Method for treating leukemia

Abstract

A method is provided for treating chronic myeloid leukemia in chronic phase and / or accelerated phase and / or blast phase, and / or acute lymphoblastic leukemia in a subject by administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate, or hydrate thereof. The use of the compound of formula (I) or the pharmaceutically acceptable salt, crystal, solvate, or hydrate thereof in combination with an ATP-competitive BCR-ABL1 inhibitor is also provided. (I)

Description

Treatments for leukemia Technical Field

[0001] The present invention belongs to the field of medicine and specifically relates to the use and method of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate, or hydrate thereof in the treatment of chronic myeloid leukemia and / or acute lymphocytic leukemia in the chronic phase, accelerated phase, and / or blast phase. The present invention also relates to a pharmaceutical combination for treating diseases regulated by wild-type and / or mutant BCR-ABL1 kinases, comprising a BCR-ABL1 allosteric inhibitor and an ATP-competitive inhibitor, and the use thereof in treating diseases regulated by wild-type and / or mutant BCR-ABL1 kinases. Background Art

[0002] Chronic myelogenous leukemia (CML) and some adult acute lymphoblastic leukemias (ALL) are caused by a chromosomal translocation (9;22)(q34;q11), which results in the fusion of the BCR and ABL1 genes on the Philadelphia chromosome, forming the BCR-ABL1 fusion gene. The BCR-ABL1 fusion gene translates into the BCR-ABL1 fusion protein, which abnormally increases BCR-ABL1 tyrosine kinase activity, promoting cell proliferation, inhibiting apoptosis, and weakening cell adhesion. CML has a slow onset, and its natural course includes the chronic phase (CP), accelerated phase (AP), and blast phase (BP). Most patients are initially diagnosed in the chronic phase. The emergence of BCR-ABL1 tyrosine kinase inhibitors (TKIs) has completely changed the treatment of CML. They inhibit the BCR-ABL1 pathway and significantly reduce the proliferation of CML cells expressing BCR-ABL1. Currently, the ATP-competitive BCR-ABL1 inhibitors for the treatment of CML include imatinib, a type II tyrosine kinase inhibitor that binds to the DFG-out conformation. ) and nilotinib ( ), and the type I inhibitor dasatinib (dasatinib, ) and bosutinib ( However, continued drug treatment is often caused by the occurrence of BCR-ABL1 T315I Although the type II inhibitor ponatinib (ponatinib, ) can significantly inhibit the T315I mutation, but it has adverse reactions due to off-target effects on other kinases. Therefore, in patients with Philadelphia chromosome-positive CML, the failure of ATP-competitive TKIs may be due to TKI resistance, unacceptable side effects, or both.

[0003] In 2003, the Kuriyan and Superti-Furga groups reported that the myristoyl group participates in the autoregulation of ABL kinase, inducing cross-linking of the SH3-SH2-kinase domain, playing a key role in negatively regulating ABL kinase activity and enabling normal cell proliferation. However, when the BCR-ABL1 fusion protein is formed, the BCR occupies the myristoyl binding site in the N-terminal cap region of ABL, preventing the induction of SH3-SH2-kinase domain cross-linking. This leads to structural activation of BCR-ABL1, causing cells to undergo continuous differentiation and proliferation, leading to malignant transformation.

[0004] Asiciminib ) is an allosteric inhibitor that binds to the myristoyl pocket of ABL. Assinib is active in the low nanomolar range against all catalytic ATP site mutations in BCR-ABL1, including the T315I mutation. Some mutations in the myristoyl binding site (e.g., P465S, ​​V468F, I502L, A337V, A424T) confer resistance to assinib.

[0005] Therefore, it is necessary to further develop BCR-ABL1 allosteric inhibitors for the treatment of CML, and it is necessary to further develop the combination of BCR-ABL1 allosteric inhibitors and ATP competitive inhibitors.

[0006] SUMMARY OF THE INVENTION

[0007] The present invention provides uses and methods of treating chronic phase and / or accelerated phase and / or blast phase CML and / or ALL with a compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof, wherein the compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof is as described below.

[0008] The present invention also provides a drug combination comprising a BCR-ABL1 allosteric inhibitor (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate, or hydrate thereof) and an ATP-competitive inhibitor. This combination significantly inhibits BCR-ABL1 mutations, particularly refractory complex mutations, and can be used to treat diseases regulated by wild-type and / or mutant BCR-ABL1 kinases.

[0009] To this end, the present invention adopts the following technical solutions:

[0010] Technical Solution 1. Use of a compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof in the preparation of a medicament for treating chronic myeloid leukemia (CML) or acute lymphocytic leukemia (ALL), wherein the compound of formula (I) has the following structure:

[0011] in:

[0012] Y1 is independently selected from CR a or N;

[0013] Y is independently selected from CR a or N;

[0014] R1 is selected from hydrogen, halogen, nitrile, nitro, C 1-6 Alkyl or C 1-6 haloalkyl, wherein the C 1-6 Alkyl or C 1- 6 haloalkyl is optionally replaced by R 1a group substitution;

[0015] R2 is selected from hydrogen, C 1-6 Alkyl or C 1-6 haloalkyl, wherein the C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally replaced by R 2a group substitution;

[0016] Z is a chemical bond, O, S(O) 0-2 or NR b ;

[0017] Or -Z-R2 together means -SF5;

[0018] Ar is a six-membered heteroaryl group containing at least one N atom, which is optionally substituted by an R group;

[0019] Het

[0020] wherein X9 is selected from O, S, NR b or C(R)2;

[0021] m is 0, 1, or 2;

[0022] n is 0, 1, 2, 3, 4, 5 or 6;

[0023] R a Independently selected from hydrogen, halogen, nitrile, nitro, hydroxyl, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl or C1-6 alkoxy;

[0024] R b are independently selected from hydrogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0025] R 1a 、R 2a and R is independently selected from hydrogen, halogen, hydroxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1- 6 alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C 6-10 Aryl or C 5-10 heteroaryl;

[0026] Alternatively, two R groups on the same atom or adjacent atoms may form a C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C 6-10 Aryl or C 5-10 Heteroaryl.

[0027] Technical Solution 2. A method for treating chronic myeloid leukemia (CML) or acute lymphocytic leukemia (ALL) in a patient, comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof, wherein the compound of formula (I) has the following structure:

[0028] in:

[0029] Y1 is selected from CR a or N;

[0030] Y is independently selected from CR a or N;

[0031] R1 is selected from hydrogen, halogen, nitrile, nitro, C 1-6 Alkyl or C 1-6 haloalkyl, wherein the C 1-6 Alkyl or C 1- 6 haloalkyl is optionally replaced by R 1a group substitution;

[0032] R2 is selected from hydrogen, C 1-6 Alkyl or C 1-6 haloalkyl, wherein the C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally replaced by R 2agroup substitution;

[0033] Z is a chemical bond, O, S(O) 0-2 or NR b ;

[0034] Or -Z-R2 together means -SF5;

[0035] Ar is a six-membered heteroaryl group containing at least one N atom, which is optionally substituted by an R group;

[0036] Het

[0037] wherein X9 is selected from O, S, NR b or C(R)2;

[0038] m is 0, 1, or 2;

[0039] n is 0, 1, 2, 3, 4, 5 or 6;

[0040] R a Independently selected from hydrogen, halogen, nitrile, nitro, hydroxyl, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 alkoxy;

[0041] R b are independently selected from hydrogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0042] R 1a 、R 2a and R is independently selected from hydrogen, halogen, hydroxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1- 6 alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C 6-10 Aryl or C 5-10 heteroaryl;

[0043] Alternatively, two R groups on the same atom or adjacent atoms may form a C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C 6-10 Aryl or C 5-10 Heteroaryl.

[0044] Technical Solution 3. A compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof, for use in treating chronic myeloid leukemia (CML) or acute lymphocytic leukemia (ALL), wherein the compound of formula (I) has the following structure:

[0045] in:

[0046] Y1 is independently selected from CR a or N;

[0047] Y is independently selected from CR a or N;

[0048] R1 is selected from hydrogen, halogen, nitrile, nitro, C 1-6 Alkyl or C 1-6 haloalkyl, wherein the C 1-6 Alkyl or C 1- 6 haloalkyl is optionally replaced by R 1a group substitution;

[0049] R2 is selected from hydrogen, C 1-6 Alkyl or C 1-6 haloalkyl, wherein the C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally replaced by R 2a group substitution;

[0050] Z is a chemical bond, O, S(O) 0-2 or NR b ;

[0051] Or -Z-R2 together means -SF5;

[0052] Ar is a six-membered heteroaryl group containing at least one N atom, which is optionally substituted by an R group;

[0053] Het

[0054] wherein X9 is selected from O, S, NR b or C(R)2;

[0055] m is 0, 1, or 2;

[0056] n is 0, 1, 2, 3, 4, 5 or 6;

[0057] R a Independently selected from hydrogen, halogen, nitrile, nitro, hydroxyl, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6alkoxy;

[0058] R b are independently selected from hydrogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0059] R 1a 、R 2a and R is independently selected from hydrogen, halogen, hydroxy, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1- 6 alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C 6-10 Aryl or C 5-10 heteroaryl;

[0060] Alternatively, two R groups on the same atom or adjacent atoms may form a C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C 6-10 Aryl or C 5-10 Heteroaryl.

[0061] Technical Solution 4. The use according to Technical Solution 1, the method according to Technical Solution 2, or the use of the compound according to Technical Solution 3, wherein the compound of formula (I) is (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof.

[0062] Technical Solution 5. The use, method or compound according to any one of Technical Solutions 1-4, wherein the chronic myeloid leukemia is chronic phase chronic myeloid leukemia, preferably a relapse of central nervous system leukemia, such as brain metastasis.

[0063] Technical Solution 6. The use, method or compound according to any one of Technical Solutions 1-4, wherein the chronic myeloid leukemia is accelerated phase chronic myeloid leukemia, preferably a relapse of central nervous system leukemia, such as brain metastasis.

[0064] Technical Solution 7. The use, method or compound according to any one of Technical Solutions 1-4, wherein the chronic myeloid leukemia is blast crisis chronic myeloid leukemia, preferably a relapse of central nervous system leukemia, such as brain metastasis.

[0065] Technical Solution 8. The use, method or compound according to any one of Technical Solutions 1 to 7, wherein the chronic myeloid leukemia is Philadelphia chromosome positive (Ph+).

[0066] Technical Solution 9. The use, method or compound according to any one of Technical Solutions 1-4, wherein the acute lymphoblastic leukemia is Philadelphia chromosome positive (Ph+), preferably a relapse of central nervous system leukemia, such as brain metastasis.

[0067] Technical solution 10. The use, method or compound according to any one of technical solutions 1 to 9, wherein the chronic myeloid leukemia is positive for the BCR-ABL1 fusion gene;

[0068] Preferably, the BCR-ABL1 fusion gene is wild type;

[0069] Preferably, the BCR-ABL1 fusion gene is a mutant; preferably, the mutation is selected from G250E, Q252H, Y253H, E255K / V, M244V, H396P, F317L, E459K, E355G, V299L, T315I, M351T, F359V, P223S and I502L, preferably G250E, Q252H, Y253H, E255K / V, E459K, T315I and M351T, preferably T315I.

[0070] Technical solution 11. The use, method or compound according to any one of technical solutions 1 to 10, wherein the chronic myeloid leukemia progresses after treatment with another therapy;

[0071] Preferably, the other therapy is selected from radiotherapy, drug therapy or surgical therapy; preferably, the drug therapy is chemotherapy, targeted therapy or immunotherapy;

[0072] Preferably, the drug therapy is chemotherapy;

[0073] Preferably, the drug therapy is targeted therapy;

[0074] Preferably, the drug of the drug therapy is selected from one or more of imatinib, dasatinib, nilotinib, BCR-ABL tyrosine kinase inhibitors, orebactinib, hydroxyurea, ponatinib, aspartame, interferon, cytarabine, azacitidine, interferon ALFA-1B, homoharringtonine, decitabine, pegylated interferon A-2A, thalidomide, chidamide or recombinant interferon A-2B.

[0075] Technical Solution 12. The use, method or compound according to any one of Technical Solutions 1-11, wherein the chronic myeloid leukemia progresses after treatment with a BCR-ABL tyrosine kinase inhibitor; preferably, the BCR-ABL tyrosine kinase inhibitor is selected from imatinib, dasatinib, nilotinib, orebactinib, ponatinib or aspartame.

[0076] Technical Solution 13. The use, method or use of a compound according to any one of Technical Solutions 1 to 12, wherein the patient is an adult patient.

[0077] Technical solution 14. The use, method or use of a compound according to any one of technical solutions 1 to 13, wherein the patient is a pediatric patient.

[0078] Technical Solution 15. The use, method or compound according to any one of Technical Solutions 1-14, wherein the patient has received first-line or more treatment; preferably, wherein the patient has received second-line or more treatment; preferably, wherein the patient has received third-line or more treatment; preferably, the patient has received first-line, second-line, third-line, fourth-line or fifth-line treatment.

[0079] Technical solution 16. The use, method or compound according to any one of technical solutions 1 to 15, wherein the patient has previously received treatment with ≥1 different BCR-ABL1 tyrosine kinase inhibitors and the disease has progressed to the accelerated phase or blast phase, and the treatment evaluation result is failure, warning or intolerance;

[0080] Preferably, the patient has previously received treatment with ≥2 different BCR-ABL1 tyrosine kinase inhibitors and the disease has progressed to the accelerated phase or blast phase, and the treatment evaluation result is failure, warning, or intolerance;

[0081] Preferably, the patient has previously received treatment with ≥3 different BCR-ABL1 tyrosine kinase inhibitors and the disease has progressed to the accelerated phase or blast phase, and the treatment evaluation result is failure, warning, or intolerance;

[0082] Preferably, the patient has previously received treatment with ≥4 different BCR-ABL1 tyrosine kinase inhibitors and the disease has progressed to the accelerated phase or blast phase, and the treatment evaluation result is failure, warning, or intolerance;

[0083] Preferably, the patient has previously received treatment with ≥1 different BCR-ABL1 ATP-competitive tyrosine kinase inhibitors, and the disease has progressed to the accelerated phase or blast phase, and the treatment evaluation result is failure, warning, or intolerance;

[0084] Preferably, the patient has previously received treatment with ≥2 different BCR-ABL1 ATP-competitive tyrosine kinase inhibitors, and the disease has progressed to the accelerated phase or blast phase, and the treatment evaluation result is failure, warning, or intolerance;

[0085] Preferably, the patient has previously received treatment with ≥3 different BCR-ABL1 ATP-competitive tyrosine kinase inhibitors, and the disease has progressed to the accelerated phase or blast phase, and the treatment evaluation result is failure, warning, or intolerance;

[0086] Preferably, the patient has previously received treatment with ≥4 different BCR-ABL1 ATP-competitive tyrosine kinase inhibitors, and the disease has progressed to the accelerated phase or blast phase, and the treatment evaluation result is failure, warning, or intolerance.

[0087] Technical solution 17. The use, method or compound according to any one of technical solutions 1 to 16, wherein the patient has previously received ≥1 different BCR-ABL1 tyrosine kinase inhibitors for treatment and has relapsed or is refractory;

[0088] Preferably, the patient has previously received treatment with ≥2 different BCR-ABL1 tyrosine kinase inhibitors and has relapsed or is refractory;

[0089] Preferably, the patient has previously received treatment with ≥3 different BCR-ABL1 tyrosine kinase inhibitors and has relapsed or is refractory;

[0090] Preferably, the patient has previously received treatment with ≥4 different BCR-ABL1 tyrosine kinase inhibitors and has relapsed or is refractory;

[0091] Preferably, the patient has previously received treatment with ≥1 different BCR-ABL1 ATP-competitive tyrosine kinase inhibitors and has relapsed or is refractory;

[0092] Preferably, the patient has previously received treatment with ≥2 different BCR-ABL1 ATP-competitive tyrosine kinase inhibitors and has relapsed or is refractory;

[0093] Preferably, the patient has previously received treatment with ≥3 different BCR-ABL1 ATP-competitive tyrosine kinase inhibitors and has relapsed or is refractory;

[0094] Preferably, the patient has previously received treatment with ≥4 different BCR-ABL1 ATP-competitive tyrosine kinase inhibitors and the disease has relapsed or is refractory.

[0095] Technical solution 18. The use, method or compound according to any one of technical solutions 16-17, wherein the BCR-ABL1 tyrosine kinase inhibitor is selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, ponatinib, orebactinib, rafitinib, bafitinib, vodobatinib, CHMFL-ABL-039, CHMFL-ABL-053, CHMFL-ABL-KIT-155, PF-114, paclitinib, rebasinib, darusetib, tauzertib, AT9283, KW-2449, XL228, asinibuccal or HS-10382;

[0096] Preferably, the BCR-ABL1 tyrosine kinase inhibitor is selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, ponatinib, orebactinib, raducinib or aspergillus;

[0097] Preferably, the BCR-ABL1 tyrosine kinase inhibitor is selected from imatinib, dasatinib, nilotinib, ponatinib, orebactinib or aspergillus;

[0098] Preferably, the BCR-ABL1 tyrosine kinase inhibitor is selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib or raducinib;

[0099] Preferably, the BCR-ABL1 tyrosine kinase inhibitor is selected from imatinib, dasatinib or nilotinib;

[0100] Preferably, the BCR-ABL1 tyrosine kinase inhibitor is selected from ponatinib, orebactinib, aspartame or HS-10382;

[0101] Preferably, the BCR-ABL1 tyrosine kinase inhibitor is selected from ponatinib or orebactinib;

[0102] Preferably, the BCR-ABL1 tyrosine kinase inhibitor is selected from asinib or HS-10382;

[0103] Preferably, the BCR-ABL1 tyrosine kinase inhibitor is a first-line, second-line, third-line, fourth-line or fifth-line treatment drug;

[0104] Preferably, the BCR-ABL1 tyrosine kinase inhibitor is a first-line, second-line or third-line treatment drug.

[0105] Technical solution 19. The use, method or compound according to any one of technical solutions 16-17, wherein the BCR-ABL1 ATP-competitive tyrosine kinase inhibitor is selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, ponatinib, orebactinib, rafitinib, bafitinib, vodobatinib, CHMFL-ABL-039, CHMFL-ABL-053, CHMFL-ABL-KIT-155, PF-114, paclitinib, rebasinib, daruselutib, tauzertinib, AT9283, KW-2449 or XL228;

[0106] Preferably, the BCR-ABL1 ATP-competitive tyrosine kinase inhibitor is selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, ponatinib, orebactinib or radurinib;

[0107] Preferably, the BCR-ABL1 ATP-competitive tyrosine kinase inhibitor is selected from imatinib, dasatinib, nilotinib, ponatinib or orebactinib;

[0108] Preferably, the BCR-ABL1 ATP-competitive tyrosine kinase inhibitor is selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib or raducinib;

[0109] Preferably, the BCR-ABL1 ATP-competitive tyrosine kinase inhibitor is selected from imatinib, dasatinib or nilotinib;

[0110] Preferably, the BCR-ABL1 ATP-competitive tyrosine kinase inhibitor is selected from ponatinib or orebactinib;

[0111] Preferably, the BCR-ABL1 ATP-competitive tyrosine kinase inhibitor is a first-line, second-line, third-line, fourth-line or fifth-line treatment drug;

[0112] Preferably, the BCR-ABL1 ATP-competitive tyrosine kinase inhibitor is a first-line, second-line or third-line treatment drug.

[0113] Technical solution 20. The use, method or compound according to any one of technical solutions 1 to 19, wherein the patient has previously received treatment with ≥1 different first-generation and / or second-generation and / or third-generation BCR-ABL1 ATP-competitive tyrosine kinase inhibitors and developed resistance or intolerance;

[0114] Preferably, the patient has previously received treatment with ≥2 different first-generation and / or second-generation and / or third-generation BCR-ABL1 ATP-competitive tyrosine kinase inhibitors and developed drug resistance or intolerance;

[0115] Preferably, the patient has previously received treatment with ≥3 different first-generation and / or second-generation and / or third-generation BCR-ABL1 ATP-competitive tyrosine kinase inhibitors and developed drug resistance or intolerance;

[0116] Preferably, the patient has previously received treatment with ≥4 different first-generation and / or second-generation and / or third-generation BCR-ABL1 ATP-competitive tyrosine kinase inhibitors and developed resistance or intolerance.

[0117] Technical solution 21. The use, method or compound according to any one of technical solutions 1 to 20, wherein the drug resistance is derived from a point mutation in the BCR-ABL1 kinase domain;

[0118] Preferably, the BCR-ABL1 kinase domain point mutation is selected from one or more of T315I / A, Y253F / H, E255V / K, M351T, G250E, F359V / I / C, H396P / R, M244V, E355G, F317L / V / I / C, F311L, M237I, Q252H / R, D276G, L248V, V379I, L384M, L387M, E279K, F486S, E459K, P223S, I502L or V299L mutations;

[0119] Preferably, the BCR-ABL1 kinase domain point mutation is selected from one or more of T315I, Y253H, E255V / K, M351T, G250E, F359V / , H396P, M244V, E355G, F317L, Q252H, E459K, P223S, I502L or V299L mutations.

[0120] Technical solution 22. The use, method or compound according to any one of technical solutions 1 to 21, wherein the patient has previously received ≥1 different first-generation and / or second-generation and / or third-generation BCR-ABL1 ATP-competitive tyrosine kinase inhibitors and has relapsed or is refractory;

[0121] Preferably, the patient has previously received treatment with ≥2 different first-generation and / or second-generation and / or third-generation BCR-ABL1 ATP-competitive tyrosine kinase inhibitors and has relapsed or is refractory;

[0122] Preferably, the patient has previously received ≥3 different first-generation and / or second-generation and / or third-generation BCR-ABL1 ATP-competitive tyrosine kinase inhibitors and has relapsed or is refractory;

[0123] Preferably, the patient has previously received treatment with ≥4 different first-generation and / or second-generation and / or third-generation BCR-ABL1 ATP-competitive tyrosine kinase inhibitors and the disease has relapsed or is refractory.

[0124] Technical solution 23. The use, method or compound according to any one of technical solutions 20-22, wherein the first-generation and / or second-generation and / or third-generation BCR-ABL1 ATP-competitive tyrosine kinase inhibitor is selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib or radotinib;

[0125] Preferably, the first-generation and / or second-generation and / or third-generation BCR-ABL1 ATP-competitive tyrosine kinase inhibitor is selected from imatinib, dasatinib or nilotinib;

[0126] Preferably, the first-generation and / or second-generation and / or third-generation BCR-ABL1 ATP-competitive tyrosine kinase inhibitor is selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, raducinib, ponatinib or orebactinib;

[0127] Preferably, the first-generation and / or second-generation and / or third-generation BCR-ABL1 ATP-competitive tyrosine kinase inhibitor is selected from imatinib, dasatinib, nilotinib, flumatinib, ponatinib or orebactinib;

[0128] Preferably, the first-generation and / or second-generation and / or third-generation BCR-ABL1 ATP-competitive tyrosine kinase inhibitor is a first-line, second-line, third-line, fourth-line or fifth-line treatment drug;

[0129] Preferably, the first-generation and / or second-generation and / or third-generation BCR-ABL1 ATP-competitive tyrosine kinase inhibitor is a first-line or second-line treatment drug.

[0130] Technical solution 24. The use, method or use of any one of technical solutions 1 to 23, wherein the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof (preferably Compound A) is about 20 mg / day to about 400 mg / day;

[0131] Preferably, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof (preferably Compound A) is about 20 mg / day to about 240 mg / day;

[0132] Preferably, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof (preferably Compound A) is about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day, about 120 mg / day, about 160 mg / day or about 240 mg / day;

[0133] Preferably, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof (preferably Compound A) is about 20 mg / day, about 40 mg / day, about 80 mg / day, about 160 mg / day or about 240 mg / day.

[0134] Technical Solution 25. The use, method or use of a compound according to any one of Technical Solutions 1-24, wherein the compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof (preferably Compound A) is administered orally or intranasally; preferably, administered orally; preferably, administered orally on an empty stomach.

[0135] Technical Solution 26. The use, method or use of a compound according to any one of Technical Solutions 1 to 25, wherein the compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof (preferably Compound A) is administered once a day (QD), twice a day (BID) or three times a day (TID).

[0136] Technical solution 27. The use, method or use of any one of technical solutions 1-26, wherein the compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof (preferably compound A) is administered at a dosage of about 10 mg BID, about 20 mg BID, about 40 mg QD, about 40 mg BID, about 80 mg QD, about 80 mg BID, about 160 mg QD or about 240 mg QD.

[0137] Technical solution 28. The use, method or use of any one of technical solutions 1-27, wherein the compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof (preferably compound A) is administered until disease progression, intolerable toxicity or death.

[0138] Technical solution 29. A drug combination comprising:

[0139] (a) a compound of formula (I) according to technical solution 1 or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof; and

[0140] (b) an ATP-competitive BCR-ABL1 inhibitor or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof.

[0141] Technical solution 30. A pharmaceutical combination according to technical solution 29, wherein the compound of formula (I) is (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof.

