A combination of BCR:ABL-1 inhibitor and a second tyrosine kinase inhibitor for use in cancer treatment.

Abstract

This specification provides combinations and compositions for inhibiting the tyrosine kinase activity of a protein selected from Avelson protein (ABL1), Avelson-related protein (ABL2), or chimeric protein BCR-ABL1; methods for inhibiting the tyrosine kinase enzyme activity of a protein selected from Avelson protein (ABL1), Avelson-related protein (ABL2), or chimeric protein BCR-ABL1; and methods for treating diseases by preventing, inhibiting, or improving the pathology and / or symptoms of a disease by regulating BCR-ABL1 activity.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority and interest in U.S. Provisional Patent Application No. 63 / 535,881, filed on 31 August 2023, which is incorporated herein by reference in its entirety for all purposes.

[0002] Reference to electronic sequence listings The contents of the electronic sequence listing (TRPH_048_001WO_SeqList_ST26.xml; size: 44,747 bytes; and creation date: August 29, 2024) are incorporated herein by reference in their entirety. [Background technology]

[0003] In chronic myeloid leukemia (CML), the Philadelphia chromosome (Ph) is formed by a reciprocal translocation between chromosomes 9 and 22 of myeloid progenitor cells. This chromosome contains the BCR-ABL1 oncogene, which encodes the chimeric BCR-ABL1 protein. Drugs that inhibit the tyrosine kinase activity of BCR-ABL1 via ATP competition, such as Gleevec® / Glivec® (imatinib), Tasigna® (nilotinib), Iclusig® (ponatinib), and Sprycel® (dasatinib), may be effective in treating CML. However, some patients relapse due to the emergence of drug-resistant clones or drug intolerance. Therefore, additional treatment options are needed. [Overview of the project]

[0004] This disclosure relates to a method for treating cancer in subjects requiring such treatment, the method comprising administering a BCR:ABL1 inhibitor in combination with a tyrosine kinase inhibitor, wherein the BCR:ABL1 inhibitor is a compound of formula (I). [ka] or a tautomer or N-oxide thereof, or a pharmaceutically acceptable salt of any of the foregoing, L is -NH-CO-, -CO-NH-, -NH-SO2-, or -SO2-NH-, R 1 is optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted 4- to 10-membered heterocycle, C(O)NR 6 R 7 , S(O)2NR 6 R 7 , NR 6 COR 7 , NR 6 SO2R 7 , or C(O)OR 6 , R 2 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4- to 10-membered heterocycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C6-C 10 aryl, or optionally substituted 5- to 10-membered heteroaryl, R 3 is H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, OR 6 , or NR 6 R 7 , or R 2 and R 3 together with the intervening atoms form an optionally substituted C3-C8 cycloalkyl or an optionally substituted 4- to 10-membered heterocycloalkyl, R 4 is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl, X is either O or S, Y is CH, C-(C1-C2 alkyl), C-halo, or N. Z, CR 5 or N, R 5 However, it is H or halogen, R 6 However, H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 member heterocycloalkyl, optionally substituted C6-C 10 An aryl, or a 5-10 member heteroaryl that has been optionally substituted, R 7 However, H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 member heterocycloalkyl, optionally substituted C6-C 10 An aryl, or a 5-10 member heteroaryl that has been optionally substituted, Or R 6 and R 7 However, together with the nitrogen atoms to which they are bonded, they form optionally substituted 4- to 7-membered heterocycles. However, the compound is other than (i) 1H-benzimidazole-7-carboxylic acid, 5-[[(4-methoxyphenyl)sulfonyl]amino]-1-methyl-, or (ii) 1H-benzimidazole-7-carboxylic acid, 5-[[(4-ethoxyphenyl)sulfonyl]amino]-1-methyl-.

[0005] In some embodiments, the BCR:ABL1 inhibitor is a compound of formula (IA-1). [ka] or a pharmaceutically acceptable salt thereof.

[0006] This disclosure relates to (R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-1-(1-hydroxypropan-2-yl)-7-(pyrimidine-5-yl)-1H-benzo[d]imidazole-5-carboxamide (compound A) [ka] or relating to the use of a pharmaceutically acceptable salt thereof in combination with a tyrosine kinase inhibitor to do so in subjects requiring cancer treatment.

[0007] This disclosure relates to compound A [ka] The present invention relates to the use of a pharmaceutically acceptable salt thereof in combination with a tyrosine kinase inhibitor selected from imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib, to do so in subjects requiring treatment for cancer.

[0008] The disclosure also relates to a method for treating cancer in subjects requiring such treatment, the method comprising administering compound A or a pharmaceutically acceptable salt thereof in combination with a tyrosine kinase inhibitor.

[0009] The disclosure also relates to a method for treating cancer in subjects requiring treatment, the method comprising administering compound A or a pharmaceutically acceptable salt thereof in combination with a tyrosine kinase inhibitor selected from imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib.

[0010] This disclosure further relates to the use of compound A or a pharmaceutically acceptable salt thereof for preparing a drug to do so in subjects requiring the treatment of cancer, in combination with a tyrosine kinase inhibitor.

[0011] This disclosure further relates to the use of compound A or a pharmaceutically acceptable salt thereof for the preparation of a drug for treating cancer in subjects requiring such treatment, in combination with a tyrosine kinase inhibitor selected from imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib.

[0012] This disclosure relates to the use of compound A or a pharmaceutically acceptable salt thereof in combination with a tyrosine kinase inhibitor to treat cancer in subjects requiring such treatment.

[0013] This disclosure relates to the use of compound A or a pharmaceutically acceptable salt thereof in combination with a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib to treat cancer in subjects requiring such treatment.

[0014] The disclosure also relates to a method for treating cancer, the method comprising administering compound A or a pharmaceutically acceptable salt thereof in combination with a tyrosine kinase inhibitor.

[0015] The disclosure also relates to a method for treating cancer, the method comprising administering compound A or a pharmaceutically acceptable salt thereof in combination with a tyrosine kinase inhibitor, the tyrosine kinase inhibitor binding to an active site on a tyrosine kinase.

[0016] The disclosure also relates to a method for treating cancer, the method comprising administering compound A or a pharmaceutically acceptable salt thereof in combination with a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib.

[0017] This disclosure relates to the use of compound A or a pharmaceutically acceptable salt thereof in combination with a tyrosine kinase inhibitor to treat a patient requiring treatment for lymphoma or leukemia.

[0018] This disclosure relates to the use of compound A or a pharmaceutically acceptable salt thereof in combination with a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib to treat subjects requiring treatment for lymphoma or leukemia.

[0019] The disclosure also relates to a method for treating lymphoma or leukemia in subjects requiring treatment, the method comprising administering compound A or a pharmaceutically acceptable salt thereof in combination with a tyrosine kinase inhibitor.

[0020] The disclosure also relates to a method for treating lymphoma or leukemia in subjects requiring treatment, the method comprising administering compound A or a pharmaceutically acceptable salt thereof in combination with a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib.

[0021] This disclosure further relates to the use of compound A or a pharmaceutically acceptable salt thereof for preparing a drug to be used in combination with a tyrosine kinase inhibitor to treat lymphoma or leukemia in subjects requiring such treatment.

[0022] This disclosure further relates to the use of compound A or a pharmaceutically acceptable salt thereof in combination with a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib, for preparing a drug to do so in subjects requiring treatment for lymphoma or leukemia.

[0023] The disclosure further relates to a method for inhibiting the tyrosine kinase enzyme activity of a protein selected from the group consisting of Abelson protein (ABL1), Abelson-related protein (ABL2), and the chimeric protein BCR-ABL1, the method comprising contacting the protein with an effective amount of compound A in combination with an effective amount of an acyrosine kinase inhibitor.

[0024] The disclosure further relates to a method for treating a disease in which the pathogenesis and / or symptoms of a patient are prevented, inhibited, or improved by modulating BCR-ABL1 activity, the method comprising administering to the patient a therapeutically effective amount of compound A in combination with a therapeutically effective amount of a tyrosine kinase inhibitor.

[0025] The disclosure further relates to a method for treating a patient's leukemia, the method comprising administering to the patient a therapeutically effective amount of compound A in combination with a therapeutically effective amount of a tyrosine kinase inhibitor, wherein the leukemia is chronic myeloid leukemia (CML), acute myeloid leukemia (AML), or acute lymphoblastic leukemia (ALL).

[0026] In some embodiments, the combination involves administering compound A and a tyrosine kinase inhibitor selected from aceminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib in a ratio of approximately 1:1, approximately 1:2, approximately 1:3, approximately 1:4, approximately 1:5, approximately 2:1, approximately 2:3, approximately 2:5, approximately 3:1, approximately 3:2, approximately 3:4, approximately 3:5, approximately 4:1, approximately 4:3, or approximately 4:5.

[0027] In some embodiments, the combination comprises a BCR:ABL1 inhibitor, a tyrosine kinase inhibitor, and at least one pharmaceutically acceptable excipient, wherein the BCR:ABL1 inhibitor is a compound of formula (I). [ka] or its tautomer or N-oxide, or a pharmaceutically acceptable salt of any of the foregoing.

[0028] In some embodiments, the combination is used to treat a patient's leukemia and comprises administering to the patient a therapeutically effective dose of a BCR:ABL1 inhibitor and a therapeutically effective dose of a tyrosine kinase inhibitor, wherein the leukemia is chronic myeloid leukemia (CML), acute myeloid leukemia (AML), or acute lymphoblastic leukemia (ALL).

[0029] In some embodiments, the leukemia is CML or ALL, and the tyrosine kinase inhibitor is selected from the group consisting of aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib.

[0030] In some embodiments, CML is resistant to standard treatment.

[0031] In some embodiments, CML is resistant to treatment with one or more of imatinib, ponatinib, nilotinib, and dasatinib.

[0032] In some embodiments, AML is secondary AML that develops after myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN). [Brief explanation of the drawing]

[0033] [Figure 1] This is a schematic diagram of allosteric inhibition of BCR::ABL1 oncoprotein. [Figure 2] This study demonstrates the efficacy and selectivity of compound A and aciminib against BCR::ABL1+ and BCR::ABL1- cell lines. [Figure 3-1] Representative cytotoxicity curves (L) are shown for molar combinations of compound A with dasatinib (top) and ponatinib (bottom). The right panel shows representative synergistic isobolograms set for IC75 values ​​of the monotherapy and fixed molar combinations with dasatinib (top) or ponatinib (bottom). Points below the blue additive line indicate synergistic interactions. [Figure 3-2] Representative cytotoxicity curves (L) are shown for molar combinations of compound A with dasatinib (top) and ponatinib (bottom). The right panel shows representative synergistic isobolograms set for IC75 values ​​of the monotherapy and fixed molar combinations with dasatinib (top) or ponatinib (bottom). Points below the blue additive line indicate synergistic interactions. [Figure 4A]This shows representative heatmaps of K562 cells treated with compound A and dasatinib. Higher values ​​indicate a stronger synergistic effect. [Figure 4B] This shows representative heatmaps of BaF3-BCR-ABL-T315I cells treated with compound A and ponatinib. Higher values ​​indicate stronger synergistic effects. [Figure 5A] This shows representative heatmaps of BaF3-BCR-ABL-T315I cells treated with compound A and ponatinib. Higher values ​​indicate stronger synergistic effects. [Figure 5B] This shows representative heatmaps of BaF3-BCR-ABL-T315I cells treated with compound A and dasatinib. Higher values ​​indicate stronger synergistic effects. [Figure 6A] Representative cytotoxicity curves (L) for molar combinations of compound A and dasatinib are shown. The right panel shows representative synergistic isobolograms set for IC75 values ​​of the compound A alone and fixed molar combinations with dasatinib. Points below the blue additive line indicate synergistic interactions. [Figure 6B] Representative cytotoxicity curves (L) for molar combinations of compound A and dasatinib are shown. The right panel shows representative synergistic isobolograms set for IC75 values ​​of the compound A alone and fixed molar combinations with dasatinib. Points below the blue additive line indicate synergistic interactions. [Figure 7] The image shows tumors from an in vivo BCR::ABL1-T315I CML model, measured on day 15, in animals treated with a combination of compound A and a second TKI. [Figure 8] This shows the change in median tumor volume over 15 days in an in vivo BCR::ABL1-T315I CML model in which animals were treated with a combination of compound A and a second TKI. [Modes for carrying out the invention]

[0034] definition When used herein, unless otherwise indicated, the following definitions shall apply. Furthermore, with respect to terms or symbols used herein, if no definition is provided below, they shall have the meanings they ordinarily have in the art.

[0035] As used herein, in the context of tyrosine kinase proteins, “active site” is intended to refer to the region of a tyrosine kinase protein where a phosphate group is catalytically transferred from adenosine triphosphate (ATP) to a substrate.

[0036] "Comprising" is intended to mean that a composition and method encompasses the enumerated elements but does not exclude others. When used to define a composition and method, "consisting essentially of" means excluding other elements that have any essential importance to the combination. For example, a composition essentially consisting of the elements defined herein does not exclude other elements that do not substantially affect the basic and novel features(s) of the claimed invention. "Consisting of" means, for example, excluding trace amounts or more of other components described and substantial method steps. Embodiments defined by each of these transition terms are within the scope of the present invention.

[0037] The “effective amount” or dose of a compound or composition refers to the amount of the compound or composition that produces the desired result based on the disclosure herein. The effective amount is determined by standard pharmaceutically procedures in cell cultures or experimental animals, for example, by LD 50 (A lethal dose for 50% of the population) and ED 50 This may be determined by determining the dose that is therapeutically effective in 50% of the population, but is not limited to this.

[0038] "Combination therapy" or "combination treatment" refers to the use of two or more drugs or agents in treatment, for example, the use of compounds of formula (I), (Ii), (IA), (IA-1), (IIA), (IIB), (IIE), or (Id), such as compound A, which is used herein with tyrosine kinase inhibitors that are useful for treating cancers such as lymphoma and leukemia, and their respective symptoms and signs, is combination therapy. "Combination administration" refers to the administration of two drugs (for example, compounds of formula (I), (Ii), (IA), (IA-1), (IIA), (IIB), (IIE), or (Id), such as compound A, which is used herein, and tyrosine kinase inhibitors) in any manner in which both pharmacological effects occur simultaneously in the patient. Therefore, combination administration does not require that a single pharmaceutical composition, the same dosage form, or the same route of administration be used for the administration of both drugs, or that the two drugs be administered at exactly the same time. Both drugs can also be formulated as a single pharmaceutically acceptable composition. Non-limiting examples of such a single composition are oral compositions or oral dosage forms. For example, compounds of formula (I), (Ii), (IA), (IA-1), (IIA), (IIB), (IIE), or (Id), such as compound A, are intended to be administered in combination therapy with the tyrosine kinase inhibitors according to the present invention, but are not limited thereto.

[0039] As used herein, the term “excipient” means an inert or inactive substance that may be used in the manufacture of drugs or pharmaceuticals, such as tablets, containing the compounds of the present invention as active ingredients. A variety of substances may be included in the term “excipient,” including, but are 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 granulator. Binders include, for example, carbomer, povidone, xanthan gum; coatings include, for example, cellulose phthalate acetate, ethylcellulose, gellan gum, maltodextrin, enteric coatings; compression / encapsulation aids include, for example, calcium carbonate, dextrose, 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 The ingredients include maltodextrin, carrageenan, etc.; lubricants include, for example, magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; chewable tablet materials include, for example, dextrose, fructose dc, lactose (monohydrate, optionally combined with aspartame or cellulose), etc.; suspension / gelling agents include, for example, carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, for example, aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc.; wet granulation agents include, for example, calcium carbonate, maltodextrin, microcrystalline cellulose, etc.

[0040] The terms “subject” or “patient” include human and non-human animals, as well as cell lines, cell cultures, tissues, and organs. In some embodiments, the subject is a mammal. Mammals may be, for example, humans or suitable non-human mammals, such as primates, mice, rats, hamsters, dogs, rabbits, cats, cattle, horses, goats, camels, sheep, guinea pigs, or pigs. The subject may also be a bird or poultry. In some embodiments, the subject is human. In some embodiments, the patient is human.

[0041] The term “pharmaceutical composition” refers to a formulation containing the compounds of this disclosure in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is a bulk or unit dosage form. The unit dosage form is any variety of form, including, for example, capsules, IV bags, tablets, single pumps of aerosol inhalers, or vials. The amount of the active ingredient (e.g., formulations of the disclosed compound or its salts, hydrates, solvates, or isomers) in a unit dose of the composition is an effective amount and varies according to the specific treatment involved. Those skilled in the art will understand that it is sometimes necessary to make customary adjustments to the dosage depending on the patient’s age and condition. The dosage also depends on the route of administration. Various routes are considered, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrathoracic, intrathecal, and intranasal. Dosage forms for topical or transdermal administration of the compounds of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives, buffers, or propellants.

