compound of formula (IA), each X is independently N, S, O, CO, NR_a or CR_b, wherein R_a is H or C₁-C₆ alkyl and R_b is a group selected from H, cyano, halo, alkoxy, C1-C6 alkyl, trifluoro C1-C6 alkyl, and cyclo C2-C8 alkyl; wherein alkyl is optionally substituted with C₁-C₆ alkyl or hetero C₂-C₆ alkyl; and wherein the bond between neighboring groups X-X or X-C in a 5-membered ring can be a single bond or a double bond. [0054] In some embodiments, the Y in the compound of formula (I) or (IA) is:

  .

,

. [0056] In some embodiments, the Y in the compound of formula (I) or (IA) is:    

[0057] In some embodiments, each X is independently selected from CH2, O, S, S=O, SO2, NH, C₁-C₆ N-alkyl, N-hetero C₂-C₆ alkyl, amide, sulfonamide, urea and carbamate. [0058] In some embodiments, the Y in the compound of formula (I) or (IA) is:  

  .

[0059] In some embodiments, the Y in the compound of formula (I) or (IA) is: N NH₂ OH NH₂ OH  

  F _F F OH OMe OH ^F e 1_0f F . 

[0060] In some embodiments, the Q in the compound of formula (I) or (IA) is selected from O, S, S=O, SO₂, NH, C₁-C₆ N-alkyl, N-hetero C₂-C₆ alkyl, N-amide, N-sulfonamide, CH₂, CHF, CF₂, C-hydroxy C1-C6 alkyl, C-alkoxy C1-C6 alkyl, C-amino C1-C6 alkyl, C-hydroxyheteroaryl, C- alkoxy heteroaryl, C-amino heteroaryl, CHOH, CHNH₂, C(C₁-C₆ alkyl)₂, C(hetero C₂-C₆ alkyl)₂, and a spiro ring such as C(cyclic C3-C8 alkyl)2 or C(cyclic hetero C2-C6 alkyl)2; [0061] In some embodiments of the compound of formula (IA), the Y is:

  N OMe N N N N N O N O O O O O .

[0062] In some embodiments, the compound of formula (IA) is:       

   

 

 

     

     

  H_N ^N      

  H_N ^N O  

  [0063] In some embodiments, the compound of formula (I) and (IA) are TAK1 inhibitors. The compounds can inhibit the proliferation of several cancers and can treat inflammatory diseases such as arthritis. [0064] 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. [0065] 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, C1-C6 alkyl, acyl, C3-C8 cycloalkyl, aryl, ar C1-C6 alkyl, heterocyclyl, heteroaryl, or heteroaryl C1-C6 alkyl, 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. [0066] 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. [0067] 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. [0068] 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. [0069] 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-C_6, C₂-C₄ alkynyl, and the like. [0070] The term "hydroxyalkyl" refers to alkyl groups substituted with at least one hydroxyl (- OH) group. [0071] 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, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like. [0072] 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. [0073] 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. [0074] 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. [0075] The term "halogen" refers to an atom selected from fluorine, chlorine, bromine, and iodine. [0076] 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 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 triple bonds. [0077] 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. [0078] 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, 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. [0079] 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. [0080] The term "compound" as used herein, is meant to include all stereoisomers, geometric isomers, and tautomers of the structures depicted. [0081] 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. [0082] 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. [0083] The term "SP³ carbon" 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 109.5^o due to which the central carbon atom is tetrahedral in shape. The steric number of carbon is 4. [0084] The term "SP² carbon" 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. [0085] Provided are pharmaceutically acceptable salts of the above-described compounds and the preparation and use thereof. Salts can be prepared during the final isolation and purification of the compound or separately by reacting the compound with a suitable acid. [0086] The term "pharmaceutically acceptable salt" refers to salts or zwitterionic forms of compounds described herein. Examples of the salts of the compounds described herein include, but are not limited to, hydrochloride salt, hydrobromide salt, hydroiodide salt, sulfate salt, bisulfate salt, 2-hydroxyethansulfonate salt, phosphate salt, hydrogen phosphate salt, acetate salt, adipate salt, alginate salt, aspartate salt, benzoate salt, bisulfate salt, butyrate salt, camphorate salt, camphorsulfonate salt, digluconate salt, glycerolphosphate salt, hemisulfate salt, heptanoate salt, hexanoate salt, formate salt, succinate salt, fumarate salt, maleate salt, ascorbate salt, isethionate salt, salicylate salt, methanesulfonate salt, mesitylenesulfonate salt, naphthylenesulfonate salt, nicotinate salt, 2-naphthalenesulfonate salt, oxalate salt, pamoate salt, pectinate salt, persulfate salt, 3-phenylproprionate salt, picrate salt, pivalate salt, propionate salt, trichloroacetate salt, trifluoroacetate salt, phosphate salt, glutamate salt, bicarbonate salt, paratoluenesulfonate salt, undecanoate salt, lactate salt, citrate salt, tartrate salt, gluconate salt, methanesulfonate salt, ethanedisulfonate salt, benzene sulfonate salt, and p-toluenesulfonate salt. Any reference compounds of the present disclosure appearing herein are intended to include compounds of the present disclosure as well as pharmaceutically acceptable salts or hydrates thereof.   [0087] 5/6-5/6-bisaryl compounds of the present disclosure comprises imidazo[1,2-b] pyridazine core. The compounds can be synthesized through a nucleophilic aromatic substitution (S_NAr) reaction at the C6 position. The final compounds were obtained by performing a Suzuki-Miyaura cross-coupling reaction with aromatic boronic acid substrates. This reaction was carried out using   potassium carbonate as a base, a palladium catalyst, and a solvent mixture of acetonitrile and water in a 3:1 ratio (see Scheme 1).

wherein, Ar is 5/6 bi-cyclic aryl moiety. [0088] In some embodiments, the compounds of formula (I) or (IA) are TAK1 inhibitors. 6- substituted morpholine or piperazine imidazo[1,2-b]pyridazines or related hinge binders such as pyrazolo[1,5-a]pyrimidine, with appropriate aryl substituent at position 3 (C3) can inhibit TAK1 at nanomolar concentrations. The compound of formula (I) or (IA) can inhibit TAK1 with Kd < 500 nM or IC50 < 500 nM (in presence of [ATP] > 10 µM) when cyclic moiety Y can be selected from morpholine, morpholine bioisostere, tetrahydro-2H-pyran, 3,6-dihydro-2H-pyran, 3- oxabicyclo [4.1.0]heptane, spiro cyclic moiety, piperazine derivative and piperidine derivatives. [0089] In some embodiments, provided is a pharmaceutical composition comprising a compound of formula (I) or (IA) or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof, 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, 23^rd ed. (2020)). [0090] Provided is a method of inhibiting a transforming growth factor-β activated kinase (TAK1) in a patient in need thereof, 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 TAK1 in the patient is inhibited. [0091] In some embodiments, the patient has a disease or condition such as cancer or inflammatory diseases. In some embodiments, the inflammatory disease is arthritis. [0092] Provided is a method of treating or inhibiting cancer in a patient, which method comprises administering to the patient a therapeutically effective amount of a compound of formula (I) or (IA) or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof, optionally as a pharmaceutical composition comprising the compound and a pharmaceutically acceptable   carrier, excipient, or diluent, whereupon the cancer in the patient is treated or inhibited. The method comprises inhibition of TAK1. [0093] Examples of cancers include, but are not limited to, 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. In some embodiments, the cancer can be multiple myeloma. [0094] In some embodiments, the compound of formula (I) or (IA), or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof, can be administered orally, intravenously, intramuscularly, dermally, rectally, nasally, otically or ocularly. [0095] The terms “treat,” “treating,” “treated,” or “treatment” (with respect to a disease or condition) are used to describe 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 the quality of life of one suffering from a disease, prolonging survival and/or prophylactic or preventative treatment. [0096] 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. [0097] 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. [0098] 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. [0099] 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. [0100] 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. [0101] 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. [0102] The compositions comprising the compound (s) can be formulated in a unit dosage form, each dosage containing from about 5 to about 1,000 mg (1 g), more usually about 100 mg to about 500 mg, of the active ingredient. [0103] In some embodiments, the compositions provided herein contain from about 5 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 5 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. [0104] 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 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.   [0105] 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. [0106] 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. [0107] 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. [0108] The term "patient" includes human and non-human animals such as companion animals (dogs and cats and the like) and livestock animals. Livestock animals are animals raised for food production. The patient to be treated is preferably a mammal, in particular a human being. [0109] 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.   [0110] 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. [0111] 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. [0112] 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. 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. [0113] Compound screening and structure-activity relationship (SAR) [0114] To evaluate the impact of substitution at C6 of the imidazo[1,2-b] pyridazine core, compound 1 was synthesized with and without a substitution at the C6 position and the differences in activity were compared. A kinase screening of the initial compounds at 100 nM was carried out against TAK1 utilizing the ADP-Glo™ Kinase Assay. Preliminary data suggested that compound 3, containing a cis-dimethyl morpholine moiety, showed the best inhibition of TAK1 (95%) compared to the compound with no substituent (1, 26% inhibition), the unsubstituted morpholine moiety (2, 91% inhibition), or the piperidine substituent (4, 46% inhibition). A SAR study was evaluated based on compound 3.   [0115] SAR: [0116] Molecular docking studies of compound 3 and takinib against TAK1 (FIGs. 2A-2B) were performed to investigate the potential binding mode of preliminary compounds. It was found that the oxygen in the cis-dimethyl morpholine interacts with the conserved lysine residue Lys-63 in the ATP-binding site of TAK1 (FIGs.2A-2B), which is crucial for kinase activity as observed in the kinase inhibition data for compounds 2 and 3. The methyl groups of the morpholine formed favorable hydrophobic interactions with the surrounding residues, Cys-174, Lys-63, and Gly-45. In addition, a hydrogen bonding interaction between Ala-107 and H2 of the imidazo[1,2-b] pyridazine core was identified. Blocking this position with a methyl group at position 2 of the imidazo[1,2-b] pyridazine (as in compound 28) would sterically hinder this hydrogen bonding and lead to reduced activity, vide infra. [0117] Three types of compound 3 analogs were synthesized where series A explores the use of phenyl derivatives in place of the indazole, series B examines indazole derivatives, and series C evaluates the effect of modifying the morpholine moiety. In series A, the use of substituted phenyls and pyridine rings was explored in place of the indazole as found in compound 3. Specifically, compounds were synthesized with privileged moieties, such as nitrile, halides, -OCF3, and -CF3, at the C3 position. These groups are known to enhance the potency of a drug by increasing its binding affinity to the target protein and improve the pharmacokinetic properties of a drug by increasing its lipophilicity, which can enhance its membrane permeability and metabolic stability. The use of a pyridine ring (bioisosteres of phenyl (5) at this position (compounds 17 and 18)) was explored, as the presence of nitrogen in a drug enhances solubility and could act as a hydrogen bond donor. Additionally, substituents such as cyano on the phenyl were tested (compounds 14, 16 and 19) as their polarity, electron-withdrawing, and hydrogen-bonding ability are known to improve the potency and selectivity of a drug by enhancing its binding affinity to the target protein or receptor. Compounds 8 and 15 were made with sulfonyl and sulfonamide groups, which can enhance the metabolic stability of drugs (compared to amides) by resisting enzymatic degradation. [0118] Different indazole derivatives in series B were explored. In this series, analogs with

different indazole derivatives attached to the imidazo[1,2-b] pyridazine core scaffold at positions C4, C5, and C7 of the indazole (compounds 20, 21, and 22) were synthesized. Methylated analogs   (compounds 23 and 24) at the 1H-position of compounds 21 and 20, respectively, were also synthesized. Based on the activity of compound 3, compounds 25 and 26 were synthesized, as they could potentially improve the interactions within the protein site. The introduction of different indazole derivatives at the C3 position of the imidazo[1,2-b] pyridazine scaffold was expected to modulate the steric and electronic properties of the molecule, which, in turn, could affect its interactions with the target protein kinase.

[0119] T e ntroduct on o t e morp o ne at C6 o t e m dazo[1,2-b] pyr daz ne core mproved TAK1 kinase inhibition when compared to compound 1, which has no substitution at C6 position, and compound 4, which has a piperazine moiety at C6. For series C, analogs of compound 3 were made, exploring the substitution of different substituted morpholine moieties at the C6 position. Morpholines in drugs are known to enhance the water solubility and metabolic stability of a drug and improve its bioavailability. Morpholines can also be used to enhance the receptor binding affinity of a drug by engaging in additional hydrogen-bonding interactions with the protein target. This can improve the potency and selectivity of the drug, as well as reduce its off-target effects. As the cis-dimethyl morpholine analog showed higher inhibition compared to the unsubstituted morpholine (2), analogs of 3 were made by exploring the substitution of different substituted morpholines at the C6 position.

 

[0120] Table 1 shows the IC50 values against TAK 1. Table 1 Compound No. TAK1 IC₅₀ (M) 25 7.98E-08

  [0121] Assays: [0122] Cell viability assays MPC-11 and H929 the myeloma cell lines were used. MPC-11 cells were maintained in DMEM with 10% FBS and H292 cells were maintained in RPMI with 10% heat-inactivated FBS. All cells were cultured at 37°C in a humidified atmosphere containing 5% CO2.4-5x10³ cells were seeded in 96-well plates and incubated for 24 hours. Cells were then treated with various concentrations of indicated compounds for 72 hours. After the indicated period of treatment, CellTiter-Blue cell viability assay reagent (Promega®) was added, and the cells were incubated for 3 hours. Fluorescence (λex/em = 560/590 nm) of each well was quantified via Biotek Cytation 5 multi- mode reader. Experiments were performed in triplicates, with data reported as the mean and standard deviation of three data points. Readings from treated groups were normalized to cells treated with DMSO. [0123] Evaluation of pTAK1 levels in MPC-11 cells via Western blot MPC-11 cells (0.5-1 x 10⁶) were seeded in 6-well plates. After 24 hours, cells were treated with compounds 26, 3, and Takinib for 48 hours. Cells were then lysed with RIPA lysis buffer (50 mM Tris (pH 7.4), 150 mM NaCl, 1% Triton X-100, 0.1% sodium dodecyl sulfate (SDS), 0.5% sodium deoxycholate) with protease inhibitor cocktail and 1 mM phenylmethylsulfonyl fluoride. Cells were centrifuged, and the supernatant was collected into new 1.5 mL Eppendorf tubes. The protein assay Kit was used to quantify total protein. Next, the proteins were separated using 10% SDS polyacrylamide gel electrophoresis and transferred to a polyvinylidene difluoride (PVDF) membrane. The membrane was probed with pTAK1, TAK1, and β-actin antibodies overnight at 4 °C. After overnight incubation, the membrane was washed and further incubated with the corresponding horseradish peroxidase (HRP)-conjugated secondary antibodies at 24 °C for 2 hours. SuperSignal™ West Pico PLUS Chemiluminescent Substrate was used for signal detection on the Azure 300 imaging system. All antibodies were purchased from Cell Signaling Technology. [0124] Efficacy experiment The RPMI-8226 tumor cells are cultured in RPMI1640 medium supplemented with 10% heat- inactivated fetal bovine serum, 100U/ml penicillin and 100 µg/ml streptomycin at 37 ℃ in an atmosphere of 5% CO2 in air. The cells growing in an exponential growth phase were harvested and counted for tumor inoculation. Each mouse was inoculated subcutaneously at the right flank with the RPMI-8226 tumor cells (1e⁷ per mouse) in 0.1 mL RPMI 1640 medium with 50% matrigel for tumor development. Eighteen animals were randomized using block randomization by Excel based upon their tumor volume (around 100 mm³). This ensured that all the groups were   comparable at the baseline. Tumor volume was measured three times per week in two dimensions using a caliper, and the volume was expressed in mm³ using the formula: V = 0.5 a x b², where a and b are the long and short diameters of the tumor, respectively. [0125] Cytokine Analysis Using ELISA The levels of pro-inflammatory cytokines IL-6 and TNF-α are measured using ELISA kits from RayBiotech. THP-1 cells are seeded at a density of 1x10⁵/well and treated with 50 ng/mL PMA (phorbol 12-myristate 13-acetate) for 24 hours to differentiate them into macrophages. After 24 hours, the PMA-containing medium was replaced with PMA-free medium, and the cells were incubated for another 24 hours to allow them to stabilize. Differentiated THP-1 macrophages were treated with TAK1 inhibitors following the stimulation with 100 nM LPS to induce cytokine production. After 24 hours of LPS stimulation and treatment, the supernatants were collected. ELISA plates were coated with specific antibodies for TNF-α and IL-6. Supernatants were added to the wells and protocol was performed. The intensity of the color was measured at 450 nm using a plate reader (Fig.15). [0126] Results: [0127] The compounds were screened against TAK1 using the ADP-Glo Kinase Assay (Promega®) at a compound concentration of 500 nM (FIG.3). The best-performing compounds were identified as exhibiting over 50% inhibition at 500 nM. Then, these compounds were subjected to further screening at a concentration of 100 nM. The remaining compounds, which had >50% inhibition at 100 nM, were screened at a concentration of 20 nM (FIG.3). [0128] To evaluate the significance of kinase inhibition, a cutoff value of 50% was used to classify compounds as having good kinase inhibition or not. At 500 nM screening, 16 compounds out of the 35 demonstrated good kinase inhibition, surpassing the 50% cutoff. Notably, compounds 3, 25, 26, 31, and 33 exhibited exceptional potency, achieving 100% kinase inhibition. Conversely, all the compounds in series A apart from 12 (74%) showed less than 50% kinase inhibition, with compounds 6, 7, 8, 9, 13, 14, 16, and 17 showing moderate kinase inhibition. Compounds 5, 11, 18, and 19 exhibited negligible kinase inhibition. Additionally, compounds 21, 22, 24, 27, and 28 in Series B also showed moderate kinase inhibition below the 50% cutoff. These compounds may not effectively target the kinase of interest but may still have some inhibitory potential with further modifications. The compounds demonstrating kinase inhibition above 50% were subjected to a second round of screening at a lower concentration of 100 nM. Comparing the kinase inhibition at 100 nM to the previous screening at 500 nM, some compounds showed consistent inhibition,   while others demonstrated variations in their inhibitory activities. Notably, compounds 2, 3, 25, 26, 31, 32, 33, and 35 continued to exhibit significant TAK1 kinase inhibition above the 50% cutoff, indicating their consistent inhibitory potential. Compounds 4 and 12 showed a decrease in TAK1 kinase inhibition compared to the previous screening, suggesting a potential concentration- dependent effect. Again, all compounds in the series, i.e., compounds 29-35, exhibited excellent TAK1 kinase inhibition. [0129] An enzymatic IC50 reaction was performed to confirm in-house kinase assay results on the top ten compounds, and Takinib was used as control. The results showed that compound 26 was the most potent TAK1 inhibitor, with an IC50 value of 55 nM, while under similar experimental conditions, the IC₅₀ for the known TAK1 inhibitor, Takinib, was 187 nM. Additionally, six of the ten analogs tested also had a lower IC50 than Takinib (FIG.4). Studies have shown that TAK1 is overexpressed in many multiple myeloma cells. The performance of these compounds in cell culture was investigated by exploring the effect of the compounds on MM cell growth inhibition (FIG.5). Compounds were screened at 1 and 0.2 µM against the MPC-11 cell line. [0130] The compounds showed a relative consistency between activity against TAK1 and antiproliferative activity against multiple myeloma cells. All compounds in Series compounds 29- 35 showed excellent inhibitory activity against TAK1, and, with the exception of compound 33, had significant cellular growth inhibition. It is interesting to note that compounds 32 and 33 are enantiomers and show similar TAK1 inhibitions but display different cellular activities. Compound 32 inhibited ~50% of MPC-11 at 200 nM, while at the same concentrations, compound 33 was inactive. Before a compound can engage with cellular targets, it has to get into the cell, and differences in permeation and/or compound stability might account for such differences. [0131] Based on cell growth inhibition results, GI₅₀ values of the top compounds collected to evaluate their effectiveness (FIGs. 6A and 6B). The GI50 values of these compounds were determined against two distinct multiple myeloma (MM) cell lines: H929, a human plasma MM cell line, and MPC-11, a murine plasmacytoma cell line. All the top compounds demonstrated remarkable potency against the H929 cells, with compound 31 exhibiting the most exceptional activity, recording a GI50 value of 0.024 μM (24 nM). The lead compounds 3 and 25 displayed GI₅₀ values of 0.087 μM (87 nM) and 0.030 μM (30 nM), respectively, indicating their high efficacy against the H929 cells. In comparison, takinib, a known Tak-1 inhibitor, exhibited a significantly higher GI₅₀ value of 51 μM (51000 nM), making it over 500 times less effective than the least active compound 3 (GI50 = 0.087 μM). [0132] Similarly, the evaluation of these top compounds against the MPC-11 cells demonstrated promising results, with all compounds exhibiting favorable GI50 values ranging from 0.041 μM   (compound 26) to 0.155 μM (compound 29). Once again, Takinib proved to be substantially less potent with a GI₅₀ value of 8.5 μM against the MPC-11 cells. These findings highlight the outstanding potential of the identified compounds as potent inhibitors against both human and murine MM cell lines. Notably, their efficacy against the H929 cells, particularly compound 31, stands out as a highly promising avenue for further investigation. [0133] The phosphorylation of TAK1 in samples of murine MM MPC-11 cells was investigated and compared (FIG. 7). The results showed that both compounds 3 and 26 were successful in reducing levels of phosphorylated TAK1 compared to DMSO control. Treating with 0.5 µM of compound decreased phosphorylation levels more significantly than treatment at 0.1 µM. Additionally, Takinib did not show a significant difference in phosphorylated TAK1 levels at 0.1 or 0.5 µM. [0134] In vivo efficacy: PK analysis in mice indicated that the morpholine-containing compounds are orally bioavailable. Based on the PK data, the compounds were therefore evaluated in vivo. Evaluation of a model compound, compound 33, indicated that, when dosed orally at 15 mg/Kg, the compound was able to reduce the size of RPMI-8226 subcutaneous xenograft (see FIG.8). [0135] Experimental General methods for synthesis and characterization of compounds All reactions utilizing air-sensitive or moisture-sensitive reagents were performed in dried glassware under an atmosphere of argon (Ar), using commercially purchased solvents and reagents without further purification unless otherwise noted. ¹H NMR(500 MHz) and ¹³C NMR(126 MHz) spectra were recorded using a Bruker AV-III-500-HD NMR (Bruker, USA), Coupling constants were reported in Hertz, and peak shifts are reported in δ (ppm) relative to CDCl₃ (¹H 7.26 ppm, ¹³C 77.16 ppm), CD₃OD (¹H 3.31 ppm, ¹³C 49.00 ppm), dimethyl sulfoxide (DMSO)-d6 (¹H 2.50 ppm, ¹³C 39.52 ppm) using Me4Si as an internal standard.¹H NMR data were reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant (Hz), and integration). Multiplicities are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, or combinations thereof. High-resolution mass spectroscopy (HRMS) spectra were recorded using the electron spray ionization (ESI) technique and TOF mass analysis on LTQ Orbitrap (Research Instrumentation Center in the Department of Chemistry at Purdue University). All the synthesized compounds were characterized using ¹H and ¹³C NMR and HRMS data.   [0136] General procedure for the synthesis of substituted imidazo[1,2-b] pyridazine substrates: In a sealed tube 3-Bromo-6-chloroimidazo[1,2-b] pyridazine (500 mg) and appropriate amine (4 equiv.) in n-propanol (1 mL), refluxed at 150 °C overnight. After completion, the reaction was extracted with ethyl acetate and washed with brine. The organic layer was collected, dried over sodium sulfate, and concentrated under reduced pressure. The crude was purified via silica gel column chromatography to yield the desired product. [0137] Suzuki Cross-Coupling Synthesis of Compound 3 and Analogs: A solution of (2S,6R)-4-(3-bromoimidazo[1,2-b] pyridazin-6-yl)-2,6-dimethyl morpholine (0.5 mmol), respective boronic acid substrates, Pd(dppf)₂Cl₂ (5 mol%), K₂PO₄ (3.5 equiv.) in degassed acetonitrile (3 mL) and water (1 mL) was stirred at 160 °C in a sealed microwave vial for 30 minutes in a microwave oven. The organic layer was collected after workup with water and ethyl acetate, and the organic layer was washed with brine, followed by concentration under a rotary evaporator and purification by silica gel column chromatography to obtain the final product. [0138] General procedure for amination:

