Combinations comprising BCR: ABL-1 inhibitor and second tyrosine kinase inhibitor for treatment of cancer

Abstract

Provided herein are combinations for inhibiting tyrosine kinase activity of a protein selected from the group consisting of an Abelson protein (ABL1), an Abelson-associated protein (ABL2), or a chimeric protein BCR-ABL1, compositions thereof, methods of inhibiting tyrosine kinase enzyme activity of a protein selected from the group consisting of an Abelson protein (ABL1), an Abelson-associated protein (ABL2), or a chimeric protein BCR-ABL1, and methods for treating a disease, wherein modulation of BCR-ABL1 activity prevents, inhibits or ameliorates the pathology and / or symptoms of disease.

Description

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

[0002] Reference to electronic sequence listing The contents of the electronic sequence list (TRPH_048_001WO_SeqList_ST26.xml; size: 44,747 bytes; generated on 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 the reciprocal translocation of chromosomes 9 and 22 in bone marrow progenitor cells. This chromosome carries the BCR-ABL1 oncogene, which encodes the chimeric BCR-ABL1 protein. Drugs that inhibit the tyrosine kinase activity of BCR-ABL1 via ATP competition (e.g., Gleevec® / Glivec® (imatinib), Tasigna® (nilotinib), Iclusig® (ponatinib), and Sprycel® (dasatinib)) are effective in treating CML. However, some patients relapse due to the development of resistant clones or drug intolerance. Therefore, there is a need for alternative treatment options. Summary of the Invention

[0004] This disclosure relates to a method of treating cancer in a subject of need, the method comprising administering a combination of a BCR:ABL1 inhibitor and a tyrosine kinase inhibitor, wherein the BCR:ABL1 inhibitor is a compound of formula (I): (I) Or its tautomers or N-oxides, or pharmaceutically acceptable salts of any of the foregoing, wherein: L can be -NH-CO-, -CO-NH-, -NH-SO2-, or -SO2-NH-; R 1 C6-C as an optional substitute 10 Aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 membered heterocycle, C(O)NR 6 R 7 S(O)2NR 6 R 7 NR6 COR 7 NR 6 SO2R 7 or C(O)OR 6 ; R 2 H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocyclic alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C6-C 10 Aryl or optionally substituted 5-10 heteroaryl groups; R 3 H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, 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 intermediate atom, it can form an optionally substituted C3-C8 cycloalkyl or an optionally substituted 4-10 membered heterocyclic alkyl; R 4 It can be an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, or an optionally substituted C2-C6 alkynyl; X is either O or S; Y is CH, C-(C1-C2 alkyl), C-halogenated, or N; Z is CR 5 Or N; R 5 It is H or halogen; R 6 H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocyclic alkyl, optionally substituted C6-C 10 aryl or optionally substituted 5-10 heteroaryl groups; and R 7 H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocyclic alkyl, optionally substituted C6-C 10 Aryl or optionally substituted 5-10 heteroaryl groups; Or R 6 and R 7 Together with the nitrogen to which it is attached, it forms an optionally substituted 4-7 membered heterocycle. The condition is that the compound is not (i) 5-[[(4-methoxyphenyl)sulfonyl]amino]-1-methyl-1H-benzimidazole-7-carboxylic acid or (ii) 5-[[(4-ethoxyphenyl)sulfonyl]amino]-1-methyl-1H-benzimidazole-7-carboxylic acid.

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

[0006] This disclosure relates to the use of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-1-(1-hydroxypropyl-2-yl)-7-(pyrimidin-5-yl)-1H-benzo[d]imidazolium-5-carboxamide (compound A): (Compound A) Or a pharmaceutically acceptable salt thereof in combination with a tyrosine kinase inhibitor to treat cancer in subjects in need.

[0007] This disclosure relates to the use of compound A: (Compound A) Or a pharmaceutically acceptable salt thereof in combination with a tyrosine kinase inhibitor selected from imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib to treat cancer in subjects in need.

[0008] This disclosure also relates to a method of treating cancer in a subject in need, the method comprising administering a combination of compound A or a pharmaceutically acceptable salt thereof with a tyrosine kinase inhibitor.

[0009] This disclosure also relates to a method of treating cancer in a subject in need, the method comprising administering a combination of compound A or a pharmaceutically acceptable salt thereof with a tyrosine kinase inhibitor selected from imatinib, nilotinib, dasatinib, bosutinib, ponatinib and barfetinib.

[0010] This disclosure further relates to the use of compound A or a pharmaceutically acceptable salt thereof in combination with a tyrosine kinase inhibitor in the preparation of a medicament for treating cancer in a subject of need.

[0011] 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 imatinib, nilotinib, dasatinib, bosutinib, ponatinib and barfetinib in the preparation of a medicament for the treatment of cancer in subjects of need.

[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 a subject in need.

[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 asciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and barfetinib to treat cancer in a subject of need.

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

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

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

[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 lymphoma or leukemia in a subject in need.

[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 lymphoma or leukemia in a subject in need.

[0019] This disclosure also relates to a method of treating a subject with lymphoma or leukemia in need, the method comprising administering compound A or a pharmaceutically acceptable salt thereof in combination with a tyrosine kinase inhibitor.

[0020] This disclosure also relates to a method of treating a subject with lymphoma or leukemia, 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 barfetinib.

[0021] This disclosure further relates to the use of compound A or a pharmaceutically acceptable salt thereof in combination with a tyrosine kinase inhibitor in the preparation of a medicament for the treatment of lymphoma or leukemia in a subject in need.

[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 in the preparation of a medicament for the treatment of lymphoma or leukemia in a subject in need.

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

[0024] This disclosure further relates to a method of treating a patient’s disease, wherein modulating BCR-ABL1 activity prevents, inhibits, or improves the pathology and / or symptomology of the disease, said method comprising administering to the patient a combination of a therapeutically effective amount of compound A and a therapeutically effective amount of a tyrosine kinase inhibitor.

[0025] This disclosure further relates to a method of treating a patient with leukemia, 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 comprises administering compound A and a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and barfetinib 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.

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

[0028] In some embodiments, the combination is used to treat a patient’s leukemia, comprising administering to the patient a therapeutically effective amount of a BCR:ABL1 inhibitor and 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).

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

[0030] In some embodiments, CML is tolerated by standard care.

[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 myelodyplastic syndrome (MDS) or myeloproliferative neoplasm (MPN). Attached Figure Description

[0033] Figure 1 This is a schematic diagram illustrating the allosteric inhibition of the BCR::ABL1 oncogene.

[0034] Figure 2 This study demonstrates the potency and selectivity of compounds A and acimini against BCR::ABL1+ and BCR::ABL1- cell lines.

[0035] Figure 3 The graph shows representative cytotoxicity curves (L) for molar combinations of compound A with dasatinib (top) and ponatinib (bottom). The right graph shows IC50 values ​​for single reagents and fixed molar combinations with either dasatinib (top) or ponatinib (bottom). 75 A representative synergistic effect equivalent line plot with set values. Points below the blue additive line indicate synergistic interactions.

[0036] Figure 4A This shows a representative heatmap of K562 cells treated with compound A and dasatinib. Higher values ​​indicate a stronger synergistic effect.

[0037] Figure 4B This shows a representative thermogram of BaF3-BCR-ABL-T315I cells treated with compound A and ponatinib. Higher values ​​indicate stronger synergistic effects.

[0038] Figure 5A This shows a representative thermogram of BaF3-BCR-ABL-T315I cells treated with compound A and ponatinib. Higher values ​​indicate stronger synergistic effects.

[0039] Figure 5B This shows a representative thermogram of BaF3-BCR-ABL-T315I cells treated with compound A and dasatinib. Higher values ​​indicate a stronger synergistic effect.

[0040] Figure 6A The figure shows representative cytotoxicity curves (L) for the molar combination of compound A and dasatinib. The right figure shows the IC50 values ​​for single reagent and fixed molar combination with dasatinib. 75 A representative synergistic effect equivalent line plot with set values. Points below the blue additive line indicate synergistic interactions.

[0041] Figure 6B The figure shows representative cytotoxicity curves (L) for the molar combination of compound A and dasatinib. The right figure shows the IC50 values ​​for single reagent and fixed molar combination with dasatinib. 75 A representative synergistic effect equivalent line plot with set values. Points below the blue additive line indicate synergistic interactions.

[0042] Figure 7 The tumor was measured on day 15 in an in vivo BCR::ABL1-T315I CML model, in which the animals were treated with a combination of compound A and a second TKI.

[0043] Figure 8 This study showed 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. Detailed Implementation

[0044] definition As used herein, unless otherwise indicated, the following definitions shall apply. Furthermore, if any term or symbol used herein is not defined as described below, it shall have its ordinary meaning in the art.

[0045] As used in this article, in the context of tyrosine kinase proteins, "active site" refers to the region in a tyrosine kinase protein where the phosphate ester group is catalytically transferred from adenosine triphosphate (ATP) to the substrate.

[0046] "Comprising" means that a composition and method includes the listed elements, but does not exclude other elements. When used to define compositions and methods, "consisting essentially of" should mean excluding other elements that have any essential significance to the composition. For example, a composition consisting essentially of elements as defined herein will not exclude other elements that do not substantially affect the essential and novel features of the claimed invention. "Consisting of" should mean excluding, in greater than trace amounts, other ingredients and the listed essential process steps. Embodiments defined by each of these transitional terms are within the scope of this invention.

[0047] The “effective amount” or dosage of a compound or composition refers to the amount of a compound or composition that produces the expected results as desired, based on the disclosure herein. The effective amount can be determined by standard pharmaceutical procedures in cell cultures or laboratory animals, for example (but not limited to) determining the LD50. 50 (Dose lethal to 50% of the population) and ED 50 (The dose that is effective in 50% of the population).

[0048] "Combination therapy" or "combination treatment" refers to the use of two or more drugs or agents in treatment, such as compounds of formula (I), (Ii), (IA), (IA-1), (IIA), (IIB), (IIE), or (Id) (e.g., compound A as used herein), and tyrosine kinase inhibitors that can be used to treat cancers (e.g., lymphoma and leukemia), and the symptoms and clinical presentations of each constitute combination therapy. "Combination" administration means administering two agents (e.g., compounds of formula (I), (Ii), (IA), (IA-1), (IIA), (IIB), (IIE), or (Id)) and a tyrosine kinase inhibitor in any manner, wherein the pharmacological effects of said two agents are simultaneously manifested in the patient. Therefore, combination administration does not require the use of a single drug composition, the same dosage form, or even the same route of administration for the two agents, or precise simultaneous administration of the two agents. The two agents may also be formulated into a single pharmaceutically acceptable composition. Non-limiting examples of such single compositions are oral compositions or oral dosage forms. For example (but not limited to), according to the invention, compounds of formula (I), formula (Ii), formula (IA), formula (IA-1), formula (IIA), formula (IIB), formula (IIE) or formula (Id) (e.g., compound A) are intended to be administered in combination therapy with a tyrosine kinase inhibitor.

[0049] As used herein, the term "excipient" refers to an inert or inactive substance that can be used in the preparation of pharmaceuticals (e.g., tablets containing compounds of the present invention as active ingredients). The term "excipient" can encompass a wide range of substances, including (but not limited to) any substance used as a binder, disintegrant, coating agent, compression / encapsulation aid, cream or lotion, lubricant, parenteral solution, chewable tablet material, sweetener or flavoring agent, suspending / gelling agent, or wet granulation agent. Binders include, for example, carbomer, povidone, xanthan gum, etc.; coating agents include, for example, cellulose acetate phthalate, ethyl cellulose, gellan gum, maltodextrin, enteric coating, etc.; compression / encapsulation aids include, for example, calcium carbonate, dextrose, fructose DC (DC = The following ingredients are listed: (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 carboxymethyl starch, etc.; creams or lotions include, for example, maltodextrin, carrageenan, etc.; lubricants include, for example, magnesium stearate, stearic acid, sodium stearoyl fumarate, etc.; chewable tablet materials include, for example, dextrose, fructose DC, lactose (monhydrate, optionally combined with aspartame or cellulose), etc.; suspending agents / gelling agents include, for example, carrageenan, sodium carboxymethyl starch, xanthan gum, etc.; sweeteners include, for example, aspartame, dextrose, fructose DC, sorbitol, sucrose DC, etc.; and wet granulation agents include, for example, calcium carbonate, maltodextrin, microcrystalline cellulose, etc.

[0050] The terms "subject" or "patient" include humans and non-human animals, as well as cell lines, cell cultures, tissues, and organs. In some embodiments, the subject is a mammal. Mammals can be, for example, humans or suitable non-human mammals such as primates, mice, rats, hamsters, dogs, rabbits, cats, cows, horses, goats, camels, sheep, guinea pigs, or pigs. Subjects can also be birds or poultry. In some embodiments, the subject is a human. In some embodiments, the patient is a human.

[0051] The term "pharmaceutical composition" refers to a formulation containing a compound of the present disclosure in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or unit dosage form. Unit dosage form is any of a variety of forms, including, for example, capsules, IV bags, tablets, single-stage pumps on aerosol inhalers, or vials. The amount of active ingredient (e.g., a formulation of the disclosed compound or its salts, hydrates, solvates, or isomers) in a unit dose of the composition is an effective amount and varies depending on the specific treatment involved. Those skilled in the art will understand that doses may sometimes need to be routinely varied based on the patient's age and symptoms. Dosage is also determined by the route of administration. A variety of routes are covered, including oral, pulmonary, rectal, parenteral, percutaneous, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, intranasal, etc. Dosage forms of the compounds of the present disclosure for topical or percutaneous application include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalers. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any desired preservative, buffer, or propellant.

