BCR-ABL targeting degradation agent and application thereof

Abstract

The invention discloses a target BCR-ABL degradation agent and application thereof. The degradation agent has a structure as shown in a general formula (I) in the specification. The degradation agent disclosed by the invention can effectively reduce the BCR-ABL protein level in K562 cells to cause apoptosis, so that the degradation agent can be used for treating neoplastic diseases caused by abnormal expression of various wild-type and mutant BCR-ABL including chronic granulocytic leukemia and acute lymphocytic leukemia. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a novel degradation agent targeting BCR-ABL and its application. The present invention belongs to the field of medical technology. Background Art

[0002] Chronic myelogenous leukemia (CML) is a myeloproliferative tumor originating from hematopoietic stem cells, accounting for about 40% of all adult leukemias. The initiating mutation of CML is the formation of the BCR-ABL fusion gene. The tyrosine kinase (Abelson, ABL) gene on chromosome 9 and the breakpoint cluster region (BCR) gene on chromosome 22 are ectopically fused to produce a new chromosome, called the Philadelphia chromosome (Ph). The protein encoded by this fusion gene has abnormal tyrosine kinase activity, which leads to abnormal cell proliferation and the appearance of a large number of neutrophils in the body at various stages, thus inducing the occurrence of CML. Patients with this disease often suffer from anemia and obvious bleeding tendency. The BCR-ABL fusion gene on the Philadelphia chromosome (Ph) can be detected in about 90% of patients with chronic myeloid leukemia and 30% to 35% of patients with acute lymphoblastic leukemia (ALL), but it is not expressed in normal cells, so it is suitable as a target for treating the disease. In recent years, multiple small molecule inhibitors targeting the activity of BCR-ABL protein kinase have been designed and used in the clinical targeted treatment of CML with good results. These include imatinib, dasatinib, nilotinib and ponatinib, as well as the allosteric modulator asciminib. While these drugs have achieved clinical benefits, they have also brought acquired drug resistance. About 60% of CML-BP patients and almost all ALL patients relapse within a few weeks or months after treatment. Known causes of acquired resistance include point mutations in the BCR-ABL kinase domain, dysregulated expression of resistance genes, and alternating signaling pathways. More than 70 point mutations can be observed in CML patients who develop resistance after initial treatment. The most common mutations in patients who relapse after imatinib treatment are T315I, E225K, Y253F, and M351T; the most common mutations in dasatinib treatment include T315I, F317L / V / I / C, and V299L. Although bosutinib and ponatinib can inhibit a variety of BCR-ABL1 mutants and have good efficacy in patients with PH+CML in the slow phase, accelerated phase, or fulminant phase, they are limited in clinical application due to severe adverse reactions such as gastrointestinal toxicity, elevated transaminases, rash and thrombocytopenia, or arterial thrombosis. Therefore, there is an urgent need for drugs with good safety that can deal with abnormal expression of the BCR-ABL gene or resistance mutations.

[0003] Targeted Protein Degradation technology, represented by PROTAC, is a novel strategy for selectively knocking out target proteins through small molecules. It induces ubiquitination of target proteins by connecting E3 ligase ligands to the structure of targeted protein ligands, so that they are recognized and degraded by the protein quality control system in the cell. Unlike traditional protein function regulators including inhibitors, targeted protein degradation agents can have a similar effect of "knocking out" specific genes, and can overcome the problems of incomplete inhibition, negative feedback regulation, and easy generation of drug-resistant mutations of small molecule inhibitors. At the same time, because the function of the target protein can be restored only after re-expression in the body, its duration of action is also more lasting, and the dosage can also be reduced, thereby improving drug safety. These properties are particularly suitable for targeted treatment of BCR-ABL, especially for the treatment of diseases such as CML and AML associated with drug-resistant mutations of BCR-ABL. Summary of the invention

[0004] The object of the present invention is to provide a degradation agent targeting BCR-ABL and use thereof.

[0005] In order to achieve the above object, the present invention adopts the following technical means:

[0006] In one aspect, the present invention relates to a compound of general formula (I), or a pharmaceutically acceptable salt thereof:

[0007]

[0008] in,

[0009] R1 and R2 are independently selected from H, D, C 1-6 Alkyl or C 1-6 Haloalkyl; or R1 and R2 together form =O or =S;

[0010] L is absent or L is selected from -(CH2) 0-4 C(R5)(R6)-;

[0011] Wherein R5 is selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH2) 0-4 C 3-8 Cycloalkyl, -(CH2) 0-4 4-6 membered heterocyclic group, -(CH2) 0-4 C 6-10 Aryl, -(CH2) 0-4 5-10 membered heteroaryl, -(CH2) 1-6 C(O)ORa 、-(CH2) 1-6 C(O)NR b R c 、-(CH2) 1-6 OC(O)R a 、-(CH2) 1-6 N(R b )C(O)R a 、-(CH2) 1-6 OC(O)OR a 、-(CH2) 1-6 N(R b )C(O)OR a 、-(CH2) 1-4 OR a 、-(CH2) 1-4 SR a or natural amino acid side chains;

[0012] R6 is selected from H or D;

[0013] Or R5 and R6 together form =O or =S;

[0014] R3 is selected from H, D, C 1-6 Alkyl or C 1-6 Haloalkyl;

[0015] R4 is selected from H, D, -C(O)R a 、-C(O)OR a 、-C(O)CNR b R c 、-C(O)C(R f )NR d R e , -C 1-6 Alkyl or C 1-6 Haloalkyl;

[0016] Or R3 and R5 are connected together to form -(CH2) 3-5 ;

[0017] or R3 and R4 together with the N atom to which they are attached form a 5-6 membered heterocyclic group;

[0018] Where R a , R b and R c Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic group, C 6-10Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2, 3 or more halogen, OH, NH2;

[0019] R d and R e are independently selected from H, -C(O)R a or-C(O)OR a ;

[0020] R f Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 1-4 C(O)R a or -(CH2) 1-4 C(O)OR a .

[0021] Wherein, preferably, R1 is selected from H or D;

[0022] R2 is selected from H or D;

[0023] Or R1 and R2 together form =O or =S;

[0024] L does not exist or L is -(CH2) 0-4 C(R5)(R6)-;

[0025] Wherein R5 is selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 1-4 Phenyl, -(CH2) 1-6 C(O)OR a 、-(CH2) 1- 6C(O)NR b R c 、-(CH2) 1-6 N(R b )C(O)R a 、-(CH2) 1-6 N(R b )C(O)OR a or -(CH2) 1-4 SR a ;

[0026] R6 is selected from H or D;

[0027] Or R5 and R6 together form =O or =S;

[0028] R3 is selected from H, D, C 1-6 Alkyl or C 1-6 Haloalkyl;

[0029] R4 is selected from H, D, C(O)Ra 、C(O)OR a 、C(O)C(R f )NR d R e , C 1-6 Alkyl or C 1-6 Haloalkyl;

[0030] Or R3 and R5 are connected together to form -(CH2) 3-5 ;

[0031] or R3 and R4 together with the N atom to which they are attached form a 5-6 membered heterocyclic group;

[0032] Where R a , R b and R c Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2, 3 or more halogen, OH, NH2;

[0033] R d and R e are independently selected from H, C(O)R a C(O)OR a ;

[0034] R f Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 1-4 C(O)R a or -(CH2) 1-4 C(O)OR a .

[0035] Wherein, preferably, R1 is H;

[0036] R2 is H;

[0037] Or R1 and R2 together form =O;

[0038] L is absent or L is -C(R5)(R6)-, -CH2C(R5)(R6)- or -CH2CH2C(R5)(R6)-;

[0039] Where R5 is selected from H, CH2CH2CH3, CH2CH(CH3)2, CH2Ph, CH2C(O)OC(CH3)3, CH2C(O)NH2, CH2C(O)NHC(CH3)3, CH2CH2CH2CH2NHC(O)CH3, CH2CH2CH2CH2NHC(O)CH2CH3, CH2CH2CH2CH2NHC(O)C H(OH)CH3, CH2CH2CH2CH2NHC(O)C(OH)(CH3)2, CH2CH2CH2CH2NHC(O)CH=CHCH3, CH2CH2CH2CH2NHC(O)Ph, CH2CH2CH2CH2NHC(O)Py, CH2CH2CH2CH2NHC(O)OC(CH3)3 or CH2SC(CH3)3;

[0040] R6 is H;

[0041] Or R5 and R6 together form =O;

[0042] R3 is selected from H or CH3;

[0043] R4 is selected from H, CH3, C(O)CH3, C(O)CH2CH3, C(O)CH2C(CH3)3, C(O)CH(OH)CH3, C(O)C(OH)(CH3)2, C(O)CH=CHCH3, C(O)Ph, C(O)Py, C(O)OC(CH3)3,

[0044] Or R3 and R5 are linked together to form -CH2CH2CH2-;

[0045] Alternatively, R3 and R4 together with the N atom to which they are attached form a morpholinyl group.

[0046] Wherein, preferably, the compound has the structure of general formula (II):

[0047]

[0048] in,

[0049] L is -(CH2) 0-4 CH(R5)-;

[0050] Wherein R5 is selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH2) 0-4 C 3-8 Cycloalkyl, -(CH2)0-4 4-6 membered heterocyclic group, -(CH2) 0-4 C 6-10 Aryl, -(CH2) 0-4 5-10 membered heteroaryl, -(CH2) 1-6 C(O)NR b R c or natural amino acid side chains;

[0051] R3 is selected from H, D, C 1-6 Alkyl or C 1-6 Haloalkyl;

[0052] R4 is selected from H, D, C(O)R a 、C(O)OR a 、C(O)CNR b R c 、C(O)C(R f )NR d R e , C 1-6 Alkyl or C 1-6 Haloalkyl;

[0053] Or R3 and R5 are connected together to form -(CH2) 3-5 ;

[0054] or R3 and R4 together with the N atom to which they are attached form a 5-6 membered heterocyclic group;

[0055] Where R a , R b and R c Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2, 3 or more halogen, OH, NH2;

[0056] R d and R e are independently selected from H, C(O)R a C(O)OR a ;

[0057] R f Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 1-4 C(O)R a or -(CH2) 1-4 C(O)ORa .

