Nicotinamide and benzamide compounds, conjugates and compositions as inhibitors of translation- and transcription-associated kinases - Patents.com

Abstract

Compounds comprising nicotinamide or benzamide linked to a bicyclic heterocycle, such as an alkynyl imidazo-[1,2-b]-pyridazine substituted with one or more ring moieties, and conjugates and compositions comprising same. Methods for treating kinase-related diseases and disorders are also provided.

Description

[Technical field]

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

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

[0003] This section introduces aspects that may be helpful in facilitating a further understanding of the present disclosure. As such, these statements are to be read in this light, and not understood as admissions of prior art or non-prior art.

[0004] There are more than 500 kinases in human cells that regulate important processes such as cell cycle, cell proliferation, apoptosis and migration. Protein kinase inhibitors have the potential to treat many diseases that may be controlled by dysregulation of protein kinases. To date, more than 20 kinase inhibitors have been approved by the US Food and Drug Administration (FDA) to treat various diseases.

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

[0006] Ponatinib has been shown to potently inhibit a variety of cancers, including chronic myeloid leukemia (CML), acute myeloid leukemia (AML), and various FGFR- and RET-driven cancers (e.g., non-small cell lung cancer and thyroid cancer). Currently, ponatinib is one of only a few drugs approved by the FDA for the treatment of imatinib-resistant CML harboring the T315I mutation, and is also undergoing various clinical trials for the treatment of AML, lung, and several other cancers. However, ponatinib and its nicotinamide analogs with linear substituents have been ineffective in inhibiting the growth of solid tumor cancers and / or their associated kinases, such as ribosomal protein S6 kinase beta-1 (p70S6K), AXL receptor tyrosine kinase (AXL), and MER proto-oncogene tyrosine kinase (MERTK).

[0007] Despite ponatinib's potential efficacy against several cancer types, the drug is relatively toxic and has been associated with cardiovascular adverse events (e.g., induction of cardiac inflammation, reduced cardiac function, etc.), at least in part because it is a potent human delayed rectifier potassium ion channel gene (hERG) inhibitor. Patients taking ponatinib have also shown side effects of hypertension, platelet dysfunction and peripheral arterial occlusive disease, as well as myocardial infarction, stroke, and liver failure. Additionally, approximately 40% of patients taking ponatinib have developed some form of thrombosis, and the drug was temporarily withdrawn from the market in 2014 due to these adverse side effects. Currently, ponatinib is generally only administered as a drug of last resort for CML patients with the ABL(T315I) mutation who have not responded to any other therapies. Gainor et al., Ponatinib: Accelerated Disapproval, Oncologist 20(8): 847-848 (2015);Talbert et al., A Multi-Parameter In Vitro Screen in Human Stem Cell-Derived Cardiomyocytes Identifies Ponatinib-Induced Structural and Functional Cardiac Toxicity, Toxicology Sci 143(1): 147-155 (2015). These unfavorable cardiovascular toxic effects are likely related to the concomitant inhibition of cardiovascular-related kinases such as hERG by ponatinib.

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

[0009] In general, the present disclosure provides that the addition of one or more ring moieties (e.g., morpholine or piperazine-type moieties) to the imidazo[1,2-b]pyridazine moiety of nicotinamide ponatinib analogs can dramatically improve the inhibitory activity of these new 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 not inhibited or at best only weakly inhibited by ponatinib or by HSN748, a nicotinamide analog with linear substituents. The compounds herein, such as HSND80, are orally bioavailable and potently inhibit several solid tumors, including breast, ovarian, lung, and colon.

[0010] In certain embodiments, the compound has the structure of formula (XX): R4-LZ-R3(XX) or a pharma- ceutically acceptable salt thereof, 、 nicotinamide or benzamide, each of which is optionally substituted; L is a linker containing at least one atom; and Z is a bicyclic heterocycle substituted with R3, wherein R3 contains one or more ring moieties.

[0011] The compound has the structure of formula (I):

[0012] [ka] or a pharma- ceutically acceptable salt thereof, wherein R1 is a pyridine, an alkyl, an isoxazole, a pyrazole, or a phenyl group, each of which is optionally substituted with one or more of a trifluoromethyl group, a piperazine (e.g., an alkylpiperazine), a pyrazine (e.g., an alkylpyrazine), an imidazole (e.g., an alkylimidazole), a cyanide, an amine, a halogen, an N-containing heterocycle, and / or an alkyl; Y1 is N or C; R2 is H, an alkyl, a heteroalkyl, or a halogen; Z is an imidazo[1,2-b]pyridazine, an imidazo[1,2-b]pyrazole, or an imidazo[2,1-b][1,3,4]thiadiazole; and R3 is a structure of formula (II), formula (III), or formula (IV):

[0013] [ka] [In the formula,

[0014] [ka] is the point of attachment, each X is independently alkyl or H with the proviso 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, carbocycle or heterocycle, and / or carbonyl, and Y is O or amine with the proviso that Y is not NH and n is 0 or 1. The linker (L) can be an alkyne.

[0015] R3 can be a substituted morpholine. R3 can be an azetidine optionally substituted with one or more of an alkyl, halogen, amine, O-alkyl, and / or -OH group. R3 can be a pyrrolidine optionally substituted with an oxetane. R3 can be

[0016] [ka] It may be or may include.

[0017] Z has the following structure:

[0018] [ka] [In the formula,

[0019] [ka] is the attachment point and W is C or S] may have the following structure:

[0020] In certain embodiments, the compound has the structure of formula (V):

[0021] [ka] or a pharma- ceutically acceptable salt thereof.

[0022] In certain embodiments where R3 has the structure of formula (III), Y is methylamine (-NMe) or ethylamine (-NEt). Q can be O. R3 can have the structure of formula (II) and at least two Xs can be linked to form a bicyclic heterocycle. R3 can include morpholine. R3 can include unsubstituted morpholine. R3 can include morpholine substituted with at least two methyl groups. R3 can include a 6-membered heterocycle. R3 can include a 4- to 6-membered heterocycle. R3 can include an oxygen-containing heterocycle.

[0023] The compound has the following structure:

[0024] [ka] may have the following structure:

[0025] The compound has the following structure:

[0026] [ka] may have the following structure:

[0027] The compound has the following structure:

[0028] [ka]

[0029] [ka]

[0030] [ka]

[0031] [ka]

[0032] [ka]

[0033] [ka] may have the following structure:

[0034] The compound has the following structure:

[0035] [ka]

[0036] [ka] may have the following structure:

[0037] The compound has the following structure:

[0038] [ka]

[0039] [ka] may have the following structure:

[0040] The compound has the following structure:

[0041] [ka]

[0042] [ka] may have the following structure:

[0043] The compound has the following structure:

[0044] [ka]

[0045] [ka] may have the following structure:

[0046] The compound has the following structure:

[0047] [ka]

[0048] [ka] may have the following structure:

[0049] The compound has the following structure:

[0050] [ka]

[0051] [ka] may have the following structure:

[0052] The compound has the following structure:

[0053] [ka]

[0054] [ka] may have the following structure:

[0055] The compound has the following structure:

[0056] [ka]

[0057] [ka]

[0058] [ka] may have the following structure:

[0059] The compound has the following structure:

[0060] [ka]

[0061] [ka]

[0062] [ka] may have the following structure:

[0063] The compound has the following structure:

[0064] [ka]

[0065] [ka] may have the following structure:

[0066] The compound has the following structure:

[0067] [ka]

[0068] [ka]

[0069] [ka] may have the following structure:

[0070] The compound has the following structure:

[0071] [ka]

[0072] [ka] may have the following structure:

[0073] The compound has the following structure:

[0074] [ka]

[0075] [ka]

[0076] [ka] may have the following structure:

[0077] The compound has the following structure:

[0078] [ka]

[0079] [ka]

[0080] [ka] may have the following structure:

[0081] The compound has the following structure:

[0082] [ka]

[0083] [ka] may have the following structure:

[0084] In certain embodiments, R is

[0085] [ka] [Wherein,

[0086] [ka] is the point of attachment and X' is O, C, or N.

[0087] The compound is

[0088] [ka] or a pharma- ceutically acceptable salt thereof.

[0089] The compound is

[0090] [ka] or a pharma- ceutically acceptable salt thereof.

[0091] The compound is

[0092] [ka] or a pharma- ceutically acceptable salt thereof.

[0093] The compound is

[0094] [ka] or a pharma- ceutically acceptable salt thereof.

[0095] The compound is

[0096] [ka] or a pharma- ceutically acceptable salt thereof.

[0097] The compound is

[0098] [ka] or a pharma- ceutically acceptable salt thereof.

[0099] The compound is

[0100] [ka] or a pharma- ceutically acceptable salt thereof.

[0101] The compound is

[0102] [ka] or a pharma- ceutically acceptable salt thereof.

[0103] The compound is

[0104] [ka] or a pharma- ceutically acceptable salt thereof.

[0105] The compound is

[0106] [ka] or a pharma- ceutically acceptable salt thereof.

[0107] The compound is

[0108] [ka] or a pharma- ceutically acceptable salt thereof.

[0109] PROTAC conjugates are also provided. In certain embodiments, the PROTAC conjugate has the chemical structure of formula (X): A-L'-D (X) or a pharma- ceutically acceptable salt thereof, wherein A is a radical of any one of the compounds herein, L' is a linker connecting A and D or is absent, and D is a ubiquitin pathway protein-binding moiety.

[0110] Additionally provided is a pharmaceutical composition comprising a compound herein, a conjugate herein, or a pharma- ceutically acceptable salt, N-oxide, hydrate, solvate, tautomer, or optical isomer of the compound or conjugate; and a pharma- ceutically acceptable carrier or excipient.

[0111] Methods are also provided. In certain embodiments, a method for treating a condition or disorder in a subject is provided, comprising administering to the subject a first therapeutic agent comprising an effective amount of a compound herein, a conjugate herein, or a pharma- ceutically 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 pharma- ceutically acceptable salt, N-oxide, hydrate, solvate, tautomer, or optical isomer of the compound or conjugate.

[0112] In certain embodiments, the method further comprises administering to the subject an effective amount of a second therapeutic agent comprising a chemotherapeutic, immunotherapeutic, or hormonal therapeutic agent; or radiation therapy.

[0113] The subject's disease or disorder can be cancer.The disease or disorder can be 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 gastric cancer.

[0114] The method can further include imaging the tumor microenvironment, the cancer cell population, or the solid tumor in the subject.

[0115] Also provided is a method for suppressing T cell response in tumor microenvironment (TME) of a subject.Such a method can include administering to the subject 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.The subject can have cancer.

[0116] In certain embodiments, administration of an effective amount to a subject inhibits one or more of MERTK and AXL in the subject.

[0117] Also provided is a compound herein or a conjugate herein for use in treating a condition regulated by one or more kinases. For example, the condition can be cancer.

[0118] The disclosed embodiments and other features, advantages, and aspects contained herein, as well as the accomplishments thereof, will become apparent in light of the following detailed description of various exemplary embodiments of the present disclosure, which is better understood when taken in conjunction with the accompanying drawings. [Brief description of the drawings]

[0119] [Figure 1] FIG. 1 shows the expansion of ponatinib into nicotinamide analogs. [Diagram 2] FIG. 1 shows various 6-position substitutions of compound HSN748 having a ring moiety according to the present disclosure, each of which is a potent MAP kinase interacting serine / threonine protein kinase 2 (MNK2) and ribosomal protein S6 kinase beta-1 (p70S6K) inhibitor. [Figure 3-1] FIG. 3A shows graphical data depicting the anticancer activity of compound HSND41 against NCI-60 (value at 0 represents a GI50 of 1 μM). [Figure 3-2] FIG. 3B shows graphical data depicting the anticancer activity of compound HSND37 against NCI-60 (value at 0 represents a GI50 of 1 μM). [Figure 3-3] FIG. 3C shows graphical data depicting the anticancer activity of compound HSN748 against NCI-60 (value at 0 represents a GI50 of 1 μM). [Figure 4] FIG. 1 shows graphical data depicting the anticancer activity of compound HSND80 against NCI-60 (value at 0 represents a GI50 of 1 μM). [Diagram 5] FIG. 1 shows graphical data relating to the PK profiles of various compounds herein in rats following oral gavage. [Figure 6] FIG. 6 shows graphical data relating to HSND80 binding affinity to AXL receptor tyrosine kinase (AXL), where data for replicate 1 is shown in FIG. 6A (1Kd=0.77 nM) and data for replicate 2 is shown in FIG. 6B (2Kd=1.3 nM). [Figure 7] FIG. 7 shows graphical data relating to HSND80 binding affinity to MER proto-oncogene tyrosine kinase (MERTK), with data for replicate 1 shown in FIG. 7A (1Kd=1.6 nM) and data for replicate 2 shown in FIG. 7B (2Kd=2.1 nM). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0120] While the present disclosure is susceptible to various modifications and alternative forms, exemplary embodiments thereof have been shown by way of example in the drawings and will herein be described in detail.

[0121] Although the concepts of the present disclosure have been illustrated and described in detail in the description herein, the results in the description are to be considered as exemplary in character and not restrictive, it being understood that only exemplary embodiments have been shown and described, and that all changes and modifications that come within the spirit of the disclosure are to be protected.

[0122] The present disclosure generally relates to nicotinamide or benzamide compounds linked to (or substituted with) a bicyclic heterocycle 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.

[0123] In certain embodiments, the compound includes modification of the benzamide portion of ponatinib to nicotinamide and substitution of the 6-position of the nicotinamide alkynylimidazo[1,2-b]pyridazine with a substituent containing one or more ring moieties, such as morpholine or piperazine.

[0124] The nicotinamide or benzamide compounds herein are compounds with potent activity against MAP kinase interacting serine / threonine-protein kinase 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 without substitution at the 6-position or substituted with a linear heteroalkyl group at the 6-position. Indeed, p70S6K kinase is only weakly inhibited by ponatinib and by the compound HSN748 (a nicotinamide analog with a linear heteroalkyl group instead of one or more ring moieties of the compound), whereas the compounds herein dramatically inhibit the activity of p70S6k kinase. Additionally, at least the nicotinamide compounds herein also inhibit TAM kinases that are not targets of the parent ponatinib or HSN748 compounds, AXL receptor tyrosine kinase (AXL) and MER proto-oncogene tyrosine kinase (MERTK). Furthermore, the compounds herein are orally bioavailable and potentially inhibit several solid tumor cancers (e.g., breast, ovarian, lung, colon, etc.), but do not inhibit or only weakly inhibit human delayed rectifier potassium ion channel gene (hERG).

[0125] Also provided are PROTAC conjugates, pharmaceutical compositions, and methods of use thereof (e.g., in treating certain kinase-mediated diseases, such as cancer). The compounds, compositions, conjugates, and methods are useful for modulating protein activity and treating diseases and conditions associated with protein activity.