[0052] It should be understood that the compounds or pharmaceutical compositions disclosed herein can be administered to subjects using many well-known methods currently used for chemotherapy. For example, the compounds disclosed may be injected into the bloodstream or body cavity, or administered orally, or applied through the skin as 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. During treatment and for a reasonable period after treatment, close monitoring of the patient's disease condition (e.g., the disease or symptom disclosed herein) and health status is preferred.

[0053] "Pharmaceutical acceptable" means safe and non-toxic, preferably for use in vivo, and more preferably for human use.

[0054] "Pharmaceutically acceptable salt" means a salt that is pharmaceutically acceptable. The compounds described herein can be administered as pharmaceutically acceptable salts.

[0055] The term "pharmaceuticalally acceptable excipient" means an excipient that can be used to prepare a pharmaceutical composition, which is generally safe, non-toxic, and biologically and otherwise undesirable, and includes excipients acceptable for veterinary and human pharmaceutical use. As used in the specification and claims, "pharmaceuticalally acceptable excipient" includes one or more such excipients.

[0056] The term "therapeutic effective amount" refers to the amount of a pharmaceutical agent that treats, improves, or prevents an identified disease or condition, or exhibits a detectable therapeutic or inhibitory effect. This effect can be detected by any analytical method known in the art. The precise effective amount for a subject will be determined based on the subject's weight, size, and health status; the nature and severity of the condition; and the chosen therapeutic agent or combination of therapeutic agents used for administration. The therapeutic effective amount for a given situation can be determined through routine laboratory testing within the skill and judgment of a clinician.

[0057] As used in this article, the term "co-administration" refers to the administration of a selected therapeutic agent to a single patient and is intended to include treatment regimens in which the agent is administered via the same or different routes of administration or at the same or different times.

[0058] As used herein, the term "about," relating to numerical values ​​or ranges, reflects the fact that a certain level of variation is recognized and permissible in the art due to practical and / or theoretical limitations. For example, small variations are allowed due to inherent differences in the operation of certain devices and / or the manner of measurement. Based on the foregoing, the phrase "about" is generally used to encompass values ​​within the standard deviation or standard error.

[0059] "Prodrug" refers to a compound that, upon administration, is metabolized or otherwise transformed into a biologically active compound (or drug) or at least one compound with more active properties. Compared to a drug, a prodrug is chemically modified in a manner that reduces or eliminates its activity relative to the drug, but the modification allows the drug to be produced via metabolism or other biological processes upon administration. Compared to an active drug, a prodrug may have altered metabolic stability or transport characteristics, fewer side effects or lower toxicity, or improved flavor (e.g., see reference Nogrady, 1985, Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pp. 388-392, which is incorporated herein by reference). Prodrugs may be synthesized using reactants instead of the corresponding drug. For illustrative purposes and without limitation, prodrugs include carboxyl esters, linear and cyclic phosphates and phosphoramides and aminophosphates, carbamates, preferably phenolic carbamates (i.e., carbamates in which the hydroxyl group is part of an aryl or heteroaryl moiety, wherein the aryl and heteroaryl groups may optionally be substituted), and so on.

[0060] “Salt” refers to an ionic compound formed between an acid and a base. When the compounds described herein contain acidic functional groups, such salts include (but are not limited to) alkali metal salts, alkaline earth metal salts, and ammonium salts. Ammonium salts, as used herein, include salts of bases containing protonated nitrogen and bases containing alkylated nitrogen. A “therapeuticly effective amount” or dose of a compound or composition refers to the amount of compound or composition that reduces or inhibits a patient’s symptoms or prolongs survival. Multiple doses of the compound or composition may be required to achieve the desired effect.

[0061] The term "treating" or "treatment" in relation to a patient's disease refers to: 1) preventing the occurrence of the disease in patients susceptible to the disease or who have not yet exhibited symptoms of the disease; 2) suppressing the disease or halting its progression; or 3) improving the disease or causing its remission. As used herein, "treatment" or "treating" refers to a method of obtaining a beneficial or desired outcome (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 caused by the disease or condition; alleviating the severity of the disease or condition; stabilizing the disease or condition (e.g., preventing or delaying the worsening of the disease or condition); delaying the onset or recurrence of the disease or condition; delaying or slowing the progression of the disease or condition; improving the state of the disease or condition; providing remission of the disease or condition (whether partial or complete remission); reducing the dosage of one or more other drugs required to treat the disease or condition; enhancing the effect of another drug used to treat the disease or condition; delaying the progression of the disease or condition; improving the patient's quality of life; and / or prolonging the patient's survival. "Treatment" also encompasses reducing the pathological outcomes of the disease or condition. The methods of this invention cover any one or more of these therapeutic aspects.

[0062] As used herein, “delaying” the development of a disease means postponing, hindering, slowing, halting, stabilizing, and / or delaying the development of a disease and / or slowing its progression, or altering the underlying disease process and / or course after its development. This delay can have varying durations, depending on the patient’s medical history and / or the subject being treated. As will be apparent to those skilled in the art, sufficient or significant delay can effectively encompass prevention, namely, the absence of disease-related clinical symptoms in the individual. Methods of “delaying” the development of a disease refer to methods that reduce the probability of disease development and / or the severity of the disease over a given period of time compared to not using said methods, including stabilizing one or more symptoms caused by the disease.

[0063] Individuals at "risk" of developing a disease may or may not have a detectable disease, and may or may not have exhibited a detectable disease prior to the treatments described herein. "At risk" means that an individual possesses one or more so-called risk factors, which are measurable parameters associated with disease development. 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, presence of pre-existing conditions, and genetic (i.e., heritability) considerations. In some embodiments, the compound may be administered to subjects (including humans) at risk of developing a disease or condition or with a family history of a disease or condition.

[0064] An "isotope" of a compound is a compound in which one or more atoms of the compound have been replaced by isotopes of those same atoms. For example, where H has been replaced by D or T, or 12 C has been 11 C alternative, or 14 N has been 15 Nitrogen substitution. For example (but not limited to), D substitution can lead to a decrease in metabolic rate and thus a prolonged half-life in some cases. T substitution for H can provide potentially useful radioligands for binding studies. Short-lived isotopes. 11 C substitute 12 C can provide ligands that can be used in positron emission tomography (PET) scans. 15 N substitution 14 N provides access via 15 Compounds detected / monitored by N NMR spectroscopy. For example, the isotope of a compound containing -CH2CH3 is -CD2CD3 instead of -CH2CH. 3的 The compound.

[0065] A stereoisomer is a compound whose constituent atoms have different stereoisomeric origins (e.g., chirality of one or more stereocenters, or chirality of the stereocenters associated with the cis or trans conformation of the carbon-carbon or carbon-nitrogen double bond). Stereoisomers include enantiomers and diastereomers.

[0066] "Tautomers" refer to alternative forms of compounds with different proton positions, such as enol-ketone and imine-enamine tautomers, or heteroaryl tautomers containing ring atoms attached to the ring-NH- and ring=N- moieties, such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetraazoles.

[0067] "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group having 1 to 12 carbon atoms, preferably 1 to 10 carbon atoms, and more preferably 1 to 6 carbon atoms. This term includes, for example, straight-chain and branched hydrocarbon groups, such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), tert-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-). Cx alkyl refers to an alkyl group having x carbon atoms.

[0068] "Alkenyl" refers to a straight-chain or branched monovalent hydrocarbon group having 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms, and having at least 1, preferably 1 to 2 vinyl (>C=C<) unsaturated sites. Examples of such groups include, for example, vinyl, allyl, and but-3-en-1-yl. This term includes cis and trans isomers or mixtures of these isomers. Cx alkenyl refers to an alkenyl group having x carbon atoms.

[0069] "Alynyl" refers to a straight-chain or branched monovalent hydrocarbon group having 2 to 6 carbon atoms, preferably 2 to 3 carbon atoms, and having at least 1, preferably 1 to 2 acetylene (-C≡C-) unsaturated sites. Examples of such alkynyl groups include acetylenyl (-C≡CH) and propynyl (-CH2C≡CH). Cx alkynyl refers to an alkynyl group having x carbon atoms.

[0070] "Substituted alkyl" refers to an alkyl group having 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the following: alkoxy, substituted alkoxy, acyl, amide, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, formamidinyl, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, arylamino, substituted arylamino, heteroarylamino, substituted heteroarylamino, cycloalkylamino, substituted cycloalkylamino, heterocycloalkylamino, substituted heterocyclic. Amino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidinyl, substituted guanidinyl, halogenated, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclic oxy, substituted heterocyclic oxy, heterocyclic thio, substituted heterocyclic thio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioyl, mercapto, alkylthio, and substituted alkylthio, wherein these substituents are as defined herein.

[0071] "Substituted alkenyl" refers to an alkenyl group having 1 to 3 substituents, preferably 1 to 2 substituents, selected from the following: alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, formamidinyl, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, arylamino, substituted arylamino, heteroarylamino, substituted heteroarylamino, cycloalkylamino, substituted cycloalkylamino, heterocycloalkylamino, substituted heterocycloalkylamino, carboxyl, carboxyl ester, (carboxyl ester) Amino, (carboxylate)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidinyl, substituted guanidinyl, halogenated, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclic oxy, substituted heterocyclic oxy, heterocyclic thio, substituted heterocyclic thio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioyl, mercapto, alkylthio, and substituted alkylthio, wherein these substituents are as defined herein and the condition is that any hydroxyl or mercapto substitution is not attached to a vinyl (unsaturated) carbon atom.

[0072] "Substituted alkynyl" refers to an alkynyl group having 1 to 3 substituents, preferably 1 to 2 substituents, selected from the following: alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, formamidinyl, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, arylamino, substituted arylamino, heteroarylamino, substituted heteroarylamino, cycloalkylamino, substituted cycloalkylamino, heterocycloalkylamino, substituted heterocycloalkylamino, carboxyl, carboxyl ester, ( (Carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidinyl, substituted guanidinyl, halogenated, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclic oxy, substituted heterocyclic oxy, heterocyclic thio, substituted heterocyclic thio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioyl, mercapto, alkylthio, and substituted alkylthio, wherein these substituents are as defined herein and the condition is that any hydroxyl or mercapto substitution is not attached to an acetylene carbon atom.

[0073] "Alkoxy" refers to the -O-alkyl group, where the alkyl group is as defined herein. Alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, and n-pentoxy.

[0074] "Substituted alkoxy" refers to the group -O- (substituted alkyl), wherein the substituted alkyl is as defined herein. Preferred substituted alkyl groups in -O- (substituted alkyl) include haloalkyl, especially halomethyl, such as trifluoromethyl, difluoromethyl, fluoromethyl, etc.

[0075] "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)-, wherein 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 are as defined herein. Acyl groups include "acetyl" CH3C(O)-.

[0076] "Acylamino" refers to the -NR group. 30 C(O)alkyl, -NR 30 C(O) substituted alkyl, -NR 30 C(O)cycloalkyl, -NR 30 C(O) substituted cycloalkyl, -NR 30 C(O) alkenyl, -NR 30 C(O) substituted alkenyl, alkoxy, substituted alkoxy-NR 30 C(O) ynyl group, -NR 30 C(O) substituted alkynyl group, -NR 30 C(O) aryl, -NR 30 C(O) substituted aryl, -NR 30 C(O) heteroaryl, -NR 30 C(O)-substituted heteroaryl, -NR 30 C(O) heterocycle and -NR 30 C(O) replaces the heterocyclic ring, where R 30 The alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl or substituted cycloalkyl; and wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0077] “Acyloxy” refers to the group 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-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0078] "Amino" refers to the -NH2 group.

[0079] "Substituted amino" refers to the -NR group. 31 R 32 , where R 31 and R 32 Independently selected from: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, arylamino, substituted arylamino, heteroarylamino, substituted heteroarylamino, cycloalkylamino, substituted cycloalkylamino, heterocycloalkylamino, substituted heterocycloylamino, sulfonylamino, and substituted sulfonyl, wherein R 31 and R 32 The nitrogen linked to it can be used to form a heterocyclic group or to substitute a heterocyclic group, provided that R 31 and R 32 None of them are hydrogen, and the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein. When R 31 It is hydrogen and R 32 When R is alkyl, the substituted amino group is sometimes referred to as alkylamino in this text. 31 and R 32 When the amino group is alkyl, the substituted amino group is sometimes referred to as dialkylamino in this text. When referring to a monosubstituted amino group, it means R 31 Or R 32 It contains hydrogen, but not both. When referring to a disubstituted amino group, it means R 31 and R 32 None of them are hydrogen.