[0058] Among them, preferably, L is -(CH2) 0-4 CH(R5)-;

[0059] Wherein R5 is selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 1-4 Phenyl or -(CH2) 1-6 C(O)NR b R c ;

[0060] R3 is selected from H, D, C 1-6 Alkyl or C 1-6 Haloalkyl;

[0061] R4 is selected from H, D, C(O)R a 、C(O)OR a 、C(O)C(R f )NR d R e , C 1-6 Alkyl or C 1-6 Haloalkyl;

[0062] Or R3 and R5 are connected together to form -(CH2) 3-5 ;

[0063] or R3 and R4 together with the N atom to which they are attached form a 5-6 membered heterocyclic group;

[0064] Where R a , R b and R c Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2, 3 or more halogen, OH, NH2;

[0065] R d and R e are independently selected from H, -C(O)R a or-C(O)OR a ;

[0066] R f Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 1-4 C(O)R a or -(CH2)1-4 C(O)OR a .

[0067] Wherein, preferably, L is selected from -CH(R5)-, -CH2CH(R5)- or -CH2CH2CH(R5)-;

[0068] R5 is selected from H, -CH2CH2CH3, -CH2CH(CH3)2, -CH2Ph, -CH2C(O)NH2 or -CH2C(O)NHC(CH3)3;

[0069] R3 is selected from H or CH3;

[0070] R4 is selected from H, -CH3, -C(O)CH3, -C(O)CH2CH3, -C(O)CH2C(CH3)3, -C(O)CH(OH)CH3, -C(O)C(OH)(CH3)2, -C(O)CH=CHCH3, -C(O)Ph, -C(O)Py, -C(O)OC(CH3)3,

[0071] Or R3 and R5 are linked together to form -CH2CH2CH2-;

[0072] Alternatively, R3 and R4 together with the N atom to which they are attached form a morpholinyl group.

[0073] Preferably, the compound has a structure of general formula (III):

[0074]

[0075] in,

[0076] L is -(CH2) 0-4 CH(R5)-;

[0077] Wherein R5 is selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 1-4 Phenyl or -(CH2) 1-6 C(O)NR b R c ;

[0078] R3 is selected from H, D, C 1-6 Alkyl or C 1-6 Haloalkyl;

[0079] R4 is selected from H, D, -C(O)R a 、-C(O)OR a , C 1-6 Alkyl or C 1-6 Haloalkyl;

[0080] Or R3 and R5 are connected together to form -(CH2) 3-5 ;

[0081] or R3 and R4 together with the N atom to which they are attached form a 5-6 membered heterocyclic group;

[0082] Where R a and R b Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 6-10 Aryl;

[0083] R c Selected from C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0084] Wherein, preferably, L is selected from -CH(R5)-, -CH2CH(R5)- or -CH2CH2CH(R5)-;

[0085] wherein R5 is selected from H, -CH2CH2CH3, -CH2CH(CH3)2, -CH2Ph ​​or -CH2C(O)NHC(CH3)3;

[0086] R3 is selected from H or -CH3;

[0087] R4 is selected from H, -CH3, -C(O)CH3, -C(O)CH2CH3, -C(O)CH2C(CH3)3, -C(O)CH=CHCH3, -C(O)Ph or -C(O)OC(CH3)3;

[0088] Or R3 and R5 are linked together to form -CH2CH2CH2-;

[0089] Alternatively, R3 and R4 together with the N atom to which they are attached form a morpholinyl group.

[0090] Wherein, preferably, the compound is selected from the following:

[0091]

[0092]

[0093]

[0094] Furthermore, the present invention also provides a pharmaceutical composition, which comprises the compound described in any one of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0095] Furthermore, the present invention also proposes the use of the compound, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition in the preparation of a drug for treating tumor diseases caused by abnormal expression of BCR-ABL or drug-resistant mutation.

[0096] Among them, preferably, the disease is selected from chronic myeloid leukemia, acute lymphocytic leukemia, atypical chronic myeloid leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, B lymphocytic leukemia / lymphoma, lymphoblastic lymphoma, Tatton-Brown-Rahman syndrome or acute promyelocytic leukemia.

[0097] Compared with the prior art, the present invention has the following beneficial effects:

[0098] The present invention adds a hydrophobic tag to the known small molecule inhibitor structure of BCR-ABL, designs and synthesizes a series of BCR-ABL-targeted degraders, which can effectively reduce the BCR-ABL protein level in K562 cells and induce cell apoptosis. It can be used to treat various tumor diseases caused by abnormal expression of wild-type and mutant BCR-ABL, including chronic myeloid leukemia and acute lymphocytic leukemia. BRIEF DESCRIPTION OF THE DRAWINGS

[0099] Figures 1A-1C Western Blot experiment was used to detect the effect of the compound of the present invention on the content of BCR-ABL protein in K562 cells. DETAILED DESCRIPTION

[0100] The present invention is further described below in conjunction with specific embodiments, but the embodiments are only used to illustrate the present invention and do not constitute any limitation to the protection scope of the present invention. It should be understood by those skilled in the art that the details and forms of the technical solution of the present invention can be modified or replaced without departing from the spirit and scope of the present invention, but these modifications and replacements all fall within the protection scope of the present invention.

[0101] definition

[0102] Chemical Definition

[0103] Definitions of specific functional groups and chemical terms are described in more detail below.

[0104] 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 , C1-2 , 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.

[0105] “C 1-6 "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C 1-4 Alkyl groups are preferred. 1-6 Specific examples of alkyl include: 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). The alkyl group may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent. Conventional alkyl abbreviations include: Me (-CH3), Et (-CH2CH3), iPr (-CH(CH3)2), nPr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3) or i-Bu (-CH2CH(CH3)2).

[0106] “C 2-6 "Alkenyl" refers to a straight or branched hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2-4 Alkenyl is preferred. 2-6 Specific examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. The alkenyl group may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0107] “C 2-6 "Alkynyl" refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 2-4 Alkynyl is preferred. 2-6Specific examples of alkynyl include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), hexynyl (C6), etc. The alkynyl group may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0108] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0109] Therefore, “C 1-6 "Haloalkyl" and "C 1-4 "Haloalkyl" refers to the above-mentioned "C 1-6 Alkyl" and "C 1-4 "alkyl", which is substituted by one or more halogen groups. In some embodiments, C 1-4 Haloalkyl is particularly preferred, more preferably C 1-2 Haloalkyl. Exemplary haloalkyls include, but are not limited to, -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like. The haloalkyl group may be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0110] “C 3-12 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 12 ring carbon atoms and zero heteroatoms, which is monocyclic, bicyclic or polycyclic and optionally contains double bonds. 4-12 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 4 to 12 ring carbon atoms and zero heteroatoms, which is monocyclic, bicyclic or polycyclic, and optionally contains double bonds. In some embodiments, C 3-6 Cycloalkyl, more preferably C 5-6 Cycloalkyl. Exemplary cycloalkyl groups 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. The cycloalkyl group may be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0111] "4-10 membered heterocyclyl" refers to a 4 to 10 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms. In some embodiments, a 5-10 membered heterocyclyl is preferably a 5 to 10 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms. In some embodiments, a 4-6 membered heterocyclyl is preferably a 4 to 6 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms. In some embodiments, a 5-6 membered heterocyclyl is preferably a 5 to 6 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms. The heterocyclyl group may be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0112] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, aziridine, oxirane, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azetidine, oxetane, and thietane. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, hexahydrotriazine (triazinanyl). Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thianyl.

[0113] “C 6-10 "Aryl" refers to a monocyclic or 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 provided in the aromatic ring system. In some embodiments, aryl has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, aryl has ten ring carbon atoms ("C 10 "Aryl"; for example, naphthyl, e.g., 1-naphthyl and 2-naphthyl). The aryl group can be substituted at any available point of attachment, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0114] "5-10 membered heteroaryl" refers to a group of 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 some embodiments, a 5-6 membered heteroaryl is preferred, which is a group of a 5-6 membered monocyclic 4n+2 aromatic ring system (e.g., having 6 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 some embodiments, a 5 membered heteroaryl is preferred, which is a group of a 5 membered monocyclic 4n+2 aromatic ring system (e.g., having 6 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 some embodiments, 6-membered heteroaryl is preferred, which is a group of a 6-membered monocyclic 4n+2 aromatic ring system (e.g., having 6 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. The heteroaryl group can be substituted at any available point of attachment, e.g., 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

[0115] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, 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, pyridyl. 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.

[0116] "Natural amino acids" are the basic structural units of proteins and the basis for later protein modification in organisms. There are 20 natural amino acids essential to the human body. "Natural amino acid side chains" refer to the substituents on the α carbon atom of natural amino acids. The 20 most common natural amino acids and their side chains are shown in Table 1 below:

[0117] Table 1

[0118] abbreviation name Sidechain Gly G Glycine -H Ala A Alanine <![CDATA[-CH3]]> Val V Valine <![CDATA[-CH-(CH3)2]]> Leu L Leucine <![CDATA[-CH2-CH(CH3)2]]> Ile I Isoleucine <![CDATA[-CH(CH3)-CH2-CH3]]> Phe F Phenylalanine <![CDATA[-CH2-C6H5]]> Trp W Tryptophan <![CDATA[-C8NH6]]> Tyr Y Tyrosine <![CDATA[-CH2-C6H4-OH]]> Asp D Aspartic acid <![CDATA[-CH2-COOH]]> Asn N Asparagine <![CDATA[-CH2-CONH2]]> Glu E Glutamate <![CDATA[-(CH2)2-COOH]]> Lys K Lysine <![CDATA[-(CH2)4-NH2]]> Gln Q Glutamine <![CDATA[-(CH2)2-CONH2]]> Met M Methionine <![CDATA[-(CH2)2-S-CH3]]> Ser S Serine <![CDATA[-CH2-OH]]> Thr T Threonine <![CDATA[-CH(CH3)-OH]]> Cys C Cysteine <![CDATA[-CH2-SH]]> Pro P Proline <![CDATA[-C3H6]]> His H Histidine <![CDATA[-CH2-C3H3N2]]> Arg R Arginine <![CDATA[-(CH2)3-NHC(NH)NH2]]>

[0119] The present invention also includes D-amino acids that are in the opposite configuration to the naturally occurring amino acids.

[0120] Other definitions

[0121] 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 reactions, etc., and that 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. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed of amino groups 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, or salts formed using methods used in the art, such as ion exchange methods. 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 suitable 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 salts, and the like. Further pharmaceutically acceptable salts include non-toxic ammonium salts, quaternary ammonium salts and amine cations formed using counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates, if appropriate.

