WO2024099225A1

WO2024099225A1 - Ulk inhibitors

Info

Publication number: WO2024099225A1
Application number: PCT/CN2023/129511
Authority: WO
Inventors: 谢雨礼; 吴应鸣; 钱立晖
Original assignee: 微境生物医药科技(上海)有限公司
Priority date: 2022-11-08
Filing date: 2023-11-03
Publication date: 2024-05-16

Abstract

Disclosed are a class of ULK inhibitors. Specifically, the present invention relates to a compound as represented by general formula (1) and a preparation method therefor, and the use of the compound of general formula (1) and an isomer, a crystal form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof as an ULK inhibitor in the preparation of an anti-tumor drug.

Description

ULK inhibitors

This application claims the priority of Chinese patent application No. 202211394301.8, filed on November 8, 2022. This application cites the entire text of the above Chinese patent application.

Technical Field

The present invention belongs to the field of medicinal chemistry, and more specifically, relates to a new compound with ULK inhibitory effect, a preparation method thereof and the use of the new compound in the preparation of anti-tumor drugs.

Background technique

Autophagy is a process in which cells, under conditions of energy deficiency or environmental stress, produce a double-membrane structure to encapsulate part of their own cytoplasm or organelles and transport them to lysosomes for degradation into amino acids, lipids and carbohydrates, which are then reused by the cells (Klionsky, Nat. Rev. Mol. Cell Biol. 2007; 8: 931–937.). Tumor cells tend to activate autophagy because these cells have high metabolic demands, experience cellular stress, and are often in an oxygen-deficient environment with limited blood flow and nutrient supply. Therefore, autophagy may lead to the progression of certain cancers and drug resistance (Rabinowitz, Science. 2010; 330: 1344–1348.). There are also some animal studies that indicate that autophagy is particularly important for tumor survival and growth, especially KRAS-driven tumors (Eng, Proc. Natl. Acad. Sci. USA. 2016; 113: 182–187.; Guo, Genes Dev. 2013; 27: 1447–1461.). Inhibition of autophagy is currently being explored as a means to improve the effectiveness of existing cancer treatments, as well as a therapeutic strategy in its own right (Chude, Int. J. Mol. Sci. 2017; 18: 1–11.). In addition, chemotherapy and targeted therapies have been shown to induce autophagy as a mechanism of treatment resistance, and the combination of autophagy inhibition (either through loss-of-function mutations in autophagy genes or through pharmacological means) with chemotherapy has been shown to inhibit tumor growth and trigger tumor cell apoptosis to a greater extent than single-agent chemotherapy.

Autophagy induction is mainly controlled by serine/threonine kinases, ULK1 and ATG1. Among them, ULK1 is part of a complex composed of ATG13 (Autophagy Related 13), RB1CC1 (RB1 inducible coiled-coil; also known as FIP200) and ATG101 (Autophagy Related 101) (Ganley, J. Biol. Chem. 2009; 284: 12297–12305.). Through this complex, ULK1 integrates upstream signals from mTORC1 and AMPK to induce the production of early autophagosomes. Related cell experiments have also confirmed that the loss of ULK1 affects cellular autophagy. ULK1 gene loss inhibits autophagy in cancer cells, reduces FOX3A conversion and the upregulation of pro-apoptotic protein PUMA. In addition to the classical activation of typical autophagy, it has also been shown that ULK1 kinase activity requires Bcl-2-L-13-mediated mitophagy (autophagy of damaged mitochondria). It has also been confirmed that ULK1 and ULK2 kinases reshape cancer cell glucose metabolism. (Lee, Autophagy. 2011; 7: 689–695.). Due to the key role that ULK1 plays in the activation of related cell pathways and cell autophagy, this target is considered to be an important drug target for inhibiting cell autophagy. Recently, a variety of ULK small molecule inhibitors have been reported (Egan, Mol. Cell. 2015; 59: 285–297.; Lazarus, ACS Chem. Biol. 2015; 10: 257–261.; Petherick, J. Biol. Chem. 2015; 290: 28726.; Wood, ACS Med. Chem. Lett. 2017; 8: 1258–1263.). The above compounds have deepened the understanding of ULK structure by researchers, verified that the use of ULK inhibitors is an effective means to inhibit cell autophagy, and also provided practical proof for the drugability of ULK. However, the existing ULK inhibitors are not satisfactory in terms of efficacy and selectivity, and their use is subject to certain restrictions. Therefore, the development of more effective ULK New targeted therapies that combine inhibitors with existing chemotherapeutic agents and/or other targeted therapeutic agents have important clinical value.

Summary of the invention

The present invention provides a compound represented by general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

In the general formula (1):

Y is C(R ³ ) or N;

R ¹ is selected from: halogen, cyano, C ₁ -C ₅ alkyl or C ₃ -C ₅ cycloalkyl, wherein the C ₁ -C ₅ alkyl or C ₃ -C ₅ cycloalkyl may be optionally substituted by one, two or three fluorine groups;

^R2 is selected from: H, halogen, cyano, _C1 - _C5 alkyl, _C3 - _C6 cycloalkyl, C2- _C5 alkenyl, _C2 - _C5 alkynyl, _C1 - _C5 alkoxy or _C1 - _C5 alkoxy-( _C2 - _C5 )alkylene, wherein the _C1 - _C5 alkyl, _C3 - _C6 cycloalkyl, _C2 - _C5 alkenyl, _C2 _-C5 _alkynyl and _C1 - _C5 alkoxy may be optionally substituted with one, two or three fluorine or cyano groups;

R ³ is selected from: H, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy, wherein the C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy may be optionally substituted with one or more fluorines;

Z is selected from the following group: a) a 4-membered lactam ring bonded via a nitrogen atom or a 6-10-membered lactam ring bonded via a nitrogen atom, wherein when the lactam ring is a 6-10-membered ring, the atoms on the lactam ring may be optionally carbon, oxygen or NR ⁶ , and the carbon atoms on the 4-membered lactam ring or the 6-10-membered lactam may be optionally substituted by R ³⁶ ; b) or an amide bonded via a nitrogen atom, wherein the carbonyl carbon atom of the amide is substituted by R ³⁷ ;

R ³⁶ is independently selected at each occurrence from H, C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl, wherein the C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl may be optionally substituted with one or more fluorine, or two R ³⁶ are joined together to the carbon atom to which they are attached to form a C ₃ -C ₆ cycloalkyl;

R ³⁷ is independently selected from C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or (3-6 membered) heterocycloalkyl, wherein the carbon atoms on the C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or (3-6 membered) heterocycloalkyl may be optionally substituted by R ³⁶ , and the heteroatom on the (3-6 membered) heterocycloalkyl may be optionally oxygen or NR ⁶ ;

When Z is an amide bonded via a nitrogen atom, wherein the carbonyl carbon atom of the amide is substituted by R ³⁷ , R ⁴ is selected from B ¹ or D ¹ ;

B ¹ is selected from heterocycloalkyl or heteroaryl attached through a nitrogen atom, wherein B ¹ is optionally substituted on one or more available carbons with R ⁷ and optionally substituted on an available nitrogen with R ⁹ ;

D ¹ is selected from heterocycloalkyl or heteroaryl attached through a carbon atom, wherein D ¹ is optionally substituted on one or more available carbons with R ⁷ and optionally substituted on an available nitrogen with R ⁹ ;

R ⁷ is independently selected at each occurrence from: H, cyano, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, -N(R ⁵ ) ₂ , -(C ₁ -C ₆ ) alkylene-N(R ⁵ ) ₂ or (3-6 membered) heterocycloalkyl, wherein said C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or (3-6 membered) heterocycloalkyl may be optionally substituted with one or more H or F; or two R ⁷ together with the atoms to which they are attached form an oxo group;

R ⁹ is independently selected at each occurrence from: H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or (3-6 membered) heterocycloalkyl, wherein said C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or (3-6 membered) heterocycloalkyl may be optionally substituted with one or more H, D or F;

When Z is a 4-membered lactam ring bonded via a nitrogen atom or a 6-10-membered lactam ring bonded via a nitrogen atom, wherein when the lactam ring is a 6-10-membered ring, the atoms on the lactam ring may optionally be carbon, oxygen or NR ⁶ , and the carbon atoms on the 4-membered lactam ring or the 6-10-membered lactam may optionally be substituted by R ³⁶ , R ⁴ is selected from B ² or D ² ;

^B2 is selected from heterocycloalkyl or heteroaryl attached through a nitrogen atom, wherein ^B2 is optionally substituted with ^R8 on one or more available carbons and optionally substituted with ^R10 on an available nitrogen;

^D2 is selected from heterocycloalkyl or heteroaryl attached through a carbon atom, wherein ^D2 is optionally substituted with ^R8 on one or more available carbons and optionally substituted with ^R10 on an available nitrogen;

R ⁸ is independently selected at each occurrence from: H, cyano, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, -N(R ⁵ ) ₂ , -(C ₁ -C ₆ ) alkylene-N(R ⁵ ) ₂ or (3-6 membered) heterocycloalkyl, wherein said C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or (3-6 membered) heterocycloalkyl may be optionally substituted with one or more H or F; or two R ⁸ together with the atoms to which they are attached form an oxo group;

R ¹⁰ is independently selected at each occurrence from: C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or (3-6 membered) heterocycloalkyl, wherein said C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or (3-6 membered) heterocycloalkyl may be optionally substituted with one or more H, D or F;

R ⁵ is independently selected at each occurrence from: H, C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl, wherein said C ₁ -C ₆ alkyl and C ₃ -C ₆ cycloalkyl may be optionally substituted with one or more F;

R ⁶ is independently selected at each occurrence from: H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or (3-6 membered) heterocycloalkyl, wherein said C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or (3-6 membered) heterocycloalkyl may be optionally substituted with one or more F;

and n is 2, 3, or 4.

In another preferred embodiment, in the general formula (1), Z is selected from:

in,

V is selected from the group consisting of oxygen, C(R ³⁴ ) ₂ and NR ⁹ ;

R ³⁴ is independently selected at each occurrence from H or R ³⁶ , wherein R ³⁶ is independently selected at each occurrence from C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl, or two R ³⁶ are joined together to the carbon atom to which they are attached to form a C ₃ -C ₆ cycloalkyl;

R ³⁷ is independently selected from C ₁ -C ₃ alkyl, C ₃ -C ₅ cycloalkyl or (3-6 membered) heterocycloalkyl, wherein the carbon atoms on the C ₁ -C ₃ alkyl, C ₃ -C ₅ cycloalkyl or (3-6 membered) heterocycloalkyl may be optionally substituted by R ³⁶ , and the heteroatom on the (3-6 membered) heterocycloalkyl may be optionally oxygen or NR ⁶ ;

q is 0, 1, 2 or 3; r is 2 or 4; and if q is 0, then r is not 2.

wherein R ³⁴ at each occurrence is independently selected from H or R ³⁶ , wherein R ³⁶ at each occurrence is independently selected from C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl, or two R ³⁶ are joined together to the carbon to which they are attached to form a C ₃ -C ₆ cycloalkyl.

In another preferred embodiment, in the general formula (1), when Z is When ^R4 is selected from:

wherein R ⁷ at each occurrence is independently selected from: H, cyano, -N(R ⁵ ) ₂ , C ₁ -C ₃ alkyl, C ₃ -C ₅ cycloalkyl, or (3-5 membered) heterocycloalkyl, wherein said C ₁ -C ₃ alkyl, C ₃ -C ₅ cycloalkyl, or (3-6 membered) heterocycloalkyl may be optionally substituted with one or more H or F, or two R ⁷ are linked together to the atoms to which they are attached to form an oxo group;

^R9 is independently selected at each occurrence from: H, _C1 - _C3 alkyl, _C3 - _C5 cycloalkyl or (3-5 membered)heterocycloalkyl, wherein said _C1 - _C3 alkyl, _C3 - _C5 cycloalkyl or (3-5 membered)heterocycloalkyl may be optionally substituted with one or more H, D or F; wherein ^R5 is independently selected at each occurrence from: H, _C1 - _C6 alkyl or _C3 - _C6 cycloalkyl, wherein said _C1 - _C6 alkyl and _C3 - _C6 cycloalkyl may be optionally substituted with one or more F.

In another preferred embodiment, in the general formula (1), when Z is When ^R4 is selected from: wherein R ⁸ is independently selected at each occurrence from: H, cyano, C ₁ -C ₃ alkyl, C ₃ -C ₅ cycloalkyl, or (3-5 membered) heterocycloalkyl, wherein said C ₁ -C ₃ alkyl, C ₃ -C ₅ cycloalkyl, or (3-5 membered) heterocycloalkyl may be optionally substituted with one or more H or F, or two R ⁸ are linked together with the atoms to which they are attached to form an oxo group; R ¹⁰ is independently selected at each occurrence from: C ₁ -C ₃ alkyl, C ₃ -C ₅ cycloalkyl, or (3-5 membered) heterocycloalkyl, wherein said C ₁ -C ₃ alkyl, C ₃ -C ₅ cycloalkyl, or (3-5 membered) heterocycloalkyl may be optionally substituted with one or more H or F; wherein R ⁵ is independently selected at each occurrence from: H, C ₁ -C ₆ alkyl, or C ₃ -C ₆ cycloalkyl, wherein said C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl may be optionally substituted with one or more F.

In another preferred embodiment, in the general formula (1), R ¹ is selected from: halogen, C ₁ -C ₃ alkyl or C ₃ -C ₅ cycloalkyl, wherein the C ₁ -C ₃ alkyl or C ₃ -C ₅ cycloalkyl may be optionally substituted by one, two or three fluorine groups.

In another preferred embodiment, in the general formula (1), R ¹ is selected from: trifluoromethyl, F, Cl, Br, I or cyclopropyl.

In another preferred embodiment, in the general formula (1), ^R2 is selected from: H, F, Cl, Br, cyano, _C1 - _C3 alkyl, _C3 - _C5 cycloalkyl, C2- _C4 alkenyl, _C2 - _C4 alkynyl, _C1 _- _C3 alkoxy or _C1 - _C3 alkoxy-( _C2 - _C5 )alkylene, wherein the _C1 - _C3 alkyl, _C3 - _C5 cycloalkyl, _C2 - _C4 alkenyl, _C2 - _C4 alkynyl or _C1 - _C3 alkoxy may be optionally substituted by one, two or three fluorine or cyano groups.

In another preferred embodiment, in the general formula (1), R ² is selected from: H, F, Cl, Br, or -OCH ₃ .

In another preferred embodiment, in the general formula (1), n=3.

In another preferred embodiment, the present invention provides a compound as described in general formula (2a) or (2b):

Wherein R ¹ , R ² , R ⁴ , Z and n are as defined above and are exemplified in the specific examples.

In another preferred embodiment, the present invention provides a compound as described in general formula (3a), (3b) or (3c):

wherein R ¹ , R ² , R ⁴ , R ³⁴ , R ³⁷ , Y, q, r and n are as defined above and exemplified in the specific examples.

In another preferred embodiment, the present invention provides a compound as described in general formula (4a), (4b) or (4c):

wherein R ¹ , R ² , R ⁴ , R ³⁴ , R ³⁷ , Y, q and r are as defined above and are illustrated in the specific examples.

In various embodiments of the present invention, the compound of formula (1) has one of the following structures:

Another object of the present invention is to provide a pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent and/or excipient, and a compound of the general formula (1) of the present invention, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as active ingredients.

Another object of the present invention is to provide the use of the compound represented by the general formula (1) of the present invention, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the above pharmaceutical compositions for preparing drugs for treating, regulating or preventing diseases related to ULK1 and/or ULK2. The disease is preferably cancer, and the cancer is blood cancer and solid tumor.

Another object of the present invention is to provide a method for treating, regulating or preventing diseases related to ULK1 and/or ULK2, comprising administering to a subject a therapeutically effective amount of a compound represented by the general formula (1) of the present invention, or its isomers, crystalline forms, pharmaceutically acceptable Acceptable salt, hydrate or solvate or the above-mentioned pharmaceutical composition.

It is to be understood that both the foregoing general description and the following detailed description of the present invention are exemplary and explanatory and are intended to provide further explanation of the invention as claimed.

Synthesis of compounds

The following is a detailed description of the preparation methods of the compounds of the general formula (1) of the present invention, but these specific methods do not constitute any limitation to the present invention.