[0080] "Amino carbonyl" refers to the group -C(O)NR 33 R 34 , where R 33 and R 34Independently selected from: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle, wherein R 33 and R 34 The nitrogen group to which it is attached may optionally form a heterocyclic or substituted heterocyclic group, wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0081] "Aminothiocarbonyl" refers to the group -C(S)NR 33 R 34 , where R 33 and R 34 Independently selected from: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle, wherein R 33 and R 34 The nitrogen group to which it is attached may optionally form a heterocyclic or substituted heterocyclic group, wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0082] "Aminocarbonylamino" refers to the -NR group. 30 C(O)NR 33 R 34 , where R 30 It is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or substituted cycloalkyl, and R 33 and R 34 Independently selected from: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle, wherein R 33 and R 34 The nitrogen group to which it is attached may optionally form a heterocyclic or substituted heterocyclic group, wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0083] "Aminothiocarbonylamino" refers to the -NR group. 30 C(S)NR 33 R 34 , where R30 It is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or substituted cycloalkyl, and R 33 and R 34 Independently selected from: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle, wherein R 33 and R 34 The nitrogen group to which it is attached may optionally form a heterocyclic or substituted heterocyclic group, wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0084] "Aminocarbonyloxy group" refers to the group -OC(O)NR 33 R 34 , where R 33 and R 34 Independently selected from: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle, wherein R 33 and R 34 The nitrogen group to which it is attached may optionally form a heterocyclic or substituted heterocyclic group, wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0085] "Aminosulfonyl" refers to the group -SO2NR 33 R 34 , where R 33 and R 34 Independently selected from: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle, wherein R 33 and R 34 The nitrogen group optionally attached thereto forms a heterocyclic or substituted heterocyclic group, wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein. "Aminosulfonyloxy" refers to the group -O-SO2NR. 33 R 34 , where R 33 and R 34Independently selected from: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle, wherein R 33 and R 34 The nitrogen group to which it is attached may optionally form a heterocyclic or substituted heterocyclic group, wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0086] "Aminosulfonylamino" refers to the -NR group. 30 -SO2NR 33 R 34 , where R 30 It is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or substituted cycloalkyl, and R 33 and R 34 Independently selected from: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle, wherein R 33 and R 34 The nitrogen group to which it is attached may optionally form a heterocyclic or substituted heterocyclic group, wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0087] "Formamidinyl" refers to the group -C (=NR) 35 )NR 33 R 34 , where R 33 R 34 and R 35 Independently selected from: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle, wherein R 33 and R 34 The nitrogen group to which it is attached may optionally form a heterocyclic or substituted heterocyclic group, wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0088] "Aryl" or "Ar" refers to a monovalent aromatic carbocyclic group having 6 to 14 carbon atoms, consisting of a single ring (e.g., phenyl (Ph)) or multiple fused rings (e.g., naphthyl or anthracene). These fused rings may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-1,4-benzoxazine-3(4H)-one-7-yl, etc.), provided that the bonding point is at an aromatic carbon atom. Preferred aryl groups include phenyl and naphthyl groups.

[0089] "Substituted aryl" refers to an aryl group substituted with 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the following: 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, formamidinyl, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, arylamino, substituted arylamino, heteroarylamino, substituted heteroarylamino, cycloalkylamino, substituted cycloalkylamino Heterocyclic alkylamino, substituted heterocyclic amino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidinyl, substituted guanidinyl, halogenated, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclicoxy, substituted heterocyclicoxy, heterocyclicthio, substituted heterocyclicthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioyl, mercapto, alkylthio, and substituted alkylthio, wherein these substituents are as defined herein.

[0090] "Aryloxy" refers to the group -O-aryl, where aryl is as defined herein, including, for example, phenoxy and naphthoxy.

[0091] "Substituted aryloxy group" refers to the group -O- (substituted aryl), where the substituted aryl group is as defined herein.

[0092] "Arylthio" refers to the group -S-aryl, where aryl is as defined in this article.

[0093] "Substituted aryl thio" refers to the group -S- (substituted aryl), where the substituted aryl group is as defined herein.

[0094] "Arylamino" refers to the -NR group. 37 (aryl), where aryl is as defined herein, and R 37 It is hydrogen, alkyl, or substituted alkyl.

[0095] "Substituted arylamino" refers to the -NR group.37 (replacing aryl), where R 37 It is hydrogen, alkyl or substituted alkyl, wherein the substituted aryl group is as defined herein.

[0096] "Carbonyl" refers to the divalent group -C(O)-, which is equivalent to -C(=O)-.

[0097] "Carboxy" or "carboxyl" refers to -COOH or its salt.

[0098] “Carboxyl ester” or “carboxy ester” refers to the group -C(O)O-alkyl, -C(O)O-substituted alkyl, -C(O)O-alkenyl, -C(O)O-substituted alkenyl, -C(O)O-ynyl, -C(O)O-substituted ynyl, -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 and -C(O)O-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, ynyl, substituted ynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[0099] "(Carboxylate)amino" refers to the -NR group. 30 -C(O)O-alkyl, -NR 30 -C(O)O-substituted alkyl group, -NR 30 -C(O)O-alkenyl, -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, -NR 30 -C(O)O-substituted aryl, -NR 30 -C(O)O-cycloalkyl, -NR 30 -C(O)O-substituted cycloalkyl, -NR 30 -C(O)O-heteroaryl, -NR 30 -C(O)O-substituted heteroaryl, -NR 30 -C(O)O- heterocycle and -NR 30 -C(O)O- Substituted heterocycle, where R 30 It is alkyl or hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0100] "(Carboxyl ester)oxy" refers to the group -OC(O)O-alkyl, -OC(O)O-substituted alkyl, -OC(O)O-alkenyl, -OC(O)O-substituted alkenyl, -OC(O)O-ynyl, -OC(O)O-substituted ynyl, -OC(O)O-aryl, -OC(O)O-substituted aryl, -OC(O)O-cycloalkyl, OC(O)O-substituted cycloalkyl, -OC(O)O-heteroaryl, -OC(O)O-substituted heteroaryl, -OC(O)O-heterocyclic and -OC(O)O-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, ynyl, substituted ynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[0101] "Cyano" refers to the group -C≡N.

[0102] "Cycloalkyl" refers to a saturated or unsaturated but non-aromatic cycloalkyl group with 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, and more preferably 3 to 6 carbon atoms, having a single or multiple rings, including fused rings, bridged rings, and spirocyclic systems. Cx cycloalkyl refers to a cycloalkyl group having x ring carbon atoms. Suitable examples of cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl. One or more rings may be aryl, heteroaryl, or heterocyclic, provided that the linkage is via a non-aromatic, non-heterocyclic saturated carbon ring. "Substituted cycloalkyl" refers to a cycloalkyl group having 1 to 5, or preferably 1 to 3, substituents selected from the following: oxoyl, thion, 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, formamidinyl, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, ( (Carboxyester)amino, (carboxyester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidinyl, substituted guanidinyl, halogen, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclic oxy, substituted heterocyclic oxy, heterocyclic thio, substituted heterocyclic thio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, thioyl, mercapto, alkylthio and substituted alkylthio, wherein these substituents are as defined herein.

[0103] “Cycloalkyloxy” refers to -O-cycloalkyl.

[0104] "Substituted cycloalkyloxy" refers to -O- (substituted cycloalkyl).

[0105] "Cycloalkylamino" refers to the -NR group. 37 (cycloalkyl), where R 37 It is hydrogen, alkyl, or substituted alkyl.

[0106] "Substituted cycloalkylamino" refers to the -NR group. 37 (Substituted cycloalkyl), wherein R 37 It is hydrogen, alkyl, or substituted alkyl, and substituted cycloalkyl is as defined herein.

[0107] “Cycloalkylthio” refers to -S-cycloalkyl.

[0108] "Substituted cycloalkyl thio" refers to -S- (substituted cycloalkyl).

[0109] "Guidinyl" refers to the group -NHC(=NH)NH2.

[0110] "Substituted guanidine" refers to -NR 36 C(=NR 36 )N(R 36 )2, where each R 36 The two R atoms independently selected from: hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle, and attached to a common guanidinium atom. 36 The group may optionally form a heterocyclic group or a substituted heterocyclic group together with the nitrogen to which it is attached, provided that at least one R 36 It is not hydrogen, and these substituents are as defined herein.

[0111] "Halogen" or "halogen" refers to fluorine, chlorine, bromine and iodine, with fluorine or chlorine being preferred.

[0112] "Hydroxyl" or "hydroxyl" refers to the -OH group.

[0113] "Heteroaryl" refers to an aromatic group having 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur within a ring. Such heteroaryls can be monocyclic (e.g., pyridyl or furanyl) or polycyclic fused rings (e.g., indazinyl or benzothiopheneyl), wherein the fused ring may or may not be aromatic and / or contain heteroatoms, provided the connection point is via an atom of the aromatic heteroaryl group. In one embodiment, the nitrogen and / or sulfur ring atoms of the heteroaryl group are optionally oxidized to provide an N-oxide (N→O), sulfinyl, or sulfonyl moiety. Preferred heteroaryls include 5- or 6-membered heteroaryls, such as pyridyl, pyrroleyl, thiopheneyl, and furanyl. Other preferred heteroaryls include 9- or 10-membered heteroaryls, such as indolyl, quinolinyl, quinoloneyl, isoquinolinyl, and isoquinoloneyl.

[0114] "Substituted heteroaryl" refers to a heteroaryl group substituted by 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the same group of substituents defined for substituted aryl groups.

[0115] "Heteroaryloxy" refers to -O-heteroaryl.

[0116] "Substituted heteroaryloxy group" refers to the group -O- (substituted heteroaryl).

[0117] "Heteroarylthio" refers to the -S-heteroaryl group.

[0118] "Substituted heteroaryl thio" refers to the group -S- (substituted heteroaryl).

[0119] "Heteroarylamino" refers to the -NR group. 37 (Heteroarylene), of which R 37 It is hydrogen, alkyl, or substituted alkyl.

[0120] "Substituted heteroarylamino" refers to the -NR group. 37 (Substituted heteroaryl), where R 37 It is hydrogen, alkyl or substituted alkyl, and the substituted heteroaryl group is as defined herein.

[0121] The terms "heterocycle," "heterocyclic," "heterocyclic alkyl," or "heterocyclic group" refer to a saturated or partially saturated but non-aromatic group having 1 to 10 ring carbon atoms, preferably 1 to 8 carbon atoms, and 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 nitrogen, sulfur, or oxygen. Cx heterocyclic alkyl refers to a heterocyclic alkyl group having x ring atoms, including ring heteroatoms. Heterocycles encompass monocyclic or multi-ring fused rings, including fused rings, bridged rings, and spirocyclic systems. In fused ring systems, one or more rings may be cycloalkyl, aryl, or heteroaryl, provided the connection point is via a non-aromatic ring. In one embodiment, the nitrogen and / or sulfur atoms of the heterocyclic group are optionally oxidized to provide an N-oxide, sulfinyl, or sulfonyl moiety.

[0122] Examples of heterocyclic and heteroaryl groups include (but are not limited to) aza-butyl, pyrroloyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indazinyl, isoindolyl, indoleyl, dihydroindolyl, indazolyl, purine, quinazinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphthylpyridinyl, quinoxalinyl, quinazolinyl, cenylinyl, pteridinyl, carbazole, carbolinyl, phenanthridine, acridineyl, phenanthridine, isothiazolyl, phenazinyl, and phenazinyl. Isoxazolyl, phenoxazinyl, phenthiazinyl, imidazoalkyl, imidazolinyl, piperidinyl, piperazinyl, indolinyl, phthalimino, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrobenzo[b]thiophenyl, thiazolyl, thiazoalkyl, thiophenyl, benzo[b]thiophenyl, morpholinyl, thiomorpholinyl (also known as thiomorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidinyl, and tetrahydrofuranyl.

[0123] "Substituted heterocycle" or "substituted heterocyclic alkyl" or "substituted heterocyclic group" refers to a heterocyclic group that is substituted with 1 to 5, or preferably 1 to 3, substituents that are the same as those defined for substituted cycloalkyl.

[0124] "Heterocyclic oxygen group" refers to the -O-heterocyclic group.

[0125] "Substituted heterocyclic oxygen group" refers to the group -O- (substituted heterocyclic group).

[0126] "Heterocyclic thio group" refers to the -S-heterocyclic group.

[0127] "Substituted heterocyclic thio group" refers to the group -S- (substituted heterocyclic group).

[0128] "Heterocyclic amino" refers to the -NR group. 37 (heterocyclic group), where R 37 It is hydrogen, alkyl, or substituted alkyl.

[0129] "Substituted heterocyclic amino" refers to the group -NR 37 (Substituted heterocyclic group), where R 37 It is hydrogen, alkyl or substituted alkyl, and the substituted heterocyclic group is as defined herein.

[0130] "Nitro" refers to the group -NO2.

[0131] "O" refers to an atom (=O) or (O).

[0132] A "spirocyclic system" refers to a bicyclic system in which two rings share a single carbon atom.

[0133] "Sulinate" refers to the divalent group -S(O)- or -S(=O)-.

[0134] "Sulfoyl" refers to the divalent group -S(O)2- or -S(=O)2-.

[0135] "Substituted sulfonyl" refers to groups such as -SO2-alkyl, -SO2-substituted alkyl, -SO2-OH, -SO2-alkenyl, -SO2-substituted alkenyl, -SO2-cycloalkyl, -SO2-substituted cycloalkyl, -SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted heteroaryl, -SO2-heterocyclic, -SO2-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, ynyl, substituted ynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. Substituted sulfonyl groups include groups such as methyl-SO2-, phenyl-SO2-, and 4-methylphenyl-SO2-. Preferred substituted alkyl groups on substituted alkyl-SO2- include haloalkyl, especially halomethyl, such as trifluoromethyl, difluoromethyl, fluoromethyl, etc.

[0136] "Sulfoyloxy" or "substituted sulfonyloxy" refers to the group -OSO2-alkyl, -OSO2-substituted alkyl, -OSO2-OH, -OSO2-alkenyl, -OSO2-substituted alkenyl, -OSO2-cycloalkyl, -OSO2-substituted cycloalkyl, -OSO2-aryl, -OSO2-substituted aryl, -OSO2-heteroaryl, -OSO2-substituted heteroaryl, -OSO2-heterocyclic, -OSO2-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[0137] "Sulfoamino" refers to the -NR group. 37 (Substituted sulfonyl group), where R 37 It is hydrogen, alkyl or substituted alkyl, and the substituted sulfonyl group is as defined herein.

[0138] "Thioyl" 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)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0139] "Mercapto" or "thiol" refers to the -SH group.

[0140] "Thiocarbonyl" refers to the divalent group -C(S)-, which is equivalent to -C(=S)-.

[0141] "Thione" refers to the S atom (=S).

[0142] "alkylthio" refers to the group -S-alkyl, where alkyl is as defined herein.

[0143] "Substituted alkyl thio" refers to the group -S-(substituted alkyl), wherein the substituted alkyl is as defined herein. Preferred substituted alkyl groups on -S-(substituted alkyl) include haloalkyl, especially halomethyl, such as trifluoromethyl, difluoromethyl, fluoromethyl, etc.