[0122] The chemical synthesis route of the embodiment of the present invention is: (1)

[0124] (2)

[0126] (3)

[0128] (4)

[0130] (5)

[0132] (6)

[0134]

[0135] Example 1 Preparation of N-(2-chloro-6-methylphenyl)-2-((2-methyl-6-(piperazin-1-yl)pyrimidin-4-yl)amino)thiazole-5-carboxamide (2)

[0136]

[0137] 395 mg (1 mmol) of compound 1, 1.734 g (20 mmol) of piperazine, 20 ml of 1,4-dioxane, and 280 μl of TEA were added to a 100 ml two-necked flask, heated to 130°C, and reacted for 6 h to obtain a white solid. The suspension was washed with ethyl acetate three times, filtered, and dried to obtain 326 mg of a white powdery solid with a crude yield of 73%. 1 H NMR (400MHz, DMSO) δ9.96 (s, 1H), 8.28 (s, 1H), 7.39 (d, J = 7.4Hz, 1H), 7.33–7.21 (m, 2H), 6.09(s,2H),3.53(d,J=33.1Hz,4H),2.79(s,4H),2.51(s,1H),2.41(s,3H),2.25(s,3H). 13 C NMR(101MHz,DMSO)δ165.62,162.89,160.48,157.41,141.39,139.29,134.00,132.93,12 9.49,128.64,127.47,126.16,83.12,45.11,44.42,43.56,26.03,18.78.LRMS(ESI+):m / z calculated forC 20 H 22 ClN7OS(M+H + ):444.1368; found444.1362.

[0138] Example 2 Preparation of tert-butyl (2-(4-(6-(5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2-yl)amino)-2-methylpyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)carbamate (3, DSC0BGly)

[0139]

[0140] 222 mg (0.5 mmol) of compound 2 and 105 mg (0.6 mmol) of Boc-Gly-OH, 285 mg of HATU (0.75 mmol), 180 μl of NMM, and 3 ml of DMF were added into a 25 ml round-bottom flask and stirred at room temperature at 25°C for 1 h. 100 ml of saturated brine was added and extracted twice with 100 ml of ethyl acetate. The organic phases were combined and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to obtain a yellow oil. Silica gel column chromatography was performed using EA as the eluent. The solvent was evaporated to obtain 70 mg of a white powdery solid with a yield of 23% and MP of 160.0-160.4°C. 1 H NMR (400MHz, DMSO-d6) δ11.51(s,1H),9.89(s,1H),8.23(s,1H),7.40(d,J=6.8Hz,1H),7.32–7.16(m,2H),6. 78(t,J=5.8Hz,1H),6.08(s,1H),3.84(d,J=5.8Hz,2H),3.56(s,8H),2.43(s,3H),2.25(s,3H),1.40(s,9H). 13 C NMR (101MHz, DMSO) δ167.69,165.26,162.55,162.24,159.95,157.00,155.83,140.87,138.86,133.54,132.47, 129.08,128.23,127.05,125.80,82.81,77.98,43.38,43.29,43.20,43.15,41.77,28.24,25.62,18.35.MS(ESI + )m / z calculated for C 27 H 34 ClN8O4S(M+H) + :601.21; found 601.21

[0141] Example 3 Preparation of (S)-tert-butyl (4-amino-1-(4-(6-((5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2-yl)amino)-2-methylpyrimidin-4-yl)piperazin-1-yl)-1,4-dioxobutane-2-yl)carbamate (4,DSCOBAsn)

[0142]

[0143] 222 mg (0.5 mmol) of compound 2 was reacted with 139 mg (0.6 mmol) of Boc-L-Asn-OH, and the operation process was the same as compound 3 to obtain 50 mg of white powdery solid, with a yield of 15%, and MP of 179.9-180.1°C. 1 H NMR (400MHz, DMSO-d6) δ11.52(s,1H),9.88(s,1H),8.23(s,1H),7.40(d,J=7.5Hz,1H),7.26(ddd,J=28.2,14.3,8.3Hz,4H),6.85(s,1H),6.08(s ,1H),4.75(q,J=8.1,7.6Hz,1H),3.74–3.41(m,8H),2.58(dd,J=15.0,7 .5Hz,1H),2.43(s,3H),2.28(d,J=6.5Hz,1H),2.24(s,3H),1.38(s,9H). 13 CNMR(101MHz,DMSO-d6)δ171.39,169.74,165.23,162.53,162.31,159.93,157.00,154.93,140.86,138.84,133.53,132. 45,129.04,128.19,127.02,125.78,82.87,78.29,47.06,44.18,43.58,43.18,41.30,37.50,28.19,25.59,18.31.MS(ESI + )m / z calculated forC 29 H 37 ClN9O5S(M+H) + :658.23; found 658.23

[0144] Example 4 Preparation of tert-butyl (R)-(1-(4-(6-(5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2-yl)amino)-2-methylpyrimidin-4-yl)piperazin-1-yl)-1-oxohexan-3-yl)carbamate (5, DSC0BNva)

[0145]

[0146] 222 mg (0.5 mmol) of compound 2 was reacted with 130 mg (0.6 mmol) of Boc-L-Nva-OH, and the operation process was the same as compound 3 to obtain 185 mg of white powdery solid, with a yield of 58%, MP 186.1-186.3°C. 1 H NMR (400MHz, DMSO-d6) δ11.52(s,1H),9.88(s,1H),8.23(s,1H),7.40(d,J=6. 5Hz,1H),7.30–7.24(m,2H),6.96(d,J=8.2Hz,1H),6.07(s,1H),4.40(q,J=8.5 Hz,1H),3.65–3.46(m,8H),2.69(s,2H),2.43(s,3H),2.24(s,3H),1.50(dd,J =17.7,8.2Hz,2H),1.38(s,9H),1.26(d,J=27.0Hz,2H),0.86(d,J=7.3Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ170.73,165.23,162.54,162.27,159.94,157.01,155.35,140.86,138.85,133.53,132.46,129.06,128.20 ,127.03,125.80,82.86,78.03,49.91,44.15,43.71,43.25,41.13,38.26,33.62,28.22,25.58,18.59,18.32,13.73.MS(ESI+)m / z calculated for C 31 H 42 ClN8O4S(M+H) + :643.26; found 643.26

[0147] Example 5 Preparation of tert-butyl (R)-(3-(tert-butylthio)-1-(4-(6-((5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2-yl)amino)-2-methylpyrimidin-4-yl)piperazin-1-yl)-1-oxopropan-2-yl)carbamate (6,DSCOBCys)

[0148]

[0149] 222 mg (0.5 mmol) of compound 2 was reacted with 166 mg (0.6 mmol) of Boc-L-Cys-OH, and the operation process was the same as compound 3 to obtain 195 mg of white powdery solid, with a yield of 55%, MP128.8-129.0°C.

[0150] 1 H NMR (400MHz, DMSO) δ11.52(s,1H),9.88(s,1H),8.23(s,1H),7.40(d,J=7.6Hz,1H),7.27(d,J=11.2Hz,3H),6.08(s, 1H),4.48(dd,J=16.3,8.0Hz,1H),3.69(s,8H),2.86–2.80(m,2H),2.43(s,3H),2.24(s,3H),1.38(d,J=5.2Hz,18H).

[0151] 13 C NMR(101MHz,DMSO-d6)δ168.80,165.18,162.51,162.51,156.99,154.94,154.92,138.82,133.51,132.43,131.62,129.02, 128.68,128.16,126.99,82.88,78.43,52.57,50.72,44.26,43.12,42.03,38.23,30.69,29.83,28.14,25.52,18.28.MS(ESI + )m / z calculated for C 32 H 44 ClN8O4S2(M+H) + :703.26; found 703.29

[0152] Example 6 Preparation of tert-butyl 1-(4-(6-(5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2-yl)amino)-2-methylpyrimidin-4-yl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl)carbamate (7, DSCOBPhe)

[0153]

[0154] 222 mg (0.5 mmol) of compound 2 was reacted with 159 mg (0.6 mmol) of Boc-L-Phe-OH, and the operation process was the same as compound 3 to obtain 195 mg of white powdery solid, with a yield of 55%, MP118.3-118.5°C. 1H NMR (400MHz, DMSO-d6) δ11.53(s,1H),9.90(s,1H),8.22(s,1H),7.40(d,J=7.7Hz,1H),7.32–7.16(m,8H),6.01(s ,1H),4.62(q,J=7.7Hz,1H),3.68–3.38(m,8H),2.89(s,1H),2.73(s,1H),2.41(s,3H),2.23(s,3H),1.32(s,9H). 13 C NMR(101MHz,DMSO-d6)δ170.17,165.20,162.15,159.94,156.99,155.11,140.85,138.85,137.62,133.54,132.46,129.48,1 29.05,128.11,127.03,126.38,125.82,82.79,78.14,51.43,44.22,43.35,43.08,41.10,38.26,28.17,25.56,18.32.MS(ESI + )m / z calculated for C 34 H 40 ClN8O4S(M+H) + :691.26; found 691.27

[0155] Example 7 Preparation of (S)-tert-butyl 2-(4-(6-((5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2-yl)amino)-2-methylpyrimidin-4-yl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate (8, DSC0BPro)

[0156]

[0157] 222 mg (0.5 mmol) of compound 2 was reacted with 129 mg (0.6 mmol) of Boc-L-Pro-OH, and the operation process was the same as compound 3 to obtain 105 mg of white powdery solid, with a yield of 33%, MP159.3-159.5°C. 1H NMR (400MHz, DMSO-d6) δ11.52(s,1H),9.88(s,1H),8.23(s,1H),7.40(d,J=7.3Hz,1H),7.30–7.23(m,2H),6.0 8(s,1H),4.65–4.61(m,1H),3.57(d,J=17.9Hz,8H),2.43(s,3H),2.24(s,3H),1.83–1.71(m,6H),1.38(s,9H). 13 C NMR(101MHz,DMSO-d6)δ170.67,170.33,165.20,162.27,159.87,156.98,153.11,140.79,138.80,133.50,132.42,128.99, 128.14,126.97,125.77,78.37,78.19,56.40,46.49,46.32,43.50,43.36,40.92,29.91,28.05,25.54,23.02,18.27.MS(ESI + )m / z calculated for C 30 H 38 ClN8O4S(M+H) + :641.24; found 641.26

[0158] Example 8 Preparation of tert-butyl (4-(4-(6-(5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2-yl)amino)-2-methylpyrimidin-4-yl)piperazin-1-yl)-4-oxobutyl)carbamate (9, DSC0BGABA)

[0159]

[0160] 222 mg (0.5 mmol) of compound 2 was reacted with 122 mg (0.6 mmol) of Boc-GABA-OH, and the operation process was the same as compound 3 to obtain 50 mg of white powdery solid with a yield of 16% and MP of 110.1-110.3°C. 1 H NMR (400MHz, DMSO-d6) δ11.51(s,1H),9.88(s,1H),8.22(s,1H),7.40(d,J=7.3Hz,1H),7.34–7.15(m,2H ),6.81(s,1H),6.06(s,1H),3.55(s,8H),2.93(q,J=6.9Hz,6H),2.42(s,3H),2.24(s,3H),1.37(s,9H). 13CNMR(101MHz,DMSO-d6)δ170.58,165.21,162.53,162.26,156.97,155.62,138.83,133.52,13 2.43,129.03,127.01,125.77,77.41,41.14,29.64,28.26,25.58,25.08,18.30.MS(ESI+)m / z calculated for C 29 H 38 ClN8O4S(M+H) + :629.24; found 629.24

