Nicotinamide and benzamide-based compounds, conjugates and compositions as inhibitors of translation and transcription related kinases

Abstract

Compounds comprising nicotinamide or benzamide linked to a bicyclic heterocycle (e.g., alkynylimidazo-[1, 2-b]-pyridazine) and substituted with one or more ring moieties, as well as conjugates and compositions comprising the same. Methods for treating kinase-related diseases and disorders are also provided.

Description

priority

[0001] This application is related to and claims priority to U.S. Provisional Patent Application No. 63 / 327,984, filed on April 6, 2022. The contents of the foregoing application are hereby incorporated by reference in their entirety into the present disclosure. Technical Field

[0002] The present disclosure generally relates to compounds including nicotinamide- or benzamide-based compounds comprising bicyclic heterocycles, such as alkynyl imidazo-[1,2-b]-pyridazines substituted with one or more ring moieties, which can inhibit certain kinases (e.g., tyrosine protein kinase ABL1), compositions comprising the compounds, and methods of using such compounds and compositions to treat cancer (e.g., solid tumor cancer) and other disease states. Background Art

[0003] This section introduces aspects that may be helpful in better understanding the present disclosure. Therefore, these statements should be read in this light and not as admissions of what is or is not prior art.

[0004] There are more than 500 kinases in human cells that regulate important processes such as the cell cycle, cell proliferation, apoptosis, and migration. Protein kinase inhibitors have the potential to treat many diseases that can be controlled by protein kinase dysregulation. To date, the U.S. Food and Drug Administration (FDA) has approved more than twenty kinase inhibitors for the treatment of various diseases.

[0005] Ponatinib is an oral drug developed by ARIAD Pharmaceuticals, Inc. for the treatment of chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. It is a multi-targeted tyrosine kinase inhibitor approved by the FDA in 2012. The kinases targeted by Ponatinib may include, for example, non-receptor tyrosine protein kinase ABL1 (ABL1), T315I mutant kinase, Fms-like tyrosine kinase 3 (FLT3), vascular endothelial growth factor receptor (VEGF) kinase family members, platelet-derived growth factor receptor (PDGFR) kinase family members, ephrin (EPH) receptor kinase family members, Src kinase family members, fibroblast growth factor receptors 1, 2, 3, and 4 (FGFR1-4), and rearranged during transfection (RET).

[0006] Ponatinib has been shown to effectively inhibit a variety of cancers, including chronic myeloid leukemia (CML), acute myeloid leukemia (AML), and a variety of FGFR and RET-driven cancers (such as non-small cell lung cancer and thyroid cancer). Currently, ponatinib is one of the few drugs approved by the FDA for the treatment of imatinib-resistant CML carrying the T315I mutation, and is also undergoing various clinical trials for the treatment of AML, lung cancer, and a variety of other cancers; however, ponatinib and its nicotinamide analogs with linear substituents cannot effectively inhibit the growth of solid tumor cancers and / or kinases associated therewith (such as ribosomal protein S6 kinase β-1 (p70S6K), AXL receptor tyrosine kinase (AXL), and MER proto-oncogene tyrosine kinase (MERTK)).

[0007] Although ponatinib has potential efficacy against a variety of cancer types, the drug is relatively toxic and has been associated with adverse cardiovascular events (such as inducing cardiac inflammation and decreased cardiac function), at least in part because it is a potent human Ether-à-go-go-Related Gene (hERG) inhibitor. Patients taking ponatinib also exhibit side effects such as hypertension, platelet dysfunction, and peripheral arterial occlusive disease, as well as myocardial infarction, stroke, and liver failure. In addition, approximately 40% of patients taking ponatinib experience some form of thrombosis, and the drug was even temporarily withdrawn from the market in 2014 due to these adverse side effects. Currently, ponatinib is usually only used as a last resort drug for patients with ABL (T315I) mutant CML who have not responded to any other therapy. Gainor et al., Ponatinib: Accelerated Disapproval, Oncologist 20(8): 847-848 (2015); Talbert et al., A Multi-Parameter InVitro Screen in Human Stem Cell-Derived Cardiomyocytes Identifies Ponatinib-Induced Structural and Functional Cardiac Toxicity, Toxicology Sci 143(1): 147-155 (2015). These adverse cardiovascular toxic effects may be related to the simultaneous inhibition of cardiovascular-related kinases (such as hERG) by ponatinib.

[0008] There remains a need for compounds (eg, drugs) that are potent inhibitors of disease-associated kinases (eg, p70S6K) but do not cause adverse side effects such as cardiovascular toxicity seen with conventional kinase inhibitors. Summary of the invention

[0009] In general, the present disclosure proposes that the addition of one or more cyclic moieties (e.g., morpholine or piperazine-type moieties) to the imidazo[1,2-b]pyridazine portion of nicotinamide ponatinib analogs can significantly enhance the inhibitory activity of these novel compounds against at least ribosomal protein S6 kinase beta-1 (p70S6K), AXL receptor tyrosine kinase (AXL), and MER proto-oncogene tyrosine kinase (MERTK), which are either not inhibited by ponatinib and the nicotinamide analog HSN748 with linear substituents, or are only weakly inhibited at best. The compounds herein (e.g., HSND80) are orally bioavailable and can effectively inhibit a variety of solid tumors, such as breast cancer, ovarian cancer, lung cancer, colon cancer, etc.

[0010] In certain embodiments, the compound has the structure of Formula (XX): R 4 —L—Z—R 3 (XX) or a pharmaceutically acceptable salt thereof, wherein: R 4 is nicotinamide or benzamide, each of which is optionally substituted; L is a linker comprising at least one atom; Z is replaced by R 3 substituted bicyclic heterocycle; and R 3 Contains one or more ring moieties.

[0011] The compound may have the structure of formula (I): or a pharmaceutically acceptable salt thereof, wherein: R 1 is pyridine, alkyl, isoxazole, pyrazole or phenyl, each optionally substituted with one or more of trifluoromethyl, piperazine (e.g., alkylpiperazine), pyrazine (e.g., alkylpyrazine), imidazole (e.g., alkylimidazole), cyanide, amine, halogen, N-containing heterocycle and / or alkyl; 1 N or C; R 2 is H, alkyl, heteroalkyl or halogen; Z is imidazo[1,2-b]pyridazine, imidazo[1,2-b]pyrazole or imidazo[2,1-b][1,3,4]thiadiazole; and R 3 Having the structure of formula (II), formula (III) or formula (IV): in: is the point of attachment; each X is independently alkyl or H, provided that not all X are H; Q is O, S, N or C, and is optionally substituted with one or more of alkyl, halogen, O-alkyl, amine, -OH group, alkoxy, piperazine, morpholine, aziridine, carbocyclic or heterocyclic ring and / or carbonyl; Y is O or amine, provided that Y is not NH; and n is 0 or 1. The linker (L) may be an alkyne. R 3 It may be a substituted morpholine. 3 R may be azetidine, optionally substituted by one or more of alkyl, halogen, amine, O-alkyl and / or -OH groups. 3 R may be pyrrolidine, which is optionally substituted with oxetane. 3 Can be or include

[0012] Z can have the following structure: in is the attachment point, W is C or S.

[0013] In certain embodiments, the compound has the structure of Formula (V): or a pharmaceutically acceptable salt thereof.

[0014] In certain embodiments, when R 3 When having the structure of formula (III), Y is methylamine (-NMe) or ethylamine (-NEt). Q can be O. R 3 It may have a structure of formula (II), and at least two X may be linked together to form a bicyclic heterocycle. 3 May contain morpholine. 3 May contain unsubstituted morpholine. 3 It may contain morpholine substituted with at least two methyl groups. 3 It may contain a 6-membered heterocyclic ring. 3 It may contain 4-6 membered heterocyclic ring. 3 Oxygen-containing heterocycles may be included.

[0015] The compound may have the following structure:

[0016] The compound may have the following structure:

[0017] The compound may have the following structure:

[0018] The compound may have the following structure:

[0019] The compound may have the following structure:

[0020] The compound can have the following structure:

[0021] The compound may have the following structure:

[0022] The compound may have the following structure:

[0023] The compound may have the following structure:

[0024] The compound may have the following structure:

[0025] The compound may have the following structure:

[0026] The compound may have the following structure:

[0027] The compound may have the following structure:

[0028] The compound may have the following structure:

[0029] The compound may have the following structure:

[0030] The compound may have the following structure:

[0031] The compound may have the following structure:

[0032] The compound may have the following structure:

[0033] In certain embodiments, R 1 for in is the attachment point and X' is O, C or N.

[0034] The compound can have the following structure or a pharmaceutically acceptable salt thereof.

[0035] The compound can have the following structure or a pharmaceutically acceptable salt thereof.

[0036] The compound can have the following structure or a pharmaceutically acceptable salt thereof.

[0037] The compound can have the following structure or a pharmaceutically acceptable salt thereof.

[0038] The compound can have the following structure or a pharmaceutically acceptable salt thereof.

[0039] The compound can have the following structure or a pharmaceutically acceptable salt thereof.

[0040] The compound can have the following structure or a pharmaceutically acceptable salt thereof.

[0041] The compound can have the following structure or a pharmaceutically acceptable salt thereof.

[0042] The compound can have the following structure or a pharmaceutically acceptable salt thereof.

[0043] The compound can have the following structure or a pharmaceutically acceptable salt thereof.

[0044] The compound can have the following structure or a pharmaceutically acceptable salt thereof.

[0045] A PROTAC conjugate is also provided. In certain embodiments, the PROTAC conjugate has a chemical structure of formula (X): A—L'—D(X) or a pharmaceutically acceptable salt thereof, wherein: A is a compound group of any compound described herein; L' is a linker connecting A and D, or is absent; and D is a ubiquitin pathway protein binding moiety.

[0046] Furthermore, provided is a pharmaceutical composition comprising a compound described herein, a conjugate described herein, or a pharmaceutically acceptable salt, N-oxide, hydrate, solvate, tautomer or optical isomer of the compound or conjugate; and a pharmaceutically acceptable carrier or excipient.

[0047] Methods are also provided. In certain embodiments, methods of treating a disease state or condition in a subject are provided, the method comprising administering to the subject a first therapy comprising an effective amount of: a compound herein, a conjugate herein, or a pharmaceutically acceptable salt, N-oxide, hydrate, solvate, tautomer, or optical isomer of the compound or conjugate; or a pharmaceutical composition comprising one or more of a compound herein, a conjugate herein, or a pharmaceutically acceptable salt, N-oxide, hydrate, solvate, tautomer, or optical isomer of the compound or conjugate.

[0048] In certain embodiments, the method further comprises administering to the subject a second therapy comprising: an effective amount of a chemotherapeutic, immunotherapeutic, or hormonal therapeutic; or radiation therapy.

[0049] The disease state or condition of the subject can be cancer. The disease state or condition can be a solid tumor cancer. The cancer can be selected from the group consisting of acute myeloid leukemia, chronic myeloid leukemia, ovarian cancer, cervical cancer, pancreatic cancer, breast cancer, brain cancer, skin cancer, lung cancer, prostate cancer, lymphoma, leukemia, colon cancer, head cancer, neck cancer, thyroid cancer, kidney cancer, liver cancer and stomach cancer.

[0050] The method may also include imaging the tumor microenvironment, cancer cell populations, or solid tumors in the subject.

[0051] Also provided is a method for suppressing T cell responses in a subject's tumor microenvironment (TME). Such methods may include administering to a subject an effective amount of: a pharmaceutically acceptable salt, N-oxide, hydrate, solvate, tautomer or optical isomer of a compound herein, a conjugate herein, or a compound or conjugate; or a pharmaceutical composition comprising one or more of a pharmaceutically acceptable salt, N-oxide, hydrate, solvate, tautomer or optical isomer of a compound herein, a conjugate herein, or a compound or conjugate. The subject may suffer from cancer.

[0052] In certain embodiments, an effective amount of a peptide is administered to a subject to inhibit one or more of MERTK and AXL in the subject.

[0053] Also provided are compounds herein or conjugates herein for use in treating a disease state regulated by one or more kinases. For example, the disease state may be cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] In view of the following detailed description of various exemplary embodiments of the present disclosure, the embodiments disclosed herein and other features, advantages and aspects included therein and methods of achieving them will become apparent. These detailed descriptions will be better understood in conjunction with the accompanying drawings.

[0055] Figure 1 Diagram showing the evolution of ponatinib into nicotinamide analogs.

[0056] Figure 2 Compound HSN748 according to the present disclosure is shown with substitutions at position 6 of the ring moiety, each of which is a potent inhibitor of MAP kinase interacting serine / threonine protein kinase 2 (MNK2) and ribosomal protein S6 kinase beta-1 (p70S6K).

[0057] Figure 3A Graphical data showing the anticancer activity of compound HSND41 against NCI-60 are shown (the value at 0 represents a GI50 of 1 μM).

[0058] Figure 3BGraphical data showing the anticancer activity of compound HSND37 against NCI-60 are shown (the value at 0 represents a GI50 of 1 μM).

[0059] Figure 3C Graphical data showing the anticancer activity of compound HSN748 against NCI-60 are shown (the value at 0 represents a GI50 of 1 μM).

[0060] Figure 4 Graphical data showing the anticancer activity of compound HSND80 against NCI-60 are shown (the value at 0 represents a GI50 of 1 μM).

[0061] Figure 5 Shown are graphical data relating to the PK profiles of various compounds herein in rats following administration by oral gavage.

[0062] Fig. 6A and 6B Shown are graphical data relating to the binding affinity of HSND80 to AXL receptor tyrosine kinase (AXL), wherein Fig. 6A Data from replicate 1 are shown (1 Kd = 0.77 nM), while Figure 6B Data from replicate 2 are shown (2Kd = 1.3 nM).

[0063] Fig. 7A and 7B Shown are graphical data relating to the binding affinity of HSND80 to MER proto-oncogene tyrosine kinase (MERTK), wherein Fig. 7A Data from replicate 1 are shown (1 Kd = 1.6 nM), Figure 7B Data from replicate 2 are shown (2Kd = 2.1 nM).

[0064] While the disclosure is susceptible to various modifications and alternative forms, exemplary embodiments thereof have been shown by way of example in the drawings and are herein described in detail. DETAILED DESCRIPTION

[0065] Although the concepts of the present disclosure have been elaborated and described in detail in the specification herein, the results of the specification should be regarded as illustrative rather than restrictive; it should be understood that only illustrative embodiments have been shown and described and that all changes and modifications that come within the spirit of the disclosure are intended to be protected.

[0066] The present disclosure generally relates to compounds based on nicotinamide or benzamide, which are connected to (or substituted with) a bicyclic heterocycle, which is substituted with one or more ring moieties at the 6 position of nicotinamide or benzamide. Such compounds are kinase inhibitors. In certain embodiments, the bicyclic heterocycle is an alkynyl imidazo[1,2-b]pyridazine, imidazo[1,2-b]pyrazole, or imidazo[2,1-b][1,3,4]thiadiazole.

[0067] In certain embodiments, the compound comprises modifying the benzamide moiety of ponatinib to nicotinamide and substituting the 6-position of the nicotinamide alkynyl imidazo[1,2-b]pyridazine with a substituent comprising one or more ring moieties (eg, morpholine or piperazine).

[0068] The nicotinamide or benzamide-based compounds herein have potent activity against MAP kinase-interacting serine / threonine protein kinases 1 and 2 (MNK1 / 2) and ribosomal protein S6 kinase β1 (p70S6K), and can exhibit significant anticancer activity (e.g., against solid tumor cancers) compared to analogs that are not substituted at position 6 or substituted with linear heteroalkyl groups at position 6. In fact, p70S6K kinase is only weakly inhibited by ponatinib and compound HSN748 (a nicotinamide analog having a linear heteroalkyl group instead of one or more ring moieties of the compounds of the present invention), while the compounds herein significantly inhibit the activity of p70S6k kinase. In addition, the nicotinamide-based compounds herein at least also inhibit TAM kinases, AXL receptor tyrosine kinases (AXL), and MER proto-oncogene tyrosine kinases (MERTK), which are not targeted by the parent ponatinib or HSN748 compounds. In addition, the compounds herein are orally bioavailable and may inhibit a variety of solid tumors (e.g., breast cancer, ovarian cancer, lung cancer, colon cancer, etc.), but do not inhibit or only weakly inhibit human Ether-à-go-go-Related Gene (hERG).

[0069] PROTAC conjugates, pharmaceutical compositions, and methods of use thereof (e.g., for treating certain kinase-mediated diseases, such as cancer) are also provided. These compounds, compositions, conjugates, and methods can be used to modulate protein activity, and to treat diseases and disorders associated with protein activity.

[0070] Nicotinamide alkynyl imidazo[1,2-b]pyridazine compounds have been described as kinase inhibitors with anticancer activity (International Patent Application No. PCT / IB2019 / 057711, International Publication No. WO / 2020 / 053812, and International Publication No. WO2013170770A1). However, to date, the rules for how various substitutions on the nicotinamide alkynyl imidazo[1,2-b]pyridazine moiety affect kinase selectivity and anticancer properties have not been well described, making it difficult to optimize the biological properties of the compounds in advance.

[0071] First, substituted acetylenic imidazo[1,2-b]pyridazine compounds containing a benzamide unit are known kinase inhibitors. One such compound, ponatinib, is a multikinase inhibitor that is described as an inhibitor of the non-receptor tyrosine protein kinase ABL1 (ABL1). However, the administration of ponatinib is associated with a number of adverse toxicities, at least in part due to the simultaneous inhibition of many essential kinases (e.g., hERG). Ponatinib analogs have reduced inhibitory effects on cardiovascular-related kinases (e.g., VEGFR1-3, c-Src, c-KIT, etc.) and are expected to exhibit lower adverse toxicities. In addition, ponatinib does not inhibit (or at most weakly inhibits) MNK1 / 2 and p70S6K kinases.

[0072] MNK1 / 2 and p70S6K kinases regulate the translation of oncogenic proteins through the RAS-MEK-ERK and PI3K-AKT-mTORC1 axes, respectively. Xie et al., The MAP Kinase-Interacting Kinases (MNKs) as Targets in Oncology, Expert Opinion on Therapeutic Targets 23 (3): 187-199 (2019); Roux & Topisirovic, Signaling Pathways Involved in the Regulation of mRNA Translation, Molecular Cell Biology 38: e00070-18 (2018). MNK is also involved in the transcriptional regulation of key oncogenic proteins, such as E2F1, FOXM1 and WEE1. Ke et al., MNK1 and MNK2 Enforce Expression of E2F1, FOXM1, and WEE1 to Drive Soft Tissue Sarcoma, Oncogene 40:1851–1867 (2021). Due to the importance of these proteins in tumorigenesis, several inhibitors of these key kinases (MNK and p70S6K) have been developed and / or evaluated as potential anticancer agents.Jin et al.,Progress in Developing MNKInhibitors,European J Med Chemistry219:113420(2021);Spaan et al.,DirectP70S6K1 Inhibition to Replace Dexamethasone in Synergistic Combination withMCL-1Inhibition in Multiple Myeloma,Blood Advances 5:2593–2607(2021);El-Khoueiry et al.,APhase II,Open-Label Study of Tomivosertib(eFT508)Added on toContinued Checkpoint Inhibitor Therapy in Patients(pts)with InsufficientResponse to Single-Agent Treatment,J Clinical Oncology 38(15):suppl DOI:10.1200 / JCO.2020.38.15_suppl.3112(2020);Tolcher et al.,APhase I TrialofLY2584702Tosylate,a p70 S6 Kinase Inhibitor,in Patients with Advanced SolidTumours,European J Cancer 50(5):867-75,doi:10.1016 / j.ejca.2013.11.039(2014);Tsimberidou et al.,Phase 1Study of M2698,a p70S6K / AKT Dual Inhibitor,inPatients with Advanced Cancer,J Hematology&Oncology 14(1):127.doi:10.1186 / s13045-021-01132-z(2021).。

[0073] MNK1 and 2 are immunosuppressive kinases, and inhibition of MNK1 and 2 by tomivosertib (eFT-508), a potent and selective MNK1 / 2, has been shown to result in blocked expression of programmed cell death protein 1 (PD-1), programmed cell death ligand 1 (PD-L1), and lymphocyte activation gene 3 (LAG-3), which are checkpoint proteins (El-Khoueiry et al. 2020), supra. Tomivosertib, when used in combination with checkpoint therapy, has been shown to result in objective clinical responses in patients who have not responded adequately to checkpoint inhibitors alone, as previously described.

[0074] Several p70S6K inhibitors, such as LY2584702 and M2698, have been developed and are being tested clinically. Tolcher et al. (2014), supra; Tsimberidou et al. (2021), supra. While LY2584702 did not show good clinical activity, M2698 showed antitumor activity when combined with various treatment options, such as trastuzumab or tamoxifen, in patients with advanced breast cancer. Tsimberidou et al. (2021), supra.

[0075] Since single inhibition of MNK results in tumor growth inhibition but does not eliminate the tumor, it has been proposed that simultaneous inhibition of MNK and other key cancer targets (using drug combinations or single agents with polypharmacological effects) is a rational approach to anticancer therapy through MNK inhibition. Xie et al. (2019), supra. Given that both MNK and p70S6K regulate translation, the data herein support that dual inhibition of these kinases translates into a more profound inhibition of cancer cell growth than inhibition of a single kinase.

[0076] In earlier studies, the inventors of this article observed that a linear heteroalkyl-containing ponatinib nicotinamide analog (i.e., compound HSN748) was a potent inhibitor of MNK2 (IC50 = 9 nM; [ATP] = 100 μM), but only moderately inhibited p70S6K (IC50 = 273 nM). Larocque et al., Nicotinamide–Ponatinib Analogues as Potent Anti-CML and Anti-AML Compounds, ACS Omega 5(6), 2690–2698 (2020). Figure 1Ponatinib is shown to evolve into other analogs of compounds HSN748 and HSND748, which contain nicotinamide alkynyl imidazo [1,2-b] pyridazine substituted with linear heteroalkyl groups at position 6. Ponatinib also moderately inhibits p70S6K (IC50 = 273nM; [ATP] = 100μM), but does not inhibit MNK2. As mentioned above. Considering that the binding rate of ponatinib, compound HSN748 and analogs of HSN748 to proteins is greater than 90%, it is unlikely to find a therapeutic dose that covers the IC90 for inhibiting both MNK and p70S6K.

[0077] However, the compounds herein (e.g., compounds comprising benzamide or nicotinamide substituted at position 6 with, for example, an alkynyl imidazo[1,2-b]pyridazine having one or more ring moieties (e.g., morpholine or piperazine)) have potent activity against MNK1 / 2 and p70S6K. These compounds exhibit significant anticancer activity compared to analogs that are not substituted at position 6 or are not substituted with linear heteroalkyl groups. Figure 2 Various compounds are shown herein that include compounds in which the 6-position of the nicotinamide alkynyl imidazo[1,2-b]pyridazine is substituted with one or more ring moieties.

[0078] Compound

[0079] The compound can inhibit kinases. The compound can selectively and effectively inhibit cancer-mediating kinases, thereby killing and / or reducing cancer cells (e.g., MNK and p70S6K), and is also a weak hERG inhibitor, which can significantly reduce off-target toxicity (e.g., cardiovascular toxicity).

[0080] Based on the discovery that the benzamide or nicotinamide forms of ponatinib (which also contain one or more ring moieties) impart different and desirable properties compared to conventional compounds, the compounds herein may have the general structure of Formula (XX): R 4 —L—Z—R 3 (XX) or a pharmaceutically acceptable salt thereof, wherein: R 4 is niacinamide or benzamide, wherein each of niacinamide or benzamide is optionally substituted; L is a linker comprising at least one atom (e.g., linked to position 6 of nicotinamide or benzamide); Z is R 3 substituted bicyclic heterocycle; and R 3 Contains one or more ring moieties.

[0081] The linker (L) may be any suitable linker. The linker may have a backbone of varying lengths, such that there may be as few as one atom to as many as 100 or more contiguous atoms in the backbone of the linker. The "backbone" of the linker is the length of the backbone that forms R. 4 The shortest chain of consecutive atoms covalently bonded between Z and Z. In some embodiments, the linker is a multivalent linker having a branched backbone, with each branch being part of the backbone linker until a terminus is reached. The linker (L) can be an alkyne, for example, or any other linker comprising one or more atoms.

[0082] For example, the chain length of the linker is at least about 7 atoms. In some embodiments, the length of the linker is at least about 3 atoms. In some embodiments, the length of the linker is at least about 10 atoms. In some embodiments, the length of the linker is about 7 to about 31 atoms (e.g., about 7 to 31, 7 to about 31, or 7 to 31 atoms), about 7 to about 24 atoms (e.g., about 7 to 24, 7 to about 24, or 7 to 24 atoms), or about 7 to about 20 atoms (e.g., about 7 to 20, 7 to about 20, or 7 to 20 atoms). In some embodiments, the linker is about 14 to about 31 atoms (e.g., about 14 to 31, 14 to about 31, or 14 to 31 atoms), about 14 to about 24 atoms (e.g., about 14 to 24, 14 to about 24, or 14 to 24 atoms), or about 14 to about 20 atoms (e.g., about 14 to 20, 14 to about 20, or 14 to 20 atoms). In some embodiments, the chain length of the linker is at least 7 atoms, at least 14 atoms, at least 20 atoms, at least 25 atoms, at least 30 atoms, or at least 40 atoms; or 1 to 15 atoms, 1 to 5 atoms, 5 to 10 atoms, 5 to 20 atoms, 10 to 40 atoms, or 25 to 100 atoms.

