Alkynyl nicotinamide compounds as kinase inhibitors

Abstract

The present invention relates to alkynyl nicotinamide compounds and their derivatives as kinase inhibitors. In addition, the invention discloses their use in treating diseases such as cancer, in particular acute myeloid leukemia.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Patent Application No. 62 / 730,046, filed on September 12, 2018. The entire contents and disclosure of this patent application are incorporated herein by reference. Background Art

[0003] In human cells, there are more than 500 kinases that regulate important processes such as cell cycle regulation, proliferation, apoptosis, and migration. Protein kinase inhibitors have the potential to treat a variety of diseases controlled by the dysregulation of protein kinases. To date, more than 20 kinase inhibitors have been approved by the FDA for the treatment of various diseases.

[0004] Ponatinib, a multikinase inhibitor developed by Ariad Pharmaceuticals, was first commercialized in 2012. 1 It was approved by the U.S. Food and Drug Administration (FDA) in 2007. It currently targets multiple cancer-driving kinases. This includes kinases such as ABL1, FLT3, FGFR1-4, and RET. Due to its impressive kinase inhibitory properties, it has been shown to effectively inhibit various cancers, including CML, AML, various FGFR and RET-driven cancers (such as non-small cell lung cancer). 2 and thyroid cancer 3 Currently, ponatinib is the only FDA-approved drug for imatinib-resistant CML with the T315I mutation. 4 It is also conducting various clinical trials for AML, lung cancer, and other cancers (NCT02428543; Ponatinib for FLT3-ITD acute myeloid leukemia (PONATINIB-AML) 5 , NCT02265341; Advanced cholangiocarcinoma with FGFR2 fusions 6 , NCT01813734; Ponatinib for advanced NSCLC with RET translocation 7 ).

[0005] Despite the impressive array of cancer types for which ponatinib is currently being evaluated, the drug is relatively toxic and has been associated with adverse cardiovascular events. 8 Patients taking ponatinib also showed side effects of high blood pressure, abnormal platelet function, and peripheral arterial occlusive disease. 9 Other more serious side effects, such as myocardial infarction, stroke and liver failure, have also occurred in patients taking ponatinib. 10. In addition, approximately 40% of patients taking ponatinib develop some form of thrombosis. Due to this adverse issue, the FDA temporarily halted the sale of ponatinib in 2014, and it is now used as a last resort drug for CML patients with the ABL(T315I) mutation who have not responded to any other treatment. See Gainor, JF et al., Ponatinib: Accelerated Rejection, Oncologist, 20(8), 847–848 (2015); Talbert, DR et al., Toxicological Sciences, 143(1), 147-155 (2015). The adverse toxicities associated with ponatinib may be due to the simultaneous inhibition of cardiovascular-related kinases. 11 .

[0006] In the effort to develop inhibitors for several disease-related kinases, 4-substituted isoquinolines were found to be privileged kinase inhibitors. Furthermore, the substitution forms of these 4-substituted isoquinolines play a key role in kinase selectivity and thus cancer selectivity. 4-Alkynyl-substituted aminoisoquinolines in particular exhibit excellent activity against various kinases and effectively inhibit the spread of cancer. This important discovery facilitated the modification of 4-substituted aminoisoquinolines into compounds that inhibit various cancers. In addition, 4-Alkynyl-substituted 1- or 3-aminoisoquinolines can be tuned for selectivity and toxicity, thus representing a new generation of alkyne-containing kinase inhibitors with desirable drug-like properties. See U.S. Application No. 16 / 325,022 filed on August 15, 2017. The entire contents and disclosures of this patent application are incorporated herein by reference. Summary of the invention

[0007] According to a first broad aspect, the present invention provides nicotinamide analogs of ponatinib, wherein the benzamide moiety of ponatinib is replaced by a nicotinamide analog, which may be a better and less toxic alternative to ponatinib.

[0008]

[0009] In another aspect, the present invention relates to a pharmaceutical composition comprising one or more compounds described herein or a pharmaceutically acceptable salt, N-oxide, hydrate, solvate, tautomer or optical isomer thereof, and a pharmaceutically acceptable carrier or diluent.

[0010] In another aspect, the present invention relates to a method for treating, preventing, inhibiting or lessening the severity of a disease or condition associated with protein kinase in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, N-oxide, hydrate, solvate, tautomer or optical isomer thereof, or a pharmaceutical composition comprising one or more compounds described herein.

[0011] The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.

[0012] BRIEF DESCRIPTION OF THE DRAWINGS

[0013] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate exemplary embodiments of the invention and, together with the general description given above and the detailed description given below, serve to explain the features of the invention.

[0014] FIG1 shows a schematic diagram of partially replacing methylbenzamide with nicotinamide in ponatinib according to one embodiment of the present invention.

[0015] Figure 2 shows a schematic representation of the general structure of a compound of the invention according to one embodiment of the invention.

[0016] Figure 3 shows a representation of the structure of Group 1 of compounds of the present invention according to one embodiment of the present invention.

[0017] Figure 4 shows a representation of the structure of Group 2 of compounds of the invention according to one embodiment of the invention.

[0018] Figure 5 shows a representation of the structures of Group 3 of compounds of the invention according to one embodiment of the invention.

[0019] Figure 6 shows a representation of the structure of Group 4 of compounds of the present invention according to one embodiment of the present invention.

[0020] 7A and 7B show diagrams of the structures of Group 5 of compounds of the present invention according to one embodiment of the present invention.

[0021] Figure 8 shows a representation of the structures of Group 6 of compounds of the present invention according to one embodiment of the present invention.

[0022] Figure 9 shows a representation of the structures of Group 7 of compounds of the present invention according to one embodiment of the present invention.

[0023] Figure 10 shows a representation of the structures of Group 8 of compounds of the present invention according to one embodiment of the present invention.

[0024] Figure 11 shows a representation of the structure of the 9th group of compounds of the present invention according to one embodiment of the present invention.

[0025] Figure 12 shows a representation of the structures of Group 10 of compounds of the present invention according to one embodiment of the present invention.

[0026] Figure 13 shows a representation of the structure of Group 11 of compounds of the present invention according to one embodiment of the present invention.

[0027] Figure 14 shows a representation of the structures of Group 12 of compounds of the present invention according to one embodiment of the present invention.

[0028] Figure 15 shows a representation of the structure of Group 13 of compounds of the present invention according to one embodiment of the present invention.

[0029] Figure 16 shows a representation of the structures of Group 14 of compounds of the present invention according to one embodiment of the present invention.

[0030] Figure 17 shows a representation of the structure of Group 15 of compounds of the present invention according to one embodiment of the present invention.

[0031] Figure 18 shows a representation of the structures of Group 16 of compounds of the present invention according to one embodiment of the present invention.

[0032] Figure 19 shows a representation of the structure of Group 17 of compounds of the present invention according to one embodiment of the present invention.

[0033] Figure 20 shows a representation of the structure of Group 18 of compounds of the present invention according to one embodiment of the present invention.

[0034] Figure 21 shows a representation of the structure of Group 19 of compounds of the present invention according to one embodiment of the present invention.

[0035] Figure 22 shows a representation of the structures of Group 20 of compounds of the present invention according to one embodiment of the present invention.

[0036] Figure 23 shows a representation of the structures of Group 21 of compounds of the present invention according to one embodiment of the present invention.

[0037] Figure 24 shows a representation of the structures of Group 22 of compounds of the present invention according to one embodiment of the present invention.

[0038] Figure 25 shows a representation of the structures of Group 23 of compounds of the present invention according to one embodiment of the present invention.

[0039] Figure 26 shows a representation of the structures of Group 24 of compounds of the present invention according to one embodiment of the present invention.

[0040] Figure 27 shows a representation of the structures of Group 25 of compounds of the present invention according to one embodiment of the present invention.

[0041] Figure 28 shows a representation of the structures of Group 26 of compounds of the present invention according to one embodiment of the present invention.

[0042] Figure 29 shows a representation of the structures of Group 27 of compounds of the present invention according to one embodiment of the present invention.

[0043] Fig.30 is a schematic diagram of a therapeutic delivery device according to one embodiment of the present invention.

[0044] Detailed description of the invention

[0045] definition

[0046] Unless otherwise defined, all technical terms and scientific terms used herein have the same meaning as the commonly understood meaning of the claimed subject matter. If a term herein has multiple definitions, the definition in this section shall prevail. All patents, patent applications, publications, and disclosed nucleotide and amino acid sequences (e.g., sequences available in GenBank or other databases) cited herein are incorporated herein by reference. Where a URL or other such identifier or address is mentioned, it should be understood that such identifiers may change and specific information on the Internet may be replaced from time to time, but equivalent information may be found by searching the Internet. Reference to it proves the availability and public dissemination of such information.

[0047] It should be understood that the foregoing general description and the following detailed description are exemplary and illustrative only and do not limit any subject matter claimed. In this application, the use of the singular includes the plural, unless otherwise expressly stated. It must be noted that the singular forms "a", "an" and "the" used in the specification and the appended claims include plural objects unless the context clearly indicates otherwise. In this application, unless otherwise stated, the use of "or" means "and / or". In addition, the use of the term "including" and other forms (such as "include", "includes" and "included") is not restrictive.

[0048] For the purposes of the present invention, the terms "comprising", the term "having", the term "including" and variations of these terms are intended to be open ended and mean that there may be additional elements other than the listed elements.

[0049] For purposes of the present invention, directional terms such as "top", "bottom", "upper", "lower", "above", "below", "left", "right", "horizontal", "vertical", "upward", "downward", etc., are used merely for convenience in describing various embodiments of the present invention. Embodiments of the present invention may be oriented in various ways. For example, the illustrations, devices, etc. shown in the accompanying drawings may be flipped, rotated 90° in any direction, inverted, etc.

[0050] For purposes of the present invention, a value or attribute is "based on" a particular value, attribute, satisfied condition, or other factor if the value is derived by performing a mathematical calculation or logical determination using the particular value, attribute, or other factor.

