Kinase inhibitors and their uses

Abstract

Kinase inhibitors, pharmaceutical compositions comprising such compounds, and methods of using such compounds or compositions are provided, e.g., methods of treating a proliferative disorder such as a cancer or tumor, or in some embodiments, a disease or disorder associated with dysregulation of a kinase, such as, but not limited to, MEK, COT1, FGFR4, MINK, MYO3A, PKG1B, and PLK3.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority and benefits of U.S. Provisional Application No. 63 / 126,364, filed on 16 December 2020, the disclosure of which is incorporated herein by reference in whole.

[0002] field This disclosure relates to compounds, pharmaceutical compositions comprising such compounds, and the use of such compounds or compositions in methods for treating or in pharmaceuticals for treating diseases or disorders related to proliferation abnormalities, cancer or tumors, or, in some embodiments, not limited to, dysregulation of kinases such as MEK kinase. [Background technology]

[0003] background This disclosure relates to the treatment of abnormal cell growth in mammals, particularly humans, such as cancer, more specifically solid tumors and brain tumors, by novel cyclic amines and their isotopic derivatives described herein, and pharmaceutical compositions containing such compounds. In addition, this disclosure relates to methods for preparing such compounds.

[0004] Kinases are enzymes that catalyze the transfer of phosphate groups from high-energy phosphate donor molecules to specific substrates. This process is known as phosphorylation, in which the substrate acquires a phosphate group and a high-energy ATP molecule donates a phosphate group. This transesterification produces a phosphorylated substrate and ADP.

[0005] Kinases are broadly classified into protein kinases, lipid kinases, and carbohydrate kinases based on the substrates they act on. Kinases can be found in a wide variety of species, from bacteria and fungi to helminths and mammals. More than 500 different kinases have been identified in humans.

[0006] MAP kinases (MAPKs) are a family of serine / threonine kinases that respond to various extracellular growth signals. For example, growth hormone, epidermal growth factor, platelet-derived growth factor, and insulin are all thought to be pro-mitotic stimuli that may be involved in the MAPK pathway. Activation of this pathway at the receptor level initiates a signaling cascade, in which Ras GTPase replaces GDP with GTP. Ras then activates Raf kinase (also known as MAPKKK), which in turn activates MEK (MAPKK). MEK then activates MAPK (also known as ERK), which can subsequently regulate transcription and translation. Both RAF and MAPK are serine / threonine kinases, while MAPKK is a tyrosine / threonine kinase.

[0007] The oncogenic potential of the MAPK pathway makes this clinically significant. It is associated with cellular processes that can lead to uncontrolled growth and subsequent tumorigenesis. Mutations within this pathway alter their regulatory effects on cell differentiation, proliferation, survival, and apoptosis, all of which are associated with various forms of cancer.

[0008] Such kinases are known to be abnormally expressed at high frequencies in common human cancers such as melanoma, colorectal cancer, thyroid cancer, glioma, breast cancer, and lung cancer.

[0009] Kinase inhibition is a useful method for inhibiting the growth of mammalian cancer cells and, consequently, for treating certain forms of cancer. Various compounds, such as pyrrolopyridine and anilinopyrimidine derivatives, have been shown to possess kinase inhibitory properties. Many patent publications refer to specific bicyclic derivatives, particularly quinazolinone derivatives.

[0010] Several compounds with diverse chemical structures have evolved into MEK inhibitors, and four of them (trametinib, cobimetinib, binimetinib, and selumetinib) are described as potent allosteric MEK1 / 2 inhibitors. For example, trametinib inhibits the MEK1 / 2 enzyme in the low nanomolar range. TIFF2023554391000001.tif106131

[0011] However, due to their structural characteristics, the pharmacokinetic properties exhibited by many of these kinase inhibitors are insufficient, and some of them become substrates for active transporters such as P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP), and have a very low tendency to penetrate cell membranes and the brain. Therefore, they are not suitable for use in the treatment of tumors or cancers in the brain protected by the blood-brain barrier (BBB).

[0012] Therefore, the compounds of the present disclosure, which are selective inhibitors of specific kinases, are useful in the treatment of abnormal cell growth in mammals, particularly cancer. In addition, these compounds have good cell membrane permeability and are thus useful for treating tumors or cancers including brain tumors in humans. Summary of the Invention

[0013] Summary In one aspect, compounds of formula (I), or pharmaceutically acceptable salts, solvates or isotope derivatives thereof are provided: TIFF2023554391000002.tif72128 wherein, G 1 is CH or CR 2 and G 2 , G 3 , and G 4 are independently of each other N, CH, or CR 2 but; provided that G 2 , G 3 , and G 4At least two of them are CH or CR, independently of each other. 2 and; Furthermore, however, G 1 If it is CH, then G 2 , G 3 , and G 4 At least one of them is N or CR 2 and; m is 0, 1, 2, 3, 4, or 5; p is 0, 1, 2, 3, or 4; q is 1, 2, or 3; Each R 1 These are independently selected from the group consisting of halogens, OH, NH2, NO2, CN, optionally substituted C1-C6 alkyls, optionally substituted C2-C6 alkenyls, optionally substituted C2-C6 alkynyls, optionally substituted C1-C6 alkoxys, -O-[(optionally substituted C1-C6 alkylene)-(optionally substituted C1-C6 alkoxy)], -NH(optionally substituted C1-C6 alkyl), -N(optionally substituted C1-C6 alkyl)2, -NH[(optionally substituted C1-C6 alkylene)-(optionally substituted C1-C6 alkoxy)], -N[(optionally substituted C1-C6 alkylene)-(optionally substituted C1-C6 alkoxy)]2, -C(=O)-(optionally substituted C1-C6 alkyl), -C(=O)-(optionally substituted C2-C6 alkenyl), and -C(=O)-(optionally substituted C2-C6 alkynyl); Each R 2These are independently halogens, OH, NH2, NO2, CN, optionally substituted C1-C6 alkyls, optionally substituted C2-C6 alkenyls, optionally substituted C2-C6 alkynyls, optionally substituted C1-C6 haloalkyls, optionally substituted C1-C6 alkoxys, -[(optionally substituted C1-C6 alkylene)-(optionally substituted C1-C6 alkoxy)], -O-[(optionally substituted C1-C6 alkylene)-(optionally substituted C1-C6 alkoxy)], -NH(optionally substituted Selected from the group consisting of good C1-C6 alkyl, -N(optionally substituted C1-C6 alkyl)2, -NH[(optionally substituted C1-C6 alkylene)-(optionally substituted C1-C6 alkoxy)], -N[(optionally substituted C1-C6 alkylene)-(optionally substituted C1-C6 alkoxy)]2, -C(=O)-(optionally substituted C1-C6 alkyl), -C(=O)-(optionally substituted C2-C6 alkenyl), and -C(=O)-(optionally substituted C2-C6 alkynyl); Each R 3These are independently halogen, OH, NH2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, -[(optionally substituted C1-C6 alkylene)-(optionally substituted C1-C6 alkoxy)], optionally substituted C1-C6 alkylene-COOH, optionally substituted C1-C6 alkylene-C(=O)-O-(optionally substituted C1-C6 alkyl), optionally substituted C1-C6 alkoxy, -O-[(optionally substituted C1-C6 alkylene)-(optionally substituted C1-C6 alkoxy)] Selected from the group consisting of -NH (may be substituted C1-C6 alkyl), -N (may be substituted C1-C6 alkyl)², -NH[(may be substituted C1-C6 alkylene)-(may be substituted C1-C6 alkoxy)], -N[(may be substituted C1-C6 alkylene)-(may be substituted C1-C6 alkoxy)]², -C(=O)-(may be substituted C1-C6 alkyl), -C(=O)-(may be substituted C2-C6 alkenyl), and -C(=O)-(may be substituted C2-C6 alkynyl); and R 4This includes halogens, OH, NH2, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 haloalkyls, -[(optionally substituted C1-C6 alkylene)-(optionally substituted C1-C6 alkoxy)], optionally substituted C1-C6 alkylene-COOH, optionally substituted C1-C6 alkylene-C(=O)-O-(optionally substituted C1-C6 alkyl), optionally substituted C1-C6 alkoxy, -O-[(optionally substituted C1-C6 alkylene)-(optionally substituted C1-C6 alkoxy)], - The group is selected from NH (may be substituted C1-C6 alkyl), -N (may be substituted C1-C6 alkyl)2, -NH[(may be substituted C1-C6 alkylene)-(may be substituted C1-C6 alkoxy)], -N[(may be substituted C1-C6 alkylene)-(may be substituted C1-C6 alkoxy)]2, -C(=O)-(may be substituted C1-C6 alkyl), -C(=O)-(may be substituted C2-C6 alkenyl), and -C(=O)-(may be substituted C2-C6 alkynyl).

[0014] In another context, compounds of formula (I-1), or pharmaceutically acceptable salts, solvates, or isotopic derivatives thereof are provided. TIFF2023554391000003.tif69128 formula, G 1 , G 2 , G 3 , G 4 , p, q, R 1 , R 2 , R 3 , and R 4 This is as defined with respect to equation (I).

[0015] In another context, compounds of formula (I-2a), (I-2b), or (I-2c), or pharmaceutically acceptable salts, solvates, or isotopic derivatives thereof are provided. TIFF2023554391000004.tif69128TIFF2023554391000005.tif143128In formula, G 1 , G2 , G 3 , G 4 , p, R 1 , R 2 , R 3 , and R 4 This is as defined with respect to equation (I).

[0016] In another context, compounds of formula (I-3a), (I-3b), or (I-3c), or pharmaceutically acceptable salts, solvates, or isotopic derivatives thereof are provided. TIFF2023554391000006.tif218106 formula, G 1 , G 2 , G 3 , G 4 , R 1 , R 2 , R 3 , and R 4 This is as defined with respect to equation (I).

[0017] In some embodiments, the compounds listed in Table 1, or pharmaceutically acceptable salts, solvates, or isotopic derivatives thereof are provided.

[0018] In some aspects, pharmaceutical compositions are provided that contain a compound of any of the formulas described herein, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, and a pharmaceutically acceptable diluent or carrier.

[0019] In some cases, combinations are provided that include at least one compound of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-3a), (I-3b), (I-3c), or a compound from Table 1, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, and a second prophylactic or therapeutic agent.

[0020] In some aspects, compounds of formula (I), such as (I-1), (I-2a), (I-2b), (I-2c), (I-3a), (I-3b), (I-3c), or compounds of Table 1, or pharmaceutically acceptable salts, solvates, or isotopic derivatives thereof, are provided for use in the treatment and / or prevention of proliferation abnormalities such as cancer or tumors in a subject. In some embodiments, the proliferation abnormality or cancer is selected from the group consisting of malignant or benign tumors of the liver, kidney, bladder, breast, stomach, ovary, colorectal, prostate, pancreas, lung, vulva, thyroid, liver cancer, sarcoma, glioblastoma, head and neck, melanoma, as well as other hyperplastic conditions such as benign hyperplasia of the skin and benign hyperplasia of the prostate.

[0021] In some aspects, methods are provided for treating and / or preventing growth abnormalities such as cancer or tumors in a subject, comprising the step of administering to the subject an effective amount of a compound of any of the formulas shown herein or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, or a pharmaceutical composition containing a compound of any of the formulas disclosed herein, or a combination containing any of the formulas disclosed herein. In some embodiments, the growth abnormalities or cancers are selected from the group consisting of malignant or benign tumors of the liver, kidney, bladder, breast, stomach, ovary, colorectal, prostate, pancreas, lung, vulva, thyroid, hepatocellular carcinoma, sarcoma, glioblastoma, head and neck, melanoma, and other hyperplastic conditions such as benign hyperplasia of the skin and benign hyperplasia of the prostate.

[0022] In some aspects, this disclosure provides the use of at least one compound of any of the formulas described herein or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof for the manufacture of pharmaceuticals.

[0023] In some aspects, the present disclosure provides a method for inducing an antiproliferative or antimetastatic effect in subjects having a proliferative disorder, cancer, or tumor that is sensitive to inhibition of relevant kinases such as MEK, comprising the step of administering to the subject an effective amount of a compound of any of the formulas disclosed herein or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, or a pharmaceutical composition containing a compound of any of the formulas disclosed herein, or a combination containing any of the formulas disclosed herein.

[0024] In some aspects, compounds of formula (I), such as compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-3a), (I-3b), (I-3c), or compounds of Table 1, or pharmaceutically acceptable salts, solvates, or isotopic derivatives thereof, are provided for use in the treatment of neurodegenerative diseases. In some embodiments, the neurodegenerative disease is selected from the group consisting of amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, and Huntington's disease.

[0025] In some aspects, this disclosure provides methods for treating neurodegenerative diseases in subjects. In some embodiments, the method comprises administering to a subject an effective amount of a compound of any of the formulas disclosed herein or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, or a pharmaceutical composition containing a compound of any of the formulas disclosed herein, or a combination containing any of the formulas disclosed herein. In some embodiments, the neurodegenerative disease is selected from the group consisting of amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, and Huntington's disease.

[0026] In some aspects, this disclosure provides methods for treating immunodeficiency disorders in subjects. In some embodiments, the method comprises administering to a subject an effective amount of a compound of any of the formulas disclosed herein or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, or a pharmaceutical composition containing a compound of any of the formulas disclosed herein, or a combination containing any of the formulas disclosed herein. In some embodiments, the immunodeficiency disorders are selected from the group consisting of cancer, infectious diseases, and several genetic diseases.

[0027] In another aspect, a method is provided for inhibiting the activity of one or more kinases in cells, such as MEK, COT1, FGFR4, MINK, MYO3A, PKG1B, and PLK3, comprising the step of contacting cells in vitro, ex vivo, or in vivo with an effective amount of a compound of any of the formulas disclosed herein or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, or a pharmaceutical composition containing a compound of any of the formulas disclosed herein, or a combination containing any of the formulas disclosed herein. [Modes for carrying out the invention]

[0028] Detailed explanation definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly interpreted by those skilled in the art in which the present invention pertains. All patents, applications, published applications, and other publications referenced herein are incorporated by reference in their entirety. If any definition set forth in this section conflicts with or otherwise does not match any definition set forth in a patent, application, or other publication incorporated herein by reference, the definition set forth in this section shall prevail over the definition set forth in the patent, application, or other publication incorporated herein by reference.

[0029] As used herein, “a” or “an” means “at least one” or “one or more.”

[0030] As used herein, any reference to a value or parameter preceded by "approximately" includes (and refers to) the value or parameter itself. For example, a reference to "approximately X" includes a reference to "X".

[0031] Unless otherwise specified, the terms “individual” or “subject” as used herein are intended to refer to mammals, including, but not limited to, humans, cattle, primates, horses, dogs, cats, pigs, and sheep. Therefore, the compositions and methods provided herein have applications in both human medical and veterinary contexts, including applications in agricultural animals and domestic pets. An individual may be a human who has been diagnosed with or is suspected of having one of the conditions described herein, such as cancer. An individual may be a human exhibiting one or more symptoms associated with one or more of the conditions described herein, such as cancer. An individual may be a human with mutated or abnormal genes associated with one of the conditions described herein, such as cancer. An individual may be a human who is genetically predisposed to or at risk of developing one of the conditions described herein, such as cancer.

[0032] As used herein, “treatment” or “to treat” means an approach to obtain a beneficial or desired outcome, including a clinical outcome. For the purposes of the compositions and methods provided herein, a beneficial or desired clinical outcome includes, but is not limited to, one or more of the following: reducing one or more symptoms caused by a condition; reducing the severity of a condition; stabilizing a condition (e.g., preventing or delaying worsening of the condition); preventing or delaying the spread of a condition (e.g., metastasis); delaying or slowing the progression of a condition; improving a condition; achieving remission of the disease (whether partial or complete); reducing the dose of one or more other agents required to treat a condition; enhancing the effect of another agent used to treat a condition; improving the quality of life of an individual with a condition; and / or extending survival. Methods of treating cancer encompass a reduction of the pathological outcomes of cancer. Methods described herein aim to achieve any one or more of these aspects of treatment.

[0033] As used herein, a “at-risk” individual is an individual at risk of developing a disease or condition as described herein, such as cancer. A “at-risk” individual may or may not have a detectable disease, and may or may not have shown a detectable disease prior to the treatment methods described herein. “At-risk” means that an individual has one or more so-called risk factors, which are measurable parameters that correlate with the development of a disease or condition as described herein, such as cancer. An individual having one or more of these risk factors is more likely to develop the disease or condition than an individual without these risk factors.

[0034] As used herein, “combination therapy” means a therapy comprising two or more different compounds. Thus, in one aspect, combination therapies are provided that include the compounds detailed herein with other compounds. In some variations, combination therapy optionally includes one or more pharmaceutically acceptable carriers or excipients, non-pharmaceutically active compounds, and / or inactive substances. In various embodiments, treatment with combination therapy may result in additive or even synergistic (e.g., greater than additive) results compared to the administration of a single compound provided herein alone. In some embodiments, each compound is used as part of the combination therapy in smaller amounts compared to the amounts commonly used for the individual therapies. Preferably, the same or greater therapeutic benefit is achieved with combination therapy than with the use of any of the individual compounds alone. In some embodiments, the same or greater therapeutic benefit is achieved by using the compounds in the combination therapy in smaller amounts (e.g., lower doses or less frequent dosing schedules) compared to the amounts commonly used for the individual compounds or therapies. Preferably, the use of smaller amounts of a compound results in a reduction in the number, severity, frequency, and / or duration of one or more side effects associated with the compound.

