Pyridopyrimidine compounds and their uses

Abstract

The present invention provides a pyridopyrimidine compound having the structure represented by formula (I) or its pharma- ceutically acceptable salt, its stereoisomer or its prodrug molecule, and its use. The compound according to the present invention can degrade AKT3 protein in cells efficiently and highly selectively without affecting AKT1 / 2, thereby significantly inhibiting the proliferation of tumor cells mediated by AKT3 overexpression, and is useful for the manufacture of drugs for treating cancer and other related diseases associated with abnormal expression of AKT3 protein. JPEG2024508901000191.jpg36170

Description

[Technical Field]

[0001] The present invention relates to the field of medicinal chemistry, and in particular to pyridopyrimidine compounds and their uses. [Background technology]

[0002] AKT (AK mouse plus transforming or thymoma), also known as protein kinase B (PKB), is a serine / threonine protein kinase with a molecular weight of approximately 57 kD. This family includes three subtypes: AKT1, AKT2, and AKT3. Each AKT subtype has many similarities and differences in function and histological distribution, and their abnormal expression is closely associated with the development and progression of various diseases. AKT1 is widely expressed in many tissues, including the heart, liver, and muscle. AKT2 is primarily distributed in insulin-sensitive tissues, such as skeletal muscle and adipose tissue. AKT3 is primarily distributed in tissues such as the brain, heart, and kidney. AKT1 expression is upregulated in approximately 40% of breast and ovarian cancers and in over 50% of prostate cancers. AKT2 is overexpressed in 40% of liver cancers and 57% of colorectal cancers. Deficiency of AKT2 leads to hyperglycemia, type 2 diabetes, and impaired glucose uptake, and overexpression of AKT1 and AKT2 is also associated with paclitaxel resistance in ovarian cancer. High expression of AKT3 is observed in breast cancer, prostate cancer, and some osimertinib-resistant non-small cell lung cancers. Therefore, selective regulation of each subtype of AKT protein may play a positive role in the treatment of related diseases.

[0003] AKT is an important target for tumor therapy. Currently, many AKT kinase inhibitors are in clinical trials and have demonstrated favorable antitumor effects. However, these inhibitors lack selectivity for each AKT subtype, and indiscriminate inhibition may result in certain clinical toxicities and side effects. Furthermore, as with conventional targeted drugs, prolonged drug treatment may lead to resistance to AKT inhibitors, further weakening the therapeutic effect. Furthermore, AKT proteins possess both kinase and nonkinase functions, and simply inhibiting their kinase function may not be sufficient to fully exert antitumor effects. Targeting and degrading intact AKT3 proteins not only inhibits their kinase function but also controls their nonkinase function, resulting in even stronger antitumor effects.

[0004] Therefore, the development and synthesis of small molecule degraders that can selectively degrade AKT3 protein is of great significance for the development of therapeutic drugs for AKT3-mediated related diseases. Summary of the Invention [Problem to be solved by the invention]

[0005] In response to the above problems, the present invention provides novel pyridopyrimidine compounds that can inhibit the proliferation of multiple types of tumor cells and are useful for treating diseases and tumors associated with AKT3 protein, and novel pyridopyrimidine compounds that can selectively degrade AKT3 protein with high activity. [Means for solving the problem]

[0006] Specific technical solutions include:

[0007] A pyridopyrimidine compound having a structure represented by formula (I), or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a prodrug molecule thereof. JPEG0007756374000001.jpg36170 (where, E is hydrogen, C1-C 15 Alkyl groups, substituted C1-C 15 Alkyl groups, C3-C 15 Cycloalkyl groups, substituted C3-C 15 is selected from a cycloalkyl group, a 3- to 15-membered heterocycloalkyl group, and a substituted 3- to 15-membered heterocycloalkyl group; L is absent or is a linking unit consisting of one or more of an alkylene group, an ether group, a thioether group, an ester group, an amino group, an amide group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, and a -N=N- group; Y is absent or selected from -O-, -NH-, -NHCO-, -CH2-, -S-, -CO-; Z is absent or selected from -O-, -NH-, -N(C1-C6 alkyl group)-, -NHCO-, -CH2-, -S-, -CO-, and -SO-; R1 is selected from hydrogen, a C1-C6 alkyl group, a halogen or a halogen-substituted C1-C6 alkyl group; R2 is C3~C 15 Cycloalkyl groups, substituted C3-C 15 Cycloalkyl groups, 3-15 membered heterocycloalkyl groups, substituted 3-15 membered heterocycloalkyl groups, C6-C 10 Aryl groups, substituted C6-C 10 an aryl group, a 5- to 10-membered heteroaryl group, or a substituted 5- to 10-membered heteroaryl group; JPEG0007756374000002.jpg7170A is selected from -NH- and -NHR-, and R is C to C 10 Aryl groups, substituted C6-C 10 an aryl group, a 5- to 10-membered heteroaryl group, or a substituted 5- to 10-membered heteroaryl group; B does not exist or C3~C 15 Cycloalkyl groups, substituted C3-C 15 Cycloalkyl groups, 3- to 15-membered heterocycloalkyl groups, substituted 3- to 15-membered heterocycloalkyl groups, 3- to 15-membered heterocycloalkanone groups, R8-substituted 3- to 15-membered heterocycloalkanone groups, C3-C 12Cycloalkyl-substituted amino group, 3- to 12-membered heterocycloalkyl-substituted amino group In some embodiments, E is hydrogen, a C1-C8 alkyl group, an R5 substituted C1-C8 alkyl group, a C3-C 12 Cycloalkyl groups, R6 substituted C3-C 12 is selected from a cycloalkyl group, a 3- to 12-membered heterocycloalkyl group, and an R-substituted 3- to 12-membered heterocycloalkyl group; R5 is halogen, C3~C 12 Cycloalkyl groups, C1-C3 alkyl substituted C3-C 12 Cycloalkyl groups, halogen-substituted C3-C 12 cycloalkyl groups, R6 is selected from halogen, a C1 to C6 alkyl group, and a halogen-substituted C1 to C6 alkyl group.

[0008] In some embodiments, E is hydrogen, a C1-C6 alkyl group, an R5 substituted C1-C6 alkyl group, a C3-C 10 Cycloalkyl groups, R6 substituted C3-C 10 cycloalkyl groups, R5 is halogen, C6~C 10 Cycloalkyl groups, methyl-substituted C6-C 10 Cycloalkyl groups, halogen-substituted C6-C 10 cycloalkyl groups, R6 is selected from halogen and C1-C3 alkyl groups.

[0009] In some embodiments, E is hydrogen, a cyclopropyl group, JPEG0007756374000004.jpg57140, where x is an integer between 0 and 3, and y is an integer between 0 and 3.

[0010] In some embodiments, L is JPEG0007756374000005.jpg85140, where n and m are each independently an integer from 0 to 14.

[0011] In some embodiments, L is JPEG0007756374000006.jpg22137, where n is an integer from 0 to 7, and m is an integer from 0 to 3.

[0012] In some embodiments, L is JPEG0007756374000007.jpg9131, where n is an integer from 2 to 7, or is absent.

[0013] In some embodiments, Y is selected from -CH2-, -CO-, -O-, or is absent, and Z is selected from -NHCO-, -NH-, or is absent.

[0014] In some embodiments, R1 is selected from hydrogen, halogen, and a C1-C3 alkyl group.

[0015] In some embodiments, R2 is C5-C 10 Cycloalkyl groups, R9 substituted C5-C 10 Cycloalkyl groups, 5-10 membered heterocycloalkyl groups, R9 substituted 5-10 membered heterocycloalkyl groups, C6-C 10 Aryl group, R9 substituted C6-C 10 an aryl group, a 5- to 10-membered heteroaryl group, an R9-substituted 5- to 10-membered heteroaryl group, a 5- to 10-membered heteroaryl ketone group, or an R9-substituted 5- to 10-membered heteroaryl ketone group; R9 is an amino group, -N(C1-C6 alkyl group)2, halogen, C1-C6 alkyl group, C1-C6 alkoxy group, halogen-substituted C1-C6 alkyl group, halogen-substituted C1-C6 alkoxy group, -NH(R4), -N(R4)2, -O(R4), -C=O-NH(R4), -C=O-NH(C3-C6 cycloalkyl group), R 10 Substituted C1-C6 alkyl groups, C3-C 10 Cycloalkyl group, 3-10 membered heterocycloalkyl group, R 10 Substitution C3~C 10 Cycloalkyl group, R 10Substituted 3- to 10-membered heterocycloalkyl group, -NH(R4) substituted 3- to 10-membered heterocycloalkyl group, 5- to 10-membered heteroaryl group, -COR 11 is selected from R4 is absent or is a hydrogen atom, an amino group, an ester group, a carboxy group, a hydroxy group, a mercapto group, a sulfone group, a sulfoxide group, a C1 to C 15 Alkyl group, R 10 Substitution C1~C 15 Alkyl groups, C3-C 15 Cycloalkyl group, 3-15 membered heterocycloalkyl group, R 10 Substitution C3~C 15 Cycloalkyl group, R 10 Substituted 3- to 15-membered heterocycloalkyl group, -COR 11 is selected from R 10 is selected from a C1-C6 alkyl group, an amino-substituted C1-C6 alkyl group, a C3-C6 cycloalkyl group, a dimethylamine-substituted C1-C6 alkyl group, a 3- to 6-membered heterocycloalkyl group, a dimethylamino group, a C1-C3 alkoxy-substituted C1-C6 alkyl group, a hydroxy-substituted C1-C6 alkyl group, a C1-C6 alkyl-substituted 3- to 6-membered heterocycloalkyl group, a C1-C6 alkylacyl group, a hydroxy group, a C1-C6 alkyl-substituted C3-C6 cycloalkyl group, a dimethylaminoethyl-substituted 5- to 6-membered heterocycloalkyl group, and a C1-C6 alkoxy group; R 11 is selected from a vinyl group, a C1-C6 alkyl group, an amino-substituted C1-C6 alkyl group, a C3-C6 cycloalkyl group, an amino-substituted C3-C6 cycloalkyl group, a halogen-substituted C3-C6 cycloalkyl group, a 3- to 6-membered heterocycloalkyl group, a C1-C6 alkyl-substituted 3- to 6-membered heterocycloalkyl group, a dimethylamine-substituted C1-C6 alkyl group, and a dimethylamineethyl-substituted 5- to 6-membered heterocycloalkyl group.

[0016] In some embodiments, R2 is Selected from JPEG0007756374000008.jpg199143JPEG0007756374000009.jpg190144JPEG0007756374000010.jpg50143.

[0017] In some embodiments, R2 is selected from a C5-C8 cycloalkyl group, an R9-substituted C5-C8 cycloalkyl group, a 5-8 membered heterocycloalkyl group, an R9-substituted 5-8 membered heterocycloalkyl group, a phenyl group, an R9-substituted phenyl group, a 5-6 membered heteroaryl group, and an R9-substituted 5-6 membered heteroaryl group; R9 is H, dimethylamino group, amino group, halogen, C1-C3 alkyl group, C1-C3 alkoxy group, halogen-substituted C1-C3 alkyl group, halogen-substituted C1-C3 alkoxy group, -NH(R4), -N(R4)2, -OR4, -C=O-NH (cyclopropyl group), R 10 Substituted C1-C3 alkyl group, C3-C6 cycloalkyl group, 3-6 membered heterocycloalkyl group, R 10 Substituted C3-C6 cycloalkyl group, R 10 Substituted 3- to 6-membered heterocycloalkyl group, -NH(R4) Substituted 3- to 6-membered heterocycloalkyl group, -COR 11 is selected from R4 is H, C1-C6 alkyl group, R 10 Substituted C1-C6 alkyl group, C3-C6 cycloalkyl group, 3-6 membered heterocycloalkyl group, R 10 Substituted C3-C6 cycloalkyl group, R 10 Substituted 3- to 6-membered heterocycloalkyl group, -CHR 11 , -COR 11 is selected from R 10 is selected from a C1-C3 alkyl group, a dimethylamino group, a C3-C6 cycloalkyl group, a 3- to 6-membered heterocycloalkyl group, a C1-C3 alkyl-substituted 3- to 6-membered heterocycloalkyl group, and a C1-C3 alkyl-substituted C3-C6 cycloalkyl group; R 11 is selected from a vinyl group, a C1 to C4 alkyl group, a C3 to C6 cycloalkyl group, and a halogen-substituted C3 to C6 cycloalkyl group.

[0018] In some embodiments, R2 is selected from a C5-C6 cycloalkyl group, an R9-substituted C5-C6 cycloalkyl group, a 5-6 membered heterocycloalkyl group, an R9-substituted 5-6 membered heterocycloalkyl group, a phenyl group, and an R9-substituted phenyl group; R9 is H, dimethylamino group, amino group, C1-C3 alkyl group, -NH(R4), -OR4, -C=O-NH (cyclopropyl group), R 10 Substituted C1-C3 alkyl group, C3-C6 cycloalkyl group, 5-6 membered heterocycloalkyl group, R 10 Substituted C3-C6 cycloalkyl group, R 10 Substituted 5-6 membered heterocycloalkyl group, -COR 11 is selected from R4 is H, C1-C3 alkyl group, R 10 Substituted C1-C3 alkyl group, C3-C6 cycloalkyl group, 5-6 membered heterocycloalkyl group, R 10 Substituted C3-C6 cycloalkyl group, R 10 Substituted 5-6 membered heterocycloalkyl group, -CHR 11 , -COR 11 is selected from R 10 is selected from a C1 to C3 alkyl group and a C3 to C6 cycloalkyl group, R 11 is selected from a vinyl group, a C1 to C4 alkyl group, and a C3 to C6 cycloalkyl group.

[0019] In some embodiments, R2 is JPEG0007756374000011.jpg21170 Wherein, R9 is H, a dimethylamino group, a C1 to C3 alkyl group, -NH(R4), -OR4, -COR 11 is selected from R4 is H, a methylpiperidinyl group, -CH2R 11 , -COR 11 Selected from R 11 is selected from a vinyl group, a C1 to C4 alkyl group, a cyclopropyl group, a cyclobutyl group, and a cyclopentyl group.

[0020] In some embodiments, A is selected from -NH-, -NHR-, and R is selected from a phenyl group, an R7-substituted phenyl group, a 6-membered heteroaryl group, and an R7-substituted 6-membered heteroaryl group; R7 is selected from a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a halogen, a C1-C6 alkoxy group, a halogen-substituted C1-C6 alkoxy group, a deuterium-C1-C6 alkoxy group, a halogen-substituted C1-C6 alkyl group, a cyano-substituted C1-C6 alkyl group, a deuterium-C1-C6 alkyl group, a trifluoromethyl-substituted C3-C6 cycloalkyl group, a C1-C6 alkyl-substituted C3-C6 cycloalkyl group, a hydroxy group, an amino group, -SO(C1-C6 alkyl group), -S(O)2(C1-C6 alkyl group), and a C1-C6 alkylthio group; B does not exist or C3~C 12 Cycloalkyl groups, R8 substituted C3-C 12 Cycloalkyl group, 3- to 12-membered heterocycloalkyl group, R8-substituted 3- to 12-membered heterocycloalkyl group, 3- to 12-membered heterocycloalkanone group, R8-substituted 3- to 12-membered heterocycloalkanone group, C3-C 12 cycloalkyl-substituted amino group, 3- to 12-membered heterocycloalkyl-substituted amino group, JPEG0007756374000012.jpg27170R8 is a C1 to C6 alkyl group, C3 to C 12 It is selected from a cycloalkyl group, a 3- to 12-membered heterocycloalkyl group, an amino group, a cyano-substituted C1-C6 alkyl group, a halogen, a C1-C6 alkoxy group, a halogen-substituted C1-C6 alkyl group, a hydroxy group, and an amino group.

[0021] In some embodiments, A is JPEG0007756374000013.jpg63139JPEG0007756374000014.jpg186140, and B is not present or Selected from JPEG0007756374000015.jpg195140JPEG0007756374000016.jpg57142.

[0022] In some embodiments, A is selected from -NH-, -NHR-, and R is selected from a phenyl group, a 6-membered heteroaryl group, an R7-substituted phenyl group, or an R7-substituted 6-membered heteroaryl group; R7 is selected from a C1-C3 alkyl group, a halogen, a C1-C3 alkoxy group, a halogen-substituted C1-C3 alkoxy group, a halogen-substituted C1-C3 alkyl group, and a cyano-substituted C1-C3 alkyl group; B is not present or C4~C 12 Cycloalkyl groups, R8 substituted C4-C 12 cycloalkyl groups, 4- to 12-membered heterocycloalkyl groups, R8-substituted 4- to 12-membered heterocycloalkyl groups, JPEG0007756374000017.jpg14170R8 is selected from a C1 to C3 alkyl group, a C4 to C6 cycloalkyl group, a 4 to 6 membered heterocycloalkyl group, a cyano substituted C1 to C3 alkyl group, a halogen, a C1 to C3 alkoxy group, and a halogen substituted C1 to C3 alkyl group.

[0023] In some embodiments, A is selected from -NH-, -NHR-, and R is selected from a phenyl group, a 6-membered nitrogen-containing heteroaryl group, an R7-substituted phenyl group, or an R7-substituted 6-membered nitrogen-containing heteroaryl group; R7 is selected from a C1-C3 alkoxy group; B is absent or a C4-C8 cycloalkyl group, R is a substituted C4-C 10 cycloalkyl groups, 4- to 10-membered heterocycloalkyl groups, R8-substituted 4- to 10-membered heterocycloalkyl groups, JPEG0007756374000018.jpg14170R8 is selected from a C1 to C3 alkyl group and a C1 to C3 alkoxy group.

[0024] In some embodiments, R3 is Selected from JPEG0007756374000019.jpg43137.

[0025] The present invention further provides the use of the above pyridopyrimidine compound or its pharmaceutically acceptable salt, stereoisomer or prodrug molecule, including the following technical solutions:

[0026] Use of the above pyridopyrimidine compound or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a prodrug molecule thereof in the manufacture of an agent for degrading AKT3 protein.

[0027] Use of the above pyridopyrimidine compound or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a prodrug molecule thereof in the manufacture of a drug for preventing and / or treating a disease associated with the abnormal expression of AKT3 protein.

[0028] In some embodiments, the diseases associated with abnormal expression of AKT3 protein include tumors, cardiovascular diseases, diabetes, hypertension, muscular dystrophy, Parkinson's disease, and Alzheimer's disease.

[0029] Use of the above pyridopyrimidine compound or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a prodrug molecule thereof in the manufacture of a drug for preventing and / or treating tumors or preventing postoperative tumor recurrence.

[0030] In some embodiments, the tumor is non-small cell lung cancer, malignant melanoma, prostate cancer, kidney cancer, liver cancer, bladder cancer, ovarian cancer, colon cancer, rectal cancer, breast cancer, cervical cancer, lung cancer, laryngeal cancer, nasopharyngeal cancer, pancreatic cancer, multiple myeloma, B lymphoma, leukemia, or cutaneous squamous cell carcinoma.

[0031] The present invention further provides an AKT3 protein degrading agent, including the following technical solutions:

[0032] An AKT3 protein degrading agent containing the above pyridopyrimidine compound or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a prodrug molecule thereof as an active ingredient.

[0033] The present invention further provides a pharmaceutical composition for treating and / or preventing tumors or preventing tumor recurrence after surgery, including the following technical solutions:

[0034] A pharmaceutical composition for treating and / or preventing tumors or preventing postoperative tumor recurrence, which is prepared using an active ingredient and a pharmaceutically acceptable carrier or excipient, and the active ingredient includes the above-mentioned pyridopyrimidine compound or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a prodrug molecule thereof.

[0035] The present invention provides a pyridopyrimidine compound having a novel structure, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a prodrug molecule thereof. Such a compound can efficiently and highly selectively degrade AKT3 protein in cells without affecting AKT1 / 2, thereby significantly inhibiting tumor cell proliferation mediated by high AKT3 expression, and is useful for producing drugs for treating diseases associated with abnormal expression of AKT3 protein and various types of tumors. [Brief explanation of the drawings]

[0036] [Figure 1] 1 shows the degradation activity of compound ZX-HYT-11 against AKT1 / 2 / 3 in H1975, PC-9, H1299, and A549 cells. DETAILED DESCRIPTION OF THE INVENTION

[0037] In the compounds of the present invention, any variable (e.g., R 4 , R 5When any group (e.g., ) occurs more than once for any constituent, its definition at each occurrence is independent of its definition at each other occurrence. Similarly, combinations of substituents and variables are permissible so long as such combinations result in stable compounds. Lines drawn from substituents to ring systems indicate that the bond may be attached to any of the substitutable ring atoms. If the ring system is polycyclic, the bond may be attached only to any of the suitable carbon atoms on the adjacent ring. Those skilled in the art will understand that the substituents and substitution patterns of the compounds of the present invention will be selected to provide compounds that are chemically stable and can be readily synthesized from readily available starting materials using techniques in the art or the methods set forth below. When a substituent is itself substituted with multiple groups, these groups may be located on the same or different carbon atoms, as long as the structure is stable.

[0038] As used herein, the term "alkyl group" refers to a saturated aliphatic hydrocarbon group, including branched and straight chains, having a specific number of carbon atoms. For example, the "C1-C6" in "C1-C6 alkyl group" is defined to include groups having 1, 2, 3, 4, 5, or 6 carbon atoms arranged in a straight or branched chain. For example, "C1-C6 alkyl group" specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, and hexyl groups.

[0039] As used herein, the term "cycloalkyl group" refers to a saturated alkyl group whose ring atoms consist of carbon atoms. of It refers to a monocyclic, bicyclic or polycyclic hydrocarbon group, and the bicyclic or polycyclic group includes spirocyclic, fused ring and JPEG0007756374000020.jpg55170

[0040] As used herein, the term "alkoxy group" refers to groups having an -O-alkyl structure, such as -OCH3, -OCH2CH3, -OCH2CH2CH3, -O-CH2CH(CH3)2, -OCH2CH2CH2CH3, and -O-CH(CH3)2.