In a 20 mL microwave vial 3-bromo-6-chloroimidazo[1,2-b]pyridazine (1 mmol) was dissolved in 1-propanol (2 mL) followed by addition of 1.2 equiv. of amine and 3 equiv of TEA. Reaction was stirred at 100 °C for two hours. After completion, the reaction was concentrated and purified via flash column chromatography using ethyl acetate: hexanes (80:20) to yield the desired product. [0139] General procedure for the Suzuki Coupling via boronic ester formation: A solution of bromo indazole substrate (1equiv), bis(pinacolato) diboron (1.05 equiv.), potassium acetate (3 equiv.), 1,1- [Bis(diphenylphosphino)ferrocene]-dichloropalladium (II) (5 mol%) and 1,4 dioxane (5 mL) was stirred at 100 ^C in a sealed microwave vial for 20 h. After stirring for 20 hours, the reaction mixture was cooled to room temperature and was concentrated under vacuum. This boronic ester substrate extract was further reacted with bromo substrate (1 equiv), Pd(dppf)Cl₂ ^DCM (10 mol%), Cs₂CO₃ (1.5 equiv), K₃PO₄ (1.5 equiv) and 0.5 mL water in degassed 1,4 dioxane (5 mL) was stirred at 130 ^C in a sealed microwave vial for 16 h. After completion the reaction was extracted with ethyl acetate and water. The organic   phase was concentrated and purified via flash silica gel column chromatography to yield the desired product. [0140] Example 1: 3-(3-methyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazine (1) Pale yellow solid (69 mg, 49%). ¹H NM

z, Methanol-d4) δ 8.58 – 8.52 (m, 2H), 8.09 (s, 1H), 8.05 (dd, J = 9.2, 1.7 Hz, 1H),7.99 (dd, J = 8.8, 1.6 Hz, 1H), 7.55 (dd, J = 8.7, 0.9 Hz, 1H), 7.25 (dd, J = 9.2, 4.4 Hz, 1H), 2.60 (s, 3H). ¹³C NMR (126 MHz, Methanol-d4) δ 143.5, 142.8, 140.6, 139.7, 130.9, 129.1, 126.2, 124.9, 122.2, 120.3, 118.4, 117.1, 110.0, 10.3. HRMS (ESI) m/z calcd for C14H11N5 [M+H]⁺ 250.1093, found 250.1090. [0141] Example 2: 4-(3-bromoimidazo[1,2-b]pyridazin-6-yl)morpholine (Substrate (S)1) Brown solid (552 mg, 87%) ¹H NM

, ol-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. [0142] Example 3: 4-(3-(3-methyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine (2)

  Synthesized using substrate S1. Brown solid (95 mg, 50%).¹H NMR (500 MHz, Methanol-d4) δ 8.60 – 8.56 (m, 1H), 7.93 (dd, J = 8.8, 1.6 Hz, 1H), 7.84 (s, 1H), 7.75 (d, J = 9.9 Hz, 1H), 7.49 (dd, J = 8.8, 0.8 Hz, 1H), 7.09 (d, J = 9.9 Hz, 1H), 3.86 – 3.78 (m, 4H), 3.57 – 3.48 (m, 4H), 2.55 (d, J = 2.3 Hz, 4H).¹³C NMR (126 MHz, DMSO-d₆) δ 155.4, 142.2, 140.3, 137.3, 130.9, 128.0, 126.7, 125.3, 122.7, 121.0, 117.5, 110.7, 109.9, 66.2, 46.7, 12.1. HRMS (ESI) m/z calcd for C₁₈H₁₈N₆O [M+H]⁺ 335.1621, found 335.1621. [0143] Example 4: (2S,6R)-4-(3-Bromoimidazo[1,2-b] pyridazin-6-yl)-2,6-dimethylmorpholine (S2) Pale yellow solid (640 mg, 95%).

loroform-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. [0144] Example 5: (2S,6R)-2,6-dimethyl-4-(3-(3-methyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6- yl)morpholine (3) Synthesized using substrate S2. Off-

w te so ( mg, 42%). ¹H NMR (500 MHz, Methanol- d₄) δ 8.69 (dd, J = 1.6, 0.8 Hz, 1H), 7.86 (dd, J = 8.8, 1.6 Hz, 1H), 7.84 (s, 1H), 7.69 (d, J = 9.8 Hz, 1H), 7.46 (dd, J = 8.8, 0.9 Hz, 1H), 7.06 (d, J = 10.0 Hz, 1H), 3.97 – 3.90 (m, 2H), 3.73 (dqd, J = 12.4, 6.2, 2.4 Hz, 2H), 2.57 – 2.51 (m, 2H), 2.51 (s, 3H), 1.22 (d, J = 6.3 Hz, 6H). ¹³C NMR (126 MHz, Methanol-d4) δ 154.9, 142.5, 140.2, 137.0, 128.8, 128.2, 125.6, 124.8, 122.0, 121.0, 117.2, 109.9, 71.3, 51.4, 17.8, 10.5. HRMS (ESI) m/z calcd for C₂₀H₂₂N₆O [M+H]⁺ 363.1928, found 363.1939. [0145] Example 6:   3-Bromo-6-(4-(2-methoxyethyl)piperazin-1-yl)imidazo[1,2-b]pyridazine (S3) Off-white solid (583 mg, 79%).

anol-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. [0146] Example 7: 6-(4-(2-methoxyethyl)piperazin-1-yl)-3-(3-methyl-1H-indazol-5-yl)imidazo[1,2- b]pyridazine (4) Synthesized using substrate S

, H NMR (500 MHz, Methanol-d4) δ 8.54 (dd, J = 1.6, 0.8 Hz, 1H), 7.86 (dd, J = 8.8, 1.6 Hz, 1H), 7.78 (s, 1H), 7.64 (d, J = 9.9 Hz, 1H), 7.44 (dd, J = 8.8, 0.9 Hz, 1H), 6.98 (d, J = 9.9 Hz, 1H), 3.55 (t, J = 5.5 Hz, 2H), 3.54 – 3.48 (m, 4H), 3.34 (s, 3H), 2.65 – 2.62 (m, 4H), 2.60 (d, J = 5.5 Hz, 2H), 2.50 (s, 3H).¹³C NMR (126 MHz, Methanol-d4) δ 154.8, 142.5, 140.2, 136.8, 128.8, 128.3, 125.6, 124.7, 122.0, 121.0, 117.4, 110.0, 109.9, 69.5, 57.6, 57.2, 52.6, 45.5, 10.3. HRMS (ESI) m/z calcd for C₂₁H₂₅N₇O [M+H]⁺ 392.2199, found 392.2202. [0147] Example 8: (2S,6R)-2,6-dimethyl-4-(3-phenylimidazo[1,2-b]pyridazin-6-yl)morpholine (5)

  Synthesized using substrate S2. Off-white solid (241 mg, 81%). ¹H NMR (500 MHz, Methanol- d₄) δ 8.05 (dd, J = 8.4, 1.2 Hz, 2H), 7.80 (s, 1H), 7.72 (d, J = 9.9 Hz, 1H), 7.44 (dd, J = 8.5, 7.1 Hz, 2H), 7.36 – 7.29 (m, 1H), 7.11 (d, J = 10.0 Hz, 1H), 4.01 – 3.94 (m, 2H), 3.72 (dqd, J = 10.6, 6.2, 2.4 Hz, 2H), 2.57 (dd, J = 12.9, 10.6 Hz, 2H), 1.22 (d, J = 6.3 Hz, 6H).¹³C NMR (126 MHz, Methanol-d4) δ 154.8, 137.1, 129.4, 128.9, 128.2, 128.2, 127.3, 126.2, 125.0, 110.5, 71.2, 51.4, 17.7. HRMS (ESI) m/z calcd for C₁₈H₂₀N₄O [M+H]⁺ 309.1715, found 309.1718. [0148] Example 9: 4-(6-((2S,6R)-2,6-dimethylmorpholino)imidazo[1,2-b]pyridazin-3-yl)benzonitrile (6) Synthesized using substrate S2. Off

, 77%).¹H NMR (500 MHz, Methanol- d₄) δ 8.32 – 8.25 (m, 2H), 7.99 (s, 1H), 7.78 (dd, J = 9.3, 8.4 Hz, 3H), 7.22 (d, J = 10.0 Hz, 1H), 4.05 – 3.98 (m, 2H), 3.76 (dqd, J = 12.6, 6.2, 2.4 Hz, 2H), 2.63 (dd, J = 12.8, 10.6 Hz, 2H), 1.26 (d, J = 6.2 Hz, 6H).¹³C NMR (126 MHz, Methanol-d₄) δ 155.1, 138.1, 133.5, 132.1, 131.2, 126.2, 126.0, 125.2, 118.4, 111.5, 109.9, 71.3, 51.3, 17.7. HRMS (ESI) m/z calcd for C19H19N5O [M+H]⁺ 334.1668, found 334.1671. [0149] Example 10: (2S,6R)-2,6-dimethyl-4-(3-(4-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6- yl)morpholine (7) Synthesized using substrate S2. Pale

yellow solid (248 mg, 68%).¹H NMR (500 MHz, Methanol- d₄) δ 8.34 – 8.28 (m, 2H), 7.97 (s, 1H), 7.81 (d, J = 9.9 Hz, 1H), 7.78 – 7.72 (m, 2H), 7.23 (d, J = 10.0 Hz, 1H), 4.04 (ddd, J = 12.0, 2.3, 1.0 Hz, 2H), 3.78 (dqd, J = 10.5, 6.2, 2.4 Hz, 2H), 2.65 (dd, J = 12.9, 10.6 Hz, 2H), 1.26 (d, J = 6.2 Hz, 6H). ¹³C NMR (126 MHz, Methanol-d₄) δ 155.1, 137.8, 132.8, 130.6, 128.8, 128.5, 126.7, 126.2, 125.2, 125.1, 111.3, 71.3, 51.4, 17.7. HRMS (ESI) m/z calcd for C₁₉H₁₉F₃N₄O [M+H]⁺ 377.1589, found 377.1590.   [0150] Example 11: (2S,6R)-2,6-dimethyl-4-(3-(3-(methylsulfonyl)phenyl)imidazo[1,2-b]pyridazin-6- yl)morpholine (8) Synthesized using substrate S2. Pal

, 68%).¹H NMR (500 MHz, Methanol- d₄) δ 9.25 (t, J = 1.8 Hz, 1H), 8.23 (ddd, J = 7.9, 1.8, 1.0 Hz, 1H), 8.05 (s, 1H), 7.89 (ddd, J = 7.8, 1.9, 1.1 Hz, 1H), 7.81 (d, J = 10.0 Hz, 1H), 7.71 (t, J = 7.9 Hz, 1H), 7.24 (d, J = 10.0 Hz, 1H), 4.11 (dt, J = 12.1, 2.2 Hz, 2H), 3.78 (dqd, J = 10.5, 6.2, 2.4 Hz, 2H), 3.16 (s, 3H), 2.63 (dd, J = 12.9, 10.6 Hz, 2H), 1.29 (d, J = 6.3 Hz, 6H).¹³C NMR (126 MHz, Methanol-d4) δ 155.1, 141.2, 137.8, 130.4, 130.4, 130.3, 129.4, 125.9, 125.5, 125.2, 123.9, 110.9, 71.5, 51.2, 43.2, 17.7. HRMS (ESI) m/z calcd for C19H22N4O3S [M+H]⁺ 387.1491, found 387.1493. [0151] Example 12: (2S,6R)-4-(3-(4-fluorophenyl) imidazo[1,2-b]pyridazin-6-yl)-2,6-dimethylmorpholine (9) Synthesized using substrate S2. Yel

ow so ( mg, 9%).¹H NMR (500 MHz, Methanol-d4) δ 8.10 – 8.02 (m, 2H), 7.78 (s, 1H), 7.73 (d, J = 9.9 Hz, 1H), 7.22 – 7.14 (m, 2H), 7.13 (d, J = 9.9 Hz, 1H), 4.01 – 3.94 (m, 2H), 3.73 (dqd, J = 10.5, 6.2, 2.4 Hz, 2H), 2.58 (dd, J = 12.9, 10.6 Hz, 2H), 1.23 (d, J = 6.3 Hz, 6H). ¹³C NMR (126 MHz, DMSO-d₆) δ 162.6, 160.7, 155.0, 137.5, 131.4, 128.4, 128.3, 126.7, 126.5, 126.1, 116.1, 115.9, 110.6, 71.1, 51.5, 19.2. HRMS (ESI) m/z calcd for C18H19FN4O [M+H]⁺ 327.1621, found 327.1623. [0152] Example 13: (2S,6R)-4-(3-(4-chlorophenyl)imidazo[1,2-b]pyridazin-6-yl)-2,6-dimethylmorpholine (10)   Synthesized using substrate S2. Y ).¹

H NMR (500 MHz, Methanol-d4) δ 8.08 – 8.01 (m, 2H), 7.83 (s, 1H), 7.74 (d, J = 9.9 Hz, 1H), 7.48 – 7.40 (m, 2H), 7.15 (d, J = 9.9 Hz, 1H), 3.98 (ddd, J = 12.1, 2.3, 1.0 Hz, 2H), 3.74 (dqd, J = 10.5, 6.2, 2.4 Hz, 2H), 2.59 (dd, J = 12.9, 10.6 Hz, 2H), 1.24 (d, J = 6.3 Hz, 6H).¹³C NMR (126 MHz, Methanol-d₄) δ 154.9, 137.4, 132.8, 129.6, 128.3, 127.6, 127.5, 127.0, 125.0, 110.7, 71.3, 51.4, 17.7. HRMS (ESI) m/z calcd for C₁₈H₁₉ClN₄O [M+H]⁺ 343.1326, found 343.1331. [0153] Example 14: (2S,6R)-2,6-dimethyl-4-(3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6- yl)morpholine (11) Synthesized using substrate S2. Y

g, ).¹H NMR (500 MHz, Methanol-d₄) δ 8.22 – 8.15 (m, 2H), 7.87 (s, 1H), 7.77 (d, J = 10.0 Hz, 1H), 7.37 (ddt, J = 7.9, 2.1, 1.0 Hz, 2H), 7.18 (d, J = 9.9 Hz, 1H), 4.01 (ddd, J = 12.1, 2.3, 1.0 Hz, 2H), 3.76 (dqd, J = 10.4, 6.2, 2.4 Hz, 2H), 2.62 (dd, J = 12.9, 10.6 Hz, 2H), 1.24 (d, J = 6.2 Hz, 6H). ¹³C NMR (126 MHz, Methanol- d₄) δ 155.0, 148.2, 129.8, 128.1, 127.7, 126.9, 125.1, 121.6, 120.7, 119.6, 110.9, 71.3, 51.4, 17.7. HRMS (ESI) m/z calcd for C19H19F3N4O2 [M+H]⁺ 393.1538, found 393.1539. [0154] Example 15: 2-(4-(6-((2S,6R)-2,6-dimethylmorpholino)imidazo[1,2-b]pyridazin-3-yl)phenyl)acetonitrile (14)   Synthesized using substrate S2. O 6 ¹

%). H NMR (500 MHz, Methanol- d₄) δ 8.07 – 8.01 (m, 2H), 7.80 (s, 1H), 7.68 (d, J = 9.9 Hz, 1H), 7.42 – 7.36 (m, 2H), 7.06 (d, J = 10.0 Hz, 1H), 3.91 (d, J = 14.4 Hz, 4H), 3.69 (dqd, J = 10.6, 6.2, 2.4 Hz, 2H), 2.52 (dd, J = 12.8, 10.6 Hz, 2H), 1.21 (d, J = 6.3 Hz, 6H).¹³C NMR (126 MHz, Methanol-d₄) δ 153.3, 135.7, 128.5, 128.1, 127.0, 126.3, 125.8, 124.9, 123.4, 116.6, 109.0, 69.7, 49.8, 20.2, 16.2. HRMS (ESI) m/z calcd for C₂₀H₂₁N₅O [M+H]⁺ 348.1824, found 348.1815. [0155] Example 16: 4-(6-((2S,6R)-2,6-dimethylmorpholino)imidazo[1,2-b]pyridazin-3-yl)benzenesulfonamide (15) Synthesized using substrate S2. O

g, 2%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.34 (d, J = 8.6 Hz, 2H), 8.12 (s, 1H), 7.96 (d, J = 9.9 Hz, 1H), 7.90 (d, J = 8.6 Hz, 2H), 7.37 (s, 2H), 7.28 (d, J = 10.0 Hz, 1H), 4.08 – 4.02 (m, 2H), 3.69 (dqd, J = 12.4, 6.1, 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-d6) δ 155.2, 142.5, 138.3, 132.8, 132.7, 126.8, 126.5, 126.1, 126.0, 111.3, 71.2, 51.5, 19.2. HRMS (ESI) m/z calcd for C18H21N5O3S [M+H]⁺ 388.1443, found 388.1441. [0156] Example 17: 5-(6-((2S,6R)-2,6-dimethylmorpholino)imidazo[1,2-b]pyridazin-3-yl)-2-fluorobenzonitrile (16)   ol- J = Hz,

2H), 3.80 (dqd, J = 10.5, 6.2, 2.4 Hz, 2H), 2.65 (dd, J = 12.9, 10.7 Hz, 2H), 1.29 (d, J = 6.3 Hz, 6H).¹³C NMR (126 MHz, Methanol-d4) δ 162.6, 160.6, 155.0, 137.6, 132.7, 132.6, 130.3, 130.1, 126.6, 125.2, 124.9, 116.6, 116.4, 113.4, 111.1, 100.9, 100.8, 71.3, 71.2, 51.3, 17.7. HRMS (ESI) m/z calcd for C19H18FN5O [M+H]⁺ 352.1574, found 352.1571. [0157] Example 18: (2S,6R)-2,6-dimethyl-4-(3-(pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine (17) Synthesized using substrate S2. O

g, 9%). ¹H NMR (500 MHz, Methanol- d4) δ 8.56 – 8.51 (m, 2H), 8.15 – 8.10 (m, 2H), 8.09 (s, 1H), 7.76 (d, J = 10.0 Hz, 1H), 7.21 (d, J = 10.0 Hz, 1H), 3.99 (ddd, J = 12.1, 2.3, 1.0 Hz, 2H), 3.75 (dqd, J = 10.4, 6.2, 2.4 Hz, 2H), 2.62 (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, 148.9, 138.6, 137.3, 131.9, 125.2, 124.8, 119.7, 111.7, 71.2, 51.3, 17.7. HRMS (ESI) m/z calcd for C₁₇H₁₉N₅O [M+H]⁺ 310.1668, found 310.1668. [0158] Example 19: (2S,6R)-2,6-dimethyl-4-(3-(pyridin-3-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine (18)

  Synthesized using substrate S2. Off-white solid (227 mg, 78%).¹H NMR (500 MHz, Methanol- d₄) δ 9.28 (d, J = 2.4 Hz, 1H), 8.48 – 8.39 (m, 2H), 7.92 (d, J = 2.0 Hz, 1H), 7.73 (dd, J = 10.0, 2.0 Hz, 1H), 7.49 (ddd, J = 7.7, 5.0, 2.0 Hz, 1H), 7.15 (dd, J = 10.0, 2.0 Hz, 1H), 3.95 (dd, J = 13.2, 2.5 Hz, 2H), 3.77 – 3.67 (m, 2H), 2.56 (td, J = 11.7, 2.1 Hz, 2H), 1.23 (d, J = 6.3 Hz, 6H). ¹³C NMR (126 MHz, Methanol-d4) δ 155.0, 147.1, 145.9, 137.7, 133.8, 130.1, 126.0, 125.1, 124.6, 123.8, 111.2, 71.2, 51.2, 17.7. HRMS (ESI) m/z calcd for C₁₇H₁₉N₅O [M+H]⁺ 310.1668, found 310.1667. [0159] Example 20: 3-(6-((2S,6R)-2,6-dimethylmorpholino)imidazo[1,2-b]pyridazin-3-yl)benzonitrile (19) Synthesized using substrate S2. Br

%). ¹H NMR (500 MHz, Methanol-d4) δ 8.66 – 8.61 (m, 1H), 8.23 – 8.17 (m, 1H), 7.93 (s, 1H), 7.76

– 7.64 (m, 1H), 7.64 – 7.51 (m, 2H), 7.15 (dt, J = 10.1, 1.9 Hz, 1H), 4.01 – 3.93 (m, 2H), 3.75 (dqd, J = 12.5, 6.2, 2.1 Hz, 2H), 2.60 (dd, J = 12.8, 10.5 Hz, 2H), 1.25 (d, J = 6.2 Hz, 6H). ¹³C NMR (126 MHz, DMSO-d₆) δ 154.8, 138.1, 132.4, 130.7, 130.4, 130.1, 130.0, 128.7, 126.6, 124.9, 119.2, 112.1, 110.9, 71.2, 71.0, 51.4, 19.1. HRMS (ESI) m/z calcd for C₁₉H₁₉N₅O [M+H]⁺ 334.1668, found 334.1667. [0160] Example 21: (2S,6R)-4-(3-(1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-2,6-dimethylmorpholine (20) Synthesized using substrate S2. Pal

e yellow solid (90 mg, 27%).¹H NMR (500 MHz, Methanol- d4) δ 8.57 (dd, J = 1.6, 0.8 Hz, 1H), 8.06 (d, J = 1.0 Hz, 1H), 7.99 (dd, J = 8.8, 1.6 Hz, 1H), 7.82 (s, 1H), 7.75 (d, J = 9.9 Hz, 1H), 7.61 (dt, J = 8.8, 1.0 Hz, 1H), 7.13 (d, J = 10.0 Hz, 1H), 4.02 (ddd, J = 12.1, 2.3, 1.0 Hz, 2H), 3.75 (dqd, J = 12.5, 6.2, 2.4 Hz, 2H), 2.61 (dd, J = 12.9, 10.6 Hz, 2H), 1.24 (d, J = 6.2 Hz, 6H). ¹³C NMR (126 MHz, Methanol-d4) δ 154.9, 139.5, 136.9, 134.0,   129.1, 128.6, 126.0, 125.0, 123.0, 121.8, 118.5, 110.3, 109.9, 71.2, 51.5, 17.7. HRMS (ESI) m/z calcd for C₁₉H₂₀N₆O [M+H]⁺ 349.1772, found 349.1785. [0161] Example 22: (2S,6R)-4-(3-(1H-indazol-6-yl)imidazo[1,2-b]pyridazin-6-yl)-2,6-dimethylmorpholine (21) Synthesized using substrate S2. Pa ¹

g, 33%). H NMR (500 MHz, DMSO- d₆) δ 8.50 (d, J = 1.5 Hz, 1H), 8.07 (d, J = 2.5 Hz, 2H), 7.95 (d, J = 9.9 Hz, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.72 (dd, J = 8.5, 1.4 Hz, 1H), 7.26 (d, J = 10.0 Hz, 1H), 4.11 – 4.04 (m, 2H), 3.71 (dqd, J = 12.4, 6.1, 2.2 Hz, 2H), 2.59 (dd, J = 12.8, 10.6 Hz, 2H), 1.20 (d, J = 6.2 Hz, 7H). ¹³C NMR (126 MHz, DMSO-d6) δ 155.1, 140.6, 137.9, 134.0, 132.1, 127.6, 127.1, 126.8, 122.2, 121.1, 119.7, 110.5, 106.9, 71.2, 51.6, 19.3. HRMS (ESI) m/z calcd for C₁₉H₂₀N₆O [M+H]⁺ 349.1772, found 349.1783. [0162] Example 23: (2S,6R)-4-(3-(1H-indazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)-2,6-dimethylmorpholine (22) Synthesized using substrate S2. Ye

ow so ( mg, %).¹H NMR (500 MHz, Methanol-d₄) δ 8.17 (s, 1H), 7.90 (s, 1H), 7.81 – 7.75 (m, 2H), 7.57 (d, J = 8.4 Hz, 1H), 7.47 (dd, J = 8.5, 7.1 Hz, 1H), 7.15 (d, J = 10.0 Hz, 1H), 3.96 – 3.89 (m, 2H), 3.67 (dqd, J = 12.4, 6.2, 2.2 Hz, 2H), 2.51 (dd, J = 12.9, 10.6 Hz, 2H), 1.16 (d, J = 6.2 Hz, 6H). ¹³C NMR (126 MHz, Methanol-d4) δ 154.7, 140.6, 137.2, 133.9, 130.8, 127.2, 126.4, 125.0, 121.4, 120.5, 120.0, 110.9, 109.6, 71.3, 51.2, 17.6. HRMS (ESI) m/z calcd for C₁₉H₂₀N₆O [M+H]⁺ 349.1772, found 349.1783. [0163] Example 24: (2S,6R)-2,6-dimethyl-4-(3-(1-methyl-1H-indazol-6-yl)imidazo[1,2-b]pyridazin-6- yl)morpholine (23)   Synthesized using substrate S2. 90%) ¹