[0161] Example 9 Preparation of tert-butyl (3-(4-(6-(5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2-yl)amino)-2-methylpyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl)carbamate (10, DSC0Bβ-Ala)

[0162]

[0163] 222 mg (0.5 mmol) of compound 2 was reacted with 114 mg (0.6 mmol) of Boc-β-Ala-OH, and the operation process was the same as compound 3 to obtain 208 mg of yellow powdery solid, with a yield of 68% and MP of 89.0-89.2°C. 1 H NMR(400MHz,DMSO-d6)δ11.52(s,1H),9.88(s,1H),8.23(s,1H),7.40(d,1H),7.32–7.16(m,2H),6.71( s,1H),6.07(s,1H),3.57(d,J=12.7Hz,8H),3.22–3.11(m,4H),2.42(s,3H),2.24(s,3H),1.37(s,9H). 13 C NMR(101MHz,DMSO-d6)δ169.43,165.25,164.65,162.36,159.97,156.03,155.51,140.88,138.87,133.56,132.48,1 29.07,128.22,127.05,125.81,82.83,77.69,44.57,44.23,43.54,43.19,38.26,30.79,28.26,25.60,18.33.MS(ESI + )m / z calculated forC 28 H 36 ClN8O4S(M+H)+ :615.23; found 615.24

[0164] Example 10 Preparation of tert-butyl (2-(4-(6-(5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2-yl)amino)-2-methylpyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)(methyl)carbamate (11, DSCOBSar)

[0165]

[0166] 222 mg (0.5 mmol) of compound 2 and 114 mg (0.6 mmol) of Boc-Sar-OH were reacted, 285 mg of HATU (0.75 mmol), 180 μl of NMM, and 3 ml of DMF were added to a 25 ml round-bottom flask, and stirred at room temperature at 25°C for 1 h. 100 ml of saturated brine was added, and the mixture was extracted twice with 100 ml of ethyl acetate. The organic phases were combined and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to obtain a yellow oil. Silica gel column chromatography was performed using EA / EtOH=5:1 as the eluent. The solvent was evaporated to obtain 10 mg of a white powdery solid with a yield of 3% and MP of 138.5-138.7°C. 1 H NMR (400MHz, DMSO-d6) δ11.53(s,1H),9.89(s,1H),8.23(s,1H),7.40(d,J=7.3Hz,1H),7.28(s,2H),6 .07(s,1H),4.07(s,2H),3.56(s,8H),2.79(d,J=12.4Hz,3H),2.42(s,3H),2.24(s,3H),1.40(s,9H). 13 C NMR (101MHz, DMSO) δ167.03,165.33,162.61,160.04,157.05,138.90,133.57,132.51,131.61,129.73,129.12,128.73,12 8.28,127.09,125.84,78.88,78.65,65.13,50.24,49.71,43.39,43.35,35.46,28.14,28.05,26.61,25.62,18.35.MS(ESI + )m / z calculated for C 28 H 36 ClN8O4S(M+H) + :615.23; found 615.23

[0167] Example 11 Preparation of N-(2-chloro-6-methylphenyl)-2-((6-(4-(2-(dimethylamino)-2-oxoacetyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide (12, DSCONN)

[0168]

[0169] 444 mg (1.0 mmol) of compound 2 was reacted with 140 mg (1.2 mmol) of N,N-dimethyloxamic acid, and the operation process was the same as compound 3 to obtain 520 mg of white powdery solid, with a yield of 96%, MP125.1-125.3°C. 1 H NMR (400MHz, DMSO-d6) δ11.54(s,1H),9.90(s,1H),8.22(s,1H),7.39(dd,J=7.4,2.1Hz,1H) ,7.29–7.24(m,2H),6.09(s,1H),3.64–3.56(m,8H),2.92(s,6H),2.42(s,3H),2.23(s,3H). 13 C NMR (101MHz, DMSO) δ165.51,164.89,164.39,163.64,162.42,160.18,157.20,141.01,139.01,133.6 3,132.60,129.24,128.41,127.20,125.96,83.19,45.98,44.79,43.94,43.06,38.42,25.72,18.45.

[0170] MS (ESI + )m / z calculated for C 24 H 28 ClN8O3S(M+H) + :543.17; found 573.16

[0171] Example 12 Preparation of 2-((6-(4-(L-phenylalanyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)-N-(2-chloro-6-methylphenyl)thiazole-5-amide (13, DSCOPhe)

[0172]

[0173] 2 ml of 1,4-dioxane was added to the solid compound 7 (0.12 mmol) in the reaction flask and stirred to dissolve. Then 2 ml of 1,4-dioxane solution containing 4 M HCl was added and stirred at room temperature for 1.5 h. The solvent was evaporated under reduced pressure to obtain 70 mg of a white powdery solid with a yield of 100%. 1 H NMR(400MHz,DMSO-d6)δ9.94(s,1H),8.36(s,2H),8.25(s,1H),7.37–7.23(m,9H),6.01( s,1H),4.62(d,J=33.6Hz,2H),4.22(s,1H),3.30–3.08(m,8H),2.40(s,3H),2.23(s,3H). 13 C NMR (101MHz, DMSO) δ167.01,165.25,162.02,159.93,159.25,157.03,138.84,134.46,133.97,133.54,133.17,129.78, 129.63,129.06,128.68,127.46,125.52,123.64,82.83,51.90,49.89,44.21,42.87,42.74,37.04,25.57,18.33.MS(ESI + )m / z calculated for C 29 H 31 ClN8O2S(M+H) + :590.20; found 620.20

[0174] Example 13 Preparation of tert-butyl (1-((((R)-1-(4-(6-((5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2-yl)amino)-2-methylpyrimidin-4-yl)piperazin-1-yl)-4-methyl-1-oxopentan-2-yl)amine)-4-methyl 1-oxopentan-2-yl)carbamate (14, DSC0Bleu-leu)

[0175]

[0176] 222 mg (0.5 mmol) of compound 2 was reacted with 124 mg (0.6 mmol) of Boc-leu-leu-OH. The operation process was the same as compound 3 to obtain 133 mg of white powdery solid. The yield was 58%, and the MP was 162.3-162.5°C. 1H NMR (400MHz, DMSO-d6) δ11.53(s,1H),9.88(s,1H),8.22(s,1H),7.40(d,J=8.2Hz,1H),7.31–7.20(m,2H),6.89(s,1H),6.06(s,1H ),4.79(s,1H),3.82(d,J=4.7Hz,2H),3.65–3.41(m,8H),2.42(s,3H),2.24(s,3H),1.59(s,4H),1.34(m,11H),0.91–0.81(m,12H). 13 C NMR (101MHz, DMSO) δ172.16,170.26,165.22,164.63,162.54,159.94,157.01,155.24,140.85,138.85,133.54,132.46,129.06,128.21,127 .04,125.81,82.85,78.11,46.46,44.18,43.60,43.15,40.85,38.26, 28.16,25.58,24.30,23.99,23.23,22.98,21.72,21.54,18.32.MS(ESI + )m / z calculated for C 37 H 53 ClN9O5S(M+H) + :770.36; found 770.35

[0177] Example 14 Preparation of N-(2-chloro-6-methylphenyl)-2-((6-(4-(leucyl-L-leucine)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide (15, DSCOleu-leu)

[0178]

[0179] Compound 14 was added to the reaction flask and dissolved with 2 ml of 1,4-dioxane. 2 ml of 1,4-dioxane solution (4 M) of HCL was added to the reaction flask and stirred at room temperature for 1-1.5 h. The solvent was evaporated under reduced pressure and concentrated to obtain 210 mg of a white powdery solid without purification. The crude yield was 100%, and MP was 176.2-178.0°C. 1H NMR (400MHz, DMSO-d6) δ9.95(s,1H),8.73(d,J=7.9Hz,1H),8.24(s,1H),8.15(d,J=5.3Hz,2H),7.90(d,J=8.3Hz,1H),7.39(d,J=7.1Hz,1H),7. 32–7.18(m,2H),6.12(s,1H),4.78(m,1H),3.94(t,J=8.4Hz,8H),3.39( s,1H),2.44(s,3H),2.23(s,3H),1.59–1.48(m,6H),0.88–0.80(m,12H). 13 C NMR (101MHz, DMSO) δ172.17,170.32,170.18,169.99,168.68,156.74,155.24,138.82,137.63,133.48,132.45,131.67,129.05,128.72, 127.03,66.38,58.97,50.66,47.07,46.48,44.01,43.63,28.15,24.06,23.49,23.22,23.11,22.97,22.74,21.94,21.63,18.33.MS(ESI + )m / z calculated for C 32 H 44 ClN9O3S(M+H) + :670.27; found670.30

[0180] Example 15 Preparation of bis-tert-butyl (6-(4-(6-((5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2-yl)amino)-2-aminopyrimidin-4-yl)piperazin-1-yl)-6-oxohexane-1,5-diyl) (R)-dicarbamate (16, DSCODB2Lys)

[0181]

[0182] 444 mg (1 mmol) of compound 2 was reacted with 380 μL (1.2 mmol) of Boc-D-Lys(Boc)-OH, and 570 mg (1.5 mmol) of HATU was added as a condensing agent, 320 μL of NMM as a base, and 4 mL of DMF as a solvent. The reaction process was the same as that of compound 3, and the solid was 333 mg with a yield of 43.1%. 1H NMR (400MHz, DMSO-d6) δ11.53(s,1H),9.89(s,1H),8.23(s,1H),7.40(d,J=7.6 Hz,1H),7.31~7.24(m,2H),6.94(d,J=8.1Hz,1H),6.76(t,J=5.6Hz,1H),6.08(s 1H),4.36(s,1H),3.63~3.48(m,8H),2.89(s,2H),2.43(s,3H),2.24(s,3H),1.53~1.47(m,2H),1.37(s,18H),1.28~1.23(m,4H). 13 C NMR(101MHz,DMSO)δ171.15,165.68,163.00,162.72,160.38,157.46,156.08,15 5.80,141.31,139.29,133.99,132.91,129.50,128.64,127.48,126.24,83.28,7 8.48,77.82,50.65,44.62,44.12,43.70,41.58,40.61,40.40,40.19,39.98,39. 77,39.56,39.36,38.71,31.46,29.70,28.74,28.67,26.03,23.01,18.76.MS(ESI + )m / z calculated for C 36 H 50 ClN9O6S(M+H) + :772.3367; found:772.3389