The compounds of formula (1) described above can be synthesized using standard synthetic techniques or known techniques in combination with the methods described herein. In addition, the solvents, temperatures and other reaction conditions mentioned herein can be varied. The starting materials used for the synthesis of the compounds can be synthesized or obtained from commercial sources. The compounds described herein and other related compounds with different substituents can be synthesized using known techniques and raw materials, including those found in March, ADVANCED ORGANIC CHEMISTRY ^4th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY ^4th Ed., Vols. A and B (Plenum 2000, 2001), Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS ^3rd Ed., (Wiley 1999). The general method for preparing the compounds can be varied by using appropriate reagents and conditions for introducing different groups into the molecular formula provided herein.

On the one hand, the compounds described herein are prepared according to methods known in the art. However, the conditions of the method, such as reactants, solvents, bases, the amount of compounds used, reaction temperature, reaction time, etc., are not limited to the following explanation. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such a combination can be easily performed by a person skilled in the art to which the present invention belongs. On the one hand, the present invention also provides a method for preparing the compound represented by the general formula (1), wherein the compound of the general formula (1) can be prepared using the following general reaction scheme 1:

General reaction scheme 1

The compound of formula (1) can be prepared according to general reaction scheme 1, wherein R ¹ , R ² , R ⁴ , Y, and Z are as defined above, H represents hydrogen, N represents nitrogen, Cl represents chlorine, O represents oxygen, and S represents sulfur. As shown in general reaction scheme 1, compounds 1-1 and 1-2 undergo aromatic nucleophilic substitution reaction under alkaline conditions to generate compound 1-3, compound 1-3 is oxidized to obtain compound 1-4, and 1-4 and 1-5 undergo aromatic nucleophilic substitution reaction under acidic conditions to generate target compound 1-6.

Further forms of compounds

"Pharmaceutically acceptable" as used herein refers to a material, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively non-toxic, i.e., a material that, when administered to a subject, does not cause undesirable biological effects or interact in a deleterious manner with any of its constituent components.

The term "pharmaceutically acceptable salt" refers to a compound in a form that does not cause significant irritation to an organism to which it is administered. And will not make the biological activity and properties of the compound disappear. In some specific aspects, pharmaceutically acceptable salts are obtained by reacting the general formula compound with an acid or base, wherein the acid or base includes, but is not limited to, the acid and base found in Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use ^1st Ed., (Wiley, 2002).

It should be understood that references to pharmaceutically acceptable salts include solvent-added forms or crystal forms, particularly solvates or polymorphs. Solvates contain stoichiometric or non-stoichiometric amounts of solvent and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is ethanol. Solvates of compounds of formula (1) are conveniently prepared or formed according to the methods described herein. For example, hydrates of compounds of formula (1) are conveniently prepared by recrystallization from a mixed solvent of water/organic solvent, and the organic solvents used include, but are not limited to, tetrahydrofuran, acetone, ethanol or methanol. In addition, the compounds mentioned herein can exist in unsolvated and solvated forms. In general, for the purposes of the compounds and methods provided herein, the solvated form is considered to be equivalent to the unsolvated form.

In other specific embodiments, the compound of formula (1) is prepared in different forms, including but not limited to amorphous, crushed and nano-particle forms. In addition, the compound of formula (1) includes crystalline forms and can also be used as polymorphs. Polymorphs include different lattice arrangements of the same elemental composition of the compound. Polymorphs usually have different X-ray diffraction spectra, infrared spectra, melting points, density, hardness, crystal form, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvents, crystallization rate and storage temperature may cause a single crystal form to dominate.

In another aspect, the compounds of formula (1) may have chiral centers and/or axial chirality, and thus appear in the form of racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers, and cis-trans isomers. Each chiral center or axial chirality will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures as well as pure or partially purified compounds are included within the scope of the present invention. The present invention is meant to include all such isomeric forms of these compounds.

The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more atoms constituting the compound. For example, compounds may be labeled with radioactive isotopes, such as tritium ( ^3H ), iodine-125 ( ^125I ) and C-14 ( ^14C ). For another example, deuterated compounds may be formed by replacing hydrogen atoms with heavy hydrogen. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs generally have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending the half-life of drugs in vivo. All isotopic composition changes of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.

Unless otherwise specified, any atom of the compounds of the present invention refers to the isotope of the atom in its stable state. Unless otherwise specified, when a site on the molecular structure is selected as "H" or "hydrogen", the site should be understood to have the natural abundance of hydrogen isotopes. Similarly, unless otherwise specified, when a site is selected as "D" or "deuterium", the site should be understood to have a deuterium isotope abundance of at least 3000 times its natural abundance (the natural abundance of deuterium isotopes is 0.015%).

More preferably, the deuterium atom abundance at each deuterated site of the deuterated compound of the present invention is at least 3500 times its natural abundance (52.2% deuterium atom enrichment). More preferably, it is at least 4500 times (67.5% deuterium atom enrichment). More preferably, it is at least 5000 times (75% deuterium atom enrichment). More preferably, it is at least 6000 times (90% deuterium atom enrichment). More preferably, it is at least 6333 times (95% deuterium atom enrichment). More preferably, it is at least 6466.7 times (97% deuterium atom enrichment). More preferably, it is at least 6600 times (99% deuterium atom enrichment). More preferably, it is at least 6633.3 times (99.5% deuterium atom enrichment).

the term

Unless otherwise indicated, the terms used in this application, including the specification and claims, are defined as follows. It must be noted that in the specification and the appended claims, the singular forms "a" and "an" include plural meanings unless otherwise clearly indicated in the text. If not otherwise indicated, conventional methods of mass spectrometry, nuclear magnetic resonance, HPLC, protein chemistry, biochemistry, recombinant DNA technology and pharmacology are used. In this application, if not otherwise indicated, the use of "or" or "and" means "and/or".

Unless otherwise specified, "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 6 carbon atoms, preferably a lower alkyl group containing 1 to 4 carbon atoms. Exemplary alkyl groups include, but are not limited to, straight or branched chain hydrocarbons having 1-6, 1-5, 1-4, 1-3, or 1-2 carbon atoms, referred to herein as C ₁ -C ₆ alkyl, C ₁ -C ₅ alkyl, C ₁ -C ₄ alkyl, C ₁ -C ₃ alkyl, and C ₁ -C ₂ alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-butyl, 3-methyl-2-butyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, and the like.

Unless otherwise specified, "alkylene" refers to a divalent alkyl group as defined above. Examples of alkylene groups include, but are not limited to, methylene and ethylene.

Unless otherwise specified, "alkenyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon double bond, including straight or branched groups of 1 to 14 carbon atoms, preferably lower alkenyl groups containing 1 to 4 carbon atoms. Exemplary alkenyl groups include, but are not limited to, straight or branched groups with 2-6 or 3-4 carbon atoms, respectively referred to herein as _C2 - _C6 alkenyl and _C3 - _C4 alkenyl. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, etc.

Unless otherwise specified, "alkenylene" refers to a divalent alkenyl group as defined above.

Unless otherwise specified, "alkynyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon triple bond, including straight and branched groups of 1 to 14 carbon atoms, preferably lower alkynyl groups containing 1 to 4 carbon atoms. Exemplary alkynyl groups include, but are not limited to, straight or branched groups with 2-6 or 3-6 carbon atoms, respectively referred to herein as _C2 - _C6 alkynyl and _C3 - _C6 alkynyl. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, and the like.

Unless otherwise specified, "alkynylene" refers to a divalent alkynyl group as defined above.

Unless otherwise specified, "cycloalkyl" refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic or polycyclic), preferably a non-aromatic hydrocarbon ring system containing 3-14 ring carbon atoms (C _3-14 cycloalkyl). In some embodiments, the cycloalkyl has 3-10 ring carbon atoms (C _3-10 cycloalkyl). In some embodiments, the cycloalkyl has 3-8 ring carbon atoms (C _3-8 cycloalkyl). In some embodiments, the cycloalkyl has 3-7 ring carbon atoms (C _3-7 cycloalkyl). In some embodiments, the cycloalkyl has 3-6 ring carbon atoms (C _3-6 cycloalkyl). In some embodiments, the cycloalkyl has 4-6 ring carbon atoms (C _4-6 cycloalkyl). In some embodiments, the cycloalkyl has 5-6 ring carbon atoms (C _5-6 cycloalkyl). In some embodiments, the cycloalkyl has 5-10 ring carbon atoms (C _5-10 cycloalkyl). Cycloalkyl If the carbocyclic ring contains at least one double bond, the partially unsaturated cycloalkyl group may be referred to as a "cycloalkenyl group", or if the carbocyclic ring contains at least one triple bond, the partially unsaturated cycloalkyl group may be referred to as a "cycloalkynyl group". Cycloalkyl groups may include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spirocyclic groups. In some embodiments, cycloalkyl groups are monocyclic. In some embodiments, cycloalkyl groups are bicyclic. In some embodiments, cycloalkyl groups are monocyclic or bicyclic. In some embodiments, cycloalkyl groups are tricyclic. The ring-forming carbon atoms of cycloalkyl groups may be optionally oxidized to form oxo or thio groups. Cycloalkyl groups also include cycloalkylene groups. In some embodiments, cycloalkyl groups contain In some embodiments, cycloalkyl contains 1 or 2 double bonds. In some embodiments, cycloalkyl contains 1 or 2 double bonds (partially unsaturated cycloalkyl). In some embodiments, cycloalkyl can be fused with aryl, heteroaryl, cycloalkyl and heterocycloalkyl. In some embodiments, cycloalkyl can be fused with aryl, cycloalkyl and heterocycloalkyl. In some embodiments, cycloalkyl can be fused with aryl and heterocycloalkyl. In some embodiments, cycloalkyl can be fused with aryl and heterocycloalkyl. In some embodiments, cycloalkyl can be fused with aryl and cycloalkyl. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinenyl, norcarbyl, bicyclo [1.1.1] pentyl, bicyclo [2.1.1] hexyl and the like.

Unless otherwise specified, "cycloalkylene" refers to a divalent cycloalkyl group as defined above.

Unless otherwise specified, "alkoxy" refers to an alkyl group bonded to the rest of the molecule by an ether oxygen atom. Representative alkoxy groups are alkoxy groups having 1-6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy. As used herein, "alkoxy" includes unsubstituted and substituted alkoxy groups, especially alkoxy groups substituted by one or more halogens. Preferred alkoxy groups are selected from OCH ₃ , OCF ₃ , CHF ₂ O, CF ₃ CH ₂ O, ^i- PrO, ^n- PrO, ^i- BuO, ^n- BuO or ^t- BuO. As used herein, the term "alkoxyalkyl" refers to a straight or branched alkyl group (alkyl-O-alkyl-) attached to oxygen, attached to a second straight or branched alkyl group. Exemplary alkoxyalkyl groups include, but are not limited to, alkoxyalkyl groups wherein the alkyl groups each independently contain 1-6 carbon atoms, referred to herein as C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl. Exemplary alkoxyalkyl groups include, but are not limited to, methoxymethyl, 2-methoxyethyl, 1-methoxyethyl, 2-methoxypropyl, ethoxymethyl, 2-isopropoxyethyl, and the like.

Unless otherwise specified, "aryl" refers to a hydrocarbon aromatic group, which is monocyclic or polycyclic, for example, a monocyclic aryl ring fused to one or more carbocyclic aromatic groups. Examples of aryl include, but are not limited to, phenyl, naphthyl and phenanthrenyl.

Unless otherwise specified, "aryloxy" refers to an aryl group bonded to the rest of the molecule through an ethereal oxygen atom. Examples of aryloxy include, but are not limited to, phenoxy and naphthoxy.

Unless otherwise specified, "arylene" refers to a divalent aromatic radical as defined above. Examples of arylene radicals include, but are not limited to, phenylene, naphthylene, and phenanthrenylene.

Unless otherwise specified, "heteroaryl" refers to a substituted or unsubstituted aromatic group containing one or more heteroatoms, preferably a 5-14-membered aromatic group containing 1-4 heteroatoms selected from oxygen, sulfur and nitrogen, more preferably a 5-9-membered aromatic group containing 1-2 heteroatoms selected from oxygen, sulfur or nitrogen, the heteroatoms are independently selected from O, N or S, and the number of heteroatoms is preferably 1, 2 or 3. The heteroaryl group is monocyclic or polycyclic. The monocyclic heteroaryl group is preferably a 5-6-membered aromatic group containing 1-3 heteroatoms selected from oxygen, nitrogen or sulfur. More preferably, it is a 5-6-membered aromatic group containing 1-2 heteroatoms selected from oxygen, nitrogen or sulfur. More preferably, it is a 5-6-membered aromatic group containing 1 heteroatom selected from oxygen, nitrogen or sulfur. In some embodiments, the monocyclic heteroaryl ring is fused with one or more carbocyclic aromatic groups or other monocyclic heterocycloalkyl groups. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, benzopyridinyl, pyrrolopyrimidinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl,

Unless otherwise specified, "heteroarylene" refers to a divalent heteroaryl group as defined above.

Unless otherwise specified, "heterocycloalkyl" refers to a non-aromatic ring or ring system, which may optionally contain one or more alkenylene groups as part of the ring structure, having at least one heteroatom ring member independently selected from boron, phosphorus, nitrogen, sulfur, oxygen and selenium, preferably a saturated or partially unsaturated ring containing 1-4 heteroatoms selected from oxygen, sulfur or nitrogen, and more preferably a saturated or partially unsaturated ring containing 1-2 heteroatoms selected from oxygen, sulfur or nitrogen. In some embodiments, heterocycloalkyl is a 5-8-membered non-aromatic ring containing ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen or sulfur (5-8-membered heterocycloalkyl). Heterocycloalkyl is a 5-6-membered non-aromatic ring containing ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen or sulfur (5-6-membered heterocycloalkyl). In some embodiments, 5-6-membered heterocycloalkyl contains 1-3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, 5-6 yuan heterocycloalkyl contains 1-2 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, 5-6 yuan heterocycloalkyl contains 1 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. If heterocycloalkyl contains at least one double bond, then partially unsaturated heterocycloalkyl can be referred to as "heterocycloalkenyl", or if heterocycloalkyl contains at least one triple bond, then partially unsaturated heterocycloalkyl can be referred to as "heterocycloalkynyl". Heterocycloalkyl can include monocyclic, bicyclic, spirocyclic or polycyclic (e.g., having two fused or bridged rings) ring systems. In some embodiments, heterocycloalkyl is a monocyclic group with 1,2 or 3 heteroatoms independently selected from nitrogen, sulfur and oxygen. The ring-forming carbon atoms and heteroatoms of heterocycloalkyl can be optionally oxidized to form oxo or thio or other oxidized bonds (e.g., C(O), S(O), C(S) or S(O) ₂ , N-oxides, etc.), or nitrogen atoms can be quaternized. Heterocycloalkyl can be connected via ring-forming carbon atoms or ring-forming heteroatoms. In some embodiments, heterocycloalkyl contains 0 to 3 double bonds. In some embodiments, heterocycloalkyl contains 0 to 2 double bonds. The definition of heterocycloalkyl also includes a portion (also referred to as partially unsaturated heterocycle) of an aromatic ring having one or more fused to a heterocycloalkyl ring (i.e., sharing a key with it), such as a benzo derivative of piperidine, morpholine, azacycloheptatriene or thienyl, etc. The heterocycloalkyl containing a fused aromatic ring can be connected via any ring-forming atoms, including the ring-forming atoms of the fused aromatic ring. Examples of heterocycloalkyl include, but are not limited to, azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa-9-azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl, quinuclyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, tropanediyl, 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, 4,5,6,7-tetrahydro-1H-imidazole, oxazolo[4,5-c]pyridine, N-methylpiperidinyl, tetrahydroimidazolyl, pyrazolidinyl, butyrolactamyl, valerolactamyl, imidazolinyl, hydantoinyl, dioxolanyl, phthalimide, pyrimidine-2,4(1H,3H)-dione, 1,4-dioxane, morpholinyl, thiomorpholinyl, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazinyl, pyranyl, pyridone, 3-pyrrolinyl, thiopyranyl, pyranone, tetrahydrothiophenyl, 2-azaspiro[3.3]heptanyl, indolyl,

Unless otherwise specified, "heterocycloalkylene" refers to a divalent heterocycloalkyl group as defined above.

As used herein, the term "lactam" refers to a cyclic amide of a carbamic acid having a 1-azacycloalkane-2-one structure, or an analog having unsaturation or a heteroatom replacing one or more carbon atoms of the ring. "α-lactam" refers to a lactam consisting of a 3-membered ring. "β-lactam" refers to a lactam consisting of a 4-membered ring. "γ-lactam" refers to a lactam consisting of a 5-membered ring. "δ-lactam" refers to a lactam consisting of a 6-membered ring. "ε-lactam" refers to a lactam composed of a 7-membered ring.