[0041] As used herein, the term "heterocycloalkyl group" refers to a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic ring substituent, where one or more ring atoms are selected from N, O, or S(O)m heteroatoms, where m is an integer from 0 to 2, and the remaining ring atoms are carbon, and bicyclic or polycyclic rings include spirocyclic, fused, and bridged rings. For example, a morpholinyl group, a piperidinyl group, a tetrahydropyrrolyl group, a pyrrolidinyl group, a dihydroimidazolyl group, a dihydroisoxazolyl group, a dihydroisothiazolyl group, a dihydrooxadiazolyl group, a dihydrooxazolyl group, a dihydropyrazinyl group, a dihydropyrazolyl group, a dihydropyridinyl group, a dihydropyrimidinyl group, a dihydropyrrolyl group, a dihydrotriazolyl group, a dihydrothiadiazolyl group, a dihydrothiazolyl group, a dihydrothienyl group, a dihydrotriazolyl group, a dihydroazetidinyl group, a tetrahydrofuryl group, a tetrahydrothienyl group, JPEG0007756374000021.jpg18136, and N-oxides thereof. Attachment of heterocyclic substituents may occur via a carbon atom or via a heteroatom.

[0042] As used herein, the term "heteroaryl group" refers to an aromatic ring containing one or more heteroatoms selected from O, N, or S, which may be monocyclic, bicyclic, or polycyclic, including, but not limited to, quinolinyl, pyrazolyl, pyrrolyl, thienyl, furyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, imidazolyl, oxazolyl, isoxazolyl, pyridazinyl, and the like. A "heteroaryl group" is also understood to include any N-oxide derivative of a nitrogen-containing heteroaryl group. Attachment of a heteroaryl group can occur through a carbon atom or through a heteroatom.

[0043] The term "heteroaryl ketone group," as used herein, refers to an aromatic ring containing one or more cyclic carbonyl groups and containing one or more heteroatoms selected from O, N, or S, which may be monocyclic, bicyclic, or polycyclic, such as, for example: JPEG0007756374000022.jpg17137. Attachment of the heteroaryl ketone group can occur through a carbon atom or through a heteroatom.

[0044] The term "heterocycloalkanone group," as used herein, refers to a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic cyclic substituent containing one or more cyclic carbonyl groups, where one or more ring atoms are selected from N, O, or S(O)m heteroatoms, where m is an integer from 0 to 2, and the remaining ring atoms are carbon, and the bicyclic or polycyclic ring includes spirocyclic fused rings and bridged rings, such as JPEG0007756374000023.jpg17136. Attachment of the heterocycloalkanone group can occur via a carbon atom or a heteroatom.

[0045] As will be understood by those skilled in the art, "halo" or "halogen" as used herein refers to chlorine, fluorine, bromine and iodine.

[0046] The present invention provides pyridopyrimidine compounds having the structure shown in formula (I): JPEG0007756374000024.jpg36170 (where, E is hydrogen, C1-C 15 Alkyl groups, substituted C1-C 15 Alkyl groups, C3-C 15 Cycloalkyl groups, substituted C3-C 15 is selected from a cycloalkyl group, a 3- to 15-membered heterocycloalkyl group, and a substituted 3- to 15-membered heterocycloalkyl group; L is absent or is a linking unit consisting of one or more of an alkylene group, an ether group, a thioether group, an ester group, an amino group, an amide group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, and a -N=N- group; Y is absent or selected from -O-, -NH-, -NHCO-, -CH2-, -S-, -CO-; Z is absent or selected from -O-, -NH-, -N(C1-C6 alkyl group)-, -NHCO-, -CH2-, -S-, -CO-, and -SO-; R1 is selected from hydrogen, a C1-C6 alkyl group, a halogen or a halogen-substituted C1-C6 alkyl group; R2 is C3~C 15 Cycloalkyl groups, substituted C3-C 15 Cycloalkyl groups, 3-15 membered heterocycloalkyl groups, substituted 3-15 membered heterocycloalkyl groups, C6-C 10 Aryl groups, substituted C6-C 10 an aryl group, a 5- to 10-membered heteroaryl group, or a substituted 5- to 10-membered heteroaryl group; JPEG0007756374000025.jpg7170A is selected from -NH- and -NHR-, and R is C to C 10 Aryl groups, substituted C6-C 10 an aryl group, a 5- to 10-membered heteroaryl group, or a substituted 5- to 10-membered heteroaryl group; B does not exist or C3~C 15 Cycloalkyl groups, substituted C3-C 15 Cycloalkyl groups, 3- to 15-membered heterocycloalkyl groups, substituted 3- to 15-membered heterocycloalkyl groups, 3- to 15-membered heterocycloalkanone groups, R8-substituted 3- to 15-membered heterocycloalkanone groups, C3-C 12 cycloalkyl-substituted amino group, 3- to 12-membered heterocycloalkyl-substituted amino group, JPEG0007756374000026.jpg26170

[0047] The present invention encompasses both the free form of the compound of Formula I and its pharmaceutically acceptable salts and stereoisomers. Some specific exemplary compounds herein are protonated salts of amine-based compounds. The term "free form" refers to the amine-based compound in non-salt form. The pharmaceutically acceptable salts included include not only the exemplary salts of the specific compounds described herein, but also all typical pharmaceutically acceptable salts of the free form of the compound of Formula I. The free form of a specific salt of the compound can be isolated using techniques known in the art. The free form can be regenerated by treating the salt with a suitable dilute aqueous base, such as dilute aqueous NaOH, potassium carbonate, ammonia, or sodium bicarbonate. While the free forms may differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, for purposes of the invention, such acid and base salts are otherwise pharmaceutically equivalent to their respective free forms.

[0048] The pharmaceutically acceptable salts of the present invention may be synthesized from the compounds of the present invention containing a basic or acidic moiety by conventional chemical methods. Typically, salts of basic compounds are prepared by ion exchange chromatography or by reacting the free base with an excess or a chemically calculated amount of an inorganic or organic acid in the desired salt form in a suitable solvent or combination of solvents. Similarly, salts of acidic compounds are formed by reacting with a suitable inorganic or organic base.

[0049] Thus, pharmaceutically acceptable salts of the compounds of this invention include conventional non-toxic salts of the compounds of this invention formed by reaction of a basic compound of this invention with an inorganic or organic acid, such as, for example, salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid, and salts derived from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetoxymonobenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, and trifluoroacetic acid.

[0050] When the compound of the present invention is acidic, suitable "pharmaceutically acceptable salts" refer to salts prepared with pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganic salts, manganous salts, potassium salts, sodium salts, zinc salts, etc. Ammonium salts, calcium salts, magnesium salts, potassium salts, and sodium salts are particularly preferred. For salts derived from pharmaceutically acceptable organic non-toxic bases, the bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, aminoglucose, histidine, hydroxycobaltamine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, guar gum, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, trometamol, and the like.

[0051] Berg et al., "Pharmaceutical Salts," J. Pharm. Sci. '77:66:1-19, provides more details on the preparation of the aforementioned pharmaceutically acceptable salts and other exemplary pharmaceutically acceptable salts.

[0052] In one embodiment, the present application provides the use of compounds of Formula I and pharmaceutically acceptable salts thereof for the treatment of diseases associated with abnormal expression of AKT3 protein in humans or other mammals, such as tumors, cardiovascular diseases, diabetes, hypertension, muscular dystrophy, Parkinsonism, and Alzheimer's disease.

[0053] In one embodiment, the compounds of the present application and pharmaceutically acceptable salts thereof are useful for the prevention and / or treatment of tumors such as non-small cell lung cancer, malignant melanoma, prostate cancer, kidney cancer, bladder cancer, ovarian cancer, colon cancer, rectal cancer, breast cancer, cervical cancer, lung cancer, laryngeal cancer, nasopharyngeal cancer, pancreatic cancer, multiple myeloma, B lymphoma, and leukemia, or for the prevention of tumor recurrence after surgery. Drug Metabolites and Prodrugs

[0054] Metabolites of the compounds according to the present invention and pharmaceutically acceptable salts thereof, as well as prodrugs that can be converted in vivo into the structures of the compounds according to the present application and pharmaceutically acceptable salts thereof, are also included within the scope of the present invention. Pharmaceutical Composition

[0055] The present invention further provides a pharmaceutical composition comprising an active ingredient within a safe and effective amount, and a pharmaceutically acceptable carrier or excipient.

[0056] The "active ingredient" of the present invention refers to the compound of formula I of the present invention, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a prodrug molecule thereof.

[0057] The "active ingredient" and pharmaceutical composition of the present invention are useful as AKT3 protein degraders and are useful for producing drugs for preventing and / or treating tumors, cardiovascular diseases, diabetes, hypertension, muscular dystrophy, Parkinsonism, Alzheimer's disease, etc.

[0058] "Safe and effective amount" refers to an amount of an active ingredient sufficient to clearly improve the condition without causing serious side effects. Typically, a pharmaceutical composition contains 1 to 2000 mg of an active ingredient / agent, more preferably 10 to 200 mg of an active ingredient / agent. Preferably, the "agent" is one tablet.

[0059] A "pharmaceutically acceptable carrier or excipient" means one or more compatible solid or liquid fillers or gel-like substances which must be of sufficient purity and sufficiently low toxicity to be suitable for human use.

[0060] "Compatibility" herein refers to the ability of the components of the composition to be blended with the active ingredients of the present invention and with each other without significantly reducing the efficacy of the active ingredients.

[0061] Some examples of pharmaceutically acceptable carriers or excipients include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyhydric alcohols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., Twen®), wetting agents (e.g., sodium dodecyl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0062] In another preferred embodiment, the compound of formula I of the present invention may form a complex with a polymeric compound or polymer through non-binding interactions. In another preferred embodiment, the compound of formula I of the present invention may be linked to a polymeric compound or polymer as a small molecule through a chemical bond. The polymeric compound may be a biopolymer such as a polysaccharide, protein, nucleic acid, or polypeptide.

[0063] The method of administration of the active ingredient or pharmaceutical composition of the present invention is not particularly limited, and representative administration methods include (but are not limited to) oral administration, intratumoral administration, rectal administration, parenteral administration (intravenous administration, intramuscular administration, or subcutaneous administration), etc.

[0064] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.

[0065] In these solid dosage forms, the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or is mixed with the following ingredients: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) adhesives, such as hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, gum arabic; (c) humectants, e.g., glycerin; (d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate; (e) dissolution retarders, e.g., paraffin; (f) absorption enhancers, e.g., quaternary amine compounds; (g) humectants, such as cetyl alcohol and monostearate glyceride; (h) an adsorbent, such as kaolin; and (i) Lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage forms may also comprise buffering agents.

[0066] The solid dosage forms may also be prepared using shell materials, such as coatings and other materials known to those skilled in the art. These may also contain opacifying agents, and the release of the active ingredient in such compositions may be delayed in a certain part of the gastrointestinal tract. Examples of embedding materials that can be used include polymeric substances and waxy substances.

[0067] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active ingredient, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizing and emulsifying agents, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures thereof. In addition to these inert diluents, the compositions may also contain auxiliary agents such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and perfumes.

[0068] Suspensions may contain, in addition to the active ingredient, suspending agents such as ethoxylated isooctadecanol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these.

[0069] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or non-aqueous 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.

[0070] The compounds of the invention may be administered alone or in combination with other therapeutic agents.

[0071] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., human) in need of treatment, and the dosage upon administration is a dosage considered to be pharmaceutically effective, and the daily dosage for a human weighing 60 kg is usually 1 to 2000 mg, preferably 20 to 500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician. Concomitant medications

[0072] The compound of Formula I may be used in combination with other known drugs that treat or improve similar conditions. In the case of combined administration, the administration method and dosage of the original drug remain the same, and the compound of Formula I is taken at the same time or after the original drug. When the compound of Formula I is taken simultaneously with one or more other drugs, it is preferable to use a pharmaceutical composition containing one or more known drugs and the compound of Formula I at the same time. The combination of drugs also includes taking the compound of Formula I and one or more other known drugs during overlapping periods. When the compound of Formula I is used in combination with one or more other drugs, the dosage of the compound of Formula I or the known drug may be lower than when administered alone.

[0073] Drugs or active ingredients that may be used in pharmaceutical combination with compounds of Formula I include, but are not limited to: Estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic / cell proliferation inhibitors, antiproliferative agents, protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protein kinase inhibitors, reverse transcriptase inhibitors, angiogenesis inhibitors, cell proliferation and survival signal inhibitors, drugs that interfere with cell cycle checkpoints and inducers of apoptosis, cytotoxic drugs, tyrosine protein inhibitors, EGFR inhibitors, VEGFR inhibitors, serine / threonine protein inhibitors, Bcr-Abl inhibitors, c-Kit inhibitors, Met inhibitors, Raf inhibitors, MEK inhibitors, MMP inhibitors, topoisomerase inhibitors, histidinyl acid deacetylase inhibitors, proteasome inhibitors, CDK inhibitors, Bcl-2 family protein inhibitors, MDM2 family protein inhibitors, IAP family protein inhibitors, STAT family protein inhibitors, PI3K inhibitors, AKT inhibitors, integrin blockers, interferon-α, interleukin-12, COX-2 inhibitors, p53, p53 activators, VEGF antibodies, EGF antibodies, JAK inhibitors, etc.

[0074] In one embodiment, the drug or active ingredient obtainable in combination with the compound of Formula I includes aldesleukin, alendronic acid, interferon, alitretinoin, allopurinol, alloprim, palonosetron hydrochloride, altretamine, aminoglutethimide, amifostine, amrubicin, amsacrine, anastrozole, dolasetron, aranesp, arglabin, arsenic trioxide, aromasin, 5-azacytidine, azathioprine, BBC or ticeBBC, bestatin, betamethasone acetate, betamethasone riboflavin, benzodiazepine, benzodiazepine, benzophenone, benzotriazole, benzophenone-3, benzotriazole, benzotriazole-3, benzotriazole-4, benzotriazole-5, benzotriazole-6, benzotriazole-7, benzotriazole-8, benzotriazole-9, benzotriazole-10, benzotriazole-11, benzotriazole-12, benzotriazole-13, benzotriazole-14, benzotriazole-15, benzotriazole-15, benzotriazole-16, benzotriazole-17, benzotriazole-18, benzotriazole-19, benzotriazole-20, benzotriazole-21, benzotriazole-22, benzotriazole-23, benzotriazole-24, benzotriazole-25, benzotriazole-26, benzotriazole-27, benzotriazole-28, benzotriazole-29, benzotriazole-30, benzotriazole-31, benzotriazole-32, benzotriazole-33, benzotriazole-34, benzotriazole-35, benzotriazole-36, benzotriazole-37, benzotriazole-38, benzotriazole-39, benzotriazole-41, benzotriazole-42, sodium phosphate, bexarotene, bleomycin sulfate, broxuridine, bortezomib, busulfan, calcitonin, Campath, capecitabine, carboplatin, casodex, cefesone, cermoleukin, cerbidine, chlorambucil, cisplatin, cladribine, clodronate, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin liposome (DAUNOXOME), decadron, decadron phosphate, delestrogen, denileukin diftitox, de Pomedrol, deslorelin, dexrazoxane, diethylstilbestrol, diflucan, docetaxel, doxifluridine, doxorubicin, DW-166HC, Eligard, Elitek, epirubicin hydrochloride, aprepitant, epirubicin, epoetin alfa, epogen, eptaplatin, ergamisol, eslase, estradiol, estramustine sodium phosphate, ethinyl estradiol, amifostine (ETHYOL), etidronic acid, etopofos, etoposide, fadrozole, ta Moxifen preparations, filgrastim, finasteride, filgrastim, floxuridine, fluconazole, fludarabine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil, fluoxymesterone, flutamide, formestane, fostearin, fotemustine, fulvestrant, gamaguard, gemcitabine, gemtuzumab, imatinib mesylate, gliadel, goserelin, granisetron hydrochloride, histrelin, hycamtin, hydrocortone, eiltro-hydroxynonyladenine, hydroxyurea,Ibritumomab tiusetan, idarubicin, ifosfamide, interferon alpha, interferon-alpha 2, interferon alpha-2A, interferon alpha-2B, interferon alpha-nl, interferon alpha-n3, interferon beta, interferon gamma-la, interleukin-2, intron A, Iressa, irinotecan, Kytril, lentinan sulfate, letrozole, leucovorin, leuprolide, leuprolide acetate, lenalidomide, levamisole, levofolinic acid calcium salt, levoxil, lomustine, lonidamine, Marinol, Mechlorethamine, mecobalamin, medroxyprogesterone acetate, megestrol acetate, melphalan, menest, 6-mercaptopurine, mesna, methotrexate, Metobix, miltefosine, minocycline, mitomycin C, mitotane, mitoxantrone, modrenal, myoset, nedaplatin, neulasta, neumega, neupogen, nilutamide, NSC-631570, recombinant human interleukin-1-beta, ondansetron hydrochloride, Oraled, oxaliplatin, paclitaxel, Pediapred, Pediapred Gaspargas, Pegasys, Pentostatin, Picibanil, Pilocarpine Hydrochloride, Pirarubicin, Plicamycin, Porfimer Sodium, Prednimustine, Prednisolone, Prednisone Premarin, Procarbazine, Procrit, Raltitrexed, Rebif, Etidronate Rhenium-186, Rituximab, Roferon-A, Romultide, Salagen, Sandostatin, Sargramostim, Semustine, Sizofiran, Sobuzoxane, Solumedrol, Sparfoic Acid, Stem Cell Therapy, Streptozocin, Strontium-89 Chloride, Synthroid, Tamoxifen, tamsulosin, tazonermin, tastolactone, taxotere, tecerequin, temozolomide, teniposide, testosterone propionate, testred, thioguanine, thiotepa, thyroid-stimulating hormone, tiludronic acid, topotecan, toremifene, tositumomab, trastuzumab, treosulfan, tretinoin, trexol, trimethylmelamine, trimetrexate, triptorelin acetate, triptorelin pamoate, UFT, uridine, valrubicin, vesnarinone, vinblastine, vincristine,Vandesin, vinorelbine, viruridine, Zincard, zinostatin stimalamer, Zofran, ABI-007, acolbifene, interferon r-lb, affinitak, aminopterin, arzoxifene, asoprisnil, atamestane, atrasentan, BAY43-9006, Avastin, CCI-779, CDC-501, Celebrex, cetuximab, crisnatol, cyproterone Acetate, decitabine, DN-101, doxorubicin-MTC, dSLIM, dutasteride, edotecarin, eflornithine, exatecan, fenretinide, histamine dihydrochloride, histrelin hydrogel implant, holmium-166DOTMP, ibandronic acid, interferon gamma, Intron-PEG, ixabepilone, keyhole limpet hemocyanin, L-651582, lanreotide, lasofoxifen phenytoin, libra, lonafamib, miproxifene, minodronate, MS-209, liposomal MTP-PE, MX-6, nafarelin, nemorubicin, neovastat, nolatrexed, oblimersen, onco-TCS, osidem, paclitaxel polyglutamate, pamidronate disodium, PN-401, QS-21, quazepam, R-1549, raloxifene, ranpirnase, 13-cis-retinoin Acid, satraplatin, seocalcitol, T-138067, tarceva, paclitaxel docosahexaenoate, thymosin al, tiazofurin, tipifarnib, tirapazamine, TLK-286, toremifene, transMID-lo7R, valspodar, vapreotide, vatalanib, verteporfin, vinflunine, Z-100, zoledronic acid, or a combination thereof.

[0075] The advantages of the present invention are as follows: (1) To provide a pyridopyrimidine compound having a novel structure. (2) This pyridopyrimidine compound can efficiently and highly selectively degrade AKT3 protein in cells without affecting AKT1 / 2, and can effectively inhibit the proliferation of various tumor cells, making it useful for the production of antitumor agents. The present invention will be further described below with reference to specific examples. Note that these examples are used only to illustrate the present invention and are not intended to limit the scope of the present invention. The conditions described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989) or the conditions recommended by the manufacturer are followed. Unless otherwise specified, percentages and parts are by weight. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those familiar to those skilled in the art. Furthermore, methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred implementation methods and materials described herein are merely illustrative. The starting materials in the following examples are either commercially available or can be prepared according to methods known to those skilled in the art or as described herein. The structure of the compound was determined by nuclear magnetic resonance ( 1 The chromatographic properties were determined by H-NMR and / or mass spectrometry (MS). NMR measurements were performed using a Bruker AV-400 nuclear magnetic resonance spectrometer, with deuterated chloroform (CDCl3) or deuterated dimethyl sulfoxide (DMSO-D6) as the solvent, and TMS as the internal standard. MS measurements were performed using an LCQAD-40000 mass spectrometer. Column chromatography was performed using 200-300 mesh silica gel (manufactured by Qingdao Ocean Chemical Plant).