[0083] The linker comprises at least one carbon-carbon bond and / or at least one amide bond. The linker may comprise one or more L- or D- configurations, natural or non-natural amino acids, PEG monomers, PEG oligomers, PEG polymers, or any combination thereof. For linkers comprising one or more PEG units, unless otherwise specified, all carbon atoms and oxygen atoms of the PEG units are part of the backbone.

[0084] In certain embodiments, a linker is a group comprising one or more covalently linked building blocks.

[0085] In certain embodiments, the linker group is an optionally substituted (poly) ethylene glycol, which has 1 to about 100 ethylene glycol units, about 1 to about 50 ethylene glycol units, 1 to about 25 ethylene glycol units, about 1 to 10 ethylene glycol units, 1 to about 8 ethylene glycol units and 1 to 6 ethylene glycol units, 2 to 4 ethylene glycol units, and / or an optionally substituted alkyl, wherein there is dispersed with optionally substituted O, N, S, P or Si atoms. In certain embodiments, the linker is substituted by aryl, phenyl, benzyl, alkyl, alkylene or heterocyclic groups. In certain embodiments, the linker is asymmetric. In certain embodiments, the linker is symmetrical.

[0086] Alternatively, or in addition to chain length, in some embodiments, the linker may have suitable substituents that affect hydrophobicity or hydrophilicity. Thus, for example, the linker may have hydrophobic side chain groups, such as alkyl, cycloalkyl, aryl, aralkyl or similar groups, each of which is optionally substituted. If the linker includes one or more amino acids, the linker may contain hydrophobic amino acid side chains, such as one or more amino acid side chains from Phe and Tyr, including substituted variants thereof, and analogs and derivatives of such side chains.

[0087] The linker may comprise a spacer (e.g., conjugated to and / or comprising a spacer). The spacer may be any suitable spacer. The spacer of the linker may comprise hydrophilic, hydrophobic, amphiphilic, non-peptidic, peptidic and / or aromatic monomers. The length of the spacer may be 1 to 30 (e.g., 1 to 30 carbon atoms, PEG having 1-30 units, etc.).

[0088] In certain embodiments, the compound has the structure of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: R1 is alkyl, pyridine, isoxazole, pyrazole or aryl (e.g. phenyl), each optionally substituted with one or more of piperazine (e.g. alkylpiperazine), pyrazine (e.g. alkylpyrazine), imidazole (e.g. alkylimidazole), cyanide, amine, halogen, trifluoromethyl, N-containing heterocycle and / or alkyl; Y 1 is nitrogen (N) or carbon (C); R 2 is hydrogen (H), alkyl, heteroalkyl or halogen; Z is R 3 substituted bicyclic heterocycle, wherein the bicyclic heterocycle is imidazo[1,2-b]pyridazine, imidazo[1,2-b]pyrazole or imidazo[2,1-b][1,3,4]thiadiazole; and R 3is a substituent comprising one or more ring moieties.

[0089] R 3 It may have a structure of formula (II), formula (III) or formula (IV): in: is the attachment point; Each X is independently alkyl or H, provided that not all X are H; Q is O, S, N or C, and is optionally substituted by one or more of alkyl, halogen, O-alkyl, amine, -OH group, alkoxy, piperazine, morpholine, aziridine, carbocycle (e.g. 3-membered carbocycle) or heterocycle, and / or carbonyl; Y is O or an amine, provided that Y is not NH; and n is 0 or 1.

[0090] In certain embodiments, the compound R 3 has the structure of formula (II) and Q is O. In certain embodiments, each X is independently alkyl or H, provided that not all X are H.

[0091] In certain exemplary embodiments, R 3 In certain embodiments, the linker is an alkyne.

[0092] In certain embodiments, Y 1 is C, and thus the compound is based on benzamide. In certain embodiments, Y 1 is N, and thus the compound is based on nicotinamide. 1 is N, and N is not located at the position shown in formula (I), but is located at any position on the nicotinamide ring.

[0093] The compound can be prepared by partially replacing the methylbenzamide in ponatinib with nicotinamide and further 3 Incorporating one or more heterocyclic groups into the

[0094] In certain embodiments, R 1 for In certain embodiments, R 1 for in is the point of attachment, and X' is O, C or N. In certain embodiments, R 1 for in is the attachment point, and X' is O, C or N.

[0095] Z can have the following structure: or in is the attachment point, and W is either C or S.

[0096] R 3 It may be a heterocyclic ring. 3 It may be a 4-6 membered heterocyclic ring (eg, a 4-membered heterocyclic ring, a 5-membered heterocyclic ring or a 6-membered heterocyclic ring). 3 It may be an oxygen-containing (O) heterocycle and / or R 3 It may be a nitrogen (N)-containing heterocyclic ring. 3 It may be a sulfur (S)-containing heterocycle.

[0097] R 3 May contain bicyclic moieties. 3 It may include a bicyclic moiety containing two 6-membered heterocyclic rings. 3 Bicyclic moieties containing 6-membered heterocyclic rings and 5-membered heterocyclic rings may be included. 3 It may include bicyclic moieties containing two 5-membered heterocyclic rings. 3 Bicyclic moieties containing 6-membered heterocyclic rings and 4-membered heterocyclic rings may be included. 3 Bicyclic moieties containing 6-membered heterocyclic rings and 3-membered carbocyclic or heterocyclic rings may be included. 3 Bicyclic moieties containing 5-membered heterocyclic rings and 4-membered heterocyclic rings or carbocyclic rings may be included.

[0098] R 3 Can have structure

[0099] In certain embodiments, R 3 has a straight chain alkyl group and a bicyclic ring portion. 3 It can have a straight chain heteroalkyl group (e.g., a straight chain heteroalkyl group containing O and / or N) and a bicyclic portion. In certain embodiments, R 3 With structure

[0100] In certain embodiments, R 3 Having the structure of formula (II): and Q is O. In certain embodiments, R 3 has the structure of formula (II) and is morpholine (eg, Q is O). 3 R may be or include unsubstituted morpholine. 3 Can be or include substituted morpholine. For example, but not limited to, R 3 It may be or include morpholine substituted with at least two methyl groups.

[0101] In certain embodiments, R3 has the structure of formula (II) and is piperidine (eg, Q is C). In certain embodiments, R 3 has a structure of formula (III) and Q is N (e.g., R 3 including piperidine).

[0102] R 3 It may have a structure of formula (II), wherein at least two X are H. 3 R3 may have a structure of formula (II), wherein at least three X are H. R3 may have a structure of formula (II), wherein at least four X are H. 3 It may have a structure of formula (II), wherein at least five X are H. 3 It may have a structure of formula (II), wherein at least six X are H. 3 It may have a structure of formula (II), wherein seven Xs are H.

[0103] R 3 It may have the structure of formula (II), and at least two Xs may be linked together to form a bicyclic heterocycle. In certain embodiments, R 3 for or

[0104] In certain embodiments, R 3 is azetidine, which is optionally substituted with one or more of an alkyl, halogen, amine, O-alkyl and / or -OH group. In certain embodiments, R 3 is pyrrolidine, which is optionally substituted with oxetane.

[0105] R 3 It may have a structure of formula (III): Wherein Y is methylamine (-NMe) or ethylamine (-NEt). Y in formula (III) can be a straight chain alkyl group. Y in formula (III) can be a straight chain heteroalkyl group. In certain embodiments, R 3 is or includes (For example, wherein Y in formula (III) is a linear alkyl group containing O).

[0106] In certain embodiments, R 3 is or comprises tetrahydro-2H-pyran.

[0107] In certain embodiments, the compound has the structure of Formula (V): in: R1 is alkyl, pyridine, isoxazole, pyrazole or aryl (e.g. phenyl), each optionally substituted with one or more of piperazine (e.g. alkylpiperazine), pyrazine (e.g. alkylpyrazine), imidazole (e.g. alkylimidazole), cyanide, amine, halogen, trifluoromethyl, N-containing heterocycle and / or alkyl; R 2 is H, alkyl, heteroalkyl or halogen; and R 3 is a substituent comprising one or more ring moieties.

[0108] The compound may have the following structure:

[0109] The compound may have the following structure:

[0110] The compound may have the following structure:

[0111] The compound may have the following structure:

[0112] The compound may have the following structure:

[0113] The compound may have the following structure:

[0114] The compound may have the following structure:

[0115] The compound may have the following structure:

[0116] The compound may have the following structure:

[0117] The compound may have the following structure:

[0118] The compound may have the following structure:

[0119] The compound may have the following structure:

[0120] The compound may have the following structure:

[0121] The compound may have the following structure:

[0122] The compound may have the following structure:

[0123] The compound may have the following structure:

[0124] The compound may have the following structure:

[0125] The compound may have the following structure:

[0126] The compound may have the following structure: or a pharmaceutically acceptable salt thereof.

[0127] The compound may have the following structure: or a pharmaceutically acceptable salt thereof.

[0128] The compound may have the following structure: or a pharmaceutically acceptable salt thereof.

[0129] The compound may have the following structure: or a pharmaceutically acceptable salt thereof.

[0130] The compound may have the following structure: or a pharmaceutically acceptable salt thereof.

[0131] The compound may have the following structure: or a pharmaceutically acceptable salt thereof.

[0132] The compound may have the following structure: or a pharmaceutically acceptable salt thereof.

[0133] The compound may have the following structure: or a pharmaceutically acceptable salt thereof.

[0134] The compound may have the following structure: or a pharmaceutically acceptable salt thereof.

[0135] The compound may have the following structure: or a pharmaceutically acceptable salt thereof.

[0136] The compound may have the following structure: or a pharmaceutically acceptable salt thereof.

[0137] It is expected that the compounds herein can be provided in the form of prodrugs. The term "prodrug" refers to an inactive derivative of a parent compound / drug that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to provide an active compound, particularly a compound herein. Prodrugs can be created to overcome one or more obstacles to the effective use of potential active compounds, such as obstacles to the instability and / or possible toxicity of active compounds. Examples of prodrugs include, but are not limited to, derivatives and metabolites of compounds, including bio-hydrolyzable parts, such as bio-hydrolyzable amides, bio-hydrolyzable esters, bio-hydrolyzable carbamates, bio-hydrolyzable carbonates, bio-hydrolyzable ureides, and bio-hydrolyzable phosphate analogs. Specific prodrugs of compounds with carboxyl functional groups are lower alkyl esters of carboxylic acids. Carboxylic acid esters can be conveniently formed by any carboxylic acid moiety present on the esterified molecule. In certain embodiments, the prodrug form of the compounds herein may include a protecting group, which, in addition to protecting the compound from oxidation and the like, also allows targeting of specific sites (e.g., tumor microenvironment) in the subject's body. Prodrugs can generally be prepared using well-known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery 6th edition (Donald J. Abraham, ed., 2001, Wiley) and Design and Application of Prodrugs (H. Bundgaard, ed., 1985, Harwood Academic Publishers GmbH). PROTAC conjugates

[0138] Also provided are PROTAC conjugates comprising the compounds herein. The PROTAC conjugate may have a chemical structure of formula (X): A—L'—D(X) wherein A is a compound described herein (eg, a kinase inhibitor described herein); L' is a linker or is absent; and D is a ubiquitin pathway protein binding moiety.

[0139] While protein inhibitors can block or reduce protein activity in cells, protein degradation in cells can also reduce activity or completely remove target proteins. Therefore, exploiting the protein degradation pathways of the cell can provide an additional way to reduce or remove protein activity. One of the main degradation pathways of the cell is called the ubiquitin-proteasome system. In this system, proteins are marked for degradation by the proteasome through ubiquitination. Ubiquitination of proteins can be achieved by ubiquitin pathway protein binding moieties, which bind to proteins and add ubiquitin molecules to the protein.

[0140] In order to take advantage of this degradation pathway, PROTAC has been developed. The term "PROTAC" refers to a proteolytic targeting chimeric molecule comprising a ubiquitin pathway protein binding portion, an optional linker and a targeting portion. PROTAC combines a ubiquitin pathway protein binding portion (e.g., E3 ubiquitin ligase) with a protein to be targeted for degradation. In order to promote protein degradation by proteasomes, PROTAC consists of a group bound to a ubiquitin ligase and a group bound to a protein targeted for degradation (optionally, these groups are connected to a linker). This molecular structure can bring the ubiquitin pathway protein binding portion to the vicinity of the protein, thereby making it ubiquitinated and marked for degradation.

[0141] The ubiquitin pathway protein binding portion is any suitable structure that can recognize and bind to ubiquitin pathway proteins. In general, ubiquitin pathway proteins are any entities or complexes that can catalyze or cause catalysis of ubiquitin or ubiquitin-like modified polypeptides (e.g., Nedd8, APG12 or ISG15 / UCRP) transferred to another protein. In certain embodiments, the ubiquitin pathway protein is a ubiquitin protein ligase or E3 protein. At least 100 different E3 proteins are encoded by the human genome. Winston et al., A Family of Mammalian F-Box proteins, Current Biology 9(20): 1180-1182(1999).

[0142] In certain embodiments, the ubiquitin pathway protein is a protein that participates in the ubiquitin-like pathway or its components, which transfers ubiquitin-like modified polypeptides (e.g., SUMO, Nedd8, APG12, or ISG15 / UCRP). The components of the ubiquitin-like modification pathway are generally homologs of the ubiquitin pathway. For example, the ubiquitin-like pathway of SUMO includes homologs of ubiquitin protein activating enzymes or E1 proteins, ubiquitin protein conjugating enzymes or E2 proteins, and ubiquitin ligases or E3 proteins.

[0143] In certain embodiments, the ubiquitin pathway protein binding portion is any suitable ligand of a ubiquitin pathway protein, such as a ubiquitin protein ligase or an E3 protein or a homologue thereof. In certain embodiments, the ubiquitin pathway protein binds to a peptide, a domain or region of a ubiquitin pathway protein ligand. In certain embodiments, the ubiquitin pathway protein binding portion recognizes and binds to a ubiquitin pathway protein in a regulated manner.

[0144] The A component is a compound herein that binds to a target protein for degradation (eg, a targeted kinase inhibitor). The term "protein" includes oligopeptides and sufficiently long polypeptide sequences that can bind to the A component.

[0145] Particular A groups are any of the compounds described herein.

[0146] The compound and the ubiquitin pathway protein binding portion can be optionally connected to a linker. The linker can be any suitable linker. The linker can include atoms selected from C, N, O, S, Si and P; selected from C, N, O, S and P; or selected from C, N, O and S. The linker can have a main chain of varying lengths, so that there can be as few as two atoms in the linker main chain to up to 100 or more continuous atoms in the linker main chain. The "main chain" of the linker is the shortest continuous atomic chain that forms a covalent bond connection between A and D. In some embodiments, the multivalent linker has a branched main chain, and each branch is used as a part of the main chain linker until the end is reached.

[0147] For example, the linker can have a chain length of at least about 7 atoms. In some embodiments, the length of the linker is at least about 10 atoms. In some embodiments, the length of the linker is at least about 14 atoms. In some embodiments, the length of the linker is about 7 to about 31 atoms (e.g., about 7 to 31, 7 to about 31, or 7 to 31 atoms), about 7 to about 24 atoms (e.g., about 7 to 24, 7 to about 24, or 7 to 24 atoms) or about 7 to about 20 atoms (e.g., about 7 to 20, 7 to about 20, or 7 to 20 atoms). In some embodiments, the linker is about 14 to about 31 atoms (e.g., about 14 to 31, 14 to about 31, or 14 to 31 atoms), about 14 to about 24 atoms (e.g., about 14 to 24, 14 to about 24, or 14 to 24 atoms), or about 14 to about 20 atoms (e.g., about 14 to 20, 14 to about 20, or 14 to 20 atoms). In some embodiments, the chain length of the linker is at least 7 atoms, at least 14 atoms, at least 20 atoms, at least 25 atoms, at least 30 atoms, or at least 40 atoms; or 1 to 15 atoms, 1 to 5 atoms, 5 to 10 atoms, 5 to 20 atoms, 10 to 40 atoms, or 25 to 100 atoms.

[0148] The linker may comprise at least one carbon-carbon bond and / or at least one amide bond. The linker may comprise one or more L- or D- configurations, natural or non-natural amino acids, PEG monomers, PEG oligomers, PEG polymers, or any combination thereof. For linkers comprising one or more PEG units, unless otherwise specified, all carbon atoms and oxygen atoms of the PEG units are part of the backbone.

[0149] In certain embodiments, a linker is a group comprising one or more covalently linked building blocks.

[0150] In certain embodiments, the linker group is an optionally substituted (poly) ethylene glycol, which has 1 to about 100 ethylene glycol units, about 1 to about 50 ethylene glycol units, 1 to about 25 ethylene glycol units, about 1 to 10 ethylene glycol units, 1 to about 8 ethylene glycol units and 1 to 6 ethylene glycol units, 2 to 4 ethylene glycol units, and / or an optionally substituted alkyl, wherein dispersed with optionally substituted O, N, S, P or Si atoms. In certain embodiments, the linker group is substituted by aryl, phenyl, benzyl, alkyl, alkylene or heterocyclic groups. In certain embodiments, the linker group is asymmetric. In certain embodiments, the linker group is symmetrical.

[0151] Alternatively, or in addition to chain length, in some embodiments, the linker may have suitable substituents that affect hydrophobicity or hydrophilicity. Thus, for example, the linker may have hydrophobic side chain groups, such as alkyl, cycloalkyl, aryl, aralkyl or similar groups, each of which is optionally substituted. If the linker includes one or more amino acids, the linker may contain hydrophobic amino acid side chains, such as one or more amino acid side chains from Phe and TyR, including substituted variants thereof, and analogs and derivatives of such side chains.

[0152] The linker may include a spacer (e.g., conjugated to and / or including a spacer). The spacer may be any suitable spacer. The spacer of the linker may include hydrophilic, hydrophobic, amphiphilic, non-peptide, peptide and / or aromatic monomers. The length of the spacer may be 1 to 30 (e.g., 1 to 30 carbon atoms, PEG with 1-30 units, etc.). Examples of hydrophilic spacers include, but are not limited to, polyethylene glycol polymers and derivatives thereof. Examples of hydrophobic spacers include, but are not limited to, pure or mixed branched hydrocarbons, fluorocarbons, alkanes, alkenes and / or alkyne polymers. Examples of amphiphilic spacers include, but are not limited to, pure or mixed phospholipids and / or derivatives thereof. Examples of peptide spacers include, but are not limited to, pure and mixed single, branched, L- or D- configurations, essential, non-essential, natural and non-natural amino acids and derivatives thereof. Examples of aromatic spacers include, but are not limited to, pure and mixed repeating quinones.

[0153] In some embodiments, the linker is formed by a click chemistry / click chemistry-derived synthesis method. Those skilled in the art understand that the terms "click chemistry" and "click chemistry-derived" generally refer to a class of small molecule reactions commonly used for conjugation, allowing a selected substrate to be connected to a specific molecule. Click chemistry is not a single specific reaction, but describes a way to generate products following examples from nature, which also generates substances by connecting small modular units. In many applications, click reactions connect biomolecules and reporter molecules. Click chemistry is not limited to biological conditions; the concept of "click" reactions has been used in pharmacology and various biomimetic applications. However, they are very useful in the detection, localization and identification of biomolecules.

[0154] Click reactions can be performed in a single reaction vessel, are typically undisturbed by water, produce minimal byproducts, and are “spring-loaded”—characterized by a high thermodynamic driving force that rapidly and irreversibly drives them to produce a single reaction product in high yield, with high reaction specificity (and, in some cases, both regio- and stereo-specificity). These properties make click reactions suitable for problems of isolating and targeting molecules in complex biological environments, where the products correspondingly need to be physiologically stable and any byproducts need to be nontoxic (e.g., to in vivo systems).

[0155] Salt

[0156] The compounds and conjugates may be present in the form of pharmaceutically acceptable salts. Examples of acceptable salts include, but are not limited to, alkali metal (e.g., sodium, potassium or lithium) or alkaline earth metal (e.g., calcium) salts; however, any salt that is generally non-toxic and effective when administered to a subject is acceptable. Similarly, "pharmaceutically acceptable salts" refer to those salts having counterions that can be used in medicines. More specifically, for purposes of the present disclosure, the terms "salts" and "pharmaceutically acceptable salts" as used herein refer to derivatives of the disclosed compounds in which the parent compound is modified by making an acid salt or a basic salt thereof.

[0157] Such salts may include, but are not limited to: (1) acid addition salts, which may be obtained by reacting the free base of the parent compound with an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, perchloric acid, etc.) or an organic acid (e.g., acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, succinic acid, or malonic acid, etc.); or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion) or coordinated with an organic base (e.g., ethanolamine, diethanolamine, triethanolamine, trimethylamine, N-methylglucamine, etc.). Pharmaceutically acceptable salts are well known to those skilled in the art, and any such pharmaceutically acceptable salts are contemplated.

[0158] Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids. Pharmaceutically acceptable salts include quaternary ammonium salts or conventional non-toxic salts of the parent compound, which are formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid and nitric acid; and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzoic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid and isethionic acid, etc.

[0159] Pharmaceutically acceptable salts can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods. In some cases, such salts can be prepared by reacting the free acid or base forms of these compounds with stoichiometric amounts of appropriate bases or acids in water or organic solvents or in a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. A list of suitable salts can be found in Remington's Pharmaceutical Sciences 17th edition (Mack Publishing Company, Easton, Pa., 1985), the disclosure of which is incorporated herein by reference.

[0160] Acceptable salts can be obtained by standard methods known in the art including, but not limited to, reacting a sufficiently acidic compound with a suitable base to yield a physiologically acceptable anion. Suitable acid addition salts are formed from acids which form non-toxic salts. Illustrative (but not limiting) examples include acetate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydroxybenzoate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, saccharate, stearate, succinate, tartrate, mesylate, and trifluoroacetate. Suitable base salts of the compounds can be formed from bases that form non-toxic salts. Illustrative, non-limiting examples include arginine, benzathine penicillin, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, and zinc salts. Hemisalts of acids and bases can also be formed, such as hemisulphate and hemicalcium salts.

[0161] The compounds and conjugates herein can be "deuterated," meaning that one or more hydrogen atoms can be replaced by deuterium. Since deuterium and hydrogen have nearly identical physical properties, deuterium substitution is the smallest structural change that can be made. Deuteration is well known to those of ordinary skill in the art.

[0162] In some embodiments, compounds and conjugates may contain one or more asymmetric centers, thereby producing enantiomers, diastereomers and other stereoisomeric forms, which are defined as (R) or (S) in terms of absolute stereochemistry. In certain embodiments, the compound or conjugate is an R configuration. In certain embodiments, the compound or conjugate is an S configuration. Unless otherwise stated, all stereoisomeric forms of the compound and / or conjugate are intended to be considered. When the compound and / or conjugate contains an olefin double bond, unless otherwise stated, it is intended to include E and Z geometric isomers (e.g., cis or trans) and / or optical isomers. In certain embodiments, for example, the D and A of the conjugate are arranged in a relative cis orientation. In certain embodiments, the D and A of the conjugate are arranged in a relative trans orientation. Similarly, it is also intended to include all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms. The term "geometric isomer" refers to an E or Z geometric isomer (e.g., cis or trans) of an olefin double bond. The term "positional isomers" refers to structural isomers around a central ring, for example, ortho-, meta-, and para-isomers around a benzene ring.

[0163] In addition, in each of the above and following examples, it is understood that these formulas include and represent not only all pharmaceutically acceptable salts of the compounds, but also any and all hydrates and / or solvates of the compound / conjugate formula or its salts. In fact, hydrates, solvates and N-oxides of the compounds and conjugates are also contemplated. The term "solvate" refers to a compound or a salt thereof that further comprises a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.

[0164] It should be understood that certain functional groups, such as hydroxyl, amino and the like, form complexes and / or coordination compounds with water and / or various solvents, having the physical forms of various compounds and conjugates. Therefore, the above formula should be understood to include and represent these various hydrates and / or solvates.

[0165] In each of the foregoing and following embodiments, it is also to be understood that the formula includes and represents any and all crystalline forms, partially crystalline forms, and non-crystalline and / or amorphous forms of the compounds.

[0166] Pharmaceutical composition

[0167] In view of the above, a pharmaceutical composition comprising any compound or conjugate is further provided. In certain embodiments, a pharmaceutical composition is provided herein, comprising a compound (e.g., a compound of formula (I)) or a conjugate (e.g., a conjugate of formula (X)) and one or more pharmaceutically acceptable carriers or excipients. The term "composition" generally refers to any product comprising more than one ingredient (including a compound or conjugate). The composition can be prepared from an isolated compound or conjugate or from salts, solutions, hydrates, solvates and other forms of the compound and / or conjugate.

[0168] In certain embodiments, the compound of the composition includes a compound of formula (XX) (or a pharmaceutically acceptable salt thereof): R 4 —L—Z—R 3 (XX) in: R 4 is niacinamide or benzamide, wherein each of niacinamide or benzamide is optionally substituted; L is a linker comprising at least one atom; Z is R 3 substituted bicyclic heterocycle; and R 3 Contains one or more ring moieties.

[0169] In certain embodiments, the compound of the composition includes a compound of formula (I) (or a pharmaceutically acceptable salt thereof): Where R 1 is alkyl, pyridine, isoxazole, pyrazole or aryl (e.g. phenyl), each optionally substituted with one or more of piperazine (e.g. alkylpiperazine), pyrazine (e.g. alkylpyrazine), imidazole (e.g. alkylimidazole), cyanide, amine, halogen, trifluoromethyl, N-containing heterocycle and / or alkyl; Y 1 N or C; R 2 is H, alkyl, heteroalkyl or halogen; Z is 3 substituted bicyclic heterocycle, wherein the bicyclic heterocycle is imidazo[1,2-b]pyridazine or imidazo[1,2-b]pyrazole; and R 3 is a substituent comprising one or more ring moieties.