Unless otherwise specified, "oxo" means =0; for example, a carbonyl radical substituted with an oxo radical is a "carbonyl radical." "; the group formed by sulfur being replaced by an oxo group is called "sulfinyl ", the group formed by sulfur being replaced by two oxo groups is called "sulfonyl" ”.

Unless otherwise specified, "halogen" (or halo) refers to fluorine, chlorine, bromine or iodine. The term "halo" (or "halogen substituted") appearing before the name of a group means that the group is partially or fully halogenated, that is, substituted by F, Cl, Br or I in any combination, preferably substituted by F or Cl.

Unless otherwise specified, the term "substituted" refers to the case where one or more hydrogen atoms on a specified atom or group are replaced by one or more substituents other than hydrogen, without exceeding the normal valence of the specified atom. For example, one or more hydrogens of an alkyl, alkylene, alkenyl, alkynyl, hydroxyl or amine group, etc., may be replaced by one or more substituents. Wherein the substituent includes but is not limited to alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxylate, cyano, guanidino, halogen, haloalkyl, heteroalkyl, heteroaryl, heterocyclic radical, hydroxyl, hydrazine, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, mercaptan, thioketone or a combination thereof. The definition of "substituted" does not include similar indefinite structures obtained by defining a substituent with a further substituent attached to infinity (for example, a substituted aryl having a substituted alkyl is itself substituted by a substituted aryl, which is further substituted by a substituted heteroalkyl, etc.). Unless otherwise specified, the maximum number of consecutive substitutions in the compounds described herein is three. For example, substituted aryl is continuously substituted by two other substituted aryl groups to be limited to aryl substituted by ((substituted aryl) substituted aryl). Similarly, the above definition does not include unallowed substitution patterns (e.g., methyl substituted by 5 fluorines or heteroaryl with two adjacent oxygen ring atoms). Such unallowed substitution patterns are well known to those skilled in the art. Whenever used to modify a chemical group, "substituted" can describe other chemical groups defined herein. For example, the term "substituted aryl" includes but is not limited to "alkyl aryl". Unless otherwise specified, if a group is described as optionally substituted, any substituent of the group itself is unsubstituted.

"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

Unless otherwise specified, it will be understood that the word "comprise", or variations such as "comprises" or "comprising", means the inclusion of stated elements or integers, or groups of elements or integers, but not the exclusion of any other elements or integers, or groups of elements or integers.

When one of the variables is selected from a chemical bond, it means that the two groups it connects are directly connected. For example, when L in X-L-Y represents a chemical bond, it means that the structure is actually X-Y.

The term "membered ring" includes any cyclic structure. The term "membered" means the number of backbone atoms that make up the ring. For example, cyclohexyl, pyridyl, pyranyl, thiopyranyl are six-membered rings, and cyclopentyl, pyrrolyl, furanyl, and thiophenyl are five-membered rings.

The term "fragment" refers to a specific part or functional group of a molecule. A chemical fragment is generally considered to be a chemical entity contained in or attached to a molecule.

The term "isomer" refers to any tautomer, stereoisomer, isotope, enantiomer, or The compounds of the present invention may have one or more chiral centers or double bonds, and therefore exist in stereoisomeric form, for example, double bond isomers (i.e., E/Z geometric isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis/trans isomers). Therefore, the compounds of the present invention encompass all corresponding stereoisomers, i.e., stereoisomerically pure (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) forms as well as enantiomers and stereoisomer mixtures, such as racemates. Enantiomers and stereoisomer mixtures of the compounds of the present invention can be separated into their component enantiomers or stereoisomers by well-known methods, such as chiral gas chromatography, chiral high performance liquid chromatography, and crystallization of the compounds in the form of chiral salt complexes or crystallization of the compounds in chiral solvents. Enantiomers and stereoisomers may also be obtained from stereomerically or enantiomerically pure intermediates, reagents and catalysts by well-known asymmetric synthetic methods.

The term "isotope isomers" refers to different molecules whose structures differ only in their isotopes but are otherwise identical.

Unless otherwise specified, the key is a solid wedge. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond. and straight dashed key To indicate the relative configuration of a stereocenter, use a wavy line Denotes a solid wedge bond or dotted wedge key Or use a wavy line Represents a straight solid bond or straight dashed key

Unless otherwise stated, Indicates a single bond or a double bond.

Specific pharmaceutical and medical terms

The term "acceptable," as used herein, means that a formulation component or active ingredient has no undue deleterious effect on health and well-being for the general purpose of treatment.

The terms "treat", "treatment" or "therapy" as used herein include alleviating, inhibiting or improving symptoms or conditions of a disease; inhibiting the occurrence of complications; improving or preventing potential metabolic syndrome; inhibiting the occurrence of a disease or symptom, such as controlling the development of a disease or condition; alleviating a disease or symptom; reducing a disease or symptom; alleviating complications caused by a disease or symptom, or preventing or treating signs caused by a disease or symptom. As used herein, a compound or pharmaceutical composition, after administration, can improve a disease, symptom or condition, especially improve its severity, delay the onset, slow the progression of the disease, or reduce the duration of the disease. Whether fixed or temporary administration, continuous administration or intermittent administration, can be attributed to or related to the administration.

"Active ingredient" refers to the compound shown in the general formula (1), and the pharmaceutically acceptable inorganic or organic salt of the compound of the general formula (1). The compounds of the present invention may contain one or more asymmetric centers (chiral centers or axial chirality), and therefore appear in the form of racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers. The asymmetric center that may exist depends on the properties of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures as well as pure or partially pure compounds are included within the scope of the present invention. The present invention is meant to include all such isomeric forms of these compounds.

The terms "compound", "composition", "agent" or "medicine or medicament" are used interchangeably herein and refer to a compound or composition that, when administered to a subject (human or animal), is capable of inducing a desired pharmaceutical and/or physiological response through local and/or systemic action.

The term "administered,""administering," or "administration" as used herein refers to directly administering the compound or composition, or administering a prodrug, derivative, or analog of the active compound.

Although the numerical ranges and parameters used to define the broader scope of the present invention are approximate values, the relevant numerical values in the specific embodiments have been presented as accurately as possible. However, any numerical value inherently inevitably contains standard deviations due to individual test methods. Here, "about" generally means that the actual value is within plus or minus 10%, 5%, 1% or 0.5% of a specific value or range. Alternatively, the term "about" means that the actual value falls within the acceptable standard error of the mean value, depending on the consideration of those skilled in the art. Except for the experimental examples, or unless otherwise explicitly stated, it is understood that all ranges, quantities, values and percentages used herein (for example, to describe the amount of material, the length of time, temperature, operating conditions, quantitative ratios and the like) are modified by "about". Therefore, unless otherwise stated to the contrary, the numerical parameters disclosed in this specification and the attached claims are all approximate values and can be changed as needed. At least these numerical parameters should be understood as the number of significant digits indicated and the values obtained using the general rounding method.

Unless otherwise defined in this specification, the meanings of scientific and technical terms used herein are the same as those commonly understood by those skilled in the art. In addition, singular nouns used in this specification include plural forms of the nouns, and plural nouns used also include singular forms of the nouns, unless they conflict with the context.

Therapeutic Uses

The compounds or compositions described herein are generally useful for inhibiting ULK1 and/or ULK2 kinases, and are therefore useful for treating one or more conditions associated with ULK1 and/or ULK2 kinase activity. Therefore, in certain embodiments, the invention provides methods for treating conditions mediated by ULK1 and/or ULK2 kinases, comprising the step of administering a compound of the invention, or a pharmaceutically acceptable composition thereof, to a patient in need thereof (e.g., cancer).

In some embodiments, a method for treating cancer is provided, comprising administering to an individual in need thereof an effective amount of any of the aforementioned pharmaceutical compositions comprising a compound of formula (1). In some embodiments, the cancer is mediated by ULK1 and/or ULK2 kinases. In other embodiments, the cancer is a blood cancer and a solid tumor, including but not limited to leukemia, breast cancer, lung cancer, pancreatic cancer, colon cancer, bladder cancer, brain cancer, urothelial cancer, prostate cancer, liver cancer, ovarian cancer, head and neck cancer, gastric cancer, mesothelioma, or all cancer metastases.

Route of administration

The compounds of the present invention and their pharmaceutically acceptable salts can be prepared into various preparations, which contain the compounds of the present invention or their pharmaceutically acceptable salts within the safe and effective amount range and pharmacologically acceptable excipients or carriers. The "safe and effective amount" means that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. The safe and effective amount of the compound is determined according to the specific circumstances such as the age, condition, and course of treatment of the subject.

"Pharmaceutically acceptable excipients or carriers" refer to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmacologically acceptable excipients or carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

The compounds of the present invention may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), or topically.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrators, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain a buffer.

Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microcapsules with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.

Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

Dosage forms for topical administration of the compounds of the invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds. When using a pharmaceutical composition, a safe and effective amount of the compounds of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill range of a skilled physician.

The above features mentioned in the present invention or the features mentioned in the embodiments can be combined in any way. All the features disclosed in the specification of this case can be used in any combination form, and each feature disclosed in the specification can be replaced by any alternative feature that can provide the same, equal or similar purpose. Therefore, unless otherwise specified, the disclosed features are only general examples of equal or similar features.

Detailed ways

In the following description, each specific aspect, characteristic and advantage of the above-mentioned compounds, methods and pharmaceutical compositions will be described in detail to make the content of the present invention become very clear. It should be understood that the following detailed description and examples describe specific embodiments and are only for reference. After reading the description of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent situations also fall within the scope defined by the application.

In all the examples, ¹ H-NMR was recorded by Varian Mercury 400 nuclear magnetic resonance instrument, and chemical shift was expressed in δ (ppm); silica gel used for separation was 200-300 mesh unless otherwise specified, and the ratio of eluent was volume ratio.

The present invention uses the following abbreviations: AlCl ₃ represents aluminum chloride; (Boc) ₂ O represents di-tert-butyl dicarbonate; CDCl ₃ represents deuterated chloroform; CH ₃ NO ₂ represents nitromethane; EtOAc represents ethyl acetate; Hex represents n-hexane; HPLC represents high performance liquid chromatography; ACN represents acetonitrile; DCE represents 1,2-dichloroethane; DCM represents dichloromethane; DIPEA represents diisopropylethylamine; 1,4-Dioxane represents 1,4-dioxane; DMF represents N,N-dimethylformamide; DMAP represents 4-(dimethylamino)pyridine; DMSO represents dimethyl sulfoxide; HATU represents O-(7-azabenzotriazol-1-yl)-NNN′N′-tetramethyluronium hexafluorophosphate; IPA represents isopropyl alcohol; min represents minutes; K ₂ CO ₃ represents potassium carbonate; KOAc represents potassium acetate; MeOH represents methanol; MS represents mass spectrometry; LC-MS represents liquid chromatography-mass spectrometry; NMR represents nuclear magnetic resonance; Pd/C represents palladium on carbon; POCl ₃ represents phosphorus oxychloride; TEA represents triethylamine; TFA represents trifluoroacetic acid; m-CPBA represents meta-chloroperbenzoic acid; and TLC represents thin layer chromatography.

Example 1 Preparation of N-(3-((2-((2-cyclopropyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenylamino-5-(trifluoromethylpyrimidin-4-yl)aminopropylcyclobutanecarbonylamide (1)

Step 1: Synthesis of compound int1_2

Int1_1 (500 mg, 2.19 mmol) and tert-butyl carbamate (457 mg, 2.62 mmol) were placed in a 250 mL round-bottom flask, IPA (20 mL) was added to dissolve, DIPEA (1.12 g, 8.75 mmol) was added and reacted at room temperature for 1 hour. The reaction was completed by LC-MS detection, and the solvent was removed by concentration under reduced pressure to obtain int1_2 (810 mg, yield 100%) which was directly used in the next step reaction.

ESI-MS m/z: 367 [M+H] ⁺ .

Step 2: Synthesis of compound int1_3

Int1_2 (810 mg, 2.19 mmol) was placed in a 250 mL round-bottom flask, DCM (10 mL) was added to dissolve, and TFA (7 mL) was added to react at room temperature for 1 hour. The reaction was completed by LC-MS. The solvent was removed by concentration under reduced pressure to obtain a crude product which was directly used in the next step.

ESI-MS m/z: 267 [M+H] ⁺ .

Step 3: Synthesis of compound int1_4

The crude product of int1_3 was added to TEA, the pH value was adjusted to 10-11, and cyclobutane acyl chloride (354 mg, 2.99 mmol) was added to react at room temperature for 0.5 hours. The reaction was completed by LC-MS. The reaction was analyzed by rapid preparative liquid chromatography (120 g C-18 Flash Column, ACN/1‰ TFA aqueous solution) was purified to give int1_4 (342 mg, yield 35.7%).

ESI-MS m/z: 349 [M+H] ⁺ .

Step 4: Synthesis of compound int1_5

Int1_4 (60 mg, 172 μmol) was placed in a 250 mL round-bottom flask, DCM (4 mL) was added to dissolve, and then m-CPBA (45 mg, 258 μmol) was added to react at room temperature for 0.5 hours. The reaction was completed by LC-MS. The reaction solution was filtered, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent to obtain int1_5 (62 mg, yield: 98.8%) for the next step reaction.

ESI-MS m/z: 365 [M+H] ⁺ .

Step 4: Synthesis of compound int1_8

Int1_6 (2.0 g, 9.1 mmol) and int1_7 (3.0 g, 13.6 mmol) were placed in a 250 mL round-bottom flask, and DMF (20 mL) was added to dissolve, and potassium carbonate (3.86 g, 29.6 mmol) was added to react at room temperature overnight. The reaction was complete by LC-MS. The reaction solution was stirred with water, and the filter cake was filtered and dried to obtain int1_8 (3.5 g, yield 100%) for the next step reaction.

ESI-MS m/z: 383 [M+H] ⁺ .

Step 5: Synthesis of compound int1_9

Int1_8 (667 mg, 1.74 mmol) and cyclopropylboronic acid (450 mg, 5.27 mmol) were placed in a 250 mL round-bottom flask, 1,4-dioxane (10 mL) was added to dissolve, and potassium carbonate (552 mg, 4.00 mmol) and dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium (127.7 mg, 174 μmol) were added, and the mixture was heated to 90°C under argon protection and reacted overnight. The reaction was completed by LC-MS. After concentration under reduced pressure, the residue was purified by rapid liquid preparative chromatography (120 g C-18 Flash Column, ACN/1‰ TFA aqueous solution) was purified to give int1_9 (50 mg, yield 8.3%).

ESI-MS m/z: 345 [M+H] ⁺ .

Step 6: Synthesis of compound int1_10

Int1_9 (50 mg, 145 μmol) was placed in a 100 mL round-bottom flask, methanol (5 mL) was added to dissolve, acetic acid (0.4 mL) and zinc powder (400 mg) were added to react at room temperature for 0.5 hours, and the reaction was completed by LC-MS. The reaction solution was added with a saturated sodium bicarbonate solution to adjust the pH value to 7-8, filtered, and the filtrate was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. Int1_10 (46 mg, yield 92%) was obtained by concentration under reduced pressure.

ESI-MS m/z: 315 [M+H] ⁺ .

Step 7: Preparation of N-(3-((2-((2-cyclopropyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenylamino-5-(trifluoromethylpyrimidin-4-yl)aminopropylcyclobutanecarbonylamide (1)

Int1_5 (63 mg, 172 μmol) was dissolved in DMF (5 mL), int1_10 (54 mg, 172 μmol) was added, and then TFA (88 mg, 774 μmol) was reacted at 80 °C for 6 h under argon protection. The reaction was completed by LC-MS. The reaction solution was directly subjected to rapid liquid preparative chromatography (120 g C-18 Flash Column, ACN/10 nM aqueous ammonium bicarbonate solution) to obtain compound 1 (12.8 mg, yield 11.2%).

ESI-MS m/z: 616 [M+H] ⁺ .

Example 2 Preparation of N-(3-((2-((2-ethyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl))amino)propyl)cyclobutanecarboxamide (2)

Step 1: Synthesis of compound int2_1

Int1_8 (382 mg, 1.00 mmol) and potassium trifluoroborate (268 mg, 2.00 mmol) were placed in a 100 mL round-bottom flask, 1,4-dioxane (10 mL) and water (2 mL) were added to dissolve, and potassium carbonate (553 mg, 4.00 mmol) and dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium (78 mg, 100 μmol) were added, and the mixture was heated to 90°C under argon protection and reacted overnight. The reaction was completed by LC-MS. After concentration under reduced pressure, the residue was purified by rapid liquid preparative chromatography (120 g C-18 Flash Column, ACN/1‰ TFA aqueous solution) to obtain int2_1 (88 mg, yield 26.7%).