[0126] Nicotinamide alkynylimidazo[1,2-b]pyridazine compounds have been described as kinase inhibitors with anticancer activity (International Application No. PCT / IB2019 / 057711, International Publication No. WO2020 / 053812 and International Publication No. WO2013170770(A1)). However, the rules governing how various substitutions on the nicotinamide alkynylimidazo[1,2-b]pyridazine moiety affect both kinase selectivity and anticancer properties have not been well described, making it difficult to pre-optimize the biological properties of said compounds.

[0127] 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 described as a non-receptor tyrosine-protein kinase ABL1 (ABL1) inhibitor. However, ponatinib administration is associated with many adverse toxicities, at least in part due to the simultaneous inhibition of many essential kinases (e.g., hERG). Ponatinib analogs with reduced inhibition of cardiovascular-related kinases, such as VEGFR1-3, c-Src, and c-KIT, are expected to show reduced adverse toxicities. Additionally, ponatinib does not inhibit (or at best only weakly inhibits) MNK1 / 2 and p70S6K kinases.

[0128] 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). MNKs are also involved in the transcriptional regulation of important 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 tumor development, several inhibitors of these key kinases (MNK and p70S6K) have been developed and / or evaluated as potential anticancer drugs.Jin et al., Progress in Developing MNK Inhibitors, European J Med Chemistry 219: 113420 (2021);Spaan et al., Direct P70S6K1 Inhibition to Replace Dexamethasone in Synergistic Combination with MCL-1 Inhibition in Multiple Myeloma, Blood Advances 5: 2593-2607 (2021);El-Khoueiry et al., A Phase II, Open-Label Study of Tomivosertib (eFT508) Added on to Continued Checkpoint Inhibitor Therapy in Patients (pts) with Insufficient Response to Single-Agent Treatment, J Clinical Oncology 38(15): suppl DOI: 10.1200 / JCO.2020.38.15_suppl.3112 (2020);Tolcher et al., A Phase I Trial of LY2584702 Tosylate, a p70 S6 Kinase Inhibitor, in Patients with Advanced Solid Tumours, European J Cancer 50(5): 867-75, doi: 10.1016 / j.ejca.2013.11.039 (2014);Tsimberidou et al., Phase 1 Study of M2698, a p70S6K / AKT Dual Inhibitor, in Patients with Advanced Cancer, J Hematology & Oncology 14(1): 127. doi: 10.1186 / s13045-021-01132-z (2021)。

[0129] MNK1 and 2 are immunosuppressive kinases, and it has been shown that inhibition of MNK1 and 2 with the potent and selective MNK1 / 2 tomivosertib (eFT-508) resulted in blockade of expression of the checkpoint proteins programmed cell death protein 1 (PD-1), programmed cell death ligand 1 (PD-L1), and lymphocyte activation gene 3 (LAG-3). See El-Khoueiry et al. (2020), supra. When added to checkpoint therapy, tomivosertib resulted in objective clinical responses in patients who had an inadequate response to checkpoint inhibitors alone. Ibid.

[0130] Several p70S6K inhibitors have been developed and clinically tested, including LY2584702 and M2698. Tolcher et al. (2014), see above; Tsimberidou et al. (2021), see above. LY2584702 has not shown promising clinical activity in patients with advanced breast cancer, whereas M2698 demonstrates antitumor activity when combined with various treatment regimens (e.g., trastuzumab or tamoxifen). Tsimberidou et al. (2021), see above.

[0131] Single inhibition of MNK can result in inhibition of tumor growth but not tumor elimination, and simultaneous inhibition of MNK and other important cancer targets using drug combinations or single drugs and polypharmacology has been shown to be a logical approach to anticancer therapy via MNK inhibition (Xie et al. (2019), see above). Given that MNK and p70S6K together regulate translation, the data herein support that dual inhibition of these kinases translates into greater inhibition of cancer cell growth than inhibition of individual kinases.

[0132] In early studies, the inventors herein observed that a nicotinamide analog of ponatinib containing a linear heteroalkyl group (i.e., compound HSN748) was a potent inhibitor of MNK2 (IC50=9nM; [ATP]=100μM) but only moderately inhibited p70S6K (IC50=273nM). Larocque et al., Nicotinamide-Ponatinib Analogues as Potent Anti-CML and Anti-AML Compounds, ACS Omega 5(6), 2690-2698 (2020). Figure 1 shows the expansion of ponatinib to compound HSN748 and other analogs HSND748 that contain substitutions at the 6-position of the nicotinamide alkynylimidazo[1,2-b]pyridazine with linear heteroalkyl groups. Ponatinib also moderately inhibited p70S6K (IC50=273 nM; [ATP]=100 μM) but did not inhibit MNK2. Ibid. Given that ponatinib, compound HSN748, and analogs of HSN748 are greater than 90% protein bound, it is unlikely that a therapeutic dose covering the IC90 for inhibition of both MNK and p70S6K will be found.

[0133] However, compounds herein (including substitution at the 6-position of benzamide or nicotinamide, e.g., with an alkynyl imidazo[1,2-b]pyridazine, with one or more ring moieties, such as morpholine or piperazine) have potent activity against MNK1 / 2 and p70S6K. These compounds exhibit significant anticancer activity compared to analogs without substitution at the 6-position or substituted with a linear heteroalkyl group at the 6-position. Figure 2 shows various compounds herein that include substitution at the 6-position of a nicotinamide alkynyl imidazo[1,2-b]pyridazine with one or more ring moieties.

[0134] compound The compound can inhibit kinases. The compound can selectively and potently inhibit cancer-mediated kinases (e.g., MNK and p70S6K) to kill and / or improve cancer cells, but is also a low hERG inhibitor, and off-target toxicity (e.g., cardiovascular toxicity) is significantly reduced.

[0135] Based on the discovery that benzamide or nicotinamide versions of ponatinib that further comprise one or more ring moieties impart different desirable properties compared to conventional compounds, the compounds herein have the general structure of formula (XX): R4-LZ-R3(XX) or a pharma- ceutically acceptable salt thereof, R4 is nicotinamide or benzamide, each of which is optionally substituted; L is a linker containing at least one atom (e.g., linked to the 6-position of a nicotinamide or benzamide); Z is a bicyclic heterocycle substituted with R3; R3 includes one or more ring moieties.

[0136] The linker (L) can be any suitable linker. The linker can have a backbone ranging in length from as little as one atom in the backbone of the linker to as many as 100 or more adjacent atoms in the backbone of the linker. The "backbone" of the linker is the shortest chain of adjacent atoms that form a covalent bond linkage between R4 and Z. In some embodiments, the linker is a multivalent linker with a branched backbone, with each branch serving as a section of the backbone linker until a terminus is reached. The linker (L) can be an alkyne, for example, or any other linker containing one or more atoms.

[0137] For example, the linker can have a chain length of at least about 7 atoms. In some embodiments, the linker is at least about 3 atoms long. In some embodiments, the linker is at least about 10 atoms long. In some embodiments, 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), about 14 to about 24 atoms (e.g., about 14 to 24, 14 to about 24, or 14 to 24), or about 14 to about 20 atoms (e.g., about 14 to 20, 14 to about 20, or 14 to 20). In some embodiments, the linker has a chain length of 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.

[0138] 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-configuration, natural or unnatural amino acids, PEG monomers, PEG oligomers, PEG polymers, or any combination of the above. In linkers that comprise one or more PEG units, all carbon and oxygen atoms of the PEG units are part of the backbone unless otherwise specified.

[0139] In certain embodiments, the linker is a group that includes one or more covalently bonded structural units.

[0140] In certain embodiments, the linker group is an optionally substituted (poly)ethylene glycol having 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, 1 to 6 ethylene glycol units, 2 to 4 ethylene glycol units, and / or an optionally substituted alkyl group having an optionally substituted O, N, S, P, or Si atom dispersed therein. In certain embodiments, the linker is substituted with an aryl, phenyl, benzyl, alkyl, alkylene, or heterocyclic group. In certain embodiments, the linker is asymmetric. In certain embodiments, the linker is symmetric.

[0141] Alternatively, or in addition to chain length, in some embodiments, the linker can have suitable substituents that affect hydrophobicity or hydrophilicity.Thus, for example, the linker can have hydrophobic side groups, such as alkyl, cycloalkyl, aryl, arylalkyl, or similar groups, each of which is optionally substituted.When the linker comprises one or more amino acids, the linker can include hydrophobic amino acid side chains, such as one or more amino acid side chains derived from Phe and Tyr (including substitution variants thereof), as well as analogs and derivatives of such side chains.

[0142] The linker can include a spacer (e.g., conjugated to and / or including a spacer). The spacer can be any suitable spacer. The linker's spacer can include hydrophilic, hydrophobic, amphiphilic, non-peptidic, peptidic, and / or aromatic monomers. The length of the spacer can range from 1 to 30 (e.g., 1 to 30 carbon atoms, 1 to 30 units of PEG, etc.).

[0143] In certain embodiments, the compound has the structure of Formula (I):

[0144] [ka] or a pharma- ceutically acceptable salt thereof, R1 is an alkyl, pyridine, isoxazole, pyrazole, or aryl (e.g., a phenyl group), each of which is optionally substituted with one or more of piperazine (e.g., an alkylpiperazine), pyrazine (e.g., an alkylpyrazine), imidazole (e.g., an alkylimidazole), cyanide, amine, halogen, trifluoromethyl group, N-containing heterocycle, and / or alkyl; Y1 is nitrogen (N) or carbon (C); R2 is hydrogen (H), alkyl, heteroalkyl, or halogen; Z is a bicyclic heterocycle substituted with R3, the bicyclic heterocycle being an imidazo[1,2-b]pyridazine, an imidazo[1,2-b]pyrazole, or an imidazo[2,1-b][1,3,4]thiadiazole; R3 is a substituent containing one or more ring moieties.

[0145] R3 has the structure of formula (II), formula (III), or formula (IV):

[0146] [ka]

[0023]

[0147] [ka] 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, optionally substituted with 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 with the proviso that Y is not NH; [n is 0 or 1].

[0148] In certain embodiments, R of the compound 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.

[0149] In some exemplary embodiments, R3 is a substituted morpholine. In certain embodiments, the linker is an alkyne.

[0150] In certain embodiments, Y1 is C such that the compound is a benzamide. In certain embodiments, Y1 is N such that the compound is a nicotinamide. In certain embodiments, Y1 is N, and instead of being positioned as shown in formula (I), N is present at any position on the nicotinamide ring.

[0151] Compounds can result from replacement of the methylbenzamide in ponatinib with a nicotinamide moiety and further incorporation of one or more heterocyclic groups into R3.

[0152] In certain embodiments, R is

[0153] [ka] In certain embodiments, R is

[0154] [ka] [Wherein,

[0155] [ka] is the point of attachment and X' is O, C, or N. In certain embodiments, R1 is

[0156] [ka] [Wherein,

[0157] [ka] is the point of attachment and X' is O, C, or N.

[0158] Z has the following structure:

[0159] [ka]

[0023]

[0160] [ka] is the attachment point and W is C or S].

[0161] R3 can be a heterocycle. R3 can be a 4-6 membered heterocycle (e.g., a 4-membered heterocycle, a 5-membered heterocycle, or a 6-membered heterocycle). R3 can be an oxygen (O)-containing heterocycle and / or R3 can be a nitrogen (N)-containing heterocycle. R3 can be a sulfur (S)-containing heterocycle.

[0162] R3 can include a bicyclic ring moiety. R3 can include a bicyclic ring moiety containing two 6-membered heterocycles. R3 can include a bicyclic ring moiety containing a 6-membered heterocycle and a 5-membered heterocycle. R3 can include a bicyclic ring moiety containing two 5-membered heterocycles. R3 can include a bicyclic ring moiety containing a 6-membered heterocycle and a 4-membered heterocycle. R3 can include a bicyclic ring moiety containing a 6-membered heterocycle and a 3-membered carbocycle or heterocycle. R3 can include a bicyclic ring moiety containing a 5-membered heterocycle and a 4-membered heterocycle or carbocycle.

[0163] R3 has the following structure:

[0164] [ka] may have the following structure:

[0165] In certain embodiments, R3 has a linear alkyl group and a bicyclic ring moiety. For example, R3 can have a linear heteroalkyl group (e.g., an O-containing and / or N-containing linear heteroalkyl group) and a bicyclic ring moiety. In certain embodiments, R3 has the following structure:

[0166] [ka] has.

[0167] In certain embodiments, R3 has the structure of formula (II):

[0168] [ka] and Q is O. In certain embodiments, R3 has the structure of formula (II) and is morpholine (e.g., Q is O). R3 can be or include unsubstituted morpholine. R3 can be or include substituted morpholine. For example, but not limited to, R3 can be or include morpholine substituted with at least two methyl groups.

[0169] In certain embodiments, R3 has the structure of formula (II) and is piperidine (e.g., Q is C). In certain embodiments, R3 has the structure of formula (III) and Q is N (e.g., R3 includes piperidine).

[0170] R3 can have the structure of formula (II) where at least two Xs are H. R3 can have the structure of formula (II) where at least three Xs are H. R3 can have the structure of formula (II) where at least four Xs are H. R3 can have the structure of formula (II) where at least five Xs are H. R3 can have the structure of formula (II) where at least six Xs are H. R3 can have the structure of formula (II) where at least seven Xs are H.

[0171] R3 can have the structure of formula (II), and at least two X can be linked to form a bicyclic heterocycle. In certain embodiments, R3 is

[0172] [ka] It is.

[0173] In certain embodiments, R3 is azetidine optionally substituted with one or more of alkyl, halogen, amine, O-alkyl, and / or -OH groups. In certain embodiments, R3 is pyrrolidine optionally substituted with oxetane.

[0174] R3 has the structure of formula (III):

[0175] [ka] wherein Y is methylamine (-NMe) or ethylamine (-NEt). Y in formula (III) can be a linear alkyl group. Y in formula (III) can be a linear heteroalkyl group. In certain embodiments, R3 is

[0176] [ka] or comprises (eg, Y in formula (III) is an O-containing linear alkyl group).

[0177] In certain embodiments, R3 is or includes tetrahydro-2H-pyran.

[0178] In certain embodiments, the compound has the structure of formula (V):

[0179] [ka] [In the formula, R1 is an alkyl, pyridine, isoxazole, pyrazole, or aryl (e.g., a phenyl group), each of which is optionally substituted with one or more of piperazine (e.g., an alkylpiperazine), pyrazine (e.g., an alkylpyrazine), imidazole (e.g., an alkylimidazole), cyanide, amine, halogen, trifluoromethyl group, N-containing heterocycle, and / or alkyl; R2 is H, alkyl, heteroalkyl, or halogen; R3 is a substituent that contains one or more ring moieties.