[0035] As used herein, the term “effective dose” refers to the amount of a compound provided herein that is effective in a given therapeutic form, in combination with its efficacy and toxicity parameters. As understood in the Art, an effective dose may be one or more doses, i.e., a single dose or multiple doses may be required to achieve a desired therapeutic endpoint. An effective dose may be considered in the context of administering one or more therapeutic agents, or a single agent may be considered to be administered in an effective dose if a desired or beneficial outcome can or can be achieved in combination with one or more other agents. The preferred dose of any concurrently administered compound may be optionally reduced by the combined effects of the compounds (e.g., additive or synergistic effects). In various embodiments, an effective amount of a composition or therapeutic agent may (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, delay, to some extent delay, or preferably halt, the invasion of cancer cells into peripheral organs; (iv) inhibit tumor metastasis (e.g., to some extent delay, preferably halt); (v) inhibit tumor growth; (vi) prevent or delay tumor development and / or recurrence; and / or (vii) alleviate to some extent one or more symptoms associated with cancer. In various embodiments, the amount may be sufficient to improve, alleviate, reduce, and / or delay one or more symptoms of a disease or condition described herein, such as cancer.

[0036] As is understood in the art, an “effective dose” may be one or more doses, i.e., a single dose or multiple doses may be required to achieve a desired therapeutic endpoint. An effective dose may be considered in the context of administering one or more therapeutic agents, or it may be considered that a compound or a pharmaceutically acceptable salt thereof is given in an effective dose if a desired or beneficial outcome can or can be achieved in combination with one or more other agents.

[0037] "Therapeutic dose" means the amount of a compound or a salt thereof sufficient to produce a desired therapeutic outcome (e.g., to reduce the severity or duration of one or more symptoms of one or more symptoms of a disease or condition described herein, such as cancer, to stabilize the severity of symptoms, or to eliminate symptoms). For therapeutic use, beneficial or desired outcomes include, for example, reducing one or more symptoms (biochemical, histological, and / or behavioral) resulting from the disease or condition, including its complications and intermediate pathological phenotypes that appear at the onset of the disease or condition; improving the quality of life of a person suffering from the disease or condition; reducing the dose of other drugs required to treat the disease or condition; enhancing the effect of another drug; delaying the progression of the disease or condition; and / or extending the patient's survival time.

[0038] An effective dose of a compound or a pharmaceutically acceptable salt thereof, including a prophylactic effective dose, may be administered to an individual in an adjuvant setting, which refers to a clinical setting in which the individual has a history of cancer and has generally (but not necessarily) responded to therapies including surgery (e.g., surgical resection), radiotherapy, and chemotherapy without limitation. However, these individuals are considered to be at risk of developing cancer due to their history of cancer. Treatment or administration in an “adjuvant setting” refers to the subsequent mode of treatment.

[0039] As used herein, “pharmaceutically acceptable” or “pharmacologically acceptable” means a material that is not biologically or otherwise undesirable, for example, that can be incorporated into a pharmaceutical composition administered to a patient without causing any significant or undesirable biological effect or interacting in an adverse manner with any other component of the composition containing it. Pharmacochemically acceptable carriers or excipients are preferably those that meet toxicological and manufacturing testing requirements and / or are included in the Inactive Ingredient Guide prepared by the U.S. Food and Drug Administration.

[0040] A "pharmaceutically acceptable salt" is a salt that retains at least some of the biological activity of a free (non-salt) compound and can be administered to an individual as a drug or pharmaceutical. Such salts include, for example: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, or with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, and tartaric acid; and (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 when it coordinates with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, and triethanolamine. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydroxide. Pharmaceutically acceptable salts can be prepared by reacting the purified compounds provided herein, either in situ or in the form of their free acids or bases, separately with suitable organic or inorganic bases or acids during the manufacturing process, and then isolating the salts thus formed during subsequent purification.

[0041] As used herein, the term “excipient” means an inert or non-active substance that may be used in the manufacture of drugs or pharmaceuticals, such as tablets, containing the compounds provided herein as active ingredients. The term “excipient” may encompass a wide range of substances, not limited to any substance used as a binder, disintegrant, coating, compression / encapsulation aid, cream or lotion, lubricant, parenteral solution, chewable tablet material, sweetener or flavoring, suspension / gelling agent, or wet granulation agent. Examples of binders include carbomer, povidone, and xanthan gum; examples of coatings include cellulose phthalate acetate, ethylcellulose, gellan gum, maltodextrin, and enteric coatings; examples of compression / encapsulation aids include calcium carbonate, dextrose, and fructose dc(dc = "Directly compressible," honey DC, lactose (anhydrous or monohydrate; optionally combined with aspartame, cellulose, or microcrystalline cellulose), starch DC, sucrose, etc.; disintegrants include, for example, croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; creams or lotions include, for example, maltodextrin, carrageenan, etc.; lubricants include, for example, magnesium stearate, stearic acid, sodium stearyl fumarate, etc. The ingredients for the chewable tablets include, for example, dextrose, fructose dc, lactose (monohydrate, optionally combined with aspartame or cellulose); the suspension / gelling agents include, for example, carrageenan, sodium starch glycolate, xanthan gum; the sweeteners include, for example, aspartame, dextrose, fructose dc, sorbitol, sucrose dc; and the wet granulating agents include, for example, calcium carbonate, maltodextrin, microcrystalline cellulose.

[0042] "Alkyl" refers to and includes saturated linear or branched monovalent hydrocarbon structures and combinations thereof. Specific alkyl groups have 1 to 20 carbon atoms ("C1-C20"). 20Alkyl groups are defined as those having 1 to 8 carbon atoms ("C1-C8 alkyl") or 1 to 6 carbon atoms ("C1-C6 alkyl"). When the name of an alkyl residue with a specific number of carbon atoms is given, it is intended to include and describe all geometric isomers having that number of carbon atoms; for example, "butyl" means including n-butyl, sec-butyl, iso-butyl, and tert-butyl; and "propyl" means including n-propyl and iso-propyl. This term is exemplified by groups such as methyl, t-butyl, n-heptyl, and octyl.

[0043] "Alkenyl" refers to an unsaturated hydrocarbon group having at least one olefinic unsaturated moiety (i.e., at least one C=C moiety), preferably having 2 to 10 carbon atoms, more preferably 2 to 8 carbon atoms. Examples of alkenyls include, non-limitingly, -CH2-CH=CH-CH3 and -CH=CH-CH=CH2.

[0044] "Alkynyl" refers to an unsaturated hydrocarbon group having at least one acetylene unsaturated moiety (i.e., at least one C≡C moiety), preferably having 2 to 10 carbon atoms, more preferably 2 to 8 carbon atoms.

[0045] The term "alkoxy" refers to an -O-alkyl group, where O is a bond site to the rest of the molecule, and alkyl is as defined above.

[0046] The term "thioalkoxy" refers to an -S-alkyl group, where S is the bond site to the rest of the molecule, and alkyl is as defined above.

[0047] "Haloalkyl" refers to an alkyl group having one or more halo substituents, such as 1, 2, 3, 4, 5, 6, 7, 8, or 9 halo substituents. Examples of haloalkyl groups include -CF3, -(CH2)F, -CHF2, CH2Br, -CH2CF3, -CH2CHF2, and -CH2CH2F.

[0048] "Carbocyclic," "carbocyclic formula," or "carbocykryl" refers to saturated or unsaturated non-aromatic cyclic hydrocarbon groups having a monocyclic or multiple fused rings with 3 to 13 ring carbon atoms. Carbocyclics containing one or more rings can be fused, spiro, or bridging, or any combination thereof. In fused ring systems, one or more rings can be aryl. Carbocyclics having one or more rings, at least one of which is aromatic, may be bonded to the parent structure at either an aromatic or non-aromatic ring position. In one variation, carbocyclics having one or more rings, at least one of which is aromatic, are bonded to the parent structure at an aromatic ring position.

[0049] A "heterocycle," "heterocyclic formula," or "heterocyclyl" refers to a saturated or unsaturated non-aromatic group having a monocycle or multiple fused rings, with 1 to 10 ring carbon atoms and 1 to 4 ring heteroatoms such as nitrogen, sulfur, or oxygen. Heterocycles containing one or more rings can be fused, spiro, or bridging, or any combination thereof. In fused ring systems, one or more rings can be aryl or heteroaryl. Heterocycles having one or more rings, at least one of which is aromatic, may be bonded to the parent structure at either an aromatic or non-aromatic ring position. In one variation, heterocycles having one or more rings, at least one of which is aromatic, are bonded to the parent structure at an aromatic ring position.

[0050] "Aryl" or "Ar" refers to an unsaturated aromatic carbocyclic group having a monocyclic ring (e.g., phenyl) or multiple fused rings (e.g., naphthyl or anthryl), the fused rings may or may not be aromatic. In one variation, the aryl group contains 6 to 14 ring carbon atoms. An aryl group having one or more rings, at least one of which is non-aromatic, may be bonded to the parent structure at either an aromatic or non-aromatic ring position. In one variation, an aryl group having one or more rings, at least one of which is non-aromatic, is bonded to the parent structure at an aromatic ring position.

[0051] "HetAr" refers to an unsaturated aromatic carbocyclic group having 1 to 10 ring carbon atoms and at least one ring heteroatom containing non-restrictive heteroatoms such as nitrogen, oxygen, and sulfur. HetAr groups may have a monocyclic ring (e.g., pyridyl, furyl) or multiple fused rings (e.g., indolidinyl, benzothienyl), the fused rings may or may not be aromatic. HetAr groups having one or more rings, at least one of which is non-aromatic, may be bonded to the parent structure at either an aromatic or non-aromatic ring position. In one variation, heteroaryl groups having one or more rings, at least one of which is non-aromatic, are bonded to the parent structure at an aromatic ring position.

[0052] The term "halogen" refers to chlorine, fluorine, bromine, or iodine. The term "halo" refers to chloro, fluoro, bromo, or iodine. The terms "halogen" and "halo" are understood to be equivalent and may be used interchangeably when referring to substituents.

[0053] The term "substituted" means that the identified group or part has one or more substituents, including, but not limited to, alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, cycloalkyl, cycloalkenyl, aryl, heteroaryl, aryloxy, cyano, azide, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, cycloalkyl, cycloalkenyl, carbocykyl, alkyl, alkenyl, alkynyl, heterocyclyl, aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, and carbonylalkylenealkoxy substituents. The term "unsubstituted" means that the identified group does not have substituents. The term "may be substituted" means that the identified group is either unsubstituted or substituted by one or more substituents. When the term "substituted" is used to describe a structural system, substitution means that it occurs at a position permissible by the valence on the system.

[0054] A “substantially pure” compound composition means that the composition contains 15% or less, preferably 10% or less, more preferably 5% or less, even more preferably 3% or less, and most preferably 1% or less, of impurities which may be compounds in different stereochemical forms. For example, a substantially pure (S) compound composition means that the composition contains 15% or less, preferably 10% or less, preferably 5% or less, preferably 3% or less, or 1% or less of the (R) form of the compound.

[0055] Any formula given herein is intended to represent compounds having the structure illustrated by the structural formula, as well as specific variations or forms. In particular, compounds of any formula given herein, such as compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-3a), (I-3b), or (I-3c), may have a chiral center and therefore may exist in different enantiomer forms. These stereoisomer mixtures can be separated into their individual stereomers based on their physicochemical or optical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization. All such isomers, including diastereomers and enantiomers, are considered part of the invention. All optical and stereoisomers of compounds of the general formula, as well as mixtures thereof in any ratio, are considered to be within the range of the formula. Thus, any formula given herein is intended to represent a racemate, one or more enantiomer forms, one or more diastereomer forms, one or more atropisomer forms, and mixtures thereof in any ratio. Furthermore, certain structures may exist as geometric isomers (i.e., cis and trans isomers), tautomers, or atrop isomers. In addition, any formula given herein is also intended to refer to any one of the hydrates, solvates, amorphous and polymorphic forms, or mixtures thereof of such compounds, even if such forms are not explicitly enumerated. In some embodiments, the solvent is water, and the solvate is a hydrate.

[0056] Any formula given herein is intended to represent both the unlabeled and isotope-labeled forms of the compound. An isotope-labeled compound has the structure shown by the formula given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that may be incorporated into the compounds described herein are, respectively 2 H, 3 H, 11 C,13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, and 125 It contains isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as I. Deuterium (i.e., 2 Substitution with heavier isotopes, such as H), may result in certain therapeutic benefits due to greater metabolic stability, e.g., an extension of the in vivo half-life or a reduction in the required dose. The isotope-labeled compounds and their prodrugs described herein can generally be prepared by replacing the unlabeled reagents with readily available isotope-labeled reagents and performing the procedures disclosed in the schemes or examples and preparations described below.

[0057] When referring to any formula given herein, the specific choices from the list of possible species for a given variable are not intended to prescribe the same choices from the list of species for the same variable elsewhere. In other words, if a variable appears more than once, the choices from the list of species for a given variable are independent of the choices of species for the same variable elsewhere in the formula, unless otherwise stated.

[0058] In accordance with the aforementioned interpretive considerations regarding assignment and nomenclature, any explicit reference to a set herein, unless otherwise specified and having chemical significance, is understood to imply an independent reference to a portion of such set, and a reference to any possible portion of a subset of the explicitly referred set.

[0059] Exemplary compounds Compounds and their salts (including pharmaceutically acceptable salts) are described in detail herein, including in the summary and appendix claims. All compounds described herein, including geometric isomers (cis / trans), E / Z isomers, enantiomers, diastereomers, and any mixture thereof in any ratio, as well as the use of salts and solvates of the compounds described herein, and methods for preparing such compounds are also provided. Any compound described herein may also be referred to as a drug.

[0060] In one aspect, compounds of formula (I), or pharmaceutically acceptable salts, solvates, or isotopic derivatives thereof are provided. TIFF2023554391000007.tif69128 formula, G 1 is CH or CR 2 And, G 2 , G 3 , and G 4 These are N, CH, or CR, independently of each other. 2 However; However, G 2 , G 3 , and G 4 At least two of them are CH or CR, independently of each other. 2 and; Furthermore, however, G 1 If it is CH, then G 2 , G 3 , and G 4 At least one of them is N or CR 2 and; m is 0, 1, 2, 3, 4, or 5; p is 0, 1, 2, 3, or 4; q is 1, 2, or 3; Each R 1These are independently selected from the group consisting of halogens, OH, NH2, NO2, CN, optionally substituted C1-C6 alkyls, optionally substituted C2-C6 alkenyls, optionally substituted C2-C6 alkynyls, optionally substituted C1-C6 alkoxys, -O-[(optionally substituted C1-C6 alkylene)-(optionally substituted C1-C6 alkoxy)], -NH(optionally substituted C1-C6 alkyl), -N(optionally substituted C1-C6 alkyl)2, -NH[(optionally substituted C1-C6 alkylene)-(optionally substituted C1-C6 alkoxy)], -N[(optionally substituted C1-C6 alkylene)-(optionally substituted C1-C6 alkoxy)]2, -C(=O)-(optionally substituted C1-C6 alkyl), -C(=O)-(optionally substituted C2-C6 alkenyl), and -C(=O)-(optionally substituted C2-C6 alkynyl); Each R 2 These are independently halogens, OH, NH2, NO2, CN, optionally substituted C1-C6 alkyls, optionally substituted C2-C6 alkenyls, optionally substituted C2-C6 alkynyls, optionally substituted C1-C6 haloalkyls, optionally substituted C1-C6 alkoxys, -[(optionally substituted C1-C6 alkylene)-(optionally substituted C1-C6 alkoxy)], -O-[(optionally substituted C1-C6 alkylene)-(optionally substituted C1-C6 alkoxy)], -NH(optionally substituted Selected from the group consisting of good C1-C6 alkyl, -N(optionally substituted C1-C6 alkyl)2, -NH[(optionally substituted C1-C6 alkylene)-(optionally substituted C1-C6 alkoxy)], -N[(optionally substituted C1-C6 alkylene)-(optionally substituted C1-C6 alkoxy)]2, -C(=O)-(optionally substituted C1-C6 alkyl), -C(=O)-(optionally substituted C2-C6 alkenyl), and -C(=O)-(optionally substituted C2-C6 alkynyl); Each R 3These are independently halogen, OH, NH2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, -[(optionally substituted C1-C6 alkylene)-(optionally substituted C1-C6 alkoxy)], optionally substituted C1-C6 alkylene-COOH, optionally substituted C1-C6 alkylene-C(=O)-O-(optionally substituted C1-C6 alkyl), optionally substituted C1-C6 alkoxy, -O-[(optionally substituted C1-C6 alkylene)-(optionally substituted C1-C6 alkoxy)] Selected from the group consisting of -NH (may be substituted C1-C6 alkyl), -N (may be substituted C1-C6 alkyl)², -NH[(may be substituted C1-C6 alkylene)-(may be substituted C1-C6 alkoxy)], -N[(may be substituted C1-C6 alkylene)-(may be substituted C1-C6 alkoxy)]², -C(=O)-(may be substituted C1-C6 alkyl), -C(=O)-(may be substituted C2-C6 alkenyl), and -C(=O)-(may be substituted C2-C6 alkynyl); and R 4This includes halogens, OH, NH2, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 haloalkyls, -[(optionally substituted C1-C6 alkylene)-(optionally substituted C1-C6 alkoxy)], optionally substituted C1-C6 alkylene-COOH, optionally substituted C1-C6 alkylene-C(=O)-O-(optionally substituted C1-C6 alkyl), optionally substituted C1-C6 alkoxy, -O-[(optionally substituted C1-C6 alkylene)-(optionally substituted C1-C6 alkoxy)], - The group is selected from NH (may be substituted C1-C6 alkyl), -N (may be substituted C1-C6 alkyl)2, -NH[(may be substituted C1-C6 alkylene)-(may be substituted C1-C6 alkoxy)], -N[(may be substituted C1-C6 alkylene)-(may be substituted C1-C6 alkoxy)]2, -C(=O)-(may be substituted C1-C6 alkyl), -C(=O)-(may be substituted C2-C6 alkenyl), and -C(=O)-(may be substituted C2-C6 alkynyl).