ESI-MS m/z: 331 [M+H] ⁺ .

Step 2: Synthesis of compound int2_2

Int2_1 (88 mg, 267 μmol) was placed in a 50 mL round-bottom flask, methanol (5 mL) was added to dissolve, and palladium carbon (10%, 20 mg) was added to react at room temperature for 2 hours under a hydrogen atmosphere. The reaction was completed by LC-MS. The reaction solution was filtered and the residue was washed with methanol. The filtrate was concentrated under reduced pressure to obtain int2_2 (78 mg, yield 96.7%).

ESI-MS m/z: 303 [M+H] ⁺ .

Step 3: Preparation of N-(3-((2-((2-ethyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl))amino)propyl)cyclobutanecarboxamide (2)

Int1_5 (94 mg, 258 μmol) was dissolved in DMF (5 mL), int2_2 (78 mg, 258 μmol) was added, and then TFA (88 mg, 774 μmol) was added dropwise. The mixture was reacted at 80 °C for 6 h under argon protection. The reaction was completed by LC-MS. The reaction solution was directly purified by rapid preparative liquid chromatography (120 g C-18 Flash Column, ACN/10 nM aqueous ammonium bicarbonate solution) to obtain compound 2 (17.1 mg, yield 11.0%).

ESI-MS m/z: 603 [M+H] ⁺ .

Example 3 Preparation of N-(3-((2-((2-isopropyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl))amino)propyl)cyclobutanecarboxamide (3)

Step 1: Synthesis of compound int3_1

Int1_8 (382 mg, 1.00 mmol) and isopropenylboronic acid pinacol ester (336 mg, 2.00 mmol) were placed in a 100 mL round-bottom flask, 1,4-dioxane (10 mL) and water (2 mL) were added to dissolve, and potassium carbonate (553 mg, 4.00 mmol) and dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium (78 mg, 100 μmol) were added, and the mixture was heated to 90 ° C under argon protection and reacted overnight. The reaction was completed by LC-MS. After concentration under reduced pressure, the residue was purified by rapid liquid preparative chromatography (120 g C-18 Flash Column, ACN/1‰ TFA aqueous solution) was purified to obtain int3_1 (104 mg, yield 30.1%).

ESI-MS m/z: 331 [M+H] ⁺ .

Step 2: Synthesis of compound int3_2

Int3_1 (104 mg, 301 μmol) was placed in a 50 mL round-bottom flask, methanol (5 mL) was added to dissolve, and palladium carbon (10%, 50 mg) was added to react at room temperature for 2 hours under a hydrogen atmosphere. The reaction was completed by LC-MS. The reaction solution was filtered and the filter residue was washed with methanol. The filtrate was concentrated under reduced pressure to obtain int3_2 (81 mg, yield 85.0%).

ESI-MS m/z: 317 [M+H] ⁺ .

Step 3: Preparation of N-(3-((2-((2-isopropyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl))amino)propyl)cyclobutanecarboxamide (3)

Int1_5 (93 mg, 256 μmol) was dissolved in DMF (5 mL), int3_2 (81 mg, 256 μmol) was added, and then TFA (88 mg, 768 μmol) was added dropwise. The mixture was reacted at 80 °C for 6 h under argon protection. The reaction was completed by LC-MS. The reaction solution was directly purified by rapid preparative liquid chromatography (120 g C-18 Flash Column, ACN/10 nM aqueous ammonium bicarbonate solution) to obtain compound 3 (22.0 mg, yield 13.8%).

ESI-MS m/z: 617 [M+H] ⁺ .

Example 4 Preparation of N-(3-((2-((2-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl))amino)propyl)cyclobutanecarboxamide (4)

Step 1: Synthesis of compound int4_1

Int1_8 (382 mg, 1.00 mmol) and potassium methyl trifluoroborate (244 mg, 2.00 mmol) were placed in a 100 mL round-bottom flask. 1,4-dioxane (10 mL) and water (2 mL) were added to dissolve, and then potassium carbonate (553 mg, 4.00 mmol) and dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium (78 mg, 100 μmol) were added. The mixture was heated to 90°C under argon protection and reacted overnight. The reaction was completed by LC-MS. After concentration under reduced pressure, the residue was purified by rapid liquid preparative chromatography (120 g C-18 Flash Column, ACN/1‰ TFA aqueous solution) to obtain int4_1 (77 mg, yield 24.2%).

ESI-MS m/z: 319 [M+H] ⁺ .

Step 2: Synthesis of compound int4_2

Int4_1 (77 mg, 242 μmol) was placed in a 100 mL round-bottom flask, methanol (5 mL) was added to dissolve, acetic acid (0.4 mL) and zinc powder (400 mg) were added to react at room temperature for 0.5 hours, and the reaction was completed by LC-MS. The reaction solution was added with a saturated sodium bicarbonate solution to adjust the pH value to 7-8, filtered, and the filtrate was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. Int4_2 (69 mg, yield 98.8%) was obtained by concentration under reduced pressure.

ESI-MS m/z: 289 [M+H] ⁺ .

Step 3: Preparation of N-(3-((2-((2-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl))amino)propyl)cyclobutanecarboxamide (4)

Int1_5 (87 mg, 239 μmol) was dissolved in DMF (5 mL), int4_2 (88 mg, 239 μmol) was added, and then TFA (81 mg, 717 μmol) was added dropwise. The mixture was reacted at 80 °C for 6 h under argon protection. The reaction was completed by LC-MS. The reaction solution was directly purified by rapid preparative liquid chromatography (120 g C-18 Flash Column, ACN/10 nM aqueous ammonium bicarbonate solution) to obtain compound 4 (9.5 mg, yield 6.8%).

ESI-MS m/z: 589 [M+H] ⁺ .

Example 5 Preparation of N-(3-((2-((2-cyclobutyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl))amino)propyl)cyclobutanecarboxamide (5)

Step 1: Synthesis of compound int5_1

Int1_8 (382 mg, 1.00 mmol) and cyclobutylboronic acid pinacol ester (364 mg, 2.00 mmol) were placed in a 100 mL round-bottom flask, 1,4-dioxane (10 mL) and water (2 mL) were added to dissolve, and potassium carbonate (553 mg, 4.00 mmol) and dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium (78 mg, 100 μmol) were added, and the mixture was heated to 90 ° C under argon protection and reacted overnight. The reaction was completed by LC-MS. After concentration under reduced pressure, the residue was purified by rapid liquid preparative chromatography (120 g C-18 Flash Column, ACN/1‰ TFA aqueous solution) to obtain int5_1 (105 mg, yield 29.3%).

ESI-MS m/z: 319 [M+H] ⁺ .

Step 2: Synthesis of compound int5_2

Int5_1 (77 mg, 242 μmol) was placed in a 100 mL round-bottom flask, methanol (5 mL) was added to dissolve, acetic acid (0.4 mL) and zinc powder (400 mg) were added to react at room temperature for 0.5 hours, and the reaction was completed by LC-MS. The reaction solution was added with a saturated sodium bicarbonate solution to adjust the pH value to 7-8, filtered, and the filtrate was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. Int5_2 (61 mg, yield 76.7%) was obtained by concentration under reduced pressure.

ESI-MS m/z: 329 [M+H] ⁺ .

Step 3: Preparation of N-(3-((2-((2-cyclobutyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl))amino)propyl)cyclobutanecarboxamide (5)

Int1_5 (68 mg, 186 μmol) was dissolved in DMF (5 mL), int5_2 (61 mg, 186 μmol) was added, and then TFA (64 mg, 558 μmol) was added dropwise. The mixture was reacted at 80 °C for 6 h under argon protection. The reaction was completed by LC-MS. The reaction solution was directly purified by rapid preparative liquid chromatography (120 g C-18 Flash Column, ACN/10 nM aqueous ammonium bicarbonate solution) to obtain compound 5 (10.2 mg, yield 8.7%).

ESI-MS m/z: 629 [M+H] ⁺ .

Example 6 Preparation of N-(3-((2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl))amino)propyl)cyclobutanecarboxamide (7)

Step 1: Preparation of N-(3-((2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl))amino)propyl)cyclobutanecarboxamide (7)

Int1_5 (182 mg, 500 μmol) was dissolved in DMF (5 mL), int6_1 (152 mg, 500 μmol) was added, and then TFA (171 mg, 1.5 mmol) was added dropwise. The mixture was reacted at 80 °C for 6 h under argon protection. The reaction was completed by LC-MS. The reaction solution was directly purified by rapid preparative liquid chromatography (120 g C-18 Flash Column, ACN/10 nM aqueous ammonium bicarbonate solution) to obtain compound 7 (55.9 mg, yield 18.5%).

ESI-MS m/z: 605 [M+H] ⁺ .

Example 7 Preparation of N-(3-((2-((4-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin)-4-yl)amino)propyl)cyclobutanecarboxamide (12)

Step 1: Synthesis of compound int7_2

Int7_1 (338 mg, 1.00 mmol) and potassium methyl trifluoroborate (134 mg, 1.1 mmol) were placed in a 100 mL round-bottom flask, 1,4-dioxane (10 mL) and water (2 mL) were added to dissolve, and potassium carbonate (553 mg, 4.00 mmol) and dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium (78 mg, 100 μmol) were added, and the mixture was heated to 80 °C under argon protection for 1.0 hour. The reaction was completed by LC-MS. Ethyl acetate was added to the reaction solution, and the mixture was washed with saturated brine three times. The organic phase was dried over anhydrous sodium sulfate. After the solvent was removed by concentration under reduced pressure, the residue was purified by normal phase chromatography (silica gel chromatography, PE/EA) to obtain int7_2 (155 mg, yield 64.0%).

ESI-MS m/z: 243 [M+H] ⁺ .

Step 2: Synthesis of compound int7_3

Int1_6 (141 mg, 768 μmol) and int7_2 (155 mg, 640 μmol) were placed in a 25 mL round-bottom flask, and DMF (5 mL) was added to dissolve them. After that, triethylamine (194 mg, 1.92 mmol) was added and reacted at 90 ° C for 3 hours. The reaction was complete by LC-MS. The reaction solution was stirred with water, and the filter cake was filtered and dried to obtain int7_3 (249 mg, yield 100%) for the next step reaction.

ESI-MS m/z: 390 [M+H] ⁺ .

Step 3: Synthesis of compound int7_4

Int7_3 (249 mg, 640 μmol) was added to a solution of DCM (4 mL) and TFA (1 mL) and stirred at room temperature for 2 hours. The reaction was completed by LC-MS. Saturated sodium bicarbonate solution was added to the reaction solution to adjust the pH to 7-8, and ethyl acetate was added to extract 3 times. The organic phase was dried over anhydrous sodium sulfate. After concentrated under reduced pressure to remove the solvent, int7_4 (180 mg, yield 97.3%) was directly used in the next step.

ESI-MS m/z: 290 [M+H] ⁺ .

Step 4: Preparation of N-(3-((2-((4-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin)-4-yl)amino)propyl)cyclobutanecarboxamide (12)

Int1_5 (126 mg, 345 μmol) was dissolved in DMF (5 mL), and int7_4 (100 mg, 345 μmol) was added, followed by dropwise addition of TFA (118 mg, 1035 μmol). The mixture was reacted at 80 °C for 6 h under argon protection. The reaction was completed by LC-MS. The reaction solution was directly purified by rapid preparative liquid chromatography (120 g C-18 Flash Column, ACN/10 nM aqueous ammonium bicarbonate solution) to give compound 12 (33.1 mg, yield 16.3%).

ESI-MS m/z: 590 [M+H] ⁺ .

Example 8 Preparation of N-(3-((2-((4-ethyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin)-4-yl)amino)propyl)cyclobutanecarboxamide (13)

Step 1: Synthesis of compound int8_2

Int7_1 (338 mg, 1.00 mmol) and potassium ethyl trifluoroborate (148 mg, 1.1 mmol) were placed in a 100 mL round-bottom flask, 1,4-dioxane (10 mL) and water (2 mL) were added to dissolve, and potassium carbonate (553 mg, 4.00 mmol) and dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium (78 mg, 100 μmol) were added, and the mixture was heated to 80 °C under argon protection for 1.0 hour. The reaction was completed by LC-MS. Ethyl acetate was added to the reaction solution, and the mixture was washed with saturated brine three times. The organic phase was dried over anhydrous sodium sulfate. After the solvent was removed by concentration under reduced pressure, the residue was purified by normal phase chromatography (silica gel chromatography, PE/EA) to obtain int8_2 (199 mg, yield 77.5%).

ESI-MS m/z: 257 [M+H] ⁺ .

Step 2: Synthesis of compound int8_3

Int1_6 (170 mg, 930 μmol) and int8_2 (199 mg, 775 μmol) were placed in a 25 mL round bottom flask and DMF (5 After dissolving in 5% paraformaldehyde (200 mL), triethylamine (234 mg, 2.32 mmol) was added and reacted at 90°C for 3 hours. The reaction was complete as detected by LC-MS. The reaction solution was stirred with water, and the filter cake was filtered and dried to obtain int8_3 (309 mg, yield 98.9%) for the next step reaction.

ESI-MS m/z: 404 [M+H] ⁺ .

Step 3: Synthesis of compound int8_4

Int8_3 (309 mg, 767 μmol) was added to a solution of DCM (10 mL) and TFA (2 mL) and stirred at room temperature for 2 hours. The reaction was completed by LC-MS. Saturated sodium bicarbonate solution was added to the reaction solution to adjust the pH to 7-8, and ethyl acetate was added to extract 3 times. The organic phase was dried over anhydrous sodium sulfate. After the solvent was removed by concentration under reduced pressure, int8_4 (231 mg, yield 99.1%) was obtained and used directly in the next step.

ESI-MS m/z: 304 [M+H] ⁺ .

Step 4: Preparation of N-(3-((2-((4-ethyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin)-4-yl)amino)propyl)cyclobutanecarboxamide (13)

Int1_5 (78 mg, 215 μmol) was dissolved in DMF (5 mL), int8_4 (130 mg, 215 μmol) was added, and then TFA (74 mg, 645 μmol) was added dropwise. The mixture was reacted at 80 °C for 6 h under argon protection. The reaction was completed by LC-MS. The reaction solution was directly purified by rapid preparative liquid chromatography (120 g C-18 Flash Column, ACN/10 nM aqueous ammonium bicarbonate solution) to give compound 13 (21.7 mg, yield 16.7%).

ESI-MS m/z: 604 [M+H] ⁺ .

Example 9 Preparation of N-(3-((2-((4-cyclopropyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin)-4-yl)amino)propyl)cyclobutanecarboxamide (14)

Step 1: Synthesis of compound int9_2

Int7_1 (338 mg, 1.00 mmol) and isopropylboric acid (97 mg, 1.1 mmol) were placed in a 100 mL round-bottom flask, 1,4-dioxane (10 mL) and water (2 mL) were added to dissolve, and potassium carbonate (553 mg, 4.00 mmol) and dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium (78 mg, 100 μmol) were added, and the mixture was heated to 80 ° C under argon protection for 1.0 hour. The reaction was completed by LC-MS. Ethyl acetate was added to the reaction solution, and the mixture was washed with saturated brine three times. The organic phase was dried over anhydrous sodium sulfate. After the solvent was removed by concentration under reduced pressure, the residue was purified by normal phase chromatography (silica gel chromatography, PE/EA) to obtain int9_2 (104 mg, yield 38.4%).

ESI-MS m/z: 271 [M+H] ⁺ .

Step 2: Synthesis of compound int9_3

Int1_6 (84 mg, 461 μmol) and int9_2 (104 mg, 384 μmol) were placed in a 25 mL round-bottom flask, and DMF (5 mL) was added to dissolve, and triethylamine (116 mg, 1.15 mmol) was added to react at 90 ° C for 3 hours. The reaction was complete by LC-MS. The reaction solution was stirred with water, and the filter cake was filtered and dried to obtain int9_3 (160 mg, yield 100%) for the next step reaction.

ESI-MS m/z: 418 [M+H] ⁺ .

Step 3: Synthesis of compound int9_4

Int9_3 (160 mg, 384 μmol) was added to a solution of DCM (5 mL) and TFA (1 mL) and stirred at room temperature for 2 hours. The reaction was completed by LC-MS. Saturated sodium bicarbonate solution was added to the reaction solution to adjust the pH to 7-8, and ethyl acetate was added to extract 3 times. The organic phase was dried over anhydrous sodium sulfate. After concentrated under reduced pressure to remove the solvent, int9_4 (114 mg, yield 93.7%) was directly used in the next step.