[0180] The compound has the following structure:

[0181] [ka] may have the following structure:

[0182] The compound has the following structure:

[0183] [ka]

[0184] [ka] may have the following structure:

[0185] The compound has the following structure:

[0186] [ka]

[0187] [ka]

[0188] [ka]

[0189] [ka]

[0190] [ka]

[0191] [ka] may have the following structure:

[0192] The compound has the following structure:

[0193] [ka]

[0194] [ka] may have the following structure:

[0195] The compound has the following structure:

[0196] [ka]

[0197] [ka] may have the following structure:

[0198] The compound has the following structure:

[0199] [ka]

[0200] [ka] may have the following structure:

[0201] The compound has the following structure:

[0202] [ka]

[0203] [ka] may have the following structure:

[0204] The compound has the following structure:

[0205] [ka]

[0206] [ka] may have the following structure:

[0207] The compound has the following structure:

[0208] [ka]

[0209] [ka] may have the following structure:

[0210] The compound has the following structure:

[0211] [ka]

[0212] [ka] may have the following structure:

[0213] The compound has the following structure:

[0214] [ka]

[0215] [ka] may have the following structure:

[0216] The compound has the following structure:

[0217] [ka]

[0218] [ka] may have the following structure:

[0219] The compound has the following structure:

[0220] [ka]

[0221] [ka] may have the following structure:

[0222] The compound has the following structure:

[0223] [ka]

[0224] [ka] may have the following structure:

[0225] The compound has the following structure:

[0226] [ka]

[0227] [ka] may have the following structure:

[0228] The compound has the following structure:

[0229] [ka]

[0230] [ka]

[0231] [ka] may have the following structure:

[0232] The compound has the following structure:

[0233] [ka]

[0234] [ka]

[0235] [ka]

[0236] [ka] may have the following structure:

[0237] The compound has the following structure:

[0238] [ka]

[0239] [ka] may have the following structure:

[0240] The compound is

[0241] [ka] or a pharma- ceutically acceptable salt thereof.

[0242] The compound is

[0243] [ka] or a pharma- ceutically acceptable salt thereof.

[0244] The compound is

[0245] [ka] or a pharma- ceutically acceptable salt thereof.

[0246] The compound is

[0247] [ka] or a pharma- ceutically acceptable salt thereof.

[0248] The compound is

[0249] [ka] or a pharma- ceutically acceptable salt thereof.

[0250] The compound is

[0251] [ka] or a pharma- ceutically acceptable salt thereof.

[0252] The compound is

[0253] [ka] or a pharma- ceutically acceptable salt thereof.

[0254] The compound is

[0255] [ka] or a pharma- ceutically acceptable salt thereof.

[0256] The compound is

[0257] [ka] or a pharma- ceutically acceptable salt thereof.

[0258] The compound is

[0259] [ka] or a pharma- ceutically acceptable salt thereof.

[0260] The compound is

[0261] [ka] or a pharma- ceutically acceptable salt thereof.

[0262] It is contemplated that the compounds herein may 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 yield an active compound, particularly the compounds herein. Prodrugs may be created to overcome one or more barriers to effective use of the underlying active compound, such as instability and / or possible toxicity barriers present with the active compound. Examples of prodrugs include, but are not limited to, derivatives and metabolites of compounds that contain a biohydrolyzable moiety, such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogs. Certain prodrugs of compounds with carboxyl functionality are lower alkyl esters of carboxylic acids. Carboxylic acid esters are conveniently formed by esterifying any of the carboxylic acid moieties present in the molecule. In certain embodiments, the prodrug forms of the compounds herein may include protecting groups that, in addition to protecting the compound from oxidation, etc., allow for targeting to specific sites within the subject's body (e.g., tumor microenvironment). Prodrugs can typically be prepared using well-known methods, such as those described by Burger's Medicinal Chemistry and Drug Discovery 6th ed. (Donald J. Abraham ed., 2001, Wiley) and Design and Application of Prodrugs (H. Bundgaard ed., 1985, Harwood Academic Publishers GmbH).

[0263] PROTAC Conjugates Also provided is a PROTAC conjugate comprising the compound of the present invention. The PROTAC conjugate has the chemical structure of formula (X): A-L'-D (X) where A is a compound described herein (e.g., a kinase inhibitor described herein), L' is a linker or absent, and D is a ubiquitin pathway protein binding moiety.

[0264] Protein inhibitors can block or reduce protein activity in cells, but protein degradation in cells can also reduce activity or completely remove target proteins. Thus, utilizing the cell's protein degradation pathways provides an additional means of reducing or removing protein activity. One of the major degradation pathways in cells is known as the ubiquitin-proteasome system. In this system, proteins are tagged for degradation by the proteasome by ubiquitinating the protein. Protein ubiquitination can be achieved by ubiquitin pathway protein binding moieties that bind to proteins and add ubiquitin molecules to the proteins.

[0265] To take advantage of this degradation pathway, PROTAC has been developed. The term "PROTAC" refers to a proteolytic chimeric molecule that includes a ubiquitin pathway protein binding moiety, optionally a linker, and a targeting moiety. PROTAC combines a ubiquitin pathway protein binding moiety (e.g., E3 ubiquitin ligase) with a protein targeted for degradation. To promote a protein for degradation by the proteasome, PROTAC consists of a group that binds to ubiquitin ligase and a group that binds to a protein targeted for degradation (optionally linked with a linker). This molecular construct can bring the ubiquitin pathway protein binding moiety into close proximity with the protein, so that it is ubiquitinated and marked for degradation.

[0266] The ubiquitin pathway protein binding moiety is any suitable structure that recognizes and binds to a ubiquitin pathway protein. In general, a ubiquitin pathway protein is any entity or complex that can catalyze or cause to catalyze the transfer of ubiquitin or a ubiquitin-like modified polypeptide (e.g., Nedd8, APG12, or ISG15 / UCRP) to another protein. In certain embodiments, the ubiquitin pathway protein is a ubiquitin protein ligase or an E3 protein. There are at least 100 different E3 proteins encoded by the human genome. Winston et al., A Family of Mammalian F-Box Proteins, Current Biology 9(20): 1180-1182 (1999).

[0267] In certain embodiments, the ubiquitin pathway protein is a protein that is involved in or is a component of the ubiquitin-like pathway, and transfers ubiquitin-like modified polypeptides (e.g., SUMO, Nedd8, APG12, or ISG15 / UCRP).Components of the ubiquitin-like modification pathway are usually homologs of the ubiquitin pathway.For example, the SUMO ubiquitin-like pathway includes ubiquitin protein activating enzyme or E1 protein, ubiquitin protein conjugating enzyme or E2 protein, and ubiquitin ligase or E3 protein homologs.

[0268] In certain embodiments, the ubiquitin pathway protein binding moiety is any suitable ligand to a ubiquitin pathway protein, such as a ubiquitin protein ligase or E3 protein or its homologue. In certain embodiments, the ligand to a ubiquitin pathway protein is a ubiquitin pathway protein binding peptide, domain or region. In certain embodiments, the ubiquitin pathway protein binding moiety recognizes and binds to a ubiquitin pathway protein in a regulated manner.

[0269] A component is a compound herein (e.g., a targeted kinase inhibitor) that binds to a target protein intended to be degraded. The term "protein" includes oligopeptide and polypeptide sequences of sufficient length to be capable of binding to the A component.

[0270] Particular A groups are any of the compounds described herein.

[0271] The compound and the ubiquitin pathway protein binding moiety can be optionally linked by a linker. The linker can be any suitable linker. The linker can include atoms selected from C, N, O, S, Si, and P; C, N, O, S, and P; or C, N, O, and S. The linker can have a backbone that ranges in length from as few as two atoms in the backbone of the linker to as many as 100 or more adjacent atoms in the backbone of the linker. The "backbone" of the linker is the shortest chain of adjacent atoms that forms a covalent bond between A and D. In some embodiments, the multivalent linker has a branched backbone, with each branch serving as a section of the backbone linker until a terminus is reached.

[0272] For example, the linker can have a chain length of at least about 7 atoms. In some embodiments, the linker is at least about 10 atoms long. In some embodiments, the linker is at least about 14 atoms long. In some embodiments, 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), about 14 to about 24 atoms (e.g., about 14 to 24, 14 to about 24, or 14 to 24), or about 14 to about 20 atoms (e.g., about 14 to 20, 14 to about 20, or 14 to 20). In some embodiments, the linker has a chain length of 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.

[0273] 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-configuration, natural or unnatural amino acids, PEG monomers, PEG oligomers, PEG polymers, or any combination of the above. In linkers that comprise one or more PEG units, all carbon and oxygen atoms of the PEG units are part of the backbone unless otherwise specified.

[0274] In certain embodiments, the linker is a group that includes one or more covalently bonded structural units.

[0275] In certain embodiments, the linker group is an optionally substituted (poly)ethylene glycol having 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, 1 to 6 ethylene glycol units, 2 to 4 ethylene glycol units, and / or an optionally substituted alkyl group having an optionally substituted O, N, S, P, or Si atom dispersed therein. In certain embodiments, the linker is substituted with an aryl, phenyl, benzyl, alkyl, alkylene, or heterocyclic group. In certain embodiments, the linker is asymmetric. In certain embodiments, the linker is symmetric.

[0276] Alternatively, or in addition to chain length, in some embodiments, the linker can have suitable substituents that affect hydrophobicity or hydrophilicity.Thus, for example, the linker can have hydrophobic side groups, such as alkyl, cycloalkyl, aryl, arylalkyl, or similar groups, each of which is optionally substituted.When the linker comprises one or more amino acids, the linker can include hydrophobic amino acid side chains, such as one or more amino acid side chains derived from Phe and Tyr (including substitution variants thereof), as well as analogs and derivatives of such side chains.

[0277] The linker can include a spacer (e.g., conjugated to and / or including a spacer). The spacer can be any suitable spacer. The spacer of the linker can include hydrophilic, hydrophobic, amphiphilic, non-peptidic, peptidic, and / or aromatic monomers. The length of the spacer can range from 1 to 30 (e.g., 1 to 30 carbon atoms, 1 to 30 units of PEG, etc.). Examples of hydrophilic spacers include, but are not limited to, polyethylene glycol polymers and their derivatives. Examples of hydrophobic spacers include, but are not limited to, pure or mixed branched hydrocarbon, fluorocarbon, alkane, alkene, and / or alkyne polymers. Examples of amphiphilic spacers include, but are not limited to, pure or mixed phospholipids and / or their derivatives. Examples of peptidic spacers include, but are not limited to, pure and mixed single, branched L- or D-configuration, essential, non-essential, natural, and non-natural amino acids and their derivatives. Examples of aromatic spacers include, but are not limited to, pure and mixed repeating quinoids.

[0278] In some embodiments, the linker is formed via click chemistry / click chemistry derived synthesis. Those skilled in the art will understand that the terms "click chemistry" and "click chemistry derived" refer broadly to a class of small molecule reactions commonly used in conjugation that allow the linking of a substrate of choice with a specific molecule. Click chemistry describes a method to generate products that mimic examples in nature, rather than a single specific reaction, and also generate substances by linking small modular units. In many applications, click reactions link biomolecules and reporter molecules. Click chemistry is not limited to biological conditions. The concept of "click" reactions has been used in pharmacological applications and various biomimetic applications. However, they have become significantly useful in the detection, localization and quality control of biomolecules.

[0279] Click reactions can be carried out in one pot, are typically not hindered by water, produce minimal by-products, are "spring-loaded", and are characterized by a high thermodynamic driving force. The high thermodynamic driving force drives the click reaction rapidly and irreversibly, giving a single reaction product in high yield and with high reaction specificity (sometimes both regiospecificity and stereospecificity). These qualities make the click reaction suitable for the problem of isolating and targeting molecules in complex biological environments. In such environments, the products must therefore be physiologically stable and any by-products must be non-toxic (e.g., to in vivo systems).

[0280] salt Compounds and conjugates may be presented as pharmaceutically acceptable salts. Examples of acceptable salts include, but are not limited to, alkali metal (e.g., sodium, potassium, or lithium) salts or alkaline earth metal (e.g., calcium) salts. However, any salt that is generally non-toxic and effective when administered to the subject being treated is acceptable. Similarly, "pharmaceutically acceptable salts" refers to salts with counterions that can be used in pharmaceutical preparations. More specifically with respect to the present disclosure, as used herein, the terms "salt" and "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds, where the parent compound is modified by making acid or base salts thereof.

[0281] Such salts include, but are not limited to, (1) acid addition salts, which may be obtained by reaction of the free base of the parent compound with an inorganic acid, such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, perchloric acid, and the like, or an organic acid, such as 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, and the like; or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth ion, or an aluminum ion, or is coordinated with an organic base, such as ethanolamine, diethanolamine, triethanolamine, trimethamine, N-methylglucamine, and the like. Pharmaceutically acceptable salts are well known to those of skill in the art, and all such pharma-ceutically acceptable salts are contemplated.

[0282] Examples of pharmaceutically acceptable salts include, but are not limited to, mineral salts 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, for example, the conventional non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids.For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid; and those 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, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, and isethionic acid.

[0283] Pharmaceutically acceptable salts can be synthesized by conventional chemical methods from parent compounds that contain a basic or acidic moiety. In some cases, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent, or 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 ed., Mack Publishing Company, Easton, Pa., 1985, the disclosure of which is hereby incorporated by reference.

[0284] Acceptable salts can be obtained using standard procedures known in the art, including, but not limited to, reacting sufficiently acidic compounds with a suitable base to provide a physiologically acceptable anion. Suitable acid addition salts are formed from acids which form non-toxic salts. Illustrative, but non-limiting examples include acetate, aspartate, benzoate, besylate, bicarbonate / carbonate, hydrogensulfate / sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate. Suitable base salts of compounds may be formed from bases which form non-toxic salts. Illustrative, but non-limiting, examples include arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Acid and base hemisalts can also be formed, such as hemisulfate and hemicalcium salts.

[0285] The compounds and conjugates herein can be "deuterated", meaning that one or more hydrogen atoms can be replaced with deuterium.Since deuterium and hydrogen have almost the same physical properties, deuterium replacement can cause minimal structural changes.Deuteration is well known to those skilled in the art.

