ULK inhibitors

Abstract

A class of ULK inhibitors is disclosed. Specifically, the invention relates to a compound as shown in a general formula (1) and a preparation method thereof, and application of the compound as shown in the general formula (1) and isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates of the compound as ULK inhibitors in preparation of antitumor drugs. # imgabs0 #

Description

ULK inhibitors

[0001] This application claims priority to Chinese patent application No. 202211394301.8, filed on November 8, 2022. This application incorporates the entire text of the aforementioned Chinese patent application. Technical Field

[0002] The present invention belongs to the field of medicinal chemistry, and more specifically, relates to a new class of compounds with ULK inhibitory effect, a preparation method thereof, and the use of the new compounds in the preparation of anti-tumor drugs. Background Art

[0003] 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 cell (Klionsky, Nat. Rev. Mol. Cell Biol. 2007; 8: 931–937.). Tumor cells tend to activate autophagy because they 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 contribute to the progression of certain cancers and drug resistance (Rabinowitz, Science. 2010; 330: 1344–1348.). Some animal studies have also shown that autophagy is particularly important for tumor survival and growth, particularly in KRAS-driven tumors (Eng, Proc. Natl. Acad. Sci. USA. 2016;113:182–187; Guo, Genes Dev. 2013;27:1447–1461). Inhibiting 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). Furthermore, 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 approaches) with chemotherapy has been shown to suppress tumor growth and trigger tumor cell apoptosis to a greater extent than single-agent chemotherapy.

[0004] Autophagy induction is primarily controlled by the serine / threonine kinases ULK1 and ATG1. 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 generation of early autophagosomes. Cell-based experiments have also demonstrated that ULK1 deficiency affects autophagy. ULK1 gene deletion inhibits autophagy in cancer cells, reduces FOX3A conversion, and reduces the upregulation of the pro-apoptotic protein PUMA. In addition to the classical activation of canonical autophagy, ULK1 kinase activity has also been shown to require Bcl-2-L-13-mediated mitophagy (autophagy of damaged mitochondria). ULK1 and ULK2 kinases have also been shown to remodel glucose metabolism in cancer cells (Lee, Autophagy. 2011;7:689–695). Because ULK1 plays a key role in activating related cellular pathways and autophagy, it is considered an important druggable target for inhibiting autophagy. Recently, several 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;290:287–26; Wood, ACS Med. Chem. Lett. 2017;8:1258–1263). These compounds have deepened researchers' understanding of the ULK structure, validated the use of ULK inhibitors as an effective means of inhibiting autophagy, and provided practical evidence for the druggability of ULK. However, existing ULK inhibitors are not satisfactory in terms of efficacy and selectivity, and their use is limited. Therefore, the development of new targeted therapies with more potent ULK inhibitors and their combination with existing chemotherapeutics and / or other targeted therapeutics has important clinical value.

[0005] Summary of the Invention

[0006] The present invention provides a compound represented by general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

[0007] In the general formula (1):

[0008] Y is C(R 3) or N;

[0009] R 1 is selected from: halogen, cyano, C1-C5 alkyl or C3-C5 cycloalkyl, wherein the C1-C5 alkyl or C3-C5 cycloalkyl may be optionally substituted with one, two or three fluorine groups;

[0010] R 2 is selected from the group consisting of: 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 are optionally substituted with one, two, or three fluoro or cyano groups;

[0011] R 3 is selected from: H, halogen, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy may be optionally substituted with one or more fluorines;

[0012] Z is selected from the following groups: a) a 4-membered lactam ring bound via a nitrogen atom or a 6-10-membered lactam ring bound via a nitrogen atom, wherein when the lactam ring is a 6-10-membered ring, the atoms on the lactam ring can optionally be carbon, oxygen or NR 6 , and the carbon atoms on the 4-membered lactam ring or the 6-10-membered lactam can be optionally replaced by R 36 b) or an amide bonded via a nitrogen atom, wherein the carbonyl carbon atom of the amide is R 37 replace;

[0013] R 36 is independently selected at each occurrence from H, C1-C6 alkyl or C3-C6 cycloalkyl, wherein said C1-C6 alkyl or C3-C6 cycloalkyl may be optionally substituted with one or more fluorine, or two R 36 joined together with the carbon atom to which it is attached to form a C3-C6 cycloalkyl group;

[0014] R 37 independently selected from C1-C6 alkyl, C3-C6 cycloalkyl or (3-6 membered) heterocycloalkyl, wherein the carbon atoms on the C1-C6 alkyl, C3-C6 cycloalkyl or (3-6 membered) heterocycloalkyl may be optionally replaced by R 36 The heteroatom on the (3-6 membered) heterocycloalkyl group may optionally be oxygen or NR 6 ;

[0015] When Z is an amide bonded via a nitrogen atom, wherein the carbonyl carbon atom of the amide is replaced by R 37 When substituted, R 4 Selected from B1 or D 1 ;

[0016] B 1 is selected from heterocycloalkyl or heteroaryl groups connected via a nitrogen atom, wherein B 1 Optionally, one or more available carbons may be replaced by R 7 and optionally substituted on an available nitrogen by R 9 replace;

[0017] D 1 is selected from heterocycloalkyl or heteroaryl groups connected through carbon atoms, wherein D 1 Optionally, one or more available carbons may be replaced by R 7 and optionally substituted on an available nitrogen by R 9 replace;

[0018] R 7 is independently selected at each occurrence from: H, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, -N(R 5 )2, -(C1-C6)alkylene-N(R 5 )2 or (3-6 membered) heterocycloalkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl or (3-6 membered) heterocycloalkyl may be optionally substituted with one or more H or F; or two R 7 together with the atom to which it is attached to form an oxo group;

[0019] R 9 is independently selected at each occurrence from: H, C1-C6 alkyl, C3-C6 cycloalkyl, or (3-6 membered) heterocycloalkyl, wherein said C1-C6 alkyl, C3-C6 cycloalkyl, or (3-6 membered) heterocycloalkyl may be optionally substituted with one or more H, D, or F;

[0020] When Z is a 4-membered lactam ring bound via a nitrogen atom or a 6-10-membered lactam ring bound 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 can be optionally replaced by R 36 When substituted, R 4 Selected from B 2 or D 2 ;

[0021] B 2 is selected from heterocycloalkyl or heteroaryl groups connected via a nitrogen atom, wherein B 2 Optionally, one or more available carbons may be replaced by R 8 and optionally substituted on an available nitrogen by R 10 replace;

[0022] D 2 is selected from heterocycloalkyl or heteroaryl groups connected through carbon atoms, wherein D 2 Optionally, one or more available carbons may be replaced by R 8 and optionally substituted on an available nitrogen by R 10 replace;

[0023] R 8 is independently selected at each occurrence from: H, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, -N(R 5 )2, -(C1-C6)alkylene-N(R 5 )2 or (3-6 membered) heterocycloalkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl or (3-6 membered) heterocycloalkyl may be optionally substituted with one or more H or F; or two R 8 together with the atom to which it is attached to form an oxo group;

[0024] R 10 is independently selected at each occurrence from: C1-C6 alkyl, C3-C6 cycloalkyl, or (3-6 membered) heterocycloalkyl, wherein said C1-C6 alkyl, C3-C6 cycloalkyl, or (3-6 membered) heterocycloalkyl may be optionally substituted with one or more H, D, or F;

[0025] R 5 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;

[0026] R 6 is independently selected at each occurrence from: H, C1-C6 alkyl, C3-C6 cycloalkyl, or (3-6 membered) heterocycloalkyl, wherein said C1-C6 alkyl, C3-C6 cycloalkyl, or (3-6 membered) heterocycloalkyl may be optionally substituted with one or more F;

[0027] and n is 2, 3, or 4.

[0028] In another preferred embodiment, in the general formula (1), Z is selected from:

[0029] in,

[0030] V is selected from: oxygen, C(R 34 )2 and NR 9 ;

[0031] R 34 independently selected at each occurrence from H or R 36 , where R 36is independently selected at each occurrence from C1-C6 alkyl or C3-C6 cycloalkyl, or two R 36 joined together with the carbon atom to which it is attached to form a C3-C6 cycloalkyl group;

[0032] R 37 independently selected from C1-C3 alkyl, C3-C5 cycloalkyl or (3-6 membered) heterocycloalkyl, wherein the carbon atoms on the C1-C3 alkyl, C3-C5 cycloalkyl or (3-6 membered) heterocycloalkyl may be optionally replaced by R 36 The heteroatom on the (3-6 membered) heterocycloalkyl group may optionally be oxygen or NR 6 ;

[0033] q is 0, 1, 2, or 3; r is 2 or 4; and if q is 0, then r is not 2.

[0034] In another preferred embodiment, in the general formula (1), Z is selected from:

[0035] where R 34 independently selected at each occurrence from H or R 36 , where R 36 is independently selected at each occurrence from C1-C6 alkyl or C3-C6 cycloalkyl, or two R 36 Joined together with the carbon to which it is attached to form a C3-C6 cycloalkyl group.

[0036] In another preferred embodiment, in the general formula (1), Z is selected from:

[0037] In another preferred embodiment, wherein in the general formula (1), when Z is When R 4 Selected from:

[0038] where R 7 is independently selected at each occurrence from: H, cyano, -N(R 5 )2, C1-C3 alkyl, C3-C5 cycloalkyl or (3-5 membered) heterocycloalkyl, wherein the C1-C3 alkyl, C3-C5 cycloalkyl or (3-6 membered) heterocycloalkyl may be optionally substituted with one or more H or F, or two R 7 are linked together with the atom to which they are attached to form an oxo group;

[0039] R 9is 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 R 5 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.

[0040] In another preferred embodiment, wherein in the general formula (1), when Z is When R 4 Selected from:

[0041] In another preferred embodiment, wherein in the general formula (1), when Z is When R 4 Selected from:

[0042] In another preferred embodiment, wherein in the general formula (1), when Z is When R 4 Selected from:

[0043] In another preferred embodiment, wherein in the general formula (1), when Z is When R 4 Selected from: where R 8 is independently selected at each occurrence from: H, cyano, 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 or F, or two R 8 and the atoms to which they are attached to form an oxo group; R 10 is independently selected at each occurrence from: 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 or F; wherein R 5 is independently selected at each occurrence from: H, C1-C6 alkyl or C3-C6 cycloalkyl, wherein said C1-C6 alkyl or C3-C6 cycloalkyl may be optionally substituted with one or more F.

[0044] In another preferred embodiment, wherein in the general formula (1), when Z is When R 4 Selected from:

[0045] In another preferred embodiment, wherein in the general formula (1), when Z is When R 4 Selected from:

[0046] In another preferred embodiment, wherein in the general formula (1), when Z is When R 4 Selected from:

[0047] In another preferred embodiment, wherein in the general formula (1), R 1 is selected from the group consisting of halogen, C1-C3 alkyl or C3-C5 cycloalkyl, wherein the C1-C3 alkyl or C3-C5 cycloalkyl may be optionally substituted with one, two or three fluorine groups.

[0048] In another preferred embodiment, wherein in the general formula (1), R 1 Selected from: trifluoromethyl, F, Cl, Br, I or cyclopropyl.