[0170] R 3 It may also have a structure of formula (II), formula (III), or formula (IV): in is the point of attachment; each X is independently alkyl or H, provided that not all X are H; Q is O, S, N or C, and is optionally substituted with one or more of alkyl, halogen, O-alkyl, amine, -OH group, alkoxy, piperazine, morpholine, aziridine, carbocyclic or heterocyclic ring and / or carbonyl; Y is O or amine, provided that Y is not NH; and n is 0 or 1.

[0171] In certain embodiments, the conjugate of the composition includes a PROTAC conjugate having a chemical structure of Formula (X) (or a pharmaceutically acceptable salt thereof): A—L'—D(X) wherein A is a group of a compound described herein; L' is a linker that binds A and D, or is absent; and D is a ubiquitin pathway protein binding moiety.

[0172] The composition can be prepared from various amorphous, non-amorphous, partially crystalline, crystalline and / or other morphological forms of the compound and / or conjugate, and the composition can be prepared from various hydrates and / or solvates of the compound and / or conjugate. Therefore, such pharmaceutical compositions can include each, any combination or individual form of various morphological forms and / or solvates or hydrate forms of the compound and / or conjugate.

[0173] The pharmaceutical composition may comprise one or more pharmaceutically acceptable carriers, adjuvants, diluents, excipients and / or vehicles (e.g., conventional nontoxic pharmaceutically acceptable carriers, adjuvants and vehicles) and combinations thereof. Any pharmaceutically acceptable carrier, diluent and excipient known in the art may be used. Examples include, but are not limited to, excipients, colorants, preservatives and stabilizers. More specific examples include crystalline cellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose and magnesium stearate.

[0174] Solutions of the compounds, conjugates or pharmaceutical compositions may be aqueous solutions, optionally mixed with non-toxic surfactants, and / or may contain carriers or excipients, such as salts, carbohydrates and buffers (preferably pH 3 to 9), but for some applications they may be more suitably formulated as sterile non-aqueous solutions or dry forms for use with suitable carriers (e.g., sterile, pyrogen-free water or phosphate-buffered saline). For example, dispersions may be prepared in glycerol, liquid PEG, triacetin and mixtures thereof, and in oils. Under ordinary conditions of storage and use, these preparations may also contain preservatives to prevent the growth of microorganisms.

[0175] The pharmaceutical composition may also include an immunotherapeutic agent, a chemotherapeutic agent, an anticancer agent, and / or a hormonal therapeutic agent. Alternatively, the compound or conjugate (or a pharmaceutical composition comprising the compound or conjugate) may be administered simultaneously or sequentially with an immunotherapeutic agent, an anticancer agent, a chemotherapeutic agent, and / or a hormonal therapeutic agent (or a pharmaceutical composition comprising any of the foregoing) in any order.

[0176] The immunotherapeutic agent can be any suitable immunotherapeutic drug. Examples of suitable immunotherapeutic drugs include, but are not limited to, transforming growth factor beta (TGF-β) inhibitors, such as R268712, or PD-L1 inhibitors, such as Keytruda.

[0177] The anticancer agent may be any suitable anticancer drug. Examples of suitable anticancer drugs include, but are not limited to, kinase inhibitors, such as dasatinib.

[0178] The chemotherapeutic drug may be any suitable chemotherapeutic drug. Examples of suitable chemotherapeutic drugs include, but are not limited to, anthracyclines, such as doxorubicin, taxanes, such as docetaxel, cyclophosphamides, such as cyclophosphamide or 5-fluorouracil.

[0179] The hormone or hormone-related therapeutic agent can be any suitable hormone or hormone-related therapeutic agent. Examples include, but are not limited to, hormone production inhibitors, such as Zolade or Letrozole.

[0180] The compounds and / or conjugates can be formulated into pharmaceutical compositions and administered to a mammalian host, such as a human patient, in a variety of forms suitable for a selected route of administration. Pharmaceutical compositions can be formulated, for example, for a given route of administration and manufactured according to methods of the art, such as described in Remington, The Science and Practice of Pharmacy, 22nd edition (2012). The composition can be an infusion or an injectable composition, such as a composition that can be injected subcutaneously or intravenously.

[0181] The pharmaceutical composition can be administered to a mammalian host, such as a human patient, in a variety of forms suitable for the selected route of administration. In certain embodiments, the pharmaceutical composition is formulated for subcutaneous administration. In certain embodiments, the pharmaceutical composition is formulated for oral administration. In certain embodiments, the pharmaceutical composition is formulated for intramuscular, intravenous, intraarterial, intraperitoneal, or any other art-recognized parenteral administration route.

[0182] In certain embodiments, the pharmaceutical composition is administered systemically in combination with a pharmaceutically acceptable carrier. The composition and formulation component percentages may vary, and may be from about 1 to about 99% by weight of active ingredient (e.g., compound or conjugate) and binder, excipient, disintegrant, lubricant, and / or sweetener (as known in the art). The amount of active compound or conjugate in such therapeutically useful compositions is such that an effective dose level (e.g., in serum or target tissue or cell) may be obtained.

[0183] Exemplary parenteral administration methods include needle (including microneedle) syringes, needle-free syringes and infusion techniques, as well as any other parenteral administration methods recognized in the art. Parenteral preparations are typically aqueous solutions, which may contain excipients such as salts, carbohydrates and buffers (preferably at a pH in the range of about 3 to about 9), but for some applications, they may be more suitable for formulation into sterile non-aqueous solutions or dry forms to be used with suitable carriers (e.g., sterile pyrogen-free water). Preparation of parenteral preparations under sterile conditions, such as by lyophilization, can be easily accomplished using standard pharmaceutical techniques well known to those skilled in the art.

[0184] The pharmaceutical dosage form suitable for use can include sterile aqueous solution or dispersion or sterile powder, which comprises the active ingredient suitable for temporary preparation of sterile injectable or infusible solution or dispersion, optionally encapsulated in liposome, nanocrystal or polymer nanoparticle. In all cases, the final dosage form should be sterile, mobile and stable under manufacturing and storage conditions. Liquid carrier or vehicle can be solvent or liquid dispersion medium, including, for example but not limited to water, electrolyte, sugar, ethanol, polyol (such as glycerol, propylene glycol, liquid polyethylene glycol etc.), vegetable oil, nontoxic glyceride and / or its suitable mixture. In at least one embodiment, it is possible to maintain required fluidity by forming liposome, maintaining required particle size in the case of dispersion or by using surfactant.

[0185] Sterile injections can be prepared by mixing the pharmaceutical composition with the required amount of an appropriate solvent and one or more of the above-mentioned other ingredients (as required), and then filtering and sterilizing. For sterile powders for the preparation of sterile injections, vacuum drying and freeze drying techniques can be used, which can produce active ingredient powders and any additional desired ingredients present in the previously sterile filtered solution.

[0186] method

[0187] The present invention also provides a method for treating a disease state (e.g., cancer and / or solid tumor) of a subject. The method includes administering to the subject an effective amount of: (a) a compound herein (e.g., a compound of formula (I) and / or formula (XX)); (b) a conjugate herein (e.g., a conjugate of formula (X)); (c) a pharmaceutically acceptable salt, N-oxide, hydrate, solvate, tautomer or optical isomer of a compound or conjugate; or (d) a pharmaceutical composition comprising one or more of a compound (a), a conjugate (b) and / or a pharmaceutically acceptable salt, N-oxide, hydrate, solvate, tautomer or optical isomer of (c). In certain embodiments, the pharmaceutical composition may also include an immunotherapeutic agent, a chemotherapeutic agent, an anticancer drug or a hormone therapy agent and a pharmaceutically acceptable carrier or excipient.

[0188] In addition, as desired, the method may further include administering to the subject an effective amount of (a), (b), (c) or (d), alone or in combination with administration of a second pharmaceutical composition, wherein the second pharmaceutical composition comprises an active agent and a second pharmaceutically acceptable carrier or excipient. The active agent may be, for example, an immunotherapeutic agent, a chemotherapeutic agent, an anticancer agent or a hormonal therapeutic agent.

[0189] As used herein, the term "administering" and variations thereof include all ways of introducing the compounds and compositions described herein into a subject, including, but not limited to, orally (po), intravenously (iv), intramuscularly (im), subcutaneously (sc), transdermally, by inhalation (e.g., intranasally (in)), intrabuccally, intraocularly, sublingually, vaginally, rectally, and the like.

[0190] As used herein, "effective amount" refers to an amount sufficient to achieve the desired result or to have an effect on an adverse condition. For example, an effective amount may refer to an amount sufficient to achieve the desired therapeutic result or to have an effect on a symptom. For any subject, the specific effective dosage level (e.g., amount) will depend on a variety of factors, including the disease / disorder being treated and the severity of the disease / disorder (e.g., the type, location, and severity of fractures, bone injuries, or cancer); the specific composition, compound, and / or conjugate employed (i.e., its efficacy and / or bioavailability); the age, weight, general health, sex, and diet of the subject; the subject's response; the time of administration; the route of administration; the excretion rate of the specific conjugate employed; the duration of treatment; the drugs / active agents used in combination or concomitantly with the specific conjugate or compound employed, and similar factors well known in the medical field. For example, it is fully within the capability of a person skilled in the art to start adding a dose of a conjugate / composition from a dose level lower than that required to achieve the desired therapeutic effect, and gradually increase the dose until the desired effect is achieved. If necessary, the effective amount may be divided into multiple doses for administration. Therefore, a single dose of a compound / conjugate / composition may contain such an amount or a submultiple thereof to constitute a daily dose. If there are any contraindications, the individual physician may adjust the dosage. In addition, pharmacogenomic (the effect of genotype on the pharmacokinetic, pharmacodynamic or efficacy characteristics of an antigen or composition) information about a particular patient may affect the dosage used to achieve an effective amount.

[0191] Depending on the route of administration, various permissible doses may be considered. For example, the effective amount of the compound, conjugate and / or pharmaceutical composition may be from about 0.1 μg / kg / day, such as 0.5 μg / kg / day, 0.7 μg / kg / day or 0.01 mg / kg / day to about 1000 mg / kg / day. Intravenous doses may be several orders of magnitude lower.

[0192] When the compound, conjugate and / or first pharmaceutical composition is administered with an active agent or a second pharmaceutical composition (comprising an active agent), the compound / conjugate / first pharmaceutical composition and the active agent / second pharmaceutical composition can be administered to the subject simultaneously or sequentially in any order and using any delivery method. For example, but not limited to, the compound / conjugate / first pharmaceutical composition can be administered intravenously (e.g., as an intravenous solution), while the active agent / second pharmaceutical composition can be administered subcutaneously. In other embodiments, the compound / conjugate / first pharmaceutical composition and the active agent / second pharmaceutical composition are both administered intravenously. It is within the scope of the present disclosure to use a pharmaceutical composition comprising more than one drug / active agent.

[0193] The method may further comprise administering to the subject a second therapy comprising an effective amount of a chemotherapeutic agent, an immunotherapeutic agent, or a hormonal therapeutic agent; or radiation therapy.

[0194] The compound, conjugate and / or any other active agent administered therewith (or administered sequentially therewith) may be administered at a therapeutically effective dose to obtain a clinically acceptable result, e.g., to alleviate or eliminate symptoms or tumors. Thus, the conjugate, any active agent and / or any second therapy may be administered simultaneously or sequentially in a treatment regimen. Any active agent and / or second therapy may be administered according to a treatment regimen known in the art.

[0195] Those skilled in the art will appreciate that treatment regimens can vary according to the needs of the subject. Thus, the combination of the conjugates and other compounds (drugs) used in the methods herein can be administered according to variations of the regimens described herein. For example, the conjugates and / or active agents can be administered discontinuously rather than continuously during a treatment cycle.

[0196] The method may also include administering an effective amount of an active agent, which is a free immunotherapeutic agent, a chemotherapeutic agent, an anticancer drug or a hormonal therapeutic agent, or a pharmaceutical composition (e.g., a second pharmaceutical composition) comprising the active agent and a pharmaceutically acceptable carrier or excipient, simultaneously or sequentially in any order.

[0197] The disease state of the subject can be any type of disease or condition modulated by one or more kinases. In certain embodiments, the disease or condition is cancer, a disease, an inflammatory state, or a neurological disease modulated by one or more kinases. The disease or condition may be modulated by one or more protein kinases selected from the group consisting of AB1, AB12, AFK, ALK, AMPK_group, ATM, ATR, Aurora A, Aurora B, AXL, BCKDK, BLK, BMPR1B, BMX, Brk, BRSK1, BTK, CaM-KIalpha, CaM-Kllalpha, CaMKK group, CaM-KIV, CaM-KKalpha, CaM-KKbeta, CCDPK, CCRK, CDK1, CDK11, CDK2, CDK4, CDK5, CDK6, CDK7, CDK9, CDK group, CDPK, Chak1, CHK1, CHK2, CK1 alpha, CK1 delta, CK1 epsilon, CK1 group, CK2alpha, CK2 beta, CK2 group, CLKJCSFIR, Csk, DAPK1, DAPK2, DAPK3, DAPK group, DCAMKL1, DMPK group, DNA-PK, DYRK1A, DYRK1B, DYRK2, DYRK3, eEF2K, Eg 3-kinase, EGFR, EIF2AK2, EphA2, EphA3, EphA4, EphA8, EphBl, EphB2, EphB3, EphB5, ErbB2, FAK, Fer, Fes, FGFR1, FGFR3, FGFR4, FGFR group, Fgr, FLT1, FLT3, FLT4, Fyn , GRK-1, GRK-2, GRK-3, GRK-4, GRK-5, GRK-6, GRK group, GSK-3alpha, GSK-3beta, GSK-3 group, HCK, HIPK2, HIPK3, HRI, ICK, IGF1R, IKK-alpha, IKK-beta, IKK-epsilonILK, InsR, IPL1, IRAKI, IRAK4, ITK, JAK1, JAK2, JAK3, JAK group, JNK group, KDR, KIS, Kit, KSR1, Lck, LIMK1, LIMK2, LKB1, LOK, Lyn, MAP2K1, MAP2K2, MAP2K3, MAP2K 4. MAP2K6, MAP2K7, MAPK2 group, MAP3K1, MAP3K11, MAP3K14, MAP3K5, MAP3K7, MAP3K8, MAPK3 group, MAP4K1, MAP4K2, MAP4K4, MAPK1, MAPK10, MAPK11, MAPK12, MAPK1 3. MAPK14, MAPK3, MAPK4, MAPK6, MAPK7, MAPK8, MAPK9, MAPK group, MAPKAPK2, MARK group, Mer, Met, MHCK, MLCK group, Mnkl, Mnk2, MOS, MRCKa, MSTI, MST3, mTOR, NDR1, NDR2, NEK1, NEK2, NEK6, NEK9, NEK group, NLK, NuaKl, p37 kinase, p38 group, p70S6K, p70R6Kb, P70S6K group, PAKI, PAK2, PAK3, PAK5, PAK6, PAK group, PASK, P-CIP2, PCTAIRE1, PDGFR alpha, PDGFR beta, PDGFR group, PDHK1, PDHK2, PDHK3, PDHK4, PDK-1, PDK-2, PDK group, PHK group, PIK3CA, PIK3CB, PIK3CD, PIK3CG, Pim-1, PKA alpha, PKA group, PKB beta, PKB group, PKC alpha, PKC beta, PKC delta, PKC epsilon, PKC eta, PKC gamma, PKC iota, PKC theta, PKC zeta, PKC group, PKD1, PKD2, PKD3, PKGl / cGK-I, PKG2 / cGK-II, PKG2 / cGK group, PKN1, PLK1, PLK2, PLK3, PRP4, PYK2, RAF1, Ret, ROCK1, ROCK2, Ron, RPL10, RSK-1, RSK-2, RSK-3, RSK-5, SDK1, SGK group, SIK, Sky, Src, Src group, STLK3, Syk, TBK1, Tec, TESK1, TESK2, TGFbR1, TGFbR2, Tiel, Tie2, Titin kinase, TNK2, TRKA, TRKB, tropomyosin kinase, TSSK3, TXK, Tyk2, TYK2, I KK1, Wee 1, Wnk1, WNK 1, Yes and ZAP70. In certain embodiments, the disease state is regulated by MERTK and AXL, both of which are inhibited by administering an effective amount of a compound, conjugate, composition or prodrug herein.

[0198] In certain embodiments, the disease state is cancer, such as acute myeloid leukemia, chronic myeloid leukemia, ovarian cancer, cervical cancer, pancreatic cancer, breast cancer, brain cancer, cervical cancer, pancreatic cancer, breast cancer (e.g., metastatic breast cancer), brain cancer, skin cancer, lung cancer, prostate cancer, lymphoma, leukemia, colon cancer, head cancer, neck cancer, thyroid cancer, kidney cancer, liver cancer, or stomach cancer. In certain embodiments, the cancer is a solid tumor cancer (e.g., breast cancer, colon cancer, lung cancer, etc.).

[0199] In certain embodiments, the method may also include imaging a cancer cell population in the subject (e.g., after administering a compound, a conjugate, a first pharmaceutical composition comprising a compound or a conjugate, or a first pharmaceutical composition comprising a compound or a conjugate and an immunotherapeutic agent, a chemotherapeutic agent, an anticancer agent, and / or a hormonal therapeutic agent). The cancer cell population in the subject may be a solid tumor. Imaging may be performed by any imaging technique now known or later developed in the medical field. In certain embodiments, imaging may be performed by hybrid scanning, utilizing functional imaging modalities such as single photon emission computed tomography (SPECT) or PET in combination with computed tomography (CT) and / or magnetic resonance imaging (MRI) techniques, and combinations thereof. Ultrasound imaging may also be used.

[0200] When imaging a population of cancer cells in a subject (either in conjunction with or independently of the method), the method may also include diagnosing whether the subject has cancer.

[0201] When the subject has received cancer treatment and the subject's bones are imaged, the method may further include evaluating or monitoring the effectiveness of treatment. For example, compounds, conjugates and / or pharmaceutical compositions can be used to quantitatively monitor the growth and proliferation of tumors or lesions in vivo. In certain embodiments, a method for monitoring the progress of a subject's cancer (e.g., bone marrow cancer) is provided, including administering a compound, a conjugate, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound or a conjugate or a pharmaceutically acceptable salt thereof to the subject. This method may further include imaging the subject's cancer. In certain embodiments, compared to the size of a tumor microenvironment (TME), a cancer cell group and / or a solid tumor in a subject before or during early treatment, the size of such TME, a group and / or a solid tumor is reduced, indicating that therapy or treatment is effective.

[0202] The TME, cancer cell populations and / or solid tumors of the subject can be imaged regularly during the treatment process, and the doctor can compare the images and / or otherwise quantify the lesion or cancer growth to determine the therapeutic effect (e.g., whether the killing effect of cancer cells is different during the treatment process, or the lesion size or cancer growth is relatively increased). Therefore, a method for determining the possibility of successful treatment of a subject is provided. It should be understood that those skilled in the art can use such information to affect the dosage of the compound, conjugate or pharmaceutical composition, depending on whether a positive result is detected (i.e., the treatment is effective, or if the TME, cancer cell population and / or solid tumor size are not reduced, the dosage or administration regimen may be adjusted).

[0203] Also provided is a method of inhibiting T cell responses in a subject's TME, the method comprising administering to the subject an effective amount of: (a) a compound herein (e.g., a compound of formula (I) and / or formula (XX)); (b) a conjugate herein (e.g., a conjugate of formula (X)); (c) a pharmaceutically acceptable salt, N-oxide, hydrate, solvate, tautomer or optical isomer of the compound or conjugate; or (d) a pharmaceutical composition comprising one or more of a compound of (a), a conjugate of (b) and / or a pharmaceutically acceptable salt, N-oxide, hydrate, solvate, tautomer or optical isomer of (c). The subject may have cancer. The subject may have solid tumor cancer. Because the compounds (e.g., compounds comprising morpholine substituents), conjugates, and pharmaceutical compositions of the present invention can inhibit at least MERTK and AXL, thereby inhibiting the innate inflammatory immune response in the TME (and, for example, the recruitment of myeloid suppressor macrophages to the TME), administering an effective amount of the compound to a subject can inhibit the proinflammatory T cell response in the TME, thereby further promoting an anti-cancer environment using the subject's own immune system.

[0204] The compounds, conjugates and pharmaceutical compositions may be administered in unit dosage forms and / or compositions.

[0205] For the methods described herein, the compounds, conjugates and compositions can be administered in a single dose or in a multiple dose combination, which can be administered simultaneously, continuously or separately in any suitable manner. When the dose is administered in a separate dosage form, the number of doses administered per day for each compound, conjugate or composition can be the same or different. The compound, conjugate and / or composition doses can be administered by the same or different routes of administration. The compound, conjugate or composition can be administered simultaneously in separate or single forms at the same or different times during the treatment according to a simultaneous or alternating regimen.

[0206] Dosages may vary and may be administered once or more times per day for one or more days. Guidance on appropriate dosages for a given class of drug products can be found in the literature. In further various aspects, the formulation may be administered in a "prophylactically effective amount"; that is, an amount effective to prevent a disease state or condition.

[0207] The compound / conjugate / composition may be administered multiple times, for example daily (1-3 times a day or more; qd (once a day), bid (twice a day), tid (three times a day)), weekly (including 1-3 times or more on a given day), biweekly (including 1-3 times or more on a given day), monthly (including 1-3 times or more on a given day), or bimonthly (including 1-3 times or more on a given day). In each case, it is understood that the effective amount described herein corresponds to the administration situation, or to the total daily, weekly, monthly or quarterly dose determined according to the administration regimen.

[0208] Some definitions

[0209] As used herein, the following terms and phrases shall have the following meanings. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0210] The term "about" can allow for a certain degree of variation in values ​​or ranges, for example, within 10%, within 5%, or within 1% of a stated value or a stated range limit. The term "substantially" can allow for a certain degree of variation in values ​​or ranges, for example, within 90%, within 95%, within 99%, within 99.5%, within 99.9%, within 99.99%, or within at least about 99.999% or more of a stated value or a stated range limit.

[0211] Unless the context clearly dictates otherwise, the terms "a", "an" or "the" are used to include one or more. Unless otherwise stated, the term "or" is used to refer to a non-exclusive "or".

[0212] In addition, it should be understood that the words or terms used herein (and not otherwise defined) are for descriptive purposes only and not for limiting purposes. The use of any section headings is intended to assist in reading the document and should not be construed as limiting. In addition, information related to a section heading may appear within or outside that particular section. In addition, all publications, patents, and patent documents mentioned in this document are incorporated herein by reference in their entirety, as if incorporated by reference alone. If there is an inconsistent usage between this document and those documents incorporated by reference, the usage in the incorporated reference shall be deemed to supplement this document; for irreconcilable inconsistencies, the usage in this document shall prevail.

[0213] The term "substituted" as used herein refers to the replacement of one or more hydrogen atoms contained in a functional group by one or more non-hydrogen atoms. The term "functional group" or "substituent" as used herein refers to a group that can be substituted or has been substituted on a molecule. Examples of substituents or functional groups include, but are not limited to, halogens (e.g., F, Cl, Br, and I); oxygen atoms in groups such as hydroxyl, alkoxy, aryloxy, aralkyloxy, oxo (carbonyl), carboxyl (including carboxylic acid, carboxylate, and carboxylate); sulfur atoms in groups such as thiol, alkyl and aryl sulfide, sulfoxide, sulfone, sulfonyl, and sulfonamide; nitrogen atoms in groups such as amine, azide, hydroxylamine, cyano, nitro, N-oxide, hydrazide, and enamine; and other heteroatoms in various other groups.

[0214] The term "alkyl" as used herein refers to a group having 1 to about 20 carbon atoms (C 1 -C 20 ), 1 to 12 carbon atoms (C 1 -C 12 ), 1 to 8 carbon atoms (C 1 -C 8 ) or in certain embodiments have 1 to 6 carbon atoms (C 1 -C 6 ) substituted or unsubstituted straight and branched alkyl and cycloalkyl. Examples of straight chain alkyls include alkyls having 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl and n-octyl. Examples of branched alkyls include, but are not limited to, isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, isopentyl and 2,2-dimethylpropyl. The term "alkyl" as used herein includes n-alkyl, isoalkyl and anteisoalkyl and other branched forms of alkyl. Representative substituted alkyls may be substituted once or more by any of the groups listed herein, such as amino, hydroxyl, cyano, carboxyl, nitro, sulfenyl, alkoxy and halogen groups.

[0215] The term "alkenyl" as used herein refers to substituted or unsubstituted straight chain and branched divalent alkenyl and cycloalkenyl groups having 2 to 20 carbon atoms (C 2 -C 20 ), 2 to 12 carbon atoms (C 2 -C 12 ), 2 to 8 carbon atoms (C 2 -C 8 ) or in certain embodiments has 2 to 4 carbon atoms (C 2 -C 4 ) and at least one carbon-carbon double bond. Examples of straight-chain alkenyl groups include alkenyl groups having 2 to 8 carbon atoms, such as -CH=CH-, -CH=CHCH 2 - etc. Examples of branched alkenyl groups include, but are not limited to, -CH=C(CH 3 )-wait.

[0216] An alkynyl group is a fragment containing an open point of attachment on a carbon atom that would form when a hydrogen atom bonded to a triple-bonded carbon is removed from an alkyne molecule. The term "hydroxyalkyl" as used herein refers to an alkyl group as defined herein substituted with at least one hydroxy (-OH) group.