[0142] Technical solution 31. The drug combination according to technical solution 29 or 30, wherein the ATP-competitive BCR-ABL1 inhibitor is selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, ponatinib, orebactinib, rafitinib, bafitinib, vodobatinib, CHMFL-ABL-039, CHMFL-ABL-053, CHMFL-ABL-KIT-155, PF-114, paclitinib, rebasinib, daruselutib, tauzertinib, AT9283, KW-2449 or XL228;

[0143] Preferably, the ATP-competitive BCR-ABL1 inhibitor is selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, ponatinib, orebactinib or PF-114;

[0144] Preferably, the ATP-competitive BCR-ABL1 inhibitor is selected from imatinib, nilotinib, rafatinib, flumatinib, ponatinib, bafitinib, CHMFL-ABL-039, CHMFL-ABL-053, CHMFL-ABL-KIT-155, vodobatinib, PF-114, orebactinib or rebastinib;

[0145] Preferably, the ATP-competitive BCR-ABL1 inhibitor is selected from ponatinib, PF-114, orebactinib or rebastinib;

[0146] Preferably, the ATP-competitive BCR-ABL1 inhibitor is selected from ponatinib, orebactinib or PF-114;

[0147] Preferably, the ATP-competitive BCR-ABL1 inhibitor is selected from ponatinib or orebactinib;

[0148] Preferably, the ATP-competitive BCR-ABL1 inhibitor is selected from ponatinib.

[0149] Technical solution 32. The pharmaceutical combination according to any one of technical solutions 29-31, wherein the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof (preferably Compound A) is about 1-500 mg;

[0150] Preferably, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof (preferably Compound A) is about 1-250 mg;

[0151] Preferably, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof (preferably Compound A) is about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg g, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 160mg, 165mg, 170mg, 175mg, 180mg , 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240mg, 245mg or 250mg;

[0152] Preferably, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof (preferably Compound A) is about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 80 mg, 160 mg or 240 mg;

[0153] Preferably, the compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof (preferably Compound A) is taken once or twice a day.

[0154] Technical solution 33. The pharmaceutical combination according to any one of technical solutions 29-32, wherein the dosage of the ATP-competitive BCR-ABL1 inhibitor is about 0.1-200 mg, preferably about 0.1-60 mg.

[0155] Technical solution 34. The drug combination according to technical solution 32, wherein the ATP-competitive BCR-ABL1 inhibitor is ponatinib, and its dosage is about 0.1-200 mg, preferably about 0.1-60 mg;

[0156] Preferably, the dose of ponatinib is 0.1 mg, 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg , 15.5mg, 16mg, 16.5mg, 17mg, 17.5mg, 18mg, 18.5mg, 19mg, 19.5mg, 20mg, 20.5mg, 21mg, 21.5mg, 22mg, 22.5m g, 23mg, 23.5mg, 24mg, 24.5mg, 25mg, 25.5mg, 26mg, 26.5mg, 27mg, 27.5mg, 28mg, 28.5mg, 29mg, 29.5mg, 30mg , 30.5mg, 31mg, 31.5mg, 32mg, 32.5mg, 33mg, 33.5mg, 34mg, 34.5mg, 35mg, 35.5mg, 36mg, 36.5mg, 37mg, 37.5m g, 38mg, 38.5mg, 39mg, 39.5mg, 40mg, 40.5mg, 41mg, 41.5mg, 42mg, 42.5mg, 43mg, 43.5mg, 44mg, 44.5mg, 45mg , 45.5mg, 46mg, 46.5mg, 47mg, 47.5mg, 48mg, 48.5mg, 49mg, 49.5mg, 50mg, 50.5mg, 51mg, 51.5mg, 52mg, 52.5m g, 53mg, 53.5mg, 54mg, 54.5mg, 55mg, 55.5mg, 56mg, 56.5mg, 57mg, 57.5mg, 58mg, 58.5mg, 59mg, 59.5mg or 60mg;

[0157] Preferably, the dose of ponatinib is 2 mg, 4 mg, 8 mg, 15 mg, 30 mg, 45 mg or 60 mg;

[0158] Preferably, ponatinib is administered once daily or twice daily.

[0159] Technical solution 35. The drug combination according to technical solution 32, wherein the ATP-competitive BCR-ABL1 inhibitor is orebactinib, and its dosage is about 0.1-200 mg, preferably about 0.1-60 mg;

[0160] Preferably, the dose of orebactinib is 0.1 mg, 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg g, 15.5mg, 16mg, 16.5mg, 17mg, 17.5mg, 18mg, 18.5mg, 19mg, 19.5mg, 20mg, 20.5mg, 21mg, 21.5mg, 22mg, 22.5 mg, 23mg, 23.5mg, 24mg, 24.5mg, 25mg, 25.5mg, 26mg, 26.5mg, 27mg, 27.5mg, 28mg, 28.5mg, 29mg, 29.5mg, 30mg , 30.5mg, 31mg, 31.5mg, 32mg, 32.5mg, 33mg, 33.5mg, 34mg, 34.5mg, 35mg, 35.5mg, 36mg, 36.5mg, 37mg, 37.5m g, 38mg, 38.5mg, 39mg, 39.5mg, 40mg, 40.5mg, 41mg, 41.5mg, 42mg, 42.5mg, 43mg, 43.5mg, 44mg, 44.5mg, 45mg , 45.5mg, 46mg, 46.5mg, 47mg, 47.5mg, 48mg, 48.5mg, 49mg, 49.5mg, 50mg, 50.5mg, 51mg, 51.5mg, 52mg, 52.5m g, 53mg, 53.5mg, 54mg, 54.5mg, 55mg, 55.5mg, 56mg, 56.5mg, 57mg, 57.5mg, 58mg, 58.5mg, 59mg, 59.5mg or 60mg;

[0161] Preferably, the dose of orebactinib is 1 mg, 2 mg, 4 mg, 8 mg, 12 mg, 20 mg, 30 mg, 40 mg, 45 mg, 50 mg or 60 mg;

[0162] Preferably, oregano is administered once daily or twice daily.

[0163] Technical Solution 36. A drug combination according to any one of Technical Solutions 29-35, wherein the (a) compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof; and (b) an ATP-competitive BCR-ABL1 inhibitor or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof are present in the same dosage form.

[0164] Technical solution 37. A drug combination according to any one of technical solutions 29-35, wherein the (a) compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof; and (b) the ATP-competitive BCR-ABL1 inhibitor or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof are present in different dosage forms.

[0165] Technical solution 38. A pharmaceutical composition comprising the drug combination of any one of Technical Solutions 29-35.

[0166] Technical Solution 39. Use of (a) the compound of formula (I) of Technical Solution 1 or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof and (b) an ATP-competitive BCR-ABL1 inhibitor or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof in the preparation of a medicament for treating diseases regulated by wild-type or mutant BCR-ABL1 kinase.

[0167] Technical Solution 40. (a) Use of the compound of formula (I) of Technical Solution 1 or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof in the preparation of a medicament for use in combination with (b) an ATP-competitive BCR-ABL1 inhibitor or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof for treating diseases regulated by wild-type or mutant BCR-ABL1 kinase.

[0168] Technical Solution 41. (b) Use of an ATP-competitive BCR-ABL1 inhibitor or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof in the preparation of a medicament for use in combination with the compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof according to Technical Solution 1 (a) for treating diseases regulated by wild-type or mutant BCR-ABL1 kinase.

[0169] Technical Solution 42. A pharmaceutical combination of (a) a compound of formula (I) according to Technical Solution 1 or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof and (b) an ATP-competitive BCR-ABL1 inhibitor or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof, for treating diseases regulated by wild-type or mutant BCR-ABL1 kinase.

[0170] Technical Solution 43. (a) The compound of formula (I) of Technical Solution 1 or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof, which is used in combination with (b) an ATP-competitive BCR-ABL1 inhibitor or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof for the treatment of diseases regulated by wild-type or mutant BCR-ABL1 kinase.

[0171] Technical Solution 44. (b) An ATP-competitive BCR-ABL1 inhibitor or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof, which is used in combination with the compound of formula (I) of Technical Solution 1 (a) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof for the treatment of diseases regulated by wild-type or mutant BCR-ABL1 kinase.

[0172] Technical solution 45. A method for treating a wild-type or mutant BCR-ABL1 kinase-regulated disease, comprising administering to a patient in need thereof (a) a compound of formula (I) according to Technical Solution 1 or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof, and (b) an ATP-competitive BCR-ABL1 inhibitor or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof.

[0173] Technical Solution 46. The method according to Technical Solution 45, wherein (a) and (b) are administered simultaneously, separately or continuously.

[0174] Technical solution 47. The use according to any one of technical solutions 39-41 or the use of the compound and / or inhibitor according to any one of technical solutions 42-44 or the method according to technical solution 45 or 46, wherein the disease regulated by the wild-type and / or mutant BCR-ABL1 kinase is a hematological malignancy or a relapse of a central nervous system leukemia, such as brain metastasis;

[0175] Preferably, the diseases regulated by the wild-type and / or mutant BCR-ABL1 kinase are leukemia, neurodegenerative diseases, neurofibromas, melanomas, breast cancer, colon cancer, lung cancer, prostate cancer, Kaposi's sarcoma, gastrointestinal stromal tumors, mesothelioma, systemic mastocytosis, hypereosinophilic syndrome, hepatic fibrosis, renal fibrosis, rheumatoid arthritis, polyarthritis, scleroderma, lupus erythematosus, graft-versus-host disease, pulmonary hypertension, seminoma, dysgerminoma and psoriasis;

[0176] Preferably, the leukemia is acute lymphocytic leukemia, acute granulocytic leukemia, acute promyelocytic leukemia, chronic myeloid leukemia, chronic myelomonocytic leukemia, chronic neutrophilic leukemia, acute undifferentiated leukemia, prolymphocytic leukemia, juvenile myelomonocytic leukemia, adult T-cell leukemia, acute myeloid leukemia with trilineage myelodysplasia and mixed lineage leukemia;

[0177] Preferably, the leukemia is chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia;

[0178] Preferably, the neurodegenerative disease is Parkinson's disease, Alzheimer's disease, Down's syndrome, memory and cognitive impairment, dementia, amyloid neuropathy or brain inflammation;

[0179] Preferably, the diseases regulated by the wild-type and / or mutant BCR-ABL1 kinase are chronic myeloid leukemia, Philadelphia chromosome-positive acute lymphoblastic leukemia, Parkinson's disease, Alzheimer's disease, neurofibromatosis, gastrointestinal stromal tumors, systemic mastocytosis, hypereosinophilic syndrome, hepatic fibrosis, renal fibrosis, and scleroderma.

[0180] Technical solution 48. The use or use of the compound and / or inhibitor or method according to any one of technical solutions 39 to 47, wherein the mutation of the mutant BCR-ABL1 kinase is one or more of T315I, T315M, F317L, E355G, V299L, M244V, G250E, Q252H, Y253H, E255K, E255V, H396P, H396R, H396A, A397P, P223S, K294E, M351T, F359V, E459K, P465S, ​​V468F, I502L, A337V or A424T;

[0181] Preferably, the mutation of the mutant BCR-ABL1 kinase is one or more of T315I, T315M, Y253H / T315I, E255V / T315I, Q252H / T315I, F317L / T315I, F359V / T315I, Y253H / E255K, and Y253H / F359V;

[0182] Preferably, the mutation of the mutant BCR-ABL1 kinase is T315I, T315M, Y253H / T315I, E255V / T315I or Q252H / T315I;

[0183] Preferably, the mutation of the mutant BCR-ABL1 kinase is T315M, Y253H / T315I, E255V / T315I or Q252H / T315I.

[0184] Technical Solution 49. The use or use or method of a compound and / or inhibitor according to any one of Technical Solutions 39-48, wherein the compound of formula (I) is (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof.

[0185] Technical solution 50. The use or use or method of any one of technical solutions 39 to 49, wherein the ATP-competitive BCR-ABL1 inhibitor is selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, ponatinib, orebactinib, rafitinib, bafitinib, vodobatinib, CHMFL-ABL-039, CHMFL-ABL-053, CHMFL-ABL-KIT-155, PF-114, paclitinib, rebasinib, daruselutib, tauzertinib, AT9283, KW-2449 or XL228;

[0186] Preferably, the ATP-competitive BCR-ABL1 inhibitor is selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, ponatinib, orebactinib or PF-114;

[0187] Preferably, the ATP-competitive BCR-ABL1 inhibitor is selected from imatinib, nilotinib, rafatinib, flumatinib, ponatinib, bafitinib, CHMFL-ABL-039, CHMFL-ABL-053, CHMFL-ABL-KIT-155, vodobatinib, PF-114, orebactinib or rebastinib;

[0188] Preferably, the ATP-competitive BCR-ABL1 inhibitor is selected from ponatinib, PF-114, orebactinib or rebastinib;

[0189] Preferably, the ATP-competitive BCR-ABL1 inhibitor is selected from ponatinib, orebactinib or PF-114;

[0190] Preferably, the ATP-competitive BCR-ABL1 inhibitor is selected from ponatinib or orebactinib;

[0191] Preferably, the ATP-competitive BCR-ABL1 inhibitor is selected from ponatinib.

[0192] Technical solution 51. The use or use of the compound and / or inhibitor or method according to any one of technical solutions 39-50, wherein the dose of the compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof (preferably Compound A) is about 1-500 mg;

[0193] Preferably, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof (preferably Compound A) is about 1-250 mg;

[0194] Preferably, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof (preferably Compound A) is about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg g, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 160mg, 165mg, 170mg, 175mg, 180mg , 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240mg, 245mg or 250mg;

[0195] Preferably, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof (preferably Compound A) is about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 80 mg, 160 mg or 240 mg;

[0196] Preferably, the compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof (preferably Compound A) is taken once or twice a day.

[0197] Technical solution 52. The use or use or method of any one of technical solutions 39-51, wherein the dosage of the ATP-competitive BCR-ABL1 inhibitor is about 0.1-200 mg, preferably about 0.1-60 mg.

[0198] Technical solution 53. The use or use of the compound and / or inhibitor or method according to Technical Solution 52, wherein the ATP-competitive BCR-ABL1 inhibitor is ponatinib, and its dosage is about 0.1-200 mg, preferably about 0.1-60 mg;

[0199] Preferably, the dose of ponatinib is 0.1 mg, 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg g, 18.5mg, 19mg, 19.5mg, 20mg, 20.5mg, 21mg, 21.5mg, 22mg, 22.5mg, 23mg, 23.5mg, 24mg, 24.5mg, 25m g, 25.5mg, 26mg, 26.5mg, 27mg, 27.5mg, 28mg, 28.5mg, 29mg, 29.5mg, 30mg, 30.5mg, 31mg, 31.5mg, 32mg , 32.5mg, 33mg, 33.5mg, 34mg, 34.5mg, 35mg, 35.5mg, 36mg, 36.5mg, 37mg, 37.5mg, 38mg, 38.5mg, 39mg , 39.5mg, 40mg, 40.5mg, 41mg, 41.5mg, 42mg, 42.5mg, 43mg, 43.5mg, 44mg, 44.5mg, 45mg, 45.5mg, 46mg , 46.5mg, 47mg, 47.5mg, 48mg, 48.5mg, 49mg, 49.5mg, 50mg, 50.5mg, 51mg, 51.5mg, 52mg, 52.5mg, 53mg , 53.5mg, 54mg, 54.5mg, 55mg, 55.5mg, 56mg, 56.5mg, 57mg, 57.5mg, 58mg, 58.5mg, 59mg, 59.5mg or 60mg;

[0200] Preferably, the dose of ponatinib is 2 mg, 4 mg, 8 mg, 15 mg, 30 mg, 45 mg or 60 mg;

[0201] Preferably, ponatinib is administered once daily or twice daily.

[0202] Technical solution 54. The use or use of the compound and / or inhibitor or method according to Technical Solution 52, wherein the ATP-competitive BCR-ABL1 inhibitor is orebactinib, and its dosage is about 0.1-200 mg, preferably about 0.1-60 mg;

[0203] Preferably, the dose of orebactinib is 0.1 mg, 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg g, 15.5mg, 16mg, 16.5mg, 17mg, 17.5mg, 18mg, 18.5mg, 19mg, 19.5mg, 20mg, 20.5mg, 21mg, 21.5mg, 22mg, 22.5 mg, 23mg, 23.5mg, 24mg, 24.5mg, 25mg, 25.5mg, 26mg, 26.5mg, 27mg, 27.5mg, 28mg, 28.5mg, 29mg, 29.5mg, 30mg , 30.5mg, 31mg, 31.5mg, 32mg, 32.5mg, 33mg, 33.5mg, 34mg, 34.5mg, 35mg, 35.5mg, 36mg, 36.5mg, 37mg, 37.5m g, 38mg, 38.5mg, 39mg, 39.5mg, 40mg, 40.5mg, 41mg, 41.5mg, 42mg, 42.5mg, 43mg, 43.5mg, 44mg, 44.5mg, 45mg , 45.5mg, 46mg, 46.5mg, 47mg, 47.5mg, 48mg, 48.5mg, 49mg, 49.5mg, 50mg, 50.5mg, 51mg, 51.5mg, 52mg, 52.5m g, 53mg, 53.5mg, 54mg, 54.5mg, 55mg, 55.5mg, 56mg, 56.5mg, 57mg, 57.5mg, 58mg, 58.5mg, 59mg, 59.5mg or 60mg;

[0204] Preferably, the dose of orebactinib is 1 mg, 2 mg, 4 mg, 8 mg, 12 mg, 20 mg, 30 mg, 40 mg, 45 mg, 50 mg or 60 mg;

[0205] Preferably, oregano is administered once daily or twice daily.

[0206] Technical Solution 55. The use or use or method of a compound and / or inhibitor according to any one of Technical Solutions 39-54, wherein the (a) compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof; and (b) an ATP-competitive BCR-ABL1 inhibitor or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof are present in the same dosage form.

[0207] Technical Solution 56. The use or use or method of a compound and / or inhibitor according to any one of Technical Solutions 39-54, wherein the (a) compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof; and (b) the ATP-competitive BCR-ABL1 inhibitor or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof are present in different dosage forms.

[0208] Technical solution 57. A method for inhibiting mutant BCR-ABL1 kinase, comprising:

[0209] (a) a compound of formula (I) according to technical solution 1 or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof; and

[0210] (b) an ATP-competitive BCR-ABL1 inhibitor or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof.

[0211] Technical solution 58. The method according to technical solution 57, wherein the mutant BCR-ABL1 kinase is one or more of T315I, T315M, F317L, E355G, V299L, M244V, G250E, Q252H, Y253H, E255K, E255V, H396P, H396R, H396A, A397P, P223S, K294E, M351T, F359V, E459K, P465S, ​​V468F, I502L, A337V or A424T;

[0212] Preferably, the mutant BCR-ABL1 kinase is T315I, T315M, Y253H / T315I, E255V / T315I, Q252H / T315I, F317L / T315I, F359V / T315I, Y253H / E255K or Y253H / F359V;

[0213] Preferably, the mutant BCR-ABL1 kinase is T315I, T315M, Y253H / T315I, E255V / T315I or Q252H / T315I;

[0214] Preferably, the mutant BCR-ABL1 kinase is T315M, Y253H / T315I, E255V / T315I or Q252H / T315I.

[0215] Technical Solution 59. Commercial packaging, comprising:

[0216] (a) Compound A of Technical Solution 4 or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof; and

[0217] (b) an ATP-competitive BCR-ABL1 inhibitor or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof;

[0218] wherein (a) and (b) are present in one unit dosage form or in two separate unit dosage forms.

[0219] Technical Solution 60. Commercial packaging, comprising:

[0220] (a) Compound A of Technical Solution 4 or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof; and

[0221] (b) ponatinib or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof;

[0222] wherein (a) and (b) are present in one unit dosage form or in two separate unit dosage forms.

[0223] Technical Solution 61. Commercial packaging, comprising:

[0224] (a) Compound A of Technical Solution 4 or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof; and

[0225] (b) orebactinib or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof;

[0226] wherein (a) and (b) are present in one unit dosage form or in two separate unit dosage forms.

[0227] Technical Solution 62. Commercial packaging, comprising:

[0228] (a) Compound A of Technical Solution 4 or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof; and

[0229] (b) PF-114 or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof;

[0230] wherein (a) and (b) are present in one unit dosage form or in two separate unit dosage forms.

[0231] Technical Solution 63. A commercial package according to any one of Technical Solutions 59-62, wherein the unit dosage form is a fixed combination.

[0232] Technical solution 64. A commercial package according to any one of technical solutions 59-63, which is used to treat diseases regulated by wild-type or mutant BCR-ABL1 kinase.

[0233] Other objects and advantages of the present invention will be apparent to those skilled in the art from the following detailed description, examples and claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0234] Figure 1 shows the inhibitory effects of Compound A, ponatinib, and orebactinib, alone and in combination, on BCR-ABL1 Y253H / T315I cells. Figures 1a and 1b show the effects of Compound A and ponatinib, alone and in combination; Figures 1c and 1d show the effects of Compound A and orebactinib, alone and in combination; and Figures 1e and 1f show the CI coefficients for the two combinations, respectively (both less than 0.3).

[0235] Figure 2 shows the inhibitory effect of the combination of Compound A with ponatinib and orebactinib on the viability of Ba / F3 BCR-ABL1 Y253H / T315I cells. Figure 2a shows the combination of Compound A with ponatinib, and Figure 2b shows the combination of Compound A with orebactinib.

[0236] Figure 3 shows the inhibitory effects of ponatinib alone or in combination with compound A and aspergillus nivolumab (ABL001) on the viability of Ba / F3 BCR-ABL1 Y253H / T315I cells.

[0237] Figure 4 shows the inhibitory effects of ponatinib alone or in combination with compound A and two concentrations of aspartame on the viability of Ba / F3 BCR-ABL11 E255V / T315I cells.

[0238] FIG5 shows the inhibitory effects of ponatinib alone or in combination with compound A and two concentrations of aspartame on the viability of Ba / F3 BCR-ABL1 Q252H / T315I cells.

[0239] Figure 6 shows the inhibitory effects of ponatinib alone or in combination with compound A and two concentrations of aspartame on the viability of Ba / F3 BCR-ABL1 T315M cells.

[0240] Figure 7 shows the inhibitory effects of ponatinib alone, compound A alone, and their combination on the viability of Ba / F3 BCR-ABL11 T315I, Y253H / F359V, Y253H / E255K, and F359V cells.

[0241] FIG8 shows the changes in bioluminescent imaging (BLI) fluorescence intensity of each group of mice treated with compound A over the administration time in the K562-luc brain metastasis model.

[0242] Detailed Description of the Invention

[0243] The present invention has discovered that the compound of formula (I) can be used to treat chronic phase and / or accelerated phase CML. Therefore, the present invention discloses the use and method of the compound of formula (I) or a pharmaceutically acceptable salt thereof for treating chronic phase and / or accelerated phase CML.

[0244] Abbreviations

[0245] definition

[0246] The present invention may be more readily understood by reference to the following detailed description of embodiments of the invention and the examples included herein. It should be understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting. It should be further understood that, unless otherwise specifically defined herein, the terms used herein should be given their ordinary meanings known in the relevant art.

[0247] Chemical definition

[0248] Definitions of specific functional groups and chemical terms are described in more detail below.

[0249] When a numerical range is listed, it is intended to include every value and sub-range within the stated range. For example, "C 1-6 "Alkyl" includes C1, C2, C3, C4, C5, C6, C 1-6 、C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-5 、C 2-4 、C 2-3 、C 3-6 、C 3- 5. C 3-4 、C 4-6 、C 4-5 and C 5-6 alkyl.

[0250] It should be understood that when described herein, any of the moieties defined below may be substituted with a number of substituents, and that the corresponding definitions are within their scope listed below, including such substituted moieties. Unless otherwise stated, the term "substituted" is as defined below.

[0251] “C 1-6"Alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms, also referred to herein as "lower alkyl". In some embodiments, C 1-4 Alkyl is particularly preferred. Examples of the alkyl include, but are not limited to, methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5) and n-hexyl (C6). Unless otherwise specified, each of the alkyl groups is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted ("substituted alkyl") with one or more substituents; for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In some embodiments, the alkyl group is unsubstituted C 1-6 In some embodiments, the alkyl group is a substituted C 1-6 alkyl.

[0252] “C 1-6 "Alkoxy" refers to a group -OR, where R is a substituted or unsubstituted C 1-6 In some embodiments, C 1-4 Alkoxy groups are particularly preferred. Specific alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0253] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). In some embodiments, the halo group is F, Cl, or Br. In some embodiments, the halo group is Cl. In some embodiments, the halo group is F. In some embodiments, the halo group is Br.

[0254] Therefore, “C 1-6 "Haloalkyl" refers to the above-mentioned "C 1-6 Alkyl", which is substituted by one or more halogen groups. In some embodiments, C 1-4 Halogenated alkyl is particularly preferred, more preferably C 1-2 Haloalkyl. Exemplary haloalkyl groups include, but are not limited to, -CF3, -CH2F, -CHF2, -CClF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CF2CClF2, -CF2CH3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like.

[0255] “C 3-7"Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 7 ring carbon atoms and zero heteroatoms. In some embodiments, C 3-6 Cycloalkyl is particularly preferred, more preferably C 5-6 Cycloalkyl. Cycloalkyl also includes a ring system in which the above-mentioned cycloalkyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring, and in such a case, the number of carbons continues to represent the number of carbons in the cycloalkyl system. Exemplary cycloalkyls include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), and the like. Unless otherwise stated, each of the cycloalkyl groups is independently optionally substituted, i.e., unsubstituted ("unsubstituted cycloalkyl") or substituted ("substituted cycloalkyl") with one or more substituents. In some embodiments, the cycloalkyl group is unsubstituted C 3-7 In some embodiments, the carbocyclyl group is a substituted C 3-7 Cycloalkyl.