[0042] It should be understood that the compounds or pharmaceutical compositions of this disclosure can be administered to subjects by many of the well-known methods currently used in chemotherapy. For example, the compounds of this disclosure may be injected into the bloodstream or body cavities, taken orally, or applied to the skin using a patch. The selected dose should be sufficient to constitute an effective treatment but should not be so high as to cause unacceptable side effects. The stage of the medical condition (e.g., the disease or disorder disclosed herein) and the patient's health condition should preferably be carefully monitored for a reasonable period during and after the treatment.

[0043] "Pharmacologically acceptable" means that the drug is safe and non-toxic, preferably in vivo, and more preferably in human administration.

[0044] "Pharmacologically acceptable salt" refers to a pharmaceutically acceptable salt. The compounds described herein may be administered as pharmaceutically acceptable salts.

[0045] The term “pharmaceutically acceptable excipient” means an excipient that is generally safe, non-toxic, and useful for preparing a pharmaceutical composition that is not biologically or otherwise undesirable, and includes excipients that are acceptable for human pharmaceutical use as well as veterinary use. As used herein and in the claims, “pharmaceutically acceptable excipient” includes both one and two or more such excipients.

[0046] The term "therapeutic effective dose" refers to the amount of an agent that treats, remits, or prevents a confirmed disease or condition, or that exhibits a detectable therapeutic or inhibitory effect. This effect can be detected by any assay known in the art. The exact effective dose for a subject depends on the subject's weight, size, and health status; the nature and severity of the condition; and the therapeutic agent or combination of therapeutic agents selected for administration. The therapeutic effective dose for a given situation can be determined by conventional experimentation within the scope of the clinician's skill and judgment.

[0047] As used herein, terms such as "co-administration" mean the administration of a selected therapeutic agent to a single patient and include a treatment plan in which the agent is administered by the same or different routes of administration or at the same or different times.

[0048] Terms such as “about” as used herein in relation to numerical values ​​or ranges reflect the fact that, due to practical and / or theoretical limitations, there is a certain level of variation that is recognized and acceptable in the art. For example, small variations are acceptable because there are inherent differences in how a particular device operates and / or how measurements are taken. Accordingly, the phrase “about” is typically used to encompass values ​​within the standard deviation or standard error.

[0049] A “prodrug” refers to a compound that, after administration, is metabolized or otherwise converted to become a biologically active or more active compound (or drug) with respect to at least one property. Compared to a drug, a prodrug is chemically modified to be less active or inactive, but the chemical modification is such that, after administration of the prodrug, the corresponding drug is produced by metabolism or other biological processes. Compared to the active drug, a prodrug may have altered metabolic stability or transport properties, fewer side effects or lower toxicity, or improved flavor (see, for example, Nogrady, 1985, Medicinal Chemistry: A Biochemical Approach, Oxford University Press, New York, pages 388–392, incorporated herein by reference). Prodrugs may be synthesized using reactants other than the corresponding drug. For illustrative purposes, prodrugs include, but are not limited to, carboxyesters, linear and cyclic phosphate esters and phosphoramides and phosphoramidates, carbamates, preferably phenolic carbamates (i.e., carbamates in which the hydroxyl group is part of an aryl or heteroaryl moiety, and the aryl and heteroaryl moieties may be optionally substituted).

[0050] "Salt" refers to an ionic compound formed between an acid and a base. If the compounds provided herein contain an acidic functional group, such salts include, but are not limited to, alkali metals, alkaline earth metals, and ammonium salts. As used herein, ammonium salts include salts containing protonated nitrogen bases and alkylated nitrogen bases. "Therapeutic dose" or amount of a compound or composition refers to the amount of the compound or composition that results in the reduction or inhibition of symptoms or the extension of survival in a patient. Results may require multiple administrations of the compound or composition.

[0051] "Treating" or "treating" a patient's disease means: 1) preventing the onset of the disease in a patient who is susceptible to the disease or who has not yet presented symptoms of the disease; 2) inhibiting or suppressing its development; or 3) alleviating or causing regression of the disease. As used herein, "treating" or "treating" refers to an approach to obtain beneficial or desirable outcomes, including clinical outcomes. For the purposes of this disclosure, beneficial or desired outcomes include, but are not limited to, one or more of the following: reducing one or more symptoms resulting from a disease or disorder; reducing the extent of the disease or disorder; stabilizing the disease or disorder (e.g., preventing or delaying the exacerbation of the disease or disorder); delaying the onset or recurrence of the disease or disorder; delaying or delaying the progression of the disease or disorder; improving the state of the disease or disorder; providing remission (partial or complete) of the disease or disorder; reducing the dose of one or more other agents required to treat the disease or disorder; enhancing the effect of another agent used to treat the disease or disorder; delaying the progression of the disease or disorder; improving the quality of life; and / or extending the patient's survival time. Furthermore, “treatment” also encompasses the reduction of the pathological consequences of a disease or disorder. The methods of the present invention aim to achieve any one or more of these aspects of treatment.

[0052] As used herein, “delaying” the onset of a disease means delaying, preventing, slowing, stabilizing, and / or postponing the onset of a disease, and / or slowing its progression once it has occurred, or altering the underlying disease process and / or course. This delay can be of varying lengths depending on the medical history and / or the individual being treated. As will be apparent to those skilled in the art, a sufficient or significant delay in which the individual does not develop clinical symptoms associated with the disease can, in practice, encompass prevention. A method for “delaying” the onset of a disease is a method for reducing the probability of disease onset in a given time frame and / or reducing the severity of the disease in a given time frame compared to not using the method, and includes stabilizing one or more symptoms resulting from the disease.

[0053] Individuals “at risk” of developing the disease 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” indicates that an individual has one or more so-called risk factors, which are measurable parameters that correlate with the development of the disease. Individuals with one or more of these risk factors are more likely to develop the disease than individuals without these risk factors. These risk factors include, but are not limited to, age, sex, race, diet, medical history of previous diseases, presence of progenitor diseases, and genetic (i.e., heritability) considerations. In some embodiments, the compound may be administered to subjects (including humans) who are at risk of or have a family history of the disease or condition.

[0054] An "isotopomer" of a compound is a compound in which one or more atoms of the compound are replaced with isotopes of those same atoms. For example, when H is replaced by D or T, or 12 C 11 If replaced by C, or 14 N 15When replaced with N, for example, replacement with D may, in some cases, decrease the metabolic rate and therefore prolong the half-life. Replacing H with T yields radioligands that are potentially useful for binding studies. 12 C is a short-lived isotope 11 Replacing it with C yields a ligand useful for positron emission tomography (PET) scans. 14 N 15 If we replace it with N, 15 Compounds that can be detected / monitored by NMR spectroscopy are obtained. For example, an isotopomer of a compound containing -CH2CH3 is the same compound, but containing -CD2CD3 instead of -CH2CH3.

[0055] A "stereoisomer" refers to a compound that differs in the stereogenicity of its constituent atoms, such as, but not limited to, the chirality of one or more stereocenters or the cis or trans configuration of carbon-carbon or carbon-nitrogen double bonds. Stereoiomers include enantiomers and diastereomers.

[0056] A "tautomer" refers to an alternative form of a compound in which the position of the proton differs, such as enol-keto and imine-enamine tautomers, or a tautomer of a heteroaryl group having a ring atom bonded to both the ring-NH- and ring-N- moieties, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole.

[0057] "Alkyl" refers to a monovalent saturated aliphatic hydrocarbyl group having 1 to 12 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms. This term includes, for example, linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), t-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-). x Alkyl refers to an alkyl group that has x carbon atoms.

[0058] "Alkenyl" refers to a linear or branched monovalent hydrocarbyl group having 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms, and having at least one, preferably 1 to 2, vinyl (>C=C<) unsaturated sites. Such groups are exemplified by vinyl, allyl, and buta-3-en-1-yl. This term includes cis and trans isomers, or mixtures thereof. x An alkenyl refers to an alkenyl group that has x carbon atoms.

[0059] "Alkynyl" refers to a linear or branched monovalent hydrocarbyl group having 2 to 6 carbon atoms, preferably 2 to 3 carbon atoms, and having at least one, preferably 1 to 2, acetylene (-C≡C-) unsaturated sites. Examples of such alkynyl groups include acetylenyl (-C≡CH) and propargyl (-CH2C≡CH). x An alkynyl refers to an alkynyl group that has x carbon atoms.

[0060] "Substituting alkyl" refers to alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, arylamino, substituted arylamino, heteroarylamino, substituted heteroarylamino, cycloalkylamino, substituted cycloalkylamino, heterocycloalkylamino, substituted heterocyclylamino, carboxyl, carboxylester, (carboxylester)amino, (carboxylester)oxy, cyano, cyclo This refers to an alkyl group having 1 to 5 substituents, preferably 1 to 3, more preferably 1 to 2, selected from the group consisting of alkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic group, substituted heterocyclic group, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, alkylthio, and substituted alkylthio, where the substituents described above are defined herein.

[0061] "Substituting alkenyl" refers to alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, arylamino, substituted arylamino, heteroarylamino, substituted heteroarylamino, cycloalkylamino, substituted cycloalkylamino, heterocycloalkylamino, substituted heterocyclylamino, carboxyl, carboxylester, (carboxylester)amino, (carboxylester)oxy, cyano, cycloalkyl, substituted cycloalkyl, This refers to an alkenyl group having 1 to 3 substituents, preferably 1 to 2 substituents, selected from the group consisting of cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic group, substituted heterocyclic group, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein the substituents described above are defined herein, provided that the hydroxy or thiol substitution is not bonded to a vinyl (unsaturated) carbon atom.

[0062] "Substituted alkynyl" refers to alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, arylamino, substituted arylamino, heteroarylamino, substituted heteroarylamino, cycloalkylamino, substituted cycloalkylamino, heterocycloalkylamino, substituted heterocyclylamino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl This refers to an alkynyl group having 1 to 3 substituents, preferably 1 to 2 substituents, selected from the group consisting of cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic group, substituted heterocyclic group, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein the substituents described above are defined herein, provided that the hydroxyl or thiol substitution is not bonded to the acetylene carbon atom.

[0063] "Alkoxy" refers to an -O-alkyl group, where alkyl is defined herein. Examples of alkoxys include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, and n-pentoxy.

[0064] "Substituting alkoxy" refers to an -O-(substituted alkyl) group, where substituted alkyl is defined herein. Preferred substituted alkyl groups for -O-(substituted alkyl) include halogenated alkyl groups, particularly methyl halogenated groups such as trifluoromethyl, difluoromethyl, and fluoromethyl.

[0065] "Acyl" refers to the groups HC(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocyclic-C(O)-, and substituted heterocyclic-C(O)-, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic group, and substituted heterocyclic group are as defined herein. Acyls include the "acetyl" group CH3C(O)-.

[0066] "Acylamino" means -NR 30 C(O) alkyl group, -NR 30 C(O) substituted alkyl group, -NR 30 C(O) cycloalkyl group, -NR 30 C(O)-substituted cycloalkyl groups, -NR 30 C(O) alkenyl group, -NR 30 C(O)-substituted alkenyl group, alkoxy group, substituted alkoxy-NR 30 C(O) alkynyl group, -NR 30 C(O) substituted alkynyl group, -NR 30 C(O)aryl group, -NR 30 C(O) substituted aryl group, -NR 30 C(O) heteroaryl group, -NR 30 C(O)-substituted heteroaryl group, -NR 30 C(O) heterocyclic group, and -NR 30This refers to a C(O) substituted heterocyclic group, where R 30 The group is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or substituted cycloalkyl, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic group, and substituted heterocyclic group are as defined herein.

[0067] "Acyloxy" refers to the groups alkyl-C(O)O-, substituted alkyl-C(O)O-, alkenyl-C(O)O-, substituted alkenyl-C(O)O-, alkynyl-C(O)O-, substituted alkynyl-C(O)O-, aryl-C(O)O-, substituted aryl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, heteroaryl-C(O)O-, substituted heteroaryl-C(O)O-, heterocyclic-C(O)O-, and substituted heterocyclic-C(O)O-, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic group, and substituted heterocyclic group are as defined herein.

[0068] "Amino" refers to the group -NH2.

[0069] "Substituting amino acid" refers to the group -NR 31 R 32 This refers to R 31 and R 32R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic group, substituted heterocyclic group, arylamino, substituted arylamino, heteroarylamino, substituted heteroarylamino, cycloalkylamino, substituted cycloalkylamino, heterocycloalkylamino, substituted heterocyclylamino, sulfonylamino, and substituted sulfonyl, where R 31 and R 32 These are optional, and together with the nitrogen bonded to them, they form a heterocyclic group or a substituted heterocyclic group, however, R 31 and R 32 Both are not hydrogen, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic group, and substituted heterocyclic group are as defined herein. 31 is hydrogen and R 32 If the substituted amino group is alkyl, the substituted amino group may be referred to as alkylamino in this specification. 31 and R 32 When R is alkyl, the substituted amino group may be referred to as a dialkylamino in this specification. When referred to as a monosubstituted amino, R 31 or R 32 It means that one of them is hydrogen, but not both. When referred to as a disubstituted amino acid, R 31 and R 32 This means that neither of them is hydrogen.

[0070] "Aminocarbonyl" refers to the group -C(O)NR 33 R 34 This refers to R 33 and R 34R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl heteroaryl, substituted heteroaryl, heterocyclic group, and substituted heterocyclic group, where R 33 and R 34 These can optionally form a heterocyclic or substituted heterocyclic group together with the nitrogen bonded to them, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic group, and substituted heterocyclic group are as defined herein.

[0071] "Aminothiocarbonyl" refers to the group -C(S)NR 33 R 34 This refers to R 33 and R 34 R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic group, and substituted heterocyclic group, where R 33 and R 34 These can optionally form a heterocyclic or substituted heterocyclic group together with the nitrogen bonded to them, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic group, and substituted heterocyclic group are as defined herein.

[0072] "Aminocarbonylamino" refers to the base-NR 30 C(O)NR 33 R 34 This refers to R 30is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or substituted cycloalkyl, and R 33 and R 34 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic group, and substituted heterocyclic group, wherein R 33 and R 34 optionally together with the nitrogen bound thereto form a heterocyclic group or a substituted heterocyclic group, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic group and substituted heterocyclic group are as defined herein.

[0073] "Aminothiocarbonylamino" refers to the group -NR 30 C(S)NR 33 R 34 , wherein R 30 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or substituted cycloalkyl, and R 33 and R 34 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic group, and substituted heterocyclic group, wherein R 33 and R 34These may optionally form heterocyclic or substituted heterocyclic groups together with the nitrogen atoms bonded to them, and alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic groups are as defined herein.

[0074] "Aminocarbonyloxy" refers to the group -OC(O)NR 33 R 34 This refers to R 33 and R 34 R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic group, and substituted heterocyclic group, where R 33 and R 34 These can optionally form a heterocyclic or substituted heterocyclic group together with the nitrogen bonded to them, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic group, and substituted heterocyclic group are as defined herein.

[0075] "Aminosulfonyl" refers to the group -SO2NR 33 R 34 This refers to R 33 and R 34 R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic group, and substituted heterocyclic group, where R 33 and R 34These can optionally form a heterocyclic or substituted heterocyclic group together with the nitrogen bonded to them, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic group, and substituted heterocyclic group are as defined herein.

[0076] "Aminosulfonyloxy" refers to the group -O-SO2NR 33 R 34 This refers to R 33 and R 34 R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, and substitution. R is independently selected from the group consisting of alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic groups, where R 33 and R 34 These can optionally form a heterocyclic or substituted heterocyclic group together with the nitrogen bonded to them, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic group, and substituted heterocyclic group are as defined herein.

[0077] "Aminosulfonylamino" refers to the group -NR 30 -SO2NR 33 R 34 This refers to R 30 However, R is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or substituted cycloalkyl, 33 and R 34R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic group, and substituted heterocyclic group, where R 33 and R 34 These can optionally form a heterocyclic or substituted heterocyclic group together with the nitrogen bonded to them, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic group, and substituted heterocyclic group are as defined herein.

[0078] "Amidino" is a base-C (=NR 35 )NR 33 R 34 This refers to R 33 , R 34 , and R 35 R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic group, and substituted heterocyclic group, where R 33 and R 34 These can optionally form a heterocyclic or substituted heterocyclic group together with the nitrogen bonded to them, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic group, and substituted heterocyclic group are as defined herein.