[0286] The compounds and conjugates may, in some embodiments, contain one or more asymmetric centers, thus resulting in enantiomers, diastereomers, and other stereoisomers defined in terms of absolute stereochemistry as (R)- or (S)-. In certain embodiments, the compounds or conjugates are in the R-configuration. In certain embodiments, the compounds or conjugates are in the S-configuration. Unless otherwise stated, all stereoisomers of the compounds and / or conjugates are intended to be contemplated. When the compounds and / or conjugates contain an alkene double bond, both E and Z geometric isomers (e.g., cis or trans) and / or optical isomers are intended to be included unless otherwise specified. In certain embodiments, for example, D and A of the conjugate are arranged in a relative cis orientation. In certain embodiments, D and A of the conjugate are arranged in a relative trans orientation. Similarly, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are intended to be included. The term "geometric isomer" refers to the E or Z geometric isomers (e.g., cis or trans) of an alkene double bond. The term "positional isomer" refers to structural isomers about a central ring, e.g., ortho-, meta-, and para-isomers about a benzene ring.

[0287] Furthermore, in each of the above and below embodiments, the formula should be understood to include and represent all pharma- ceutically acceptable salts of the compound, as well as any and all hydrates and / or solvates of the compound / conjugate formula or its salt.Indeed, hydrates, solvates, and N-oxides of the compound and conjugate are also contemplated.The term "solvate" refers to a compound or its salt that further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces.When the solvent is water, the solvate is a hydrate.

[0288] It should be recognized that certain functional groups, such as hydroxy, amino, and similar groups, form complexes and / or coordination compounds with water and / or various solvents in various physical forms of the compounds and conjugates. Thus, the above formulas should be understood to include and represent various hydrates and / or solvates.

[0289] In each of the above and below embodiments, the formulas are also to be understood to include and represent any and all crystalline, partially crystalline, and non-crystalline and / or amorphous forms of the compounds.

[0290] Pharmaceutical Compositions In view of the above, pharmaceutical compositions comprising either the compound or the conjugate are further provided. In certain embodiments, pharmaceutical compositions comprising the compound (e.g., the compound of formula (I)) or the conjugate (e.g., the conjugate of formula (X)) and one or more pharma- ceutically acceptable carriers or excipients are provided herein. The term "composition" generally refers to any product that comprises more than one material, including the compound or the 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.

[0291] In certain embodiments, the compound of the composition is a compound of formula (XX) (or a pharma- ceutically acceptable salt thereof): R4-LZ-R3(XX) [Wherein, R4 is nicotinamide or benzamide, each of which is optionally substituted; L is a linker containing at least one atom, Z is a bicyclic heterocycle substituted with R3; R3 includes one or more ring moieties.

[0292] In certain embodiments, the compound of the composition is a compound of formula (I) (or a pharma- ceutically acceptable salt thereof):

[0293] [ka] wherein R1 is alkyl, pyridine, isoxazole, pyrazole, or aryl (e.g., a phenyl group), each of which is optionally substituted with one or more of piperazine (e.g., an alkylpiperazine), pyrazine (e.g., an alkylpyrazine), imidazole (e.g., an alkylimidazole), cyanide, amine, halogen, trifluoromethyl group, N-containing heterocycle, and / or alkyl; Y1 is N or C; R2 is H, alkyl, heteroalkyl, or halogen; and Z is a bicyclic heterocycle substituted with R3, where the bicyclic heterocycle is imidazo[1,2-b]pyridazine or imidazo[1,2-b]pyrazole, and R3 is a substituent comprising one or more ring moieties.

[0294] R3 of the compound has the structure of formula (II) or formula (III) or formula (IV):

[0295] [ka]

[0023]

[0296] [ka] is the point of attachment; each X is independently alkyl or H with the proviso 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, carbocycle or heterocycle, and / or carbonyl; and Y is O or amine with the proviso that Y is not NH; and n is 0 or 1.

[0297] In certain embodiments, the conjugate of the composition is a PROTAC conjugate having a chemical structure of formula (X) (or a pharma- ceutically acceptable salt thereof): A-L'-D (X) where A is a radical of a compound herein, L' is a linker connecting A and D or is absent, and D is a ubiquitin pathway protein binding moiety.

[0298] The compositions can be prepared from various amorphous, non-amorphous, partially crystalline, crystalline, and / or other morphological forms of the compounds and / or conjugates, and the compositions can be prepared from various hydrates and / or solvates of the compounds and / or conjugates. Thus, such pharmaceutical compositions can include each of the various morphological forms and / or solvates or hydrate forms of the compounds and / or conjugates, or any combination or individual forms.

[0299] The pharmaceutical composition can include one or more pharma- ceutically acceptable carriers, adjuvants, diluents, additives, and / or vehicles (e.g., conventional non-toxic pharma-ceutically acceptable carriers, adjuvants, and vehicles), and combinations thereof. Any pharma-ceutically acceptable carriers, diluents, and additives known in the art can be used. Examples include, but are not limited to, additives, color additives, preservatives, and stabilizers. More specific examples include crystalline cellulose, calcium carmellose, sodium carmellose, hydropropyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, and magnesium stearate.

[0300] Solutions of the compounds, conjugates or pharmaceutical compositions may be aqueous, optionally mixed with non-toxic surfactants and / or contain carriers or additives such as salts, carbohydrates and buffers (preferably pH 3-9), but for some applications may be more suitably formulated as sterile non-aqueous solutions or as dry forms to be used with a suitable vehicle such as sterile pyrogen-free water or phosphate-buffered saline. For example, dispersions may be prepared in glycerol, liquid PEG, triacetin, and mixtures thereof, as well as in oils. Under ordinary conditions of storage and use, these preparations may further contain a preservative to prevent the growth of microorganisms.

[0301] The pharmaceutical composition may further comprise an immunotherapeutic agent, a chemotherapeutic agent, an anti-cancer agent, and / or a hormonal therapy agent. Alternatively, the compound or conjugate (or a pharmaceutical composition comprising the compound or conjugate) may be administered simultaneously or sequentially, in any order, with an immunotherapeutic agent, an anti-cancer agent, a chemotherapeutic agent, and / or a hormonal therapy agent (or a pharmaceutical composition comprising any of the above).

[0302] The immunotherapeutic agent can be any suitable immunotherapeutic agent. Examples of suitable immunotherapeutic agents include, but are not limited to, transforming growth factor beta (TGF-β) inhibitors such as R268712, or PD-L1 inhibitors such as Keytruda.

[0303] The anti-cancer drug can be any suitable anti-cancer drug. Examples of suitable anti-cancer drugs include, but are not limited to, kinase inhibitors such as dasatinib.

[0304] The chemotherapeutic agent can be any suitable chemotherapeutic agent. Examples of suitable chemotherapeutic agents include, but are not limited to, anthracyclines such as doxorubicin, taxanes such as docetaxel, cyclophosphamides such as Cytoxan, or 5-fluoro-uracil.

[0305] The hormone or hormone-related therapeutic agent can be any suitable hormone or hormone-related therapeutic agent, examples of which include, but are not limited to, hormone production inhibitors such as Zoladex or Letrozole.

[0306] The compounds and / or conjugates can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient, in a variety of forms adapted to a selected route of administration. Pharmaceutical compositions can be, for example, formulated for a given route of administration and described in the art, for example, in Remington, the Science and Practice of Pharmacy, 22 nd The composition may be prepared according to the methods described in the above-mentioned US Pat. No. 6,399,363, issued on 23 / 02 / 2012. The composition may be an infusion or injectable composition, such as a composition that may be injected subcutaneously or intravenously.

[0307] Pharmaceutical compositions can be administered to a mammalian host, such as a human patient, in a variety of forms adapted to the selected route of administration. In certain embodiments, the pharmaceutical composition is formulated to be administered subcutaneously. In certain embodiments, the pharmaceutical composition is formulated to be administered orally. In certain embodiments, the pharmaceutical composition is formulated to be administered intramuscularly, intravenously, intraarterially, intraperitoneally, or any other parenteral route of administration recognized in the art.

[0308] In certain embodiments, the pharmaceutical composition is administered systemically in combination with a pharma- ceutically acceptable vehicle. The percentage of the components of the compositions and preparations may vary and may be from about 1 to about 99% by weight of the active ingredient (e.g., compound or conjugate), as well as binders, additives, disintegrants, lubricants, and / or sweeteners (known in the art). The amount of active compound or conjugate in such therapeutically useful compositions is such that an effective dose level is obtained (e.g., in serum or target tissue or cells).

[0309] Exemplary means of parenteral administration include needle (including microneedle) injectors, needle-free injectors, and injection techniques, as well as any other means of parenteral administration recognized in the art. Parenteral formulations are typically aqueous solutions and may contain additives such as salts, carbohydrates, and buffers (preferably with a pH ranging from about 3 to about 9), but for some applications may be more suitably formulated as sterile non-aqueous solutions or as dry forms used with a suitable vehicle such as sterile pyrogen-free water. Preparation of parenteral formulations under sterile conditions, for example by lyophilization, can be readily accomplished using standard formulation techniques well known to those skilled in the art.

[0310] Pharmaceutical dosage forms suitable for administration can include sterile aqueous solutions or dispersions or sterile powders containing the active ingredient adapted for extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes, nanocrystals, or polymer nanoparticles. In any case, the final dosage form should be sterile, fluid, and stable under the conditions of manufacture and storage. Liquid carriers or vehicles can be solvents or liquid dispersion media, including, but not limited to, water, electrolytes, sugars, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, non-toxic glyceryl esters, and / or suitable mixtures thereof. In at least one embodiment, the desired fluidity can be maintained by the formation of liposomes, by maintaining the required particle size in the case of dispersions, or by the use of surfactants.

[0311] Sterile injectable solutions can be prepared by incorporating the pharmaceutical composition and one or more of the other ingredients listed above in the required amount in a suitable solvent, followed by filtration sterilization as required. In the case of sterile powders for the preparation of sterile injectable solutions, vacuum drying and freeze-drying techniques can be utilized to obtain a powder of the active ingredient plus any additional desired ingredients present in a previously sterile-filtered solution.

[0312] method Further provided is a method of treating a condition (e.g., cancer and / or solid tumor) in a subject. The method comprises administering to the subject an effective amount of a pharmaceutical composition comprising one or more 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, solvent, tautomer, or optical isomer of the compound or conjugate; or (d) a compound of (a), a conjugate of (b), and / or a pharmaceutically acceptable salt, N-oxide, hydrate, solvent, tautomer, or optical isomer of (c). In certain embodiments, the pharmaceutical composition may further comprise an immunotherapeutic agent, a chemotherapeutic agent, an anticancer drug, or a hormonal therapy agent, and a pharmaceutically acceptable carrier or excipient.

[0313] Additionally, as desired, the method can further include administering to the subject an effective amount of (a), (b), (c), or (d), alone or in further combination with administration of a second pharmaceutical composition comprising an active agent and a second pharma- ceutically acceptable carrier or excipient. The active agent can be, for example, an immunotherapeutic agent, a chemotherapeutic agent, an anti-cancer agent, or a hormonal therapy agent.

[0314] As used herein, the term "administering" and variations thereof includes all means 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, via inhalation (e.g., intranasally (in)), bucally, ocular, sublingually, vaginally, rectally, etc.

[0315] As used herein, "effective amount" refers to an amount sufficient to achieve a desired result or to affect an undesired condition. For example, an effective amount can refer to an amount sufficient to achieve a desired therapeutic result or to affect a symptom. The specific effective amount level (e.g., amount) for any subject depends on a variety of factors, including the disorder / condition and the severity of the disorder / condition (e.g., type, site, and severity of fracture, bone injury, or cancer); the specific composition, compound, and / or conjugate utilized (i.e., its potency and / or bioavailability); the age, weight, general health, sex, and diet of the subject; the subject's response; the timing of administration; the route of administration; the excretion rate of the specific conjugate utilized; the duration of treatment; the drug / active agent used in combination with or simultaneously with the specific conjugate or compound utilized, and similar factors well known in the medical arts. For example, it is well within the skill of the art to start the dose of the compound / conjugate / composition at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved. If desired, the effective amount can be divided into multiple doses for administration. Thus, a single dose of the compound / conjugate / composition can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. Additionally, pharmacogenomic (the effect of genotype on the pharmacokinetic, pharmacodynamic or efficacy profile of an antigen or composition) information about a particular patient can affect the dosage used to achieve an effective amount.

[0316] Depending on the route of administration, a wide range of acceptable dosages is contemplated.For example, the effective amount of the compound, conjugate, and / or pharmaceutical composition may range from about 0.1 μg / kg / day, for example 0.5 μg / kg / day, 0.7 μg / kg / day, or 0.01 mg / kg / day up to about 1,000 mg / kg / day.Intravenous dosages may be several orders of magnitude lower.

[0317] When the compound, conjugate, and / or first pharmaceutical composition is administered together with an active agent or a second pharmaceutical composition comprising an active agent, the subject can be administered the compound / conjugate / first pharmaceutical composition and the active agent / second pharmaceutical composition simultaneously or sequentially in any order and using any delivery modality. For example, but not limited to, the compound / conjugate / first pharmaceutical composition can be administered intravenously (e.g., as an intravenous solution) and the active agent / second pharmaceutical composition can be administered subcutaneously. In other embodiments, both the compound / conjugate / first pharmaceutical composition and the active agent / second pharmaceutical composition are administered intravenously. The use of pharmaceutical compositions comprising more than one drug / active agent is within the scope of this disclosure.

[0318] The method can further include administering to the subject an effective amount of a second treatment comprising a chemotherapeutic, immunotherapeutic, or hormonal therapeutic agent; or radiation therapy.

[0319] The compound, the conjugate, and / or any other active agent administered together (or sequentially together) can be administered in a therapeutically effective dose to obtain a clinically acceptable result, such as reduction or elimination of symptoms or tumors. Thus, the conjugate, any active agent, and / or any second treatment can be administered simultaneously or sequentially in a treatment protocol. The administration of any active agent and / or second treatment can be performed according to treatment protocols already known in the art.

[0320] Those skilled in the art will recognize that treatment protocols can be changed according to the needs of the subject.Therefore, the combination of conjugate and other compounds (drugs) used in the methods herein can be administered with the modification of the protocol described herein.For example, conjugate and / or active agent can be administered discontinuously instead of continuously during treatment cycle.

[0321] The method can further include the simultaneous or sequential administration, in any order, of an effective amount of an active agent that is a free immunotherapeutic agent, a chemotherapeutic agent, an anti-cancer drug, or a hormonal therapy agent, or a pharmaceutical composition comprising same and a pharma- ceutically acceptable carrier or excipient (e.g., a second pharmaceutical composition).