[0076] Example 1: N-(3-(2-((4-(4-(2-(2-(2-(2-(2-(((3R,5R,7R)-adamantan-1-yl)acetamido)ethoxy)ethoxy)ethoxy)ethyl))piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (ZX-HYT-01) JPEG0007756374000027.jpg106170Step 1: Synthesis of (3-((5-bromo-2-chloropyrimidin-4-yl)amino)phenyl) t-butylcarbamate (3a) 5-Bromo-2,4-dichloropyrimidine (1) (0.45 g, 2.0 mmol) and (3-aminophenyl) t-butylcarbamate (2a) (0.42 g, 2.0 mmol) were dissolved in N,N-dimethylformamide (DMF) (10 mL) sequentially, followed by the addition of potassium carbonate (0.55 g, 4.0 mmol). The suspension was stirred overnight at room temperature. After completion of the reaction was monitored by TLC, 50 mL of ice water was added to the reaction mixture, resulting in the formation of a large amount of white precipitate. The mixture was suction filtered under reduced pressure, and the filter cake was washed with ice water and anhydrous ether (3 × 20 mL). The filter cake was suction filtered and dried, then added to 10 mL of acetone to form a slurry, and suction filtered again under reduced pressure. The resulting filter cake was dried to give a relatively pure white solid, Compound 3a (0.67 g, 84.2% yield). MS (ESI), m / z: 399.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1 H), 7.78 (s, 1 H), 7.45 (d, 1 H, J = 7.2 Hz), 7.32-7.28 (m, 2 H), 7.03 (dd, 1 H, J = 1.2, 8.0 Hz), 6.56 (s, 1 H), 1.53 (s, 9 H). Step 2: Synthesis of (3-(2-chloro-5-methyl-7-oxypyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl) t-butylcarbamate (4a) Compound 3a (2.57 g, 6.43 mmol) and crotonic acid (5.54 g, 64.3 mmol) were placed in a 250 mL two-neck round-bottom flask. Anhydrous tetrahydrofuran (40 mL) and N,N-diisopropylethylamine (11.2 mL) were added under argon protection. The mixture was stirred until homogeneous and then purged with argon three times. Bis(cyanophenyl)palladium(II) dichloride (0.12 g, 5%) and tris(o-methylphenyl)phosphine (96 mg, 5%) were added, and the mixture was purged with argon three times. The mixture was then slowly heated to 70 °C. After the completion of the reaction of starting material 3a was confirmed by TLC, 1.5 mL of acetic anhydride was added. The reaction mixture was heated to 80 °C and stirred for an additional 8 h. After TLC showed that the reaction was complete, most of the organic solvent was evaporated under reduced pressure, and the residue was diluted with 100 mL of ethyl acetate. The organic layer was washed with 1 N HCl (3 × 100 mL) and saturated sodium chloride solution (2 × 100 mL), respectively. The separated organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluted with petroleum ether / ethyl acetate = 2:1) to give compound 4a (0.71 g, 30% yield) as a white solid. MS (ESI), m / z: 387.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 9.10 (s, 1H), 7.51-7.38 (m, 3H), 6.89 (dt, J = 7.4, 1.7 Hz, 1H), 6.73 (d, J = 1.4 Hz, 1H), 2.53 (d, J = 1.3 Hz, 3H), 1.47 (s, 9H). Step 3: Synthesis of N-(3-(2-chloro-5-methyl-7-oxypyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (5) JPEG0007756374000030.jpg39170 To a solution of compound 4a (0.50 g, 1.29 mmol) in DCM (10 mL) was added TFA (2 mL) and stirred at room temperature for 0.5 hours. After completion of the reaction, the organic solvent was evaporated under reduced pressure. The resulting residue was dissolved in 10 mL of acetonitrile, and anhydrous potassium carbonate (0.36 g, 2.58 mmol) and acryloyl chloride (0.17 g, 1.94 mmol) were added to the solution in that order, and stirring was continued at room temperature for 0.5 hours. After completion of the reaction was monitored by TLC, the organic solvent was evaporated, 50 mL of ice water was added, and stirring was continued at room temperature for 1 hour. The mixture was suction filtered under reduced pressure, and the filter cake was washed with anhydrous acetone (2 × 25 mL). The filter cake was dried to obtain a white solid intermediate 5 (0.41 g, 93% yield). The crude intermediate was used in the next step without purification. MS (ESI), m / z: 341.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.69 (br, 1 H), 9.11 (s, 1 H), 7.78 (d, J = 8.22 Hz, 1 H), 7.71 (br, 1 H), 7.49 (t, J = 7.92 Hz, 1 H), 7.00 (d, J = 7.63 Hz, 1 H), 6.74 (s, 1 H), 6.56 (dd, J = 10.27, 16.92 Hz, 1 H), 6.26 (d, J = 16.82 Hz, 1 H), 5.76 (d, J = 10.17 Hz, 1 H), 2.55 (s, 3 H). Step 4: Synthesis of t-butyl 4-(4-((8-(3-acrylamidophenyl)-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-ethoxyphenyl)piperazine-1-carboxylate (7) Compound 5 (0.68 g, 2 mmol) and compound 6 (0.67 g, 2.2 mmol) were added to 25 mL of s-butanol, and a catalytic amount of trifluoroacetic acid was added dropwise to the mixture. Under argon protection, the reaction mixture was heated to 95°C and stirred overnight. After completion of the reaction was confirmed by TLC, the mixture was cooled to room temperature, and the organic solvent was evaporated under reduced pressure. The residue was purified by column chromatography (eluting with chloroform / methanol = 25:1) to give compound 7 (1.11 g, 92% yield) as a yellow solid. MS (ESI), m / z: 612.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.81 (s, 1H), 8.14 (s, 1H), 7.90 (d, J = 8.2 Hz, 1H), 7.56 (t, J = 2.0 Hz, 1H), 7.51 (t, J = 8.1 Hz, 1H), 7.28 (d, J = 8.9 Hz, 1H), 6.98 (ddd, J = 7.9, 2.0, 1.0 Hz, 1H), 6.56 (d, J = 2.5 Hz, 1H), 6.50‐6.38 (m, 1H), 6.33 (d, J = 1.3 Hz, 1H), 6.30-6.21 (m, 1H), 6.03 (s, 1H), 5.77 (dd, J = 10.1, 2.1 Hz, 1H), 3.78 (s, 3H), 3.51‐3.40 (m, 4H), 3.05‐2.89 (m, 4H), 2.46 (s, 3H), 1.44 (s, 9H). Step 5: Synthesis of N-(3-(2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (8) To a solution of compound 7 (1.22 g, 2 mmol) in DCM (20 mL) was added TFA (3 mL), and the resulting solution was stirred at room temperature for 0.5 h. After completion of the reaction was monitored by TLC, the organic solvent was evaporated and the resulting crude product was purified by column chromatography (eluting with chloroform / methanol / aqueous ammonia = 25:1:0.1) to give a yellow solid product 8 (0.91 g, 90% yield). MS (ESI), m / z: 510.3 [M−H] - . 1 H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.90 (s, 1H), 8.82 (s, 1H), 8.18 (s, 1H), 7.90 (d, J = 8.3 Hz, 1H), 7.56-7.45 (m, 2H), 7.31 (d, J = 8.8 Hz, 1H), 7.00 (dd, J = 7.9, 2.0 Hz, 1H), 6.60 (d, J = 2.6 Hz, 1H), 6.45 (dd, J = 16.9, 10.1 Hz, 1H), 6.35‐6.23 (m, 2H), 6.06 (s, 1H), 5.77 (dd, J = 10.1, 2.1 Hz, 1H), 3.79 (s, 3H), 3.24 (s, 8H), 2.48-2.44 (m, 3H) Step 6: Synthesis of N-(3-(2-((4-(4-(2-(2-(2-(2-(2-(((3R,5R,7R)-adamantan-1-yl)acetamido)ethoxy)ethoxy)ethoxy)ethyl))piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (ZX-HYT-01) JPEG0007756374000033.jpg41170 Compound 8 (0.20 g, 0.39 mmol), 2-(2-(2-(2-(2-(((3R,5R,7R)-adamantan-1-yl)acetamido)ethoxy)ethoxy)ethyl 4-toluenesulfonate 10a (0.23 g, 0.47 mmol), and anhydrous potassium carbonate (0.11 g, 0.8 mmol) were added to DMF (10 mL), and the reaction system was heated to 90°C. The mixture was stirred overnight. After the completion of the reaction was confirmed by TLC, it was cooled to room temperature, saturated sodium chloride solution (50 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (40 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by column chromatography (eluted with chloroform / methanol = 30 / 1) to obtain the target compound ZX-HYT-01 (0.21 g, 66% yield) as a yellow solid. HRMS (ESI) for C 46 H 58 N8O6Na [M+Na] + Calculated: 841.4377; Found: 841.4372. HPLC analysis: MeOH-HO (97:3), RT = 4.747 min, 98.07% purity. 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.81 (s, 1H), 8.12 (s, 1H), 7.89 (d, J = 8.1 Hz, 1H), 7.72 (t, J = 5.7 Hz, 1H), 7.57 (t, J = 2.1 Hz, 1H), 7.51 (t, J = 8.1 Hz, 1H), 7.27 (d, J = 8.9 Hz, 1H), 6.98 (dd, J = 7.8, 2.0 Hz, 1H), 6.56‐6.49 (m, 1H), 6.49‐6.39 (m, 1H), 6.37-6.21 (m, 2H), 6.00 (s, 1H), 5.77 (dd, J = 10.0, 2.1 Hz, 1H), 3.78 (s, 3H), 3.60-3.49 (m, 6H), 3.42 (t, J = 5.9 Hz, 2H), 3.19 (q, J = 5.9 Hz, 2H), 3.02 (s, 4H), 2.63-2.52 (m, 6H), 2.46 (s, 3H), 1.91 (s, 3H), 1.83 (s, 2H), 1.70-1.61 (m, 3H), 1.60-1.50 (m, 9H). 13 C NMR (101 MHz, DMSO) δ 170.52, 163.73, 162.63, 157.05, 156.73, 147.43, 140.39, 137.52, 132.15, 129.97, 127.66, 124.52, 120.13, 119.20, 116.98, 106.60, 100.06, 70.15, 69.99, 69.65, 56.15, 53.52, 50.47, 49.12, 42.54, 38.82, 36.93, 32.61, 28.52, 17.48.

[0077] Example 2: N-(3-(2-((4-(4-(6-(2-(((3R,5R,7R)-adamantan-1-yl)acetamido)hexyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (ZX-HYT-02) JPEG0007756374000034.jpg47170 The synthesis method of compound ZX-HYT-02 was the same as that of ZX-HYT-01. Compound 8 (0.20 g, 0.39 mmol) and hexyl 6-(2-(((3R,5R,7R)-adamantan-1-yl)acetamido)-4-toluenesulfonate (0.21 g, 0.47 mmol) were used as starting materials, and a nucleophilic substitution reaction was carried out to obtain yellow solid compound ZX-HYT-02 (0.18 g, 59% yield). HRMS (ESI) for C 46 H 58 N8O4Na [M+Na] + Calculated: 809.4479; Found: 809.4473. HPLC analysis: MeOH-H2O (97:3), RT = 5.260 min, 98.05% purity. 1 H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.81 (s, 1H), 8.11 (s, 1H), 7.90 (d, J = 8.2 Hz, 1H), 7.65 (t, J = 5.6 Hz, 1H), 7.59‐7.55 (m, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.27 (d, J = 8.9 Hz, 1H), 6.98 (ddd, J = 7.9, 2.1, 1.0 Hz, 1H), 6.52 (d, J = 2.5 Hz, 1H), 6.49‐6.39 (m, 1H), 6.37-6.21 (m, 2H), 6.00 (s, 1H), 5.77 (dd, J = 10.1, 2.1 Hz, 1H), 3.78 (s, 3H), 3.09‐2.95 (m, 6H), 2.48‐2.43 (m, 6H), 2.30 (t, J = 7.3 Hz, 2H), 1.91 (d, J = 5.0 Hz, 3H), 1.81 (s, 2H), 1.69-1.63 (m, 3H), 1.61-1.54 (m, 9H), 1.49-1.43 (m, 2H), 1.42-1.36 (m, 2H), 1.33-1.27 (m, 4H). 13C NMR (101 MHz, DMSO) δ 170.22, 163.72, 162.64, 157.06, 156.73, 147.44, 140.39, 137.52, 132.16, 129.98, 127.63, 124.52, 120.12, 119.20, 116.97, 106.60, 100.06, 58.24, 56.14, 53.17, 50.60, 49.14, 42.62, 38.67, 36.94, 32.62, 29.65, 28.52, 27.11, 26.84, 26.70, 17.48.

[0078] Example 3: N-(3-(2-((4-(4-(8-(2-(((3R,5R,7R)-adamantan-1-yl)acetamido)octyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (ZX-HYT-03) JPEG0007756374000035.jpg42170 The synthesis method of compound ZX-HYT-03 was the same as that of ZX-HYT-01. Compound 8 (0.20 g, 0.39 mmol) and 8-(2-(((3R,5R,7R)-adamantan-1-yl)acetylamino)octyl-4-toluenesulfonate (0.20 g, 0.47 mmol) were used as starting materials, and a nucleophilic substitution reaction was carried out to obtain yellow solid compound ZX-HYT-03 (0.17 g, 55% yield). HRMS (ESI) for C 48 H 62 N8O4Na [M+Na] + Calculated: 837.4792; Found: 837.4786. HPLC analysis: MeOH-HO (97:3), RT = 5.925 min, 98.11% purity. 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.81 (s, 1H), 8.11 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.63 (t, J = 5.6 Hz, 1H), 7.56 (t, J = 2.0 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.27 (d, J = 8.9 Hz, 1H), 6.98 (dd, J = 8.0, 2.0 Hz, 1H), 6.52 (d, J = 2.5 Hz, 1H), 6.49‐6.39 (m, 1H), 6.36‐6.21 (m, 2H), 6.00 (s, 1H), 5.79‐5.74 (m, 1H), 3.78 (s, 3H), 3.12‐2.94 (m, 6H), 2.49‐2.43 (m, 6H), 2.31 (q, J = 8.5, 7.4 Hz, 2H), 1.91 (s, 3H), 1.81 (s, 2H), 1.71‐1.62 (m, 3H), 1.61‐1.52 (m, 9H), 1.48‐1.42 (m, 2H), 1.41‐1.35 (m, 2H), 1.33‐1.21 (m, 11H). 13 C NMR (101 MHz, DMSO) δ 170.15, 163.71, 162.57, 156.97, 156.77, 147.32, 140.41, 137.53, 132.22, 130.11, 129.89, 127.45, 124.48, 120.19, 119.20, 116.99, 106.75, 106.61, 100.08, 58.32, 56.17, 53.20, 50.61, 49.22, 42.64, 42.59, 38.69, 36.98, 36.93, 32.62, 29.64, 29.43, 29.15, 28.57, 28.52, 27.36, 26.87, 26.76, 17.44.

[0079] Example 4: N-(3-(2-((4-(4-(10-(2-(((3R,5R,7R)-adamantan-1-yl)acetylamino)decyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (ZX-HYT-04) JPEG0007756374000036.jpg39170 The synthesis method for compound ZX-HYT-04 was the same as that for ZX-HYT-01. Compound 8 (0.20 g, 0.39 mmol) and 10-(2-(((3R,5R,7R)-adamantan-1-yl)acetylamino)4-decyltoluenesulfonate (0.24 g, 0.47 mmol) were used as starting materials, and a nucleophilic substitution reaction was carried out to obtain yellow solid compound ZX-HYT-04 (0.19 g, 59% yield). HRMS (ESI) for C 50 H 66 N8O4Na [M+Na] + Calculated: 865.5105; Found: 865.5099. HPLC analysis: MeOH-HO (97:3), RT = 6.906 min, 97.22% purity. 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.81 (s, 1H), 8.11 (s, 1H), 7.96‐7.82 (m, 1H), 7.63 (t, J = 5.6 Hz, 1H), 7.58‐7.54 (m, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.27 (d, J = 8.9 Hz, 1H), 6.98 (dd, J = 7.7, 1.9 Hz, 1H), 6.52 (d, J = 2.5 Hz, 1H), 6.44 (dd, J = 16.9, 10.1 Hz, 1H), 6.35‐6.21 (m, 2H), 6.00 (s, 1H), 5.79‐5.74 (m, 1H), 3.78 (s, 3H), 3.01 (q, J = 6.3 Hz, 6H), 2.46 (s, 6H), 2.35‐2.23 (m, 2H), 1.93‐1.87 (m, 3H), 1.80 (s, 2H), 1.66 (d, J = 12.2 Hz, 3H), 1.61‐1.52 (m, 9H), 1.45 (d, J = 6.6 Hz, 2H), 1.41‐1.35 (m, 2H), 1.32‐1.23 (m, 13H). 13 C NMR (101 MHz, DMSO) δ 170.18, 163.71, 162.63, 157.04, 156.73, 147.42, 140.39, 137.52, 132.17, 129.97, 127.61, 124.51, 120.13, 119.20, 116.97, 106.60, 100.06, 58.30, 56.14, 55.37, 53.15, 50.59, 49.13, 42.62, 38.66, 36.94, 32.61, 29.64, 29.48, 29.46, 29.43, 29.17, 28.53, 27.42, 26.87, 26.67, 17.48.

[0080] Example 5: N-(3-(2-((4-(4-(12-(2-(((3R,5R,7R)-adamantan-1-yl)acetamido)dodecyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (ZX-HYT-05) The synthesis method for compound ZX-HYT-05 was the same as that for ZX-HYT-01. Compound 8 (0.20 g, 0.39 mmol) and 12-(2-((3R,5R,7R)-adamantan-1-yl)acetylamino)dodecyl 4-toluenesulfonate (0.25 g, 0.47 mmol) were used as starting materials, and a nucleophilic substitution reaction was carried out to obtain yellow solid compound ZX-HYT-05 (0.18 g, 54% yield). HRMS (ESI) for C 52 H70N8O4Na [M+Na] + Calculated: 893.5418; Found: 893.5412. HPLC analysis: MeOH-HO (95:5), RT = 9.127 min, 97.17% purity. 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.81 (s, 1H), 8.11 (s, 1H), 7.90 (d, J = 8.2 Hz, 1H), 7.62 (t, J = 5.7 Hz, 1H), 7.56 (t, J = 2.0 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.27 (d, J = 8.9 Hz, 1H), 6.98 (ddd, J = 7.9, 2.0, 1.0 Hz, 1H), 6.52 (d, J = 2.5 Hz, 1H), 6.44 (dd, J = 16.9, 10.1 Hz, 1H), 6.33 (d, J = 1.3 Hz, 1H), 6.26 (dd, J = 17.0, 2.1 Hz, 1H), 6.00 (s, 1H), 5.76 (dd, J = 10.1, 2.1 Hz, 1H), 3.78 (s, 3H), 3.09‐2.94 (m, 6H), 2.49‐2.41 (m, 7H), 2.30 (t, J = 7.4 Hz, 2H), 1.94‐1.87 (m, 3H), 1.80 (s, 2H), 1.66 (d, J = 12.1 Hz, 3H), 1.58 (s, 2H), 1.56‐1.52 (m, 7H), 1.50‐1.42 (m, 2H), 1.40‐1.33 (m, 2H), 1.31‐1.21 (m, 16H). 13 C NMR (101 MHz, DMSO) δ 170.14, 163.69, 162.61, 157.01, 156.73, 147.37, 140.41, 137.52, 132.19, 129.95, 127.55, 124.50, 120.24, 120.14, 119.19, 116.98, 106.65, 106.58, 100.02, 58.36, 56.13, 53.22, 50.59, 49.22, 42.62, 38.66, 36.95, 32.61, 29.64, 29.54, 29.52, 29.48, 29.43, 29.19, 28.54, 27.47, 26.88, 26.77, 17.48.

[0081] Example 6: N-(3-(2-((4-(4-(14-(2-((3R,5R,7R)-adamantan-1-yl)acetylamino)tetradecyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (ZX-HYT-06) JPEG0007756374000038.jpg39170 The synthesis method for compound ZX-HYT-06 was the same as that for ZX-HYT-01. Compound 8 (0.20 g, 0.39 mmol) and 14-(2-(((3R,5R,7R)-adamantan-1-yl)acetylamino)4-tetradecyltoluenesulfonate (0.26 g, 0.47 mmol) were used as starting materials, and a nucleophilic substitution reaction was carried out to obtain yellow solid compound ZX-HYT-06 (0.15 g, 43% yield). HRMS (ESI) for C 54 H 74 N8O4Na [M+Na]+: Calculated, 921.5731; Found, 921.5725. HPLC analysis: MeOH-H2O (95:5), RT = 14.347 min, 98.68% purity. 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.80 (s, 1H), 8.11 (s, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.62 (t, J = 5.6 Hz, 1H), 7.56 (t, J = 2.0 Hz, 1H), 7.51 (t, J = 8.1 Hz, 1H), 7.27 (d, J = 8.9 Hz, 1H), 6.98 (ddd, J = 7.8, 2.0, 1.0 Hz, 1H), 6.51 (d, J = 2.5 Hz, 1H), 6.48‐6.39 (m, 1H), 6.36‐6.21 (m, 2H), 6.00 (s, 1H), 5.76 (dd, J = 10.1, 2.1 Hz, 1H), 3.78 (s, 3H), 3.06‐2.93 (m, 6H), 2.49‐2.40 (m, 7H), 2.30 (t, J = 7.4 Hz, 2H), 1.90 (s, 3H), 1.80 (s, 2H), 1.69‐1.61 (m, 3H), 1.60‐1.53 (m, 9H), 1.50‐1.41 (m, 2H), 1.40‐1.33 (m, 2H), 1.32‐1.20 (m, 20H). 13 C NMR (101 MHz, DMSO) δ 170.22, 163.72, 162.64, 157.04, 156.72, 147.44, 140.39, 137.51, 132.15, 129.97, 127.62, 124.51, 120.12, 119.20, 116.96, 106.60, 100.04, 58.29, 56.51, 56.14, 53.15, 50.59, 49.12, 42.60, 38.65, 36.93, 32.61, 29.60, 29.51, 29.48, 29.43, 29.40, 29.15, 28.53, 27.41, 26.84, 26.65, 18.99, 17.47.