[0049] In another preferred embodiment, wherein in the general formula (1), R 2 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 with one, two or three fluoro or cyano groups.

[0050] In another preferred embodiment, wherein in the general formula (1), R 2 Selected from: H, F, Cl, Br, Or -OCH3.

[0051] In another preferred embodiment, in the general formula (1), n=3.

[0052] In another preferred embodiment, the present invention provides a compound as described in formula (2a) or (2b):

[0053] where R 1 、R 2 、R 4 , Z and n are as defined above and are exemplified in the specific examples.

[0054] In another preferred embodiment, the present invention provides a compound as described in general formula (3a), (3b) or (3c):

[0055] where R 1 、R 2 、R 4 、R 34 、R 37 , Y, q, r and n are as defined above and are exemplified in the specific embodiments.

[0056] In another preferred embodiment, the present invention provides a compound as described in general formula (4a), (4b) or (4c):

[0057] where R 1 、R 2 、R 4 、R 34 、R 37 , Y, q and r are as defined above and are exemplified in the specific embodiments.

[0058] In various embodiments of the present invention, the compound of formula (1) has one of the following structures:

[0059] In various embodiments of the present invention, the compound of formula (1) has one of the following structures:

[0060] 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.

[0061] Another object of the present invention is to provide the use of the compound represented by general formula (1) of the present invention, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the pharmaceutical composition thereof, for preparing a medicament for treating, regulating or preventing diseases associated with ULK1 and / or ULK2. The disease is preferably cancer, and the cancer is a blood cancer or a solid tumor.

[0062] Another object of the present invention is to provide a method for treating, regulating or preventing diseases mediated by 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 salts, hydrates or solvates, or the above-mentioned pharmaceutical composition.

[0063] 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.

[0064] Synthesis of compounds

[0065] The following specifically describes the preparation methods of the compound of general formula (1) of the present invention, but these specific methods do not constitute any limitation to the present invention.

[0066] 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 may vary. The starting materials used in the synthesis of the compounds can be synthesized or obtained from commercial sources. The compounds described herein and other related compounds having different substituents can be synthesized using known techniques and starting materials, including those found in March, ADVANCED ORGANIC CHEMISTRY 4 th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 th Ed., Vols.A and B (Plenum 2000, 2001), Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3 rd Ed., (Wiley 1999). The general methods for the preparation of compounds can be modified by using appropriate reagents and conditions to introduce various groups into the formulae provided herein.

[0067] In one aspect, the compounds described herein are prepared according to methods known in the art. However, the conditions of the methods, such as reactants, solvents, bases, amounts of the compounds used, reaction temperatures, reaction times, etc., are not limited to the following explanations. 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 combinations can be easily performed by those skilled in the art. In one aspect, the present invention also provides a method for preparing the compound of formula (1), wherein the compound of formula (1) can be prepared using the following general reaction scheme 1:

[0068] General reaction scheme 1

[0069] The compound of formula (1) can be prepared according to the 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 an aromatic nucleophilic substitution reaction under alkaline conditions to produce compound 1-3. Compound 1-3 is oxidized to produce compound 1-4. 1-4 and 1-5 undergo an aromatic nucleophilic substitution reaction under acidic conditions to produce target compound 1-6.

[0070] Further forms of compounds

[0071] "Pharmaceutically acceptable" as used herein refers to a substance, 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 substance that does not cause undesirable biological effects or interact in a deleterious manner with any of its components when administered to a subject.

[0072] The term "pharmaceutically acceptable salt" refers to a form of a compound that does not cause significant irritation to the organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain specific aspects, pharmaceutically acceptable salts are obtained by reacting a compound of the formula with an acid or base, wherein the acid or base includes, but is not limited to, those found in Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use. st Acids and Bases in Ed., (Wiley, 2002).

[0073] It should be understood that references to pharmaceutically acceptable salts include solvent-added forms or crystallized 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, using organic solvents including, but 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 forms are considered to be equivalent to the unsolvated forms.

[0074] In other 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 polymorphic. Polymorphs include different lattice arrangements of the same elemental composition of the compound. Polymorphs generally 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 solvent, crystallization rate and storage temperature may cause a single crystalline form to dominate.

[0075] In another aspect, compounds of formula (1) may have chiral centers and / or axial chirality and thus occur as 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 intended to include all such isomeric forms of these compounds.

[0076] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I) and C-14( 14 C). For example, deuterated compounds can 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 non-deuterated drugs, deuterated drugs generally have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged drug half-life in vivo. All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of this invention.

[0077] Unless otherwise specified, any reference to an atom in the compounds of the present invention refers to its stable atomic isotope. Unless otherwise specified, when a position in a molecular structure is designated as "H" or "hydrogen," such position should be understood to have the natural abundance of the hydrogen isotope. Similarly, when a position is designated as "D" or "deuterium," such position should be understood to have a deuterium isotope abundance at least 3000 times its natural abundance (the natural abundance of the deuterium isotope is 0.015%).

[0078] 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).

[0079] the term

[0080] Unless otherwise indicated, the terms used in this application, including the specification and claims, are defined as follows. It should be noted that, throughout the specification and the appended claims, the singular forms "a," "an," and "an" include plural referents unless the context clearly indicates otherwise. Conventional methods, such as mass spectrometry, nuclear magnetic resonance, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology, are employed unless otherwise indicated. Throughout this application, the use of "or" or "and" means "and / or," unless otherwise indicated.

[0081] Unless otherwise specified, "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups having 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 C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, and C1-C2 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.

[0082] 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.

[0083] Unless otherwise specified, "alkenyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon double bond, including straight or branched chain 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 chain groups having 2-6 or 3-4 carbon atoms, referred to herein as C2-C6 alkenyl and C3-C4 alkenyl, respectively. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, and the like.

[0084] Unless otherwise specified, "alkenylene" refers to a divalent alkenyl group as defined above.

[0085] Unless otherwise specified, "alkynyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon triple bond, including straight and branched chain 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 chain groups having 2 to 6 or 3 to 6 carbon atoms, referred to herein as C2-C6 alkynyl and C3-C6 alkynyl, respectively. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, and the like.

[0086] Unless otherwise specified, "alkynylene" refers to a divalent alkynyl group as defined above.

[0087] Unless otherwise specified, "cycloalkyl" refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic or polycyclic), preferably containing 3 to 14 ring carbon atoms (C 3-14 In some embodiments, the cycloalkyl group has 3-10 ring carbon atoms (C 3-10 In some embodiments, a cycloalkyl group has 3-8 ring carbon atoms (C 3-8 In some embodiments, the cycloalkyl group has 3-7 ring carbon atoms (C 3-7 In some embodiments, the cycloalkyl group has 3-6 ring carbon atoms (C 3-6 In some embodiments, the cycloalkyl group has 4-6 ring carbon atoms (C 4-6 In some embodiments, the cycloalkyl group has 5-6 ring carbon atoms (C 5-6 In some embodiments, a cycloalkyl group has 5-10 ring carbon atoms (C 5-10Cycloalkyl). 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 spirocycles. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is bicyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is tricyclic. The ring-forming carbon atoms of the cycloalkyl group may optionally be oxidized to form an oxo or thio group. Cycloalkyl groups also include cycloalkylene groups. In some embodiments, the cycloalkyl group contains 0, 1, or 2 double bonds. In some embodiments, the cycloalkyl group contains 1 or 2 double bonds (partially unsaturated cycloalkyl groups). In some embodiments, the cycloalkyl group may be fused with an aryl group, a heteroaryl group, a cycloalkyl group, and a heterocycloalkyl group. In some embodiments, the cycloalkyl group may be fused with an aryl group, a cycloalkyl group, and a heterocycloalkyl group. In some embodiments, cycloalkyl groups can be fused with aryl groups and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused with aryl groups and cycloalkyl groups. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcaryl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, and the like.

[0088] Unless otherwise specified, "cycloalkylene" refers to a divalent cycloalkyl group as defined above.

[0089] Unless otherwise specified, "alkoxy" refers to an alkyl group bonded to the rest of the molecule through an ether oxygen atom. Representative alkoxy groups are those having 1 to 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 those substituted with one or more halogens. Preferred alkoxy groups are selected from OCH3, OCF3, CHF2O, CF3CH2O, i- PrO, n- PrO, i- BuO, n- BuO or t- BuO. As used herein, the term "alkoxyalkyl" refers to a straight or branched chain alkyl group attached to an oxygen group attached to a second straight or branched chain alkyl group (alkyl-O-alkyl-). Exemplary alkoxyalkyl groups include, but are not limited to, alkoxyalkyl groups in which each alkyl group independently contains 1 to 6 carbon atoms, referred to herein as C1-C6 alkoxy-C1-C6 alkyl. Exemplary alkoxyalkyl groups include, but are not limited to, methoxymethyl, 2-methoxyethyl, 1-methoxyethyl, 2-methoxypropyl, ethoxymethyl, 2-isopropoxyethyl, and the like.

[0090] Unless otherwise specified, "aryl" refers to a hydrocarbon aromatic group. Aryl 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.

[0091] Unless otherwise specified, "aryloxy" refers to an aryl group bonded to the rest of the molecule through an ethereal oxygen atom. Examples of aryloxy groups include, but are not limited to, phenoxy and naphthoxy.

[0092] 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.

[0093] 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 being independently selected from O, N or S, and the number of heteroatoms being 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, benzothienyl, 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,

[0094] Unless otherwise specified, "heteroarylene" refers to a divalent heteroaryl group as defined above.

[0095] 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, 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 membered heterocycloalkyl contains 1-2 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, 5-6 membered 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 certain embodiments, heterocycloalkyl is a monocyclic group having 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 thioxo or other oxidized bonds (e.g., C(O), S(O), C(S) or S(O) 2, N-oxide, etc.), or the nitrogen atom 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 the heterocycloalkyl ring (i.e., sharing a key therewith), such as a benzo derivative of piperidine, morpholine, azacycloheptatriene or thienyl. The heterocycloalkyl containing a fused aromatic ring can be connected via any ring-forming atom, including the ring-forming atom of the fused aromatic ring.Examples of heterocycloalkyl groups 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 , 4-nitro-2-nitro-1-pyridine, 4 ...1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine,

[0096] Unless otherwise specified, "heterocycloalkylene" refers to a divalent heterocycloalkyl group as defined above.

[0097] 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 substituted for 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 consisting of a 7-membered ring.

[0098] Unless otherwise specified, "oxo" refers to =0; for example, a carbonyl group substituted with an oxo group is a "carbonyl group." "; the group formed by sulfur being replaced by an oxo group is called "sulfinyl" ", the group formed by sulfur being substituted by two oxo groups is called "sulfonyl" ”.

[0099] 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 indicates 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.