[0051] For the purpose of the present invention, it should be noted that in order to make the description more concise, some quantitative expressions given herein are not qualified with the term "about". It should be understood that, whether or not the term "about" is explicitly used, each quantity given herein refers to the actual given value, and also refers to the approximate value of the given value reasonably inferred based on ordinary skills in the art, including the approximate value caused by the experimental conditions and / or measurement conditions of the given value.

[0052] For the purposes of the present invention, the term "analogue" and the term "analog" refer to one of a group of compounds that have similar structure and / or function but different elemental composition. A structural analog is a compound that has a structure similar to another compound but differs in one or more components (e.g., one or more atoms, functional groups, or substructures, etc.). A functional analog is a compound that has similar physical, chemical, biochemical, or pharmacological properties. Functional analogs are not necessarily structural analogs with similar chemical structures.

[0053] For purposes of the present invention, the terms "ameliorate" and the term "amelioration" refer to the lessening of severity, delaying onset, slowing progression, or shortening of duration, whether permanent or temporary, maintaining or shortening the symptoms of a particular disease, disorder or condition by the administration of a drug or pharmaceutical composition.

[0054] For the purposes of the present invention, the term "amino acid" refers to a molecule consisting of a terminal amine and a carboxylic acid functional group, wherein the carbon atom between the terminal amine and the carboxylic acid functional group sometimes includes a side chain functional group connected to the carbon atom (e.g., a methoxy functional group forming the amino acid serine). Typically, amino acids are divided into natural amino acids and non-natural amino acids. Examples of natural amino acids include glycine, alanine, valine, leucine, isoleucine, proline, phenylpurine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, arginine, histidine, aspartic acid and glutamic acid, etc. Examples of non-natural amino acids include L-3,4-dihydroxyphenylalanine, 2-aminobutyric acid, dehydrated alanine, g-carboxyglutamic acid, carnitine, γ-aminobutyric acid, hydroxyproline and selenomethionine, etc. In the context of this specification, it should be understood that amino acids can be L-optical isomers or D-optical isomers.

[0055] For the purposes of the present invention, the term "analyte" refers to the conventional meaning of the term "analyte", i.e., the substance or chemical component of a sample that is detected or measured in a sample. In one embodiment of the present invention, the sample to be analyzed can be an aqueous sample, but other types of samples can also be analyzed using the device of the present invention.

[0056] For purposes of the present invention, the term "antagonist" refers to a compound that binds to a receptor and blocks or disrupts the effect of an agonist on the receptor.

[0057] For the purposes of the present invention, the term "biomolecule" refers to the conventional meaning of the term biomolecule, ie, a molecule produced by or found in living cells, such as proteins, carbohydrates, lipids, phospholipids, nucleic acids, and the like.

[0058] For the purposes of the present invention, the term "capsule" refers to a gelatinous coating encapsulating an active substance. Capsules may be soft-shell capsules (softgels) or hard-shell capsules. Capsules may be designed to remain intact for several hours after ingestion to delay absorption. They may also contain a mixture of slow-release particles and fast-release particles to produce rapid and sustained absorption at the same dose.

[0059] For the purposes of this invention, the term "carrier" refers to relatively nontoxic compounds or agents that facilitate the incorporation of a drug into cells or tissues.

[0060] For the purposes of the present invention, the term "co-administration" refers to the administration of two or more compositions or compounds to a single subject. Each of the two or more compositions can be administered at the same time or at different times by the same or different routes of administration. The co-administration of a first therapeutically effective compound and a second therapeutically effective compound, for example, can be dissolved or mixed in the same pharmaceutically acceptable carrier.

[0061] For the purposes of the present invention, the term "combination" refers to a "fixed dose combination" or a "co-packaged drug product". A "fixed dose combination" or a "fixed combination" is a preparation comprising two or more pharmaceutically active ingredients (e.g., drugs, compounds) physically combined in a single dosage form. In other words, the drugs or compounds can be dissolved or mixed in the same pharmaceutically acceptable carrier. The form of a single dosage form can be, but is not limited to, tablets, soft gelatin capsules, capsules, hard gelatin capsules, caplets, chewable tablets, soft candies, injections, transdermal patches, etc. "Combination product" refers to a product that combines drugs, devices, and / or biological products together. Sometimes, a combination product can be a multiple pill or combined pill in a dosage form such as a tablet, capsule, etc. Sometimes, a "combination product" can be a "non-fixed combination" or a "co-packaged drug product", in which two or more separate dosage forms are packaged together in one package or as a unit. Drugs, devices, or biological products can be packaged separately according to specific requirements (e.g., recommended labels). The contents of a "non-fixed combination" can be administered to a subject simultaneously, concurrently or sequentially at different time intervals or without specific intervening time limits, wherein such administration provides an effective level of the drug or compound in the subject. "Combined administration" includes co-administration of multiple compounds in therapeutically effective amounts, wherein the multiple compounds may be in the form of a "fixed dose combination" or a "non-fixed combination". "Simultaneous administration" includes administering various compounds simultaneously or sequentially in any order at different time points to provide an effect suitable for treatment. Concomitant therapy or sequential therapy may depend on the characteristics of the other drugs or compounds used, the onset and duration of action, plasma levels, clearance rate and other characteristics.

[0062] For the purposes of the present invention, the term "controlled release" refers to time-dependent release. Timed release has several different variations, such as sustained release intended to extend the release, pulsed release, delayed release, etc. Time-dependent release may be in the form of oral dosage forms (such as pills, capsules, gels), and may also be in the form of carriers, implants and devices such as injectable drugs and transdermal patches.

[0063] For the purposes of this invention, the term "delayed release" refers to an oral medication that does not immediately disintegrate and release the active ingredient into the body. For example, an enteric-coated oral medication dissolves in the intestines rather than in the stomach.

[0064] For the purposes of this invention, the term "dietary supplement" refers to a product taken by mouth that contains "dietary ingredients" intended to supplement the diet. The "dietary ingredients" in these products may include vitamins, minerals, herbs or other botanicals, amino acids, and substances such as enzymes and metabolites. Dietary supplements may also be extracts or concentrates and may appear in many dosage forms, such as tablets, hard capsules, soft capsules, chewable tablets, gummies, liquids, or powders. Dietary supplements may also exist in other dosage forms, such as bars, but if so, the information on the dietary supplement label may not indicate that the product is a regular food or the only meal or diet.

[0065] For purposes of the present invention, the term "diagnosis" refers to identifying the nature of a disease, illness, condition or other problem by examining symptoms in an individual or patient.

[0066] For purposes of the present invention, the term "diluent" refers to a compound used to dilute a drug prior to delivery. Diluents can also be used to stabilize agents because they can provide a more stable environment. Pharmaceutically acceptable salts dissolved in buffered solutions (which can also provide control or maintenance of pH) are used as diluents in the art, including but not limited to phosphate buffered saline solutions.

[0067] For the purposes of this invention, the term "dose" refers to a dose of a specific amount, a specific number, and a specific frequency administered over a specific period of time. A dose refers to a duration of time. A "dosage regimen" is a therapeutic plan for administering medication over a period of time.

[0068] For the purposes of this invention, "dosage form" and the term "unit dose" refer to an individual dose of a drug product. A dosage form may contain a mixture of active drug ingredients and non-drug ingredients (excipients), as well as other non-reusable materials that may not be considered ingredients or packaging.

[0069] For the purposes of this invention, the term "dose" refers to a specified amount of a drug taken at one time.

[0070] For the purposes of the present invention, the term "drug" refers to a material that may have a biological effect on cells, including but not limited to small organic molecules, inorganic compounds, polymers (such as nucleic acids, polypeptides, carbohydrates) or other biological materials, nanoparticles, etc.

[0071] For the purposes of the present invention, the term "effective amount" or "effective dose" or grammatical variations thereof refers to an amount of a pharmaceutical agent sufficient to produce one or more desired effects. The effective amount can be determined by those skilled in the art based on the guidance provided herein.

[0072] For purposes of the present invention, the terms "enhance" and "enhancing" refer to increasing or prolonging the potency or duration of a desired effect. For example, "enhancing" the effect of therapeutic agents, alone or in combination, refers to the ability to increase or prolong in potency, duration, and / or intensity the therapeutic effect of a therapeutic agent on a disease, disorder, or condition. When used in a patient, the effective amount used depends on the severity and course of the disease, disorder, or condition, previous treatment, the patient's health status and response to the drugs, and the judgment of the treating physician.

[0073] For the purposes of this invention, the term "enteric coating" refers to a polymeric barrier applied to oral medications.

[0074] For the purposes of the present invention, the term "fluid" refers to a liquid or a gas.

[0075] For the purposes of the present invention, the term "subject" refers to an individual mammal, such as a human.

[0076] For the purposes of the present invention, the term "ligand" refers to a substance, such as a small molecule, that forms a complex with a biomolecule for biological purposes. In protein-ligand binding, the ligand is typically a signal triggering molecule that binds to a site on the target protein. The binding of a ligand to a receptor protein (receptor) changes the chemical conformation (three-dimensional shape) of the receptor. The conformational state of the receptor determines its functional state. Ligands include substrates, inhibitors, activators, and neurotransmitters.

[0077] For the purposes of the present invention, the term "lipid" refers to a hydrophobic or amphipathic molecule, including but not limited to biologically derived lipids, such as phospholipids, triacylglycerols, fatty acids, cholesterol; or synthetic lipids, such as surfactants, organic solvents, oils, etc.

[0078] For the purposes of the present invention, the term "long chain fatty acids" refers to fatty acids having an aliphatic tail of 13 or more carbon atoms.

[0079] For the purposes of the present invention, the term "long chain fatty acid group" refers to an ester group derived from a long chain fatty acid. An example of a long chain fatty acid group is a stearate group.

[0080] For the purposes of the present invention, the term "medical therapy" refers to prophylactic, diagnostic and therapeutic regimens performed on humans or other mammals, either in vivo or ex vivo.

[0081] For the purposes of the present invention, the term "mg / kg" refers to the dose of a substance administered to an individual or subject in milligrams per kilogram of body weight of the individual or subject.