[0079] "Aryl" or "Ar" refers to a monovalent aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring (e.g., phenyl (Ph)) or multiple fused rings (e.g., naphthyl or anthryl), where the multiple fused rings may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-1,4-benzoxazine-3(4H)-on-7-yl), but the bond site is located at an aromatic carbon atom. Phenyl and naphthyl are examples of preferred aryl groups.

[0080] "Substituted aryl" refers to alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, arylamino, substituted arylamino, heteroarylamino, substituted heteroarylamino, cycloalkylamino, substituted cycloalkylamino, heterocycloalkylamino, substituted heterocyclylaminocarboxyl, carboxyl ester, (carboxyl ester)amino, (carb This refers to an aryl group substituted with 1 to 5 substituents, preferably 1 to 3, more preferably 1 to 2 substituents, selected from the group consisting of xylester, oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic group, substituted heterocyclic group, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, alkylthio, and substituted alkylthio, where the substituents described above are defined herein.

[0081] "Aryloxy" refers to the group -O-aryl, where aryl is as defined herein, and includes, for example, phenoxy and naphthoxy.

[0082] "Substituting aryloxy" refers to the group -O-(substituted aryl), where substituted aryl is defined herein.

[0083] "Arylthio" refers to an -S-aryl group, where aryl is as defined herein.

[0084] "Substituting arylthio" refers to an -S-(substituted aryl) group, where substituted aryl is as defined herein.

[0085] "Arylamino" means -NR 37 (aryl) refers to an aryl group, where aryl is as defined herein, R 37 However, it is hydrogen, alkyl, or substituted alkyl. "Substituting arylamino" means -NR 37 This refers to a (substituted aryl) group, where R 37 However, the element is hydrogen, alkyl, or substituted alkyl, where substituted aryl is as defined herein.

[0086] "Carbonyl" refers to the divalent group -C(O)- which is equivalent to -C(=O)-.

[0087] "Carboxylate" or "carboxyl" refers to the -COOH group or its salts.

[0088] "Carboxyl ester" or "carboxyester" refers to an alkyl group, -C(O)O-substituted alkyl group, -C(O)O-alkenyl group, -C(O)O-substituted alkenyl group, -C(O)O-alkynyl group, -C(O)O-substituted alkynyl group, -C(O)O-aryl group, C(O)O-substituted aryl group, -C(O)O-cycloalkyl groups, -C(O)O-substituted cycloalkyl groups, -C(O)O-heteroaryl groups, -C(O)O-substituted heteroaryl groups, -C(O)O-heterocyclic groups, and -C(O)O-substituted heterocyclic groups, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic groups, and substituted heterocyclic groups are as defined herein.

[0089] "(carboxyl ester)amino" means -NR 30 -C(O)O-alkyl group, -NR 30 -C(O)O-substituted alkyl group, -NR 30 -C(O)O-alkenyl group, -NR 30 -C(O)O-substituted alkenyl group, -NR 30 -C(O)O-alkynyl group, -NR 30 -C(O)O-substituted alkynyl group, -NR 30 -C(O)O-aryl group, -NR 30 -C(O)O-substituted aryl group, -NR 30 -C(O)O-cycloalkyl group, -NR 30 -C(O)O-substituted cycloalkyl groups, -NR 30 -C(O)O-heteroaryl group, -NR 30 -C(O)O-substituted heteroaryl group, -NR 30 -C(O)O- heterocyclic group, and -NR 30 This refers to a -C(O)O- substituted heterocyclic group, where R 30 The group is alkyl or hydrogen, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic group, and substituted heterocyclic group are as defined herein.

[0090] "(carboxyl ester) oxy" refers to -OC(O)O-alkyl groups, -OC(O)O-substituted alkyl groups, -OC(O)O-alkenyl groups, -OC(O)O-substituted alkenyl groups, -OC(O)O-alkynyl groups, -OC(O)O-substituted alkynyl group, -OC(O)O-aryl group, -OC(O)O-substituted aryl group, -OC(O)O-cycloalkyl group, OC(O)O-substituted cycloalkyl group, -OC(O)O-heteroaryl group, -OC(O)O-substituted heteroaryl groups, -OC(O)O-heterocyclic groups, and -OC(O)O-substituted heterocyclic groups, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic group, and substituted heterocyclic group are as defined herein.

[0091] "Cyano" refers to the group -C≡N.

[0092] "Cycloalkyl" refers to a saturated or unsaturated but non-aromatic cyclic alkyl group having 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, and more preferably 3 to 6 carbon atoms, and having one or more cyclic rings, including fused ring systems, bridging ring systems, and spiro ring systems. xA cycloalkyl group refers to a cycloalkyl group having x ring carbon atoms. Examples of suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl. One or more rings may be aryl, heteroaryl, or heterocyclic, provided that the bonding site is via a non-aromatic ring, a non-heterocyclic saturated carbon ring, etc. "Substituting cycloalkyl" refers to oxo, thione, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxylester, (carboxylester)amino, (carboxylester)oxy, cyano, cycloalkyl, substituted cyclo This refers to a cycloalkyl group having 1 to 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic group, substituted heterocyclic group, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, where the substituents are defined herein.

[0093] "Cycloalkyloxy" refers to -O-cycloalkyl.

[0094] "Substituted cycloalkyloxy" refers to -O- (substituted cycloalkyl).

[0095] "Cycloalkylamino" means -NR37 (Cycloalkyl) group refers to a group where R 37 However, it is hydrogen, alkyl, or substituted alkyl.

[0096] "Substituting cycloalkylamino" means -NR 37 This refers to a (substituted cycloalkyl) group, where R 37 However, these are hydrogen, alkyl, or substituted alkyl, and substituted cycloalkyl is as defined herein.

[0097] "Cycloalkylthio" refers to -S-cycloalkyl.

[0098] "Substituted cycloalkylthio" refers to -S- (substituted cycloalkyl).

[0099] "Guanidino" refers to the group -NHC (=NH)NH2.

[0100] "Substituting guanidino" means -NR 36 C(=NR 36 )N(R 36 ) refers to 2, and here each R 36 Two R groups are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic groups, and are bonded to a common guanidino nitrogen atom. 36 The groups are of any choice and, together with the nitrogen atoms bonded to them, form a heterocyclic group or a substituted heterocyclic group, provided that at least one R is present. 36 Here, the substituent is not hydrogen, and the substituent is as defined herein.

[0101] "Halo" or "halogen" refers to fluoro, chloro, bromo, and iodine, preferably fluoro or chloro.

[0102] "Hydroxy" or "hydroxyl" refers to the group -OH.

[0103] A "heteroaryl" refers to an aromatic group consisting of 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur within the ring. Such heteroaryl groups may have a monocyclic (e.g., pyridinyl or furyl) or a plurality of fused rings (e.g., indolidinyl or benzothienyl), the fused rings may or may not be aromatic, and / or may or may not have heteroatoms, provided that the bonding site is through the atoms of the aromatic heteroaryl group. In one embodiment, the nitrogen and / or sulfur ring atoms(s) of the heteroaryl group are optionally oxidized to an N-oxide (N→O), sulfinyl, or sulfonyl moiety. Preferred heteroaryls include 5-membered or 6-membered heteroaryls such as pyridinyl, pyrrolyl, thiophenyl, and furanyl. Other preferred heteroaryls include 9-membered or 10-membered heteroaryls such as indolyl, quinolinyl, quinolonyl, isoquinolinyl, and isoquinolonyl.

[0104] A "substituted heteroaryl" refers to a heteroaryl group substituted with 1 to 5 substituents, preferably 1 to 3, more preferably 1 to 2, selected from the group consisting of identical substituents defined for substituted aryls.

[0105] "Heteroaryloxy" refers to -O-heteroaryl.

[0106] "Substituted heteroaryloxy" refers to the -O- (substituted heteroaryl) group.

[0107] "Heteroarylthio" refers to the -S-heteroaryl group.

[0108] "Substituting heteroarylthio" refers to the -S- (substituted heteroaryl) group.

[0109] "Heteroarylamino" means -NR 37 (Heteroaryl) group refers to a group where R 37 However, it is hydrogen, alkyl, or substituted alkyl.

[0110] "Substituting heteroarylamino" means -NR 37 This refers to a (substituted heteroaryl) group, where R 37 However, the element is hydrogen, alkyl, or substituted alkyl, and the substituted heteroaryl is as defined herein.

[0111] "Heterocyclic" or "heterocyclic group" or "heterocycloalkyl" or "heterocyclyl" refers to a saturated or partially saturated but non-aromatic group having 1 to 10 ring carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, and 1 to 4 ring heteroatoms, preferably 1 to 3 heteroatoms, more preferably 1 to 2 heteroatoms, selected from the group consisting of nitrogen, sulfur, or oxygen. x A heterocycloalkyl group refers to a heterocycloalkyl group having x ring atoms, including a ring heteroatom. Heterocycles include monocycles or multiple fused rings, and fused rings include fused-ring systems, bridging-ring systems, and spiro-ring systems. In fused-ring systems, one or more rings can be cycloalkyl, aryl, or heteroaryl, provided that the bonding site is via a non-aromatic ring. In one embodiment, the nitrogen and / or sulfur atoms (or more) of the heterocycle are optionally oxidized to form an N-oxide, sulfinyl, or sulfonyl moiety.

[0112] Examples of heterocyclyls and heteroaryls include azetidinil, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazyl, pyrimidyl, pyridazyl, indolidyl, isoindolyl, indolyl, dihydroindolyl, indazolyl, prinyl, quinolidinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphthylpyridinyl, quinoxalinyl, quinazolinyl, cinolinyl, pteridinyl, carbazolyl, carborinyl, phenanthridine, acridinyl, phenanthrolinyl, isothiazolyl, phenadinyl, isoxazoli Examples include, but are not limited to, phenoxadinyl, phenothiazinyl, imidazolidinyl, imidazolinyl, piperidinyl, piperazinyl, indolinyl, phthalimidyl, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrobenzo[b]thiophenyl, thiazolyl, thiazolidinyl, thiophenyl, benzo[b]thiophenyl, morpholinyl, thiomorpholinyl (also called thiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidinyl, and tetrahydrofuranyl.

[0113] "Substituting heterocyclic group," "substituted heterocycloalkyl," or "substituted heterocyclil" refers to a heterocyclil group substituted with 1 to 5 substituents, preferably 1 to 3 substituents, which are the same as defined for substituted cycloalkyl groups.

[0114] "Heterocyclyloxy" refers to the -O-heterocyclyl group.

[0115] "Substituting heterocyclyloxy" refers to the -O- (substituted heterocyclyl) group.

[0116] "Heterocyclilthio" refers to the -S-heterocyclyl group.

[0117] "Substituting heterocyclylthio" refers to the -S- (substituted heterocyclyl) group.

[0118] "Heterocyclylamino" refers to -NR 37(Heterocyclyl) group refers to the group, where R 37 However, it is hydrogen, alkyl, or substituted alkyl.

[0119] "Substituting heterocyclylamino" means -NR 37 This refers to a (substituted heterocyclyl) group, where R 37 However, the element is hydrogen, alkyl, or substituted alkyl, and a substituted heterocyclyl is as defined herein.

[0120] "Nitro" refers to the group -NO2.

[0121] "Oxo" refers to an atom (=O) or (O).

[0122] A "spiro ring system" refers to a bicyclic ring system that has a single ring carbon atom shared by both rings.

[0123] "Sulfinyl" refers to the divalent group -S(O)- or -S(=O)-.

[0124] "Sulfonyl" refers to the divalent group -S(O)2- or -S(=O)2-.

[0125] "Substituting sulfonyl" refers to -SO2-alkyl groups, -SO2-substituted alkyl groups, -SO2-OH, -SO2-alkenyl groups, -SO2-substituted alkenyl groups, -SO2-cycloalkyl groups, -SO2-substituted cycloalkyl groups, -SO2-aryl groups, -SO2-substituted aryl groups, -SO2-heteroaryl groups, -SO2-substituted heteroaryl groups, -SO2-heterocyclic groups, and -SO2-substituted heterocyclic groups, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic groups, and substituted heterocyclic groups are as defined herein. Substituting sulfonyls include groups such as methyl-SO2-, phenyl-SO2-, and 4-methylphenyl-SO2-. Suitable substituted alkyl groups on substituted alkyl-SO2- include halogenated alkyl groups, particularly methyl halogenated groups such as trifluoromethyl, difluoromethyl, and fluoromethyl. "Sulfonyloxy" or "substituted sulfonyloxy" refers to -OSO2-alkyl groups, -OSO2-substituted alkyl groups, -OSO2-OH, -OSO2-alkenyl groups, -OSO2-substituted alkenyl groups, -OSO2-cycloalkyl groups, -OSO2-substituted cycloalkyl groups, -OSO2-aryl groups, -OSO2-substituted aryl groups, -OSO2-heteroaryl groups, -OSO2-substituted heteroaryl groups, -OSO2-heterocyclic groups, and -OSO2-substituted heterocyclic groups, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic groups, and substituted heterocyclic groups are as defined herein.

[0126] "Sulfonylamino" means -NR 37 This refers to a (substituted sulfonyl) group, where R 37 However, the substituted element is hydrogen, alkyl, or substituted alkyl, and the substituted sulfonyl is as defined herein.

[0127] "Thioacyl" refers to the group HC(S)-, alkyl-C(S)-, substituted alkyl-C(S)-, alkenyl-C(S)-, substituted alkenyl-C(S)-, alkynyl-C(S)-, substituted alkynyl-C(S)-, cycloalkyl-C(S)-, substituted cycloalkyl-C(S)-, aryl-C(S)-, substituted aryl-C(S)-, heteroaryl-C(S)-, substituted heteroaryl-C(S)-, heterocyclic-C(S)-, and substituted heterocyclic-C(S)-, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic group, and substituted heterocyclic group are as defined herein.

[0128] "Mercapto" or "thiol" refers to the -SH group.

[0129] "Thiocaunal" refers to the divalent group -C(S)- which is equivalent to -C(=S)-.

[0130] "Thion" refers to an atom (=S).

[0131] "Alkylthio" refers to an -S-alkyl group, where alkyl is as defined herein.

[0132] "Substituted alkylthio" refers to an -S-(substituted alkyl) group, where substituted alkyl is as defined herein. Preferred substituted alkyl groups on the -S-(substituted alkyl) include halogenated alkyl groups, particularly methyl halogenated groups such as trifluoromethyl, difluoromethyl, and fluoromethyl.

[0133] "Vinyl" refers to the unsaturated hydrocarbon radical -CH=CH2 derived from ethylene.

[0134] The terms “optional” or “optionally” as used throughout this specification mean that the events or situations described below may occur but do not have to, and that this description includes both cases in which the events or situations occur and cases in which they do not. For example, “The nitrogen atom is optionally oxidized to provide an N-oxide (N→O) moiety” means that the nitrogen atom may be oxidized but does not have to, and this description includes both cases in which the nitrogen atom is not oxidized and cases in which the nitrogen atom is oxidized.

[0135] The term "optionally substituted" refers to a substituted or unsubstituted group. A substituted group may be substituted with one or more substituents, e.g., 1, 2, 3, 4, or 5 substituents. Preferably, the substituents are selected from the functional groups provided herein. In certain more preferred embodiments, the substituents are oxo, halo, -CN, NO2, -CO2R 100 , -OR 100 , -SR 100 -SOR 100 , -SO2R 100 , -NR 101 R 102 ,-CONR 101 R 102 -SO2NR 101 R 102 , C1-C6 alkyl, C1-C6 alkoxy, -CR 100 =C(R 100 )2, -CCR 100 , C3~C 10 Cycloalkyl, C4~C 10 Heterocycline, C6~C 14 Aryl and C5~C 12 Heteroaryl, where each R 100 These independently consist of hydrogen or C1-C8 alkyl; C3-C 12 Cycloalkyl; C4~C 10 Heterocycline; C6~C 14 Aryl; or C2~C 12Heteroaryl; where each alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally composed of 1-3 halo, 1-3 C1-C6 alkyl, 1-3 C1-C6 haloalkyl, or 1-3 C1-C6 alkoxy groups. More preferably, the substituent is selected from the group consisting of chloro, fluoro, -OCH3, methyl, ethyl, isopropyl, cyclopropyl, -OCF3, -CF3, and -OCHF2.

[0136] R 101 and R 102 These independently include hydrogen; C1-C8 alkyl (optionally substituted with -CO2H or its ester), C1-C6 alkoxy, oxo, and -CR. 103 =C(R 103 )2, -CCR, C3~C 10 Cycloalkyl, C3-C 10 Heterocycline, C6~C 14 Aryl, or C2~C 12 Heteroaryl (where each R 103 (Independently, hydrogen or C1-C8 alkyl); C3-C 12 Cycloalkyl; C4~C 10 Heterocycline; C6~C 14 Aryl; or C2~C 12 A heteroaryl group, where each cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1 to 3 alkyl groups or 1 to 3 halo groups, or R 101 and R 102 However, together with the nitrogen atoms to which they are bonded, they form a 5- to 7-membered heterocycle.