[0217] The term "cycloalkyl" as used herein refers to substituted or unsubstituted cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the cycloalkyl group may have 3 to about 8-12 ring members, while in other embodiments, the number of ring carbon atoms ranges from 3 to 4, 5, 6, or 7. In some embodiments, the cycloalkyl group may have 3 to 6 carbon atoms (C 3 -C 6 Cycloalkyl also includes polycyclic cycloalkyl, such as but not limited to norbornyl, adamantyl, bornyl, camphenyl, isobornyl and carbyl, and fused rings, such as but not limited to decahydronaphthyl and the like.

[0218] The term "acyl" as used herein refers to a group containing a carbonyl moiety, wherein the group is bonded through a carbonyl carbon atom. The carbonyl carbon atom is also bonded to another carbon atom, which may be part of a substituted or unsubstituted alkyl, aryl, aralkylcycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, etc. In the special case where the carbonyl carbon atom is bonded to hydrogen, the group is a "formyl", i.e., an acyl group as defined herein. The acyl group may include 0 to about 12-40, 6-10, 1-5, or 2-5 additional carbon atoms bonded to the carbonyl group. Acryloyl is an example of an acyl group. Acyl groups may also include heteroatoms as defined herein. Nicotinoyl (pyridyl-3-carbonyl) is an example of an acyl group as defined herein. Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl, etc. When the group of carbon atoms bonded to the carbonyl carbon atom contains a halogen, the group is referred to as a "haloacyl". An example is trifluoroacetyl.

[0219] The term "aryl" as used herein refers to a substituted or unsubstituted cyclic aromatic hydrocarbon containing no heteroatoms in the ring. Thus, aryl includes, but is not limited to, phenyl, azulenyl, heptenyl, biphenyl, indoletenyl, fluorenyl, phenanthrenyl, triphenyl, pyrenyl, naphthenyl, In some embodiments, the aryl group contains about 6 to about 14 carbon atoms (C 6 -C 14 ) or 6 to 10 carbon atoms (C 6 -C 10 ). Aryl can be unsubstituted or substituted, as defined herein. Representative substituted aryl groups can be monosubstituted or multiply substituted, such as, but not limited to, 2-, 3-, 4-, 5- or 6-substituted phenyl or 2-8 substituted naphthyl, which can be substituted with carbon or non-carbon groups (such as those listed herein).

[0220] As used herein, the terms "aralkyl" and "arylalkyl" refer to an alkyl group as defined herein, wherein a hydrogen bond or carbon bond of the alkyl group is replaced by an aryl bond as defined herein. Representative aralkyl groups include benzyl and phenethyl groups, as well as fused (cycloalkylaryl)alkyl groups, such as 4-ethyl-indanyl. Aralkenyl groups are alkenyl groups as defined herein, wherein a hydrogen bond or carbon bond of the alkyl group is replaced by an aryl bond as defined herein.

[0221] The term "heterocyclyl" as used herein refers to substituted or unsubstituted aromatic and non-aromatic ring compounds containing 3 or more ring members, one or more of which is a heteroatom, such as but not limited to B, N, O and S. Thus, the heterocyclyl group can be a cycloheteroalkyl or heteroaryl group, or if polycyclic, any combination thereof. In some embodiments, the heterocyclyl group includes 3 to about 20 ring members, while other such groups have 3 to about 15 ring members. In some embodiments, the heterocyclyl group includes 3 to 8 carbon atoms (C 3 -C 8 ), 3 to 6 carbon atoms (C 3 -C 6 ) or 6 to 8 carbon atoms (C 6 -C 8 ) of a heterocyclic group.

[0222] Heteroaromatic ring is an embodiment of heterocyclic radical. The phrase "heterocyclic radical" includes fused ring species, including those ring species comprising fused aromatic and non-aromatic groups. Representative heterocyclic radicals include but are not limited to pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl, morpholinyl, chromanyl, indolinone, isoindolinone, furanyl, pyrrolidinyl, pyridyl, pyrazinyl, pyrimidinyl, triazine, thienyl, tetrahydrofuranyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl, tetrazolyl, benzoxazoline, benzothiazoline and benzimidazoline.

[0223] The term "heterocycloalkyl" as used herein refers to an alkyl group in which a hydrogen bond or a carbon bond in an alkyl group as defined herein is replaced by a heterocyclyl bond as defined herein. Representative heterocycloalkyl groups include, but are not limited to, furan-2-ylmethyl, furan-3-ylmethyl, pyridin-3-ylmethyl, tetrahydrofuran-2-ylmethyl and indol-2-ylpropyl.

[0224] The term "heteroaralkyl" as used herein refers to an alkyl group as defined herein wherein a hydrogen or carbon bond of the alkyl group is replaced by a bond to a heteroaryl group as defined herein.

[0225] The term "alkoxy" as used herein refers to an oxygen atom connected to an alkyl group (including a cycloalkyl group), as defined herein. Examples of straight chain alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, etc. Examples of branched chain alkoxy groups include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, etc. Examples of cyclic alkoxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc. Alkoxy groups may also include double or triple bonds and may also include heteroatoms. For example, allyloxy is an alkoxy group defined herein. Methoxyethoxy is also an alkoxy group defined herein, and in the case where two adjacent atoms of the structure are substituted by it, methylenedioxy is also an alkoxy group defined herein.

[0226] As used herein, the term "amine" refers to an amine having a formula such as N(group) 3 Primary amines, secondary amines and tertiary amines, wherein each group can be independently H or non-H, such as alkyl, aryl, etc. Amines include but are not limited to R-NH 2 , such as alkylamine, arylamine, alkylarylamine; R 2 NH, wherein each R is independently selected, such as dialkylamine, diarylamine, arylalkylamine, heterocyclic amine, etc.; and R 3 N, wherein each R is independently selected, such as trialkylamine, dialkylarylamine, alkyldiarylamine, triarylamine, etc. The term "amine" as used herein also includes ammonium ions.

[0227] The term "amino" as used herein refers to -NH 2 , -NHR, -NR 2 、-NR 3 + Substituents of the form wherein each R is independently selected, and the protonated form of each, but -NR 3 + Except for, it cannot be protonated. Therefore, any compound substituted by amino group can be regarded as amine. "Amino group" referred to herein can be primary, secondary, tertiary or quaternary amino group. "Alkylamino" includes monoalkylamino, dialkylamino and trialkylamino.

[0228]

[0046] The terms "halo," "halogen," or "halide" group, as used herein, alone or as part of another substituent, refer, unless otherwise stated, to a fluorine, chlorine, bromine, or iodine atom.

[0229] The term "haloalkyl" as used herein includes monohaloalkyl, polyhaloalkyl (wherein all halogen atoms may be the same or different) and perhaloalkyl (wherein all hydrogen atoms are replaced by halogen atoms (e.g., fluorine)). Examples of haloalkyl include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3-difluoropropyl, perfluorobutyl, -CF(CH 3 ) 2 wait.

[0230] As used herein, the term "optionally substituted" or "optionally substituted" means that the group in question is unsubstituted or substituted with one or more specified substituents. When the group in question is substituted with multiple substituents, the substituents may be the same or different. When the terms "independently," "independently are," and "independently selected from" are used, it means that the group in question may be the same or different. Certain terms defined herein may appear multiple times in a structure, and when they appear, each term should be defined independently of the other terms.

[0231] The compounds described herein may contain one or more chiral centers, or may otherwise exist as multiple stereoisomers. It should be understood that, in one embodiment, the invention described herein is not limited to any particular stereochemical requirements, and the compounds and compositions, methods, uses, and medicaments comprising them may be optically pure, or may be any of a variety of stereoisomer mixtures, including racemates and other enantiomeric mixtures, other diastereomeric mixtures, etc. It should also be understood that such stereoisomer mixtures may include a single stereochemical configuration at one or more chiral centers, and a mixture of stereochemical configurations at one or more other chiral centers.

[0232] Similarly, the compounds described herein may include geometric centers, such as cis, trans, E and Z double bonds. It should be understood that, in another embodiment, the invention described herein is not limited to any particular geometric isomer requirements, and the compounds and compositions, methods, uses and medicaments including them may be pure, or may be any of a variety of geometric isomer mixtures. It should also be understood that such geometric isomer mixtures may include a single configuration at one or more double bonds, and a mixture of geometric configurations at one or more other double bonds.

[0233] The term "pharmaceutically acceptable carrier" is recognized in the art and refers to a pharmaceutically acceptable material, composition or vehicle for carrying or transporting any subject composition or its components, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be "acceptable", that is, compatible with the subject composition and its components and not harmful to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer solution; and (21) other nontoxic compatible substances used in pharmaceutical preparations.

[0234] The terms "patient" and "subject" are used interchangeably and include human patients, laboratory animals, such as rodents (e.g., mice, rats, or hamsters), rabbits, monkeys, chimpanzees, livestock, such as dogs, cats, or rabbits, agricultural animals, such as cattle, horses, pigs, sheep, or goats, or captive wild animals, such as bears, pandas, lions, tigers, leopards, elephants, zebras, giraffes, gorillas, dolphins, or whales. The patient to be treated is preferably a mammal, particularly a human.

[0235] Although the concepts of the present disclosure are elaborated and described in detail in the drawings and descriptions of this article, the results in the drawings and descriptions should be regarded as exemplary rather than restrictive; it should be understood that only illustrative embodiments are shown and described herein, and it is intended to protect all changes and modifications within the spirit of the present disclosure. In fact, many specific details are provided to provide a thorough understanding of the present disclosure.

[0236] The use of any section headings is intended to aid in reading the document and should not be construed as limiting. In addition, the information associated with a section heading may appear within or outside of that particular section.

[0237] All patents, patent application publications, journal articles, textbooks, and other publications mentioned in the specification are indicative of the level of skill of those skilled in the art to which the present disclosure pertains. All such publications are incorporated herein by reference to the same extent as if each publication were specifically and individually indicated to be incorporated by reference. If there is an inconsistency in usage between this document and those documents incorporated by reference, the usage in the incorporated references shall be deemed supplementary to that of this document; for irreconcilable inconsistencies, the usage in this document shall prevail.

[0238] Various techniques and mechanisms of the present disclosure sometimes describe a connection or link between two components. Unless otherwise specified or the context clearly indicates a difference, words such as attached, linked, coupled, connected, bound, and similar terms and their inflectional morphemes are used interchangeably. These words and expressions do not necessarily mean direct connection, but include connections through intermediate components. It should be noted that a connection between two components does not necessarily mean a direct, unimpeded connection, as various other components may exist between the two components. Therefore, unless otherwise specified, connection does not necessarily mean a direct, unimpeded connection. Example

[0239] 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. Example 1 Effect of Substituents on the Imidazolo[1,2-b]pyridazine Moiety

[0240] In vitro studies conducted by Reaction Biology Corporation (Malvern, PA) evaluated the properties of the imidazo[1,2-b]pyridazine partial substituent at position 6. The results showed that specific substituents significantly affected the inhibition of p70S6K. For example, at 25 nM, ponatinib and compound HSN748 (containing a linear substituent at position 6) inhibited p70S6K by only 38% and 55%, respectively ([ATP] = 10 uM), while compounds HSND77, HSND79, and HSND80 (analogs with ring substitutions at position 6) inhibited p70S6K by 95%, 95%, and 97%, respectively, under the same conditions.

[0241] At 50 nM compound and 10 uM ATP, compounds HSND77, HSND79 and HSND80 herein also showed superior inhibitory effects on MNK2 compared to compound HSN748 (92% (compound HSND77), 94% (compound HSND79) and 96% (compound HSND80) compared to 89% (compound HSN748 containing a linear substituent at position 6). This data supports that modification of the imidazo[1,2-b]pyridazine moiety has a positive impact on the inhibition of p70S6K by nicotinamide kinase inhibitors. Example 2 Compounds with 6-position ring substitution inhibit TAM kinases, AXL and MERTK

[0242] Several compounds herein having substituents on the imidazo[1,2-b]pyridazine moiety at position 6, wherein the substituents comprise one or more ring moieties, were evaluated for affinity against two TAM kinases, AXL and MERTK. Perhaps more specifically, the affinity of the compounds described herein with substituents on the imidazo[1,2-b]pyridazine moiety at position 6 was evaluated using KINOMEscan TM The equilibrium dissociation constants between each compound HSND141, compounds HSND149, HSND150, HSND151, and HSND80 and AXL and MERTK were evaluated using KINOMEscan TM Is a competitive binding assay that quantitatively measures the ability of each test compound to displace an immobilized active site-directed ligand. The assay uses a DNA-labeled kinase, an immobilized ligand, and a test compound. A quantitative polymerase chain reaction (PCR) using a DNT tag is then used to measure the ability of the test compound to displace the immobilized ligand.

[0243] Figures 6A-7B The graphical results of such an evaluation are shown, with HSND80 as the test compound and the measured K values ​​for all test compounds shown in Table 1. D(Unit: nM) (K obtained using DiscoverX (Eurofins Discovery) D value). Table 1: Kd (unit: nM). Kd was obtained from DiscoverX Eurofins Compound AXL MERTK HSND141 1.2 0.22 HSND149 3.7 0.2 HSND150 2.8 <0.17 HSND151 3.3 <0.17 HSND80 1.1 <0.17 In summary, each of compound HSND141, compound HSND149, HSND150, HSND151, and HSND80 exhibit high affinity / strong binding to AXL and MERTK, which are clearly not targeted by ponatinib or HSN748 compounds, especially HSND80, which has strong binding to MERTK. Example 3 Compound HSND80 and its analogs have better inhibitory effects on NCI-60 cell lines than ponatinib and the parent compound with linear substituents

[0244] The 6-linear substituted ponatinib analogs were evaluated in the NCI-60 human tumor cell line screen for their inhibition of various kinase-driven cancers compared to the compounds herein. At 200 nM, compound HSND80 and its analogs completely inhibited (100%) the growth of Caki-1 (renal cancer) or MDA-MB-231 (breast cancer) (see Figure 4 ). Compound HSND80 inhibits the IC of MDA-MB-231 50 (72 hours) was 8.6 nM. Compound HSND80 and its analogs also potently inhibited the proliferation of multiple myeloma cell lines ( Figure 4 ).

[0245] Interestingly, other 6-substituted compounds, such as compounds HSND37, HSND39 and HSND40, were only moderate inhibitors of MDA-MB-231, with GI50 values ​​(NCI-60 screening) of 413 nM (compound HSND37), 571 nM (compound HSND39) and 889 nM (compound HSND40), respectively. Under similar conditions, compound HSND41 (a ring analog containing unsubstituted morpholine) inhibited MDA-MB-231 with a GI50 value of 35 nM.

[0246] This confirms that the nature of the 6-substitution on the imidazo[1,2-b]pyridazine moiety is critical for anticancer activity (compare compounds HSN748, HSND37, and HSND41, respectively, see Figures 3A-3C ). Example 4 Bioavailability studies

[0247] The bioavailability and C max .

[0248] Briefly, the compounds were dissolved in 10% dimethyl sulfoxide (DMSO) / 90% (20% HP-β-CD in water (w / w)). Male CD1 mice (n=3) were orally administered 10 mg / Kg of each compound (HSND80, HSND41, HSND101, HSND102, HSND141 and HSND156). Blood samples were collected at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after administration, and the concentration of the compound in the blood at each specific time point was determined by liquid chromatography-mass spectrometry (LC-MS) (High Performance Liquid Chromatography (HPLC) instrument: Shimadzu; MS instrument: AB API 5500LC / MS / MS; Chromatographic column: HALO C1890A2.7 μm (30*2.1 mm); Mobile phase A: 5% acetonitrile aqueous solution (0.1% formic acid); Mobile phase B: 95% acetonitrile aqueous solution (0.1% formic acid)).

[0249] Figure 5 The data shown in indicate that all compounds tested were bioavailable, with the dimethylmorpholine compound HSND80 showing higher bioavailability than the unsubstituted morpholine (compound HSND41). Example 5 Efficacy study: HSND80 reduces 4T1 tumors in vivo

[0250] 0.5x 10 6 4T1 cells were injected subcutaneously (SQ) into the right side of female Balb-C mice. Each group consisted of 5 tumor-bearing mice. Seven days after tumor implantation, mice were orally dosed once a day with vehicle control (5% DMSO, 40% PEG300, 5% Tween 80, 50% water) or HSND80 (15 mg / Kg). Mice were dosed for 5 days and stopped for 2 days (drug withdrawal period). Tumors (length, width, height) were measured every other day to obtain tumor volume (in mm 3 ).

[0251] At 15 mg / kg, HSND80 reduced the growth of 4T1 (breast) syngeneic tumors by approximately 60% (data not shown). Example 6 Efficacy study - HSND80 and HSND100 reduce CT-26 tumors in vivo

[0252] Each BALB / c female mouse was inoculated subcutaneously on the right flank with CT-26C2 tumor cells (0.3×10 6 / mouse) for tumor growth. Efficacy studies were performed on day 10 after tumor inoculation, when the average tumor size reached approximately 71 mm 3 . Each group consisted of 6 tumor-bearing mice. The vehicle control was 25 mM citrate buffer (pH 2.5). HSND80 was orally administered once a day at a dose of 15 mg / Kg for 4 consecutive days, followed by administration at a dose of 10 mg / Kg. HSND100 was administered at 15 mg / Kg. The mice were administered for 5 days and then stopped for 2 days (withdrawal period). Tumors (length, width, height) were measured every other day to obtain tumor volume (in mm 3 ).

[0253] On day 17 (from the start of dosing), HSND80 reduced tumor size by 45% (compared to vehicle control), while HSND100 reduced tumor size by 36%. Example 7 Compound synthesis and characterization

[0254] General procedure for the synthesis of substituted imidazo[1,2-b]pyridazine substrates :

[0255] In a sealed tube, 3-bromo-6-chloroimidazo[1,2-b]pyridazine (500 mg) and appropriate amine (4 equivalents) were dissolved in n-propanol (1 mL) or amine as solvent and refluxed overnight at 150 °C. After completion, the reactant 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 product was purified by silica gel column chromatography to obtain the desired product.

[0256] General steps of Sonogashira coupling :

[0257] Substituted imidazo[1,2-b]pyridazine base (1 mmol), alkyne base (1.1 mmol), PdCl 2 (PPh 3 ) 2 (3mol%), XPhos (2mol%), Cs 2 CO 3 (3 equivalents) and CuI (1 mol%) were deoxygenated using argon. Anhydrous N,N-dimethylformamide (DMF) (5 mL) and N,N-diisopropylethylamine (DIPEA) (2.5 mL) were then added to the deoxygenated solution under inert conditions. The reaction mixture was stirred at 60 °C overnight.

[0258] After completion, the reaction mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with brine solution (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and then purified by silica gel column chromatography to obtain the desired product.

[0259] Specific compounds / products and their substrates are described below, along with data confirming the structures of the synthesized compounds.

[0260] (R)-3-Bromo-6-((tetrahydrofuran-3-yl)oxy)imidazo[1,2-b]pyridazine

[0261] According to the general procedure above, the reaction mixture of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (500 mg) and (R)-tetrahydrofuran-3-ol (2.3 equivalents) in anhydrous tetrahydrofuran (THF) (20 mL) was cooled to 0 ° C, and then sodium hydride (NaH) (2.5 equivalents) was added. The reaction mixture was stirred at room temperature overnight. After completion, the reactant was extracted with ethyl acetate and washed with brine. The organic layer was collected and dried with sodium sulfate and concentrated under reduced pressure to obtain the desired product. Off-white solid, the yield was 84%.

[0262] (R)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-5-((6-((tetrahydrofuran-3-yl)oxy)imidazo[1,2-b]pyridazin-3-yl)ethynyl)nicotinamide (Compound HSND-28)

[0263] Off-white solid, yield: 58%. 1 H NMR (500 MHz, DMSO-d 6 )δ10.79(s,1H),9.10(s,1H),8.96(d,J=1.9Hz,1H),8.53–8.45(m,1H),8.19(s,1H ),8.12(d,J=9.6Hz,1H),8.04(d,J=15.3Hz,2H),7.71(d,J=8.5Hz,1H),7.03(d,J= 9.6Hz,1H),5.61–5.53(m,1H),4.04–3.89(m,2H),3.86(q,J=7.7Hz,1H),3.75(td, J=8.3,4.9Hz,1H),3.56(s,2H),2.53–2.29(m,9H),2.22(s,3H),2.17–2.07(m,1H); 13 C NMR (126 MHz, DMSO-d 6)δ163.8,160.0,153.8,148.7,138.4,138.3,137.8,137.4,132.8,131.8,130.3,128.7,127.8(q,J=30.2Hz),125 .8(q,J=274.6Hz),123.9,119.2,117.6,114.4,111.9,94.9,81.2,78.6,72.8,66.8,57.7,54.9,52.6,45.6,32.9.

[0264] (S)-3-Bromo-6-((tetrahydrofuran-3-yl)oxy)imidazo[1,2-b]pyridazine

[0265] According to the general procedure above, the anhydrous THF (20 mL) reaction mixture of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (500 mg) and (S)-tetrahydrofuran-3-ol (2.3 equiv.) was cooled to 0 ° C, and then NaH (2.5 equiv.) was added thereto. The reaction mixture was stirred at room temperature overnight. After completion, the reactant was extracted with ethyl acetate and washed with brine. The organic layer was collected and dried with sodium sulfate and concentrated under reduced pressure to obtain the desired product. Off-white solid with a yield of 77%.

[0266] 1 H NMR (500 MHz, chloroform-d) δ7.74 (d, J = 9.6 Hz, 1H), 7.57 (s, 1H), 6.69 (d, J = 9.6 Hz, 1H), 5.58–5.51 (m, 1H), 4.13–4.06 (m, 1H), 4.03–3.92 (m, 2H), 3.92–3.82 (m, 1H), 2.34 (dtd, J = 14.5, 8.0, 6.5 Hz, 1H), 2.23–2.14 (m, 1H); 13 C NMR (126 MHz, CDCl 3 )δ159.4,137.7,132.7,127.7,112.1,100.8,78.0,73.1,67.1,32.8.

[0267] (S)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-5-((6-((tetrahydrofuran-3-yl)oxy)imidazo[1,2-b]pyridazin-3-yl)ethynyl)nicotinamide (Compound HSND-29)

[0268] Off-white solid, yield: 59%. 1H NMR (500 MHz, DMSO-d 6 )δ10.81(s,1H),9.10(d,J=2.2Hz,1H),8.95(d,J=2.0Hz,1H),8.49(t,J=2.1Hz,1H),8.19 (d,J=2.2Hz,1H),8.12(d,J=9.7Hz,1H),8.07–8.00(m,2H),7.71(d,J=8.5Hz,1H),7.03(d ,J=9.7Hz,1H),5.59–5.54(m,1H),4.01–3.97(m,1H),3.95–3.90(m,1H),3.85(t,J=7.7Hz ,1H),3.78–3.70(m,1H),3.56(s,2H),2.44–2.30(m,9H),2.19(s,3H),2.16–2.08(m,1H); 13 C NMR (126 MHz, DMSO-d 6 )δ163.8,160.0,153.8,148.7,138.4,138.3,137.8,137.4,132.9,131.8,130.3,128.7,128.0(q,J=30.2Hz),125 .8(q,J=274.6Hz),123.9,119.2,117.6,114.4,111.9,94.9,81.2,78.6,72.8,66.8,57.8,55.0,52.8,45.8,32.9.

[0269] 3-Bromo-6-((tetrahydro-2H-pyran-4-yl)oxy)imidazo[1,2-b]pyridazine

[0270] According to the general procedure above, the reaction mixture of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (500 mg) and tetrahydro-2H-pyran-4-ol (2.3 equivalents) was cooled to 0 ° C in anhydrous THF (20 mL), and NaH (2.5 equivalents) was added thereto. The reaction mixture was then stirred at room temperature overnight. After completion, the reactant was extracted with ethyl acetate and washed with brine. The organic layer was collected and dried with sodium sulfate and concentrated under reduced pressure to obtain the desired product. Off-white solid with a yield of 82%.

[0271] 1H NMR (500MHz, chloroform-d) δ7.77(d,J=9.6Hz,1H),7.59(s,1H),6.71(d,J=9.6Hz,1H),5.27(dt,J=8.5,4 .3Hz,1H),4.01(dt,J=11.8,4.5Hz,2H),3.73–3.54(m,2H),2.29–2.11(m,3H),1.95–1.77(m,2H); 13 C NMR (126 MHz, CDCl 3 )δ159.2,137.8,132.6,127.6,112.4,100.6,72.2,65.3,31.5.

[0272] N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-5-((6-((tetrahydro-2H-pyran-4-yl)oxy)imidazo[1,2-b]pyridazin-3-yl)ethynyl)nicotinamide (Compound HSND-34)

[0273] 1 H NMR (500 MHz, methanol-d 4 )δ9.05(d,J=2.1Hz,1H),8.84(d,J=2.0Hz,1H),8.42(t,J=2.1Hz,1H),8.13 (d,J=2.2Hz,1H),7.97–7.86(m,3H),7.76(d,J=8.5Hz,1H),6.96(d,J=9.6Hz ,1H),5.36–5.25(m,1H),3.99(dt,J=11.7,4.5Hz,2H),3.71–3.62(m,4H),2 .73(s,5H),2.59(s,4H),2.45(s,3H),2.28–2.20(m,2H),1.92–1.84(m,2H); 13 C NMR (126 MHz, methanol-d 4 )δ163.9,159.8,152.9,147.1,138.1,137.6,137.5,136.1,132.7,131.2,130.5,128.9(q,J=30.2Hz),127.0,1 25.3 (q, J=273.4Hz), 123.5, 120.0, 117.7, 114.6, 112.3, 93.8, 80.2, 72.7, 64.9, 57.3, 54.3, 51.5, 43.9, 31.3.