[0061] In some embodiments of the compound of formula (I), m is 0. In some embodiments of the compound of formula (I), m is 1. In some embodiments of the compound of formula (I), m is 2. In some embodiments of the compound of formula (I), m is 3. In some embodiments of the compound of formula (I), m is 4. In some embodiments of the compound of formula (I), m is 5.

[0062] In some embodiments, the compound of formula (I) is the compound of formula (I-1) or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof. TIFF2023554391000008.tif69128 formula, G 1 , G 2 , G 3 , G 4 , p, q, R 1 , R 2 , R 3 , and R 4 This is as defined with respect to equation (I).

[0063] In some embodiments of the compounds of formula (I) and (I-1), q is 1. In some of the compounds of formula (I) or (I-1), q is 2. In some embodiments of the compounds of formula (I) or (I-1), q is 3.

[0064] In some embodiments, the compound of formula (I) is a compound of formula (I-2a), (I-2b) or (I-2c), or a pharmaceutically acceptable salt, solvate or isotope derivative thereof, TIFF2023554391000009.tif144128TIFF2023554391000010.tif69128where G 1 、G 2 、G 3 、G 4 、p, R 1 、R 2 、R 3 、and R 4 are as defined for formula (I).

[0065] In some embodiments of the compounds of formula (I), (I-1), (I-2a), (I-2b), and (I-2c), p is 0. In some embodiments of the compounds of formula (I), (I-1), (I-2a), (I-2b), and (I-2c), p is 1. In some embodiments of the compounds of formula (I), (I-1), (I-2a), (I-2b), and (I-2c), p is 2. In some embodiments of the compounds of formula (I), (I-1), (I-2a), (I-2b), and (I-2c), p is 3. In some embodiments of the compounds of formula (I), (I-1), (I-2a), (I-2b), and (I-2c), p is 4.

[0066] In some embodiments, the compound of formula (I) is a compound of formula (I-3a), (I-3b), or (I-3c) or a pharmaceutically acceptable salt, solvate or isotope derivative thereof, TIFF2023554391000011.tif69128TIFF2023554391000012.tif143128where G1 , G 2 , G 3 , G 4 , R 1 , R 2 , R 3 , and R 4 is as defined for formula (I).

[0067] In some embodiments of the compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-3a), (I-3b), or (I-3c), G 1 is CH or CR 2 . In some embodiments, G 1 is CH. In some embodiments, G 1 is CR 2 . In some embodiments, G 1 is CR 2 , and the R of G 1 2 is halogen. In some embodiments, G 1 is CR 2 , and the R of G 1 2 is fluoro.

[0068] In some embodiments of the compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-3a), (I-3b), or (I-3c), G 2 is N, CH, or CR 2 . In some embodiments, G 2 is N. In some embodiments, G 2 is CH or CR 2 . In some embodiments, G 2 is CH. In some embodiments, G 2 is CR 2 . In some embodiments, G 2 is CR 2 , and the R of G 2 2 is halogen. In some embodiments, G 2 is CR 2 , and the R of G 2 2 is fluoro.​​​​

[0069] In some embodiments of compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-3a), (I-3b), or (I-3c), G 3 is N, CH, or CR 2 In some cases, G 3 is N. In some embodiments, G 3 is CH or CR 2 In some cases, G 3 is CH. In some embodiments, G 3 CR 2 In some cases, G 3 CR 2 G 3 R 2 is a halogen. In some embodiments, G 3 CR 2 G 3 R 2 It is fluoro.

[0070] In some embodiments of compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-3a), (I-3b), or (I-3c), G 4 is N, CH, or CR 2 In some cases, G 4 is N. In some embodiments, G 4 is CH or CR 2 In some cases, G 4 is CH. In some embodiments, G 4 CR 2 In some cases, G 4 CR 2 G 4 R 2 is a halogen. In some embodiments, G 4 CR 4 G 2 R 2 is fluoro. In some embodiments, G 4 CR 4 G 2 R2 It is chloroform.

[0071] In some embodiments of compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-3a), (I-3b), or (I-3c), G 1 CH is G 2 is CF, G 3 CH is G 4 It is CF.

[0072] In some embodiments of compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-3a), (I-3b), or (I-3c), G 1 is CF, G 2 is CF, G 3 is CF, G 4 It is CF.

[0073] In some embodiments of compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-3a), (I-3b), or (I-3c), G 1 CH is G 2 is N, G 3 CH is G 4 It is CH.

[0074] In some embodiments of compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-3a), (I-3b), or (I-3c), G 1 CH is G 2 is N, G 3 CH is G 4 It is CF.

[0075] In some embodiments of compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-3a), (I-3b), or (I-3c), CH, G 2 is N, G 3 CH is G 4 It is CCl.

[0076] In some embodiments of compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-3a), (I-3b), or (I-3c), CH, G 2 CH is G 3 is N, G 4 It is CH.

[0077] In some embodiments of the compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-3a), (I-3b), or (I-3c), m is 0.

[0078] In some embodiments of compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-3a), (I-3b), or (I-3c), m is 1. In some embodiments, R 1 The group is selected from halogens, OH, NH2, NO2, CN, optionally substituted C1-C6 alkyls, optionally substituted C2-C6 alkenyls, optionally substituted C2-C6 alkynyls, optionally substituted C1-C6 alkoxys, -O-[(optionally substituted C1-C6 alkylene)-(optionally substituted C1-C6 alkoxy)], -NH(optionally substituted C1-C6 alkyl), -N(optionally substituted C1-C6 alkyl)2, -NH[(optionally substituted C1-C6 alkylene)-(optionally substituted C1-C6 alkoxy)], -N[(optionally substituted C1-C6 alkylene)-(optionally substituted C1-C6 alkoxy)]2, -C(=O)-(optionally substituted C1-C6 alkyl), -C(=O)-(optionally substituted C2-C6 alkenyl), and -C(=O)-(optionally substituted C2-C6 alkynyl). In some embodiments, R 1 R is selected from the group consisting of halogens, optionally substituted C2-C6 alkynyls, and -C(=O)-(optionally substituted C1-C6 alkyls). In some embodiments, R 1 is a halogen. In some embodiments, R 1 is fluoro. In some embodiments, R 1is chloro. In some embodiments, R 1 is bromo. In some aspects, R 1 is iodine. In some embodiments, R 1 R is a C2-C6 alkynyl which may be substituted. In some embodiments, R 1 is ethynyl. In some embodiments, R 1 is -C(=O)- (a C1-C6 alkyl which may be substituted). In some embodiments, R 1 It is -C(=O)-CH3.

[0079] In some embodiments of the compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-3a), (I-3b), or (I-3c), m is 2. In some embodiments, each R 1 The following are independently selected from the group consisting of halogens, OH, NH2, NO2, CN, optionally substituted C1-C6 alkyls, optionally substituted C2-C6 alkenyls, optionally substituted C2-C6 alkynyls, optionally substituted C1-C6 alkoxys, -O-[(optionally substituted C1-C6 alkylene)-(optionally substituted C1-C6 alkoxy)], -NH(optionally substituted C1-C6 alkyl), -N(optionally substituted C1-C6 alkyl)2, -NH[(optionally substituted C1-C6 alkylene)-(optionally substituted C1-C6 alkoxy)], -N[(optionally substituted C1-C6 alkylene)-(optionally substituted C1-C6 alkoxy)]2, -C(=O)-(optionally substituted C1-C6 alkyl), -C(=O)-(optionally substituted C2-C6 alkenyl), and -C(=O)-(optionally substituted C2-C6 alkynyl). In some embodiments, each R 1 R is independently selected from the group consisting of halogens, optionally substituted C2-C6 alkynyls, and -C(=O)-(optionally substituted C1-C6 alkyls). In some embodiments, each R 1 R is independently selected from the group consisting of fluoro, chloro, bromo, and iodine. In some embodiments, one R 1One is fluoro, and the other is R 1 It is iodine. In some embodiments, one R 1 is chloro, and the other R 1 is bromo. In some embodiments, one R 1 R is a halogen, and the other R is a halogen. 1 is a C2-C6 alkynyl which may be substituted. In some embodiments, one R 1 One is fluoro, and the other is R 1 is ethynyl. In some embodiments, one R 1 R is a halogen, and the other R is a halogen. 1 is -C(=O)- (a C1-C6 alkyl which may be substituted). In some embodiments, one R 1 One is fluoro, and the other is R 1 It is -C(=O)-CH3.

[0080] In some embodiments of the compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-3a), (I-3b), or (I-3c), m is 3. In some embodiments, each R 1 The following are independently selected from the group consisting of halogens, OH, NH2, NO2, CN, optionally substituted C1-C6 alkyls, optionally substituted C2-C6 alkenyls, optionally substituted C2-C6 alkynyls, optionally substituted C1-C6 alkoxys, -O-[(optionally substituted C1-C6 alkylene)-(optionally substituted C1-C6 alkoxy)], -NH(optionally substituted C1-C6 alkyl), -N(optionally substituted C1-C6 alkyl)2, -NH[(optionally substituted C1-C6 alkylene)-(optionally substituted C1-C6 alkoxy)], -N[(optionally substituted C1-C6 alkylene)-(optionally substituted C1-C6 alkoxy)]2, -C(=O)-(optionally substituted C1-C6 alkyl), -C(=O)-(optionally substituted C2-C6 alkenyl), and -C(=O)-(optionally substituted C2-C6 alkynyl). In some embodiments, each R 1R is independently selected from the group consisting of halogens, optionally substituted C2-C6 alkynyls, and -C(=O)-(optionally substituted C1-C6 alkyls). In some embodiments, each R 1 These are independently selected from the group consisting of fluoro, chloro, bromo, and iodine.

[0081] In some embodiments of the compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-3a), (I-3b), or (I-3c), m is 4. In some embodiments, each R 1 The following are independently selected from the group consisting of halogens, OH, NH2, NO2, CN, optionally substituted C1-C6 alkyls, optionally substituted C2-C6 alkenyls, optionally substituted C2-C6 alkynyls, optionally substituted C1-C6 alkoxys, -O-[(optionally substituted C1-C6 alkylene)-(optionally substituted C1-C6 alkoxy)], -NH(optionally substituted C1-C6 alkyl), -N(optionally substituted C1-C6 alkyl)2, -NH[(optionally substituted C1-C6 alkylene)-(optionally substituted C1-C6 alkoxy)], -N[(optionally substituted C1-C6 alkylene)-(optionally substituted C1-C6 alkoxy)]2, -C(=O)-(optionally substituted C1-C6 alkyl), -C(=O)-(optionally substituted C2-C6 alkenyl), and -C(=O)-(optionally substituted C2-C6 alkynyl). In some embodiments, each R 1 R is independently selected from the group consisting of halogens, optionally substituted C2-C6 alkynyls, and -C(=O)-(optionally substituted C1-C6 alkyls). In some embodiments, each R 1 These are independently selected from the group consisting of fluoro, chloro, bromo, and iodine.

[0082] In some embodiments of the compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-3a), (I-3b), or (I-3c), m is 5. In some embodiments, each R 1The following are independently selected from the group consisting of halogens, OH, NH2, NO2, CN, optionally substituted C1-C6 alkyls, optionally substituted C2-C6 alkenyls, optionally substituted C2-C6 alkynyls, optionally substituted C1-C6 alkoxys, -O-[(optionally substituted C1-C6 alkylene)-(optionally substituted C1-C6 alkoxy)], -NH(optionally substituted C1-C6 alkyl), -N(optionally substituted C1-C6 alkyl)2, -NH[(optionally substituted C1-C6 alkylene)-(optionally substituted C1-C6 alkoxy)], -N[(optionally substituted C1-C6 alkylene)-(optionally substituted C1-C6 alkoxy)]2, -C(=O)-(optionally substituted C1-C6 alkyl), -C(=O)-(optionally substituted C2-C6 alkenyl), and -C(=O)-(optionally substituted C2-C6 alkynyl). In some embodiments, each R 1 R is independently selected from the group consisting of halogens, optionally substituted C2-C6 alkynyls, and -C(=O)-(optionally substituted C1-C6 alkyls). In some embodiments, each R 1 These are independently selected from the group consisting of fluoro, chloro, bromo, and iodine.

[0083] In some embodiments of compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-3a), (I-3b), or (I-3c), R 4This includes hydrogen, halogen, OH, NH2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, -[(optionally substituted C1-C6 alkylene)-(optionally substituted C1-C6 alkoxy)], optionally substituted C1-C6 alkylene-COOH, optionally substituted C1-C6 alkylene-C(=O)-O-(optionally substituted C1-C6 alkyl), optionally substituted C1-C6 alkoxy, -O-[(optionally substituted C1-C6 alkylene)-(optionally substituted C1-C6 alkoxy)]. Selected from the group consisting of -NH (optionally substituted C1-C6 alkyl), -N (optionally substituted C1-C6 alkyl)², -NH[(optionally substituted C1-C6 alkylene)-(optionally substituted C1-C6 alkoxy)], -N[(optionally substituted C1-C6 alkylene)-(optionally substituted C1-C6 alkoxy)]², -C(=O)-(optionally substituted C1-C6 alkyl), -C(=O)-(optionally substituted C2-C6 alkenyl), and -C(=O)-(optionally substituted C2-C6 alkynyl). In some embodiments, R 4 R is selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, and -[(optionally substituted C1-C6 alkylene)-(optionally substituted C1-C6 alkoxy)]. In some embodiments, R 4 R is selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, -[(optionally substituted C1-C6 alkylene)-(optionally substituted C1-C6 alkoxy)], and optionally substituted C1-C6 alkylene-COOH. In some embodiments, R 4 R is selected from the group consisting of methyl, ethyl, prop-2-yl, 2-fluoroetho-1-yl, 2-methoxyetho-1-yl, -CH2-CH2-COOH and -CH2-CH2-CH2-COOH. In some embodiments, R 4 is hydrogen. In some embodiments, R 4R is a C1-C6 alkyl which may be substituted. In some embodiments, R 4 R is selected from the group consisting of methyl, ethyl, and prop-2-yl. In some embodiments, R 4 is methyl. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is ethylprop-2-yl. In some embodiments, R 4 R is a C1-C6 haloalkyl which may be substituted. In some embodiments, R 4 is 2-fluoroetho-1-yl. In some embodiments, R 4 is -[(may be substituted C1-C6 alkylene)-(may be substituted C1-C6 alkoxy)]. In some embodiments, R 4 is 2-methoxyetho-1-yl. In some embodiments, R 4 R is a C1-C6 alkylene-COOH which may be substituted. In some embodiments, R 4 is -CH2-CH2-COOH. In some embodiments, R 4 It is -CH2-CH2-CH2-COOH.

[0084] In some embodiments, compounds of formulas (I), (I-1), (I-2a), (I-2b), (I-2c), (I-3a), (I-3b), and (I-3c) or pharmaceutically acceptable salts thereof are provided herein.

[0085] In some embodiments, compounds and salts thereof listed in Table 1, as well as their uses, are provided herein.

[0086] [Table 1] TIFF2023554391000014.tif215166TIFF2023554391000015.tif215166TIFF2023554391000016.tif87166 and their pharmaceutically acceptable salts.

[0087] Any formula or compound given herein, such as formulas (I), (I-1), (I-2a), (I-2b), (I-2c), (I-3a), (I-3b), or (I-3c), or the compounds in Table 1, is intended to represent compounds having the structure illustrated by their structural formulas, as well as specific variations or forms. In particular, any compound of any formula given herein has a chiral center and therefore may exist in different enantiomer or diastereomer forms. All optical isomers and stereoisomers of a compound of a general formula, as well as mixtures thereof in any ratio, are considered to be within the range of the formula. Thus, any formula given herein is intended to represent a racemate, one or more enantiomer forms, one or more diastereomer forms, one or more atropisomer forms, and mixtures thereof in any ratio. Where a compound in Table 1 is shown in a specific stereochemical configuration, any alternative stereochemical configuration of the compound, as well as mixtures of stereoisomers of the compound in any ratio, are also provided herein. For example, if a compound in Table 1 has a stereocenter in the "S" stereochemical configuration, an enantiomer of a compound with that stereocenter in the "R" stereochemical configuration is also provided herein. Similarly, if a compound in Table 1 has a stereocenter in the "R" configuration, an enantiomer of a compound with the "S" stereochemical configuration is also provided herein. Mixtures of compounds having both "S" and "R" stereochemical configurations are also provided. In addition, if a compound in Table 1 has two or more stereocenters, any enantiomer or diastereomer of the compound is also provided. Furthermore, certain structures may exist as geometric isomers (i.e., cis and trans isomers), tautomers, or atropisomers. In addition, any compound in Table 1 is intended to represent a racemate, one or more enantiomer forms, one or more diastereomer forms, one or more atropisomer forms, and mixtures thereof in any ratio. Furthermore, certain structures may exist as geometric isomers (i.e., cis and trans isomers), tautomers, or atropisomers.In addition, any formula given herein, such as formulas (I), (I-1), (I-2a), (I-2b), (I-2c), (I-3a), (I-3b), or (I-3c), is intended to refer to hydrates, solvates, and amorphous forms of such compounds, as well as mixtures thereof, even if such forms are not explicitly enumerated. In some embodiments, the solvent is water, and the solvate is a hydrate.