[0137] Unless otherwise specified, the nomenclature of substituents not explicitly defined herein is obtained by naming the functional group adjacent to the bond point following the terminal portion of the functional group. For example, the substituent "alkoxycarbonylalkyl" refers to the group (alkoxy)-C(O)-(alkyl)-.

[0138] Naturally, polymers obtained by defining substituents that themselves have further substituents (for example, substituted aryl groups having substituted aryl groups as substituents, where the substituents themselves are substituted with substituted aryl groups) are not intended to be included herein. In such cases, the maximum number of such substituents is three. In other words, each of the above definitions is constrained by a limitation, for example, that the substituted aryl group is limited to -substituted aryl-(substituted aryl)-substituted aryl.

[0139] In some embodiments of the substitution portion, this portion is substituted with a group that can be substituted with further groups, but no further groups can be additionally substituted. For example, in some embodiments of "substituted alkyl," the alkyl portion is substituted with a group that can be further substituted (e.g., substituted alkoxy, substituted amino, substituted aryl, substituted aryloxy, substituted arylthio, substituted arylamino, substituted heteroarylamino, substituted cycloalkylamino, substituted heterocyclylamino, substituted cycloalkyl, substituted cycloalkyloxy, substituted cycloalkylthio, substituted guanidino, substituted heteroaryl, substituted heteroaryloxy, substituted heteroarylthio, substituted heterocyclic group, substituted heterocyclyloxy, substituted heterocyclylthio, substituted sulfonyl, or substituted alkylthio), but the substituted alkoxy, substituted amino, substituted aryl, substituted aryloxy, substituted arylthio, substituted arylamino, substituted heteroarylamino, substituted cycloalkylamino, substituted heterocyclylamino, substituted cycloalkyl, substituted cycloalkyloxy, substituted cycloalkylthio, substituted guanidino, substituted heteroaryl, substituted heteroaryloxy, substituted heteroarylthio, substituted heterocyclic group, substituted heterocyclyloxy, substituted heterocyclylthio, substituted sulfonyl, or substituted alkylthio on the alkyl portion is not substituted with a group that can be further substituted itself. As an example, a "substituted alkyl" is provided, but such embodiments apply to each of the substituted moieties described herein.

[0140] In some embodiments of the substituted moiety, this moiety is further substituted with an unsubstituted group. Thus, in some embodiments, the "substituted alkyl" is an alkyl moiety substituted with one or more, in some embodiments 1, 2, 3, 4, or 5 moieties independently selected from the group consisting of alkoxy, acyl, acylamino, acyloxy, amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, aryloxy, arylthio, arylamino, heteroarylamino, cycloalkylamino, heterocycloalkylamino, carboxyl, carboxylester, (carboxylester)amino, (carboxylester)oxy, cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, guanidino, halo, hydroxy, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclic group, heterocyclyloxy, heterocyclylthio, nitro, SO3H, sulfonyloxy, sulfonylamino, thioacyl, thiol, and alkylthio. As an example, a "substituted alkyl" is provided, but such embodiments apply to each of the substituted moieties described herein.

[0141] Naturally, the above definition is not intended to include unacceptable substitution patterns (e.g., methyl substituted with four fluoro groups). Such unacceptable substitution patterns are well known to those skilled in the art.

[0142] It should be understood that certain features of the present invention, described in the context of separate embodiments for clarity, may also be provided in combination in a single embodiment. Conversely, various features of the present invention, described in the context of a single embodiment for brevity, may also be provided separately or in any preferred partial combination. All combinations of embodiments relating to chemical groups represented by variables are specifically encompassed by the present invention and are disclosed herein as if every possible combination were individually and explicitly disclosed, insofar as such combinations include compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity). In addition, all subcombinations of chemical groups enumerated in embodiments describing such variables are also specifically encompassed by the present invention and are disclosed herein as if every such subcombination of chemical groups were individually and explicitly disclosed herein.

[0143] BCR: ABL1 inhibitor This disclosure relates to the use of a BCR:ABL1 inhibitor in combination with a tyrosine kinase inhibitor to treat cancer in subjects requiring such treatment.

[0144] In some embodiments, the BCR:ABL1 inhibitor is a compound of formula (I). [ka] or its tautomers or N-oxides, or their respective isotopomers, or each of the aforementioned prodrugs, or each of the aforementioned stereoisomers, or each of the aforementioned pharmaceutically acceptable salts, or each of the aforementioned solvates, where, L is -NH-CO-, -CO-NH-, -NH-SO2-, or -SO2-NH-, R 1 However, C6~C were replaced by arbitrary selection. 10 Aryls, optionally substituted 5-10 member heteroaryls, optionally substituted 4-10 member heterocycles, C(O)NR 6 R 7, S(O)2NR 6 R 7 , NR 6 COR 7 , or NR 6 SO2R 7 , or C(O)OR 6 And, R 2 However, H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 member heterocycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C6-C 10 An aryl, or a 5-10 member heteroaryl that has been optionally substituted, R 3 However, H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, OR 6 , or NR 6 R 7 And, or R 2 and R 3 However, together with the intervening atom, it forms a cycloalkyl or heterocycloalkyl, preferably an optionally substituted C3-C8 cycloalkyl or an optionally substituted 4-10 member heterocycloalkyl. R 4 However, these are optionally substituted C1-C6 alkyl groups, preferably C1-C3 haloalkyl groups, such as CF3 or CF2Cl, optionally substituted C2-C6 alkenyl groups, or optionally substituted C2-C6 alkynyl groups. X is either O or S, Y is CH, C-(C1-C2 alkyl), C-halo, or N. Z, CR 5 or N, R 5 However, it is H or halogen, R 6However, H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 member heterocycloalkyl, optionally substituted C6-C 10 An aryl, or a 5-10 member heteroaryl that has been optionally substituted, R 7 However, H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 member heterocycloalkyl, optionally substituted C6-C 10 An aryl, or a 5-10 member heteroaryl that has been optionally substituted, or R 6 and R 7 However, together with the nitrogen atoms to which they are bonded, they form optionally substituted 4- to 7-membered heterocycles. However, the compound is other than (i) 1H-benzimidazole-7-carboxylic acid, 5-[[(4-methoxyphenyl)sulfonyl]amino]-1-methyl-, or (ii) 1H-benzimidazole-7-carboxylic acid, 5-[[(4-ethoxyphenyl)sulfonyl]amino]-1-methyl-.

[0145] In some embodiments, the BCR:ABL1 inhibitor is a compound of formula (Ii). [ka] or its tautomers or N-oxides, or their respective isotopomers, or each of the aforementioned prodrugs, or each of the aforementioned stereoisomers, or each of the aforementioned pharmaceutically acceptable salts, or each of the aforementioned solvates, where, L is -NH-CO-, -CO-NH-, or -NH-SO2-, R 1 However, C6~C were replaced by arbitrary selection. 10 Aryls, optionally substituted 5-10 member heteroaryls, optionally substituted 4-10 member heterocycles, C(O)NR 6 R 7 , S(O)2NR 6 R7 , NR 6 COR 7 , or NR 6 SO2R 7 , or C(O)OR 6 and R 2 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4- to 10-membered heterocycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C6-C 10 aryl, or optionally substituted 5- to 10-membered heteroaryl, and R 3 is H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, OR 6 , or NR 6 R 7 and, alternatively R 2 and R 3 , together with the intervening atoms, form cycloalkyl or heterocycloalkyl, preferably optionally substituted C3-C8 cycloalkyl or optionally substituted 4- to 10-membered heterocycloalkyl, R 4 is optionally substituted C1-C6 alkyl, preferably C1-C3 haloalkyl, for example CF3 or CF2Cl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, X is O or S, and Y is CH, C-(C1-C2 alkyl), or C-halo or N, and Z is CR 5 or N, and R 5 is H or halogen, and R 6is H, optionally substituted C1~C6 alkyl, optionally substituted C3~C8 cycloalkyl, optionally substituted 4- to 10-membered heterocycloalkyl, optionally substituted C6~C 10 aryl, or optionally substituted 5- to 10-membered heteroaryl, R 7 is H, optionally substituted C1~C6 alkyl, optionally substituted C3~C8 cycloalkyl, optionally substituted 4- to 10-membered heterocycloalkyl, optionally substituted C6~C 10 aryl, or optionally substituted 5- to 10-membered heteroaryl, or R 6 and R 7 , together with the nitrogen to which they are bonded, form an optionally substituted 4- to 7-membered heterocyclic ring.

[0146] In some embodiments, the BCR:ABL1 inhibitor is a compound of formula (IA)

化

[0147] It is understood that when Z is N, R 5 is absent. Similarly, it is understood that when R 5 is present, R 5 is bonded to a carbon atom in the aryl ring such that Z is CR 5 .

[0148] In some embodiments, the BCR:ABL1 inhibitor is a compound of formula (IA-1)

化

[0149] In some embodiments, the BCR:ABL1 inhibitor is a compound selected from formula (IIA), (IIB), or (IIE)

化

[0150] In some embodiments, the BCR:ABL1 inhibitor is a compound of formula (Id). [ka] or a pharmaceutically acceptable salt thereof, where the remaining variables are as defined herein.

[0151] In some embodiments, the BCR:ABL1 inhibitor is compound A [ka] or a pharmaceutically acceptable salt thereof.

[0152] Suitable BCR:ABL1 inhibitors that can be used according to the methods described herein include, but are not limited to, compounds of formula (I), (Ii), (IA), (IA-1), (IIA), (IIB), (IIE), or (Id), such as compound A, or pharmaceutically acceptable salts.

[0153] Compounds of formula (I), (Ii), (IA), (IA-1), (IIA), (IIB), (IIE), or (Id), particularly compounds of formula (I), (Ii), (IA), (IA-1), (IIA), (IIB), (IIE), or (Id), or pharmaceutically acceptable salts thereof, as well as methods for preparing and using them, are disclosed in U.S. Patent No. 10,889,571, which is incorporated by reference in its entirety.

[0154] This disclosure includes all salts of the compounds referred to herein, including pharmaceutically acceptable salts. This disclosure also includes any or all of the stereochemical forms of the described compounds, including any enantiomer or diastereomer forms, and any tautomers or other forms, such as N-oxides, solvates, prodrugs, or isotopomers. Unless otherwise expressly indicated by a chemical structure or name, the structure or name is intended to encompass all possible stereoisomers of the compound shown. In addition, if a particular stereochemical form is shown, it is understood that other stereochemical forms are also encompassed by the invention. All forms of the compound, such as crystalline or amorphous forms of the compound, are also encompassed by the invention. Compositions containing the compounds of the invention, such as substantially pure compositions of the compound (including its particular stereochemical form), are also intended. The invention also includes compositions containing mixtures of the compounds of the invention in any ratio, including mixtures of two or more stereochemical forms of the compounds of the invention in any ratio, and consequently encompasses racemic, non-racemic, enantio-enriched, and scaremic mixtures of the compound.

[0155] Tyrosine kinase inhibitors In some embodiments, the tyrosine kinase inhibitor is selected from imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib.

[0156] In some embodiments, a tyrosine kinase inhibitor binds to the active site of tyrosine kinase.

[0157] In some embodiments, the tyrosine kinase inhibitor is imatinib.

[0158] In some embodiments, the tyrosine kinase inhibitor is nilotinib.

[0159] In some embodiments, the tyrosine kinase inhibitor is dasatinib.

[0160] In some embodiments, the tyrosine kinase inhibitor is bosutinib.

[0161] In some embodiments, the tyrosine kinase inhibitor is ponatinib.

[0162] In some embodiments, the tyrosine kinase inhibitor is bafetinib.

[0163] Combination of a BCR:ABL1 inhibitor and a tyrosine kinase inhibitor In certain embodiments, disclosed herein is a combination comprising a BCR:ABL1 inhibitor (e.g., a compound of formula (I), (I-i), (IA), (IA-1), (IIA), (IIB), (IIE), or (Id), for example Compound A), or a pharmaceutically acceptable salt thereof, and a tyrosine kinase inhibitor (e.g., imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib).

[0164] In certain embodiments, further disclosed herein is a pharmaceutical combination comprising a BCR:ABL1 inhibitor (e.g., a compound of formula (I), (I-i), (IA), (IA-1), (IIA), (IIB), (IIE), or (Id), for example Compound A), or a pharmaceutically acceptable salt thereof, and a tyrosine kinase inhibitor (e.g., imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib).

[0165] In certain embodiments, combinations comprising compound A and a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib are disclosed herein.

[0166] In certain embodiments, combinations of drugs comprising compound A and a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib are further disclosed herein.

[0167] In some embodiments, compound A and a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib are co-administered simultaneously (e.g., simultaneously, essentially simultaneously, or within the same therapeutic protocol) or sequentially.

[0168] In some embodiments, co-administration of compound A with a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib increases the bioavailability of compound A. In some embodiments, co-administration of compound A with a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib increases the bioavailability of compound A. max The AUC of compound A increases. In some embodiments, co-administration of compound A with a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib and bafetinib increases the AUC of compound A. In some embodiments, co-administration of compound A with a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib and bafetinib increases the AUC of compound A. 1 / 2 It increases.

[0169] The compositions or therapies disclosed herein may be administered to a patient individually or in combination (e.g., simultaneously, sequentially, or separately). In some embodiments, compound A is administered before a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib. In some embodiments, a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib is administered before compound A.

[0170] In some embodiments, compound A and a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib are administered in close proximity in time (for example, compound A and a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib may be administered simultaneously at the beginning). Accordingly, the present disclosure provides a method for treating or preventing cancer, comprising administering compound A and a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib in close proximity in time. In some embodiments, “close proximity in time” means that the administration of one therapeutic agent takes place within a period before or after the administration of another therapeutic agent, and the therapeutic effect of the first therapeutic agent overlaps with the therapeutic effect of the second therapeutic agent. In some embodiments, the therapeutic effect of one therapeutic agent completely overlaps with the therapeutic effect of another therapeutic agent.

[0171] In some embodiments, “temporal proximity” means that the administration of one therapeutic agent occurs within a certain period before or after the administration of another therapeutic agent, and that there is a synergistic effect between the two therapeutic agents. “Temporal proximity” can vary depending on a variety of factors, including but not limited to the age, sex, weight, genetic background, medical condition, medical history, and treatment history of the person to whom the therapeutic agent is administered, the disease or condition being treated or improved, the therapeutic outcome to be achieved, the dosage, frequency, and duration of administration of the therapeutic agent, the pharmacokinetics and pharmacodynamics of the therapeutic agent, and the route through which the therapeutic agent is administered. In some embodiments, “temporal proximity” means within 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 18 hours, 24 hours, 36 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, or 8 weeks. In some embodiments, multiple doses of one therapeutic agent may occur in close proximity in time to a single dose of another therapeutic agent. In some embodiments, this temporal proximity may vary during a treatment cycle or within a dosing plan.

[0172] In some embodiments, the Disclosure provides synergistic combinations of compound A and a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib, wherein compound A and the tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib come into contact with each other in the human body (for example, only in the human body).

[0173] In some embodiments, compound A and a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib are co-administered simultaneously (e.g., simultaneously, essentially simultaneously, or within the same therapeutic protocol) or sequentially.

[0174] In some embodiments, compound A and a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib are co-administered in separate dosage forms. In some embodiments, compound A and a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib are co-administered in a combined dosage form.

[0175] Pharmaceutical compositions and preparations Any pharmaceutical composition of any of the compounds detailed herein is encompassed by the present invention. Accordingly, the present invention includes a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. In one embodiment, the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid. The pharmaceutical composition according to the present invention may be in a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration, or in a form suitable for administration by inhalation.