[0082] For the purposes of the present invention, the term "functional food" refers to compounds and compositions that can be used in the field of nutrition and pharmaceutical applications. Therefore, the functional food composition of the present invention can be used as a supplement to food and beverages, and can be used as a pharmaceutical preparation for enteral or parenteral application, which can be a solid preparation, such as a capsule or tablet, or a liquid preparation, such as a solution or suspension. In some embodiments of the present invention, the functional food composition may also include food and beverages, which contain a therapeutically effective amount of one or more corresponding selective dopamine D4 receptor agonists and / or a pharmaceutically acceptable analog, a pharmaceutically acceptable salt or a hydrate of the one or more corresponding selective dopamine D4 receptor agonists, and a supplement composition, such as a dietary supplement.

[0083] For purposes of the present invention, the term "parenteral route" refers to administration of a composition, such as a drug, in a manner other than through the digestive tract. Parenteral routes include routes such as intravenous, intraarterial, transdermal, intranasal, sublingual, and intraosseous. For example, intravenous, also known as intravenous, is an injection directly into a vein. When a drug enters the systemic circulation directly, it reaches the site of action, resulting in the onset of action.

[0084] For the purposes of the present invention, the term "patient" and the term "subject" refer to a mammal, animal, fish, reptile, bird, or object of treatment, observation, or experiment. By way of example only, a subject can be, but is not limited to, a mammal, including, but not limited to, a human.

[0085] For purposes of the present invention, the term "pharmaceutically acceptable" refers to compounds or drugs that are listed or listable in the U.S. Pharmacopeia or other generally recognized pharmacopeia and approved or approvable by a regulatory agency of the Federal or state government for use in mammals, including humans.

[0086] For purposes of the present invention, the term "pharmaceutically acceptable carrier" refers to a carrier that contains a pharmaceutically acceptable material. Pharmaceutically acceptable carriers include, but are not limited to, saline solutions and buffered solutions. Pharmaceutically acceptable carriers are described in standard reference texts in the field, such as Gennaro, Alfonso, Ed., Remington's Pharmacy, 18th Edition, 1990, Mack Publishing, Easton, Pennsylvania. The pharmaceutical carrier can be selected based on the intended route of administration and standard pharmaceutical practice.

[0087] For the purposes of the present invention, the term "pharmaceutically acceptable salt" refers to those salts of compounds that are suitable for contact with the tissues of humans and lower animals without abnormal toxicity, irritation, allergic reactions, etc. and commensurate with a reasonable benefit / risk ratio within the scope of reasonable medical judgment. Pharmaceutically acceptable salts are well known in the art. When the compounds of the present invention are finally separated and purified, they can be prepared in situ, or prepared separately by reacting them with pharmaceutically acceptable non-toxic bases or acids (including inorganic bases or organic bases and inorganic or organic acids). Pharmaceutically acceptable salts can be obtained using standard methods well known in the art, for example, by mixing the compounds of the present invention with suitable acids such as inorganic acids or organic acids. Pharmaceutically acceptable salts include salts of acidic or basic groups present in the compounds of the present invention. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, gulonate, sucrose, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoic acid)) salts. Certain compounds of the present invention can form pharmaceutically acceptable salts with various amino acids. Suitable base salts include, but are not limited to, aluminum salts, calcium salts, lithium salts, magnesium salts, potassium salts, sodium salts, zinc salts and diethanolamine salts.

[0088] For the purposes of the present invention, the term "pharmaceutical composition" refers to a product comprising one or more active ingredients and one or more other components such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners and / or excipients. The pharmaceutical composition contains enough active target compound to produce the desired effect on the progression or condition of the disease and facilitates the application of the active ingredient to the organism. A variety of techniques for administering the active ingredient exist in the art, including but not limited to topical administration, ophthalmic administration, intraocular administration, periocular administration, intravenous administration, oral administration, aerosol administration, parenteral administration. By "pharmaceutically acceptable" is meant that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and harmless to its recipient, i.e., the subject.

[0089] For the purposes of the present invention, the term "pharmaceutical formulation" and the term "drug formulation" refer to a mixture or structure in which different chemical substances, including active drugs, are combined to form a final drug product, such as a sterile product, capsule, tablet, powder, granule, solution, emulsion, topical preparation, unconventional product (such as semisolid or sustained release preparation), liquid, etc. A pharmaceutical formulation is prepared according to a specific procedure ("recipe"). The formed drug varies depending on the route of administration. For example, oral drugs are usually taken in tablet or capsule form.

[0090] For the purposes of the present invention, the term "multi-pill" refers to a drug product in pill form (i.e., tablet or capsule) that combines multiple active pharmaceutical ingredients. In a given "pill", the multi-pill contains multiple different drugs. It can be made into a fixed-dose combination drug product.

[0091] For purposes of the present invention, the term "prophylactically effective amount" refers to an amount of a drug, compound, agent, combination or pharmaceutical composition that alleviates to some extent one or more symptoms of the disease, condition or disorder being treated in a patient. In such prophylactic applications, such an amount may depend on the patient's health status, body weight, etc. Such prophylactically effective amounts are generally determined by routine experimentation within the skill of the art, including but not limited to dose escalation clinical trials.

[0092] For the purposes of the present invention, the term "synergistic effect" refers to the combined effect when two or more substances or biological structures interact to produce an overall effect that is greater than the sum of the individual effects of any of the two or more substances or biological structures. For example, a synergistic effect of two therapeutic compounds means that the effect of the combined administration of the two therapeutic compounds is greater than the sum of each effect of each of the two therapeutic compounds when administered alone.

[0093] For the purposes of the present invention, the term "tablet" refers to a pharmaceutical dosage form. Tablets contain a mixture of active substances, usually in powder form, and excipients, which are flattened or pressed from the powder into a solid dose. Excipients may include diluents, binders or granulating agents, glidants and lubricants to ensure effective tableting; disintegrants promote the disintegration of tablets in the digestive tract; sweeteners or flavoring agents enhance the taste; and pigments make the tablets visually attractive. Polymer coatings are often used to make tablets smoother and easier to swallow, control the release rate of active ingredients, make them more resistant to the environment (extend their shelf life) or enhance the appearance of the tablet. Disintegration time can be changed to obtain rapid effects or sustained release. For example, some tablets are designed to have an osmotic core surrounded by an impermeable membrane with holes. This allows the drug to seep out of the tablet at a constant rate as the tablet moves in the digestive tract. Tablets can also be coated with sugar, varnish or wax to mask the taste. Tablets in one embodiment of the present invention may include tablets without or with one or more coatings. Tablets can also have one or more layers. The tablets may be mini-tablets, dissolvable tablets, chewable tablets, effervescent tablets or orally disintegrating tablets.

[0094] For the purposes of the present invention, the term "target" refers to a living organism or biological molecule that is directed against and / or bound by some other entity, such as a ligand or a drug. For example, a "target protein" can be a biological molecule, such as a protein or protein complex, a receptor or a portion of a biological molecule, etc., that can be bound and regulated by a biologically active composition (such as a pharmacologically active drug compound).

[0095] For purposes of the present invention, the term "timed release", the term "sustained release" or "controlled release" refers to the extended absorption of a drug with a short half-life, thereby allowing longer dosing intervals while minimizing fluctuations in serum drug levels. For example, a drug in a timed-release tablet or capsule may dissolve over time and be released more slowly and more continuously into the bloodstream, with the advantage of being taken less frequently than an immediate-release formulation of the same drug.

[0096] For purposes of the present invention, the terms "therapeutically effective amount" and "treatment-effective amount" refer to the amount of a drug, compound or composition that is sufficient to affect the treatment of a disease, disorder or symptom when the drug, compound or composition is administered to a subject for the treatment of a disease or condition, or at least one clinical symptom of a disease or condition. A "therapeutically effective amount" can vary according to, for example, the compound, disease, condition, and / or symptoms of the disease or condition, the severity of the disease and condition, and / or the symptoms of the disease or condition, the age, weight and / or health of the subject to be treated, and the judgment of the prescribing physician. The appropriate amount in any given case can be readily determined by those skilled in the art or can be determined by routine experimentation.

[0097] For the purposes of this invention, the term "transdermal patch" refers to a drug-containing adhesive patch that is placed on the skin to deliver a specific dose of a drug through the skin into the bloodstream. Transdermal patches can control the release of a drug into the body of a subject.

[0098] For purposes of the present invention, the term "treating" or the term "treatment" of any disease or condition refers to preventing or ameliorating a naturally occurring condition (e.g., due to aging), a disease, a condition, or at least one clinical symptom of a disease or condition, reducing the development of a disease, a condition, or at least one clinical symptom of a disease or condition, reducing the risk of developing a disease, a condition, or at least one clinical symptom of a disease or condition. "Treating" or "treatment" also refers to slowing the progression of a condition physically (e.g., stabilization of discernible symptoms) or physiologically (e.g., stabilization of a physical parameter), or both physically and physiologically, inhibiting a disease or disorder, and inhibiting or slowing the development of at least one human physiological parameter that may or may not be recognized by the subject. In some embodiments of the present invention, the terms "treating" and "treatment" refer to delaying the onset of a disease or condition or at least one or more symptoms thereof in a subject that may be exposed to or susceptible to a disease or condition, even if the subject has not yet experienced or displayed symptoms of the disease or condition. As used herein, the term "treatment" also refers to any treatment of a subject, such as a human condition or disease, and includes: (1) inhibiting the disease or condition, i.e., arresting the development or progression of the disease or condition, (2) relieving the disease or condition, i.e., causing disease recovery, (3) arresting disease symptoms, and / or (4) improving a desired condition.

[0099] For the purpose of the present invention, the term "carrier" refers to a substance without therapeutic value that is used to transport an active drug for administration.

[0100] For the purposes of the present invention, the term "room temperature" refers to a temperature of about 20°C to about 25°C.

[0101] For the purpose of the present invention, the term "slightly soluble in water" refers to a substance with a solubility of 0.1 g per 100 ml of water to 1 g per 100 ml of water. Unless otherwise specified, the terms "slightly soluble" and "slightly soluble in water" are used interchangeably in the following description of the present invention to refer to substances that are slightly soluble in water.