[0144] "Vinyl" refers to the unsaturated hydrocarbon group -CH=CH2 derived from ethylene.

[0145] As used throughout this specification, the terms "optionally" or "optionally" mean that an event or condition described below may occur but does not need to occur, and the description includes both cases where the event or condition occurs and cases where the event or condition does not occur. For example, "nitrogen atoms may be optionally oxidized to provide an N-oxide (N→O) moiety" means that nitrogen atoms may be oxidized but do not need to be oxidized, and the description includes both cases where nitrogen atoms are not oxidized and cases where nitrogen atoms are oxidized.

[0146] The term "optional substitution" refers to a substituted or unsubstituted group. The substituted group may be substituted by one or more substituents, such as one, two, three, four, or five substituents. Preferably, the substituents are selected from the functional groups provided herein. In some more preferred embodiments, the substituents are selected from oxo groups, halogenated groups, -CN, NO2, and -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 Heterocyclic group, C6-C 14 Aryl and C5-C 12 Heteroaryl, wherein each R 100 Independently hydrogen or C1-C8 alkyl; C3-C 12 cycloalkyl; C4-C10 Heterocyclic group; C6-C 14 Aryl; or C2-C 12 Heteroaryl; wherein each alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with 1-3 halohalogens, 1-3 C1-C6 alkyl groups, 1-3 C1-C6 haloalkyl groups, or 1-3 C1-C6 alkoxy groups. More preferably, the substituents are selected from: chlorine, fluorine, -OCH3, methyl, ethyl, isopropyl, cyclopropyl, -OCF3, -CF3, and -OCHF2.

[0147] R 101 and R 102 Independently hydrogen; optionally substituted with -CO2H or its esters, C1-C8 alkyl, C1-C6 alkoxy, oxo, -CR 103 =C(R 103 )2、-CCR、C3-C 10 cycloalkyl, C3-C 10 Heterocyclic group, C6-C 14 Aryl or C2-C 12 Heteroaryl, wherein each R 103 Independently hydrogen or C1-C8 alkyl; C3-C 12 cycloalkyl; C4-C 10 Heterocyclic group; C6-C 14 Aryl; or C2-C 12 Heteroaryl; wherein each cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by 1-3 alkyl groups or 1-3 halohalogens, or R 101 and R 102 Together with the nitrogen atom it is attached to, it forms a 5-7 membered heterocycle.

[0148] Unless otherwise indicated, the naming of substituents not explicitly defined herein is achieved by naming the terminal portion of the functional group, followed by the adjacent functional group toward the junction. For example, the substituent “alkoxycarbonylalkyl” refers to the group (alkoxy)-C(O)-(alkyl)-.

[0149] It should be understood that polymers obtained by defining substituents that themselves have other substituents (e.g., substituted aryl groups having substituted aryl groups as substituents that are themselves replaced by substituted aryl groups, etc.) are not included herein. In this case, the maximum number of such substituents is three. That is, each of the above definitions is subject to the following restrictions: for example, substituted aryl groups are limited to -substituted aryl-(substituted aryl)-substituted aryl.

[0150] In some embodiments of the substituted portion, the portion is substituted by a group, which may also be substituted by another group, but the other group cannot be further substituted. For example, in some embodiments of "substituted alkyl", the alkyl portion is substituted by a group, which may be further substituted (e.g., substituted alkoxy, substituted amino, substituted aryl, substituted aryloxy, substituted arylthio, substituted arylamino, substituted heteroarylamino, substituted cycloalkylamino, substituted heterocyclic amino, substituted cycloalkyl, substituted cycloalkyloxy, substituted cycloalkylthio, substituted guanidine, substituted heteroaryl, substituted heteroaryloxy, substituted heteroarylthio, substituted heterocyclic, substituted heterocyclicoxy, substituted heterocyclicthio, substituted sulfonyl). Acyl, substituted alkyl thioyl), but the substituted alkoxy, substituted amino, substituted aryl, substituted aryloxy, substituted aryl thioyl, substituted arylamino, substituted heteroarylamino, substituted cycloalkylamino, substituted heterocyclic amino, substituted cycloalkyl, substituted cycloalkyloxy, substituted cycloalkyl thioyl, substituted guanidine, substituted heteroaryl, substituted heteroaryloxy, substituted heteroaryl thioyl, substituted heterocyclic, substituted heterocyclicoxy, substituted heterocyclic thioyl, substituted sulfonyl, or substituted alkyl thioyl is not partially substituted by itself. Although “substituted alkyl” is provided as an example, this embodiment is intended for use with each substituted moiety described herein.

[0151] In some embodiments of the substituted portion, the portion is substituted with groups that are not further substituted. Therefore, in some embodiments, "substituted alkyl" refers to an alkyl moiety that is partially substituted by one or more, and in some aspects by one, two, three, four, or five independently selected from the following: alkoxy, acyl, acylamino, acyloxy, amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, formamidinyl, aryl, aryloxy, arylthio, arylamino, heteroarylamino, cycloalkylamino, heterocycloalkylamino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, guanidinyl, halogenated, hydroxyl, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclic, heterocyclic oxy, heterocyclic thio, nitro, SO3H, sulfonyloxy, sulfonylamino, thioyl, mercapto, and alkylthio. Although “substituted alkyl” is provided as an example, this embodiment is intended for use with each substituted part described herein.

[0152] It should be understood that the above definition does not include unacceptable substitution modes (e.g., methyl groups substituted with four fluorine atoms). Such unacceptable substitution modes are well known to those skilled in the art.

[0153] It should be understood that certain features set forth in the context of individual embodiments for clarity may also be provided in combination in a single embodiment. Conversely, various features set forth in the context of a single embodiment for simplicity may also be provided individually or in any suitable sub-combination. All combinations of embodiments relating to chemical groups, represented by variables, are explicitly covered in this invention and disclosed herein, as each and every combination is individually and explicitly disclosed, to the extent that such combinations cover compounds that are stable compounds (i.e., compounds whose biological activity can be isolated, characterized, and tested). Furthermore, all sub-combinations of chemical groups listed in embodiments elaborating such variables are also explicitly covered in this invention and disclosed herein, as each and every such sub-combination of chemical groups is individually and explicitly disclosed herein.

[0154] BCR: ABL1 inhibitor This disclosure relates to the treatment of cancer in subjects in need using a combination of a BCR:ABL1 inhibitor and a tyrosine kinase inhibitor.

[0155] In some implementations, the BCR:ABL1 inhibitor is a compound of formula (I): (I) Or its tautomers or N-oxides, or isotopes of each thereof, or prodrugs of each thereof, or stereoisomers of each thereof, or pharmaceutically acceptable salts of each thereof, or solvates of each thereof, wherein: L can be -NH-CO-, -CO-NH-, -NH-SO2-, or -SO2-NH-; R 1 C6-C as an optional substitute 10 Aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 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 H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocyclic alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C6-C 10 Aryl or optionally substituted 5-10 heteroaryl groups; R3 H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, 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 intermediate atom, it forms a cycloalkyl or heterocycloalkyl group, preferably a C3-C8 cycloalkyl group or a 4-10 heterocycloalkyl group with optional substitution; R 4 The C1-C6 alkyl group is optionally substituted, preferably a C1-C3 haloalkyl group, such as CF3 or CF2Cl, an optional C2-C6 alkenyl group, or an optional C2-C6 alkynyl group. X is either O or S; Y is CH, C-(C1-C2 alkyl), C-halogenated, or N; Z is CR 5 Or N; R 5 It is H or halogen; R 6 H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocyclic alkyl, optionally substituted C6-C 10 aryl or optionally substituted 5-10 heteroaryl groups; and R 7 H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocyclic alkyl, optionally substituted C6-C 10 Aryl or optionally substituted 5-10 heteroaryl groups; Or R 6 and R 7 Together with the nitrogen to which it is attached, it forms an optionally substituted 4-7 membered heterocycle. The condition is that the compound is not (i) 5-[[(4-methoxyphenyl)sulfonyl]amino]-1-methyl-1H-benzimidazole-7-carboxylic acid or (ii) 5-[[(4-ethoxyphenyl)sulfonyl]amino]-1-methyl-1H-benzimidazole-7-carboxylic acid.

[0156] In some respects, BCR:ABL1 inhibitors are compounds of formula (Ii): (Ii) Or its tautomers or N-oxides, or isotopes of each thereof, or prodrugs of each thereof, or stereoisomers of each thereof, or pharmaceutically acceptable salts of each thereof, or solvates of each thereof, wherein: L can be -NH-CO-, -CO-NH-, or -NH-SO2-; R 1 C6-C as an optional substitute 10 Aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 membered heterocycle, 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 ; R 2 H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocyclic alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C6-C 10 Aryl or optionally substituted 5-10 heteroaryl groups; R 3 H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, 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 intermediate atom, it forms a cycloalkyl or heterocycloalkyl group, preferably a C3-C8 cycloalkyl group or a 4-10 heterocycloalkyl group with optional substitution; R 4 The C1-C6 alkyl group is optionally substituted, preferably a C1-C3 haloalkyl group (e.g., CF3 or CF2Cl), an optional C2-C6 alkenyl group, or an optional C2-C6 alkynyl group. X is either O or S; Y is CH, C-(C1-C2 alkyl), C-halogenated, or N; Z is CR 5 Or N; R 5 It is H or halogen; R 6H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocyclic alkyl, optionally substituted C6-C 10 aryl or optionally substituted 5-10 heteroaryl groups; and R 7 H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocyclic alkyl, optionally substituted C6-C 10 aryl or optionally substituted 5-10 heteroaryl groups; or R 6 and R 7 Together with the nitrogen to which it is attached, it forms an optionally substituted 4-7 membered heterocycle.

[0157] In some implementations, the BCR:ABL1 inhibitor is a compound of formula (IA): (IA), Or its pharmaceutically acceptable salt.

[0158] It should be understood that when Z is N, then R 5 It does not exist. Similarly, it should be understood that when R... 5 If it exists, then R 5 The carbon atom attached to the aryl ring makes Z = CR 5 .

[0159] In some implementations, the BCR:ABL1 inhibitor is a compound of formula (IA-1): (IA-1), Or its pharmaceutically acceptable salt.

[0160] In some embodiments, the BCR:ABL1 inhibitor is a compound selected from formula (IIA), formula (IIB), or formula (IIE): ; or its pharmaceutically acceptable salt Where R 10 The substituted 5-6 membered heteroaryl group is preferred, and the heteroaryl moiety preferably has at most 2 cyclic nitrogen atoms; R 20 The substituted C1-C3 alkyl, the substituted C3-C4 cycloalkyl, or the substituted 4-6 membered heterocyclic alkyl are optionally substituted, preferably R. 20 It is methyl, optionally substituted isopropyl or cyclopropyl; R 30H, optionally substituted C1-C3 alkyl, optionally substituted C3-C4 cycloalkyl, or optionally substituted 5-6 membered heterocyclic alkyl, preferably optionally substituted cyclopropyl; and The remaining variables are as defined in this paper.

[0161] In some implementations, the BCR:ABL1 inhibitor is a compound of formula (Id): (Id); Or its pharmaceutically acceptable salt, wherein the remaining variables are as defined herein.

[0162] In some implementations, the BCR:ABL1 inhibitor is compound A: (Compound A) Or its pharmaceutically acceptable salt.

[0163] Suitable BCR:ABL1 inhibitors that may be used according to the methods described herein include, but are not limited to, compounds of formula (I), formula (Ii), formula (IA), formula (IA-1), formula (IIA), formula (IIB), formula (IIE) or formula (Id) (e.g., compound A) or pharmaceutically acceptable salts.

[0164] Compounds of formula (I), (Ii), (IA), (IA-1), (IIA), (IIB), (IIE), or (Id), including compound A, are disclosed in U.S. Patent No. 10,889,571, the entire contents of which are incorporated herein by reference, relating specifically to compounds of formula (I), (Ii), (IA), (IA-1), (IIA), (IIB), (IIE), or (Id), including compound A, or pharmaceutically acceptable salts thereof, and methods of manufacturing and using said compounds or pharmaceutically acceptable salts thereof.

[0165] This disclosure also includes all salts of the compounds mentioned herein, such as pharmaceutically acceptable salts. This disclosure also includes any or all stereochemical forms of the said compounds, including any enantiomers or diastereomers, and any tautomers or other forms, such as N-oxides, solvates, prodrugs, or isotopes. Unless the stereochemistry is explicitly indicated in the chemical structure or name, the structure or name is intended to cover all possible stereoisomers of the described compound. Furthermore, when a particular stereochemical form is described, it should be understood that other stereochemical forms are also covered by this invention. This invention also covers all forms of the compounds, such as crystalline or amorphous forms of the compounds. Compositions comprising the compounds of this invention, such as compositions of substantially pure compounds, including their particular stereochemical forms, are also contemplated. This invention also covers compositions comprising mixtures of the compounds of this invention in any proportion, including mixtures of two or more stereochemical forms of the compounds of this invention in any proportion, such that the covered compounds are enriched in racemic, non-racemic, diastereomers, and scalemic mixtures.

[0166] Tyrosine kinase inhibitors In some implementations, the tyrosine kinase inhibitor is selected from imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and baffitinib.

[0167] In some implementations, tyrosine kinase inhibitors bind to the active site of the tyrosine kinase.

[0168] In some implementations, the tyrosine kinase inhibitor is imatinib.

[0169] In some implementations, the tyrosine kinase inhibitor is nilotinib.

[0170] In some implementations, the tyrosine kinase inhibitor is dasatinib.

[0171] In some implementations, the tyrosine kinase inhibitor is bosutinib.