[0176] The compounds detailed herein may, in one embodiment, be in a purified form, and compositions containing the purified compounds are detailed herein. Compositions containing the compounds or salts thereof detailed herein, for example, substantially pure compositions of the compounds, are provided. In some embodiments, compositions containing the compounds or salts thereof detailed herein are in a substantially pure form. In one variant, “substantially pure” means a composition containing 35% or less impurities, where impurities mean compounds other than the compound or salts thereof that constitute the majority of the composition. For example, a substantially pure composition of a compound of formula (I), (Ii), (IA), (IA-1), (IIA), (IIB), (IIE), or (Id), such as compound A, is intended to contain 35% or less impurities, where impurities mean compounds other than the compound or salts thereof. In one variant, a substantially pure composition of the compound or salt thereof is provided, where this composition contains 25% or less impurities. In another variant, a substantially pure composition of the compound or salt thereof is provided, where this composition contains 20% or less impurities. In yet another variation, a composition of a substantially pure compound or a salt thereof is provided, wherein the composition contains 10% or less impurities. In yet another variation, a composition of a substantially pure compound or a salt thereof is provided, wherein the composition contains 5% or less impurities. In yet another variation, a composition of a substantially pure compound or a salt thereof is provided, wherein the composition contains 3% or less impurities. In yet another variation, a composition of a substantially pure compound or a salt thereof is provided, wherein the composition contains 1% or less impurities. In yet another variation, a composition of a substantially pure compound is provided, wherein the composition contains 15% or less impurities, preferably 10% or less, more preferably 5% or less, even more preferably 3% or less, and most preferably 1% or less, wherein the impurities may be compounds in different stereochemical forms.For example, a substantially pure (S) compound composition means, but is not limited to, a composition containing 15% or less, 10% or less, 5% or less, 3% or less, or 1% or less of the (R) form of the compound.

[0177] In one variant, the compounds described herein are synthetic compounds prepared for administration to an organism such as a human. In another variant, a composition containing a substantially pure form of the compound is provided. In yet another variant, the present invention encompasses a pharmaceutical composition comprising the compounds detailed herein and a pharmaceutically acceptable carrier or excipient. In yet another variant, a method for administering the compound is provided. The purified form, pharmaceutical composition, and method for administering the compound are suitable for any of the compounds or forms described herein.

[0178] The compound may be formulated for any available delivery route, including oral, mucosal (e.g., nasal cavity, sublingual, vaginal, cheek, or rectal), parenteral (e.g., intramuscular, subcutaneous, or intravenous), topical, or transdermal delivery forms. The compound may be formulated with a suitable carrier to provide a delivery form, including, but not limited to, tablets, caplets, capsules (such as rigid gelatin capsules or soft elastic gelatin capsules), cachets, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal sprays or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions), solutions, and elixirs.

[0179] One or more compounds described herein may be used in the preparation of pharmaceutical formulations, such as medicinal formulations, by combining the compound as an active ingredient with a pharmaceutically acceptable carrier, such as those described above. Depending on the therapeutic form of the system (e.g., transdermal patch versus oral tablet), the carrier may be in various forms. Furthermore, the medicinal formulation may contain preservatives, solubilizers, stabilizers, re-wetters, emulsifiers, sweeteners, colorants, modifiers, and salts, buffers, coatings, or antioxidants for adjusting osmotic pressure. Formulations containing the compounds may also contain other substances having beneficial therapeutic properties. The medicinal formulations may be prepared by known compounding methods. Suitable formulations are, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21 st This can be found in the ed. (2005), which is incorporated herein by reference.

[0180] The compounds described herein may be administered to an individual (e.g., a human) in the form of generally acceptable oral compositions such as tablets, coated tablets, and hard or soft-shelled gel capsules, emulsions, or suspensions. Examples of carriers that can be used in the preparation of such compositions include lactose, corn starch or its derivatives, talc, stearic acid or its salts. Acceptable carriers for soft-shelled gel capsules include, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols. Furthermore, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetters, emulsifiers, sweeteners, colorants, modifiers, and salts, buffers, coatings, or antioxidants for adjusting osmotic pressure.

[0181] Any of the compounds described herein can be formulated into tablets of any of the described dosage forms.

[0182] Compositions containing the compounds provided herein are also described. In one variant, the composition comprises the compound and a pharmaceutically acceptable carrier or excipient. In another variant, a substantially pure composition of the compound is provided.

[0183] BCR:ABL-1 variant In some embodiments, the BCR:ABL-1 protein is the wild-type BCR:ABL-1 protein. In some embodiments, the BCR:ABL-1 protein contains a single amino acid mutation compared to wild-type BCR:ABL-1. In some embodiments, the BRC:ABL-1 protein contains multiple amino acid mutations compared to wild-type BCR:ABL-1.

[0184] In some embodiments, the BRC:ABL-1 protein contains a single amino acid mutation selected from F359V, F359C, F359I, H396R, E255V, T315I, A337V, A344P, P465S, ​​T315M, and V468F. In some embodiments, the BCR:ABL-1 protein contains multiple amino acid mutations selected from (i) G250E and T315I, (ii) Y253H and T315I, (iii) E255V and T315I, (iv) H396R and T315I, (v) E255V and V299L, (vi) Y253H and F317L, (vii) A337V and T315I, (viii) A344P and T315I, (ix) P465S and T315I, and (x) V468F and T315I.

[0185] Wild-type BCR: ABL-1, isoform P00519 (SEQ ID NO: 1)

[0186] BCR:ABL-1, isoform P00519F359V single mutant, (SEQ ID NO: 2)

[0187] BCR:ABL-1, isoform P00519F359C single mutant, (SEQ ID NO: 3)

[0188] BCR:ABL-1, isoform P00519F359I single mutant, (SEQ ID NO: 4)

[0189] BCR:ABL-1, isoform P00519H396R single mutant, (SEQ ID NO: 5)

[0190] BCR:ABL-1, isoform P00519E255V single mutant, (SEQ ID NO: 6)

[0191] BCR:ABL-1, isoform P00519T315I single mutant, (SEQ ID NO: 7)

[0192] BCR:ABL-1, isoform P00519A337V single mutant, (SEQ ID NO: 8)

[0193] BCR:ABL-1, isoform P00519A344P single mutant, (SEQ ID NO: 9)

[0194] BCR:ABL-1, isoform P00519P465S single mutant, (SEQ ID NO: 10)

[0195] BCR:ABL-1, isoform P00519T315M single mutant, (SEQ ID NO: 11)

[0196] BCR:ABL-1, isoform P00519V468F single mutant, (SEQ ID NO: 12)

[0197] BCR:ABL-1, isoform P00519 G250E / T315I double mutant, (SEQ ID NO: 13)

[0198] BCR:ABL-1, isoform P00519 Y253H / T315I double mutant (SEQ ID NO: 14)

[0199] BCR: ABL-1, isoform P00519 E255V / T315I, double mutant (SEQ ID NO: 15)

[0200] BCR: ABL-1, isoform P00519 H396R / T315I, double mutant (SEQ ID NO: 16)

[0201] BCR: ABL-1, isoform P00519 E255V / V299L, double mutant (SEQ ID NO: 17)

[0202] BCR:ABL-1, isoform P00519 Y253H / F317L double mutant, (SEQ ID NO: 18)

[0203] BCR: ABL-1, isoform P00519 A337V / T315I, double mutant (SEQ ID NO: 19)

[0204] BCR:ABL-1, isoform P00519 A344P / T315I, double mutant, (SEQ ID NO: 20)

[0205] BCR:ABL-1, isoform P00519 P465S / T315I, double mutant, (SEQ ID NO: 21)

[0206] BCR:ABL-1, isoform P00519 V468F / T315I, double mutant, (SEQ ID NO: 22)

[0207] Instructions for use / treatment Compounds and compositions detailed herein, for example, pharmaceutical compositions comprising a compound or salt thereof provided herein and a pharmaceutically acceptable carrier or excipient, may be used in methods of administration and treatment provided herein. Compounds and compositions may also be used in in vitro methods, for example, in vitro methods for administering a compound or composition to cells for screening purposes and / or for performing quality control assays.

[0208] The compounds and compositions described herein may be used in some embodiments for the treatment of cancer. In some embodiments, a method for doing so in a subject requiring treatment for cancer includes administering a BCR:ABL1 inhibitor and a tyrosine kinase inhibitor (TKI) to the subject.

[0209] In some embodiments, the method involves administering to a subject a BCR:ABL1 inhibitor (e.g., a compound of formula (I), (Ii), (IA), (IA-1), (IIA), (IIB), (IIE), or (Id), such as compound A) or a pharmaceutically acceptable salt thereof, and a tyrosine kinase inhibitor (e.g., imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib).

[0210] In some embodiments, the BCR:ABL1 inhibitor is compound A or a pharmaceutically acceptable salt thereof, and the tyrosine kinase inhibitor is imatinib. In some embodiments, the BCR:ABL1 inhibitor is compound A or a pharmaceutically acceptable salt thereof, and the tyrosine kinase inhibitor is dasatinib. In some embodiments, the BCR:ABL1 inhibitor is compound A or a pharmaceutically acceptable salt thereof, and the tyrosine kinase inhibitor is ponatinib.

[0211] While not bound by theory, it is believed that the combination of a BCR:ABL1 inhibitor (e.g., a compound of formula (I), (Ii), (IA), (IA-1), (IIA), (IIB), (IIE), or (Id), such as compound A) or a pharmaceutically acceptable salt thereof, with a tyrosine kinase inhibitor (e.g., imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib) as described herein may provide more effective treatment compared to monotherapy and thus mitigate the dose-dependent side effects that may be associated with monotherapy.

[0212] In one embodiment, a method for treating a patient's cancer is provided herein, comprising administering a therapeutically effective amount of a compound or composition provided herein to the patient. In some embodiments, the cancer is melanoma, hereditary leiomyomatosis, renal cell carcinoma (HLRCC), or other solid tumors. In some embodiments, the cancer is lymphoma and leukemia. In some embodiments, the cancer is chronic myeloid leukemia (CML).

[0213] This specification provides a method for treating cancer in patients (e.g., human patients) in combination with a BCR:ABL1 inhibitor (e.g., a compound of formula (I), (Ii), (IA), (IA-1), (IIA), (IIB), (IIE), or (Id), such as compound A) or a pharmaceutically acceptable salt thereof, and a tyrosine kinase inhibitor (e.g., imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib), wherein the method comprises administering a therapeutically effective dose of the BCR:ABL1 inhibitor or a pharmaceutically acceptable salt thereof and a therapeutically effective dose of the tyrosine kinase inhibitor, where cancer is melanoma, hereditary leiomyomatosis, renal cell carcinoma (HLRCC), or other solid tumors.

[0214] This specification provides a method for treating cancer in patients (e.g., human patients) in combination with a BCR:ABL1 inhibitor (e.g., a compound of formula (I), (Ii), (IA), (IA-1), (IIA), (IIB), (IIE), or (Id), such as compound A) or a pharmaceutically acceptable salt thereof, and a tyrosine kinase inhibitor (e.g., imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib), wherein the method comprises administering a therapeutically effective dose of the BCR:ABL1 inhibitor or a pharmaceutically acceptable salt thereof and a therapeutically effective dose of the tyrosine kinase inhibitor, where cancer is lymphoma and leukemia.

[0215] This specification provides a method for treating cancer in patients (e.g., human patients) in combination with a BCR:ABL1 inhibitor (e.g., a compound of formula (I), (Ii), (IA), (IA-1), (IIA), (IIB), (IIE), or (Id), such as compound A) or a pharmaceutically acceptable salt thereof, and a tyrosine kinase inhibitor (e.g., imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib), wherein the method comprises administering a therapeutically effective dose of the BCR:ABL1 inhibitor and a therapeutically effective dose of the tyrosine kinase inhibitor, where the cancer is CML.

[0216] In some embodiments, the patient had received one or more prior treatments. In some embodiments, the cancer progressed during treatment.

[0217] In some embodiments, a BCR:ABL1 inhibitor (e.g., a compound of formula (I), (Ii), (IA), (IA-1), (IIA), (IIB), (IIE), or (Id), such as compound A) or a pharmaceutically acceptable salt thereof and a tyrosine kinase inhibitor (e.g., imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib) are administered simultaneously. In some such embodiments, a BCR:ABL1 inhibitor (e.g., a compound of formula (I), (Ii), (IA), (IA-1), (IIA), (IIB), (IIE), or (Id), such as compound A) or a pharmaceutically acceptable salt thereof and a tyrosine kinase inhibitor (e.g., imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib) may be provided in a single pharmaceutical composition. In other embodiments, a BCR:ABL1 inhibitor (e.g., a compound of formula (I), (Ii), (IA), (IA-1), (IIA), (IIB), (IIE), or (Id), such as compound A) or a pharmaceutically acceptable salt thereof and a tyrosine kinase inhibitor (e.g., imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib) are administered sequentially.

[0218] BCR:ABL1 inhibitors (e.g., compounds of formula (I), (Ii), (IA), (IA-1), (IIA), (IIB), (IIE), or (Id), such as compound A) or pharmaceutically acceptable salts thereof, along with tyrosine kinase inhibitors (e.g., imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib), may be administered at doses typically used when either drug is administered alone.

[0219] Alternatively, as a result of the synergistic effects that may be observed in combination, BCR:ABL1 inhibitors (e.g., compounds of formula (I), (Ii), (IA), (IA-1), (IIA), (IIB), (IIE), or (Id), such as compound A) or their pharmaceutically acceptable salts and / or tyrosine kinase inhibitors (e.g., imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib) may be administered at lower doses than those given when each drug is administered alone.

[0220] In some embodiments, a BCR:ABL1 inhibitor (e.g., compounds of formula (I), (Ii), (IA), (IA-1), (IIA), (IIB), (IIE), or (Id), such as compound A) or a pharmaceutically acceptable salt thereof, used according to the methods described herein, may be administered to the individual in a once-daily dose during the first period, with the administration of the compound being interrupted during the subsequent second period, and a tyrosine kinase inhibitor (e.g., imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib) may be maintained during both the first and second periods.

[0221] In one embodiment, a method is provided herein for inhibiting the tyrosine kinase enzyme activity of a protein selected from Avelson protein (ABL1), Avelson-related protein (ABL2), or chimeric protein BCR-ABL1, the method comprising contacting the protein with an effective amount of compound A in combination with an effective amount of tyrosine kinase inhibitor. In another embodiment, a method is provided herein for inhibiting the tyrosine kinase enzyme activity of Avelson protein (ABL1), the method comprising contacting ABL1 with an effective amount of compound A in combination with an effective amount of tyrosine kinase inhibitor. In yet another embodiment, a method is provided herein for inhibiting the tyrosine kinase enzyme activity of Avelson-related protein (ABL2), the method comprising contacting ABL2 with an effective amount of compound A in combination with an effective amount of tyrosine kinase inhibitor. In a further embodiment, a method is provided herein for inhibiting the tyrosine kinase enzyme activity of chimeric protein BCR-ABL1, the method comprising contacting the chimeric protein with an effective amount of compound A in combination with an effective amount of tyrosine kinase inhibitor.

[0222] In one embodiment, a method for treating a disease in a patient requiring treatment is provided herein, the method comprising administering to the patient a therapeutically effective amount of compound A or a salt thereof in combination with a therapeutic amount of a tyrosine kinase inhibitor.

[0223] The compounds or their salts, combinations, and compositions described herein are considered effective in treating a variety of diseases and disorders. In some embodiments, the compounds or their salts, combinations, and compositions described herein may be used in methods for treating diseases mediated by ABL1, ABL2, and / or BCR-ABL1.

[0224] In one embodiment, a method for treating a disease is provided herein, which involves preventing, inhibiting, or improving the disease state and / or symptoms of a patient by regulating BCR-ABL1 activity, the method comprising administering a therapeutically effective amount of compound A to the patient in combination with a therapeutically effective amount of a tyrosine kinase inhibitor. In one embodiment, a method for treating a disease is provided herein, which involves preventing the disease state and / or symptoms of a patient by regulating BCR-ABL1 activity, the method comprising administering a therapeutically effective amount of compound A to the patient in combination with a therapeutically effective amount of a tyrosine kinase inhibitor. In one embodiment, a method for treating a disease is provided herein, which involves inhibiting the disease state and / or symptoms of a patient by regulating BCR-ABL1 activity, the method comprising administering a therapeutically effective amount of compound A to the patient in combination with a therapeutically effective amount of a tyrosine kinase inhibitor. In one embodiment, a method for treating a disease is provided herein, which involves improving the disease state and / or symptoms of a patient by regulating BCR-ABL1 activity, the method comprising administering a therapeutically effective amount of compound A to the patient in combination with a therapeutically effective amount of a tyrosine kinase inhibitor.

[0225] In some embodiments, the disease is leukemia. In some embodiments, the leukemia is chronic myeloid leukemia (CML), acute myeloid leukemia (AML), or acute lymphoblastic leukemia (ALL). In some embodiments, the leukemia is chronic myeloid leukemia (CML).

[0226] In one embodiment, a method for treating a patient's leukemia is provided herein, the method comprising administering to the patient a therapeutically effective amount of compound A in combination with a therapeutically effective amount of a tyrosine kinase inhibitor. In one embodiment, a method for treating a patient's leukemia is provided herein, the method comprising administering to the patient a therapeutically effective amount of compound A in combination with a therapeutically effective amount of a tyrosine kinase inhibitor, wherein the leukemia is chronic myeloid leukemia (CML), acute myeloid leukemia (AML), or acute lymphoblastic leukemia (ALL).