[0102] describe

[0103] Although the present invention is susceptible to various modifications and alternative forms, its specific embodiments have been shown in the accompanying drawings by way of example and will be described in detail below. However, it should be understood that it is not intended to limit the present invention to the specific form disclosed, on the contrary, the present invention will cover all modifications, equivalent forms and alternative forms that fall within the spirit and scope of the present invention.

[0104] US8,114,874B2 teaches that substituted alkynyl imidazo-[1,2-B]pyridazine compounds containing a benzamide unit are kinase inhibitors. Ponatinib, one of these compounds, is a multi-kinase inhibitor that effectively inhibits ABL1, FLT3, RET, c-Src, c-Kit, FGFR, VEGFR, PDGFRα, PDGFRβ, BRAF and other kinases. To date, ponatinib has been shown to effectively inhibit cancers driven by a variety of cell lines. 1-7 .

[0105] Ponatinib administration is associated with a number of adverse toxicities, in part due to the simultaneous inhibition of many essential kinases. Ponatinib analogs with reduced inhibition of cardiovascular-related kinases, such as VEGFR1-3, c-Src, c-Kit, etc., are expected to have lower adverse toxicities. 8-11 .

[0106] The mechanistic target of rapamycin (mTOR) is an important drug target because mTOR integrates many stimuli and coordinates the adaptive responses of many cellular processes. 12 Rapamycin is an inhibitor of mTOR. MAPK-interacting kinases (MNKs) enhance rapamycin resistance by maintaining mTORC1 activity after rapamycin treatment in cancer cells 12 Therefore, simultaneous inhibition of MNK1 and / or MNK2 and any cancer-driving kinases, such as FLT3, ABL1, RET, BRAF, c-Kit, PDGFRα, PDGFRβ, may result in more durable inhibition of cancer growth.

[0107] MNK1 and MNK2 regulate the function of eIF4E, a key component in translational control that is elevated in human cancers. MNK1 and MNK2 phosphorylate the conserved serine (Ser209) of eIF4E to regulate function. Simultaneous inhibition of MNK1 and MNK2 has been shown to produce growth inhibition in cancers. 12 .

[0108] However, ponatinib is not effective in inhibiting the kinases MNK1 and MNK2, which play an important role in cancer progression. However, we have found that replacing the benzamide group in ponatinib with a nicotinamide group produces new compounds, such as HSN748, which can effectively inhibit MNKs. Referring to Figure 1, a nicotinamide moiety is used to replace the methylbenzamide in ponatinib.

[0109] As shown in Figure 1, in the compounds of the present invention, the length, substitution pattern and relative position of the amide head group relative to the alkynyl group significantly affect the anticancer activity against the MV4-11 cell line (AML cell line). For example, the nature of the amide group in the molecules shown in Figure 1 has a significant impact on the anticancer activity of the tested molecules.

[0110] Ponatinib effectively inhibits FLT3-ITD, but has weak activity against drug-resistant FLT3-D835Y and / or FLT3-ITD-D835Y. Therefore, the secondary mutation FLT3-ITD-D835Y is a possible escape mechanism for the treatment of acute myeloid leukemia with ponatinib. Nicotinamide analogs of ponatinib, such as HSN748, are effective inhibitors of FLT3-ITD-D835Y. HSN748 is about 100 times more potent than ponatinib in inhibiting the Molm14 (FLT3-ITD, D835Y) cell line.

[0111] The difference between ponatinib and HSN748 is the replacement of the benzamide core in ponatinib with a nicotinamide core and the replacement of the methyl group on the benzamide of ponatinib with hydrogen. These two modifications form the compound HSN748 and analogs with a reduced LogP (or reduced hydrophobicity). The calculated LogP changes from 4.47 (ponatinib) to 3.44 (HSN748) 13 Therefore, HSN748 and ponatinib have different drug properties.

[0112] Ponatinib is an effective inhibitor of platelet-associated c-Src in vitro, while nicotinamide without methyl HSN748 is not a strong c-Src inhibitor in vitro. c-Src is important for platelet function, so effective and sustained inhibition of c-Src may lead to adverse reactions, and the compounds described in the present invention can avoid these adverse reactions.

[0113] Based on the discovery of nicotinamide forms of ponatinib with different and desirable properties, the compounds of the present invention have the general structure shown in Figure 2 and are provided below:

[0114]

[0115] Wherein Y == amide;

[0116] O-alkyl, such as OMe, OEt, OPr, OBu, OiPr, OCF2, OCF;

[0117] NH2, NH-alkyl, such as NHMe, NHEt;

[0118] N-(alkyl)2 or N-(heteroalkyl)2, e.g. NMe2, morpholinyl, piperazinyl;

[0119] CN, Cl, Br, iPr, Et, cyclopropyl, butyl, CF3, CHF2, CH2-piperazinyl analogs, CH2-morpholinyl analogs, CH2-piperidinyl analogs, CH2-pyrrolidinyl analogs, CH2-azetidinyl analogs, etc., X1-X7 = CH, CY or N. This general compound is hereinafter referred to as formula (I).

[0120] In some embodiments, the compounds of the invention are:

[0121]

[0122] These compounds are hereinafter referred to as Group 1 compounds and are illustrated in FIG3 .

[0123] In some embodiments, the compounds of the invention are:

[0124]

[0125]

[0126] These compounds are hereinafter referred to as Group 2 compounds and are illustrated in FIG4 .

[0127] In some embodiments, the compounds of the invention are:

[0128]

[0129] These compounds are hereinafter referred to as Group 3 compounds and are illustrated in FIG5 .

[0130] In some embodiments, the compounds of the invention are:

[0131]

[0132] Wherein Y == amide;

[0133] O-alkyl, such as OMe, OEt, OPr, OBu, OiPr, OCF2, OCF;

[0134] NH2, NH-alkyl, such as NHMe, NHEt;

[0135] N-(alkyl)2 or N-(heteroalkyl)2, e.g. NMe2, morpholinyl, piperazinyl;

[0136] CN, Cl, Br, iPr, Et, cyclopropyl, butyl, etc.

[0137] These compounds are hereinafter referred to as Group 4 compounds and are illustrated in FIG6 .

[0138] In some embodiments, the compounds of the invention are:

[0139]

[0140]

[0141] These compounds are hereinafter referred to as Group 5 compounds and are illustrated in Figures 7A and 7B.

[0142] In some embodiments, the compounds of the invention are:

[0143]

[0144] These compounds are hereinafter referred to as Group 6 compounds and are illustrated in FIG8 .

[0145] In some embodiments, the compounds of the invention are:

[0146]

[0147] These compounds are hereinafter referred to as Group 7 compounds and are illustrated in FIG. 9 .

[0148] In some embodiments, the compounds of the invention are:

[0149]

[0150] These compounds are hereinafter referred to as Group 8 compounds and are illustrated in FIG10 .

[0151] In some embodiments, the compounds of the invention are:

[0152]

[0153] These compounds are hereinafter referred to as Group 9 compounds and are illustrated in FIG11 .

[0154] In some embodiments, the compounds of the invention are:

[0155]

[0156] These compounds are hereinafter referred to as Group 10 compounds and are illustrated in FIG12 .

[0157] In some embodiments, the compounds of the invention are:

[0158]

[0159] These compounds are hereinafter referred to as Group 11 compounds and are illustrated in FIG13 .

[0160] In some embodiments, the compounds of the invention are:

[0161]

[0162] These compounds are hereinafter referred to as Group 12 compounds and are illustrated in FIG14 .

[0163] In some embodiments, the compounds of the invention are:

[0164]

[0165] These compounds are hereinafter referred to as Group 13 compounds and are illustrated in FIG15 .

[0166] In some embodiments, the compounds of the invention are:

[0167]

[0168] These compounds are hereinafter referred to as Group 14 compounds and are illustrated in FIG16 .

[0169] In some embodiments, the compounds of the invention are:

[0170]

[0171] These compounds are hereinafter referred to as Group 15 compounds and are illustrated in FIG17 .

[0172] In some embodiments, the compounds of the invention are:

[0173]

[0174] These compounds are hereinafter referred to as Group 16 compounds and are illustrated in FIG18 .

[0175] In some embodiments, the compounds of the invention are:

[0176]

[0177] These compounds are hereinafter referred to as Group 17 compounds and are illustrated in FIG19 .

[0178] In some embodiments, the compounds of the invention are:

[0179]

[0180] These compounds are hereinafter referred to as Group 18 compounds and are illustrated in FIG20 .

[0181] In some embodiments, the compounds of the invention are:

[0182]

[0183] These compounds are hereinafter referred to as Group 19 compounds and are illustrated in FIG21 .

[0184] In some embodiments, the compounds of the invention are:

[0185]

[0186] These compounds are hereinafter referred to as Group 21 compounds and are illustrated in FIG22 .

[0187] In some embodiments, the compounds of the invention are:

[0188]

[0189] These compounds are hereinafter referred to as Group 21 compounds and are illustrated in FIG23 .

[0190] In some embodiments, the compounds of the invention are:

[0191]

[0192] These compounds are hereinafter referred to as Group 22 compounds and are illustrated in FIG24 .

[0193] In some embodiments, the compounds of the invention are:

[0194]

[0195] These compounds are hereinafter referred to as Group 23 compounds and are illustrated in FIG25 .

[0196] In some embodiments, the compounds of the invention are:

[0197]

[0198] These compounds are hereinafter referred to as Group 24 compounds and are illustrated in FIG26 .

[0199] In some embodiments, the compounds of the invention are:

[0200]

[0201] These compounds are hereinafter referred to as Group 25 compounds and are illustrated in FIG27 .

[0202] In some embodiments, the compounds of the invention are:

[0203]

[0204] These compounds are hereinafter referred to as Group 26 compounds and are illustrated in FIG28 .

[0205] In some embodiments, the compounds of the invention are:

[0206]

[0207] These compounds are hereinafter referred to as Group 27 compounds and are illustrated in FIG29 .