. H NMR (500 MHz, Methanol- d₄) δ 8.57 (s, 1H), 7.98 (s, 1H), 7.96 (s, 1H), 7.77 – 7.71 (m, 2H), 7.68 (d, J = 8.6 Hz, 1H), 7.14 (dt, J = 10.0, 1.7 Hz, 1H), 4.03 – 3.95 (m, 5H), 3.77 (dtt, J = 12.4, 6.1, 3.6 Hz, 2H), 2.59 (t, J = 11.5 Hz, 2H), 1.24 (d, J = 6.2 Hz, 6H).¹³C NMR (126 MHz, Methanol-d4) δ 154.9, 139.8, 137.5, 132.2, 130.1, 127.4, 127.1, 124.8, 122.4, 120.7, 119.0, 110.3, 105.4, 71.2, 51.3, 34.1, 17.8. HRMS (ESI) m/z calcd for C20H22N6O [M+H]⁺ 363.1928, found 363.1932. [0164] Example 25: (2S,6R)-2,6-dimethyl-4-(3-(1-methyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6- yl)morpholine (24) Synthesized using substrate S2. Off

, 96%). ¹H NMR (500 MHz, Methanol- d₄) δ 8.50 (dd, J = 1.6, 0.8 Hz, 1H), 8.01 – 7.95 (m, 2H), 7.80 (s, 1H), 7.72 (d, J = 9.9 Hz, 1H), 7.57 (dt, J = 8.9, 0.9 Hz, 1H), 7.09 (d, J = 9.9 Hz, 1H), 4.07 (s, 3H), 3.97 (ddd, J = 12.0, 2.3, 1.0 Hz, 2H), 3.71 (ddt, J = 12.5, 6.2, 3.1 Hz, 2H), 2.56 (dd, J = 12.8, 10.6 Hz, 2H), 1.22 (d, J = 6.2 Hz, 6H). ¹³C NMR (126 MHz, Methanol-d4) δ 154.8, 139.1, 136.9, 132.8, 129.1, 128.3, 125.7, 124.9, 123.8, 121.7, 118.5, 110.2, 109.0, 71.2, 51.4, 34.3, 17.7. HRMS (ESI) m/z calcd for C20H22N6O [M+H]⁺ 363.1928, found 363.1934. [0165] Example 26: (2S,6R)-4-(3-(3-ethyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-2,6- dimethylmorpholine (25)   Synthesized using substrate S2. Off 25%).¹H NMR (500 MHz, DMSO-d6

) δ 8.85 (dd, J = 1.6, 0.8 Hz, 1H), 8.02 (s, 1H), 7.96 – 7.87 (m, 2H), 7.56 – 7.50 (m, 1H), 7.22 (d, J = 9.9 Hz, 1H), 4.10 – 4.03 (m, 2H), 3.72 (dqd, J = 12.3, 6.0, 2.2 Hz, 2H), 2.96 (q, J = 7.6 Hz, 2H), 2.58 (dd, J = 12.6, 10.5 Hz, 2H), 1.34 (t, J = 7.6 Hz, 3H), 1.18 (d, J = 6.2 Hz, 6H).¹³C NMR (126 MHz, DMSO-d6) δ 155.2, 147.5, 140.4, 137.5, 131.0, 127.9, 126.6, 125.4, 121.8, 121.1, 116.9, 111.0, 110.1, 71.2, 51.7, 20.3, 19.2, 14.1. HRMS (ESI) m/z calcd for C₂₁H₁₄N₆O [M+H]⁺ 377.2089, found 377.2089. [0166] Example 27: (2S,6R)-4-(3-(3-cyclopropyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-2,6- dimethylmorpholine (26) Synthesized using substrate S2. Pa

y g, 0%).¹H NMR (500 MHz, DMSO-d6) δ 8.83 (d, J = 1.2 Hz, 1H), 8.00 (s, 1H), 7.96 – 7.86 (m, 2H), 7.54 – 7.49 (m, 1H), 7.22 (d, J = 10.0 Hz, 1H), 4.10 – 4.04 (m, 2H), 3.71 (dqd, J = 12.3, 6.1, 2.2 Hz, 2H), 2.58 (dd, J = 12.7, 10.6 Hz, 2H), 2.27 (tt, J = 7.6, 6.1 Hz, 1H), 1.16 (d, J = 6.2 Hz, 6H), 1.03 – 0.96 (m, 4H). ¹³C NMR (126 MHz, DMSO-d6) δ 155.2, 147.3, 140.5, 137.5, 131.0, 127.9, 126.6, 125.6, 122.0, 121.1, 116.9, 111.0, 110.1, 71.2, 51.7, 19.2, 8.5, 7.9. HRMS (ESI) m/z calcd for C22H24N6O [M+H]⁺ 389.2089, found 389.2086. [0167] Example 28: (2S,6R)-4-(3-bromo-2-methylimidazo[1,2-b]pyridazin-6-yl)-2,6-dimethylmorpholine (S4)   Pale yellow solid (425 mg, 82%)

thanol-d₄) δ 7.56 (d, J = 9.8 Hz, 1H), 7.04 (d, J = 9.9 Hz, 1H), 4.00 (ddd, J = 12.1, 2.4, 1.1 Hz, 2H), 3.70 (dqd, J = 10.5, 6.2, 2.4 Hz, 2H), 2.51 (dd, J = 12.9, 10.6 Hz, 2H), 2.33 (s, 3H), 1.22 (d, J = 6.3 Hz, 6H).¹³C NMR (126 MHz, Methanol-d4) δ 154.9, 139.1, 136.0, 124.0, 110.2, 98.3, 71.3, 51.0, 17.7, 12.2. HRMS (ESI) m/z calcd for C13H17BrN4O [M+H]⁺ 325.2189, found 325.2186. [0168] Example 29: (2S,6R)-2,6-dimethyl-4-(2-methyl-3-(3-methyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6- yl)morpholine (28) Synthesized using substrate S4. Y

, %).¹H NMR (500 MHz, Methanol-d4) δ 8.04 (dd, J = 1.6, 0.9 Hz, 1H), 7.67 – 7.57 (m, 2H), 7.51 (dd, J = 8.7, 0.9 Hz, 1H), 6.99 (d, J = 9.9 Hz, 1H), 3.89 – 3.81 (m, 2H), 3.63 (dqd, J = 12.3, 6.1, 2.2 Hz, 2H), 2.52 (s, 3H), 2.50 – 2.38 (m, 5H), 1.13 (d, J = 6.2 Hz, 6H). ¹³C NMR (126 MHz, Methanol-d₄) δ 154.4, 142.3, 140.3, 138.1, 134.8, 127.9, 125.0, 123.9, 122.0, 120.7, 120.5, 109.8, 109.4, 71.3, 71.2, 51.3, 51.2, 17.7, 13.4, 10.3. HRMS (ESI) m/z calcd for C21H24N6O [M+H]⁺ 377.2089, found 377.2087. [0169] Example 30: (1R,4R)-5-(3-Bromoimidazo[1,2-b]pyridazin-6-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (S5) 1

Off-white solid (478 mg, 75%). H NMR (500 MHz, Methanol-d₄) δ 7.66 (d, J = 9.8 Hz, 1H), 7.45 (s, 1H), 6.86 (d, J = 9.8 Hz, 1H), 4.90 – 4.86 (m, 1H), 4.73–4.69 (m, 1H), 3.88 (s, 2H), 3.59 (dd, J = 10.0, 1.6 Hz, 1H), 3.48 – 3.42 (m, 1H), 2.06 – 1.96 (m, 2H); ¹³C NMR (126 MHz,   Methanol-d4) δ 153.3, 136.7, 130.3, 124.8, 111.0, 99.7, 76.2, 72.7, 57.2, 56.2, 35.9. HRMS (ESI) m/z calcd for C₁₁H₁₂BrN₄O [M+H]⁺ 295.0194, found 295.0193. [0170] Example 31: (1R,4R)-5-(3-(3-methyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-2-oxa-5- azabicyclo[2.2.1]heptane (29) Synthesized using substrate S5. Off ¹

4%). H NMR (500 MHz, Methanol-d4) δ 8.66 (s, 1H), 7.96 (dd, J = 8.8, 1.6 Hz, 1H), 7.84 (s, 1H), 7.75 (d, J = 9.8 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 6.88 (d, J = 9.8 Hz, 1H), 4.74 (d, J = 2.4 Hz, 1H), 3.98 (d, J = 7.6 Hz, 1H), 3.92 (dd, J = 7.6, 1.5 Hz, 1H), 3.66 (dd, J = 9.8, 1.5 Hz, 1H), 3.50 (d, J = 9.8 Hz, 1H), 2.57 (s, 3H), 2.11 – 1.94 (m, 2H), 1.27 (s, 1H).¹³C NMR (126 MHz, Methanol-d4) δ 152.8, 142.6, 128.6, 125.8, 125.0, 122.1, 121.2, 117.6, 110.1, 109.9, 76.3, 72.6, 57.5, 56.5, 47.1, 36.1, 10.3. HRMS (ESI) m/z calcd for C19H18N6O [M+H]⁺ 347.1620, found 347.1624. [0171] Example 32: (1S,4S)-5-(3-Bromoimidazo[1,2-b]pyridazin-6-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (S6) Off-white solid (506 mg, 79%).¹H N

(500 z, ethanol-d₄) δ 7.71 – 7.63 (m, 1H), 7.48 – 7.43 (m, 1H), 6.91 – 6.84 (m, 1H), 4.89 (d, J = 5.3 Hz, 2H), 4.72 (s, 1H), 3.91 – 3.86 (m, 2H), 3.63 – 3.56 (m, 1H), 3.49 – 3.43 (m, 1H), 2.07 – 1.95 (m, 2H); ¹³C NMR (126 MHz, Methanol- d4) δ 153.3, 136.7, 130.3, 124.8, 111.0, 99.8, 76.2, 72.7, 57.3, 56.2, 35.9. HRMS (ESI) m/z calcd for C₁₁H₁₂BrN₄O [M+H]⁺ 295.0194, found 295.0193. [0172] Example 33: (1S,4S)-5-(3-(3-methyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-2-oxa-5- azabicyclo[2.2.1]heptane (30)   H_N ^N O Synthesized using substrate S6. Of

3%).¹H NMR (500 MHz, Methanol-d₄) δ 8.69 (t, J = 1.1 Hz, 1H), 8.00 (dd, J = 8.8, 1.5 Hz, 1H), 7.90 – 7.69 (m, 2H), 7.54 (d, J = 8.8 Hz, 1H), 6.92 (d, J = 9.7 Hz, 1H), 4.00 (d, J = 7.6 Hz, 1H), 3.94 (dd, J = 7.6, 1.5 Hz, 1H), 3.69 (dd, J = 9.9, 1.5 Hz, 1H), 3.52 (d, J = 9.7 Hz, 1H), 2.59 (s, 3H), 2.13 – 2.01 (m, 2H), 1.28 (s, 1H). ¹³C NMR (126 MHz, Methanol-d₄) δ 152.8, 142.6, 140.4, 131.5, 126.4, 125.8, 125.0, 122.1, 121.2, 117.6, 110.1, 109.9, 108.8, 76.3, 72.6, 57.5, 56.5, 36.1, 10.3, 10.2. HRMS (ESI) m/z calcd for C₁₉H₁₈N₆O [M+H]⁺ 347.1620, found 347.1625. [0173] Example 34: 4-(3-bromoimidazo[1,2-b]pyridazin-6-yl)-2,2-dimethylmorpholine (S7) Off-white solid (571 mg, 85%).¹H N

, SO-d6) δ 7.86 (d, J = 10.0 Hz, 1H), 7.58 (s, 1H), 7.21 (d, J = 9.9 Hz, 1H), 3.77 – 3.67 (m, 2H), 3.48 (dd, J = 6.2, 4.0 Hz, 2H), 1.19 (s, 6H); ¹³C NMR (126 MHz, Chloroform-d) δ 155.3, 136.9, 132.2, 126.1, 109.4, 100.3, 71.3, 60.4, 55.4, 45.7, 24.6. HRMS (ESI) m/z calcd for C₁₂H₁₆BrN₄O [M+H]⁺ 311.0507, found 311.0506. [0174] Example 35: 2,2-dimethyl-4-(3-(3-methyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine (31)

  Synthesized using substrate S7. Yellow solid (178 mg, 51%).¹H NMR (500 MHz, Methanol-d4) δ 8.68 (s, 1H), 7.95 (dt, J = 8.9, 1.8 Hz, 1H), 7.87 (d, J = 2.4 Hz, 1H), 7.79 (dd, J = 9.9, 2.3 Hz, 1H), 7.54 (dd, J = 8.8, 2.4 Hz, 1H), 7.15 (dd, J = 9.9, 2.4 Hz, 1H), 3.90 (q, J = 3.9 Hz, 2H), 3.57 (dt, J = 6.9, 3.0 Hz, 2H), 3.45 (d, J = 2.4 Hz, 2H), 2.59 (d, J = 2.5 Hz, 3H), 1.32 (d, J = 2.4 Hz, 6H). ¹³C NMR (126 MHz, DMSO-d6) δ 155.4, 142.1, 140.2, 137.3, 130.9, 127.8, 126.6, 125.3, 122.7, 121.1, 117.2, 110.8, 109.9, 71.2, 60.1, 55.3, 46.2, 24.9, 12.1. HRMS (ESI) m/z calcd for C20H22N6O [M+H]⁺ 363.1933, found 363.1931. [0175] Example 36: (R)-4-(3-bromoimidazo[1,2-b]pyridazin-6-yl)-2-methylmorpholine (S8) Off-white solid (501 mg, 78%).¹H

SO-d6) δ 7.87 (d, J = 9.9 Hz, 1H), 7.59 (s, 1H), 7.22 (d, J = 10.0 Hz, 1H), 4.14 – 3.84 (m, 3H), 3.71 – 3.51 (m, 2H), 2.92 (ddd, J = 12.9, 11.9, 3.5 Hz, 1H), 2.70 – 2.54 (m, 1H), 1.15 (d, J = 6.2 Hz, 3H); ¹³C NMR (126 MHz, DMSO-d6) δ 155.6, 137.1, 132.0, 126.5, 111.0, 99.8, 71.3, 65.8, 51.8, 45.4, 19.1. HRMS (ESI) m/z calcd for C11H14BrN4O [M+H]⁺ 297.0351, found 297.0348. [0176] Example 37: (R)-2-methyl-4-(3-(3-methyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine (32) Synthesized using substrate S8. Of

-w te so d (151 mg, 42%). ¹H NMR (500 MHz, DMSO-d6) δ 8.77 (dd, J = 1.6, 0.8 Hz, 1H), 8.02 (s, 1H), 7.98 – 7.87 (m, 2H), 7.52 (dd, J = 8.7, 0.8 Hz, 1H), 7.20 (d, J = 10.0 Hz, 1H), 4.07 (dt, J = 12.5, 2.1 Hz, 1H), 4.03 – 3.92 (m, 2H), 3.71 – 3.61 (m, 2H), 3.02 – 2.93 (m, 1H), 2.67 (dd, J = 12.7, 10.4 Hz, 1H), 2.51 (s, 3H), 1.18 (d, J = 6.2 Hz, 3H). ¹³C NMR (126 MHz, DMSO-d6) δ 155.2, 142.1, 140.2, 137.4, 130.9, 127.9, 126.6, 125.3, 122.7, 121.1, 117.2, 110.8, 109.9, 71.2, 66.0, 52.3, 46.1, 19.3, 12.0. HRMS (ESI) m/z calcd for C19H20N6O [M+H]⁺ 349.1777, found 349.1779.   [0177] Example 38: (S)-4-(3-bromoimidazo[1,2-b]pyridazin-6-yl)-2-methylmorpholine (S9) Off-white solid (449 mg, 69%). ¹H

ethanol-d4) δ 7.71 (d, J = 10.0 Hz, 1H), 7.50 (s, 1H), 7.17 (d, J = 10.0 Hz, 1H), 4.12 – 3.96 (m, 3H), 3.76 – 3.65 (m, 2H), 3.02 (ddd, J = 13.0, 11.9, 3.5 Hz, 1H), 2.69 (dd, J = 12.9, 10.4 Hz, 1H), 1.24 (d, J = 6.3 Hz, 3H); ¹³C NMR (126 MHz, Methanol-d₄) δ 155.5, 136.9, 130.7, 124.9, 110.8, 100.2, 71.4, 65.8, 51.6, 45.1, 17.6. HRMS (ESI) m/z calcd for C11H14BrN4O [M+H]⁺ 297.0351, found 297.0348. [0178] Example 39: (S)-2-methyl-4-(3-(3-methyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine (33) Synthesized using substrate S9. Of

, 41%). ¹H NMR (500 MHz, DMSO-d6) δ 8.79 – 8.75 (m, 1H), 8.01 (s, 1H), 7.97 – 7.89 (m, 2H), 7.52 (dd, J = 8.8, 0.8 Hz, 1H), 7.19 (d, J = 9.9 Hz, 1H), 4.06 (dt, J = 12.5, 2.1 Hz, 1H), 3.96 (dddd, J = 12.9, 8.4, 3.1, 1.3 Hz, 2H), 3.71 – 3.61 (m, 2H), 3.02 – 2.92 (m, 1H), 2.66 (dd, J = 12.7, 10.4 Hz, 1H), 2.51 (s, 3H), 1.18 (d, J = 6.2 Hz, 3H).¹³C NMR (126 MHz, DMSO-d₆) δ 155.2, 142.1, 140.2, 137.4, 130.9, 127.9, 126.6, 125.3, 122.7, 121.1, 117.2, 110.8, 109.9, 71.2, 66.0, 52.3, 46.1, 19.3, 12.0. HRMS (ESI) m/z calcd for C₁₉H₂₀N₆O [M+H]⁺ 349.1779, found 349.1774. [0179] Example 40: 3-(3-bromoimidazo[1,2-b]pyridazin-6-yl)-8-oxa-3-azabicyclo[3.2.1]octane (S10)

  Off-white solid (514 mg, 77%).¹H NMR (500 MHz, DMSO-d6) δ 7.85 (d, J = 10.0 Hz, 1H), 7.58 (s, 1H), 7.13 (d, J = 10.0 Hz, 1H), 4.57 – 4.37 (m, 2H), 3.78 (d, J = 12.3 Hz, 2H), 3.06 (dd, J = 12.6, 2.6 Hz, 2H), 1.95 – 1.67

(m, 4H); ¹³C NMR (126 MHz, DMSO-d6) δ 156.3, 137.1, 131.9, 126.3, 110.4, 99.6, 73.1, 51.3, 28.0. HRMS (ESI) m/z calcd for C₁₂H₁₄BrN₄O [M+H]⁺ 309.0351, found 309.0349. [0180] Example 41: 3-(3-(3-methyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-8-oxa-3- azabicyclo[3.2.1]octane (34) Synthesized using substrate S10.