[0100] Unless otherwise specified, the term "substituted" refers to a substituent group other than one or more hydrogen atoms on a specified atom or group that is substituted by one or more hydrogen atoms, without exceeding the normal valence of the specified atom. For example, one or more hydrogen atoms of an alkyl, alkylene, alkenyl, alkynyl, hydroxyl or amido group can be substituted by one or more substituent groups. Wherein the substituent group 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, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, mercaptan, thioketone or its combination. The definition of "substituted" does not include similar indefinite structures obtained by defining a substituent group having a further substituent group attached to infinity (for example, a substituted aryl group itself substituted by a substituted aryl group with a substituted alkyl group, which is further substituted by a substituted heteroalkyl group, etc.). Unless otherwise specified, the maximum number of consecutive substitutions in the compounds described herein is three. For example, a substituted aryl group is continuously substituted by two other substituted aryls to an aryl group substituted by ((substituted aryl) substituted aryl). Similarly, the above definition does not include substitution patterns that are not allowed (for example, a methyl group substituted by 5 fluorines or a heteroaryl group with two adjacent oxygen ring atoms). This substitution pattern that is not allowed is 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.

[0101] "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.

[0102] Unless otherwise specified, it will be understood that the word "comprise", or variations such as "comprises" or "comprising", imply the inclusion of a stated element or integer, or group of elements or integers, but not the exclusion of any other element or integer, or group of elements or integers.

[0103] 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 XLY represents a chemical bond, it means that the structure is actually XY.

[0104] The term "membered ring" includes any cyclic structure. The term "membered" refers to the number of atoms that make up the ring. For example, cyclohexyl, pyridyl, pyranyl, and thiopyranyl are six-membered rings, while cyclopentyl, pyrrolyl, furanyl, and thiophenyl are five-membered rings.

[0105] 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.

[0106] The term "isomer" means any tautomer, stereoisomer, isotope, enantiomer or diastereomer of any compound of the present invention. The compounds of the present invention may have one or more chiral centers or double bonds and therefore exist in stereoisomeric form, for example, as 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. Enantiomeric and stereoisomeric 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 as chiral salt complexes or crystallization of the compounds in chiral solvents. Enantiomers and stereoisomers can also be obtained from stereoisomerically pure or enantiomerically pure intermediates, reagents and catalysts by well-known asymmetric synthetic methods.

[0107] The term "isotopomers" refers to different molecules whose structures differ only in one isotope but are otherwise identical.

[0108] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed bond Indicate the relative configuration of stereocenters with a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Indicates a straight solid bond or straight dashed key

[0109] Unless otherwise stated, Indicates a single bond or a double bond.

[0110] Specific pharmaceutical and medical terms

[0111] The term "acceptable," as used herein, means that a prescribed ingredient or active ingredient has no undue adverse effect on health and well-being for the general purpose of treatment.

[0112] The terms "treat," "treatment," or "therapy" as used herein include alleviating, inhibiting, or ameliorating the symptoms of a disease or condition; inhibiting the development of complications; ameliorating or preventing underlying metabolic syndrome; inhibiting the development of a disease or symptom, such as controlling the progression of a disease or condition; alleviating a disease or symptom; causing a regression of 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, upon administration, can improve a disease, symptom, or condition, particularly by improving its severity, delaying its onset, slowing its progression, or reducing its duration. Whether the administration is fixed or temporary, continuous or intermittent, the circumstances attributable to or related to the administration can be explained.

[0113] "Active ingredient" refers to the compound of formula (1), as well as pharmaceutically acceptable inorganic or organic salts of the compound of 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 centers that may exist depend 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.

[0114] 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), induces a desired pharmaceutical and / or physiological response through local and / or systemic action.

[0115] The term "administered," "administering," or "administration" as used herein refers to the direct administration of the compound or composition, or the administration of a prodrug, derivative, or analog of the active compound.

[0116] Although the numerical ranges and parameters used to define the broader scope of the present invention are approximate, the numerical values ​​of the specific examples are presented herein as precisely as possible. However, any numerical value inherently and inevitably contains standard deviations resulting from individual testing methods. As used herein, "about" generally refers to the actual value being within plus or minus 10%, 5%, 1%, or 0.5% of a particular value or range. Alternatively, the term "about" means that the actual value falls within an acceptable standard error of the mean, as determined by one skilled in the art. Except in the experimental examples, or unless otherwise expressly indicated, all ranges, amounts, values, and percentages used herein (e.g., to describe material amounts, time periods, temperatures, operating conditions, quantitative ratios, and the like) are to be understood as modified by the word "about." Therefore, unless otherwise indicated, the numerical parameters disclosed in this specification and the appended claims are approximate and may be modified as needed. At a minimum, these numerical parameters should be understood to include the number of significant digits indicated and to include normal rounding.

[0117] Unless otherwise defined in this specification, the scientific and technical terms used herein have the same meanings as commonly understood by those skilled in the art. In addition, unless otherwise defined in this specification, singular terms used in this specification include the plural form of the term, and plural terms also include the singular form of the term, unless otherwise defined in the context.

[0118] Therapeutic uses

[0119] 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. Accordingly, in certain embodiments, the present 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).

[0120] In some embodiments, a method for treating cancer is provided, comprising administering to a subject 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 hematological cancer or 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.

[0121] Route of administration

[0122] The compounds of the present invention and their pharmaceutically acceptable salts can be formulated into various formulations containing a safe and effective amount of the compounds of the present invention or their pharmaceutically acceptable salts and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. The safe and effective amount of the compound will be determined based on the patient's age, condition, and duration of treatment, among other factors.

[0123] "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, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0124] The compounds of the present invention may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), or topically.

[0125] 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, starches, 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) disintegrants, for example, agar, calcium carbonate, potato 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 glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0126] Solid dosage forms such as tablets, dragees, 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 opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0127] 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, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0128] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0129] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0130] Compositions for parenteral injection may comprise 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.

[0131] Dosage forms for topical administration of the compounds of this 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.

[0132] 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 (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 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 patient's health status, all of which are within the skill of a skilled physician.

[0133] The features described above, or in the embodiments, may be combined in any combination. All features disclosed in this specification may be used in any combination, and each feature disclosed in this specification may be replaced by any alternative feature that serves the same, equivalent, or similar purpose. Therefore, unless otherwise specified, the features disclosed are merely general examples of equivalent or similar features. DETAILED DESCRIPTION

[0134] The following description will elaborate on various specific aspects, characteristics, and advantages of the above-mentioned compounds, methods, and pharmaceutical compositions so that the present invention will be readily apparent. It should be understood that the following detailed description and examples describe specific embodiments and are provided for reference only. After reading the present description, those skilled in the art may make various changes or modifications to the present invention, and such equivalents are within the scope of the present invention.

[0135] In all embodiments, 1 H-NMR was recorded on a Varian Mercury 400 nuclear magnetic resonance instrument, and chemical shifts are expressed in δ (ppm). Silica gel used for separation was 200-300 mesh unless otherwise specified, and the eluent ratios were by volume.

[0136] The present invention uses the following abbreviations: AlCl3 represents aluminum chloride; (Boc)2O represents di-tert-butyl dicarbonate; CDCl3 represents deuterated chloroform; CH3NO2 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)propane )pyridine; DMSO represents dimethyl sulfoxide; HATU represents O-(7-azabenzotriazol-1-yl)-NNN′N′-tetramethyluronium hexafluorophosphate; IPA represents isopropyl alcohol; min represents minute; K2CO3 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; POCl3 represents phosphorus oxychloride; TEA represents triethylamine; TFA represents trifluoroacetic acid; m-CPBA represents m-chloroperbenzoic acid; and TLC represents thin-layer chromatography.

[0137] 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)

[0138] Step 1: Synthesis of compound int1_2

[0139] 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 and dissolved in IPA (20 mL). DIPEA (1.12 g, 8.75 mmol) was added and reacted at room temperature for 1 hour. The reaction was complete as detected by LC-MS. The solvent was removed by concentration under reduced pressure to obtain int1_2 (810 mg, yield 100%), which was directly used in the next reaction.

[0140] ESI-MS m / z:367[M+H] + .

[0141] Step 2: Synthesis of compound int1_3

[0142] Int1_2 (810 mg, 2.19 mmol) was placed in a 250 mL round-bottom flask and dissolved in DCM (10 mL). TFA (7 mL) was then added and allowed to react at room temperature for 1 hour. LC-MS confirmed the reaction was complete. The solvent was removed by concentration under reduced pressure to obtain the crude product, which was used directly in the next step.

[0143] ESI-MS m / z:267[M+H] + .

[0144] Step 3: Synthesis of compound int1_4

[0145] The crude product of int1_3 was added to TEA, and the pH value was adjusted to 10-11, and cyclobutanecarboxylic acid chloride (354 mg, 2.99 mmol) was added and reacted at room temperature for 0.5 hours. The reaction was completed by LC-MS detection, and the reaction was carried out by rapid liquid preparative chromatography (120 g C-18 Flash Column, ACN / 1‰ TFA aqueous solution) was purified to give int1_4 (342 mg, yield 35.7%).

[0146] ESI-MS m / z:349[M+H] + .

[0147] Step 4: Synthesis of compound int1_5

[0148] Int1_4 (60 mg, 172 μmol) was placed in a 250 mL round-bottom flask and dissolved in DCM (4 mL). m-CPBA (45 mg, 258 μmol) was then added and allowed to react at room temperature for 0.5 hours. LC-MS confirmed the reaction was complete. The reaction mixture was filtered, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent, yielding int1_5 (62 mg, 98.8% yield), which was used in the next step.

[0149] ESI-MS m / z:365[M+H] + .

[0150] Step 4: Synthesis of compound int1_8

[0151] 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 dissolved in DMF (20 mL). Potassium carbonate (3.86 g, 29.6 mmol) was then added and allowed to react overnight at room temperature. LC-MS confirmed the reaction was complete. The reaction mixture was stirred with water, and the filter cake was filtered and dried to yield int1_8 (3.5 g, 100% yield), which was used in the next step.

[0152] ESI-MS m / z:383[M+H] + .

[0153] Step 5: Synthesis of compound int1_9

[0154] 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 the mixture. Potassium carbonate (552 mg, 4.00 mmol) and dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium (127.7 mg, 174 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 chromatography (120 g C-18 Flash Column, ACN / 1‰ TFA aqueous solution) was purified to give int1_9 (50 mg, yield 8.3%).

[0155] ESI-MS m / z:345[M+H] + .

[0156] Step 6: Synthesis of compound int1_10

[0157] Int1_9 (50 mg, 145 μmol) was placed in a 100 mL round-bottom flask and dissolved in methanol (5 mL). Acetic acid (0.4 mL) and zinc powder (400 mg) were then added and allowed to react at room temperature for 0.5 hours. LC-MS confirmed the reaction was complete. The reaction mixture was adjusted to pH 7-8 by adding saturated sodium bicarbonate solution, filtered, and the filtrate was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded int1_10 (46 mg, 92% yield).

[0158] ESI-MS m / z:315[M+H] + .

[0159] 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)

[0160] Int1_5 (63 mg, 172 μmol) was dissolved in DMF (5 mL), int1_10 (54 mg, 172 μmol) was added, and 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 fast liquid chromatography (120 g The residue was purified by C-18 Flash Column (ACN / 10 nM aqueous ammonium bicarbonate solution) to give compound 1 (12.8 mg, yield 11.2%).

[0161] ESI-MS m / z:616[M+H] + .