[0256] “C 3-7 "Heterocycloalkyl" refers to a group of a 3- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocycloalkyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as valence permits. In some embodiments, C 3-6 Heterocycloalkyl is particularly preferred, which is a 3- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; more preferably C 5-6 Heterocycloalkyl is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms. Unless otherwise specified, each member of a heterocycloalkyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocycloalkyl”) or substituted (a “substituted heterocycloalkyl”) with one or more substituents. In some embodiments, a heterocycloalkyl group is an unsubstituted C 3-7 In some embodiments, heterocycloalkyl is substituted C 3-7Heterocycloalkyl. Heterocycloalkyl also includes a ring system in which the above-mentioned heterocycloalkyl ring is fused to one or more cycloalkyl groups, wherein the point of attachment is on the cycloalkyl ring, or a ring system in which the above-mentioned heterocycloalkyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocycloalkyl ring; and in such a case, the number of ring members continues to represent the number of ring members in the heterocycloalkyl ring system. Exemplary 3-membered heterocycloalkyl groups containing one heteroatom include, but are not limited to, aziridine, oxirane, and thiorenyl. Exemplary 4-membered heterocycloalkyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetane, and thietidinyl. Exemplary 5-membered heterocycloalkyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocycloalkyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocycloalkyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocycloalkyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocycloalkyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocycloalkyl groups containing three heteroatoms include, but are not limited to, hexahydrotriazinyl. Exemplary 7-membered heterocycloalkyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thienyl. Exemplary 5-membered heterocycloalkyl groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocycloalkyl groups) include, but are not limited to, dihydroindolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocycloalkyl groups fused to a C6 aryl ring (also referred to herein as 6,6-bicyclic heterocycloalkyl groups) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0257] “C 6-10 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having 6-10 ring carbon atoms and zero heteroatoms. In some embodiments, an aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C 10Aryl also includes ring systems in which the above-described aryl ring is fused to one or more cycloalkyl or heterocycloalkyl groups, and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Unless otherwise specified, each member of the aryl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted aryl") or substituted with one or more substituents (a "substituted aryl"). In some embodiments, aryl is an unsubstituted C 6-10 In some embodiments, aryl is substituted C 6-10 Aryl.

[0258] “C 5-10 "Heteroaryl" refers to a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom as long as the valence permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the above-mentioned heteroaryl ring is fused to one or more cycloalkyl or heterocycloalkyl groups, and the point of attachment is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, C 5-6Heteroaryl is particularly preferred and is a 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms. Unless otherwise specified, each of the heteroaryl groups is independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted ("substituted heteroaryl") with one or more substituents. In some embodiments, the heteroaryl group is an unsubstituted 5-10 membered heteroaryl group. In some embodiments, the heteroaryl group is a substituted 5-10 membered heteroaryl group. Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furyl, and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azacycloheptatrienyl, oxepantatrienyl, and thiepantatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indanizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0259] "Cyano" refers to the radical -CN.

[0260] "Nitro" means the radical -NO2.

[0261] Other definitions

[0262] The term "pharmaceutically acceptable salt" refers to salts that are suitable for contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reaction, etc., and are commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids and bases.

[0263] Pharmaceutically acceptable salts of the compounds of this invention include salts derived from suitable inorganic and organic acids and inorganic and organic bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or salts formed with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid. Salts formed using conventional methods in the art, for example, ion exchange methods, are also included. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, gluconate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include non-toxic ammonium salts, quaternary ammonium salts, and amine cations formed with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, if appropriate.

[0264] Those skilled in the art will appreciate that organic compounds can form complexes with solvents in which they react or from which they precipitate or crystallize. These complexes are referred to as "solvates." When the solvent is water, the complex is referred to as a "hydrate." The present invention encompasses all solvates of the compounds of the present invention.

[0265] The term "solvate" refers to a form of a compound or its salt that is combined with a solvent, usually formed by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. The compounds described herein can be prepared, for example, in a crystalline form and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be able to separate, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" includes solvates in the solution state and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0266] The term "hydrate" refers to a compound that is combined with water. Generally, the ratio of the number of water molecules contained in the hydrate of a compound to the number of molecules of the compound in the hydrate is determined. Therefore, the hydrate of a compound can be represented by the general formula R·x H2O, for example, where R is the compound and x is a number greater than 0. A given compound can form more than one type of hydrate, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, for example, hemihydrate (R·0.5H2O)) and polyhydrates (x is a number greater than 1, for example, dihydrates (R·2H2O) and hexahydrates (R·6H2O)).

[0267] The component compounds of the present invention can be in amorphous or crystalline form (crystal form or polymorph). In addition, the component compounds of the present invention can exist in one or more crystalline forms. Therefore, the present invention includes all amorphous or crystalline forms of the component compounds of the present invention within its scope. The term "polymorph" refers to the crystalline form (or its salt, hydrate or solvate) of a compound with a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, photoelectric properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature and other factors can cause one crystalline form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0268] The component compounds of the pharmaceutical combination of the present invention also include isotope-labeled compounds, which are identical to those of the active ingredients of components (a) and (b), but one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number commonly found in nature. Examples of isotopes that can be introduced include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, for example 2 H. 3 H. 13 C. 11 C.14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36 Certain isotope-labeled compounds of the present invention, for example, radioactive isotopes (e.g. 3 H and 14 C) can be used in drug and / or substrate tissue distribution assays. 3 H and carbon-14, i.e. 14 C isotopes are particularly preferred because they are easy to prepare and detect. 2 H, may be preferred in some circumstances because greater metabolic stability may provide therapeutic benefits, such as increased in vivo half-life or reduced dosage requirements.

[0269] As used herein, the singular forms "a," "an," and "the" include plural references unless otherwise indicated. For example, "a" compound includes one or more compounds.

[0270] As used herein, the use of "or" means "and / or" unless stated otherwise.

[0271] Use of the term "include," as well as other forms such as "including," "containing," and "having," is not limiting.

[0272] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, guidelines, and treatises, are hereby expressly incorporated herein by reference in their entirety for any purpose.

[0273] The term "about" is used herein to mean approximately, within the range, roughly, or approximately. When the term "about" is used in conjunction with a numerical range, it modifies the range by extending the boundaries above and below the stated values. Generally, the term "about" is used herein to modify a numerical value above and below the stated value by 10%.

[0274] The term "including" means "including but not limited to".

[0275] "Subject" includes, but is not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, e.g., mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0276] "Disease," "disorder," and "condition" are used interchangeably herein.

[0277] "Fasting" is defined as not eating within 30 minutes before and 60 minutes after taking the medicine.

[0278] The term "administering" includes delivering a compound or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof, or a pharmaceutical composition containing the same, to a subject using any suitable formulation or route of administration.

[0279] “Stages of CML (i.e., CP, AP, and BP)” refer to the ELN criteria disclosed in Table 1 of Baccarani et al., European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013, Blood, 2013, Volume 122, Number 6, which is incorporated herein by reference for all purposes.

[0280] “BCR-ABL1 TKIs” include “ATP-competitive BCR-ABL1 TKIs” and “BCR-ABL1 allosteric TKIs”.

[0281] The terms “ATP-competitive BCR-ABL1 TKIs,” “BCR-ABL1 orthosteric TKIs,” and “BCR-ABL1 catalytic TKIs” are used interchangeably and are defined as inhibitors that bind to the “hinge region” of the ATP-binding site, inhibiting autophosphorylation and substrate phosphorylation of the BCR-ABL1 kinase, thereby inhibiting cancer cell proliferation and tumor formation.

[0282] The term “BCR-ABL1 allosteric TKIs” refers to drugs that mimic the role of the myristoylated N-terminus in ABL1 by binding to the myristoyl pocket, thereby restoring the negative regulatory function of BCR-ABL1 kinase activity.

[0283] In a specific embodiment, Y.-L Pan et.al., (The progress of small-molecules and degraders against BCR-ABL1 for the treatment of CML, European Journal of Medicine Chemistry 238 (2022) 114442) discloses information such as the structure, cellular activity, in vivo activity, and development status of some BCR-ABL1 TKIs, which is incorporated herein by reference for all purposes.

[0284] "First-line BCR-ABL1 TKIs" drugs refer to the first-line treatment drugs approved by the FDA, EMA and NMPA CDE, including imatinib, nilotinib, dasatinib, bosutinib, flumatinib and radotinib.

[0285] "Second-line BCR-ABL1 TKIs" refers to second-line treatment drugs selected based on the type of ABL mutation. Please see Table 1 for details:

[0286] Table 1 Treatment options based on ABL mutation status

[0287] Note: *, if it occurs during dasatinib treatment. Currently, there is little clinical data on bosutinib for imatinib-resistant mutations, and some in vitro data show that the E255K / V mutation is insufficiently sensitive to bosutinib.

[0288] For the definitions of "failure" and "warning" in the context of "failure or warning in the treatment evaluation after TKIs treatment," please refer to the "Guidelines for the Diagnosis and Treatment of Adult Chronic Myeloid Leukemia (2018 Edition)" issued by the National Health Commission of the People's Republic of China in December 2018. For details, please refer to Tables 4 and 7 therein, which are excerpted as follows:

[0289] Table 4 of the "Guidelines for the Diagnosis and Treatment of Adult Chronic Myeloid Leukemia (2018 Edition)" describes the treatment response evaluation criteria for patients with CML-CP receiving first-line TKI therapy.

[0290] Note: IS: International Standardization

[0291] Table 7 of the "Guidelines for the Diagnosis and Treatment of Adult Chronic Myeloid Leukemia (2018 Edition)" describes the treatment response evaluation criteria for patients with CML-CP receiving second-line TKI therapy.

[0292] According to the criteria of the "Guidelines for the Diagnosis and Treatment of Adult Chronic Myeloid Leukemia (2018 Edition)", the hematologic response (HR), cytogenetic response (CyR), molecular response (MR), progression-free survival (PFS), and overall survival (OS) of CML patients were evaluated. The definitions of the treatment responses for hematologic response, cytogenetic response, and molecular response are shown in Table 3 and are excerpted as follows:

[0293] Table 3 Definition of treatment response in the "Guidelines for the Diagnosis and Treatment of Adult Chronic Myeloid Leukemia (2018 Edition)"

[0294] "Major hematologic response (MaHR)" included complete hematologic response (CHR) or no evidence of leukemia (NEL).

[0295] "Major cytogenetic response (MCyR)" includes complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR). If all patients have PCyR results before and after treatment, they are considered to have not achieved a major cytogenetic response.

[0296] "Major molecular response (MMR)" was defined as BCR-ABL1(IS) ≤ 0.1% (ABL1 transcripts > 10,000).

[0297] "Molecular response MR4" was defined as BCR-ABL1(IS) ≤ 0.01% (ABL1 transcripts > 10,000).

[0298] "Molecular response MR4.5" was defined as BCR-ABL1(IS)≤0.0032% (ABL1 transcripts>32,000).

[0299] "Molecular response MR5" was defined as BCR-ABL1(IS) ≤ 0.001% (ABL1 transcripts > 100,000).

[0300] Progression-free survival (PFS) is defined as the time from the first dose of trial drug to disease progression (PD) or death from any cause, whichever occurs first. For subjects with chronic-phase CML, PD is defined as death or a diagnosis of accelerated-phase or blast-phase CML by the investigator; for subjects with accelerated-phase CML, PD is defined as death or a diagnosis of blast-phase CML by the investigator.

[0301] Overall survival (OS) was defined as the time from the first dose of trial drug to death from any cause.

[0302] Event-free survival (EFS) was defined as the time from the day of randomization to the occurrence of any of the following events (whichever occurred first): progression to AP or BP; death from any cause (including but not limited to leukemia-related or drug-related); loss of MCyR or CCyR; failure to achieve a complete hematologic response after three cycles of treatment; loss of previously achieved CHR (confirmed by two consecutive examinations at least 7 days apart); or a doubling of the peripheral blood WBC count exceeding 20,000 / mm3. 3 , and lasted for ≥14 days (excluding secondary causes other than leukemia); discontinuation of treatment drugs due to treatment toxicity (subjects who withdrew from treatment due to treatment toxicity must be discussed and confirmed by the investigator and the sponsor.

[0303] As used herein, and unless otherwise indicated, the term "treating" includes actions that occur while a subject has a particular disease, disorder, or condition that reduce the severity of, or delay or slow the development of, the disease, disorder, or condition ("therapeutic treatment"), as well as actions that occur before a subject becomes ill with a particular disease, disorder, or condition ("prophylactic treatment").

[0304] treat

[0305] Chronic myeloid leukemia in chronic phase (CML-CP)

[0306] In one embodiment, the present invention relates to the use and method of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML or a relapse of central nervous system leukemia thereof, such as brain metastasis. In another embodiment, the present invention relates to the use and method of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML or a relapse of central nervous system leukemia thereof, such as brain metastasis.

[0307] In another specific embodiment, the CML is Ph+ CML. In another specific embodiment, the CML is BCR-ABL1+ CML. In another specific embodiment, the CML is CML with a T315I mutation. In another specific embodiment, the CML is CML without a T315I mutation. In another more specific embodiment, the CML is Ph+ CML-CP. In another more specific embodiment, the CML is Ph+ CML-CP with a T315I mutation. In another more specific embodiment, the CML is Ph+ and BCR-ABL1+ CML-CP with a T315I mutation.

[0308] In another embodiment, the uses and methods are for adult subjects. In another embodiment, the uses and methods are for pediatric subjects. In another embodiment, the uses and methods are for subjects with brain metastases.

[0309] In another specific embodiment, the subject has previously received treatment with ≥1 different BCR-ABL1 TKIs, with disease progression to accelerated or blastic phase, and the treatment evaluation result was failure, warning, or intolerance. In another specific embodiment, the subject has previously received treatment with ≥2 different BCR-ABL1 TKIs, with disease progression to accelerated or blastic phase, and the treatment evaluation result was failure, warning, or intolerance. In another specific embodiment, the subject has previously received treatment with ≥3 different BCR-ABL1 TKIs, with disease progression to accelerated or blastic phase, and the treatment evaluation result was failure, warning, or intolerance. In another specific embodiment, the subject has previously received treatment with ≥4 different BCR-ABL1 TKIs, with disease progression to accelerated or blastic phase, and the treatment evaluation result was failure, warning, or intolerance. In another more specific embodiment, the BCR-ABL1 TKIs are first-line, second-line, third-line, fourth-line, or fifth-line treatment drugs. In another more specific embodiment, the BCR-ABL1 TKIs are first-line, second-line, or third-line treatments. In another more specific embodiment, the BCR-ABL1 TKIs are first-line or second-line treatments. In another more specific embodiment, the BCR-ABL1 TKIs are first-line treatments. In another more specific embodiment, the BCR-ABL1 TKIs are second-line treatments. In another more specific embodiment, the BCR-ABL1 TKIs are second-line or higher-line treatments. In another more specific embodiment, the BCR-ABL1 TKIs include at least third-generation TKIs (e.g., ponatinib or olverembatinib). In another more specific embodiment, the BCR-ABL1 TKIs include at least third-generation TKIs (e.g., ponatinib or olverembatinib) and / or fourth-generation TKIs (e.g., asciminib or HS-10382). In another more specific embodiment, the BCR-ABL1 TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, ponatinib, olverembatinib, raducinib, bafetinib, vodobatinib, CHMFL-ABL-039, CHMFL-ABL-053, CHMFL-ABL-KIT-155, PF-114, pacritinib, rebasinib, danusertib, tozasertib, AT9283, KW-2449, XL228, asciminib or HS-10382.In another more specific embodiment, the BCR-ABL1 TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, ponatinib, orebactinib, radutinib or assinib. In another more specific embodiment, the BCR-ABL1 TKIs are selected from imatinib, dasatinib, nilotinib, ponatinib, orebactinib or assinib. In another more specific embodiment, the BCR-ABL1 TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib or radutinib. In another more specific embodiment, the BCR-ABL1 TKIs are selected from ponatinib, orebactinib, assinib or HS-10382. In another more specific embodiment, the BCR-ABL1 TKIs are selected from imatinib, dasatinib or nilotinib. In another more specific embodiment, the BCR-ABL1 TKIs are selected from ponatinib or orebactinib. In another more specific embodiment, the BCR-ABL1 TKIs are selected from aspartame or HS-10382. In another more specific embodiment, the BCR-ABL1 TKIs are selected from aspartame.

[0310] In another specific embodiment, the subject has previously received treatment with ≥1 different BCR-ABL1 TKIs, which has resulted in relapse or refractory disease. In another specific embodiment, the subject has previously received treatment with ≥2 different BCR-ABL1 TKIs, which has resulted in relapse or refractory disease. In another specific embodiment, the subject has previously received treatment with ≥3 different BCR-ABL1 TKIs, which has resulted in relapse or refractory disease. In another specific embodiment, the subject has previously received treatment with ≥4 different BCR-ABL1 TKIs, which has resulted in relapse or refractory disease. In another more specific embodiment, the BCR-ABL1 TKIs are first-line, second-line, third-line, fourth-line, or fifth-line treatments. In another more specific embodiment, the BCR-ABL1 TKIs are first-line, second-line, or third-line treatments. In another more specific embodiment, the BCR-ABL1 TKIs are first-line or second-line treatments. In another more specific embodiment, the BCR-ABL1 TKIs are first-line treatments. In another more specific embodiment, the BCR-ABL1 TKIs are second-line treatment drugs. In another more specific embodiment, the BCR-ABL1 TKIs are second-line or higher-line treatment drugs. In another more specific embodiment, the BCR-ABL1 TKIs include at least third-generation TKIs (e.g., ponatinib or orebactinib). In another more specific embodiment, the BCR-ABL1 TKIs include at least third-generation TKIs (e.g., ponatinib or orebactinib) and / or fourth-generation TKIs (e.g., aspartame or HS-10382). In another more specific embodiment, the BCR-ABL1 TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, ponatinib, orebactinib, raducinib, bafitinib, vodobatinib, CHMFL-ABL-039, CHMFL-ABL-053, CHMFL-ABL-KIT-155, PF-114, paclitinib, rebasinib, daruselutib, tauzerti, AT9283, KW-2449, XL228, aspartame or HS-10382. In another more specific embodiment, the BCR-ABL1 TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, ponatinib, orebactinib, raducinib or aspartame. In another more specific embodiment, the BCR-ABL1 TKIs are selected from imatinib, dasatinib, nilotinib, ponatinib, orebactinib or aspartame. In another more specific embodiment, the BCR-ABL1 TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib or radotinib.In another more specific embodiment, the BCR-ABL1 TKIs are selected from ponatinib, orebactinib, aspartame, or HS-10382. In another more specific embodiment, the BCR-ABL1 TKIs are selected from imatinib, dasatinib, or nilotinib. In another more specific embodiment, the BCR-ABL1 TKIs are selected from ponatinib or orebactinib. In another more specific embodiment, the BCR-ABL1 TKIs are selected from aspartame or HS-10382. In another more specific embodiment, the BCR-ABL1 TKIs are selected from aspartame.

[0311] In another specific embodiment, the subject has previously received treatment with ≥1 different BCR-ABL1 ATP-competitive TKIs, with disease progression to accelerated or blastic phase, and the treatment evaluation result was failure, warning, or intolerance. In another specific embodiment, the subject has previously received treatment with ≥2 different BCR-ABL1 ATP-competitive TKIs, with disease progression to accelerated or blastic phase, and the treatment evaluation result was failure, warning, or intolerance. In another specific embodiment, the subject has previously received treatment with ≥3 different BCR-ABL1 ATP-competitive TKIs, with disease progression to accelerated or blastic phase, and the treatment evaluation result was failure, warning, or intolerance. In another specific embodiment, the subject has previously received treatment with ≥4 different BCR-ABL1 ATP-competitive TKIs, with disease progression to accelerated or blastic phase, and the treatment evaluation result was failure, warning, or intolerance. In another more specific embodiment, the BCR-ABL1 ATP-competitive TKIs are first-line, second-line, third-line, fourth-line, or fifth-line treatment drugs. In another more specific embodiment, the BCR-ABL1 ATP competitive TKIs are first-line, second-line or third-line therapeutic drugs. In another more specific embodiment, the BCR-ABL1 ATP competitive TKIs are first-line or second-line therapeutic drugs. In another more specific embodiment, the BCR-ABL1 ATP competitive TKIs are first-line therapeutic drugs. In another more specific embodiment, the BCR-ABL1 ATP competitive TKIs are second-line therapeutic drugs. In another more specific embodiment, the BCR-ABL1 ATP competitive TKIs are second-line or higher-line therapeutic drugs. In another more specific embodiment, the BCR-ABL1 ATP competitive TKIs include at least three generations of TKIs (e.g., ponatinib or orebactinib). In another more specific embodiment, the BCR-ABL1 ATP competitive TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, ponatinib, orebactinib, raducinib, bafitinib, vodobatinib, CHMFL-ABL-039, CHMFL-ABL-053, CHMFL-ABL-KIT-155, PF-114, paclitinib, rebasinib, daruselutib, tauzerti, AT9283, KW-2449 or XL228. In another more specific embodiment, the BCR-ABL1 ATP competitive TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, ponatinib, orebactinib or raducinib. In another more specific embodiment, the BCR-ABL1 ATP-competitive TKIs are selected from imatinib, dasatinib, nilotinib, ponatinib, or orebactinib.In another more specific embodiment, the BCR-ABL1 ATP-competitive TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib or radurinib. In another more specific embodiment, the BCR-ABL1 ATP-competitive TKIs are selected from imatinib, dasatinib or nilotinib. In another more specific embodiment, the BCR-ABL1 ATP-competitive TKIs are selected from ponatinib or orebactinib.

[0312] In another specific embodiment, the subject has previously received treatment with ≥1 different BCR-ABL1 ATP-competitive TKIs and has relapsed or is refractory. In another specific embodiment, the subject has previously received treatment with ≥2 different BCR-ABL1 ATP-competitive TKIs and has relapsed or is refractory. In another specific embodiment, the subject has previously received treatment with ≥3 different BCR-ABL1 ATP-competitive TKIs and has relapsed or is refractory. In another specific embodiment, the subject has previously received treatment with ≥4 different BCR-ABL1 ATP-competitive TKIs and has relapsed or is refractory. In another more specific embodiment, the BCR-ABL1 ATP-competitive TKIs are first-line, second-line, third-line, fourth-line, or fifth-line treatments. In another more specific embodiment, the BCR-ABL1 ATP-competitive TKIs are first-line, second-line, or third-line treatments. In another more specific embodiment, the BCR-ABL1 ATP-competitive TKIs are first-line or second-line treatments. In another more specific embodiment, the BCR-ABL1 ATP-competitive TKIs are first-line treatment drugs. In another more specific embodiment, the BCR-ABL1 ATP-competitive TKIs are second-line treatment drugs. In another more specific embodiment, the BCR-ABL1 ATP-competitive TKIs are second-line or higher-line treatment drugs. In another more specific embodiment, the BCR-ABL1 ATP-competitive TKIs include at least third-generation TKIs (e.g., ponatinib or orebactinib). In another more specific embodiment, the BCR-ABL1 ATP competitive TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, ponatinib, orebactinib, raducinib, bafitinib, vodobatinib, CHMFL-ABL-039, CHMFL-ABL-053, CHMFL-ABL-KIT-155, PF-114, pactinib, rebasinib, daruselutib, tauzerti, AT9283, KW-2449 or XL228. In another more specific embodiment, the BCR-ABL1 ATP competitive TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, ponatinib, orebactinib or raducinib. In another more specific embodiment, the BCR-ABL1 ATP-competitive TKIs are selected from imatinib, dasatinib, nilotinib, ponatinib or orebactinib. In another more specific embodiment, the BCR-ABL1 ATP-competitive TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib or radurinib. In another more specific embodiment, the BCR-ABL1 ATP-competitive TKIs are selected from imatinib, dasatinib or nilotinib.In another more specific embodiment, the BCR-ABL1 ATP-competitive TKIs is selected from ponatinib or orebactinib.

[0313] In another specific embodiment, the subject has previously received treatment with ≥1 different first- and / or second-generation BCR-ABL1 ATP-competitive TKIs and developed resistance or intolerance. In another specific embodiment, the subject has previously received treatment with ≥2 different first- and / or second-generation BCR-ABL1 ATP-competitive TKIs and developed resistance or intolerance. In another specific embodiment, the subject has previously received treatment with ≥3 different first- and / or second-generation BCR-ABL1 ATP-competitive TKIs and developed resistance or intolerance. In another specific embodiment, the subject has previously received treatment with ≥4 different first- and / or second-generation BCR-ABL1 ATP-competitive TKIs and developed resistance or intolerance. In another more specific embodiment, the drug resistance is a point mutation in the BCR-ABL1 kinase region, such as one or more of T315I / A, Y253F / H, E255V / K, M351T, G250E, F359V / I / C, H396P / R, M244V, E355G, F317L / V / I / C, F311L, M237I, Q252H / R, D276G, L248V, V379I, L384M, L387M, E279K, F486S, E459K, P223S, I502L or V299L. In another more specific embodiment, the resistance is in a point mutation in the BCR-ABL1 kinase domain selected from one or more of T315I, Y253H, E255V / K, M351T, G250E, F359V / , H396P, M244V, E355G, F317L, Q252H, E459K, P223S, I502L, or V299L mutations. In another more specific embodiment, the resistance is T315I. In another more specific embodiment, the first- or second-generation BCR-ABL1 ATP-competitive TKIs are first-, second-, third-, fourth-, or fifth-line treatments. In another more specific embodiment, the first- or second-generation BCR-ABL1 ATP-competitive TKIs are first-, second-, or third-line treatments. In another more specific embodiment, the first- or second-generation BCR-ABL1 ATP-competitive TKIs are first- or second-line treatments. In another more specific embodiment, the first- or second-generation BCR-ABL1 ATP-competitive TKIs are first-line treatments. In another more specific embodiment, the first- or second-generation BCR-ABL1 ATP-competitive TKIs are second-line treatments. In another more specific embodiment, the first- or second-generation BCR-ABL1 ATP-competitive TKIs are second-line or higher-line treatments. In another more specific embodiment, the first-generation BCR-ABL1 ATP-competitive TKIs are imatinib.In another more specific embodiment, the second generation BCR-ABL1 ATP competitive TKIs are selected from dasatinib, nilotinib, bosutinib, flumatinib or radotinib. In another more specific embodiment, the first and / or second generation BCR-ABL1 ATP competitive TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib or radotinib. In another more specific embodiment, the first and / or second generation BCR-ABL1 ATP competitive TKIs are selected from imatinib, dasatinib or nilotinib.