[0208] It should be understood that the teachings of the present invention include prodrugs of the above-mentioned compounds. In addition, the conjugates of the above-mentioned compounds, wherein the compound is a conjugate of a targeting agent or an agent (such as a PROTAC strategy) that contributes to target degradation. It should also be understood that WO2015 / 001098A1 teaches (the entire contents and disclosures of this patent application are incorporated herein by reference) the polymorphic salt forms of disclosed compounds and variants thereof, and pharmaceutically acceptable salts can be HCl, acetate, sulfate, phosphate, citrate and other salts apparent to those skilled in the art are also within the scope of the present invention.

[0209] In some embodiments, the protein kinase inhibited by the claimed compounds is one known in the art. In some embodiments, the protein kinase includes, but is not limited to, FLT3 and Haspin. In some embodiments, the protein kinase is Abl, Abl2, AFK, ALK, AKT1, AMPK_group, ATM, ATR, Aurora kinase A, Aurora kinase B, Aurora kinase C, Axl, BCKDK, BLK, BMPR1B, BMX, BRAF, Brk, BRSK1, BTK, CaM-KIα, CaM-KIIα, CaMKK_group, CaM-KIV, CaM-KKα, CaM-KKβ, CCDPK, CCRK, CDK1, CDK11, CDK2, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK18, CDK19, CD K_group, CDPK, Chak1, CHK1, CHK2, CK1α, CK1β, CK1ε, CK1_group, CK2α, CK2_β, CK2_group, CLK1, CSF1R, Csk, DAPK1, DAPK2, DAPK3, DAPK_group, DCAMKL1, DMPK_group, DNA-PK, DYRK1A, DYRK1B, DYRK2, DYRK3, eEF2K, Eg3 kinase, EGFR, EIF2AK2, EphA2, EphA3, EphA4, EphA8, EphB1, EphB2, EphB3, EphB5, ErbB2, ERK 1. ERK2, ERK5, ERK7, ERN1 / IRE1, FAK, Fer, Fes, FGFR1, FGFR3, FGFR4, FGFR_group, Fgr, FLT1, FLT3, FLT4, Fyn, GRK-1, GRK-2, GRK-3, GRK-4, GRK-5 , GRK-6, GRK_group, GSK-3α, GSK-3β, GSK-3_group, HER2, HER4, HCK, HIPK2, HIPK3, HRI, ICK, IGF1R, IKK-α, IKK-β, IKK-εILK, InsR, IPL1, IRAK1, IRAK4 , ITK, JAK1, JAK2, JAK3, JAK_Group, JNK_Group, KDR, KIS, Kit, KSR1, Lck, LIMK1, LIMK2, LKB1, LOK, LRRK2, Lyn, MAP2K1, MAP2K2, MAP2K3, MAP2K4, MAP2K 6. MAP2K7, MAPK2_group, MAP3K1, MAP3K11, MAP3K14, MAP3K5, MAP3K7, MAP3K8, MAPK3_group, MAP4K1, MAP4K2, MAP4K4, MAPK1, MAPK10, MAPK11, MAPK12,MAPK13, MAPK14, MAPK3, MAPK4, MAPK6, MAPK7, MAPK8, MAPK9, MAPK_Group, MAPKAPK2, MARK_Group, Mer, MEK1, MEK2, Met, MERTK, MHCK , MLCK_group, MLKL, MK2, Mnk1, Mnk2, MOS, MRCKa, MST1, MST3, mTOR, NDR1, NDR2, NEK1, NEK2, NEK6, NEK9, NEK_group, NLK, NuaK1, p37 activator enzyme, p38_group, p70S6K, p70S6Kb, PBK / TOPK, P70S6K_group, PAK1, PAK2, PAK3, PAK5, PAK6, PAK_group, PASK, P-CIP2, PCTAIRE1, PDGFRα, PDGFRβ, PDGFR_group, PDHK1, PDHK2, PDHK3, PDHK4, PDK-1, PDK-2, PDK_group, PHK_group, PIK3CA, PIK3CB, PIK3CD, PIK3CG, Pim-1, PKAα, Pk a_group, PKBβ, PKB_group, PKCα, PKCβ, PKCδ, PKCε, PKCε, PKCγ, PKCι, PKCθ, PKCδ, PKC_group, PKD1, PKD2, PKD3, PKG1 / cGK-I, PKG2 / cGK-II, PKG2 / cGK_group, PKN1, PLK1, PLK2, PLK3, PRP4, PYK2, RAF1, Ret, RIPK1, RIPK2, RIPK3, RIPK4, ROCK1, ROCK2, Ron, ROS, RPL10 、RSK-1、RSK-2、RSK-3、RSK-5、SDK1、SGK_group、SIK、Sky、Src、Src_group、STLK3、Syk、TBK1、Tec、TESK1、TESK2、TGFbR1、TGFbR2、Tie1、Tie2、Titin kinase、TNK2、TRKA、TRKB、TRKC、tropomyosin kinase、TSSK3、TXK、Tyk2、TYK2、ULK1、ULK2、VRK1、Wee1、Wnk1、WNK1、Yes、ZAP70。、

[0210] The present invention relates to a pharmaceutical composition comprising one or more compounds described herein, or a pharmaceutically acceptable salt, N-oxide, hydrate, solvate, tautomer or optical isomer thereof, and a pharmaceutically acceptable carrier or diluent.

[0211] In another aspect, the present invention relates to a method for treating, inhibiting, preventing or reducing the severity of cancer in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, N-oxide, hydrate, solvate, tautomer or optical isomer thereof, or a pharmaceutical composition comprising one or more compounds described herein.

[0212] In another aspect, the present invention relates to a method for treating, inhibiting, preventing or reducing the severity of a disease or condition associated with protein kinase in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a compound as described herein, or a pharmaceutically acceptable salt, N-oxide, hydrate, solvate, tautomer or optical isomer thereof, or a pharmaceutical composition comprising one or more compounds as described herein. Example

[0213] Example 1

[0214] Ponatinib is more promiscuous than HSN748 for cardiovascular-related kinases

[0215] Ponatinib and HSN748 were screened against various disease-related kinases that have been shown to be inhibited by ponatinib (see Table 1). Interestingly, HSN748 showed similar inhibition of ABL1(T315I) and FLT3-ITD as ponatinib, but with some notable differences for certain kinases.

[0216] Table 1: IC50 of Ponatinib and HSN748 against several kinases

[0217]

[0218] The results were determined in Reaction Biology (Malvern, PA). a IC50. [ATP] = 100 μM

[0219] As shown in Table 1, HSN748 was inactive against c-Src kinase (IC50>1 μM), while Ponatinib effectively inhibited c-Src (IC50 of 4.6 nM). Src has been shown to play a variety of roles in cardiac function. For example, Src plays a key role in maintaining the structure of myocytes. 14 Src has also recently been found to regulate hERG current amplitude 15 Therefore, inhibition of Src may lead to the disorganization of myofibrils and affect cardiac ion channels. Src is also present in large quantities in human platelets and is key to the initiation and propagation of αIIbβ3 signaling, one of the most abundant receptors found in platelets. 16,17 .

[0220] Therefore, although Src plays an oncogenic role in multiple cancers, inhibition of Src may be accompanied by dysregulation of normal cells and platelets. Therefore, it is noteworthy that HSN748 does not inhibit Src as effectively as ponatinib.

[0221] Ponatinib has been shown to inhibit FGFRs and is currently in clinical trials for the treatment of cholangiocarcinoma with FGFR2 fusions. 7 Although many drugs targeting FGFRs are currently in clinical trials, FGFRs have important cardiac and liver functions, so inhibition of FGFRs may have adverse effects. Hyperphosphatemia is a major complication associated with FGFR inhibition due to disruption of the FGF23 signaling pathway. 18 Pan-FGFR inhibition is associated with cardiovascular dysfunction 19 Ponatinib showed greater in vitro activity against FGFR1-4 compared with HSN748.

[0222] ABL1 and FLT3 are mutated in CML and AML, respectively. Ponatinib and HSN748 have similar activity against ABL1, ABL1(T315I), and FLT3-ITD. Interestingly, the IC50 of HSN748 against FLT3(D835Y) kinase is significantly lower than that of ponatinib (14 nM for HSN748 and 173 nM for ponatinib, see Table 2). Most FLT3 inhibitors used clinically show initial efficacy, but patients relapse after a few months due to kinase mutations, which reduces the therapeutic effect. 20 The D835 mutation is one of the most common mutations observed in studies using the TKI quizartinib. 21 Therefore, HSN748 may be a better treatment option than ponatinib for drug-resistant AML (due to kinase mutations).

[0223] Example 2

[0224] HSN748 is more effective than ponatinib in inhibiting AML cell lines

[0225] Table 2: Activity of HSN748 and Ponatinib against FLT3, ABL1, FGFR, and RET driven cancers.

[0226]

[0227] We went on to test whether the extent of inhibition of FLT3, ABL1, RET, and FGFR-driven cancers by ponatinib and HSN748 reflected the order of kinase inhibition. Both compounds had similar IC50s for growth inhibition of MV4-11 (FLT3), K562 (ABL1), and LC2 / ad (RET). HSN748 inhibited Quizartinib-resistant AML (MOLM14-D835Y cell line) better than ponatinib (IC50 of 0.69nM for HSN748 and 52.6nM for ponatinib). HSN748 was also more potent than ponatinib for the gilteritinib-resistant AML cell line Molm14 (ITD, F691L) (IC50 of 0.18nM for HSN748 and 6.8nM for ponatinib).