[0162] 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)

[0163] Step 1: Synthesis of compound int2_1

[0164] Int1_8 (382 mg, 1.00 mmol) and potassium vinyl 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. 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 chromatography (120 g C-18 Flash Column, ACN / 1‰ TFA aqueous solution) was used to obtain int2_1 (88 mg, yield 26.7%).

[0165] ESI-MS m / z:331[M+H] + .

[0166] Step 2: Synthesis of compound int2_2

[0167] Int2_1 (88 mg, 267 μmol) was placed in a 50 mL round-bottom flask and dissolved in methanol (5 mL). Palladium on carbon (10%, 20 mg) was then added and the mixture was allowed to react at room temperature for 2 hours under a hydrogen atmosphere. LC-MS confirmed the reaction was complete. The reaction mixture was filtered, and the residue was washed with methanol. The filtrate was concentrated under reduced pressure to yield int2_2 (78 mg, 96.7% yield).

[0168] ESI-MS m / z:303[M+H] + .

[0169] 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)

[0170] Int1_5 (94 mg, 258 μmol) was dissolved in DMF (5 mL), int2_2 (78 mg, 258 μmol) was added, and 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 fast liquid chromatography (120 g The product was purified by C-18 Flash Column (ACN / 10 nM aqueous ammonium bicarbonate solution) to give compound 2 (17.1 mg, yield 11.0%).

[0171] ESI-MS m / z:603[M+H] + .

[0172] 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)

[0173] Step 1: Synthesis of compound int3_1

[0174] 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. 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 chromatography (120 g The product was purified by C-18 Flash Column (ACN / 1‰ TFA aqueous solution) to afford int3_1 (104 mg, yield 30.1%).

[0175] ESI-MS m / z:331[M+H] + .

[0176] Step 2: Synthesis of compound int3_2

[0177] Int3_1 (104 mg, 301 μmol) was placed in a 50 mL round-bottom flask and dissolved in methanol (5 mL). Palladium on carbon (10%, 50 mg) was then added and the mixture was allowed to react at room temperature for 2 hours under a hydrogen atmosphere. LC-MS confirmed the reaction was complete. The reaction mixture was filtered, and the residue was washed with methanol. The filtrate was concentrated under reduced pressure to yield int3_2 (81 mg, 85.0% yield).

[0178] ESI-MS m / z:317[M+H] + .

[0179] 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)

[0180] Int1_5 (93 mg, 256 μmol) was dissolved in DMF (5 mL), int3_2 (81 mg, 256 μmol) was added, and 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 fast liquid chromatography (120 g The residue was purified by C-18 Flash Column (ACN / 10 nM aqueous ammonium bicarbonate solution) to give compound 3 (22.0 mg, yield 13.8%).

[0181] ESI-MS m / z:617[M+H] + .

[0182] 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)

[0183] Step 1: Synthesis of compound int4_1

[0184] 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 the mixture. 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 preparative liquid chromatography (120 g C-18 Flash Column, ACN / 1‰ TFA aqueous solution) was purified to give int4_1 (77 mg, yield 24.2%).

[0185] ESI-MS m / z:319[M+H] + .

[0186] Step 2: Synthesis of compound int4_2

[0187] Int4_1 (77 mg, 242 μmol) was placed in a 100 mL round-bottom flask and dissolved in methanol (5 mL). Acetic acid (0.4 mL) and zinc powder (400 mg) were then added and allowed to react at room temperature for 0.5 hours. LC-MS confirmed the reaction was complete. The reaction mixture was adjusted to pH 7-8 by adding saturated sodium bicarbonate solution, filtered, and the filtrate was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded int4_2 (69 mg, 98.8% yield).

[0188] ESI-MS m / z:289[M+H] + .

[0189] 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)

[0190] Int1_5 (87 mg, 239 μmol) was dissolved in DMF (5 mL), int4_2 (88 mg, 239 μmol) was added, and 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 fast liquid chromatography (120 g The residue was purified by C-18 Flash Column (ACN / 10 nM aqueous ammonium bicarbonate solution) to give compound 4 (9.5 mg, yield 6.8%).

[0191] ESI-MS m / z:589[M+H] + .

[0192] 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)

[0193] Step 1: Synthesis of compound int5_1

[0194] 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. 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 chromatography (120 g The product was purified by C-18 Flash Column (ACN / 1‰ TFA aqueous solution) to give int5_1 (105 mg, yield 29.3%).

[0195] ESI-MS m / z:319[M+H] + .

[0196] Step 2: Synthesis of compound int5_2

[0197] Int5_1 (77 mg, 242 μmol) was placed in a 100 mL round-bottom flask and dissolved in methanol (5 mL). Acetic acid (0.4 mL) and zinc powder (400 mg) were then added and allowed to react at room temperature for 0.5 hours. LC-MS confirmed the reaction was complete. The reaction mixture was adjusted to pH 7-8 by adding saturated sodium bicarbonate solution, filtered, and the filtrate was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded int5_2 (61 mg, 76.7% yield).

[0198] ESI-MS m / z:329[M+H] + .

[0199] 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)

[0200] Int1_5 (68 mg, 186 μmol) was dissolved in DMF (5 mL), int5_2 (61 mg, 186 μmol) was added, and 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 subjected to fast liquid preparative chromatography (120 g The product was purified by C-18 Flash Column (ACN / 10 nM aqueous ammonium bicarbonate solution) to give compound 5 (10.2 mg, yield 8.7%).

[0201] ESI-MS m / z:629[M+H] + .

[0202] 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)

[0203] 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)

[0204] Int1_5 (182 mg, 500 μmol) was dissolved in DMF (5 mL), int6_1 (152 mg, 500 μmol) was added, and 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 fast liquid chromatography (120 g The product was purified by C-18 Flash Column, ACN / 10 nM aqueous ammonium bicarbonate solution to give compound 7 (55.9 mg, yield 18.5%).

[0205] ESI-MS m / z:605[M+H] + .

[0206] 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)

[0207] Step 1: Synthesis of compound int7_2

[0208] Int7_1 (338 mg, 1.00 mmol) and potassium methyltrifluoroborate (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 the mixture. Potassium carbonate (553 mg, 4.00 mmol) and dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium (78 mg, 100 μmol) were then added. The mixture was heated to 80°C under argon for 1.0 hour. LC-MS confirmed the reaction was complete. Ethyl acetate was added to the reaction solution, which was washed three times with saturated brine. The organic phase was dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure, and the residue was purified by normal phase silica gel chromatography (PE / EA) to afford int7_2 (155 mg, 64.0% yield).

[0209] ESI-MS m / z:243[M+H] + .

[0210] Step 2: Synthesis of compound int7_3

[0211] Int1_6 (141 mg, 768 μmol) and int7_2 (155 mg, 640 μmol) were placed in a 25 mL round-bottom flask and dissolved in DMF (5 mL). Triethylamine (194 mg, 1.92 mmol) was then added and allowed to react at 90°C for 3 hours. LC-MS confirmed the reaction was complete. The reaction mixture was stirred with water, and the filter cake was filtered and dried to yield int7_3 (249 mg, 100% yield), which was used in the next step.

[0212] ESI-MS m / z:390[M+H] + .

[0213] Step 3: Synthesis of compound int7_4

[0214] 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. LC-MS confirmed the reaction was complete. The reaction mixture was adjusted to pH 7-8 by adding saturated sodium bicarbonate solution, extracted three times with ethyl acetate, and the organic phase dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure to afford int7_4 (180 mg, 97.3% yield), which was used directly in the next step.

[0215] ESI-MS m / z:290[M+H] + .

[0216] 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)

[0217] Int1_5 (126 mg, 345 μmol) was dissolved in DMF (5 mL), int7_4 (100 mg, 345 μmol) was added, and TFA (118 mg, 1035 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 (120 g The product was purified by C-18 Flash Column, ACN / 10 nM aqueous ammonium bicarbonate solution to give compound 12 (33.1 mg, yield 16.3%).

[0218] ESI-MS m / z:590[M+H] + .

[0219] 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)

[0220] Step 1: Synthesis of compound int8_2

[0221] Int7_1 (338 mg, 1.00 mmol) and potassium ethyltrifluoroborate (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 the mixture. Potassium carbonate (553 mg, 4.00 mmol) and dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium (78 mg, 100 μmol) were then added. The mixture was heated to 80°C under argon for 1.0 hour. LC-MS confirmed the reaction was complete. Ethyl acetate was added to the reaction solution, which was washed three times with saturated brine. The organic phase was dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure, and the residue was purified by normal phase silica gel chromatography (PE / EA) to afford int8_2 (199 mg, 77.5% yield).

[0222] ESI-MS m / z:257[M+H] + .

[0223] Step 2: Synthesis of compound int8_3

[0224] Int1_6 (170 mg, 930 μmol) and int8_2 (199 mg, 775 μmol) were placed in a 25 mL round-bottom flask and dissolved in DMF (5 mL). Triethylamine (234 mg, 2.32 mmol) was then added and allowed to react at 90°C for 3 hours. LC-MS confirmed the reaction was complete. The reaction mixture was stirred with water, and the filter cake was filtered and dried to yield int8_3 (309 mg, 98.9% yield), which was used in the next step.

[0225] ESI-MS m / z:404[M+H] + .

[0226] Step 3: Synthesis of compound int8_4

[0227] 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. LC-MS confirmed the reaction was complete. The reaction mixture was adjusted to pH 7-8 by adding saturated sodium bicarbonate solution, extracted three times with ethyl acetate, and the organic phase dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure to afford int8_4 (231 mg, 99.1% yield), which was used directly in the next step.

[0228] ESI-MS m / z:304[M+H] + .

[0229] 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)

[0230] Int1_5 (78 mg, 215 μmol) was dissolved in DMF (5 mL), int8_4 (130 mg, 215 μmol) was added, and 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 fast liquid chromatography (120 g The residue was purified by C-18 Flash Column (ACN / 10 nM aqueous ammonium bicarbonate solution) to give compound 13 (21.7 mg, yield 16.7%).

[0231] ESI-MS m / z:604[M+H] + .

[0232] 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)

[0233] Step 1: Synthesis of compound int9_2

[0234] 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 the mixture. Potassium carbonate (553 mg, 4.00 mmol) and dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium (78 mg, 100 μmol) were then added. The mixture was heated to 80°C under argon for 1.0 hour. LC-MS confirmed the reaction was complete. Ethyl acetate was added to the reaction solution, which was washed three times with saturated brine. The organic phase was dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure, and the residue was purified by normal phase silica gel chromatography (PE / EA) to afford int9_2 (104 mg, 38.4% yield).

[0235] ESI-MS m / z:271[M+H] + .

[0236] Step 2: Synthesis of compound int9_3

[0237] Int1_6 (84 mg, 461 μmol) and int9_2 (104 mg, 384 μmol) were placed in a 25 mL round-bottom flask and dissolved in DMF (5 mL). Triethylamine (116 mg, 1.15 mmol) was then added and allowed to react at 90°C for 3 hours. LC-MS confirmed the reaction was complete. The reaction mixture was stirred with water, and the filter cake was filtered and dried to yield int9_3 (160 mg, 100% yield), which was used in the next step.

[0238] ESI-MS m / z:418[M+H] + .