[0322] The disease state of interest can be any type of disease or disorder that is regulated by one or more kinases.In certain embodiments, the disease or disorder is a cancer disease, an inflammatory disease, or a neurological disease that is regulated by one or more kinases.The disease or disorder can be regulated by one or more kinases, such as AB1, AB12, AFK, ALK, AMPK group, ATM, ATR, Aurora A, Aurora B, Aurora C, Aurora D, Aurora E, Aurora F ... B, AXL, BCKDK, BLK, BMPR1B, BMX, Brk, BRSK1, BTK, CaM-KI alpha, CaM-Kll alpha, CaMKK group, CaM-KIV, CaM-KK alpha, CaM-KK beta, CCDPK, CCRK, CDK1, CDK11, CDK2, CDK4, CDK5, CDK6, CDK7, CDK9, CDK group, CDPK, Chakl, CHK1, CHK2, CK1 alpha, CK1 delta, CK1 epsilon, CK1 group, CK2 alpha, 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 family, Fgr, FLT1, FLT3, FLT4, Fyn, GRK-1, GRK-2, GRK-3, GRK-4, GRK-5, GRK-6, GRK family, GSK-3 alpha, GSK-3 beta, GSK-3 family, 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, MAP2K4, MAP2K6, MAP2K7, MAPK2 group, MAP3K1, MAP3K11, MAP3K14, MAP3K5, MAP3K7, MAP3K8, MAPK3 group, MAP4K1, MAP4K2, M AP4K4, MAPK1, MAPK10, MAPK11, MAPK12, MAPK13, 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, PKG1 / 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, Sr Group c, STLK3, Syk, TBK1, Tec, TESK1, TESK2, TGFbR1, TGFbR2, Tie1, Tie2, Titin kinase, TNK2, TRKA, TRKB, tropomyosin kinase, TSSK3, TXK, Tyk2, TYK2, I KK l, WeeThe disease state may be regulated by one or more protein kinases selected from the group consisting of MERTK, Wnkl, WNK I, Yes, and ZAP70. In certain embodiments, the disease state is regulated by MERTK and AXL, both of which are inhibited by administration of an effective amount of a compound, conjugate, composition, or prodrug herein.

[0323] In certain embodiments, the condition is a 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 gastric cancer. In certain embodiments, the cancer is a solid tumor cancer (e.g., breast cancer, colon cancer, lung cancer, etc.).

[0324] In certain embodiments, the method can further include imaging the cancer cell population in the subject (e.g., after administration of the compound, the conjugate, the first pharmaceutical composition comprising the compound or conjugate, or the first pharmaceutical composition comprising the compound or conjugate and an immunotherapeutic agent, a chemotherapeutic agent, an anti-cancer agent, and / or a hormonal therapy agent). The cancer cell population in the subject can be a solid tumor. The imaging can be performed by any imaging technique now known or hereafter developed related to medical technology. In certain embodiments, the imaging can be performed by hybrid scanning using functional imaging modalities, such as single photon emission computed tomography (SPECT) or a combination of PET and computed tomography (CT) and / or magnetic resonance imaging (MRI) techniques, and combinations thereof. Ultrasound imaging can also be used.

[0325] When imaging a cancer cell population in a subject (either in conjunction with or separate from the method), the method can further include a step of diagnosing whether the subject has cancer.

[0326] When treating a subject's cancer and imaging the subject's bone, the method can further include evaluating or monitoring the effectiveness of the treatment. For example, the compound, conjugate and / or pharmaceutical composition can be used to quantitatively monitor the growth and proliferation of a tumor or lesion in vivo. In certain embodiments, a method is provided for monitoring the progression of a cancer (e.g., bone marrow cancer) in a subject, comprising administering to the subject a compound, a conjugate, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or conjugate or a pharma- ceutically acceptable salt thereof. Such a method can further comprise imaging the subject's cancer. In certain embodiments, a reduction in the tumor microenvironment (TME), cancer cell population, and / or size of a solid tumor in the subject compared to the size of such TME, population, and / or solid tumor prior to or early in the treatment indicates an effective therapy or treatment.

[0327] The subject's TME, cancer cell mass, and / or solid tumor can be imaged periodically throughout the course of therapeutic treatment, and the practitioner can compare the images and / or otherwise quantitate the lesion or cancer growth to determine therapeutic effectiveness (e.g., whether there is a differential killing effect of cancer cells or a relative increase in lesion size or cancer growth over the course of therapeutic treatment). Thus, methods are provided for determining the likelihood of success of a therapeutic treatment in a subject. It will be appreciated that such information can be utilized by one of skill in the art to affect administration of a compound, conjugate, or pharmaceutical composition depending on whether a positive result is detected (i.e., the treatment is effective, or perhaps adjusting the dosage or administration regimen if the TME, cancer cell mass, and / or solid tumor size does not decrease).

[0328] Also provided is a method of suppressing a T cell response in the TME of a subject, 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, solvent, tautomer, or optical isomer of the compound or conjugate; or (d) a pharmaceutical composition comprising one or more of the compound of (a), the conjugate of (b), and / or the pharmaceutically acceptable salt, N-oxide, hydrate, solvent, tautomer, or optical isomer of (c). The subject may have cancer. The subject may have a solid tumor cancer. The compounds herein (e.g., compounds herein that include a morpholine substituent), conjugates, and pharmaceutical compositions can inhibit at least MERTK and AXL, and by administering an effective amount thereof to a subject, the innate inflammatory immune response in the TME is suppressed (e.g., recruitment of myeloid suppressor macrophages to the TME), thereby suppressing pro-inflammatory T cell responses in the TME, thus leveraging the subject's own immune system to further promote an anti-cancer environment.

[0329] The compounds, conjugates, and pharmaceutical compositions may be administered as unit dosage forms and / or compositions.

[0330] In the methods described herein, the compounds, conjugates, and compositions can be administered in a single dose or via a combination of multiple doses, and can be administered contemporaneously, simultaneously, sequentially, or separately by any suitable means. When the doses are administered in separate dosage forms, the number of doses administered per day for each compound, conjugate, or composition can be the same or different. The doses of the compounds, conjugates, and / or compositions can be administered via the same or different routes of administration. The compounds, conjugates, or compositions can be administered in divided or single forms at the same time, at the same or different times during the course of treatment, according to simultaneous or alternating regimens.

[0331] Dosage may vary and may be administered in one or more doses per day for one or several days.Guidelines can be found in the literature for appropriate dosages for a given class of pharmaceutical agent.In further various embodiments, the preparation may be administered in a "prophylactically effective amount", i.e., an amount effective for preventing a disease state or disorder.

[0332] The compounds / conjugates / compositions can be administered more than once, for example daily (1-3 or more times per day; qd (once a day), bid (twice a day), tid (three times a day)), weekly (including 1-3 or more times on a given day), biweekly (including 1-3 or more times on a given day), monthly (including 1-3 or more times on a given day), or bimonthly (including 1-3 or more times on a given day). In any case, it is understood that the effective amounts described herein correspond to the dosage examples or correspond to the total dose per day, week, month, or trimonthly as determined by the administration protocol.

[0333] Some definitions As used herein, the following terms and phrases shall have the meanings set forth below: 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.

[0334] The term "about" allows for some variation in value or range, such as within 10%, within 5%, or within 1% of a stated value or stated range limit. The term "substantially" allows for some variation in value or range, such as within 90%, within 95%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more of a stated value or stated range limit.

[0335] The terms "a," "an," or "the" are used to include one or more than one, unless the context clearly dictates otherwise. The term "or" is used to refer to a non-exclusive "or" unless otherwise indicated.

[0336] Furthermore, it should be understood that the words or terms used herein, unless otherwise defined, are for descriptive purposes only and not for limiting purposes. Any use of section headings is intended to aid in the reading of the document and should not be construed as limiting. Furthermore, information associated with a section heading may appear within or outside that particular section. Furthermore, all publications, patents, and patent documents referred to in this document are incorporated herein by reference in their entirety as if individually incorporated by reference. In the event of a conflict in usage between this document and a document so incorporated by reference, the usage in the incorporated reference should be considered as supplementary to the usage in this document. In the event of an irreconcilable conflict, the usage in this document shall prevail.

[0337] The term "substituted" as used herein refers to a functional group in which one or more hydrogen atoms contained therein are replaced by one or more non-hydrogen atoms. The term "functional group" or "substituent" as used herein refers to a group that can be or is 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 of groups such as hydroxyl groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxyl groups, including carboxylic acids, carboxylates, and carboxylic acid esters; sulfur atoms of groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; nitrogen atoms of groups such as amines, azides, hydroxylamines, cyanos, nitro groups, N-oxides, hydrazides, and enamines; and other heteroatoms of various other groups.

[0338] As used herein, the term "alkyl" refers to an alkyl group having from 1 to about 20 carbon atoms (C1-C 20 ), 1 to 12 carbons (C1-C 12 ), 1 to 8 carbon atoms (C1-C8), or in some embodiments, 1 to 6 carbon atoms (C1-C6), substituted or unsubstituted straight-chain and branched alkyl and cycloalkyl groups. Examples of straight-chain alkyl groups include those having 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. The term "alkyl" as used herein encompasses n-alkyl, isoalkyl, and anteisoalkyl groups, as well as other branched forms of alkyl. Representative substituted alkyl groups may be substituted one or more times with any of the groups enumerated herein, such as amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.

[0339] As used herein, the term "alkenyl" refers to an alkyl group having 2 to 20 carbon atoms (C-C 20 ), 2-12 carbons (C2-C 12 ), 2 to 8 carbon atoms (C2-C8), or in some embodiments, 2 to 4 carbon atoms (C2-C4) and at least one carbon-carbon double bond. Examples of straight chain alkenyl groups include those having 2 to 8 carbon atoms, such as -CH=CH-, -CH=CHCH2-, and the like. Examples of branched alkenyl groups include, but are not limited to, -CH=C(CH3)-, and the like.

[0340] An alkynyl group is a fragment containing an open attachment point on a carbon atom that is formed when a hydrogen atom attached to a triple-bonded carbon is removed from an alkyne molecule. As used herein, the term "hydroxyalkyl" refers to an alkyl group, as defined herein, substituted with at least one hydroxyl (-OH) group.

[0341] 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 groups. In some embodiments, cycloalkyl groups can have from 3 to about 8-12 ring members, and in other embodiments, the number of ring carbon atoms ranges from 3 to 4, 5, 6, or 7. In some embodiments, cycloalkyl groups can have from 3 to 6 carbon atoms (C3-C6). Cycloalkyl groups further include polycyclic cycloalkyl groups, such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, as well as fused rings, such as, but not limited to, decalinyl.

[0342] The term "acyl" as used herein refers to a group that contains a carbonyl moiety and is bonded through the carbonyl carbon atom. The carbonyl carbon atom can also be bonded to another carbon atom and be part of a substituted or unsubstituted alkyl, aryl, aralkylcycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl group, and the like. In the special case where the carbonyl carbon atom is bonded to a hydrogen, the group is a "formyl" group, and is defined herein under the term acyl group. An acyl group can contain 0 to about 12 to 40, 6 to 10, 1 to 5, or 2 to 5 additional carbon atoms bonded to the carbonyl group. An acryloyl group is an example of an acyl group. An acyl group can also contain heteroatoms within the meaning herein. A nicotinoyl group (pyridyl-3-carbonyl) is an example of an acyl group within the meaning herein. Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups, and the like. When the group containing the carbon atom bonded to the carbonyl carbon atom contains a halogen, the group is referred to as a "haloacyl" group. An example is the trifluoroacetyl group.

[0343] The term "aryl" as used herein refers to a substituted or unsubstituted cyclic aromatic hydrocarbon that does not contain heteroatoms in the ring. Thus, aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, an aryl group is one having from about 6 to about 14 carbons (C6-C8) in the ring portion of the group. 14 ) or 6 to 10 carbon atoms (C6-C 10) Aryl groups can be unsubstituted or substituted aryl groups, as defined herein. Representative substituted aryl groups can be mono-substituted aryl groups or aryl groups substituted more than once, such as, but not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl groups or 2-8 substituted naphthyl groups, which can be substituted with carbon or non-carbon groups such as those enumerated herein.

[0344] The terms "aralkyl" and "arylalkyl" as used herein refer to an alkyl group, as defined herein, in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to an aryl group, as defined herein. Representative aralkyl groups include benzyl and phenylethyl groups, as well as fused (cycloalkylaryl)alkyl groups, such as 4-ethyl-indanyl. An aralkenyl group is an alkenyl group, as defined herein, in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to an aryl group, as defined herein.

[0345] The term "heterocyclyl" as used herein refers to substituted or unsubstituted aromatic and non-aromatic ring compounds containing three or more ring members, one or more of which are heteroatoms, such as, but not limited to, B, N, O, and S. Thus, a heterocyclyl can be a cycloheteroalkyl, or heteroaryl, or, if polycyclic, any combination thereof. In some embodiments, heterocyclyl groups contain from 3 to about 20 ring members, while other such groups have from 3 to about 15 ring members. In some embodiments, heterocyclyl groups include heterocyclyl groups containing from 3 to 8 carbon atoms (C3-C8), from 3 to 6 carbon atoms (C3-C6), or from 6 to 8 carbon atoms (C6-C8).

[0346] Heteroaryl rings are embodiments of heterocyclyl groups. The phrase "heterocyclyl group" includes fused ring species, including those containing fused aromatic and non-aromatic groups. Representative heterocyclyl groups include, but are not limited to, pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl, morpholinyl, chromanyl, indolinonyl, isoindolinyl, furanyl, pyrrolidinyl, pyridinyl, pyrazinyl, pyrimidinyl, triazinyl, thiophenyl, tetrahydrofuranyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl, tetrazolyl, benzoxazolinyl, benzothiazolinyl, and benzimidazolinyl groups.

[0347] The term "heterocyclylalkyl" as used herein refers to an alkyl group, as defined herein, in which a hydrogen or carbon bond of the alkyl group, as defined herein, is replaced with a bond to a heterocyclyl group, as defined herein. Representative heterocyclylalkyl groups include, but are not limited to, furan-2-ylmethyl, furan-3-ylmethyl, pyridin-3-ylmethyl, tetrahydrofuran-2-ylmethyl, and indol-2-ylpropyl.

[0348] The term "heteroarylalkyl," as used herein, refers to an alkyl group, as defined herein, in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a heteroaryl group, as defined herein.

[0349] The term "alkoxy" as used herein refers to an oxygen atom linked to an alkyl group, including cycloalkyl groups, as defined herein. Examples of linear alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like. Examples of branched alkoxy groups include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like. Examples of cyclic alkoxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. An alkoxy group may further include a double or triple bond and may also include a heteroatom. For example, an allyloxy group is an alkoxy group within the meaning herein. A methoxyethoxy group is also an alkoxy group within the meaning herein, as is a methylenedioxy group in the context that two adjacent atoms of the structure are replaced with it.