[0088] Compounds illustrated herein may exist as salts even if salts are not illustrated, and as will be well understood by those skilled in the art, the compositions and methods provided herein are understood to encompass all salts and solvates of the compounds illustrated herein, as well as unsalted and unsolvated forms of the compounds. In some embodiments, the salts of the compounds provided herein are pharmaceutically acceptable salts.

[0089] In one variation, the compounds described herein are synthetic compounds prepared for administration to an individual. In another variation, a composition containing a substantially pure form of the compound is provided. In yet another variation, a pharmaceutical composition comprising the compound detailed herein and a pharmaceutically acceptable carrier is provided. In yet another variation, a method for administering the compound is provided. The purified forms, pharmaceutical compositions, and methods for administering the compound are suitable for any compound or any form of the compound detailed herein.

[0090] G provided herein 1 , G 2 , G 3 , G 4 , m, p, q, R 1 , R 2 , R 3 , and R 4 Any variation or form of G 1 , G 2 , G 3 , G 4 , m, p, q, R 1 , R 2 , R 3, and R 4 It can be combined with any other variation or aspect thereof, as each combination is described individually and specifically.

[0091] composition Compositions such as pharmaceutical compositions comprising compounds disclosed and / or described herein with one or more additional agents, pharmaceuticals, adjuvants, carriers, excipients, etc. Suitable agents and pharmaceuticals include those described herein. In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable excipient or adjuvant and at least one chemical substance, as described herein. Examples of pharmaceutically acceptable excipients include, but are not limited to, mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, sodium croscarmellose, glucose, gelatin, sucrose, and magnesium carbonate. In some embodiments, the disclosure provides a pharmaceutical composition comprising the above compounds mixed with at least one pharmaceutically acceptable carrier or excipient. In some embodiments, compositions such as pharmaceutical compositions containing one or more compounds described herein or pharmaceutically acceptable salts thereof are provided.

[0092] In some embodiments, pharmaceutically acceptable compositions are provided comprising compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-3a), (I-3b), (I-3c), or compounds of Table 1, or pharmaceutically acceptable salts thereof. In some aspects, the compositions may contain synthetic intermediates that may be used in the preparation of the compounds described herein. The compositions described herein may contain any other suitable active or inactive agents.

[0093] Any of the compositions described herein may be sterile or may contain sterile components. Sterilization can be achieved by methods known in the art. Any of the compositions described herein may contain one or more substantially pure compounds.

[0094] Packaged pharmaceutical compositions are also provided, comprising a pharmaceutical composition described herein and instructions for using the composition to treat a patient suffering from a disease or condition described herein.

[0095] Pharmaceutical preparations This disclosure also provides compositions containing one or more of the compounds described herein, formulated with a pharmaceutically acceptable carrier, such as pharmaceutical compositions. The pharmaceutical compositions of the invention may be administered in combination therapy, i.e., in combination with other agents. For example, combination therapy may include the compounds described herein in combination with at least one other active agent.

[0096] A pharmaceutically acceptable carrier may include any physiologically compatible carrier, excipient, stabilizer, solvent, dispersion medium, coating, antimicrobial and antifungal agents, isotonic and absorption retardants, etc. Preferably, the carrier is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal, or epidermal administration (e.g., by injection or infusion). Depending on the route of administration, the active compound, i.e., the compounds described herein, may be coated with materials to protect the compound from the action of acids and other natural conditions that may inactivate the compound.

[0097] Acceptable carriers, excipients, or stabilizers are non-toxic to the recipient at standard doses and concentrations administered, and include buffers such as phosphoric acid, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl, or benzyl alcohol; alkylparabens such as methyl or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than approximately 10 residues) polypeptides; blood The material comprises proteins such as clear albumin, gelatin, or immunoglobulin; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or nonionic surfactants such as TWEEN® or polyethylene glycol (PEG).

[0098] The pharmaceutical composition of the invention may contain one or more pharmaceutically acceptable salts. The pharmaceutically acceptable salts retain the desired biological activity of the parent compound and do not impart any undesirable toxicological effects. Examples of such salts include acid addition salts and base addition salts. Acid addition salts include those derived from non-toxic inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphorous acid, as well as non-toxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanos, hydroxyalkanoics, aromatic acids, and aliphatic and aromatic sulfonic acids. Base addition salts include those derived from alkaline earth metals such as sodium, potassium, magnesium, and calcium, as well as non-toxic organic amines such as N,N'-dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, and procaine.

[0099] The pharmaceutical composition of the invention may also contain pharmaceutically acceptable antioxidants. Examples of pharmaceutically acceptable antioxidants include (1) water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium bisulfite, and sodium sulfite; (2) oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, and alpha-tocopherol; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid. Examples of suitable aqueous and non-aqueous carriers that may be used in the pharmaceutical composition of the invention include water, ethanol, polyhydric alcohols (such as glycerol, propylene glycol, and polyethylene glycol), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Appropriate fluidity can be maintained, for example, by using a coating material such as lecithin, by maintaining the required particle size in the case of a dispersion, and by using a surfactant.

[0100] Any suitable formulation of the compounds described herein can be prepared. Generally, see Remington's Pharmaceutical Sciences, (2000) Hoover, JE editor, 20th edition, Lippincott Williams and Wilkins Publishing Company, Easton, Pa., pages 780–857. The formulation is selected to suit the appropriate route of administration. Administration of the compound as a salt may be appropriate if the compound is sufficiently basic or acidic to form a stable, non-toxic acid or base salt. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids that form physiologically acceptable anions, such as tosylates, methanesulfonates, acetates, citrates, malons, tartrates, succinates, benzoates, ascorbicates, α-ketoglutarates, and α-glycerophosphates. Suitable inorganic salts, including hydrochlorides, sulfates, nitrates, bicarbonates, and carbonates, may also be formed. Pharmaceutically acceptable salts are obtained, for example, by a suitable acid yielding a physiologically acceptable anion and a sufficiently basic compound such as an amine, using standard procedures well known in the art. Alkali metal (e.g., sodium, potassium, or lithium) or alkaline earth metal (e.g., calcium) salts of carboxylic acids are also prepared.

[0101] When the compound intended is administered in a pharmacological composition, it is intended that the compound may be formulated in combination with pharmaceutically acceptable excipients and / or carriers. For example, the compound intended may be administered orally as a neutral compound or as a pharmaceutically acceptable salt, or intravenously in physiological saline. Conventional buffers such as phosphates, bicarbonates, or citrates may be used for this purpose. Of course, those skilled in the art may modify formulations within the scope of the teachings herein to provide a number of formulations for specific routes of administration. In particular, the compounds intended may be modified to make them more soluble in water or other vehicles, which can be easily achieved, for example, by minor modifications (such as salt formation or esterification) that are well within the ordinary art. It is also well within the ordinary art to modify the route of administration and dosage regimen of a particular compound to control the pharmacokinetics of the compound for the maximum beneficial effect in the patient.

[0102] Compounds having formulas (I), (I-1), (I-2a), (I-2b), (I-2c), (I-3a), (I-3b), and (I-3c) as described herein are generally soluble in organic solvents such as chloroform, dichloromethane, ethyl acetate, ethanol, methanol, isopropanol, acetonitrile, glycerol, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide. In one embodiment, the present invention provides formulations prepared by mixing compounds having formulas (I), (I-1), (I-2a), (I-2b), (I-2c), (I-3a), (I-3b), and (I-3c) with a pharmaceutically acceptable carrier. In one aspect, the formulation may be prepared by a method comprising: a) preparing a solution by dissolving the compound described in a water-soluble organic solvent, a nonionic solvent, a water-soluble lipid, cyclodextrin, vitamins such as tocopherol, fatty acids, fatty acid esters, phospholipids, or a combination thereof; and b) adding a physiological saline or buffer containing a 1-10% carbohydrate solution. In one example, the carbohydrate is dextrose. The pharmaceutical composition obtained using this method is stable and useful for animal and clinical applications.

[0103] In some embodiments, the compounds or salts thereof described herein, or the compositions described herein, may be used in methods for treating musculoskeletal disorders. In some embodiments, the quantity, quality, and / or strength of skeletal muscle is increased. In some embodiments, muscle protein synthesis is increased. In some embodiments, atrophy of skeletal muscle fibers is inhibited.

[0104] Examples of water-soluble organic solvents for use in this method include, but are not limited to, polyethylene glycol (PEG), alcohols, acetonitrile, N-methyl-2-pyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, or combinations thereof. Examples of alcohols include, but are not limited to, methanol, ethanol, isopropanol, glycerol, or propylene glycol.

[0105] Examples of water-soluble nonionic surfactants for use in this method include, but are not limited to, CREMOPHOR® EL, polyethylene glycol-modified CREMOPHOR® (polyoxyethylene glycerol trilicinolate 35), hydrogenated CREMOPHOR® RH40, hydrogenated CREMOPHOR® RH60, PEG succinate, polysorbate 20, polysorbate 80, SOLUTOL® HS (polyethylene glycol 12-hydroxystearate 660), sorbitan monooleate, poloxamer, LABRAFIL® (ethoxylated apricot kernel oil), LABRASOL® (caprylic-caproyl macrogol-8-glyceride), GELUCIRE® (glycerol ester), SOFTIGEN® (PEG-6 caprylic acid glyceride), glycerin, glycol-polysorbate, or combinations thereof.

[0106] Examples of water-soluble lipids for use in this method include, but are not limited to, vegetable oils, triglycerides, plant oils, or combinations thereof. Examples of lipid oils include, but are not limited to, castor oil, polyoxyl castor oil, corn oil, olive oil, cottonseed oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil, coconut oil triglycerides, palm seed oil, and their hydrogenated forms, or combinations thereof.

[0107] Examples of fatty acids and fatty acid esters for use in this method include, but are not limited to, oleic acid, monoglycerides, diglycerides, mono or di fatty acid esters of PEG, or combinations thereof.

[0108] Examples of cyclodextrins for use in this method include, but are not limited to, alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, or sulfobutyl ether-beta-cyclodextrin.

[0109] Examples of phospholipids for use in this method include, but are not limited to, soy phosphatidylcholine or distearoyl phosphatidylglycerol, and their hydrogenated forms, or combinations thereof.

[0110] Those skilled in the art may modify formulations within the scope of the teachings herein to provide a number of formulations for specific routes of administration. In particular, compounds may be modified to make them more soluble in water or other vehicles. It is also well within the ordinary art to modify the route of administration and dosage regimen of specific compounds to control the pharmacokinetics of the compound for the maximum beneficial effect in the patient.

[0111] Drug combinations The method of the embodiment includes the step of administering an effective amount of at least one exemplary compound of the present disclosure, but optionally, the compound may be administered in combination with one or more additional therapeutic agents. In some embodiments, the additional therapeutic agent is known to be useful for treating proliferative abnormalities such as cancer or tumors in a subject. In some embodiments, the additional therapeutic agent is known to be useful for treating neurodegenerative disorders. In some embodiments, the additional therapeutic agent is known to be useful for treating immunodeficiency diseases. In some embodiments, the additional therapeutic agent is an anticancer agent selected from the group consisting of RAS inhibitors, RAF inhibitors, and ERK inhibitors. In some embodiments, the additional therapeutic agent is an immunotherapy agent such as a PD-1 antibody.

[0112] Additional active ingredients may be administered in a separate pharmaceutical composition from the at least one exemplary compound of this disclosure, or they may be included together with the at least one exemplary compound of this disclosure in a single pharmaceutical composition. Additional active ingredients may be administered simultaneously with, before, or after the administration of the at least one exemplary compound of this disclosure.

[0113] Dosage and dosage form For the prevention or treatment of disease, the appropriate dosage of the compounds described herein will vary depending on the type of disease being treated, its severity and course, whether the compound is administered for preventive or therapeutic purposes, the mode of delivery, previous therapies, and the patient's medical history. The compounds described herein are suitably administered to the patient in a single dose or over a series of treatments. Depending on the type and severity of the disease, a typical daily dose may range from approximately 0.0001 mg / kg to 100 mg / kg or more, depending on the above factors. For repeated administrations of several days or more, treatment is continued, depending on the patient's condition, until the desired suppression of disease symptoms occurs.

[0114] For example, the dosage may be 0.3 mg / kg body weight, 1 mg / kg body weight, 3 mg / kg body weight, 5 mg / kg body weight, or 10 mg / kg body weight, or within the range of 1 to 10 mg / kg. The treatment regimen may include administration once a week, once every two weeks, once every three weeks, once every four weeks, once a month, once every three months, or once every three to six months. In another embodiment, a sustained-release formulation may be administered, which would reduce the frequency of administration compared to a non-sustained-release formulation.

[0115] The amount of active ingredient that can be combined with a carrier material to form a single dosage form will generally be the amount of composition that produces a therapeutic effect without causing toxicity to the target. Generally, this amount will range from about 0.01 percent to about 99 percent of the active ingredient, preferably about 0.1 percent to about 70 percent, and most preferably about 1 percent to about 30 percent, when combined with a pharmaceutically acceptable carrier.

[0116] Administration The compositions described herein may be administered via one or more routes of administration using one or more of the various methods known in the art. As will be understood by those skilled in the art, the route and / or mode of administration will vary depending on the desired outcome. Routes of administration for the compounds and compositions described herein include oral, sublingual, buccal, intranasal, topical, rectal, intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, spinal, or other parenteral routes of administration, such as by injection or infusion. As used herein, the term “parenteral administration” means a mode of administration other than enteral and topical administration, usually by injection, and does not limit itself to intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injections and infusions.

[0117] Treatment methods The compounds and pharmaceutical compositions described herein may be used for any suitable purpose. For example, the compounds may be used in therapy and / or testing.

[0118] The compounds and pharmaceutically acceptable compositions described herein may be used to treat and / or prevent growth abnormalities such as cancer or tumors in an individual. In some embodiments, a method is provided for treating or preventing growth abnormalities such as cancer or tumors in an individual, comprising the step of administering to an individual in need a compound of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-3a), (I-3b), (I-3c), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, a method is provided for treating or preventing growth abnormalities such as cancer or tumors in a subject, comprising the step of administering to a subject in need a therapeutically effective amount of at least one of the chemicals described herein.

[0119] In some embodiments, the compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-3a), (I-3b), (I-3c), or the compounds in Table 1, or their pharmaceutically acceptable salts, are inhibitors of one or more kinases selected from the group consisting of MEK, COT1, FGFR4, MINK, MYO3A, PKG1B, and PLK3, and are therefore all suitable for therapeutic use as antiproliferative or anti-metastatic agents (e.g., anticancer agents) in mammals, particularly in humans. In particular, the compounds of the present invention are useful for the prevention and treatment of various human hyperproliferative disorders, including malignant and benign tumors of the liver, kidney, bladder, breast, stomach, ovary, colorectal, prostate, pancreas, lung, vulva, thyroid, liver cancer, sarcoma, glioblastoma, head and neck, melanoma, and other hyperplastic conditions such as benign hyperplasia of the skin (e.g., psoriasis) and benign hyperplasia of the prostate (e.g., BPH). In addition, the compounds of the present invention are expected to potentially possess activity against brain metastases resulting from these disorders.

[0120] In some embodiments, compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-3a), (I-3b), (I-3c), or the compounds in Table 1, or their pharmaceutically acceptable salts, may also be useful in treating additional disorders involving abnormal expression ligand / receptor interactions or activation or signaling events associated with various kinases. Such disorders may include neuronal, glial, astrocytic, hypothalamic, as well as other glandular, macrophagous, epithelial, stromal, and cleavage-type disorders involving abnormal function, expression, activation, or signaling of tyrosine kinases.

[0121] The use of compounds of formulas (I), (I-1), (I-2a), (I-2b), (I-2c), (I-3a), (I-3b), (I-3c), or compounds listed in Table 1, or pharmaceutically acceptable salts thereof, in the manufacture of pharmaceuticals for the treatment of proliferative disorders or tumors such as cancer in a subject is also provided herein.

[0122] In some embodiments, the proliferative disorders or cancers are selected from the group consisting of malignant or benign tumors of the liver, kidney, bladder, breast, stomach, ovary, colorectal, prostate, pancreas, lung, vulva, thyroid, liver cancer, sarcoma, glioblastoma, head and neck, melanoma, and other hyperplastic conditions such as benign hyperplasia of the skin (e.g., psoriasis) and benign hyperplasia of the prostate (e.g., BPH). In some embodiments, compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-3a), (I-3b), (I-3c), or the compounds in Table 1 may be active against brain metastases resulting from these disorders.