[0239] Step 3: Synthesis of compound int9_4

[0240] 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. LC-MS confirmed the reaction was complete. The reaction mixture was adjusted to pH 7-8 by adding saturated sodium bicarbonate solution, extracted three times with ethyl acetate, and the organic phase dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure to afford int9_4 (114 mg, 93.7% yield), which was used directly in the next step.

[0241] ESI-MS m / z:318[M+H] + .

[0242] 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)

[0243] Int1_5 (131 mg, 360 μmol) was dissolved in DMF (5 mL), int9_4 (114 mg, 360 μmol) was added, and 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 fast liquid chromatography (120 g The residue was purified by C-18 Flash Column (ACN / 10 nM aqueous ammonium bicarbonate solution) to give compound 14 (39.0 mg, yield 17.5%).

[0244] ESI-MS m / z:618[M+H] + .

[0245] 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)

[0246] Step 1: Synthesis of compound int10_2

[0247] 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 the mixture. Potassium carbonate (553 mg, 4.00 mmol) and dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium (78 mg, 100 μmol) were then added. The mixture was heated to 80°C under argon for 1.0 hour. LC-MS confirmed the reaction was complete. Ethyl acetate was added to the reaction solution, which was washed three times with saturated brine. The organic phase was dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure, and the residue was purified by normal phase silica gel chromatography (PE / EA) to afford int10_2 (98 mg, 36.5% yield).

[0248] ESI-MS m / z:269[M+H] + .

[0249] Step 2: Synthesis of compound int10_3

[0250] Int1_6 (80 mg, 438 μmol) and int10_2 (98 mg, 365 μmol) were placed in a 25 mL round-bottom flask and dissolved in DMF (5 mL). Triethylamine (111 mg, 1.09 mmol) was then added and the mixture was allowed to react at 90°C for 3 hours. LC-MS confirmed the reaction was complete. The reaction mixture was stirred with water, and the filter cake was filtered and dried to yield int10_3 (138 mg, 90.8% yield), which was used in the next step.

[0251] ESI-MS m / z:416[M+H] + .

[0252] Step 3: Synthesis of compound int10_4

[0253] 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. LC-MS confirmed the reaction was complete. The reaction mixture was adjusted to pH 7-8 by adding saturated sodium bicarbonate solution, extracted three times with ethyl acetate, and the organic phase dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure to afford int10_4 (97 mg, 92.9% yield), which was used directly in the next step.

[0254] ESI-MS m / z:316[M+H] + .

[0255] 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)

[0256] Int1_5 (112 mg, 307 μmol) was dissolved in DMF (5 mL), int10_4 (97 mg, 307 μmol) was added, and 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 fast liquid chromatography (120 g The residue was purified by C-18 Flash Column (ACN / 10 nM aqueous ammonium bicarbonate solution) to give compound 15 (10.4 mg, yield 5.5%).

[0257] ESI-MS m / z:616[M+H] + .

[0258] 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)

[0259] Step 1: Synthesis of compound int11_2

[0260] 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 the mixture. Potassium carbonate (553 mg, 4.00 mmol) and dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium (78 mg, 100 μmol) were then added. The mixture was heated to 80°C under argon for 1.0 hour. LC-MS confirmed the reaction was complete. Ethyl acetate was added to the reaction solution, which was washed three times with saturated brine. The organic phase was dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure, and the residue was purified by normal phase silica gel chromatography (PE / EA) to afford int11_2 (105 mg, 37.4% yield).

[0261] ESI-MS m / z:283[M+H] + .

[0262] Step 2: Synthesis of compound int11_3

[0263] Int1_6 (82 mg, 449 μmol) and int11_2 (105 mg, 374 μmol) were placed in a 25 mL round-bottom flask and dissolved in DMF (5 mL). Triethylamine (113 mg, 1.12 mmol) was then added and allowed to react at 90°C for 3 hours. LC-MS confirmed the reaction was complete. The reaction mixture was stirred with water, and the filter cake was filtered and dried to yield int11_3 (152 mg, 94.5% yield), which was used in the next step.

[0264] ESI-MS m / z:430[M+H] + .

[0265] Step 3: Synthesis of compound int11_4

[0266] 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. LC-MS confirmed the reaction was complete. The reaction mixture was adjusted to pH 7-8 by adding saturated sodium bicarbonate solution, extracted three times with ethyl acetate, and the organic phase dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure to afford int11_4 (113 mg, 97.0% yield), which was used directly in the next step.

[0267] ESI-MS m / z:330[M+H] + .

[0268] 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)

[0269] Int1_5 (125 mg, 342 μmol) was dissolved in DMF (5 mL), int11_4 (113 mg, 342 μmol) was added, and 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 fast liquid chromatography (120 g The residue was purified by C-18 Flash Column (ACN / 10 nM aqueous ammonium bicarbonate solution) to give compound 16 (18.6 mg, yield 8.6%).

[0270] ESI-MS m / z:630[M+H] + .

[0271] 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)

[0272] Step 1: Synthesis of compound int12_2

[0273] Int1_6 (220 mg, 1200 μmol) and int12_1 (188 mg, 1000 μmol) were placed in a 25 mL round-bottom flask and dissolved in DMF (5 mL). Triethylamine (303 mg, 3.00 mmol) was then added and reacted at 90°C for 3 hours. LC-MS confirmed the reaction was complete. The reaction mixture was stirred with water, and the filter cake was filtered and dried to yield int11_3 (307 mg, 91.6% yield), which was used in the next step.

[0274] ESI-MS m / z:336[M+H] + .

[0275] Step 2: Synthesis of compound int12_3

[0276] Int12_3 (307 mg, 916 μmol) was placed in a 50 mL round-bottom flask and dissolved in methanol (15 mL). Palladium on carbon (10%, 50 mg) was then added and the mixture was allowed to react at room temperature for 2 hours under a hydrogen atmosphere. LC-MS confirmed the reaction was complete. The reaction mixture was filtered, and the residue was washed with methanol. The filtrate was concentrated under reduced pressure to yield int12_3 (206 mg, 73.6% yield).

[0277] ESI-MS m / z:306[M+H] + .

[0278] 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)

[0279] Int1_5 (119 mg, 327 μmol) was dissolved in DMF (5 mL), int12_3 (100 mg, 327 μmol) was added, and 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 fast liquid chromatography (120 g The residue was purified by C-18 Flash Column (ACN / 10 nM aqueous ammonium bicarbonate solution) to give compound 16 (19.9 mg, yield 10.0%).

[0280] ESI-MS m / z:606[M+H] + .

[0281] 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)

[0282] Step 1: Synthesis of compound int13_2

[0283] 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 dissolved in DMF (10 mL). Potassium carbonate (829 mg, 6.0 mmol) was then added and allowed to react at room temperature overnight. LC-MS confirmed the reaction was complete. The reaction mixture was stirred with water, and the filter cake was filtered and dried to yield int13_2 (680 mg, 99.1% yield), which was used in the next step.

[0284] ESI-MS m / z:344[M+H] + .

[0285] Step 2: Synthesis of compound int13_3

[0286] 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 the mixture was heated to 65°C under argon protection for 2 hours. The reaction was completed by LC-MS. The reaction solution was added with a saturated sodium bicarbonate solution to adjust the pH to 7-8, and the solvent was removed by concentration under reduced pressure. The residue was purified by fast liquid chromatography (120 g C-18 Flash Column, ACN / 1‰ TFA aqueous solution) was used to obtain int13_3 (346 mg, yield 58.6%).

[0287] ESI-MS m / z:299[M+H] + .

[0288] Step 3: Synthesis of compound int13_5

[0289] Int13_3 (346 mg, 1161 μmol) was placed in a 100 mL round-bottom flask, and dichloroethane (10 mL) was added to dissolve it. Int13_4 (290 mg, 2.3 mmol) and a drop of acetic acid were added and reacted at room temperature for 0.5 hours. 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. The reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was purified by fast liquid chromatography (120 g C-18 Flash Column, ACN / 1‰ TFA aqueous solution) was used for purification to afford int13_5 (299 mg, yield 63.0%).

[0290] ESI-MS m / z:409[M+H] + .

[0291] Step 4: Synthesis of compound int13_6

[0292] 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. 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, washed with saturated brine 3 times, and the organic phase was dried over anhydrous sodium sulfate. After concentrating 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) was purified to give int13_6 (114 mg, yield 42.1%).

[0293] ESI-MS m / z:371[M+H] + .

[0294] Step 5: Synthesis of compound int13_7

[0295] Int13_7 (114 mg, 308 μmol) was placed in a 50 mL round-bottom flask and dissolved in methanol (5 mL). Palladium on carbon (10%, 50 mg) was then added and the mixture was allowed to react at room temperature for 2 hours under a hydrogen atmosphere. LC-MS confirmed the reaction was complete. The reaction mixture was filtered, and the residue was washed with methanol. The filtrate was concentrated under reduced pressure to yield int13_7 (99 mg, 94.4% yield).

[0296] ESI-MS m / z:341[M+H] + .

[0297] 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)

[0298] Int1_5 (106 mg, 291 μmol) was dissolved in DMF (5 mL), int13_7 (99 mg, 291 μmol) was added, and 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 fast liquid chromatography (120 g The residue was purified by C-18 Flash Column (ACN / 10 nM aqueous ammonium bicarbonate solution) to give compound 1 (28.7 mg, yield 15.4%).

[0299] ESI-MS m / z:641[M+H] + .

[0300] 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)

[0301] Step 1: Synthesis of compound int14_2

[0302] 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 and dissolved in IPA (20 mL). DIPEA (1.03 g, 8.00 mmol) was added and allowed to react at room temperature for 1 hour. LC-MS confirmed the reaction was complete, and the solvent was removed by concentration under reduced pressure to afford int14_2 (755 mg, 100% yield), which was used directly in the next step.

[0303] ESI-MS m / z:377[M+H] + .

[0304] Step 2: Synthesis of compound int14_3

[0305] Int14_2 (755 mg, 2.00 mmol) was placed in a 250 mL round-bottom flask and dissolved in DCM (10 mL). TFA (7 mL) was then added and allowed to react at room temperature for 1 hour. LC-MS confirmed the reaction was complete. The solvent was removed by concentration under reduced pressure to obtain the crude product, which was used directly in the next step.

[0306] ESI-MS m / z:277[M+H] + .

[0307] Step 3: Synthesis of compound int14_4

[0308] The crude product of int14_3 was added to TEA, and the pH value was adjusted to 10-11, and cyclobutanecarboxylic acid chloride (355 mg, 3.00 mmol) was added and reacted at room temperature for 0.5 hours. The reaction was completed by LC-MS detection, and the reaction was carried out by rapid liquid preparative chromatography (120 g C-18 Flash Column, ACN / 1‰ TFA aqueous solution) was used to obtain int14_4 (318 mg, yield 44.2%).

[0309] ESI-MS m / z:359[M+H] + .