[0314] In another specific embodiment, the subject has previously received treatment with ≥1 different first- and / or second-generation BCR-ABL1 ATP-competitive TKIs, which has resulted in relapse or refractory disease. In another specific embodiment, the subject has previously received treatment with ≥2 different first- and / or second-generation BCR-ABL1 ATP-competitive TKIs, which has resulted in relapse or refractory disease. In another specific embodiment, the subject has previously received treatment with ≥3 different first- and / or second-generation BCR-ABL1 ATP-competitive TKIs, which has resulted in relapse or refractory disease. In another specific embodiment, the subject has previously received treatment with ≥4 different first- and / or second-generation BCR-ABL1 ATP-competitive TKIs, which has resulted in relapse or refractory disease. In another more specific embodiment, the first- or second-generation BCR-ABL1 ATP-competitive TKIs are first-, second-, third-, fourth-, or fifth-line treatments. In another more specific embodiment, the first- or second-generation BCR-ABL1 ATP-competitive TKIs are first-, second-, or third-line treatments. In another more specific embodiment, the first- or second-generation BCR-ABL1 ATP-competitive TKIs are first- or second-line treatments. In another more specific embodiment, the first- or second-generation BCR-ABL1 ATP-competitive TKIs are first-line treatments. In another more specific embodiment, the first- or second-generation BCR-ABL1 ATP-competitive TKIs are second-line treatments. In another more specific embodiment, the first- or second-generation BCR-ABL1 ATP-competitive TKIs are second-line or higher-line treatments. In another more specific embodiment, the first-generation BCR-ABL1 ATP-competitive TKIs are imatinib. In another more specific embodiment, the second-generation BCR-ABL1 ATP-competitive TKIs are selected from dasatinib, nilotinib, bosutinib, flumatinib, or raducinib. In another more specific embodiment, the first and / or second generation BCR-ABL1 ATP-competitive TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib or radotinib. In another more specific embodiment, the first and / or second generation BCR-ABL1 ATP-competitive TKIs are selected from imatinib, dasatinib or nilotinib.

[0315] In another specific embodiment, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof (preferably Compound A) is about 20 mg / day to about 400 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof (preferably Compound A) is about 20 mg / day to about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof (preferably Compound A) is about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day, about 120 mg / day, about 140 mg / day, about 160 mg / day, about 180 mg / day, about 200 mg / day, about 220 mg / day, about 240 mg / day, about 260 mg / day, about 270 mg / day, about 280 mg / day, about 300 mg / day, about 320 mg / day, about 340 mg / day, about 360 mg / day, about 380 mg / day or about 400 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day, about 120 mg / day, about 160 mg / day or about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg / day, about 40 mg / day, about 80 mg / day, about 160 mg / day or about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 40 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 60 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 80 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 100 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 120 mg / day.In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 140 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 160 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 180 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 200 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 220 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 260 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 270 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 280 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 300 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 320 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 340 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 360 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 380 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 400 mg / day.In another specific embodiment, the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is administered orally or intranasally. In another specific embodiment, the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is administered orally on an empty stomach. In another specific embodiment, the administration mode of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is QD, BID or TID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 10 mg BID, 20 mg BID, 40 mg QD, 40 mg BID, 80 mg QD, 80 mg BID, 160 mg QD or 240 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 10 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 40 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 40 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 80 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 80 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 160 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 240 mg QD.

[0316] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered until disease progression, intolerable toxicity, or death. In another embodiment, compound A or a pharmaceutically acceptable salt thereof is administered until disease progression, intolerable toxicity, or death.

[0317] Chronic myeloid leukemia (CML-CP) in the chronic phase that has progressed to accelerated phase or blast phase after previous treatment with ≥1 different BCR-ABL1 TKIs, or whose treatment evaluation results are failure, warning, or intolerance

[0318] In one embodiment, the present invention relates to the use and method of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML or relapse of central nervous system leukemia, such as brain metastasis, wherein the CML has previously been treated with ≥1 different BCR-ABL1 TKIs and the disease has progressed to accelerated phase or blast phase, and the treatment evaluation result is failure, warning or intolerance. In another embodiment, the present invention relates to the use and method of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML, wherein the CML has previously been treated with ≥1 different BCR-ABL1 TKIs and the disease has progressed to accelerated phase or blast phase, and the treatment evaluation result is failure, warning or intolerance.

[0319] In another embodiment, the present invention relates to the use and method of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML, wherein the CML has previously been treated with ≥2 different BCR-ABL1 TKIs and the disease has progressed to the accelerated phase or blast phase, and the treatment evaluation result is failure, warning or intolerance. In another embodiment, the present invention relates to the use and method of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML, wherein the CML has previously been treated with ≥2 different BCR-ABL1 TKIs and the disease has progressed to the accelerated phase or blast phase, and the treatment evaluation result is failure, warning or intolerance.

[0320] In another embodiment, the present invention relates to the use and method of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML, wherein the CML has previously been treated with ≥3 different BCR-ABL1 TKIs and the disease has progressed to the accelerated phase or blast phase, and the treatment evaluation result is failure, warning or intolerance. In another embodiment, the present invention relates to the use and method of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML, wherein the CML has previously been treated with ≥3 different BCR-ABL1 TKIs and the disease has progressed to the accelerated phase or blast phase, and the treatment evaluation result is failure, warning or intolerance.

[0321] In another embodiment, the present invention relates to the use and method of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML, wherein the CML has previously been treated with ≥4 different BCR-ABL1 TKIs and the disease has progressed to the accelerated phase or blast phase, and the treatment evaluation result is failure, warning or intolerance. In another embodiment, the present invention relates to the use and method of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML, wherein the CML has previously been treated with ≥4 different BCR-ABL1 TKIs and the disease has progressed to the accelerated phase or blast phase, and the treatment evaluation result is failure, warning or intolerance.

[0322] In one embodiment, the BCR-ABL1 TKIs are first-line, second-line, third-line, fourth-line, or fifth-line treatments. In another embodiment, the BCR-ABL1 TKIs are first-line, second-line, or third-line treatments. In another embodiment, the BCR-ABL1 TKIs are first-line or second-line treatments. In another embodiment, the BCR-ABL1 TKIs are first-line treatments. In another embodiment, the BCR-ABL1 TKIs are second-line treatments. In another embodiment, the BCR-ABL1 TKIs are second-line or higher-line treatments. In another more specific embodiment, the BCR-ABL1 TKIs include at least third-generation TKIs (e.g., ponatinib or orebactinib). In another more specific embodiment, the BCR-ABL1 TKIs include at least third-generation TKIs (e.g., ponatinib or orebactinib) and / or fourth-generation TKIs (e.g., aspergillus or HS-10382). In another specific embodiment, the BCR-ABL1 TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, ponatinib, orebactinib, raducinib, bafitinib, vodobatinib, CHMFL-ABL-039, CHMFL-ABL-053, CHMFL-ABL-KIT-155, PF-114, paclitinib, rebasinib, daruselutib, tauzerti, AT9283, KW-2449, XL228, aspartame or HS-10382. In another specific embodiment, the BCR-ABL1 TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, ponatinib, orebactinib, raducinib or aspartame. In another specific embodiment, the BCR-ABL1 TKIs are selected from imatinib, dasatinib, nilotinib, ponatinib, orebactinib, or aspartate. In another specific embodiment, the BCR-ABL1 TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, or radutinib. In another more specific embodiment, the BCR-ABL1 TKIs are selected from ponatinib, orebactinib, aspartate, or HS-10382. In another specific embodiment, the BCR-ABL1 TKIs are selected from ponatinib, orebactinib, or aspartate. In another specific embodiment, the BCR-ABL1 TKIs are selected from imatinib, dasatinib, or nilotinib. In another specific embodiment, the BCR-ABL1 TKIs are selected from ponatinib or orebactinib. In another specific embodiment, the BCR-ABL1 TKIs are selected from aspartame or HS-10382.In another specific embodiment, the BCR-ABL1 TKIs is selected from aspartame.

[0323] In another specific embodiment, the CML is Ph+ CML. In another specific embodiment, the CML is BCR-ABL1+ CML. In another specific embodiment, the CML is CML with a T315I mutation. In another specific embodiment, the CML is CML without a T315I mutation. In another more specific embodiment, the CML is Ph+ CML-CP. In another more specific embodiment, the CML is Ph+ CML-CP with a T315I mutation. In another more specific embodiment, the CML is Ph+ and BCR-ABL1+ CML-CP with a T315I mutation.

[0324] In another embodiment, the uses and methods are for adult subjects. In another embodiment, the uses and methods are for pediatric subjects. In another embodiment, the uses and methods are for subjects with brain metastases.

[0325] In another specific embodiment, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof (preferably Compound A) is about 20 mg / day to about 400 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof (preferably Compound A) is about 20 mg / day to about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof (preferably Compound A) is about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day, about 120 mg / day, about 140 mg / day, about 160 mg / day, about 180 mg / day, about 200 mg / day, about 220 mg / day, about 240 mg / day, about 260 mg / day, about 270 mg / day, about 280 mg / day, about 300 mg / day, about 320 mg / day, about 340 mg / day, about 360 mg / day, about 380 mg / day or about 400 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day, about 120 mg / day, about 160 mg / day or about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg / day, about 40 mg / day, about 80 mg / day, about 160 mg / day or about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 40 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 60 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 80 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 100 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 120 mg / day.In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 140 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 160 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 180 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 200 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 220 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 260 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 270 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 280 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 300 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 320 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 340 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 360 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 380 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 400 mg / day.In another specific embodiment, the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is administered orally or intranasally. In another specific embodiment, the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is administered orally on an empty stomach. In another specific embodiment, the administration of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is QD, BID or TID. In another specific embodiment, the administration of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 10 mg BID, 20 mg BID, 40 mg QD, 40 mg BID, 80 mg QD, 80 mg BID, 160 mg QD or 240 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 10 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 40 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 40 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 80 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 80 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 160 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 240 mg QD.

[0326] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered until disease progression, intolerable toxicity, or death. In another embodiment, compound A or a pharmaceutically acceptable salt thereof is administered until disease progression, intolerable toxicity, or death.

[0327] Chronic myeloid leukemia (CML-CP) in the chronic phase who has progressed to accelerated phase or blast phase after receiving ≥1 different BCR-ABL1 ATP-competitive TKIs, or whose treatment evaluation results are failure, warning, or intolerance

[0328] In one embodiment, the present invention relates to the use and method of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML or relapse of central nervous system leukemia, such as brain metastasis, wherein the CML has previously been treated with ≥1 different BCR-ABL1 ATP-competitive TKIs and the disease has progressed to accelerated phase or blast phase, and the treatment evaluation result is failure, warning or intolerance. In another embodiment, the present invention relates to a method of treating chronic phase CML with (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof, wherein the CML has previously been treated with ≥1 different BCR-ABL1 ATP-competitive TKIs and the disease has progressed to accelerated phase or blast phase, and the treatment evaluation result is failure, warning or intolerance.

[0329] In another embodiment, the present invention relates to the use and method of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML, wherein the CML has previously been treated with ≥2 different BCR-ABL1 ATP-competitive TKIs and the disease has progressed to the accelerated phase or blast phase, and the treatment evaluation result is failure, warning or intolerance. In another embodiment, the present invention relates to the use and method of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML, wherein the CML has previously been treated with ≥2 different BCR-ABL1 ATP-competitive TKIs and the disease has progressed to the accelerated phase or blast phase, and the treatment evaluation result is failure, warning or intolerance.

[0330] In another embodiment, the present invention relates to the use and method of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML, wherein the CML has previously been treated with ≥3 different BCR-ABL1 ATP-competitive TKIs and the disease has progressed to the accelerated phase or blast phase, and the treatment evaluation result is failure, warning or intolerance. In another embodiment, the present invention relates to the use and method of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML, wherein the CML has previously been treated with ≥3 different BCR-ABL1 ATP-competitive TKIs and the disease has progressed to the accelerated phase or blast phase, and the treatment evaluation result is failure, warning or intolerance.

[0331] In another embodiment, the present invention relates to the use and method of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML, wherein the CML has previously been treated with ≥4 different BCR-ABL1 ATP-competitive TKIs and the disease has progressed to the accelerated phase or blast phase, and the treatment evaluation result is failure, warning or intolerance. In another embodiment, the present invention relates to the use and method of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML, wherein the CML has previously been treated with ≥4 different BCR-ABL1 ATP-competitive TKIs and the disease has progressed to the accelerated phase or blast phase, and the treatment evaluation result is failure, warning or intolerance.

[0332] In one embodiment, the BCR-ABL1 ATP competitive TKIs are first-line, second-line, third-line, fourth-line or fifth-line treatment drugs. In another embodiment, the BCR-ABL1 ATP competitive TKIs are first-line, second-line or third-line treatment drugs. In another embodiment, the BCR-ABL1 ATP competitive TKIs are first-line or second-line treatment drugs. In another embodiment, the BCR-ABL1 ATP competitive TKIs are first-line treatment drugs. In another embodiment, the BCR-ABL1 ATP competitive TKIs are second-line treatment drugs. In another embodiment, the BCR-ABL1 ATP competitive TKIs are second-line or higher-line treatment drugs. In another more specific embodiment, the BCR-ABL1 ATP competitive TKIs include at least three generations of TKIs (e.g., ponatinib or orebactinib). In another specific embodiment, the BCR-ABL1 ATP-competitive TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, ponatinib, orebactinib, raducinib, bafitinib, vodobatinib, CHMFL-ABL-039, CHMFL-ABL-053, CHMFL-ABL-KIT-155, PF-114, pactinib, HS-10382, rebasinib, daruselutib, tauzerti, AT9283, KW-2449 or XL228. In another specific embodiment, the BCR-ABL1 ATP-competitive TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, ponatinib, orebactinib or raducinib. In another specific embodiment, the BCR-ABL1 ATP-competitive TKIs are selected from imatinib, dasatinib, nilotinib, ponatinib, or orebactinib. In another more specific embodiment, the BCR-ABL1 ATP-competitive TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, or radurinib. In another specific embodiment, the BCR-ABL1 ATP-competitive TKIs are selected from imatinib, dasatinib, or nilotinib. In another specific embodiment, the BCR-ABL1 ATP-competitive TKIs are selected from ponatinib or orebactinib.

[0333] In another specific embodiment, the CML is Ph+ CML. In another specific embodiment, the CML is BCR-ABL1+ CML. In another specific embodiment, the CML is CML with a T315I mutation. In another specific embodiment, the CML is CML without a T315I mutation. In another more specific embodiment, the CML is Ph+ CML-CP. In another more specific embodiment, the CML is Ph+ CML-CP with a T315I mutation. In another more specific embodiment, the CML is Ph+ and BCR-ABL1+ CML-CP with a T315I mutation.

[0334] In another embodiment, the uses and methods are for adult subjects. In another embodiment, the uses and methods are for pediatric subjects. In another embodiment, the uses and methods are for subjects with brain metastases.

[0335] In another specific embodiment, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof (preferably Compound A) is about 20 mg / day to about 400 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof (preferably Compound A) is about 20 mg / day to about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof (preferably Compound A) is about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day, about 120 mg / day, about 140 mg / day, about 160 mg / day, about 180 mg / day, about 200 mg / day, about 220 mg / day, about 240 mg / day, about 260 mg / day, about 270 mg / day, about 280 mg / day, about 300 mg / day, about 320 mg / day, about 340 mg / day, about 360 mg / day, about 380 mg / day or about 400 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day, about 120 mg / day, about 160 mg / day or about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg / day, about 40 mg / day, about 80 mg / day, about 160 mg / day or about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 40 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 60 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 80 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 100 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 120 mg / day.In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 140 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 160 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 180 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 200 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 220 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 260 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 270 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 280 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 300 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 320 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 340 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 360 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 380 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 400 mg / day.In another specific embodiment, the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is administered orally or intranasally. In another specific embodiment, the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is administered orally on an empty stomach. In another specific embodiment, the administration of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is QD, BID or TID. In another specific embodiment, the administration of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 10 mg BID, 20 mg BID, 40 mg QD, 40 mg BID, 80 mg QD, 80 mg BID, 160 mg QD or 240 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 10 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 40 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 40 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 80 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 80 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 160 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 240 mg QD.

[0336] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered until disease progression, intolerable toxicity, or death. In another embodiment, compound A or a pharmaceutically acceptable salt thereof is administered until disease progression, intolerable toxicity, or death.

[0337] Chronic myeloid leukemia (CML-CP) in the chronic phase that has developed resistance or intolerance after previous treatment with ≥1 different first- and / or second-generation BCR-ABL1 ATP-competitive TKIs

[0338] In one embodiment, the present invention relates to the use and method of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML or relapse of central nervous system leukemia, such as brain metastasis, wherein the CML has previously been treated with ≥1 different first- and / or second-generation BCR-ABL1 ATP-competitive TKIs and has developed resistance or intolerance. In another embodiment, the present invention relates to the use and method of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML, wherein the CML has previously been treated with ≥1 different first- and / or second-generation BCR-ABL1 ATP-competitive TKIs and has developed resistance or intolerance.

[0339] In another embodiment, the present invention relates to the use and method of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML, wherein the CML has previously been treated with ≥2 different first- and / or second-generation BCR-ABL1 ATP-competitive TKIs and developed resistance or intolerance. In another embodiment, the present invention relates to the use and method of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML, wherein the CML has previously been treated with ≥2 different first- and / or second-generation BCR-ABL1 ATP-competitive TKIs and developed resistance or intolerance.

[0340] In another embodiment, the present invention relates to the use and method of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML, wherein the CML has previously been treated with ≥3 different first- and / or second-generation BCR-ABL1 ATP-competitive TKIs and has developed resistance or intolerance. In another embodiment, the present invention relates to the use and method of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML, wherein the CML has previously been treated with ≥3 different first- and / or second-generation BCR-ABL1 ATP-competitive TKIs and has developed resistance or intolerance.

[0341] In another embodiment, the present invention relates to the use and method of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML, wherein the CML has previously been treated with ≥4 different first- and / or second-generation BCR-ABL1 ATP-competitive TKIs and has developed resistance or intolerance. In another embodiment, the present invention relates to the use and method of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML, wherein the CML has previously been treated with ≥4 different first- and / or second-generation BCR-ABL1 ATP-competitive TKIs and has developed resistance or intolerance.

[0342] In a specific embodiment, the drug resistance is a point mutation in the BCR-ABL1 kinase region, such as one or more of T315I / A, Y253F / H, E255V / K, M351T, G250E, F359V / I / C, H396P / R, M244V, E355G, F317L / V / I / C, F311L, M237I, Q252H / R, D276G, L248V, V379I, L384M, L387M, E279K, F486S, E459K, P223S, I502L or V299L. In another embodiment, the drug resistance is a point mutation in the BCR-ABL1 kinase region selected from one or more of T315I, Y253H, E255V / K, M351T, G250E, F359V / , H396P, M244V, E355G, F317L, Q252H, E459K, P223S, I502L, or V299L mutations. In another embodiment, the drug resistance is T315I.

[0343] In another specific embodiment, the first- or second-generation BCR-ABL1 ATP-competitive TKIs are first-, second-, third-, fourth-, or fifth-line treatments. In another specific embodiment, the first- or second-generation BCR-ABL1 ATP-competitive TKIs are first-, second-, or third-line treatments. In another specific embodiment, the first- or second-generation BCR-ABL1 ATP-competitive TKIs are first- or second-line treatments. In another specific embodiment, the first- or second-generation BCR-ABL1 ATP-competitive TKIs are first-line treatments. In another specific embodiment, the first- or second-generation BCR-ABL1 ATP-competitive TKIs are second-line treatments. In another specific embodiment, the first- or second-generation BCR-ABL1 ATP-competitive TKIs are second-line treatments or higher-line treatments. In another specific embodiment, the first-generation BCR-ABL1 ATP-competitive TKIs are imatinib. In another specific embodiment, the second-generation BCR-ABL1 ATP-competitive TKIs are selected from dasatinib, nilotinib, bosutinib, flumatinib, or radotinib. In another specific embodiment, the first- and / or second-generation BCR-ABL1 ATP-competitive TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, or radotinib. In another specific embodiment, the first- and / or second-generation BCR-ABL1 ATP-competitive TKIs are selected from imatinib, dasatinib, or nilotinib.

[0344] In another specific embodiment, the CML is Ph+ CML. In another specific embodiment, the CML is BCR-ABL1+ CML. In another specific embodiment, the CML is CML with a T315I mutation. In another specific embodiment, the CML is CML without a T315I mutation. In another more specific embodiment, the CML is Ph+ CML-CP. In another more specific embodiment, the CML is Ph+ CML-CP with a T315I mutation. In another more specific embodiment, the CML is Ph+ and BCR-ABL1+ CML-CP with a T315I mutation.

[0345] In another embodiment, the uses and methods are for adult subjects. In another embodiment, the uses and methods are for pediatric subjects. In another embodiment, the uses and methods are for subjects with brain metastases.

[0346] In another specific embodiment, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof (preferably Compound A) is about 20 mg / day to about 400 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof (preferably Compound A) is about 20 mg / day to about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof (preferably Compound A) is about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day, about 120 mg / day, about 140 mg / day, about 160 mg / day, about 180 mg / day, about 200 mg / day, about 220 mg / day, about 240 mg / day, about 260 mg / day, about 270 mg / day, about 280 mg / day, about 300 mg / day, about 320 mg / day, about 340 mg / day, about 360 mg / day, about 380 mg / day or about 400 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day, about 120 mg / day, about 160 mg / day or about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg / day, about 40 mg / day, about 80 mg / day, about 160 mg / day or about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 40 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 60 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 80 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 100 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 120 mg / day.In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 140 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 160 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 180 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 200 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 220 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 260 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 270 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 280 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 300 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 320 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 340 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 360 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 380 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 400 mg / day.In another specific embodiment, the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is administered orally or intranasally. In another specific embodiment, the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is administered orally on an empty stomach. In another specific embodiment, the administration of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is QD, BID or TID. In another specific embodiment, the administration of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 10 mg BID, 20 mg BID, 40 mg QD, 40 mg BID, 80 mg QD, 80 mg BID, 160 mg QD or 240 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 10 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 40 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 40 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 80 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 80 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 160 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 240 mg QD.

[0347] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered until disease progression, intolerable toxicity, or death. In another embodiment, compound A or a pharmaceutically acceptable salt thereof is administered until disease progression, intolerable toxicity, or death.

[0348] Chronic myeloid leukemia (CML-CP) that has relapsed or is refractory after prior treatment with ≥1 different BCR-ABL1 TKIs

[0349] In one embodiment, the present invention relates to the use and method of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML or relapsed central nervous system leukemia thereof, such as brain metastasis, wherein the CML has previously been treated with ≥1 different BCR-ABL1 TKIs and has relapsed or is refractory. In another embodiment, the present invention relates to the use and method of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML, wherein the CML has previously been treated with ≥1 different BCR-ABL1 TKIs and has relapsed or is refractory.

[0350] In another embodiment, the present invention relates to the use and method of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML, wherein the CML has relapsed or is refractory after previously receiving treatment with ≥2 different BCR-ABL1 TKIs. In another embodiment, the present invention relates to the use and method of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML, wherein the CML has relapsed or is refractory after previously receiving treatment with ≥2 different BCR-ABL1 TKIs.

[0351] In another embodiment, the present invention relates to the use and method of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML, wherein the CML has relapsed or is refractory after previous treatment with ≥3 different BCR-ABL1 TKIs. In another embodiment, the present invention relates to the use and method of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML, wherein the CML has relapsed or is refractory after previous treatment with ≥3 different BCR-ABL1 TKIs.

[0352] In another embodiment, the present invention relates to the use and method of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML, wherein the CML has relapsed or is refractory after previously receiving treatment with ≥4 different BCR-ABL1 TKIs. In another embodiment, the present invention relates to the use and method of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML, wherein the CML has relapsed or is refractory after previously receiving treatment with ≥4 different BCR-ABL1 TKIs.