[0082] Example 7: N-(3-(2-((4-(4-(12-(2-((3R,5R,7R)-adamantan-1-yl)acetylamino)dodecanoyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (ZX-HYT-07) To a solution of compound 8 (0.15 g, 0.29 mmol) in DMF (10 mL) was added 12-(2-((3R,5R,7R)-adamantan-1-yl)acetamido)dodecanoic acid 9 (0.12 g, 0.29 mmol), HATU (0.17 g, 0.43 mmol), and potassium carbonate (82 mg, 0.58 mmol), and the reaction was stirred at room temperature for 0.5 h. After completion of the reaction was monitored by TLC, the reaction was diluted with ethyl acetate (20 mL), and the organic layer was washed with saturated sodium chloride solution (1 × 30 mL) and water (3 × 30 mL), respectively. The mixture was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by column chromatography (eluted with chloroform / methanol = 30 / 1) to obtain a yellow solid compound ZX-HYT-07 (0.13 g, 51% yield). HRMS (ESI) for C 52 H 68 N8O5Na [M+Na]+: Calculated, 907.5210; Found, 907.5205. HPLC analysis: MeOH-H2O (95:5), RT = 6.582 min, 100.00% purity . 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.81 (s, 1H), 8.11 (s, 1H), 7.90 (d, J = 8.2 Hz, 1H), 7.62 (t, J = 5.7 Hz, 1H), 7.56 (t, J = 2.0 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.27 (d, J = 8.9 Hz, 1H), 6.98 (ddd, J = 7.9, 2.0, 1.0 Hz, 1H), 6.52 (d, J = 2.5 Hz, 1H), 6.44 (dd, J = 16.9, 10.1 Hz, 1H), 6.33 (d, J = 1.3 Hz, 1H), 6.26 (dd, J = 17.0, 2.1 Hz, 1H), 6.00 (s, 1H), 5.76 (dd, J = 10.1, 2.1 Hz, 1H), 3.78 (s, 3H), 3.09‐2.94 (m, 6H), 2.49‐2.41 (m, 7H), 2.30 (t, J = 7.4 Hz, 2H), 1.94‐1.87 (m, 3H), 1.80 (s, 2H), 1.66 (d, J = 12.1 Hz, 3H), 1.58 (s, 2H), 1.56‐1.52 (m, 7H), 1.50‐1.42 (m, 2H), 1.40‐1.33 (m, 2H), 1.31‐1.21 (m, 16H). 13C NMR (101 MHz, DMSO) δ 174.77, 171.05, 170.10, 163.66, 162.59, 157.04, 156.70, 147.38, 140.39, 137.52, 132.20, 129.97, 127.61, 124.51, 120.88, 120.15, 119.21, 117.05, 107.22, 106.64, 100.82, 56.15, 50.57, 50.02, 49.59, 45.24, 42.61, 41.25, 38.65, 36.93, 35.58, 32.71, 32.61, 29.65, 29.54, 29.51, 29.45, 29.42, 29.32, 29.21, 28.52, 26.90, 25.60, 25.34, 17.50.

[0083] Example 8: N-(3-(2-((4-(4-(12-(2-((3R,5R,7R)-adamantan-1-yl)acetylamino)dodecyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)propionamide (ZX-HYT-08) JPEG0007756374000040.jpg68170 Step 1: 1-(3-Methoxy-4-nitrophenyl)piperazine (12) 5-Fluoro-2-nitroanisole 11 (3.00 g, 17.5 mmol), piperazine (7.53 g, 87.5 mmol), and anhydrous potassium carbonate (3.63 g, 26.3 mmol) were added sequentially to acetonitrile (50 mL), and the mixture was stirred at 80 °C for 6 h. After completion of the reaction was monitored by TLC, the organic solvent was evaporated under reduced pressure. The resulting residue was added to 20 mL of distilled water and stirred for 1 h. The organic solvent was then filtered under reduced pressure. The filter cake was again added to 40 mL of anhydrous ether and stirred for 1 h. The filter cake was then filtered under reduced pressure and washed with ice-cooled anhydrous ether (3 × 20 mL). The dried filter cake yielded relatively pure compound 12 (3.95 g, 95% yield). MS (ESI), m / z: 238.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.21 (s, 2H), 7.97-7.87 (m, 1H), 6.69-6.58 (m, 2H), 3.93 (s, 3H), 3.70-3.63 (m, 4H), 3.28-3.19 (m, 4H). Step 2: 2-((3R,5R,7R)-adamantan-1-yl)-N-(12-(4-(3-methoxy-4-nitrophenyl)piperazin-1-yl)dodecyl)acetamide (13) Compound 12 (0.95 g, 4 mmol), potassium carbonate (0.83 g, 6 mmol), and 12-(2-(((3R,5R,7R)-adamantan-1-yl)acetamido)dodecyl 4-toluenesulfonate (2.34 g, 4.4 mmol) were added sequentially to DMF (30 mL), and the mixture was heated at 80 °C and stirred overnight. After the reaction was complete, it was cooled to room temperature. The reaction mixture was added to 50 mL of saturated aqueous sodium chloride solution, extracted with ethyl acetate, and the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate and concentrated. The remaining residue was purified by column chromatography (eluted with chloroform / methanol = 100 / 1) to obtain the target compound 13 (2.05 g, 86% yield) as a yellow oil. MS (ESI), m / z: 619.3 [M+Na] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J = 9.4 Hz, 1H), 7.62 (t, J = 5.6 Hz, 1H), 6.58 (dd, J = 9.5, 2.5 Hz, 1H), 6.52 (d, J = 2.6 Hz, 1H), 3.91 (s, 3H), 3.42 (t, J = 5.1 Hz, 4H), 3.00 (q, J = 6.5 Hz, 2H), 2.45 (t, J = 5.1 Hz, 4H), 2.33‐2.25 (m, 2H), 1.94‐1.86 (m, 3H), 1.80 (s, 2H), 1.65 (dt, J = 12.2, 2.9 Hz, 3H), 1.56 (dd, J = 12.7, 2.3 Hz, 9H), 1.44 (t, J = 7.2 Hz, 2H), 1.36 (t, J = 6.5 Hz, 2H), 1.26-1.20 (m, 16H). Step 3: 2-((3R,5R,7R)-adamantan-1-yl)-N-(12-(4-(4-amino-3-methoxyphenyl)piperazin-1-yl)dodecyl)acetamide (14) Palladium carbon (0.55 g) was added to a methanol solution of compound 13 (2.98 g, 5 mmol), and the atmosphere was purged with hydrogen gas three times. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was suction filtered under reduced pressure, and the filtrate was evaporated to dryness. The resulting colorless oily liquid was compound 14 (2.8 g, 99% yield). This compound was highly susceptible to oxidation in air, and was used in the next step without further purification. MS (ESI), m / z: 567.4 [M+H] + . Step 4: t-Butyl (3-(2-((4-(4-(12-(2-(((3R,5R,7R)-adamantan-1-yl)acetamido)dodecyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxypyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (15a) Intermediate 14 (1.13 g, 2 mmol) and compound 4a (0.72 g, 2 mmol) were quickly added to 30 mL of s-butanol, and TFA was added dropwise. The atmosphere was purged with argon gas three times, and the reaction mixture was stirred overnight at 95°C. After completion of the reaction was confirmed by TLC, the mixture was cooled to room temperature, and the organic solvent in the reaction mixture was evaporated under reduced pressure. The resulting residue was purified by column chromatography (eluted with chloroform / methanol = 50 / 1) to give compound 15a (1.11 g, 61% yield) as a yellow solid. MS (ESI), m / z: 917.5 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 8.64 (s, 1H), 7.85 (s, 1H), 7.63 (s, 1H), 7.37 (t, J = 7.9 Hz, 1H), 6.85 (ddd, J = 8.1, 2.4, 0.9 Hz, 1H), 6.69 (ddd, J = 7.8, 2.0, 0.9 Hz, 1H), 6.61 (t, J = 2.1 Hz, 1H), 6.48 (d, J = 2.5 Hz, 1H), 6.39 (d, J = 1.3 Hz, 1H), 6.21 (s, 1H), 5.36 (s, 1H), 3.85 (s, 3H), 3.81 (s, 1H), 3.25 (td, J = 7.2, 5.8 Hz, 2H), 3.14 (t, J = 5.0 Hz, 4H), 2.64 (t, J = 5.0 Hz, 4H), 2.47 (d, J = 1.2 Hz, 3H), 2.45-2.39 (m, 2H), 1.99 (p, J = 3.1 Hz, 3H), 1.92 (s, 2H), 1.72 (dt, J = 12.2, 3.1 Hz, 3H), 1.65 (dd, J = 10.9, 2.5 Hz, 9H), 1.52 (dq, J = 20.4, 6.8, 6.3 Hz, 4H), 1.36‐1.26 (m, 16H). Step 5: N-(3-(2-((4-(4-(12-(2-((3R,5R,7R)-adamantan-1-yl)acetylamino)dodecyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)propionamide (ZX-HYT-08) 10 mL of DCM and 0.50 mL of TFA were added to a round-bottom flask containing compound 15a (0.25 g, 0.27 mmol), and the reaction mixture was stirred at room temperature for 0.5 h. After completion of the reaction, the organic solvent was evaporated under reduced pressure. The resulting residue was directly dissolved in 5 mL of anhydrous acetonitrile, and anhydrous potassium carbonate (0.14 g, 1.01 mmol) and propionyl chloride (0.04 g, 0.43 mmol) were added sequentially to the solution. The reaction mixture was stirred at room temperature for 1 h. After completion of the reaction was monitored by TLC, the organic solvent was evaporated. The resulting residue was directly blended with silica gel and purified by column chromatography (eluting with chloroform / methanol = 30 / 1) to give compound ZX-HYT-08 (0.18 g, 78% yield) as a yellow powder. HRMS (ESI) for C 52 H 72 N8O4Na [M+Na] + Calculated: 895.5574; Found: 895.5569. HPLC analysis: MeOH-HO (97:3), RT = 8.712 min, 95.41% purity. 1 H NMR (400 MHz, DMSO-d6) δ 10.06 (s, 1H), 8.79 (s, 1H), 8.09 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.62 (t, J = 5.8 Hz, 1H), 7.53‐7.41 (m, 2H), 7.27 (d, J = 8.8 Hz, 1H), 6.92 (d, J = 7.8 Hz, 1H), 6.52 (s, 1H), 6.31 (s, 1H), 6.01 (s, 1H), 3.78 (s, 3H), 3.10‐2.94 (m, 6H), 2.45 (m, 5H), 2.37-2.25 (m, 4H), 1.90 (s, 3H), 1.80 (s, 2H), 1.68-1.62 (m, 3H), 1.61-1.51 (m, 9H), 1.48-1.41 (m, 2H), 1.41-1.33 (m, 2H), 1.32-1.21 (m, 18H), 1.07 (t, J = 7.5 Hz, 3H). 13C NMR (101 MHz, DMSO) δ 172.54, 170.10, 162.60, 157.00, 156.75, 147.32, 140.79, 137.45, 130.11, 129.79, 123.85, 120.27, 119.70, 118.79, 116.98, 106.68, 106.57, 100.04, 58.35, 56.13, 53.25, 50.59, 49.26, 42.62, 38.65, 36.96, 32.61, 30.05, 29.65, 29.57, 29.54, 29.52, 29.48, 29.43, 29.19, 28.54, 27.46, 26.88, 26.77, 17.47, 10.08.

[0084] Example 9: N-(12-(4-(4-((8-(3-acetylaminophenyl)-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino)-3-methoxyphenyl)piperazin-1-yl)dodecyl)-2-((3R,5R,7R)-adamantan-1-yl)acetamide (ZX-HYT-09) Similar to the synthesis of ZX-HYT-08, compound 15a (0.25 g, 0.27 mmol) and acetyl chloride (0.04 g, 0.51 mmol) were used as starting materials, and the target compound ZX-HYT-09 (0.11 g, 47% yield) was obtained as a yellow powder through a two-step reaction. HRMS (ESI) for C 51 H 71 N8O4[M+H] + Calculated: 859.5598; Found: 859.5593. HPLC analysis: MeOH-HO (97:3), RT = 9.171 min, 98.91% purity. 1H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.80 (s, 1H), 8.13 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.63 (t, J = 5.7 Hz, 1H), 7.55‐7.42 (m, 2H), 7.27 (d, J = 8.8 Hz, 1H), 7.02-6.90 (m, 1H), 6.56 (s, 1H), 6.32 (s, 1H), 6.05 (s, 1H), 3.79 (s, 3H), 3.20-2.93 (m, 3H), 2.49-2.41 (m, 6H), 2.05 (s, 4H), 1.95-1.87 (m, 3H), 1.80 (s, 2H), 1.75-1.61 (m, 4H), 1.61-1.44 (m, 11H), 1.42-1.02 (m, 22H). 13 C NMR (101 MHz, DMSO) δ 170.14, 168.91, 162.60, 157.00, 156.73, 147.33, 140.74, 137.44, 129.76, 123.96, 120.63, 119.69, 118.81, 117.02, 106.87, 106.62, 100.29, 57.54, 56.18, 52.51, 50.59, 48.30, 42.62, 38.66, 36.95, 32.61, 29.65, 29.53, 29.50, 29.47, 29.44, 29.33, 29.20, 28.69, 28.55, 27.17, 26.90, 25.66, 24.52, 17.47.

[0085] Example 10: N-(3-(2-((4-(4-(12-(2-(((3R,5R,7R)-adamantan-1-yl)acetamido)dodecyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)isobutyramide (ZX-HYT-10) Similar to the synthesis of ZX-HYT-08, compound 15a (0.25 g, 0.27 mmol) and isobutyryl chloride (0.04 g, 0.37 mmol) were used as starting materials, and the target compound ZX-HYT-10 (0.16 g, 67% yield) was obtained as a yellow powder through a two-step reaction. HRMS (ESI) for C 53 H 74 N8O4Na [M+Na] + Calculated: 909.5731; Found: 909.5725. HPLC analysis: MeOH-HO (97:3), RT = 8.363 min, 98.82% purity. 1 H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.80 (s, 1H), 8.11 (s, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.62 (t, J = 5.6 Hz, 1H), 7.56‐7.42 (m, 2H), 7.27 (d, J = 8.8 Hz, 1H), 6.93 (dd, J = 7.8, 1.9 Hz, 1H), 6.53 (d, J = 2.5 Hz, 1H), 6.32 (s, 1H), 6.02 (s, 1H), 3.78 (s, 3H), 3.14‐2.91 (m, 6H), 2.59 (p, J = 6.9 Hz, 2H), 2.49-2.23 (m, 7H), 1.91 (s, 3H), 1.80 (s, 2H), 1.68-1.62 (m, 3H), 1.61-1.52 (m, 9H), 1.50-1.41 (m, 2H), 1.40-1.34 (m, 2H), 1.33-1.18 (m, 17H), 1.11-1.05 (m, 6H). 13C NMR (101 MHz, DMSO) δ 178.31, 175.78, 170.12, 162.60, 157.00, 156.75, 147.33, 140.86, 137.45, 129.79, 123.88, 120.31, 119.83, 118.94, 116.98, 106.68, 106.56, 100.04, 58.21, 56.13, 53.14, 50.59, 49.11, 42.62, 42.46, 38.65, 36.96, 35.43, 33.59, 32.61, 29.65, 29.52, 29.45, 29.43, 29.19, 28.54, 27.40, 26.88, 26.61, 19.93, 19.90, 19.38, 17.47.

[0086] Example 11: N-(3-(2-((4-(4-(12-(2-(((3R,5R,7R)-adamantan-1-yl)acetamido)dodecyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX-HYT-11) Similar to the synthesis of ZX-HYT-08, compound 15a (0.25 g, 0.27 mmol) and cyclopropanecarbonyl chloride (0.04 g, 0.38 mmol) were used as starting materials, and the target compound ZX-HYT-11 (0.15 g, 63% yield) was obtained as a yellow powder through a two-step reaction. HRMS (ESI) for C 53 H 72 N8O4Na [M+Na] + Calculated: 907.5574; Found: 907.5569. HPLC analysis: MeOH-H2O (95:5), RT = 10.249 min, 100% purity. 1H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.80 (s, 1H), 8.11 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.62 (t, J = 5.7 Hz, 1H), 7.55‐7.41 (m, 2H), 7.28 (d, J = 8.9 Hz, 1H), 6.99-6.88 (m, 1H), 6.53 (d, J = 2.5 Hz, 1H), 6.32 (d, J = 1.4 Hz, 1H), 6.02 (s, 1H), 3.79 (s, 3H), 3.12-2.94 (m, 6H), 2.49-2.41 (m, 4H), 2.32 (q, J = 13.4, 7.5 Hz, 2H), 1.94-1.87 (m, 3H), 1.80 (s, 2H), 1.69-1.62 (m, 3H), 1.61-1.52 (m, 9H), 1.52-1.44 (m, 2H), 1.42-1.33 (m, 2H), 1.32-1.15 (m, 18H), 0.88-0.75 (m, 6H). 13 C NMR (101 MHz, DMSO) δ 176.01, 172.17, 170.08, 162.58, 157.02, 156.73, 147.32, 140.77, 137.47, 129.85, 123.83, 119.68, 118.75, 116.99, 106.72, 106.57, 100.12, 56.15, 53.19, 50.58, 49.20, 42.62, 38.64, 36.95, 32.61, 29.65, 29.51, 29.45, 29.42, 29.18, 28.53, 27.41, 26.87, 17.48, 15.04, 12.87, 8.16, 7.64.

[0087] Example 12: N-(3-(2-((4-(4-(12-(2-(((3R,5R,7R)-adamantan-1-yl)acetamido)dodecyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)pivalamide (ZX-HYT-12) Similar to the synthesis of ZX-HYT-08, compound 15a (0.25 g, 0.27 mmol) and pivaloyl chloride (0.04 g, 0.33 mmol) were used as starting materials, and the target compound ZX-HYT-12 (0.18 g, 73% yield) was obtained as a yellow powder through a two-step reaction. HRMS (ESI) for C 54 H 76 N8O4Na [M+Na] + Calculated: 923.5887; Found: 923.5882. HPLC analysis: MeOH-HO (97:3), RT = 10.083 min, 97.50% purity. 1 H NMR (400 MHz, DMSO-d6) δ 9.37 (s, 1H), 8.81 (s, 1H), 8.10 (s, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.62 (t, J = 5.7 Hz, 1H), 7.56 (t, J = 2.0 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.28 (d, J = 8.9 Hz, 1H), 6.93 (dt, J = 7.9, 1.2 Hz, 1H), 6.52 (d, J = 2.5 Hz, 1H), 6.40‐6.26 (m, 1H), 6.02 (s, 1H), 3.78 (s, 3H), 3.11-2.94 (m, 6H), 2.49-2.42 (m, 7H), 2.36-2.25 (m, 2H), 1.91 (t, J = 3.4 Hz, 3H), 1.80 (s, 2H), 1.70-1.62 (m, 3H), 1.61-1.52 (m, 9H), 1.49-1.42 (m, 2H), 1.40-1.33 (m, 2H), 1.33-1.23 (m, 18H), 1.23-1.18 (m, 9H). 13C NMR (101 MHz, DMSO) δ 179.87, 177.00, 170.12, 162.63, 157.01, 156.76, 147.34, 140.89, 137.28, 129.57, 123.96, 120.60, 120.24, 119.79, 116.95, 106.73, 106.54, 99.97, 58.31, 56.13, 53.23, 50.59, 49.25, 42.62, 38.65, 38.18, 36.95, 32.61, 29.64, 29.53, 29.51, 29.46, 29.42, 29.18, 28.54, 27.58, 27.48, 27.43, 26.87, 26.74, 17.48.

[0088] Example 13: N-(3-(2-((4-(4-(12-(2-(((3R,5R,7R)-adamantan-1-yl)acetamido)dodecyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclohexanecarboxamide (ZX-HYT-13) Similar to the synthesis of ZX-HYT-08, compound 15a (0.25 g, 0.27 mmol) and cyclohexanecarboxylic acid chloride (0.05 g, 0.35 mmol) were used as starting materials, and the target compound ZX-HYT-13 (0.13 g, 52% yield) was obtained as a yellow powder through a two-step reaction. HRMS (ESI) for C 56 H 78 N8O4Na [M+Na] + Calculated: 949.6044; Found: 949.6038. HPLC analysis: MeOH-HO (97:3), RT = 12.082 min, 96.21% purity. 1H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.80 (s, 1H), 8.10 (s, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.62 (t, J = 5.7 Hz, 1H), 7.54 (t, J = 2.0 Hz, 1H), 7.46 (t, J = 8.1 Hz, 1H), 7.27 (d, J = 8.9 Hz, 1H), 6.91 (ddd, J = 7.8, 2.0, 1.0 Hz, 1H), 6.52 (d, J = 2.5 Hz, 1H), 6.32 (d, J = 1.3 Hz, 1H), 6.01 (s, 1H), 3.78 (s, 3H), 3.11‐2.95 (m, 6H), 2.50‐2.40 (m, 6H), 2.36‐2.24 (m, 3H), 1.90 (s, 3H), 1.85‐1.70 (m, 6H), 1.68‐1.62 (m, 4H), 1.60‐1.52 (m, 8H), 1.50‐1.44 (m, 2H), 1.41‐1.33 (m, 4H), 1.32‐1.13 (m, 21H). 13 C NMR (101 MHz, DMSO) δ 174.86, 170.11, 162.61, 157.02, 156.74, 147.34, 140.92, 137.43, 130.12, 129.78, 123.79, 120.27, 119.72, 118.83, 116.99, 106.68, 106.57, 100.04, 58.30, 56.14, 53.25, 50.59, 49.29, 45.34, 42.62, 38.64, 36.95, 32.61, 29.64, 29.60, 29.53, 29.50, 29.48, 29.42, 29.18, 28.54, 27.43, 26.87, 26.77, 25.86, 25.65, 17.47.