ESI-MS m/z: 318 [M+H] ⁺ .

Step 4: Preparation of N-(3-((2-((4-isopropyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin)-4-yl)amino)propyl)cyclobutanecarboxamide (14)

Int1_5 (131 mg, 360 μmol) was dissolved in DMF (5 mL), int9_4 (114 mg, 360 μmol) was added, and then TFA (123 mg, 1080 μmol) was added dropwise. The mixture was reacted at 80 °C for 6 h under argon protection. The reaction was completed by LC-MS. The reaction solution was directly purified by rapid preparative liquid chromatography (120 g C-18 Flash Column, ACN/10 nM aqueous ammonium bicarbonate solution) to give compound 14 (39.0 mg, yield 17.5%).

ESI-MS m/z: 618 [M+H] ⁺ .

Example 10 Preparation of N-(3-((2-((4-cyclopropyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin)-4-yl)amino)propyl)cyclobutanecarboxamide (15)

Step 1: Synthesis of compound int10_2

Int7_1 (338 mg, 1.00 mmol) and cyclopropylboronic acid (95 mg, 1.1 mmol) were placed in a 100 mL round-bottom flask, 1,4-dioxane (10 mL) and water (2 mL) were added to dissolve, and potassium carbonate (553 mg, 4.00 mmol) and dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium (78 mg, 100 μmol) were added, and the mixture was heated to 80 ° C under argon protection for 1.0 hour. The reaction was completed by LC-MS. Ethyl acetate was added to the reaction solution, and the mixture was washed with saturated brine three times. The organic phase was dried over anhydrous sodium sulfate. After the solvent was removed by concentration under reduced pressure, the residue was purified by normal phase chromatography (silica gel chromatography, PE/EA) to obtain int10_2 (98 mg, yield 36.5%).

ESI-MS m/z: 269 [M+H] ⁺ .

Step 2: Synthesis of compound int10_3

Place int1_6 (80 mg, 438 μmol) and int10_2 (98 mg, 365 μmol) in a 25 mL round-bottom flask and add DMF (5 mL). After dissolution, triethylamine (111 mg, 1.09 mmol) was added and reacted at 90°C for 3 hours. The reaction was complete by LC-MS. Water was added to the reaction solution and stirred, and the filter cake was filtered and dried to obtain int10_3 (138 mg, yield 90.8%) for the next reaction.

ESI-MS m/z: 416 [M+H] ⁺ .

Step 3: Synthesis of compound int10_4

Int10_3 (138 mg, 331 μmol) was added to a solution of DCM (5 mL) and TFA (1 mL) and stirred at room temperature for 2 hours. The reaction was completed by LC-MS. Saturated sodium bicarbonate solution was added to the reaction solution to adjust the pH to 7-8, and ethyl acetate was added to extract 3 times. The organic phase was dried over anhydrous sodium sulfate. After concentrated under reduced pressure to remove the solvent, int10_4 (97 mg, yield 92.9%) was directly used in the next step.

ESI-MS m/z: 316 [M+H] ⁺ .

Step 4: Preparation of N-(3-((2-((4-cyclopropyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin)-4-yl)amino)propyl)cyclobutanecarboxamide (15)

Int1_5 (112 mg, 307 μmol) was dissolved in DMF (5 mL), int10_4 (97 mg, 307 μmol) was added, and then TFA (105 mg, 921 μmol) was added dropwise. The mixture was reacted at 80 °C for 6 h under argon protection. The reaction was completed by LC-MS. The reaction solution was directly purified by rapid preparative liquid chromatography (120 g C-18 Flash Column, ACN/10 nM aqueous ammonium bicarbonate solution) to give compound 15 (10.4 mg, yield 5.5%).

ESI-MS m/z: 616 [M+H] ⁺ .

Example 11 Preparation of N-(3-((2-((4-cyclobutyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin)-4-yl)amino)propyl)cyclobutanecarboxamide (16)

Step 1: Synthesis of compound int11_2

Int7_1 (338 mg, 1.00 mmol) and cyclobutylboronic acid pinacol ester (200 mg, 1.1 mmol) were placed in a 100 mL round-bottom flask, 1,4-dioxane (10 mL) and water (2 mL) were added to dissolve, and potassium carbonate (553 mg, 4.00 mmol) and dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium (78 mg, 100 μmol) were added, and the mixture was heated to 80 ° C under argon protection for 1.0 hour. The reaction was completed by LC-MS. Ethyl acetate was added to the reaction solution, and the mixture was washed with saturated brine three times, and the organic phase was dried over anhydrous sodium sulfate. After the solvent was removed by concentration under reduced pressure, the residue was purified by normal phase chromatography (silica gel chromatography, PE/EA) to obtain int11_2 (105 mg, yield 37.4%).

ESI-MS m/z: 283 [M+H] ⁺ .

Step 2: Synthesis of compound int11_3

Int1_6 (82 mg, 449 μmol) and int11_2 (105 mg, 374 μmol) were placed in a 25 mL round-bottom flask, and DMF (5 mL) was added to dissolve them. After that, triethylamine (113 mg, 1.12 mmol) was added and reacted at 90 ° C for 3 hours. The reaction was complete by LC-MS. The reaction solution was stirred with water, and the filter cake was filtered and dried to obtain int11_3 (152 mg, yield 94.5%) for the next step reaction.

ESI-MS m/z: 430 [M+H] ⁺ .

Step 3: Synthesis of compound int11_4

Int10_3 (152 mg, 353 μmol) was added to a solution of DCM (5 mL) and TFA (1 mL) and stirred at room temperature for 2 hours. The reaction was completed by LC-MS. Saturated sodium bicarbonate solution was added to the reaction solution to adjust the pH to 7-8, and ethyl acetate was added to extract 3 times. The organic phase was dried over anhydrous sodium sulfate. After the solvent was removed by concentration under reduced pressure, int11_4 (113 mg, yield 97.0%) was obtained and used directly in the next step.

ESI-MS m/z: 330 [M+H] ⁺ .

Step 4: Preparation of N-(3-((2-((4-cyclobutyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin)-4-yl)amino)propyl)cyclobutanecarboxamide (16)

Int1_5 (125 mg, 342 μmol) was dissolved in DMF (5 mL), int11_4 (113 mg, 342 μmol) was added, and then TFA (117 mg, 1026 μmol) was added dropwise. The mixture was reacted at 80 °C for 6 h under argon protection. The reaction was completed by LC-MS. The reaction solution was directly purified by rapid preparative liquid chromatography (120 g C-18 Flash Column, ACN/10 nM aqueous ammonium bicarbonate solution) to give compound 16 (18.6 mg, yield 8.6%).

ESI-MS m/z: 630 [M+H] ⁺ .

Example 12 Preparation of N-(3-((2-((4-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin)-4-yl)amino)propyl)cyclobutanecarboxamide (18)

Step 1: Synthesis of compound int12_2

Int1_6 (220 mg, 1200 μmol) and int12_1 (188 mg, 1000 μmol) were placed in a 25 mL round-bottom flask, and DMF (5 mL) was added to dissolve them. After that, triethylamine (303 mg, 3.00 mmol) was added and reacted at 90 ° C for 3 hours. The reaction was complete by LC-MS. The reaction solution was stirred with water, and the filter cake was filtered and dried to obtain int11_3 (307 mg, yield 91.6%) for the next step reaction.

ESI-MS m/z: 336 [M+H] ⁺ .

Step 2: Synthesis of compound int12_3

Int12_3 (307 mg, 916 μmol) was placed in a 50 mL round-bottom flask, methanol (15 mL) was added to dissolve, and palladium carbon (10%, 50mg) was reacted at room temperature under hydrogen atmosphere for 2 hours, and the reaction was completed by LC-MS. The reaction solution was filtered and the filter residue was washed with methanol. The filtrate was concentrated under reduced pressure to obtain int12_3 (206mg, yield 73.6%).

ESI-MS m/z: 306 [M+H] ⁺ .

Step 3: Preparation of N-(3-((2-((4-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin)-4-yl)amino)propyl)cyclobutanecarboxamide (18)

Int1_5 (119 mg, 327 μmol) was dissolved in DMF (5 mL), int12_3 (100 mg, 327 μmol) was added, and then TFA (112 mg, 981 μmol) was added dropwise. The mixture was reacted at 80 °C for 6 h under argon protection. The reaction was completed by LC-MS. The reaction solution was directly purified by rapid preparative liquid chromatography (120 g C-18 Flash Column, ACN/10 nM aqueous ammonium bicarbonate solution) to give compound 16 (19.9 mg, yield 10.0%).

ESI-MS m/z: 606 [M+H] ⁺ .

Example 13 Preparation of N-(3-((2-((2-cyclopropyl-4-(4-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl))piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide (24)

Step 1: Synthesis of compound int13_2

Int13_1 (286 mg, 2.0 mmol) and int1_7 (440 mg, 2.0 mmol) were placed in a 100 mL round-bottom flask, and DMF (10 mL) was added to dissolve them. Potassium carbonate (829 mg, 6.0 mmol) was added and reacted at room temperature overnight. The reaction was complete by LC-MS. The reaction solution was stirred with water, and the filter cake was filtered and dried to obtain int13_2 (680 mg, yield 99.1%) for the next step reaction.

ESI-MS m/z: 344 [M+H] ⁺ .

Step 2: Synthesis of compound int13_3

Int13_2 (680 mg, 1.98 mmol) was placed in a 100 mL round-bottom flask, 1,4-dioxane/hydrogen chloride solution (4 M, 10 mL) was added to dissolve, and then heated to 65 ° C under argon protection for 2 hours. The reaction was completed by LC-MS. Saturated sodium bicarbonate solution was added to the reaction solution to adjust the pH to 7-8, and the solvent was removed by concentration under reduced pressure. The residue was purified by rapid liquid preparative chromatography (120 g C-18 Flash Column, ACN/1‰ TFA aqueous solution) to obtain int13_3 (346 mg, yield 58.6%).

ESI-MS m/z: 299 [M+H] ⁺ .

Step 3: Synthesis of compound int13_5

Int13_3 (346 mg, 1161 μmol) was placed in a 100 mL round-bottom flask, and dichloroethane (10 mL) was added to dissolve it. Then, int13_4 (290 mg, 2.3 mmol) and a drop of acetic acid were added to react at room temperature for 0.5 hours. Then, sodium triacetoxyborohydride (738 mg, 3.48 mmol) was added to the reaction solution, and stirred at room temperature overnight. The reaction was complete by LC-MS. After the reaction solution was concentrated under reduced pressure to remove the solvent, the residue was purified by rapid liquid preparative chromatography (120 g C-18 Flash Column, ACN/1‰ TFA aqueous solution) to obtain int13_5 (299 mg, yield 63.0%).

ESI-MS m/z: 409 [M+H] ⁺ .

Step 4: Synthesis of compound int13_6

Int13_5 (299 mg, 730 μmol) and cyclopropylboronic acid (125 mg, 1.46 mmol) were placed in a 50 mL round-bottom flask, 1,4-dioxane (8 mL) and water (2 mL) were added to dissolve, and potassium carbonate (403 mg, 2.92 mmol) and dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium (50 mg, 73 μmol) were added, and the mixture was heated to 80 ° C under argon protection and reacted overnight. The reaction was completed by LC-MS. Ethyl acetate was added to the reaction solution, and the mixture was washed three times with saturated brine. The organic phase was dried over anhydrous sodium sulfate. After the solvent was removed by concentration under reduced pressure, the residue was purified by rapid liquid preparative chromatography (120 g C-18 Flash Column, ACN/1‰ TFA aqueous solution) to obtain int13_6 (114 mg, yield 42.1%).

ESI-MS m/z: 371 [M+H] ⁺ .

Step 5: Synthesis of compound int13_7

Int13_7 (114 mg, 308 μmol) was placed in a 50 mL round-bottom flask, methanol (5 mL) was added to dissolve, and palladium carbon (10%, 50 mg) was added to react at room temperature for 2 hours under a hydrogen atmosphere. The reaction was completed by LC-MS. The reaction solution was filtered and the residue was washed with methanol. The filtrate was concentrated under reduced pressure to obtain int13_7 (99 mg, yield 94.4%).

ESI-MS m/z: 341 [M+H] ⁺ .

Step 7: Preparation of N-(3-((2-((2-cyclopropyl-4-(4-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl))piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide (24)

Int1_5 (106 mg, 291 μmol) was dissolved in DMF (5 mL), int13_7 (99 mg, 291 μmol) was added, and then TFA (99 mg, 873 μmol) was added dropwise. The mixture was reacted at 80 °C for 6 h under argon protection. The reaction was completed by LC-MS. The reaction solution was directly purified by rapid preparative liquid chromatography (120 g C-18 Flash Column, ACN/10 nM aqueous ammonium bicarbonate solution) to obtain compound 1 (28.7 mg, yield 15.4%).

ESI-MS m/z: 641 [M+H] ⁺ .

Example 14 Preparation of N-(3-((5-bromo-2-((2-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino))propyl)cyclobutanecarboxamide (46)

Step 1: Synthesis of compound int14_2

Int14_1 (479 mg, 2.00 mmol) and tert-butyl carbamate (418 mg, 2.40 mmol) were placed in a 100 mL round-bottom flask, IPA (20 mL) was added to dissolve, and DIPEA (1.03 g, 8.00 mmol) was added to react at room temperature for 1 hour. The reaction was detected to be complete by LC-MS, and the solvent was removed by concentration under reduced pressure to obtain int14_2 (755 mg, yield 100%), which was directly used for the next step reaction.

ESI-MS m/z: 377 [M+H] ⁺ .

Step 2: Synthesis of compound int14_3

Int14_2 (755 mg, 2.00 mmol) was placed in a 250 mL round-bottom flask, DCM (10 mL) was added to dissolve, and TFA (7 mL) was added to react at room temperature for 1 hour. The reaction was completed by LC-MS. The solvent was removed by concentration under reduced pressure to obtain a crude product which was directly used in the next step.

ESI-MS m/z: 277 [M+H] ⁺ .

Step 3: Synthesis of compound int14_4

The crude product of int14_3 was added to TEA, the pH value was adjusted to 10-11, and cyclobutane acyl chloride (355 mg, 3.00 mmol) was added to react at room temperature for 0.5 hours. The reaction was completed by LC-MS. The reaction was analyzed by rapid preparative liquid chromatography (120 g C-18 Flash Column, ACN/1‰ TFA aqueous solution) to obtain int14_4 (318 mg, yield 44.2%).

ESI-MS m/z: 359 [M+H] ⁺ .

Step 4: Synthesis of compound int1_5

Int14_4 (100 mg, 278 μmol) was placed in a 50 mL round-bottom flask, DCM (4 mL) was added to dissolve, and then m-CPBA (85 mg, 417 μmol) was added to react at room temperature for 0.5 hours. The reaction was completed by LC-MS. The reaction solution was filtered, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent to obtain int14_5 (97 mg, yield 92.9%) for the next step reaction.

ESI-MS m/z: 375 [M+H] ⁺ .

Step 5: Preparation of N-(3-((5-bromo-2-((2-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino))propyl)cyclobutanecarboxamide (46)

Int14_5 (97 mg, 258 μmol) was dissolved in DMF (5 mL), int4_2 (74 mg, 258 μmol) was added, and then TFA (88 mg, 774 μmol) was added dropwise. The mixture was reacted at 80 °C for 6 h under argon protection. The reaction was completed by LC-MS. The reaction solution was directly purified by rapid preparative liquid chromatography (120 g C-18 Flash Column, ACN/10 nM aqueous ammonium bicarbonate solution) to give compound 46 (12.3 mg, yield 8.0%).

ESI-MS m/z: 599 [M+H] ⁺ .

Example 15 Preparation of N-(3-((5-bromo-2-((2-ethyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino))propyl)cyclobutanecarboxamide (47)

Step 1: Preparation of N-(3-((5-bromo-2-((2-ethyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino))propyl)cyclobutanecarboxamide (47)

Int14_5 (100 mg, 266 μmol) was dissolved in DMF (5 mL), int2_2 (81 mg, 266 μmol) was added, and TFA (91 mg, 799 μmol) was added dropwise. The mixture was reacted at 80 °C for 6 h under argon protection. The reaction was completed by LC-MS. The reaction solution was directly purified by rapid preparative liquid chromatography (120 g C-18 Flash Column, ACN/10 nM aqueous ammonium bicarbonate solution) to give compound 47 (20.0 mg, yield 12.2%).