[0310] Step 4: Synthesis of compound int1_5

[0311] Int14_4 (100 mg, 278 μmol) was placed in a 50 mL round-bottom flask and dissolved in DCM (4 mL). m-CPBA (85 mg, 417 μmol) was then added and allowed to react at room temperature for 0.5 hours. LC-MS confirmed the reaction was complete. The reaction mixture was filtered, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent, yielding int14_5 (97 mg, 92.9% yield), which was used in the next step.

[0312] ESI-MS m / z:375[M+H] + .

[0313] 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)

[0314] Int14_5 (97 mg, 258 μmol) was dissolved in DMF (5 mL), int4_2 (74 mg, 258 μmol) was added, and 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 subjected to fast preparative liquid chromatography (120 g The residue was purified by C-18 Flash Column (ACN / 10 nM aqueous ammonium bicarbonate solution) to give compound 46 (12.3 mg, yield 8.0%).

[0315] ESI-MS m / z:599[M+H] + .

[0316] 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)

[0317] 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)

[0318] 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 fast liquid chromatography (120 g The residue was purified by C-18 Flash Column, ACN / 10 nM aqueous ammonium bicarbonate solution to afford compound 47 (20.0 mg, yield 12.2%).

[0319] ESI-MS m / z:613[M+H] + .

[0320] 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)

[0321] 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)

[0322] Int14_5 (100 mg, 266 μmol) was dissolved in DMF (5 mL), int3_2 (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 fast liquid chromatography (120 g The residue was purified by C-18 Flash Column, ACN / 10 nM aqueous ammonium bicarbonate solution to afford compound 48 (25.7 mg, yield 15.4%).

[0323] ESI-MS m / z:627[M+H] + .

[0324] 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)

[0325] 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)

[0326] 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 fast liquid chromatography (120 g The residue was purified by C-18 Flash Column, ACN / 10 nM aqueous ammonium bicarbonate solution) to give compound 49 (23.2 mg, yield 13.9%).

[0327] ESI-MS m / z:625[M+H] + .

[0328] 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)

[0329] 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)

[0330] Int14_5 (100 mg, 266 μmol) was dissolved in DMF (5 mL), int5_2 (88 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 fast liquid chromatography (120 g The residue was purified by C-18 Flash Column, ACN / 10 nM aqueous ammonium bicarbonate solution) to give compound 50 (30.4 mg, yield 17.8%).

[0331] ESI-MS m / z:639[M+H] + .

[0332] 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)

[0333] 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)

[0334] Int14_5 (100 mg, 266 μmol) was dissolved in DMF (5 mL), int5_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 fast liquid chromatography (120 g The residue was purified by C-18 Flash Column (ACN / 10 nM aqueous ammonium bicarbonate solution) to give compound 52 (22.5 mg, yield 13.7%).

[0335] ESI-MS m / z:615[M+H] + .

[0336] 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)

[0337] Step 1: Synthesis of compound int20_1

[0338] 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 the mixture. Potassium carbonate (829 mg, 6.00 mmol) and dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium (147 mg, 200 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 preparative liquid chromatography (120 g C-18 Flash Column, ACN / 1‰ TFA aqueous solution) was purified to give int1_9 (399 mg, yield 62.1%).

[0339] ESI-MS m / z:321[M+H] + .

[0340] Step 2: Synthesis of compound int20_2

[0341] Int20_1 (100 mg, 297 μmol) was placed in a 50 mL round-bottom flask and dissolved in DCM (4 mL). m-CPBA (90 mg, 446 μmol) was then added and allowed to react at room temperature for 0.5 hours. LC-MS confirmed the reaction was complete. The reaction mixture was filtered, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent, yielding int20_2 (100 mg, 95.2% yield), which was used in the next step.

[0342] ESI-MS m / z:337[M+H] + .

[0343] Step 3: 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)

[0344] Int20_2 (100 mg, 297 μmol) was dissolved in DMF (5 mL), int4_2 (86 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 subjected to fast preparative liquid chromatography (120 g The residue was purified by C-18 Flash Column, ACN / 10 nM aqueous ammonium bicarbonate solution) to give compound 91 (23.1 mg, yield 13.8%).

[0345] ESI-MS m / z:561[M+H] + .

[0346] 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)

[0347] 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)

[0348] 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 subjected to fast preparative liquid chromatography (120 g The residue was purified by C-18 Flash Column, ACN / 10 nM aqueous ammonium bicarbonate solution) to give compound 92 (28.3 mg, yield 16.6%).

[0349] ESI-MS m / z:575[M+H] + .

[0350] 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)

[0351] 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)

[0352] Int20_2 (100 mg, 297 μmol) was dissolved in DMF (5 mL), int3_2 (94 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 subjected to fast preparative liquid chromatography (120 g The residue was purified by C-18 Flash Column, ACN / 10 nM aqueous ammonium bicarbonate solution to afford compound 93 (27.0 mg, yield 15.4%).

[0353] ESI-MS m / z:589[M+H] + .

[0354] 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)

[0355] 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)

[0356] Int20_2 (100 mg, 297 μmol) was dissolved in DMF (5 mL), int1_10 (94 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 (120 g The residue was purified by C-18 Flash Column (ACN / 10 nM aqueous ammonium bicarbonate solution) to give compound 94 (31.5 mg, yield 18.1%).

[0357] ESI-MS m / z:587[M+H] + .

[0358] 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)

[0359] 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)

[0360] Int20_2 (100 mg, 297 μmol) was dissolved in DMF (5 mL), int5_2 (98 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 subjected to fast preparative liquid chromatography (120 g The product was purified by C-18 Flash Column, ACN / 10 nM aqueous ammonium bicarbonate solution to afford compound 95 (29.6 mg, yield 16.6%).

[0361] ESI-MS m / z:601[M+H] + .

[0362] 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)

[0363] 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)

[0364] Int20_2 (100 mg, 297 μmol) was dissolved in DMF (5 mL), int6_1 (92 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 (120 g The product was purified by C-18 Flash Column, ACN / 10 nM aqueous ammonium bicarbonate solution to give compound 97 (25.8 mg, yield 15.0%).

[0365] ESI-MS m / z:577[M+H] + .

[0366] 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)

[0367] Step 1: Synthesis of compound int26_1

[0368] 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 and dissolved in IPA (10 mL). DIPEA (516 mg, 4.00 mmol) was then added and reacted at 80°C for 2 hours. LC-MS confirmed the reaction was complete. 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, yielding int26_1 (234 mg, 70.0% yield), which was used directly in the next step.

[0369] ESI-MS m / z:335[M+H] + .

[0370] Step 2: Synthesis of compound int26_2

[0371] Int26_1 (100 mg, 299 μmol) was placed in a 50 mL round-bottom flask and dissolved in DCM (4 mL). m-CPBA (91 mg, 448 μmol) was then added and allowed to react at room temperature for 0.5 hours. LC-MS confirmed the reaction was complete. The reaction mixture was filtered, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent, yielding int26_2 (99 mg, 94.5% yield), which was used in the next step.

[0372] ESI-MS m / z:351[M+H] + .

[0373] 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)

[0374] Int26_2 (99 mg, 282 μmol) was dissolved in DMF (5 mL), int1_10 (92 mg, 282 μmol) was added, and 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 (120 g The residue was purified by C-18 Flash Column, ACN / 10 nM aqueous ammonium bicarbonate solution to afford compound 136 (11.7 mg, yield 6.90%).

[0375] ESI-MS m / z:601[M+H] + .

[0376] 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)

[0377] Step 1: Synthesis of compound int27_2

[0378] Sodium hydride (60%, 400 mg, 10.0 mmol) was added to a 100 mL round-bottom flask, and TFA (7 mL) was added. Int27_1 (498 mg, 5.0 mmol) and tert-butyl (3-bromopropyl) carbamate (1190 mg, 5.0 mmol) were added under ice-cooling. After the addition was complete, the reaction was allowed to proceed 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-cooling 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 chromatography (120 g The product was purified by C-18 Flash Column, ACN / 1‰ TFA aqueous solution = 10%-60%) to give int27_2 (207 mg, yield 16.1%).

[0379] ESI-MS m / z:259[M+H] + .

[0380] Step 2: Synthesis of compound int27_3

[0381] 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. The mixture was reacted at room temperature for 1 hour. The reaction was completed by LC-MS detection. After concentration under reduced pressure, int27_3 (TFA salt, 453 mg) was obtained.

[0382] ESI-MS m / z:159[M+H] + .

[0383] Step 3: Synthesis of compound int27_4

[0384] Int27_3 (306 mg, 2.0 mmol) and int1_1 (453 mg, 2.0 mmol) were placed in a 100 mL round-bottom flask. IPA (25 mL) and DIPEA (1032 mg, 8.0 mmol) were added and reacted 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 chromatography (120 g The product was purified by C-18 Flash Column, ACN / 1‰ TFA aqueous solution = 20%-80%) to give int27_4 (356 mg, yield 50.8%).

[0385] ESI-MS m / z:351[M+H] + .

[0386] Step 4: Synthesis of compound int27_5

[0387] Int27_4 (100 mg, 273 μmol) was placed in a 250 mL round-bottom flask and dissolved in DCM (4 mL). m-CPBA (83 mg, 409 μmol) was added and allowed to react at room temperature for 0.5 hours. LC-MS confirmed the reaction was complete. The reaction mixture was adjusted to pH 7-8 by adding saturated sodium bicarbonate solution, filtered, and the filtrate was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to yield int27_5 (86 mg, 86.1% yield), which was used in the next step.

[0388] ESI-MS m / z:367[M+H] + .

[0389] Step 5: Preparation of Example 1-(3-((2-(2-((2-cyclopropyl-4-(4-methylpiperazin-1-piperidin-1-yl))amino-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one (139)

[0390] To int27_5 (86 mg, 234 μmol) was added DMF (5 mL) followed by int1_10 (74 mg, 234 μmol) and then TFA (80 mg, 702 μmol) was added dropwise and the mixture was reacted at 80°C under argon protection for 6 hours. The reaction was completed by LC-MS. The reaction solution was directly purified by fast liquid chromatography (120 g The product was purified by C-18 Flash Column, ACN / 10 nM aqueous ammonium bicarbonate solution = 10%-85%) to give compound 139 (23.7 mg, yield 16.4%).

[0391] ESI-MS m / z:617[M+H] + .

[0392] 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)azacyclo-2-one (140)

[0393] Step 1: Synthesis of compound int28_1

[0394] 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 and dissolved in IPA (10 mL). DIPEA (516 mg, 4.00 mmol) was added and reacted at 80°C for 2 hours. LC-MS confirmed the reaction was complete. 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, yielding int28_1 (199 mg, 54.9% yield), which was used directly in the next step.

[0395] ESI-MS m / z:363[M+H] + .

[0396] Step 2: Synthesis of compound int28_2

[0397] Int26_1 (100 mg, 276 μmol) was placed in a 50 mL round-bottom flask and dissolved in DCM (4 mL). m-CPBA (84 mg, 414 μmol) was then added and allowed to react at room temperature for 0.5 hours. LC-MS confirmed the reaction was complete. The reaction mixture was filtered, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent, yielding int26_2 (105 mg, 100% yield), which was used in the next step.

[0398] ESI-MS m / z:379[M+H] + .