[0350] The term "amine" as used herein refers to primary, secondary, and tertiary amines, for example with the formula N(group)3, where each group can be independently H or non-H, such as alkyl, aryl, etc. Amines include, but are not limited to, R-NH2, such as alkylamines, arylamines, alkylarylamines; R2NH, such as dialkylamines, diarylamines, aralkylamines, heterocyclylamines, etc., where each R is independently selected; and R3N, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, etc., where each R is independently selected. The term "amine" as used herein also includes ammonium ions.

[0351] As used herein, the term "amino group" refers to -NH2, -NHR, -NR2, -NR3 + where each R is independently selected, and -NR3 which cannot be protonated. +refers to each protonated form of the substituent, except for . Thus, any compound substituted with an amino group can be considered an amine. An "amino group" within the meaning herein can be a primary, secondary, tertiary, or quaternary amino group. An "alkylamino" group includes monoalkylamino, dialkylamino, and trialkylamino groups.

[0352] The terms "halo," "halogen," or "halide" group as used herein, by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0353] As used herein, the term "haloalkyl" group includes monohaloalkyl groups, polyhaloalkyl groups (wherein all halo atoms can be the same or different), and perhaloalkyl groups (wherein all hydrogen atoms are replaced by halogen atoms such as fluoro). Examples of haloalkyl groups include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3-difluoropropyl, perfluorobutyl, -CF(CH3)2, and the like.

[0354] As used herein, the term "optionally substituted" or "optional substituents" means that the group is unsubstituted or substituted with one or more of the specified substituents. When the group is substituted with more than one substituent, the substituents may be the same or different. When the term "independently" is used, "independently is" and "independently selected from" mean that the groups may be the same or different. Some of the terms defined herein may occur more than one time in the structures, and upon such occurrence, each term shall be defined independently of the others.

[0355] The compounds described herein may contain one or more chiral centers or may otherwise exist as multiple stereoisomers. In one embodiment, it should be understood that the invention described herein is not limited to any particular stereochemical requirement, and that the compounds, as well as the compositions, methods, uses, and pharmaceuticals comprising them, may be optically pure or may be any of a variety of stereoisomeric mixtures, including racemic and other mixtures of enantiomers, other mixtures of diastereomers, and the like. It should also be understood that such mixtures of stereoisomers may contain a single stereochemical configuration at one or more chiral centers, while containing a mixture of stereochemical configurations at one or more other chiral centers.

[0356] Similarly, the compounds described herein may include geometric centers such as cis, trans, E and Z double bonds. In another embodiment, it should be understood that the invention described herein is not limited to any particular geometric isomer requirement, and that the compounds, and compositions, methods, uses and pharmaceuticals comprising them, may be pure or may be any of various geometric isomeric mixtures. It should also be understood that such mixtures of geometric isomers may include a single configuration at one or more double bonds, while including a mixture of geometries at one or more other double bonds.

[0357] The term "pharmacologically acceptable carrier" is art-recognized and refers to a pharma- ceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, involved in carrying or transporting any of the subject compositions or their components. Each carrier must be "acceptable" in the sense of being compatible with the subject compositions and their components and not harmful to the patient. Some examples of materials that can serve as pharma- ceutically 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 carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) 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 glycerin, 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) ethyl alcohol; (20) phosphate buffers; and (21) other non-toxic compatible substances utilized in pharmaceutical formulations.

[0358] 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, farm animals such as dogs, cats, or rabbits, agricultural animals such as dairy cows, 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.

[0359] Although the concepts of the present disclosure have been illustrated and described in detail in the figures and descriptions herein, the results in the figures and descriptions thereof should be considered as exemplary in character and not restrictive. It is understood that exemplary embodiments have been shown and described only, and that all changes and modifications that come within the spirit of the present disclosure should be protected. Indeed, numerous specific details have been presented and described to provide a thorough understanding of the present disclosure.

[0360] Any use of section headings is intended to aid in the reading of the document and should not be construed as limiting. Additionally, information associated with a section heading may appear within or outside of that particular section.

[0361] All patents, patent application publications, academic papers, textbooks, and other publications mentioned in this specification indicate the level of skill in the art to which this disclosure pertains.All such publications are incorporated herein by reference to the same extent as if each individual publication was specifically and individually indicated and incorporated by reference.If there is a discrepancy in usage between this document and the document so incorporated by reference, the usage in the incorporated reference should be considered as supplementary to the usage in this document.In the case of irreconcilable discrepancy, the usage in this document shall prevail.

[0362] Various techniques and mechanisms of the present disclosure may describe a connection or association between two components. Words such as attached, associated, coupled, connected, tethered, and similar terms and their inflected morphemes are used synonymously unless a difference is noted or made clear from the context. These words and expressions do not necessarily represent a direct connection, but include connections through indirect components. It should be noted that a connection between two components does not necessarily mean a direct and unobstructed connection, since various other components may exist between the two components of interest. Thus, a connection does not necessarily mean a direct and unobstructed connection, unless otherwise noted. EXAMPLES

[0363] The following examples serve to illustrate the present disclosure and are not intended to limit the scope of the claimed invention in any way.

[0364] [Example 1] Effect of Substituents on the Imidazole[1,2-b]pyridazine Moiety The nature of the substituents at the 6-position of the imidazo[1,2-b]pyridazine moiety was evaluated in an in vitro study conducted at Reaction Biology Corporation (Malvern, PA). Results indicated that certain substituents dramatically affected the inhibition of p70S6K. For example, at 25 nM, both ponatinib and compound HSN748 (containing a linear substituent at the 6-position) inhibited p70S6K by only 38% and 55%, respectively ([ATP] = 10 μM), whereas compounds HSND77, HSND79 and HSND80 (6-ring substituted analogs) inhibited p70S6K by 95%, 95% and 97%, respectively, under the same conditions.

[0365] At 50 nM compound and 10 μM ATP, compounds HSND77, HSND79 and HSND80 herein also inhibited MNK2 better than compound HSN748 (92% (compound HSND77), 94% (compound HSND79) and 96% (compound HSND80), versus 89% (compound HSN748, which contains a linear substituent at position 6)). This data supports that modifications of the imidazo[1,2-b]pyridazine moiety positively affect the inhibition of p70S6K by the nicotinamide class of kinase inhibitors.

[0366] [Example 2] 6-ring-substituted compounds inhibit the TAM kinases, AXL and MERTK The affinity of several compounds herein having a substituent at the 6-position of the imidazo[1,2-b]pyridazine moiety (wherein the substituent comprises one or more ring moieties) was evaluated for two TAM kinases: AXL and MERTK. Perhaps more specifically, the equilibrium dissociation constants between compound HSND141, compound HSND149, HSND150, HSND151, and HSND80, respectively, and AXL and MERTK were evaluated on Eurofins DiscoverX using KINOMEscan™, 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-tagged kinase, an immobilized ligand, and a test compound. Quantitative polymerase chain reaction (PCR) of the DNT tag was then used to measure the ability of the test compound to displace the immobilized ligand.

[0367] 6A-7B show the graphical results from such an evaluation, with HSND80 as the test compound, and Table 1 shows the measured K D (Unit: nM) (K obtained using DiscoverX (The Eurofins Discovery) D value).

[0368] [Table 1] In summary, each of compounds HSND141, HSND149, HSND150, HSND151, and HSND80 showed high affinity / strong binding to both AXL and MERTK, which are not specifically targeted by ponatinib or HSN748 compounds. HSND80 in particular bound strongly to MERTK.

[0369] [Example 3] Compound HSND80 and its analogs inhibit the NCI-60 cell line better than ponatinib and the parent compound with linear substituents The extent of inhibition of various kinase-driven cancers by 6-linear substituted ponatinib analogs was evaluated in the NCI-60 human tumor cell line screen in comparison to 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). IC of inhibition of MDA-MB-231 by compound HSND80 (72 h) 50 was 8.6 nM. Compound HSND80 and analogs also potently inhibited multiple myeloma cell lines (Figure 4).

[0370] 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). Under similar conditions, compound HSND41 (a ring analogue containing unsubstituted morpholine) inhibited MDA-MB-231 with a GI50 value of 35 nM.

[0371] This confirms that the 6-substituted nature of the imidazo[1,2-b]pyridazine moiety is important for anticancer activity (compare compounds HSN748, HSND37 and HSND41, Figures 3A-3C, respectively).

[0372] [Example 4] bioavailability studies Bioavailability and C of ring-6-substituted imidazo[1,2-b]pyridazine compounds max was also evaluated.

[0373] Briefly, compounds were dissolved in 10% dimethyl sulfoxide (DMSO) / 90% (20% HP-β-CD (w / w) in water). Male CD1 mice (n=3) were orally administered 10 mg / Kg of each compound (HSND80, HSND41, HSND101, HSND102, HSND141, and HSND156). Blood was collected at 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration, and the concentration of compounds in blood at each specific time point was determined via liquid chromatography-mass spectrometry (LC-MS) (High Performance Liquid Chromatography (HPLC) equipment: Shimadzu; MS equipment: AB API 5500 LC / MS / MS; Column: HALO C18 90A 2.7μm (30*2.1mm); Mobile phase A: 5% acetonitrile / water (0.1% formic acid); Mobile phase B: 95% acetonitrile / water (0.1% formic acid)).

[0374] The data presented in FIG. 5 confirms that all tested compounds were bioavailable, with the dimethylmorpholine compound HSND80 exhibiting greater bioavailability than the unsubstituted morpholine (compound HSND41).

[0375] [Example 5] Efficacy Study - 4T1 In Vivo Tumor Reduction with HSND80 0.5×10 6 4T1 cells were injected subcutaneously (SQ) into the right flank of female Balb-C mice. Each group consisted of 5 tumor-bearing mice. Seven days after tumor implantation, mice were orally dosed once daily with vehicle control (5% DMSO, 40% PEG300, 5% Tween 80, 50% water) or HSND80 (15 mg / Kg). Mice were dosed for 5 days and rested for 2 days (rest period). Tumors (L, W, H) were measured every other day to determine tumor volume (in mm 3 ) was obtained.

[0376] At 15 mg / kg, HSND80 reduced the growth of 4T1 (breast) syngeneic tumors by approximately 60% (data not shown).

[0377] [Example 6] Efficacy Study - CT-26 In Vivo Tumor Reduction with HSND80 and HSND100 Each BALB / c female mouse was injected with CT-26 C2 tumor cells (0.3 × 10 6 Tumors were generated by subcutaneously injecting 0.1 mL of PBS into the right flank of each mouse. Ten days after tumor inoculation, the average tumor size was approximately 71 mm. 3 Treatment for efficacy studies was initiated when tumor volume reached 100 mmHg. Each group consisted of 6 tumor-bearing mice. Vehicle control was 25 mM citrate buffer (pH 2.5). HSND80 was administered orally at 15 mg / Kg once daily for 4 days, followed by 10 mg / Kg orally. HSND100 was administered at 15 mg / Kg. Mice were dosed for 5 days and rested for 2 days (rest period). Tumors (L, W, H) were measured every other day to determine tumor volume (in mm 3 ) was obtained.

[0378] At day 17 (from start of dosing), HSND80 caused a 45% tumor reduction (compared to vehicle control) and HSND100 caused a 36% tumor reduction.

[0379] [Example 7] Compound synthesis and characterization General procedure for the synthesis of substituted imidazo[1,2-b]pyridazine substrates: In a sealed tube, 3-bromo-6-chloroimidazo[1,2-b]pyridazine (500 mg) and the appropriate amine (4 eq.) were refluxed overnight at 150° C. in n-propanol (1 mL) or amine as solvent. Upon completion, the reaction was extracted with ethyl acetate and washed with brine. The organic layer was collected, dried over sodium sulfate, and concentrated under reduced pressure. The crude was purified by silica gel column chromatography to give the desired product.

[0380] General procedure for Sonogashira coupling: Substituted imidazo[1,2-b]pyridazine substrate (1 mmol), alkyne substrate (1.1 mmol), PdCl2(PPh3)2 (3 mol%), XPhos (2 mol%), Cs2CO3 (3 equiv.) and CuI (1 mol%) were deoxygenated using argon gas. To the deoxygenated solution was then added a solution of anhydrous N,N-dimethylformamide (DMF) (5 mL) and N,N-diisopropylethylamine (DIPEA) (2.5 mL) under inert conditions. The reaction mixture was allowed to stir at 60° C. overnight.

[0381] After completion, the reaction mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with water and brine solution (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated in vacuum, and then purified by silica gel column chromatography to obtain the desired product.

[0382] The specific compounds / products and their substrates are listed below along with data confirming the structures of the synthesized compounds.

[0383] (R)-3-Bromo-6-((tetrahydrofuran-3-yl)oxy)imidazo[1,2-b]pyridazine

[0384] [ka] Following the general procedure above, a reaction mixture of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (500 mg) and (R)-tetrahydrofuran-3-ol (2.3 equiv.) in dry tetrahydrofuran (THF) (20 mL) was cooled to 0° C., then sodium hydride (NaH) (2.5 equiv.) was added. The reaction mixture was stirred at room temperature overnight. Upon completion, the reaction was extracted with ethyl acetate and washed with brine. The organic layer was collected, dried over sodium sulfate, and concentrated under reduced pressure to give the desired product. Off-white solid, 84% yield.

[0385] (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)

[0386] [ka] Off-white solid, yield: 58%. 1 H NMR (500 MHz, DMSO-d6) δ 10.79 (s, 1H), 9.10 (s, 1H), 8.96 (d, J = 1.9 Hz, 1H), 8.53 - 8.45 (m, 1H), 8.19 (s, 1H), 8.12 (d, J = 9.6 Hz, 1H), 8.04 (d, J = 15.3 Hz, 2H), 7.71 (d, J = 8.5 Hz, 1H), 7.03 (d, J = 9.6 Hz, 1H), 5.61 - 5.53 (m, 1H), 4.04 - 3.89 (m, 2H), 3.86 (q, J = 7.7 Hz, 1H), 3.75 (td, J = 8.3, 4.9 Hz, 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-d6) δ 163.8, 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 = 30.2 Hz), 125.8 (q, J = 274.6 Hz), 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.

[0387] (S)-3-Bromo-6-((tetrahydrofuran-3-yl)oxy)imidazo[1,2-b]pyridazine

[0388]

change

[0389] (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)

[0390] [ka] Off-white solid, yield: 59%. 11H NMR (500 MHz, DMSO-d6) δ 10.81 (s, 1H), 9.10 (d, J = 2.2 Hz, 1H), 8.95 (d, J = 2.0 Hz, 1H), 8.49 (t, J = 2.1 Hz, 1H), 8.19 (d, J = 2.2 Hz, 1H), 8.12 (d, J = 9.7 Hz, 1H), 8.07 - 8.00 (m, 2H), 7.71 (d, J = 8.5 Hz, 1H), 7.03 (d, J = 9.7 Hz, 1H), 5.59 - 5.54 (m, 1H), 4.01 - 3.97 (m, 1H), 3.95 - 3.90 (m, 1H), 3.85 (t, J = 7.7 Hz, 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 13C NMR (126 MHz, DMSO-d6) δ 163.8, 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 = 30.2 Hz), 125.8 (q, J = 274.6 Hz), 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.