[0183] Example 16 Preparation of N-(2-chloro-6-methylphenyl)-2-((2-methyl-6-(4-(2-morpholinoacetyl)piperazin-1-yl)pyrimidin-4-yl)amino)thiazole-5-carboxamide (17, DSC0Mor)

[0184]

[0185] 222 mg (0.5 mmol) of compound 2 was reacted with 87 mg (0.6 mmol) of morpholin-4-yl acetic acid, and the operation process was the same as compound 3 to obtain 136 mg of white powdery solid, with a yield of 48%, MP192.7-193.0℃. 1H NMR (400MHz, DMSO-d6) δ11.52(s,1H),9.91(s,1H),8.21(s,1H),7.39(dd,J=7.4,2.0Hz,1H),7.30 –7.24(m,2H),6.06(s,1H),3.61–3.56(m,8H),3.54(s,4H),3.19(s,2H),2.42(s,7H),2.23(s,3H). 13 C NMR(101MHz,DMSO-d6)δ167.68,165.37,162.65,162.54,160.10,157.07,140.96,138.94,133.60,132.55,129.18,1 28.35,127.14,125.88,82.94,66.30,60.88,56.19,53.06,45.92,44.60,44.02,43.34,40.94,25.68,18.41.MS(ESI + )m / z calculated forC 26 H 32 ClN8O3S(M+H) + :571.20; found 571.20

[0186] Preparation of Example 17 (18, DSCOXGly)

[0187]

[0188] 530 mg (0.882 mmol) of compound 3 was de-Boced and reacted with 149 μL (1.2 mmol) of 3,3-dimethylbutyric acid, and 570 mg (1.5 mmol) of HATU, 700 μL of NMM, and 6 mL of DMF were added. The operation process was the same as that of compound 3. A total of 274 mg of product 18 was obtained with a yield of 51.9%. 1 H NMR (400MHz, DMSO) δ11.52(s,1H),9.89(s,1H),8.23(s,1H),7.41(d,J=7.5Hz,1H),7.31~7.24(m,2H) ,6.08(s,1H),3.99(d,J=3.9Hz,2H),3.57(s,8H),2.43(s,3H),2.24(s,3H),2.06(s,2H),0.98(s,9H). 13C NMR (101MHz, DMSO) δ171.46,167.87,165.70,162.98,162.68,160.39,157.44,139.29,133.97,132.90,129.50,128.68,127.48,126.25 ,83.26,56.51,49.09,43.84,43.59,40.82,40.59,40.38,40.17,39.96,39.75,39.55,39.34,30.96,30.16,26.03,19.01,18.76.MS(ESI + )m / z calculated forC 28 H 36 ClN8O3S(M+H) + :599.23; found 599.23

[0189] Example 18 Preparation of tert-butyl 1-(4-(6-(5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2-yl)amino)-2-methylpyrimidin-4-yl)piperazin-1-yl)-1-oxopentan-2-yl)carbamate (19, DSCOBPA)

[0190]

[0191] 222 mg (0.5 mmol) of compound 2 was reacted with 130 mg (0.6 mmol) of 2-((tert-butyloxycarbonyl)amino)pentanoic acid, and the operation process was the same as compound 3 to obtain 243 mg of white powdery solid, with a yield of 75%, and MP 82.4-82.6°C. 1 H NMR (400MHz, DMSO-d6) δ11.54(s,1H),9.92(s,1H),8.22(s,1H),7.40(dd,J=7.4,2.0Hz,1H),7.30–7.24(m,2H),6.97(d,J=8.2Hz,1H),6.07(s,1H) ,3.62–3.57(m,5H),3.43(s,4H),3.42(s,2H),2.43(s,3H),2.24(s,3H), 1.55–1.46(m,2H),1.37(s,9H),1.24–1.15(m,2H),0.87(t,J=7.3Hz,3H). 13C NMR(101MHz,DMSO-d6)δ170.72,165.19,162.54,162.23,159.92,157.00,155.33,140.84,138.83,133.52,132.45,129.02,128 .18,127.00,125.79,82.86,78.01,49.88,44.15,43.69,43.23,41.10,38.23,33.62,28.20,25.52,18.55,18.28,13.69.MS(ESI + )m / z calculated for C 31 H 42 ClN8O4S(M+H) + :643.26; found643.26

[0192] Example 19 Preparation of tert-butyl (S)-(1-(4-(6-(5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2-yl)amino)-2-methylpyrimidin-4-yl)piperazin-1-yl)-4-methyl-1-oxopentan-2-yl)carbamate (20, DSC0Bleu)

[0193]

[0194] 222 mg (0.5 mmol) of compound 2 was reacted with 139 mg (0.6 mmol) of Boc-L-Leu-OH, and the operation process was the same as compound 3 to obtain 101 mg of white powdery solid, with a yield of 31%, and MP of 147.3-147.5°C. 1 H NMR (400MHz, DMSO-d6) δ11.54(s,1H),9.89(s,1H),8.23(s,1H),7.40(dd,J=7.5,2.0Hz,1H),7.32–7.21(m,2H),7.02(d,J=8.3Hz,1H),6.07(s,1 H),4.45–4.39(m,1H),3.65–3.48((m,8H),2.43(s,3H),2.24(s,3H),1. 62(s,1H),1.54–1.42(m,2H),1.37(s,9H),0.88(dt,J=12.3,6.3Hz,6H). 13CNMR(101MHz,DMSO)δ170.95,165.24,162.56,162.29,159.95,157.01,155.38,140.84,138.85,133.54,132.46,129.06,1 28.21,127.04,125.80,82.84,78.05,48.54,44.19,44.15,43.59,43.28,28.23,25.59,24.32,23.12,21.57,18.33.MS(ESI + )m / z calculated for C 31 H 42 ClN8O4S(M+H) + :657.27; found 657.27

[0195] Example 20 Preparation of di-tert-butyl (6-(4-(6-((5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2-yl)amino)-2-methylpyrimidin-4-yl)piperazin-1-yl)-6-oxohexane-1,5-diyl) (S)-dicarbamate (21, DSC0B2Lys)

[0196]

[0197] 222 mg (0.5 mmol) of compound 2 was reacted with 208 mg (0.6 mmol) of Boc-L-Lys(Boc)-OH, and the operation process was the same as compound 3 to obtain 69 mg of white powdery solid, yield = 15%, MP 158.7-160.0°C. 1 H NMR (400MHz, DMSO) δ11.52(s,1H),9.88(s,1H),8.23(s,1H),7.40(dd,J=7.5,1. 9Hz,1H),7.30~7.23(m,2H),6.93(d,J=8.0Hz,1H),6.76(t,J=5.6Hz,1H),6.07(s 1H),4.36(m,1H),3.63~3.51(m,8H),2.92~2.86(m,2H),2.43(s,3H),2.2 4(s,3H),1.56~1.46(m,2H),1.38(s,9H),1.36(s,9H),1.28~1.23(m,4H); 13C NMR (101MHz, DMSO) δ170.69,165.23,162.54,162.26,159.92,157.00,155.62,155.35,140.85,138.83,133.52,132.45,129.04,128. 18,127.02,125.78,82.82,78.02,77.36,50.19,44.18,43.69,43.25,41.13,38.26,31.00,29.25,28.29,28.22,25.58,22.56,18.31. MS(ESI+)m / z calculated for C 36 H 50 ClN9O6S(M+H) + :772.3367; found:772.3370.

[0198] Example 21 Preparation of (S)-N,N'-(6-(4-(6-((5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2-yl)amino)-2-methylpyrimidin-4-yl)piperazine-1-yl)-6-oxohexane-1,5-diyl)diethylamide (22,DSC0A2Lys)

[0199]

[0200] 222 mg (0.5 mmol) of compound 2 was reacted with 138 mg (0.6 mmol) of Ac-L-Lys(Ac)-OH, and the operation process was the same as compound 3 to obtain 117 mg of white powdery solid, yield = 36%, MP 145.1-146.3°C. 1 H NMR (400MHz, DMSO) δ11.52 (s, 1H), 9.90 (s, 1H), 8.24 (s, 1H), 8.14 (d, J = 8.1Hz, 1H), 7. 79(t,J=5.6Hz,1H),7.39(d,J=7.5Hz,1H),7.29~7.23(m,2H),6.09(s,1H),4.71(dt,J= 7.0,7.3Hz,1H),3.68~3.52(m,8H),3.00(dt,J=6.4,6.7Hz,2H),2.43(s,3H),2.24(s,3 H),1.85(s,3H),1.78(s,3H),1.65~1.44(m,2H),1.40~1.34(m,2H),1.30~1.22(m,2H); 13C NMR (101MHz, DMSO) δ170.35,168.93,165.20,162.52,162.25,159.93,157.00,140.86,138.82,133.55,132.46,129.00,128.14,1 26.99,125.77,82.85,59.74,48.15,44.26,43.68,43.15,41.05,38.26,31.33,28.92,25.56,22.63,22.61,22.32,20.74,18.30. MS(ESI + )m / z calculated for C 30 H 38 ClN9O4S(M+H) + :656.2529; found:656.2568.

[0201] Example 22 Preparation of (S)-N,N'-(6-(4-(6-((5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2-yl)amino)-2-methylpyrimidin-4-yl)piperazine-1-yl)-6-oxohexane-1,5-diyl)dipropionamide (23, DS-CO-LYS-PROP2)

[0202]

[0203] Take compound 21386mg (0.5mmol) and add 3mL of 4M HCl 1,4-Dioxane solution, add 3mL of 1,4-Dioxane and stir, react at room temperature for 2 hours, then remove the solvent by vacuum distillation to obtain a yellow powder solid partially adhering to the bottle wall; add 3mL of DMF to dissolve, add 320μL of NMM, 90μL of propanoic acid (1.2mmol), add 570mg of HATU (1.5mmol) as a condensing agent, react at room temperature overnight, add NaCl aqueous solution to the reaction solution, extract with EA (20mL*3), collect the organic phase. EA and EtOH as eluents (EA~EA:EtOH=3:1) are used for column chromatography separation to obtain 22mg of white powder solid, yield=6.4%, MP136.3-137.8℃. 1H NMR (400MHz, DMSO) δ11.51(s,1H),9.89(s,1H),8.24(s,1H),8.04(d,J=8.1Hz,1H),7.69(t,J=4. 2Hz,1H),7.39(d,J=7.4Hz,1H),7.29~7.23(m,2H),6.08(s,1H),4.71(dt,J=5.8,7.6Hz,1H),3.68 ~3.51(m,8H),3.01(dt,J=6.8,7.2Hz,2H),2.43(s,3H),2.24(s,3H),2.16~2.10(m,2H),2.04(q, J=7.6Hz,2H),1.46~1.49(m,2H),1.39~1.34(m,2H),0.99(t,J=7.3Hz,3H),0.97(t,J=7.3Hz,3H); 13 C NMR(101MHz,DMSO)δ172.68,172.66,170.38,166.96,165.21,162.54,162.26,159.93, 157.00,140.84,138.82,133.54,132.46,131.73,131.54,129.00,128.64,128.13,126 .99,125.78,82.85,67.41,48.07,44.23,43.69,43.18,41.06,38.17,31.34,29.81,28 .96,28.53,28.36,28.17,25.55,23.26,22.60,22.39,18.29,13.86,10.78,9.98,9.93. MS(ESI+)m / zcalculated for C 32 H 42 ClN9O4S(M+H) + :684.2842; found:684.2861.