[0089] Example 14: N-(4-(2-((4-(4-(12-(2-(((3R,5R,7R)-adamantan-1-yl)acetamido)dodecyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (ZX-HYT-14) Similar to the synthesis of ZX-HYT-08, compound 14 (1.13 g, 2 mmol), compound 4b (0.72 g, 2 mmol), and acryloyl chloride (0.03 g, 0.38 mmol) were used as starting materials, and the target compound ZX-HYT-14 (0.21 g, 86% yield) was obtained as a yellow powder through a three-step reaction. HRMS (ESI) for C 52 H 70 N8O4Na [M+Na] + Calculated: 893.5418; Found: 893.5412. HPLC analysis: MeOH-HO (97:3), RT = 10.934 min, 96.59% purity. 1 H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.79 (s, 1H), 8.07 (s, 1H), 7.85 (m, 2H), 7.62 (t, J = 5.7 Hz, 1H), 7.26‐7.17 (m, 3H), 6.58-6.46 (m, 2H), 6.38-6.28 (m, 2H), 5.96 (s, 1H), 5.81 (dd, J = 10.1, 2.1 Hz, 1H), 3.78 (s, 3H), 3.04-2.91 (m, 6H), 2.45 (s, 3H), 2.41 (s, 4H), 2.28 (t, J = 7.3 Hz, 2H), 1.90 (s, 3H), 1.80 (s, 2H), 1.69-1.62 (m, 3H), 1.59-1.52 (m, 9H), 1.47-1.41 (m, 2H), 1.40-1.33 (m, 2H), 1.32-1.22 (m, 16H). 13C NMR (101 MHz, DMSO) δ 170.21, 163.68, 162.78, 157.00, 156.90, 147.24, 139.19, 132.48, 132.22, 129.86, 127.38, 120.46, 120.19, 117.00, 106.61, 99.72, 58.30, 56.11, 53.23, 50.60, 49.03, 42.61, 38.67, 36.94, 32.61, 29.63, 29.54, 29.52, 29.49, 29.44, 29.19, 28.54, 27.44, 26.88, 26.77, 17.43.

[0090] Example 15: N-(4-(2-((4-(4-(12-(2-(((3R,5R,7R)-adamantan-1-yl)acetamido)dodecyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX-HYT-15) Similar to the synthesis of ZX-HYT-08, compound 14 (1.13 g, 2 mmol), compound 4b (0.72 g, 2 mmol), and cyclopropanecarbonyl chloride (0.04 g, 0.38 mmol) were used as starting materials, and the target compound ZX-HYT-15 (0.21 g, 86% yield) was obtained as a yellow powder through a three-step reaction. HRMS (ESI) for C 53 H 72 N8O4Na [M+Na] + Calculated: 907.5574; Found: 907.5569. HPLC analysis: MeOH-HO (97:3), RT = 9.243 min, 96.18% purity. 1H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 8.79 (s, 1H), 8.07 (s, 1H), 7.80‐7.71 (m, 2H), 7.63 (t, J = 5.7 Hz, 1H), 7.27‐7.14 (m, 3H), 6.53 (d, J = 2.6 Hz, 1H), 6.31 (d, J = 1.4 Hz, 1H), 5.99 (s, 1H), 3.79 (s, 3H), 3.16‐2.92 (m, 6H), 2.49‐2.23 (m, 6H), 1.93‐1.83 (m, 4H), 1.80 (s, 2H), 1.69-1.61 (m, 3H), 1.60-1.52 (m, 9H), 1.48 (s, 2H), 1.41-1.19 (m, 20H), 0.92-0.79 (m, 4H). 13 C NMR (101 MHz, DMSO) δ 172.24, 170.20, 162.81, 157.01, 156.93, 147.21, 139.50, 131.85, 129.74, 120.42, 120.04, 117.05, 106.65, 100.03, 58.03, 56.17, 53.03, 50.59, 48.83, 42.61, 38.65, 36.94, 32.61, 29.62, 29.49, 29.41, 29.17, 28.53, 27.32, 26.86, 26.42, 17.44, 14.96, 7.68.

[0091] Example 16: 2-((3R,5R,7R)-adamantan-1-yl)-N-(12-(4-(4-((8-(3-ethylphenyl)-5-methyl-7-oxo-7,8-dihydro-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)dodecyl)acetamide (ZX-HYT-16) JPEG0007756374000053.jpg28170Step 1: 5-Bromo-2-chloro-N-(3-ethylphenyl)pyrimidin-4-amine (3c) JPEG0007756374000054.jpg26170 Compound 5-bromo-2,4-dichloropyrimidine (4.9 g, 21.5 mmol), 3-ethylaniline (2.6 g, 21.5 mmol), and potassium carbonate (5.9 g, 43 mmol) were added to 60 mL of DMF in this order and reacted at room temperature for 6 hours. After monitoring the completion of the reaction by TLC, the reaction mixture was added to 200 mL of ice water, resulting in the formation of a large amount of white solid. The mixture was suction filtered under reduced pressure, and the filter cake was washed with ice water. The filter cake, which had been dried by suction filtering, was added to 50 mL of acetone and stirred at room temperature for 2 hours to form a slurry. The mixture was then suction filtered under reduced pressure to obtain the filter cake. White intermediate 3c (6.5 g, 92% yield) was obtained. MS (ESI), m / z: 312.1 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.30 (s, 1H), 7.53‐7.48 (m, 1H), 7.40 (t, J = 2.5 Hz, 1H), 7.33 (td, J = 7.8, 2.9 Hz, 1H), 7.28 (s, 1H), 7.06 (dt, J = 8.2, 1.9 Hz, 1H), 2.70 (qd, J = 7.7, 2.8 Hz, 2H), 1.29 (t, J = 7.7, 3.0 Hz, 3H). Step 2: 2-chloro-8-(3-ethylphenyl)-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (3-4c) Compound 3c (2.19 g, 7.01 mmol), crotonic acid (6.04 g, 70.1 mmol), bis(cyanophenyl)palladium(II) dichloride (0.13 g, 5%), and tris(o-methylphenyl)phosphine (104 mg, 5%) were placed in a 250 mL two-necked round-bottom flask and purged with argon gas three to five times. Anhydrous tetrahydrofuran (45 mL) and N,N-diisopropylethylamine (12 mL) were added via syringe, followed by purging with argon three times. The reaction mixture was then stirred at 70 °C for 6 h. After completion of the reaction of starting material 3c was confirmed by TLC, 5 mL of acetic anhydride was added, and the reaction mixture was heated to 80 °C and stirred for 8 h. After TLC showed that the reaction was complete, most of the organic solvent was evaporated under reduced pressure, and the residue was diluted with 100 mL of ethyl acetate. The organic layer was washed with 1 N HCl (3 × 100 mL) and saturated sodium chloride solution (2 × 100 mL), respectively. The separated organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluted with petroleum ether / ethyl acetate = 3:1) to give compound 4c (1.66 g, 80% yield) as a white solid. MS (ESI), m / z: 300.2 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.83 (s, 1H), 7.49 (dd, J = 9.0, 7.3 Hz, 1H), 7.38‐7.32 (m, 1H), 7.08‐7.01 (m, 2H), 6.73‐6.67 (m, 1H), 2.76 (q, J = 7.6 Hz, 2H), 2.56 (s, 3H), 1.30 (t, J = 7.6 Hz, 3H). Step 3: 2-((3R,5R,7R)-adamantan-1-yl)-N-(12-(4-(4-((8-(3-ethylphenyl)-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)dodecyl)acetamide (ZX-HYT-16) Compound 4c (0.31 g, 1 mmol), 2-((3R,5R,7R)-adamantan-1-yl)-N-(12-(4-(4-amino-3-methoxyphenyl)piperazin-1-yl)dodecyl)acetamide (0.57 g, 1 mmol), and a catalytic amount of trifluoroacetic acid were added to 20 mL of s-butanol in this order and stirred at 90 °C for 10 hours. After completion of the reaction was monitored by TLC, the organic solvent was evaporated under reduced pressure, and the resulting residue was separated by column chromatography (chloroform / methanol = 30:1) to obtain the target compound ZX-HYT-16 (0.24 g, 29% yield). HRMS (ESI) for C 51 H 72 N7O3[M+H] + Calculated: 830.5618; Found: 830.5622. HPLC analysis: MeOH-H2O (97:3), RT = 13.173 min, 100% purity. 1 H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.05 (s, 1H), 7.61 (t, J = 5.7 Hz, 1H), 7.46 (t, J = 7.7 Hz, 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.16 (d, J = 8.7 Hz, 1H), 7.10 (s, 1H), 7.06 (d, J = 7.8 Hz, 1H), 6.52 (s, 1H), 6.30 (s, 1H), 5.93 (s, 1H), 3.77 (s, 3H), 3.08‐2.95 (m, 6H), 2.67 (q, J = 7.6 Hz, 2H), 2.49-2.38 (m, 7H), 2.29 (t, J = 7.4 Hz, 2H), 1.90 (s, 3H), 1.80 (s, 2H), 1.68-1.62 (m, 3H), 1.60-1.51 (m, 9H), 1.48-1.41 (m, 2H), 1.39‐1.34 (m, 2H), 1.30‐1.16 (m, 19H). 13C NMR (101 MHz, DMSO) δ 170.07, 162.72, 156.88, 147.13, 145.34, 137.26, 129.51, 128.68, 127.72, 126.70, 120.39, 117.07, 106.60, 100.19, 58.38, 56.14, 53.27, 50.59, 49.34, 42.63, 38.64, 36.96, 32.61, 29.65, 29.51, 29.47, 29.42, 29.18, 28.55, 28.42, 27.46, 26.88, 26.79, 17.44, 15.88.

[0092] Example 17: 2-((3R,5R,7R)-adamantan-1-yl)-N-(12-(4-(4-((8-(3-aminophenyl)-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)dodecyl)acetamide (ZX-HYT-17) Intermediate 14 (1.13 g, 2 mmol), compound 4a (0.72 g, 2 mmol), and a catalytic amount of trifluoroacetic acid were added to 30 mL of s-butanol in this order and stirred at 95 °C for 10 hours. After completion of the reaction was monitored by TLC, the organic solvent was evaporated under reduced pressure. The residue was purified by column chromatography (eluting with chloroform / methanol = 50 / 1). The purified intermediate was redissolved in DCM (8 mL) and TFA (0.50 mL) and stirred at room temperature for 0.5 hours. The organic solvent was evaporated, and the residue was separated by column chromatography to obtain the yellow powder compound ZX-HYT-17 (0.13 g, 54% yield). HRMS (ESI) for C 49 H 68 N8O3Na [M+Na] + Calculated: 839.5312; Found: 839.5307. HPLC analysis: MeOH-H2O (97:3), 14.595 min, 100% purity. 1H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.04 (s, 1H), 7.63 (t, J = 5.6 Hz, 1H), 7.45 (d, J = 8.9 Hz, 1H), 7.17 (t, J = 7.9 Hz, 1H), 6.70 (dd, J = 8.1, 2.3 Hz, 1H), 6.55 (d, J = 2.5 Hz, 1H), 6.40 (t, J = 2.1 Hz, 1H), 6.38‐6.33 (m, 1H), 6.28 (d, J = 1.4 Hz, 1H), 6.14 (s, 1H), 5.26 (s, 2H), 3.80 (s, 3H), 3.06 (t, J = 5.0 Hz, 4H), 3.00 (q, J = 6.5 Hz, 2H), 2.51‐2.48 (m, 4H), 2.43 (s, 3H), 2.38‐2.25 (m, 2H), 1.94‐1.87 (m, 3H), 1.80 (s, 2H), 1.69‐1.62 (m, 3H), 1.60‐1.53 (m, 9H), 1.45 (q, J = 6.9, 6.2 Hz, 2H), 1.36 (q, J = 6.5, 6.0 Hz, 2H), 1.30‐1.23 (m, 16H). 13 C NMR (101 MHz, DMSO) δ 170.11, 162.63, 156.84, 156.81, 150.26, 146.96, 137.84, 130.12, 129.81, 120.54, 117.12, 116.29, 114.57, 113.78, 107.13, 106.53, 100.12, 58.32, 56.16, 53.24, 50.59, 49.30, 46.16, 42.62, 38.65, 36.96, 32.61, 29.65, 29.52, 29.47, 29.43, 29.18, 28.54, 27.45, 26.88, 26.71, 17.42.

[0093] Example 18: 2-((3R,5R,7R)-adamantan-1-yl)-N-(12-(4-(3-methoxy-4-((5-methyl-8-(3-((1-methylpiperidin-4-yl)amino)phenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)dodecyl)acetamide (ZX-HYT-18) Compound ZX-HYT-17 (200 mg, 0.24 mmol), 1-methylpiperidin-4-one (27 mg, 0.24 mmol), sodium triacetoxyborohydride (0.25 g, 1.2 mmol), and a catalytic amount of glacial acetic acid were added to 20 mL of ultra-anhydrous toluene and stirred at 40 °C under argon protection for 2 hours. After completion of the reaction was monitored by TLC, the organic solvent was evaporated and the resulting residue was directly purified by silica gel column chromatography (eluted with chloroform / methanol = 25:1) to give the yellow target compound ZX-HYT-18 (0.16 mg, 73% yield). HRMS (ESI) for C 55 H 80 NO3[M+H] + Calculated: 914.6384; Found: 914.6379. HPLC analysis: MeOH-H2O (97:3), RT = 13.264 min, 99.75% purity. 1H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.03 (s, 1H), 7.63 (t, J = 5.7 Hz, 1H), 7.42 (d, J = 8.9 Hz, 1H), 7.22 (t, J = 7.9 Hz, 1H), 6.72 (d, J = 7.7 Hz, 1H), 6.54 (d, J = 2.5 Hz, 1H), 6.43 (t, J = 2.2 Hz, 1H), 6.34 (dd, J = 7.4, 1.9 Hz, 1H), 6.28 (s, 1H), 6.05 (s, 1H), 5.70 (d, J = 7.7 Hz, 1H), 3.79 (s, 3H), 3.05‐2.97 (m, 6H), 2.79 (s, 3H), 2.49‐2.46 (m, 4H), 2.44 (s, 3H), 2.31 (t, J = 7.4 Hz, 3H), 2.23 (s, 3H), 2.16 (s, 2H), 1.96‐1.85 (m, 6H), 1.80 (s, 2H), 1.68‐1.62 (m, 3H), 1.58‐1.51 (m, 9H), 1.46‐1.42 (m, 2H), 1.39‐1.34 (m, 2H), 1.30‐1.21 (m, 16H). 13 C NMR (101 MHz, DMSO) δ 170.19, 162.67, 156.83, 149.34, 147.02, 138.08, 130.03, 117.14, 115.99, 113.36, 111.76, 106.92, 106.55, 100.20, 58.30, 56.18, 55.35, 54.28, 53.24, 50.59, 49.39, 45.85, 42.61, 38.65, 36.94, 32.61, 31.73, 29.61, 29.48, 29.39, 29.15, 28.53, 27.42, 26.84, 26.73, 17.40.

[0094] Example 19: 2-((3R,5R,7R)-adamantan-1-yl)-N-(12-(4-(4-((8-(3-((cyclopropylmethyl)amino)phenyl)-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)dodecyl)acetamide (ZX-HYT-19) JPEG0007756374000059.jpg48170 Using the same synthesis method as for compound ZX-HYT-18, compound ZX-HYT-17 (0.20 g, 0.24 mmol) and cyclopropaneformaldehyde (17 mg, 0.24 mmol) were used as raw materials to obtain yellow solid compound ZX-HYT-19 (0.18 g, 86% yield). HRMS (ESI) for C 53 H 75 N8O3[M+H] + Calculated: 871.5962; Found: 871.5957. HPLC analysis: MeOH-HO (97:3), RT = 11.992 min, 97.65% purity. 1H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.02 (s, 1H), 7.61 (t, J = 5.7 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.23 (t, J = 7.9 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H), 6.54 (d, J = 2.5 Hz, 1H), 6.44 (d, J = 2.2 Hz, 1H), 6.37 (dd, J = 7.4, 1.9 Hz, 1H), 6.29 (s, 1H), 6.07 (s, 1H), 5.86 (t, J = 5.5 Hz, 1H), 3.80 (s, 3H), 3.08‐2.97 (m, 5H), 2.89 (d, J = 6.3 Hz, 2H), 2.49‐2.40 (m, 7H), 2.35‐2.26 (m, 2H), 1.94‐1.86 (m, 3H), 1.80 (s, 2H), 1.70‐1.62 (m, 3H), 1.60‐1.57 (m, 2H), 1.56‐1.52 (m, 7H), 1.49‐1.43 (m, 2H), 1.39‐1.33 (m, 2H), 1.30‐1.21 (m, 16H), 1.04 (hept, J = 5.8 Hz, 2H), 0.43 (dt, J = 8.5, 3.0 Hz, 2H), 0.17 (t, J = 4.8 Hz, 2H). 13 C NMR (101 MHz, DMSO) δ 170.09, 162.63, 156.84, 150.61, 146.94, 137.97, 129.89, 117.17, 116.08, 113.05, 111.55, 106.92, 106.56, 100.17, 56.18, 53.23, 50.59, 49.35, 48.11, 42.63, 38.64, 36.96, 32.61, 29.64, 29.50, 29.45, 29.41, 29.17, 28.54, 27.41, 26.87, 17.41, 11.03, 4.02, 3.93.

[0095] Example 20: N-((1R,3S)-3-(2-((4-(4-(12-(2-((3R,5R,7R)-adamantan-1-yl)acetylamino)dodecyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)cyclopentyl)cyclopropanecarboxamide (ZX-HYT-20) JPEG0007756374000060.jpg64170Step 1: N-((1R,3S)-3-((5-bromo-2-chloropyrimidin-4-yl)amino)cyclopentyl)cyclopropanecarboxamide (26a) JPEG0007756374000061.jpg30170 Compound 5-bromo-2,4-dichloropyrimidine (0.91 g, 4 mmol), N-((1R,3S)-3-((5-bromo-2-chloropyrimidin-4-yl)amino)cyclopentyl)cyclopropanecarboxamide (0.67 g, 4 mmol), and potassium carbonate (0.57 g, 8 mmol) were added to 25 mL of DMF in this order and reacted at room temperature for 6 hours. After monitoring the completion of the reaction by TLC, the reaction system was added to 40 mL of ice water, and a large amount of white solid was produced. The mixture was suction filtered under reduced pressure, and the filter cake was washed with ice water. The filter cake, which had been suction filtered to dryness, was added to 15 mL of acetone and stirred at room temperature for 2 hours to form a slurry, followed by suction filtering under reduced pressure to obtain a filter cake. White intermediate 26a (0.96 g, 67% yield) was obtained. MS (ESI), m / z: 359.6 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.34 (d, J = 7.3 Hz, 1H), 7.23 (s, 1H), 5.67 (p, J = 9.4, 8.9 Hz, 1H), 4.17‐4.04 (m, 1H), 2.31-2.21 (m, 2H), 2.02-1.92 (m, 2H), 1.89-1.79 (m, 2H), 1.63-1.54 (m, 1H), 0.81-0.62 (m, 4H). Step 2: N-((1R,3S)-3-(2-chloro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)cyclopentyl)cyclopropanecarboxamide (27a) Compound 26a (1.92 g, 5.35 mmol), crotonic acid (4.61 g, 70.1 mmol), bis(cyanophenyl)palladium(II) dichloride (0.14 g, 5%), and tris(o-methylphenyl)phosphine (114 mg, 5%) were placed in a 250 mL two-necked round-bottom flask and purged with argon gas three to five times. Anhydrous tetrahydrofuran (30 mL) and N,N-diisopropylethylamine (5 mL) were added via syringe, followed by purging with argon three times. The reaction mixture was then stirred at 70 °C for 6 h. After completion of the reaction of starting material 26a was confirmed by TLC, 5 mL of acetic anhydride was added, and the reaction mixture was heated to 80 °C and stirred for 8 h. After TLC showed the reaction was complete, most of the organic solvent was evaporated under reduced pressure, and the residue was diluted with 100 mL of ethyl acetate. The organic layer was washed with 1 N HCl (3 × 100 mL) and saturated sodium chloride solution (2 × 100 mL), respectively. The separated organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluted with petroleum ether / ethyl acetate = 2:1) to give compound 27a (0.87 g, 47% yield) as a white solid. MS (ESI), m / z: 347.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.24 (d, J = 7.4 Hz, 1H), 6.63 (d, J = 1.5 Hz, 1H), 5.77 (p, J = 9.4, 8.9 Hz, 1H), 4.18‐4.05 (m, 1H), 2.46 (s, 3H), 2.25-2.15 (m, 2H), 2.07-1.97 (m, 2H), 1.95-1.85 (m, 2H), 1.61-1.52 (m, 1H), 0.69-0.59 (m, 4H). Step 3: N-((1R,3S)-3-(2-((4-(4-(12-(2-((3R,5R,7R)-adamantan-1-yl)acetylamino)dodecyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)cyclopentyl)cyclopropanecarboxamide (ZX-HYT-20) Compound 27a (0.17 g, 0.5 mmol), compound 14 (0.28 g, 0.5 mmol), and a catalytic amount of trifluoroacetic acid were added to 10 mL of s-butanol in this order, and the mixture was stirred at 90 °C for 10 hours. After monitoring the completion of the reaction by TLC, the organic solvent was evaporated under reduced pressure, and the residue was separated by column chromatography (chloroform / methanol = 35:1) to obtain the target compound ZX-HYT-20 (0.13 g, 30% yield). HRMS (ESI) for C 52 H 77 N8O4[M+H] + Calculated: 877.6068; Found: 877.6062. HPLC analysis: MeOH-H2O (95:5), 13.792 min, 100% purity. 1H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.62 (s, 1H), 8.16 (s, 1H), 7.62 (t, J = 5.6 Hz, 1H), 7.51 (d, J = 8.6 Hz, 1H), 6.63 (d, J = 2.5 Hz, 1H), 6.51 (dd, J = 8.8, 2.5 Hz, 1H), 6.16 (d, J = 1.3 Hz, 1H), 5.84 (s, 1H), 4.08 (q, J = 7.8 Hz, 1H), 3.79 (s, 3H), 3.14 (t, J = 4.8 Hz, 4H), 3.00 (q, J = 6.5 Hz, 2H), 2.51‐2.45 (m, 6H), 2.35 (s, 3H), 2.33‐2.19 (m, 4H), 2.04‐1.87 (m, 4H), 1.86‐1.72 (m, 4H), 1.69‐1.61 (m, 3H), 1.60‐1.52 (m, 9H), 1.50‐1.41 (m, 2H), 1.40‐1.32 (m, 2H), 1.32‐1.17 (m, 16H), 0.75‐0.53 (m, 4H). 13 C NMR (101 MHz, DMSO) δ 172.23, 170.08, 163.06, 160.29, 157.37, 155.88, 153.16, 149.92, 146.19, 119.63, 117.24, 107.10, 106.87, 100.36, 58.38, 55.93, 53.27, 50.57, 50.14, 49.89, 49.18, 42.60, 38.62, 36.94, 34.09, 32.60, 31.65, 29.65, 29.53, 29.49, 29.43, 29.19, 28.51, 27.46, 26.88, 26.78, 25.90, 17.19, 14.15, 12.89, 8.19, 6.67, 6.62.