[0391] 3-Bromo-6-((tetrahydro-2H-pyran-4-yl)oxy)imidazo[1,2-b]pyridazine

[0392]

Chem.

[0393] 1 H NMR (500 MHz, chloroform-d) δ 7.77 (d, J = 9.6 Hz, 1H), 7.59 (s, 1H), 6.71 (d, J = 9.6 Hz, 1H), 5.27 (dt, J = 8.5, 4.3 Hz, 1H), 4.01 (dt, J = 11.8, 4.5 Hz, 2H), 3.73 - 3.54 (m, 2H), 2.29 - 2.11 (m, 3H), 1.95 - 1.77 (m, 2H); 13 C NMR (126 MHz, CDCl3) δ 159.2, 137.8, 132.6, 127.6, 112.4, 100.6, 72.2, 65.3, 31.5.

[0394] 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)

[0395] [ka] 1H NMR (500 MHz, methanol-d4) δ 9.05 (d, J = 2.1 Hz, 1H), 8.84 (d, J = 2.0 Hz, 1H), 8.42 (t, J = 2.1 Hz, 1H), 8.13 (d, J = 2.2 Hz, 1H), 7.97 - 7.86 (m, 3H), 7.76 (d, J = 8.5 Hz, 1H), 6.96 (d, J = 9.6 Hz, 1H), 5.36 - 5.25 (m, 1H), 3.99 (dt, J = 11.7, 4.5 Hz, 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-d4) δ 163.9, 159.8, 152.9, 147.1, 138.1, 137.6, 137.5, 136.1, 132.7, 131.2, 130.5, 128.9 (q, J = 30.2 Hz), 127.0, 125.3 (q, J = 273.4 Hz), 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.

[0396] 3-Bromo-6-isopropoxyimidazo[1,2-b]pyridazine

[0397] [ka] Following the general procedure above, a reaction mixture of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (500 mg) and isopropanol (0.75 equiv.) in dry THF (20 mL) was cooled to 0° C., and then NaH (2.5 equiv.) was added. The reaction mixture was then stirred at room temperature overnight. Upon completion, the reaction was extracted with ethyl acetate and washed with brine. The organic layer was collected, dried over sodium sulfate, and concentrated under reduced pressure to give the desired product.

[0398] Off-white solid, 1 H NMR (500 MHz, クロロホルム-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, CDCl3) δ 159.5, 137.7, 132.4, 127.3, 112.7, 100.6, 70.8, 21.6.

[0399] 5-((6-isopropoxyimidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (compound HSND-35)

[0400]

change

[0401] 5-((6-aminoimidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (compound HSND-37)

[0402]

change

[0403] 2-((3-bromoimidazo[1,2-b]pyridazin-6-yl)amino)ethan-1-ol

[0404]

change

[0405] 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)

[0406]

Chem.

[0407] N 1 -(3-Bromoimidazo[1,2-b]pyridazin-6-yl)-N 2 ,N 2 -Dimethylethane-1,2-diamine

[0408]

change

[0409] 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)

[0410]

change

[0411] N 1 -(3-Bromoimidazo[1,2-b]pyridazin-6-yl)-N 1 ,N 2 ,N 2 -Trimethylethane-1,2-diamine

[0412] [ka] 1 H NMR (500 MHz, methanol-d4) δ 7.77 (dd, J = 10.0, 1.9 Hz, 1H), 7.53 (s, 1H), 7.12 (dd, J = 10.0, 1.8 Hz, 1H), 4.05 (t, J = 6.4 Hz, 2H), 3.50 (t, J = 6.4 Hz, 2H), 3.21 (s, 3H), 3.05 (s, 6H); 13 C NMR (126 MHz, methanol-d4) δ 155.2, 136.7, 130.7, 125.4, 110.0, 99.9, 54.7, 45.1, 43.1, 36.0.

[0413] 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)

[0414] [ka] 1H NMR (500 MHz, メタノール-d4) δ 8.99 (d, J = 2.2 Hz, 1H), 8.77 (d, J = 2.0 Hz, 1H), 8.37 (t, J = 2.3 Hz, 1H), 8.10 (d, J = 2.2 Hz, 1H), 7.92 (dd, J = 8.4, 2.4 Hz, 1H), 7.77 - 7.70 (m, 2H), 7.68 (d, J = 10.0 Hz, 1H), 7.03 (d, J = 9.9 Hz, 1H), 3.72 (t, J = 7.4 Hz, 2H), 3.62 (s, 2H), 3.13 (d, J = 1.1 Hz, 3H), 2.61 (t, J = 7.4 Hz, 2H), 2.58 - 2.37 (m, 8H), 2.31 (s, 6H), 2.27 (s, 3H); 13 C NMR (126 MHz, メタノール-d4) δ 163.8, 154.6, 152.9, 146.9, 137.5, 137.2, 136.7, 135.3, 133.0, 131.2, 130.3, 128.8 (q, J = 30.2 Hz), 125.3 (q, J = 273.4 Hz), 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.

[0415] 4-(3-Bromoimidazo[1,2-b]pyridazin-6-yl)morpholine

[0416]

change

[0417] N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-5-((6-morpholinoimidazo[1,2-b]pyridazin-3-yl)ethynyl)nicotinamide (compound HSND-41)

[0418]

change

[0419] (R)-2-((3-bromoimidazo[1,2-b]pyridazin-6-yl)amino)butan-1-ol

[0420]

change

[0421] (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)

[0422]

change

[0423] (S)-2-((3-bromoimidazo[1,2-b]pyridazin-6-yl)amino)butan-1-ol

[0424] [ka] 1 H NMR (500 MHz, methanol-d4) δ 7.53 (d, J = 9.7 Hz, 1H), 7.38 (s, 1H), 6.73 (d, J = 9.7 Hz, 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 = 7.5 Hz, 3H); 13 C NMR (126 MHz, methanol-d4) δ 154.5, 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.

[0425] (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)

[0426] [ka] 11H NMR (500 MHz, methanol-d4) δ 9.00 (d, J = 2.2 Hz, 1H), 8.82 (d, J = 2.0 Hz, 1H), 8.49 (t, J = 2.1 Hz, 1H), 8.10 (d, J = 2.3 Hz, 1H), 7.93 (dd, J = 8.5, 2.3 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.68 (s, 1H), 7.57 (d, J = 9.6 Hz, 1H), 6.80 (d, J = 9.6 Hz, 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 = 7.4 Hz, 3H); 13 13C NMR (126 MHz, methanol-d4) δ 164.1, 154.8, 153.0, 147.0, 137.7, 137.4, 134.5, 132.2, 131.2, 130.4, 128.8 (q, J = 28.9 Hz ), 125.3 (q, J = 274.6 Hz), 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.

[0427] 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)

[0428]

Chem.

[0429] 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)

[0430]

Chem.

[0431] 3-Bromo-6-(piperazin-1-yl)imidazo[1,2-b]pyridazine

[0432]

change

[0433] 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)

[0434] [ka] 1 H NMR (500 MHz, methanol-d4) δ 9.15 - 8.93 (m, 1H), 8.93 - 8.78 (m, 1H), 8.52 - 8.37 (m, 1H), 8.14 (q, J = 2.8 Hz, 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 = 4.0 Hz, 3H); 13 C NMR (125 MHz, methanol-d4) δ 164.1, 155.8, 153.0, 147.1, 137.5, 137.4, 137.1, 135.7, 133.0, 131.2, 130.5, 128.6 (q, J = 31.2 Hz), 125.3 (q, J = 270 Hz), 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.

[0435] 3-Bromo-6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazine

[0436] [ka] 1 H NMR (500 MHz, methanol-d4) δ 7.69 (d, J = 10.0 Hz, 1H), 7.49 (s, 1H), 7.15 (d, J = 10.0 Hz, 1H), 3.64 - 3.57 (m, 4H), 2.63 - 2.55 (m, 4H), 2.35 (s, 3H). 13C NMR (125 MHz, methanol-d4) δ155.4, 136.7, 130.7, 124.8, 110.9, 100.1, 54.0, 45.1, 44.7.

[0437] 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)

[0438] [ka] 1 H NMR (500 MHz, methanol-d4) δ 9.01 (s, 1H), 8.81 (s, 1H), 8.45 - 8.38 (m, 1H), 8.12 (d, J = 2.2 Hz, 1H), 7.92 (dd, J = 8.5, 2.3 Hz, 1H), 7.83 - 7.71 (m, 3H), 7.22 (dd, J = 10.0, 3.2 Hz, 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-d4) δ 164.0, 155.5, 153.0, 147.0, 137.5, 137.3, 135.7, 132.8, 131.2, 130.4, 128.8 (q, J = 30 Hz), 125.3 (q, J = 272.5 Hz), 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.

[0439] 3-Bromo-6-(piperidin-1-yl)imidazo[1,2-b]pyridazine

[0440] [ka] 11H NMR (500 MHz, methanol-d4) δ 7.60 (d, J = 10.0 Hz, 1H), 7.43 (s, 1H), 7.06 (d, J = 10.0 Hz, 1H), 3.53 (dd, J = 6.1, 3.9 Hz, 4H), 1.64 (dt, J = 5.4, 2.8 Hz, 6H); 13 13C NMR (125 MHz, methanol-d4) δ 155.3, 136.5, 130.3, 124.5, 111.1, 99.9, 46.6, 25.0, 24.1.

[0441] 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)

[0442]

Chem.

[0443] 4-(3-Bromoimidazo[1,2-b]pyridazin-6-yl)thiomorpholine

[0444]

Chem.

[0445] N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-5-((6-thiomorpholinoimidazo[1,2-b]pyridazin-3-yl)ethynyl)nicotinamide (compound HSND-79)

[0446]

change

[0447] (2S,6R)-4-(3-bromoimidazo[1,2-b]pyridazin-6-yl)-2,6-dimethylmorpholine

[0448]

change

[0449] 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)

[0450]

change

[0451] N-(4-chloro-3-(trifluoromethyl)phenyl)-5-ethynylnicotinamide

[0452]

Chem.

[0453] N-(4-chloro-3-(trifluoromethyl)phenyl)-5-((6-morpholinoimidazo[1,2-b]pyridazin-3-yl)ethynyl)nicotinamide (compound HSND-91)

[0454]

Chem.

[0455] 5-Ethynyl-N-(3-(trifluoromethyl)phenyl)nicotinamide

[0456] [ka] 1 H NMR (500 MHz, methanol-d4) δ 9.04 (d, J = 2.1 Hz, 1H), 8.78 (d, J = 1.9 Hz, 1H), 8.40 (t, J = 2.1 Hz, 1H), 8.14 (d, J = 2.0 Hz, 1H), 7.97 - 7.87 (m, 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.45 - 7.38 (m, 1H), 3.91 (s, 1H); 13 C NMR (125 MHz, methanol-d4) δ 164.1, 154.1, 147.5, 139.0, 138.4, 130.9 (q, J = 31.2 Hz), 130.4, 129.3, 125.1 (q, J = 270 Hz), 123.6, 120.7, 119.7, 116.9, 82.5, 78.6.

[0457] 5-((6-morpholinoimidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(3-(trifluoromethyl)phenyl)nicotinamide (compound HSND-92)

[0458] [ka] 1H NMR (500 MHz, DMSO-d6) δ 10.80 (s, 1H), 9.09 (d, J = 2.1 Hz, 1H), 8.99 - 8.92 (m, 1H), 8.49 (t, J = 2.1 Hz, 1H), 8.23 ​​(d, J = 2.0 Hz, 1H), 8.09 - 7.91 (m, 3H), 7.69 - 7.59 (m, 1H), 7.50 - 7.44 (m, 1H), 7.32 (d, J = 9.9 Hz, 1H), 3.74 (t, J = 4.9 Hz, 4H), 3.58 - 3.50 (m, 4H); 13 C NMR (125 MHz, DMSO-d6) δ 164.0, 155.9, 153.9, 148.6, 140.0, 137.4, 130.5, 130.3, 130.0 (q, J = 31.2 Hz), 126.6, 125.6 (q, J = 273.4 Hz), 124.2, 120.9, 119.4, 116.8, 112.3, 94.5, 82.0, 66.2, 46.0.

[0459] 3-Bromo-6-((3S,5R)-3,5-dimethylpiperazin-1-yl)imidazo[1,2-b]pyridazine

[0460]

change

[0461] 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)

[0462]

change

[0463] 3-Bromo-6-(4-(2-methoxyethyl)piperazin-1-yl)imidazo[1,2-b]pyridazine

[0464]

change

[0465] 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)

[0466] [ka] 1 H NMR (500 MHz, methanol-d4) δ8.96 (d, J = 2.2 Hz, 1H), 8.73 (d, J = 2.0 Hz, 1H), 8.35 (t, J = 2.1 Hz, 1H), 8.07 (d, J = 2.2 Hz, 1H), 7.89 (dd, J = 8.4, 2.3 Hz, 1H), 7.74 - 7.61 (m, 3H), 7.12 (d, J = 10.0 Hz, 1H), 3.59 (dd, J = 9.3, 3.9 Hz, 6H), 3.51 (t, J = 5.5 Hz, 2H), 3.31 (s, 3H), 2.66 - 2.41 (m, 14H), 2.28 (s, 3H). 13C NMR (125 MHz, 131.1, 130.2, 128.7 (q, 137.4, 137.2, 136.9, 135.6, 132.9, 131.1, 130.2, 128.7) J = 30 Hz), 128.5, 125.3 (q, J = 272.5 Hz), 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.

[0467] 3-Bromo-6-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)imidazo[1,2-b]pyridazine

[0468]

change

[0469] 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)

[0470]

change

[0471] (2S,6S)-4-(3-bromoimidazo[1,2-b]pyridazin-6-yl)-2,6-dimethylmorpholine

[0472]

change

[0473] 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)

[0474]

change

[0475] (S)-4-(3-bromoimidazo[1,2-b]pyridazin-6-yl)-2-methylmorpholine

[0476]

change

[0477] (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)

[0478]

change

[0479] 4-(3-Bromoimidazo[1,2-b]pyridazin-6-yl)-2,2,6,6-tetramethylmorpholine

[0480] [ka] 1 H NMR (500 MHz, chloroform-d) δ 7.68 (dd, J = 9.9, 1.3 Hz, 1H), 7.52 (s, 1H), 6.77 (d, J = 9.9 Hz, 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.