ESI-MS m/z: 613 [M+H] ⁺ .

Example 16 Preparation of N-(3-((5-bromo-2-((2-isopropyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino))propyl)cyclobutanecarboxamide (48)

Step 1: Preparation of N-(3-((5-bromo-2-((2-isopropyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino))propyl)cyclobutanecarboxamide (48)

Dissolve int14_5 (100 mg, 266 μmol) in DMF (5 mL), add int3_2 (84 mg, 266 μmol), and then dropwise add TFA (91 mg, 799 μmol) was reacted at 80 °C for 6 h under argon protection. The reaction was completed by LC-MS. The reaction solution was directly subjected to rapid liquid preparative chromatography (120 g C-18 Flash Column, ACN/10 nM aqueous ammonium bicarbonate solution) to give compound 48 (25.7 mg, yield 15.4%).

ESI-MS m/z: 627 [M+H] ⁺ .

Example 17 Preparation of N-(3-((5-bromo-2-((2-cyclopropyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino))propyl)cyclobutanecarboxamide (49)

Step 1: Preparation of N-(3-((5-bromo-2-((2-cyclopropyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino))propyl)cyclobutanecarboxamide (49)

Int14_5 (100 mg, 266 μmol) was dissolved in DMF (5 mL), int1_10 (84 mg, 266 μmol) was added, and TFA (91 mg, 799 μmol) was added dropwise. The mixture was reacted at 80 °C for 6 h under argon protection. The reaction was completed by LC-MS. The reaction solution was directly purified by rapid preparative liquid chromatography (120 g C-18 Flash Column, ACN/10 nM aqueous ammonium bicarbonate solution) to give compound 49 (23.2 mg, yield 13.9%).

ESI-MS m/z: 625 [M+H] ⁺ .

Example 18 Preparation of N-(3-((5-bromo-2-((2-cyclobutyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino))propyl)cyclobutanecarboxamide (50)

Step 1: Preparation of N-(3-((5-bromo-2-((2-cyclobutyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino))propyl)cyclobutanecarboxamide (50)

Int14_5 (100 mg, 266 μmol) was dissolved in DMF (5 mL), int5_2 (88 mg, 266 μmol) was added, and then TFA (91 mg, 799 μmol) was added dropwise. The mixture was reacted at 80 °C for 6 h under argon protection. The reaction was completed by LC-MS. The reaction solution was directly purified by rapid preparative liquid chromatography (120 g C-18 Flash Column, ACN/10 nM aqueous ammonium bicarbonate solution) to give compound 50 (30.4 mg, yield 17.8%).

ESI-MS m/z: 639 [M+H] ⁺ .

Example 19 Preparation of N-(3-((5-bromo-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino))propyl)cyclobutanecarboxamide (52)

Step 1: Preparation of N-(3-((5-bromo-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino))propyl)cyclobutanecarboxamide (52)

Int14_5 (100 mg, 266 μmol) was dissolved in DMF (5 mL), int5_2 (81 mg, 266 μmol) was added, and then TFA (91 mg, 799 μmol) was added dropwise. The mixture was reacted at 80 °C for 6 h under argon protection. The reaction was completed by LC-MS. The reaction solution was directly purified by rapid preparative liquid chromatography (120 g C-18 Flash Column, ACN/10 nM aqueous ammonium bicarbonate solution) to give compound 52 (22.5 mg, yield 13.7%).

ESI-MS m/z: 615 [M+H] ⁺ .

Example 20 Preparation of N-(3-((5-cyclopropyl-2-((2-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino))propyl)cyclobutanecarboxamide (91)

Step 1: Synthesis of compound int20_1

Int14_4 (718 mg, 2.00 mmol) and cyclopropylboronic acid (215 mg, 5.00 mmol) were placed in a 100 mL round-bottom flask, 1,4-dioxane (20 mL) was added to dissolve, and potassium carbonate (829 mg, 6.00 mmol) and dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium (147 mg, 200 μmol) were added, and the mixture was heated to 90°C under argon protection and reacted overnight. The reaction was completed by LC-MS. After concentration under reduced pressure, the residue was purified by rapid liquid preparative chromatography (120 g C-18 Flash Column, ACN/1‰ TFA aqueous solution) was purified to give int1_9 (399 mg, yield 62.1%).

ESI-MS m/z: 321 [M+H] ⁺ .

Step 2: Synthesis of compound int20_2

Int20_1 (100 mg, 297 μmol) was placed in a 50 mL round-bottom flask, DCM (4 mL) was added to dissolve, and then m-CPBA (90 mg, 446 μmol) was added to react at room temperature for 0.5 hours. The reaction was completed by LC-MS. The reaction solution was filtered, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent to obtain int20_2 (100 mg, yield 95.2%) for the next step reaction.

ESI-MS m/z: 337 [M+H] ⁺ .

Step 3: N-(3-((5-cyclopropyl-2-((2-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino Preparation of cyclobutanecarboxamide (91)

Int20_2 (100 mg, 297 μmol) was dissolved in DMF (5 mL), int4_2 (86 mg, 297 μmol) was added, and then TFA (102 mg, 892 μmol) was added dropwise. The mixture was reacted at 80 °C for 6 h under argon protection. The reaction was completed by LC-MS. The reaction solution was directly purified by rapid preparative liquid chromatography (120 g C-18 Flash Column, ACN/10 nM aqueous ammonium bicarbonate solution) to give compound 91 (23.1 mg, yield 13.8%).

ESI-MS m/z: 561 [M+H] ⁺ .

Example 21 Preparation of N-(3-((5-cyclopropyl-2-((2-ethyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino))propyl)cyclobutanecarboxamide (92)

Step 1: Preparation of N-(3-((5-cyclopropyl-2-((2-ethyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino))propyl)cyclobutanecarboxamide (92)

Int20_2 (100 mg, 297 μmol) was dissolved in DMF (5 mL), int2_2 (90 mg, 297 μmol) was added, and TFA (102 mg, 892 μmol) was added dropwise. The mixture was reacted at 80 °C for 6 h under argon protection. The reaction was completed by LC-MS. The reaction solution was directly purified by fast liquid chromatography Preparative chromatography (120 g C-18 Flash Column, ACN/10 nM aqueous ammonium bicarbonate solution) to give compound 92 (28.3 mg, yield 16.6%).

ESI-MS m/z: 575 [M+H] ⁺ .

Example 22 Preparation of N-(3-((5-cyclopropyl-2-((2-isopropyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino))propyl)cyclobutanecarboxamide (93)

Step 1: Preparation of N-(3-((5-cyclopropyl-2-((2-isopropyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino))propyl)cyclobutanecarboxamide (93)

Dissolve int20_2 (100 mg, 297 μmol) in DMF (5 mL), add int3_2 (94 mg, 297 μmol), and then drop TFA (102 mg, 892 μmol) into the mixture. The mixture is reacted at 80 °C for 6 h under argon protection. The reaction is complete as detected by LC-MS. The reaction solution is directly purified by rapid preparative liquid chromatography (120 g C-18 Flash Column, ACN/10 nM aqueous ammonium bicarbonate solution) to give compound 93 (27.0 mg, yield 15.4%).

ESI-MS m/z: 589 [M+H] ⁺ .

Example 23 Preparation of N-(3-((5-cyclopropyl-2-((2-cyclopropyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino))propyl)cyclobutanecarboxamide (94)

Step 1: Preparation of N-(3-((5-cyclopropyl-2-((2-cyclopropyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino))propyl)cyclobutanecarboxamide (94)

Int20_2 (100 mg, 297 μmol) was dissolved in DMF (5 mL), int1_10 (94 mg, 297 μmol) was added, and then TFA (102 mg, 892 μmol) was added dropwise. The mixture was reacted at 80 °C for 6 h under argon protection. The reaction was completed by LC-MS. The reaction solution was directly purified by rapid preparative liquid chromatography (120 g C-18 Flash Column, ACN/10 nM aqueous ammonium bicarbonate solution) to give compound 94 (31.5 mg, yield 18.1%).

ESI-MS m/z: 587 [M+H] ⁺ .

Example 24 Preparation of N-(3-((5-cyclopropyl-2-((2-cyclobutyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino))propyl)cyclobutanecarboxamide (95)

Step 1: Preparation of N-(3-((5-cyclopropyl-2-((2-cyclobutyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino))propyl)cyclobutanecarboxamide (95)

Int20_2 (100 mg, 297 μmol) was dissolved in DMF (5 mL), int5_2 (98 mg, 297 μmol) was added, and then TFA (102 mg, 892 μmol) was added dropwise. The mixture was reacted at 80 °C for 6 h under argon protection. The reaction was completed by LC-MS. The reaction solution was directly purified by rapid preparative liquid chromatography (120 g C-18 Flash Column, ACN/10 nM aqueous ammonium bicarbonate solution) to give compound 95 (29.6 mg, yield 16.6%).

ESI-MS m/z: 601 [M+H] ⁺ .

Example 25 Preparation of N-(3-((5-cyclopropyl-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino))propyl)cyclobutanecarboxamide (97)

Step 1: Preparation of N-(3-((5-cyclopropyl-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino))propyl)cyclobutanecarboxamide (97)

Int20_2 (100 mg, 297 μmol) was dissolved in DMF (5 mL), int6_1 (92 mg, 297 μmol) was added, and then TFA (102 mg, 892 μmol) was added dropwise. The mixture was reacted at 80 °C for 6 h under argon protection. The reaction was completed by LC-MS. The reaction solution was directly purified by rapid preparative liquid chromatography (120 g C-18 Flash Column, ACN/10 nM aqueous ammonium bicarbonate solution) to obtain compound 97 (25.8 mg, Yield: 15.0%).

ESI-MS m/z: 577 [M+H] ⁺ .

Example 26 Preparation of 1-(3-((2-((2-cyclopropyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl))amino)propyl)pyrrolidin-2-one (136)

Step 1: Synthesis of compound int26_1

Int1_1 (229 mg, 1.00 mmol) and N-(3'-propylamino)-2-pyrrolidone (170 mg, 1.20 mmol) were placed in a 100 mL round-bottom flask, IPA (10 mL) was added to dissolve, and DIPEA (516 mg, 4.00 mmol) was added to react at 80°C for 2 hours. The reaction was complete as detected by LC-MS, and the reaction solution was washed with 0.5 M dilute hydrochloric acid, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent to obtain int26_1 (234 mg, yield 70.0%), which was directly used in the next step.

ESI-MS m/z: 335 [M+H] ⁺ .

Step 2: Synthesis of compound int26_2

Int26_1 (100 mg, 299 μmol) was placed in a 50 mL round-bottom flask, DCM (4 mL) was added to dissolve, and then m-CPBA (91 mg, 448 μmol) was added to react at room temperature for 0.5 hours. The reaction was completed by LC-MS. The reaction solution was filtered, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent to obtain int26_2 (99 mg, yield 94.5%) for the next step reaction.

ESI-MS m/z: 351 [M+H] ⁺ .

Step 3: Preparation of 1-(3-((2-((2-cyclopropyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl))amino)propyl)pyrrolidin-2-one (136)

Int26_2 (99 mg, 282 μmol) was dissolved in DMF (5 mL), int1_10 (92 mg, 282 μmol) was added, and then TFA (96 mg, 846 μmol) was added dropwise. The mixture was reacted at 80 °C for 6 h under argon protection. The reaction was completed by LC-MS. The reaction solution was directly purified by fast liquid chromatography Preparative chromatography (120 g C-18 Flash Column, ACN/10 nM aqueous ammonium bicarbonate solution) to give compound 136 (11.7 mg, yield 6.90%).

ESI-MS m/z: 601 [M+H] ⁺ .

Example 27 Preparation of 3-(3-((2-((2-cyclopropyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl))amino)propyl)-1,3-oxazinan-2-one (139)

Step 1: Synthesis of compound int27_2

Sodium hydride (60%, 400 mg, 10.0 mmol) was added to a 100 mL round-bottom flask, and TFA (7 mL) was added. Then, int27_1 (498 mg, 5.0 mmol) and tert-butyl (3-bromopropyl) carbamate (1190 mg, 5.0 mmol) were added under ice bath. After the addition was completed, the reaction was allowed to react at room temperature for 5 hours. The reaction was completed by LC-MS. Water was added to the reaction solution under ice bath to quench the reaction solution, and then the solution was extracted with ethyl acetate. After the solvent was removed by concentration under reduced pressure, the residue was purified by rapid liquid preparative chromatography (120 g C-18 Flash Column, ACN/1‰ TFA aqueous solution = 10%-60%) to obtain int27_2 (207 mg, yield 16.1%).

ESI-MS m/z: 259 [M+H] ⁺ .

Step 2: Synthesis of compound int27_3

Int27_2 (207 mg, 0.86 mmol) was placed in a 100 mL round-bottom flask, and DCM (10 mL) and TFA (3 mL) were added to react at room temperature for 1 hour. The reaction was completed by LC-MS detection, and int27_3 (TFA salt, 453 mg) was obtained after concentration under reduced pressure.

ESI-MS m/z: 159 [M+H] ⁺ .

Step 3: Synthesis of compound int27_4

Int27_3 (306 mg, 2.0 mmol) and int1_1 (453 mg, 2.0 mmol) were placed in a 100 mL round-bottom flask, and IPA (25 mL) and DIPEA (1032 mg, 8.0 mmol) were added to react at 80°C for 3 hours. The reaction was completed by LC-MS. After concentration under reduced pressure, the residue was purified by rapid liquid preparative chromatography (120 g C-18 Flash Column, ACN/1‰ TFA aqueous solution = 20%-80%) to obtain int27_4 (356 mg, yield 50.8%).

ESI-MS m/z: 351 [M+H] ⁺ .

Step 4: Synthesis of compound int27_5

Int27_4 (100 mg, 273 μmol) was placed in a 250 mL round-bottom flask, DCM (4 mL) was added to dissolve, and m-CPBA (83 mg, 409 μmol) was added to react at room temperature for 0.5 hours. The reaction was detected to be complete by LC-MS. The reaction solution was added with a saturated sodium bicarbonate solution to adjust the pH value to 7-8, filtered, and the filtrate was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain int27_5 (86 mg, yield 86.1%) for the next step reaction.

ESI-MS m/z: 367 [M+H] ⁺ .

Step 5: Preparation of Example 1-(3-((2-(2-((2-cyclopropyl-4-4-(4-methylpiperazine-1-piperidin-1-yl))amino-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one (139)

DMF (5 mL) was added to int27_5 (86 mg, 234 μmol), int1_10 (74 mg, 234 μmol) was added, and TFA (80 mg, 702 μmol) was added dropwise. The mixture was reacted at 80°C for 6 hours under argon protection. The reaction was completed by LC-MS. The reaction solution was directly purified by rapid preparative liquid chromatography (120 g C-18 Flash Column, ACN/10 nM aqueous ammonium bicarbonate solution = 10% -85%) to obtain compound 139 (23.7 mg, yield 16.4%).

ESI-MS m/z: 617 [M+H] ⁺ .

Example 28 Preparation of 1-(3-((2-((2-cyclopropyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl))amino)propyl)azacyclopentane-2-one (140)

Step 1: Synthesis of compound int28_1

Int1_1 (229 mg, 1.00 mmol) and 1-(3-aminopropyl)azepan-2-one (204 mg, 1.20 mmol) were placed in a 100 mL round-bottom flask, IPA (10 mL) was added to dissolve, and DIPEA (516 mg, 4.00 mmol) was added to react at 80°C for 2 hours. The reaction was complete by LC-MS detection, and the reaction solution was washed with 0.5 M dilute hydrochloric acid, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent to obtain int28_1 (199 mg, yield 54.9%) was directly used in the next reaction.

ESI-MS m/z: 363 [M+H] ⁺ .

Step 2: Synthesis of compound int28_2

Int26_1 (100 mg, 276 μmol) was placed in a 50 mL round-bottom flask, DCM (4 mL) was added to dissolve, and then m-CPBA (84 mg, 414 μmol) was added to react at room temperature for 0.5 hours. The reaction was completed by LC-MS. The reaction solution was filtered, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent to obtain int26_2 (105 mg, yield 100%) for the next step reaction.

ESI-MS m/z: 379 [M+H] ⁺ .

Step 3: Preparation of 1-(3-((2-((2-cyclopropyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl))amino)propyl)azacyclopentane (140)

Int28_2 (105 mg, 276 μmol) was dissolved in DMF (5 mL), int1_10 (87 mg, 276 μmol) was added, and then TFA (94 mg, 828 μmol) was added dropwise. The mixture was reacted at 80 °C for 6 h under argon protection. The reaction was completed by LC-MS. The reaction solution was directly purified by rapid preparative liquid chromatography (120 g C-18 Flash Column, ACN/10 nM aqueous ammonium bicarbonate solution) to give compound 140 (23.4 mg, yield 13.5%).