[0228] Cellular activities of other nicotinamide compounds:

[0229]

[0230] Characterization of compounds

[0231] HSN748: 5-(Imidazolo[1,2-b]pyridazin-3-ylethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide

[0232]

[0233] A solution of bromide (72 mg, 0.37 mmol, 1 eq.), Pd(PPh3)4 (10 mol%), CuI (5 mol%) and triphenylphosphine (10 mg) in triethylamine (1.5 mL, 10.78 mmol, 29.13 eq.) was deoxygenated with argon. A deoxygenated solution of alkyne (171 mg, 0.43 mmol, 1.2 eq.) in DMF (4 mL) was added to the solution within 10 min. The reaction temperature was then raised to 55 °C and stirred for 12 h. The reaction solution was diluted with ethyl acetate (300 mL). The organic layer was washed with water (5×50 mL), saturated NH4Cl (1×50 mL) and brine (1×50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The pure product was obtained by flash column chromatography. Yield: 100 mg, 53%; TLCR f :0.2(10%MeOH / CH2Cl2)

[0234] 1H NMR (500MHz, DMSO-d6) δ10.77 (s, 1H), 9.10 (d, J = 2.2Hz, 1H), 8.97 (d, J = 2.0Hz, 1H), 8.72 (d, J = 2.9Hz, 1H), 8.55 (s, 1H), 8.27 (d, J = 8.6 Hz, 2H), 8.19 (s, 1H), 8.03 (d, J=8.4Hz, 1H), 7.72 (d, J=8.5Hz, 1H), 7.41 (dd, J=9.2, 4.5Hz, 1H), 3.56 (s, 2H), 2.38 (s, 8H), 2.16 (s, 3H); 13 C NMR (126MHz, DMSO-d6) δ163.74, 154.01, 149.01, 145.57, 140.32, 139.44, 138.26, 137.60, 133.01, 131.82, 1 30.29, 126.67, 124.00, 119.90, 119.04, 117.72, 111.59, 94.86, 81.09, 57.88, 55.13, 53.06, 46.08; HRMS (ESI + ):C 27 H 25 F3N7O(MH + ) was calculated to be 520.2067 and the measured value was 520.2066.

[0235] HSL338: N-(5-(imidazo[1,2-b]pyridazin-3-ylethynyl)pyridin-3-yl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide

[0236]

[0237] A solution of bromide (80 mg, 0.404 mmol, 1 eq.), Pd(PPh3)2Cl2 (10 mol%), CuI (5 mol%) and triphenylphosphine (10.5 mg, 0.04 mmol, 10 mol%) in triethylamine (1.5 mL, 10.78 mmol, 26.6 eq.) was deoxygenated with argon. A deoxygenated solution of alkyne (194.9 mg, 0.484 mmol, 1.2 eq.) in DMF (4 mL) was added slowly over 10 min. The reaction temperature was then raised to 50°C and allowed to proceed for 15 h. The reaction was cooled to room temperature, diluted with ethyl acetate (150 mL), and washed with water (5×50 mL) and brine (1×50 mL). The combined organic layers were concentrated in vacuo and purified by column chromatography. Yield: 72.1 mg, 28.6%.

[0238] 1H NMR (500MHz, DMSO-d6) δ10.76 (s, 1H), 8.97–8.90 (m, 1H), 8.71 (dd, J=4.4, 1.5Hz, 1H), 8.57–8.51 (m, 1H), 8.45 (t, J=2.2Hz, 1H), 8.28 (d, J=1. 8Hz, 1H), 8.25 (ddd, J=8.4, 5.4, 1.7Hz, 3H), 7.95 (d, J=8.1Hz, 1H), 7.40 (dd, J=9.2, 4.4Hz, 1H), 3.69 (s, 2H), 2.50–2.37 (m, 8H), 2.26 (s, 3H). 13 C NMR (126MHz, DMSO-d6) δ165.1, 146.5, 145.5, 142.0, 139.2, 135.9, 133.5, 132.2, 131.3, 129.2, 128.0, 127.7, 126. 6, 125.6, 123.5, 119.8, 119.0, 111.8, 95.3, 80.2, 57.8, 54.8, 52.7, 45.6, 40.5, 40.3, 40.1, 40.0, 39.8, 39.6, 39.5.

[0239] HSL381: 5-(Imidazolo[1,2-a]pyridin-3-ylethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide

[0240]

[0241] A solution of bromide (75 mg, 0.381 mmol, 1 eq.), Pd(PPh3)2Cl2 (10 mol%), CuI (5 mol%) and triphenylphosphine (10.5 mg, 0.04 mmol, 10 mol%) in triethylamine (1.5 mL, 10.78 mmol, 28.29 eq.) was deoxygenated with argon. A deoxygenated solution of alkyne (183.6 mg, 0.456 mmol, 1.2 eq.) in DMF (4 mL) was added slowly over 10 min. The reaction temperature was then raised to 50°C and allowed to proceed for 15 h. The reaction was cooled to room temperature, diluted with ethyl acetate (150 mL), and washed with water (5×50 mL) and brine (1×50 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by column chromatography. Yield: 47.8 mg, 24.2%.

[0242] 1H NMR (500MHz, DMSO-d6) δ10.81 (s, 1H), 9.11–9.02 (m, 2H), 8.80 (d, J = 6.7Hz, 1H), 8.62 (d, J = 2.2Hz, 1H), 8.21 (d, J = 2.2Hz, 1H), 8.09 (s, 1H), 8.05 ( dd, J=8.5, 2.2Hz, 1H), 7.73 (t, J=9.4Hz, 2H), 7.46 (dd, J=9.0, 6.7Hz, 1H), 7.17 (t, J=6.7Hz, 1H), 3.58 (s, 3H), 2.48 (s, J=1.7Hz, 8H), 2.25 (s, 3H). 13 C NMR (126MHz, DMSO-d6) δ164.0, 153.9, 148.4, 139.5, 138.3, 137.4, 132.8, 131.8, 130.3, 128.1, 127.8, 127.5, 126.7, 125. 8, 124.0, 123.6, 119.4, 118.0, 117.7, 114.5, 96.0, 81.4, 57.7, 54.8, 52.5, 45.5, 40.5, 40.3, 40.1, 40.0, 39.8, 39.6, 39.5.

[0243] HSL382: 5-(Imidazolo[1,2-a]pyrimidin-3-ylethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide

[0244]

[0245] A solution of bromide (75 mg, 0.378 mmol, 1 eq.), Pd(PPh3)2Cl2 (10 mol%), CuI (5 mol%) and triphenylphosphine (10.5 mg, 0.04 mmol, 10 mol%) in triethylamine (1.5 mL, 10.78 mmol, 28.5 eq.) was deoxygenated with argon. A deoxygenated solution of alkyne (194.9 mg, 0.484 mmol, 1.2 eq.) in DMF (4 mL) was added slowly over 10 min. The reaction temperature was then raised to 50°C and allowed to proceed for 15 h. The reaction was cooled to room temperature, diluted with ethyl acetate (150 mL), and washed with water (5×50 mL) and brine (1×50 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated in vacuo and purified by column chromatography. Yield: 57.6 mg, 29.3%.

[0246] 1H NMR (500MHz, DMSO-d6) δ10.92 (s, 1H), 9.28 (dd, J=6.8, 2.0Hz, 1H), 9.12 (d, J=2.2Hz, 1H), 9.06 (d, J=2.0Hz, 1H), 8.71 (dt, J=4.2, 2.4Hz, 2H), 8.24 (d, J=2.2Hz, 2H), 8.08 (dd, J=8.5, 2.2Hz, 1H), 7.72 (d, J=8.5Hz, 1H), 7.30 (dd, J=6.7, 4.2Hz, 1H), 3.57 (s, 3H), 2.42 (s, 8H), 2.22 (s, 3H). 13 C NMR (126MHz, DMSO-d6) δ163.9, 153.9, 152.6, 149.0, 148.7, 140.4, 138.4, 137.8, 135.3, 132.8, 131.8, 130.2, 128.0, 127. 8, 124.1, 123.6, 119.1, 117.8, 110.8, 106.4, 95.7, 80.6, 57.8, 54.9, 52.7, 45.7, 40.5, 40.3, 40.1, 40.0, 39.8, 39.6, 39.5.

[0247] HSL385: 5-(Imidazolo[1,2-a]pyrazin-3-ylethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide

[0248]

[0249] A solution of bromide (70 mg, 0.353 mmol, 1 eq.), Pd(PPh3)2Cl2 (10 mol%), CuI (5 mol%) and triphenylphosphine (10.5 mg, 0.04 mmol, 10 mol%) in triethylamine (1.5 mL, 10.78 mmol, 30.5 eq.) was deoxygenated with argon. A deoxygenated solution of alkyne (170 mg, 0.424 mmol, 1.2 eq.) in DMF (4 mL) was added slowly over 10 min. The reaction was then moved to 50 °C and allowed to proceed for 15 h. The reaction was cooled to room temperature, diluted with ethyl acetate (150 mL), and washed with water (5×50 mL) and brine (1×50 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated in vacuo and purified by column chromatography. Yield: 71.9 mg, 39.2%.

[0250] 1H NMR (500MHz, DMSO-d6) δ10.85 (s, 1H), 9.21 (d, J = 1.5Hz, 1H), 9.11 (dd, J = 18.4, 2.1Hz, 2H), 8.88 (dd, J = 4.5, 1.5Hz, 1H), 8.69 (d, J = 2.2Hz, 1H), 8.28 ( s, 1H), 8.21 (d, J=2.2Hz, 1H), 8.14 (d, J=4.5Hz, 1H), 8.05 (dd, J=8.4, 2.2H z, 1H), 7.72 (d, J=8.5Hz, 1H), 3.57 (s, 3H), 2.48–2.28 (m, 8H), 2.23 (s, 3H). 13 C NMR (126MHz, DMSO-d6) δ163.9, 154.1, 148.9, 143.7, 140.9, 140.4, 138.3, 137.9, 132.9, 131.8, 131.3, 130.3, 128.0, 127.8, 1 25.8, 124.0, 123.6, 119.9, 118.8, 117.8, 108.9, 96.7, 79.8, 57.8, 54.9, 52.7, 45.7, 40.5, 40.3, 40.1, 40.0, 39.8, 39.6, 39.5.

[0251] HSL407: 5-(Imidazolo[1,2-a]pyrazin-5-ylethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide

[0252]

[0253] A solution of bromide (56 mg, 0.283 mmol, 1 eq.), Pd(PPh3)2Cl2 (10 mol%), CuI (5 mol%) and triphenylphosphine (7.86 mg, 0.03 mmol, 10 mol%) in triethylamine (1.5 mL, 10.78 mmol, 38.1 eq.) was deoxygenated with argon. A deoxygenated solution of alkyne (137 mg, 0.341 mmol, 1.2 eq.) in DMF (4 mL) was added slowly over 10 min. The reaction was then moved to 50 °C and allowed to proceed for 15 h. The reaction was cooled to room temperature, diluted with ethyl acetate (150 mL), and washed with water (5×50 mL) and brine (1×50 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated in vacuo and purified by column chromatography. Yield: 125.8 mg, 85.6%.