[0399] 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)azacyclo-2-one (140)

[0400] Int28_2 (105 mg, 276 μmol) was dissolved in DMF (5 mL), int1_10 (87 mg, 276 μmol) was added, and 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 fast liquid chromatography (120 g The residue was purified by C-18 Flash Column, ACN / 10 nM aqueous ammonium bicarbonate solution) to give compound 140 (23.4 mg, yield 13.5%).

[0401] ESI-MS m / z:629[M+H] + .

[0402] 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-oxazepine-3-one (143)

[0403] Step 1: Synthesis of compound int29_2

[0404] 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-cooling. After the addition was complete, the mixture was reacted at room temperature for 5 hours. The reaction was completed by LC-MS. Water was added to the reaction mixture under ice-cooling to quench the mixture. The mixture was then extracted with ethyl acetate and concentrated under reduced pressure to remove the solvent. The residue was purified by rapid preparative liquid chromatography (120 g The product was purified by C-18 Flash Column, ACN / 1‰ TFA aqueous solution = 10%-60%) to give int29_2 (354 mg, yield 26.0%).

[0405] ESI-MS m / z:273[M+H] + .

[0406] Step 2: Synthesis of compound int29_3

[0407] 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. The mixture was reacted at room temperature for 1 hour. The reaction was completed by LC-MS detection. After concentration under reduced pressure, int27_3 (TFA salt, 441 mg) was obtained.

[0408] ESI-MS m / z:173[M+H] + .

[0409] Step 3: Synthesis of compound int29_4

[0410] Int29_3 (172 mg, 1.0 mmol) and int1_1 (229 mg, 1.0 mmol) were placed in a 100 mL round-bottom flask. IPA (10 mL) and DIPEA (516 mg, 4.0 mmol) were added and reacted 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 chromatography (120 g The product was purified by C-18 Flash Column, ACN / 1‰ TFA aqueous solution = 20%-80%) to give int29_4 (122 mg, yield 33.5%).

[0411] ESI-MS m / z:365[M+H] + .

[0412] Step 4: Synthesis of compound int29_5

[0413] Int27_4 (100 mg, 274 μmol) was placed in a 250 mL round-bottom flask and dissolved in DCM (4 mL). m-CPBA (83 mg, 409 μmol) was added and allowed to react at room temperature for 0.5 hours. LC-MS confirmed the reaction was complete. The reaction mixture was adjusted to pH 7-8 by adding saturated sodium bicarbonate solution, filtered, and the filtrate was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to yield int29_5 (98 mg, 93.9% yield), which was used in the next step.

[0414] ESI-MS m / z:381[M+H] + .

[0415] Step 5: 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-oxazepine-3-one (143)

[0416] To int29_5 (98 mg, 257 μmol) was added DMF (5 mL) followed by int1_10 (81 mg, 257 μmol) 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 fast preparative liquid chromatography (120 g The product was purified by C-18 Flash Column, ACN / 10 nM aqueous ammonium bicarbonate solution = 10%-85%) to give compound 139 (30.0 mg, yield 18.5%).

[0417] ESI-MS m / z:631[M+H] + .

[0418] Example 30 Preparation of 1-(3-((2-(2-((2-cyclopropyl-4-(4-methylpiperazine-1-piperidin-1-yl))amino-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one (151)

[0419] Step 1: Synthesis of compound int30_2

[0420] 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-cooling. After the addition was complete, the mixture was reacted at room temperature for 5 hours. The reaction was detected to be complete by LC-MS. Water was added to the reaction mixture under ice-cooling to quench the mixture. The mixture was then extracted with ethyl acetate and concentrated under reduced pressure to remove the solvent. The residue was purified by rapid liquid chromatography (120 g The product was purified by C-18 Flash Column, ACN / 1‰ TFA aqueous solution = 10%-60%) to give int30_2 (207 mg, yield 16.1%).

[0421] ESI-MS m / z:257[M+H] + .

[0422] Step 2: Synthesis of compound int30_3

[0423] 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. The mixture was reacted at room temperature for 1 hour. The reaction was completed by LC-MS detection. After concentration under reduced pressure, int30_3 (TFA salt, 453 mg) was obtained.

[0424] ESI-MS m / z:157[M+H] + .

[0425] Step 3: Synthesis of compound int30_4

[0426] Int2_3 (309 mg, 1.98 mmol) and int1_1 (453 mg, 1.98 mmol) were placed in a 100 mL round-bottom flask. IPA (25 mL) and DIPEA (1023 mg, 7.93 mmol) were added and reacted 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 chromatography (120 g The residue was purified by C-18 Flash Column, ACN / 1‰ TFA aqueous solution = 20%-80%) to afford int2_4 (245 mg, yield 33%).

[0427] ESI-MS m / z:349[M+H] + .

[0428] Step 4: Synthesis of compound int30_5

[0429] Int30_4 (60 mg, 172 μmol) was placed in a 250 mL round-bottom flask and dissolved in DCM (4 mL). m-CPBA (44 mg, 258 μmol) was added and allowed to react at room temperature for 0.5 h. LC-MS confirmed the reaction was complete. The reaction mixture was adjusted to pH 7-8 by adding saturated sodium bicarbonate solution, filtered, and the filtrate was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to yield int30_5, which was used in the next step.

[0430] ESI-MS m / z:365[M+H] + .

[0431] Step 5: Preparation of Example 1-(3-((2-(2-((2-cyclopropyl-4-(4-methylpiperazin-1-piperidin-1-yl))amino-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one (151)

[0432] To int30_5 was added DMF (5 mL), int1_10 (54 mg, 172 μmol), and then 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 subjected to rapid preparative liquid chromatography (120 g The product was purified by C-18 Flash Column, ACN / 10 nM aqueous ammonium bicarbonate solution = 10%-85%) to give compound 151 (21.9 mg, yield 19.2%).

[0433] ESI-MS m / z:616[M+H] + .

[0434] 1 H-NMR(400MHz,Chloroform-d)δ8.43(s,1H),8.11(s,1H),7.93(d,J=8.9Hz,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).

[0435] Example 31 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)

[0436] 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)

[0437] Int30_5 (100 mg, 274 μmol) was dissolved in DMF (5 mL), int2_2 (83 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 fast liquid chromatography (120 g The residue was purified by C-18 Flash Column (ACN / 10 nM aqueous ammonium bicarbonate solution) to give compound 152 (30.5 mg, yield 18.4%).

[0438] ESI-MS m / z:603[M+H] + .

[0439] Example 32 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)

[0440] 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)

[0441] Int30_5 (100 mg, 274 μmol) was dissolved in DMF (5 mL), int3_2 (87 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 subjected to fast liquid preparative chromatography (120 g The residue was purified by C-18 Flash Column, ACN / 10 nM aqueous ammonium bicarbonate solution) to give compound 153 (28.6 mg, yield 16.9%).

[0442] ESI-MS m / z:617[M+H] + .

[0443] Example 33 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)

[0444] 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)

[0445] 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 subjected to fast liquid preparative chromatography (120 g The residue was purified by C-18 Flash Column, ACN / 10 nM aqueous ammonium bicarbonate solution) to give compound 154 (22.3 mg, yield 13.8%).

[0446] ESI-MS m / z:589[M+H] + .

[0447] Example 34 Preparation of 1-(3-((2-(2-((2-cyclobutyl-4-(4-methylpiperazine-1-piperidin-1-yl))amino-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one (155)

[0448] 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)

[0449] Int30_5 (100 mg, 274 μmol) was dissolved in DMF (5 mL), int5_2 (90 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 subjected to fast liquid preparative chromatography (120 g The residue was purified by C-18 Flash Column, ACN / 10 nM aqueous ammonium bicarbonate solution) to give compound 155 (33.4 mg, yield 19.3%).

[0450] ESI-MS m / z:629[M+H] + .

[0451] Example 35 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)

[0452] 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)

[0453] Int30_5 (100 mg, 274 μmol) was dissolved in DMF (5 mL), int2_2 (84 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 fast liquid chromatography (120 g The residue was purified by C-18 Flash Column, ACN / 10 nM aqueous ammonium bicarbonate solution to afford compound 157 (33.0 mg, yield 19.9%).

[0454] ESI-MS m / z:605[M+H] + .

[0455] 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)

[0456] 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)

[0457] 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 subjected to fast liquid preparative chromatography (120 g The product was purified by C-18 Flash Column, ACN / 10 nM aqueous ammonium bicarbonate solution) to give compound 274 (22.0 mg, yield 13.6%).

[0458] ESI-MS m / z:591[M+H] + .

[0459] 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)

[0460] 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)

[0461] Int27_5 (100 mg, 273 μmol) was dissolved in DMF (5 mL), int4_2 (83 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 fast liquid chromatography (120 g The product was purified by C-18 Flash Column, ACN / 10 nM aqueous ammonium bicarbonate solution) to give compound 275 (26.9 mg, yield 16.3%).

[0462] ESI-MS m / z:605[M+H] + .

[0463] 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)

[0464] 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)

[0465] Int27_5 (100 mg, 273 μmol) was dissolved in DMF (5 mL), int3_2 (87 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 fast liquid chromatography (120 g The product was purified by C-18 Flash Column, ACN / 10 nM aqueous ammonium bicarbonate solution) to give compound 276 (26.1 mg, yield 15.4%).

[0466] ESI-MS m / z:619[M+H] + .

[0467] 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)

[0468] 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)

[0469] Int27_5 (100 mg, 273 μmol) was dissolved in DMF (5 mL), int4_2 (90 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 subjected to fast liquid preparative chromatography (120 g The product was purified by C-18 Flash Column, ACN / 10 nM aqueous ammonium bicarbonate solution) to give compound 277 (35.9 mg, yield 20.8%).

[0470] ESI-MS m / z:631[M+H] + .

[0471] 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)

[0472] 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)

[0473] Int27_5 (100 mg, 273 μmol) was dissolved in DMF (5 mL), int4_2 (84 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 fast liquid chromatography (120 g The product was purified by C-18 Flash Column, ACN / 10 nM aqueous ammonium bicarbonate solution) to give compound 279 (29.1 mg, yield 17.6%).

[0474] ESI-MS m / z:607[M+H] + .

[0475] 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)

[0476] 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-oxazepine-3-one (313)

[0477] Int29_5 (100 mg, 263 μmol) was dissolved in DMF (5 mL), int4_2 (76 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 fast liquid chromatography (120 g The residue was purified by C-18 Flash Column, ACN / 10 nM aqueous ammonium bicarbonate solution) to afford compound 313 (23.0 mg, yield 14.5%).

[0478] ESI-MS m / z:605[M+H] + .

[0479] 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-oxazepine-3-one (314)

[0480] 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-oxazepine-3-one (314)

[0481] 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 fast liquid chromatography (120 g The residue was purified by C-18 Flash Column, ACN / 10 nM aqueous ammonium bicarbonate solution) to afford compound 314 (24.2 mg, 14.8% yield).

[0482] ESI-MS m / z:619[M+H] + .

[0483] 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-oxazacyclo-3-one (315)

[0484] 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-oxazepine-3-one (315)

[0485] Int29_5 (100 mg, 263 μmol) was dissolved in DMF (5 mL), int3_2 (83 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 fast liquid chromatography (120 g The residue was purified by C-18 Flash Column, ACN / 10 nM aqueous ammonium bicarbonate solution to afford compound 315 (31.4 mg, yield 18.9%).