[0096] Example 21: (1R,3S)-3-(2-((4-(4-(12-(2-((3R,5R,7R)-adamantan-1-yl)acetylamino)dodecyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxypyrido[2,3-d]pyrimidin-8(7H)-yl)-N-cyclopropylcyclohexane-1-carboxamide (ZX-HYT-21) JPEG0007756374000064.jpg41170 Compound ZX-HYT-20 was synthesized in the same manner as in Example 4, except that compound 14 (0.28 g, 0.5 mmol) and N-(((1R,3S)-3-aminocyclohexyl)cyclopropanecarboxamide (0.18 g, 0.5 mmol) were used as starting materials to obtain yellow solid compound ZX-HYT-21 (0.13 g, 29% yield). HRMS (ESI) for C 53 H 79 N8O4[M+H] + Calculated: 891.6224; Found: 891.6219. HPLC analysis: MeOH-H2O (95:5), RT = 11.542 min, 100% purity. 1 H NMR (400 MHz, DMSO-d6) δ 8.82-8.44 (m, 2H), 7.82-7.08 (m, 3H), 6.65 (s, 1H), 6.52 (d, J = 8.7 Hz, 1H), 6.12 (s, 1H), 5.41-4.88 (m, 1H), 3.78 (s, 3H), 3.16 (s, 4H), 3.00 (q, J = 6.4 Hz, 2H), 2.71‐2.53 (m, 4H), 2.44‐2.21 (m, 7H), 2.17‐1.94 (m, 2H), 1.90 (s, 3H), 1.80 (s, 2H), 1.71-1.61 (m, 4H), 1.59-1.51 (m, 10H), 1.50-1.42 (m, 3H), 1.39-1.33 (m, 2H), 1.30-1.18 (m, 19H), 0.60-0.51 (m, 2H), 0.38-0.28 (m, 2H). 13C NMR (101 MHz, DMSO) δ 175.49, 170.09, 157.15, 128.32, 128.23, 115.89, 107.36, 106.56, 100.65, 100.56, 100.49, 58.25, 55.50, 53.17, 52.03, 50.58, 48.92, 44.47, 42.62, 38.64, 36.95, 32.61, 29.64, 29.49, 29.42, 29.17, 28.54, 27.75, 27.38, 26.87, 25.49, 22.67, 17.13, 6.16, 6.05.

[0097] Example 22: 2-((3R,5R,7R)-adamantan-1-yl)-N-(12-(4-(4-((8-((S)-1-(cyclopropanecarbonyl)piperidin-3-yl)-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)dodecyl)acetamide (ZX-HYT-22) JPEG0007756374000065.jpg37170 Compound ZX-HYT-20 was synthesized in the same manner as compound 14 (0.28 g, 0.5 mmol) and (S)-(3-aminopiperidin-1-yl)(cyclopropyl)methyl ketone (0.15 g, 0.5 mmol) to obtain yellow solid compound ZX-HYT-22 (0.13 g, 29% yield). HRMS (ESI) for C 52 H 77 N8O4[M+H] + Calculated: 877.6068; Found: 877.6067. HPLC analysis: MeOH-H2O (97:3), 11.956 min, 100% purity. 1H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.70 (s, 1H), 7.61 (t, J = 5.6 Hz, 1H), 7.09 (s, 1H), 6.61 (s, 1H), 6.48 (s, 1H), 6.14 (s, 1H), 5.35-4.74 (m, 1H), 4.50-3.76 (m, 4H), 3.73 (s, 3H), 3.14 (s, 4H), 3.00 (q, J = 6.4 Hz, 2H), 2.50-2.39 (m, 4H), 2.38-2.29 (m, 5H), 2.00-1.86 (m, 4H), 1.80 (s, 3H), 1.69-1.61 (m, 4H), 1.59-1.52 (m, 10H), 1.48-1.42 (m, 3H), 1.39-1.34 (m, 2H), 1.29-1.21 (m, 16H), 0.77-0.55 (m, 4H). 13 C NMR (101 MHz, DMSO) δ 171.40, 171.11, 170.08, 157.36, 155.90, 146.49, 119.19, 115.82, 107.01, 106.57, 100.16, 58.34, 55.75, 53.27, 50.58, 48.98, 47.11, 43.60, 42.62, 38.65, 36.95, 32.60, 29.65, 29.51, 29.47, 29.42, 29.18, 28.55, 27.45, 26.88, 26.73, 25.48, 17.16, 10.89, 7.28, 7.15.

[0098] Example 23: N-((1R,3S)-3-(2-((4-(4-(12-(2-((3R,5R,7R)-adamantan-1-yl)acetylamino)dodecyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)cyclohexyl)cyclopropanecarboxamide (ZX-HYT-23) JPEG0007756374000066.jpg39170 Compound ZX-HYT-20 was synthesized in the same manner as compound 14 (0.28 g, 0.5 mmol) and (1R,3S)-3-amino-N-cyclopropylcyclohexane-1-carboxamide (0.18 g, 0.5 mmol) to obtain yellow solid compound ZX-HYT-23 (0.26 g, 58% yield). HRMS (ESI) for C 53 H 79 N8O4[M+H] + Calculated: 891.6224; Found: 891.6219. HPLC analysis: MeOH-H2O (95:5), RT = 11.070 min, 100% purity. 1 H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.63 (s, 1H), 8.09 (s, 1H), 7.62 (t, J = 5.6 Hz, 1H), 6.66 (d, J = 2.5 Hz, 1H), 6.55 (d, J = 8.8 Hz, 1H), 6.10 (s, 1H), 5.33 (s, 1H), 3.79 (s, 3H), 3.67 (s, 1H), 3.17 (s, 4H), 3.00 (q, J = 6.5 Hz, 2H), 2.68‐2.51 (m, 4H), 2.43-2.24 (m, 6H), 1.90 (s, 3H), 1.83-1.71 (m, 4H), 1.69-1.61 (m, 4H), 1.61-1.52 (m, 10H), 1.51-1.41 (m, 4H), 1.40-1.32 (m, 3H), 1.31-1.17 (m, 18H), 0.68-0.54 (m, 4H). 13C NMR (101 MHz, DMSO) δ 171.87, 170.09, 157.18, 145.86, 120.00, 117.81, 116.08, 107.22, 106.72, 100.51, 58.20, 55.90, 52.99, 50.58, 48.86, 48.13, 42.62, 38.64, 36.95, 34.95, 32.60, 32.41, 29.64, 29.49, 29.41, 29.17, 28.54, 27.38, 27.31, 26.87, 24.13, 17.12, 14.03, 6.57.

[0099] Example 24: 2-(((3R,5R,7R)-adamantan-1-yl)-N-(12-(4-(4-((8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridyl[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)dodecyl)acetamide (ZX-HYT-24) JPEG0007756374000067.jpg39170 Compound ZX-HYT-20 was synthesized in the same manner as compound 14 (0.28 g, 0.5 mmol) and cyclopentylamine (0.13 g, 0.5 mmol) to obtain a yellow solid compound ZX-HYT-24 (0.21 g, 53% yield). HRMS (ESI) for C 48 H 72 N7O3[M+H] + Calculated: 794.5697; Found: 794.5699. HPLC analysis: MeOH-H2O (97:3), 14.410 min, 100% purity. 1H NMR (400 MHz, DMSO-d6) δ 8.73‐8.63 (m, 2H), 7.61 (t, J = 5.6 Hz, 1H), 7.31 (d, J = 8.7 Hz, 1H), 6.62 (d, J = 2.5 Hz, 1H), 6.49 (dd, J = 8.7, 2.5 Hz, 1H), 6.12 (s, 1H), 5.60 (s, 1H), 3.74 (s, 3H), 3.18‐3.09 (m, 4H), 3.00 (q, J = 6.4 Hz, 2H), 2.51‐2.42 (m, 4H), 2.36-2.26 (m, 5H), 2.19-2.08 (m, 2H), 1.90 (s, 3H), 1.80 (s, 2H), 1.69-1.61 (m, 4H), 1.60-1.52 (m, 12H), 1.48-1.42 (m, 3H), 1.40-1.32 (m, 3H), 1.29-1.22 (m, 16H). 13 C NMR (101 MHz, DMSO) δ 170.08, 163.14, 160.65, 157.19, 155.91, 154.16, 150.52, 145.91, 126.66, 119.56, 116.67, 107.18, 106.80, 100.38, 58.38, 55.82, 53.24, 52.51, 50.58, 49.27, 42.62, 38.64, 36.96, 32.61, 29.64, 29.49, 29.45, 29.40, 29.17, 28.54, 27.66, 27.45, 26.87, 26.75, 25.07, 17.14.

[0100] Example 25: N-(3-(2-((4-(4-(12-(2-((3R,5R,7R)-adamantan-1-yl)acetylamino)dodecyl)piperazin-1-yl)phenyl)amino)-5-methyl-7-oxapyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX-HYT-25) Compound 28a (0.27 g, 0.5 mmol), compound 21 (0.18 g, 0.5 mmol), and a catalytic amount of trifluoroacetic acid were added to 10 mL of s-butanol in this order, and the mixture was stirred at 95°C for 10 hours. After monitoring the completion of the reaction by TLC, the organic solvent was evaporated under reduced pressure, and the residue was separated by column chromatography (chloroform / methanol = 45:1) to obtain the target compound ZX-HYT-25 (0.25 g, 52% yield). HRMS (ESI) for C 52 H 71 N8O3[M+H] + : Calculated value, 855.5649; Measured value, 855.5644. 1 H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 9.83 (s, 1H), 8.82 (s, 1H), 7.86 (d, J = 8.3 Hz, 1H), 7.61 (t, J = 5.7 Hz, 1H), 7.52‐7.43 (m, 2H), 7.19 (d, J = 8.4 Hz, 2H), 6.93 (d, J = 7.8 Hz, 1H), 6.55 (d, J = 8.3 Hz, 2H), 6.30 (s, 1H), 3.05‐2.93 (m, 6H), 2.49‐2.39 (m, 7H), 2.30 (t, J = 7.3 Hz, 2H), 1.90 (s, 3H), 1.82-1.74 (m, 3H), 1.68-1.63 (m, 3H), 1.59-1.52 (m, 9H), 1.47-1.41 (m, 2H), 1.39-1.34 (m, 2H), 1.30-1.22 (m, 16H), 0.83-0.74 (m, 4H). 13C NMR (101 MHz, DMSO) δ 172.18, 170.09, 162.61, 158.77, 156.91, 156.73, 147.36, 146.73, 140.86, 137.68, 132.24, 129.93, 123.84, 119.72, 118.75, 116.73, 115.74, 106.23, 58.35, 53.27, 50.59, 49.31, 42.63, 38.65, 36.96, 32.61, 29.65, 29.52, 29.48, 29.43, 29.19, 28.54, 27.45, 26.88, 26.78, 17.46, 15.03, 7.72, 7.60.

[0101] Example 26: N-(3-(2-((4-(4-(12-(2-((3R,5R,7R)-adamantan-1-yl)acetylamino)dodecyl)piperazin-1-yl)-2-methylphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX-HYT-26) JPEG0007756374000069.jpg35170 Using the same synthesis method as for compound ZX-HYT-25, compound 21 (0.18 g, 0.5 mmol) and compound 28b (0.28 g, 0.5 mmol) were used as starting materials to obtain yellow solid compound ZX-HYT-26 (0.14 g, 33% yield). HRMS (ESI) for C 53 H 73 N8O3[M+H] + Calculated: 869.5806; Found: 869.5800. HPLC analysis: MeOH-HO (95:5), RT = 6.397 min, 96.91% purity. 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.84 (s, 1H), 8.76 (s, 1H), 7.65 (dd, J = 11.6, 7.0 Hz, 2H), 7.49 (s, 1H), 7.38 (t, J = 8.1 Hz, 1H), 7.15-7.03 (m, 1H), 6.86 (d, J = 7.8 Hz, 1H), 6.64 (s, 1H), 6.42 (s, 1H), 6.26 (s, 1H), 3.00 (q, J = 6.3 Hz, 6H), 2.51-2.39 (m, 7H), 2.30 (t, J = 7.3 Hz, 2H), 2.10 (s, 3H), 1.91 (s, 3H), 1.85-1.75 (m, 3H), 1.71-1.62 (m, 3H), 1.61-1.51 (m, 9H), 1.50-1.42 (m, 2H), 1.40-1.34 (m, 2H), 1.32‐1.21 (m, 16H), 0.89‐0.69 (m, 4H). 13 C NMR (101 MHz, DMSO) δ 172.15, 170.08, 162.70, 157.06, 156.72, 147.27, 140.56, 137.23, 129.56, 129.20, 123.92, 119.68, 118.52, 117.42, 116.50, 112.99, 106.37, 58.40, 53.27, 50.59, 49.14, 42.62, 38.64, 36.96, 32.61, 29.65, 29.52, 29.48, 29.43, 29.18, 28.54, 27.46, 26.88, 26.79, 18.84, 17.48, 15.04, 7.67.

[0102] Example 27: N-(3-(2-((4-(2-((12-(2-((3R,5R,7R)-adamantan-1-yl)acetylamino)dodecyl)oxy)ethoxy)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX-HYT-27) JPEG0007756374000070.jpg38170 The synthesis method of compound ZX-HYT-25 is the same as that of compound 21 (0.18g, 0.5m mol) and compound 28c (0.27g, 0.5mmol) were used as raw materials, and a yellow solid compound ZX-HYT-27 (0.22g, yield 51%) was obtained. HRMS (ESI) for C 51 H 69 N6O6[M+H] + Calculated, 861.5279; Found, 861.5273. HPLC analysis: MeOH-H2O (90:10), RT = 7.673 min, 100% purity. 1 H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.82 (s, 1H), 8.19 (s, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.64 (t, J = 5.7 Hz, 1H), 7.53 (t, J = 2.0 Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.31 (d, J = 8.9 Hz, 1H), 6.93 (dd, J = 7.8, 2.0 Hz, 1H), 6.55 (d, J = 2.6 Hz, 1H), 6.33 (s, 1H), 6.03 (s, 1H), 4.01 (t, J = 4.6 Hz, 2H), 3.78 (s, 3H), 3.70‐3.63 (m, 2H), 3.44 (t, J = 6.6 Hz, 2H), 2.99 (q, J = 6.4 Hz, 2H), 2.46 (s, 3H), 1.94‐1.86 (m, 3H), 1.83‐1.74 (m, 3H), 1.68‐1.61 (m, 3H), 1.58‐1.47 (m, 11H), 1.38‐1.19 (m, 18H), 0.85‐0.71 (m, 4H). 13C NMR (101 MHz, DMSO) δ 172.20, 170.09, 162.56, 157.06, 156.72, 147.31, 140.75, 137.47, 129.80, 123.87, 121.49, 119.76, 118.81, 117.13, 106.70, 104.65, 99.36, 70.87, 69.09, 67.72, 56.29, 50.58, 42.62, 38.65, 36.94, 32.60, 29.68, 29.64, 29.53, 29.51, 29.44, 29.38, 29.18, 28.53, 26.88, 26.14, 17.47, 15.03, 7.69, 7.63.

[0103] Example 28: N-(3-(2-((4-((12-(2-((3R,5R,7R)-adamantan-1-yl)acetylamino)dodecyl)oxy)-2-methoxyphenyl)amino)-5-methyl-7-oxypyrimidino[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX-HYT-28) JPEG0007756374000071.jpg27170 Compound ZX-HYT-25 was synthesized in the same manner as compound 21 (0.18 g, 0.5 mmol) and compound 28d (0.25 g, 0.5 mmol) as starting materials to obtain yellow solid compound ZX-HYT-28 (0.24 g, 59% yield). HRMS (ESI) for C 49 H 65 N6O5[M+H] + Calculated: 817.5016; Found: 817.5011. HPLC analysis: MeOH-HO (95:5), RT = 9.932 min, 95.18% purity. 1H NMR (400 MHz, DMSO-d6) δ 10.43‐10.34 (m, 1H), 8.86‐8.75 (m, 1H), 8.14 (s, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.60 (d, J = 6.2 Hz, 1H), 7.51 (d, J = 2.6 Hz, 1H), 7.46 (td, J = 8.1, 2.5 Hz, 1H), 7.31 (dd, J = 8.8, 2.5 Hz, 1H), 6.93 (d, J = 7.8 Hz, 1H), 6.51 (s, 1H), 6.32 (s, 1H), 6.04 (s, 1H), 3.87 (q, J = 5.7 Hz, 2H), 3.78 (s, 3H), 2.99 (td, J = 7.1, 3.3 Hz, 2H), 2.45 (s, 3H), 1.90 (s, 3H), 1.83‐1.75 (m, 3H), 1.71‐1.61 (m, 5H), 1.60‐1.51 (m, 9H), 1.43‐1.32 (m, 5H), 1.31‐1.21 (m, 13H), 0.84‐0.72 (m, 4H). 13 C NMR (101 MHz, DMSO) δ 172.18, 170.10, 162.57, 157.06, 156.72, 147.31, 140.75, 137.47, 129.80, 123.87, 121.31, 119.74, 118.82, 117.11, 106.68, 104.55, 99.29, 67.98, 56.27, 50.59, 42.62, 38.65, 36.94, 32.61, 29.65, 29.51, 29.45, 29.29, 29.23, 29.19, 28.54, 26.89, 26.05, 17.46, 15.01, 7.64.

[0104] Example 29: N-(3-(2-((4-(4-(12-((2-((3R,5R,7R)-adamantan-1-yl)ethyl)amino)dodecyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxypyrano[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX-HYT-29) JPEG0007756374000072.jpg71170 Step 1: N-(3-(2-((4-(4-(12-(1,3-dioxoisoindol-2-yl-yl)dodecyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxypyrano[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (31) Compound 29 (0.26 mg, 0.5 mmol), compound 30a (0.20 g, 0.5 mmol), and anhydrous potassium carbonate (0.14 g, 1 mmol) were added to DMF (8 mL) and stirred at 70 °C for 7 hours. After completion of the reaction was confirmed by TLC, 100 mL of ethyl acetate was added. The organic layer was washed sequentially with saturated brine (2 × 40 mL) and distilled water (3 × 40 mL), separated, dried, and evaporated. The resulting residue was purified by column chromatography (eluting with chloroform / methanol = 45:1) to give compound 31 (0.31 g, 76% yield) as a yellow powder. HRMS (ESI) for C 49 H 59 N8O5[M+H] + Calculated: 839.4608; Found: 839.4602. HPLC analysis: MeOH-H2O (95:5), RT = 9.870 min, 100% purity. 1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.78 (s, 1H), 8.07 (s, 1H), 7.83 (s, 5H), 7.56‐7.40 (m, 2H), 7.26 (d, J = 8.9 Hz, 1H), 6.91 (s, 1H), 6.51 (s, 1H), 6.30 (s, 1H), 6.01 (s, 1H), 3.77 (s, 3H), 3.58‐3.51 (m, 2H), 3.02 (s, 4H), 2.48‐2.36 (m, 7H), 2.28 (s, 2H), 1.81-1.69 (m, 2H), 1.60-1.53 ​​(m, 2H), 1.46-1.40 (m, 2H), 1.32-1.17 (m, 15H), 0.83-0.71 (m, 4H). Step 2: N-(3-(2-((4-(4-(12-aminododecyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (32) Compound 31 (0.84 mg, 1 mmol) and 80% hydrazine hydrate (2 mL) were added to 40 mL of absolute ethanol and stirred at 70 °C for 3 hours. After the completion of the reaction was confirmed by TLC, the organic solvent was evaporated under reduced pressure. The residue was added to 50 mL of DCM and stirred thoroughly, then filtered with suction. The filtrate was evaporated to dryness and subjected to column chromatography (eluting with chloroform / methanol = 10:1) to give compound 32 (0.67 g, 94% yield) as a yellow solid. HRMS (ESI) for C 41 H 57 N8O3[M+H] + Calculated: 709.4554; Found: 709.4548. HPLC analysis: MeOH-HO (95:5), RT = 7.589 min, 97.81% purity. 1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.78 (s, 1H), 8.08 (s, 1H), 7.81 (s, 1H), 7.56-7.38 (m, 2H), 7.27 (d, J = 8.9 Hz, 1H), 6.91 (d, J = 7.8 Hz, 1H), 6.52 (s, 1H), 6.31 (s, 1H), 6.01 (s, 1H), 3.78 (s, 3H), 3.03 (s, 6H), 2.49‐2.38 (m, 7H), 2.29 (t, J = 7.4 Hz, 2H), 1.78 (d, J = 9.6 Hz, 1H), 1.45 (s, 3H), 1.31-1.20 (m, 17H), 0.85-0.70 (m, 4H). Step 3: N-(3-(2-((4-(4-(12-((2-((3R,5R,7R)-adamantan-1-yl)ethyl)amino)dodecyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxypyrano[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX-HYT-29) Compound 32 (177 mg, 0.25 mmol), adamantaneacetaldehyde (45 mg, 0.25 mmol), sodium triacetoxyborohydride (0.27 g, 1.25 mmol), and a catalytic amount of glacial acetic acid were added to 20 mL of ultra-anhydrous toluene and stirred at 40 °C under argon protection for 2 hours. After completion of the reaction was monitored by TLC, the organic solvent was evaporated and the resulting residue was subjected to silica gel column chromatography (eluting with chloroform / methanol = 15:1) to obtain the target compound ZX-HYT-29 (0.12 mg, 55% yield) as a yellow solid. HRMS (ESI) for C 52 H 73 N8O3[M+H] + Calculated: 857.5806; Found: 857.5801. HPLC analysis: MeOH-H2O (97:3), RT = 6.096 min, 99.17% purity. 1H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.80 (s, 1H), 8.09 (s, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.51‐7.42 (m, 2H), 7.27 (d, J = 8.9 Hz, 1H), 6.92 (dd, J = 7.7, 2.0 Hz, 1H), 6.53 (d, J = 2.5 Hz, 1H), 6.32 (s, 1H), 6.02 (s, 1H), 3.78 (s, 3H), 3.03 (t, J = 4.8 Hz, 4H), 2.50-2.42 (m, 11H), 2.30 (t, J = 7.4 Hz, 2H), 1.93-1.86 (m, 3H), 1.81-1.73 (m, 1H), 1.70-1.62 (m, 3H), 1.62-1.55 (m, 3H), 1.45 (s, 8H), 1.38 (t, J = 6.9 Hz, 2H), 1.33-1.22 (m, 17H), 1.21-1.16 (m, 2H), 0.82-0.74 (m, 4H). 13 C NMR (101 MHz, DMSO) δ 172.17, 162.58, 157.00, 156.75, 147.31, 140.79, 137.47, 129.84, 123.82, 119.69, 118.74, 116.99, 106.70, 106.56, 100.07, 58.34, 56.15, 53.28, 50.01, 49.29, 44.49, 44.15, 42.62, 37.12, 31.86, 29.87, 29.80, 29.47, 28.52, 27.43, 27.32, 26.79, 17.47, 15.03, 7.70, 7.62.