[0123] Methods are also provided for inhibiting the activity of one or more kinases, such as MEK, COT1, FGFR4, MINK, MYO3A, PKG1B, and PLK3, the method comprising administering a therapeutically effective amount of at least one chemical described herein to an individual in need. In some embodiments, a method is provided for inhibiting one or more kinases, such as MEK, COT1, FGFR4, MINK, MYO3A, PKG1B, and PLK3, in cells, the method comprising contacting the cells with at least one chemical described herein, such as a compound of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-3a), (I-3b), (I-3c), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. In addition, the use of at least one of the chemicals described herein, such as compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-3a), (I-3b), (I-3c), or compounds from Table 1, or pharmaceutically acceptable salts thereof, in the manufacture of a pharmacopoeia for inhibiting the activity of one or more kinases such as MEK, COT1, FGFR4, MINK, MYO3A, PKG1B, and PLK3 in an individual, is provided herein.

[0124] A method for treating and / or preventing growth abnormalities such as cancer or tumors in a subject is also provided, comprising the step of administering to an individual in need a therapeutically effective amount of at least one of the chemicals described herein, such as a compound of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-3a), (I-3b), (I-3c), or a compound from Table 1, or a pharmaceutically acceptable salt thereof. In addition, the use of at least one of the chemicals described herein, such as a compound of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-3a), (I-3b), (I-3c), or a compound from Table 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating and / or preventing growth disorders, cancer, or tumors in a subject is also provided herein.

[0125] In one embodiment, the disease or condition being treated or prevented is an abnormal cell proliferation such as cancer. The term “cancer” refers to precancerous conditions, non-malignant, low-grade, high-grade, and malignant cancers. Any histological type of cancer is intended for treatment or prevention with the compounds disclosed herein. Exemplary types of cancer include carcinoma, lymphoma, blastoma, sarcoma, leukemia, and lymphoid malignancies. More specifically, in certain embodiments, cancer includes squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), lung cancer including small cell lung cancer, non-small cell lung cancer, adenocarcinoma and squamous cell carcinoma of the lung, peritoneal cancer, hepatocellular carcinoma, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine cancer, salivary gland cancer, kidney cancer or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, anal cancer, penile cancer, and head and neck cancer.

[0126] A method for treating cancer in an individual requiring treatment of cancer is provided herein by administering a therapeutically effective amount of the compound or composition described herein to the individual. The use of the compound or composition described herein in the manufacture of a pharmaceutical for the treatment of cancer in an individual requiring treatment of cancer is also provided herein. The use of the compound or composition described herein for the treatment of cancer in an individual requiring treatment of cancer is also provided herein. The compound or composition described herein for use in the treatment of cancer in an individual requiring treatment of cancer is also provided herein.

[0127] In another aspect, the disease or condition to be treated or prevented is a neurodegenerative disease. Exemplary types of neurodegenerative diseases include, but are not limited to, amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, and Huntington's disease, which result from neurodegenerative processes.

[0128] In some embodiments, methods are provided for treating or preventing neurodegenerative diseases such as amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, and Huntington's disease, comprising the step of administering to an individual in need a compound of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-3a), (I-3b), (I-3c), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, methods are provided for treating or preventing neurodegenerative diseases such as amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, and Huntington's disease, comprising the step of administering a therapeutically effective amount to a target of at least one of the chemicals described herein.

[0129] A method for treating neurodegenerative diseases in individuals requiring treatment of neurodegenerative diseases is provided herein by administering a therapeutically effective amount of the compound or composition described herein to the individual. The use of the compound or composition described herein in the manufacture of a pharmaceutical for the treatment of neurodegenerative diseases in individuals requiring treatment of neurodegenerative diseases is also provided herein. The use of the compound or composition described herein for the treatment of neurodegenerative diseases in individuals requiring treatment of neurodegenerative diseases is also provided herein. The compound or composition described herein for use in the treatment of neurodegenerative diseases in individuals requiring treatment of neurodegenerative diseases is also provided herein.

[0130] In one aspect, a kit comprising a compound or composition described herein and instructions for use is provided herein. In some embodiments, the kit may include instructions for use in the treatment of cancer in an individual requiring treatment for cancer. In another embodiment, the kit may include instructions for use in the treatment of neurodegenerative diseases in an individual requiring treatment for neurodegenerative diseases. The kit may further include any materials or instruments that may be used in administering the compound or composition, such as vials, syringes, or IV bags. The kit may also include sterile packaging.

[0131] General synthesis method The compounds of formula (I) are described below with reference to the exemplary synthetic schemes for their general preparation and the specific examples that follow. Those skilled in the art will recognize that, in order to obtain the various compounds herein, the starting materials may be appropriately selected so that the ultimately desired substituents are appropriately protected or carried over throughout the reaction scheme without protection to obtain the desired product. Alternatively, it may be necessary or desirable to employ a suitable group instead of the ultimately desired substituent, which may be carried over throughout the reaction scheme and appropriately substituted with the desired substituent. In addition, those skilled in the art will recognize that protecting groups may be used to protect certain functional groups (amino, carboxy, or side-chain groups) from the reaction conditions, and that such groups may be removed under standard conditions where appropriate. Unless otherwise specified, the variables are as defined above with reference to formula (I).

[0132] If it is desirable to obtain a specific enantiomer of a compound, this may be achieved from a mixture of the corresponding enantiomers using any suitable conventional procedure for separating or resolving the enantiomers. For example, a diastereomer derivative may be produced by the reaction of a mixture of enantiomers, e.g., a racemate, with a suitable chiral compound. The diastereomers may then be separated by any convenient means, e.g., crystallization, to recover the desired enantiomer. In another resolving process, the racemate may be separated using chiral high-performance liquid chromatography. Alternatively, if desired, a specific enantiomer may be obtained by using a suitable chiral intermediate in one of the described processes.

[0133] If it is desired to obtain a specific isomer of the compound or otherwise purify the reaction product, chromatography, recrystallization, and other conventional separation procedures may also be used on the intermediate or final product.

[0134] A general method for preparing the compounds described herein is illustrated in the illustrative method below. The modifiable groups in the schemes provided herein are specified with respect to formulas (I), (I-1), (I-2a), (I-2b), (I-2c), (I-3a), (I-3b), (I-3c), or any variation thereof. Other compounds described herein may be prepared by similar methods.

[0135] In some embodiments, the compound of formula (I) is synthesized via the procedure shown in scheme A, where G 1 , G 2 , G 3 , G 4 , p, q, R 1 , R 2 , R 3 , and R 4 This is either as defined with respect to formula (I), or any variation thereof as detailed herein. Specific examples are provided in the Examples section below.

[0136] Scheme A TIFF2023554391000017.tif142155 Starting materials not specifically described above for synthesis are either commercially available or can be prepared using methods well known to those skilled in the art.

[0137] In some embodiments, the compound of formula (I) is synthesized via the procedure shown in scheme B, where G 1 , G 2 , G 3 , G 4 , p, q, R 1 , R 2 , R 3 , and R 4 This is either as defined with respect to formula (I), or any variation thereof as detailed herein. Specific examples are provided in the Examples section below.

[0138] Scheme B TIFF2023554391000018.tif43143 Starting materials not specifically described above for synthesis are either commercially available or can be prepared using methods well known to those skilled in the art.

[0139] In some embodiments, the compound of formula (I) is synthesized via the procedure shown in scheme C, where G 1 , G 2 , G 3 , G 4 , p, q, R 1 , R 2 , R 3 , and R 4 is as defined with respect to formula (I), or any variation thereof as detailed herein, where X is a leaving group suitable for coupling reactions, such as halogens (e.g., bromo, iodine), and R 1 -M is a compound suitable for coupling reactions, including, but not limited to, boronic acids, boronic acid esters, organotin compounds, organozinc compounds, organosilicon compounds, and terminal alkynes. Specific examples are provided in the Examples section below.

[0140] Scheme C TIFF2023554391000019.tif43151 Starting materials not specifically described above for synthesis are either commercially available or can be prepared using methods well known to those skilled in the art.

[0141] In some embodiments, the compound of formula (I) is synthesized via the procedure shown in scheme D, where G 1 , G 2 , G 3 , G 4 , p, q, R 1 , R 2 , R 3 , and R 4 This is either as defined with respect to formula (I), or any variation thereof as detailed herein. Specific examples are provided in the Examples section below.

[0142] Scheme D TIFF2023554391000020.tif130158 Starting materials not specifically described above for synthesis are either commercially available or can be prepared using methods well known to those skilled in the art. [Examples]

[0143] The following examples are presented to illustrate, not to limit, the compositions, uses, and methods provided herein. Those skilled in the art will recognize that the following synthetic reactions and schemes may be modified by selecting suitable starting materials and reagents to access other compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-3a), (I-3b), (I-3c) or their salts. The compounds are prepared using the general methods described above.

[0144] The following chemical abbreviations will be used throughout the examples: ACN (acetonitrile), AcOH (acetic acid), CuI (copper(I) iodide), DCM (dichloromethane), DIEA (N,N-diisopropylethylamine), DMF (dimethylformamide), DMSO (dimethyl sulfoxide), Et3N (triethylamine), SiO (ethyl acetate), Et2O (diethyl ether), 1¹H NMR (Proton Nuclear Magnetic Resonance), HATU ((1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate)), HCl (hydrochloric acid), HPLC (High-Performance Liquid Chromatography), K₂CO₃ (potassium carbonate), LC-MS (Liquid Chromatography-Mass Spectrometry), LiHMDS (Lithium bis(trimethylsilyl)amide), LiNH₂ (Lithium amide), MeOH (Methanol), Na₂SO₄ (Sodium sulfate), N aBH3CN (sodium borocyanohydride), NaOH (sodium hydroxide), n-BuLi (n-butyllithium), NH3.H2O (aqueous ammonia), PdCl2 (dppf) (1,1'-bis(diphenylphosphin)ferrocenepalladium dichloride), PE (petroleum ether), prep-HPLC (preparative high-performance liquid chromatography), POCl3 (phosphoryl chloride), TBAF (tetrabutylammonium fluoride), THF (tetrahydrofuran), and TFA (trifluoroacetic acid).

[0145] Example 1: Preparation of N-(azetidine-3-yl)-2,4-difluoro-6-((2-fluoro-4-iodophenyl)amino)benzamide (compound 1) TIFF2023554391000021.tif53141 Step 1: Synthesis of 2,4-difluoro-6-((2-fluoro-4-iodophenyl)amino)benzoic acid A mixture of 2,4,6-trifluorobenzoic acid (646 mg, 3.67 mmol) and 2-fluoro-4-iodoaniline (1000 mg, 4.22 mmol) in MeCN (30 mL) was mixed with LiNH2 (295 mg, 12.8 mmol) under N2 conditions. The reaction was stirred at 60°C for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, and then 1N HCl was added until the pH became 2. The mixture was stirred for 30 minutes and then filtered. The resulting cake was dried to obtain 2,4-difluoro-6-((2-fluoro-4-iodophenyl)amino)benzoic acid (1.22 g, yield 85%) as a pink solid.

[0146] Step 2: Synthesis of 3-(2,4-difluoro-6-((2-fluoro-4-iodophenyl)amino)benzamide)azetidine-1-carboxylate tert-butyl POCl3 (20 mg, 0.13 mmol) was added to a solution of 2,4-difluoro-6-((2-fluoro-4-iodophenyl)amino)benzoic acid (200 mg, 0.51 mmol), 3-aminoazetidine-1-carboxylate tert-butyl (263 mg, 1.53 mmol), and pyridine (141 mg, 1.78 mmol) in CH2Cl2 (20 mL). The reaction was stirred at room temperature for 16 hours. After the reaction was complete, the solvent was removed. The residue was purified by column chromatography (PE / siRNA = 4 / 1) on silica gel to obtain 3-(2,4-difluoro-6-((2-fluoro-4-iodophenyl)amino)benzamide)azetidine-1-carboxylate tert-butyl (230 mg, yield 82%) as a white solid.

[0147] Step 3: Synthesis of N-(azetidine-3-yl)-2,4-difluoro-6-((2-fluoro-4-iodophenyl)amino)benzamide To a solution of 3-(2,4-difluoro-6-((2-fluoro-4-iodophenyl)amino)benzamide)azetidine-1-carboxylate tert-butyl (170 mg, 0.31 mmol) in CH2Cl2 (10 mL), TFA (2 mL) was added. The reaction was stirred at room temperature for 16 hours. After the reaction was complete, the solvent was removed, the residue was dissolved in CH2Cl2, NH3,H2O was added until the pH > 7, and the mixture was concentrated to dryness. The residue was purified by prep-HPLC to obtain N-(azetidine-3-yl)-2,4-difluoro-6-((2-fluoro-4-iodophenyl)amino)benzamide (TFA salt, 17 mg, yield 10%) as a yellow solid. TIFF2023554391000022.tif34159

[0148] Example 2: Preparation of 2,4-difluoro-6-((2-fluoro-4-iodophenyl)amino)-N-(pyrrolidine-3-yl)benzamide (compound 2) TIFF2023554391000023.tif54128 Step 1: Synthesis of 3-(2,4-difluoro-6-((2-fluoro-4-iodophenyl)amino)benzamide)pyrrolidine-1-carboxylate tert-butyl POCl3 (20 mg, 0.13 mmol) was added to a solution of 2,4-difluoro-6-((2-fluoro-4-iodophenyl)amino)benzoic acid (200 mg, 0.51 mmol), 3-aminopyrrolidine-1-carboxylate tert-butyl (285 mg, 1.53 mmol), and pyridine (141 mg, 1.78 mmol) in CH2Cl2 (20 mL). The reaction was stirred at room temperature for 16 hours. After the reaction was complete, the solvent was removed. The residue was purified by column chromatography (PE / siRNA = 4 / 1) on silica gel to obtain 3-(2,4-difluoro-6-((2-fluoro-4-iodophenyl)amino)benzamide)pyrrolidine-1-carboxylate tert-butyl (170 mg, yield 60%) as a white solid.

[0149] Step 2: Synthesis of 2,4-difluoro-6-((2-fluoro-4-iodophenyl)amino)-N-(pyrrolidine-3-yl)benzamide To a solution of 3-(2,4-difluoro-6-((2-fluoro-4-iodophenyl)amino)benzamide)pyrrolidine-1-carboxylate tert-butyl (170 mg, 0.30 mmol) in CH2Cl2 (10 mL), TFA (2 mL) was added. The reaction was stirred at room temperature for 16 hours. After the reaction was complete, the solvent was removed, the residue was dissolved in CH2Cl2, and NH3.H2O was added until the pH > 7, and the mixture was concentrated to dryness. The residue was purified by column chromatography on silica gel (CH2Cl2 / MeOH = 25 / 1 + 0.5% NH3.H2O) to obtain 2,4-difluoro-6-((2-fluoro-4-iodophenyl)amino)-N-(pyrrolidine-3-yl)benzamide (TFA salt, 130 mg, yield 75%) as a white solid. TIFF2023554391000024.tif34158

[0150] Example 3: Preparation of 2,4-difluoro-6-((2-fluoro-4-iodophenyl)amino)-N-(piperidine-3-yl)benzamide (compound 3) TIFF2023554391000025.tif59128 Step 1: Synthesis of 3-(2,4-difluoro-6-((2-fluoro-4-iodophenyl)amino)benzamide)piperidine-1-carboxylate tert-butyl A solution of 2,4-difluoro-6-((2-fluoro-4-iodophenyl)amino)benzoic acid (200 mg, 0.50 mmol), 3-aminopiperidine-1-carboxylate tert-butyl (200 mg, 1.00 mmol), POCl3 (3 drops), and pyridine (120 mg, 1.5 mmol) in CH2Cl2 (20 mL) was stirred overnight at room temperature. The reaction mixture was extracted with ELISA, washed with brine, dried over Na2SO4, concentrated, and the residue was purified by column chromatography (CH2Cl2 / MeOH 30:1~20:1, v / v) on silica gel to obtain 3-(2,4-difluoro-6-((2-fluoro-4-iodophenyl)amino)benzamide)piperidine-1-carboxylate tert-butyl (170 mg, yield 59%) as a white solid.

[0151] Step 2: Synthesis of 2,4-difluoro-6-((2-fluoro-4-iodophenyl)amino)-N-(piperidine-3-yl)benzamide A mixture of 3-(2,4-difluoro-6-((2-fluoro-4-iodophenyl)amino)benzamide)piperidine-1-carboxylate tert-butyl (170 mg, 0.30 mmol) in CH2Cl2 / TFA (10 mL / 1 mL) was stirred at room temperature for 3 hours. After the reaction was complete, the solvent was evaporated, and the residue was purified by prep-HPLC to obtain 2,4-difluoro-6-((2-fluoro-4-iodophenyl)amino)-N-(piperidine-3-yl)benzamide (50 mg, yield 35%) as a white solid. TIFF2023554391000026.tif34157

[0152] Example 4: Preparation of N-(azetidine-3-yl)-2,3,4,5-tetrafluoro-6-((2-fluoro-4-iodophenyl)amino)benzamide (compound 4) TIFF2023554391000027.tif57144 Step 1: Synthesis of 2,3,4,5-tetrafluoro-6-((2-fluoro-4-iodophenyl)amino)benzoic acid A mixture of 2,3,4,5,6-pentafluorobenzoic acid (500 mg, 2.36 mmol) and 2-fluoro-4-iodoaniline (559 mg, 2.36 mmol) in THF (20 mL) was mixed with LiHMDS (7 mL, 1 M in THF) under N2 conditions, and the reaction was stirred at room temperature for 16 hours. After the reaction was complete, the solvent was removed, and the residue was purified by column chromatography on silica gel (CH2Cl2 / MeOH = 10 / 1) to obtain 2,3,4,5-tetrafluoro-6-((2-fluoro-4-iodophenyl)amino)benzoic acid (700 mg, yield 69%) as a yellow solid.