[0172] In some implementations, the tyrosine kinase inhibitor is ponatinib.

[0173] In some implementations, the tyrosine kinase inhibitor is barfetinib.

[0174] BCR: A combination of ABL1 inhibitors and tyrosine kinase inhibitors In some embodiments, this document discloses a combination comprising 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 barfetinib).

[0175] In some embodiments, this document further discloses pharmaceutical combinations comprising 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 barfetinib).

[0176] In some embodiments, this document discloses a combination comprising compound A and a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and barfetinib.

[0177] In some embodiments, this document further discloses a pharmaceutical combination comprising compound A and a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and barfetinib.

[0178] In some implementations, compound A and a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and barfetinib are co-administered concurrently (e.g., simultaneously, substantially simultaneously, or within the same treatment regimen) or sequentially.

[0179] In some embodiments, co-administration of compound A with a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and barfetinib 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 barfetinib increases the Cmax 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 barfetinib 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 barfetinib increases the Tmax of compound A. 1 / 2 .

[0180] The compositions or therapies disclosed herein may be administered individually to a patient or in combination (e.g., concurrently, sequentially, or alone). In some embodiments, compound A is administered prior to a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and barfetinib. In some embodiments, a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and barfetinib is administered prior to compound A.

[0181] In some embodiments, compound A and a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and barfetinib are administered approximately in time (e.g., compound A and the tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and barfetinib may initially be administered simultaneously). Therefore, this disclosure provides a method of treating or preventing cancer comprising administering compound A and a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and barfetinib approximately in time. In some embodiments, "approaching in time" means that one therapeutic agent is administered within a certain time period before or after the administration of another therapeutic agent, such that the therapeutic effect of one therapeutic agent overlaps with the therapeutic effect of the other. In some embodiments, the therapeutic effect of one therapeutic agent completely overlaps with the therapeutic effect of the other.

[0182] In some implementations, "temporally proximate" means that a therapeutic agent is administered within a certain time period before or after the administration of another therapeutic agent, resulting in a synergistic effect between the two agents. "Temporally proximate" 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 subject to whom the therapeutic agent is to be administered; the disease or condition to be treated or improved; the desired therapeutic outcome; the dosage, frequency, and duration of administration of the therapeutic agent; the pharmacokinetics and pharmacodynamics of the therapeutic agent; and the route of administration. In some implementations, "temporally proximate" means within 15 minutes, within 30 minutes, within 1 hour, within 2 hours, within 4 hours, within 6 hours, within 8 hours, within 12 hours, within 18 hours, within 24 hours, within 36 hours, within 2 days, within 3 days, within 4 days, within 5 days, within 6 days, within 1 week, within 2 weeks, within 3 weeks, within 4 weeks, within 6 weeks, or within 8 weeks. In some embodiments, multiple administrations of one therapeutic agent may be time-proximity to a single administration of another therapeutic agent. In some embodiments, this temporal proximity may vary during a treatment cycle or within a dosing regimen.

[0183] In some embodiments, this disclosure provides a synergistic combination of compound A with a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and barfetinib, wherein compound A and the tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and barfetinib are in contact with each other in the human body (e.g., only in the human body).

[0184] In some implementations, compound A and a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and barfetinib are co-administered concurrently (e.g., simultaneously, substantially simultaneously, or within the same treatment regimen) or sequentially.

[0185] In some embodiments, compound A and a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and barfetinib are co-administered in a single dose. In some embodiments, compound A and a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and barfetinib are co-administered in a combined dose.

[0186] Pharmaceutical compositions and formulations This invention covers pharmaceutical compositions of any of the compounds detailed herein. Therefore, this invention includes pharmaceutical compositions comprising the compounds of this invention or pharmaceutically acceptable salts thereof and pharmaceutically acceptable carriers or excipients. In one aspect, the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid. The pharmaceutical compositions of this invention are available in forms suitable for oral, buccal, parenteral, intranasal, topical, or rectal administration, or in forms suitable for inhalation administration.

[0187] In one aspect, compounds as detailed herein may be in purified form, and compositions comprising compounds in purified form are detailed herein. Compositions comprising compounds as detailed herein or salts thereof are provided, such as compositions of substantially pure compounds. In some embodiments, compositions comprising compounds as detailed herein or salts thereof are in substantially pure form. In one variation, “substantially pure” means a composition containing no more than 35% impurities, wherein impurities represent compounds other than the compound or salt thereof constituting the majority of the composition. For example, compositions of substantially pure compounds of formula (I), (Ii), (IA), (IA-1), (IIA), (IIB), (IIE), or (Id) (e.g., compound A) are intended to contain no more than 35% impurities, wherein impurities represent compounds other than said compound or salt thereof. In one variation, compositions of substantially pure compounds or salts thereof are provided, wherein said compositions contain no more than 25% impurities. In another variation, compositions of substantially pure compounds or salts thereof are provided, wherein said compositions contain or do not exceed 20% impurities. In another variation, a composition of substantially pure compound or its salt is provided, wherein the composition contains or does not exceed 10% impurities. In another variation, a composition of substantially pure compound or its salt is provided, wherein the composition contains or does not exceed 5% impurities. In another variation, a composition of substantially pure compound or its salt is provided, wherein the composition contains or does not exceed 3% impurities. In another variation, a composition of substantially pure compound or its salt is provided, wherein the composition contains or does not exceed 1% impurities. In another variation, a composition of substantially pure compound or its salt is provided, wherein the composition contains or does not exceed 0.5% impurities. In other variations, the composition of substantially pure compound is intended to contain no more than 15%, or preferably no more than 10%, or more preferably no more than 5%, or even more preferably no more than 3%, and most preferably no more than 1% impurities, which may be compounds in different stereochemical forms. For example (but not limited to), a composition of substantially pure (S) compound is intended to contain no more than 15%, or no more than 10%, or no more than 5%, or no more than 3%, or no more than 1% of the (R) form of said compound.

[0188] In one variant, the compounds described herein are synthetic compounds prepared for administration to an individual (e.g., a human). In another variant, compositions comprising the compounds in substantially pure form are provided. In yet another variant, the invention covers pharmaceutical compositions comprising the compounds detailed herein and pharmaceutically acceptable carriers or excipients. In yet another variant, methods of administering the compounds are provided. The purified form, pharmaceutical composition, and method of administering the compounds are suitable for any of the compounds or forms thereof detailed herein.

[0189] The compounds can be formulated for any available route of delivery, including oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., intramuscular, subcutaneous, or intravenous), topical, or percutaneous delivery. The compounds can be formulated with suitable carriers to provide delivery forms, including but not limited to tablets, capsules (e.g., hard gelatin capsules or soft elastic gelatin capsules), flat capsules, sugar tablets, rhomboid tablets, gels, dispersants, suppositories, ointments, 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 emulsions), solutions, and elixirs.

[0190] The compounds described herein can be used to prepare formulations, such as pharmaceutical preparations, by combining one or more compounds as active ingredients with a pharmaceutically acceptable carrier (such as the carriers mentioned above). The carrier can take various forms depending on the systemic therapeutic form (e.g., transdermal patch versus oral tablet). Additionally, pharmaceutical preparations may contain preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, dyes, regulators, and salts, buffers, coating agents, or antioxidants for adjusting osmotic pressure. Formulations containing the compounds may also contain other substances with valuable therapeutic properties. Pharmaceutical preparations can be prepared using known pharmaceutical methods. Suitable formulations can be found, for example, in Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21st edition (2005), which is incorporated herein by reference.

[0191] The compounds described herein can be administered to an individual (e.g., a human) in the form of generally acceptable oral compositions (e.g., tablets, coated tablets, and gel capsules, emulsions, or suspensions in hard or soft shells). Examples of carriers that can be used to prepare such compositions include lactose, corn starch or derivatives thereof, talc, stearates or salts thereof. Acceptable carriers for gel capsules with soft shells include, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols. Additionally, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, dyes, regulators, and salts, buffers, coating agents, or antioxidants for adjusting osmotic pressure.

[0192] Any of the compounds described herein can be formulated into tablets in any of the dosage forms described herein.

[0193] Compositions comprising 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 composition of substantially pure compounds is provided.

[0194] 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 relative to wild-type BCR:ABL-1. In some embodiments, the BCR:ABL-1 protein contains multiple amino acid mutations relative to wild-type BCR:ABL-1.

[0195] In some implementations, the BRC:ABL-1 protein contains a single amino acid mutation selected from the following: F359V, F359C, F359I, H396R, E255V, T315I, A337V, A344P, P465S, ​​T315M, and V468F. In some implementations, the BCR:ABL-1 protein contains a plurality of amino acid mutations selected from the following: (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.

[0196] Wild-type BCR:ABL-1, isotype P00519 (SEQ ID NO: 1) BCR:ABL-1, a single mutant of isotype P00519 F359V (SEQ ID NO: 2) BCR:ABL-1, a single mutant of isotype P00519 F359C (SEQ ID NO: 3) BCR:ABL-1, a single mutant of isotype P00519 F359I (SEQ ID NO: 4) BCR:ABL-1, a single mutant of isotype P00519 H396R (SEQ ID NO: 5) BCR:ABL-1, a single mutant of isotype P00519 E255V (SEQ ID NO: 6) BCR:ABL-1, isotype P00519 T315I single mutant (SEQ ID NO: 7) BCR:ABL-1, a single mutant of isotype P00519 A337V (SEQ ID NO: 8) BCR:ABL-1, isotype P00519 A344P single mutant (SEQ ID NO: 9) BCR:ABL-1, isotype P00519 P465S single mutant (SEQ ID NO: 10) BCR:ABL-1, isotype P00519 T315M single mutant (SEQ ID NO: 11) BCR:ABL-1, a single mutant of isotype P00519 V468F (SEQ ID NO: 12) BCR:ABL-1, isotype P00519 G250E / T315I double mutant (SEQ ID NO: 13) BCR:ABL-1, isotype P00519 Y253H / T315I double mutant (SEQ ID NO: 14) BCR:ABL-1, isotype P00519 E255V / T315I, dual mutant (SEQ ID NO: 15) BCR:ABL-1, isotype P00519 H396R / T315I, double mutant (SEQ ID NO: 16) BCR:ABL-1, isotype P00519 E255V / V299L, dual mutant (SEQ ID NO: 17) BCR:ABL-1, isotype P00519 Y253H / F317L double mutant (SEQ ID NO: 18) BCR:ABL-1, isotype P00519 A337V / T315I, dual mutant (SEQ ID NO: 19) BCR:ABL-1, isotype P00519 A344P / T315I, double mutant (SEQ ID NO: 20) BCR:ABL-1, isotype P00519 P465S / T315I, double mutant (SEQ ID NO: 21) BCR:ABL-1, isotype P00519 V468F / T315I, double mutant (SEQ ID NO: 22) Methods of use / treatment The compounds and compositions detailed herein (e.g., pharmaceutical compositions containing the compounds provided herein or their salts and pharmaceutically acceptable carriers or excipients) may be used in the administration and treatment methods provided herein. The compounds and compositions may also be used in in vitro methods, such as in vitro methods for administering the compounds or compositions to cells for screening purposes and / or for performing quality control analyses.

[0197] In some respects, the compounds and compositions described herein can be used to treat cancer. In some embodiments, methods of treating cancer in a subject of need include administering a BCR:ABL1 inhibitor and a tyrosine kinase inhibitor (TKI) to the subject.

[0198] In some embodiments, the method includes 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 barfetinib).

[0199] 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.

[0200] Without being limited to theory, it is believed that, compared with monotherapy, the combination of 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 with tyrosine kinase inhibitors (e.g., imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and barfetinib) according to the methods described herein can effectively provide treatment and thus reduce dose-dependent adverse reactions that may accompany monotherapy.

[0201] In one aspect, this document provides a method of treating a patient with cancer, comprising administering to the patient a therapeutically effective amount of the compound or composition provided herein. 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).

[0202] This article provides methods for treating cancer in patients in need (e.g., human patients) with a 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 barfetinib), comprising administering a therapeutically effective amount of a BCR:ABL1 inhibitor or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a tyrosine kinase inhibitor, wherein the cancer is melanoma, hereditary leiomyomatosis, renal cell carcinoma (HLRCC), or other solid tumor.

[0203] This article provides methods for treating cancer in patients in need (e.g., human patients) with a 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 barfetinib), comprising administering a therapeutically effective amount of a BCR:ABL1 inhibitor or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a tyrosine kinase inhibitor, wherein the cancer is lymphoma or leukemia.

[0204] This article provides methods for treating cancer in patients in need (e.g., human patients) with a 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 barfetinib), comprising administering a therapeutically effective amount of a BCR:ABL1 inhibitor and a therapeutically effective amount of a tyrosine kinase inhibitor, wherein the cancer is CML.

[0205] In some implementations, the patient has received one or more prior therapies. In some implementations, the cancer progresses during the treatment.

[0206] In some embodiments, the BCR:ABL1 inhibitor (e.g., a compound of formula (I), (Ii), (IA), (IA-1), (IIA), (IIB), (IIE), or (Id), such as compound A) or its pharmaceutically acceptable salt and tyrosine kinase inhibitor (e.g., imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and barfetinib) is administered simultaneously. In some such embodiments, the BCR:ABL1 inhibitor (e.g., a compound of formula (I), (Ii), (IA), (IA-1), (IIA), (IIB), (IIE), or (Id), such as compound A) or its pharmaceutically acceptable salt and tyrosine kinase inhibitor (e.g., imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and barfetinib) may be provided as a single pharmaceutical composition. In other embodiments, 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 tyrosine kinase inhibitors (e.g., imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and barfetinib) are administered sequentially.

[0207] 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 tyrosine kinase inhibitors (e.g., imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and barfetinib) may be administered alone at the doses usually applied.