[0353] In one embodiment, the BCR-ABL1 TKIs are first-line, second-line, third-line, fourth-line, or fifth-line treatments. In another embodiment, the BCR-ABL1 TKIs are first-line, second-line, or third-line treatments. In another embodiment, the BCR-ABL1 TKIs are first-line or second-line treatments. In another embodiment, the BCR-ABL1 TKIs are first-line treatments. In another embodiment, the BCR-ABL1 TKIs are second-line treatments. In another embodiment, the BCR-ABL1 TKIs are second-line or higher-line treatments. In another more specific embodiment, the BCR-ABL1 TKIs include at least third-generation TKIs (e.g., ponatinib or orebactinib). In another more specific embodiment, the BCR-ABL1 TKIs include at least third-generation TKIs (e.g., ponatinib or orebactinib) and / or fourth-generation TKIs (e.g., aspergillus or HS-10382). In another specific embodiment, the BCR-ABL1 TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, ponatinib, orebactinib, raducinib, bafitinib, vodobatinib, CHMFL-ABL-039, CHMFL-ABL-053, CHMFL-ABL-KIT-155, PF-114, paclitinib, rebasinib, daruselutib, tauzerti, AT9283, KW-2449, XL228, aspartame or HS-10382. In another specific embodiment, the BCR-ABL1 TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, ponatinib, orebactinib, raducinib or aspartame. In another specific embodiment, the BCR-ABL1 TKIs are selected from imatinib, dasatinib, nilotinib, ponatinib, or aspirinib. In another specific embodiment, the BCR-ABL1 TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, or radutinib. In another specific embodiment, the BCR-ABL1 TKIs are selected from ponatinib, or aspirinib, or HS-10382. In another specific embodiment, the BCR-ABL1 TKIs are selected from imatinib, dasatinib, or nilotinib. In another specific embodiment, the BCR-ABL1 TKIs are selected from ponatinib or or aspirinib. In another specific embodiment, the BCR-ABL1 TKIs are selected from aspirinib or HS-10382. In another specific embodiment, the BCR-ABL1 TKIs are selected from aspirinib.

[0354] In another specific embodiment, the CML is Ph+ CML. In another specific embodiment, the CML is BCR-ABL1+ CML. In another specific embodiment, the CML is CML with a T315I mutation. In another specific embodiment, the CML is CML without a T315I mutation. In another more specific embodiment, the CML is Ph+ CML-CP. In another more specific embodiment, the CML is Ph+ CML-CP with a T315I mutation. In another more specific embodiment, the CML is Ph+ and BCR-ABL1+ CML-CP with a T315I mutation.

[0355] In another embodiment, the uses and methods are for adult subjects. In another embodiment, the uses and methods are for pediatric subjects. In another embodiment, the uses and methods are for subjects with brain metastases.

[0356] In another specific embodiment, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof (preferably Compound A) is about 20 mg / day to about 400 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof (preferably Compound A) is about 20 mg / day to about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof (preferably Compound A) is about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day, about 120 mg / day, about 140 mg / day, about 160 mg / day, about 180 mg / day, about 200 mg / day, about 220 mg / day, about 240 mg / day, about 260 mg / day, about 270 mg / day, about 280 mg / day, about 300 mg / day, about 320 mg / day, about 340 mg / day, about 360 mg / day, about 380 mg / day or about 400 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day, about 120 mg / day, about 160 mg / day or about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg / day, about 40 mg / day, about 80 mg / day, about 160 mg / day or about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 40 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 60 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 80 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 100 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 120 mg / day.In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 140 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 160 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 180 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 200 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 220 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 260 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 270 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 280 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 300 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 320 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 340 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 360 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 380 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 400 mg / day.In another specific embodiment, the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is administered orally or intranasally. In another specific embodiment, the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is administered orally on an empty stomach. In another specific embodiment, the administration of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is QD, BID or TID. In another specific embodiment, the administration of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 10 mg BID, 20 mg BID, 40 mg QD, 40 mg BID, 80 mg QD, 80 mg BID, 160 mg QD or 240 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 10 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 40 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 40 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 80 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 80 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 160 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 240 mg QD.

[0357] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered until disease progression, intolerable toxicity, or death. In another embodiment, compound A or a pharmaceutically acceptable salt thereof is administered until disease progression, intolerable toxicity, or death.

[0358] Chronic myeloid leukemia (CML-CP) that has relapsed or is refractory after prior treatment with ≥1 different BCR-ABL1 ATP-competitive TKIs

[0359] In one embodiment, the present invention relates to the use and method of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML or relapsed central nervous system leukemia thereof, such as brain metastasis, wherein the CML has previously been treated with ≥1 different BCR-ABL1 ATP-competitive TKIs and has relapsed or is refractory. In another embodiment, the present invention relates to the use and method of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML, wherein the CML has previously been treated with ≥1 different BCR-ABL1 ATP-competitive TKIs and has relapsed or is refractory.

[0360] In another embodiment, the present invention relates to the use and method of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML, wherein the CML has relapsed or is refractory after previously receiving treatment with ≥2 different BCR-ABL1 ATP-competitive TKIs. In another embodiment, the present invention relates to the use and method of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML, wherein the CML has relapsed or is refractory after previously receiving treatment with ≥2 different BCR-ABL1 ATP-competitive TKIs.

[0361] In another embodiment, the present invention relates to the use and method of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML, wherein the CML has relapsed or is refractory after previously receiving treatment with ≥3 different BCR-ABL1 ATP-competitive TKIs. In another embodiment, the present invention relates to the use and method of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML, wherein the CML has relapsed or is refractory after previously receiving treatment with ≥3 different BCR-ABL1 ATP-competitive TKIs.

[0362] In another embodiment, the present invention relates to the use and method of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML, wherein the CML has relapsed or is refractory after previously receiving treatment with ≥4 different BCR-ABL1 ATP-competitive TKIs. In another embodiment, the present invention relates to the use and method of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML, wherein the CML has relapsed or is refractory after previously receiving treatment with ≥4 different BCR-ABL1 ATP-competitive TKIs.

[0363] In a specific embodiment, the BCR-ABL1 ATP competitive TKIs are first-line, second-line, third-line, fourth-line or fifth-line treatment drugs. In a specific embodiment, the BCR-ABL1 ATP competitive TKIs are first-line, second-line or third-line treatment drugs. In another specific embodiment, the BCR-ABL1 ATP competitive TKIs are first-line or second-line treatment drugs. In another specific embodiment, the BCR-ABL1 ATP competitive TKIs are first-line treatment drugs. In another specific embodiment, the BCR-ABL1 ATP competitive TKIs are second-line treatment drugs. In another specific embodiment, the BCR-ABL1 ATP competitive TKIs are second-line or higher-line treatment drugs. In another more specific embodiment, the BCR-ABL1 ATP competitive TKIs include at least three generations of TKIs (e.g., ponatinib or orebactinib). In another specific embodiment, the BCR-ABL1 ATP-competitive TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, ponatinib, orebactinib, raducinib, bafitinib, vodobatinib, CHMFL-ABL-039, CHMFL-ABL-053, CHMFL-ABL-KIT-155, PF-114, pactinib, HS-10382, rebasinib, daruselutib, tauzerti, AT9283, KW-2449 or XL228. In another specific embodiment, the BCR-ABL1 ATP-competitive TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, ponatinib, orebactinib or raducinib. In another specific embodiment, the BCR-ABL1 ATP-competitive TKIs are selected from imatinib, dasatinib, nilotinib, ponatinib, or orebactinib. In another specific embodiment, the BCR-ABL1 ATP-competitive TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, or radutinib. In another specific embodiment, the BCR-ABL1 ATP-competitive TKIs are selected from imatinib, dasatinib, or nilotinib. In another specific embodiment, the BCR-ABL1 ATP-competitive TKIs are selected from ponatinib or orebactinib.

[0364] In another specific embodiment, the CML is Ph+ CML. In another specific embodiment, the CML is BCR-ABL1+ CML. In another specific embodiment, the CML is CML with a T315I mutation. In another specific embodiment, the CML is CML without a T315I mutation. In another more specific embodiment, the CML is Ph+ CML-CP. In another more specific embodiment, the CML is Ph+ CML-CP with a T315I mutation. In another more specific embodiment, the CML is Ph+ and BCR-ABL1+ CML-CP with a T315I mutation.

[0365] In another embodiment, the uses and methods are for adult subjects. In another embodiment, the uses and methods are for pediatric subjects. In another embodiment, the uses and methods are for subjects with brain metastases.

[0366] In another specific embodiment, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof (preferably Compound A) is about 20 mg / day to about 400 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof (preferably Compound A) is about 20 mg / day to about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof (preferably Compound A) is about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day, about 120 mg / day, about 140 mg / day, about 160 mg / day, about 180 mg / day, about 200 mg / day, about 220 mg / day, about 240 mg / day, about 260 mg / day, about 270 mg / day, about 280 mg / day, about 300 mg / day, about 320 mg / day, about 340 mg / day, about 360 mg / day, about 380 mg / day or about 400 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day, about 120 mg / day, about 160 mg / day or about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg / day, about 40 mg / day, about 80 mg / day, about 160 mg / day or about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 40 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 60 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 80 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 100 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 120 mg / day.In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 140 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 160 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 180 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 200 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 220 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 260 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 270 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 280 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 300 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 320 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 340 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 360 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 380 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 400 mg / day.In another specific embodiment, the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is administered orally or intranasally. In another specific embodiment, the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is administered orally on an empty stomach. In another specific embodiment, the administration of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is QD, BID or TID. In another specific embodiment, the administration of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 10 mg BID, 20 mg BID, 40 mg QD, 40 mg BID, 80 mg QD, 80 mg BID, 160 mg QD or 240 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 10 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 40 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 40 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 80 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 80 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 160 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 240 mg QD.

[0367] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered until disease progression, intolerable toxicity, or death. In another embodiment, compound A or a pharmaceutically acceptable salt thereof is administered until disease progression, intolerable toxicity, or death.

[0368] Chronic myeloid leukemia (CML-CP) that has relapsed or is refractory after prior treatment with ≥1 different first- and / or second-generation BCR-ABL1 ATP-competitive TKIs

[0369] In one embodiment, the present invention relates to the use and method of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML or relapsed central nervous system leukemia thereof, such as brain metastasis, wherein the CML has previously been treated with ≥1 different first-generation and / or second-generation BCR-ABL1 ATP-competitive TKIs and has relapsed or is refractory. In another embodiment, the present invention relates to the use and method of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML, wherein the CML has previously been treated with ≥1 different first-generation and / or second-generation BCR-ABL1 ATP-competitive TKIs and has relapsed or is refractory.

[0370] In another embodiment, the present invention relates to the use and method of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML, wherein the CML has relapsed or is refractory after previously receiving treatment with ≥2 different first- and / or second-generation BCR-ABL1 ATP-competitive TKIs. In another embodiment, the present invention relates to the use and method of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML, wherein the CML has relapsed or is refractory after previously receiving treatment with ≥2 different first- and / or second-generation BCR-ABL1 ATP-competitive TKIs.

[0371] In another embodiment, the present invention relates to the use and method of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML, wherein the CML has relapsed or is refractory after previously receiving treatment with ≥3 different first- and / or second-generation BCR-ABL1 ATP-competitive TKIs. In another embodiment, the present invention relates to the use and method of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML, wherein the CML has relapsed or is refractory after previously receiving treatment with ≥3 different first- and / or second-generation BCR-ABL1 ATP-competitive TKIs.

[0372] In another embodiment, the present invention relates to the use and method of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML, wherein the CML has relapsed or is refractory after previously receiving treatment with ≥4 different first-generation and / or second-generation BCR-ABL1 ATP-competitive TKIs. In another embodiment, the present invention relates to the use and method of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML, wherein the CML has relapsed or is refractory after previously receiving treatment with ≥4 different first-generation and / or second-generation BCR-ABL1 ATP-competitive TKIs.

[0373] In one embodiment, the first- or second-generation BCR-ABL1 ATP-competitive TKIs are first-, second-, third-, fourth-, or fifth-line treatments. In another more specific embodiment, the first- or second-generation BCR-ABL1 ATP-competitive TKIs are first-, second-, or third-line treatments. In another specific embodiment, the first- or second-generation BCR-ABL1 ATP-competitive TKIs are first- or second-line treatments. In another specific embodiment, the first- or second-generation BCR-ABL1 ATP-competitive TKIs are first-line treatments. In another specific embodiment, the first- or second-generation BCR-ABL1 ATP-competitive TKIs are second-line treatments. In another specific embodiment, the first- or second-generation BCR-ABL1 ATP-competitive TKIs are second-line treatments or higher-line treatments. In another specific embodiment, the first-generation BCR-ABL1 ATP-competitive TKIs are imatinib. In another specific embodiment, the second-generation BCR-ABL1 ATP-competitive TKIs are selected from dasatinib, nilotinib, bosutinib, flumatinib, or radotinib. In another specific embodiment, the first- and / or second-generation BCR-ABL1 ATP-competitive TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, or radotinib. In another specific embodiment, the first- and / or second-generation BCR-ABL1 ATP-competitive TKIs are selected from imatinib, dasatinib, or nilotinib.

[0374] In another specific embodiment, the CML is Ph+ CML. In another specific embodiment, the CML is BCR-ABL1+ CML. In another specific embodiment, the CML is CML with a T315I mutation. In another specific embodiment, the CML is CML without a T315I mutation. In another more specific embodiment, the CML is Ph+ CML-CP. In another more specific embodiment, the CML is Ph+ CML-CP with a T315I mutation. In another more specific embodiment, the CML is Ph+ and BCR-ABL1+ CML-CP with a T315I mutation.

[0375] In another embodiment, the uses and methods are for adult subjects. In another embodiment, the uses and methods are for pediatric subjects. In another embodiment, the uses and methods are for subjects with brain metastases.

[0376] In another specific embodiment, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof (preferably Compound A) is about 20 mg / day to about 400 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof (preferably Compound A) is about 20 mg / day to about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof (preferably Compound A) is about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day, about 120 mg / day, about 140 mg / day, about 160 mg / day, about 180 mg / day, about 200 mg / day, about 220 mg / day, about 240 mg / day, about 260 mg / day, about 270 mg / day, about 280 mg / day, about 300 mg / day, about 320 mg / day, about 340 mg / day, about 360 mg / day, about 380 mg / day or about 400 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day, about 120 mg / day, about 160 mg / day or about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg / day, about 40 mg / day, about 80 mg / day, about 160 mg / day or about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 40 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 60 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 80 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 100 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 120 mg / day.In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 140 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 160 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 180 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 200 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 220 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 260 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 270 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 280 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 300 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 320 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 340 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 360 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 380 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 400 mg / day.In another specific embodiment, the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is administered orally or intranasally. In another specific embodiment, the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is administered orally on an empty stomach. In another specific embodiment, the administration of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is QD, BID or TID. In another specific embodiment, the administration of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 10 mg BID, 20 mg BID, 40 mg QD, 40 mg BID, 80 mg QD, 80 mg BID, 160 mg QD or 240 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 10 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 40 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 40 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 80 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 80 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 160 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 240 mg QD.

[0377] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered until disease progression, intolerable toxicity, or death. In another embodiment, compound A or a pharmaceutically acceptable salt thereof is administered until disease progression, intolerable toxicity, or death.

[0378] Chronic myeloid leukemia (CML-CP) in the chronic phase that has failed or is intolerant to three or more generations of BCR-ABL1 TKIs

[0379] In one embodiment, the present invention relates to the use and method of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML or relapse of central nervous system leukemia, such as brain metastasis, wherein the CML has previously failed or is intolerant to three or more generations of BCR-ABL1 TKIs. In another embodiment, the present invention relates to the use and method of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML, wherein the CML has previously failed or is intolerant to three or more generations of BCR-ABL1 TKIs.

[0380] In one embodiment, the BCR-ABL1 TKIs are first-line, second-line, third-line, fourth-line or fifth-line treatments. In another embodiment, the BCR-ABL1 TKIs are first-line, second-line or third-line treatments. In another embodiment, the BCR-ABL1 TKIs are first-line or second-line treatments. In another embodiment, the BCR-ABL1 TKIs are first-line or first-line treatments. In another embodiment, the BCR-ABL1 TKIs are second-line or second-line treatments. In another embodiment, the BCR-ABL1 TKIs are third-line or third-line treatments. In another more specific embodiment, the BCR-ABL1 TKIs include at least three generations of TKIs (e.g., ponatinib or orebactinib). In another more specific embodiment, the BCR-ABL1 TKIs include at least third-generation TKIs (e.g., ponatinib or orebactinib) and / or fourth-generation TKIs (e.g., aspartame or HS-10382). In another specific embodiment, the BCR-ABL1 TKIs are selected from ponatinib, orebactinib, PF-114, rebasinib, daruselutib, tauzerti, AT9283, KW-2449, XL228, aspartame or HS-10382. In another specific embodiment, the BCR-ABL1 TKIs are selected from ponatinib, orebactinib, PF-114, aspartame or HS-10382. In another specific embodiment, the BCR-ABL1 TKIs are selected from ponatinib, orebactinib or PF-114. In another specific embodiment, the BCR-ABL1 TKIs is selected from ponatinib or orebactinib. In another specific embodiment, the BCR-ABL1 TKIs is selected from ponatinib.

[0381] In another specific embodiment, the CML is Ph+ CML. In another specific embodiment, the CML is BCR-ABL1+ CML. In another specific embodiment, the CML is CML with a T315I mutation. In another specific embodiment, the CML is CML without a T315I mutation. In another more specific embodiment, the CML is Ph+ CML-CP. In another more specific embodiment, the CML is Ph+ CML-CP with a T315I mutation. In another more specific embodiment, the CML is Ph+ and BCR-ABL1+ CML-CP with a T315I mutation.

[0382] In another embodiment, the uses and methods are for adult subjects. In another embodiment, the uses and methods are for pediatric subjects. In another embodiment, the uses and methods are for subjects with brain metastases.

[0383] In another specific embodiment, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof (preferably Compound A) is about 20 mg / day to about 400 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof (preferably Compound A) is about 20 mg / day to about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof (preferably Compound A) is about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day, about 120 mg / day, about 140 mg / day, about 160 mg / day, about 180 mg / day, about 200 mg / day, about 220 mg / day, about 240 mg / day, about 260 mg / day, about 270 mg / day, about 280 mg / day, about 300 mg / day, about 320 mg / day, about 340 mg / day, about 360 mg / day, about 380 mg / day or about 400 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day, about 120 mg / day, about 160 mg / day or about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg / day, about 40 mg / day, about 80 mg / day, about 160 mg / day or about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 40 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 60 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 80 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 100 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 120 mg / day.In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 140 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 160 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 180 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 200 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 220 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 260 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 270 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 280 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 300 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 320 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 340 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 360 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 380 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 400 mg / day.In another specific embodiment, the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is administered orally or intranasally. In another specific embodiment, the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is administered orally on an empty stomach. In another specific embodiment, the administration of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is QD, BID or TID. In another specific embodiment, the administration of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 10 mg BID, 20 mg BID, 40 mg QD, 40 mg BID, 80 mg QD, 80 mg BID, 160 mg QD or 240 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 10 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 40 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 40 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 80 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 80 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 160 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 240 mg QD.

[0384] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered until disease progression, intolerable toxicity, or death. In another embodiment, compound A or a pharmaceutically acceptable salt thereof is administered until disease progression, intolerable toxicity, or death.

[0385] Chronic myeloid leukemia (CML-CP) that has developed resistance or intolerance to third-generation BCR-ABL1 TKIs

[0386] In one embodiment, the present invention relates to the use and method of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML or a relapse of central nervous system leukemia thereof, such as brain metastasis, wherein the CML is previously treated with three generations of BCR-ABL1 TKIs and is resistant or intolerant. In another embodiment, the present invention relates to the use and method of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating chronic phase CML, wherein the CML is previously treated with three generations of BCR-ABL1 TKIs and is resistant or intolerant.

[0387] In another embodiment, treatment resistance in CML-CP is defined as meeting at least one of the following criteria:

[0388] a. Failure to achieve complete hematologic response (before 3 months of treatment);

[0389] b. Failure to achieve a minimal cytogenetic response (before 6 months of treatment);

[0390] c. Failure to achieve major cytogenetic response (before 12 months of treatment);

[0391] d. Emergence of new BCR-ABL1 kinase domain mutations or new clonal evolution;

[0392] e. Patients with CML-CP who experience loss of response at any time during TKI treatment or develop kinase domain mutations or progress to CML-AP or CML-BP without achieving a complete cytogenetic response are also considered resistant.

[0393] In another specific embodiment, treatment intolerance in CML-CP is defined as an inability to tolerate current TKI treatment due to toxicity, or disease progression on current TKI and an inability to receive a higher dose due to toxicity.

[0394] In another specific embodiment, the CML has previously been treated with first- and / or second-generation BCR-ABL1 TKIs and has become resistant or intolerant. In another specific embodiment, the CML has previously been treated with first- and / or second-generation BCR-ABL1 TKIs and has become resistant or intolerant before receiving third-generation BCR-ABL1 TKIs. In another specific embodiment, the CML has not previously been treated with first- and / or second-generation BCR-ABL1 TKIs and has become resistant or intolerant. In another specific embodiment, the CML has not previously been treated with fourth-generation BCR-ABL1 TKIs and has become resistant or intolerant. In another specific embodiment, the CML has not previously been treated with fourth-generation BCR-ABL1 TKIs and has become resistant or intolerant. In another specific embodiment, the CML has previously been treated with first- and / or second- and / or fourth-generation BCR-ABL1 TKIs and has become resistant or intolerant.

[0395] In another specific embodiment, the first- or second-generation BCR-ABL1 TKI is a first- or second-line treatment. In another more specific embodiment, the first- or second-generation BCR-ABL1 TKI is a first-line treatment. In another more specific embodiment, the first- or second-generation BCR-ABL1 TKI is a second-line treatment. In another more specific embodiment, the first- or second-generation BCR-ABL1 TKI is a second-line treatment or higher. In another more specific embodiment, the first-generation BCR-ABL1 TKI is imatinib. In another more specific embodiment, the second-generation BCR-ABL1 ATP-competitive TKI is selected from dasatinib, nilotinib, bosutinib, flumatinib, or radotinib. In another more specific embodiment, the first- and / or second-generation BCR-ABL1 TKI is selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, or radotinib. In another more specific embodiment, the first and / or second generation BCR-ABL1 ATP-competitive TKIs are selected from imatinib, dasatinib, nilotinib, or flumatinib. In another specific embodiment, the third generation BCR-ABL1 TKIs are ponatinib or orebactinib. In another specific embodiment, the fourth generation BCR-ABL1 TKIs are aspartame or HS-10382.

[0396] In another specific embodiment, the CML is Ph+ CML. In another specific embodiment, the CML is BCR-ABL1+ CML. In another specific embodiment, the CML is CML with a T315I mutation. In another specific embodiment, the CML is CML without a T315I mutation. In another more specific embodiment, the CML is Ph+ CML-CP. In another more specific embodiment, the CML is Ph+ CML-CP with a T315I mutation. In another more specific embodiment, the CML is Ph+ and BCR-ABL1+ CML-CP with a T315I mutation.

[0397] In another embodiment, the uses and methods are for adult subjects. In another embodiment, the uses and methods are for pediatric subjects. In another embodiment, the uses and methods are for subjects with brain metastases.

[0398] In another specific embodiment, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof (preferably Compound A) is about 20 mg / day to about 400 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof (preferably Compound A) is about 20 mg / day to about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof (preferably Compound A) is about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day, about 120 mg / day, about 140 mg / day, about 160 mg / day, about 180 mg / day, about 200 mg / day, about 220 mg / day, about 240 mg / day, about 260 mg / day, about 270 mg / day, about 280 mg / day, about 300 mg / day, about 320 mg / day, about 340 mg / day, about 360 mg / day, about 380 mg / day or about 400 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day, about 120 mg / day, about 160 mg / day or about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg / day, about 40 mg / day, about 80 mg / day, about 160 mg / day or about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 40 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 60 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 80 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 100 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 120 mg / day.In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 140 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 160 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 180 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 200 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 220 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 260 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 270 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 280 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 300 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 320 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 340 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 360 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 380 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 400 mg / day.In another specific embodiment, the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is administered orally or intranasally. In another specific embodiment, the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is administered orally on an empty stomach. In another specific embodiment, the administration of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is QD, BID or TID. In another specific embodiment, the administration of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 10 mg BID, 20 mg BID, 40 mg QD, 40 mg BID, 80 mg QD, 80 mg BID, 160 mg QD or 240 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 10 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 40 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 40 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 80 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 80 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 160 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 240 mg QD.

[0399] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered until disease progression, intolerable toxicity, or death. In another embodiment, compound A or a pharmaceutically acceptable salt thereof is administered until disease progression, intolerable toxicity, or death.

[0400] Chronic myeloid leukemia in accelerated phase (CML-AP)

[0401] In one embodiment, the present invention relates to the use and method of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating accelerated phase CML or a relapse of central nervous system leukemia thereof, such as brain metastasis. In another embodiment, the present invention relates to the use and method of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating accelerated phase CML.

[0402] In another specific embodiment, the CML is Ph+ CML. In another specific embodiment, the CML is BCR-ABL1+ CML. In another specific embodiment, the CML is CML with a T315I mutation. In another specific embodiment, the CML is CML without a T315I mutation. In another more specific embodiment, the CML is Ph+ CML-AP. In another more specific embodiment, the CML is Ph+ CML-AP with a T315I mutation. In another more specific embodiment, the CML is Ph+ and BCR-ABL1+ CML-AP with a T315I mutation.

[0403] In another embodiment, the uses and methods are for adult subjects. In another embodiment, the uses and methods are for pediatric subjects. In another embodiment, the uses and methods are for subjects with brain metastases.