[0153] Step 2: Synthesis of 3-(2,3,4,5-tetrafluoro-6-((2-fluoro-4-iodophenyl)amino)benzamide)azetidine-1-carboxylate tert-butyl POCl3 (20 mg, 0.13 mmol) was added to a solution of 2,3,4,5-tetrafluoro-6-((2-fluoro-4-iodophenyl)amino)benzoic acid (200 mg, 0.47 mmol), 3-aminoazetidine-1-carboxylate tert-butyl (240 mg, 1.4 mmol), and pyridine (129 mg, 1.63 mmol) in CH2Cl2 (20 mL). The reaction was stirred at room temperature for 16 hours. After the reaction was complete, the solvent was removed to obtain 3-(2,3,4,5-tetrafluoro-6-((2-fluoro-4-iodophenyl)amino)benzamide)azetidine-1-carboxylate tert-butyl (crude), which was used in the next step without purification.

[0154] Step 3: Synthesis of N-(azetidine-3-yl)-2,3,4,5-tetrafluoro-6-((2-fluoro-4-iodophenyl)amino)benzamide To a solution of 3-(2,3,4,5-tetrafluoro-6-((2-fluoro-4-iodophenyl)amino)benzamide)azetidine-1-carboxylate tert-butyl (274 mg, 0.47 mmol) in CH2Cl2 (20 mL), TFA (2 mL) was added. The reaction was stirred at room temperature for 2 hours. After the reaction was complete, the solvent was removed, the residue was dissolved in CH2Cl2, and NH3.H2O was added until the pH > 7, and the mixture was concentrated to dryness. The residue was purified by column chromatography on silica gel (CH2Cl2 / MeOH = 25 / 1 + 0.5% NH3.H2O) to obtain N-(azetidine-3-yl)-2,3,4,5-tetrafluoro-6-((2-fluoro-4-iodophenyl)amino)benzamide (73 mg, 32% yield in 2 steps) as a yellow solid. TIFF2023554391000028.tif27158

[0155] Example 5: Preparation of N-(azetidine-3-yl)-3-fluoro-5-((2-fluoro-4-iodophenyl)amino)isonicotinamide (compound 5) TIFF2023554391000029.tif51149 Step 1: Synthesis of 3-fluoro-5-((2-fluoro-4-iodophenyl)amino)isonicotinic acid A mixture of 3,5-difluoroisonicotinic acid (5.00 g, 31.5 mmol) and 2-fluoro-4-iodoaniline (7.45 g, 31.5 mmol) in THF (200 mL) was cooled to 0°C under N2. LiHMDS (95 mL, 1 M in THF) was added, and the reaction was stirred at room temperature for 16 hours. After the reaction was complete, the solvent was removed, the residue was dissolved in CH2Cl2, and washed with aqueous NaOH solution (2 N, 500 mL). The aqueous layer was treated with concentrated hydrochloric acid (100 mL) until the pH = 1, the mixture was filtered, and the cake was dried to obtain 3-fluoro-5-((2-fluoro-4-iodophenyl)amino)isonicotinic acid (10 g, yield 85%) as a yellow solid.

[0156] Step 2: Synthesis of 3-(3-fluoro-5-((2-fluoro-4-iodophenyl)amino)isonicotinamide)azetidine-1-carboxylate tert-butyl A mixture of 3-fluoro-5-((2-fluoro-4-iodophenyl)amino)isonicotinic acid (10 g, 26.6 mmol) and 3-aminoazetidine-1-carboxylate tert-butyl (13.7 g, 79.8 mmol) in CH2Cl2 (300 mL) was mixed with pyridine (7.4 g, 93 mmol) and POCl3 (1 mL) under N2 conditions. The reaction was stirred at room temperature for 16 hours. After the reaction was complete, the solvent was removed and the residue was purified by column chromatography (100% ELISA) on silica gel to obtain 3-(3-fluoro-5-((2-fluoro-4-iodophenyl)amino)isonicotinamide)azetidine-1-carboxylate tert-butyl (6.7 g, 48% yield).

[0157] Step 3: Synthesis of N-(azetidine-3-yl)-3-fluoro-5-((2-fluoro-4-iodophenyl)amino)isonicotinamide To a solution of 3-(3-fluoro-5-((2-fluoro-4-iodophenyl)amino)isonicotinamide)azetidine-1-carboxylate tert-butyl (6.7 g, 12.6 mmol) in CH2Cl2 (200 mL), TFA (10 mL) was added. The reaction was stirred at room temperature for 2 hours. After the reaction was complete, the solvent was removed. The residue was dissolved in CH2Cl2 / MeOH (100 mL, 1 / 10), NH3 / H2O was added until pH > 7, the mixture was concentrated to dryness, and the residue was treated with CH2Cl2 (100 mL). After 30 minutes, a yellow solid was formed, filtered, and dried to obtain N-(azetidine-3-yl)-3-fluoro-5-((2-fluoro-4-iodophenyl)amino)isonicotinamide (100% purity, 4.13 g, yield 76%). The organic layer was concentrated to dryness, and the residue was purified by column chromatography (CH2Cl2 / MeOH = 10 / 1) on silica gel to obtain N-(azetidine-3-yl)-3-fluoro-5-((2-fluoro-4-iodophenyl)amino)isonicotinamide (containing some salts, 1.7 g, 31%) as a yellow solid. TIFF2023554391000030.tif19159

[0158] Example 6: Preparation of N-(1-ethylazetidine-3-yl)-3-fluoro-5-((2-fluoro-4-iodophenyl)amino)isonicotinamide (compound 6) A mixture of N-(azetidine-3-yl)-3-fluoro-5-((2-fluoro-4-iodophenyl)amino)isonicotinamide (3.82 g, 8.88 mmol) in MeOH (350 mL), AcOH (20 mg), and acetaldehyde (45 mL, 17.8 mmol) was stirred at room temperature for 1 hour. NaBH3CN (1.12 g, 17.8 mmol) was added, and the reaction was stirred at room temperature for 16 hours. After the reaction was complete, the solvent was removed. The residue was dissolved in CH2Cl2 (200 mL) and washed with water. The organic layer was dried and concentrated, and the residue was purified by column chromatography on silica gel (CH2Cl2 / MeOH = 25 / 1 + 0.5% NH3.H2O) to obtain a yellow oily substance. Et2O (50 mL) was added, the mixture was stirred for 30 minutes, filtered, and dried to obtain N-(1-ethylazetidine-3-yl)-3-fluoro-5-((2-fluoro-4-iodophenyl)amino)isonicotinamide (3 g, yield 74%) as a yellow solid. TIFF2023554391000032.tif33158

[0159] Example 7: Preparation of 3-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(1-methylazetidine-3-yl)isonicotinamide (compound 7) TIFF2023554391000033.tif25141 A solution of 3-fluoro-5-((2-fluoro-4-iodophenyl)amino)isonicotinic acid (100 mg, 0.26 mmol) and 1-methylazetidine-3-amine (70 mg, 0.81 mmol) in CH2Cl2 (10 mL) was mixed with pyridine (73 mg, 0.93 mmol) and POCl3 (10 mg) under N2 conditions, and the reaction was stirred at room temperature for 16 hours. After the reaction was complete, the solvent was removed. The residue was purified by prep-HPLC to obtain 3-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(1-methylazetidine-3-yl)isonicotinamide (25 mg, yield 21%) as a yellow solid. TIFF2023554391000034.tif27156

[0160] Example 8: Preparation of 3-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(1-isopropylazetidine-3-yl)isonicotinamide (Compound 8) TIFF2023554391000035.tif26142 A solution of N-(azetidine-3-yl)-3-fluoro-5-((2-fluoro-4-iodophenyl)amino)isonicotinamide (215 mg, 0.50 mmol) in MeOH (10 mL), acetone (1 mL), NaBH3CN (63 mg, 1.0 mmol), and AcOH (3 drops) was stirred overnight at room temperature. After the reaction was complete, the solvent was evaporated, and the residue was purified by prep-HPLC to obtain 3-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(1-isopropylazetidine-3-yl)isonicotinamide (50 mg, yield 21%) as a yellow solid. TIFF2023554391000036.tif33159

[0161] Example 9: Preparation of 3-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(1-(2-fluoroethyl)azetidine-3-yl)isonicotinamide (Compound 9) TIFF2023554391000037.tif24128 A mixture of N-(azetidine-3-yl)-3-fluoro-5-((2-fluoro-4-iodophenyl)amino)isonicotinamide (130 mg, 0.3 mmol) and K2CO3 (82 mg, 0.6 mmol) in DMF (10 mL) was mixed with 1-fluoro-2-iodoethane (42 mg, 0.24 mmol) at 0°C. The reaction was then stirred overnight at room temperature. After removal of the solvent, the residue was dissolved in H2O (20 mL). The mixture was extracted with ELISA (50 mL x 3) and dried over Na2SO4. The organic layer was concentrated, and the residue was purified by prep-HPLC to obtain 3-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(1-(2-fluoroethyl)azetidine-3-yl)isonicotinamide (10 mg, yield 7%) as a yellow solid. TIFF2023554391000038.tif34158

[0162] Example 10: Preparation of 3-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(1-(2-methoxyethyl)azetidine-3-yl)isonicotinamide (Compound 10) TIFF2023554391000039.tif25133 A solution of N-(azetidine-3-yl)-3-fluoro-5-((2-fluoro-4-iodophenyl)amino)isonicotinamide (200 mg, 0.46 mmol) and K2CO3 (190 mg, 1.38 mmol) in DMF (5 mL) was mixed with 1-bromo-2-methoxyethane (58 mg, 0.41 mmol) at 0°C. The reaction was then stirred overnight at room temperature. After removing the solvent, the residue was dissolved in H2O (20 mL), the mixture was extracted with Âx (50 mL x 3), dried over Na2SO4, and the organic layer was concentrated. The residue was purified by prep-HPLC to obtain 3-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(1-(2-methoxyethyl)azetidine-3-yl)isonicotinamide (38 mg, yield 17%) as a yellow solid. TIFF2023554391000040.tif33159

[0163] Example 11: Preparation of N-(azetidine-3-yl)-3-((4-ethynyl-2-fluorophenyl)amino)-5-fluoroisonicotinamide (compound 11) TIFF2023554391000041.tif61128 Step 1: Synthesis of N-(azetidine-3-yl)-3-fluoro-5-((2-fluoro-4-((trimethylsilyl)ethynyl)phenyl)amino)isonicotinamide A mixture of N-(azetidin-3-yl)-3-fluoro-5-((2-fluoro-4-iodophenyl)amino)isonicotinamide (400 mg, 0.93 mmol) and ethynyltrimethylsilane (238 mg, 2.42 mmol) in DMF (10 mL) was added with PdCl2(dppf) (101 mg, 0.14 mmol), CuI (50 mg, 0.28 mmol) and Et3N (187 mg, 1.86 mmol) under N2 at room temperature. The reaction was stirred at room temperature for 1 hour, the solvent was removed, the residue was dissolved in H2O (100 mL), the mixture was extracted with CH2Cl2 (50 mL×3), and dried over Na2SO4. The organic layer was concentrated to obtain N-(azetidin-3-yl)-3-fluoro-5-((2-fluoro-4-((trimethylsilyl)ethynyl)phenyl)amino)isonicotinamide (150 mg, yield 40%) as a yellow solid.

[0164] Step 2: Synthesis of N-(azetidin-3-yl)-3-((4-ethynyl-2-fluorophenyl)amino)-5-fluoroisonicotinamide TBAF (1 M, 0.38 mL) was added to a mixture of N-(azetidin-3-yl)-3-fluoro-5-((2-fluoro-4-((trimethylsilyl)ethynyl)phenyl)amino)isonicotinamide (153 mg, 0.38 mmol) in DMSO (2 mL), and the reaction mixture was stirred at room temperature for 30 minutes. The reaction was concentrated, and the crude residue was purified by prep-HPLC to obtain N-(azetidin-3-yl)-3-((4-ethynyl-2-fluorophenyl)amino)-5-fluoroisonicotinamide (TFA salt, 40 mg, yield 24%) as a yellow solid. TIFF2023554391000042.tif27158

[0165] Example 12: Preparation of N-(1-ethylazetidin-3-yl)-3-((4-ethynyl-2-fluorophenyl)amino)-5-fluoroisonicotinamide (Compound 12) TIFF2023554391000043.tif57137 Project 1: Synthesis of N-(1-Ethylazetidin-3-yl)-3-fluoro-5-((2-fluoro-4-((trimethylsilyl)ethynyl)phenyl)amino)isonicotinamide To a solution of N-(1-Ethylazetidin-3-yl)-3-fluoro-5-((2-fluoro-4-iodophenyl)amino)isonicotinamide (400 mg, 0.87 mmol) and ethynyltrimethylsilane (255 mg, 2.61 mmol) in DMF (10 mL) were added PdCl2(dppf) (94 mg, 0.13 mmol), CuI (50 mg, 0.26 mmol), and Et3N (175 mg, 1.74 mmol) under N2 at room temperature. The reaction mixture was stirred at room temperature for 2 hours, the solvent was removed, the residue was dissolved in H2O (100 mL), the mixture was extracted with CH2Cl2 (50 mL×3), and dried over Na2SO4. The organic layer was concentrated, and the residue was purified by column chromatography on silica gel (CH2Cl2 / MeOH = 10 / 1) to give N-(1-Ethylazetidin-3-yl)-3-fluoro-5-((2-fluoro-4-((trimethylsilyl)ethynyl)phenyl)amino)isonicotinamide (340 mg, yield 91%) as a yellow solid.

[0166] Project 2: Synthesis of N-(1-Ethylazetidin-3-yl)-3-((4-ethynyl-2-fluorophenyl)amino)-5-fluoroisonicotinamide To a solution of N-(1-Ethylazetidin-3-yl)-3-fluoro-5-((2-fluoro-4-((trimethylsilyl)ethynyl)phenyl)amino)isonicotinamide (340 mg, 0.79 mmol) in DMSO (2 mL) was added TBAF (1 M, 0.79 mL) at room temperature for 30 minutes. The reaction was concentrated to give the crude product, and the residue was purified by prep-HPLC to give N-(1-Ethylazetidin-3-yl)-3-((4-ethynyl-2-fluorophenyl)amino)-5-fluoroisonicotinamide (TFA salt, 27 mg, yield 7%) as a yellow solid. TIFF2023554391000044.tif27156

[0167] Example 13: Preparation of N-(azetidine-3-yl)-3-chloro-5-((2-fluoro-4-iodophenyl)amino)isonicotinamide (compound 13) TIFF2023554391000045.tif55152 Step 1: Synthesis of 3-chloro-5-fluoroisonicotinic acid To a solution of 3-chloro-5-fluoropyridine (500 mg, 3.8 mmol) in THF (20 mL) cooled to -78°C under N2, n-BuLi (4.75 mL, 1.6 M in hexane) was added. The reaction was stirred at -78°C for 1 hour, solid CO2 was added, and the reaction was stirred at room temperature for 16 hours. The reaction was not completed (90% desired compound and 8% starting material). The solvent was removed, the residue was washed with CH2Cl2, filtered, and dried to obtain 3-chloro-5-fluoroisonicotinic acid (670 mg, crude) as a white solid, which was used directly in the next step without purification.

[0168] Step 2: Synthesis of 3-chloro-5-((2-fluoro-4-iodophenyl)amino)isonicotinic acid A mixture of 3-chloro-5-fluoroisosonic acid (670 mg, 3.8 mmol) and 2-fluoro-4-iodoaniline (900 mg, 3.8 mmol) in THF (30 mL) was cooled to 0°C under N2. LiHMDS (11.4 mL, 1 M in THF) was added, and the reaction was stirred at room temperature for 16 hours. After the reaction was complete, the solvent was removed, the residue was washed with CH2Cl2 and 2N NaOH, and the combined aqueous layer was treated with concentrated HCl until pH = 1. The mixture was stirred at room temperature for 16 hours. The mixture was filtered and dried to obtain 3-chloro-5-((2-fluoro-4-iodophenyl)amino)isosonic acid (240 mg, 16% yield in two steps) as a yellow solid.

[0169] Step 3: Synthesis of 3-(3-chloro-5-((2-fluoro-4-iodophenyl)amino)isonicotinamide)azetidine-1-carboxylate tert-butyl To a solution of 3-chloro-5-((2-fluoro-4-iodophenyl)amino)isonicotinic acid (240 mg, 0.61 mmol) and 3-aminoazetidine-1-carboxylate tert-butyl (316 mg, 1.84 mmol) in CH2Cl2 (20 mL), pyridine (170 mg, 2.14 mmol) and POCl3 (30 mg) were added under N2 conditions, and the reaction was stirred at room temperature for 16 hours. After the reaction was complete, the solvent was removed to obtain 3-(3-chloro-5-((2-fluoro-4-iodophenyl)amino)isonicotinamide)azetidine-1-carboxylate tert-butyl, which was used in the next step without purification.