[0254] 1H NMR (500MHz, DMSO-d6) δ10.87 (s, 1H), 9.17 (d, J = 2.0Hz, 3H), 8.76 (q, J = 2.5Hz, 1H), 8.57 (s, 1H), 8.32 (s, 1H), 8.21 (d, J=2.2Hz, 1H), 8.07–8.00 (m, 2H), 7.72 (d, J=8.5Hz, 1H), 3.57 (s, 3H), 2.47–2.27 (m, 8H), 2.22 (s, 3H). 13 C NMR (126MHz, DMSO-d6) δ163.8, 154.8, 149.7, 143.7, 140.0, 138.7, 138.3, 136.8, 134.2, 133.0, 131.8, 130.4, 128.1 , 125.8, 124.0, 117.9, 117.7, 115.4, 114.9, 96.8, 82.9, 57.8, 54.9, 52.7, 45.7, 40.5, 40.3, 40.1, 40.0, 39.8, 39.6.

[0255] HSL420: 5-(imidazo[1,2-b]pyridazin-3-ylethynyl)-6-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide

[0256]

[0257] A solution of bromide (100 mg, 0.510 mmol, 1 eq.), Pd(PPh3)2Cl2 (10 mol%), CuI (5 mol%) and triphenylphosphine (13.1 mg, 0.05 mmol, 10 mol%) in triethylamine (1.5 mL, 10.78 mmol, 21.1 eq.) was deoxygenated with argon. A deoxygenated solution of alkyne (254.6 mg, 0.612 mmol, 1.2 eq.) in DMF (4 mL) was added slowly over 10 min. The reaction was then moved to 50 °C and allowed to proceed for 15 h. The reaction was cooled to room temperature, diluted with ethyl acetate (150 mL), and washed with water (5×50 mL) and brine (1×50 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated in vacuo and purified by column chromatography. Yield: 104.5 mg, 38.4%.

[0258] 1H NMR (500MHz, DMSO-d6) δ10.69 (s, 1H), 8.99 (d, J=2.2Hz, 1H), 8.73 (dd, J=4.3, 2.2Hz, 1H), 8.49 (d, J=2.3Hz, 1H), 8.28–8.24 (m, 2H), 8.19 (d, J=2 .5Hz, 1H), 8.04 (d, J=8.4Hz, 1H), 7.70 (d, J=8.5Hz, 1H), 7.40 (ddd, J=9.1, 4.5, 1.9Hz, 1H), 3.56 (s, 2H), 2.80 (s, 3H), 2.41 (s, 8H), 2.21 (s, 3H). 13 C NMR (126MHz, DMSO-d6) δ163.8, 162.7, 148.4, 145.6, 140.3, 139.1, 138.4, 137.7, 132.8, 131.8, 128.0, 127.8, 126. 7, 124.0, 119.8, 117.8, 111.8, 95.2, 83.7, 57.8, 55.0, 52.8, 45.8, 40.5, 40.3, 40.2, 40.0, 39.8, 39.7, 39.5, 24.0.

[0259] HSL432: 5-((6-chloroimidazo[1,2-b]pyridazin-3-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide

[0260]

[0261] A solution of bromide (100 mg, 0.43 mmol, 1 eq.), Pd(PPh3)2Cl2 (10 mol%), CuI (5 mol%) and triphenylphosphine (10.5 mg, 0.04 mmol, 10 mol%) in triethylamine (1.5 mL, 10.78 mmol, 25.1 eq.) was deoxygenated with argon. A deoxygenated solution of alkyne (207.5 mg, 0.52 mmol, 1.2 eq.) in DMF (4 mL) was added slowly over 10 min. The reaction was then moved to 50 °C and allowed to proceed for 15 h. The reaction was cooled to room temperature, diluted with ethyl acetate (150 mL), and washed with water (5×50 mL) and brine (1×50 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated in vacuo and purified by column chromatography. Yield: 96.3 mg, 40.4%.

[0262] 1H NMR (500MHz, DMSO-d6) δ10.81 (s, 1H), 9.12 (d, J = 2.2Hz, 1H), 8.98 (d, J = 2.0Hz, 1H), 8.57 (t, J = 2.1Hz, 1H), 8.34 (d, J = 9.5Hz, 1H), 8.29 (s, 1H), 8.20 (d, J = 2.2Hz, 1H), 8.06–8.01 (m, 1H), 7.71 (d, J = 8.5Hz, 1H), 7.54 (d, J = 9.4Hz, 1H), 3.57 (s, 2H), 2.44 (s, 8H), 2.24 (s, 3H).

[0263] HSL442: N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-5-(pyrazolo[1,5-a]pyridin-3-ylethynyl)nicotinamide

[0264]

[0265] A solution of bromide (80 mg, 0.406 mmol, 1 eq.), Pd(PPh3)2Cl2 (10 mol%), CuI (5 mol%) and triphenylphosphine (10.5 mg, 0.04 mmol, 10 mol%) in triethylamine (1.5 mL, 10.78 mmol, 26.5 eq.) was deoxygenated with argon. A deoxygenated solution of alkyne (195.9 mg, 0.487 mmol, 1.2 eq.) in DMF (4 mL) was added slowly over 10 min. The reaction was then moved to 50 °C and allowed to proceed for 15 h. The reaction was cooled to room temperature, diluted with ethyl acetate (150 mL), and washed with water (5×50 mL) and brine (1×50 mL). The combined organic layers were concentrated in vacuo and purified by column chromatography. Yield: 30.2 mg, 14.3%.

[0266] 1 H NMR (500MHz, DMSO-d6) δ10.79 (s, 1H), 9.04 (d, J = 2.2Hz, 1H), 8.95 (d, J = 2.0Hz, 1H) , 8.82 (d, J = 7.0Hz, 1H), 8.52 (t, J = 2.1Hz, 1H), 8.36 (s, 1H), 8.21 (d, J = 2.2Hz, 1H), 8 .05(dd, J=8.5, 2.2Hz, 1H), 7.94(d, J=8.8Hz, 1H), 7.72(d, J=8.5Hz, 1H), 7.50–7.4 3(m, 1H), 7.08(td, J=6.9, 1.4Hz, 1H), 3.57(s, 2H), 2.46–2.30(m, 8H), 2.23(s, 3H).

[0267] HSL412: N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-5-(pyrazolo[1,5-a]pyrimidin-6-ylethynyl)nicotinamide

[0268]

[0269] A solution of bromide (80 mg, 0.404 mmol, 1 eq.), Pd(PPh3)2Cl2 (10 mol%), CuI (5 mol%) and triphenylphosphine (10.5 mg, 0.04 mmol, 10 mol%) in triethylamine (1.5 mL, 10.78 mmol, 26.6 eq.) was deoxygenated with argon. A deoxygenated solution of alkyne (194.9 mg, 0.484 mmol, 1.2 eq.) in DMF (4 mL) was added slowly over 10 min. The reaction was then moved to 50 °C and allowed to proceed for 15 h. The reaction was cooled to room temperature, diluted with ethyl acetate (150 mL), and washed with water (5×50 mL) and brine (1×50 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated in vacuo and purified by column chromatography. Yield: 67.9 mg, 32.2%.

[0270] 1 H NMR (500MHz, DMSO-d6) δ10.86 (s, 1H), 9.58 (d, J=2.0Hz, 1H), 9.13 (d, J=2.2 Hz, 1H), 8.97 (d, J=2.0Hz, 1H), 8.71 (d, J=2.1Hz, 1H), 8.55 (t, J=2.2Hz, 1H), 8.34 (d, J=2.3Hz, 1H), 8.21 (d, J=2.2Hz, 1H), 8.05 (dd, J=8.5, 2.2Hz, 1H), 7 .72 (d, J=8.5Hz, 1H), 6.84 (d, J=2.2Hz, 1H), 2.50–2.34 (m, 8H), 2.28 (s, 3H). 13 C NMR (126MHz, DMSO-d6) δ163.8, 154.4, 151.3, 149.0, 147.1, 147.0, 139.2, 138.3, 138.1, 132.8, 131.9, 130.3, 127.8, 1 25.8, 124.0, 119.0, 117.8, 104.5, 98.0, 89.2, 87.6, 57.7, 54.7, 52.4, 45.3, 40.5, 40.3, 40.1, 40.0, 39.8, 39.6, 39.5.

[0271] According to some embodiments, the compositions disclosed herein can be delivered to a subject by injection. A composition of one or more groups of compounds selected from lncRNA transcript cluster Mhrt RNA selected from Group 1 to Group 1 or species modified by minerals can be prepared in an injection form and loaded into an injectable device (e.g., a syringe) to be injected into the subject's body. Fig.30 is an illustration of a therapeutic delivery device (9100) comprising an injectable drug delivery device (9120) and a composition or combination of compositions disclosed herein in the form of an injection fluid (9110). The compositions disclosed herein can be delivered and enter a body part or organ (9140) of a subject by injection through a wall (9150) of the body part or organ (9140) of the subject. In selected embodiments, the injectable drug delivery device can reside outside (9142) of the body part or organ (9140) of the subject.

[0272] Fig.30 Only one illustrative embodiment for delivering the disclosed pharmaceutical composition into a subject is represented. The delivery device may not be limited to a syringe-type device. One of ordinary skill in the art will readily appreciate that any injectable device suitable for delivering the disclosed product or medicament to the patient's body may be used in accordance with aspects of the present invention. For example, the therapeutic delivery device may be a capsule, a pill, a tablet, a transdermal patch, or a dietary supplement, or a combination thereof, etc. It should also be understood that the delivery device may be designed to control the release or delay the release of the disclosed compound.