[0227] In some embodiments, the leukemia treated herein is CML or ALL, and the method comprises administering a therapeutically effective amount of compound A in combination with a therapeutically effective amount of a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib.

[0228] In some embodiments, the leukemia is resistant to treatment. In some embodiments, the leukemia is resistant to treatment with aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and / or bafetinib. In some embodiments, CML is resistant to standard treatment, such as treatment with one or more of aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib. In some embodiments, the leukemia progressed during prior treatment. In some embodiments, prior treatment included administration of aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and / or bafetinib.

[0229] In some embodiments, AML is secondary AML that develops after myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN).

[0230] In another embodiment, a method is provided for delaying the onset and / or onset of a BCR-ABL1 activity-mediated disease or disorder in a patient (such as a human) at risk of developing the disease or disorder. It is understood that delaying onset may include prevention in which the individual or patient does not develop the disease or disorder. In one embodiment, an individual or patient at risk of developing a BCR-ABL1 activity-mediated disease or disorder has one or more risk factors for developing the disease or disorder, e.g., a family history of an individual or patient having the disease or disorder or an underlying genetic condition associated with an increased likelihood of developing the disease or disorder.

[0231] In one embodiment, a method is provided herein for delaying attacks and / or the onset of leukemia in a patient, the method comprising administering a therapeutically effective amount of compound A in combination with a therapeutically effective amount of a tyrosine kinase inhibitor to the patient. In one variant, a method is provided herein for delaying attacks and / or the onset of CML in a patient, the method comprising administering a therapeutically effective amount of compound A in combination with a therapeutically effective amount of a tyrosine kinase inhibitor to the patient. In one variant, a method is provided herein for delaying attacks and / or the onset of AML in a patient, the method comprising administering a therapeutically effective amount of compound A in combination with a therapeutically effective amount of a tyrosine kinase inhibitor to the patient. In one variant, a method is provided herein for delaying attacks and / or the onset of ALL in a patient, the method comprising administering a therapeutically effective amount of compound A in combination with a therapeutically effective amount of a tyrosine kinase inhibitor to the patient.

[0232] Treatment methods for diseases mediated by BCR-ABL1, such as various types of leukemia, are well known to those skilled in the art, and combinations of compound A and a tyrosine kinase inhibitor can be applied to the treatment of such diseases.

[0233] In some embodiments, the patient is a mammal. In some embodiments, the patient is a primate, dog, cat, rabbit, or rodent. In some embodiments, the patient is a primate. In some embodiments, the patient is a human. In some embodiments, the human is at least about or about 18, 21, 30, 50, 60, 65, 70, 75, 80, or 85 years old. In some embodiments, the human is a child. In some embodiments, the human is about 21, 18, 15, 10, 5, 4, 3, 2, or 1 year old or less. In some embodiments, the patient has a genetic condition associated with an increased likelihood of developing a disease such as leukemia. In some embodiments, the patient has a mutation in the ABL1 and / or ABL2 genes. In some embodiments, the patient is Philadelphia chromosome positive.

[0234] The combinations, compounds, or compositions provided herein may be administered to a patient for a desired period or duration, e.g., at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer (in some variations, this may extend to the patient's lifetime), according to an effective dosing plan. In one variation, the combinations, compounds, or compositions are administered on a daily or intermittent schedule. The combinations, compounds, or compositions may be administered to a patient continuously over a period of time (e.g., at least once daily). The dosing frequency may be less than once daily, e.g., about once a week. The dosing frequency may be more than once daily, e.g., twice or three times a day. The dosing frequency may be intermittent (e.g., once daily for 7 days, followed by no administration for the next 7 days, and repeated for any 14-day period, e.g., about 2 months, about 4 months, about 6 months or longer). Any dosing frequency may be used with any of the combinations, compounds, or compositions described herein in any of the dosages described herein.

[0235] The combinations, compounds, or compositions provided herein may be administered to a patient via various routes, including, for example, intravenous, intramuscular, subcutaneous, oral, and transdermal.

[0236] The dose of a compound administered to a patient may vary depending on the specific compound or its salt, the method of administration, and the specific disease. In some embodiments, the amount of the compound or its salt is the therapeutically effective dose.

[0237] The effective dose of the compound may be in one embodiment a dose of about 0.01 to about 100 mg / kg. The effective dose or amount of the compound of this disclosure may be determined by routine methods such as modeling, dose escalation, or clinical trials, taking into account routine factors such as the mode or route of administration or drug delivery, the pharmacokinetics of the drug, the severity and course of the disease being treated, the health status, condition, and body weight of the subject. Exemplary doses are in the range of about 0.7 mg to 7 g per day, or about 7 mg to 350 mg per day, or about 350 mg to 1.75 g per day, or about 1.75 to 7 g per day.

[0238] Furthermore, the use of combinations, compounds, or compositions described herein in the manufacture of pharmaceuticals is also provided herein. In some embodiments, the manufacture of pharmaceuticals is carried out for the treatment of diseases described herein. In some embodiments, the manufacture of pharmaceuticals is carried out for the treatment of diseases mediated by ABL1, ABL2, and / or BCR-ABL1.

[0239] In some embodiments, the methods disclosed herein further include the step of determining the DNA sequence of the BCR:ABL1 gene expressed by the subject.

[0240] In some embodiments, the methods disclosed herein further include the step of determining the amino acid sequence of the BCR:ABL1 protein expressed by the subject.

[0241] Administration plan and treatment plan In some embodiments, the combination involves administering compound A and a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib in a ratio of about 1:10 to about 10:1.

[0242] In some embodiments, the combination involves administering compound A and a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib in a ratio of about 1:9 to about 9:1.

[0243] In some embodiments, the combination involves administering compound A and a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib in a ratio of about 1:8 to about 8:1.

[0244] In some embodiments, the combination involves administering compound A and a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib in a ratio of about 1:7 to about 7:1.

[0245] In some embodiments, the combination involves administering compound A and a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib in a ratio of about 1:6 to about 6:1.

[0246] In some embodiments, the combination involves administering compound A and a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib in a ratio of about 1:5 to about 5:1.

[0247] In some embodiments, the combination involves administering compound A and a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib in a ratio of approximately 1:4 to approximately 4:1.

[0248] In some embodiments, the combination involves administering compound A and a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib in a ratio of approximately 1:3 to approximately 3:1.

[0249] In some embodiments, the combination involves administering compound A and a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib in a ratio of approximately 1:2 to approximately 2:1.

[0250] In some embodiments, the combination involves administering compound A and a tyrosine kinase inhibitor selected from aceminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib in a ratio of approximately 1:1, approximately 1:2, approximately 1:3, approximately 1:4, approximately 1:5, approximately 2:1, approximately 2:3, approximately 2:5, approximately 3:1, approximately 3:2, approximately 3:4, approximately 3:5, approximately 4:1, approximately 4:3, or approximately 4:5.

[0251] In some embodiments, the combination of compound A and imatinib is more synergistic in the K562 cell line than in the Ku812 cell line.

[0252] In some embodiments, the combination of compound A and dasatinib is synergistic in the K562 cell line more than in the Ku812 cell line.

[0253] Products and kits This disclosure further provides articles containing the combinations, compounds, or compositions described herein, or one or more unit doses in appropriate packaging. In certain embodiments, the articles are intended for use in any of the methods described herein. Suitable packaging (e.g., containers) are known in the art and include, for example, vials, containers, ampoules, bottles, jars, flexible packaging, etc. The articles may be further sterilized and / or sealed.

[0254] This disclosure further provides a kit for carrying out the methods of this disclosure, the kit comprising the combinations, compounds, or compositions described herein. The kit may use any of the combinations, compounds, or compositions disclosed herein. In some embodiments, the kit uses the BCR:ABL1 inhibitors described herein (e.g., compounds of formula (I), (Ii), (IA), (IA-1), (IIA), (IIB), (IIE), or (Id), such as compound A, or pharmaceutically acceptable salts thereof) and tyrosine kinase inhibitors (e.g., imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib). The kit may be used for any one or more of the uses described herein and therefore may contain instructions for the treatment described herein.

[0255] The kit typically includes appropriate packaging. The kit may include one or more containers containing any combination described herein and any compound described herein or a pharmaceutically acceptable salt thereof. Each component may be packaged in a separate container, or some components may be combined in a single container where cross-reactivity and shelf life are acceptable. In some embodiments, the kit includes a container containing a BCR:ABL1 inhibitor (e.g., a compound of formula (I), (Ii), (IA), (IA-1), (IIA), (IIB), (IIE), or (Id), such as compound A, or a pharmaceutically acceptable salt thereof) and a tyrosine kinase inhibitor (e.g., imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib). In other embodiments, the kit comprises a first container containing a BCR:ABL1 inhibitor (e.g., a compound of formula (I), (Ii), (IA), (IA-1), (IIA), (IIB), (IIE), or (Id), such as compound A, or a pharmaceutically acceptable salt thereof) and a second container containing a tyrosine kinase inhibitor (e.g., imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib).

[0256] The kit may be in unit dosage forms, bulk packages (e.g., multi-dose packages), or subunit doses. For example, a kit may be provided containing sufficient doses of the compounds disclosed herein and / or additional pharmaceutically active compounds useful for the diseases detailed herein, to provide effective treatment of a patient over a long period, such as one week, two weeks, three weeks, four weeks, six weeks, eight weeks, three months, four months, five months, seven months, eight months, nine months, or longer. The kit may also contain multiple unit doses of the compounds and instructions for use, and may be packaged in quantities sufficient for storage and use in a pharmacy (e.g., hospital pharmacies and compounding pharmacies).

[0257] The kit may also include an electronic storage medium (e.g., a magnetic diskette or optical disc) containing instructions relating to the use of the component(s) of the method of this disclosure, but may optionally include a set of instructions, generally in writing. The instructions included in the kit generally include information about the components and their administration to an individual.

[0258] The kit may be used for any one or more of the uses described herein, and therefore may include instructions for the treatment of any disease, or, for example, instructions for the treatment of cancer, as described herein.

[0259] Exemplary Embodiments P-1. A method for treating cancer in a subject requiring treatment, comprising administering a BCR:ABL1 inhibitor in combination with a tyrosine kinase inhibitor, wherein the BCR:ABL1 inhibitor is a compound of formula (I). [ka] or its tautomer or N-oxide, or a pharmaceutically acceptable salt of any of the foregoing, L is -NH-CO-, -CO-NH-, -NH-SO2-, or -SO2-NH-, R 1 However, C6~C were replaced by arbitrary selection. 10Aryls, optionally substituted 5-10 member heteroaryls, optionally substituted 4-10 member heterocycles, C(O)NR 6 R 7 , S(O)2NR 6 R 7 , NR 6 COR 7 , NR 6 SO2R 7 , or C(O)OR 6 And, R 2 However, H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 member heterocycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C6-C 10 An aryl, or a 5-10 member heteroaryl that has been optionally substituted, R 3 However, H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, OR 6 , or NR 6 R 7 And, Or R 2 and R 3 However, together with the intervening atom, it forms an optionally substituted C3-C8 cycloalkyl or an optionally substituted 4-10 member heterocycloalkyl. R 4 However, these are optionally substituted C1-C6 alkyl groups, optionally substituted C2-C6 alkenyl groups, or optionally substituted C2-C6 alkynyl groups. X is either O or S, Y is CH, C-(C1-C2 alkyl), C-halo, or N. Z, CR 5 or N, R 5 However, it is H or halogen, R 6 However, H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 member heterocycloalkyl, optionally substituted C6-C 10 An aryl, or a 5-10 member heteroaryl that has been optionally substituted, R 7 However, H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 member heterocycloalkyl, optionally substituted C6-C 10 An aryl, or a 5-10 member heteroaryl that has been optionally substituted, Or R 6 and R 7 However, together with the nitrogen atoms to which they are bonded, they form optionally substituted 4- to 7-membered heterocycles. The method wherein the compound is (i) 1H-benzimidazole-7-carboxylic acid, 5-[[(4-methoxyphenyl)sulfonyl]amino]-1-methyl-, or (ii) 1H-benzimidazole-7-carboxylic acid, 5-[[(4-ethoxyphenyl)sulfonyl]amino]-1-methyl-.

[0260] P-2.BCR:ABL1 inhibitors are compounds of formula (IA-1) [ka] The method of Embodiment P-1, or a pharmaceutically acceptable salt thereof.

[0261] P-3.BCR:ABL1 inhibitor is (R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-1-(1-hydroxypropan-2-yl)-7-(pyrimidine-5-yl)-1H-benzo[d]imidazole-5-carboxamide (compound A) [ka] or a pharmaceutically acceptable salt thereof, which, in combination with a tyrosine kinase inhibitor, is used to do so in subjects requiring treatment for cancer, according to one of the prior embodiments.

[0262] P-4. Any one of the prior embodiments, wherein the tyrosine kinase inhibitor is selected from imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib.

[0263] P-5. A method of any one of the prior embodiments in which the cancer is lymphoma or leukemia.

[0264] P-6. A method for inhibiting the tyrosine kinase enzyme activity of a protein selected from the group consisting of Avelson protein (ABL1), Avelson-associated protein (ABL2), and the chimeric protein BCR-ABL1, wherein an effective amount of compound A [ka] A method comprising contacting a protein with a pharmaceutically acceptable salt thereof in combination with an effective amount of an acyrosine kinase inhibitor.

[0265] P-7. A method for treating a disease, wherein the method prevents, inhibits, or improves the disease state and / or symptoms of a patient by regulating BCR-ABL1 activity, and the method provides the patient with a therapeutically effective amount of compound A [ka] A method comprising administering a pharmaceutically acceptable salt thereof in combination with a therapeutically effective dose of a tyrosine kinase inhibitor.

[0266] P-8. A method for treating leukemia in a patient, wherein the patient is given a therapeutically effective amount of compound A [ka] A method comprising administering a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of a tyrosine kinase inhibitor, wherein the leukemia is chronic myeloid leukemia (CML), acute myeloid leukemia (AML), or acute lymphoblastic leukemia (ALL).

[0267] P-9. Any one of the methods of the prior embodiments, wherein the method comprises administering compound A and a tyrosine kinase inhibitor selected from imatinib, nilotinib, dasatinib, bosutinib, ponatinib and bafetinib in a ratio of about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 2:1, about 2:3, about 2:5, about 3:1, about 3:2, about 3:4, about 3:5, about 4:1, about 4:3, or about 4:5.

[0268] P-10. Use of compound A or a pharmaceutically acceptable salt thereof in combination with a tyrosine kinase inhibitor to prepare a drug for doing so in subjects requiring the treatment of cancer.

[0269] P-11. A combination comprising a BCR:ABL1 inhibitor, a tyrosine kinase inhibitor, and at least one pharmaceutically acceptable excipient, wherein the BCR:ABL1 inhibitor is a compound of formula (I). [ka] or its tautomer or N-oxide, or a pharmaceutically acceptable salt of any of the foregoing, L is -NH-CO-, -CO-NH-, -NH-SO2-, or -SO2-NH-, R 1 However, C6~C were replaced by arbitrary selection. 10 Aryls, optionally substituted 5-10 member heteroaryls, optionally substituted 4-10 member heterocycles, C(O)NR 6 R 7 , S(O)2NR 6 R 7 , NR 6 COR 7 , NR 6 SO2R 7 , or C(O)OR6 And, R 2 However, H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 member heterocycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C6-C 10 An aryl, or a 5-10 member heteroaryl that has been optionally substituted, R 3 However, H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, OR 6 , or NR 6 R 7 And, Or R 2 and R 3 However, together with the intervening atom, it forms an optionally substituted C3-C8 cycloalkyl or an optionally substituted 4-10 member heterocycloalkyl. R 4 However, these are optionally substituted C1-C6 alkyl groups, optionally substituted C2-C6 alkenyl groups, or optionally substituted C2-C6 alkynyl groups. X is either O or S, Y is CH, C-(C1-C2 alkyl), C-halo, or N. Z, CR 5 or N, R 5 However, it is H or halogen, R 6 However, H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 member heterocycloalkyl, optionally substituted C6-C 10 An aryl, or a 5-10 member heteroaryl that has been optionally substituted, R 7However, H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 member heterocycloalkyl, optionally substituted C6-C 10 An aryl, or a 5-10 member heteroaryl that has been optionally substituted, Or R 6 and R 7 However, together with the nitrogen atoms to which they are bonded, they form optionally substituted 4- to 7-membered heterocycles. However, if the compound is (i) 1H-benzimidazole-7-carboxylic acid, 5-[[(4-methoxyphenyl)sulfonyl]amino]-1-methyl-, or (ii) 1H-benzimidazole-7-carboxylic acid, 5-[[(4-ethoxyphenyl)sulfonyl]amino]-1-methyl-, combination.