[0208] Optionally, due to the potential synergistic effects 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 barfetinib) may be administered at a lower dose than when each agent is administered alone.

[0209] In some embodiments, the 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, used according to the methods described herein, may be administered to an individual at a dose once daily for a first time period, and then the administration of the compound may be interrupted for a second time period, wherein a tyrosine kinase inhibitor (e.g., imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and barfetinib) may be maintained during the first and second time periods.

[0210] In one aspect, this document provides a method for inhibiting the tyrosine kinase activity of a protein selected from Abelson protein (ABL1), Abelson-associated protein (ABL2), or the chimeric protein BCR-ABL1, comprising contacting said protein with a combination of an effective amount of compound A and an effective amount of a tyrosine kinase inhibitor. In one embodiment, this document provides a method for inhibiting the tyrosine kinase activity of Abelson protein (ABL1), comprising contacting ABL1 with a combination of an effective amount of compound A and an effective amount of a tyrosine kinase inhibitor. In another embodiment, this document provides a method for inhibiting the tyrosine kinase activity of Abelson-associated protein (ABL2), comprising contacting ABL2 with a combination of an effective amount of compound A and an effective amount of a tyrosine kinase inhibitor. In yet another embodiment, this document provides a method for inhibiting the tyrosine kinase activity of the chimeric protein BCR-ABL1, comprising contacting the chimeric protein with a combination of an effective amount of compound A and an effective amount of a tyrosine kinase inhibitor.

[0211] In one aspect, this article provides a method for treating a disease in a patient in need, the method comprising administering to the patient a therapeutically effective amount of compound A or a salt thereof in combination with a therapeutically effective amount of a tyrosine kinase inhibitor.

[0212] The compounds described herein, or their salts, combinations, and compositions thereof, are believed to be effective in treating a variety of diseases and conditions. In some embodiments, the compounds described herein, or their salts, combinations, and compositions thereof, can be used in methods for treating diseases mediated by ABL1, ABL2, and / or BCR-ABL1.

[0213] In one aspect, this document provides a method for treating a patient's disease, wherein modulating BCR-ABL1 activity prevents, inhibits, or improves the pathology and / or symptomology of the disease, the method comprising administering to the patient a combination of a therapeutically effective amount of compound A and a therapeutically effective amount of a tyrosine kinase inhibitor. In one embodiment, this document provides a method for treating a patient's disease, wherein modulating BCR-ABL1 activity prevents the pathology and / or symptomology of the disease, the method comprising administering to the patient a combination of a therapeutically effective amount of compound A and a therapeutically effective amount of a tyrosine kinase inhibitor. In one embodiment, this document provides a method for treating a patient's disease, wherein modulating BCR-ABL1 activity inhibits the pathology and / or symptomology of the disease, the method comprising administering to the patient a combination of a therapeutically effective amount of compound A and a therapeutically effective amount of a tyrosine kinase inhibitor. In one embodiment, this document provides a method for treating a patient's disease, wherein modulating BCR-ABL1 activity improves the pathology and / or symptomology of the disease, the method comprising administering to the patient a combination of a therapeutically effective amount of compound A and a therapeutically effective amount of a tyrosine kinase inhibitor.

[0214] In some implementations, the disease is leukemia. In some implementations, the leukemia is chronic myeloid leukemia (CML), acute myeloid leukemia (AML), or acute lymphoblastic leukemia (ALL). In some implementations, the leukemia is chronic myeloid leukemia (CML).

[0215] In one aspect, this article provides a method for treating a patient with leukemia, comprising administering to the patient a therapeutically effective amount of compound A combined with a therapeutically effective amount of a tyrosine kinase inhibitor. In another aspect, this article provides a method for treating a patient with leukemia, comprising administering to the patient a therapeutically effective amount of compound A combined 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).

[0216] 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 barfetinib.

[0217] In some implementations, the leukemia is resistant to treatment. In some implementations, the leukemia is resistant to treatment with aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and / or barfetinib. In some implementations, CML is resistant to standard of care (e.g., treatment with one or more of aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and barfetinib). In some implementations, the leukemia progressed during prior treatment. In some implementations, prior treatment included administration of aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and / or barfetinib.

[0218] In some implementations, AML is secondary AML, which develops after myelodyplastic syndrome (MDS) or myeloproliferative neoplasm (MPN).

[0219] On the other hand, methods are provided to delay the onset and / or development of a disease or condition mediated by BCR-ABL1 activity in patients (e.g., humans) who are at risk of developing the disease or condition. It should be understood that delaying development may encompass prevention in the absence of the disease or condition in an individual or patient. In one aspect, an individual or patient at risk of developing a disease or condition mediated by BCR-ABL1 activity has one or more risk factors for developing the disease or condition, such as having the disease or condition, or having a family history of an underlying genetic condition that increases the likelihood of developing the disease or condition.

[0220] In one aspect, this article provides a method for delaying the onset and / or development of leukemia in patients in need, comprising administering to the patient a therapeutically effective amount of a combination of compound A and a therapeutically effective amount of a tyrosine kinase inhibitor. In one variant, this article provides a method for delaying the onset and / or development of CML in patients in need, comprising administering to the patient a therapeutically effective amount of compound A and a therapeutically effective amount of a tyrosine kinase inhibitor. In one variant, this article provides a method for delaying the onset and / or development of AML in patients in need, comprising administering to the patient a therapeutically effective amount of compound A and a therapeutically effective amount of a tyrosine kinase inhibitor. In one variant, this article provides a method for delaying the onset and / or development of ALL in patients in need, comprising administering to the patient a therapeutically effective amount of compound A and a therapeutically effective amount of a tyrosine kinase inhibitor.

[0221] Methods for treating diseases mediated by BCR-ABL1 (such as various types of leukemia) are well known to those skilled in the art, and are suitable for treating such diseases with a combination of compound A and a tyrosine kinase inhibitor.

[0222] 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 18 years of age, 21 years of age, 30 years of age, 50 years of age, 60 years of age, 65 years of age, 70 years of age, 75 years of age, 80 years of age, or 85 years of age. In some embodiments, the human is a child. In some embodiments, the human is less than about 21 years of age, 18 years of age, 15 years of age, 10 years of age, 5 years of age, 4 years of age, 3 years of age, 2 years of age, or 1 year of age. In some embodiments, the patient has a genetic condition associated with an increased likelihood of developing a disease (e.g., 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.

[0223] The combinations, compounds, or compositions described herein may be administered to a patient for a desired period of time or duration, depending on an effective dosing regimen, such as 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, and in some variations, for a lifetime. In one variation, the combination, compound, or composition is administered on a daily or intermittent schedule. The combination, compound, or composition may be administered to a patient continuously (e.g., at least once daily) for a period of time. The dosing frequency may also be less than once daily, such as about once a week. The dosing frequency may be more than once daily, such as twice or three times daily. The dosing frequency may also be intermittent (e.g., once daily for 7 days, followed by no dosing for 7 days, repeated within any 14-day period, such as about 2 months, about 4 months, about 6 months, or longer). Any dosing frequency may be achieved using any of the combinations, compounds, or compositions described herein and any of the doses described herein.

[0224] The combinations, compounds, or compositions described herein can be administered to patients via various routes, including, for example, intravenous, intramuscular, subcutaneous, oral, and transdermal.

[0225] The dosage of the compound administered to the 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 a therapeutically effective amount.

[0226] In one aspect, the effective amount of the compound may be a dose between about 0.01 mg / kg and about 100 mg / kg. The effective amount or dose of the compound disclosed herein may be determined by conventional methods (e.g., modeling, dose escalation, or clinical trials), taking into account conventional factors such as the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and duration of the disease to be treated, the health status, ailment, and weight of the subject. Illustrative doses range from about 0.7 mg to 7 g daily, or from about 7 mg to 350 mg daily, or from about 350 mg to 1.75 g daily, or from about 1.75 g to 7 g daily.

[0227] This document also provides the use of the combinations, compounds, or compositions described herein for the manufacture of a medicament. In some embodiments, the manufacture of the medicament is for the treatment of the diseases described herein. In some embodiments, the manufacture of the medicament is for the treatment of diseases mediated by ABL1, ABL2, and / or BCR-ABL1.

[0228] In some implementations, the methods disclosed herein further include the step of determining the DNA sequence of the BCR:ABL1 gene expressed by the subject.

[0229] In some implementations, the methods disclosed herein further include the step of determining the amino acid sequence of the BCR:ABL1 protein expressed by the subject.

[0230] Dosage and treatment regimen In some embodiments, the combination comprises administering compound A and a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and barfetinib in a ratio of about 1:10 to about 10:1.

[0231] In some embodiments, the combination comprises administering compound A and a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and barfetinib in a ratio of about 1:9 to about 9:1.

[0232] In some embodiments, the combination comprises administering compound A and a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and barfetinib in a ratio of about 1:8 to about 8:1.

[0233] In some embodiments, the combination comprises administering compound A and a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and barfetinib in a ratio of about 1:7 to about 7:1.

[0234] In some embodiments, the combination comprises administering compound A and a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and barfetinib in a ratio of about 1:6 to about 6:1.

[0235] In some embodiments, the combination comprises administering compound A and a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and barfetinib in a ratio of about 1:5 to about 5:1.

[0236] In some embodiments, the combination comprises administering compound A and a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and barfetinib in a ratio of about 1:4 to about 4:1.

[0237] In some embodiments, the combination comprises administering compound A and a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and barfetinib in a ratio of about 1:3 to about 3:1.

[0238] In some embodiments, the combination comprises administering compound A and a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and barfetinib in a ratio of about 1:2 to about 2:1.

[0239] In some embodiments, the combination comprises administering compound A and a tyrosine kinase inhibitor selected from aciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and barfetinib 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.

[0240] In some implementations, the combination of compound A and imatinib has a synergistic effect in the K562 cell line relative to the Ku812 cell line.

[0241] In some implementations, the combination of compound A and dasatinib has a synergistic effect in the K562 cell line relative to the Ku812 cell line.

[0242] Products and reagent kits This disclosure further provides articles comprising the combinations, compounds, or compositions described herein, or one or more unit doses, in suitable packaging. In some embodiments, the articles are used in any of the methods described herein. Suitable packaging (e.g., containers) is known in the art and includes, for example, vials, vessels, ampoules, bottles, wide-mouth bottles, flexible packaging, etc. The articles may be further sterilized and / or sealed.

[0243] This disclosure further provides kits for carrying out the methods of this disclosure, comprising the combinations, compounds, or compositions described herein. The kit may employ any of the combinations, compounds, or compositions disclosed herein. In some embodiments, the kit employs 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 a pharmaceutically acceptable salt thereof) and tyrosine kinase inhibitors (e.g., imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and barfetinib). The kit may be used for any one or more of the purposes described herein and may therefore contain instructions for use as described herein for the treatment.

[0244] Kits typically include suitable packaging. A kit may contain one or more containers containing any combination described herein, any compound described herein, or a pharmaceutically acceptable salt thereof. Where cross-reactivity and shelf life permit, each component may be packaged in a separate container, or several components may be combined in one container. 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 barfetinib). In other embodiments, the kit includes 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 barfetinib).

[0245] The kits may be available in unit dose form, in bulk packaging (e.g., multi-dose packaging), or in subunit doses. For example, kits may be provided containing sufficient doses of a compound as disclosed herein and / or another pharmaceutically active compound applicable to the diseases detailed herein, to provide effective treatment to patients over extended periods (e.g., any of 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or longer). Kits may also include multiple unit doses of the compound and instructions for use, packaged in quantities sufficient for storage and use in a pharmacy (e.g., hospital pharmacies and multi-functional pharmacies).

[0246] The kit may optionally include a set of instructions, typically in written form, but electronic storage media (e.g., disks or optical discs) containing instructions are also acceptable, relating to the use of the components of the methods disclosed herein. The instructions accompanying the kit typically include information about the components and the individual to whom they are administered.

[0247] The kit may be used for any one or more of the purposes described herein, and may therefore contain instructions for use in treating any of the diseases described herein (e.g., for treating cancer).

[0248] Exemplary implementation plan P-1. A method for treating cancer in a subject of need, the method comprising administering a combination of a BCR:ABL1 inhibitor and a tyrosine kinase inhibitor, wherein the BCR:ABL1 inhibitor is a compound of formula (I): (I) Or its tautomers or N-oxides, or pharmaceutically acceptable salts of any of the foregoing, wherein: L can be -NH-CO-, -CO-NH-, -NH-SO2-, or -SO2-NH-; R 1 C6-C as an optional substitute 10 Aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 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 2H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocyclic alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C6-C 10 Aryl or optionally substituted 5-10 heteroaryl groups; R 3 H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, 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 intermediate atom, it can form an optionally substituted C3-C8 cycloalkyl or an optionally substituted 4-10 membered heterocyclic alkyl; R 4 It can be an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, or an optionally substituted C2-C6 alkynyl; X is either O or S; Y is CH, C-(C1-C2 alkyl), C-halogenated, or N; Z is CR 5 Or N; R 5 It is H or halogen; R 6 H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocyclic alkyl, optionally substituted C6-C 10 aryl or optionally substituted 5-10 heteroaryl groups; and R 7 H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocyclic alkyl, optionally substituted C6-C 10 Aryl or optionally substituted 5-10 heteroaryl groups; Or R 6 and R 7 Together with the nitrogen to which it is attached, it forms an optionally substituted 4-7 membered heterocycle. The condition is that the compound is not (i) 5-[[(4-methoxyphenyl)sulfonyl]amino]-1-methyl-1H-benzimidazole-7-carboxylic acid or (ii) 5-[[(4-ethoxyphenyl)sulfonyl]amino]-1-methyl-1H-benzimidazole-7-carboxylic acid.

[0249] P-2. The method as described in embodiment P-1, wherein the BCR:ABL1 inhibitor is a compound of formula (IA-1): (IA-1), Or its pharmaceutically acceptable salt.