[0481] 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)

[0482] [ka] 1H NMR (500 MHz, メタノール-d4) δ 9.03 (d, J = 2.1 Hz, 1H), 8.83 (d, J = 2.0 Hz, 1H), 8.47 - 8.39 (m, 1H), 8.12 (d, J = 2.2 Hz, 1H), 7.94 (dd, J = 8.4, 2.3 Hz, 1H), 7.84 - 7.70 (m, 3H), 7.22 (d, J = 9.9 Hz, 1H), 3.71 - 3.62 (m, 2H), 3.54 (s, 4H), 2.57 (s, 8H), 2.36 (d, J = 1.5 Hz, 3H), 1.29 (d, J = 1.5 Hz, 12H); 13 C NMR (125 MHz, メタノール-d4) δ164.0, 155.5, 152.9, 146.9, 137.5, 137.4, 135.5, 132.9, 131.2, 130.5, 128.8 (q, J = 30 Hz), 125.3 (q, J = 271.2 Hz), 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.

[0483] 3-Bromo-6-(3,5-dimethylpiperidin-1-yl)imidazo[1,2-b]pyridazine

[0484]

change

[0485] 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

[0486]

change

[0487] N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-5-((6-morpholinoimidazo[1,2-b]pyridazin-3-yl)ethynyl)nicotinamide (compound HSND-105)

[0488]

change

[0489] 5-((6-((2S,6R)-2,6-dimethylmorpholino)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(3-(trifluoromethyl)phenyl)nicotinamide (compound HSND-106)

[0490]

Chem.

[0491] 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)

[0492]

Chem.

[0493] 1313C NMR (126 MHz, DMSO-d6) δ 165.30, 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 = 30.2 Hz), 126.55, 125.89(q, J = 274.6 Hz), 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.

[0494] 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)

[0495]

Chem.

[0496] 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)

[0497]

Chem.

[0498] 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)

[0499]

Chem.

[0500] 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)

[0501]

Chem.

[0502] 3-Bromo-6-(4-methyl-1,4-diazepan-1-yl)imidazo[1,2-b]pyridazine

[0503]

change

[0504] 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)

[0505]

change

[0506] (S)-3-Bromo-6-(3-methoxypyrrolidin-1-yl)imidazo[1,2-b]pyridazine

[0507]

Chem.

[0508] (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)

[0509]

Chem.

[0510] 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)

[0511]

Chem.

[0512] 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)

[0513]

Chem.

[0514] 5-(3-bromoimidazo[1,2-b]pyridazin-6-yl)-2-oxa-5-azabicyclo[2.2.2]octane

[0515]

change

[0516] (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)

[0517] [Chemical] 1 H NMR (500 MHz, DMSO-d6) δ 10.76 (s, 1H), 9.07 (t, J = 1.7 Hz, 1H), 8.92 (d, J = 1.8 Hz, 1H), 8.47 (q, J = 1.9 Hz, 1H), 8.19 (d, J = 2.1 Hz, 1H), 8.02 (d, J = 8.5 Hz, 1H), 7.93 - 7.86 (m, 2H), 7.71 (d, J = 8.5 Hz, 1H), 6.96 (d, J = 9.8 Hz, 1H), 4.09 (p, J = 3.4 Hz, 1H), 3.63 - 3.55 (m, 5H), 3.49 (q, J = 8.8 Hz, 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-d6) δ 163.87, 153.82, 153.59, 148.50, 138.30, 137.37, 137.28, 136.75, 132.97, 131.82, 130.35, 127.83(q, J = 30.2 Hz), 126.22, 125.84(q, J = 274.6 Hz), 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.

[0518] 6-(3-bromoimidazo[1,2-b]pyridazin-6-yl)-2-oxa-6-azaspiro[3.3]heptane

[0519] [Chemical] 11H NMR (500 MHz, DMSO-d6) δ 7.83 (d, J = 9.6 Hz, 1H), 7.56 (s, 1H), 6.67 (dd, J = 9.7, 1.0 Hz, 1H), 4.77 - 4.64 (m, 4H), 4.28 - 4.16 (m, 4H); 13 13C NMR (126 MHz, DMSO) δ156.45, 137.15, 131.75, 126.47, 109.97, 99.55, 80.23, 60.54.

[0520] 5-((6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (compound HSND-149)

[0521]

Chem.

[0522] (1R,4R)-5-(3-bromoimidazo[1,2-b]pyridazin-6-yl)-2-oxa-5-azabicyclo[2.2.1]heptane

[0523]

change

[0524] 5-((6-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (compound HSND-150)

[0525]

change

[0526] (1S,4S)-5-(3-bromoimidazo[1,2-b]pyridazin-6-yl)-2-oxa-5-azabicyclo[2.2.1]heptane

[0527]

change

[0528] 5-((6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (compound HSND-151)

[0529]

change

[0530] 4-(1-(3-bromoimidazo[1,2-b]pyridazin-6-yl)piperidin-4-yl)morpholine

[0531]

change

[0532] 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)

[0533]

change

[0534] 3-Bromo-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)imidazo[1,2-b]pyridazine

[0535]

change

[0536] 13 13C NMR (126 MHz, MeOD) δ 155.20, 136.64, 130.54, 124.76, 111.25, 100.09, 61.53, 54.50, 48.35, 45.13, 44.59, 27.42.

[0537] 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)

[0538]

Chem.

[0539] 13C NMR (126 MHz, メタノール-d4) δ 164.01, 155.36, 152.99, 147.01, 137.51, 137.41, 136.93, 135.52, 133.05, 131.22, 130.49, 128.84(q, J = 30.4 Hz), 125.39(q, J = 273.4 Hz), 124.78, 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.

[0540] 7-(3-bromoimidazo[1,2-b]pyridazin-6-yl)-4-oxa-7-azaspiro[2.5]octane

[0541]

change

[0542] 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)

[0543]

change

[0544] (2S,6R)-4-(3-bromo-2-methylimidazo[1,2-b]pyridazin-6-yl)-2,6-dimethylmorpholine

[0545]

Chem.

[0546] 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)

[0547]

Chem.

[0548] 6-(3-bromoimidazo[1,2-b]pyridazin-6-yl)-2-oxa-6-azaspiro[3.4]octane

[0549]

change

[0550] 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)

[0551]

change

[0552] 6-(3-bromoimidazo[1,2-b]pyridazin-6-yl)-1-oxa-6-azaspiro[3.4]octane

[0553]

Chem.

[0554] 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)

[0555]

Chem.

[0556] 1-(3-Bromoimidazo[1,2-b]pyridazin-6-yl)-4-methylpiperidin-4-ol

[0557]

Chem.

[0558] 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)

[0559]

Chemistry

[0560] N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-5-((6-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)imidazo[1,2-b]pyridazin-3-yl)ethynyl)nicotinamide (compound HSND174)

[0561]

change

[0562] 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)

[0563]

change

[0564] 3-Bromo-N-methyl-N-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b]pyridazin-6-amine

[0565]

change

[0566] 13 C NMR (126 MHz, MeOD) δ 154.81, 136.54, 130.25, 124.64, 110.63, 99.84, 67.18, 53.27, 29.53, 29.16.

[0567] 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)

[0568]

Chem.

[0569] 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)

[0570]

Chem.

[0571] N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-5-((6-(1-oxidothiomorpholino)imidazo[1,2-b]pyridazin-3-yl)ethynyl)nicotinamide (compound HSND178)

[0572]

Chem.

[0573] 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)

[0574]

Chem.

[0575] N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-5-((6-(1-oxidothiomorpholino)imidazo[1,2-b]pyridazin-3-yl)ethynyl)nicotinamide (compound HSND178)

[0576]

Chem.

[0577] 9-(3-Bromoimidazo[1,2-b]pyridazin-6-yl)-3-oxa-9-azaspiro[5.5]undecane

[0578] [Chemical formula] 1 1H NMR (500 MHz, methanol-d4) δ 7.65 (d, J = 10.0 Hz, 1H), 7.46 (s, 1H), 7.13 (d, J = 10.0 Hz, 1H), 3.69 - 3.66 (m, 4H), 3.60 - 3.46 (m, 4H), 1.73 - 1.61 (m, 4H), 1.55 (t, J = 5.4 Hz, 4H); 1313C NMR (126 MHz, methanol-d4) δ 155.50, 136.64, 130.44, 124.61, 111.19, 100.03, 63.02, 41.19, 35.85, 34.86, 29.00.

[0579] 5-((6-(3-oxa-9-azaspiro[5.5]undecan-9-yl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (compound HSND-182)

[0580]

Chem.

[0581] 8-(3-Bromoimidazo[1,2-b]pyridazin-6-yl)-2-oxa-8-azaspiro[4.5]decane

[0582]

change

[0583] 5-((6-(2-oxa-8-azaspiro[4.5]decan-8-yl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (compound HSND-183)

[0584]

change

[0585] 7-(3-bromoimidazo[1,2-b]pyridazin-6-yl)-2-oxa-7-azaspiro[3.5]nonane

[0586]

Chem.

[0587] 5-((6-(2-oxa-7-azaspiro[3.5]nonan-7-yl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (compound HSND-184)

[0588]

Chem.

[0589] 4-(2-((3-bromoimidazo[1,2-b]pyridazin-6-yl)oxy)ethyl)morpholine

[0590]

Chem.

[0591] N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-5-((6-(2-morpholinoethoxy)imidazo[1,2-b]pyridazin-3-yl)ethynyl)nicotinamide (compound HSND185)

[0592]

Chem.

[0593] (2S,6R)-4-(5-iodoimidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2,6-dimethylmorpholine

[0594]

Chem.

[0595] 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)

[0596]

Chem.

[0597] 1-((3-bromoimidazo[1,2-b]pyridazin-6-yl)oxy)-2-methylpropan-2-ol

[0598]

Chem.

[0599] 1 H NMR (500 MHz, methanol-d4) δ 7.86 (dd, J = 9.4, 1.5 Hz, 1H), 7.60 (s, 0H), 6.96 (dd, J = 9.8, 1.7 Hz, 1H), 4.23 (s, 2H), 1.16 (s, 6H); 13 C NMR (126 MHz, methanol-d4) δ 160.8, 137.9, 131.5, 126.8, 112.9, 100.8, 74.8, 68.9, 24.6.

[0600] 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)

[0601] [ka] Off-white solid, yield: 70%.

[0602] 1 H NMR (500 MHz, methanol-d4) δ 9.13 - 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 = 8.4 Hz, 1H), 7.02 (dd, J = 12.2, 8.7 Hz, 1H), 4.29 (s, 2H), 3.66 (s, 2H), 2.56 (s, 8H), 2.35 (s, 3H), 1.35 (s, 7H); 13C NMR (126 MHz, methanol-d4) δ 163.9, 160.9, 153.1, 147.3, 138.1, 137.5, 136.4, 132.9, 131.2, 130.4, 128.8 (q, J = 27.7 Hz), 126.8, 125.3 (q, J = 274.6 Hz), 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.

[0603] 3-Bromo-6-((3-methyloxetan-3-yl)methoxy)imidazo[1,2-b]pyridazine

[0604] [ka] A reaction mixture of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (500 mg) and (3-methyloxetan-3-yl)methanol (2.3 equiv.) in dry THF (20 mL) was cooled to 0° C., then NaH (2.5 equiv.) was added. The reaction mixture was stirred at room temperature overnight. Upon completion, the reaction was extracted with ethyl acetate and washed with brine. The organic layer was collected, dried over sodium sulfate, and concentrated under reduced pressure to give the desired product. Off-white solid, 90% yield.

[0605] 1 H NMR (500 MHz, methanol-d4) δ 7.89 (dd, J = 9.7, 0.6 Hz, 1H), 7.62 (s, 1H), 6.98 (dd, J = 9.6, 0.6 Hz, 1H), 4.70 (d, J = 6.0 Hz, 2H), 4.52 (s, 2H), 4.47 (d, J = 6.0 Hz, 2H), 1.46 (s, 3H); 13 C NMR (126 MHz, methanol-d4) δ 160.8, 137.9, 131.6, 126.9, 112.8, 100.8, 79.4, 71.6, 66.6, 39.1, 19.9.

[0606] 5-((6-((3-methyloxetan-3-yl)methoxy)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (HSND-26)

[0607]

change

[0608] 3-Bromo-6-(oxetan-3-ylmethoxy)imidazo[1,2-b]pyridazine

[0609]

change

[0610] 1 H NMR (500 MHz, methanol-d4) δ 7.87 (d, J = 9.7 Hz, 1H), 7.62 (s, 1H), 6.93 (d, J = 9.7 Hz, 1H), 4.89 (dd, J = 8.0, 6.2 Hz, 2H), 4.69 - 4.61 (m, 4H), 3.58 - 3.48 (m, 1H); 13 C NMR (126 MHz, methanol-d4) δ 160.6, 137.9, 131.5, 126.9, 112.8, 100.8, 74.1, 68.2, 34.1.

[0611] 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)

[0612] [ka] Off-white solid, yield: 61%. 1H NMR (500 MHz, DMSO-d6) δ 10.76 (s, 1H), 9.09 (d, J = 2.1 Hz, 1H), 8.98 (d, J = 2.0 Hz, 1H), 8.51 (t, J = 2.1 Hz, 1H), 8.18 (d, J = 2.2 Hz, 1H), 8.13 (d, J = 9.7 Hz, 1H), 8.07 (s, 1H), 8.02 (dd, J = 8.5, 2.2 Hz, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.05 (d, J = 9.7 Hz, 1H), 4.70 (dd, J = 8.0, 6.1 Hz, 2H), 4.64 (d, J = 6.5 Hz, 2H), 4.53 (t, J = 6.1 Hz, 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-d6) δ 163.8, 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 = 275.9 Hz), 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.

[0613] Those skilled in the art will recognize that numerous modifications can be made to the specific implementations described above. Implementations should not be limited to the specific limitations described. Other implementations are contemplated.

[0614] While the invention has been illustrated and described in detail in the drawings and foregoing description, the same is to be considered as illustrative in character 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.

[0615] The scope of the methods and compositions of the present invention is intended to be defined by the following claims. However, it should be understood that the present disclosure may be practiced other than as specifically described and illustrated without departing from its spirit or scope. Those skilled in the art will appreciate that various alternatives to the embodiments described herein may be utilized in practicing the following claims without departing from the spirit and scope thereof as defined in the following claims.

Claims

[Claim 1] Compounds having the structure of formula (XX): R ４ -L-Z-R ３ (XX) or its pharmaceutically acceptable salt [In the formula, R ４ is nicotinamide or benzamide, and each of the nicotinamide or benzamide is optionally substituted. L is a linker containing at least one atom, Z is R ３ It is a bicyclic heterocycle substituted with, R ３ [This includes one or more ring portions.]

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