[0270] P-12. The combination of Embodiment P-11, wherein the combination is used to treat a patient's leukemia and comprises administering to the patient a therapeutically effective dose of a BCR:ABL1 inhibitor and a therapeutically effective dose of a tyrosine kinase inhibitor, wherein the leukemia is chronic myeloid leukemia (CML), acute myeloid leukemia (AML), or acute lymphoblastic leukemia (ALL).

[0271] P-13. A combination for use according to Embodiment P-12, wherein the leukemia is CML or ALL, and the tyrosine kinase inhibitor is selected from the group consisting of imatinib, nilotinib, dasatinib, flumatinib, bosutinib, ponatinib, and bafetinib.

[0272] P-14. A combination for use in any one of the prior embodiments in which CML is resistant to standard treatment.

[0273] P-15. A combination for use in any one of the prior embodiments in which CML is resistant to treatment with one or more of imatinib, ponatinib, nilotinib, and dasatinib.

[0274] P-16.AML is a combination for use according to any one of the prior embodiments, wherein AML is secondary AML that develops after myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN). [Examples]

[0275] Example 1 - Efficacy, selectivity, and capabilities of compound A acting synergistically with the active site TKI. background Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by a reciprocal translocation between chromosome 9 and chromosome 22, leading to loss of myristoyl-directed autoregulation and constitutive activation of the BCR::ABL1 oncoprotein (Figure 1).

[0276] Compound A is BCR::ABL1 T315I It retains activity against resistance mutations, thereby conferring resistance to all approved active-site inhibitors except ponatinib.

[0277] the purpose Tyrosine kinase inhibitors (TKIs) that target the ATP binding site of the BCR::ABL1 oncoprotein are an effective treatment for chronic myeloid leukemia (CML), but patients often develop drug resistance due to ATP site mutations that inhibit drug binding. Compound A acts allosterically to specifically target the ABL myristoyl pocket (STAMP) of BCR::ABL1, resulting in its inhibition. Compound A is designed to circumvent resistance due to active site mutations and may be synergistically combined with active site TKIs.

[0278] method The ABL1 kinase domain (amino acid residues 64-515) was expressed and purified from SH9 cells by affinity chromatography. Its activity was validated using a microfluidic mobility shift assay.

[0279] The effects of compound A on BCR::ABL1 and other kinases were evaluated using substrate phosphorylation assays. The ability of compound A to inhibit the proliferation of wild-type and mutant CML cell lines was assessed using CellTiter-Glo® or ATPlite 1Step® (PerkinElmer) solution. Synergistic effects between compound A and active-site TKIs were evaluated using both fixed-molar and extended-molar combination matrices, cell viability was measured using CellTiter-Glo®, and interactions were quantified using Bliss, HSA, and Loewe models.

[0280] result Regarding selectivity, in an in vitro kinase panel, compound A did not inhibit any kinase, including full-length ABL1, by more than 50% at 1 μM. Compound A was highly potent and selective only against BCR::ABL1+ cell lines in a cancer cell line panel, and was more selective than aciminib (Figure 2). In vitro combination studies revealed that compound A acted synergistically with multiple TKIs in K562 and BaF3BCR-ABL-T315I cell lines, and at least additively in Ku812 cell lines (Figures 3-6B and Tables 1-4). When evaluated using the BLISS model, the IC50 of each single compound was... 50 The synergistic effect was strongest in the following cases.

[0281] [Table 1] [Table 2] [Table 3-1] [Table 3-2] [Table 4-1] [Table 4-2]

[0282] conclusion Compound A is a potent and selective allosteric inhibitor of BCR::ABL1 in cell-free and cell-based assays and screenings, potentially exhibiting a similar potency and synergistic profile to aciminib, but with greater selectivity. Compound A retains activity against the T315I gatekeeper mutation, thereby conferring resistance to all approved active-site TKIs except ponatinib.

[0283] This study demonstrated that compound A, an allosteric inhibitor of BCR::ABL1, is potent against mutations resistant to active-site tyrosine kinase inhibitors (TKIs) and acts synergistically with TKIs in BCR::ABL1+ cancer cell lines.

[0284] Example 2: Determination of the efficacy of compound A (ABT4) alone and in combination with dasatinib (ABT6) and ponatinib (ABT7) in BALB / c nude female mice with CML. Example 2 describes an in vivo study demonstrating that compound A, when combined with ponatinib, shows a dose-dependent reduction in tumor volume in the BCR::ABL1-T315I CML model. The results are summarized in Figures 7 and 8.

[0285] procedure 2x10 0% Matrigel sc on the flank 6 We set up CR 245 female BALB / c nude mice containing BaF3-T315I tumor cells. The cell injection volume is 0.1 mL / mouse. Age at start date: 7-10 weeks. Tumors average size 60-90 mm 3 When the condition is met, a pair match is performed and treatment begins. Weight: qdx5, then biwk until the end Caliper measurement: biwk to the end

[0286] All individuals that experienced a weight loss of more than 30% on a single occasion, or that experienced a weight loss of more than 25% on three consecutive occasions, were euthanized.

[0287] In groups where the average weight loss exceeded 20% or the mortality rate exceeded 10%, administration was discontinued. These groups were not euthanized and were allowed to recover. Within the group where weight loss exceeded 20%, individuals that reached their individual weight loss endpoint were euthanized.

[0288] If weight loss associated with group therapy recovered to within 10% of the original body weight, treatment was resumed at a lower dose or less frequent schedule. Exceptions to the recovery of the percentage of untreated body weight were permitted on a case-by-case basis.

[0289] Endpoint. Animals were monitored as a group. The experimental endpoint was when the mean tumor weight of the control group reached 2000 mm. 3 The endpoint was 15 days, whichever came first. Once the endpoint was reached, all animals were euthanized.

[0290] The animal groups were administered the compounds described below. [Table 5-1] [Table 5-2] ABT6 is a co-formulated drug - see below for dosage information. [Table 6]

[0291] Example 3: Screening of compound A against BCR:ABL1 mutants Cell proliferation assay of an expanded panel of BCR-ABL1 monomutant and compound mutant cell lines Compound A is screened against Ba / F3 cell lines expressing wild-type BCR-ABL1 (either pSRalpha or pMIG expression vector) or a panel of single or combined BCR-ABL1 mutants. BCR-ABL1 single mutants include a clinically relevant set of kinase domain mutations, as well as selected mutations in the myristoylation pocket that confer resistance to aciminib. The BCR-ABL1 compound mutants screened include both T315I-containing and non-T315I-containing compound mutants. Parental Ba / F3 cells are also tested as an on-target selectivity control. Briefly, Ba / F3 BCR-ABL1 cell lines are resuspended in fresh medium (containing 10% FBS) and plated in 384-well plates in the presence of stepwise concentrations of compound A. Plates are cultured for 3 days and subjected to an MTS-based colorimetric viability assay. Absorbance data are blanked and normalized to an untreated control, and the IC of cells is measured. 50 A nonlinear regression model is fitted for the calculation of the values.

[0292] In vitro drug synergy assay of mutant BCR-ABL1 cell lines For Ba / F3 cells expressing BCR-ABL1 wild-type, T315I, or a subset of compound mutants, compound A is evaluated using the same cell proliferation assay as described above, but in combination with approved ATP site inhibitors imatinib, dasatinib, or ponatinib to determine potential synergistic inhibition. Cells are tested against each inhibitor alone and against dose matrices of all possible dose combinations. Normalized MTS absorbance data are further analyzed using the synergyfinder R package to quantify potential synergies across multiple models (e.g., highest monotherapy (HSA), Bliss, zero interaction potency (ZIP)). Similar dose matrices are tested in Ba / F3 parental cells to confirm combined off-target toxicity.

[0293] Cell-based accelerated resistance screening Compound A is profiled using in vitro cell-based mutagenesis screening. Briefly, Ba / F3 BCR-ABL1 cells are treated overnight with ENU (to induce random mutations), resuspended in fresh medium, and plated in the presence of stepwise concentrations of the inhibitor. The grown wells are expanded and harvested, and DNA isolation and PCR amplification of the BCR-ABL1 kinase domain (approximately ABL1a residues 235-530) are performed, and Sanger sequencing is determined for the mutations. A similar mutagenesis resistance screening is performed, starting with Ba / F3 cells expressing BCR-ABL1 T315I, to identify potential compound mutant resistance mechanisms, and also in combination with ponatinib to determine the potential for inhibiting the growth of compound mutants.

[0294] Primary CML patient cell ex vivo assay Primary mononuclear cells from 3-4 newly diagnosed or T315I-resistant CML patients were thawed and treated with a constant concentration of compound A overnight or for 3 days. Imatinib treatment was included as a control. Overnight-treated cells were lysed and subjected to immunoblotting analysis at the pCRKL level, while 3-day-treated cells were analyzed for viability and / or impact on annexin V apoptosis induction.

[0295] Example 4: Characterization of compound A against native and mutant BCR:ABL-1 Studies will be conducted to determine the in vitro activity of compound A alone and in combination with dasatinib or ponatinib. These studies will include native BCR::ABL1, BCR::ABL1 single mutant mutants (F359V, F359C, F359I, H396R, E255V, T315I, A337V, A344P, P465S, ​​V468F), and BCR::ABL1 compound mutants (G250E / T315I, Y253H / T315I, E255V / T315I). Cells (H396R / T315I, E255V / V299L, T315M, Y253H / F317L, A337V / T315I, A344P / T315I, P465S / T315I, V468F / T315I) are cultured in the presence of compound A and dasatinib, or compound A and ponatinib, in a stepwise concentration range (4-log range starting from 0.1 nM). The assay is performed three times, and viable cells are quantified by the MTS assay. Synergy is analyzed using the Combinef and Synergy Finder platform, an interactive platform capable of collecting all experimental replicated samples. Synergy scores are determined using the Bliss and ZIP reference models. Data are reported in tables and graphs.

[0296] The activity of compound A alone and in combination with dasatinib or ponatinib on BCR::ABL1 signaling is measured. pSTAT5 / STAT5 is quantified by immunoblotting in BaF / 3 cells expressing native or mutant BCR::ABL1 treated with the inhibitors, using stable concentrations of compound A and the 4-log range of dasatinib and ponatinib, respectively. Data are reported as immunoblotting images, FACS histograms, and graphs.

[0297] The in vivo activity of compound A alone or in combination with dasatinib or ponatinib in a retroviral transduction / transplantation model of CML will be evaluated using native and E255V / T315I mutant BCR::ABL1. BCR::ABL1-GFP retrovirus will be introduced into the bone marrow of 5-fluorouracil-treated Balb / c mice, and the cells will be injected into syngeneic recipients irradiated with a lethal dose of radiation. Once leukemic engraftment (GFP+ cells detected in the blood by FACS) is demonstrated, mice (N=10 / group) will be initiated with compound A, dasatinib, ponatinib, compound A + dasatinib, compound A + ponatinib, or the vehicle. Mice will be monitored daily by examination and weight measurement, weekly complete blood count, and FACS+ for GFP+ blood cells. Mice were sacrificed at the onset of pain or 6 weeks later (end of treatment, EOT), and detailed dissection, histology of the affected organs, and quantification of leukemia burden by flow cytometry were performed. The treatment groups were compared for survival rates using Kaplan-Meyer statistics, and differences in continuing variables were compared by t-tests.

Claims

1. A method for treating cancer in a patient requiring treatment, comprising administering a BCR:ABL1 inhibitor in combination with a second tyrosine kinase inhibitor (TKI), wherein the BCR:ABL1 inhibitor is a compound of formula (I). 【Chemistry 1】 or its tautomer or N-oxide, or a pharmaceutically acceptable salt of any of the foregoing, in the formula, L is -NH-CO-, -CO-NH-, -NH-SO ２ -, or -SO ２ -NH-, R １ is optionally substituted C ６ -C １０ aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 membered heterocycle, C(O)NR ６ R ７ , S(O) ２ NR ６ R ７ , NR ６ COR ７ , NR ６ SO ２ R ７ , or C(O)OR ６ , and R ２ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl, optionally substituted C ３ ~C ８ Cycloalkyl groups, optionally substituted 4- to 10-membered heterocycloalkyl groups, optionally substituted C ２ ~C ６ Alkenyl, C substituted by choice ２ ~C ６ Alkinyl, optionally replaced with C ６ ~C １０ An aryl, or a 5- to 10-membered heteroaryl that is optionally substituted, R ３ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl, optionally substituted C ２ ~C ６ Alkenyl, C substituted by choice ２ ~C ６ Alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, OR ６ , or NR ６ R ７ And, Or R ２ and R ３ However, together with the intervening atom, C is optionally substituted. ３ ~C ８ Forming cycloalkyl or optionally substituted 4- to 10-membered heterocycloalkyl groups, R ４ However, C was replaced by an arbitrary choice. １ ~C ６ Alkyl, optionally substituted C ２ ~C ６ Alkenils, or C as optionally replaced. ２ ~C ６ It is alkinyl, X is either O or S, Y is CH, C-(C １ ~C ２ Alkyl, or C-halo or N, Z is CR ５ or N, R ５ However, it is H or halogen, R ６ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl, optionally substituted C ３ ~C ８ Cycloalkyl groups, optionally substituted 4- to 10-membered heterocycloalkyl groups, optionally substituted C ６ ~C １０ An aryl, or a 5- to 10-membered heteroaryl that is optionally substituted, R ７ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl, optionally substituted C ３ ~C ８ Cycloalkyl groups, optionally substituted 4- to 10-membered heterocycloalkyl groups, optionally substituted C ６ ~C １０ An aryl, or a 5- to 10-membered heteroaryl that is optionally substituted, Or R ６ and R ７ However, together with the nitrogen atoms to which they are bonded, they form optionally substituted 4- to 7-membered heterocycles. The method, wherein the compound is other than (i) 1H-benzimidazole-7-carboxylic acid, 5-[[(4-methoxyphenyl)sulfonyl]amino]-1-methyl-, or (ii) 1H-benzimidazole-7-carboxylic acid, 5-[[(4-ethoxyphenyl)sulfonyl]amino]-1-methyl-.

2. A method for inhibiting the tyrosine kinase enzyme activity of BCR:ABL1, wherein an effective amount of a BCR:ABL-1 inhibitor of formula (I) is used. 【Chemistry 2】 The formula comprises contacting a protein with an effective amount of a tyrosine kinase inhibitor, or a tautomer thereof or an N-oxide, or a pharmaceutically acceptable salt of any of the foregoing, wherein, L is -NH-CO-, -CO-NH-, -NH-SO ２ -, or -SO ２ -NH-, R １ However, C was replaced by an arbitrary choice. ６ ~C １０ Aryl, optionally substituted 5- to 10-membered heteroaryls, optionally substituted 4- to 10-membered heterocycles, C(O)NR ６ R ７ , S(O) ２ NR ６ R ７ , NR ６ COR ７ , NR ６ SO ２ R ７ , or C(O)OR ６ And, R ２ is H, optionally substituted C １ -C ６ alkyl, optionally substituted C ３ -C ８ cycloalkyl, optionally substituted 4- to 10-membered heterocycloalkyl, optionally substituted C ２ -C ６ alkenyl, optionally substituted C ２ -C ６ alkynyl, optionally substituted C ６ -C １０ aryl, or optionally substituted 5- to 10-membered heteroaryl, R ３ is H, optionally substituted C １ to C ６ alkyl, optionally substituted C ２ to C ６ alkenyl, optionally substituted C ２ to C ６ alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, OR ６ , or NR ６ R ７ , and Or R ２ and R ３ However, together with the intervening atom, C is optionally substituted. ３ ~C ８ Forming cycloalkyl or optionally substituted 4- to 10-membered heterocycloalkyl groups, R ４ However, C was replaced by an arbitrary choice. １ ~C ６ Alkyl, optionally substituted C ２ ~C ６ Alkenils, or C as optionally replaced. ２ ~C ６ It is alkinyl, X is either O or S, Y is CH, C-(C １ ~C ２ Alkyl, or C-halo or N, Z is CR ５ or N, R ５ However, it is H or halogen, R ６ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl, optionally substituted C ３ ~C ８ Cycloalkyl groups, optionally substituted 4- to 10-membered heterocycloalkyl groups, optionally substituted C ６ ~C １０ An aryl, or a 5- to 10-membered heteroaryl that is optionally substituted, R ７ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl, optionally substituted C ３ ~C ８ Cycloalkyl groups, optionally substituted 4- to 10-membered heterocycloalkyl groups, optionally substituted C ６ ~C １０ An aryl, or a 5- to 10-membered heteroaryl that is optionally substituted, Or R ６ and R ７ However, together with the nitrogen atoms to which they are bonded, they form optionally substituted 4- to 7-membered heterocycles. However, the compound is other than (i) 1H-benzimidazole-7-carboxylic acid, 5-[[(4-methoxyphenyl)sulfonyl]amino]-1-methyl-, or (ii) 1H-benzimidazole-7-carboxylic acid, 5-[[(4-ethoxyphenyl)sulfonyl]amino]-1-methyl-. The aforementioned method.