[0404] In another specific embodiment, the CML has previously been treated with ≥1 different BCR-ABL1 TKIs, with the disease progressing to blast crisis, and the treatment evaluation result was failure, warning, or intolerance. In another specific embodiment, the CML has previously been treated with ≥2 different BCR-ABL1 TKIs, with the disease progressing to blast crisis, and the treatment evaluation result was failure, warning, or intolerance. In another specific embodiment, the CML has previously been treated with ≥3 different BCR-ABL1 TKIs, with the disease progressing to blast crisis, and the treatment evaluation result was failure, warning, or intolerance. In another specific embodiment, the CML has previously been treated with ≥4 different BCR-ABL1 TKIs, with the disease progressing to blast crisis, and the treatment evaluation result was failure, warning, or intolerance. In another more specific embodiment, the BCR-ABL1 TKIs are first-line, second-line, third-line, fourth-line, or fifth-line treatment drugs. In another more specific embodiment, the BCR-ABL1 TKIs are first-line, second-line, or third-line treatment drugs. In another more specific embodiment, the BCR-ABL1 TKIs are first-line or second-line treatment drugs. In another more specific embodiment, the BCR-ABL1 TKIs are first-line treatment drugs. In another more specific embodiment, the BCR-ABL1 TKIs are second-line treatment drugs. In another more specific embodiment, the BCR-ABL1 TKIs are second-line or higher-line treatment drugs. In another more specific embodiment, the BCR-ABL1 TKIs include at least third-generation TKIs (e.g., ponatinib or orebactinib). In another more specific embodiment, the BCR-ABL1 TKIs include at least third-generation TKIs (e.g., ponatinib or orebactinib) and / or fourth-generation TKIs (e.g., aspergillus or HS-10382). In another more specific embodiment, the BCR-ABL1 TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, ponatinib, orebactinib, raducinib, bafitinib, vodobatinib, CHMFL-ABL-039, CHMFL-ABL-053, CHMFL-ABL-KIT-155, PF-114, paclitinib, rebasinib, daruselutib, tauzerti, AT9283, KW-2449, XL228, aspartame or HS-10382. In another more specific embodiment, the BCR-ABL1 TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, ponatinib, orebactinib, raducinib or aspartame. In another more specific embodiment, the BCR-ABL1 TKIs is selected from imatinib, dasatinib, nilotinib, ponatinib, orebactinib, oresanib, oresanib, oresanib.In another more specific embodiment, the BCR-ABL1 TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, or radurinib. In another more specific embodiment, the BCR-ABL1 TKIs are selected from ponatinib, orebactinib, aspartame, or HS-10382. In another more specific embodiment, the BCR-ABL1 TKIs are selected from imatinib, dasatinib, or nilotinib. In another more specific embodiment, the BCR-ABL1 TKIs are selected from ponatinib or orebactinib. In another more specific embodiment, the BCR-ABL1 TKIs are selected from aspartame or HS-10382. In another more specific embodiment, the BCR-ABL1 TKIs are selected from aspartame.

[0405] In another specific embodiment, the CML has relapsed or is refractory to prior treatment with ≥1 different BCR-ABL1 TKIs. In another specific embodiment, the CML has relapsed or is refractory to prior treatment with ≥2 different BCR-ABL1 TKIs. In another specific embodiment, the CML has relapsed or is refractory to prior treatment with ≥3 different BCR-ABL1 TKIs. In another specific embodiment, the CML has relapsed or is refractory to prior treatment with ≥4 different BCR-ABL1 TKIs. In another more specific embodiment, the BCR-ABL1 TKIs are first-line, second-line, third-line, fourth-line, or fifth-line treatments. In another more specific embodiment, the BCR-ABL1 TKIs are first-line, second-line, or third-line treatments. In another more specific embodiment, the BCR-ABL1 TKIs are first-line or second-line treatments. In another more specific embodiment, the BCR-ABL1 TKIs are first-line treatments. In another more specific embodiment, the BCR-ABL1 TKIs are second-line treatment drugs. In another more specific embodiment, the BCR-ABL1 TKIs are second-line or higher-line treatment drugs. In another more specific embodiment, the BCR-ABL1 TKIs include at least third-generation TKIs (e.g., ponatinib or orebactinib). In another more specific embodiment, the BCR-ABL1 TKIs include at least third-generation TKIs (e.g., ponatinib or orebactinib) and / or fourth-generation TKIs (e.g., aspartame or HS-10382). In another more specific embodiment, the BCR-ABL1 TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, ponatinib, orebactinib, raducinib, bafitinib, vodobatinib, CHMFL-ABL-039, CHMFL-ABL-053, CHMFL-ABL-KIT-155, PF-114, paclitinib, rebasinib, daruselutib, tauzerti, AT9283, KW-2449, XL228, aspartame or HS-10382. In another more specific embodiment, the BCR-ABL1 TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, ponatinib, orebactinib, raducinib or aspartame. In another more specific embodiment, the BCR-ABL1 TKIs are selected from imatinib, dasatinib, nilotinib, ponatinib, orebactinib or aspartame. In another more specific embodiment, the BCR-ABL1 TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib or radotinib.In another more specific embodiment, the BCR-ABL1 TKIs are selected from ponatinib, orebactinib, aspartame, or HS-10382. In another more specific embodiment, the BCR-ABL1 TKIs are selected from imatinib, dasatinib, or nilotinib. In another more specific embodiment, the BCR-ABL1 TKIs are selected from ponatinib or orebactinib. In another more specific embodiment, the BCR-ABL1 TKIs are selected from aspartame or HS-10382. In another more specific embodiment, the BCR-ABL1 TKIs are selected from aspartame.

[0406] In another specific embodiment, the CML has previously received treatment with ≥1 different BCR-ABL1 ATP-competitive TKIs, with the disease progressing to blast crisis, and the treatment evaluation result was failure, warning, or intolerance. In another specific embodiment, the CML has previously received treatment with ≥2 different BCR-ABL1 ATP-competitive TKIs, with the disease progressing to blast crisis, and the treatment evaluation result was failure, warning, or intolerance. In another specific embodiment, the CML has previously received treatment with ≥3 different BCR-ABL1 ATP-competitive TKIs, with the disease progressing to blast crisis, and the treatment evaluation result was failure, warning, or intolerance. In another specific embodiment, the CML has previously received treatment with ≥4 different BCR-ABL1 ATP-competitive TKIs, with the disease progressing to blast crisis, and the treatment evaluation result was failure, warning, or intolerance. In another more specific embodiment, the BCR-ABL1 ATP-competitive TKIs are first-line, second-line, third-line, fourth-line, or fifth-line treatment drugs. In another more specific embodiment, the BCR-ABL1 ATP competitive TKIs are first-line, second-line or third-line therapeutic drugs. In another more specific embodiment, the BCR-ABL1 ATP competitive TKIs are first-line or second-line therapeutic drugs. In another more specific embodiment, the BCR-ABL1 ATP competitive TKIs are first-line therapeutic drugs. In another more specific embodiment, the BCR-ABL1 ATP competitive TKIs are second-line therapeutic drugs. In another more specific embodiment, the BCR-ABL1 ATP competitive TKIs are second-line or above therapeutic drugs. In another more specific embodiment, the BCR-ABL1 ATP competitive TKIs include at least three generations of TKIs (e.g., ponatinib or orebactinib). In another more specific embodiment, the BCR-ABL1 ATP competitive TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, ponatinib, orebactinib, raducinib, bafitinib, vodobatinib, CHMFL-ABL-039, CHMFL-ABL-053, CHMFL-ABL-KIT-155, PF-114, paclitinib, rebasinib, daruselutib, tauzerti, AT9283, KW-2449 or XL228. In another more specific embodiment, the BCR-ABL1 ATP competitive TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, ponatinib, orebactinib or raducinib. In another more specific embodiment, the BCR-ABL1 ATP-competitive TKIs are selected from imatinib, dasatinib, nilotinib, ponatinib, or orebactinib.In another more specific embodiment, the BCR-ABL1 ATP-competitive TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib or radurinib. In another more specific embodiment, the BCR-ABL1 TKIs are selected from ponatinib, orebactinib, aspartame or HS-10382. In another more specific embodiment, the BCR-ABL1 ATP-competitive TKIs are selected from imatinib, dasatinib or nilotinib. In another more specific embodiment, the BCR-ABL1 ATP-competitive TKIs are selected from ponatinib or orebactinib.

[0407] In another specific embodiment, the CML has relapsed or is refractory to prior treatment with ≥1 different BCR-ABL1 ATP-competitive TKIs. In another specific embodiment, the CML has relapsed or is refractory to prior treatment with ≥2 different BCR-ABL1 ATP-competitive TKIs. In another specific embodiment, the CML has relapsed or is refractory to prior treatment with ≥3 different BCR-ABL1 ATP-competitive TKIs. In another specific embodiment, the CML has relapsed or is refractory to prior treatment with ≥4 different BCR-ABL1 ATP-competitive TKIs. In another more specific embodiment, the BCR-ABL1 ATP-competitive TKIs are first-line, second-line, third-line, fourth-line, or fifth-line treatments. In another more specific embodiment, the BCR-ABL1 ATP-competitive TKIs are first-line, second-line, or third-line treatments. In another more specific embodiment, the BCR-ABL1 ATP-competitive TKIs are first-line or second-line treatments. In another more specific embodiment, the BCR-ABL1 ATP competitive TKIs are first-line or second-line treatment drugs. In another more specific embodiment, the BCR-ABL1 ATP competitive TKIs are first-line treatment drugs. In another more specific embodiment, the BCR-ABL1 ATP competitive TKIs are second-line treatment drugs. In another more specific embodiment, the BCR-ABL1 ATP competitive TKIs are second-line or higher-line treatment drugs. In another more specific embodiment, the BCR-ABL1 ATP competitive TKIs include at least three generations of TKIs (e.g., ponatinib or orebactinib). In another more specific embodiment, the BCR-ABL1 ATP competitive TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, ponatinib, orebactinib, raducinib, bafitinib, vodobatinib, CHMFL-ABL-039, CHMFL-ABL-053, CHMFL-ABL-KIT-155, PF-114, paclitinib, rebasinib, daruselutib, tauzerti, AT9283, KW-2449 or XL228. In another more specific embodiment, the BCR-ABL1 ATP competitive TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, ponatinib, orebactinib or raducinib. In another more specific embodiment, the BCR-ABL1 ATP-competitive TKIs are selected from imatinib, dasatinib, nilotinib, ponatinib or orebactinib. In another more specific embodiment, the BCR-ABL1 ATP-competitive TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib or radurinib.In another more specific embodiment, the BCR-ABL1 ATP competitive TKIs are selected from ponatinib, orebactinib, aspartame or HS-10382. In another more specific embodiment, the BCR-ABL1 ATP competitive TKIs are selected from imatinib, dasatinib or nilotinib. In another more specific embodiment, the BCR-ABL1 ATP competitive TKIs are selected from ponatinib or orebactinib.

[0408] In another specific embodiment, the CML has previously been treated with ≥1 different first- and / or second-generation BCR-ABL1 ATP-competitive TKIs for which resistance or intolerance has developed. In another specific embodiment, the CML has previously been treated with ≥2 different first- and / or second-generation BCR-ABL1 ATP-competitive TKIs for which resistance or intolerance has developed. In another specific embodiment, the CML has previously been treated with ≥3 different first- and / or second-generation BCR-ABL1 ATP-competitive TKIs for which resistance or intolerance has developed. In another specific embodiment, the CML has previously been treated with ≥4 different first- and / or second-generation BCR-ABL1 ATP-competitive TKIs for which resistance or intolerance has developed. In another more specific embodiment, the drug resistance is a point mutation in the BCR-ABL1 kinase region, such as one or more of T315I / A, Y253F / H, E255V / K, M351T, G250E, F359V / I / C, H396P / R, M244V, E355G, F317L / V / I / C, F311L, M237I, Q252H / R, D276G, L248V, V379I, L384M, L387M, E279K, F486S, E459K, P223S, I502L or V299L. In another more specific embodiment, the resistance is in a point mutation in the BCR-ABL1 kinase domain selected from one or more of T315I, Y253H, E255V / K, M351T, G250E, F359V / , H396P, M244V, E355G, F317L, Q252H, E459K, P223S, I502L, or V299L mutations. In another more specific embodiment, the resistance is T315I. In another more specific embodiment, the first- or second-generation BCR-ABL1 ATP-competitive TKIs are first-, second-, third-, fourth-, or fifth-line treatments. In another more specific embodiment, the first- or second-generation BCR-ABL1 ATP-competitive TKIs are first-, second-, or third-line treatments. In another more specific embodiment, the first- or second-generation BCR-ABL1 ATP-competitive TKIs are first- or second-line treatments. In another more specific embodiment, the first- or second-generation BCR-ABL1 ATP-competitive TKIs are first-line treatments. In another more specific embodiment, the first- or second-generation BCR-ABL1 ATP-competitive TKIs are second-line treatments. In another more specific embodiment, the first- or second-generation BCR-ABL1 ATP-competitive TKIs are second-line or higher-line treatments. In another more specific embodiment, the first-generation BCR-ABL1 ATP-competitive TKIs are imatinib.In another more specific embodiment, the second generation BCR-ABL1 ATP competitive TKIs are selected from dasatinib, nilotinib, bosutinib, flumatinib or radotinib. In another more specific embodiment, the first and / or second generation BCR-ABL1 ATP competitive TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib or radotinib. In another more specific embodiment, the first and / or second generation BCR-ABL1 ATP competitive TKIs are selected from imatinib, dasatinib or nilotinib.

[0409] In another specific embodiment, the CML has relapsed or is refractory to treatment with ≥1 different first- and / or second-generation BCR-ABL1 ATP-competitive TKIs. In another specific embodiment, the CML has relapsed or is refractory to treatment with ≥2 different first- and / or second-generation BCR-ABL1 ATP-competitive TKIs. In another specific embodiment, the CML has relapsed or is refractory to treatment with ≥3 different first- and / or second-generation BCR-ABL1 ATP-competitive TKIs. In another specific embodiment, the CML has relapsed or is refractory to treatment with ≥4 different first- and / or second-generation BCR-ABL1 ATP-competitive TKIs. In another more specific embodiment, the first- or second-generation BCR-ABL1 ATP-competitive TKIs are first-, second-, third-, fourth-, or fifth-line treatments. In another more specific embodiment, the first- or second-generation BCR-ABL1 ATP-competitive TKIs are first-, second-, or third-line treatments. In another more specific embodiment, the first- or second-generation BCR-ABL1 ATP-competitive TKIs are first- or second-line treatments. In another more specific embodiment, the first- or second-generation BCR-ABL1 ATP-competitive TKIs are first-line treatments. In another more specific embodiment, the first- or second-generation BCR-ABL1 ATP-competitive TKIs are second-line treatments. In another more specific embodiment, the first- or second-generation BCR-ABL1 ATP-competitive TKIs are second-line or higher-line treatments. In another more specific embodiment, the first-generation BCR-ABL1 ATP-competitive TKIs are imatinib. In another more specific embodiment, the second-generation BCR-ABL1 ATP-competitive TKIs are selected from dasatinib, nilotinib, bosutinib, flumatinib, or raducinib. In another more specific embodiment, the first and / or second generation BCR-ABL1 ATP-competitive TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib or radotinib. In another more specific embodiment, the first and / or second generation BCR-ABL1 ATP-competitive TKIs are selected from imatinib, dasatinib or nilotinib.

[0410] In another embodiment, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof (preferably Compound A) is about 20 mg / day to about 400 mg / day. In another embodiment, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof (preferably Compound A) is about 20 mg / day to about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof (preferably Compound A) is about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day, about 120 mg / day, about 140 mg / day, about 160 mg / day, about 180 mg / day, about 200 mg / day, about 220 mg / day, about 240 mg / day, about 260 mg / day, about 270 mg / day, about 280 mg / day, about 300 mg / day, about 320 mg / day, about 340 mg / day, about 360 mg / day, about 380 mg / day or about 400 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day, about 120 mg / day, about 160 mg / day or about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg / day, about 40 mg / day, about 80 mg / day, about 160 mg / day or about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 40 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 60 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 80 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 100 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 120 mg / day.In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 140 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 160 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 180 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 200 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 220 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 260 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 270 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 280 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 300 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 320 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 340 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 360 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 380 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 400 mg / day.In another specific embodiment, the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is administered orally or intranasally. In another specific embodiment, the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is administered orally on an empty stomach. In another specific embodiment, the administration of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is QD, BID or TID. In another specific embodiment, the administration of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 10 mg BID, 20 mg BID, 40 mg QD, 40 mg BID, 80 mg QD, 80 mg BID, 160 mg QD or 240 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 10 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 40 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 40 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 80 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 80 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 160 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 240 mg QD.

[0411] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered until disease progression, intolerable toxicity, or death. In another embodiment, compound A or a pharmaceutically acceptable salt thereof is administered until disease progression, intolerable toxicity, or death.

[0412] Accelerated phase chronic myeloid leukemia (CML-AP) with disease progression to blast crisis after previous treatment with ≥1 different BCR-ABL1 TKIs, and treatment evaluation results of failure, warning, or intolerance

[0413] In one embodiment, the present invention relates to the use and method of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating accelerated phase CML or relapse of central nervous system leukemia, such as brain metastasis, wherein the CML has previously received treatment with ≥1 different BCR-ABL1 TKIs and the disease has progressed to blast crisis, and the treatment evaluation result is failure, warning or intolerance. In another embodiment, the present invention relates to the use and method of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating accelerated phase CML, wherein the CML has previously received treatment with ≥1 different BCR-ABL1 TKIs and the disease has progressed to blast crisis, and the treatment evaluation result is failure, warning or intolerance.

[0414] In another embodiment, the present invention relates to the use and method of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating accelerated phase CML, wherein the CML has previously been treated with ≥2 different BCR-ABL1 TKIs and the disease has progressed to blast crisis, and the treatment evaluation result is failure, warning or intolerance. In another embodiment, the present invention relates to the use and method of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating accelerated phase CML, wherein the CML has previously been treated with ≥2 different BCR-ABL1 TKIs and the disease has progressed to blast crisis, and the treatment evaluation result is failure, warning or intolerance.

[0415] In another embodiment, the present invention relates to the use and method of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating accelerated phase CML, wherein the CML has previously been treated with ≥3 different BCR-ABL1 TKIs and the disease has progressed to blast crisis, and the treatment evaluation result is failure, warning or intolerance. In another embodiment, the present invention relates to the use and method of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating accelerated phase CML, wherein the CML has previously been treated with ≥3 different BCR-ABL1 TKIs and the disease has progressed to blast crisis, and the treatment evaluation result is failure, warning or intolerance.

[0416] In another embodiment, the present invention relates to the use and method of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating accelerated phase CML, wherein the CML has previously been treated with ≥4 different BCR-ABL1 TKIs and the disease has progressed to blast crisis, and the treatment evaluation result is failure, warning or intolerance. In another embodiment, the present invention relates to the use and method of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating accelerated phase CML, wherein the CML has previously been treated with ≥4 different BCR-ABL1 TKIs and the disease has progressed to blast crisis, and the treatment evaluation result is failure, warning or intolerance.

[0417] In one embodiment, the BCR-ABL1 TKIs are first-line, second-line, third-line, fourth-line, or fifth-line treatments. In another embodiment, the BCR-ABL1 TKIs are first-line, second-line, or third-line treatments. In another embodiment, the BCR-ABL1 TKIs are first-line or second-line treatments. In another embodiment, the BCR-ABL1 TKIs are first-line treatments. In another embodiment, the BCR-ABL1 TKIs are second-line treatments. In another embodiment, the BCR-ABL1 TKIs are second-line or higher-line treatments. In another more specific embodiment, the BCR-ABL1 TKIs include at least third-generation TKIs (e.g., ponatinib or orebactinib). In another more specific embodiment, the BCR-ABL1 TKIs include at least third-generation TKIs (e.g., ponatinib or orebactinib) and / or fourth-generation TKIs (e.g., aspergillus or HS-10382). In another specific embodiment, the BCR-ABL1 TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, ponatinib, orebactinib, raducinib, bafitinib, vodobatinib, CHMFL-ABL-039, CHMFL-ABL-053, CHMFL-ABL-KIT-155, PF-114, paclitinib, rebasinib, daruselutib, tauzerti, AT9283, KW-2449, XL228, aspartame or HS-10382. In another more specific embodiment, the BCR-ABL1 TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, ponatinib, orebactinib, raducinib or aspartame. In another more specific embodiment, the BCR-ABL1 TKIs are selected from imatinib, dasatinib, nilotinib, ponatinib, orebactinib or aspartate. In another more specific embodiment, the BCR-ABL1 TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib or radurinib. In another more specific embodiment, the BCR-ABL1 TKIs are selected from ponatinib, orebactinib, aspartate or HS-10382. In another more specific embodiment, the BCR-ABL1 TKIs are selected from imatinib, dasatinib or nilotinib. In another more specific embodiment, the BCR-ABL1 TKIs are selected from ponatinib or orebactinib. In another more specific embodiment, the BCR-ABL1 TKIs are selected from aspartate or HS-10382. In another more specific embodiment, the BCR-ABL1 TKIs are selected from aspartame.

[0418] In another specific embodiment, the CML is Ph+ CML. In another specific embodiment, the CML is BCR-ABL1+ CML. In another specific embodiment, the CML is CML with a T315I mutation. In another specific embodiment, the CML is CML without a T315I mutation. In another more specific embodiment, the CML is Ph+ CML-AP. In another more specific embodiment, the CML is Ph+ CML-AP with a T315I mutation. In another more specific embodiment, the CML is Ph+ and BCR-ABL1+ CML-AP with a T315I mutation.

[0419] In another embodiment, the uses and methods are for adult subjects. In another embodiment, the uses and methods are for pediatric subjects. In another embodiment, the uses and methods are for subjects with brain metastases.

[0420] In another specific embodiment, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof (preferably Compound A) is about 20 mg / day to about 400 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof (preferably Compound A) is about 20 mg / day to about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof (preferably Compound A) is about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day, about 120 mg / day, about 140 mg / day, about 160 mg / day, about 180 mg / day, about 200 mg / day, about 220 mg / day, about 240 mg / day, about 260 mg / day, about 270 mg / day, about 280 mg / day, about 300 mg / day, about 320 mg / day, about 340 mg / day, about 360 mg / day, about 380 mg / day or about 400 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day, about 120 mg / day, about 160 mg / day or about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg / day, about 40 mg / day, about 80 mg / day, about 160 mg / day or about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 40 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 60 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 80 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 100 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 120 mg / day.In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 140 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 160 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 180 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 200 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 220 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 260 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 270 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 280 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 300 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 320 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 340 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 360 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 380 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 400 mg / day.In another specific embodiment, the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is administered orally or intranasally. In another specific embodiment, the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is administered orally on an empty stomach. In another specific embodiment, the administration of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is QD, BID or TID. In another specific embodiment, the administration of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 10 mg BID, 20 mg BID, 40 mg QD, 40 mg BID, 80 mg QD, 80 mg BID, 160 mg QD or 240 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 10 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 40 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 40 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 80 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 80 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 160 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 240 mg QD.

[0421] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered until disease progression, intolerable toxicity, or death. In another embodiment, compound A or a pharmaceutically acceptable salt thereof is administered until disease progression, intolerable toxicity, or death.

[0422] Accelerated phase chronic myeloid leukemia (CML-AP) with disease progression to blast crisis after previous treatment with ≥1 different BCR-ABL1 ATP-competitive TKIs, or with treatment failure, warning, or intolerance as evaluated

[0423] In one embodiment, the present invention relates to the use and method of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating accelerated phase CML or relapse of central nervous system leukemia, such as brain metastasis, wherein the CML has previously been treated with ≥1 different BCR-ABL1 ATP-competitive TKIs and the disease has progressed to blast crisis, and the treatment evaluation result is failure, warning or intolerance. In another embodiment, the present invention relates to the use and method of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating accelerated phase CML, wherein the CML has previously been treated with ≥1 different BCR-ABL1 ATP-competitive TKIs and the disease has progressed to blast crisis, and the treatment evaluation result is failure, warning or intolerance.

[0424] In another embodiment, the present invention relates to the use and method of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for the treatment of accelerated phase CML, wherein the CML has previously been treated with ≥2 different BCR-ABL1 ATP-competitive TKIs and the disease has progressed to blast crisis, and the treatment evaluation result is failure, warning or intolerance. In another embodiment, the present invention relates to the use and method of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for the treatment of accelerated phase CML, wherein the CML has previously been treated with ≥2 different BCR-ABL1 ATP-competitive TKIs and the disease has progressed to blast crisis, and the treatment evaluation result is failure, warning or intolerance.

[0425] In another embodiment, the present invention relates to the use and method of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating accelerated phase CML, wherein the CML has previously been treated with ≥3 different BCR-ABL1 ATP-competitive TKIs and the disease has progressed to blast crisis, and the treatment evaluation result is failure, warning or intolerance. In another embodiment, the present invention relates to the use and method of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating accelerated phase CML, wherein the CML has previously been treated with ≥3 different BCR-ABL1 ATP-competitive TKIs and the disease has progressed to blast crisis, and the treatment evaluation result is failure, warning or intolerance.

[0426] In another embodiment, the present invention relates to the use and method of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating accelerated phase CML, wherein the CML has previously been treated with ≥4 different BCR-ABL1 ATP-competitive TKIs and the disease has progressed to blast crisis, and the treatment evaluation result is failure, warning or intolerance. In another embodiment, the present invention relates to the use and method of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating accelerated phase CML, wherein the CML has previously been treated with ≥4 different BCR-ABL1 ATP-competitive TKIs and the disease has progressed to blast crisis, and the treatment evaluation result is failure, warning or intolerance.