[0274] 3-Bromo-6-isopropoxyimidazo[1,2-b]pyridazine

[0275] According to the general procedure above, the reaction mixture of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (500 mg) and isopropanol (0.75 equiv.) was cooled to 0 ° C in anhydrous THF (20 mL), and then NaH (2.5 equiv.) was added. The reaction mixture was then stirred at room temperature overnight. After completion, the reactant was extracted with ethyl acetate and washed with brine. The organic layer was collected and dried with sodium sulfate and concentrated under reduced pressure to obtain the desired product.

[0276] Off-white solid, 1 H NMR (500 MHz, chloroform-d) δ 7.73 (dd, J = 9.6, 1.4 Hz, 1H), 7.57 (d, J = 1.3 Hz, 1H), 6.65 (dd, J = 9.6, 1.4 Hz, 1H), 5.40-5.27 (m, 1H), 1.44 (dd, J = 6.1, 1.4 Hz, 6H); 13 C NMR (126 MHz, CDCl 3 )δ159.5,137.7,132.4,127.3,112.7,100.6,70.8,21.6.

[0277] 5-((6-isopropoxyimidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (Compound HSND-35)

[0278] 1 H NMR (500 MHz, methanol-d 4 )δ9.06(s,1H),8.87(s,1H),8.45(dq,J=4.0,1.8Hz,1H),8.13(d,J=2.1Hz,1H),7.97–7.86(m,3H),7.77(dd,J=8 .6,2.2Hz,1H),6.91(dd,J=9.6,3.0Hz,1H),5.42–5.27(m,1H),2.58(s,10H),2.36(s,3H),1.47(d,J=6.1Hz,6H); 13 C NMR (126 MHz, methanol-d 4)δ164.0,160.1,153.1,147.2,137.5,137.4,136.2,132.9,131.2,130.6,128.6(q,J=31.5Hz),126.7 ,125.3(q,J=273.4Hz),123.5,120.1,117.7,114.9,93.65,80.2,71.1,57.4,54.4,51.9,44.2,20.5.

[0279] 5-((6-aminoimidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (Compound HSND-37)

[0280] 1 H NMR (500 MHz, methanol-d 4 )δ9.02(d,J=2.2Hz,1H),8.89–8.82(m,1H),8.49–8.43(m,1H),8.11(d,J=2.4Hz,1H),7.93(dd,J=8.5,2.3Hz,1H ),7.78–7.70(m,2H),7.67(dd,J=9.6,2.9Hz,1H),6.80(d,J=9.6Hz,1H),3.64(s,2H),2.52(s,8H),2.30(s,3H); 13 C NMR (126 MHz, methanol-d 4 )δ164.0,156.0,153.0,147.0,137.5,137.4,137.2,135.1,132.9,131.2,130.4,128.8(q,J=30.2Hz) ,125.3(q,J=273.4Hz),125.0,123.5,120.3,117.6,114.0,111.3,93.1,80.9,57.4,54.5,52.2,44.5.

[0281] 2-((3-Bromoimidazo[1,2-b]pyridazin-6-yl)amino)ethan-1-ol

[0282] 1 H NMR (500 MHz, DMSO-d 6)δ7.66(d,J=9.7Hz,1H),7.45(s,1H),7.14(t,J=5.4Hz,1H),6.74(d,J=9.7Hz,1H),4.76(s,1H),3.61(q,J=5.7Hz,2H),3.34–3.31(m,2H); 13 C NMR (126 MHz, D DMSO-d 6 )δ154.7,137.0,130.7,125.7,113.5,99.5,59.4,44.0.

[0283] 5-((6-((2-hydroxyethyl)amino)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (Compound HSND-38)

[0284] 1 H NMR (500 MHz, methanol-d 4 )δ8.98(d,J=2.1Hz,1H),8.78(d,J=2.0Hz,1H),8.38(t,J=2.1Hz,1H),8.08(d,J=2.2Hz,1H),7.90(dd,J=8.4,2.3Hz,1H),7.71(d,J=8.5Hz,1H) ,7.66(s,1H),7.55(d,J=9.7Hz,1H),6.73(d,J=9.7Hz,1H),3.83(t,J=5 .7Hz,2H),3.61(s,2H),3.54(t,J=5.7Hz,2H),2.49(s,8H),2.27(s,3H); 13 C NMR (126 MHz, methanol-d 4 )δ163.9,154.7,152.9,146.9,137.4,137.1,137.0,134.7,132.9,131.1,130.2,128.7(q,J=30.2Hz),125.3(q ,J=273.4Hz),124.2,123.4,123.1,120.3,117.6,114.6,111.7,93.2,81.1,60.0,57.4,54.6,52.2,44.6,43.7.

[0285] N 1 -(3-Bromoimidazo[1,2-b]pyridazin-6-yl)-N 2 ,N 2 -Dimethylethane-1,2-diamine

[0286] 1 H NMR (500MHz, chloroform-d) δ7.45 (dd, J=9.6, 1.8Hz, 1H), 7.39 (d, J=1.8Hz, 1H), 6.41 (dd, J=9 .6,1.8Hz,1H),5.40(t,J=4.9Hz,1H),3.43–3.36(m,2H),2.49(dt,J=6.2,3.0Hz,2H); 13 C NMR (126 MHz, chloroform-d) δ 153.8, 137.0, 131.0, 125.5, 112.1, 99.9, 57.2, 45.1, 38.8.

[0287] 5-((6-((2-(dimethylamino)ethyl)amino)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (Compound HSND 39)

[0288] 1 H NMR (500 MHz, methanol-d 4 )δ9.03(d,J=2.2Hz,1H),8.87–8.80(m,1H),8.49–8.39(m,1H),8.12(d,J= 2.2Hz,1H),7.93(dd,J=8.4,2.3Hz,1H),7.76(d,J=8.5Hz,1H),7.71(s,1H) ,7.60(d,J=9.7Hz,1H),6.74(d,J=9.7Hz,1H),3.64(s,2H),3.56(t,J=6.9H z,2H),2.66(t,J=6.9Hz,2H),2.60–2.40(m,8H),2.31(s,6H),2.28(s,3H); 13 C NMR (126 MHz, methanol-d 4 )δ164.0,154.5,152.9,147.0,137.5,137.3,137.1,134.7,133.0,131.2,130.4,128.8(q,J=30.2Hz),125.3( q, J=273.4),124.3,123.5,120.3,117.6,114.6,111.7,92.9,81.1,57.5,57.3,54.6,52.3,44.6,44.2,38.5.

[0289] N 1 -(3-Bromoimidazo[1,2-b]pyridazin-6-yl)-N 1 ,N 2 ,N 2 -Trimethylethane-1,2-diamine

[0290] 1 H NMR (500 MHz, methanol-d 4 )δ7.77(dd,J=10.0,1.9Hz,1H),7.53(s,1H),7.12(dd,J=10.0,1.8Hz,1H),4.05(t,J=6.4Hz,2H),3.50(t,J=6.4Hz,2H),3.21(s,3H),3.05(s,6H); 13 C NMR (126 MHz, methanol-d 4 )δ155.2,136.7,130.7,125.4,110.0,99.9,54.7,45.1,43.1,36.0.

[0291] 5-((6-((2-(Dimethylamino)ethyl)(methyl)amino)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (Compound HSND-40)

[0292] 1 H NMR (500 MHz, methanol-d 4 )δ8.99(d,J=2.2Hz,1H),8.77(d,J=2.0Hz,1H),8.37(t,J=2.3Hz,1H),8.10(d ,J=2.2Hz,1H),7.92(dd,J=8.4,2.4Hz,1H),7.77–7.70(m,2H),7.68(d,J=10.0 Hz,1H),7.03(d,J=9.9Hz,1H),3.72(t,J=7.4Hz,2H),3.62(s,2H),3.13(d,J=1 .1Hz,3H),2.61(t,J=7.4Hz,2H),2.58–2.37(m,8H),2.31(s,6H),2.27(s,3H); 13 CNMR (126MHz, methanol-d 4)δ163.8,154.6,152.9,146.9,137.5,137.2,136.7,135.3,133.0,131.2,130.3,128.8(q,J=30.2Hz),125. 3(q,J=273.4Hz),124.6,123.4,120.2,117.6,111.5,111.0,93.1,81.2,57.5,55.3,54.6,52.3,44.5,35.8.

[0293] 4-(3-Bromoimidazo[1,2-b]pyridazin-6-yl)morpholine

[0294] 1 H NMR (500MHz, chloroform-d) δ7.67(dd,J=9.9,1.8Hz,1H),7.53(s,1H),6.79(d,J=9.9Hz,1H),3.84(t,J=4.9Hz,4H),3.53(t,J=4.9Hz,4H); 13 C NMR (125 MHz, chloroform-d) δ 155.2, 137.0, 132.3, 126.1, 109.2, 100.3, 66.4, 46.3.

[0295] N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-5-((6-morpholinimidazole[1,2-b]pyridazin-3-yl)ethynyl)nicotinamide (Compound HSND-41)

[0296] 1 H NMR (500 MHz, methanol-d 4 )δ8.94(d,J=2.2Hz,1H),8.71(d,J=2.0Hz,1H),8.31(t,J=2.1Hz,1H),8.06(d,J=2.2Hz,1H),7.88(dd,J=8.4,2.3Hz,1H), 7.75–7.64(m,3H),7.10(d,J=9.9Hz,1H),3.81–3.75(m,4H),3.60(s,2H),3.52(t,J=4.8Hz,4H),2.52(s,8H),2.32(s,3H); 13 C NMR (125 MHz, methanol-d 4)δ163.7,155.6,152.9,146.9,137.4,137.2,135.8,132.8,131.1,130.1,128.7(q,J=30.2Hz),125.3(q,J= 273.4Hz), 124.9, 123.4, 120.1, 117.5 (q, J = 6.3Hz), 111.7, 93.5, 80.9, 66.0, 57.4, 54.5, 52.0, 45.7, 44.4.

[0297] (R)-2-((3-bromoimidazo[1,2-b]pyridazin-6-yl)amino)butan-1-ol

[0298] 1 H NMR (500 MHz, methanol-d 4 )δ7.53(d,J=9.7Hz,1H),7.37(s,1H),6.73(d,J=9.7Hz,1H),3.94(dq,J=8.1,5.3Hz, 1H),3.74–3.60(m,2H),1.84–1.72(m,1H),1.67–1.55(m,1H),1.01(t,J=7.5Hz,3H); 13 C NMR (126 MHz, methanol-d 4 )δ154.5,136.8,129.4,124.1,113.7,99.8,62.4,54.3,23.5,9.6.

[0299] (R)-5-((6-((1-hydroxybutan-2-yl)amino)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (Compound HSND-42)

[0300] 1 H NMR (500 MHz, methanol-d 4)δ9.01(s,1H),8.83(s,1H),8.50–8.36(m,1H),8.09(s,1H),7.91(d,J=8.6Hz,1 H),7.74(d,J=8.5Hz,1H),7.69(s,1H),7.57(dd,J=9.7,1.7Hz,1H),6.79(dd,J= 9.7,1.7Hz,1H),4.04–3.93(m,1H),3.72(d,J=5.4Hz,2H),3.64(s,2H),2.51(s, 98H),2.28(s,2H),1.82–1.69(m,1H),1.67–1.55(m,1H),1.00(t,J=7.4Hz,2H); 13 CNMR (126MHz, methanol-d 4 )δ164.1,154.8,152.9,147.0,137.4,137.3,137.0,134.5,133.0,131.1,130.5,128.8(q,J=31.5Hz),125.3 q, J=274.6Hz,124.2,123.4,120.3,117.5,114.8,111.6,93.1,81.2,62.9,57.4,54.6,52.3,44.6,23.6,9.6.

[0301] (S)-2-((3-bromoimidazo[1,2-b]pyridazin-6-yl)amino)butan-1-ol

[0302] 1 H NMR (500 MHz, methanol-d 4 )δ7.53(d,J=9.7Hz,1H),7.38(s,1H),6.73(d,J=9.7Hz,1H),3.97–3.88(m,1H), 3.73–3.65(m,2H),1.85–1.73(m,1H),1.69–1.54(m,1H),1.01(t,J=7.5Hz,3H); 13 C NMR (126 MHz, methanol-d 4 )δ154.5,136.8,129.4,129.4,124.1,124.0,113.7,99.8,62.4,54.3,54.2,23.5,23.5,9.6,9.5.

[0303] (S)-5-((6-((1-hydroxybutan-2-yl)amino)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (Compound HSND-43)

[0304] 1 H NMR (500 MHz, methanol-d 4 )δ9.00(d,J=2.2Hz,1H),8.82(d,J=2.0Hz,1H),8.49(t,J=2.1Hz,1H),8.10(d,J=2.3 Hz,1H),7.93(dd,J=8.5,2.3Hz,1H),7.73(d,J=8.5Hz,1H),7.68(s,1H),7.57(d,J=9 .6Hz,1H),6.80(d,J=9.6Hz,1H),4.07–3.95(m,1H),3.74–3.62(m,4H),3.06–2.92(m ,4H),2.72–2.57(m,7H),1.79–1.70(m,1H),1.66–1.54(m,1H),0.98(t,J=7.4Hz,3H); 13 C NMR (126 MHz, methanol-d 4 )δ164.1,154.8,153.0,147.0,137.7,137.4,134.5,132.2,131.2,130.4,128.8(q,J=28.9Hz),125.3(q,J=27 4.6Hz),124.2,123.5,120.3,117.7,114.9,111.6,93.0,81.2,63.0,57.0,54.5,54.0,50.7,43.1,23.6,9.6.

[0305] 5-((6-((2-methoxyethyl)amino)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (Compound HSND-44)

[0306] 1 H NMR (500 MHz, DMSO-d 6)δ10.79(s,1H),9.08(d,J=2.2Hz,1H),8.91(d,J=2.0Hz,1H),8.45(t,J=2.1 Hz,1H),8.20(d,J=2.2Hz,1H),8.03(dd,J=8.4,2.2Hz,1H),7.81(s,1H),7.7 4(dd,J=22.8,9.1Hz,2H),7.22(t,J=5.4Hz,1H),6.77(d,J=9.7Hz,1H),3.42 (t,J=6.2Hz,2H),3.18(s,3H),2.40(s,8H),2.19(s,3H),1.92–1.81(m,2H); 13 C NMR (126 MHz, DMSO-d 6 )δ163.8,154.7,153.7,148.4,138.3,137.5,137.2,136.1,132.9,131.8,130.3,128.0(q,J=30.2Hz),125.8,123 .9,123.6(q,J=274.6Hz),119.6,117.6,114.8,111.0,94.2,82.5,70.2,58.3,57.8,55.0,52.8,45.8,38.6,28.7.

[0307] 5-((6-((3-hydroxypropyl)amino)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (Compound HSND-45)

[0308] 1 H NMR (500 MHz, methanol-d 4 )δ9.03(d,J=2.2Hz,1H),8.87(d,J=2.0Hz,1H),8.46(t,J=2.1Hz,1H),8.1 3(d,J=2.3Hz,1H),7.94(dd,J=8.5,2.3Hz,1H),7.79–7.66(m,2H),7.60(d, J=9.7Hz,1H),6.75(d,J=9.6Hz,1H),3.70(t,J=6.2Hz,2H),3.65(d,J=1.6H z,2H),3.52(t,J=6.8Hz,2H),2.51(s,8H),2.29(s,3H),1.96–1.88(m,2H); 13 C NMR (126 MHz, methanol-d 4)δ164.1,154.9,153.0,147.0,137.5,137.2,134.6,133.0,131.2,130.4,128.8(q,J=30.2Hz),125.3(q ,J=274.6Hz),124.3,123.5,120.3,117.6,114.7,93.2,81.0,59.1,57.5,54.6,52.3,44.6,37.9,31.5.

[0309] 3-Bromo-6-(piperazin-1-yl)imidazo[1,2-b]pyridazine

[0310] 1 H NMR (500 MHz, methanol-d 4 )δ7.69(d,J=10.0Hz,1H),7.49(s,1H),7.15(d,J=10.0Hz,1H),3.65–3.56(m,4H),3.03–2.95(m,4H); 13 C NMR (125 MHz, methanol-d 4 )δ155.5,136.8,130.7,124.8,111.0,100.1,45.8,44.4. N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-5-((6-(piperazin-1-yl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)nicotinamide (Compound HSND-76)

[0311] 1 H NMR (500 MHz, methanol-d 4 )δ9.15–8.93(m,1H),8.93–8.78(m,1H),8.52–8.37(m,1H),8.14(q,J=2.8Hz,1H),7.96–7.89(m,1H),7.86 –7.73(m,3H),7.28–7.20(m,1H),3.68–3.53(m,6H),3.02–2.91(m,4H),2.52(s,8H),2.29(q,J=4.0Hz,3H); 13 C NMR (125 MHz, methanol-d 4)δ164.1,155.8,153.0,147.1,137.5,137.4,137.1,135.7,133.0,131.2,130.5,128.6(q,J=31.2Hz),125 .3(q,J=270Hz),124.8,123.5,120.2,117.6,112.3,111.9,93.3,80.8,57.4,54.5,52.2,46.0,44.6,44.5.

[0312] 3-Bromo-6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazine

[0313] 1 H NMR (500 MHz, methanol-d 4 )δ7.69(d,J=10.0Hz,1H),7.49(s,1H),7.15(d,J=10.0Hz,1H),3.64–3.57(m,4H),2.63–2.55(m,4H),2.35(s,3H). 13 C NMR (125 MHz, methanol-d 4 )δ155.4,136.7,130.7,124.8,110.9,100.1,54.0,45.1,44.7.

[0314] 5-((6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (Compound HSND-77)

[0315] 1 H NMR (500 MHz, methanol-d 4 )δ9.01(s,1H),8.81(s,1H),8.45–8.38(m,1H),8.12(d,J=2.2Hz,1H),7.92(dd,J=8.5,2.3Hz,1H),7.83–7 .71(m,3H),7.22(dd,J=10.0,3.2Hz,1H),3.69–3.61(m,6H),2.73–2.49(m,12H),2.38(s,3H),2.34(s,3H); 13 C NMR (125 MHz, methanol-d 4)δ164.0,155.5,153.0,147.0,137.5,137.3,135.7,132.8,131.2,130.4,128.8(q,J=30Hz),125.3(q, J=272.5Hz),124.9,123.5,120.2,117.6,112.2,93.4,80.9,57.3,54.4,54.0,51.9,45.0,44.7,44.2.

[0316] 3-Bromo-6-(piperidin-1-yl)imidazo[1,2-b]pyridazine

[0317] 1 H NMR (500 MHz, methanol-d 4 )δ7.60(d,J=10.0Hz,1H),7.43(s,1H),7.06(d,J=10.0Hz,1H),3.53(dd,J=6.1,3.9Hz,4H),1.64(dt,J=5.4,2.8Hz,6H); 13 C NMR (125 MHz, methanol-d 4 )δ155.3,136.5,130.3,124.5,111.1,99.9,46.6,25.0,24.1.

[0318] N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-5-((6-(piperidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)nicotinamide (Compound HSND-78)

[0319] 1 H NMR (500 MHz, methanol-d 4 )δ9.04(s,1H),8.84(s,1H),8.47–8.34(m,1H),8.12(d,J=2.2Hz,1H),7.94(dd,J=8.5,2.3Hz,1H),7.81–7.64(m,3 H),7.22(d,J=8.4Hz,1H),3.67(s,2H),3.64–3.59(m,4H),2.60(d,J=40.4Hz,8H),2.39(s,3H),1.76–1.67(m,6H).

[0320] 4-(3-Bromoimidazo[1,2-b]pyridazin-6-yl)thiomorpholine

[0321] 1 H NMR (500 MHz, methanol-d 4 )δ7.67(d,J=10.0Hz,1H),7.47(s,1H),7.11(d,J=10.0Hz,1H),3.99–3.92(m,4H),2.73–2.61(m,4H). 13 C NMR (125 MHz, methanol-d 4 )δ154.6,136.5,130.6,124.9,111.0,100.1,48.4,25.4.

[0322] N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-5-((6-thiomorpholinimidazo[1,2-b]pyridazin-3-yl)ethynyl)nicotinamide (Compound HSND-79)

[0323] 1 H NMR (500 MHz, DMSO-d 6 )δ10.81(s,1H),9.08(d,J=2.1Hz,1H),8.90(s,1H),8.51–8.41(m,1H),8.19(d,J=2.2Hz,1H),8.03(dd,J=8.5,2.2Hz,1H),7.96–7.8 8(m,2H),7.70(d,J=8.5Hz,1H),7.30(d,J=9.9Hz,1H),3.96–3.90(m,4H),3.55(s,2H),2.74–2.66(m,4H),2.40(s,8H),2.20(s,3H).; 13 C NMR (125 MHz, DMSO-d 6 )δ163.8,154.9,153.8,148.5,138.3,137.3,137.2,132.8,131.7,130.3,128.0(q,J=28.7Hz),126.6, 125.8 (J=272.5Hz), 123.9, 119.4, 117.7, 112.7, 111.2, 94.5, 82.0, 57.7, 54.9, 52.7, 48.6, 45.7, 25.8.

[0324] (2S,6R)-4-(3-bromoimidazo[1,2-b]pyridazin-6-yl)-2,6-dimethylmorpholine

[0325] 1 H NMR (500MHz, chloroform-d) δ7.66(d,J=9.9Hz,1H),7.52(s,1H),6.80(d,J=9.9Hz,1H),4.01– 3.89(m,2H),3.81–3.65(m,2H),2.65(dd,J=12.8,10.6Hz,2H),1.28(d,J=6.3Hz,6H). 13 C NMR (125 MHz, chloroform-d) δ 154.8, 136.9, 132.1, 126.0, 109.4, 100.3, 71.3, 51.3, 18.9.

[0326] 5-((6-((2S,6R)-2,6-dimethylmorpholino)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (Compound HSND-80)

[0327] 1 H NMR (500 MHz, methanol-d 4 )δ8.97(s,1H),8.73(s,1H),8.32(s,1H),8.10(s,1H),7.90(d,J=8.5Hz,1H),7.77–7.54(m,3H),7.15(d,J=8.4Hz,1 H),4.05(d,J=12.7Hz,2H),3.77–3.66(m,2H),3.64(s,2H),2.79–2.45(m,11H),2.40(s,3H),1.20(d,J=6.2Hz,6H); 13 CNMR (125MHz, methanol-d 4 )δ163.7,155.2,152.8,146.8,137.5,137.2,132.7,131.2,131.2,130.3,128.8(q,J=30Hz),127.5,125.3 (q, J=272.5Hz), 125.0, 123.4, 120.3, 117.6, 111.9, 93.7, 81.2, 71.2, 57.3, 54.4, 51.7, 50.8, 44.1, 17.7.

[0328] N-(4-Chloro-3-(trifluoromethyl)phenyl)-5-ethynylnicotinamide

[0329] 1H NMR (500 MHz, methanol-d 4 )δ9.06(d,J=2.2Hz,1H),8.81(d,J=2.0Hz,1H),8.42(t,J=2.1Hz,1H),8.26(d, J=2.6Hz,1H),7.97(dd,J=8.8,2.6Hz,1H),7.60(d,J=8.8Hz,1H),3.93(s,1H). 13 C NMR (125 MHz, methanol-d 4 )δ164.1,154.1,147.5,138.4,137.7,131.7,130.2,128.1(J=31.5Hz),126.4,124.7,123.8(J=270Hz),119.8,119.2,82.5,78.6.

[0330] N-(4-chloro-3-(trifluoromethyl)phenyl)-5-((6-morpholinimidazole[1,2-b]pyridazin-3-yl)ethynyl)nicotinamide (Compound HSND-91)

[0331] 1 H NMR (500 MHz, DMSO-d 6 )δ10.88(s,1H),9.09(s,1H),8.96(s,1H),8.48(q,J=1.8Hz,1H),8.33(t,J=1.9Hz,1H),8.15–7 .91(m,4H),7.74(d,J=8.8Hz,1H),7.32(d,J=8.1Hz,1H),3.79–3.69(m,4H),3.60–3.48(m,4H); 13 C NMR (125 MHz, DMSO-d 6 )δ164.0,155.9,154.0,148.6,138.7,137.4,132.6,130.1,127.3,126.7 ,125.4,125.2,124.2(q,J=270Hz),119.4,112.2,94.5,82.1,66.2,46.0.

[0332] 5-Ethynyl-N-(3-(trifluoromethyl)phenyl)nicotinamide

[0333] 1 H NMR (500 MHz, methanol-d 4)δ9.04(d,J=2.1Hz,1H),8.78(d,J=1.9Hz,1H),8.40(t,J=2.1Hz,1H),8.14(d,J=2. 0Hz,1H),7.97–7.87(m,1H),7.53(t,J=8.0Hz,1H),7.45–7.38(m,1H),3.91(s,1H); 13 C NMR (125 MHz, methanol-d 4 )δ164.1,154.1,147.5,139.0,138.4,130.9(q,J=31.2Hz),130.4,129.3,125.1(q,J=270Hz),123.6,120.7,119.7,116.9,82.5,78.6.