[0170] Step 4: Synthesis of N-(azetidine-3-yl)-3-chloro-5-((2-fluoro-4-iodophenyl)amino)isonicotinamide To a solution of 3-(3-chloro-5-((2-fluoro-4-iodophenyl)amino)isonicotinamide)azetidine-1-carboxylate tert-butyl (330 mg, 0.60 mmol) in CH2Cl2 (30 mL), TFA (3 mL) was added. The reaction was stirred at room temperature for 2 hours. After the reaction was complete, the solvent was removed. The residue was purified by column chromatography on silica gel (CH2Cl2 / MeOH = 25 / 1 + 0.5% NH3.H2O) to obtain N-(azetidine-3-yl)-3-chloro-5-((2-fluoro-4-iodophenyl)amino)isonicotinamide (180 mg, 66% yield in 2 steps) as a yellow solid. TIFF2023554391000046.tif27157

[0171] Example 14: Preparation of N-(azetidine-3-yl)-3-((4-bromo-2-chlorophenyl)amino)-5-fluoroisonicotinamide (compound 14) TIFF2023554391000047.tif59145 Step 1: Synthesis of 3-((4-bromo-2-chlorophenyl)amino)-5-fluoroisonicotinic acid A mixture of 3,5-difluoroisonicotinic acid (160 mg, 1.0 mmol) and 4-bromo-2-chloroaniline (207 mg, 1.0 mmol) in THF (10 mL) was cooled to 0°C under N2. LiHMDS (3 mL, 1 M in THF) was added, and the reaction was stirred at room temperature for 16 hours. After the reaction was complete, the solvent was removed, and the residue was purified by column chromatography on silica gel (CH2Cl2 / MeOH = 10 / 1) to obtain 3-((4-bromo-2-chlorophenyl)amino)-5-fluoroisonicotinic acid (180 mg, yield 52%) as a yellow solid.

[0172] Step 2: Synthesis of 3-(3-((4-bromo-2-chlorophenyl)amino)-5-fluoroisonicotinamide)azetidine-1-carboxylate tert-butyl To a solution of 3-((4-bromo-2-chlorophenyl)amino)-5-fluoroisonicotinic acid (180 mg, 0.52 mmol) and 3-aminoazetidine-1-carboxylate tert-butyl (269 mg, 1.56 mmol) in CH2Cl2 (20 mL), pyridine (144 mg, 1.83 mmol) and POCl3 (25 mg) were added under N2 conditions, and the reaction was stirred at room temperature for 16 hours. After the reaction was complete, the solvent was removed to obtain 3-(3-((4-bromo-2-chlorophenyl)amino)-5-fluoroisonicotinamide)azetidine-1-carboxylate tert-butyl (crude), which was used in the next step without purification.

[0173] Step 3: Synthesis of N-(azetidine-3-yl)-3-((4-bromo-2-chlorophenyl)amino)-5-fluoroisonicotinamide To a solution of 3-(3-((4-bromo-2-chlorophenyl)amino)-5-fluoroisonicotinamide)azetidine-1-carboxylate tert-butyl (260 mg, 0.52 mmol) in CH2Cl2 (30 mL), TFA (3 mL) was added, and the reaction was stirred at room temperature for 2 hours. After the reaction was complete, the solvent was removed. The residue was purified by column chromatography on silica gel (CH2Cl2 / MeOH = 15 / 1 + 0.5% NH3.H2O) to obtain N-(azetidine-3-yl)-3-((4-bromo-2-chlorophenyl)amino)-5-fluoroisonicotinamide (120 mg, 58% yield in 2 steps) as a yellow solid. TIFF2023554391000048.tif19154

[0174] Example 15: Preparation of N-(azetidine-3-yl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide (compound 15) TIFF2023554391000049.tif56128 Step 1: Synthesis of 3-((2-fluoro-4-iodophenyl)amino)isonicotinic acid A solution of 3-fluoroisonicotinic acid (820 mg, 5.8 mmol) and 2-fluoro-4-iodoaniline (1380 mg, 5.8 mmol) in THF (30 mL) was mixed with LiHMDS (17.4 mL, 17.4 mmol) at 0°C. The reaction mixture was stirred overnight at room temperature. 1N NaOH aqueous solution (20 mL) was added to the mixture. The mixture was extracted with ELISA (50 mL x 2). The aqueous phase was acidified by adding 1N HCl until the pH was 5-7, the mixture was stirred for 30 minutes, then filtered, and the cake was dried to obtain 3-((2-fluoro-4-iodophenyl)amino)isonicotinic acid (350 mg, yield 17%) as a white solid.

[0175] Step 2: Synthesis of 3-(3-((2-fluoro-4-iodophenyl)amino)isonicotinamide)azetidine-1-carboxylate tert-butyl A mixture of 3-((2-fluoro-4-iodophenyl)amino)isonicotinic acid (200 mg, 0.55 mmol) and 3-aminoazetidine-1-carboxylate tert-butyl (290 mg, 1.68 mmol) in pyridine (10 mL) was mixed with POCl3 (6 drops). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was purified by column chromatography (CH2Cl2 / MeOH 100:1~30:1, v / v) on silica gel to obtain 3-(3-((2-fluoro-4-iodophenyl)amino)isonicotinamide)azetidine-1-carboxylate tert-butyl (100 mg, yield 35%) as a brown solid.

[0176] Step 3: Synthesis of N-(azetidine-3-yl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide A mixture of 3-(3-((2-fluoro-4-iodophenyl)amino)isonicotinamide)azetidine-1-carboxylate tert-butyl (100 mg, 0.19 mmol) in CH2Cl2 / TFA (10 mL / 1 mL) was stirred at room temperature for 3 hours. After the reaction was complete, the solvent was evaporated to obtain N-(azetidine-3-yl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide (TFA salt, 100 mg, yield 98%) as a brown oil. TIFF2023554391000050.tif27157

[0177] Example 16: Preparation of N-(azetidine-3-yl)-4-((2-fluoro-4-iodophenyl)amino)nicotinamide (compound 16) TIFF2023554391000051.tif54146 Step 1: Synthesis of 4-((2-fluoro-4-iodophenyl)amino)nicotinic acid A solution of 4-chloronicotinic acid (1.0 g, 6.3 mmol) and 2-fluoro-4-iodoaniline (1.5 g, 6.3 mmol) in THF (40 mL) was mixed with LiHMDS (19.1 mL, 19.1 mmol) at 0°C. The reaction mixture was stirred overnight at room temperature. 1N NaOH aqueous solution (20 mL) was added to the mixture. The mixture was extracted with ELISA (60 mL x 2). The aqueous phase was acidified with the addition of 1N HCl until the pH was 5-7, the mixture was stirred for 30 minutes, then filtered, and the cake was dried to obtain 4-((2-fluoro-4-iodophenyl)amino)nicotinic acid (1.0 g, yield 45%) as a white solid.

[0178] Step 2: Synthesis of 3-(4-((2-fluoro-4-iodophenyl)amino)nicotinamide)azetidine-1-carboxylate tert-butyl A mixture of 4-((2-fluoro-4-iodophenyl)amino)nicotinic acid (200 mg, 0.55 mmol), 3-aminoazetidine-1-carboxylate tert-butyl (193 mg, 1.12 mmol), HATU (319 mg, 0.84 mmol), and DIEA (145 mg, 1.12 mmol) in DMF (10 mL) was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was purified by prep-HPLC to obtain 3-(4-((2-fluoro-4-iodophenyl)amino)nicotinamide)azetidine-1-carboxylate tert-butyl (180 mg, yield 63%) as a white solid.

[0179] Step 3: Synthesis of N-(azetidine-3-yl)-4-((2-fluoro-4-iodophenyl)amino)nicotinamide A mixture of 3-(4-((2-fluoro-4-iodophenyl)amino)nicotinamide)azetidine-1-carboxylate tert-butyl (180 mg, 0.35 mmol) in CH2Cl2 / TFA (15 mL / 1.5 mL) was stirred at room temperature for 3 hours. After the reaction was complete, the solvent was evaporated to obtain N-(azetidine-3-yl)-4-((2-fluoro-4-iodophenyl)amino)nicotinamide (TFA salt, 80 mg, yield 43%) as a brown oil. TIFF2023554391000052.tif34159

[0180] Example 17: Preparation of 3-((4-acetyl-2-fluorophenyl)amino)-N-(azetidin-3-yl)-5-fluoroisonicotinamide (Compound 17) TIFF2023554391000053.tif28132 Step 1: Synthesis of 3-((4-acetyl-2-fluorophenyl)amino)-N-(azetidin-3-yl)-5-fluoroisonicotinamide TFA (1 mL) was added to a solution of tert-butyl azetidine-1-carboxylate (500 mg, 1.2 mmol) of 3-(3-((4-ethynyl-2-fluorophenyl)amino)-5-fluoroisonicotinamide) in DCM (10 mL) at room temperature. The mixture was stirred at room temperature for 3 hours. It was concentrated to obtain the crude product, which was then purified by prep-HPLC (0.1% TFA / MeCN / H2O) to give 3-((4-acetyl-2-fluorophenyl)amino)-N-(azetidin-3-yl)-5-fluoroisonicotinamide (5 mg, yield 1%, TFA salt) as a yellow solid. TIFF2023554391000054.tif27159

[0181] Example 18: Preparation of 3-(3-(3-((2-fluoro-4-iodophenyl)amino)isonicotinamide)azetidin-1-yl)propanoic acid (Compound 18) TIFF2023554391000055.tif24132 Step 1: Synthesis of 3-(3-(3-((2-fluoro-4-iodophenyl)amino)isonicotinamide)azetidin-1-yl)propanoic acid A mixture of N-(azetidine-3-yl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide (32 mg, 0.06 mmol), K2CO3 (17 mg, 0.12 mmol), and 3-bromopropanoic acid (10 mg, 0.06 mmol) in DMF (5 mL) was stirred at room temperature for 16 hours. After the reaction was complete, the solvent was removed, and the residue was purified by prep-HPLC (0.1% TFA / MeCN / H2O) to obtain 3-(3-(3-((2-fluoro-4-iodophenyl)amino)isonicotinamide)azetidine-1-yl)propanoic acid (12 mg, yield 40%, TFA salt) as a yellow solid. TIFF2023554391000056.tif27154

[0182] Example 19: Preparation of 4-(3-(3-((2-fluoro-4-iodophenyl)amino)isonicotinamide)azetidine-1-yl)butanoic acid (compound 19) TIFF2023554391000057.tif51136 Step 1: Synthesis of 4-(3-(3-((2-fluoro-4-iodophenyl)amino)isonicotinamide)azetidine-1-yl)butanoate methyl A mixture of N-(azetidine-3-yl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide (100 mg, 0.24 mmol), methyl 4-bromobutanoate (43 mg, 0.24 mmol), and K2CO3 (67 mg, 0.49 mmol) in DMF (5 mL) was stirred at room temperature for 16 hours. After the reaction was complete, the solvent was removed, and the residue was used in the next step without purification.

[0183] Step 2: Synthesis of 4-(3-(3-((2-fluoro-4-iodophenyl)amino)isonicotinamide)azetidine-1-yl)butanoic acid A solution of methyl 4-(3-(3-((2-fluoro-4-iodophenyl)amino)isonicotinamide)azetidine-1-yl)butanoate (100 mg, 0.19 mmol) in MeOH (5 mL) was mixed with aqueous NaOH (2 N, 5 mL), and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was concentrated, and the residue was purified by prep-HPLC (0.1% TFA / MeCN / H2O) to obtain 4-(3-(3-((2-fluoro-4-iodophenyl)amino)isonicotinamide)azetidine-1-yl)butanoic acid (100 mg, yield 86%, TFA salt) as a yellow solid. TIFF2023554391000058.tif27159

[0184] Example 20: Preparation of N-(1-acetylazetidine-3-yl)-3-fluoro-5-((2-fluoro-4-iodophenyl)amino)isonicotinamide (compound 20) TIFF2023554391000059.tif28147 Step 1: Synthesis of N-(1-acetylazetidine-3-yl)-3-fluoro-5-((2-fluoro-4-iodophenyl)amino)isonicotinamide To a solution of N-(azetidine-3-yl)-3-fluoro-5-((2-fluoro-4-iodophenyl)amino)isonicotinamide (60 mg, 0.14 mmol) and acetic anhydride (21 mg, 0.21 mmol) in DMF (1 mL), K2CO3 (39 mg, 0.28 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered and purified by Prep-HPLC (0.1% NH3-H2O) to obtain N-(1-acetylazetidine-3-yl)-3-fluoro-5-((2-fluoro-4-iodophenyl)amino)isonicotinamide (34 mg, yield 52%) as a yellow solid. TIFF2023554391000060.tif33159

[0185] The above descriptions of the compounds, uses, and methods described herein will enable those skilled in the art to prepare and use the compounds, uses, and methods described herein. However, those skilled in the art will understand and recognize the existence of variations, combinations, and equivalents of the specific embodiments, methods, and examples described herein. The compounds, uses, and methods provided herein should therefore not be limited by the embodiments, methods, or examples described herein, but rather encompass all embodiments and methods that fall within the scope and spirit of the compounds, uses, and methods provided herein.

[0186] All references disclosed herein are incorporated by reference in their entirety.

[0187] The in vitro and in vivo activities of the compound of formula (I) were determined using the following procedure.

[0188] Biological Example B1 MEK1 / 2 Inhibition Assay A 10 mM stock solution was prepared by dissolving the test compound in 100% DMSO. For each test compound, a total of seven concentrations were prepared by 4-fold serial dilutions of the 100x solution. Staurosporine, as a positive control compound, was prepared at a total of 10 concentrations using 3-fold serial dilutions of the 100x solution. The final starting concentrations of the test compounds and staurosporine were 2 μM and 0.1 μM, respectively. Using an automated liquid handler, 250 nL of each compound was transferred to a 384-well plate according to the plate map. MEK1 (Carna, 07-141) was then diluted in 1x kinase buffer containing 40 nM inactive ERK2 (Carna, 04-143-10) to a final concentration of 2.5x (0.015 nM). 10 μL of the enzyme mix was added to each well of the 384-well plate. 10 μL of 1x kinase buffer was used as a negative control. The enzyme mix and compounds were pre-incubated at RT for 10 minutes. A 15 μL substrate mix containing ATP (100 μM) and kinase substrate 8 (GL BioChem, 112396) was added to a 384-well plate and reacted in RT for 30 minutes. The reaction was stopped by adding 30 μL of stop buffer. The conversion rate was read using a Caliper EZ Reader.

[0189] The inhibition rate of the compound is calculated as follows: % inhibition = (conversion %_max - conversion %_sample) / (conversion %_max - conversion %_min) × 100 Conversion %_Sample: Conversion % value of the sample Conversion %_min: Average conversion % value of the negative control Transformation %_max: The average transformed percentage value of the positive control.

[0190] The dose-response curve was fitted using GraphPad Prism 5, and the IC50 was calculated using the log(inhibitor) vs. response-variable gradient program with the following formula: Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) * Hill Slope))

[0191] Antiproliferative assay In vitro anti-proliferative studies of test compounds in the A375 cell line using CellTiter Glo. Cells were maintained as monolayer cultures in the corresponding medium at 37°C with 5% CO2 in air using conventional methods.

[0192] Exponentially growing cells were harvested by trypsin-EDTA digestion. The cell pellet was resuspended in fresh medium and the concentration was adjusted as needed (cell density per well is listed in the form below). Cell viability was over 98% according to trypan blue staining. Cells were seeded into a 96-well plate according to the plate map (90 μL / well). The plate was incubated overnight at 37°C and 5% CO2. The following day, 10x compound-containing medium was prepared according to the plate map. 10 μL of 10x compound-containing medium was transferred to each well of the assay plate (final DMSO concentration was 0.5%). The medium was gently mixed and incubated for a further 72 or 144 hours at 37°C and 5% CO2.

[0193] The reagents were prepared according to the manufacturer's instructions. 50 μL of CellTiter-Glo reagent was added to each well. The contents were mixed on an orbital shaker for 2 minutes to induce cell lysis. The plate was incubated at room temperature for 10 minutes to stabilize the luminescence signal. 100 μL of the reaction contents from each well was transferred from the clear plate to a white-walled / white-opaque 96-well plate. Luminescence was recorded using Envision.

[0194] The growth rate at each drug concentration level was calculated using luminescence measurement results [time zero (T0), control growth (C), and test growth in the presence of six drug concentration levels (Ti)].

[0195] Regarding the growth inhibition rate (GI), the concentration when Ti >= T0 is calculated as GI(%) = [(Ti - T0) / (C - T0)] × 100, and the concentration when Ti < T0 is calculated as GI(%) = [(Ti - T0) / T0] × 100. Using the XLFit (Excel) tool, the data was analyzed by fitting to a four-parameter equation to generate a concentration-response curve. The compound concentration (GI50) that inhibits 50% of the control cell growth was calculated by inverse interpolation when y is 50% of the net growth of the DMSO-treated control wells using non-linear regression according to the equation f(x)205[fit=(A + ((B - A) / (1 + ((C / x)^D))))], where A is the minimum response (Ymin), B is the maximum response (Ymax), C is the inflection point of the curve (Re GI50), and D is the Hill coefficient. The 50% growth inhibition (GI50) was calculated at 50% growth inhibition on the curve. The index value was the sum of the inhibition rates (IR) at each test compound concentration.

[0196] Table A shows the antiproliferative properties of the synthetic compounds in A375 melanoma cells and HT-29 colon cancer cells.