[0204] Example 23 Preparation of (S)-N,N'-(6-(4-(6-((5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2-yl)amino)-2-methylpyrimidin-4-yl)piperazine-1-yl)-6-oxohexane-1,5-diyl)diisonicotinamide (24,DS-CO-LYS-ISONIC2)

[0205]

[0206] The reaction raw material was replaced with isonicotinic acid 295 mg (2.4 mmol), and the reaction process was the same as 23 to obtain 33 mg of white powdery solid, yield = 4.2%, MP 129.2-132.4 ° C. 1H NMR (400MHz, DMSO) δ 11.56 (s, 1H), 9.93 (s, 1H), 8.98 (d, J = 7.6 Hz, 1H), 8.79 (t, J = 5.7 Hz, 1H), 8.71 (dd, J = 4.4, 1.7 Hz, 2H), 8.68 (dd, J = 4.4, 1.7 Hz 2H),8.27(s,1H),7.80(dd,J=4.4,1.7Hz,1H),7.30(dd,J=4.4,1.7Hz,1H),7.39(dd,J=7.5,1.9Hz,1H),7.29~7.22(m,2H),6.09(s,1H),4.95(d t,J=7.5,7.2Hz,1H),3.74~3.55(m,8H),3.33~3.27(m,1H),2.43(s,3H) ,2.25(s,3H),1.81~1.76(m,2H),1.63~1.54(m,2H),1.48~1.38(m,2H); 13 C NMR (101MHz, DMSO) δ170.04,165.24,164.78,164.59,162.58,162.27,159.99,157.02,150.17,150.13,141.55,140.87,138.85,133.57,132.49 ,129.02,128.15,127.01,125.81,121.49,121.20,82.90,59.77,49.54 ,44.36,43.68,43.21,41.22,39.01,30.71,28.67,25.58,22.89,18.33. MS (ESI+) m / z calculated for C 38 H 40 C1N 11 O4S(M+H) + :782.2747; found:782.2756.

[0207] Example 24 Preparation of (2E, 2'E)-N, N'-((S)-6-(4-(6-((5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2-yl)amino)-2-methylpyrimidin-4-yl)piperazin-1-yl)-6-oxohexane-1,5-diyl)bis(but-2-enamide) (25, DS-CO-LYS-CROT2)

[0208]

[0209] The reaction raw material was replaced with 207 mg (2.4 mmol) of crotonic acid, and the reaction process was the same as 23 to obtain 14 mg of white powdery solid, yield = 2.0%, MP 137.5-138.9 °C. 1 H NMR (400MHz, DMSO) δ11.54(s,1H),9.90(s,1H),8.24(s,1H),8.19(d,J=8.2Hz,1H),7.85(t,J=5 .6Hz,1H),7.40(dd,J=7.4,1.9Hz,1H),7.30~7.23(m,2H),6.68~6.52(m,2H),6.07(s,1H),6.02( dd,J=15.8,2.2Hz,1H),5.87(dd,J=25.3,2.0Hz,1H),4.78(dt,J=5.4,8.2Hz,1H),3.67~3.52(m, 8H),3.08(dt,J=6.56.5Hz,2H),2.43(s,3H),2.24(s,3H),1.79~1.74(m,6H),1.69~1.35(m,6H); 13 C NMR(101MHz,DMSO)δ170.29,165.20,164.77,164.50,162.53,162.25,15 9.93,156.99,140.84,138.82,138.40,137.30,133.53,132.45,129.01,1 28.15,126.99,126.00,125.77,125.44,82.84,59.74,48.10,44.29,43.6 5,43.15,41.08,38.12,31.34,28.94,25.55,22.65,18.29,17.35,17.24. MS (ESI+) m / z calculated for C 34 H 42 ClN9O4S(M+H) + :708.2842; found:708.2864.

[0210] Example 25 Preparation of (S)-N,N'-(6-(4-(6-((5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2-yl)amino)-2-methylpyrimidin-4-yl)piperazine-1-yl)-6-oxohexane-1,5-diyl)dibenzamide (26,DS-CO-LYS-BEN2)

[0211]

[0212] The reaction raw material was replaced with benzoic acid 293 mg (2.4 mmol), and the reaction process was the same as 23 to obtain 178 mg of white powdery solid, yield = 22.8%, MP 135.6-137.4 ° C. 1 H NMR (400MHz, DMSO) δ11.53(s,1H),9.89(s,1H),8.61(d,J=7.6Hz,1H),8.45(t,J=5. 7Hz,1H),8.24(s,1H),7.91~7.88(m,2H),7.83~7.81(m,2H),7.55~7.39(m,6H),7.30 ~7.23(m,2H),6.08(s,1H),4.96~4.88(m,1H),3.75~3.54(m,8H),3.30~3.25(m,2H) ,2.43(s,3H),3.25(s,3H),1.81~1.73(m,2H),1.62~1.52(m,2H),1.47~1.39(m,2H); 13 C NMR(101MHz,DMSO)δ170.39,170.36,166.22,166.15,165.20,162.55,162.26,159.93,156.99 ,140.84,138.82,134.70,133.96,133.53,132.45,131.29,130.92,129.00,128.19,128.16,1 27.48,127.08,126.99,125.77,82.86,59.73,49.33,44.30,43.67,43.19,41.16,40.16,39.9 5,39.74,39.53,39.32,39.11,38.90,38.86,30.81,28.88,25.55,22.90,20.73,18.28,14.06. MS(ESI+)m / z calculated for C 40 H 42 ClN9O4S(M+H) + :780.2842; found:780.2855.

[0213] Example 26 Preparation of (2R, 2'R)-N, N'-((S)-6-(4-(6-((5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2-yl)amino)-2-methylpyrimidin-4-yl)piperazin-1-yl)-6-oxohexane-1,5-diyl)bis(2-hydroxypropionamide) (27, DS-CO-LYS-LAC2)

[0214]

[0215] The reaction raw material was replaced with D-Lactic acid 169 mg (2.4 mmol), and the reaction process was the same as 23 to obtain 108 mg of white powdery solid, yield = 15.1%, MP 135.6-137.1 ° C. 1 H NMR (400MHz, DMSO) δ11.51(s,1H),9.90(s,1H),8.24(s,1H),7.74(d,J=4.0Hz,1H),7.65(t,J=5. 8Hz,1H),7.40(dd,J=7.4,1.9Hz,1H),7.30~7.23(m,2H),6.09(s,1H),5.59(d,J=5.0Hz,1H),5.4 3~5.42(d,J=2.4Hz,1H),4.77(dt,J=5.9,4.4Hz,1H),4.05~3.90(m,2H),3.65~3.54(m,8H),3.07 ~3.02(m,2H),2.43(s,3H),2.24(s,3H),1.70~1.57(m,2h),1.46~1.29(m,2H),1.21~1.17(m,6H); 13 C NMR (101MHz, DMSO) δ174.80,174.78,174.29,170.79,170.30,165.69,162.99,162.70,160. 40,157.48,141.33,139.30,134.01,132.93,129.48,128.62,127.46,126.24,83.32,67.72, 67.50,60.21,48.35,44.64,44.13,43.56,41.57,40.62,40.41,40.20,40.00,39.79,39.58, 39.37,38.23,32.17,29.39,26.03,22.47,21.60,21.35,21.21,20.77,20.67,18.77,14.54. MS(ESI+)m / z calculated for C 32 H 42ClN9O6S(M+H) + :716.2741; found:716.2744.

[0216] Example 27 Preparation of (S)-N,N'-(6-(4-(6-((5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2-yl)amino)-2-methylpyrimidin-4-yl)piperazine-1-yl)-6-oxohexane-1,5-diyl)bis(2-hydroxy-2-methylpropionamide) (28, DS-CO-LYS-HY2)

[0217]

[0218] The reaction raw material was replaced with 2-Hydroxyisobutyric acid 250 mg (2.4 mmol), and the reaction process was the same as 23 to obtain 238 mg of white powdery solid, yield = 32.0%, MP 125.2-126.7 ° C. 1 H NMR (400MHz, DMSO) δ11.51(s,1H),9.89(s,1H),8.25(s,1H),7.72(d,J=4.Hz,1H ),7.61(t,J=6.0Hz,1H),7.41~7.38(m,1H),7.29~7.23(m,2H),6.09(s,1H),5.54 (s,1H),5.30(s,1H),4.77(dt,J=5.8,4.3Hz,1H),3.69~3.55(m,8H),3.06(dt,J =6.9,7.3,2H),2.44(s,3H),2.25(s,3H),1.75~1.37(m,6H),1.29~1.23(m,12H); 13 C NMR(101MHz,DMSO)δ176.78,176.27,170.75,170.31,165.69,163.03,162.70,160.43,1 57.47,141.32,139.29,134.01,132.93,129.45,128.59,127.45,126.25,83.32,72.51,7 2.35,60.20,48.45,44.64,44.15,43.55,41.58,40.58,40.37,40.17,39.96,39.75,39. 54,39.33,38.47,32.30,29.41,28.47,28.28,27.80,26.01,22.33,21.18,18.76,14.52. MS(ESI+)m / z calculated for C 34H 46 ClN9O6S(M+H) + :744.3054; found:744.3074.