[0334] 5-((6-morpholinimidazole[1,2-b]pyridazin-3-yl)ethynyl)-N-(3-(trifluoromethyl)phenyl)nicotinamide (Compound HSND-92)

[0335] 1 H NMR (500 MHz, DMSO-d 6 )δ10.80(s,1H),9.09(d,J=2.1Hz,1H),8.99–8.92(m,1H),8.49(t,J=2.1Hz,1H),8.23(d,J=2.0Hz,1H),8.09–7. 91(m,3H),7.69–7.59(m,1H),7.50–7.44(m,1H),7.32(d,J=9.9Hz,1H),3.74(t,J=4.9Hz,4H),3.58–3.50(m,4H); 13 CNMR (125MHz, DMSO-d 6 )δ164.0,155.9,153.9,148.6,140.0,137.4,130.5,130.3,130.0(q,J=31.2Hz),126 .6,125.6(q,J=273.4Hz),124.2,120.9,119.4,116.8,112.3,94.5,82.0,66.2,46.0.

[0336] 3-Bromo-6-((3S,5R)-3,5-dimethylpiperazin-1-yl)imidazo[1,2-b]pyridazine

[0337] 1H NMR (500MHz, chloroform-d) δ7.64(d,J=9.9Hz,1H),7.50(s,1H),6.82(d,J=9.9Hz,1H),4.09–3.98(m,2H),2. 98(ddt,J=12.9,6.4,3.3Hz,2H),2.53(dd,J=12.7,10.6Hz,2H),2.00(s,2H),1.16(d,J=6.3Hz,6H); 13 C NMR (125 MHz, chloroform-d) δ 154.9, 136.8, 132.0, 125.9, 109.8, 100.2, 52.5, 50.4, 19.6.

[0338] 5-((6-((3S,5R)-3,5-dimethylpiperazin-1-yl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (Compound HSND-96)

[0339] 1 H NMR (500 MHz, methanol-d 4 )δ9.03(d,J=2.2Hz,1H),8.83(d,J=2.0Hz,1H),8.42(t,J=2.1Hz,1H),8.12(d,J=2.3Hz,1H),7.93(dd,J=8.5,2.3Hz,1H),7.81–7.71(m,3H), 7.25(d,J=10.0Hz,1H),4.24–4.16(m,2H),3.65(d,J=1.6Hz,2H),3.01–2.91(m,10H),2.62–2.42(m,2H),2.29(s,3H),1.17(d,J=6.4Hz,6H); 13 C NMR (125 MHz, methanol-d 4 )δ164.0,155.3,152.9,147.0,137.5,137.3,135.5,133.0,131.2,130.5,128.8(q,J=30Hz),125.3(q, J=272.5Hz),124.8,123.4,120.3,117.6,112.4,93.4,80.9,57.5,54.6,52.3,51.5,50.0,44.6,17.7.

[0340] 3-Bromo-6-(4-(2-methoxyethyl)piperazin-1-yl)imidazo[1,2-b]pyridazine

[0341] 1 H NMR (500 MHz, methanol-d 4 )δ7.66(d,J=9.9Hz,1H),7.47(s,1H),7.10(d,J=10.0Hz,1H),3.61–3.51(m,6H),3.34(s,3H),2.66–2.58(m,6H).; 13 C NMR (125 MHz, methanol-d 4 )δ155.3,136.7,130.6,124.8,110.9,100.1,69.6,57.6,57.2,52.6,45.1.

[0342] 5-((6-(4-(2-methoxyethyl)piperazin-1-yl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (Compound HSND-97)

[0343] 1 H NMR (500 MHz, methanol-d 4 )δ8.96(d,J=2.2Hz,1H),8.73(d,J=2.0Hz,1H),8.35(t,J=2.1Hz,1H),8.07(d,J=2.2Hz,1H),7.89(dd,J=8.4,2.3Hz,1H),7.74–7.6 1(m,3H),7.12(d,J=10.0Hz,1H),3.59(dd,J=9.3,3.9Hz,6H),3.51(t,J=5.5Hz,2H),3.31(s,3H),2.66–2.41(m,14H),2.28(s,3H). 13 C NMR (125 MHz, methanol-d 4 )δ163.7,155.4,152.9,146.9,137.4,137.2,136.9,135.6,132.9,131.1,130.2,128.7(q,J=30Hz),128.5,125.3(q,J=272.5Hz),124.8, 123.3,123.1,120.1,117.5,112.0,111.8,93.5,81.0,69.6,69.5,57 .6,57.4,57.2,57.2,54.6,54.5,52.7,52.6,52.2,52.2,45.1,44.6.

[0344] 3-Bromo-6-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)imidazo[1,2-b]pyridazine

[0345] 1 H NMR (500MHz, chloroform-d) δ7.66 (d, J=9.8Hz, 1H), 7.52 (s, 1H), 6.82 (dd, J=9.9, 2.6Hz, 1H), 4. 14–3.84(m,2H),2.84(t,J=11.9Hz,2H),2.35(d,J=13.4Hz,5H),1.22(d,J=6.3Hz,6H). 13 C NMR (125 MHz, chloroform-d) δ 154.5, 136.8, 132.1, 126.0, 109.5, 100.3, 57.4, 52.6, 37.6, 17.9.

[0346] N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-5-((6-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)nicotinamide (Compound HSND-99)

[0347] 1 H NMR (500 MHz, methanol-d 4 )δ9.03(s,1H),8.84(s,1H),8.44–8.40(m,1H),8.12(t,J=2.1Hz,1H),7.93(dt,J=8.6,2.1Hz,1H),7.85–7.69(m,4H),7.25(dd,J=9.9,1.4Hz, 1H),4.18–4.12(m,2H),3.65(s,2H),2.88–2.74(m,2H),2.61–2.38(m,1 0H),2.34–2.31(m,3H),2.31–2.28(m,3H),1.20(dd,J=6.2,1.8Hz,6H); 13 C NMR (125 MHz, methanol-d 4)δ164.0,155.0,152.8,147.0,137.5,137.3,135.5,133.0,131.2,130.5,128.8(q,J=30Hz),125.3(q,J= 272.5Hz),124.9,123.4,120.3,117.6,112.2,93.5,80.9,57.4,57.3,54.6,52.2,51.7,44.5,36.4,16.3.

[0348] (2S,6S)-4-(3-bromoimidazo[1,2-b]pyridazin-6-yl)-2,6-dimethylmorpholine

[0349] 1 H NMR (500MHz, chloroform-d) δ7.68(d,J=9.9Hz,1H),7.53(s,1H),6.79(d,J=9.9Hz,1H),4.27–4.06 (m,2H),3.65(dd,J=12.8,3.4Hz,2H),3.27(dd,J=12.8,6.3Hz,2H),1.30(d,J=6.4Hz,6H); 13 C NMR (125 MHz, chloroform-d) δ 155.4, 136.8, 132.0, 126.0, 109.4, 100.3, 66.0, 50.7, 17.9.

[0350] 5-((6-((2R,6R)-2,6-dimethylmorpholino)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (Compound HSND-100)

[0351] 1 H NMR (500 MHz, methanol-d 4 )δ9.08(s,1H),8.89(s,1H),8.46(s,1H),8.16(d,J=2.2Hz,1H),8.00–7.72(m,4H),7.26(d,J=6.9Hz,1H),4.21–4.11(m, 2H),3.73(dd,J=13.0,3.3Hz,2H),3.68(s,2H),3.41–3.34(m,2H),2.80–2.50(m,8H),2.42(s,3H),1.27(d,J=6.4Hz,6H). 13 C NMR (125 MHz, methanol-d4 )δ164.1,155.9,153.0,147.1,137.6,137.4,132.8,131.2,128.8,128.6,125.3,125 .1,123.5,123.2,117.7,112.0,93.4,66.0,57.3,54.3,51.7,50.1,44.0,29.3,16.6.

[0352] (S)-4-(3-Bromoimidazo[1,2-b]pyridazin-6-yl)-2-methylmorpholine

[0353] 1 H NMR (500 MHz, methanol-d 4 )δ7.71(d,J=10.0Hz,1H),7.50(s,1H),7.17(d,J=10.0Hz,1H),4.13–3.95(m,3H) ,3.76–3.65(m,2H),3.09–2.97(m,1H),2.74–2.61(m,1H),1.24(d,J=6.3Hz,3H); 13 C NMR (125 MHz, methanol-d 4 )δ155.5,136.9,130.7,124.9,110.8,100.2,71.4,65.8,51.6,45.1,17.6.

[0354] (R)-5-((6-(2-methylmorpholino)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (Compound HSND-101)

[0355] 1 H NMR (500 MHz, methanol-d 4)δ9.03(s,1H),8.84(s,1H),8.43(t,J=2.0Hz,1H),8.13(d,J=2.2Hz,1H),7.94(dd,J=8.5,2.2Hz,1H),7.88–7.71(m,3H),7.23(d,J=9.6Hz,1H), 4.15–4.04(m,2H),4.03–3.98(m,1H),3.78–3.67(m,2H),3.67(s,2H),3. 10–3.02(m,1H),2.76–2.46(m,10H),2.40(s,3H),1.23(d,J=6.2Hz,3H); 13 C NMR (125 MHz, methanol-d 4 )δ164.0,155.6,153.0,147.0,137.5,137.4,132.8,131.2,130.5,128.9(q,J=30Hz),125.3(q,J=271 .2Hz),125.0,120.2,117.6,112.0,93.4,80.9,71.4,65.8,57.3,54.4,51.8,51.6,45.0,44.1,17.6.

[0356] 4-(3-Bromoimidazo[1,2-b]pyridazin-6-yl)-2,2,6,6-tetramethylmorpholine

[0357] 1 H NMR (500MHz, chloroform-d) δ7.68(dd,J=9.9,1.3Hz,1H),7.52(s,1H),6.77(d,J=9.9Hz,1H),3.42(s,4H),1.31(s,12H). 13 C NMR (125 MHz, chloroform-d) δ 155.1, 136.8, 132.0, 126.1, 109.2, 100.2, 71.6, 54.5, 28.6.

[0358] N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-5-((6-(2,2,6,6-tetramethylmorpholino)imidazo[1,2-b]pyridazin-3-yl)ethynyl)nicotinamide (Compound HSND-102)

[0359] 1 H NMR (500 MHz, methanol-d 4)δ9.03(d,J=2.1Hz,1H),8.83(d,J=2.0Hz,1H),8.47–8.39(m,1H),8.12(d,J=2.2Hz,1H),7.94(dd,J=8.4,2.3Hz,1H),7.84–7 .70(m,3H),7.22(d,J=9.9Hz,1H),3.71–3.62(m,2H),3.54(s,4H),2.57(s,8H),2.36(d,J=1.5Hz,3H),1.29(d,J=1.5Hz,12H); 13 C NMR (125 MHz, methanol-d 4 )δ164.0,155.5,152.9,146.9,137.5,137.4,135.5,132.9,131.2,130.5,128.8(q,J=30Hz),125.3(q,J=2 71.2Hz),125.0,123.4,123.2,120.3,117.6,111.7,93.4,81.0,71.7,57.4,54.5,53.7,52.0,44.3,27.5.

[0360] 3-Bromo-6-(3,5-dimethylpiperidin-1-yl)imidazo[1,2-b]pyridazine

[0361] 1 H NMR (500 MHz, chloroform-d) δ 7.71–7.53 (m, 1H), 7.56–7.43 (m, 1H), 6.91–6.73 (m, 1H), 4.14 (dt, J = 12.4, 5.4 Hz, 2H), 2.41 (q, J = 12.2, 11.2 Hz, 2H), 1.90–1.82 (m, 1H), 1.81–1.68 (m, 2H), 1.04–0.89 (m, 6H), 0.81 (q, J = 12.0 Hz, 1H). 13 C NMR (125 MHz, chloroform-d) δ 154.9, 136.7, 131.7, 125.7, 110.2, 100.1, 53.4, 42.3, 30.7, 19.2.

[0362] 5-((6-(3,5-dimethylpiperidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide

[0363] 1H NMR (500 MHz, methanol-d 4 )δ9.11(s,1H),8.92(s,1H),8.43(s,1H),8.13(d,J=2.2Hz,1H),7.95(d, J=8.4Hz,1H),7.85–7.55(m,3H),7.32(s,1H),4.29(d,J=12.8Hz,2H),3. 68(s,2H),2.75–2.51(m,8H),2.47(t,J=12.2Hz,1H),2.41(s,2H),1.86( d,J=12.9Hz,1H),1.74(s,2H),0.96(d,J=6.5Hz,6H),0.88–0.82(m,1H).

[0364] N-(3-(4-methyl-1H-imidazo 1-1-yl)-5-(trifluoromethyl)phenyl)-5-((6-morpholinimido[1,2-b]pyridazin-3-yl)ethynyl)nicotinamide (Compound HSND-105)

[0365] 1 H NMR (500 MHz, methanol-d 4 )δ9.06(s,1H),8.85(s,1H),8.45(s,1H),8.23(d,J=2.5Hz,1H),8.17(s,1H),8.06(s,1H),7.85–7.74(m,2H),7.6 4(d,J=4.4Hz,1H),7.38(s,1H),7.22(d,J=9.8Hz,1H),3.83(t,J=4.9Hz,4H),3.59(t,J=4.9Hz,4H),2.26(s,3H).

[0366] 5-((6-((2S,6R)-2,6-dimethylmorpholino)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(3-(trifluoromethyl)phenyl)nicotinamide (Compound HSND-106)

[0367] 1 H NMR (500 MHz, methanol-d 4)δ9.03(d,J=2.1Hz,1H),8.84(d,J=2.0Hz,1H),8.43(t,J=2.1Hz,1H),8.17(s,1H),7.98–7.92(m,1H),7.83–7.71(m,2H),7.55(t,J=8.0Hz, 1H),7.45(d,J=7.8Hz,1H),7.23(d,J=9.9Hz,1H),4.12(dt,J=12.4,1.6Hz,2H),3.85–3.68(m,2H),2.73–2.54(m,2H),1.24(d,J=6.3Hz,6H); 13 C NMR (125 MHz, methanol-d 4 )δ164.1,155.4,152.9,147.0,139.1,137.4,135.6,130.9(q,J=31.2Hz),130.5,129.3,125. 1(q,J=270Hz),124.9,123.6,120.6,120.3,116.8,112.1,93.4,80.9,71.3,50.8,26.9,17.7.

[0368] 3-((6-((2S,6R)-2,6-dimethylmorpholino)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (Compound HSND-107)

[0369] 1 H NMR (500 MHz, DMSO-d 6 )δ10.63(s,1H),8.21–8.13(m,2H),8.05(dd,J=8.4,2.2Hz,1H),7.99–7.92(m,2 H),7.89(s,1H),7.76(dt,J=7.7,1.4Hz,1H),7.69(d,J=8.5Hz,1H),7.62(t,J=7. 8Hz,1H),7.31(d,J=10.0Hz,1H),4.14(dd,J=13.1,2.3Hz,2H),3.71–3.62(m,2H) ,2.57(dd,J=12.9,10.6Hz,2H),2.37(s,8H),2.14(s,3H),1.13(d,J=6.2Hz,7H).

[0370] 13 C NMR (126 MHz, DMSO-d 6)δ165.30,155.40,138.58,137.38,136.72,135.55,134.11,132.68,131.73,130.34,129.78,128.63,128.01(q,J=30.2Hz),126.5 5,125.89(q,J=274.6Hz),123.91,122.84,117.67,112.19,111.66,97.75,79.01,71.20,57.92,55.20,53.16,51.04,46.19,19.11.

[0371] 5-((6-((3R,5S)-3,5-dimethylpiperidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (Compound HSND-108)

[0372] 1 H NMR (500 MHz, DMSO-d 6 )δ10.79(s,1H),9.07(d,J=2.2Hz,1H),8.87(d,J=2.0Hz,1H),8.44(t,J=2.2Hz,1H),8.17(d,J=2.2 Hz,1H),8.03(dd,J=8.5,2.2Hz,1H),7.90–7.85(m,2H),7.70(d,J=8.5Hz,1H),7.32(d,J=10.0Hz,1 H),4.27–4.20(m,2H),3.54(s,2H),2.37(dt,J=34.7,16.7Hz,10H),2.13(s,3H),1.74(dd,J=12.7, 3.8Hz,1H),1.64(dqd,J=15.4,7.3,5.0,4.0Hz,2H),0.87(d,J=6.5Hz,6H),0.77(q,J=12.0Hz,1H); 13 CNMR (126MHz, DMSO-d 6)δ163.79,155.21,153.48,148.45,138.29,137.32,137.15,136.81,132.98,131.76,130.35,128.04(q,J=28.9Hz),126.32,125.8 3(q,J=273.4Hz),123.89,119.61,117.65,112.78,111.16,94.63,82.36,57.91,55.20,53.16,52.92,46.18,42.27,30.60,19.40.

[0373] 5-((6-(4-isopropylpiperazin-1-yl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (Compound HSND-113)

[0374] 1 H NMR (500 MHz, DMSO-d 6 )δ10.76(s,1H),9.07(d,J=2.2Hz,1H),8.92(d,J=2.0Hz,1H),8.46(t,J=2.2Hz,1H),8. 19(d,J=2.4Hz,1H),8.02(dd,J=8.5,2.2Hz,1H),7.92–7.86(m,2H),7.71(d,J=8.5Hz,1H ),7.31(d,J=10.0Hz,1H),4.25(dt,J=13.6,3.7Hz,2H),3.55(s,2H),3.00–2.81(m,2H), 2.40–2.21(m,11H),2.21–2.05(m,9H),1.85(dd,J=13.2,3.6Hz,2H),1.48–1.30(m,2H); 13 C NMR (126 MHz, DMSO-d 6 )δ163.85,155.53,153.72,148.55,138.29,137.39,137.11,133.02,131.79,130.38,128.06(q,J=28.9Hz),126.38,125.84(q ,J=275.9Hz),123.91,119.53,117.66,112.77,111.19,94.54,82.25,61.67,57.90,55.20,53.17,46.19,45.21,41.90,28.11.

[0375] 5-((6-(4-(dimethylamino)piperidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (Compound HSND-115)

[0376] 1 H NMR (500 MHz, DMSO-d 6 )δ10.75(s,1H),9.07(s,1H),8.91(s,1H),8.46(s,1H),8.18(s,1H),8.01( d,J=8.6Hz,1H),7.89(d,J=9.6Hz,2H),7.70(d,J=8.5Hz,1H),7.31(d,J=10 .0Hz,1H),4.29–4.21(m,2H),3.54(s,2H),2.99–2.90(m,2H),2.48(s,2H), 2.41–2.23(m,9H),2.15–2.11(m,9H),1.87–1.81(m,2H),1.48–1.36(m,2H); 13 C NMR (126 MHz, DMSO-d 6 )δ163.84,155.53,153.71,148.53,138.28,137.38,137.10,133.01,131.77,130.36,128.06(q,J=28.9Hz),126.37,12 5.83 (q, J=274.6Hz), 123.90, 119.53, 117.64, 112.75, 111.19, 94.53, 82.25, 61.67, 57.90, 55.20, 53.16, 41.90, 28.11.

[0377] 5-((6-(4-hydroxypiperidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (Compound HSND-116)

[0378] 1 H NMR (500 MHz, DMSO-d 6)δ10.76(s,1H),9.08(s,1H),8.92(s,1H),8.47(d,J=2.5Hz,1H),8.19(s ,1H),8.02(d,J=8.6Hz,1H),7.90(d,J=9.5Hz,2H),7.72(d,J=8.6Hz,1H) ,7.32(d,J=10.0Hz,1H),4.73(s,1H),4.02–3.94(m,2H),3.77–3.69(m,1 H),3.27–3.19(m,2H),2.16(s,3H),1.89–1.76(m,2H),1.52–1.38(m,2H); 13 C NMR (126 MHz, DMSO-d 6 )δ163.85,155.56,153.87,148.57,138.29,137.32,137.21,133.00,131.83,130.38,128.02(q,J=22.8Hz),126.39,125.8 4(q,J=274.6Hz),123.97,119.54,117.70,112.79,111.16,94.42,82.15,66.12,57.87,55.11,53.04,46.04,43.76,34.01.

[0379] 3-Bromo-6-(4-methyl-1,4-diazepan-1-yl)imidazo[1,2-b]pyridazine

[0380] 1 H NMR (500 MHz, chloroform-d) δ7.54 (d, J = 9.8 Hz, 1H), 7.40 (s, 1H), 6.63 (d, J = 9.9 Hz, 1H), 3.83–3.67 (m, 3H), 3.66–3.52 (m, 2H), 2.84–2.59 (m, 2H), 2.54–2.41 (m, 2H), 2.31 (s, 2H), 2.10–1.75 (m, 3H); 13 C NMR (126 MHz, CDCl 3 )δ153.97,136.51,131.45,125.74,108.51,99.84,57.82,57.04,47.37,47.25,46.75,27.41.

[0381] 5-((6-(4-methyl-1,4-diazepan-1-yl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (Compound HSND-117)

[0382] 1 H NMR (500 MHz, DMSO-d 6 )δ10.76(s,1H),9.07(d,J=2.1Hz,1H),8.90(d,J=2.0Hz,1H),8.44(t,J=2.1Hz,1H),8.18 (d,J=2.2Hz,1H),8.02(dd,J=8.5,2.2Hz,1H),7.89(d,J=10.1Hz,2H),7.72(d,J=8.5Hz,1 H),7.16(d,J=10.0Hz,1H),3.75(t,J=5.0Hz,2H),3.69(t,J=6.2Hz,2H),2.66(t,J=5.0Hz ,2H),2.48–2.46(m,2H),2.45–2.26(m,8H),2.24(s,3H),2.14(s,3H),1.94–1.88(m,2H); 13 C NMR (126 MHz, DMSO-d 6 )δ163.88,154.64,153.66,148.45,138.28,137.30,136.70,133.04,131.83,130.42,128.07(q,J=28.9Hz),126.29,125.84(q,J=274 .8Hz),123.93,119.65,117.65,111.57,111.00,94.47,82.44,57.90,57.44,56.76,55.20,53.16,47.53,47.36,46.49,46.19,27.22.

[0383] (S)-3-Bromo-6-(3-methoxypyrrolidin-1-yl)imidazo[1,2-b]pyridazine

[0384] 1 H NMR (500 MHz, DMSO-d 6)δ7.81(dd,J=9.9,0.7Hz,1H),7.53(s,1H),6.86(dd,J=9.8,0.8Hz,1H),4.11–4.05(m ,1H),3.59–3.49(m,3H),3.44(td,J=9.7,7.3Hz,1H),3.26(s,3H),2.13–1.99(m,2H); 13 C NMR (126MHz, DMSO) δ153.49,136.85,131.36,126.22,110.97,99.28,79.39,56.34,52.33,45.43,30.49.

[0385] (S)-5-((6-(3-methoxypyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (Compound HSND-138)

[0386] 1 H NMR (500 MHz, DMSO-d 6 )δ10.75(s,1H),9.07(d,J=2.1Hz,1H),8.93(d,J=2.0Hz,1H),8.47(t,J=2.1Hz, 1H),8.19(d,J=2.2Hz,1H),8.02(dd,J=8.5,2.2Hz,1H),7.95–7.85(m,2H),7.72( d,J=8.5Hz,1H),6.97(d,J=9.8Hz,1H),4.13–4.06(m,1H),3.65–3.54(m,5H),3.5 4–3.45(m,1H),3.26(s,3H),2.46–2.25(m,12H),2.16(s,3H),2.13–2.01(m,2H); 13 C NMR (126 MHz, DMSO-d 6)δ163.89,153.83,153.61,148.51,138.29,137.38,137.29,136.77,133.01,131.84,130.38,128.07(q,J=30.4Hz),126.24,125.84(q ,J=273.4Hz),123.96,119.63,117.66,112.41,110.87,94.38,82.44,79.40,57.89,56.31,55.16,53.09,52.36,46.12,45.39,30.43.

[0387] N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-5-((6-((2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)oxy)imidazo[1,2-b]pyridazin-3-yl)ethynyl)nicotinamide (Compound HSND-140)

[0388] 1 H NMR (500 MHz, DMSO-d 6 )δ10.72(s,1H),9.08(d,J=2.0Hz,1H),8.90(d,J=1.9Hz,1H),8.48(d,J=2.4Hz,1H ),8.15(d,J=2.2Hz,1H),8.11(d,J=9.6Hz,1H),8.07–7.97(m,2H),7.70(d,J=8.5H z,1H),6.98(d,J=9.6Hz,1H),5.50(tt,J=11.3,4.1Hz,1H),3.56(s,2H),2.46–2.3 4(m,8H),2.21(d,J=12.3Hz,5H),1.38(t,J=11.7Hz,2H),1.22(s,6H),1.12(s,6H); 13 C NMR (126 MHz, DMSO-d 6)δ163.65,159.76,153.73,148.80,138.41,138.29,137.94,137.58,1 32.86,131.84,130.20,128.76,127.87(q,J=30.4Hz),125.81(q,J=273 .4Hz),124.73,123.85,119.13,117.62,114.60,111.82,94.60,81.19, 73.12,70.85,57.77,54.91,52.67,52.39,45.66,42.03,33.83,28.51.

[0389] 5-((6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (Compound HSND-141)

[0390] 1 H NMR (500 MHz, DMSO-d 6 )δ10.75(s,1H),9.07(d,J=2.1Hz,1H),8.92(d,J=2.0Hz,1H),8.46(t,J=2.1Hz,1H),8. 18(d,J=2.2Hz,1H),8.02(dd,J=8.6,2.2Hz,1H),7.96(d,J=9.7Hz,1H),7.92(s,1H),7.7 1(d,J=8.5Hz,1H),7.22(d,J=9.9Hz,1H),4.53(d,J=4.0Hz,2H),3.73(d,J=11.0Hz,2H), 3.62–3.48(m,4H),2.48(p,J=1.9Hz,2H),2.36(s,10H),2.14(s,3H),2.03–1.92(m,4H); 13 C NMR (126 MHz, DMSO-d 6)δ163.85,153.86,153.71,148.56,138.28,137.56,137.34,137.21,133.00,131.80,130.34,128.06(q,J=30.4Hz),126.86,12 5.84 (q, J=273.4Hz), 123.92, 119.49, 117.65, 113.57, 111.22, 94.50, 82.04, 70.30, 57.89, 56.34, 55.16, 53.11, 46.12, 26.91.