9%). ¹H NMR (500 MHz, Methanol- d4) δ 8.65 (dd, J = 1.6, 0.8 Hz, 1H), 7.99 (dd, J = 8.8, 1.6 Hz, 1H), 7.87 (s, 1H), 7.79 (d, J = 9.9 Hz, 1H), 7.54 (dd, J = 8.8, 0.9 Hz, 1H), 7.11 (d, J = 10.0 Hz, 1H), 4.53 (dd, J = 4.5, 2.4 Hz, 2H), 3.85 (dt, J = 12.6, 1.1 Hz, 2H), 3.24 (dd, J = 12.4, 2.6 Hz, 2H), 2.59 (s, 3H), 2.03 – 1.88 (m, 5H). ¹³C NMR (126 MHz, Methanol-d₄) δ 155.7, 142.7, 140.3, 137.0, 128.9, 128.5, 125.9, 124.9, 122.1, 121.1, 117.8, 109.9, 109.3, 73.8, 51.3, 27.6, 10.3. HRMS (ESI) m/z calcd for C20H20N6O [M+H]⁺ 361.1777, found 361.1763. [0181] Example 42: (2S,6S)-4-(3-Bromoimidazo[1,2-b] pyridazin-6-yl)-2,6-dimethylmorpholine (S11) Off-white solid (236 mg, 35%). ¹

H NMR (500 MHz, Chloroform-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.   [0182] Example 43: (2R,6R)-2,6-dimethyl-4-(3-(3-methyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6- yl)morpholine (35) Synthesized using substrate S11. ¹

7%). H NMR (500 MHz, Methanol-d₄) δ 8.66 (s, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.84 (s, 1H), 7.72 (d, J = 9.8 Hz, 1H), 7.49 (d, J = 8.7 Hz, 1H), 7.07 (d, J = 9.8 Hz, 1H), 4.15 (tt, J = 6.4, 3.4 Hz, 2H), 3.62 (dd, J = 12.8, 3.4 Hz, 2H), 3.26 (dd, J = 12.7, 6.4 Hz, 2H), 2.54 (d, J = 5.5 Hz, 3H), 1.27 (d, J = 6.4 Hz, 6H).¹³C NMR (126 MHz, Methanol-d4) δ 155.2, 142.5, 140.2, 136.9, 128.8, 128.2, 125.5, 124.8, 122.0, 121.0, 117.2, 109.9, 109.7, 66.0, 50.6, 16.8, 10.4. HRMS (ESI) m/z calcd for C₂₀H₂₂N₆O [M+H]⁺ 363.1933, found 363.1931. [0183] Analogs: Example 44: 3-(1H-indazol-6-yl)-6-(4-(2-methoxyethyl)piperazin-1-yl)imidazo[1,2-b]pyridazine (36) ¹H NMR (500 MHz, MeOD) δ

94 (s, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.76 (d, J = 9.9 Hz, 1H), 7.73 – 7.68 (m, 1H), 7.14 (d, J = 10.0 Hz, 1H), 3.62 (t, J = 5.0 Hz, 4H), 3.58 (t, J = 5.4 Hz, 2H), 3.36 (s, 3H), 2.69 (t, J = 5.1 Hz, 4H), 2.64 (t, J = 5.4 Hz, 2H).¹³C NMR (126 MHz, DMSO) δ 155.4, 140.7, 137.8, 133.9, 132.0, 127.4, 127.1, 126.6, 122.0, 121.1, 119.6, 111.1, 110.6, 106.8, 70.5, 58.5, 57.5, 53.2, 46.4, 40.5, 40.4. [0184] Example 45: 6-((3R,5S)-3,5-dimethylpiperidin-1-yl)-3-(3-methyl-1H-indazol-5-yl)imidazo[1,2- b]pyridazine (37)   ¹H NMR (500 MHz, MeOD) δ 8.71 7.86 (m, 1H), 7.80 (s, 1H), 7.64 (dd, J

= 10.0, 2.6 Hz, 1H), 7.50 – 7.40 (m, 1H), 7.06 (d, J = 9.9 Hz, 1H), 4.14 – 4.05 (m, 2H), 2.53 (d, J = 6.1 Hz, 3H), 2.37 – 2.29 (m, 2H), 1.83 – 1.75 (m, 1H), 1.74 – 1.63 (m, 2H), 0.99 (d, J = 6.8 Hz, 1H), 0.92 (d, J = 6.5 Hz, 6H), 0.75 (q, J = 12.1 Hz, 1H). [0185] Example 46: 1-(3-(3-methyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)piperidin-4-ol (38) ¹H NMR (500 MHz, MeOD) δ 8.7

(dd, J = 8.8, 1.6 Hz, 1H), 7.83 (s, 1H), 7.71 (d, J = 9.9 Hz, 1H), 7.49 (dd, J = 8.8, 0.8 Hz, 1H), 7.12 (dd, J = 10.0, 5.8 Hz, 1H), 4.04 (dt, J = 9.2, 3.3 Hz, 2H), 3.87 (ddp, J = 18.8, 8.9, 4.3 Hz, 1H), 3.26 (ddd, J = 13.3, 10.0, 3.1 Hz, 2H), 2.55 (s, 3H), 1.99 (dt, J = 13.2, 4.1 Hz, 2H), 1.69 – 1.51 (m, 2H).¹³C NMR (126 MHz, DMSO) δ 154.9, 142.1, 140.2, 137.1, 130.7, 127.8, 126.5, 126.2, 125.3, 122.7, 121.2, 117.1, 116.9, 111.2, 110.8, 110.3, 66.3, 44.3, 33.9, 12.0. [0186] Example 47: 4-(3-(3-methyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)thiomorpholine (39) ¹

H NMR (500 MHz, MeOD) δ 8.63 (dd, J = 1.6, 0.8 Hz, 1H), 7.94 (dd, J = 8.8, 1.6 Hz, 1H), 7.86 (s, 1H), 7.77 (d, J = 9.9 Hz, 1H), 7.53 (dd, J = 8.8, 0.9 Hz, 1H), 7.14 (d, J = 10.0 Hz, 1H), 4.03 – 3.98 (m, 4H), 2.78 – 2.73 (m, 4H), 2.57 (s, 3H). ¹³C NMR (126 MHz, DMSO) δ 154.2, 142.1,   140.3, 137.1, 130.9, 128.0, 126.8, 125.4, 122.7, 121.1, 117.2, 110.8, 110.2, 49.0, 48.7, 40.5, 25.7, 25.5, 12.1. [0187] Example 48: 4-(3-(3-methyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)thiomorpholine 1,1-dioxide (40) ¹H NMR (500 MHz, DMSO) δ 8.5

7.88 (d, J = 1.9 Hz, 1H), 7.53 (dd, J = 8.4, 4.6 Hz, 2H), 7.30 (d, J = 9.9 Hz, 1H), 4.09 (t, J = 5.2 Hz, 4H), 3.22 (d, J = 4.4 Hz, 4H), 2.52 (s, 3H). [0188] Example 49: 3-(3-methyl-1H-indazol-5-yl)-6-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)imidazo[1,2- b]pyridazine (41) ¹H NMR (500 MHz, DMSO) δ 8.78

, . , , 8.00 (s, 1H), 7.95 – 7.86 (m, 2H), 7.52 (d, J = 8.7 Hz, 1H), 7.22 (d, J = 10.0 Hz, 1H), 4.08 – 4.01 (m, 2H), 2.69 (dd, J = 12.7, 10.8 Hz, 2H), 2.52 (s, 3H), 2.31 – 2.21 (m, 2H), 2.19 (s, 3H), 1.10 (d, J = 6.1 Hz, 6H).¹³C NMR (126 MHz, DMSO) δ 154.8, 142.0, 140.2, 137.3, 130.8, 127.8, 126.5, 125.4, 122.7, 121.2, 117.0, 110.8, 110.1, 57.3, 53.0, 37.8, 18.3, 12.1. [0189] Example 50: (2S,6R)-4-(3-(benzo[d]thiazol-6-yl)imidazo[1,2-b]pyridazin-6-yl)-2,6-dimethylmorpholine (42)   ¹H NMR (500 MHz, MeOD) δ 9.2

8.86 (d, J = 1.9 Hz, 1H), 8.11 (dd, J = 8.7, 1.9 Hz, 1H), 8.05 (dd, J = 8.6, 1.9 Hz, 1H), 7.91 (d, J = 1.8 Hz, 1H), 7.72 (dd, J = 10.0, 2.0 Hz, 1H), 7.11 (dd, J = 10.0, 1.9 Hz, 1H), 3.98 – 3.92 (m, 2H), 3.72 (tdd, J = 11.6, 5.7, 3.6 Hz, 2H), 2.57 (td, J = 11.6, 1.9 Hz, 2H), 1.22 (d, J = 6.3 Hz, 6H). ¹³C NMR (126 MHz, MeOD) δ 155.8, 154.8, 151.6, 137.4, 134.0, 130.0, 127.0, 126.7, 125.0, 124.7, 122.3, 118.9, 110.7, 71.1, 51.4, 17.7. [0190] Example 51: (2S,6R)-2,6-dimethyl-4-(3-(2-methylbenzo[d]thiazol-6-yl)imidazo[1,2-b]pyridazin-6- yl)morpholine (43) ¹H NMR (500 MHz, MeOD) δ 8.67

, . , , .01 (dd, J = 8.6, 1.7 Hz, 1H), 7.88 – 7.81 (m, 2H), 7.70 (d, J = 9.9 Hz, 1H), 7.09 (d, J = 9.9 Hz, 1H), 3.91 (dd, J = 13.2, 2.3 Hz, 2H), 3.76 – 3.66 (m, 2H), 2.81 (s, 3H), 2.54 (dd, J = 12.8, 10.6 Hz, 2H), 1.22 (d, J = 6.2 Hz, 6H).¹³C NMR (126 MHz, MeOD) δ 168.7, 154.7, 151.5, 137.3, 135.6, 129.8, 127.1, 125.9, 125.0, 124.4, 121.2, 118.4, 110.5, 71.1, 51.3, 18.4, 17.7. [0191] Example 52: 6-(3-(3-methyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-2-oxa-6-azaspiro[3.4]octane (44)

  ¹H NMR (500 MHz, MeOD) δ 8.73 (s, 1H), 7.92 (dt, J = 9.1, 2.2 Hz, 1H), 7.79 (d, J = 3.6 Hz, 1H), 7.61 (d, J = 9.7 Hz, 1H), 7.45 (dd, J = 8.8, 3.2 Hz, 1H), 6.69 (dd, J = 9.9, 3.3 Hz, 1H), 4.71 – 4.60 (m, 5H), 3.67 (s, 2H), 3.47 (t, J = 7.0 Hz, 2H), 2.56 – 2.49 (m, 4H), 2.29 (q, J = 5.3 Hz, 2H).¹³C NMR (126 MHz, MeOD) δ 152.3, 142.6, 140.1, 136.6, 128.0, 127.7, 125.4, 124.4, 122.0, 121.2, 117.2, 109.8, 109.3, 80.8, 55.4, 45.5, 45.2, 34.5, 10.3. [0192] Example 53: (2S,6R)-2,6-dimethyl-4-(3-(3-methyl-1H-indazol-5-yl)pyrazolo[1,5-a]pyrimidin-5- yl)morpholine (45) ¹H NMR (500 MHz, DMSO) δ 8.6 8.52 (dd, J = 1.6, 0.8 Hz, 1H), 8.43 (s,

1H), 7.94 (dd, J = 8.7, 1.6 Hz, 1H), 7.43 (dd, J = 8.7, 0.8 Hz, 1H), 6.78 (d, J = 7.9 Hz, 1H), 4.42 (d, J = 12.1 Hz, 1H), 3.66 (dqd, J = 12.4, 6.1, 2.5 Hz, 2H), 2.66 (dd, J = 13.0, 10.6 Hz, 2H), 1.19 (d, J = 6.2 Hz, 6H).¹³C NMR (126 MHz, DMSO) δ 155.6, 143.9, 142.5, 141.2, 139.4, 136.8, 125.2, 124.4, 123.1, 115.3, 110.4, 105.4, 97.4, 71.4, 50.3, 19.2, 12.0. [0193] Example 54: 5-(6-((2S,6R)-2,6-dimethylmorpholino)imidazo[1,2-b]pyridazin-3-yl)-1H-indazole-3- carbonitrile (46) ¹H NMR (500 MHz, DMSO) δ 9.

, 8.16 – 8.10 (m, 1H), 7.98 (d, J = 9.9 Hz, 1H), 7.83 (d, J = 9.0 Hz, 1H), 7.30 (d, J = 10.0 Hz, 1H), 4.10 (d, J = 12.2 Hz, 2H), 3.73 (t, J = 6.4 Hz, 2H), 2.63 (d, J = 11.0 Hz, 2H), 1.22 (d, J = 6.2 Hz, 6H). [0194] Example 55: (2S,6R)-4-(3-(1,3-dimethyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-2,6- dimethylmorpholine (47)   ¹H NMR (500 MHz, MeOD) δ 8.61 , 1H), 7.88 – 7.81 (m, 2H), 7.69 (d, J =

9.9 Hz, 1H), 7.40 (dd, J = 8.9, 0.8 Hz, 1H), 7.06 (d, J = 9.9 Hz, 1H), 3.96 (s, 3H), 3.91 (dt, J = 11.5, 2.1 Hz, 2H), 3.72 (dqd, J = 10.5, 6.2, 2.4 Hz, 2H), 2.51 (dd, J = 12.6, 10.6 Hz, 2H), 2.44 (s, 3H), 1.22 (d, J = 6.3 Hz, 6H).¹³C NMR (126 MHz, MeOD) δ 154.9, 141.5, 139.8, 137.0, 128.9, 128.0, 125.4, 124.8, 122.6, 121.0, 117.2, 109.0, 71.3, 51.4, 33.8, 17.8, 10.4. [0195] Example 56: 5-(6-((2S,6R)-2,6-dimethylmorpholino)imidazo[1,2-b]pyridazin-3-yl)indolin-2-one (48) ¹H NMR (500 MHz, Methanol-d₄) δ

), 7.75 – 7.68 (m, 2H), 7.09 (d, J = 10.0 Hz, 1H), 6.93 (d, J = 8.1 Hz, 1H), 4.00 – 3.94 (m, 2H), 3.74 (dqd, J = 12.4, 6.1, 2.3 Hz, 2H), 3.54 (s, 2H), 2.58 (dd, J = 12.8, 10.6 Hz, 2H), 1.23 (d, J = 6.2 Hz, 6H).¹³C NMR (126 MHz, Methanol- d4) δ 178.4, 154.8, 142.7, 136.9, 128.7, 128.2, 126.0, 126.0, 124.9, 123.1, 122.6, 110.1, 109.2, 71.2, 51.5, 35.7, 17.7. [0196] Example 57: (2S,6R)-2,6-dimethyl-4-(3-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[1,2- b]pyridazin-6-yl)morpholine (49) ¹H NMR (500 MHz, MeOD) δ 9.0

, , . , , 7.94 (s, 1H), 7.74 (d, J = 9.9 Hz, 1H), 7.15 (d, J = 9.9 Hz, 1H), 3.97 (d, J = 12.5 Hz, 2H), 3.77 (dq, J = 14.1, 7.0 Hz, 2H), 2.57 (d, J =   22.0 Hz, 5H), 1.25 (d, J = 6.2 Hz, 6H).¹³C NMR (126 MHz, DMSO) δ 155.2, 151.7, 147.7, 141.9, 137.6, 130.9, 126.7, 125.7, 125.4, 118.4, 114.0, 110.6, 71.2, 51.6, 19.2, 12.5. [0197] Example 58: (2S,6R)-2,6-dimethyl-4-(3-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2- b]pyridazin-6-yl)morpholine (50) ¹H NMR (500 MHz, MeOD) δ 8 1 (s, 1H), 7.78 (d, J = 9.7 Hz, 1H), 7.19

(s, 2H), 4.04 (d, J = 12.9 Hz, 2H), 3.81 – 3.74 (m, 2H), 2.62 (dd, J = 12.7, 10.5 Hz, 2H), 2.35 (t, J = 1.4 Hz, 3H), 1.25 (d, J = 6.2 Hz, 7H). ¹³C NMR (126 MHz, DMSO) δ 155.1, 148.0, 141.4, 137.3, 130.3, 126.6, 126.4, 124.4, 123.7, 120.0, 117.2, 110.1, 109.2, 71.2, 51.6, 19.2, 9.9. [0198] Example 59: (2S,6R)-2,6-dimethyl-4-(3-(3-methyl-1H-indol-5-yl)imidazo[1,2-b]pyridazin-6- yl)morpholine (51) ¹H NMR (500 MHz, MeOD) δ 8.5

1H), 7.77 (s, 1H), 7.66 – 7.57 (m, 2H), 7.35 (dd, J = 8.6, 0.7 Hz, 1H), 7.00 (q, J = 1.1 Hz, 1H), 6.91 (d, J = 9.9 Hz, 1H), 3.88 (dt, J = 11.6, 1.8 Hz, 2H), 3.63 (ddt, J = 8.7, 6.4, 3.3 Hz, 2H), 2.46 (dd, J = 12.7, 10.6 Hz, 2H), 2.29 (d, J = 1.1 Hz, 3H), 1.16 (d, J = 6.2 Hz, 6H). ¹³C NMR (126 MHz, MeOD) δ 154.7, 136.6, 136.0, 129.7, 128.2, 128.1, 124.6, 122.5, 120.0, 119.1, 116.3, 110.9, 110.6, 109.3, 71.3, 51.4, 51.2, 17.7, 8.6. [0199] Example 60: (2S,6R)-4-(3-(1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-b]pyridazin-6-yl)-2,6- dimethylmorpholine (52)   ¹H NMR (500 MHz, MeOD) δ 8.85 , 8.58 (d, J = 2.0 Hz, 1H), 7.81 (s, 1H),

7.70 (d, J = 10.0 Hz, 1H), 7.42 (d, J = 3.5 Hz, 1H), 7.08 (d, J = 10.0 Hz, 1H), 6.50 (d, J = 3.5 Hz, 1H), 3.94 (ddd, J = 12.0, 2.3, 1.0 Hz, 2H), 3.70 (dqd, J = 10.5, 6.2, 2.4 Hz, 2H), 2.54 (dd, J = 12.8, 10.6 Hz, 2H), 1.20 (d, J = 6.2 Hz, 6H).¹³C NMR (126 MHz, MeOD) δ 154.8, 147.0, 140.7, 136.9, 128.7, 126.9, 126.8, 126.5, 124.9, 120.5, 117.5, 110.3, 100.4, 71.2, 51.3, 17.7. [0200] Example 61: (2S,6R)-4-(3-(6-fluoro-3-methyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-2,6- dimethylmorpholine (53) ¹H NMR (500 MHz, DMSO) δ 8.79

7.96 (d, J = 9.9 Hz, 1H), 7.85 (d, J = 4.2 Hz, 1H), 7.40 (d, J = 11.7 Hz, 1H), 7.27 (d, J = 9.9 Hz, 1H), 4.05 – 3.93 (m, 2H), 3.70 (dqd, J = 12.4, 6.1, 2.3 Hz, 2H), 2.54 (dd, J = 12.7, 10.6 Hz, 2H), 2.50 (s, 3H), 1.15 (d, J = 6.2 Hz, 6H).¹³C NMR (126 MHz, DMSO) δ 160.0, 158.0, 155.0, 142.5, 140.1, 140.0, 137.0, 133.0, 132.9, 126.6, 122.2, 120.4, 120.4, 119.5, 110.9, 110.8, 96.7, 96.5, 71.2, 51.6, 19.2, 12.0. [0201] Example 62: (2S,6R)-2,6-dimethyl-4-(3-(6-methyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6- yl)morpholine (54)

  ¹H NMR (500 MHz, DMSO) δ 8.03 (s, 1H), 7.91 (d, J = 9.9 Hz, 1H), 7.82 (s, 1H), 7.58 (s, 1H), 7.49 (s, 1H), 7.18 (d, J = 10.0 Hz, 1H), 3.85 (dd, J = 13.0, 2.3 Hz, 2H), 3.59 (dtt, J = 12.4, 6.1, 3.8 Hz, 2H), 2.39 (dd, J = 12.8, 10.5 Hz, 2H), 2.29 (s, 3H), 1.05 (d, J = 6.2 Hz, 6H). [0202] Example 63: (2S,6R)-2,6-dimethyl-4-(3-(7-methyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6- yl)morpholine (55) ¹H NMR (500 MHz, DMSO) δ 8. 1.4 Hz, 1H), 7.96 (s, 1H), 7.94 – 7.86

(m, 2H), 7.20 (d, J = 9.9 Hz, 1H), 4.05 (dd, J = 13.0, 2.3 Hz, 2H), 3.70 (dtd, J = 12.3, 6.4, 2.2 Hz, 2H), 2.62 – 2.50 (m, 5H), 1.17 (d, J = 6.2 Hz, 6H).¹³C NMR (126 MHz, DMSO) δ 154.9, 139.7, 137.3, 134.8, 130.9, 128.1, 126.6, 125.1, 123.3, 122.2, 120.5, 115.6, 110.0, 71.1, 51.8, 19.2, 17.4. [0203] Example 64: 3-(3-methyl-1H-indazol-5-yl)-6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazine (56) ¹H NMR (500 MHz, DMSO) δ 8.73 (

, 1H), 7.95 (dd, J = 8.7, 1.6 Hz, 1H), 7.90 (d, J = 9.9 Hz, 1H), 7.53 (d, J = 8.7 Hz, 1H), 7.19 (d, J = 9.9 Hz, 1H), 3.55 (t, J = 5.0 Hz, 4H), 2.50 (s, 3H), 2.47 (s, 4H), 2.22 (s, 3H).¹³C NMR (126 MHz, DMSO) δ 155.2, 142.1, 140.2, 137.2, 130.8, 127.9, 126.5, 125.3, 122.7, 121.1, 117.3, 110.8, 110.1, 54.5, 46.2, 46.2, 12.0. [0204] Example 65: (2S,6R)-2,6-dimethyl-4-(3-(4-methyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6- yl)morpholine (57)

  ¹H NMR (500 MHz, DMSO) δ 8.21 (d, J = 1.3 Hz, 1H), 7.92 (d, J = 9.9 Hz, 1H), 7.60 (s, 1H), 7.47 (d, J = 8.6 Hz, 1H), 7.43 (d, J = 8.6 Hz, 1H), 7.20 (d, J = 10.0 Hz, 1H), 3.92 – 3.85 (m, 2H), 3.61 (dqd, J = 12.2, 6.1, 2.1 Hz, 2H), 2.49 – 2.48 (m, 3H), 2.41 (dd, J = 12.8, 10.6 Hz, 2H), 1.07 (d, J = 6.2 Hz, 6H). [0205] Example 66: 3-(3-methyl-1H-indazol-5-yl)-6-(4-(methylsulfonyl)piperazin-1-yl)imidazo[1,2-b]pyridazine (58) ¹H NMR (500 MHz, DMSO) δ 8 8.01 (s, 1H), 7.97 (d, J = 5.5 Hz, 1H),

7.96 – 7.89 (m, 1H), 7.54 (d, J = 8.7 Hz, 1H), 7.24 (d, J = 9.9 Hz, 1H), 3.71 (t, J = 4.9 Hz, 4H), 3.31 – 3.28 (m, 4H), 2.91 (s, 3H), 2.52 (s, 3H). ¹³C NMR (126 MHz, DMSO) δ 154.7, 142.2, 140.3, 137.3, 131.0, 128.1, 126.9, 125.4, 122.7, 122.6, 121.0, 117.5, 110.8, 110.2, 46.0, 45.2, 34.5, 12.1. [0206] Example 67: 1-(3-(3-methyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)piperidin-4-amine (59) ¹H NMR (500 MHz, DMSO) δ 8.7

s, 1H), 8.06 (d, J = 10.0 Hz, 1H), 8.00 – 7.97 (m, 2H), 7.94 (dd, J = 8.7, 1.6 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 10.0 Hz, 1H), 4.29 (d, J = 13.6 Hz, 2H), 3.79 (s, 1H), 3.39 (s, 1H), 3.14 (dd, J = 26.0, 2.5 Hz, 2H), 2.52 (s, 3H), 2.01 (dd, J = 13.1, 3.9 Hz, 2H), 1.65 (qd, J = 12.3, 4.1 Hz, 2H). ¹³C NMR (126 MHz, DMSO) δ 158.7, 155.2, 142.2, 140.6, 135.5, 128.4, 125.6, 125.3, 122.6, 119.9, 118.1, 112.8, 111.0, 48.0, 44.8, 29.1, 12.1. [0207] Example 68: 4-methyl-1-(3-(3-methyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)piperidin-4-amine (60)   ¹H NMR (500 MHz, DMSO) δ 8. .22 (s, 1H), 8.08 (d, J = 14.9 Hz, 4H),

7.94 (dd, J = 8.8, 1.6 Hz, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.46 (d, J = 9.9 Hz, 1H), 4.01 (dt, J = 14.1, 4.7 Hz, 2H), 3.45 (ddd, J = 13.8, 10.0, 3.3 Hz, 2H), 2.52 (s, 3H), 1.88 (ddd, J = 13.8, 9.9, 4.1 Hz, 2H), 1.79 (dt, J = 13.6, 4.0 Hz, 2H), 1.40 (s, 3H). ¹³C NMR (126 MHz, DMSO) δ 158.8, 158.5, 155.2, 142.2, 140.6, 126.8, 125.6, 125.2, 122.6, 119.9, 118.2, 112.8, 111.0, 52.5, 42.4, 34.1, 22.7, 12.1. [0208] Example 69: 5-(6-((1S,4R)-2-azabicyclo[2.2.1]heptan-2-yl)imidazo[1,2-b]pyridazin-3-yl)-3-methyl-1H- pyrazolo[3,4-b]pyridine (61) ¹H NMR (500 MHz, MeOD) δ 9.18