[0105] Example 30: N-(3-(2-((2-methoxy-4-(4-octylpiperazin-1-yl)phenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX-HYT-30) Compound 29 (0.13 mg, 0.25 mmol), compound 30b (48 mg, 0.25 mmol), and anhydrous potassium carbonate (69 mg, 0.5 mmol) were added to DMF (5 mL) and stirred at 70 °C for 7 hours. After completion of the reaction was confirmed by TLC, 30 mL of ethyl acetate was added. The organic layer was washed sequentially with saturated brine (2 × 20 mL) and distilled water (3 × 20 mL), separated, dried, and evaporated. The resulting residue was purified by column chromatography (eluting with chloroform / methanol = 50:1) to obtain the target compound ZX-HYT-30 (0.11 g, 69% yield) as a yellow powder. HRMS (ESI) for C 37 H 48 N7O3[M+H] + Calculated: 638.3819; Found: 638.3813. HPLC analysis: MeOH-HO (95:5), RT = 6.803 min, 98.91% purity. 1 H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.80 (s, 1H), 8.10 (s, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.51‐7.42 (m, 2H), 7.27 (d, J = 8.9 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H), 6.53 (d, J = 2.5 Hz, 1H), 6.31 (s, 1H), 6.02 (s, 1H), 3.78 (s, 3H), 3.03 (t, J = 4.8 Hz, 4H), 2.50‐2.43 (m, 7H), 2.31 (t, J = 7.4 Hz, 2H), 1.82-1.73 (m, 1H), 1.46 (s, 2H), 1.30-1.23 (m, 10H), 0.90-0.85 (m, 3H), 0.82-0.74 (m, 4H). 13C NMR (101 MHz, DMSO) δ 172.19, 162.60, 157.02, 156.75, 147.33, 140.79, 137.48, 129.86, 123.83, 120.30, 119.68, 118.73, 116.99, 106.70, 106.57, 100.08, 58.35, 56.15, 53.27, 49.28, 31.76, 29.44, 29.20, 27.46, 26.79, 22.57, 17.46, 15.03, 14.44, 7.69, 7.62.

[0106] Example 31: N-(3-(2-((2-methoxy-4-(4-octylpiperazin-1-yl)phenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX-HYT-31) Compound 29 (0.53 mg, 1 mmol), compound 30c (0.34 g, 1 mmol), and anhydrous potassium carbonate (0.28 g, 2 mmol) were added to 10 mL of DMF and stirred at 70 °C for 7 hours. After completion of the reaction was confirmed by TLC, 50 mL of ethyl acetate was added. The organic layer was washed sequentially with saturated brine (2 × 50 mL) and distilled water (3 × 50 mL), separated, dried, and evaporated. The residue was purified by column chromatography (eluted with chloroform / methanol = 50:1), then directly dissolved in 30 mL of absolute ethanol and 1 mL of 80% hydrazine hydrate was added dropwise. The reaction mixture was stirred at 40 °C for 2 hours. After completion of the reaction, the organic solvent was evaporated. The residue was thoroughly stirred with 50 mL of DCM, filtered under reduced pressure, and the filtrate was evaporated to dryness. The filtrate was then purified by column chromatography (eluted with chloroform / methanol = 10:1) to give the yellow solid compound ZX-HYT-31 (0.57 g, 88% yield). HRMS (ESI) for C 37 H 49 N8O3[M+H] +Calculated, 653.3928; Found, 653.3934. HPLC analysis: MeOH-H2O (95:5), RT = 7.852 min, 97.44% purity. 1 H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.79 (s, 1H), 8.10 (s, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.53‐7.41 (m, 2H), 7.27 (d, J = 8.9 Hz, 1H), 6.95‐6.87 (m, 1H), 6.52 (d, J = 2.5 Hz, 1H), 6.31 (s, 1H), 6.02 (s, 1H), 3.78 (s, 3H), 3.03 (d, J = 5.4 Hz, 4H), 2.56‐2.52 (m, 1H), 2.50-2.46 (m, 5H), 2.45 (s, 3H), 2.30 (t, J = 7.4 Hz, 2H), 1.78 (qd, J = 7.0, 5.2 Hz, 1H), 1.45 (t, J = 7.3 Hz, 2H), 1.36 (t, J = 6.8 Hz, 2H), 1.32‐1.24 (m, 10H), 0.83-0.74 (m, 4H). 13 C NMR (101 MHz, DMSO) δ 172.24, 162.63, 157.02, 156.73, 147.39, 140.77, 137.46, 129.88, 123.83, 120.25, 119.66, 118.75, 116.97, 106.69, 106.57, 100.06, 58.36, 56.15, 53.26, 49.25, 41.77, 33.00, 29.48, 29.44, 27.42, 26.83, 26.77, 17.46, 15.03, 7.72, 7.62.

[0107] Example 32: (1R,3R,5S,7R)—N-(8-(4-(4-((8-(3-(cyclopropanecarboxamido)phenyl)phenyl)-5-methyl-7-oxo-7,8-dihydropyridyl[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)octyl)-3,5-dimethyladamantane-1-carboxamide (ZX-HYT-32) Compound ZX-HYT-31 (0.13 mg, 0.2 mmol), (1R,3R,5S,7R)-3,5-dimethyladamantane-1-carboxylic acid (42 mg, 0.2 mmol), HATU (91 mg, 0.24 mmol), and DIPEA (52 mg, 0.4 mmol) were added to acetonitrile (6 mL) and stirred at room temperature for 1 hour. After completion of the reaction was confirmed by TLC, the organic solvent was evaporated off, and the residue was blended with silica gel and evaporated to dryness. The residue was directly separated by column chromatography (eluting with chloroform / methanol = 50:1) to obtain the target compound ZX-HYT-32 (93 mg, 55% yield) as a yellow powder. HRMS (ESI) for C 50 H 67 N8O4[M+H] + Calculated: 843.5285; Found: 843.5280. HPLC analysis: MeOH-H2O (95:5), 6.693 min, 99.44% purity. 1H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.79 (s, 1H), 8.09 (s, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.50‐7.42 (m, 2H), 7.31 (t, J = 5.6 Hz, 1H), 7.27 (d, J = 8.9 Hz, 1H), 6.91 (d, J = 7.9 Hz, 1H), 6.52 (d, J = 2.6 Hz, 1H), 6.31 (s, 1H), 6.01 (s, 1H), 3.78 (s, 3H), 3.09‐2.97 (m, 6H), 2.50‐2.46 (m, 4H), 2.45 (s, 3H), 2.30 (t, J = 7.5 Hz, 2H), 2.03 (p, J = 3.2 Hz, 1H), 1.77 (td, J = 7.2, 3.7 Hz, 1H), 1.60‐1.53 (m, 2H), 1.51‐1.41 (m, 3H), 1.40‐1.34 (m, 5H), 1.33 (s, 1H), 1.30‐1.22 (m, 11H), 1.14‐1.05 (m, 2H), 0.82‐0.75 (m, 10H). 13 C NMR (101 MHz, DMSO) δ 176.90, 172.21, 162.61, 157.00, 156.73, 147.36, 140.77, 137.46, 129.86, 123.83, 120.29, 119.67, 118.75, 116.97, 106.72, 106.57, 100.07, 58.35, 56.15, 53.23, 50.80, 49.21, 45.51, 42.89, 42.17, 38.93, 37.91, 31.17, 30.92, 29.53, 29.37, 29.34, 29.18, 27.35, 26.70, 17.46, 15.03, 7.72, 7.63.

[0108] Example 33: N-(3-(2-((4-(4-(8-(3,3-dimethylsuccinylamido)octyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxypyrano[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX-HYT-33) JPEG0007756374000079.jpg43170 Similar to the synthesis method for compound ZX-HYT-32, compound ZX-HYT-31 (0.13 mg, 0.2 mmol) and 3,3-dimethylbutyric acid (23 mg, 0.2 mmol) were used as raw materials, and compound ZX-HYT-33 (60 mg, 40% yield) was obtained via amide condensation. HRMS (ESI) for C 43 H 59 N8O4[M+H] + Calculated: 751.4659; Found: 751.4654. HPLC analysis: MeOH-H2O (90:10), 6.793 min, 98.37% purity. 1 H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.79 (s, 1H), 8.09 (s, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.67 (t, J = 5.5 Hz, 1H), 7.52‐7.42 (m, 2H), 7.27 (d, J = 8.8 Hz, 1H), 6.92 (d, J = 7.9 Hz, 1H), 6.52 (d, J = 2.5 Hz, 1H), 6.36‐6.28 (m, 1H), 6.02 (s, 1H), 3.78 (s, 3H), 3.08-2.98 (m, 6H), 2.50-2.46 (m, 4H), 2.45 (s, 3H), 2.30 (t, J = 7.4 Hz, 2H), 1.93 (s, 2H), 1.82‐1.73 (m, 1H), 1.45 (t, J = 7.2 Hz, 2H), 1.38 (q, J = 6.6 Hz, 2H), 1.32-1.21 (m, 8H), 0.95 (s, 9H), 0.83-0.73 (m, 4H). 13C NMR (101 MHz, DMSO) δ 172.18, 170.98, 162.58, 157.00, 156.74, 147.31, 140.78, 137.48, 129.85, 123.83, 120.27, 119.68, 118.74, 116.99, 106.71, 106.56, 100.07, 58.36, 56.15, 53.28, 49.37, 49.28, 38.70, 30.82, 30.16, 29.67, 29.44, 29.21, 27.39, 26.89, 26.78, 17.46, 15.04, 7.71, 7.62.

[0109] Example 34: N-(8-(4-(4-((8-(3-(cyclopropanecarboxamido)phenyl)phenyl)-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)octyl)-4,4-difluorocyclohexane-1-carboxamide (ZX-HYT-34) JPEG0007756374000080.jpg46170 Compound ZX-HYT-34 (73 mg, 46% yield) was obtained by amide condensation using compound ZX-HYT-31 (0.13 mg, 0.2 mmol) and 4,4-difluorocyclohexane-1-carboxylic acid (33 mg, 0.2 mmol) as raw materials in the same manner as in the synthesis of compound ZX-HYT-32. HRMS (ESI) for C 44 H 57 F2N8O4[M+H] + Calculated: 799.4471; Found: 799.4465. HPLC analysis: MeOH-H2O (97:3), RT = 4.194 min, 99.49% purity. 1H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.80 (s, 1H), 8.10 (s, 1H), 7.86‐7.74 (m, 2H), 7.50‐7.43 (m, 2H), 7.27 (d, J = 8.9 Hz, 1H), 6.92 (d, J = 7.8 Hz, 1H), 6.53 (d, J = 2.5 Hz, 1H), 6.31 (s, 1H), 6.02 (s, 1H), 3.78 (s, 3H), 3.08‐2.98 (m, 6H), 2.49‐2.46 (m, 4H), 2.45 (s, 3H), 2.30 (t, J = 7.4 Hz, 2H), 2.21 (t, J = 11.8 Hz, 1H), 2.08‐1.98 (m, 2H), 1.86‐1.71 (m, 5H), 1.61 (t, J = 11.9 Hz, 2H), 1.49‐1.42 (m, 2H), 1.41-1.35 (m, 2H), 1.31-1.23 (m, 8H), 0.82-0.75 (m, 4H). 13 C NMR (101 MHz, DMSO) δ 173.95, 172.18, 162.58, 156.99, 156.74, 147.32, 140.77, 137.47, 129.84, 124.20, 123.82, 120.26, 119.67, 118.73, 116.98, 106.70, 106.56, 100.07, 58.36, 56.14, 53.27, 49.27, 41.49, 38.79, 32.97, 32.73, 32.50, 29.53, 29.42, 29.19, 27.39, 26.78, 26.17, 26.08, 17.46, 15.04, 7.69, 7.63.

[0110] Example 35: (3R,5R,7R)—N-(8-(4-(4-((8-(3-(cyclopropanecarboxamido)phenyl)-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)octyl)adamantane-1-carboxamide (ZX-HYT-35) JPEG0007756374000081.jpg46170 Similar to the synthesis method of compound ZX-HYT-32, compound ZX-HYT-31 (0.13 mg, 0.2 mmol) and (3R,5R,7R)-adamantane-1-carboxylic acid (36 mg, 0.2 mmol) were used as raw materials, and compound ZX-HYT-35 (74 mg, 45% yield) was obtained via amide condensation. HRMS (ESI) for C 48 H 63 N8O4[M+H] + Calculated: 815.4972; Found: 815.4967. HPLC analysis: MeOH-H2O (95:5), 5.824 min, 100% purity. 1 H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.79 (s, 1H), 8.09 (s, 1H), 7.80 (s, 1H), 7.53‐7.41 (m, 2H), 7.28 (dd, J = 12.6, 7.2 Hz, 2H), 6.91 (d, J = 7.9 Hz, 1H), 6.58‐6.48 (m, 1H), 6.31 (s, 1H), 6.02 (s, 1H), 3.78 (s, 3H), 3.09‐2.97 (m, 6H), 2.47 (d, J = 19.2 Hz, 7H), 2.34-2.26 (m, 2H), 1.95 (s, 3H), 1.75 (t, J = 6.2 Hz, 7H), 1.70‐1.58 (m, 6H), 1.45 (s, 2H), 1.38 (t, J = 6.6 Hz, 2H), 1.33‐1.20 (m, 8H), 0.89‐0.70 (m, 4H). 13C NMR (101 MHz, DMSO) δ 177.08, 172.16, 162.57, 157.00, 156.73, 147.31, 140.76, 137.46, 129.83, 129.76, 123.81, 119.66, 118.72, 116.97, 116.84, 106.69, 106.55, 100.13, 100.06, 58.38, 56.14, 53.28, 49.28, 38.90, 36.65, 29.59, 29.41, 29.21, 28.15, 27.39, 26.78, 26.72, 17.46, 15.07, 15.03, 7.71, 7.70.

[0111] Example 36: 2-((3R,5R,7R)-adamantan-1-yl)-N-(12-(4-(3-methoxy-4-((5-methyl-7-oxo-8-phenyl-7,8))-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)dodecyl)acetamide (ZX-HYT-36) JPEG0007756374000082.jpg43170 See Example 16 for the synthesis of compound ZX-HYT-36. HRMS (ESI) for C 49 H 68 N7O3[M+H] + Calculated: 803.5384; Found: 803.5379. HPLC analysis: MeOH-H2O (95:5), RT= 11.983 min, 99.29% purity. 1H NMR (400 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.07 (s, 1H), 7.61 (t, J = 5.6 Hz, 1H), 7.53 (dq, J = 14.0, 7.3 Hz, 3H), 7.27 (d, J = 7.3 Hz, 2H), 7.17 (d, J = 8.8 Hz, 1H), 6.52 (s, 1H), 6.31 (s, 1H), 5.97 (s, 1H), 3.77 (s, 3H), 3.08‐2.94 (m, 6H), 2.50‐2.37 (m, 7H), 2.31 (t, J = 7.8 Hz, 2H), 1.90 (s, 3H), 1.80 (s, 2H), 1.69‐1.62 (m, 3H), 1.60‐1.52 (m, 9H), 1.45 (t, J = 7.2 Hz, 2H), 1.37 (t, J = 6.7 Hz, 2H), 1.29‐1.22 (m, 16H). 13 C NMR (101 MHz, DMSO) δ 170.08, 162.70, 156.92, 156.85, 147.20, 137.25, 129.55, 129.52, 128.33, 120.30, 117.02, 106.75, 106.60, 100.14, 79.66, 58.33, 56.12, 53.24, 50.59, 49.28, 42.63, 38.65, 36.96, 32.61, 29.65, 29.51, 29.48, 29.43, 29.18, 28.55, 27.45, 26.88, 26.74, 17.46.

[0112] Example 37: 2-((3R,5R,7R)-adamantan-1-yl)-N-(12-(4-(4-((8-((S)-1-(cyclopropanecarbonyl)pyrrolidin-3-yl))-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)dodecyl)acetamide (ZX-HYT-37) JPEG0007756374000083.jpg46170 The synthesis method of compound ZX-HYT-37 is as follows in Example 20. HRMS (ESI) for C 51 H 75 N8O4[M+H] + Calculated, 863.5911; Measured, 863.5906. HPLC analysis: MeOH-H2O (97:3), 9.734 min, 100% purity. 1 H NMR (400 MHz, Methanol-d4) δ 8.70 (s, 1H), 7.24 (s, 1H), 6.67 (s, 1H), 6.58 (d, J = 6.0 Hz, 1H), 6.19 (s, 1H), 5.75 (s, 1H), 5.39 (s, 1H), 3.80 (s, 3H), 3.27‐3.20 (m, 4H), 3.14 (t, J = 6.9 Hz, 2H), 2.81 (d, J = 30.8 Hz, 1H), 2.66 (t, J = 5.0 Hz, 4H), 2.52 (s, 1H), 2.46‐2.35 (m, 5H), 2.23‐2.11 (m, 1H), 1.95 (s, 3H), 1.91 (s, 2H), 1.74 (d, J = 12.3 Hz, 3H), 1.67 (s, 2H), 1.63 (d, J = 2.9 Hz, 7H), 1.59-1.54 (m, 2H), 1.51-1.45 (m, 2H), 1.38-1.25 (m, 16H), 0.90-0.78 (m, 1H), 0.55-0.44 (m, 2H), 0.18-0.03 (m, 2H). 13C NMR (101 MHz, DMSO) δ 171.17, 170.09, 163.11, 157.46, 155.88, 150.21, 150.05, 146.67, 131.96, 125.70, 125.40, 119.48, 116.53, 107.01, 100.18, 58.39, 55.92, 53.31, 50.58, 50.31, 49.18, 48.95, 42.61, 38.65, 36.95, 32.59, 29.63, 29.49, 29.17, 28.54, 27.45, 26.86, 17.19, 14.00, 12.41, 11.86, 7.64, 7.41.

[0113] Example 38: N-(3-(2-((4-(2-((12-(2-((3R,5R,7R)-adamantan-1-yl)ethoxy)dodecyl)oxy)ethoxy)-2-methoxyphenyl) amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX-HYT-38) JPEG0007756374000084.jpg43170 See Example 27 for the synthesis of compound ZX-HYT-38. HRMS (ESI) for C 51 H 75 N8O4[M+H] + Calculated: 847.5248; Found: 847.5351. HPLC analysis: MeOH-H2O (97:3), 4.685 min, 100% purity. 1H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.81 (s, 1H), 8.18 (s, 1H), 7.80‐7.66 (m, 1H), 7.54 (t, J = 2.1 Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.32 (d, J = 8.9 Hz, 1H), 6.93 (d, J = 7.8 Hz, 1H), 6.55 (d, J = 2.5 Hz, 1H), 6.33 (s, 1H), 6.03 (s, 1H), 4.07‐3.95 (m, 2H), 3.78 (s, 3H), 3.71‐3.63 (m, 2H), 3.45‐3.42 (m, 2H), 3.36‐3.32 (m, 2H), 3.27 (t, J = 6.4 Hz, 2H), 2.45 (s, 3H), 1.88 (s, 2H), 1.77 (p, J = 6.4 Hz, 1H), 1.61 (q, J = 12.0 Hz, 4H), 1.54‐1.37 (m, 8H), 1.31‐1.17 (m, 23H), 0.87‐0.81 (m, 2H), 0.79‐0.77 (m, 4H). 13 C NMR (101 MHz, DMSO) δ 172.22, 162.59, 157.09, 156.69, 147.36, 140.74, 137.46, 130.12, 129.84, 123.86, 121.43, 119.71, 118.78, 117.10, 106.68, 104.53, 99.27, 70.83, 70.36, 69.07, 67.66, 66.26, 56.26, 43.73, 42.59, 37.04, 31.79, 31.74, 29.68, 29.56, 29.52, 29.48, 29.45, 29.37, 29.33, 29.26, 29.22, 28.48, 26.19, 26.13, 22.59, 17.49, 15.03, 14.45, 7.74, 7.66.