[0391] 5-(3-Bromoimidazo[1,2-b]pyridazin-6-yl)-2-oxa-5-azabicyclo[2.2.2]octane

[0392] 1 H NMR (500 MHz, methanol-d 4 )δ7.69(dd,J=11.5,9.2Hz,1H),7.48–7.42(m,1H),7.00–6.93(m,1H),4.47(d,J=8.6Hz,1H),4.20–4.12(m,1H),4.11–4.04(m,2H),3.91(td ,J=9.5,8.3,5.4Hz,1H),3.66(t,J=10.8Hz,1H),3.33–3.27(m,1H),2.24–2.06(m,2H),2.06–1.95(m,1H),1.82(dp,J=12.2,7.6,6.0Hz,1H); 13 C NMR (126 MHz, methanol-d 4 )δ153.68,136.70,130.26,124.87,109.76,99.80,69.76,65.68,51.58,44.65,25.39,23.92.

[0393] (R)-5-((6-(3-methoxypyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (Compound HSND-145)

[0394] 1 H NMR (500 MHz, DMSO-d 6)δ10.76(s,1H),9.07(t,J=1.7Hz,1H),8.92(d,J=1.8Hz,1H),8.47(q,J=1.9Hz ,1H),8.19(d,J=2.1Hz,1H),8.02(d,J=8.5Hz,1H),7.93–7.86(m,2H),7.71(d,J =8.5Hz,1H),6.96(d,J=9.8Hz,1H),4.09(p,J=3.4Hz,1H),3.63–3.55(m,5H),3 .49(q,J=8.8Hz,1H),3.25(s,3H),2.38(s,8H),2.17(s,3H),2.13–1.99(m,3H); 13 C NMR (126 MHz, DMSO-d 6 )δ163.87,153.82,153.59,148.50,138.30,137.37,137.28,136.75,132.97,131.82,130.35,127.83(q,J=30.2Hz),126.22,125.84(q ,J=274.6Hz),123.95,119.63,117.65,112.39,110.87,94.38,82.44,79.40,57.87,56.31,55.11,53.01,52.35,46.02,45.38,30.43.

[0395] 6-(3-Bromoimidazo[1,2-b]pyridazin-6-yl)-2-oxa-6-azaspiro[3.3]heptane

[0396] 1 H NMR (500 MHz, DMSO-d 6 )δ7.83(d,J=9.6Hz,1H),7.56(s,1H),6.67(dd,J=9.7,1.0Hz,1H),4.77–4.64(m,4H),4.28–4.16(m,4H); 13 C NMR (126MHz, DMSO) δ156.45,137.15,131.75,126.47,109.97,99.55,80.23,60.54.

[0397] 5-((6-(2-oxa-6-azaspiro[3.3]hept-6-yl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (Compound HSND-149)

[0398] 1 H NMR (500 MHz, methanol-d 4 )δ9.05(d,J=2.1Hz,1H),8.87(d,J=1.9Hz,1H),8.46(t,J=2.1Hz,1H),8.15(d,J=2.2Hz,1H),7.95(dd,J=8.4,2.3Hz,1H),7.81–7.76( m,2H),7.74(d,J=9.7Hz,1H),6.74(d,J=9.7Hz,1H),4.86(s,4H),4.33(s,4H),3.68(d,J=1.7Hz,2H),2.76–2.45(m,9H),2.40(s,3H); 13 C NMR (126 MHz, methanol-d 4 )δ164.14,156.22,153.12,147.09,137.60,137.39,135.53,132.89,131.29,130.53,128.92(q,J=30.4Hz),125.38 (q, J=273.4Hz),124.93,123.57,120.32,117.73,110.89,93.36,80.77,59.92,57.38,54.44,51.86,44.18,39.09.

[0399] (1R,4R)-5-(3-bromoimidazo[1,2-b]pyridazin-6-yl)-2-oxa-5-azabicyclo[2.2.1]heptane

[0400] 1 H NMR (500 MHz, methanol-d 4 )δ7.66(d,J=9.8Hz,1H),7.45(s,1H),6.86(d,J=9.8Hz,1H),4.90–4.86(m,1H),4.73–4.6 9(m,1H),3.88(s,2H),3.59(dd,J=10.0,1.6Hz,1H),3.48–3.42(m,1H),2.06–1.96(m,2H); 13 C NMR (126MHz, MeOD) δ153.36,136.77,130.30,124.87,111.06,99.79,76.28,72.73,57.29,56.28,35.97.

[0401] 5-((6-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (Compound HSND-150)

[0402] 1 H NMR (500 MHz, methanol-d 4 )δ9.00(d,J=2.2Hz,1H),8.80(d,J=2.0Hz,1H),8.40(t,J=2.1Hz,1H),8.10 (d,J=2.3Hz,1H),7.91(dd,J=8.5,2.3Hz,1H),7.77–7.68(m,3H),6.92(d,J= 9.8Hz,1H),4.94–4.91(m,1H),4.73–4.66(m,1H),3.93–3.89(m,2H),3.65–3 .58(m,3H),3.52–3.46(m,1H),2.51(s,8H),2.28(s,3H),2.06–1.96(m,2H); 13 C NMR (126 MHz, methanol-d 4 )δ164.00,153.49,153.03,146.97,137.47,137.33,137.04,135.36,133.04,131.21,130.41,128.83(q,J=30.2Hz),125.37(q,J=273. 4Hz),124.90,123.49,120.30,117.63,112.26,111.61,93.34,81.04,76.27,72.82,57.49,57.38,56.29,54.59,52.29,44.59,36.04.

[0403] (1S,4S)-5-(3-bromoimidazo[1,2-b]pyridazin-6-yl)-2-oxa-5-azabicyclo[2.2.1]heptane

[0404] 1 H NMR (500 MHz, methanol-d 4)δ7.71–7.63(m,1H),7.48–7.43(m,1H),6.91–6.84(m,1H),4.89(d,J=5.3Hz,2H),4.7 2(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); 13 C NMR (126MHz, MeOD) δ 153.38, 136.78, 130.30, 124.88, 111.07, 99.80, 76.29, 72.74, 57.30, 56.28, 35.97.

[0405] 5-((6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (Compound HSND-151)

[0406] 1 H NMR (500 MHz, methanol-d 4 )δ9.00(d,J=2.1Hz,1H),8.81(d,J=2.0Hz,1H),8.40(t,J=2.1Hz,1H),8.10( d,J=2.2Hz,1H),7.91(dd,J=8.5,2.3Hz,1H),7.80–7.64(m,3H),6.93(d,J=9. 8Hz,1H),4.96–4.90(m,1H),4.75–4.66(m,1H),3.91(s,2H),3.64–3.57(m,3H ),3.49(d,J=10.0Hz,1H),2.77–2.32(m,8H),2.30(s,3H),2.07–1.96(m,2H); 13 C NMR (126 MHz, methanol-d 4)δ164.01,153.49,153.03,146.98,137.49,137.33,137.05,135.36,133.00,131.21,130.42,128.84(q,J=30.4Hz),125.37(q,J=273. 4Hz),124.90,123.49,120.30,117.64,112.26,111.62,93.34,81.04,76.27,72.82,57.47,57.38,56.29,54.56,52.22,44.52,36.04.

[0407] 4-(1-(3-bromoimidazo[1,2-b]pyridazin-6-yl)piperidin-4-yl)morpholine

[0408] 1 H NMR (500 MHz, methanol-d 4 )δ7.68(dd,J=10.1,2.9Hz,1H),7.48(s,1H),7.21–7.13(m,1H),4.38–4.30(m,2H),3.72–3.67(m,4H),3.01 –2.91(m,2H),2.63–2.56(m,4H),2.46(dtq,J=10.6,7.0,3.8Hz,1H),2.05–1.98(m,2H),1.62–1.46(m,2H).

[0409] 13 C NMR (126MHz, MeOD) δ 155.24, 136.65, 130.53, 124.76, 111.28, 100.09, 66.50, 61.87, 49.60, 45.04, 27.33.

[0410] N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-5-((6-(4-morpholinopiperidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)nicotinamide (Compound HSND-152)

[0411] 1 H NMR (500 MHz, methanol-d 4)δ8.99(d,J=2.1Hz,1H),8.80–8.74(m,1H),8.41–8.36(m,1H),8.09(d,J=2.3Hz ,1H),7.90(dd,J=8.4,2.2Hz,1H),7.79–7.70(m,2H),7.71–7.64(m,1H),7.18(d d,J=10.6,3.2Hz,1H),4.33(d,J=13.2Hz,2H),3.68–3.61(m,6H),2.96(t,J=12. 8Hz,2H),2.72–2.33(m,14H),2.28(s,3H),2.03–1.97(m,2H),1.58–1.47(m,2H); 13 CNMR (126MHz, methanol-d 4 )δ163.89,155.32,152.90,146.93,137.48,137.41,136.90,135.48,133.03,131.18,130.38,128.80(q,J=30.4Hz),125.37(q,J=274. 6Hz),124.76,123.41,120.26,117.56,112.45,111.81,93.52,81.14,66.47,61.80,57.49,54.61,52.30,49.61,45.01,44.61,27.42.

[0412] 3-Bromo-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)imidazo[1,2-b]pyridazine

[0413] 1 H NMR (500 MHz, methanol-d 4 )δ7.66(d,J=10.0Hz,1H),7.47(s,1H),7.15(d,J=10.0Hz,1H),4.37–4.29(m,2H),2.98–2. 89(m,2H),2.76–2.37(m,9H),2.27(s,3H),2.03–1.95(m,2H),1.54(qd,J=12.4,4.1Hz,2H).

[0414] 13 C NMR (126MHz, MeOD) δ155.20,136.64,130.54,124.76,111.25,100.09,61.53,54.50,48.35,45.13,44.59,27.42.

[0415] N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-5-((6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)nicotinamide (Compound HSND-153)

[0416] 1 H NMR (500 MHz, methanol-d 4 )δ9.01(s,1H),8.83(s,1H),8.43(d,J=2.3Hz,1H),8.12(d,J=2.3Hz,1H),7.9 2(dd,J=8.5,2.3Hz,1H),7.79–7.68(m,3H),7.22(dd,J=10.3,2.9Hz,1H),4.3 7(d,J=13.2Hz,2H),3.64(s,2H),2.98(t,J=12.8Hz,2H),2.91–2.34(m,17H), 2.27(d,J=15.0Hz,6H), 2.02(d,J=12.4Hz,2H), 1.56(qd,J=12.1,3.9Hz,2H).

[0417] 13 C NMR (126 MHz, methanol-d 4 )δ164.01,155.36,152.99,147.01,137.51,137.41,136.93,135.52,1 33.05,131.22,130.49,128.84(q,J=30.4Hz),125.39(q,J=273.4Hz),1 24.78,123.46,123.22,120.31,117.60,112.51,111.83,93.41,81.03, 61.51,57.51,54.62,54.47,52.33,48.37,45.12,44.63,44.56,27.49.

[0418] 7-(3-Bromoimidazo[1,2-b]pyridazin-6-yl)-4-oxa-7-azaspiro[2.5]octane

[0419] 1 H NMR (500 MHz, methanol-d 4)δ7.71(d,J=10.0Hz,1H),7.51(s,1H),7.16(d,J=10.0Hz,1H),3.95–3.82(m, 2H), 3.74–3.64 (m, 2H), 3.57 (s, 2H), 0.81 (t, J = 3.5Hz, 2H), 0.74–0.66 (m, 2H). 13 C NMR (126MHz, MeOD) δ155.65,130.71,124.92,110.95,65.16,58.24,50.97,45.39,10.57.

[0420] 5-((6-(4-oxa-7-azaspiro[2.5]octan-7-yl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (Compound HSND-156)

[0421] 1 H NMR (500 MHz, DMSO-d 6 )δ10.75(s,1H),9.07(d,J=2.1Hz,1H),8.93(d,J=2.0Hz,1H),8.46(t,J=2.1Hz,1H),8. 18(d,J=2.2Hz,1H),8.03(dd,J=8.5,2.2Hz,1H),8.00–7.92(m,2H),7.72(d,J=8.5Hz,1H ),7.31(d,J=9.9Hz,1H),3.79(dd,J=5.7,4.0Hz,2H),3.64(dd,J=5.8,4.0Hz,2H),3.56 (d,J=2.8Hz,4H),2.39–2.35(m,8H),2.15(s,3H),0.75–0.70(m,2H),0.70–0.64(m,2H); 13 C NMR (126 MHz, DMSO-d 6)δ163.87,155.94,153.78,148.58,138.28,137.61,137.39,133.03,131.84,130.38,128.07(q,J=30.4Hz),126.55,125.84(27 4.6Hz),123.93,119.47,117.63,112.66,111.26,94.63,82.07,65.43,58.64,57.90,55.17,53.13,51.21,46.16,45.61,11.51.

[0422] (2S,6R)-4-(3-bromo-2-methylimidazo[1,2-b]pyridazin-6-yl)-2,6-dimethylmorpholine

[0423] 1 H NMR (500 MHz, methanol-d 4 )δ7.62(d,J=9.9Hz,1H),7.12(d,J=9.9Hz,1H),4.07(dd,J=13.5,2.0Hz,2H),3.74(dqd,J =12.5,6.2,2.3Hz,2H),2.58(dd,J=12.9,10.6Hz,2H),2.36(s,3H),1.24(d,J=6.2Hz,6H); 13 C NMR (126MHz, MeOD) δ155.11,139.14,136.09,124.04,110.41,98.27,71.36,51.05,17.68,12.05.

[0424] 5-((6-((2S,6R)-2,6-dimethylmorpholino)-2-methylimidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (Compound HSND-157)

[0425] 1 H NMR (500 MHz, methanol-d 4)δ9.01(d,J=2.1Hz,1H),8.83(d,J=2.0Hz,1H),8.42(t,J=2.1Hz,1H),8.1 3(d,J=2.3Hz,1H),7.93(dd,J=8.4,2.3Hz,1H),7.77(d,J=8.5Hz,1H),7.6 6(d,J=9.9Hz,1H),7.17(d,J=9.9Hz,1H),4.12–4.06(m,2H),3.80–3.70(m ,2H),3.66(s,2H),2.71–2.40(m,13H),2.32(s,3H),1.23(d,J=6.2Hz,6H); 13 C NMR (126 MHz, methanol-d 4 )δ164.04,155.18,152.75,146.85,146.21,137.54,137.15,136.29,133.00,131.25,130.51,128.89(q,J=30.4Hz),125.38(q,J=2 73.4Hz),124.07,123.50,120.53,117.66,111.71,109.58,95.31,81.29,71.34,57.47,54.55,52.19,50.96,44.49,17.72,12.81.

[0426] 6-(3-Bromoimidazo[1,2-b]pyridazin-6-yl)-2-oxa-6-azaspiro[3.4]octane

[0427] 1 H NMR (500 MHz, methanol-d 4 )δ7.67(d,J=9.8Hz,1H),7.45(s,1H),6.89(d,J=9.8Hz,1H),4.74(d,J=6.2Hz,2H) ,4.68(d,J=6.2Hz,2H),3.81(s,2H),3.58(t,J=7.0Hz,2H),2.37(t,J=7.0Hz,2H); 13 C NMR (126MHz, MeOD) δ153.31,136.66,130.10,124.57,110.74,99.65,80.70,55.28,45.50,45.22,34.55.

[0428] 5-((6-(2-oxa-6-azaspiro[3.4]octan-6-yl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (Compound HSND-158)

[0429] 1 H NMR (500 MHz, DMSO-d 6 )δ10.80(s,1H),9.09(d,J=2.2Hz,1H),8.94(d,J=2.0Hz,1H),8.49(t,J=2.2Hz,1H),8. 21(d,J=2.2Hz,1H),8.04(dd,J=8.5,2.2Hz,1H),7.93–7.85(m,2H),7.72(d,J=8.5Hz,1 H),6.95(d,J=9.9Hz,1H),4.61(d,J=6.1Hz,2H),4.51(d,J=6.1Hz,2H),3.77(s,2H),3. 57(s,2H),3.52(t,J=6.9Hz,2H),2.42–2.26(m,8H),2.27(t,J=6.9Hz,2H),2.22(s,3H); 13 C NMR (126 MHz, DMSO-d 6 )δ163.89,153.88,153.51,148.55,138.35,137.36,136.85,132.89,131.85,130.36,127.85(q,J=30.2Hz),126.24,125.84(q,J= 273.4Hz),123.98,119.61,117.74,112.36,110.87,94.39,82.40,80.14,57.80,55.64,54.94,52.75,46.11,45.74,45.24,34.92.

[0430] 6-(3-Bromoimidazo[1,2-b]pyridazin-6-yl)-1-oxa-6-azaspiro[3.4]octane

[0431] 1 H NMR (500 MHz, methanol-d 4)δ7.65(dd,J=9.8,1.2Hz,1H),7.44(d,J=1.2Hz,1H),6.84(dd,J=9.9,1.2Hz,1H),4.62–4.53(m,2H),3.95(d,J=11.9Hz,1H),3.70–3.63( m,1H),3.60(d,J=12.0Hz,1H),3.54(td,J=10.0,6.6Hz,1H),2.91–2.82(m,1H),2.82–2.72(m,1H),2.54–2.45(m,1H),2.25–2.13(m,1H); 13 C NMR (126MHz, MeOD) δ153.19,136.60,130.03,124.52,110.52,99.62,90.91,65.24,57.78,44.77,37.14,27.95.

[0432] 5-((6-(1-oxa-6-azaspiro[3.4]octan-6-yl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (Compound HSND-159)

[0433] 1 H NMR (500 MHz, DMSO-d 6 )δ10.77(s,1H),9.08(d,J=2.1Hz,1H),8.94(d,J=2.0Hz,1H),8.49(t,J=2.1Hz,1H),8.19(d,J= 2.2Hz,1H),8.03(dd,J=8.5,2.2Hz,1H),7.93–7.86(m,2H),7.71(d,J=8.6Hz,1H),6.93(d,J=9.9 Hz,1H),4.45–4.36(m,2H),3.87(dd,J=11.9,1.4Hz,1H),3.67–3.57(m,2H),3.56(s,2H),3.52– 3.43(m,1H),2.81–2.72(m,1H),2.68–2.59(m,1H),2.46(s,8H),2.18(s,3H),2.16–2.09(m,1H); 13 C NMR (126 MHz, DMSO-d 6)δ163.87,153.83,153.47,148.54,138.33,137.38,136.82,132.92,131.81,130.33,128.07(q,J=30.2Hz),126.30,125.84(q,J=274.6H z),123.94,119.60,117.70,112.16,110.90,94.41,90.05,82.41,64.89,58.21,57.84,55.04,52.90,45.90,45.42,40.34,37.56,28.76.

[0434] 1-(3-Bromoimidazo[1,2-b]pyridazin-6-yl)-4-methylpiperidin-4-ol

[0435] 1 H NMR (500 MHz, methanol-d 4 )δ7.66(d,J=10.0Hz,1H),7.46(s,1H),7.17(d,J=10.0Hz,1H),3.94–3.86(m ,2H),3.46(dt,J=13.7,7.1Hz,2H),1.68(dd,J=7.1,4.4Hz,4H),1.26(s,3H); 13 C NMR (126MHz, MeOD) δ155.30, 136.61, 130.39, 124.63, 111.28, 100.03, 67.07, 42.18, 37.28, 28.49.

[0436] 5-((6-(4-hydroxy-4-methylpiperidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (Compound HSND-168)

[0437] 1 H NMR (500 MHz, DMSO-d 6)δ10.77(s,1H),9.08(d,J=2.2Hz,1H),8.92(d,J=2.0Hz,1H),8.46(t,J=2.1Hz ,1H),8.19(d,J=2.2Hz,1H),8.03(dd,J=8.4,2.2Hz,1H),7.90(d,J=10.1Hz,2H ),7.72(d,J=8.5Hz,1H),7.32(d,J=10.0Hz,1H),4.39(s,1H),3.91–3.83(m,2H ),3.57(s,2H),3.42–3.37(m,2H),2.20(s,3H),1.60–1.50(m,4H),1.14(s,3H); 13 C NMR (126 MHz, DMSO-d 6 )δ163.88,155.52,153.82,148.56,138.31,137.33,137.11,132.95,131.86,130.39,128.13(q,J=28.6Hz),126.34,125.84(q,J=2 74.6Hz),123.97,123.66,119.56,117.67,112.80,111.12,94.45,82.24,66.52,57.83,55.04,52.89,45.90,42.63,38.07,30.13.

[0438] N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-5-((6-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1,2-b]pyridazin-3-yl)ethynyl)nicotinamide (Compound HSND174)

[0439] 1 H NMR (500 MHz, methanol-d 4)δ9.07(s,1H),8.92(s,1H),8.52(td,J=2.1,1.0Hz,1H),8.14(d,J=2.3Hz,1H), 8.00–7.88(m,3H),7.78(d,J=8.5Hz,1H),7.02(dd,J=9.6,1.0Hz,1H),4.27(s,2H ),3.66(s,2H),3.10–3.02(m,2H),2.74–2.67(m,3H),2.67–2.36(m,8H),2.29(s, 3H),2.10–2.00(m,2H),1.96–1.88(m,3H),1.88–1.80(m,2H),1.79–1.71(m,2H).

[0440] 5-((6-(ethyl(tetrahydro-2H-pyran-4-yl)amino)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (Compound HSND175)

[0441] 1 H NMR (500 MHz, methanol-d 4 )δ9.05–9.01(m,1H),8.85(s,1H),8.44(t,J=2.0Hz,1H),8.10(d,J=2.3Hz,1H),7.94(dd,J= 8.4,2.3Hz,1H),7.75(dd,J=15.4,9.2Hz,3H),7.12(d,J=9.9Hz,1H),4.36(tt,J=11.8,3.9H z,1H),4.08(dd,J=11.4,4.4Hz,2H),3.65(s,2H),3.61–3.52(m,4H),2.52(s,8H),2.30(s,3 H), 2.21 (tt, J = 12.2, 6.1 Hz, 3H), 1.79 (ddd, J = 12.4, 4.0, 1.8 Hz, 2H), 1.29 (t, J = 7.0 Hz, 3H).

[0442] 3-Bromo-N-methyl-N-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b]pyridazin-6-amine

[0443] 1 H NMR (500 MHz, methanol-d 4)δ7.66(dd,J=10.0,1.1Hz,1H),7.45(d,J=1.0Hz,1H),7.10(dd,J=10.0,1.2Hz,1H),4.50–4.40(m,1H ),4.08–4.01(m,2H),3.56(td,J=11.9,1.9Hz,2H),3.00(s,3H),1.98–1.86(m,2H),1.74–1.67(m,2H).

[0444] 13 C NMR (126MHz, MeOD) δ154.81, 136.54, 130.25, 124.64, 110.63, 99.84, 67.18, 53.27, 29.53, 29.16.

[0445] 5-((6-(methyl(tetrahydro-2H-pyran-4-yl)amino)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (Compound HSND176)

[0446] 1 H NMR (500 MHz, DMSO-d 6 )δ10.74(s,1H),9.07(d,J=2.1Hz,1H),8.89(d,J=1.9Hz,1H),8.44(t,J=2.0Hz,1H),8.18( d,J=2.2Hz,1H),8.03(dd,J=8.5,2.2Hz,1H),7.92–7.86(m,2H),7.69(d,J=8.5Hz,1H),7.2 3(d,J=9.9Hz,1H),4.44–4.34(m,1H),3.92(dd,J=11.2,4.4Hz,2H),3.44(td,J=11.8,1.9H z,3H),2.96(s,3H),2.47–2.28(m,8H),2.17(s,3H),1.91–1.78(m,2H),1.67–1.60(m,2H); 13 C NMR (126 MHz, DMSO-d 6)δ163.78,154.99,153.59,148.41,138.29,137.31,137.11,136.74,132.91,131.76,130.31,128.06(q,J=30.4Hz),126.25,125.8 3(q,J=273.4Hz),123.92,119.65,117.69,112.26,111.05,94.51,82.36,67.14,57.84,55.04,53.46,52.90,45.90,30.45,29.93.

[0447] 5-((6-(2,2-dimethylmorpholino)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (Compound HSND177)

[0448] 1 H NMR (500 MHz, DMSO-d 6 )δ10.74(s,1H),9.07(d,J=2.1Hz,1H),8.92(d,J=2.0Hz,1H),8.46(t,J=2.1 Hz,1H),8.17(d,J=2.3Hz,1H),8.02(dd,J=8.4,2.2Hz,1H),7.97–7.90(m,2H ),7.70(d,J=8.5Hz,1H),7.30(d,J=10.0Hz,1H),3.75(t,J=5.0Hz,2H),3.54 (d,J=10.2Hz,4H),3.40(s,2H),2.45–2.20(m,8H),2.13(s,3H),1.20(s,6H); 13 C NMR (126 MHz, DMSO-d 6 )δ163.83,155.92,153.74,148.55,138.27,137.50,137.35,137.24,133.01,131.79,130.35,128.06(q,J=30.4Hz),126.55,125.83(q ,J=274.8Hz),123.88,119.49,117.63,112.35,111.22,94.59,82.13,71.23,60.01,57.91,55.20,54.85,53.17,46.19,45.39,24.64.