, 8.96 (d, J = 2.0 Hz, 1H), 7.94 (s, 1H), 7.80 (d, J = 9.8 Hz, 1H), 6.96 (d, J = 9.8 Hz, 1H), 4.75 (s, 2H), 3.97 (d, J = 7.6 Hz, 1H), 3.93 (d, J = 7.8 Hz, 1H), 3.68 (d, J = 9.9 Hz, 1H), 3.51 (d, J = 9.9 Hz, 1H), 2.60 (s, 3H), 2.12 – 2.07 (m, 1H), 2.04 (d, J = 11.3 Hz, 1H). [0209] Example 70: 4-methyl-1-(3-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[1,2-b]pyridazin-6- yl)piperidin-4-ol (62) ¹H NMR (500 MHz, DMSO) δ 9

. . , , . q, J = 5.4 Hz, 1H), 8.12 – 8.05 (m, 1H), 7.89 (dq, J = 8.3, 5.2 Hz, 1H), 7.23 (dq, J = 8.2, 4.6 Hz, 1H), 4.46 – 4.39 (m, 1H), 3.83 (dt, J = 13.9, 4.7 Hz, 2H), 3.42 (dt, J = 9.7, 4.7 Hz, 2H), 2.54 – 2.50 (m, 3H), 1.59 (d, J = 8.1 Hz, 4H),   1.18 – 1.13 (m, 3H). ¹³C NMR (126 MHz, DMSO) δ 155.0, 151.7, 147.7, 141.8, 137.3, 130.7, 126.5, 125.8, 125.3, 118.5, 114.0, 110.9, 66.7, 43.2, 37.9, 30.3, 12.5. [0210] Example 71: (2S,6R)-4-(3-(1H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[1,2-b]pyridazin-6-yl)-2,6- dimethylmorpholine (63) ¹H NMR (500 MHz, DMSO) δ 9.1 8.95 (d, J = 2.0 Hz, 1H), 8.21 (s, 1H),

8.07 (s, 1H), 7.96 (d, J = 9.9 Hz, 1H), 7.26 (d, J = 10.0 Hz, 1H), 4.08 – 4.03 (m, 2H), 3.70 (dqd, J = 12.4, 6.1, 2.3 Hz, 2H), 2.58 (dd, J = 12.8, 10.6 Hz, 2H), 1.17 (d, J = 6.2 Hz, 6H).¹³C NMR (126 MHz, DMSO) δ 155.1, 148.0, 137.5, 134.2, 131.2, 126.9, 126.8, 125.6, 119.1, 114.6, 110.8, 71.1, 51.6, 19.2. [0211] Example 72: (R)-2-methyl-4-(3-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[1,2-b]pyridazin-6- yl)morpholine (64) ¹H NMR (500 MHz, DMSO) δ 9.1

9.05 (d, J = 2.0 Hz, 1H), 8.12 (s, 1H), 7.95 (d, J = 9.9 Hz, 1H), 7.24 (d, J = 9.9 Hz, 1H), 4.05 (dt, J = 12.5, 2.1 Hz, 1H), 3.99 – 3.92 (m, 2H), 3.71 – 3.60 (m, 2H), 2.97 (td, J = 12.3, 3.4 Hz, 1H), 2.66 (dd, J = 12.7, 10.4 Hz, 1H), 2.52 (s, 3H), 1.18 (d, J = 6.2 Hz, 3H).¹³C NMR (126 MHz, DMSO) δ 155.33, 151.68, 147.70, 141.91, 137.54, 130.96, 126.72, 125.95, 125.48, 118.36, 114.01, 110.55, 71.21, 65.93, 52.16, 45.95, 19.25, 12.49. [0212] Example 73: (S)-2-methyl-4-(3-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[1,2-b]pyridazin-6- yl)morpholine (65)   ¹H NMR (500 MHz, DMSO) δ 9. 9.05 (d, J = 2.1 Hz, 1H), 8.12 (s, 1H),

7.96 (d, J = 9.9 Hz, 1H), 7.26 (s, 1H), 4.05 (dt, J = 12.6, 2.2 Hz, 1H), 4.00 – 3.92 (m, 2H), 3.66 (ddd, J = 11.9, 5.6, 2.6 Hz, 2H), 2.97 (td, J = 12.3, 3.5 Hz, 1H), 2.66 (dd, J = 12.7, 10.4 Hz, 1H), 2.52 (s, 3H), 1.18 (d, J = 6.2 Hz, 3H).¹³C NMR (126 MHz, DMSO) δ 155.3, 151.7, 147.7, 141.9, 137.5, 134.2, 131.0, 128.3, 126.7, 126.0, 118.4, 114.0, 110.6, 71.2, 65.9, 52.2, 45.9, 19.3, 12.5. [0213] Example 74: 2,2-dimethyl-4-(3-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[1,2-b]pyridazin-6- yl)morpholine (66) ¹H NMR (500 MHz, MeOD) δ 9.1

.95 (d, J = 2.2 Hz, 1H), 7.97 (d, J = 1.9 Hz, 1H), 7.82 (dd, J = 10.0, 2.1 Hz, 1H), 7.21 (dd, J = 10.1, 2.1 Hz, 1H), 3.90 (t, J = 4.9 Hz, 2H), 3.57 (t, J = 5.0 Hz, 2H), 3.45 (d, J = 1.8 Hz, 2H), 2.61 (d, J = 1.9 Hz, 3H), 1.32 (d, J = 1.9 Hz, 6H).¹³C NMR (126 MHz, DMSO) δ 155.6, 151.7, 147.7, 141.9, 137.5, 130.9, 126.7, 125.9, 125.5, 118.4, 114.0, 110.6, 71.2, 60.0, 55.2, 46.0, 24.8, 12.5. [0214] Example 75: 6-(6-((2S,6R)-2,6-dimethylmorpholino)imidazo[1,2-b]pyridazin-3-yl)benzo[d]oxazole (67) ¹H NMR (500 MHz, MeOD) δ 8.54

. , , . (dd, J = 8.4, 1.6 Hz, 1H), 7.90 (s, 1H), 7.74 (dd, J = 10.9, 9.2 Hz, 2H), 7.13 (d, J = 10.0 Hz, 1H), 4.00 – 3.96 (m, 3H), 3.74 (dqd, J = 12.4, 6.1, 2.3 Hz, 2H), 2.60 (dd, J = 12.9, 10.6 Hz, 2H), 1.24 (d, J = 6.3 Hz, 6H).¹³C NMR (126   MHz, MeOD) δ 154.7, 154.3, 150.0, 138.4, 137.3, 130.0, 127.0, 126.9, 124.9, 123.0, 119.4, 110.5, 107.9, 71.1, 51.3, 17.7. [0215] Example 76: (2S,6R)-2,6-dimethyl-4-(3-(1-methyl-1H-benzo[d]imidazol-6-yl)imidazo[1,2-b]pyridazin-6- yl)morpholine (68) ¹H NMR (500 MHz, DMSO) δ 8.70 , 8.20 (d, J = 8.9 Hz, 2H), 8.08 (s, 1H),

7.95 (d, J = 9.9 Hz, 1H), 7.85 (dd, J = 8.6, 1.7 Hz, 1H), 7.71 (dd, J = 8.6, 2.2 Hz, 2H), 7.46 (d, J = 10.3 Hz, 1H), 7.25 (s, 2H), 7.25 (d, J = 9.9 Hz, 1H), 4.10 (dd, J = 12.4, 2.4 Hz, 3H), 3.92 – 3.84 (m, 6H), 3.77 – 3.70 (m, 4H), 3.30 (d, J = 9.0 Hz, 25H), 2.60 (dd, J = 12.6, 10.5 Hz, 3H), 2.46 (s, 3H), 1.19 (d, J = 6.2 Hz, 13H), 0.82 (s, 1H).¹³C NMR (126 MHz, DMSO) δ 155.2, 145.7, 143.0, 137.6, 135.1, 131.4, 127.8, 126.7, 123.8, 120.6, 119.9, 110.2, 107.6, 71.3, 51.7, 31.0, 19.2. [0216] Example 77: 6-(6-((2S,6R)-2,6-dimethylmorpholino)imidazo[1,2-b]pyridazin-3-yl)-2- methylbenzo[d]oxazole (69) ¹H NMR (500 MHz, DMSO) δ 7.8

7.56 (s, 2H), 6.66 (d, J = 9.7 Hz, 3H), 5.73 (s, 1H), 4.71 (s, 10H), 4.22 (s, 10H), 3.90 – 3.79 (m, 1H), 3.15 (d, J = 5.2 Hz, 1H).¹³C NMR (126 MHz, MeOD) δ 165.4, 154.9, 151.0, 139.9, 137.3, 129.8, 127.5, 126.0, 125.1, 122.9, 118.4, 110.6, 107.7, 71.2, 51.4, 17.7, 12.8. [0217] Example 78: (2S,6R)-2,6-dimethyl-4-(3-(2-methyl-1H-benzo[d]imidazol-6-yl)imidazo[1,2-b]pyridazin-6- yl)morpholine (70)   ¹H NMR (500 MHz, MeOD) δ 8.30 7.81 (ddt, J = 9.1, 5.5, 3.3 Hz, 2H), 7.79

– 7.73 (m, 1H), 7.60 – 7.51 (m, 1H), 7.20 – 7.13 (m, 1H), 4.10 – 4.02 (m, 2H), 3.82 – 3.72 (m, 2H), 2.63 (t, J = 2.9 Hz, 2H), 2.60 (q, J = 3.4 Hz, 3H), 1.26 (d, J = 2.8 Hz, 6H). [0218] Example 79: 2,2,6,6-tetramethyl-4-(3-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[1,2- b]pyridazin-6-yl)morpholine (71) H_N ^N N ¹H NMR (500 MHz, DMSO) δ 9.14

2 (s, 1H), 7.95 (d, J = 9.9 Hz, 1H), 7.22 (d, J = 9.9 Hz, 1H), 3.49 (s, 4H), 2.53 (s, 3H), 1.23 (s, 12H). ¹³C NMR (126 MHz, DMSO) δ 155.1, 151.7, 147.7, 141.8, 137.4, 130.8, 126.8, 125.6, 125.3, 118.5, 114.0, 109.9, 71.6, 54.3, 28.8, 12.5. [0219] Example 80: 7-(3-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[1,2-b]pyridazin-6-yl)-4-oxa-7- azaspiro[2.5]octane (72) ¹H NMR (500 MHz, DMSO) δ 9.

, . , , 9.02 (d, J = 2.1 Hz, 1H), 8.11 (s, 1H), 7.96 (dd, J = 9.9, 1.7 Hz, 1H), 7.24 (d, J = 10.0 Hz, 1H), 3.83 (dd, J = 5.8, 3.7 Hz, 2H), 3.60 (t, J = 4.8 Hz, 2H), 3.53 (s, 2H), 2.51 (d, J = 1.7 Hz, 3H), 0.75 (t, J = 3.4 Hz, 2H), 0.65 (q, J = 5.0 Hz, 2H). ¹³C NMR (126 MHz, DMSO) δ 155.5, 151.7, 147.7, 141.9, 137.5, 131.0, 126.7, 126.0, 125.5, 118.3, 114.0, 110.6, 65.4, 58.6, 51.6, 46.0, 12.5, 11.6.   [0220] Example 81: (2S,6R)-4-(3-(3-cyclopropyl-1-methyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-2,6- dimethylmorpholine (73) ¹H NMR (500 MHz, DMSO) δ 8 8.04 (s, 1H), 7.99 – 7.91 (m, 2H), 7.63

(d, J = 8.8 Hz, 1H), 7.24 (d, J = 9.9 Hz, 1H), 4.07 (dd, J = 12.8, 2.3 Hz, 2H), 3.94 (s, 3H), 3.72 (ddd, J = 10.4, 6.2, 2.3 Hz, 2H), 2.59 (dd, J = 12.7, 10.6 Hz, 2H), 2.26 (tt, J = 7.7, 5.5 Hz, 1H), 1.16 (d, J = 6.1 Hz, 6H), 0.99 (dt, J = 6.7, 2.5 Hz, 4H). ¹³C NMR (126 MHz, DMSO) δ 155.2, 146.4, 140.1, 137.5, 131.1, 127.8, 126.6, 125.6, 122.5, 121.2, 116.9, 110.5, 110.2, 71.2, 51.7, 35.6, 19.2, 8.3, 8.1. [0221] Example 82: 1-(3-(3-cyclopropyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-3-methylazetidin-3-ol (74) ¹H NMR (500 MHz, DMSO) δ 8.8

(s, 1H), 7.89 (d, J = 9.7 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 6.68 (d, J = 9.6 Hz, 1H), 5.69 (s, 1H), 4.05 – 3.93 (m, 5H), 2.30 – 2.21 (m, 1H), 1.47 (s, 3H), 1.01 (d, J = 5.9 Hz, 4H). ¹³C NMR (126 MHz, DMSO) δ 156.1, 147.3, 140.5, 137.4, 130.6, 127.6, 126.6, 125.4, 121.7, 121.2, 117.0, 110.9, 108.7, 68.2, 65.4, 27.0, 8.9, 7.4. [0222] Example 83: 8-(3-(3-cyclopropyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-2,8- diazaspiro[4.5]decane (75)

  ¹H NMR (500 MHz, DMSO) δ 9.09 – 9.07 (m, 1H), 8.77 (s, 1H), 8.06 (s, 1H), 7.97 – 7.88 (m, 2H), 7.53 (d, J = 8.8 Hz, 1H),7.31 (d, J = 10.0 Hz, 1H), 3.62 (ddd, J = 19.1, 7.4, 4.3 Hz, 4H), 3.27 (q, J = 6.5 Hz, 2H), 3.07 (t, J = 5.3 Hz, 2H), 2.24 (tt, J = 8.3, 5.2 Hz, 1H), 1.86 (t, J = 7.5 Hz, 2H), 1.75 – 1.58 (m, 4H), 0.99 (ddt, J = 10.4, 4.9, 2.5 Hz, 4H).¹³C NMR (126 MHz, DMSO) δ 158.9, 155.2, 147.3, 140.7, 136.6, 129.3, 128.1, 126.0, 125.6, 121.9, 120.7, 117.4, 111.3, 54.0, 44.1, 44.0, 41.4, 34.7, 33.6, 8.6, 7.3. [0223] Example 84: 3-(3-(3-cyclopropyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-9-methyl-3,9- diazaspiro[5.5]undecane (76) ¹H NMR (500 MHz, DMSO) δ 8. .97 (s, 1H), 7.91 (dd, J = 8.8, 1.6 Hz,

1H), 7.86 (d, J = 9.9 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.19 (d, J = 10.0 Hz, 1H), 3.56 – 3.52 (m, 4H), 2.66 (s, 4H), 2.40 (s, 3H), 2.25 (p, J = 6.7 Hz, 1H), 1.58 (dt, J = 21.5, 5.7 Hz, 8H), 0.99 (d, J = 6.7 Hz, 4H). ¹³C NMR (126 MHz, DMSO) δ 155.2, 147.2, 140.5, 137.2, 130.8, 127.8, 126.4, 125.4, 121.7, 121.2, 117.0, 111.0, 110.3, 50.3, 44.7, 42.2, 33.9, 29.0, 29.0, 8.9, 7.3. [0224] Example 85: 1-(3-(3-cyclopropyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-N,N-dimethylpiperidin- 4-amine (77) ¹H NMR (500 MHz, DMSO) δ 8.8

s, 1H), 7.95 – 7.84 (m, 2H), 7.52 (d, J = 8.8 Hz, 1H), 7.20 (d, J = 10.0 Hz, 1H), 4.25 (dt, J = 13.6, 3.6 Hz, 2H), 2.99 (td, J = 12.8, 2.6 Hz, 2H), 2.28 – 2.25 (m, 1H), 2.24 (s, 6H), 1

1.84 (m, 2H), 1.52 (qd, J = 12.0, 3.9 Hz, 2H), 1.28 – 1.12 (m, 1H), 1.04 – 0.97 (m, 4H). ¹³C NMR (126 MHz, DMSO) δ 154.9, 147.2, 140.5, 137.2, 130.8, 127.8, 126.5, 125.5, 121.8, 121.2, 116.9, 111.0, 110.3, 61.8, 45.7, 41.5, 27.5, 8.7, 7.3. [0225] Example 86:   9-(3-(3-cyclopropyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-2-oxa-9- azaspiro[5.5]undecane (78) ¹H NMR (500 MHz, DMSO) δ 8. (s, 1H), 7.9 (dd, J = 8.8, 1.5 Hz, 1H),

7.9 (d, J = 9.9 Hz, 1H), 7.5 (dd, J = 8.7, 0.8 Hz, 1H), 7.2 (d, J = 9.9 Hz, 1H), 3.6 – 3.5 (m, 6H), 3.4 (s, 2H), 2.2 (p, J = 6.8 Hz, 1H), 1.6 – 1.5 (m, 8H), 1.0 (d, J = 6.7 Hz, 4H). ¹³C NMR (126 MHz, DMSO) δ 155.2, 147.2, 140.5, 137.2, 130.7, 127.8, 126.4, 125.4, 121.8, 121.2, 116.9, 111.0, 110.2, 75.5, 68.5, 42.1, 32.9, 32.5, 31.4, 21.9, 8.8, 7.2. [0226] Example 87: 9-(3-(3-cyclopropyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-3-oxa-9- azaspiro[5.5]undecane (79) H_N ^N O ¹H NMR (500 MHz, DMSO) δ 8

7.94 – 7.83 (m, 2H), 7.54 – 7.48 (m, 1H), 7.20 (d, J = 9.9 Hz, 1H), 3.60 – 3.54 (m, 8H), 2.25 (tt, J = 7.1, 6.0 Hz, 1H), 1.67 – 1.57 (m, 4H), 1.48 (t, J = 5.4 Hz, 4H), 1.04 – 0.98 (m, 4H).¹³C NMR (126 MHz, DMSO) δ 155.3, 147.3, 140.5, 137.2, 130.8, 127.8, 126.4, 125.4, 121.8, 121.2, 117.0, 111.0, 110.3, 63.0, 42.1, 36.2, 35.1, 29.5, 8.9, 7.3. [0227] Example 88: 9-(3-(3-cyclopropyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-1-oxa-4,9- diazaspiro[5.5]undecane (80)

  ¹H NMR (500 MHz, DMSO) δ 9.08 (s, 1H), 8.79 (s, 1H), 8.04 (s, 1H), 7.92 (dd, J = 12.7, 9.3 Hz, 2H), 7.52 (d, J = 8.8 Hz, 1H), 7.29 (d, J = 9.9 Hz, 1H), 3.99 (dd, J = 13.3, 4.1 Hz, 2H), 3.83 (dd, J = 6.4, 4.0 Hz, 2H), 3.30 (s, 2H), 3.07 (s, 2H), 3.04 (d, J = 10.7 Hz, 2H), 2.30 – 2.21 (m, 1H), 2.03 (d, J = 13.7 Hz, 2H), 1.77 – 1.68 (m, 2H), 1.01 (t, J = 6.5 Hz, 4H). ¹³C NMR (126 MHz, DMSO) δ 158.4, 155.0, 147.3, 140.6, 130.3, 128.0, 126.4, 125.5, 121.8, 121.0, 117.1, 111.1, 110.6, 69.0, 57.0, 49.4, 42.6, 41.6, 31.1, 8.8, 7.3. [0228] Example 89: (1-(3-(3-cyclopropyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-4-methylpiperidin-4- yl)methanamine (81) ¹H NMR (500 MHz, DMSO) δ

0 Hz, 1H), 7.93 – 7.89 (m, 1H), 7.87 (d, J = 6.6 Hz, 2H), 7.53 (d, J = 8.7 Hz, 1H), 7.38 (d, J = 9.8 Hz, 1H), 3.88 – 3.83 (m, 2H), 3.43 (ddd, J = 13.3, 9.6, 3.4 Hz, 2H), 2.80 (q, J = 5.5 Hz, 2H), 2.24 (ddd, J = 8.1, 5.2, 2.9 Hz, 1H), 1.61 (ddd, J = 13.7, 9.6, 4.0 Hz, 2H), 1.53 – 1.47 (m, 2H), 1.07 (s, 3H), 0.99 (ddd, J = 7.8, 5.6, 2.4 Hz, 4H).¹³C NMR (126 MHz, DMSO) δ 158.8, 155.3, 147.3, 140.7, 136.0, 128.1, 125.6, 125.5, 121.8, 120.4, 117.7, 111.9, 111.1, 48.6, 42.0, 33.4, 31.8, 21.4, 8.6, 7.3. [0229] Example 90: 9-(3-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[1,2-b]pyridazin-6-yl)-2-oxa-9- azaspiro[5.5]undecane (82) ¹H NMR (500 MHz, DMSO) δ 9.