[0250] P-3. The method according to any of the foregoing embodiments, wherein the BCR:ABL1 inhibitor is (R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-1-(1-hydroxypropyl-2-yl)-7-(pyrimidin-5-yl)-1H-benzo[d]imidazolium-5-carboxamide (compound A): (Compound A) Or a pharmaceutically acceptable salt thereof, in combination with a tyrosine kinase inhibitor, for the treatment of cancer in subjects in need.

[0251] P-4. The method according to any of the foregoing embodiments, wherein the tyrosine kinase inhibitor is selected from imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and baffitinib.

[0252] P-5. The method according to any of the foregoing embodiments, wherein the cancer is lymphoma or leukemia.

[0253] P-6. A method for inhibiting the tyrosine kinase activity of proteins selected from Abelson protein (ABL1), Abelson-associated protein (ABL2), and the chimeric protein BCR-ABL1, said method comprising dispensing an effective amount of compound A: (Compound A) Alternatively, a combination of a pharmaceutically acceptable salt and an effective amount of a tyrosine kinase inhibitor may be used to contact the protein.

[0254] P-7. A method for treating a patient's disease, wherein modulating BCR-ABL1 activity prevents, inhibits, or improves the pathology and / or symptomology of the disease, said method comprising administering to the patient a therapeutically effective amount of compound A: (Compound A) Or a combination of a pharmaceutically acceptable salt thereof with a therapeutically effective amount of a tyrosine kinase inhibitor.

[0255] P-8. A method for treating a patient with leukemia, the method comprising administering to the patient a therapeutically effective amount of compound A: (Compound A) Or a pharmaceutically acceptable salt thereof 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).

[0256] P-9. The method according to any of the foregoing embodiments, wherein the method comprises administering compound A and a tyrosine kinase inhibitor selected from imatinib, nilotinib, dasatinib, bosutinib, ponatinib and barfetinib 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.

[0257] P-10. Use of a compound A or a pharmaceutically acceptable salt thereof in combination with a tyrosine kinase inhibitor in the preparation of a medicament for treating cancer in a subject in need.

[0258] P-11. A combination comprising a BCR:ABL1 inhibitor and a tyrosine kinase inhibitor, and at least one pharmaceutically acceptable excipient, wherein the BCR:ABL1 inhibitor is a compound of formula (I): (I) Or its tautomers or N-oxides, or pharmaceutically acceptable salts of any of the foregoing, wherein: L can be -NH-CO-, -CO-NH-, -NH-SO2-, or -SO2-NH-; R 1 C6-C as an optional substitute 10 Aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 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 H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocyclic alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C6-C 10 Aryl or optionally substituted 5-10 heteroaryl groups; R 3H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, 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 intermediate atom, it can form an optionally substituted C3-C8 cycloalkyl or an optionally substituted 4-10 membered heterocyclic alkyl; R 4 It can be an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, or an optionally substituted C2-C6 alkynyl; X is either O or S; Y is CH, C-(C1-C2 alkyl), C-halogenated, or N; Z is CR 5 Or N; R 5 It is H or halogen; R 6 H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocyclic alkyl, optionally substituted C6-C 10 aryl or optionally substituted 5-10 heteroaryl groups; and R 7 H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocyclic alkyl, optionally substituted C6-C 10 Aryl or optionally substituted 5-10 heteroaryl groups; Or R 6 and R 7 Together with the nitrogen to which it is attached, it forms an optionally substituted 4-7 membered heterocycle. The condition is that the compound is not (i) 5-[[(4-methoxyphenyl)sulfonyl]amino]-1-methyl-1H-benzimidazole-7-carboxylic acid or (ii) 5-[[(4-ethoxyphenyl)sulfonyl]amino]-1-methyl-1H-benzimidazole-7-carboxylic acid.

[0259] P-12. A combination of embodiments P-11, wherein the combination is used to treat a patient with leukemia, comprising administering to the patient a therapeutically effective amount of a BCR:ABL1 inhibitor and 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).

[0260] P-13. As in the combination of implementation plan P-12, wherein the leukemia is CML or ALL, and the tyrosine kinase inhibitor is selected from: imatinib, nilotinib, dasatinib, flumatinib, bosutinib, ponatinib, and baffitinib.

[0261] P-14. Any combination of the foregoing implementation schemes, wherein CML is tolerated by standard care.

[0262] P-15. A combination of any of the foregoing embodiments, wherein CML is tolerable to treatment with one or more of imatinib, ponatinib, nilotinib, and dasatinib.

[0263] P-16. A combination of any of the foregoing embodiments, wherein the AML is secondary AML that develops following myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN).

[0264] Example Example 1 - The potency, selectivity and ability of compound A to synergize with the active site TKI background Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by a reciprocal translocation between chromosomes 9 and 22, resulting in the loss of myristoyl-directed autoregulation and constitutive activation of the BCR::ABL1 oncogene. Figure 1 ).

[0265] Compound A retains activity against the BCR::ABL1T315I tolerance mutation, which confers tolerance to all injected active site inhibitors except ponatinib.

[0266] Target Although tyrosine kinase inhibitors (TKIs) targeting the ATP-binding site of the BCR::ABL1 oncoprotein are effective treatments for chronic myeloid leukemia (CML), patients often develop resistance due to mutations in the ATP-binding site. Compound A undergoes allosteric modification to specifically target the ABL myristoyl pocket (STAMP) of BCR::ABL1, leading to its inhibition. Compound A is engineered to circumvent resistance caused by mutations in the active site and has the potential for synergistic combination with TKIs targeting the active site.

[0267] method The ABL1 kinase domain (amino acid residues 64-515) was expressed and purified from SH9 cells by affinity chromatography. Activity was validated using a microfluidic flow transfer assay.

[0268] 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 evaluated using CellTiter-Glo® or ATPlite 1Step™ (PerkinElmer) solutions. The synergistic effects between compound A and the active site TKIs were evaluated using fixed molar combinations and expanded combination matrices, with cell viability measured using CellTiter-Glo® and interactions quantified using Bliss, HSA, and Loewe models.

[0269] result Regarding selectivity, in the in vitro kinase assay, compound A did not inhibit >50% of any kinases, including full-length ABL1, at 1 µM. Compound A exhibited high potency and selectivity only against the BCR::ABL1+ cancer cell line, and was more selective than acimenide. Figure 2 In vitro combination studies revealed that compound A synergistically interacts with multiple TKIs in the K562 and BaF3BCR-ABL-T315I cell lines, and at least additively interacts with them in the Ku812 cell line. Figure 3-6B (and Tables 1-4). As evaluated using the BLISS model, the synergistic effect was at or below the IC50 of each individual compound. 50 It is strongest at that time.

[0270] Table 1. Summary of synergistic effects quantified through curve displacement and equivalent line plot analysis Table 2. Summary of BLISS synergistic data of compound A in combination with imatinib, dasatinib, or ponatinib Table 3. Summary of BLISS synergistic data of compound A in combination with imatinib, dasatinib, or ponatinib Table 4. Summary of synergistic effects quantified through curve displacement and equivalent line plot analysis in conclusion In cell-free and cell-based analyses and screenings, compound A was identified as a potent and selective allosteric inhibitor of BCR::ABL1, with a potency and synergistic profile comparable to aciminib, while potentially being more selective. Compound A retains activity against the T315I gate mutation, which confers tolerance to all injected active site TKIs except ponatinib.

[0271] This study confirms that compound A (BCR::ABL1 allosteric inhibitor) is effective against resistance mutations of active site tyrosine kinase inhibitors (TKIs) and synergizes with TKIs in BCR::ABL1+ cancer cell lines.

[0272] Example 2: Determining the efficacy of compound A (ABT4) alone and in combination with dasatinib (ABT6) and ponatinib (ABT7) in Ba / F3-T315O mouse CML in BALB / c nude female mice. Example 2 illustrates an in vivo study that demonstrated that compound A, when combined with ponatinib, exhibited a dose-dependent reduction in tumor burden in the BCR::ABL1-T315I CML model. Results are summarized in... Figure 7-8 middle.

[0273] program Establish CR 245 female BALB / c nude mice with 2×10⁻⁶ Matrigel in their lateral ventral region. 6 One BaF3-T315I tumor cell.

[0274] The cell injection volume was 0.1 mL / mouse.

[0275] Age at start date: 7 to 10 weeks.

[0276] When the tumor reaches 60-90 mm 3 Pairing and treatment are implemented when the average age is reached.

[0277] Weight: qd × 5, then biwk to the end. Caliper measurement: biwk to end Euthanasia shall be performed on any individual animal that shows a loss of >30% body weight in a single observation or a loss of >25% body weight in three consecutive measurements.

[0278] Dosing was discontinued in any group with an average weight loss >20% or a mortality rate >10%. Euthanasia was not performed in these groups, and recovery was permitted. Within groups with a weight loss >20%, individuals who reached their individual weight loss endpoint were euthanized. If treatment-related weight loss recovered to within 10% of original body weight, dosing was restarted at a lower dose or lower frequency. Exceptions were permitted based on the specific circumstances for non-treatment weight recovery.

[0279] Endpoint. Animals were monitored as a group. The experimental endpoint was 2000 mm in the control group. 3 Alternatively, the average tumor weight over 15 days, whichever comes first. All animals were euthanized upon reaching the endpoint.

[0280] The animal group was administered the compounds described below: Table 2-1: Drugs and Treatments: ABT6 is a co-prepared reagent - dosage instructions are as follows. Example 3: Screening for compound A against the BCR:ABL1 mutant Cell proliferation analysis of an expanded group of BCR-ABL1 single and composite mutant cell lines Compound A was screened for Ba / F3 cell lines expressing wild-type BCR-ABL1 (in pSRα or pMIG expression vectors) or a combination of single or compound BCR-ABL1 mutations. Single BCR-ABL1 mutant lines included a range of clinically relevant kinase domain mutations and selected mutants of the myristylated pocket conferring acimenide resistance; compound BCR-ABL1 mutants included both T315I mutations and non-T315I compound mutations. Parental Ba / F3 cells were also tested as a control for target-controlled selectivity. Briefly, Ba / F3 BCR-ABL1 cell lines were resuspended in fresh medium (containing 10% FBS) and plated in 384-well plates in fractionated concentrations of compound A. The plates were cultured for 3 days, and MTS-based colorimetric viability analysis was performed. Absorbance data were set as blanks, normalized to untreated controls, and fitted to a nonlinear regression model to calculate the cell IC50. 50 value.

[0281] In vitro drug synergistic effect analysis of mutant BCR-ABL1 cell line For Ba / F3 cells expressing BCR-ABL1 wild-type, T315I, or composite mutant subgroups, compound A was evaluated in a cell proliferation assay similar to that described above, but in combination with approved ATP site inhibitors imatinib, dasatinib, or ponatinib to determine synergistic inhibitory potential. Cells were tested individually for each inhibitor, as well as in a dose matrix for all possible dose combinations. Normalized MTS absorbance data were further analyzed using the synergyfinder R package to quantify potential synergistic effects using various models, such as highest single-dose (HSA), Bliss, and zero-interaction potency (ZIP). A similar dose matrix was tested on Ba / F3 parental cells to confirm combination off-target toxicities.

[0282] Cell-based accelerated tolerance screening Compound A was analyzed using cell-based in vitro mutagenesis screening. Briefly, Ba / F3 BCR-ABL1 cells were treated with ENU overnight (to induce random mutations), resuspended in fresh medium, and plated in the presence of fractionated concentrations of the inhibitor. Wells containing growth were enlarged, harvested, and DNA from the BCR-ABL1 kinase domain (approximately ABL1a residues 235-530) was isolated and amplified by PCR, with Sanger sequencing performed on the mutations. Similar mutagenesis tolerance screening was initiated from Ba / F3 cells expressing BCR-ABL1 T315I to identify potential complex mutant tolerance mechanisms, and was also performed in combination with ponatinib to determine the potential for inhibiting the growth of complex mutants.

[0283] Primary CML patient cell ex vivo analysis Primary mononuclear cells from 3–4 newly diagnosed CML patients or those with the T315I tolerance mutation were thawed and treated with multiple concentrations of compound A overnight or for 3 days; imatinib treatment was included as a control. Overnight-treated cells were lysed and subjected to Western blot analysis of pCRKL levels, and the effects of 3-day-treated cells on viability and / or annexin-V apoptosis-inducing effects were analyzed.

[0284] Example 4: Characterization of compound A for natural and mutant BCR:ABL-1 Studies were conducted to determine the in vitro activity of compound A alone and in combination with dasatinib or ponatinib. BaF / 3 cells expressing natural BCR::ABL1, BCR::ABL1 single mutants (F359V, F359C, F359I, H396R, E255V, T315I, A337V, A344P, P465S, ​​V468F), and BCR::ABL1 complex mutants (G250E / T315I, Y253H / T315I, E255V / T315I, H396R / T315I, E255V / V299L, T315M, Y253H / F317L, A337V / T315I, A344P / T315I, P465S / T315I, V468F / T315I) were subjected to graded concentrations (4-log range, from 0.1...) Cells were cultured in the presence of compound A (starting at nM) and dasatinib or compound A and ponatinib. Analysis was performed in triplicate, and viable cells were quantified by MTS analysis. Synergistic effects were analyzed using the Combenefit and Synergy Finder platforms (interactive platforms that allow for the collection of all experimental replicates). Synergistic effect scores were determined using Bliss and ZIP reference models. Data were reported in tabular and graphical form.

[0285] The activity of compound A alone and in combination with dasatinib or ponatinib in BCR::ABL1 signaling was determined. pSTAT5 / STAT5 was quantified by immunoblotting in BaF / 3 cells expressing native or mutant BCR::ABL1 treated with inhibitors, using stable concentrations of compound A and 4-log ranges of dasatinib and ponatinib, respectively. Data will be reported as immunoblotting images, FACS histograms, and graphs.