[0427] In another specific embodiment, the BCR-ABL1 ATP competitive TKIs are first-line, second-line, third-line, fourth-line or fifth-line treatment drugs. In another specific embodiment, the BCR-ABL1 ATP competitive TKIs are first-line, second-line or third-line treatment drugs. In another specific embodiment, the BCR-ABL1 ATP competitive TKIs are first-line or second-line treatment drugs. In another specific embodiment, the BCR-ABL1 ATP competitive TKIs are first-line treatment drugs. In another specific embodiment, the BCR-ABL1 ATP competitive TKIs are second-line treatment drugs. In another specific embodiment, the BCR-ABL1 ATP competitive TKIs are second-line or higher-line treatment drugs. In another more specific embodiment, the BCR-ABL1 ATP competitive TKIs include at least three generations of TKIs (e.g., ponatinib or orebactinib). In another specific embodiment, the BCR-ABL1 ATP competitive TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, ponatinib, orebactinib, raducinib, bafitinib, vodobatinib, CHMFL-ABL-039, CHMFL-ABL-053, CHMFL-ABL-KIT-155, PF-114, pactinib, rebasinib, daruselutib, tauzerti, AT9283, KW-2449 or XL228. In another specific embodiment, the BCR-ABL1 ATP competitive TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, ponatinib, orebactinib or raducinib. In another specific embodiment, the BCR-ABL1 ATP competitive TKIs are selected from imatinib, dasatinib, nilotinib, ponatinib or orebactinib. In another specific embodiment, the BCR-ABL1 ATP competitive TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib or radurinib. In another more specific embodiment, the BCR-ABL1 ATP competitive TKIs are selected from ponatinib, orebactinib, asanib or HS-10382. In another specific embodiment, the BCR-ABL1 ATP competitive TKIs are selected from imatinib, dasatinib or nilotinib. In another specific embodiment, the BCR-ABL1 ATP competitive TKIs are selected from ponatinib or orebactinib.

[0428] In another specific embodiment, the CML is Ph+ CML. In another specific embodiment, the CML is BCR-ABL1+ CML. In another specific embodiment, the CML is CML with a T315I mutation. In another specific embodiment, the CML is CML without a T315I mutation. In another more specific embodiment, the CML is Ph+ CML-AP. In another more specific embodiment, the CML is Ph+ CML-AP with a T315I mutation. In another more specific embodiment, the CML is Ph+ and BCR-ABL1+ CML-AP with a T315I mutation.

[0429] In another embodiment, the uses and methods are for adult subjects. In another embodiment, the uses and methods are for pediatric subjects. In another embodiment, the uses and methods are for subjects with brain metastases.

[0430] In another specific embodiment, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof (preferably Compound A) is about 20 mg / day to about 400 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof (preferably Compound A) is about 20 mg / day to about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof (preferably Compound A) is about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day, about 120 mg / day, about 140 mg / day, about 160 mg / day, about 180 mg / day, about 200 mg / day, about 220 mg / day, about 240 mg / day, about 260 mg / day, about 270 mg / day, about 280 mg / day, about 300 mg / day, about 320 mg / day, about 340 mg / day, about 360 mg / day, about 380 mg / day or about 400 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day, about 120 mg / day, about 160 mg / day or about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg / day, about 40 mg / day, about 80 mg / day, about 160 mg / day or about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 40 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 60 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 80 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 100 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 120 mg / day.In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 140 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 160 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 180 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 200 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 220 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 260 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 270 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 280 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 300 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 320 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 340 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 360 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 380 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 400 mg / day.In another specific embodiment, the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is administered orally or intranasally. In another specific embodiment, the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is administered orally on an empty stomach. In another specific embodiment, the administration of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is QD, BID or TID. In another specific embodiment, the administration of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 10 mg BID, 20 mg BID, 40 mg QD, 40 mg BID, 80 mg QD, 80 mg BID, 160 mg QD or 240 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 10 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 40 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 40 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 80 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 80 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 160 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 240 mg QD.

[0431] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered until disease progression, intolerable toxicity, or death. In another embodiment, compound A or a pharmaceutically acceptable salt thereof is administered until disease progression, intolerable toxicity, or death.

[0432] Accelerated phase chronic myeloid leukemia (CML-AP) that has developed resistance or intolerance after previous treatment with ≥1 different first- and / or second-generation BCR-ABL1 ATP-competitive TKIs

[0433] In one embodiment, the present invention relates to the use and method of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating accelerated phase CML or relapse of central nervous system leukemia, such as brain metastasis, wherein the CML has previously been treated with ≥1 different first-generation and / or second-generation BCR-ABL1 ATP-competitive TKIs and developed resistance or intolerance. In another embodiment, the present invention relates to the use and method of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating accelerated phase CML, wherein the CML has previously been treated with ≥1 different first-generation and / or second-generation BCR-ABL1 ATP-competitive TKIs and developed resistance or intolerance.

[0434] In another embodiment, the present invention relates to the use and method of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating accelerated phase CML, wherein the CML has previously been treated with ≥2 different first- and / or second-generation BCR-ABL1 ATP-competitive TKIs and has developed resistance or intolerance. In another embodiment, the present invention relates to the use and method of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating accelerated phase CML, wherein the CML has previously been treated with ≥2 different first- and / or second-generation BCR-ABL1 ATP-competitive TKIs and has developed resistance or intolerance.

[0435] In another embodiment, the present invention relates to the use and method of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating accelerated phase CML, wherein the CML has previously been treated with ≥3 different first- and / or second-generation BCR-ABL1 ATP-competitive TKIs and has developed resistance or intolerance. In another embodiment, the present invention relates to the use and method of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating accelerated phase CML, wherein the CML has previously been treated with ≥3 different first- and / or second-generation BCR-ABL1 ATP-competitive TKIs and has developed resistance or intolerance.

[0436] In another embodiment, the present invention relates to the use and method of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating accelerated phase CML, wherein the CML has previously been treated with ≥4 different first- and / or second-generation BCR-ABL1 ATP-competitive TKIs and has developed resistance or intolerance. In another embodiment, the present invention relates to the use and method of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating accelerated phase CML, wherein the CML has previously been treated with ≥4 different first- and / or second-generation BCR-ABL1 ATP-competitive TKIs and has developed resistance or intolerance.

[0437] In another specific embodiment, the drug resistance is a point mutation in the BCR-ABL1 kinase region, such as one or more of T315I / A, Y253F / H, E255V / K, M351T, G250E, F359V / I / C, H396P / R, M244V, E355G, F317L / V / I / C, F311L, M237I, Q252H / R, D276G, L248V, V379I, L384M, L387M, E279K, F486S, E459K, P223S, I502L or V299L. In another embodiment, the resistance is in a point mutation in the BCR-ABL1 kinase domain selected from one or more of T315I, Y253H, E255V / K, M351T, G250E, F359V / , H396P, M244V, E355G, F317L, Q252H, E459K, P223S, I502L, or V299L mutations. In another embodiment, the resistance is T315I. In another embodiment, the first- or second-generation BCR-ABL1 ATP-competitive TKIs are first-, second-, third-, fourth-, or fifth-line treatments. In another embodiment, the first- or second-generation BCR-ABL1 ATP-competitive TKIs are first-, second-, or third-line treatments. In another embodiment, the first- or second-generation BCR-ABL1 ATP-competitive TKIs are first- or second-line treatments. In another specific embodiment, the first- or second-generation BCR-ABL1 ATP-competitive TKIs are first-line treatments. In another specific embodiment, the first- or second-generation BCR-ABL1 ATP-competitive TKIs are second-line treatments. In another specific embodiment, the first- or second-generation BCR-ABL1 ATP-competitive TKIs are second-line or higher-line treatments. In another specific embodiment, the first-generation BCR-ABL1 ATP-competitive TKIs are imatinib. In another specific embodiment, the second-generation BCR-ABL1 ATP-competitive TKIs are selected from dasatinib, nilotinib, bosutinib, flumatinib, or radotinib. In another specific embodiment, the first- and / or second-generation BCR-ABL1 ATP-competitive TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, or radotinib. In another specific embodiment, the first and / or second generation BCR-ABL1 ATP competitive TKIs are selected from imatinib, dasatinib or nilotinib.

[0438] In another specific embodiment, the CML is Ph+ CML. In another specific embodiment, the CML is BCR-ABL1+ CML. In another specific embodiment, the CML is CML with a T315I mutation. In another specific embodiment, the CML is CML without a T315I mutation. In another more specific embodiment, the CML is Ph+ CML-AP. In another more specific embodiment, the CML is Ph+ CML-AP with a T315I mutation. In another more specific embodiment, the CML is Ph+ and BCR-ABL1+ CML-AP with a T315I mutation.

[0439] In another embodiment, the uses and methods are for adult subjects. In another embodiment, the uses and methods are for pediatric subjects. In another embodiment, the uses and methods are for subjects with brain metastases.

[0440] In another specific embodiment, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof (preferably Compound A) is about 20 mg / day to about 400 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof (preferably Compound A) is about 20 mg / day to about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof (preferably Compound A) is about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day, about 120 mg / day, about 140 mg / day, about 160 mg / day, about 180 mg / day, about 200 mg / day, about 220 mg / day, about 240 mg / day, about 260 mg / day, about 270 mg / day, about 280 mg / day, about 300 mg / day, about 320 mg / day, about 340 mg / day, about 360 mg / day, about 380 mg / day or about 400 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day, about 120 mg / day, about 160 mg / day or about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg / day, about 40 mg / day, about 80 mg / day, about 160 mg / day or about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 40 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 60 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 80 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 100 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 120 mg / day.In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 140 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 160 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 180 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 200 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 220 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 240 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 260 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 270 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 280 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 300 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 320 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 340 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 360 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 380 mg / day. In another specific embodiment, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 400 mg / day.In another specific embodiment, the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is administered orally or intranasally. In another specific embodiment, the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is administered orally on an empty stomach. In another specific embodiment, the administration of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is QD, BID or TID. In another specific embodiment, the administration of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 10 mg BID, 20 mg BID, 40 mg QD, 40 mg BID, 80 mg QD, 80 mg BID, 160 mg QD or 240 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 10 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 20 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 40 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 40 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 80 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 80 mg BID. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 160 mg QD. In another specific embodiment, the effective daily dose of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably Compound A) is about 240 mg QD.

[0441] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered until disease progression, intolerable toxicity, or death. In another embodiment, compound A or a pharmaceutically acceptable salt thereof is administered until disease progression, intolerable toxicity, or death.

[0442] Accelerated phase chronic myeloid leukemia (CML-AP) that has relapsed or is refractory after prior treatment with ≥1 different BCR-ABL1 TKIs

[0443] In one embodiment, the present invention relates to the use and method of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating accelerated phase CML or relapsed central nervous system leukemia thereof, such as brain metastasis, wherein the CML has previously been treated with ≥1 different BCR-ABL1 TKIs and has relapsed or is refractory. In another embodiment, the present invention relates to the use and method of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating accelerated phase CML, wherein the CML has previously been treated with ≥1 different BCR-ABL1 TKIs and has relapsed or is refractory.

[0444] In another embodiment, the present invention relates to the use and method of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for the treatment of accelerated phase CML, wherein the CML has relapsed or is refractory after previous treatment with ≥2 different BCR-ABL1 TKIs. In another embodiment, the present invention relates to the use and method of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for the treatment of accelerated phase CML, wherein the CML has relapsed or is refractory after previous treatment with ≥2 different BCR-ABL1 TKIs.

[0445] In another embodiment, the present invention relates to the use and method of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for the treatment of accelerated phase CML, wherein the CML has relapsed or is refractory after previous treatment with ≥3 different BCR-ABL1 TKIs. In another embodiment, the present invention relates to the use and method of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for the treatment of accelerated phase CML, wherein the CML has relapsed or is refractory after previous treatment with ≥3 different BCR-ABL1 TKIs.

[0446] In another embodiment, the present invention relates to the use and method of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for the treatment of accelerated phase CML, wherein the CML has relapsed or is refractory after previous treatment with ≥4 different BCR-ABL1 TKIs. In another embodiment, the present invention relates to the use and method of (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for the treatment of accelerated phase CML, wherein the CML has relapsed or is refractory after previous treatment with ≥4 different BCR-ABL1 TKIs.

[0447] In another specific embodiment, the BCR-ABL1 TKIs are first-line, second-line, third-line, fourth-line, or fifth-line treatments. In another specific embodiment, the BCR-ABL1 TKIs are first-line, second-line, or third-line treatments. In another specific embodiment, the BCR-ABL1 TKIs are first-line or second-line treatments. In another specific embodiment, the BCR-ABL1 TKIs are first-line treatments. In another specific embodiment, the BCR-ABL1 TKIs are second-line treatments. In another specific embodiment, the BCR-ABL1 TKIs are second-line or higher-line treatments. In another more specific embodiment, the BCR-ABL1 TKIs include at least third-generation TKIs (e.g., ponatinib or orebactinib). In another more specific embodiment, the BCR-ABL1 TKIs include at least third-generation TKIs (e.g., ponatinib or orebactinib) and / or fourth-generation TKIs (e.g., aspergillus or HS-10382). In another specific embodiment, the BCR-ABL1 TKIs are selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, ponatinib, orebactinib, raducinib, bafitinib, vodobatinib, CHMFL-ABL-039, CHMFL-ABL-053, CHMFL-ABL-KIT-155, PF-114, paclitinib, rebasinib, daruselutib, tauzerti, AT9283, KW-2449, XL228, aspartame or HS-10382. In another specific embodiment, the BCR-ABL1 TKIs are selected from ...

Claims

1. Use of a compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof in the preparation of a medicament for treating chronic myeloid leukemia (CML) or acute lymphocytic leukemia (ALL), wherein the compound of formula (I) has the following structure: in: Y1 is independently selected from CR a or N; Y is independently selected from CR a or N; R1 is selected from hydrogen, halogen, nitrile, nitro, C 1-6 Alkyl or C 1-6 haloalkyl, wherein the C 1-6 Alkyl or C 1- 6 haloalkyl is optionally replaced by R 1a Group substitution; R2 is selected from hydrogen, C 1-6 Alkyl or C 1-6 haloalkyl, wherein the C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally replaced by R 2a Group substitution; Z is a chemical bond, O, S(O) 0-2 or NR b ; Or -Z-R2 together means -SF5; Ar is a six-membered heteroaryl group containing at least one N atom, which is optionally substituted by an R group; Het Wherein X9 is selected from O, S, NR b or C(R)2; m is 0, 1 or 2; n is 0, 1, 2, 3, 4, 5 or 6; R a independently selected from hydrogen, halogen, nitrile, nitro, hydroxyl, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy; R b are independently selected from hydrogen, C 1-6 Alkyl or C 1-6 Haloalkyl; R 1a , R 2a and R is independently selected from hydrogen, halogen, hydroxyl, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1- 6 alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C 6-10 Aryl or C 5-10 heteroaryl; Alternatively, two R groups on the same atom or on adjacent atoms can form a C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C 6-10 Aryl or C 5-10 Heteroaryl.

2. A method for treating chronic myeloid leukemia (CML) or acute lymphocytic leukemia (ALL) in a patient, comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof, wherein the compound of formula (I) has the following structure: in: Y1 is selected from CR a or N; Y is independently selected from CR a or N; R1 is selected from hydrogen, halogen, nitrile, nitro, C 1-6 Alkyl or C 1-6 haloalkyl, wherein the C 1-6 Alkyl or C 1- 6 haloalkyl is optionally replaced by R 1a Group substitution; R2 is selected from hydrogen, C 1-6 Alkyl or C 1-6 haloalkyl, wherein the C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally replaced by R 2a Group substitution; Z is a chemical bond, O, S(O) 0-2 or NR b ; Or -Z-R2 together means -SF5; Ar is a six-membered heteroaryl group containing at least one N atom, which is optionally substituted by an R group; Het Wherein X9 is selected from O, S, NR b or C(R)2; m is 0, 1 or 2; n is 0, 1, 2, 3, 4, 5 or 6; R a independently selected from hydrogen, halogen, nitrile, nitro, hydroxyl, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy; R b are independently selected from hydrogen, C 1-6 Alkyl or C 1-6 Haloalkyl; R 1a , R 2a and R is independently selected from hydrogen, halogen, hydroxyl, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1- 6 alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C 6-10 Aryl or C 5-10 heteroaryl; Alternatively, two R groups on the same atom or on adjacent atoms can form a C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C 6-10 Aryl or C 5-10 Heteroaryl.

3. A compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof for use in treating chronic myeloid leukemia (CML) or acute lymphocytic leukemia (ALL), wherein the compound of formula (I) has the following structure: in: Y1 is independently selected from CR a or N; Y is independently selected from CR a or N; R1 is selected from hydrogen, halogen, nitrile, nitro, C 1-6 Alkyl or C 1-6 haloalkyl, wherein the C 1-6 Alkyl or C 1- 6 haloalkyl is optionally replaced by R 1a Group substitution; R2 is selected from hydrogen, C 1-6 Alkyl or C 1-6 haloalkyl, wherein the C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally replaced by R 2a Group substitution; Z is a chemical bond, O, S(O) 0-2 or NR b ; Or -Z-R2 together means -SF5; Ar is a six-membered heteroaryl group containing at least one N atom, which is optionally substituted by an R group; Het Wherein X9 is selected from O, S, NR b or C(R)2; m is 0, 1 or 2; n is 0, 1, 2, 3, 4, 5 or 6; R a independently selected from hydrogen, halogen, nitrile, nitro, hydroxyl, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy; R b are independently selected from hydrogen, C 1-6 Alkyl or C 1-6 Haloalkyl; R 1a , R 2a and R is independently selected from hydrogen, halogen, hydroxyl, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1- 6 alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C 6-10 Aryl or C 5-10 heteroaryl; Alternatively, two R groups on the same atom or on adjacent atoms can form a C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C 6-10 Aryl or C 5-10 Heteroaryl.

4. The use according to claim 1 or the method according to claim 2 or the use of the compound according to claim 3, wherein the compound of formula (I) is (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof.

5. The use, method or use of a compound according to any one of claims 1 to 4, wherein the chronic myeloid leukemia is chronic phase chronic myeloid leukemia, preferably a relapse of central nervous system leukemia, such as brain metastasis.

6. The use, method or use of a compound according to any one of claims 1 to 4, wherein the chronic myeloid leukemia is accelerated phase chronic myeloid leukemia, preferably a relapse of central nervous system leukemia, such as brain metastasis.

7. The use, method or use of a compound according to any one of claims 1 to 4, wherein the chronic myeloid leukemia is a blast crisis chronic myeloid leukemia, preferably a relapse of central nervous system leukemia, such as brain metastasis.

8. The use, method or use of a compound according to any one of claims 1 to 7, wherein the chronic myeloid leukemia is Philadelphia chromosome positive (Ph+).

9. The use, method or use of a compound according to any one of claims 1 to 4, wherein the acute lymphoblastic leukemia is Philadelphia chromosome positive (Ph+), preferably a relapse of a central nervous system leukemia, such as a brain metastasis.

10. The use, method or use of a compound according to any one of claims 1 to 9, wherein the chronic myeloid leukemia is positive for the BCR-ABL1 fusion gene; Preferably, the BCR-ABL1 fusion gene is wild type; Preferably, the BCR-ABL1 fusion gene is a mutant; preferably, the mutation is selected from G250E, Q252H, Y253H, E255K / V, M244V, H396P, F317L, E459K, E355G, V299L, T315I, M351T, F359V, P223S and I502L, preferably G250E, Q252H, Y253H, E255K / V, E459K, T315I and M351T, preferably T315I.

11. The use, method or use of a compound according to any one of claims 1 to 10, wherein the chronic myeloid leukemia progresses after treatment with another therapy; Preferably, the other therapy is selected from radiotherapy, drug therapy or surgical therapy; preferably, the drug therapy is chemotherapy, targeted therapy or immunotherapy; Preferably, the drug therapy is chemotherapy; Preferably, the drug therapy is targeted therapy; Preferably, the drug of the drug therapy is selected from one or more of imatinib, dasatinib, nilotinib, BCR-ABL tyrosine kinase inhibitor, orebactinib, hydroxyurea, ponatinib, asanib, interferon, cytarabine, azacitidine, interferon ALFA-1B, homoharringtonine, decitabine, pegylated interferon A-2A, thalidomide, cedamide or recombinant interferon A-2B.

12. The use, method or use of a compound according to any one of claims 1 to 11, wherein the chronic myeloid leukemia progresses after treatment with a BCR-ABL tyrosine kinase inhibitor; preferably, wherein the BCR-ABL tyrosine kinase inhibitor is selected from imatinib, dasatinib, nilotinib, orebactinib, ponatinib or asanib.

13. The use, method or use of a compound according to any one of claims 1 to 12, wherein the patient is an adult patient.

14. The use, method or use of a compound according to any one of claims 1 to 13, wherein the patient is a pediatric patient.

15. The use, method or use of a compound according to any one of claims 1 to 14, wherein the patient has received one or more lines of treatment; preferably, wherein the patient has received two or more lines of treatment; preferably, wherein the patient has received three or more lines of treatment; preferably, the patient has received one, two, three, four or five lines of treatment.

16. The use, method or use of a compound according to any one of claims 1 to 15, wherein the patient has previously received treatment with ≥1 different BCR-ABL1 tyrosine kinase inhibitors and the disease has progressed to the accelerated phase or blast phase, and the treatment evaluation result is failure, warning or intolerance; Preferably, the patient has previously received treatment with ≥2 different BCR-ABL1 tyrosine kinase inhibitors and the disease has progressed to the accelerated phase or blast phase, and the treatment evaluation result is failure, warning or intolerance; Preferably, the patient has previously received treatment with ≥3 different BCR-ABL1 tyrosine kinase inhibitors and the disease has progressed to the accelerated phase or blast phase, and the treatment evaluation result is failure, warning or intolerance; Preferably, the patient has previously received treatment with ≥4 different BCR-ABL1 tyrosine kinase inhibitors and the disease has progressed to the accelerated phase or blast phase, and the treatment evaluation result is failure, warning or intolerance; Preferably, the patient has previously received treatment with ≥1 different BCR-ABL1 ATP-competitive tyrosine kinase inhibitors and the disease has progressed to the accelerated phase or blast phase, and the treatment evaluation result is failure, warning or intolerance; Preferably, the patient has previously received treatment with ≥2 different BCR-ABL1 ATP-competitive tyrosine kinase inhibitors, and the disease has progressed to the accelerated phase or blast phase, and the treatment evaluation result is failure, warning, or intolerance; Preferably, the patient has previously received treatment with ≥3 different BCR-ABL1 ATP-competitive tyrosine kinase inhibitors and the disease has progressed to the accelerated phase or blast phase, and the treatment evaluation result is failure, warning or intolerance; Preferably, the patient has previously received treatment with ≥4 different BCR-ABL1 ATP-competitive tyrosine kinase inhibitors, and the disease has progressed to the accelerated phase or blast phase, and the treatment evaluation result is failure, warning, or intolerance.

17. The use, method or use of a compound according to any one of claims 1 to 16, wherein the patient has relapsed or is refractory after previous treatment with ≥1 different BCR-ABL1 tyrosine kinase inhibitors; Preferably, the patient has previously received treatment with ≥2 different BCR-ABL1 tyrosine kinase inhibitors and has relapsed or is refractory; Preferably, the patient has previously received ≥3 different BCR-ABL1 tyrosine kinase inhibitors for treatment and has relapsed or is refractory; Preferably, the patient has previously received treatment with ≥4 different BCR-ABL1 tyrosine kinase inhibitors and has relapsed or is refractory; Preferably, the patient has previously received treatment with ≥1 different BCR-ABL1 ATP-competitive tyrosine kinase inhibitors and has relapsed or is refractory; Preferably, the patient has previously received treatment with ≥2 different BCR-ABL1 ATP-competitive tyrosine kinase inhibitors and has relapsed or is refractory; Preferably, the patient has previously received ≥3 different BCR-ABL1 ATP-competitive tyrosine kinase inhibitors for treatment and has relapsed or is refractory; Preferably, the patient has previously received treatment with ≥4 different BCR-ABL1 ATP-competitive tyrosine kinase inhibitors and the disease has relapsed or is refractory.

18. The use, method or use of a compound according to any one of claims 16-17, wherein the BCR-ABL1 tyrosine kinase inhibitor is selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, ponatinib, orebactinib, radutinib, barfitinib, vodobatinib, CHMFL-ABL-039, CHMFL-ABL-053, CHMFL-ABL-KIT-155, PF-114, paclitinib, rebasinib, darusetib, tauzerti, AT9283, KW-2449, XL228, asanib or HS-10382; Preferably, the BCR-ABL1 tyrosine kinase inhibitor is selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, ponatinib, orebactinib, radutinib or aspergillus; Preferably, the BCR-ABL1 tyrosine kinase inhibitor is selected from imatinib, dasatinib, nilotinib, ponatinib, orebactinib or aspergillus; Preferably, the BCR-ABL1 tyrosine kinase inhibitor is selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib or radutinib; Preferably, the BCR-ABL1 tyrosine kinase inhibitor is selected from imatinib, dasatinib or nilotinib; Preferably, the BCR-ABL1 tyrosine kinase inhibitor is selected from ponatinib, orebactinib, aspartame or HS-10382; Preferably, the BCR-ABL1 tyrosine kinase inhibitor is selected from ponatinib or orebactinib; Preferably, the BCR-ABL1 tyrosine kinase inhibitor is selected from asanib or HS-10382; Preferably, the BCR-ABL1 tyrosine kinase inhibitor is a first-line, second-line, third-line, fourth-line or fifth-line treatment drug; Preferably, the BCR-ABL1 tyrosine kinase inhibitor is a first-line, second-line or third-line treatment drug.