[0273] All publications, patents, and patent applications cited herein are incorporated by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety.

[0274] Although the present disclosure has been disclosed with reference to certain embodiments, various modifications, variations and changes may be made to the described embodiments without departing from the scope of the present disclosure as defined by the appended claims. Therefore, the present disclosure is not limited to the described embodiments, but has the full scope defined by the language of the appended claims and their equivalents.

[0275] refer to:

[0276] 1.FDA Approves Pronatinib, US Food & Drug Administration https: / / www.fda.gov / drugs / informationondrugs / approveddrugs / ucm381452.htm

[0277] 2.Mingqiang,R.et al.Noel FGFR inhibitor ponatinib suppresses growthof non-small cell lung cancer cells overexpressing FGFR1.Oncol.Rep.29,2181-2190(2013).

[0278] 3.De Falco,V.et al.Ponatinib(AP24534)is a novel potent inhibitor ofoncogenic RET mutants associated with thyroid cancer.J.Clin.Endocrinol.Metab.98,E811-E819(2013).

[0279] 4.Gibbons,D.L.,Pricl,S.Kantargian,H.,Cortes,J.,&Quintas-Cardama,A.Therise and fall of gatekeeper mutations?The BCR-ABL T315I paradigm.Cancer.118,293-299(2011).

[0280] 5.NCT02428543 Ponatinib for FLT3-ITD acute myelogenous leukemia(PONATINIB-AML),NIH U.S.National Library of Medicine https: / / clinicaltrials.gov / ct2 / show / NCT02428543

[0281] 6.NCT02265341 Ponatinib hydrochloride in treating patients withadvanced biliary cancer with fgfr2 fusions,NIH U.S.National Library ofMedicine https: / / clinicaltrials.gov / ct2 / show / NCT02265341

[0282] 7.NCT01813734ponatinib in advanced NSCLC w / RET translocation,NIHU.S.National Library of Medicine https: / / clinicaltrials.gov / ct2 / show / NCT01813734

[0283] 8.Aghel,N.,Delgado,D.H.,&Lipton,J.H.cardiovascular toxicities of BCR-ABL tyrosine kinase inhibitors in chronic myeloid leukemia:preventivestrategies and caridovasuclar surveillance.Vasc.Health.Risk.Manag.13,293-303(2017).

[0284] 9.Pasvolsky,O.et al.Tyrosine kinase inhibitor associated vasculartoxicity in chronic myeloid leukemia.Cardio-Oncology.1; 10.1186 / s40959-015- 0008-5 (2015).

[0285] 10.Banavath,H.N.,Sharma,O.P.,Kumar,M.S.,&Baskaran,R.Identification ofnovel tyrosine kinase inhibitors for drug resistant T315I muatant BCR-ABL:avirtual screening and molecular dynamics simulations study.Sci.Rep.4,6948;DOI:10.1038 / srep06948(2014).

[0286] 11.Moslehi,J.J.,&Meininger,M.Tyrosine kinase inhibitor-associatedcardiovascular toxicity in chronic myeloid leukemia.J.Clin.Oncol.,35,4210-7218(2015).

[0287] 12.Hou J et al.,Targeting Mnks for Cancer Therapy.Oncotarget,118–131(2012).

[0288] 13.LogP was calculated using the Swiss Institute of BioinformaticsSwissADME online software.

[0289] 14.Kuppuswamy,D.et al.Association of tyrosine-phosphorylated c-Srcwith the cytoskeleton of hypertrophying myocardium.J.Biol.Chem.272,4500-4501(1997).

[0290] 15.Schlichter,L.C.et al.Regulation of hERG and hEAG channels by Srcand by SHP-1tyrosine phosphatase via an ITIM region in the cyclic nucleotidebinding domain.Plos.One.9,e90024;doi:10.1371 / journal.pone.0090024(2014).

[0291] 16.Golden,A.,Nemeth S.P.,&Brugge,J.S.Blood platelets express highlevels of the pp60c-src-specific tyrosine kinase activity.PNAS.83,852-856(1986).

[0292] 17.Shattil,S.J.,Kim,C.,&Ginsberg,M.H.The final steps of integrinactivation:the end game.Nat.Rev.Mol.Cell.Biol.11,288-300(2010).

[0293] 18.Hierro,H.,Roden,J.,&Tabernero,J.Fibroblast Growth Factor(FGF)Receptor / FGF inhibitors:novel targets and strategies for optimization ofresponse of solid tumors.Semin.Oncol.42,801-819(2015).

[0294] 19.Yanochko,G.M.et al.Pan-FGFR inhibition leads to blockade of FGF23signaling,soft tissue mineralization,and cardiovasculardysfunction.Toxicol.Sci.135,451-464(2013).

[0295] 20.Daver,N.et al.Secondary mutations as mediators of resistance totargeted therapy in leukemia.Blood.125,3236-3245(2015).

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Claims

1. Compounds having the following structure:

2. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

3. Use of the pharmaceutical composition according to claim 2 in the preparation of a medicament for improving cancers associated with protein kinases.

4. The use according to claim 3, wherein The cancer is selected from the group consisting of ovarian cancer, cervical cancer, pancreatic cancer, breast cancer, brain cancer, skin cancer, lung cancer, prostate cancer, lymphoma, leukemia, colon cancer, head cancer, neck cancer, thyroid cancer, kidney cancer, liver cancer and stomach cancer.

5. Use of the pharmaceutical composition according to claim 2 in the preparation of a medicament for improving a disease or condition associated with protein kinase.

6. The use according to claim 5, wherein the protein kinase is Abl, Abl2, AFK, ALK, ATM, ATR, Aurora kinase A, Aurora kinase B, Axl, BCKDK, BLK, BMPR1B, BMX, Brk, BRSK1, BTK, CaM-KIα, CaM-KIIα, CaM-KIV, CaM-KKα, CaM-KKβ, CCDPK, CCRK, CDK1, CDK11, CDK2, CDK4, CDK5, CDK6, CDK7, CDK9, CDPK, Chak1, CHK1, CHK2, CK1α, CK1δ, CK1ε, CK2α, CK2_β, CLK1, CSF1R , Csk, DAPK1, DAPK2, DAPK3, DCAMKL1, DNA-PK, DYRK1A, DYRK1B, DYRK2, DYRK3, eEF2K, Eg3 kinase, EGFR, EIF2AK2, EphA2, EphA3, EphA4, EphA8, EphB1, EphB2, EphB3, EphB5, ErbB2, FAK, Fer, Fes, FGFR1, FGFR3, FGFR4, Fgr, FLT1, FLT3, FLT4, Fyn, GRK-1, GRK-2, GRK-3, GRK-4, GRK-5, GRK-6, GSK-3α, GSK-3β, HCK, HIPK2, HIPK3, HRI, ICK, IGF1R, IKK-α, IKK-β, IKK-εILK, InsR, IPL1, IRAK1, IRAK4, ITK, JAK1, JAK2, JAK3, KDR, KIS, Kit, KSR1, Lck, LIMK1, LIMK2, LKB1 , LOK, Lyn, MAP2K1, MAP2K2, MAP2K3, MAP2K4, MAP2K6, MAP2K7, MAP3K1, MAP3K11, MAP3K14, MAP3K5, MAP3K7, MAP3K8, MAP4K1, MAP4K2, MAP4K4, MAPK1, MAP K10, MAPK11, MAPK12, MAPK13, MAPK14, MAPK3, MAPK4, MAPK6, MAPK7, MAPK8, MAPK9, MAPKAPK2, Mer, Met, MHCK, MLKL, MK2, MOS, MRCKa, MST1, MST3, mTOR, N DR1, NDR2, NEK1, NEK2, NEK6, NEK9, NLK, NuaK1, p37 kinase, p70S6K, p70S6Kb, PAK1, PAK2, PAK3, PAK5, PAK6, PASK, P-CIP2, PCTAIRE1, PDGFRα, PDGFRβ, PDHK1,PDHK2, PDHK3, PDHK4, PDK-1, PDK-2, PIK3CA, PIK3CB, PIK3CD, PIK3CG, Pim-1, PKAα, PKBβ, PKCα, PKCβ, PKCδ, PKCε, PKCη ,PKCγ,PKCι,PKCθ,PKCζ,PKD1,PKD2,PKD3,PKG1 / cGK-I,PKG2 / cGK-II,PKN1,PLK1,PLK2,PLK3,PRP4,PYK2,RAF1,Ret,R IPK1, ROCK2, Ron, RPL10, RSK-1, RSK-2, RSK-3, RSK-5, SDK1, SIK, Sky, Src, STLK3, Syk, TBK1, Tec, TESK1, TESK2, TGFbR1, TGFbR2, Tie1, Tie2, titin kinase, TNK2, TRKA, TRKB, tropomyosin kinase, TSSK3, TXK, Tyk2, TYK2, VRK1, Wee1, Wnk1, WNK1, Yes, ZAP70.

7. The use according to claim 5, wherein The disease or disorder is cancer, diabetes, malaria, viral infection, cardiovascular disease and hypertension, CNS and neurodegeneration, osteoporosis, pulmonary fibrosis, retinitis pigmentosa, wet macular degeneration, Duchenne muscular dystrophy, diabetic eye disease, inflammatory and autoimmune diseases or allergies.

8. A therapeutic delivery device comprising a device and at least one dose of a composition contained in the device, wherein the composition is a therapeutically effective amount of the compound of claim 1 or the pharmaceutical composition of claim 2.

9. A therapeutic delivery device comprising a delivery mechanism selected from the group consisting of: a capsule, a multi-pill, a tablet, a transdermal patch, a dietary supplement, or a combination thereof; and at least one dose of a composition contained in the delivery mechanism, wherein the composition is a therapeutically effective amount of the compound of claim 1 or the pharmaceutical composition of claim 2.

10. The therapeutic delivery device of claim 8 or 9, wherein: The therapeutic delivery device allows for the controlled release of a composition contained within the device or the delivery mechanism.

11. The therapeutic delivery device of claim 8 or 9, wherein: The therapeutic delivery device allows for delayed release of a composition contained within the device or the delivery mechanism.

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