, . , , .01 (d, J = 2.0 Hz, 1H), 8.07 (s, 1H), 7.89 (d, J = 9.9 Hz, 1H), 7.22 (d, J = 10.0 Hz, 1H), 3.60 – 3.49 (m, 6H), 3.39 (s, 2H), 2.51 (s, 3H), 1.53 (qq, J = 13.3, 5.6 Hz, 8H).¹³C NMR (126 MHz, DMSO) δ 155.1, 151.7, 147.6, 141.8, 137.3, 130.7, 126.5, 126.0, 125.4, 118.5, 114.0, 110.8, 75.3, 68.5, 42.1, 33.2, 32.4, 31.5, 22.0, 12.5. [0230] Example 91:   9-(3-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[1,2-b]pyridazin-6-yl)-3-oxa-9- azaspiro[5.5]undecane (83) ¹H NMR (500 MHz, DMSO) δ 9. .99 (d, J = 2.0 Hz, 1H), 8.06 (s, 1H),

7.90 (d, J = 10.0 Hz, 1H), 7.24 (d, J = 10.0 Hz, 1H), 3.57 (t, J = 5.5 Hz, 8H), 2.52 (s, 3H), 1.64 – 1.58 (m, 4H), 1.48 (t, J = 5.4 Hz, 4H).¹³C NMR (126 MHz, DMSO) δ 155.2, 151.7, 147.7, 141.9, 137.3, 130.8, 126.5, 126.1, 125.5, 118.5, 114.1, 110.9, 63.0, 42.0, 36.2, 35.0, 29.6, 12.5. [0231] Example 92: 7-(3-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[1,2-b]pyridazin-6-yl)-2-oxa-7- azaspiro[3.5]nonane (84) ¹H NMR (500 MHz, DMSO) δ 9

(s, 1H), 8.07 (s, 1H), 7.90 (d, J = 9.9 Hz, 1H), 7.25 (d, J = 10.0 Hz, 1H), 4.35 (s, 4H), 3.51 (t, J = 5.5 Hz, 4H), 2.54 (s, 3H), 1.91 (t, J = 5.7 Hz, 4H). ¹³C NMR (126 MHz, DMSO) δ 155.0, 151.7, 147.7, 141.9, 137.3, 130.8, 126.6, 126.0, 125.5, 118.4, 114.0, 111.0, 80.9, 43.7, 38.9, 33.8, 12.6. [0232] Example 93: (2S,6R)-2,6-dimethyl-4-(3-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)imidazo[1,2- b]pyridazin-6-yl)morpholine (85) ¹H NMR (500 MHz, DMSO) δ 9

. , , . , ), 8.00 (d, J = 9.9 Hz, 1H), 7.93 (d, J = 9.8 Hz, 1H), 7.80 (d, J = 9.6 Hz, 1H), 7.33 (d, J = 10.0 Hz, 1H), 4.11 (d, J = 12.2 Hz, 2H), 3.73 (d, J = 8.6 Hz, 2H), 2.74 (s, 3H), 2.62 (t, J = 11.5 Hz, 2H), 1.20 (d, J = 6.2 Hz, 7H). ¹³C NMR   (126 MHz, DMSO) δ 155.6, 148.2, 144.7, 138.4, 132.5, 126.7, 126.4, 123.2, 118.7, 115.9, 115.8, 111.2, 71.3, 51.5, 19.2, 10.2. [0233] Example 94: (2S,6R)-4-(3-([1,2,4]triazolo[4,3-a]pyridin-6-yl)imidazo[1,2-b]pyridazin-6-yl)-2,6- dimethylmorpholine (86) ¹H NMR (500 MHz, DMSO) δ 9.30 (s, 1H), 8.14 (s, 1H), 8.03 – 7.94

(m, 2H), 7.88 (d, J = 9.6 Hz, 1H), 7.32 (d, J = 10.0 Hz, 1H), 4.16 – 4.07 (m, 2H), 3.71 (ddt, J = 13.7, 7.3, 3.6 Hz, 2H), 2.60 (dd, J = 12.8, 10.6 Hz, 3H), 1.20 (d, J = 6.2 Hz, 6H).¹³C NMR (126 MHz, DMSO) δ 155.4, 147.9, 138.2, 137.9, 132.4, 127.9, 126.8, 123.3, 120.7, 116.3, 115.7, 111.3, 71.2, 51.5, 19.2. [0234] Example 95: 6-(6-((2S,6R)-2,6-dimethylmorpholino)imidazo[1,2-b]pyridazin-3-yl)imidazo[1,2- a]pyridine-3-carbonitrile (87) ¹H NMR (500 MHz, DMSO) δ 9.5

41 (d, J = 1.2 Hz, 1H), 8.22 (d, J = 2.4 Hz, 1H), 8.10 (dq, J = 9.5, 1.8 Hz, 1H), 7.95 (dd, J = 10.0, 2.7 Hz, 1H), 7.90 – 7.86 (m, 1H), 7.29 (dd, J = 10.0, 2.4 Hz, 1H), 4.04 (d, J = 12.5 Hz, 2H), 3.73 – 3.64 (m, 2H), 2.59 (t, J = 11.6 Hz, 2H), 1.20 (d, J = 6.2 Hz, 6H).¹³C NMR (126 MHz, DMSO) δ 155.5, 145.8, 143.5, 138.5, 132.8, 127.8, 126.7, 122.8, 121.3, 118.4, 118.0, 111.9, 111.3, 98.8, 71.4, 51.4, 19.3. [0235] Example 96: (2S,6R)-2,6-dimethyl-4-(3-(2-methylimidazo[1,2-a]pyridin-7-yl)imidazo[1,2-b]pyridazin-6- yl)morpholine (88)   ¹H NMR (500 MHz, DMSO) δ 9.3 8.01 (s, 1H), 7.92 (d, J = 9.9 Hz, 1H),

7.71 (dd, J = 9.4, 1.8 Hz, 1H), 7.65 (s, 1H), 7.50 (d, J = 9.4 Hz, 1H), 7.23 (d, J = 9.9 Hz, 1H), 4.09 – 3.98 (m, 2H), 3.69 (dqd, J = 12.4, 6.0, 2.1 Hz, 2H), 2.56 (dd, J = 12.7, 10.6 Hz, 2H), 2.33 (s, 3H), 1.18 (d, J = 6.2 Hz, 6H).¹³C NMR (126 MHz, DMSO) δ 155.2, 143.4, 137.7, 131.4, 126.7, 124.4, 123.9, 123.5, 123.0, 116.5, 114.4, 111.3, 110.7, 71.2, 51.6, 19.2, 14.7. [0236] Example 97: 4-(3-(6-fluoro-3-methyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-2,2,6,6- tetramethylmorpholine (89) ¹H NMR (500 MHz, DMSO) δ 8.7

95 (d, J = 9.9 Hz, 1H), 7.83 (d, J = 4.1 Hz, 1H), 7.40 (d, J = 11.6 Hz, 1H), 7.22 (d, J = 9.9 Hz, 1H), 3.44 (s, 4H), 2.50 (s, 3H), 1.21 (s, 12H). ¹³C NMR (126 MHz, DMSO) δ 160.0, 158.0, 155.0, 142.4, 140.1, 140.0, 136.9, 132.9, 132.8, 126.7, 122.1, 120.4, 120.3, 119.5, 111.0, 110.9, 110.2, 96.7, 96.5, 71.6, 54.3, 28.8, 12.1. [0237] Example 98: (2S,6R)-4-(3-(3-isopropyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-2,6- dimethylmorpholine (90) ¹

H NMR (500 MHz, CDCl₃) δ 10.10 (s, 1H), 8.73 (s, 1H), 7.93 – 7.80 (m, 3H), 7.52 (d, J = 8.7 Hz, 1H), 6.86 (d, J = 9.8 Hz, 1H), 3.98 – 3.92 (m, 2H), 3.83 – 3.74 (m, 2H), 3.48 (p, J = 7.0   Hz, 1H), 2.71 (dd, J = 12.6, 10.5 Hz, 2H), 1.52 (dd, J = 7.0, 1.3 Hz, 6H), 1.29 (d, J = 6.2 Hz, 6H).¹³C NMR (126 MHz, CDCl₃) δ 154.72, 153.02, 140.67, 137.39, 130.82, 128.67, 126.32, 126.27, 121.39, 118.42, 110.09, 109.10, 77.29, 71.44, 51.95, 27.81, 22.34, 19.00. [0238] Example 99: (2S,6R)-2,6-dimethyl-4-(3-(3-(trifluoromethyl)-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6- yl)morpholine (91) ¹H NMR (500 MHz, CDCl3) δ

7.96 (d, J = 8.8 Hz, 2H), 7.82 (d, J = 9.6 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H), 6.90 (d, J = 9.4 Hz, 1H), 3.98 – 3.92 (m, 2H), 3.84 – 3.77 (m, 2H), 2.76 – 2.68 (m, 2H), 1.32 (d, J = 6.2 Hz, 6H). HRMS (ESI) m/z calcd for C20H19F3N6O [M + H] ⁺ 363.9854, found 363.9856. [0239] Example 100: (2S,6R)-4-(3-(3-methoxy-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-2,6- dimethylmorpholine (92) ¹H NMR (500 MHz, CDCl3) δ 9

.77 (s, ), 8.73 (s, ), 7.93 – 7.85 (m, 2H), 7.78 (dd, J = 9.8, 1.6 Hz, 1H), 7.39 – 7.32 (m, 1H), 6.80 (dd, J = 9.9, 1.6 Hz, 1H), 4.12 (d, J = 1.6 Hz, 3H), 3.99 – 3.91 (m, 2H), 3.80 (ddd, J = 11.2, 6.4, 2.5 Hz, 2H), 2.71 (ddd, J = 12.5, 10.7, 1.7 Hz, 2H), 1.30 (dd, J = 6.2, 1.6 Hz, 6H).¹³C NMR (126 MHz, CDCl3) δ 158.54, 154.38, 141.67, 137.27, 130.37, 128.19, 126.83, 126.17, 121.05, 117.50, 112.65, 109.93, 108.80, 71.29, 56.10, 51.99, 18.85. HRMS (ESI) m/z calcd for C20H22N6O2 [M + H] ⁺ 363.9854, found 363.9856. [0240] Example 101: (2R,6R)-4-(3-(3-isopropyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-2,6- dimethylmorpholine (93)   ¹H NMR (500 MHz, CDCl3)

= 1.5, 0.8 Hz, 1H), 7.90 (s, 1H), 7.86 (dd, J = 8.7, 1.6 Hz, 1H), 7.81 (d, J = 9.9 Hz, 1H), 7.52 (dd, J = 8.7, 0.8 Hz, 1H), 6.81 (d, J = 9.9 Hz, 1H), 4.19 (ddt, J = 9.4, 6.4, 3.0 Hz, 2H), 3.64 (dd, J = 12.5, 3.4 Hz, 2H), 3.48 (p, J = 7.0 Hz, 1H), 3.27 (dd, J = 12.6, 6.3 Hz, 2H), 1.56 – 1.50 (m, 6H), 1.32 (d, J = 6.4 Hz, 6H). HRMS (ESI) m/z calcd for C22H26N6O [M + H] ⁺ 391.224634, found 391.22465. [0241] Example 102: 7-(3-(3-isopropyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-4-oxa-7- azaspiro[2.5]octane (94) ¹H NMR (500 MHz, CDCl3) δ 10

. , , . , .6, 0.8 Hz, 1H), 7.90 (s, 1H), 7.86 (dd, J = 8.7, 1.6 Hz, 1H), 7.82 (d, J = 9.9 Hz, 1H), 7.51 (dd, J = 8.8, 0.8 Hz, 1H), 6.82 (d, J = 9.9 Hz, 1H), 3.97 – 3.92 (m, 2H), 3.68 – 3.61 (m, 2H), 3.51 (s, 2H), 3.49 – 3.41 (m, 1H), 1.52 (d, J = 7.0 Hz, 6H), 0.94 – 0.88 (m, 2H), 0.69 – 0.62 (m, 2H). HRMS (ESI) m/z calcd for C₂₂H₂₄N₆O [M + H] ⁺ 389.208984, found 389.20924. [0242] Example 103: (R)-4-(3-(3-isopropyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-2-methylmorpholine (95)

  ¹H NMR (500 MHz, CDCl3) δ 8.73 (d, J = 1.4 Hz, 1H), 7.95 – 7.79 (m, 3H), 7.52 (d, J = 8.7 Hz, 1H), 6.85 (d, J = 9.7 Hz, 1H), 4.04 (ddd, J = 11.5, 3.5, 1.3 Hz, 1H), 3.98 – 3.88 (m, 2H), 3.83 – 3.70 (m, 2H), 3.47 (p, J = 7.0 Hz, 1H), 3.12 (td, J = 12.2, 3.5 Hz, 1H), 2.79 (dd, J = 12.5, 10.4 Hz, 1H), 1.52 (d, J = 6.9 Hz, 6H), 1.28 (d, J = 6.2 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 154.83, 152.97, 140.71, 137.38, 130.80, 128.70, 126.35, 126.22, 121.34, 118.52, 110.12, 108.97, 71.55, 66.24, 52.62, 46.12, 27.88, 22.24, 22.20, 18.97. HRMS (ESI) m/z calcd for C₂₁H₂₄N₆O [M + H] ⁺ 377.208984, found 377.20920. [0243] Example 104: (S)-4-(3-(3-isopropyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-2-methylmorpholine (96) ¹H NMR (500 MHz, CDCl₃) δ 8.7

4 – 7.81 (m, 3H), 7.52 (d, J = 8.7 Hz, 1H), 6.85 (d, J = 9.9 Hz, 1H), 4.04 (ddd, J = 11.5, 3.6, 1.4 Hz, 1H), 3.97 – 3.88 (m, 2H), 3.83 – 3.70 (m, 2H), 3.47 (p, J = 7.0 Hz, 1H), 3.12 (td, J = 12.2, 3.5 Hz, 1H), 2.79 (dd, J = 12.5, 10.4 Hz, 1H), 1.52 (d, J = 7.0 Hz, 6H), 1.28 (d, J = 6.2 Hz, 3H).¹³C NMR (126 MHz, CDCl3) δ 154.83, 152.94, 140.72, 137.37, 130.78, 128.69, 126.34, 126.20, 121.33, 121.28, 118.51, 110.14, 108.97, 71.55, 66.23, 52.61, 46.12, 27.88, 22.25, 22.21, 18.97. HRMS (ESI) m/z calcd for C21H24N6O [M + H] + 377.208984, found 377.20910. [0244] Example 105: 9-(3-(3-isopropyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-3-oxa-9- azaspiro[5.5]undecane (97)

  ¹H NMR (500 MHz, CDCl3) δ 8.81 – 8.74 (m, 1H), 7.93 – 7.85 (m, 2H), 7.79 (d, J = 9.9 Hz, 1H), 7.51 (d, J = 8.7 Hz, 1H), 6.89 (d, J = 9.6 Hz, 1H), 3.68 (t, J = 5.2 Hz, 2H), 3.57 (t, J = 5.9 Hz, 4H), 3.52 – 3.44 (m, 3H), 1.72 – 1.59 (m, 8H), 1.52 (d, J = 7.0 Hz, 6H). HRMS (ESI) m/z calcd for C₂₅H₃₀N₆O [M + H] ⁺ 431.255934, found 431.25555. [0245] Example 106: 9-(3-(3-isopropyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-2-oxa-9- azaspiro[5.5]undecane (98) ¹H NMR (500 MHz, CDCl3) δ

.98 – 7.85 (m, 2H), 7.77 (d, J = 9.8 Hz, 1H), 7.51 (d, J = 8.7 Hz, 1H), 6.86 (d, J = 9.8 Hz, 1H), 3.71 (t, J = 5.3 Hz, 4H), 3.62 – 3.53 (m, 4H), 3.48 (p, J = 7.0 Hz, 1H), 1.77 – 1.68 (m, 4H), 1.58 (t, J = 5.4 Hz, 4H), 1.53 (d, J = 7.0 Hz, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 155.02, 152.83, 140.73, 130.64, 128.61, 126.07, 121.44, 121.28, 118.44, 110.15, 109.48, 63.39, 42.35, 36.13, 35.21, 29.31, 27.97, 22.15. HRMS (ESI) m/z calcd for C₂₅H₃₀N₆O [M + H] ⁺ 431.255934, found 431.25608. [0246] Example 107: 1-(3-(3-isopropyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-4-methylpiperidin-4-ol (99) ¹

H NMR (500 MHz, DMSO) δ 8.90 (s, 1H), 7.98 (s, 1H), 7.91 – 7.84 (m, 2H), 7.53 (d, J = 8.7 Hz, 1H), 7.20 (d, J = 10.0 Hz, 1H), 4.42 (s, 1H), 3.87 (dt, J = 13.1, 4.2 Hz, 2H), 3.42 (ddd, J = 13.9, 9.4, 5.0 Hz, 2H), 3.39 – 3.34 (m, 1H), 1.65 – 1.54 (m, 4H), 1.40 (d, J = 7.0 Hz, 6H), 1.16 (s, 3H). HRMS (ESI) m/z calcd for C₂₂H₂₆N₆O [M + H] ⁺ 391.224634, found 391.22465.   [0247] Example 108: 6-(3-(3-isopropyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-2-oxa-6- azaspiro[3.3]heptane (100) ¹H NMR (500 MHz, DMSO) δ

), 7.94 – 7.86 (m, 2H), 7.53 (d, J = 8.7 Hz, 1H), 6.64 (d, J = 9.6 Hz, 1H), 4.73 (s, 4H), 4.25 (s, 4H), 3.41 (p, J = 6.9 Hz, 1H), 1.45 (d, J = 6.9 Hz, 6H). HRMS (ESI) m/z calcd for C₂₁H₂₂N₆O [M + H] ⁺ 375.193334, found 375.19321. [0248] Example 109: 4-(3-(3-isopropyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-2,2-dimethylmorpholine (101) ¹H NMR (500 MHz, CDCl3) δ 8.73

, . z, , .92 – 7.80 (m, 3H), 7.52 (dd, J = 8.8, 2.2 Hz, 1H), 6.83 (dd, J = 9.8, 2.3 Hz, 1H), 3.90 (q, J = 3.8 Hz, 2H), 3.55 (p, J = 2.7 Hz, 2H), 3.47 (pd, J = 7.0, 2.3 Hz, 1H), 3.36 (d, J = 2.3 Hz, 2H), 1.55 – 1.47 (m, 6H), 1.34 – 1.27 (m, 6H). [0249] Example 110: 4-(3-(3-methoxy-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-2,2-dimethylmorpholine (102)

  ¹H NMR (500 MHz, CDCl3) δ 9.17 (s, 1H), 8.64 (s, 1H), 7.97 – 7.90 (m, 1H), 7.88 (s, 1H), 7.84 – 7.78 (m, 1H), 7.39 (d, J = 8.5 Hz, 1H), 6.82 (dd, J = 9.8, 1.6 Hz, 1H), 4.13 (d, J = 1.5 Hz, 3H), 3.95 – 3.87 (m, 2H), 3.53 (t, J = 5.1 Hz, 2H), 3.41 (s, 2H), 1.36 (d, J = 1.7 Hz, 6H). [0250] Example 111: 4-(3-(3-isopropyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-2,2,6,6- tetramethylmorpholine (103) O ¹H NMR (500 MHz, CDCl₃) δ 8

91 – 7.79 (m, 3H), 7.53 (dd, J = 8.5, 1.7 Hz, 1H), 6.82 (dd, J = 9.8, 1.8 Hz, 1H), 3.48 (pd, J = 7.1, 1.9 Hz, 1H), 3.43 (d, J = 1.8 Hz, 4H), 1.53 (dd, J = 7.0, 1.8 Hz, 6H), 1.33 (d, J = 1.8 Hz, 12H). [0251] Example 112: 6-(3-(3-isopropyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-2-oxa-6-azaspiro [3.4]octane (104) O ¹H NMR (500 MHz, DMSO) δ 9.

05 (d, J = 7.1 Hz, 1H), 8.01 – 7.96 (m, 1H), 7.95 – 7.89 (m, 1H), 7.89 – 7.84 (m, 1H), 7.52 (t, J = 8.3 Hz, 1H), 6.84 (t, J = 9.1 Hz, 1H), 4.63 – 4.52 (m, 4H), 3.82 (d, J = 7.1 Hz, 2H), 3.58 – 3.50 (m, 2H), 3.44 – 3.38 (m, 1H), 2.34 – 2.27 (m, 2H), 1.45 (dd, J = 8.6, 6.7 Hz, 6H). ¹³C NMR (126 MHz, DMSO) δ 152.77, 151.25, 140.60, 137.19, 130.39, 127.35, 126.41, 125.15, 121.24, 120.89, 117.24, 110.99, 109.38, 80.43, 56.28, 46.31, 45.24, 34.90, 27.84, 22.68. [0252] Example 113:   8-(3-(3-isopropyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-2-oxa-8- azaspiro[4.5]decane (105) ¹H NMR (500 MHz, CDCl3) δ 8.

1H), 7.94 – 7.86 (m, 2H), 7.83 (d, J = 9.9 Hz, 1H), 7.52 (dd, J = 8.7, 0.8 Hz, 1H), 6.92 (d, J = 9.9 Hz, 1H), 3.92 (t, J = 7.1 Hz, 2H), 3.68 – 3.53 (m, 6H), 3.46 (p, J = 7.0 Hz, 1H), 1.84 (t, J = 7.1 Hz, 2H), 1.76 (ddd, J = 6.9, 4.5, 2.7 Hz, 4H), 1.52 (d, J = 7.0 Hz, 6H). [0253] Example 114: 7-(3-(3-isopropyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-2-oxa-7- azaspiro[3.5]nonane (106) ¹H NMR (500 MHz, CDCl₃) δ 8.

(s, ), . – . (m, 2H), 7.80 (d, J = 9.8 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H), 6.87 (d, J = 9.7 Hz, 1H), 4.50 (d, J = 1.4 Hz, 4H), 3.56 – 3.45 (m, 5H), 2.06 – 1.98 (m, 4H), 1.54 (dd, J = 7.0, 1.3 Hz, 6H). [0254] Example 115: 4-(3-(3-cyclopropyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-2,2,6,6- tetramethylmorpholine (107)     ¹H NMR (500 MHz, DMSO) δ 8.

7.95 – 7.86 (m, 2H), 7.52 (d, J = 8.7 Hz, 1H), 7.17 (d, J = 9.9 Hz, 1H), 3.48 (s, 4H), 2.25 (tt, J = 8.1, 5.3 Hz, 1H), 1.22 (s, 12H), 1.06 – 0.94 (m, 4H) ¹³C NMR (126 MHz, DMSO) δ 155.19, 147.21, 140.52, 137.31, 132.51, 131.99, 131.92, 130.94, 129.28, 129.19, 127.81, 126.76, 125.59, 121.95, 121.20, 116.75, 111.08, 109.56, 71.60, 54.51, 28.80, 28.75, 8.60, 7.80. HRMS (ESI), m/z calcd for C24H28N6O [M+H]⁺ 417.2403, found 417.2401. [0255] Example 116: (1S,4S)-5-(3-(3-cyclopropyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-2-oxa-5- azabicyclo[2.2.1]heptane (108) ¹H NMR (500 MHz, DMSO) δ 8.7

, . , , 7.96 (dd, J = 8.8, 1.6 Hz, 1H), 7.94 (s, 1H), 7.87 (d, J = 10.0 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.16 (d, J = 10.0 Hz, 1H), 4.35 (tt, J = 11.7, 4.1 Hz, 1H), 3.94 (dd, J = 11.2, 4.4 Hz, 2H), 3.44 (td, J = 11.7, 1.8 Hz, 2H), 2.99 (s, 3H), 2.28 (tt, J = 8.0, 5.3 Hz, 1H), 1.82 (qd, J = 12.1, 4.7 Hz, 2H), 1.67 – 1.60 (m, 2H), 0.98 (tt, J = 7.4, 2.4 Hz, 4H).¹³C NMR (126 MHz, DMSO) δ 154.42, 147.30, 140.50, 137.06, 130.62, 127.84, 126.41, 125.57, 122.22, 121.36, 117.13, 110.82, 109.59, 67.14, 53.58, 40.50, 30.45, 30.13, 8.40, 7.92. HRMS (ESI), m/z calcd for C₂₁H₂₀N₆O [M+H]⁺ 373.1777, found 373.1776. [0256] Example 117: 3-(3-(3-cyclopropyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazine-6-yl)-8-oxa-3- azabicyclo[3.2.1]octane (109)   ¹H NMR (500 MHz, DMSO) δ 8.