[0197]

Table A

[0198] Biological Example B2 MDCK-MDR1 Permeability Assay MDCK-MDR1 cells are derived from the transfection of Madin Darby canine kidney (MDCK) cells with the MDR1 gene, which encodes the efflux protein P-glycoprotein. This cell line is ideal for identifying P-gp substrates, with or without inhibitors. Cells were seeded into Multiscreen® plates to form a confluent monolayer over four days prior to the experiment. On day 4, test compounds (1–30 μM concentrations) were added to the apical side of the membrane, and the transport of compounds through the monolayer was monitored for 120 minutes. To examine drug efflux, it was also necessary to investigate the transport of compounds from the lateral-bottom compartment to the apical compartment and calculate the efflux ratio.

[0199] Transmission coefficient (P app ) was calculated from the following equation: P app =[(dQ / dt) / C0xA] In the formula, dQ / dt is the permeability of the drug through the cell, C0 is the donor compartment concentration at time zero, and A is the area of ​​the cell monolayer.

[0200] The discharge ratio is the average apical part → basolateral part (AB)P app Data and side bottom → apex (BA)P app It is calculated from the data. Emission ratio=P app (BA) / P app (AB)

[0201] Table B summarizes the permeability of compound 1 in the MDCK-MDR1 assay.

[0202] [Table B]

[0203] Biological Example B3 Caco-2 permeability assay Caco-2 cells are widely used in in vitro assays to measure drug permeability. The Caco-2 cell line is derived from human colorectal cancer, and when cultured, the cells spontaneously differentiate into a monolayer of polarized intestinal cells. Caco-2 cells express P-glycoprotein and breast cancer resistance protein, two of the most relevant cell membrane-active transporters that influence drug permeability to cells and the blood-brain barrier.

[0204] Cells were seeded into Millipore Millicell plates to form a confluent monolayer over 20 days prior to the experiment. On day 20, the test compound (1–30 μM concentration) was added to the apical side of the membrane, and the transport of the compound through the monolayer was monitored for 120 minutes. To investigate drug efflux, it was also necessary to examine the transport of the compound from the lateral-bottom compartment to the apical compartment.

[0205] Transmission coefficient (P app ) was calculated from the following equation: P app =[(dQ / dt) / C0xA] In the formula, dQ / dt is the permeability of the drug through the cell, C0 is the donor compartment concentration at time zero, and A is the area of ​​the cell monolayer. C0 is obtained from the analysis of the administered solution at the start of the experiment.

[0206] The permeability of selected compounds in the Caco-2 assay is summarized in Table C.

[0207] [Table C]

[0208] Biological Example B4 Mouse pharmacokinetic studies The pharmacokinetic properties of compounds 5 and 6 were investigated in CD-1 mice via intravenous and oral administration using a standard protocol. The test compounds were formulated in 20% hydroxypropyl-beta-cyclodextrin as either a clear solution or a fine suspension. Table D shows the pharmacokinetic characteristics of compounds 5 and 6 after intravenous injection in mice.

[0209] [Table D]

[0210] Table E shows the plasma exposure after oral administration of compound 1 in mice.

[0211] [Table E]

[0212] Biological Example B5 In vivo pharmacodynamics research The in vivo activity of the compound of formula (I) can be determined by the amount of tumor growth inhibition by the test compound compared to the control. The tumor growth inhibitory effects of various compounds are measured according to slightly modified methods of Corbett TH, et al., "Tumor Induction Relationships in Development of Transplantable Cancers of the Colon in Mice for Chemotherapy Assays, with a Note on Carcinogen Structure", Cancer Res., 35, 2434-2439 (1975) and Corbett TH, et al., "A Mouse Colon-tumor Model for Experimental Therapy", Cancer Chemother. Rep. (Part 2)", 5, 169-186 (1975). Tumors are induced in the left flank by subcutaneous injection of 1 to 5 million logarithmic-proliferating cultured tumor cells (human A375 melanoma or HT-29 colorectal cancer cells) suspended in 0.1 ml of RPMI1640 medium. After sufficient time has elapsed for the tumor to be easily identifiable (size 100-150 mm), 3 The test animals (female BALB / c nude mice) with a diameter of 5-6 mm were treated with the test compound (formulated at a concentration of 10-15 mg / ml in 20% hydroxypropyl-beta-cyclodextrin) by oral administration once or twice daily. To determine the antitumor effect, the tumors were measured in millimeters using a Vernier measuring instrument across two diameters, and the tumor size (mm³) was calculated according to the formula: Tumor size (mm³) according to Geran, RI, et al. "Protocols for Screening Chemical Agents and Natural Products Against Animal Tumors and Other Biological Systems", Third Edition, Cancer Chemother. Rep., 3, 1-104 (1972). 3 ) = (length × width) 2The result is calculated using ) / 2. The formula is: Inhibition (%) = (TuW control -TuW test ) / TuW control The inhibition rate is expressed according to ×100%. The flank position of tumor transplantation provides reproducible dose / response effects for various chemotherapeutic agents, and this measurement method (tumor diameter) is a reliable method for evaluating tumor growth rate.

[0213] The compound of the present invention (hereinafter referred to as the "active compound") may be administered by any method that enables delivery of the compound to the site of action. These methods include oral, intraduodenal, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular, or infusion), topical, and rectal administration.

[0214] The pharmaceutical composition may be in a form suitable for oral administration, such as tablets, capsules, pills, powders, sustained-release formulations, solutions, or suspensions; for parenteral injection, such as sterile solutions, suspensions, or emulsions; for topical administration, such as ointments or creams; or for rectal administration, such as suppositories. The pharmaceutical composition may also be in a unit dosage form suitable for single-dose administration of a precise dose. The pharmaceutical composition may contain a conventional pharmaceutical carrier or excipient and the compound of the invention as the active ingredient. In addition, it may contain other drugs or pharmaceuticals, carriers, adjuvants, etc.

[0215] The examples and preparations provided below further illustrate and illustrate the compounds of the present invention and methods for preparing such compounds. It should be understood that the scope of the present invention is not limited in any way by the following examples and preparations. In the following examples, unless otherwise specified, molecules having a single chiral center exist as a racemic mixture. Unless otherwise specified, molecules having two or more chiral centers exist as a racemic mixture of diastereomers. A single enantiomer / diastereomer may be obtained by methods known to those skilled in the art.

Claims

1. A compound of formula (I) or a pharma- ceutically acceptable salt, solvate or isotopic derivative thereof: During the ceremony, G 1 is CH or CR 2 and G 2 , G 3 , and G 4 are each independently N, CH, or CR 2 However; However, G 2 , G 3 , and G 4 At least two of the groups are independently CH or CR 2 and Furthermore, however, G 1 If CH, then G 2 , G 3 , and G 4 At least one of them is N or CR 2 and m is 0, 1, 2, 3, 4, or 5; p is 0, 1, 2, 3, or 4; q is 1, 2, or 3; Each R 1 are independently halogen, OH, NH 2 , NO 2 , CN, optionally substituted C 1 ~C 6 Alkyl, optionally substituted C 2 ~C 6 Alkenyl, optionally substituted C 2 ~C 6 Alkynyl, optionally substituted C 1 ~C 6 Alkoxy, -O-[(optionally substituted C 1 ~C 6 Alkylene)-(optionally substituted C 1 ~C 6 alkoxy)], -NH(optionally substituted C 1 ~C 6 alkyl), -N(optionally substituted C 1 ~C 6 Alkyl) 2 , -NH[(optionally substituted C 1 ~C 6 Alkylene)-(optionally substituted C 1 ~C 6 alkoxy)], -N[(optionally substituted C 1 ~C 6 Alkylene)-(optionally substituted C 1 ~C 6 alkoxy)] 2 , -C(=O)-(optionally substituted C 1 ~C 6 alkyl), -C(=O)-(optionally substituted C 2 ~C 6 alkenyl), and -C(=O)-(optionally substituted C 2 ~C 6 alkynyl); Each R 2 are independently halogen, OH, NH 2 , NO 2 , CN, optionally substituted C 1 ~C 6 Alkyl, optionally substituted C 2 ~C 6 Alkenyl, optionally substituted C 2 ~C 6 Alkynyl, optionally substituted C 1 ~C 6 Haloalkyl, optionally substituted C 1 ~C 6 Alkoxy, -[(optionally substituted C 1 ~C 6 Alkylene)-(optionally substituted C 1 ~C 6 alkoxy)], -O-[(optionally substituted C 1 ~C 6 Alkylene)-(optionally substituted C 1 ~C 6 alkoxy)], -NH(optionally substituted C 1 ~C 6 alkyl), -N(optionally substituted C 1 ~C 6 Alkyl) 2 , -NH[(optionally substituted C 1 ~C 6 Alkylene)-(optionally substituted C 1 ~C 6 alkoxy)], -N[(optionally substituted C 1 ~C 6 Alkylene)-(optionally substituted C 1 ~C 6 alkoxy)] 2 , -C(=O)-(optionally substituted C 1 ~C 6 alkyl), -C(=O)-(optionally substituted C 2 ~C 6 alkenyl), and -C(=O)-(optionally substituted C 2 ~C 6 alkynyl); Each R 3 are independently halogen, OH, NH 2 , optionally substituted C 1 ~C 6 Alkyl, optionally substituted C 1 ~C 6 Haloalkyl, -[(optionally substituted C 1 ~C 6 Alkylene)-(optionally substituted C 1 ~C 6 alkoxy)], optionally substituted C 1 ~C 6 Alkylene-COOH, optionally substituted C 1 ~C 6 Alkylene-C(=O)-O-(optionally substituted C 1 ~C 6 alkyl), optionally substituted C 1 ~C 6 Alkoxy, -O-[(optionally substituted C 1 ~C 6 Alkylene)-(optionally substituted C 1 ~C 6 alkoxy)], -NH(optionally substituted C 1 ~C 6 alkyl), -N(optionally substituted C 1 ~C 6 Alkyl) 2 , -NH[(optionally substituted C 1 ~C 6 Alkylene)-(optionally substituted C 1 ~C 6 alkoxy)], -N[(optionally substituted C 1 ~C 6 Alkylene)-(optionally substituted C 1 ~C 6 alkoxy)] 2 , -C(=O)-(optionally substituted C 1 ~C 6 alkyl), -C(=O)-(optionally substituted C 2 ~C 6 alkenyl), and -C(=O)-(optionally substituted C 2 ~C 6 alkynyl); and R 4 are hydrogen, halogens, OH, NH 2 , optionally substituted C 1 ~C 6 Alkyl, optionally substituted C 1 ~C 6 Haloalkyl, -[(optionally substituted C 1 ~C 6 Alkylene)-(optionally substituted C 1 ~C 6 alkoxy)], optionally substituted C 1 ~C 6 Alkylene-COOH, optionally substituted C 1 ~C 6 Alkylene-C(=O)-O-(optionally substituted C 1 ~C 6 alkyl), optionally substituted C 1 ~C 6 Alkoxy, -O-[(optionally substituted C 1 ~C 6 Alkylene)-(optionally substituted C 1 ~C 6 alkoxy)], -NH(optionally substituted C 1 ~C 6 alkyl), -N(optionally substituted C 1 ~C 6 Alkyl) 2 , -NH[(optionally substituted C 1 ~C 6 Alkylene)-(optionally substituted C 1 ~C 6 alkoxy)], -N[(optionally substituted C 1 ~C 6 Alkylene)-(optionally substituted C 1 ~C 6 alkoxy)] 2 , -C(=O)-(optionally substituted C 1 ~C 6 alkyl), -C(=O)-(optionally substituted C 2 ~C 6 alkenyl), and -C(=O)-(optionally substituted C 2 ~C 6 alkynyl).

2. The compound of formula (I) is a compound of formula (I-1) or a pharma- ceutically acceptable salt, solvate or isotopic derivative thereof, In the formula, G 1 , G 2 , G 3 , G 4 , p, q, R 1 , R 2 , R 3 , and R 4 is as defined for formula (I), 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate or isotopic derivative thereof.

3. The compound of formula (I) is a compound of formula (I-3a), (I-3b) or (I-3c), or a pharma- ceutically acceptable salt, solvate or isotopic derivative thereof; In the formula, G 1 , G 2 , G 3 , G 4 , R 1 , R 2 , R 3 , and R 4 is as defined for formula (I), 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate or isotopic derivative thereof.

4. The compound of formula (I) is a compound of formula (I-3a) or a pharma- ceutically acceptable salt, solvate or isotopic derivative thereof, wherein G1, G2, G3, G4, R1, R2, and R4 are as defined for formula (I).

4. The compound of any one of claims 1 to 3, or a pharma- ceutically acceptable salt, solvate or isotopic derivative thereof.

5. (a)G 1 is CH or G 1 CR 2 and / or (b) G 2 is N or G 2 is CH or G 2 CR 2 and / or (c)G 3 is N or G 3 is CH or G 3 CR 2 and / or (d) G 4 is N or G 4 is CH or G 4 CR 2 That is, 5. The compound of any one of claims 1 to 4, or a pharma- ceutically acceptable salt, solvate or isotopic derivative thereof.

6. G 1 is CH and G 2 is CF and G 3 is CH and G 4 is CF, or G 1 is CF and G 2 is CF and G 3 is CF and G 4 is CF, or G 1 is CH and G 2 is N and G 3 is CH and G 4 is CH, or G 1 is CH and G 2 is N and G 3 is CH and G 4 is CF, or G 1 is CH and G 2 is N and G 3 is CH and G 4 is CCl, or G 1 is CH and G 2 is CH and G 3 is N and G 4 is CH, 5. The compound of any one of claims 1 to 4, or a pharma- ceutically acceptable salt, solvate or isotopic derivative thereof.

7. Each R 1 independently represents halogen and optionally substituted C 2 ~C 6 alkynyl; or m is 2, and each R 1 independently represents halogen and optionally substituted C 2 ~C 6 alkynyl, and optionally one of R 1 is a halogen, and the other R 1 may be substituted C 2 ~C 6 alkynyl, e.g., one R 1 is fluoro and the other R 1 is ethynyl, or Each R 1 are independently selected from the group consisting of fluoro, chloro, bromo, and iodo, e.g., one R 1 is fluoro and the other R 1 is iodine or one of R 1 is chloro and the other R 1 is bromo, 7. The compound of any one of claims 1 to 6, or a pharma- ceutically acceptable salt, solvate or isotopic derivative thereof.

8. R 4 is hydrogen, or R 4 may be substituted C 1 ~C 6 Alkyl, optionally substituted C 1 ~C 6 Haloalkyl, and -[(optionally substituted C 1 ~C 6 Alkylene)-(optionally substituted C 1 ~C 6 alkoxy); and optionally, R 4 may be substituted C 1 ~C 6 alkyl, e.g., R 4 is selected from the group consisting of methyl, ethyl, and prop-2-yl, or optionally, R 4 may be substituted C 1 ~C 6 haloalkyl, e.g., R 4 is 2-fluoroeth-1-yl, or optionally, R 4 is -[(optionally substituted C 1 ~C 6 Alkylene)-(optionally substituted C 1 ~C 6 alkoxy)], for example, R 4 is 2-methoxyeth-1-yl; 8. The compound of any one of claims 1 to 7, or a pharma- ceutically acceptable salt, solvate or isotopic derivative thereof.

9. Table 1:

2. The compound of claim 1, selected from the group consisting of:

10. The following:

10. The compound of claim 9, selected from the group consisting of: or a pharma- ceutically acceptable salt, solvate or isotopic derivative thereof.

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable diluent or carrier; or 11. A combination comprising a compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt thereof, and a second prophylactic or therapeutic agent.

12. A composition comprising a compound according to any one of claims 1 to 10 or a pharma- ceutically acceptable salt thereof, a pharmaceutical composition according to claim 11 or a combination, for use in the treatment and / or prevention of a proliferative disorder, such as a cancer or a tumor, in a subject, e.g. A composition, pharmaceutical composition or combination, wherein the proliferative abnormality or cancer is selected from the group consisting of malignant or benign tumors of the liver, kidney, bladder, breast, stomach, ovary, colorectum, prostate, pancreas, lung, vulva, thyroid, hepatoma, sarcoma, glioblastoma, head and neck, melanoma, and other hyperplastic conditions such as benign hyperplasia of the skin and benign hyperplasia of the prostate.

13. Use of a compound according to any one of claims 1 to 10 for the manufacture of a medicament.

14. A composition comprising a compound according to any one of claims 1 to 10 or a pharma- ceutically acceptable salt thereof, a pharmaceutical composition according to claim 11 or a combination for use in the treatment of a neurodegenerative disease, e.g. A composition, pharmaceutical composition or combination, wherein the neurodegenerative disease is selected from the group consisting of amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, and Huntington's disease.

15. A composition comprising a compound according to any one of claims 1 to 10 or a pharma- ceutically acceptable salt thereof, a pharmaceutical composition according to claim 11 or a combination for use in the treatment of an immunodeficiency disease, e.g. The composition, pharmaceutical composition or combination, wherein the immunodeficiency disease is selected from the group consisting of cancer, infectious diseases, and some genetic diseases.

16. A method for inhibiting the activity of one or more kinases selected from the group consisting of MEK, COT1, FGFR4, MINK, MYO3A, PKG1B, and PLK3, comprising a step of contacting a cell in vitro or ex vivo with an effective amount of a compound according to any one of claims 1 to 10 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition or combination according to claim 11.

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