3. A method for treating a disease in a subject requiring treatment, wherein the method involves preventing, inhibiting, or improving the disease state and / or symptoms of the patient by regulating BCR-ABL1 activity, and the method involves administering a therapeutically effective amount of a BCR:ABL1 inhibitor of formula (I) to the subject. 【Transformation 3】 The formula comprises administering a therapeutically effective dose of a tyrosine kinase inhibitor in combination with a pharmaceutically acceptable salt thereof, or a tautomer thereof or an N-oxide, or any of the foregoing. L is -NH-CO-, -CO-NH-, -NH-SO ２ -, or -SO ２ -NH-, R １ However, C was replaced by an arbitrary choice. ６ ~C １０ Aryl, optionally substituted 5- to 10-membered heteroaryls, optionally substituted 4- to 10-membered heterocycles, C(O)NR ６ R ７ , S(O) ２ NR ６ R ７ , NR ６ COR ７ , NR ６ SO ２ R ７ , or C(O)OR ６ And, R ２ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl, optionally substituted C ３ ~C ８ Cycloalkyl groups, optionally substituted 4- to 10-membered heterocycloalkyl groups, optionally substituted C ２ ~C ６ Alkenyl, C substituted by choice ２ ~C ６ Alkinyl, optionally replaced with C ６ ~C １０ An aryl, or a 5- to 10-membered heteroaryl that is optionally substituted, R ３ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl, optionally substituted C ２ ~C ６ Alkenyl, C substituted by choice ２ ~C ６ Alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, OR ６ , or NR ６ R ７ And, Or R ２ and R ３ However, together with the intervening atom, C is optionally substituted. ３ ~C ８ Forming cycloalkyl or optionally substituted 4- to 10-membered heterocycloalkyl groups, R ４ However, C was replaced by an arbitrary choice. １ ~C ６ Alkyl, optionally substituted C ２ ~C ６ Alkenils, or C as optionally replaced. ２ ~C ６ It is alkinyl, X is either O or S, Y is CH, C-(C １ ~C ２ Alkyl, or C-halo or N, Z is CR ５ or N, R ５ However, it is H or halogen, R ６ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl, optionally substituted C ３ ~C ８ Cycloalkyl groups, optionally substituted 4- to 10-membered heterocycloalkyl groups, optionally substituted C ６ ~C １０ An aryl, or a 5- to 10-membered heteroaryl that is optionally substituted, R ７ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl, optionally substituted C ３ ~C ８ Cycloalkyl groups, optionally substituted 4- to 10-membered heterocycloalkyl groups, optionally substituted C ６ ~C １０ An aryl, or a 5- to 10-membered heteroaryl that is optionally substituted, Or R ６ and R ７ However, together with the nitrogen atoms to which they are bonded, they form optionally substituted 4- to 7-membered heterocycles. However, the compound is other than (i) 1H-benzimidazole-7-carboxylic acid, 5-[[(4-methoxyphenyl)sulfonyl]amino]-1-methyl-, or (ii) 1H-benzimidazole-7-carboxylic acid, 5-[[(4-ethoxyphenyl)sulfonyl]amino]-1-methyl-. The aforementioned method.

4. A method for treating leukemia in patients requiring treatment, wherein the therapeutic dose is of formula (I) BCR:ABL-1 inhibitor 【Chemistry 4】 The formula comprises administering to the patient a therapeutically effective dose of a tautomer thereof, an N-oxide, or a pharmaceutically acceptable salt of any of the foregoing in combination with a second tyrosine kinase inhibitor, wherein, L is -NH-CO-, -CO-NH-, -NH-SO ２ -, or -SO ２ -NH-, R １ However, C was replaced by an arbitrary choice. ６ ~C １０ Aryl, optionally substituted 5- to 10-membered heteroaryls, optionally substituted 4- to 10-membered heterocycles, C(O)NR ６ R ７ , S(O) ２ NR ６ R ７ , NR ６ COR ７ , NR ６ SO ２ R ７ , or C(O)OR ６ And, R ２ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl, optionally substituted C ３ ~C ８ Cycloalkyl groups, optionally substituted 4- to 10-membered heterocycloalkyl groups, optionally substituted C ２ ~C ６ Alkenyl, C substituted by choice ２ ~C ６ Alkinyl, optionally replaced with C ６ ~C １０ An aryl, or a 5- to 10-membered heteroaryl that is optionally substituted, R ３ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl, optionally substituted C ２ ~C ６ Alkenyl, C substituted by choice ２ ~C ６ Alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, OR ６ , or NR ６ R ７ And, Or R ２ and R ３ However, together with the intervening atom, C is optionally substituted. ３ ~C ８ Forming cycloalkyl or optionally substituted 4- to 10-membered heterocycloalkyl groups, R ４ However, C was replaced by an arbitrary choice. １ ~C ６ Alkyl, optionally substituted C ２ ~C ６ Alkenils, or C as optionally replaced. ２ ~C ６ It is alkinyl, X is either O or S, Y is CH, C-(C １ ~C ２ Alkyl, or C-halo or N, Z is CR ５ or N, R ５ However, it is H or halogen, R ６ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl, optionally substituted C ３ ~C ８ Cycloalkyl groups, optionally substituted 4- to 10-membered heterocycloalkyl groups, optionally substituted C ６ ~C １０ An aryl, or a 5- to 10-membered heteroaryl that is optionally substituted, R ７ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl, optionally substituted C ３ ~C ８ Cycloalkyl groups, optionally substituted 4- to 10-membered heterocycloalkyl groups, optionally substituted C ６ ~C １０ An aryl, or a 5- to 10-membered heteroaryl that is optionally substituted, Or R ６ and R ７ However, together with the nitrogen atoms to which they are bonded, they form optionally substituted 4- to 7-membered heterocycles. However, the compound is other than (i) 1H-benzimidazole-7-carboxylic acid, 5-[[(4-methoxyphenyl)sulfonyl]amino]-1-methyl-, or (ii) 1H-benzimidazole-7-carboxylic acid, 5-[[(4-ethoxyphenyl)sulfonyl]amino]-1-methyl-, The method wherein the leukemia is chronic myeloid leukemia (CML), acute myeloid leukemia (AML), or acute lymphoblastic leukemia (ALL).

5. Compound (I) for preparing a drug to be used in combination with a tyrosine kinase inhibitor to treat cancer in patients requiring such treatment. 【Transformation 5】 or the use of a tautomer thereof or an N-oxide, or a pharmaceutically acceptable salt of any of the foregoing, in the formula, L is -NH-CO-, -CO-NH-, -NH-SO ２ -, or -SO ２ -NH-, R １ However, C was replaced by an arbitrary choice. ６ ~C １０ Aryl, optionally substituted 5- to 10-membered heteroaryls, optionally substituted 4- to 10-membered heterocycles, C(O)NR ６ R ７ , S(O) ２ NR ６ R ７ , NR ６ COR ７ , NR ６ SO ２ R ７ , or C(O)OR ６ And, R ２ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl, optionally substituted C ３ ~C ８ Cycloalkyl groups, optionally substituted 4- to 10-membered heterocycloalkyl groups, optionally substituted C ２ ~C ６ Alkenyl, C substituted by choice ２ ~C ６ Alkinyl, optionally replaced with C ６ ~C １０ An aryl, or a 5- to 10-membered heteroaryl that is optionally substituted, R ３ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl, optionally substituted C ２ ~C ６ Alkenyl, C substituted by choice ２ ~C ６ Alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, OR ６ , or NR ６ R ７ And, Or R ２ and R ３ However, together with the intervening atom, C is optionally substituted. ３ ~C ８ Forming cycloalkyl or optionally substituted 4- to 10-membered heterocycloalkyl groups, R ４ However, C was replaced by an arbitrary choice. １ ~C ６ Alkyl, optionally substituted C ２ ~C ６ Alkenils, or C as optionally replaced. ２ ~C ６ It is alkinyl, X is either O or S, Y is CH, C-(C １ ~C ２ Alkyl, or C-halo or N, Z is CR ５ or N, R ５ However, it is H or halogen, R ６ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl, optionally substituted C ３ ~C ８ Cycloalkyl groups, optionally substituted 4- to 10-membered heterocycloalkyl groups, optionally substituted C ６ ~C １０ An aryl, or a 5- to 10-membered heteroaryl that is optionally substituted, R ７ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl, optionally substituted C ３ ~C ８ Cycloalkyl groups, optionally substituted 4- to 10-membered heterocycloalkyl groups, optionally substituted C ６ ~C １０ An aryl, or a 5- to 10-membered heteroaryl that is optionally substituted, Or R ６ and R ７ However, together with the nitrogen atoms to which they are bonded, they form optionally substituted 4- to 7-membered heterocycles. However, the compound is other than (i) 1H-benzimidazole-7-carboxylic acid, 5-[[(4-methoxyphenyl)sulfonyl]amino]-1-methyl-, or (ii) 1H-benzimidazole-7-carboxylic acid, 5-[[(4-ethoxyphenyl)sulfonyl]amino]-1-methyl-. The aforementioned use.

6. The method according to any one of the prior claims, wherein the method comprises administering the BCR:ABL1 inhibitor of formula (I) and the second TKI to the subject in a ratio of about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 2:1, about 2:3, about 2:5, about 3:1, about 3:2, about 3:4, about 3:5, about 4:1, about 4:3, or about 4:

5.

7. The BCR:ABL1 inhibitor of formula (I) is (R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-1-(1-hydroxypropan-2-yl)-7-(pyrimidine-5-yl)-1H-benzo[d]imidazole-5-carboxamide (compound A) 【Transformation 6】 The method according to any one of the prior claims, or a pharmaceutically acceptable salt thereof.

8. The method according to any one of the prior claims, wherein the subject has been previously treated with aciminib.

9. The method according to any one of the prior claims, wherein the subject has previously been treated with a combination of aciminib and a second TKI.

10. The method according to any one of the prior claims, wherein the second TKI binds to the active site of BCR:ABL-1.

11. The method according to any one of the prior claims, wherein the second TKI is selected from imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib.

12. The method according to any one of the prior claims, wherein the second TKI is selected from ponatinib and dasatinib.

13. The method according to any one of the prior claims, wherein the cancer is lymphoma or leukemia.

14. The method according to any one of the prior claims, wherein the lymphoma or leukemia is chronic myeloid leukemia (CML) or chronic lymphocytic leukemia (CLL).

15. The method described above is The steps of determining the DNA sequence of the BCR:ABL1 gene expressed by the subject, and / or The step of determining the amino acid sequence of the BCR:ABL1 protein expressed by the subject. The method according to any one of the prior claims, further comprising:

16. The method according to any one of the prior claims, wherein the subject expresses wild-type BCR:ABL-1.

17. The method according to any one of the prior claims, wherein the wild-type form of BCR:ABL-1 has the amino acid sequence of SEQ ID NO:

1.

18. The method according to any one of the prior claims, wherein the subject expresses a variant form of BCR:ABL-1.

19. The method according to any one of the prior claims, wherein the variant form of BCR:ABL-1 comprises a single amino acid mutation selected from F359V, F359C, F359I, H396R, E255V, T315I, A337V, A344P, P465S, ​​T315M, and V468F.

20. The method according to any one of the prior claims, wherein the variant form of BCR:ABL-1 comprises a plurality of amino acid mutations selected from (i) G250E and T315I, (ii) Y253H and T315I, (iii) E255V and T315I, (iv) H396R and T315I, (v) E255V and V299L, (vi) Y253H and F317L, (vii) A337V and T315I, (viiii) A344P and T315I, (ix) P465S and T315I, and (x) V468F and T315I.

21. The method according to any one of the prior claims, wherein the variant form of BCR:ABL-1 has one amino acid sequence from SEQ ID NOs: 2 to 22.

22. A combination comprising a BCR:ABL1 inhibitor, a tyrosine kinase inhibitor, and at least one pharmaceutically acceptable excipient, wherein the BCR:ABL1 inhibitor is a compound of formula (I). 【Transformation 7】 or its tautomer or N-oxide, or a pharmaceutically acceptable salt of any of the foregoing, in the formula, L is -NH-CO-, -CO-NH-, -NH-SO ２ -, or -SO ２ -NH-, R １ However, C was replaced by an arbitrary choice. ６ ~C １０ Aryl, optionally substituted 5- to 10-membered heteroaryls, optionally substituted 4- to 10-membered heterocycles, C(O)NR ６ R ７ , S(O) ２ NR ６ R ７ , NR ６ COR ７ , NR ６ SO ２ R ７ , or C(O)OR ６ And, R ２ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl, optionally substituted C ３ ~C ８ Cycloalkyl groups, optionally substituted 4- to 10-membered heterocycloalkyl groups, optionally substituted C ２ ~C ６ Alkenyl, C substituted by choice ２ ~C ６ Alkinyl, optionally replaced with C ６ ~C １０ An aryl, or a 5- to 10-membered heteroaryl that is optionally substituted, R ３ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl, optionally substituted C ２ ~C ６ Alkenyl, C substituted by choice ２ ~C ６ Alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, OR ６ , or NR ６ R ７ And, Or R ２ and R ３ However, together with the intervening atom, C is optionally substituted. ３ ~C ８ Forming cycloalkyl or optionally substituted 4- to 10-membered heterocycloalkyl groups, R ４ However, C was replaced by an arbitrary choice. １ ~C ６ Alkyl, optionally substituted C ２ ~C ６ Alkenils, or C as optionally replaced. ２ ~C ６ It is alkinyl, X is either O or S, Y is CH, C-(C １ ~C ２ Alkyl, or C-halo or N, Z is CR ５ or N, R ５ However, it is H or halogen, R ６ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl, optionally substituted C ３ ~C ８ Cycloalkyl groups, optionally substituted 4- to 10-membered heterocycloalkyl groups, optionally substituted C ６ ~C １０ An aryl, or a 5- to 10-membered heteroaryl that is optionally substituted, R ７ However, H is replaced by C by arbitrary choice. １ ~C ６ Alkyl, optionally substituted C ３ ~C ８ Cycloalkyl groups, optionally substituted 4- to 10-membered heterocycloalkyl groups, optionally substituted C ６ ~C １０ An aryl, or a 5- to 10-membered heteroaryl that is optionally substituted, Or R ６ and R ７ However, together with the nitrogen atoms to which they are bonded, they form optionally substituted 4- to 7-membered heterocycles. However, the compound is other than (i) 1H-benzimidazole-7-carboxylic acid, 5-[[(4-methoxyphenyl)sulfonyl]amino]-1-methyl-, or (ii) 1H-benzimidazole-7-carboxylic acid, 5-[[(4-ethoxyphenyl)sulfonyl]amino]-1-methyl-. The aforementioned combination.

23. The combination according to claim 21, wherein the combination is used to treat a patient's leukemia, and the treatment comprises administering to the patient a therapeutically effective amount of the BCR:ABL1 inhibitor and a therapeutically effective amount of the tyrosine kinase inhibitor, wherein the leukemia is chronic myeloid leukemia (CML), acute myeloid leukemia (AML), or acute lymphoblastic leukemia (ALL).

24. The combination for use according to claim 22, wherein the leukemia is CML or ALL, and the tyrosine kinase inhibitor is selected from the group consisting of imatinib, nilotinib, dasatinib, flumatinib, bosutinib, ponatinib, and bafetinib.

25. The combination for use according to any one of the prior claims, wherein the CML is resistant to standard treatment.

26. The combination for use according to any one of the prior claims, wherein the CML is resistant to treatment with one or more of imatinib, ponatinib, nilotinib, and dasatinib.

27. The combination for use according to any one of the prior claims, wherein the AML is a secondary AML that develops after myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN).

28. A method or combination for use according to any one of the prior claims, wherein the subject has previously been treated with at least one tyrosine kinase inhibitor.

29. A method or combination for use according to any one of the prior claims, wherein the subject has previously been treated with at least two tyrosine kinase inhibitors.

30. A method or combination for use according to any one of the prior claims, wherein the subject has previously been treated with at least one allosteric tyrosine kinase inhibitor.

31. A method or combination for use according to any one of the prior claims, wherein the subject has relapsed after prior treatment.

32. A method or combination for use according to any one of the prior claims, wherein the subject was refractory to previous treatment.

33. A method or combination for use according to any one of the prior claims, wherein the subject has relapsed and is refractory to previous treatment.

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