19. The use, method or use of a compound according to any one of claims 16-17, wherein the BCR-ABL1 ATP-competitive tyrosine kinase inhibitor is selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, ponatinib, orebactinib, radutinib, barfitinib, vodobatinib, CHMFL-ABL-039, CHMFL-ABL-053, CHMFL-ABL-KIT-155, PF-114, paclitinib, rebasinib, darusetib, tauzertib, AT9283, KW-2449 or XL228; Preferably, the BCR-ABL1 ATP-competitive tyrosine kinase inhibitor is selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, ponatinib, orebactinib or radutinib; Preferably, the BCR-ABL1 ATP-competitive tyrosine kinase inhibitor is selected from imatinib, dasatinib, nilotinib, ponatinib or orebactinib; Preferably, the BCR-ABL1 ATP-competitive tyrosine kinase inhibitor is selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib or radutinib; Preferably, the BCR-ABL1 ATP-competitive tyrosine kinase inhibitor is selected from imatinib, dasatinib or nilotinib; Preferably, the BCR-ABL1 ATP-competitive tyrosine kinase inhibitor is selected from ponatinib or orebactinib; Preferably, the BCR-ABL1 ATP-competitive tyrosine kinase inhibitor is a first-line, second-line, third-line, fourth-line or fifth-line treatment drug; Preferably, the BCR-ABL1 ATP-competitive tyrosine kinase inhibitor is a first-line, second-line or third-line treatment drug.

20. The use, method or use of a compound according to any one of claims 1 to 19, wherein the patient has previously developed resistance or intolerance after receiving treatment with ≥1 different first-generation and / or second-generation and / or third-generation BCR-ABL1 ATP-competitive tyrosine kinase inhibitors; Preferably, the patient has previously received treatment with ≥2 different first-generation and / or second-generation and / or third-generation BCR-ABL1 ATP-competitive tyrosine kinase inhibitors and developed resistance or intolerance; Preferably, the patient has previously received ≥3 different first-generation and / or second-generation and / or third-generation BCR-ABL1 ATP-competitive tyrosine kinase inhibitors and developed resistance or intolerance; Preferably, the patient has previously received treatment with ≥4 different first-generation and / or second-generation and / or third-generation BCR-ABL1 ATP-competitive tyrosine kinase inhibitors and developed resistance or intolerance.

21. The use, method or use of a compound according to any one of claims 1 to 20, wherein the drug resistance is derived from a point mutation in the BCR-ABL1 kinase domain; Preferably, the BCR-ABL1 kinase domain point mutation is selected from one or more of T315I / A, Y253F / H, E255V / K, M351T, G250E, F359V / I / C, H396P / R, M244V, E355G, F317L / V / I / C, F311L, M237I, Q252H / R, D276G, L248V, V379I, L384M, L387M, E279K, F486S, E459K, P223S, I502L or V299L mutations; Preferably, the BCR-ABL1 kinase domain point mutation is selected from one or more of T315I, Y253H, E255V / K, M351T, G250E, F359V / , H396P, M244V, E355G, F317L, Q252H, E459K, P223S, I502L or V299L mutations.

22. The use, method or use of a compound according to any one of claims 1 to 21, wherein the patient has relapsed or is refractory after previously receiving ≥1 different first-generation and / or second-generation and / or third-generation BCR-ABL1 ATP-competitive tyrosine kinase inhibitors; Preferably, the patient has previously received treatment with ≥2 different first-generation and / or second-generation and / or third-generation BCR-ABL1 ATP-competitive tyrosine kinase inhibitors and has relapsed or is refractory; Preferably, the patient has previously received ≥3 different first-generation and / or second-generation and / or third-generation BCR-ABL1 ATP-competitive tyrosine kinase inhibitors and has relapsed or is refractory; Preferably, the patient has relapsed or is refractory after previously receiving treatment with ≥4 different first-generation and / or second-generation and / or third-generation BCR-ABL1 ATP-competitive tyrosine kinase inhibitors.

23. The use, method or use of a compound according to any one of claims 20 to 22, wherein the first and / or second and / or third generation BCR-ABL1 ATP-competitive tyrosine kinase inhibitor is selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib or radurinib; Preferably, the first-generation and / or second-generation and / or third-generation BCR-ABL1 ATP-competitive tyrosine kinase inhibitor is selected from imatinib, dasatinib or nilotinib; Preferably, the first-generation and / or second-generation and / or third-generation BCR-ABL1 ATP-competitive tyrosine kinase inhibitor is selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, radutinib, ponatinib or orebactinib; Preferably, the first-generation and / or second-generation and / or third-generation BCR-ABL1 ATP-competitive tyrosine kinase inhibitor is selected from imatinib, dasatinib, nilotinib, flumatinib or, ponatinib or orebactinib; Preferably, the first-generation and / or second-generation and / or third-generation BCR-ABL1 ATP-competitive tyrosine kinase inhibitor is a first-line, second-line, third-line, fourth-line or fifth-line therapeutic drug; Preferably, the first-generation and / or second-generation and / or third-generation BCR-ABL1 ATP-competitive tyrosine kinase inhibitor is a first-line or second-line therapeutic drug.

24. The use, method or use of a compound according to any one of claims 1 to 23, wherein the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof (preferably Compound A) is from about 20 mg / day to about 400 mg / day; Preferably, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof (preferably Compound A) is about 20 mg / day to about 240 mg / day; Preferably, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day, about 120 mg / day, about 160 mg / day or about 240 mg / day; Preferably, the compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof (preferably The dosage of the compound A) is about 20 mg / day, about 40 mg / day, about 80 mg / day, about 160 mg / day or about 240 mg / day.

25. The use, method or use of a compound according to any one of claims 1 to 24, wherein the compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof (preferably compound A) is administered orally or intranasally; preferably, administered orally; preferably, administered orally on an empty stomach.

26. The use, method or use of a compound according to any one of claims 1 to 25, wherein the compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof (preferably Compound A) is administered once daily (QD), twice daily (BID) or three times daily (TID).

27. The use, method or use of a compound according to any one of claims 1 to 26, wherein the compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof (preferably Compound A) is administered at about 10 mg BID, about 20 mg BID, about 40 mg QD, about 40 mg BID, about 80 mg QD, about 80 mg BID, about 160 mg QD or about 240 mg QD.

28. The use, method or use of a compound according to any one of claims 1 to 27, wherein the compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof (preferably Compound A) is administered until disease progression, intolerable toxicity or death.

29. A pharmaceutical combination comprising: (a) a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof; and (b) an ATP-competitive BCR-ABL1 inhibitor or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof.

30. The pharmaceutical combination according to claim 29, wherein the compound of formula (I) is (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof.

31. The pharmaceutical combination according to claim 29 or 30, wherein the ATP-competitive BCR-ABL1 inhibitor is selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, ponatinib, orebactinib, radutinib, barfitinib, vodobatinib, CHMFL-ABL-039, CHMFL-ABL-053, CHMFL-ABL-KIT-155, PF-114, paclitinib, rebasinib, darusetib, tauzertib, AT9283, KW-2449 or XL228; Preferably, the ATP-competitive BCR-ABL1 inhibitor is selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, ponatinib, orebactinib or PF-114; Preferably, the ATP-competitive BCR-ABL1 inhibitor is selected from imatinib, nilotinib, radutinib, flumatinib, ponatinib, bafitinib, CHMFL-ABL-039, CHMFL-ABL-053, CHMFL-ABL-KIT-155, vodobatinib, PF-114, orebactinib or rebastinib; Preferably, the ATP-competitive BCR-ABL1 inhibitor is selected from ponatinib, PF-114, orebactinib or rebastinib; Preferably, the ATP-competitive BCR-ABL1 inhibitor is selected from ponatinib, orebactinib or PF-114; Preferably, the ATP-competitive BCR-ABL1 inhibitor is selected from ponatinib or orebactinib; Preferably, the ATP-competitive BCR-ABL1 inhibitor is selected from ponatinib.

32. A pharmaceutical combination according to any one of claims 29 to 31, wherein the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof (preferably Compound A) is about 1-500 mg; Preferably, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 1-250 mg; Preferably, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystalline form, solvate or hydrate (preferably compound A) is about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg g, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 160mg, 165mg, 170mg, 175mg, 180mg , 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240mg, 245mg or 250mg; Preferably, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystalline form, solvate or hydrate (preferably compound A) is about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 80 mg, 160 mg or 240 mg; Preferably, the compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof (preferably Compound A) is taken once or twice a day.

33. The pharmaceutical combination according to any one of claims 29 to 32, wherein the dosage of the ATP-competitive BCR-ABL1 inhibitor is about 0.1-200 mg, preferably about 0.1-60 mg.

34. The pharmaceutical combination according to claim 32, wherein the ATP-competitive BCR-ABL1 inhibitor is ponatinib, and its dosage is about 0.1-200 mg, preferably about 0.1-60 mg; Preferably, the dosage of ponatinib is 0.1 mg, 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg. g, 17.5mg, 18mg, 18.5mg, 19mg, 19.5mg, 20mg, 20.5mg, 21mg, 21.5mg, 22mg, 22.5mg, 23mg, 23.5mg, 24mg, 24.5mg, 25mg, 25. 5mg, 26mg, 26.5mg, 27mg, 27.5mg, 28mg, 28.5mg, 29mg, 29.5mg, 30mg, 30.5mg, 31mg, 31.5mg, 32mg, 32.5mg, 33mg, 33.5mg, 34 mg, 34.5mg, 35mg, 35.5mg, 36mg, 36.5mg, 37mg, 37.5mg, 38mg, 38.5mg, 39mg, 39.5mg, 40mg, 40. 5mg, 41mg, 41.5mg, 42mg, 42.5mg, 43mg, 43.5mg, 44mg, 44.5mg, 45mg, 45.5mg, 46mg, 46.5mg, 47m g, 47.5mg, 48mg, 48.5mg, 49mg, 49.5mg, 50mg, 50.5mg, 51mg, 51.5mg, 52mg, 52.5mg, 53mg, 53.5m g, 54mg, 54.5mg, 55mg, 55.5mg, 56mg, 56.5mg, 57mg, 57.5mg, 58mg, 58.5mg, 59mg, 59.5mg or 60mg; Preferably, the dose of ponatinib is 2 mg, 4 mg, 8 mg, 15 mg, 30 mg, 45 mg or 60 mg; Preferably, ponatinib is administered once daily or twice daily.

35. The pharmaceutical combination according to claim 32, wherein the ATP-competitive BCR-ABL1 inhibitor is orebactinib, and its dosage is about 0.1-200 mg, preferably about 0.1-60 mg; Preferably, the dose of orebactinib is 0.1 mg, 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg g, 15.5mg, 16mg, 16.5mg, 17mg, 17.5mg, 18mg, 18.5mg, 19mg, 19.5mg, 20mg, 20.5mg, 21mg, 21.5mg, 22mg, 22.5 mg, 23mg, 23.5mg, 24mg, 24.5mg, 25mg, 25.5mg, 26mg, 26.5mg, 27mg, 27.5mg, 28mg, 28.5mg, 29mg, 29.5mg, 30mg , 30.5mg, 31mg, 31.5mg, 32mg, 32.5mg, 33mg, 33.5mg, 34mg, 34.5mg, 35mg, 35.5mg, 36mg, 36.5mg, 37mg, 37.5m g, 38mg, 38.5mg, 39mg, 39.5mg, 40mg, 40.5mg, 41mg, 41.5mg, 42mg, 42.5mg, 43mg, 43.5mg, 44mg, 44.5mg, 45mg , 45.5mg, 46mg, 46.5mg, 47mg, 47.5mg, 48mg, 48.5mg, 49mg, 49.5mg, 50mg, 50.5mg, 51mg, 51.5mg, 52mg, 52.5m g, 53mg, 53.5mg, 54mg, 54.5mg, 55mg, 55.5mg, 56mg, 56.5mg, 57mg, 57.5mg, 58mg, 58.5mg, 59mg, 59.5mg or 60mg; Preferably, the dose of orebactinib is 1 mg, 2 mg, 4 mg, 8 mg, 12 mg, 20 mg, 30 mg, 40 mg, 45 mg, 50 mg or 60 mg; Preferably, olimbatinib is administered once daily or twice daily.

36. A pharmaceutical combination according to any one of claims 29 to 35, wherein the (a) compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof; and (b) an ATP-competitive BCR-ABL1 inhibitor or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof are present in the same dosage form.

37. A pharmaceutical combination according to any one of claims 29 to 35, wherein the (a) compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof; and (b) an ATP-competitive BCR-ABL1 inhibitor or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof are present in different dosage forms.

38. A pharmaceutical composition comprising the pharmaceutical combination according to any one of claims 29 to 35.

39. Use of (a) a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof and (b) an ATP-competitive BCR-ABL1 inhibitor or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof in the preparation of a medicament for treating a disease regulated by wild-type or mutant BCR-ABL1 kinase.

40. Use of (a) a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof in the preparation of a medicament for use in combination with (b) an ATP-competitive BCR-ABL1 inhibitor or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating diseases regulated by wild-type or mutant BCR-ABL1 kinase.

41. Use of (b) an ATP-competitive BCR-ABL1 inhibitor or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof in the preparation of a medicament for use in combination with (a) a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating diseases regulated by wild-type or mutant BCR-ABL1 kinase.

42. A pharmaceutical combination of (a) a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof and (b) an ATP-competitive BCR-ABL1 inhibitor or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for use in treating diseases regulated by wild-type or mutant BCR-ABL1 kinase.

43. (a) A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof, for use in combination with (b) an ATP-competitive BCR-ABL1 inhibitor or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating a disease regulated by wild-type or mutant BCR-ABL1 kinase.

44. (b) an ATP-competitive BCR-ABL1 inhibitor or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof, for use in combination with (a) a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof for treating diseases regulated by wild-type or mutant BCR-ABL1 kinase.

45. A method for treating a wild-type or mutant BCR-ABL1 kinase regulated disease, comprising administering to a patient in need thereof (a) a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof, and (b) an ATP-competitive BCR-ABL1 inhibitor or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof.

46. ​​The method according to claim 45, wherein: (a) and (b) are administered simultaneously, separately or sequentially.

47. The use according to any one of claims 39 to 41 or the use of a compound and / or inhibitor according to any one of claims 42 to 44 or the method according to claim 45 or 46, wherein the disease regulated by the wild-type and / or mutant BCR-ABL1 kinase is a hematological malignancy or a relapse of a central nervous system leukemia thereof, such as a brain metastasis; Preferably, the diseases regulated by the wild-type and / or mutant BCR-ABL1 kinase are leukemia, neurodegenerative diseases, neurofibroma, melanoma, breast cancer, colon cancer, lung cancer, prostate cancer, Kaposi's sarcoma, gastrointestinal stromal tumors, mesothelioma, systemic mastocytosis, eosinophilic syndrome, liver fibrosis, renal fibrosis, rheumatoid arthritis, polyarthritis, scleroderma, lupus erythematosus, graft-versus-host disease, pulmonary hypertension, spermatogenesis impaired blastoma, dysgerminoma, and psoriasis; Preferably, the leukemia is acute lymphocytic leukemia, acute granulocytic leukemia, acute promyelocytic leukemia, chronic myeloid leukemia, chronic myelomonocytic leukemia, chronic neutrophilic leukemia, acute undifferentiated leukemia, prolymphocytic leukemia, juvenile myelomonocytic leukemia, adult T-cell leukemia, acute myeloid leukemia with trilineage myelodysplasia and mixed lineage leukemia; Preferably, the leukemia is chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia; Preferably, the neurodegenerative disease is Parkinson's disease, Alzheimer's disease, Down's syndrome, memory and cognitive impairment, dementia, amyloid neuropathy or brain inflammation; Preferably, the diseases regulated by the wild-type and / or mutant BCR-ABL1 kinase are chronic myeloid leukemia, Philadelphia chromosome-positive acute lymphoblastic leukemia, Parkinson's disease, Alzheimer's disease, neurofibroma, gastrointestinal stromal tumors, systemic mastocytosis, hypereosinophilic syndrome, hepatic fibrosis, renal fibrosis, and scleroderma.

48. The use or use of a compound and / or inhibitor or method according to any one of claims 39 to 47, wherein the mutation of the mutant BCR-ABL1 kinase is one or more of T315I, T315M, F317L, E355G, V299L, M244V, G250E, Q252H, Y253H, E255K, E255V, H396P, H396R, H396A, A397P, P223S, K294E, M351T, F359V, E459K, P465S, ​​V468F, I502L, A337V or A424T; Preferably, the mutation of the mutant BCR-ABL1 kinase is one or more of T315I, T315M, Y253H / T315I, E255V / T315I, Q252H / T315I, F317L / T315I, F359V / T315I, Y253H / E255K, and Y253H / F359V; Preferably, the mutation of the mutant BCR-ABL1 kinase is T315I, T315M, Y253H / T315I, E255V / T315I or Q252H / T315I; Preferably, the mutation of the mutant BCR-ABL1 kinase is T315M, Y253H / T315I, E255V / T315I or Q252H / T315I.

49. The use or use of a compound and / or inhibitor or method according to any one of claims 39 to 48, wherein the compound of formula (I) is (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-fluoropyrrolidin-1-yl)-5-(pyrazin-2-yl)nicotinamide (Compound A) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof.

50. The use or use of a compound and / or inhibitor or method according to any one of claims 39 to 49, wherein the ATP-competitive BCR-ABL1 inhibitor is selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, ponatinib, orebactinib, radutinib, barfitinib, vodobatinib, CHMFL-ABL-039, CHMFL-ABL-053, CHMFL-ABL-KIT-155, PF-114, paclitinib, rebasinib, darusetib, tauzerti, AT9283, KW-2449 or XL228; Preferably, the ATP-competitive BCR-ABL1 inhibitor is selected from imatinib, dasatinib, nilotinib, bosutinib, flumatinib, ponatinib, orebactinib or PF-114; Preferably, the ATP-competitive BCR-ABL1 inhibitor is selected from imatinib, nilotinib, radutinib, flumatinib, ponatinib, bafitinib, CHMFL-ABL-039, CHMFL-ABL-053, CHMFL-ABL-KIT-155, vodobatinib, PF-114, orebactinib or rebastinib; Preferably, the ATP-competitive BCR-ABL1 inhibitor is selected from ponatinib, PF-114, orebactinib or rebastinib; Preferably, the ATP-competitive BCR-ABL1 inhibitor is selected from ponatinib, orebactinib or PF-114; Preferably, the ATP-competitive BCR-ABL1 inhibitor is selected from ponatinib or orebactinib; Preferably, the ATP-competitive BCR-ABL1 inhibitor is selected from ponatinib.

51. The use or use of a compound and / or inhibitor or method according to any one of claims 39-50, wherein the dose of the compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof (preferably Compound A) is about 1-500 mg; Preferably, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystal form, solvate or hydrate (preferably compound A) is about 1-250 mg; Preferably, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystalline form, solvate or hydrate (preferably compound A) is about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg g, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 160mg, 165mg, 170mg, 175mg, 180mg , 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240mg, 245mg or 250mg; Preferably, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, crystalline form, solvate or hydrate (preferably compound A) is about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 80 mg, 160 mg or 240 mg; Preferably, the compound of formula (I) or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof (preferably Compound A) is taken once or twice a day.

52. The use or use of a compound and / or inhibitor or method according to any one of claims 39 to 51, wherein the dose of the ATP-competitive BCR-ABL1 inhibitor is about 0.1-200 mg, preferably about 0.1-60 mg.

53. The use or use of a compound and / or inhibitor or method according to claim 52, wherein the ATP-competitive BCR-ABL1 inhibitor is ponatinib, and the dosage thereof is about 0.1-200 mg, preferably about 0.1-60 mg; Preferably, the dosage of ponatinib is 0.1 mg, 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg , 15.5mg, 16mg, 16.5mg, 17mg, 17.5mg, 18mg, 18.5mg, 19mg, 19.5mg, 20mg, 20.5mg, 21mg, 21.5mg, 22mg, 22.5m g, 23mg, 23.5mg, 24mg, 24.5mg, 25mg, 25.5mg, 26mg, 26.5mg, 27mg, 27.5mg, 28mg, 28.5mg, 29mg, 29.5mg, 30mg , 30.5mg, 31mg, 31.5mg, 32mg, 32.5mg, 33mg, 33.5mg, 34mg, 34.5mg, 35mg, 35.5mg, 36mg, 36.5mg, 37mg, 37.5m g, 38mg, 38.5mg, 39mg, 39.5mg, 40mg, 40.5mg, 41mg, 41.5mg, 42mg, 42.5mg, 43mg, 43.5mg, 44mg, 44.5mg, 45mg , 45.5mg, 46mg, 46.5mg, 47mg, 47.5mg, 48mg, 48.5mg, 49mg, 49.5mg, 50mg, 50.5mg, 51mg, 51.5mg, 52mg, 52.5m g, 53mg, 53.5mg, 54mg, 54.5mg, 55mg, 55.5mg, 56mg, 56.5mg, 57mg, 57.5mg, 58mg, 58.5mg, 59mg, 59.5mg or 60mg; Preferably, the dose of ponatinib is 2 mg, 4 mg, 8 mg, 15 mg, 30 mg, 45 mg or 60 mg; Preferably, ponatinib is administered once daily or twice daily.

54. The use or use of a compound and / or inhibitor or method according to claim 52, wherein the ATP-competitive BCR-ABL1 inhibitor is orebactinib, and the dose thereof is about 0.1-200 mg, preferably about 0.1-60 mg; Preferably, the dose of orebactinib is 0.1 mg, 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg g, 15.5mg, 16mg, 16.5mg, 17mg, 17.5mg, 18mg, 18.5mg, 19mg, 19.5mg, 20mg, 20.5mg, 21mg, 21.5mg, 22mg, 22.5 mg, 23mg, 23.5mg, 24mg, 24.5mg, 25mg, 25.5mg, 26mg, 26.5mg, 27mg, 27.5mg, 28mg, 28.5mg, 29mg, 29.5mg, 30mg , 30.5mg, 31mg, 31.5mg, 32mg, 32.5mg, 33mg, 33.5mg, 34mg, 34.5mg, 35mg, 35.5mg, 36mg, 36.5mg, 37mg, 37.5m g, 38mg, 38.5mg, 39mg, 39.5mg, 40mg, 40.5mg, 41mg, 41.5mg, 42mg, 42.5mg, 43mg, 43.5mg, 44mg, 44.5mg, 45mg , 45.5mg, 46mg, 46.5mg, 47mg, 47.5mg, 48mg, 48.5mg, 49mg, 49.5mg, 50mg, 50.5mg, 51mg, 51.5mg, 52mg, 52.5m g, 53mg, 53.5mg, 54mg, 54.5mg, 55mg, 55.5mg, 56mg, 56.5mg, 57mg, 57.5mg, 58mg, 58.5mg, 59mg, 59.5mg or 60mg; Preferably, the dose of orebactinib is 1 mg, 2 mg, 4 mg, 8 mg, 12 mg, 20 mg, 30 mg, 40 mg, 45 mg, 50 mg or 60 mg; Preferably, olimbatinib is administered once daily or twice daily.

55. The use or use of a compound and / or inhibitor or method according to any one of claims 39 to 54, wherein the (a) compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof; and (b) an ATP-competitive BCR-ABL1 inhibitor or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof are present in the same dosage form.

56. The use or use of a compound and / or inhibitor or method according to any one of claims 39 to 54, wherein the (a) compound of formula (I) or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof; and (b) an ATP-competitive BCR-ABL1 inhibitor or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof are present in different dosage forms.

57. A method of inhibiting mutant BCR-ABL1 kinase, comprising using: (a) a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof; and (b) an ATP-competitive BCR-ABL1 inhibitor or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof.

58. The method according to claim 57, wherein the mutant BCR-ABL1 kinase is one or more of T315I, T315M, F317L, E355G, V299L, M244V, G250E, Q252H, Y253H, E255K, E255V, H396P, H396R, H396A, A397P, P223S, K294E, M351T, F359V, E459K, P465S, ​​V468F, I502L, A337V or A424T; Preferably, the mutant BCR-ABL1 kinase is T315I, T315M, Y253H / T315I, E255V / T315I, Q252H / T315I, F317L / T315I, F359V / T315I, Y253H / E255K or Y253H / F359V; Preferably, the mutant BCR-ABL1 kinase is T315I, T315M, Y253H / T315I, E255V / T315I or Q252H / T315I; Preferably, the mutant BCR-ABL1 kinase is T315M, Y253H / T315I, E255V / T315I or Q252H / T315I.

59. Commercial packaging, comprising: (a) Compound A according to claim 4 or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof; and (b) an ATP-competitive BCR-ABL1 inhibitor or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof; Wherein (a) and (b) are present in one unit dosage form or in two separate unit dosage forms.

60. Commercial packaging, comprising: (a) Compound A according to claim 4 or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof; and (b) Ponatinib or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof; Wherein (a) and (b) are present in one unit dosage form or in two separate unit dosage forms.

61. Commercial packaging, comprising: (a) Compound A according to claim 4 or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof; and (b) orebactinib or a pharmaceutically acceptable salt, crystalline form, solvate or hydrate thereof; Wherein (a) and (b) are present in one unit dosage form or in two separate unit dosage forms.

62. Commercial packaging, comprising: (a) Compound A according to claim 4 or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof; and (b) PF-114 or a pharmaceutically acceptable salt, crystal form, solvate or hydrate thereof; Wherein (a) and (b) are present in one unit dosage form or in two separate unit dosage forms.

63. A commercial package according to any one of claims 59 to 62, wherein the unit dosage form is a fixed combination.

64. A commercial package according to any one of claims 59 to 63 for use in the treatment of diseases regulated by wild-type or mutant BCR-ABL1 kinase.