[0219] Example 28 Preparation of tert-butyl (S)-3-((tert-butyloxycarbonyl)amino)-4-(4-(6-((5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2-yl)amino)-2-methylpyrimidin-4-yl)piperazin-1-yl)-4-oxobutanoate (29)

[0220]

[0221] Compound 2 (0.45mmol, 200mg) and tert-butyloxycarbonyl-L-aspartic acid-4-tert-butyl ester (0.54mmol, 156mg) were used as raw materials, HATU (280mg) was used as a catalyst, NMM (140μL), and DMF (3ml) were added to a round-bottom flask and kept at room temperature for 1h. 50ml of saturated brine was added, and the mixture was extracted twice with 50ml of ethyl acetate. The organic phases were combined and dried over anhydrous Na2SO4. After the solvent was removed under reduced pressure, the mixture was chromatographed on a silica gel column (ethyl acetate: petroleum ether = 1:1) to obtain 81mg of a white solid with a yield of 25.2% and an MP of 187.8-188.9℃. 1 H NMR (400MHz, DMSO) δ11.52(s,1H),9.88(s,1H),8.23(s,1H),7.39(t,J=8.8Hz,2H),7.27(q,J=7.3Hz,2H),6.08(s,1H),4.73(dd,J=14. 8,7.3Hz,1H),3.73(s,4H),3.55(d,J=9.3Hz,1H),3.41(d,J=9.8Hz,3H),2.43(s,4H),2.24(s,3H),1.39(d,J=6.9Hz,18H),1.24(s,1H). 13 C NMR (101MHz, DMSO) δ170.02,169.28,165.69,162.99,162.77,160.37,157.49,155.24,141.30,139.30,133.99,132.92,12 9.50,127.48,83.37,80.46,78.99,47.54,44.55,44.04,43.59,41.85,38.20,28.62,28.17,26.04,18.76.LRMS(ESI+):m / z calculated for C 33 H 43 ClN8O6S(M+H +):715.2788; found 715.2815.

[0222] Example 29 Preparation of (S)-tert-butyl 3-amino-4-(4-(6-((5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2-yl)amino)-2-methylpyrimidin-4-yl)piperazin-1-yl)-4-oxobutanoate (30)

[0223]

[0224] Compound 29 was dissolved in a dioxane solution containing 4 M hydrochloric acid, stirred at room temperature for 1 h, and the solvent was removed under reduced pressure to obtain a white solid, which was directly used in the next reaction.

[0225] Example 30 Preparation of (S)-tert-butyl 4-(4-(6-((5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2-yl)amino)pyrimidin-4-yl)piperazin-1-yl)-3-(3,3-dimethylbutyramido)-4-oxobutanoate (31)

[0226]

[0227] Compound 30 (0.6mmol, 369mg) and tert-butylacetyl chloride (0.6mmol, 85μL) were used as raw materials, triethylamine (350μL) was used as catalyst, and dichloromethane (3ml) was used as solvent. The mixture was added into a round-bottom flask and placed in an ice bath for 3h. 50ml of saturated brine was added, and the mixture was extracted twice with 50ml of dichloromethane. The organic phases were combined and dried over anhydrous Na2SO4. After the solvent was removed under reduced pressure, the mixture was chromatographed on a silica gel column (ethyl acetate: petroleum ether = 3:1). After the solvent was removed under reduced pressure, 18mg of a white powdery solid was obtained, with a yield of 4.2%. MP163.3~164.8℃. 1 H NMR (400MHz, DMSO) δ11.52(s,1H),9.89(s,1H),8.23(s,1H),7.40(d,J=7.1Hz,1H),7.29(d,J=6.8Hz,2H),6.08(s,1H),3.83(s,1H),3.69(s,3H),3 .52(d,J=46.9Hz,4H),2.89(s,1H),2.70(d,J=8.8Hz,1H),2.51(s,1H),2 .43(s,4H),2.25(s,3H),2.00(d,J=2.8Hz,2H),1.37(s,9H),0.95(s,9H). 13C NMR (101MHz, DMSO) δ179.91,169.15,162.68,159.97,140.77,139.57,133.83,129.62,127.28,126 .55,83.85,83.46,80.78,80.52,48.70,44.64,31.01,30.20,28.16,26.03,18.77.LRMS(ESI+):m / z calculated forC 33 H 43 ClN8O5S(M+H + ):713.2995; found713.3033.

[0228] Example 31 Preparation of benzyl N2-(tert-butyloxycarbonyl)-N4-(tert-butyl)-L-asparagine (33)

[0229]

[0230] Compound Boc-L-aspartic acid 1-benzyl ester (32, 1.0mmol, 323mg) and tert-butylamine (1.5mmol, 157μL) were used as raw materials, HATU (1.5mmol, 576mg) was used as a catalyst, and NMM (2.7mmol, 280μL) and DMF (2ml) were added to a round-bottom flask. The mixture was stirred at room temperature for 1h. The reaction solution turned orange-red. 100ml of saturated brine was added, and the mixture was extracted twice with 100ml of ethyl acetate. The mixture was then washed once with 100ml of saturated sodium bicarbonate solution and 100ml of 1M hydrochloric acid aqueous solution, dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure to obtain 384mg of a white powdery solid with a yield of 95.9%. LRMS (ESI+): m / z calculated for C 20 H 30 N2O5(M+H + ):379.2228; found 379.2247.

[0231] Example 32 Preparation of benzyl N4-(tert-butyl)-L-asparagine (34)

[0232]

[0233] Compound 33 was dissolved in a dioxane solution containing 4M hydrochloric acid, stirred at room temperature for 1 h, and the solvent was dried to obtain a white solid 34, which could be directly used for the next step. LRMS (ESI+): m / z calculated for C 15 H 22 N2O3(M+H +):279.1704; found 279.1721.

[0234] Example 33 Preparation of benzyl N4-(tert-butyl)-N2-(3,3-dimethylbutyryl)-L-asparagine (35)

[0235]

[0236] Compound 34 (1.0 mmol, 278 mg) and 3,3-dimethylbutyric acid (1.0 mmol, 122 μL) were used as raw materials, HATU (1.2 mmol, 456 mg) was used as a catalyst, and DIPEA (697 μL) and DMF (2 ml) were added to a round-bottom flask, stirred at room temperature for 1 h, 100 ml of saturated brine was added, and extracted twice with 100 ml of ethyl acetate. The organic layer was then washed once with 100 ml of saturated sodium bicarbonate solution and 100 ml of 1M hydrochloric acid aqueous solution, dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure to obtain 199 mg of a white powdery solid with a yield of 52.9%. LRMS (ESI+): m / z calculated for C 21 H 32 N2O4(M+H + ):377.2435; found 377.2457.

[0237] Example 34N 4 Preparation of -(tert-butyl)-N2-(3,3-dimethylbutyryl)-L-asparagine (36)

[0238]

[0239] Compound 35 (120 mg) was used as the raw material, 10% Pd / C (10 mg), MeOH (5 mL), and H2 were added to catalyze the reaction for 4 h. After filtration, the solvent was removed under reduced pressure to obtain 69 mg of a white solid with a yield of 75.6%. LRMS (ES-): m / z calculated for C 14 H 26 N2O4(MH + ):285.1819; found 285.1831.

[0240] Example 35 Preparation of 2-((6-(4-(N4-(tert-butyl)-N2-(3,3-dimethylbutanoyl)-L-asparagine)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (37)

[0241]

[0242] Using compound 2 (0.2 mmol, 89 mg) and compound 36 (0.2 mmol, 57 mg) as raw materials, the synthesis method was the same as 3 to obtain 4 mg of white solid with a yield of 2.8% and MP of 167.4-168.0°C. 1 H NMR(400MHz,DMSO)δ11.53(s,1H),9.89(s,1H),8.23(s,1H),7.74(m,3H),7.28(s,1H),6.09(s,1H),5.06(s,1H),3.64(s,4H) ,2.59(d,J=7.9Hz,2H),2.44(s,2H),2.24(s,4H),1.99(d,J=9.0Hz,2H),1.38(s,1H),1.25(s,2H),1.22(s,9H),0.94(s,9H). 13 C NMR (101MHz, DMSO) δ170.68,170.60,170.15,169.15,169.07,165.62,162.66,160.39,157.40,141.30,139.30,133.99,132.95, 130.11,129.49,129.12,127.46,83.33,50.44,50.33,48.75,45.71,44.79,31.00,30.11,28.97,25.97,18.76.LRMS(ESI+):m / z calculated for C 34 H 46 ClN9O4S(M+H + ):712.3155; found712.3141.

[0243] Example 36 Preparation of N-(6-(4-(2-((tert-butoxycarbonyl)amino)ethyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)-5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2-amine (38)

[0244]

[0245] Compound 1 (0.45 mmol, 200 mg) and 1-(N-Boc-aminoethyl)piperazine (0.54 mmol, 124 mg) were used as raw materials, and the synthesis method was the same as 2 to obtain 110 mg of a white solid with a yield of 41.2%. LRMS (ESI+): m / z calculated for C 27 H 35 ClN8O3S(M+H +):587.2315; found 587.2322.

[0246] Example 37 Preparation of 2-((6-(4-(2-aminoethyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (39)

[0247]

[0248] Compound 38 was dissolved in a dioxane solution containing 4 M hydrochloric acid, stirred at room temperature for 1 h, and the solvent was evaporated to obtain a white solid, which could be directly used for the next reaction.

[0249] Example 38 Preparation of tert-butyl (S)-3-((tert-butyloxycarbonyl)amino)-4-((2-(4-(6-(5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2-yl)amino)-2-methylpyrimidin-4-yl)piperazin-1-yl)ethyl)amino)-4-oxobutanoate (40)

[0250]

[0251] Compound 39 (0.11mmol, 55mg) and tert-butyloxycarbonyl-L-aspartic acid-4-tert-butyl ester (0.13mmol, 37mg) were used as raw materials. The synthesis method was the same as 29 to obtain 24mg of white solid with a yield of 28.9%. MP179.3~180.1℃ 1 H NMR(400MHz,DMSO)δ11.47(s,1H),9.88(s,1H),8.23(s,1H),7.69(s,3H),7.40(s,1H),7.29(s,2H),7.08(s,1H),6.06(s,1H) ,4.39–4.18(m,2H),4.14(s,1H),3.83(s,1H),3.51(s,4H),2.24(s,3H),1.65(s,1H),1.39(s,18H),1.29(s,4H),0.88(s,3H). 13C NMR (101MHz, DMSO) δ169.99,165.65,163.03,162.88,160.39,157.43,155.53,141.31,139.30,133.99,132.91,132.13,129.50,1 29.17,83.12,80.45,78.73,53.08,52.59,51.69,44.04,38.30,36.65,30.48,28.65,28.15,26.05,19.12,18.77.LRMS(ESI+):m / z calculated for C 35 H 48 ClN9O6S(M+H + ):758.3210; found 758.3226.

[0252] Example 39 Compounds induce BCR-ABL degradation activity in K562 cells

[0253] Human myeloid leukemia cell line K562 was used as the research object. The compound was set at multiple concentrations and the administration time was 20 hours. At the same time, the ligand of BCR-ABL protein GNF-2 or Dasatinib was used as a reference. The content of BCR-ABL protein in K562 cells after administration was detected by Western Blot experiment to conduct preliminary screening of compound activity. The results are as follows Figures 1A-1C shown.