8.00 (s, 1H), 7.94 – 7.88 (m, 2H), 7.51 (d, J = 8.7 Hz, 1H), 7.11 (d, J = 10.0 Hz, 1H), 4.49 – 4.45 (m, 2H), 3.82 (d, J = 12.1 Hz, 2H), 3.15 (dd, J = 12.3, 2.6 Hz, 2H), 2.27 (tt, J = 7.5, 5.6 Hz, 1H), 1.91 – 1.80 (m, 4H), 1.07 – 0.98 (m, 4H). ¹³C NMR (126 MHz, DMSO) δ 155.28, 147.33, 140.51, 137.44, 131.03, 127.93, 126.65, 126.35, 125.51, 121.91, 121.09, 116.97, 111.01, 110.90, 109.98, 71.31, 65.92, 52.30, 52.17, 45.99, 45.74, 19.19, 8.64, 7.66, 7.59. HRMS (ESI), m/z calcd for C₂₂H₂₂N₆O [M+H]⁺ 387.1933, found 387.1932. [0257] Example 118: (R)-4-(3-(3-cyclopropyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-2-methylmorpholine (110) H_N ^N O ¹H NMR (500 MHz, DMSO) δ 8.7

, . z, , 8.01 (s, 1H), 7.95 – 7.87 (m, 2H), 7.51 (d, J = 8.7 Hz, 1H), 7.20 (d, J = 9.9 Hz, 1H), 4.09 – 3.91 (m, 3H), 3.65 (ddt, J = 11.9, 8.5, 2.6 Hz, 2H), 2.98 (td, J = 12.3, 3.5 Hz, 1H), 2.67 (dd, J = 12.6, 10.4 Hz, 1H), 2.26 (p, J = 6.7 Hz, 1H), 1.16 (d, J = 6.2 Hz, 3H), 0.99 (d, J = 6.6 Hz, 4H). ¹³C NMR (126 MHz, DMSO) δ 155.8, 147.3, 140.5, 137.4, 130.9, 127.7, 126.5, 125.4, 121.7, 121.2, 117.0, 111.0, 109.2, 73.3, 51.7, 28.2, 9.0, 7.2. HRMS (ESI), m/z calcd for C21H22N6O [M+H]⁺ 375.1933, found 375.1932. [0258] Example 119: (S)-4-(3-(3-cyclopropyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-2-methylmorpholine (111)   ¹H NMR (500 MHz, DMSO) δ 8.8

.01 (s, 1H), 7.96 – 7.87 (m, 2H), 7.51 (d, J = 8.7 Hz, 1H), 7.21 (d, J = 9.9 Hz, 1H), 4.06 (dt, J = 12.5, 2.1 Hz, 1H), 4.03 – 3.91 (m, 2H), 3.66 (ddt, J = 11.9, 6.6, 4.3 Hz, 2H), 2.99 (td, J = 12.3, 3.5 Hz, 1H), 2.67 (dd, J = 12.6, 10.4 Hz, 1H), 2.26 (p, J = 6.7 Hz, 1H), 1.16 (d, J = 6.2 Hz, 3H), 0.99 (d, J = 6.7 Hz, 4H). ¹³C NMR (126 MHz, DMSO) δ 155.3, 147.3, 140.5, 137.4, 131.0, 127.9, 126.7, 125.5, 121.9, 121.1, 117.0, 111.0, 110.0, 71.3, 65.9, 52.3, 46.0, 19.2, 8.6, 7.7, 7.6. HRMS (ESI), m/z calcd for C₂₁H₂₂N₆O [M+H]⁺ 375.1933, found 375.1932. [0259] Example 120: (1R,4R)-5-(3-(3-cyclopropyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-2-oxa-5- azabicyclo[2.2.1]heptane (112) ¹H NMR (500 MHz, DMSO) δ 8.8

, . , , 8.05 – 7.84 (m, 3H), 7.51 (d, J = 8.7 Hz, 1H), 6.94 (d, J = 9.7 Hz, 1H), 4.89 (s, 1H), 4.72 (t, J = 1.7 Hz, 1H), 3.88 – 3.77 (m, 2H), 3.62 (dd, J = 10.0, 1.5 Hz, 1H), 3.45 (d, J = 10.0 Hz, 1H), 2.25 (tt, J = 6.5, 5.4 Hz, 1H), 2.02 – 1.89 (m, 2H), 1.05 – 0.90 (m, 4H). ¹³C NMR (126 MHz, DMSO) δ 152.92, 147.28, 140.52, 137.31, 130.53, 127.59, 126.64, 125.40, 121.87, 121.30, 116.96, 111.02, 110.96, 109.95, 76.05, 72.84, 57.72, 57.03, 36.73, 8.67, 7.37, 7.28. HRMS (ESI), m/z calcd for C21H20N6O [M+H]⁺ 373.1777, found 373.1776. [0260] Example 121: 3-(3-cyclopropyl-1H-indazol-5-yl)-6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazine (113)   ¹H NMR (500 MHz, DMSO) δ 8

00 (s, 1H), 7.94 – 7.88 (m, 2H), 7.51 (d, J = 8.7 Hz, 1H), 7.21 (d, J = 9.9 Hz, 1H), 3.59 – 3.54 (m, 4H), 2.47 (s, 4H), 2.23 (s, 4H), 1.04 – 0.97 (m, 4H). ¹³C NMR (126 MHz, DMSO) δ 155.28, 147.29, 140.53, 137.31, 130.93, 127.85, 126.57, 125.46, 121.77, 121.15, 116.98, 111.02, 110.07, 54.59, 46.23, 46.04, 8.82, 7.22. HRMS (ESI), m/z calcd for C21H23N7 [M+H]⁺ 374.2093, found 374.2092.310.0 mg [0261] Example 122: 1-(4-(3-(3-cyclopropyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)ethan- 1-one (114) ¹H NMR (500 MHz, DMSO) δ 8.

. , , . s, 1H), 7.97 – 7.90 (m, 2H), 7.52 (d, J = 8.8 Hz, 1H), 7.23 (d, J = 9.9 Hz, 1H), 3.68 – 3.49 (m, 8H), 2.28 (tt, J = 7.6, 5.7 Hz, 1H), 2.05 (s, 3H), 1.05 – 0.98 (m, 4H). ¹³C NMR (126 MHz, DMSO) δ 168.96, 155.08, 147.31, 140.58, 137.33, 131.04, 128.00, 126.73, 125.50, 121.84, 121.07, 117.21, 111.01, 110.22, 46.50, 46.12, 45.48, 40.67, 40.49, 40.42, 40.33, 40.25, 40.16, 39.99, 39.83, 39.66, 39.49, 21.71, 8.78, 7.29. HRMS (ESI), m/z calcd for C22H23N7O [M+H]⁺ 402.2042, found 402.2034. [0262] Example 123: 1-(3-(3-cyclopropyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-4-methylpiperidin-4- amine (115)   H_N ^N H₂ ¹H NMR (500 MHz, MeOD)

H), 7.88 – 7.80 (m, 2H), 7.77 (d, J = 10.0 Hz, 1H), 7.47 (dd, J = 8.7, 0.8 Hz, 1H), 7.16 (d, J = 9.9 Hz, 1H), 4.02 (dt, J = 14.2, 4.6 Hz, 2H), 3.44 – 3.30 (m, 4H), 2.24 (tt, J = 7.9, 6.1 Hz, 1H), 2.01 – 1.85 (m, 4H), 1.49 (s, 3H), 1.07 – 1.00 (m, 4H). ¹³C NMR (126 MHz, DMSO) δ 158.6, 147.5, 140.7, 138.2, 131.9, 129.0, 128.8, 125.6, 122.0, 120.3, 117.7, 116.0, 114.1, 112.2, 111.1, 110.6, 65.7, 65.5, 65.3, 40.5, 40.4, 8.5, 7.5. HRMS (ESI), m/z calcd for C₂₂H₂₅N₇ [M+H]⁺ 356.1323, found 356.1314. [0263] Example 124: (S)-4-(3-(3-cyclopropyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-3-methylmorpholine (116) ¹H NMR (500 MHz, DMSO) δ 8.

, . z, , 8.13 (d, J = 9.7 Hz, 1H), 7.88 (d, J = 2.5 Hz, 1H), 7.42 (d, J = 11.1 Hz, 1H), 7.00 (d, J = 9.6 Hz, 1H), 5.15 (tt, J = 6.1, 2.8 Hz, 1H), 3.30 – 3.22 (m, 2H), 3.14 (s, 1H), 3.12 – 2.96 (m, 2H), 2.50 (s, 4H), 2.44 – 2.37 (m, 2H), 2.36 – 2.27 (m, 2H), 2.04 – 1.85 (m, 2H).¹³C NMR (126 MHz, DMSO) δ 154.42, 147.33, 140.55, 137.31, 131.97, 130.90, 127.89, 126.73, 125.49, 121.88, 121.14, 117.01, 111.02, 110.42, 109.37, 70.84, 66.44, 48.56, 48.38, 40.65, 13.23, 8.66, 7.34. HRMS (ESI), m/z calcd for C₂₁H₂₂N₆O [M+H]⁺ 375.1933, found 375.1922. [0264] Example 125: (R)-4-(3-(3-cyclopropyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-3-methylmorpholine (117)   ¹H NMR (500 MHz, DMSO) δ 8.7

.00 (s, 1H), 7.96 – 7.88 (m, 2H), 7.51 (d, J = 8.8 Hz, 1H), 7.17 (d, J = 10.0 Hz, 1H), 4.30 (d, J = 7.2 Hz, 1H), 3.98 (dd, J = 11.4, 3.6 Hz, 1H), 3.83 (dd, J = 13.4, 2.9 Hz, 1H), 3.79 – 3.64 (m, 2H), 3.58 (td, J = 11.8, 3.0 Hz, 1H), 2.25 (tt, J = 8.1, 5.2 Hz, 1H), 1.22 (d, J = 6.7 Hz, 3H), 1.19 – 1.10 (m, 1H), 0.98 (tt, J = 7.8, 2.4 Hz, 4H). ¹³C NMR (126 MHz, DMSO) δ 154.43, 147.35, 140.54, 137.34, 130.92, 127.91, 126.74, 125.50, 121.89, 121.15, 117.01, 111.02, 109.37, 70.85, 66.45, 48.56, 40.65, 13.23, 8.66, 7.34. HRMS (ESI), m/z calcd for C21H22N6O [M+H]⁺ 375.1933, found 375.1923. [0265] Example 126: (2R,6R)-4-(3-(3-cyclopropyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-2,6- dimethylmorpholine (118) ¹H NMR (500 MHz, DMSO) δ 8.

( , . z, ), .99 (s, 1H), 7.95 – 7.85 (m, 2H), 7.51 (d, J = 8.8 Hz, 1H), 7.18 (d, J = 9.9 Hz, 1H), 4.09 (pd, J = 6.3, 3.2 Hz, 2H), 3.64 (dd, J = 12.6, 3.4 Hz, 2H), 3.28 (dd, J = 12.6, 6.3 Hz, 2H), 2.26 (tt, J = 7.2, 6.0 Hz, 1H), 1.19 (d, J = 6.4 Hz, 6H), 1.03 – 0.95 (m, 4H). ¹³C NMR (126 MHz, DMSO) δ 155.57, 147.30, 140.51, 137.36, 130.95, 127.85, 126.63, 125.52, 121.89, 121.14, 116.90, 111.02, 109.91, 65.77, 50.96, 50.75, 18.20, 18.11, 8.69, 7.67, 7.57. HRMS (ESI), m/z calcd for C₂₂H₂₄N₆O [M+H]⁺ 389.2090, found 389.2081. [0266] Example 127: 7-(3-(3-cyclopropyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-4-oxa-7- azaspiro[2.5]octane (119)   ¹H NMR (500 MHz, DMSO) δ 8.7

(s, 1H), 7.98 – 7.85 (m, 3H), 7.51 (d, J = 8.7 Hz, 1H), 7.20 (d, J = 9.9 Hz, 1H), 3.86 – 3.81 (m, 2H), 3.63 (t, J = 4.9 Hz, 2H), 2.24 (tdd, J = 9.6, 5.7, 2.5 Hz, 1H), 2.07 (s, 1H), 0.99 (q, J = 3.1 Hz, 4H), 0.79 – 0.74 (m, 2H), 0.67 – 0.60 (m, 2H).¹³C NMR (126 MHz, DMSO) δ 155.44, 131.00, 127.98, 126.63, 125.55, 121.84, 121.08, 117.03, 111.06, 110.13, 65.38, 58.65, 51.75, 46.06, 21.52, 11.55, 8.67, 7.71, 7.50. HRMS (ESI), m/z calcd for C₂₂H₂₂N₆O [M+H]⁺ 387.1933, found 387.1925. [0267] Example 128: 4-(3-(3-cyclopropyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-2,2-dimethylmorpholine (120) N HN O ¹H NMR (500 MHz, DMSO) δ 8.7

, . , . , H), 7.99 (s, 1H), 7.94 – 7.85 (m, 2H), 7.51 (dd, J = 8.8, 0.8 Hz, 1H), 7.19 (d, J = 9.9 Hz, 1H), 3.79 (dd, J = 6.1, 4.0 Hz, 2H), 3.55 – 3.49 (m, 2H), 3.39 (s, 2H), 2.25 (dq, J = 7.5, 6.6 Hz, 1H), 1.22 (s, 6H), 1.00 – 0.98 (m, 4H).¹³C NMR (126 MHz, DMSO) δ 155.51, 130.91, 127.91, 126.62, 125.54, 121.87, 121.10, 116.97, 110.01, 71.22, 60.02, 55.36, 46.07, 24.77, 24.69, 8.67, 7.54. HRMS (ESI), m/z calcd for C₂₂H₂₄N₆O [M+H]⁺ 389.2090, found 387.2080. [0268] Example 129: 4-(3-(3-cyclopropyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-2-ethylmorpholine (121)   ¹H NMR (500 MHz, DMSO) δ 8.7

(s, 1H), 7.96 – 7.88 (m, 2H), 7.51 (dd, J = 8.8, 0.8 Hz, 1H), 7.22 (d, J = 9.9 Hz, 1H), 4.05 (dt, J = 12.6, 2.1 Hz, 1H), 4.02 – 3.90 (m, 2H), 3.64 (td, J = 11.7, 2.8 Hz, 1H), 3.48 – 3.40 (m, 1H), 3.01 (td, J = 12.3, 3.6 Hz, 1H), 2.70 (dd, J = 12.6, 10.4 Hz, 1H), 2.26 (p, J = 6.8 Hz, 1H), 1.50 (p, J = 7.4 Hz, 2H), 1.03 – 0.96 (m, 4H), 0.94 (t, J = 7.5 Hz, 3H). ¹³C NMR (126 MHz, DMSO) δ 155.34, 147.34, 140.53, 137.42, 131.03, 127.98, 126.65, 125.55, 121.96, 121.11, 117.08, 110.97, 110.05, 76.40, 65.94, 50.84, 46.28, 26.39, 10.18, 8.61, 7.72. [0269] Example 130: 1-(4-(3-(3-ethyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)ethan-1-one (122) ¹H NMR (500 MHz, DMSO) δ

. , . , , 7.99 (s, 1H), 7.97 – 7.87 (m, 2H), 7.54 (d, J = 8.7 Hz, 1H), 7.22 (d, J = 9.9 Hz, 1H), 3.60 (d, J = 3.6 Hz, 6H), 3.54 (dd, J = 6.8, 3.8 Hz, 2H), 2.96 (q, J = 7.6 Hz, 2H), 2.05 (s, 3H), 1.34 (t, J = 7.6 Hz, 3H).¹³C NMR (126 MHz, DMSO) δ 168.97, 155.02, 147.49, 140.47, 137.29, 130.99, 128.03, 126.73, 125.37, 121.76, 120.96, 117.38, 110.94, 110.21, 46.50, 46.09, 45.47, 21.72, 20.42, 14.12. HRMS (ESI), m/z calcd for C₂₁H₂₃N₇O [M+H]⁺ 390.2042, found 390.2029. [0270] Example 131: (3aR,6aS)-5-(3-(3-cyclopropyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)hexahydro- 1H-furo[3,4-c]pyrrole (123)   ¹H NMR (500 MHz, DMSO) δ

5.2 Hz, 2H), 7.91 – 7.83 (m, 1H), 7.51 (d, J = 8.8 Hz, 1H), 6.90 (d, J = 9.8 Hz, 1H), 3.88 – 3.82 (m, 2H), 3.72 (dd, J = 11.1, 6.7 Hz, 2H), 3.60 (dt, J = 12.4, 6.1 Hz, 2H), 3.48 (dd, J = 10.5, 3.0 Hz, 2H), 3.07 (dq, J = 7.4, 3.8 Hz, 2H), 2.27 (tt, J = 8.3, 5.4 Hz, 1H), 1.00 (t, J = 6.7 Hz, 4H). HRMS (ESI), m/z calcd for C₂₂H₂₂N₆O [M+H]⁺ 387.1933, found 387.1926. [0271] Example 132: 6-(3-(3-cyclopropyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-2-oxa-6- azaspiro[3.4]octane (124) ¹H NMR (500 MHz, DMSO) δ

. , , . . m, 2H), 7.86 (d, J = 9.7 Hz, 1H), 7.51 (d, J = 8.7 Hz, 1H), 6.82 (d, J = 9.8 Hz, 1H), 4.60 – 4.53 (m, 4H), 3.81 (s, 2H), 3.53 (t, J = 6.9 Hz, 2H), 2.29 (dd, J = 7.8, 5.9 Hz, 3H), 1.08 – 1.01 (m, 4H). [0272] Example 133: (S)-4-(3-(3-ethyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-2-methylmorpholine (125)

  ¹H NMR (500 MHz, DMSO) δ 8.81 (s, 1H), 8.01 (s, 1H), 7.96 – 7.88 (m, 2H), 7.53 (d, J = 8.7 Hz, 1H), 7.21 (d, J = 9.9 Hz, 1H), 4.10 – 4.03 (m, 1H), 4.02 – 3.91 (m, 2H), 3.66 (ddt, J = 11.6, 8.9, 2.4 Hz, 2H), 3.02 – 2.95 (m, 2H), 2.94 (d, J = 7.5 Hz, 1H), 2.67 (dd, J = 12.6, 10.4 Hz, 1H), 1.33 (t, J = 7.6 Hz, 3H), 1.18 (d, J = 6.2 Hz, 3H).¹³C NMR (126 MHz, DMSO) δ 155.3, 147.5, 140.4, 137.4, 131.0, 127.9, 126.7, 125.4, 121.8, 121.0, 117.1, 110.9, 110.0, 71.3, 65.9, 52.3, 46.0, 20.4, 19.2, 14.1. [0273] Example 134: 3-(3-(3-ethyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-8-oxa-3- azabicyclo[3.2.1]octane (126) H_N ^{N 1}H NMR (500 MHz, DMSO) δ 8.

, 7.94 – 7.89 (m, 2H), 7.53 (d, J = 8.7 Hz, 1H), 7.13 (d, J = 9.9 Hz, 1H), 4.47 (s, 2H), 3.82 (d, J = 12.1 Hz, 2H), 3.14 (dd, J = 12.3, 2.6 Hz, 2H), 2.96 (q, J = 7.6 Hz, 2H), 1.88 – 1.83 (m, 4H), 1.34 (t, J = 7.6 Hz, 3H). [0274] Example 135: (R)-4-(3-(3-ethyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-2-methylmorpholine (127) H_N ^N O ¹H NMR (500 MHz, DMSO) δ 8.8

1 (s, 1H), 8.02 (s, 1H), 7.96 – 7.87 (m, 2H), 7.53 (d, J = 8.7 Hz, 1H), 7.21 (d, J = 9.9 Hz, 1H), 4.10 – 4.01 (m, 1H), 3.96 (ddd, J = 15.1, 11.9, 2.7 Hz, 2H), 3.71 – 3.61 (m, 2H), 3.02 – 2.95 (m, 2H), 2.95 – 2.88 (m, 1H), 2.67 (dd, J = 12.6, 10.4 Hz, 1H), 1.33 (t, J = 7.6 Hz, 3H), 1.18 (d, J = 6.2 Hz, 3H). [0275] Example 136:   (1S,4S)-5-(3-(3-ethyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-2-oxa-5- azabicyclo[2.2.1]heptane (128) ¹H NMR (500 MHz, DMSO) δ

(m, 2H), 7.90 (d, J = 9.7 Hz, 1H), 7.53 (d, J = 8.7 Hz, 1H), 6.94 (d, J = 9.8 Hz, 1H), 4.88 (s, 1H), 4.72 (t, J = 1.7 Hz, 1H), 3.82 (s, 2H), 3.61 (dd, J = 9.9, 1.5 Hz, 1H), 3.43 (d, J = 10.0 Hz, 1H), 2.94 (q, J = 7.6 Hz, 2H), 2.00 (dd, J = 9.8, 2.3 Hz, 1H), 1.96 – 1.85 (m, 1H), 1.33 (t, J = 7.6 Hz, 3H). ¹³C NMR (126 MHz, DMSO) δ 110.5 (d, J = 100.1 Hz), 40.2 (d, J = 20.9 Hz), 40.0, 39.7 (d, J = 21.0 Hz). [0276] Example 137: (1R,4R)-5-(3-(3-ethyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-2-oxa-5- azabicyclo[2.2.1]heptane (129) ¹H NMR (500 MHz, DMSO) δ 8.

(s, ), . – . 2 (m, 2H), 7.89 (d, J = 9.7 Hz, 1H), 7.53 (d, J = 8.7 Hz, 1H), 6.94 (d, J = 9.8 Hz, 1H), 4.87 (s, 1H), 4.74 – 4.70 (m, 1H), 3.82 (s, 2H), 3.61 (dd, J = 10.0, 1.5 Hz, 1H), 3.43 (d, J = 10.0 Hz, 1H), 2.94 (q, J = 7.6 Hz, 2H), 2.00 (dd, J = 9.9, 2.3 Hz, 1H), 1.95 – 1.90 (m, 1H), 1.33 (t, J = 7.6 Hz, 3H). [0277] Example 138: (S)-4-(3-(3-ethyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-3-methylmorpholine (130)   ¹H NMR (500 MHz, DMSO) δ 8

8.00 (s, 1H), 7.93 (dd, J = 10.2, 2.2 Hz, 2H), 7.53 (d, J = 8.7 Hz, 1H), 7.16 (d, J = 10.0 Hz, 1H), 4.29 (p, J = 6.4 Hz, 1H), 3.96 (dd, J = 11.4, 3.7 Hz, 1H), 3.81 (dd, J = 13.2, 2.9 Hz, 1H), 3.78 – 3.69 (m, 2H), 3.58 (td, J = 11.8, 3.0 Hz, 1H), 3.26 (td, J = 12.6, 3.8 Hz, 1H), 2.94 (q, J = 7.6 Hz, 2H), 1.32 (t, J = 7.6 Hz, 3H), 1.22 (d, J = 6.7 Hz, 3H). ¹³C NMR (126 MHz, DMSO) δ 154.4, 147.5, 140.4, 137.3, 130.9, 127.9, 126.7, 125.4, 121.8, 121.1, 117.2, 110.9, 109.3, 70.8, 66.5, 48.5, 40.7, 20.4, 14.1, 13.2. [0278] Example 139: (R)-4-(3-(3-ethyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-3-methylmorpholine (131) H_N ^N O ¹H NMR (500 MHz, DMSO) δ 8

. , . , , 8.00 (s, 1H), 7.96 – 7.88 (m, 2H), 7.53 (d, J = 8.7 Hz, 1H), 7.16 (d, J = 10.0 Hz, 1H), 4.29 (q, J = 4.4 Hz, 1H), 3.96 (dd, J = 11.4, 3.7 Hz, 1H), 3.81 (dd, J = 13.1, 2.9 Hz, 1H), 3.78 – 3.68 (m, 2H), 3.58 (td, J = 11.8, 3.1 Hz, 1H), 3.26 (td, J = 12.6, 3.8 Hz, 1H), 2.94 (q, J = 7.6 Hz, 2H), 1.32 (t, J = 7.6 Hz, 3H), 1.22 (d, J = 6.7 Hz, 3H). ¹³C NMR (126 MHz, DMSO) δ 154.4, 147.5, 140.4, 137.3, 130.9, 127.9, 126.7, 125.4, 121.8, 121.1, 117.2, 110.9, 109.3, 70.8, 66.5, 48.5, 40.7, 20.4, 14.1, 13.2. [0279] Example 140: 4-(3-(3-ethyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-2,2-dimethylmorpholine (132)   ¹H NMR (500 MHz, DMSO) δ 8

8.00 (s, 1H), 7.95 – 7.88 (m, 2H), 7.53 (d, J = 8.7 Hz, 1H), 7.21 (d, J = 9.9 Hz, 1H), 3.80 (dd, J = 6.1, 4.0 Hz, 2H), 3.52 (dd, J = 6.1, 3.9 Hz, 2H), 3.40 (s, 2H), 2.95 (q, J = 7.6 Hz, 2H), 1.34 (t, J = 7.6 Hz, 3H), 1.24 (s, 6H). ¹³C NMR (126 MHz, DMSO) δ 155.5, 147.5, 140.4, 137.4, 130.9, 127.9, 126.7, 125.4, 121.8, 121.1, 117.1, 110.9, 110.0, 71.2, 60.1, 55.3, 46.2, 24.8, 20.4, 14.1. [0280] Example 141: (2R,6R)-4-(3-(3-ethyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-2,6- dimethylmorpholine (133) ¹H NMR (500 MHz, DMSO) δ 8

. s, , . s, , 7.96 – 7.85 (m, 2H), 7.53 (d, J = 8.7 Hz, 1H), 7.19 (d, J = 9.9 Hz, 1H), 4.10 (pd, J = 6.3, 3.2 Hz, 2H), 3.64 (dd, J = 12.6, 3.4 Hz, 2H), 3.32 – 3.24 (m, 4H), 2.95 (q, J = 7.6 Hz, 2H), 1.34 (t, J = 7.6 Hz, 3H), 1.21 (d, J = 6.4 Hz, 6H). ¹³C NMR (126 MHz, DMSO) δ 155.5, 147.5, 140.4, 137.3, 130.9, 127.8, 126.6, 125.4, 121.8, 121.1, 117.0, 110.9, 109.9, 65.8, 51.0, 40.6, 20.4, 18.2, 14.2. [0281] Example 142: 7-(3-(3-ethyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-4-oxa-7-azaspiro[2.5]octane (134)   ¹H NMR (500 MHz, DMSO) δ 8.7

(s, 1H), 7.96 – 7.88 (m, 2H), 7.56 – 7.50 (m, 1H), 7.20 (d, J = 9.9 Hz, 1H), 3.84 (dd, J = 5.7, 4.0 Hz, 2H), 3.62 (dd, J = 5.8, 3.9 Hz, 2H), 3.54 (s, 2H), 2.94 (q, J = 7.6 Hz, 2H), 1.33 (t, J = 7.6 Hz, 3H), 0.80 – 0.69 (m, 2H), 0.68 – 0.61 (m, 2H). ¹³C NMR (126 MHz, DMSO) δ 155.4, 147.5, 140.4, 137.4, 131.0, 127.9, 126.6, 125.4, 121.8, 121.0, 117.2, 110.9, 110.1, 65.4, 58.6, 51.7, 46.1, 20.4, 14.1, 11.6. [0282] Example 143: 4-(3-(3-ethyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)-2,2,6,6-tetramethylmorpholine (135) ¹H NMR (500 MHz, DMSO) δ 8.8

, , . , ), 7.91 (dd, J = 14.77, 9.35 Hz, 3H), 7.64 – 7.51 (m, 3H), 7.18 (d, J = 9.88 Hz, 1H), 3.48 (s, 4H), 2.96 (d, J = 7.57 Hz, 2H), 1.35 (d, J = 7.53 Hz, 3H), 1.23 (s, 13H). [0283] Example 144: 3-(3-ethyl-1H-indazol-5-yl)-6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazine (136)

  ¹H NMR (500 MHz, DMSO) δ 8.80 (s, 1H), 8.00 (s, 1H), 7.94 – 7.88 (m, 2H), 7.53 (d, J = 8.7 Hz, 1H), 7.21 (d, J = 9.9 Hz, 1H), 3.56 (t, J = 5.0 Hz, 4H), 2.95 (q, J = 7.6 Hz, 2H), 2.48 (d, J = 1.9 Hz, 4H), 2.24 (s, 3H), 1.33 (t, J = 7.6 Hz, 3H). [0284] Example 145: 3-(3-ethyl-1H-indazol-5-yl)-6-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)imidazo[1,2- b]pyridazine (137) ¹H NMR (500 MHz, DMSO) δ 8.