[0486] ESI-MS m / z:633[M+H] + .

[0487] 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-oxazepine-3-one (316)

[0488] 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-oxazepine-3-one (316)

[0489] Int29_5 (100 mg, 263 μmol) was dissolved in DMF (5 mL), int5_2 (86 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 subjected to fast liquid preparative chromatography (120 g The residue was purified by C-18 Flash Column, ACN / 10 nM aqueous ammonium bicarbonate solution) to afford compound 316 (30.1 mg, 17.8% yield).

[0490] ESI-MS m / z:645[M+H] + .

[0491] 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-oxazacyclopentane-3-one (318)

[0492] 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-oxazepine-3-one (318)

[0493] Int29_5 (100 mg, 263 μmol) was dissolved in DMF (5 mL), int6_1 (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 fast liquid chromatography (120 g The residue was purified by C-18 Flash Column, ACN / 10 nM aqueous ammonium bicarbonate solution) to afford compound 318 (17.6 mg, yield 10.8%).

[0494] ESI-MS m / z:621[M+H] + .

[0495] Using the above synthesis method and different raw materials, the target compounds in Table 1 can be obtained.

[0496] Table 1

[0497] Biological Example 1 In vitro inhibition test of ULK1 enzyme activity by the compounds of the present invention

[0498] 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 allowed to stand 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 a microplate reader and the inhibition rate was calculated using the following formula: % Inhibition = 100% - (compound-positive control) / (negative control-positive control) * 100%. Compared with the DMSO control group, the compound inhibition percentage and IC were calculated. 50 The results are shown in Table 2 below.

[0499] Table 2. Inhibitory activity of the compounds of the present invention on ULK1 enzyme (IC 50 ,nM) +++ indicates IC 50 Less than or equal to 25nM++ indicates IC 50 25nM to 50nM + indicates IC 50 Greater than 50 and less than 100nM

[0500] Biological Example 2 Pharmacokinetic Properties of Some Compounds of the Present Invention

[0501] Female CD-1 mice aged 7 to 10 weeks were selected and administered intravenously and orally at doses of 1 mg / kg and 10 mg / kg, respectively. Mice were fasted for at least 12 hours before administration and resumed feeding 4 hours after administration. Water was freely available throughout the experiment. On the day of the experiment, the intravenous group of animals was given a single injection of the corresponding compound via the tail vein with a dosing volume of 1 mL / kg. The oral group of animals was given a single injection of the corresponding compound via gavage with a dosing volume of 10 mL / kg. The animals were weighed before administration and the dosing volume was calculated based on the body weight. Sample collection times were: 0.083 (injection group), 0.25, 0.5, 1, 2, 4, 8, and 24 hours. Approximately 200 μL of whole blood was collected from the submandibular venous plexus at each time point to prepare plasma for concentration determination by high-performance liquid chromatography-tandem mass spectrometry (LC-MS / MS). All animals were euthanized by CO2 anesthesia after the PK sample was collected at the last time point. Phoenix WinNonlin was used. TM Plasma concentrations were processed using a non-compartmental model using the pharmacokinetic software version 8.3 (Certara), and pharmacokinetic parameters were calculated using the linear-log trapezoidal method. The in vivo pharmacokinetic results are shown in Table 3 below.

[0502] Table 3 In vivo pharmacokinetic evaluation results of the compounds of the present invention

[0503] 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 a high C max and a shorter T max At the same time, it has a moderate T 1 / 2 .

[0504] Although the above describes specific embodiments of the present invention, it should be understood by those skilled in the art that these are merely illustrative and that various changes or modifications may be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. 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, C1-C5 alkyl or C3-C5 cycloalkyl, wherein the C1-C5 alkyl or C3-C5 cycloalkyl may be optionally substituted with one, two or three fluorine groups; R 2 is selected from the group consisting of: 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 are optionally substituted with one, two, or three fluoro or cyano groups; R 3 is selected from: H, halogen, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy may be optionally substituted with one or more fluorines; Z is selected from the following groups: a) a 4-membered lactam ring bound via a nitrogen atom or a 6-10-membered lactam ring bound via a nitrogen atom, wherein when the lactam ring is a 6-10-membered ring, the atoms on the lactam ring can optionally be carbon, oxygen or NR 6 , and the carbon atoms on the 4-membered lactam ring or the 6-10-membered lactam can be optionally replaced by R 36 b) or an amide bonded via a nitrogen atom, wherein the carbonyl carbon atom of the amide is R 37 replace; R 36 is independently selected at each occurrence from H, C1-C6 alkyl or C3-C6 cycloalkyl, wherein said C1-C6 alkyl or C3-C6 cycloalkyl may be optionally substituted with one or more fluorine, or two R 36 joined together with the carbon atom to which it is attached to form a C3-C6 cycloalkyl group; R 37 independently selected from C1-C6 alkyl, C3-C6 cycloalkyl or (3-6 membered) heterocycloalkyl, wherein the carbon atoms on the C1-C6 alkyl, C3-C6 cycloalkyl or (3-6 membered) heterocycloalkyl may be optionally replaced by R 36 The heteroatom on the (3-6 membered) heterocycloalkyl group may optionally be oxygen or NR 6 ; When Z is an amide bonded via a nitrogen atom, wherein the carbonyl carbon atom of the amide is replaced by R 37 When substituted, R 4 Selected from B 1 or D 1 ; B 1 is selected from heterocycloalkyl or heteroaryl groups connected via a nitrogen atom, wherein B 1 Optionally, one or more available carbons may be replaced by R 7 and optionally substituted on an available nitrogen by R 9 replace; D 1 is selected from heterocycloalkyl or heteroaryl groups connected through carbon atoms, wherein D 1 Optionally, one or more available carbons may be replaced by R 7 and optionally substituted on an available nitrogen by R 9 replace; R 7 is independently selected at each occurrence from: H, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, -N(R 5 )2, -(C1-C6)alkylene-N(R 5 )2 or (3-6 membered) heterocycloalkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl or (3-6 membered) heterocycloalkyl may be optionally substituted with one or more H or F; or two R 7 together with the atom to which it is attached to form an oxo group; R 9 is independently selected at each occurrence from: H, C1-C6 alkyl, C3-C6 cycloalkyl, or (3-6 membered) heterocycloalkyl, wherein said C1-C6 alkyl, C3-C6 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 bound via a nitrogen atom or a 6-10-membered lactam ring bound 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 can be optionally replaced by R 36 When substituted, R 4 Selected from B 2 or D 2 ; B 2 is selected from heterocycloalkyl or heteroaryl groups connected via a nitrogen atom, wherein B 2 Optionally, one or more available carbons may be replaced by R 8 and optionally substituted on an available nitrogen by R 10 replace; D 2 is selected from heterocycloalkyl or heteroaryl groups connected through carbon atoms, wherein D 2 Optionally, one or more available carbons may be replaced by R 8 and optionally substituted on an available nitrogen by R 10 replace; R 8 is independently selected at each occurrence from: H, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, -N(R 5 )2, -(C1-C6)alkylene-N(R 5 )2 or (3-6 membered) heterocycloalkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl or (3-6 membered) heterocycloalkyl may be optionally substituted with one or more H or F; or two R 8 together with the atom to which it is attached to form an oxo group; R 10 is independently selected at each occurrence from: C1-C6 alkyl, C3-C6 cycloalkyl, or (3-6 membered) heterocycloalkyl, wherein said C1-C6 alkyl, C3-C6 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, 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; R 6 is independently selected at each occurrence from: H, C1-C6 alkyl, C3-C6 cycloalkyl, or (3-6 membered) heterocycloalkyl, wherein said C1-C6 alkyl, C3-C6 cycloalkyl, or (3-6 membered) heterocycloalkyl may be optionally substituted with one or more F; and n is 2, 3, or 4.

2. 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: oxygen, C(R 34 )2 and NR 9 ; R 34 independently selected at each occurrence from H or R 36 , where R 36 is independently selected at each occurrence from C1-C6 alkyl or C3-C6 cycloalkyl, or two R 36 joined together with the carbon atom to which it is attached to form a C3-C6 cycloalkyl group; R 37 independently selected from C1-C3 alkyl, C3-C5 cycloalkyl or (3-6 membered) heterocycloalkyl, wherein the carbon atoms on the C1-C3 alkyl, C3-C5 cycloalkyl or (3-6 membered) heterocycloalkyl may be optionally replaced by R 36 The heteroatom on the (3-6 membered) heterocycloalkyl group may optionally be 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.

3. 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: where R 34 independently selected at each occurrence from H or R 36 ,in, R 36 is independently selected at each occurrence from C1-C6 alkyl or C3-C6 cycloalkyl, or two R 36 Joined together with the carbon to which it is attached to form a C3-C6 cycloalkyl group.

4. 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:

5. 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 R 4 Selected from: where R 7 is independently selected at each occurrence from: H, cyano, -N(R 5 )2, C1-C3 alkyl, C3-C5 cycloalkyl or (3-5 membered) heterocycloalkyl, wherein the C1-C3 alkyl, C3-C5 cycloalkyl or (3-6 membered) heterocycloalkyl may be optionally substituted with one or more H or F, or two R 7 are linked together with the atom to which they are attached to form an oxo group; R 9 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 R 5 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.

6. 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 R 4 Selected from:

7. 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 R 4 Selected from:

8. 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 R 4 Selected from:

9. 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 R 4 Selected from: where R 8 is independently selected at each occurrence from: H, cyano, 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 or F, or two R 8 and the atoms to which they are attached to form an oxo group; R 10 is independently selected at each occurrence from: 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 or F; wherein R 5 is independently selected at each occurrence from: H, C1-C6 alkyl or C3-C6 cycloalkyl, wherein said C1-C6 alkyl or C3-C6 cycloalkyl may be optionally substituted with one or more F.

10. 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 R 4 Selected from:

11. The compound according to claim 1 or 2, or any isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), when Z is When R 4 Selected from:

12. 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 R 4 Selected from:

13. The compound according to any one of claims 1 to 12, or any isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), R 1 is selected from the group consisting of halogen, C1-C3 alkyl or C3-C5 cycloalkyl, wherein the C1-C3 alkyl or C3-C5 cycloalkyl may be optionally substituted with one, two or three fluorine groups.

14. 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 Selected from: trifluoromethyl, F, Cl, Br, I or cyclopropyl.

15. The compound according to any one of claims 1 to 14 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 2 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 with one, two or three fluoro or cyano groups.

16. 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 Selected from: H, F, Cl, Br, Or -OCH3.

17. 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.

18. The compound according to any one of claims 1 to 17, or any isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound has one of the following structures:

19. The compound according to any one of claims 1 to 17, or any isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound has one of the following structures:

20. A pharmaceutical composition, characterized in that It contains a pharmaceutically acceptable excipient or carrier, and the compound according to any one of claims 1 to 19 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as active ingredients.

21. 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.

22. The use according to claim 21, wherein the disease is cancer, and the cancer is a blood cancer and a solid tumor.

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