ESI-MS m/z: 629 [M+H] ⁺ .

Example 29 Preparation of 4-(3-((2-((2-cyclopropyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl))amino)propyl)-1,4-oxazacyclopent-3-one (143)

Step 1: Synthesis of compound int29_2

Sodium hydride (60%, 400 mg, 10.0 mmol) was added to a 100 mL round-bottom flask, and TFA (7 mL) was added. Then, int29_1 (575 mg, 5.0 mmol) and tert-butyl (3-bromopropyl) carbamate (1190 mg, 5.0 mmol) were added under ice bath. After the addition was completed, the reaction was allowed to react at room temperature for 5 hours. The reaction was completed by LC-MS. Water was added to the reaction solution under ice bath to quench the reaction solution, and then the solution was extracted with ethyl acetate. After the solvent was removed by concentration under reduced pressure, the residue was purified by rapid liquid preparative chromatography (120 g C-18 Flash Column, ACN/1‰ TFA aqueous solution = 10%-60%) to obtain int29_2 (354 mg, yield 26.0%).

ESI-MS m/z: 273 [M+H] ⁺ .

Step 2: Synthesis of compound int29_3

Int27_2 (354 mg, 1.3 mmol) was placed in a 100 mL round-bottom flask, and DCM (10 mL) and TFA (3 mL) were added to react at room temperature for 1 hour. The reaction was completed by LC-MS detection, and int27_3 (TFA salt, 441 mg) was obtained after concentration under reduced pressure.

ESI-MS m/z: 173 [M+H] ⁺ .

Step 3: Synthesis of compound int29_4

Int29_3 (172 mg, 1.0 mmol) and int1_1 (229 mg, 1.0 mmol) were placed in a 100 mL round-bottom flask, and IPA (10 mL) and DIPEA (516 mg, 4.0 mmol) were added to react at 80°C for 3 hours. The reaction was completed by LC-MS. After concentration under reduced pressure, the residue was purified by rapid liquid preparative chromatography (120 g C-18 Flash Column, ACN/1‰ TFA aqueous solution = 20%-80%) to obtain int29_4 (122 mg, yield 33.5%).

ESI-MS m/z: 365 [M+H] ⁺ .

Step 4: Synthesis of compound int29_5

Int27_4 (100 mg, 274 μmol) was placed in a 250 mL round-bottom flask, DCM (4 mL) was added to dissolve, and m-CPBA (83 mg, 409 μmol) was added to react at room temperature for 0.5 hours. The reaction was detected to be complete by LC-MS. The reaction solution was added with a saturated sodium bicarbonate solution to adjust the pH value to 7-8, filtered, and the filtrate was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain int29_5 (98 mg, yield 93.9%) for the next step reaction.

ESI-MS m/z: 381 [M+H] ⁺ .

Step 5: Preparation of Example 4-(3-((2-((2-cyclopropyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl))amino)propyl)-1,4-oxazacyclopent-3-one (143)

DMF (5 mL) was added to int29_5 (98 mg, 257 μmol), int1_10 (81 mg, 257 μmol) was added, and TFA (8/mg, 771 μmol) was added dropwise. The mixture was reacted at 80°C for 6 hours under argon protection. The reaction was completed by LC-MS. The reaction solution was directly purified by rapid preparative liquid chromatography (120 g C-18 Flash Column, ACN/10 nM aqueous ammonium bicarbonate solution = 10% -85%) to obtain compound 139 (30.0 mg, yield 18.5%).

ESI-MS m/z: 631 [M+H] ⁺ .

Example 30 Preparation of 1-(3-((2-(2-((2-cyclopropyl-4-4-(4-methylpiperazine-1-piperidin-1-yl))amino-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one (151)

Step 1: Synthesis of compound int30_2

Sodium hydride (60%, 400 mg, 10.0 mmol) was added to a 100 mL round-bottom flask, and TFA (7 mL) was added. Then, int30_1 (495 mg, 5.0 mmol) and tert-butyl (3-bromopropyl) carbamate (1190 mg, 5.0 mmol) were added under ice bath. After the addition was completed, the reaction was allowed to react at room temperature for 5 hours. The reaction was detected to be complete by LC-MS. Water was added to the reaction solution under ice bath to quench the reaction solution, and then the solution was extracted with ethyl acetate. After the solvent was removed by concentration under reduced pressure, the residue was purified by rapid liquid preparative chromatography (120 g C-18 Flash Column, ACN/1‰ TFA aqueous solution = 10%-60%) to obtain int30_2 (207 mg, yield 16.1%).

ESI-MS m/z: 257 [M+H] ⁺ .

Step 2: Synthesis of compound int30_3

Int2_2 (207 mg, 0.86 mmol) was placed in a 100 mL round-bottom flask, and DCM (10 mL) and TFA (3 mL) were added to react at room temperature for 1 hour. The reaction was completed by LC-MS detection, and int30_3 (TFA salt, 453 mg) was obtained after concentration under reduced pressure.

ESI-MS m/z: 157 [M+H] ⁺ .

Step 3: Synthesis of compound int30_4

Int2_3 (309 mg, 1.98 mmol) and int1_1 (453 mg, 1.98 mmol) were placed in a 100 mL round-bottom flask, and IPA (25 mL) and DIPEA (1023 mg, 7.93 mmol) were added to react at 80°C for 3 hours. The reaction was completed by LC-MS. After concentration under reduced pressure, the residue was purified by rapid liquid preparative chromatography (120 g C-18 Flash Column, ACN/1‰ TFA aqueous solution = 20%-80%) to obtain int2_4 (245 mg, yield 33%).

ESI-MS m/z: 349 [M+H] ⁺ .

Step 4: Synthesis of compound int30_5

Int30_4 (60 mg, 172 μmol) was placed in a 250 mL round-bottom flask, DCM (4 mL) was added to dissolve, and m-CPBA (44 mg, 258 μmol) was added to react at room temperature for 0.5 hours. The reaction was detected to be complete by LC-MS. The reaction solution was added with a saturated sodium bicarbonate solution to adjust the pH value to 7-8, filtered, and the filtrate was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain int30_5 for the next step.

ESI-MS m/z: 365 [M+H] ⁺ .

Step 5: Preparation of Example 1-(3-((2-(2-((2-cyclopropyl-4-4-(4-methylpiperazine-1-piperidin-1-yl))amino-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one (151)

DMF (5 mL) was added to int30_5, int1_10 (54 mg, 172 μmol) was added, and TFA (78 mg, 688 μmol) was added dropwise. The mixture was reacted at 80°C for 6 hours under argon protection. The reaction was completed by LC-MS. The reaction solution was directly purified by rapid preparative liquid chromatography (120 g C-18 Flash Column, ACN/10 nM aqueous ammonium bicarbonate solution = 10% -85%) to obtain compound 151 (21.9 mg, yield 19.2%).

ESI-MS m/z: 616 [M+H] ⁺ .

¹ H-NMR (400 MHz, Chloroform-d) δ8.43 (s, 1H), 8.11 (s, 1H), 7.93 (d, J = 8.9 Hz, 1H), 6.79 (dd, J = 8.8,2.8Hz,1H),6.71(d,J＝2.8Hz,1H),6.61(s,1H),3.66(d,J＝12.0Hz,2H),3.46(dt,J＝12.9,6.3Hz,2H),3.26(s,2H),2.89(s,10H),2.68(t,J＝11.9Hz,2H),2.54(s,3H),2.43(s,2H),1.96(d,J＝12.2Hz,2H),1.88–1.68(m,10H),1.04–0.93(m,2H),0.70–0.57(m,2H).

Example 31 Preparation of 1-(3-((2-(2-((2-ethyl-4-4-(4-methylpiperazine-1-piperidin-1-yl))amino-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one (152)

Step 1: Preparation of 1-(3-((2-(2-((2-ethyl-4-(4-methylpiperazin-1-piperidin-1-yl))amino-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one (152)

Int30_5 (100 mg, 274 μmol) was dissolved in DMF (5 mL), int2_2 (83 mg, 274 μmol) was added, and then TFA (94 mg, 822 μmol) was added dropwise. The mixture was reacted at 80 °C for 6 h under argon protection. The reaction was completed by LC-MS. The reaction solution was directly purified by rapid preparative liquid chromatography (120 g C-18 Flash Column, ACN/10 nM aqueous ammonium bicarbonate solution) to give compound 152 (30.5 mg, yield 18.4%).

ESI-MS m/z: 603 [M+H] ⁺ .

Example 32 Preparation of 1-(3-((2-(2-((2-isopropyl-4-(4-methylpiperazine-1-piperidin-1-yl))amino-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one (153)

Step 1: Preparation of 1-(3-((2-(2-((2-isopropyl-4-(4-methylpiperazin-1-piperidin-1-yl))amino-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one (153)

Int30_5 (100 mg, 274 μmol) was dissolved in DMF (5 mL), int3_2 (87 mg, 274 μmol) was added, and then TFA (94 mg, 822 μmol) was added dropwise. The mixture was reacted at 80 °C for 6 h under argon protection. The reaction was completed by LC-MS. The reaction solution was directly purified by rapid preparative liquid chromatography (120 g C-18 Flash Column, ACN/10 nM aqueous ammonium bicarbonate solution) to give compound 153 (28.6 mg, yield 16.9%).

ESI-MS m/z: 617 [M+H] ⁺ .

Example 33 Preparation of 1-(3-((2-(2-((2-methyl-4-4-(4-methylpiperazine-1-piperidin-1-yl))amino-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one (154)

Step 1: Preparation of 1-(3-((2-(2-((2-methyl-4-(4-methylpiperazin-1-piperidin-1-yl))amino-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one (154)

Int30_5 (100 mg, 274 μmol) was dissolved in DMF (5 mL), int4_2 (79 mg, 274 μmol) was added, and TFA (94 mg, 822 μmol) was added dropwise. The mixture was reacted at 80 °C for 6 h under argon protection. The reaction was completed by LC-MS. The reaction solution was directly purified by rapid preparative liquid chromatography (120 g C-18 Flash Column, ACN/10 nM aqueous ammonium bicarbonate solution) to give compound 154 (22.3 mg, yield 13.8%).

ESI-MS m/z: 589 [M+H] ⁺ .

Example 34 Preparation of 1-(3-((2-(2-((2-cyclobutyl-4-4-(4-methylpiperazine-1-piperidin-1-yl))amino-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one (155)

Step 1: Preparation of 1-(3-((2-(2-((2-cyclobutyl-4-(4-methylpiperazin-1-piperidin-1-yl))amino-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one (155)

Int30_5 (100 mg, 274 μmol) was dissolved in DMF (5 mL), int5_2 (90 mg, 274 μmol) was added, and then TFA (94 mg, 822 μmol) was added dropwise. The mixture was reacted at 80 °C for 6 h under argon protection. The reaction was completed by LC-MS. The reaction solution was directly purified by rapid preparative liquid chromatography (120 g C-18 Flash Column, ACN/10 nM aqueous ammonium bicarbonate solution) to obtain compound 155 (33.4 mg, yield 19.3%).

ESI-MS m/z: 629 [M+H] ⁺ .

Example 35 Preparation of 1-(3-((2-(2-((2-methoxy-4-4-(4-methylpiperazine-1-piperidin-1-yl))amino-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one (157)

Step 1: Preparation of 1-(3-((2-(2-((2-methoxy-4-(4-methylpiperazin-1-piperidin-1-yl))amino-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one (157)

Int30_5 (100 mg, 274 μmol) was dissolved in DMF (5 mL), int2_2 (84 mg, 274 μmol) was added, and then TFA (94 mg, 822 μmol) was added dropwise. The mixture was reacted at 80 °C for 6 h under argon protection. The reaction was completed by LC-MS. The reaction solution was directly purified by rapid preparative liquid chromatography (120 g C-18 Flash Column, ACN/10 nM aqueous ammonium bicarbonate solution) to give compound 157 (33.0 mg, yield 19.9%).

ESI-MS m/z: 605 [M+H] ⁺ .

Example 36 Preparation of 3-(3-((2-((2-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl))amino)propyl)-1,3-oxazinan-2-one (274)

Step 1: Preparation of 3-(3-((2-((2-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl))amino)propyl)-1,3-oxazinan-2-one (274)

Int27_5 (100 mg, 273 μmol) was dissolved in DMF (5 mL), int4_2 (79 mg, 273 μmol) was added, and TFA (93 mg, 819 μmol) was added dropwise. The mixture was reacted at 80 °C for 6 h under argon protection. The reaction was completed by LC-MS. The reaction solution was directly purified by rapid preparative liquid chromatography (120 g C-18 Flash Column, ACN/10 nM aqueous ammonium bicarbonate solution) to give compound 274 (22.0 mg, yield 13.6%).

ESI-MS m/z: 591 [M+H] ⁺ .

Example 37 Preparation of 3-(3-((2-((2-ethyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl))amino)propyl)-1,3-oxazinan-2-one (275)

Step 1: Preparation of 3-(3-((2-((2-ethyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl))amino)propyl)-1,3-oxazinan-2-one (275)

Int27_5 (100 mg, 273 μmol) was dissolved in DMF (5 mL), int4_2 (83 mg, 273 μmol) was added, and then TFA (93 mg, 819 μmol) was added dropwise. The mixture was reacted at 80 °C for 6 h under argon protection. The reaction was completed by LC-MS. The reaction solution was directly purified by rapid preparative liquid chromatography (120 g C-18 Flash Column, ACN/10 nM aqueous ammonium bicarbonate solution) to give compound 275 (26.9 mg, yield 16.3%).

ESI-MS m/z: 605 [M+H] ⁺ .

Example 38 Preparation of 3-(3-((2-((2-isopropyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl))amino)propyl)-1,3-oxazinan-2-one (276)

Step 1: Preparation of 3-(3-((2-((2-isopropyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl))amino)propyl)-1,3-oxazinan-2-one (276)

Int27_5 (100 mg, 273 μmol) was dissolved in DMF (5 mL), int3_2 (87 mg, 273 μmol) was added, and then TFA (93 mg, 819 μmol) was added dropwise. The mixture was reacted at 80 °C for 6 h under argon protection. The reaction was completed by LC-MS. The reaction solution was directly purified by rapid preparative liquid chromatography (120 g C-18 Flash Column, ACN/10 nM aqueous ammonium bicarbonate solution) to obtain compound 276 (26.1 mg, yield 15.4%).

ESI-MS m/z: 619 [M+H] ⁺ .

Example 39 Preparation of 3-(3-((2-((2-cyclobutyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl))amino)propyl)-1,3-oxazinan-2-one (277)

Step 1: Preparation of 3-(3-((2-((2-cyclobutyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl))amino)propyl)-1,3-oxazinan-2-one (277)

Int27_5 (100 mg, 273 μmol) was dissolved in DMF (5 mL), int4_2 (90 mg, 273 μmol) was added, and then TFA (93 mg, 819 μmol) was added dropwise. The mixture was reacted at 80 °C for 6 h under argon protection. The reaction was completed by LC-MS. The reaction solution was directly purified by rapid preparative liquid chromatography (120 g C-18 Flash Column, ACN/10 nM aqueous ammonium bicarbonate solution) to give compound 277 (35.9 mg, yield 20.8%).

ESI-MS m/z: 631 [M+H] ⁺ .

Example 40 Preparation of 3-(3-((2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl))amino)propyl)-1,3-oxazinan-2-one (279)

Step 1: Preparation of 3-(3-((2-((2-ethyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl))amino)propyl)-1,3-oxazinan-2-one (279)

Int27_5 (100 mg, 273 μmol) was dissolved in DMF (5 mL), int4_2 (84 mg, 273 μmol) was added, and then TFA (93 mg, 819 μmol) was added dropwise. The mixture was reacted at 80 °C for 6 h under argon protection. The reaction was completed by LC-MS. The reaction solution was directly purified by rapid preparative liquid chromatography (120 g C-18 Flash Column, ACN/10 nM aqueous ammonium bicarbonate solution) to give compound 279 (29.1 mg, yield 17.6%).

ESI-MS m/z: 607 [M+H] ⁺ .