[0286] The in vivo activity of compound A as a single agent or in combination with dasatinib or ponatinib was evaluated in a retroviral transduction / transplantation model of CML using native and E255V / T315I mutant BCR::ABL1. Bone marrow from 5-fluorouracil-treated Balb / c mice was transduced with BCR::ABL1-GFP retrovirus, and cells were injected into lethally irradiated syngeneic recipients. After confirming leukemia engraftment (detection of GFP+ cells in the blood by FACS), mice (N=10 / group) were initiated with compound A, dasatinib, ponatinib, compound A plus dasatinib, compound A plus ponatinib, or the vector. Mice were monitored by daily examination and weighing, weekly complete blood counts, and FACS+ of GFP+ blood cells. Mice were sacrificed and thoroughly dissected at the onset of distress or at 6 weeks (end of treatment, EOT), including histology of the organs involved and quantification of leukemia burden by flow cytometry. Kaplan-Meyer statistics were used to compare survival rates in the treatment groups, and t-tests were used to compare differences in continuous variables.

Claims

1. A method of treating cancer in a subject of need, the method comprising administering a combination of a BCR:ABL1 inhibitor and a second tyrosine kinase inhibitor (TKI), wherein the BCR:ABL1 inhibitor is a compound of formula (I): (I) Or its tautomers or N-oxides, or pharmaceutically acceptable salts of any of the foregoing, wherein: L can be -NH-CO-, -CO-NH-, -NH-SO2-, or -SO2-NH-; R 1 C6-C as an optional substitute 10 Aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 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 H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocyclic alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C6-C 10 Aryl or optionally substituted 5-10 heteroaryl groups; R 3 H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, 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 intermediate atom, it can form an optionally substituted C3-C8 cycloalkyl or an optionally substituted 4-10 membered heterocyclic alkyl; R 4 It can be an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, or an optionally substituted C2-C6 alkynyl; X is either O or S; Y is CH, C-(C1-C2 alkyl), C-halogenated, or N; Z is CR 5 Or N; R 5 It is H or halogen; R 6 H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocyclic alkyl, optionally substituted C6-C 10 aryl or optionally substituted 5-10 heteroaryl groups; and R 7 H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocyclic alkyl, optionally substituted C6-C 10 Aryl or optionally substituted 5-10 heteroaryl groups; Or R 6 and R 7 Together with the nitrogen to which it is attached, it forms an optionally substituted 4-7 membered heterocycle. The condition is that the compound is not (i) 5-[[(4-methoxyphenyl)sulfonyl]amino]-1-methyl-1H-benzimidazole-7-carboxylic acid or (ii) 5-[[(4-ethoxyphenyl)sulfonyl]amino]-1-methyl-1H-benzimidazole-7-carboxylic acid.

2. A method for inhibiting the tyrosine kinase activity of BCR:ABL1, said method comprising administering an effective amount of the BCR:ABL-1 inhibitor of formula (I): (I) Or its tautomers or N-oxides, or a pharmaceutically acceptable salt of any of the foregoing combined with an effective amount of a tyrosine kinase inhibitor, are contacted with the protein. in: L can be -NH-CO-, -CO-NH-, -NH-SO2-, or -SO2-NH-; R 1 C6-C as an optional substitute 10 Aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 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 H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocyclic alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C6-C 10 Aryl or optionally substituted 5-10 heteroaryl groups; R 3 H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, 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 intermediate atom, it can form an optionally substituted C3-C8 cycloalkyl or an optionally substituted 4-10 membered heterocyclic alkyl; R 4 It can be an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, or an optionally substituted C2-C6 alkynyl; X is either O or S; Y is CH, C-(C1-C2 alkyl), C-halogenated, or N; Z is CR 5 Or N; R 5 It is H or halogen; R 6 H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocyclic alkyl, optionally substituted C6-C 10 aryl or optionally substituted 5-10 heteroaryl groups; and R 7 H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocyclic alkyl, optionally substituted C6-C 10 Aryl or optionally substituted 5-10 heteroaryl groups; Or R 6 and R 7 Together with the nitrogen to which it is attached, it forms an optionally substituted 4-7 membered heterocycle. The condition is that the compound is not (i) 5-[[(4-methoxyphenyl)sulfonyl]amino]-1-methyl-1H-benzimidazole-7-carboxylic acid or (ii) 5-[[(4-ethoxyphenyl)sulfonyl]amino]-1-methyl-1H-benzimidazole-7-carboxylic acid.

3. A method for treating a disease in a subject in need, wherein modulating BCR-ABL1 activity prevents, inhibits, or improves the pathology and / or symptomology of the patient's disease, said method comprising administering to said subject a therapeutically effective amount of a BCR:ABL-1 inhibitor of formula (I): (I) Or its tautomers or N-oxides, or a pharmaceutically acceptable salt of any of the foregoing, in combination with a therapeutically effective amount of a tyrosine kinase inhibitor. in: L can be -NH-CO-, -CO-NH-, -NH-SO2-, or -SO2-NH-; R 1 C6-C as an optional substitute 10 Aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 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 H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocyclic alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C6-C 10 Aryl or optionally substituted 5-10 heteroaryl groups; R 3 H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, 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 intermediate atom, it can form an optionally substituted C3-C8 cycloalkyl or an optionally substituted 4-10 membered heterocyclic alkyl; R 4 It can be an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, or an optionally substituted C2-C6 alkynyl; X is either O or S; Y is CH, C-(C1-C2 alkyl), C-halogenated, or N; Z is CR 5 Or N; R 5 It is H or halogen; R 6 H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocyclic alkyl, optionally substituted C6-C 10 aryl or optionally substituted 5-10 heteroaryl groups; and R 7 H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocyclic alkyl, optionally substituted C6-C 10 Aryl or optionally substituted 5-10 heteroaryl groups; Or R 6 and R 7 Together with the nitrogen to which it is attached, it forms an optionally substituted 4-7 membered heterocycle. The condition is that the compound is not (i) 5-[[(4-methoxyphenyl)sulfonyl]amino]-1-methyl-1H-benzimidazole-7-carboxylic acid or (ii) 5-[[(4-ethoxyphenyl)sulfonyl]amino]-1-methyl-1H-benzimidazole-7-carboxylic acid.

4. A method for treating leukemia in a subject in need, the method comprising administering to the patient a therapeutically effective amount of a BCR:ABL-1 inhibitor of formula (I): (I) Or a combination of its tautomer or N-oxide, or a pharmaceutically acceptable salt of any of the foregoing, with a therapeutically effective amount of a second tyrosine kinase inhibitor. in: L can be -NH-CO-, -CO-NH-, -NH-SO2-, or -SO2-NH-; R 1 C6-C as an optional substitute 10 Aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 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 H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocyclic alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C6-C 10 Aryl or optionally substituted 5-10 heteroaryl groups; R 3 H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, 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 intermediate atom, it can form an optionally substituted C3-C8 cycloalkyl or an optionally substituted 4-10 membered heterocyclic alkyl; R 4 It can be an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, or an optionally substituted C2-C6 alkynyl; X is either O or S; Y is CH, C-(C1-C2 alkyl), C-halogenated, or N; Z is CR 5 Or N; R 5 It is H or halogen; R 6 H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocyclic alkyl, optionally substituted C6-C 10 aryl or optionally substituted 5-10 heteroaryl groups; and R 7 H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocyclic alkyl, optionally substituted C6-C 10 Aryl or optionally substituted 5-10 heteroaryl groups; Or R 6 and R 7 Together with the nitrogen to which it is attached, it forms an optionally substituted 4-7 membered heterocycle. The condition is that the compound is not (i) 5-[[(4-methoxyphenyl)sulfonyl]amino]-1-methyl-1H-benzimidazole-7-carboxylic acid or (ii) 5-[[(4-ethoxyphenyl)sulfonyl]amino]-1-methyl-1H-benzimidazole-7-carboxylic acid. The leukemia mentioned therein is chronic myeloid leukemia (CML), acute myeloid leukemia (AML), or acute lymphoblastic leukemia (ALL).

5. Compound of formula (I), (I) The use of, or its tautomers or N-oxides, or a pharmaceutically acceptable salt thereof, in combination with a tyrosine kinase inhibitor, for the preparation of a medicament for the treatment of cancer in subjects of need. in: L can be -NH-CO-, -CO-NH-, -NH-SO2-, or -SO2-NH-; R 1 C6-C as an optional substitute 10 Aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 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 H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocyclic alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C6-C 10 Aryl or optionally substituted 5-10 heteroaryl groups; R 3 H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, 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 intermediate atom, it can form an optionally substituted C3-C8 cycloalkyl or an optionally substituted 4-10 membered heterocyclic alkyl; R 4 It can be an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, or an optionally substituted C2-C6 alkynyl; X is either O or S; Y is CH, C-(C1-C2 alkyl), C-halogenated, or N; Z is CR 5 Or N; R 5 It is H or halogen; R 6 H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocyclic alkyl, optionally substituted C6-C 10 aryl or optionally substituted 5-10 heteroaryl groups; and R 7 H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocyclic alkyl, optionally substituted C6-C 10 Aryl or optionally substituted 5-10 heteroaryl groups; Or R 6 and R 7 Together with the nitrogen to which it is attached, it forms an optionally substituted 4-7 membered heterocycle. The condition is that the compound is not (i) 5-[[(4-methoxyphenyl)sulfonyl]amino]-1-methyl-1H-benzimidazole-7-carboxylic acid or (ii) 5-[[(4-ethoxyphenyl)sulfonyl]amino]-1-methyl-1H-benzimidazole-7-carboxylic acid.

6. The method according to any one of the preceding 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 method according to any one of the preceding claims, wherein the BCR:ABL1 inhibitor of formula (I) is (R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-1-(1-hydroxypropyl-2-yl)-7-(pyrimidin-5-yl)-1H-benzo[d]imidazolium-5-carboxamide (compound A): (Compound A) Or its pharmaceutically acceptable salt.

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

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

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

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

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

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

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

15. The method according to any one of the preceding claims, wherein the method further comprises the following steps: Determine the DNA sequence expressed by the BCR:ABL1 gene of the subject; and / or The amino acid sequence of the BCR:ABL1 protein expressed by the subject was determined.

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

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

1.

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

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

20. The method according to any one of the preceding claims, wherein the mutant form of said BCR:ABL-1 contains a plurality of amino acid mutations selected from the following: (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.

21. The method according to any one of the preceding claims, wherein the mutant form of BCR:ABL-1 has any one of the amino acid sequences in SEQ ID NO 2-22.

22. A combination comprising a BCR:ABL1 inhibitor and a tyrosine kinase inhibitor, and at least one pharmaceutically acceptable excipient, wherein the BCR:ABL1 inhibitor is a compound of formula (I): (I) Or its tautomers or N-oxides, or pharmaceutically acceptable salts of any of the foregoing. in: L can be -NH-CO-, -CO-NH-, -NH-SO2-, or -SO2-NH-; R 1 C6-C as an optional substitute 10 Aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 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 H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocyclic alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C6-C 10 Aryl or optionally substituted 5-10 heteroaryl groups; R 3 H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, 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 intermediate atom, it can form an optionally substituted C3-C8 cycloalkyl or an optionally substituted 4-10 membered heterocyclic alkyl; R 4 It can be an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, or an optionally substituted C2-C6 alkynyl; X is either O or S; Y is CH, C-(C1-C2 alkyl), C-halogenated, or N; Z is CR 5 Or N; R 5 It is H or halogen; R 6 H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocyclic alkyl, optionally substituted C6-C 10 aryl or optionally substituted 5-10 heteroaryl groups; and R 7 H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocyclic alkyl, optionally substituted C6-C 10 Aryl or optionally substituted 5-10 heteroaryl groups; Or R 6 and R 7 Together with the nitrogen to which it is attached, it forms an optionally substituted 4-7 membered heterocycle. The condition is that the compound is not (i) 5-[[(4-methoxyphenyl)sulfonyl]amino]-1-methyl-1H-benzimidazole-7-carboxylic acid or (ii) 5-[[(4-ethoxyphenyl)sulfonyl]amino]-1-methyl-1H-benzimidazole-7-carboxylic acid.

23. The combination of claim 21, wherein the combination is used to treat a patient with leukemia, comprising 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 of uses according to claim 22, wherein the leukemia is CML or ALL, and the tyrosine kinase inhibitor is selected from imatinib, nilotinib, dasatinib, flumatinib, bosutinib, ponatinib, and barfetinib.

25. The combination of uses according to any one of the preceding claims, wherein the CML is tolerated by standard care.

26. The combination of uses according to any one of the preceding claims, wherein the CML is tolerable to treatment with one or more of imatinib, ponatinib, nilotinib, and dasatinib.

27. The combination of uses according to any one of the preceding claims, wherein the AML is secondary AML that develops after myelodyplastic syndrome (MDS) or myeloproliferative neoplasm (MPN).

28. A combination of the methods or uses according to any one of the preceding claims, wherein the subject has previously received treatment with at least one tyrosine kinase inhibitor.

29. A combination of the methods or uses according to any one of the preceding claims, wherein the subject has previously received treatment with at least two tyrosine kinase inhibitors.

30. A combination of the methods or uses according to any one of the preceding claims, wherein the subject has previously received treatment with at least one allosteric tyrosine kinase inhibitor.

31. A combination of the methods or uses according to any one of the preceding claims, wherein the subject relapsed during prior treatment.

32. A combination of the methods or uses according to any one of the preceding claims, wherein the subject is refractory to prior treatment.

33. The method or combination according to any one of the preceding claims, wherein the subject has relapsed and is refractory to prior treatment.

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