[0449] N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-5-((6-(1-oxothiomorpholino)imidazo[1,2-b]pyridazin-3-yl)ethynyl)nicotinamide (Compound HSND178)

[0450] 1 H NMR (500 MHz, DMSO-d 6 )δ9.09(d,J=2.1Hz,1H),8.91(d,J=2.0Hz,1H),8.47(t,J=2.1Hz,1H),8.18(d,J=2.2Hz,1H),8.03–7.94(m,3H),7.69(d,J=8.5Hz,1H),7.40 (d,J=10.0Hz,1H),4.21–4.13(m,2H),4.03–3.94(m,2H),3.55(s,2H), 3.06–2.97(m,2H),2.81–2.74(m,2H),2.45–2.20(m,8H),2.14(s,3H); 13 C NMR (126 MHz, DMSO-d 6 )δ163.93,154.72,153.61,148.67,139.30,137.41,137.35,132.55,131.74,130.95,128.00(q,J=30.4Hz),126.85,12 5.92 (q, J=274.6Hz), 124.23, 119.38, 117.92, 112.54, 111.34, 94.74, 81.79, 57.95, 55.21, 53.18, 46.21, 43.88, 37.72.

[0451] 5-((6-(2,2-dimethylmorpholino)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (Compound HSND177)

[0452] 1 H NMR (500 MHz, DMSO-d 6)δ10.74(s,1H),9.07(d,J=2.1Hz,1H),8.92(d,J=2.0Hz,1H),8.46(t,J=2.1 Hz,1H),8.17(d,J=2.3Hz,1H),8.02(dd,J=8.4,2.2Hz,1H),7.97–7.90(m,2H ),7.70(d,J=8.5Hz,1H),7.30(d,J=10.0Hz,1H),3.75(t,J=5.0Hz,2H),3.54 (d,J=10.2Hz,4H),3.40(s,2H),2.45–2.20(m,8H),2.13(s,3H),1.20(s,6H); 13 C NMR (126 MHz, DMSO-d 6 )δ163.83,155.92,153.74,148.55,138.27,137.50,137.35,137.24,133.01,131.79,130.35,128.06(q,J=30.4Hz),126.55,125.83(q ,J=274.8Hz),123.88,119.49,117.63,112.35,111.22,94.59,82.13,71.23,60.01,57.91,55.20,54.85,53.17,46.19,45.39,24.64.

[0453] N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-5-((6-(1-oxothiomorpholino)imidazo[1,2-b]pyridazin-3-yl)ethynyl)nicotinamide (Compound HSND178)

[0454] 1 H NMR (500 MHz, DMSO-d 6 )δ9.09(d,J=2.1Hz,1H),8.91(d,J=2.0Hz,1H),8.47(t,J=2.1Hz,1H),8.18(d,J=2.2Hz,1H),8.03–7.94(m,3H),7.69(d,J=8.5Hz,1H),7.40 (d,J=10.0Hz,1H),4.21–4.13(m,2H),4.03–3.94(m,2H),3.55(s,2H), 3.06–2.97(m,2H),2.81–2.74(m,2H),2.45–2.20(m,8H),2.14(s,3H); 13C NMR (126 MHz, DMSO-d 6 )δ163.93,154.72,153.61,148.67,139.30,137.41,137.35,132.55,131.74,130.95,128.00(q,J=30.4Hz),126.85,12 5.92 (q, J=274.6Hz), 124.23, 119.38, 117.92, 112.54, 111.34, 94.74, 81.79, 57.95, 55.21, 53.18, 46.21, 43.88, 37.72.

[0455] 9-(3-Bromoimidazo[1,2-b]pyridazin-6-yl)-3-oxa-9-azaspiro[5.5]undecane

[0456] 1 H NMR (500 MHz, methanol-d 4 )δ7.65(d,J=10.0Hz,1H),7.46(s,1H),7.13(d,J=10.0Hz,1H),3.69–3.66(m,4H),3.60–3.46(m,4H),1.73–1.61(m,4H),1.55(t,J=5.4Hz,4H); 13 C NMR (126 MHz, methanol-d 4 )δ155.50,136.64,130.44,124.61,111.19,100.03,63.02,41.19,35.85,34.86,29.00.

[0457] 5-((6-(3-oxa-9-azaspiro[5.5]undec-9-yl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (Compound HSND-182)

[0458] 1 H NMR (500 MHz, methanol-d 4)δ8.97(d,J=2.2Hz,1H),8.75(d,J=2.0Hz,1H),8.37(t,J=2.1Hz,1H),8.09 (d,J=2.3Hz,1H),7.91(dd,J=8.5,2.3Hz,1H),7.73(d,J=8.6Hz,2H),7.66(d ,J=10.0Hz,1H),7.15(d,J=10.0Hz,1H),3.66–3.61(m,6H),3.60–3.55(m,4H ),2.67–2.38(m,8H),2.31(s,3H),1.70–1.59(m,4H),1.51(t,J=5.3Hz,4H); 13 C NMR (126 MHz, methanol-d 4 )δ163.89,155.56,152.87,146.89,137.49,137.36,136.90,135.40,132.98,131.20,130.35,128.83(q,J=31.5Hz),125.37(q,J=274. 6Hz),124.61,123.43,120.27,117.57,112.34,111.77,93.49,81.23,62.98,57.46,54.56,52.17,44.48,41.16,35.82,34.88,28.97.

[0459] 8-(3-Bromoimidazo[1,2-b]pyridazin-6-yl)-2-oxa-8-azaspiro[4.5]decane

[0460] 1 H NMR (500 MHz, methanol-d 4 )δ7.65(dd,J=10.0,1.3Hz,1H),7.46(s,1H),7.13(dd,J=10.0,1.4Hz,1H),3.87(td,J=7.2,1.3Hz,2H),3. 69–3.61(m,2H),3.59–3.56(m,2H),3.55–3.49(m,2H),1.83(td,J=7.2,1.3Hz,2H),1.67(t,J=5.7Hz,4H); 13 C NMR (126 MHz, methanol-d 4 )δ155.37,136.64,130.51,124.68,111.26,100.06,77.30,66.89,43.67,41.66,36.50,33.85.

[0461] 5-((6-(2-oxa-8-azaspiro[4.5]dec-8-yl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (Compound HSND-183)

[0462] 1 H NMR (500 MHz, methanol-d 4 )δ9.04(s,1H),8.84(s,1H),8.41(s,1H),8.12(d,J=2.2Hz,1H),8.01–7.90(m,1H),7.76(d,J=8.4Hz,1H),7.24(s,1H),3.86(t,J =7.1Hz,2H),3.75–3.65(m,4H),3.62–3.53(m,4H),2.73–2.47(m,8H),2.38(s,3H),1.84(t,J=7.2Hz,2H),1.71(t,J=5.7Hz,4H).

[0463] 7-(3-Bromoimidazo[1,2-b]pyridazin-6-yl)-2-oxa-7-azaspiro[3.5]nonane

[0464] 1 H NMR (500 MHz, methanol-d 4 )δ7.66(d,J=9.5Hz,1H),7.47(s,1H),7.14(d,J=10.0Hz,1H),4.49(s,4H),3.54(t,J=5.7Hz,4H),1.96(t,J=5.7Hz,4H); 13 C NMR (126 MHz, methanol-d 4 )δ155.33,136.65,130.55,124.75,111.27,100.07,81.37,42.82,38.67,33.65.

[0465] 5-((6-(2-oxa-7-azaspiro[3.5]non-7-yl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (Compound HSND-184)

[0466] 1H NMR (500 MHz, methanol-d 4 )δ9.03(s,1H),8.83(s,1H),8.42(d,J=2.4Hz,1H),8.13(d,J=2.4Hz,1H),7.94(dd,J=8.4,2.3Hz,1H),7.86 –7.65(m,3H),7.22(dd,J=9.9,2.1Hz,1H),4.55–4.44(m,4H),3.58(t,J=5.8Hz,4H),1.98(t,J=5.7Hz,4H).

[0467] 4-(2-((3-bromoimidazo[1,2-b]pyridazin-6-yl)oxy)ethyl)morpholine

[0468] 1 H NMR (500 MHz, DMSO-d 6 )δ8.09–7.95(m,1H),7.81–7.64(m,1H),7.10–6.81(m,1H),4.55–4.39(m,2H),3.64–3.46(m,4H),2.82–2.66(m,2H),2.57–2.42(m,4H); 13 C NMR (126 MHz, DMSO-d 6 )δ160.55,138.05,132.86,128.57,112.88,100.66,66.69,64.93,56.93,54.02.

[0469] N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-5-((6-(2-morpholinethoxy)imidazo[1,2-b]pyridazin-3-yl)ethynyl)nicotinamide (Compound HSND185)

[0470] 1 H NMR (500 MHz, DMSO-d 6)δ10.74(s,1H),9.07(s,1H),8.88(s,1H),8.44(s,1H),8.17(s,1H),8. 09–7.93(m,3H),7.79–7.64(m,1H),7.46–7.30(m,1H),4.45–4.30(m,2H ),4.18–4.04(m,2H),3.80–3.66(m,1H),3.55(s,2H),3.34–3.27(m,1H) ,3.24–3.03(m,3H),2.51–2.46(m,2H),2.43–2.22(m,8H),2.13(s,3H).

[0471] (2S,6R)-4-(5-iodoimidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2,6-dimethylmorpholine

[0472] 1 H NMR (500 MHz, DMSO-d 6 )δ7.09(s,1H),3.74–3.66(m,2H),3.65–3.55(m,2H),2.88–2.67(m,2H),1.14(d,J=6.2Hz,6H); 13 C NMR (126 MHz, DMSO-d 6 )δ164.76,140.45,136.62,70.91,62.98,53.11,18.83.

[0473] 5-((2-((2S,6R)-2,6-dimethylmorpholino)imidazo[2,1-b][1,3,4]thiadiazol-5-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (Compound HSND186)

[0474] 1 H NMR (500 MHz, DMSO-d 6)δ10.74(s,1H),9.08(s,1H),8.92(s,1H),8.49(s,1H),8.18(s,1H),8.06–7.95(m,1H),7.71(d,J=8.5Hz,1H),7.56( s,1H),3.76–3.63(m,4H),3.55(s,2H),2.83(t,J=11.8Hz,2H),2.45–2.20(m,8H),2.14(s,3H),1.15(d,J=6.0Hz,6H).

[0475] 1-((3-bromoimidazo[1,2-b]pyridazin-6-yl)oxy)-2-methylpropan-2-ol

[0476] The reaction mixture of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (500 mg) and 2-methylpropane-1,2-diol (2.3 equivalents) was cooled to 0 ° C in anhydrous THF (20 mL), and NaH (2.5 equivalents) was added. The reaction mixture was then stirred at room temperature overnight. After completion, the reaction was extracted with ethyl acetate and washed with brine. The organic layer was collected and dried with sodium sulfate and concentrated under reduced pressure to obtain the desired product. Off-white solid, yield 93%. Off-white solid, yield: 67%.

[0477] 1 H NMR (500 MHz, methanol-d 4 )δ7.86(dd,J=9.4,1.5Hz,1H),7.60(s,0H),6.96(dd,J=9.8,1.7Hz,1H),4.23(s,2H),1.16(s,6H); 13 C NMR (126 MHz, methanol-d 4 )δ160.8,137.9,131.5,126.8,112.9,100.8,74.8,68.9,24.6.

[0478] 5-((6-(2-hydroxy-2-methylpropoxy)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (HSND-25)

[0479] Off-white solid, yield: 70%.

[0480] 1 H NMR (500 MHz, methanol-d 4)δ9.13–8.98(m,1H),8.90–8.80(m,1H),8.51–8.41(m,1H),8.17–8.07(m,1H),8.00–7.84(m,3H),7.76(t,J =8.4Hz,1H),7.02(dd,J=12.2,8.7Hz,1H),4.29(s,2H),3.66(s,2H),2.56(s,8H),2.35(s,3H),1.35(s,7H); 13 C NMR (126 MHz, methanol-d 4 )δ163.9,160.9,153.1,147.3,138.1,137.5,136.4,132.9,131.2,130.4,128.8(q,J=27.7Hz),126.8,125. 3(q,J=274.6Hz),123.4,119.9,117.6,114.2,112.4,93.7,80.1,74.9,68.9,57.4,54.5,52.0,44.3,25.1.

[0481] 3-Bromo-6-((3-methyloxetan-3-yl)methoxy)imidazo[1,2-b]pyridazine

[0482] The reaction mixture of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (500 mg) and (3-methyloxetane-3-yl)methanol (2.3 equivalents) was cooled to 0 ° C in anhydrous THF (20 mL), and then NaH (2.5 equivalents) was added. The reaction mixture was stirred at room temperature overnight. After completion, the reactant was extracted with ethyl acetate and washed with brine. The organic layer was collected and dried with sodium sulfate and concentrated under reduced pressure to obtain the desired product. Off-white solid, yield 90%.

[0483] 1 H NMR (500 MHz, methanol-d 4 )δ7.89(dd,J=9.7,0.6Hz,1H),7.62(s,1H),6.98(dd,J=9.6,0.6Hz,1H),4.70(d,J=6.0Hz,2H),4.52(s,2H),4.47(d,J=6.0Hz,2H),1.46(s,3H); 13 C NMR (126 MHz, methanol-d 4 )δ160.8,137.9,131.6,126.9,112.8,100.8,79.4,71.6,66.6,39.1,19.9.

[0484] 5-((6-((3-methyloxetane-3-yl)methoxy)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (HSND-26)

[0485] Off-white solid, yield: 66%. 1 H NMR (500 MHz, DMSO-d 6 )δ10.79(s,1H),9.10(s,1H),8.97(s,1H),8.52(t,J=2.1Hz,1H),8.18( d,J=2.3Hz,1H),8.13(d,J=9.6Hz,1H),8.09–8.00(m,2H),7.71(d,J=8. 5Hz,1H),7.07(d,J=9.6Hz,1H),4.58(d,J=5.9Hz,2H),4.52(s,2H),4.2 9(d,J=5.9Hz,2H),3.55(s,2H),2.38(bs,8H),2.17(s,3H),1.37(s,3H); 13 CNMR (126MHz, DMSO-d 6 )δ163.79,160.9,153.8,148.8,138.2,138.0,137.5,132.9,131.8,130.3,128.6,128.0(q,J=28.9Hz),125.8(q,J =275.9Hz),123.9,119.1,117.6,117.6,114.2,111.9,95.0,81.3,79.1,72.2,57.8,55.0,52.9,46.0,39.2,21.3.

[0486] 3-Bromo-6-(oxetan-3-ylmethoxy)imidazo[1,2-b]pyridazine

[0487] The reaction mixture of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (500 mg) and oxetane-3-ylmethanol (2.3 equivalents) was cooled to 0 ° C in anhydrous THF (20 mL), and NaH (2.5 equivalents) was added. The reaction mixture was stirred at room temperature overnight. After completion, the reactant was extracted with ethyl acetate and washed with brine. The organic layer was collected and dried with sodium sulfate and concentrated under reduced pressure to obtain the desired product. Off-white solid, the yield was 93%.

[0488] 1H NMR (500 MHz, methanol-d 4 )δ7.87(d,J=9.7Hz,1H),7.62(s,1H),6.93(d,J=9.7Hz,1H),4.89(dd,J=8.0,6.2Hz,2H),4.69–4.61(m,4H),3.58–3.48(m,1H); 13 C NMR (126 MHz, methanol-d 4 )δ160.6,137.9,131.5,126.9,112.8,100.8,74.1,68.2,34.1.

[0489] N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-5-((6-(oxetan-3-ylmethoxy)imidazo[1,2-b]pyridazin-3-yl)ethynyl)nicotinamide (HSND-27)

[0490] Off-white solid, yield: 61%. 1 H NMR (500 MHz, DMSO-d 6 )δ10.76(s,1H),9.09(d,J=2.1Hz,1H),8.98(d,J=2.0Hz,1H),8.51(t,J=2.1Hz,1H),8.1 8(d,J=2.2Hz,1H),8.13(d,J=9.7Hz,1H),8.07(s,1H),8.02(dd,J=8.5,2.2Hz,1H),7.72( d,J=8.5Hz,1H),7.05(d,J=9.7Hz,1H),4.70(dd,J=8.0,6.1Hz,2H),4.64(d,J=6.5Hz,2H ),4.53(t,J=6.1Hz,2H),3.56(s,2H),3.51–3.42(m,1H),2.37-2.32(m,8H),2.14(s,3H); 13 C NMR (126 MHz, DMSO-d 6 )δ163.8,160.7,153.9,148.8,138.5,138.2,138.0,137.5,133.0,131.8,130.4,128.6,127.8,125.8(q,J=27 5.9Hz),123.9,119.2,117.6,117.6,114.2,111.8,94.9,81.3,73.6,73.6,69.0,57.9,55.2,53.1,46.2,34.1.

[0491] Those skilled in the art will recognize that various modifications may be made to the above specific embodiments. The embodiments should not be limited to the specific limitations described. Other embodiments are also possible.

[0492] While the invention has been shown and described in detail in the drawings and foregoing description, it is to be considered illustrative and not restrictive, it being understood that only certain embodiments have been shown and described and that all changes and modifications that come within the spirit of the invention are desired to be protected.

[0493] The scope of the present method and composition is intended to be limited by the following claims. However, it must be understood that the present disclosure can be implemented in ways other than specific explanations and descriptions without departing from its spirit or scope. It should be understood by those skilled in the art that various alternatives to the embodiments described herein can be adopted when implementing the claims without departing from the spirit and scope defined by the following claims.

Claims

1. A compound having the structure of formula (XX): R4—L—Z—R3(XX) or a pharmaceutically acceptable salt thereof, wherein: R4 is niacinamide or benzamide, each of which is optionally substituted; L is a linker comprising at least one atom; Z is a bicyclic heterocycle substituted with R3; and R3 comprises one or more ring moieties.

2. The compound according to claim 1, which has the structure of formula (I): or a pharmaceutically acceptable salt thereof, wherein: R1 is pyridine, alkyl, isoxazole, pyrazole or phenyl, each optionally substituted with one or more of trifluoromethyl, piperazine (e.g., alkylpiperazine), pyrazine (e.g., alkylpyrazine), imidazole (e.g., alkylimidazole), cyanide, amine, halogen, N-containing heterocycle and / or alkyl; Y1 is N or C; R2 is H, alkyl, heteroalkyl or halogen; Z is imidazo[1,2-b]pyridazine, imidazo[1,2-b]pyrazole or imidazo[2,1-b][1,3,4]thiadiazole; and R3 has a structure of formula (II), formula (III) or formula (IV): in: is the attachment point; Each X is independently alkyl or H, provided that not all X are H; Q is O, S, N or C, and is optionally substituted with one or more of alkyl, halogen, O-alkyl, amine, -OH group, alkoxy, piperazine, morpholine, aziridine, carbocyclic or heterocyclic ring, and / or carbonyl; Y is O or an amine, provided that Y is not NH, and n is 0 or 1.

3. A compound according to claim 1 or claim 2, wherein R3 is a substituted morpholine. The compound of claim 1 , wherein the linker is an alkyne.

5. A compound according to any one of claims 1, 2 or 4, wherein R3 is azetidine, which is optionally substituted by one or more of an alkyl, halogen, amine, O-alkyl and / or -OH group.

6. A compound according to any one of claims 1, 2 or 4, wherein R3 is pyrrolidine, which is optionally substituted with oxetane.

7. The compound according to claim 1, wherein R3 is or includes 8. A compound according to any one of claims 1, 2 or 4, wherein Z has the following structure: in is the attachment point, and W is either C or S.

9. The compound according to claim 1 or 2, which has the structure of formula (V):

10. The compound of claim 2, wherein R3 has the structure of formula (III) and Y is methylamine (-NMe) or ethylamine (-NEt).

11. The compound according to claim 2, wherein Q is O.

12. The compound according to claim 2, wherein R3 has a structure of formula (II) and at least two Xs are linked together to form a bicyclic heterocycle.

13. A compound according to any one of claims 1, 2 or 5-9, wherein R3 comprises morpholine.

14. A compound according to any one of claims 1, 2 or 11, wherein R3 comprises unsubstituted morpholine.

15. The compound of claim 1, wherein R3 comprises morpholine substituted with at least two methyl groups.

16. A compound according to any one of claims 1, 2, 10-12 or 15, wherein R3 comprises a 6-membered heterocyclic ring.

17. A compound according to any one of claims 1, 2, 10-12 or 15, wherein R3 comprises a 4-6 membered heterocyclic ring.

18. A compound according to any one of claims 1, 2, 10-12 or 15, wherein R3 comprises an oxygen-containing heterocycle.

19. A compound according to any one of claims 1, 2 or 9, having the following structure:

20. A compound according to any one of claims 1, 2 or 9, having the following structure:

21. A compound according to any one of claims 1, 2 or 9, having the following structure:

22. A compound according to any one of claims 1, 2 or 9, having the following structure:

23. A compound according to any one of claims 1, 2 or 9, having the following structure:

24. A compound according to any one of claims 1, 2 or 9, having the following structure:

25. A compound according to any one of claims 1, 2 or 9, having the following structure:

26. A compound according to any one of claims 1, 2 or 9, having the following structure:

27. A compound according to any one of claims 1, 2 or 9, having the following structure:

28. A compound according to any one of claims 1, 2 or 9, having the following structure:

29. A compound according to any one of claims 1, 2 or 9, having the following structure:

30. A compound according to any one of claims 1, 2 or 9 having the following structure:

31. A compound according to any one of claims 1, 2 or 9 having the following structure:

32. A compound according to any one of claims 1, 2 or 9 having the following structure:

33. A compound according to any one of claims 1, 2 or 9 having the following structure:

34. A compound according to any one of claims 1, 2 or 9 having the following structure:

35. A compound according to any one of claims 1, 2 or 9 having the following structure:

36. A compound according to any one of claims 1, 2 or 9 having the following structure:

37. A compound according to any one of claims 1, 2, 4, 7, 10-12 or 15, wherein R1 is in is the attachment point and X' is O, C or N.

38. Compounds with the following structure or a pharmaceutically acceptable salt thereof.

39. Compounds with the following structure or a pharmaceutically acceptable salt thereof.

40. Compounds with the following structure or a pharmaceutically acceptable salt thereof.

41. Compounds with the following structure or a pharmaceutically acceptable salt thereof.

42. Compounds with the following structure or a pharmaceutically acceptable salt thereof.

43. Compounds with the following structure or a pharmaceutically acceptable salt thereof.

44. Compounds with the following structure or a pharmaceutically acceptable salt thereof.

45. Compounds with the following structure or a pharmaceutically acceptable salt thereof.

46. ​​Compounds with the following structure or a pharmaceutically acceptable salt thereof.

47. Compounds with the following structure or a pharmaceutically acceptable salt thereof.

48. Compounds with the following structure or a pharmaceutically acceptable salt thereof.

49. A PROTAC conjugate having a chemical structure of formula (X): A—L'—D(X) or a pharmaceutically acceptable salt thereof, wherein: A is a group of a compound according to any one of claims 1 to 37; L' is a linker connecting A and D, or is absent; and D is the ubiquitin pathway protein binding moiety.

50. A pharmaceutical composition comprising: A compound according to any one of claims 1 to 48, a conjugate according to claim 49, or a pharmaceutically acceptable salt, N-oxide, hydrate, solvate, tautomer or optical isomer of the compound or conjugate; and Pharmaceutically acceptable carrier or excipient.

51. A method of treating a disease state or condition in a subject, the method comprising administering to the subject a first therapy comprising an effective amount of: A compound according to any one of claims 1 to 48, a conjugate according to claim 49, or a pharmaceutically acceptable salt, N-oxide, hydrate, solvate, tautomer or optical isomer of said compound or conjugate; or A pharmaceutical composition comprising a compound according to any one of claims 1 to 48, a conjugate according to claim 49, or one or more of a pharmaceutically acceptable salt, N-oxide, hydrate, solvate, tautomer or optical isomer of the compound or conjugate.

52. The method of claim 51 , further comprising administering to the subject a second therapy comprising: an effective amount of a chemotherapeutic, immunotherapeutic, or hormonal therapeutic agent; or radiation therapy.

53. The method of claim 51, wherein the subject's disease state or condition is cancer.

54. The method of claim 53, wherein the cancer is selected from the group consisting of acute myeloid leukemia, chronic myeloid leukemia, ovarian cancer, cervical cancer, pancreatic cancer, breast cancer, brain cancer, skin cancer, lung cancer, prostate cancer, lymphoma, leukemia, colon cancer, head cancer, neck cancer, thyroid cancer, kidney cancer, liver cancer, and stomach cancer.

55. The method of claim 54, further comprising imaging a tumor microenvironment, a cancer cell population, or a solid tumor in the subject.

56. A method of inhibiting T cell responses in a tumor microenvironment of a subject, the method comprising administering to the subject an effective amount of: A compound according to any one of claims 1 to 48, a conjugate according to claim 49, or a pharmaceutically acceptable salt, N-oxide, hydrate, solvate, tautomer or optical isomer of said compound or conjugate; or A pharmaceutical composition comprising a compound according to any one of claims 1 to 48, a conjugate according to claim 49, or one or more of a pharmaceutically acceptable salt, N-oxide, hydrate, solvate, tautomer or optical isomer of the compound or conjugate.

57. The method of claim 46, wherein the subject has cancer.

58. The method of claim 46, wherein an effective amount is administered to the subject to inhibit one or more of MERTK and AXL in the subject.

59. A compound according to any one of claims 1 to 48 or a conjugate according to claim 49 for use in treating a disease state modulated by one or more kinases.

60. The compound or conjugate of claim 59, wherein the disease state is cancer.

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