Example 41 Preparation of 4-(3-((2-((2-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl))amino)propyl)-1,4-oxazacyclopent-3-one (313)

Step 1: Preparation of 4-(3-((2-((2-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl))amino)propyl)-1,4-oxazacyclopent-3-one (313)

Int29_5 (100 mg, 263 μmol) was dissolved in DMF (5 mL), int4_2 (76 mg, 263 μmol) was added, and then TFA (90 mg, 789 μmol) was added dropwise. The mixture was reacted at 80 °C for 6 h under argon protection. The reaction was completed by LC-MS. The reaction solution was directly purified by rapid preparative liquid chromatography (120 g C-18 Flash Column, ACN/10 nM aqueous ammonium bicarbonate solution) to give compound 313 (23.0 mg, yield 14.5%).

ESI-MS m/z: 605 [M+H] ⁺ .

Example 42 Preparation of 4-(3-((2-((2-ethyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl))amino)propyl)-1,4-oxazacyclopent-3-one (314)

Step 1: Preparation of 4-(3-((2-((2-ethyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl))amino)propyl)-1,4-oxazacyclopent-3-one (314)

Int29_5 (100 mg, 263 μmol) was dissolved in DMF (5 mL), int2_2 (80 mg, 263 μmol) was added, and TFA (90 mg, 789 μmol) was added dropwise. The mixture was reacted at 80 °C for 6 h under argon protection. The reaction was completed by LC-MS. The reaction solution was directly purified by rapid preparative liquid chromatography (120 g C-18 Flash Column, ACN/10 nM aqueous ammonium bicarbonate solution) to obtain compound 314 (24.2 mg, yield 14.8%).

ESI-MS m/z: 619 [M+H] ⁺ .

Example 43 Preparation of 4-(3-((2-((2-isopropyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl))amino)propyl)-1,4-oxazacyclopent-3-one (315)

Step 1: Preparation of 4-(3-((2-((2-isopropyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl))amino)propyl)-1,4-oxazacyclopent-3-one (315)

Int29_5 (100 mg, 263 μmol) was dissolved in DMF (5 mL), int3_2 (83 mg, 263 μmol) was added, and then TFA (90 mg, 789 μmol) was added dropwise. The mixture was reacted at 80 °C for 6 h under argon protection. The reaction was completed by LC-MS. The reaction solution was directly purified by rapid preparative liquid chromatography (120 g C-18 Flash Column, ACN/10 nM aqueous ammonium bicarbonate solution) to give compound 315 (31.4 mg, yield 18.9%).

ESI-MS m/z: 633 [M+H] ⁺ .

Example 44 Preparation of 4-(3-((2-((2-cyclobutyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl))amino)propyl)-1,4-oxazacyclopentane-3-one (316)

Step 1: Preparation of 4-(3-((2-((2-cyclobutyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl))amino)propyl)-1,4-oxazacyclopent-3-one (316)

Int29_5 (100 mg, 263 μmol) was dissolved in DMF (5 mL), int5_2 (86 mg, 263 μmol) was added, and then TFA (90 mg, 789 μmol) was added dropwise. The mixture was reacted at 80 °C for 6 h under argon protection. The reaction was completed by LC-MS. The reaction solution was directly purified by rapid preparative liquid chromatography (120 g C-18 Flash Column, ACN/10 nM aqueous ammonium bicarbonate solution) to give compound 316 (30.1 mg, yield 17.8%).

ESI-MS m/z: 645 [M+H] ⁺ .

Example 45 Preparation of 4-(3-((2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl))amino)propyl)-1,4-oxazacyclopent-3-one (318)

Step 1: Preparation of 4-(3-((2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl))amino)propyl)-1,4-oxazacyclopent-3-one (318)

Int29_5 (100 mg, 263 μmol) was dissolved in DMF (5 mL), int6_1 (80 mg, 263 μmol) was added, and then TFA (90 mg, 789 μmol) was added dropwise. The mixture was reacted at 80 °C for 6 h under argon protection. The reaction was completed by LC-MS. The reaction solution was directly purified by rapid preparative liquid chromatography (120 g C-18 Flash Column, ACN/10 nM aqueous ammonium bicarbonate solution) to give compound 318 (17.6 mg, yield 10.8%).

ESI-MS m/z: 621 [M+H] ⁺ .

Using the above synthesis method and different raw materials, the target compounds in Table 1 can be obtained.

Table 1

Biological Example 1 In vitro inhibition test of ULK1 enzyme activity by the compounds of the present invention

ADP-Glo Kinase Assay was used to determine the inhibitory effect of the compound on the ULK1 enzyme. The compound diluted in a gradient manner with DMSO was mixed with the ULK1 enzyme and placed at room temperature for 10 minutes before adding the biotin-labeled substrate (MBP) and ATP. After reacting at room temperature for 60 minutes, the ADP-Glo reagent was added. After incubation at room temperature for 40 minutes, the kinase detection reagent was added. The results were read using an ELISA reader and calculated using the following formula Inhibition rate: %Inhibition=100%-(compound-positive control)/(negative control-positive control)*100%. Compared with the DMSO control group, the compound inhibition percentage and _IC50 were calculated. The results are shown in Table 2 below.

Table 2. Inhibitory activity of the compounds of the present invention on ULK1 enzyme (IC ₅₀ , nM)

+++ indicates _IC50 less than or equal to 25 nM
++ indicates _IC50 is 25nM to 50nM
+ indicates _IC50 greater than 50 and less than 100 nM

Biological Example 2 Pharmacokinetic properties of some compounds of the present invention

CD-1 female mice aged 7 to 10 weeks were selected, and the intravenous and oral doses were 1 mg/Kg and 10 mg/Kg, respectively. The mice were fasted for at least 12 hours before administration, and food was resumed 4 hours after administration. Water was freely available throughout the experiment. On the day of the experiment, the animals in the intravenous group were given a single injection of the corresponding compound through the tail vein, and the administration volume was 1 mL/Kg. The animals in the oral group were given a single injection of the corresponding compound by gavage, and the administration volume was 10 mL/Kg. The animals were weighed before administration, and the administration volume was calculated based on the body weight. The sample collection time was: 0.083 (injection group), 0.25, 0.5, 1, 2, 4, 8, 24h. Approximately 200 μL of whole blood was collected from the submandibular venous plexus at each time point for the preparation of plasma for high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) for concentration determination. All animals were euthanized by _CO2 anesthesia after the PK sample at the last time point was collected. The plasma concentration was processed using the non-compartmental model of Phoenix WinNonlin ^™ version 8.3 (Certara) pharmacokinetic software, and the pharmacokinetic parameters were calculated using the linear logarithmic trapezoidal method. The in vivo pharmacokinetic results are shown in Table 3 below.

Table 3 In vivo pharmacokinetic evaluation results of the compounds of the present invention

From the data in Table 3, it can be seen that in the mouse pharmacokinetic experiment, Compound 1 of the present invention has excellent oral bioavailability, and has a higher C _max and a shorter T _max , while having a moderate T _1/2 .

Although the specific embodiments of the present invention are described above, it should be understood by those skilled in the art that these are only examples, and various changes or modifications may be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the protection scope of the present invention is limited by the appended claims.

Claims

A compound represented by the general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

In the general formula (1):

Y is C(R 3 ) or N;

R 1 is selected from: halogen, cyano, C 1 -C 5 alkyl or C 3 -C 5 cycloalkyl, wherein the C 1 -C 5 alkyl or C 3 -C 5 cycloalkyl may be optionally substituted by one, two or three fluorine groups;

R2 is selected from: H, halogen, cyano, C1 - C5 alkyl, C3 - C6 cycloalkyl, C2- C5 alkenyl, C2 - C5 alkynyl, C1 - C5 alkoxy or C1 - C5 alkoxy-( C2 - C5 )alkylene, wherein the C1 - C5 alkyl, C3 - C6 cycloalkyl, C2 - C5 alkenyl, C2 -C5 alkynyl and C1 - C5 alkoxy may be optionally substituted with one, two or three fluorine or cyano groups;

R 3 is selected from: H, halogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy, wherein the C 1 -C 6 alkyl or C 1 -C 6 alkoxy may be optionally substituted with one or more fluorines;

Z is selected from the following group: a) a 4-membered lactam ring bonded via a nitrogen atom or a 6-10-membered lactam ring bonded via a nitrogen atom, wherein when the lactam ring is a 6-10-membered ring, the atoms on the lactam ring may be optionally carbon, oxygen or NR 6 , and the carbon atoms on the 4-membered lactam ring or the 6-10-membered lactam may be optionally substituted by R 36 ; b) or an amide bonded via a nitrogen atom, wherein the carbonyl carbon atom of the amide is substituted by R 37 ;

R 36 is independently selected at each occurrence from H, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, wherein the C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl may be optionally substituted with one or more fluorine, or two R 36 are joined together to the carbon atom to which they are attached to form a C 3 -C 6 cycloalkyl;

R 37 is independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or (3-6 membered) heterocycloalkyl, wherein the carbon atoms on the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or (3-6 membered) heterocycloalkyl may be optionally substituted by R 36 , and the heteroatom on the (3-6 membered) heterocycloalkyl may be optionally oxygen or NR 6 ;

When Z is an amide bonded via a nitrogen atom, wherein the carbonyl carbon atom of the amide is substituted by R 37 , R 4 is selected from B 1 or D 1 ;

B 1 is selected from heterocycloalkyl or heteroaryl attached through a nitrogen atom, wherein B 1 is optionally substituted on one or more available carbons with R 7 and optionally substituted on an available nitrogen with R 9 ;

D 1 is selected from heterocycloalkyl or heteroaryl attached through a carbon atom, wherein D 1 is optionally substituted on one or more available carbons with R 7 and optionally substituted on an available nitrogen with R 9 ;

R 7 is independently selected at each occurrence from: H, cyano, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, -N(R 5 ) 2 , -(C 1 -C 6 ) alkylene-N(R 5 ) 2 or (3-6 membered) heterocycloalkyl, wherein said C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or (3-6 membered) heterocycloalkyl may be optionally substituted with one or more H or F; or two R 7 together with the atoms to which they are attached form an oxo group;

R 9 is independently selected at each occurrence from: H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or (3-6 membered) heterocycloalkyl, wherein said C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or (3-6 membered) heterocycloalkyl may be optionally substituted with one or more H, D or F;

When Z is a 4-membered lactam ring bonded via a nitrogen atom or a 6-10-membered lactam ring bonded via a nitrogen atom, wherein when the lactam ring is a 6-10-membered ring, the atoms on the lactam ring may optionally be carbon, oxygen or NR 6 , and the carbon atoms on the 4-membered lactam ring or the 6-10-membered lactam may optionally be substituted by R 36 , R 4 is selected from B 2 or D 2 ;

B2 is selected from heterocycloalkyl or heteroaryl attached through a nitrogen atom, wherein B2 is optionally substituted with R8 on one or more available carbons and optionally substituted with R10 on an available nitrogen;

D2 is selected from heterocycloalkyl or heteroaryl attached through a carbon atom, wherein D2 is optionally substituted with R8 on one or more available carbons and optionally substituted with R10 on an available nitrogen;

R 8 is independently selected at each occurrence from: H, cyano, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, -N(R 5 ) 2 , -(C 1 -C 6 ) alkylene-N(R 5 ) 2 or (3-6 membered) heterocycloalkyl, wherein said C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or (3-6 membered) heterocycloalkyl may be optionally substituted with one or more H or F; or two R 8 together with the atoms to which they are attached form an oxo group;

R 10 is independently selected at each occurrence from: C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or (3-6 membered) heterocycloalkyl, wherein said C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or (3-6 membered) heterocycloalkyl may be optionally substituted with one or more H, D or F;

R 5 is independently selected at each occurrence from: H, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, wherein said C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl may be optionally substituted with one or more F;

R 6 is independently selected at each occurrence from: H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or (3-6 membered) heterocycloalkyl, wherein said C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or (3-6 membered) heterocycloalkyl may be optionally substituted with one or more F;

and n is 2, 3, or 4.
The compound according to claim 1 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), Z is selected from:

in,

V is selected from the group consisting of oxygen, C(R 34 ) 2 and NR 9 ;

R 34 is independently selected at each occurrence from H or R 36 , wherein R 36 is independently selected at each occurrence from C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, or two R 36 are joined together to the carbon atom to which they are attached to form a C 3 -C 6 cycloalkyl;

R 37 is independently selected from C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl or (3-6 membered) heterocycloalkyl, wherein the carbon atoms on the C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl or (3-6 membered) heterocycloalkyl may be optionally substituted by R 36 , and the heteroatom on the (3-6 membered) heterocycloalkyl may be optionally oxygen or NR 6 ;

q is 0, 1, 2 or 3; r is 2 or 4; and if q is 0, then r is not 2.
The compound according to claim 2 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), Z is selected from:
wherein R 34 at each occurrence is independently selected from H or R 36 , wherein R 36 at each occurrence is independently selected from C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, or two R 36 are joined together to the carbon to which they are attached to form a C 3 -C 6 cycloalkyl.
The compound according to claim 3 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), Z is selected from:
The compound according to claim 1 or 2 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), when Z is When R4 is selected from:
wherein R 7 at each occurrence is independently selected from: H, cyano, -N(R 5 ) 2 , C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, or (3-5 membered) heterocycloalkyl, wherein said C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, or (3-6 membered) heterocycloalkyl may be optionally substituted with one or more H or F, or two R 7 are linked together to the atoms to which they are attached to form an oxo group;

R9 is independently selected at each occurrence from: H, C1 - C3 alkyl, C3 - C5 cycloalkyl or (3-5 membered)heterocycloalkyl, wherein said C1 - C3 alkyl, C3 - C5 cycloalkyl or (3-5 membered)heterocycloalkyl may be optionally substituted with one or more H, D or F; wherein R5 is independently selected at each occurrence from: H, C1 - C6 alkyl or C3 - C6 cycloalkyl, wherein said C1 - C6 alkyl and C3 - C6 cycloalkyl may be optionally substituted with one or more F.
The compound according to claim 5 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), when Z is When R4 is selected from:
The compound according to claim 1 or 2 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), when Z is When R4 is selected from:
The compound according to claim 7 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), when Z is When R4 is selected from:
The compound according to claim 1 or 2 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), when Z is When R4 is selected from: wherein R 8 is independently selected at each occurrence from: H, cyano, C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, or (3-5 membered) heterocycloalkyl, wherein said C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, or (3-5 membered) heterocycloalkyl may be optionally substituted with one or more H or F, or two R 8 are linked together with the atoms to which they are attached to form an oxo group; R 10 is independently selected at each occurrence from: C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, or (3-5 membered) heterocycloalkyl, wherein said C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, or (3-5 membered) heterocycloalkyl may be optionally substituted with one or more H or F; wherein R 5 is independently selected at each occurrence from: H, C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl, wherein said C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl may be optionally substituted with one or more F.
The compound according to claim 9 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), when Z is When R4 is selected from:
The compound according to claim 1 or 2 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), when Z is When R4 is selected from:
The compound according to claim 11 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), when Z is When R4 is selected from:
The compound according to any one of claims 1 to 12 or its isomers, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R1 is selected from: halogen, C1 - C3 alkyl or C3 - C5 cycloalkyl, wherein the C1 - C3 alkyl or C3 - C5 cycloalkyl may be optionally substituted by one, two or three fluorine groups.
The compound according to claim 13 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 1 is selected from: trifluoromethyl, F, Cl, Br, I or cyclopropyl.
The compound according to any one of claims 1 to 14 or its isomers, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R2 is selected from: H, F, Cl, Br, cyano, C1 - C3 alkyl, C3 - C5 cycloalkyl, C2 - C4 alkenyl, C2- C4 alkynyl, C1 - C3 alkoxy or C1 - C3 alkoxy-( C2 - C5 )alkylene, wherein the C1 - C3 alkyl, C3 - C5 cycloalkyl, C2 - C4 alkenyl, C2 - C4 alkynyl or C1 - C3 alkoxy may be optionally substituted by one, two or three fluorine or cyano groups.
The compound according to claim 15 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 2 is selected from: H, F, Cl, Br, or -OCH 3 .
The compound according to any one of claims 1 to 16 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), n=3.
The compound according to any one of claims 1 to 17 or its isomers, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates, wherein the compound has one of the following structures:
The compound according to any one of claims 1 to 17 or its isomers, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates, wherein the compound has one of the following structures:
A pharmaceutical composition, characterized in that it contains a pharmaceutically acceptable excipient or carrier, and a compound according to any one of claims 1 to 19 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as active ingredients.
A use of the compound according to any one of claims 1 to 19 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the pharmaceutical composition according to claim 20 in the preparation of a drug for treating diseases mediated by ULK protein kinase.
The use according to claim 21, wherein the disease is cancer, and the cancer is blood cancer and solid tumor.