[0254] Example 40 Compound Inhibits K562 Cell Proliferation Activity

[0255] Prepare 50 μL K562 cell suspension (about 5000 cells / well) in a 96-well plate, and pre-culture the culture plate in an incubator for 24 hours (37°C, 5% CO2). Add 50 μL of the drug to be tested at different concentrations to the culture plate. Incubate in an incubator for 48 hours. Add 10 μL CCK-8 solution to each well, and incubate in the incubator for 1 to 4 hours. Then use an ELISA reader to measure the absorbance at 450 nm. Among them, the blank group added culture medium and CCK-8 solution without cells; the negative control group added cell suspension and CCK-8 solution without drugs.

[0256]

[0257] The calculation results are shown in Table 2 below:

[0258] Table 2

[0259]

[0260]

Claims

1. A compound of general formula (I), or a pharmaceutically acceptable salt thereof: in, R1 and R2 are independently selected from H, D, C 1-6 Alkyl or C 1-6 Haloalkyl; or R1 and R2 together form =O or =S; L does not exist or L is -(CH2) 0-4 C(R5)(R6)-; Wherein R5 is selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH2) 0-4 C 3-8 Cycloalkyl, -(CH2) 0-4 4-6 membered heterocyclic group, -(CH2) 0-4 C 6-10 Aryl, -(CH2) 0-4 5-10 membered heteroaryl, -(CH2) 1-6 C(O)OR a 、-(CH2) 1-6 C(O)NR b R c 、-(CH2) 1-6 OC(O)R a 、-(CH2) 1-6 N(R b )C(O)R a 、-(CH2) 1-6 OC(O)OR a 、-(CH2) 1-6 N(R b )C(O)OR a 、-(CH2) 1-4 OR a 、-(CH2) 1-4 SR a or natural amino acid side chains; R6 is selected from H or D; Or R5 and R6 together form =O or =S; R3 is selected from H, D, C 1-6 Alkyl or C 1-6 Haloalkyl; R4 is selected from H, D, C(O)R a 、C(O)OR a 、C(O)CNR b R c 、C(O)C(R f )NR d R e , C 1-6 Alkyl or C 1-6 Haloalkyl; Or R3 and R5 are connected together to form -(CH2) 3-5 ; or R3 and R4 together with the N atom to which they are attached form a 5-6 membered heterocyclic group; Where R a , R b and R c Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2, 3 or more halogen, OH, NH2; R d and R e are independently selected from H, C(O)R a C(O)OR a ; R f Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 1-4 C(O)R a or -(CH2) 1-4 C(O)OR a .

2. The compound of general formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: R1 is selected from H or D; R2 is selected from H or D; Or R1 and R2 together form =O or =S; L does not exist or L is -(CH2) 0-4 C(R5)(R6)-; Wherein R5 is selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 1-4 Phenyl, -(CH2) 1-6 C(O)OR a 、-(CH2) 1-6 C(O)NR b R c 、-(CH2) 1-6 N(R b )C(O)R a 、-(CH2) 1-6 N(R b )C(O)OR a or -(CH2) 1-4 SR a ; R6 is selected from H or D; Or R5 and R6 together form =O or =S; R3 is selected from H, D, C 1-6 Alkyl or C 1-6 Haloalkyl; R4 is selected from H, D, C(O)R a 、C(O)OR a 、C(O)C(R f )NR d R e , C 1-6 Alkyl or C 1-6 Haloalkyl; Or R3 and R5 are connected together to form -(CH2) 3-5 ; or R3 and R4 together with the N atom to which they are attached form a 5-6 membered heterocyclic group; Where R a , R b and R c Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2, 3 or more halogen, -OH, -NH2; R d and R e are independently selected from H, -C(O)R a or-C(O)OR a ; R f Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 1-4 C(O)R a or -(CH2) 1-4 C(O)OR a .

3. The compound of general formula (I) according to claim 2, or a pharmaceutically acceptable salt thereof, characterized in that: R1 is H; R2 is H; Or R1 and R2 together form =O; L is absent or L is -C(R5)(R6)-, -CH2C(R5)(R6)- or -CH2CH2C(R5)(R6)-; Where R5 is selected from H, -CH2CH2CH3, -CH2CH(CH3)2, -CH2Ph, -CH2C(O)OC(CH3)3, -CH2C(O)NH2, -CH2C(O)N HC(CH3)3, -CH2CH2CH2CH2NHC(O)CH3, -CH2CH2CH2CH2NHC(O)CH2CH3, -CH2CH2CH2CH2NHC(O) CH(OH)CH3, -CH2CH2CH2CH2NHC(O)C(OH)(CH3)2, -CH2CH2CH2CH2NHC(O)CH=CHCH3, -CH2CH2CH2CH2NHC(O)Ph, -CH2CH2CH2CH2NHC(O)Py, -CH2CH2CH2CH2NHC(O)OC(CH3)3 or -CH2SC(CH3)3; R6 is H; Or R5 and R6 together form =O; R3 is selected from H or CH3; R4H、-CH3、-C(O)CH3、-C(O)CH2CH3、-C(O)CH2C(CH3)3、-C(O)CH(OH)CH3、-C(O)C(OH)(CH3)2、-C(O)CH=CHCH3、-C(O)Ph、-C(O)Py、-C(O)OC(CH3)3、 Or R3 and R5 are linked together to form -CH2CH2CH2-; Alternatively, R3 and R4 together with the N atom to which they are attached form a morpholinyl group.

4. The compound of general formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: It has the structure of general formula (II): in, L is -(CH2) 0-4 CH(R5)-; Wherein R5 is selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH2) 0-4 C 3-8 Cycloalkyl, -(CH2) 0-4 4-6 membered heterocyclic group, -(CH2) 0-4 C 6-10 Aryl, -(CH2) 0-4 5-10 membered heteroaryl, -(CH2) 1-6 C(O)NR b R c or natural amino acid side chains; R3 is selected from H, D, C 1-6 Alkyl or C 1-6 Haloalkyl; R4 is selected from H, D, -C(O)R a 、-C(O)OR a 、-C(O)CNR b R c 、-C(O)C(R f )NR d R e , C 1-6 Alkyl or C 1-6 Haloalkyl; Or R3 and R5 are connected together to form -(CH2) 3-5 ; or R3 and R4 together with the N atom to which they are attached form a 5-6 membered heterocyclic group; Where R a , R b and R c Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2, 3 or more halogen, -OH, -NH2; R d and R e are independently selected from H, -C(O)R a or-C(O)OR a ; R f Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 1-4 C(O)R a or -(CH2) 1-4 C(O)OR a .

5. The compound of general formula (II) according to claim 4, or a pharmaceutically acceptable salt thereof, characterized in that: L is -(CH2) 0-4 CH(R5)-; Wherein R5 is selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 1-4 Phenyl or -(CH2) 1-6 C(O)NR b R c ; R3 is selected from H, D, C 1-6 Alkyl or C 1-6 Haloalkyl; R4 is selected from H, D, -C(O)R a 、-C(O)OR a 、-C(O)C(R f )NR d R e , C 1-6 Alkyl or C 1-6 Haloalkyl; Or R3 and R5 are connected together to form -(CH2) 3-5 ; or R3 and R4 together with the N atom to which they are attached form a 5-6 membered heterocyclic group; Where R a , R b and R c Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2, 3 or more halogen, -OH, -NH2; R d and R e are independently selected from H, -C(O)R a or-C(O)OR a ; R f Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 1-4 C(O)R a or -(CH2) 1-4 C(O)OR a .

6. The compound of general formula (II) according to claim 5, or a pharmaceutically acceptable salt thereof, characterized in that: L is selected from -CH(R5)-, -CH2CH(R5)- or -CH2CH2CH(R5)-; R5 is selected from H, -CH2CH2CH3, -CH2CH(CH3)2, -CH2Ph, -CH2C(O)NH2 or -CH2C(O)NHC(CH3)3; R3 is selected from H or CH3; R4H、-CH3、-C(O)CH3、-C(O)CH2CH3、-C(O)CH2C(CH3)3、-C(O)CH(OH)CH3、-C(O)C(OH)(CH3)2、-C(O)CH=CHCH3、-C(O)Ph、-C(O)Py、-C(O)OC(CH3)3、 Or R3 and R5 are linked together to form -CH2CH2CH2-; Alternatively, R3 and R4 together with the N atom to which they are attached form a morpholinyl group.

7. The compound of general formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: It has the structure of general formula (III): in, L is -(CH2) 0-4 CH(R5)-; Wherein R5 is selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 1-4 Phenyl or -(CH2) 1-6 C(O)NR b R c ; R3 is selected from H, D, C 1-6 Alkyl or C 1-6 Haloalkyl; R4 is selected from H, D, -C(O)R a 、-C(O)OR a , C 1-6 Alkyl or C 1-6 Haloalkyl; Or R3 and R5 are connected together to form -(CH2) 3-5 ; or R3 and R4 together with the N atom to which they are attached form a 5-6 membered heterocyclic group; Where R a and R b Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 6-10 Aryl; R c Selected from C 1-6 Alkyl or C 1-6 Halogenated alkyl.

8. The compound of general formula (III) according to claim 7, or a pharmaceutically acceptable salt thereof, characterized in that: L is selected from -CH(R5)-, -CH2CH(R5)- or -CH2CH2CH(R5)-; wherein R5 is selected from H, -CH2CH2CH3, -CH2CH(CH3)2, -CH2Ph ​​or -CH2C(O)NHC(CH3)3; R3 is selected from H or -CH3; R4 is selected from H, -CH3, -C(O)CH3, -C(O)CH2CH3, -C(O)CH2C(CH3)3, -C(O)CH=CHCH3, -C(O)Ph or -C(O)OC(CH3)3; Or R3 and R5 are linked together to form -CH2CH2CH2-; Alternatively, R3 and R4 together with the N atom to which they are attached form a morpholinyl group.

9. The compound of general formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from the following:

10. A pharmaceutical composition, characterized in that The invention comprises the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

11. Use of the compound of general formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 10 in the preparation of a medicament for treating tumor diseases caused by abnormal expression of BCR-ABL or drug-resistant mutation.

12. The use according to claim 11, characterized in that The disease is selected from chronic myeloid leukemia, acute lymphocytic leukemia, atypical chronic myeloid leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, B lymphocytic leukemia / lymphoma, lymphoblastic lymphoma, Tatton-Brown-Rahman syndrome or acute promyelocytic leukemia.

Images