), 7.90 (dd, J = 9.9, 7.5 Hz, 2H), 7.53 (d, J = 8.7 Hz, 1H), 7.22 (d, J = 9.9 Hz, 1H), 4.03 (d, J = 12.1 Hz, 2H), 2.96 (q, J = 7.6 Hz, 2H), 2.68 (t, J = 11.6 Hz, 2H), 2.26 (s, 2H), 2.19 (s, 3H), 1.34 (t, J = 7.5 Hz, 3H), 1.10 (d, J = 6.1 Hz, 6H). [0285] Example 146: 3-(3-cyclopropyl-1H-indazol-5-yl)-6-(4-fluoropiperidin-1-yl)imidazo[1,2-b]pyridazine (138) ¹H NMR (500 MHz, DMSO) δ 8

. – . m, , . (s, 1H), 7.91 (dd, J = 10.1, 2.4 Hz, 2H), 7.52 (d, J = 8.7 Hz, 1H), 7.24 (d, J = 10.0 Hz, 1H), 4.98 (tq, J = 7.0, 3.3 Hz, 1H), 4.88 (dq, J = 7.1, 3.5 Hz, 1H), 3.81 – 3.72 (m, 2H), 3.59 (ddd, J = 13.3, 7.2, 3.9 Hz, 2H), 2.24 (tt, J = 8.0, 5.3 Hz, 1H), 2.10 – 1.95 (m, 3H), 1.83 (dtt, J = 13.7, 6.6, 3.6 Hz, 2H), 1.04 – 0.94 (m, 4H). [0286] Example 147: 3-(3-cyclopropyl-1H-indazol-5-yl)-6-(4,4-difluoropiperidin-1-yl)imidazo[1,2-b]pyridazine (139)   ¹H NMR (500 MHz, DMSO) δ

(s, 1H), 7.97 – 7.89 (m, 2H), 7.52 (d, J = 8.8 Hz, 1H), 7.27 (d, J = 9.9 Hz, 1H), 3.78 – 3.72 (m, 4H), 2.25 (tt, J = 8.2, 5.2 Hz, 1H), 2.12 (tt, J = 14.0, 5.7 Hz, 4H), 1.04 – 0.94 (m, 4H). [0287] Example 148: 6-(4,4-difluoropiperidin-1-yl)-3-(3-ethyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazine (140) ¹H NMR (500 MHz, DMSO) δ

. , , . , , .93 (dd, J = 13.1, 9.4 Hz, 2H), 7.54 (d, J = 8.7 Hz, 1H), 7.28 (d, J = 10.0 Hz, 1H), 3.74 (t, J = 5.8 Hz, 4H), 2.95 (q, J = 7.6 Hz, 2H), 2.12 (tt, J = 13.9, 5.4 Hz, 4H), 1.33 (t, J = 7.5 Hz, 3H). [0288] Example 149: (2S,6R)-4-(3-(3-ethyl-1H-indazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-2,6- dimethylmorpholine (141) H_N ^{N 1}

H NMR (500 MHz, DMSO) δ 9.05 – 9.01 (m, 1H), 8.29 (dd, J = 8.8, 1.5 Hz, 1H), 8.16 (d, J = 10.2 Hz, 1H), 7.63 (dd, J = 8.8, 0.8 Hz, 1H), 7.43 (d, J = 10.2 Hz, 1H), 4.17 – 4.10 (m, 2H), 3.72   (dtt, J = 12.6, 6.3, 3.1 Hz, 2H), 2.98 (q, J = 7.6 Hz, 2H), 2.64 (dd, J = 12.8, 10.6 Hz, 2H), 1.35 (t, J = 7.6 Hz, 3H), 1.19 (d, J = 6.2 Hz, 6H). [0289] Example 150: (2S,6R)-4-(3-(3-cyclopropyl-1H-indazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-2,6- dimethylmorpholine (142) ¹H NMR (500 MHz, DMSO) δ

H), 8.13 (d, J = 2.7 Hz, 1H), 8.02 (s, 1H), 7.98 – 7.89 (m, 2H), 7.52 (dd, J = 8.8, 0.8 Hz, 1H), 7.22 (d, J = 9.9 Hz, 1H), 4.13 (s, 2H), 3.83 – 3.75 (m, 2H), 3.37 (t, J = 3.8 Hz, 2H), 2.31 (ddd, J = 8.3, 5.1, 3.3 Hz, 1H), 1.07 – 1.00 (m, 2H), 1.00 – 0.91 (m, 2H). [0290] Example 151: (3aS,6aS)-5-(3-(3-ethyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)hexahydro-1H- furo[3,4-c]pyrrole (143) ¹H NMR (500 MHz, DMSO) δ

8.88 (s, 1H), 8.00 – 7.94 (m, 2H), 7.87 (d, J = 9.8 Hz, 1H), 7.53 (d, J = 8.7 Hz, 1H), 6.89 (d, J = 9.8 Hz, 1H), 4.59 (t, J = 5.5 Hz, 1H), 3.88 (q, J = 7.5 Hz, 1H), 3.79 – 3.68 (m, 3H), 3.60 (dd, J = 11.7, 4.9 Hz, 1H), 3.40 (dd, J = 10.7, 5.6 Hz, 1H), 3.05 (s, 1H), 2.96 (q, J = 7.6 Hz, 2H), 2.12 (dq, J = 12.4, 7.7 Hz, 1H), 1.83 (dtd, J = 12.1, 6.1, 2.9 Hz, 1H), 1.35 (t, J = 7.6 Hz, 3H). [0291] Example 152: 6-(3-(1l2-difluoraneyl)pyrrolidin-1-yl)-3-(3-cyclopropyl-1H-indazol-5-yl)imidazo[1,2- b]pyridazine (144)   ¹H NMR (500 MHz, DMSO) δ 8

1 (s, 1H), 7.96 (dd, J = 9.3, 2.7 Hz, 2H), 7.52 (d, J = 8.8 Hz, 1H), 6.92 (d, J = 9.7 Hz, 1H), 4.05 – 3.95 (m, 2H), 3.79 (t, J = 7.3 Hz, 2H), 2.60 (tt, J = 14.4, 7.3 Hz, 2H), 2.27 (tt, J = 7.9, 5.9 Hz, 1H), 1.01 – 0.94 (m, 4H). [0292] Example 153: 6-(3-(1l2-difluoraneyl)pyrrolidin-1-yl)-3-(3-ethyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazine (145) ¹H NMR (500 MHz, DMSO) δ 8.

, , . , H), 8.00 – 7.93 (m, 2H), 7.54 (d, J = 8.7 Hz, 1H), 6.92 (d, J = 9.7 Hz, 1H), 4.05 – 3.94 (m, 2H), 3.79 (t, J = 7.3 Hz, 2H), 2.96 (q, J = 7.6 Hz, 2H), 2.61 (tt, J = 14.3, 7.3 Hz, 2H), 1.34 (t, J = 7.6 Hz, 3H). [0293] Example 154: (3aS,6aS)-5-(3-(3-cyclopropyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)hexahydro- 2H-thieno[2,3-c]pyrrole 1,1-dioxide (146) ¹

H NMR (500 MHz, DMSO) δ 8.91 (s, 1H), 8.02 (s, 1H), 7.97 – 7.88 (m, 2H), 7.51 (d, J = 8.7 Hz, 1H), 6.97 (d, J = 9.8 Hz, 1H), 4.17 – 4.11 (m, 1H), 3.83 (p, J = 8.5 Hz, 2H), 3.75 (dd, J =   10.5, 8.3 Hz, 1H), 3.60 (dd, J = 10.5, 4.7 Hz, 1H), 3.52 – 3.44 (m, 1H), 3.21 (ddd, J = 13.3, 10.1, 5.6 Hz, 3H), 2.29 (dddd, J = 19.4, 10.2, 8.2, 6.5 Hz, 2H), 2.01 (dq, J = 12.8, 5.9 Hz, 1H), 0.99 (d, J = 7.6 Hz, 4H). [0294] Example 155: 3-(3-ethyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazine (147) H_N ^{N 1}H NMR (500 MHz, DMSO) δ 8.64 (

7 Hz, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.23 (s, 1H), 8.19 (dd, J = 9.2, 1.6 Hz, 1H), 8.01 (dd, J = 8.7, 1.6 Hz, 1H), 7.60 – 7.58 (m, 1H), 7.26 (dd, J = 9.1, 4.4 Hz, 1H), 2.97 (q, J = 7.6 Hz, 2H), 1.35 (t, J = 7.6 Hz, 3H). [0295] Example 156: 4-(3-(3-ethyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine (148) ¹H NMR (500 MHz, DMSO) δ 8.7

(s, ), . (s, H), 7.97 – 7.93 (m, 1H), 7.93 – 7.90 (m, 1H), 7.53 (d, J = 8.7 Hz, 1H), 7.20 (d, J = 9.9 Hz, 1H), 3.77 (t, J = 4.8 Hz, 4H), 3.53 (dd, J = 5.9, 3.8 Hz, 4H), 2.95 (q, J = 7.6 Hz, 2H), 1.33 (t, J = 7.6 Hz, 3H). [0296] Example 157: 4-(3-(3-cyclopropyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine (149)   N HN O ¹H NMR (500 MHz, DMSO) δ 8.

H), 7.96 – 7.89 (m, 2H), 7.52 (d, J = 8.8 Hz, 1H), 7.21 (d, J = 9.8 Hz, 1H), 3.77 (t, J = 4.9 Hz, 4H), 3.54 (t, J = 4.9 Hz, 4H), 2.26 (tt, J = 8.1, 5.4 Hz, 1H), 1.04 – 0.94 (m, 4H). [0297] Example 158: 2-ethyl-4-(3-(3-ethyl-1H-indazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine (150) ¹H NMR (500 MHz, DMSO) δ 9

. , . , , 9.00 (t, J = 1.5 Hz, 1H), 8.10 (d, J = 1.2 Hz, 1H), 7.95 (dd, J = 9.9, 1.2 Hz, 1H), 7.25 (dd, J = 10.0, 1.2 Hz, 1H), 4.05 (d, J = 12.5 Hz, 1H), 4.01 – 3.93 (m, 2H), 3.62 (td, J = 12.1, 3.0 Hz, 1H), 3.43 (qd, J = 6.6, 3.1 Hz, 1H), 2.99 (td, J = 12.3, 3.6 Hz, 1H), 2.69 (dd, J = 12.6, 10.5 Hz, 1H), 2.51 (d, J = 1.2 Hz, 3H), 1.56 – 1.47 (m, 2H), 0.94 (td, J = 7.4, 1.2 Hz, 3H). [0298] Example 159: (2S,6R)-2,6-dimethyl-4-(3-(3-methyl-1H-indazol-5-yl)imidazo[1,2-a]pyridin-6- yl)morpholine (151)

  ¹H NMR (500 MHz, DMSO) δ 7.94 (d, J = 9.1 Hz, 1H), 7.70 (d, J = 2.2 Hz, 1H), 7.64 – 7.50 (m, 4H), 7.30 (dd, J = 9.8, 2.2 Hz, 1H), 3.76 – 3.65 (m, 2H), 3.42 (d, J = 11.2 Hz, 2H), 2.52 (s, 3H), 2.18 (t, J = 10.9 Hz, 2H), 1.10 (d, J = 6.2 Hz, 6H). [0299] Example 160: (2S,6R)-4-(3-(3-ethyl-1H-indazol-5-yl)imidazo[1,2-a]pyridin-6-yl)-2,6-dimethylmorpholine (152) ¹H NMR (500 MHz, DMSO) δ 8 7.75 (d, J = 2.2 Hz, 1H), 7.63 – 7.60

(m, 2H), 7.56 – 7.52 (m, 2H), 7.30 (dd, J = 9.8, 2.2 Hz, 1H), 3.71 (ddd, J = 10.1, 6.0, 2.1 Hz, 2H), 3.43 (d, J = 11.1 Hz, 2H), 3.21 (d, J = 11.2 Hz, 1H), 2.97 (q, J = 7.7 Hz, 2H), 2.18 (t, J = 10.9 Hz, 2H), 1.33 (t, J = 7.6 Hz, 3H), 1.09 (d, J = 6.3 Hz, 6H). [0300] Example 161: (2S,6R)-4-(3-(3-cyclopropyl-1H-indazol-5-yl)imidazo[1,2-a]pyridin-6-yl)-2,6- dimethylmorpholine (153) ¹H NMR (500 MHz, DMSO) δ 7

7.74 (d, J = 2.2 Hz, 1H), 7.63 – 7.58 (m, 3H), 7.57 – 7.52 (m, 2H), 7.31 (dd, J = 9.8, 2.2 Hz, 1H), 3.71 (ddd, J = 10.2, 6.0, 2.0 Hz, 2H), 3.43 (d, J = 11.1 Hz, 2H), 2.34 (p, J = 6.8 Hz, 1H), 2.19 (t, J = 10.9 Hz, 2H), 1.11 (d, J = 6.2 Hz, 6H), 0.98 (d, J = 6.6 Hz, 4H). [0301] EXAMPLE 162: 6-(3-(3-ethyl-1H-indazol-5-yl) imidazo[1,2-b]pyridazin-6-yl)-2-oxa-6-azaspiro[3.3]heptane (154)   ¹H NMR (500 MHz, DMSO) δ 8.78 H), 7.88 (d, J = 9.5 Hz, 1H), 7.53 (d, J = 8.7 Hz, 1H), 6.65 (d, J = 9.6 Hz, 1H)

, . s, , . s, H), 2.99 (q, J = 7.6 Hz, 2H), 1.38 (t, J = 7.6 Hz, 3H). [0302] Example 163: (2S,6R)-4-(3-(3-ethyl-1H-indazol-5-yl)-2-methylimidazo[1,2-b]pyridazin-6-yl)-2,6- dimethylmorpholine (155) ¹H NMR (500 MHz, DMSO) δ 8.17 (d, d, J = 9.8 Hz, 1H), 7.66 – 7.60 (m, 1H), 7.60 – 7.51 (m, 2H), 3.93 (dd, J = 12.9, 2.3

z, ), . ( , = 11.3, 7.6, 5.6 Hz, 2H), 2.92 (dq, J = 15.5, 7.6 Hz, 2H), 2.46 (s, J = 3.3 Hz, 3H), 2.45 – 2.40 (m, 2H), 1.33 (t, J = 7.6 Hz, 3H), 1.10 (d, J = 6.2 Hz, 6H). [0303] Example 164: (2S,6R)-4-(3-(3-ethyl-1H-indazol-5-yl)-2,8-dimethylimidazo[1,2-b] pyridazin-6-yl)-2,6- dimethylmorpholine (156) HN N O ¹H NMR (500 MHz, DMSO) δ 8.15 (

H), 7.03 (t, J = 1.3 Hz, 1H), 3.92 (d, J = 12.8 Hz, 2H), 3.69 – 3.60 (m, 2H), 2.94 (qd, J = 7.5, 1.2 Hz, 2H), 2.47 – 2.36 (d, 6H), 1.32 (td, J = 7.6, 1.3 Hz, 3H), 1.10 (dd, J = 6.2, 1.3 Hz, 6H).   [0304] 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. [0305] 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. [0306] 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. [0307] 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). [0308] 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. [0309] 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.

Claims

  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-cyclic aryl moiety represented by a structure: wherein each X dently N, S, O, CO, 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, alkoxy, alkyl, trifluoroalkyl, haloalkyl, dihaloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heteroalkyl, aminoalkyl, cyanoalkyl, dialkylaminoalkyl, morpholinylalkyl, piperazinylalkyl, dialkylaminocarbonyl, dialkylaminosulfonyl, hydroxyaryl, alkoxyaryl, carboxylic acid, ester, OR_d, and NR_dR_d, wherein each Rd is independently selected from hydrogen, alkyl, heteroalkyl and heteroaryl; wherein alkyl is optionally substituted with alkyl or heteroalkyl; The bond between X-X or X-C in a 5-membered ring can be a single bond or a 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 is independentl

y o ; each G is independently N or CR’c, wherein R’c is H, halogen or C1-C6 alkyl;   W is N or CRb, wherein Rb is selected from H, cyano, halo, alkoxy, alkyl, trifluoroalkyl, haloalkyl, dihaloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heteroalkyl, aminoalkyl, cyanoalkyl, dialkylaminoalkyl, morpholinylalkyl, piperazinylalkyl, dialkylaminocarbonyl, dialkylaminosulfonyl, hydroxyaryl, alkoxyaryl, carboxylic acid, ester, OR_d, and NR_dR_d, wherein each Rd is independently selected from alkyl, heteroalkyl and heteroaryl; wherein alkyl is optionally substituted with alkyl or heteroalkyl; and B is as defined above; (iii) Y is a 4- to 12-membered mono- 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, R_7, and R₈ is independently selected from H, halo, nitro, cyano, alkyl, aminoalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, and heteroalkyl; 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, NR_a, or CR_bR_b, wherein each R_b 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, which optionally contains one or more heteroatoms, wherein each heteroatom is independently N, S or O. 2. The compound of claim 1, wherein the B is:

 

 

   

R is H, cyano, halo, alkyl, trifluoroalkyl, haloalkyl, dihaloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heteroalkyl, aminoalkyl, cyanoalkyl, dialkylaminoalkyl, morpholinylalkyl, piperazinylalkyl, dialkylaminocarbonyl, dialkylaminosulfonyl, hydroxyaryl, alkoxyaryl, carboxylic acid, or ester; wherein alkyl group is optionally substituted with alkyl or heteroalkyl;  with the proviso that B and Y are not (a) 3-unsubstituted indazole and unsubstituted morpholine, respectively, at the same time, (b) 3-unsubstituted indazole and unsubstituted piperazine, respectively, at the same time, or (c) 3-unsubstituted indazole and methyl piperazine, respectively, at the same time.  3. The compound of claim 1, wherein the P is:

    yl, and heteroaryl.

4. A compound of formula (IA), or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof: wherein each X is independently N,

Rb, wherein Ra is selected from H, alkyl, cycloalkyl, heteroalkyl, alkylcarbonyl, arylcarbonyl, heteroalkylcarbonyl, amide, and sulfonamide; and R_b is selected from H, cyano, halo, alkoxy, alkyl, trifluoroalkyl, haloalkyl, dihaloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heteroalkyl, aminoalkyl, cyanoalkyl, dialkylaminoalkyl, morpholinylalkyl, piperazinylalkyl, dialkylaminocarbonyl, dialkylaminosulfonyl, hydroxyaryl, alkoxyaryl, carboxylic acid, ester, ORd, and NRdRd, wherein each R_d is independently selected from hydrogen, alkyl, heteroalkyl and heteroaryl; wherein alkyl is optionally substituted with alkyl or heteroalkyl; The bond between X-X or X-C in a 5-membered ring can be a single bond or a double bond; and   Y is a 4- to 12-membered mono- 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-carbo

each R₁, R₂, R₃, R₄, R₅, R₆, R_7, and R₈ is independently selected from H, halo, nitro, cyano, alkyl, aminoalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, and heteroalkyl; 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 each Rb is independently as defined above or the two R_b, together with the carbon atom to which they are attached, form a 3- to 6-membered cyclic ring, which optionally contains one or more heteroatoms, wherein each heteroatom is independently N, S or O. 5. The compound of claim 4, wherein each X is independently N, S, O, CO, NR_a or CR_b, wherein Ra is H or alkyl; and Rb is a group selected from H, cyano, halo, alkoxy, alkyl, trifluoroalkyl and cycloalkyl; wherein alkyl is optionally substituted with alkyl or heteroalkyl. 6. The compound of claim 1 or 4, wherein the Y is:

  .

7. The compound of claim 1 or 4, wherein the Y is:

. 8. The compound of claim 1 or 4, wherein the Y is:

    wher

9. The compounds of claim 8, wherein each X is independently selected from CH₂, O, S, S=O, SO2, NH, N-alkyl, N-heteroalkyl, amide, sulfonamide, urea and carbamate. 10. The compound of claim 1 or 4, wherein the Y is: NH N OH N OMe N N

  .

 

  .

12. The compound of claim 4, wherein the Y is: N OMe N N N N N O N O O O  

  .

13. A pharmaceutical composition comprising a compound of formula (I) or (IA), or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof, and a pharmaceutically acceptable carrier, excipient, or diluent. 14. A method of inhibiting transforming growth factor-β activated kinase (TAK1) in a patient in need thereof, which method comprises administering to the patient (i) a therapeutically effective amount of the compound of any one of claims 1-12, (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 TAK1 in the patient is inhibited. 15. The method of claim 14, wherein the patient has cancer or an inflammatory disease. 16. The method of claim 14, 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 1-12, (ii)a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer of (i), (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 multiple myeloma. 20.The method of claim 17, wherein the compound is administered orally, intravenously, intramuscularly, dermally, rectally, nasally, otically, or ocularly.