[0114] Example 39: 2-((3R,5R,7R)-adamantan-1-yl)-N-(12-(4-(4-((8-(3-((cyclobutylmethyl)amino)phenyl)-5-methyl-7)-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)dodecyl)acetamide (ZX-HYT-39) JPEG0007756374000085.jpg43170 See Example 19 for the synthesis of compound ZX-HYT-39. HRMS (ESI) for C 54 H 77 N8O3[M+H] + Calculated: 885.6119; Found: 885.6114. HPLC analysis: MeOH-H2O (97:3), 13.507 min, 100% purity. 1 H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.01 (s, 1H), 7.61 (t, J = 5.9 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.22 (t, J = 8.0 Hz, 1H), 6.69 (d, J = 8.2 Hz, 1H), 6.54 (s, 1H), 6.42 (s, 1H), 6.35 (d, J = 7.7 Hz, 1H), 6.28 (s, 1H), 6.05 (s, 1H), 5.72 (t, J = 5.7 Hz, 1H), 3.79 (s, 3H), 3.09‐2.95 (m, 8H), 2.60-2.52 (m, 2H), 2.50-2.45 (m, 4H), 2.43 (s, 3H), 2.29 (t, J = 7.4 Hz, 2H), 2.00 (q, J = 8.0 Hz, 2H), 1.90 (s, 3H), 1.85-1.77 (m, 4H), 1.73-1.65 (m, 3H), 1.65-1.61 (m, 2H), 1.59-1.56 (m, 2H), 1.56-1.52 (m, 6H), 1.47-1.41 (m, 2H), 1.39-1.34 (m, 2H), 1.30-1.21 (m, 16H). 13C NMR (101 MHz, DMSO) δ 170.12, 162.63, 156.82, 150.68, 146.95, 137.95, 129.90, 120.56, 117.16, 115.92, 113.01, 111.30, 106.86, 106.55, 100.17, 58.32, 56.17, 53.27, 50.59, 49.42, 49.25, 42.62, 38.64, 36.95, 34.72, 32.61, 29.63, 29.49, 29.45, 29.40, 29.16, 28.54, 27.42, 26.86, 26.76, 26.17, 18.42, 17.41.

[0115] Example 40: 2-((3R,5R,7R)-adamantan-1-yl)-N-(12-(4-(4-((8-(3-(cyclopropylmethoxy)phenyl)-5-methyl-7-oxo-))7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)dodecyl)acetamide (ZX-HYT-40) JPEG0007756374000086.jpg46170 See Example 16 for the synthesis of compound ZX-HYT-40. HRMS (ESI) for C 53 H 73 N7O4[M+H] + : Calculated value, 872.5797; Measured value, 872.5789. 1H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.08 (s, 1H), 7.61 (t, J = 5.7 Hz, 1H), 7.44 (t, J = 8.1 Hz, 1H), 7.28 (d, J = 8.8 Hz, 1H), 7.08 (dd, J = 8.4, 2.6 Hz, 1H), 6.86 (t, J = 2.2 Hz, 1H), 6.81 (dd, J = 7.6, 1.9 Hz, 1H), 6.54 (d, J = 2.5 Hz, 1H), 6.30 (d, J = 1.4 Hz, 1H), 6.00 (s, 1H), 3.86‐3.73 (m, 5H), 3.10‐2.94 (m, 6H), 2.50‐2.40 (m, 7H), 2.30 (s, 2H), 1.95‐1.85 (m, 3H), 1.80 (s, 2H), 1.69‐1.62 (m, 3H), 1.60‐1.52 (m, 9H), 1.49‐1.42 (m, 2H), 1.37 (t, J = 6.7 Hz, 2H), 1.30‐1.23 (m, 17H), 0.53 (dt, J = 10.2, 3.0 Hz, 2H), 0.28 (dt, J = 6.1, 3.0 Hz, 2H). 13 C NMR (101 MHz, DMSO) δ 170.08, 162.59, 159.85, 156.88, 156.81, 147.13, 138.33, 130.22, 121.48, 117.06, 115.85, 114.49, 106.60, 100.18, 72.76, 58.34, 56.13, 53.25, 50.59, 49.32, 42.63, 38.64, 36.96, 32.61, 29.65, 29.51, 29.47, 29.42, 29.18, 28.54, 27.44, 26.87, 17.44, 10.57, 3.54.

[0116] Example 41: N-((1R,3S,5R,7S)-3-(2-((4-(4-(12-(2-((3R,5R,7R)-adamantan-1-yl)acetylamino)dodecyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)adamantan-1-yl)cyclopropanecarboxamide (ZX-HYT-41) JPEG0007756374000087.jpg45170 See Example 16 for the synthesis of compound ZX-HYT-41. HRMS (ESI) for C 57 H 82 N8O4[M+H] + : Calculated value, 943.6532; Measured value, 943.6541. 1 H NMR (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 9.15 (s, 1H), 8.79 (s, 1H), 8.08 (s, 1H), 7.64 (t, J = 5.7 Hz, 1H), 6.53 (d, J = 2.6 Hz, 1H), 6.31 (d, J = 1.4 Hz, 1H), 5.99 (s, 1H), 3.79 (s, 3H), 3.16-2.92 (m, 6H), 2.49-2.23 (m, 6H), 1.93-1.83 (m, 4H), 1.80 (s, 2H), 1.69-1.61 (m, 6H), 1.60-1.52 (m, 9H), 1.48 (s, 2H), 1.41-1.19 (m, 32H), 1.02-0.79 (m, 4H).

[0117] Example 42: 2-((3R,5R,7R)-adamantan-1-yl)-N-(12-(4-(4-((8-(8-(cyclopropanecarbonyl)-8-azabicyclo[3.2.1]octane))3-yl)-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)dodecyl)acetamide (ZX-HYT-42) JPEG0007756374000088.jpg42170 The synthesis method of compound ZX-HYT-42 is as follows: Example 16 is as follows: HRMS (ESI) for C 54 H 78 N8O4[M+H] + Calculated, 903.6224; Found, 903.6231. HPLC analysis: MeOH-H2O (97:3), 12.782 min, 100% purity. 1 H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.37 (s, 1H), 7.61 (t, J = 5.7 Hz, 2H), 6.65 (d, J = 2.5 Hz, 1H), 6.57 (d, J = 8.9 Hz, 1H), 6.15 (s, 1H), 5.31 (s, 1H), 4.65‐4.47 (m, 2H), 3.81 (s, 3H), 3.23‐3.07 (m, 4H), 3.00 (q, J = 6.5 Hz, 2H), 2.69‐2.52 (m, 4H), 2.38‐2.26 (m, 5H), 2.22‐2.13 (m, 2H), 1.90 (s, 4H), 1.80 (s, 2H), 1.68‐1.62 (m, 3H), 1.59‐1.52 (m, 8H), 1.50‐1.44 (m, 2H), 1.39‐1.33 (m, 2H), 1.30‐1.21 (m, 22H), 0.84‐0.74 (m, 2H), 0.71‐0.60 (m, 2H). 13 C NMR (101 MHz, DMSO) δ 170.36, 170.09, 162.97, 157.33, 146.18, 107.72, 106.90, 100.54, 58.19, 56.09, 53.19, 51.44, 50.58, 48.96, 42.62, 38.64, 36.95, 33.32, 32.60, 32.35, 31.76, 31.13, 30.93, 29.64, 29.48, 29.41, 29.17, 28.54, 27.37, 26.87, 23.32, 22.57, 18.30, 17.19, 14.42, 11.72, 7.21, 7.15, 6.53.

[0118] Example 43: 2-((3R,5R,7R)-adamantan-1-yl)-N-(12-(4-(4-((8-(3-(dimethylamino)phenyl)-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)dodecyl)acetamide (ZX-HYT-43) JPEG0007756374000089.jpg47170 See Example 16 for the synthesis of compound ZX-HYT-43. HRMS (ESI) for C 51 H 72 N8O3[M+H] + Calculated: 845.5806; Found: 845.5797. HPLC analysis: MeOH-HO (95:5), RT = 12.901 min, 99.52% purity. 1 H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.03 (s, 1H), 7.61 (t, J = 5.7 Hz, 1H), 7.40‐7.30 (m, 2H), 6.85 (dd, J = 8.4, 2.5 Hz, 1H), 6.62 (t, J = 2.2 Hz, 1H), 6.54 (d, J = 2.5 Hz, 1H), 6.50 (dd, J = 7.5, 1.8 Hz, 1H), 6.29 (s, 1H), 5.98 (s, 1H), 3.79 (s, 3H), 3.09-2.97 (m, 6H), 2.90 (s, 6H), 2.50‐2.46 (m, 4H), 2.44 (s, 3H), 2.32 (d, J = 8.7 Hz, 2H), 1.94‐1.87 (m, 3H), 1.80 (s, 2H), 1.65 (d, J = 12.2 Hz, 3H), 1.58 (s, 2H), 1.56-1.54 (m, 6H), 1.45 (t, J = 7.1 Hz, 2H), 1.36 (q, J = 6.5, 5.9 Hz, 2H), 1.32-1.23 (m, 17H). 13C NMR (101 MHz, DMSO) δ 170.07, 162.68, 156.91, 156.77, 151.82, 146.91, 138.12, 129.87, 120.57, 117.20, 116.85, 113.36, 112.11, 106.62, 100.22, 58.33, 56.16, 55.38, 53.24, 50.59, 49.32, 42.63, 38.65, 36.96, 32.61, 29.65, 29.51, 29.46, 29.43, 29.19, 28.55, 27.44, 26.88, 26.72, 17.41.

[0119] Example 44: 2-((3R,5R,7R)-adamantan-1-yl)-N-(12-(4-(4-((8-(3-((azetidin-3-ylmethyl)amino)phenyl)-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)dodecyl)acetamide (ZX-HYT-44) JPEG0007756374000090.jpg45170 See Example 17 for the synthesis of compound ZX-HYT-44. HRMS (ESI) for C 53 H 75 NO3[M+H] + Calculated: 886.6071; Found: 886.6066. HPLC analysis: MeOH-HO (95:5), RT = 8.652 min, 98.25% purity. 1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.79 (s, 1H), 8.69 (s, 1H), 8.13 (s, 1H), 7.64 (t, J = 5.7 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.25 (t, J = 8.0 Hz, 1H), 6.72 (d, J = 8.3 Hz, 1H), 6.64 (d, J = 2.5 Hz, 1H), 6.50‐6.39 (m, 2H), 6.30 (s, 1H), 6.06 (s, 1H), 3.95 (s, 2H), 3.81 (s, 3H), 3.76‐3.64 (m, 4H), 3.57 (s, 2H), 3.30‐3.23 (m, 4H), 3.13 (s, 4H), 3.04‐2.89 (m, 5H), 2.45 (s, 3H), 1.90 (s, 3H), 1.80 (s, 2H), 1.70‐1.61 (m, 4H), 1.60‐1.51 (m, 8H), 1.40‐1.34 (m, 2H), 1.33‐1.19 (m, 16H). 13 C NMR (101 MHz, DMSO) δ 170.15, 162.64, 158.69, 158.40, 156.89, 156.81, 150.09, 147.02, 138.15, 129.96, 121.57, 119.19, 117.24, 116.80, 116.21, 112.57, 112.28, 107.27, 106.71, 100.91, 56.31, 55.97, 51.27, 50.58, 49.41, 46.70, 45.42, 42.61, 38.65, 36.94, 32.61, 31.46, 29.64, 29.49, 29.41, 29.27, 29.16, 28.97, 28.52, 26.88, 26.49, 23.66, 17.42.

[0120] Example 45: 2-((3R,5R,7R)-adamantan-1-yl)-N-(12-(4-(4-((8-(3-(azetidin-3-ylamino)phenyl)-5-methyl-7-oxy-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)dodecyl)acetamide (ZX-HYT-45) JPEG0007756374000091.jpg42170 See Example 17 for the synthesis of compound ZX-HYT-45. HRMS (ESI) for C 52 H 73 NO3[M+H] + Calculated: 872.5915; Found: 872.5926. HPLC analysis: MeOH-HO (95:5), RT = 4.763 min, 98.21% purity. 1 H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.01 (s, 1H), 7.61 (s, 1H), 7.43‐7.32 (m, 1H), 7.23 (s, 1H), 6.67‐6.57 (m, 1H), 6.53 (s, 1H), 6.46-6.22 (m, 4H), 6.03 (s, 1H), 4.18 (s, 1H), 3.94-3.64 (m, 7H), 3.06-2.96 (m, 6H), 2.48-2.35 (m, 7H), 2.29 (s, 2H), 1.89 (s, 3H), 1.79 (s, 2H), 1.67-1.61 (m, 3H), 1.59-1.50 (m, 9H), 1.47-1.41 (m, 2H), 1.38-1.34 (m, 2H), 1.29-1.17 (m, 16H). 13C NMR (101 MHz, DMSO) δ 170.11, 162.61, 156.82, 148.94, 147.00, 138.05, 130.10, 120.51, 117.14, 113.44, 111.57, 106.87, 106.55, 100.11, 58.40, 56.16, 54.58, 54.44, 53.29, 50.59, 49.35, 47.79, 42.62, 38.65, 36.95, 32.60, 29.64, 29.51, 29.42, 29.18, 28.54, 27.48, 26.88, 26.80, 17.41.

[0121] Example 46: N-((1S,4S)-4-(2-((4-(4-(12-(2-((3R,5R,7R)-adamantan-1-yl)acetylamino)dodecyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)cyclohexyl)cyclopropanecarboxamide (ZX-HYT-46) JPEG0007756374000092.jpg45170 See Example 20 for the synthesis of compound ZX-HYT-46. HRMS (ESI) for C 53 H 78 N8O4[M+H] + : Calculated value, 891.6219; Measured value, 891.6223. 1H NMR (500 MHz, Chloroform-d) δ 9.07 (s, 1H), 8.51 (s, 1H), 7.48 (t, J = 5.9 Hz, 1H), 7.07 (d, J = 7.5 Hz, 1H), 6.91 (d, J = 11.5 Hz, 1H), 6.76 (dd, J = 7.5, 1.5 Hz, 1H), 6.45 (q, J = 1.1 Hz, 1H), 6.31 (d, J = 1.6 Hz, 1H), 4.11 (p, J = 7.0 Hz, 1H), 3.86 (s, 3H), 3.59 (dp, J = 11.4, 7.0 Hz, 1H), 3.27 (t, J = 7.1 Hz, 4H), 3.07 (td, J = 7.1, 5.9 Hz, 2H), 2.63 (t, J = 7.1 Hz, 4H), 2.50-2.41 (m, 4H), 2.38 (t, J = 7.1 Hz, 2H), 2.28 (s, 2H), 2.10 (s, 3H), 1.78‐1.70 (m, 2H), 1.70‐1.54 (m, 15H), 1.54‐1.48 (m, 5H), 1.41‐1.38 (m, 4H), 1.34‐1.18 (m, 14H), 1.00‐0.86 (m, 4H).

[0122] Example 47: N-(3-(2-((4-(4-(8-(2-((3R,5R,7R)-adamantan-1-yl)acetylamino)octyl)piperazin-1-yl)-2-methoxyphenyl))amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX-HYT-47) JPEG0007756374000093.jpg46170 See Example 8 for the synthesis of compound ZX-HYT-47. HRMS (ESI) for C 49 H 64 N8O4[M+H] + : Calculated value, 829.5123; Measured value, 829.5135. 1H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.80 (s, 1H), 8.11 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.62 (t, J = 5.7 Hz, 1H), 7.55‐7.41 (m, 2H), 7.28 (d, J = 8.9 Hz, 1H), 6.99-6.88 (m, 1H), 6.53 (d, J = 2.5 Hz, 1H), 6.32 (d, J = 1.4 Hz, 1H), 6.02 (s, 1H), 3.79 (s, 3H), 3.12-2.94 (m, 6H), 2.49-2.41 (m, 4H), 2.32 (q, J = 13.4, 7.5 Hz, 2H), 1.94-1.87 (m, 3H), 1.80 (s, 3H), 1.69-1.62 (m, 4H), 1.61-1.52 (m, 9H), 1.52-1.44 (m, 2H), 1.42-1.33 (m, 2H), 1.32-1.15 (m, 10H), 0.88-0.75 (m, 4H).

[0123] Example 48: N-(3-(2-((4-(4-(8-(2-((3R,5R,7R)-adamantan-1-yl)acetylamino)octyl)piperazin-1-yl)-2-methoxyphenyl))amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)pivalamide (ZX-HYT-48) JPEG0007756374000094.jpg49170 See Example 8 for the synthesis of compound ZX-HYT-48. HRMS (ESI) for C 50 H 68 N8O4[M+H] + : Calculated value, 845.5436; Measured value, 845.5441. 1H NMR (400 MHz, DMSO-d6) δ 9.38 (s, 1H), 8.80 (s, 1H), 8.11 (s, 1H), 7.91 (d, J = 8.2 Hz, 1H), 7.64 (t, J = 5.6 Hz, 1H), 7.55 (t, J = 2.1 Hz, 1H), 7.46 (t, J = 8.1 Hz, 1H), 7.28 (d, J = 8.9 Hz, 1H), 6.93 (dd, J = 7.7, 2.0 Hz, 1H), 6.52 (d, J = 2.5 Hz, 1H), 6.32 (s, 1H), 6.03 (s, 1H), 3.78 (s, 3H), 3.15-3.04 (m, 4H), 3.01 (q, J = 6.5 Hz, 2H), 2.71-2.52 (m, 4H), 2.48-2.38 (m, 5H), 1.90 (s, 3H), 1.80 (s, 2H), 1.68-1.62 (m, 3H), 1.58-1.53 ​​(m, 9H), 1.51-1.43 (m, 2H), 1.41-1.35 (m, 2H), 1.30-1.25 (m, 8H), 1.21 (s, 9H).

[0124] Example 49: N-(3-(2-((4-(4-(8-(2-((3R,5R,7R)-adamantan-1-yl)acetylamino)octyl)piperazin-1-yl)-2-methoxyphenyl))amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)propionamide (ZX-HYT-49) JPEG0007756374000095.jpg44170 See Example 8 for the synthesis of compound ZX-HYT-49. HRMS (ESI) for C 48 H 64 N8O4[M+H] + : Calculated value, 817.5123; Measured value, 817.5134. 1H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.80 (s, 1H), 8.10 (s, 1H), 7.82-7.75 (m, 1H), 7.63 (t, J = 5.7 Hz, 1H), 7.51-7.43 (m, 2H), 7.26 (d, J = 8.9 Hz, 1H), 6.96-6.89 (m, 1H), 6.53 (d, J = 2.6 Hz, 1H), 6.35-6.29 (m, 1H), 6.01 (s, 1H), 3.78 (s, 3H), 3.10-2.96 (m, 6H), 2.49‐2.41 (m, 7H), 2.36-2.25 (m, 4H), 1.91 (s, 3H), 1.80 (s, 2H), 1.70-1.62 (m, 3H), 1.60-1.52 (m, 9H), 1.49-1.43 (m, 2H), 1.40-1.35 (m, 2H), 1.31-1.23 (m, 8H), 1.07 (t, J = 7.5 Hz, 3H).

[0125] Example 50: N-(3-(2-((4-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX-HYT-50) JPEG0007756374000096.jpg57170 See Example 8 for the synthesis of compound ZX-HYT-50. HRMS (ESI) for C 41 H 47 N7O4[M+H] + : Calculated value, 702.3702; Measured value, 702.3713. 1H NMR (600 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.81 (s, 1H), 8.14 (s, 1H), 7.80 (s, 1H), 7.54-7.41 (m, 2H), 7.29 (d, J = 8.8 Hz, 1H), 6.98-6.87 (m, 1H), 6.66-6.50 (m, 1H), 6.33 (s, 1H), 6.03 (s, 1H), 3.80 (s, 3H), 3.70-3.57 (m, 4H), 3.09-2.94 (m, 4H), 2.46 (s, 3H), 2.16 (s, 2H), 1.94 (s, 3H), 1.78 (p, J = 6.3 Hz, 1H), 1.69‐1.60 (m, 12H), 0.82‐0.73 (m, 4H).

[0126] Example 51: N-(3-(2-((4-(4-(2-(2-((3R,5R,7R)-adamantan-1-yl)acetylamino)ethyl)piperazin-1-yl)-2-methoxyphenyl))amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX-HYT-51) JPEG0007756374000097.jpg49170 See Example 8 for the synthesis of compound ZX-HYT-51. HRMS (ESI) for C 43 H 52 N8O4[M+H] + : Calculated value, 745.4184; Measured value, 745.4191. 1H NMR (600 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.80 (s, 1H), 8.11 (s, 1H), 7.79 (s, 1H), 7.61 (t, J = 5.7 Hz, 1H), 7.54‐7.42 (m, 2H), 7.28 (d, J = 8.9 Hz, 1H), 6.93 (dt, J = 8.1, 1.6 Hz, 1H), 6.53 (d, J = 2.5 Hz, 1H), 6.32 (s, 1H), 6.00 (s, 1H), 3.79 (s, 3H), 3.20 (q, J = 6.4 Hz, 2H), 3.09-2.98 (m, 4H), 2.57‐2.52 (m, 4H), 2.46 (s, 3H), 2.40 (t, J = 6.6 Hz, 2H), 1.91 (s, 3H), 1.86‐1.82 (m, 2H), 1.78 (tt, J = 7.3, 3.7 Hz, 1H), 1.69-1.64 (m, 3H), 1.60-1.56 (m, 9H), 0.80-0.74 (m, 4H).

[0127] Example 52: N-(3-(2-((4-(4-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetylamino)butyl)piperazin-1-yl)-2-methoxyphenyl))amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX-HYT-52) JPEG0007756374000098.jpg52170 See Example 8 for the synthesis of compound ZX-HYT-52. HRMS (ESI) for C 45 H 56 N8O4[M+H] + : Calculated value, 773.4497; Measured value, 773.4485. 1H NMR (600 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.81 (s, 1H), 8.14 (s, 1H), 7.81 (s, 1H), 7.71 (s, 1H), 7.50‐7.43 (m, 2H), 7.29 (d, J = 8.8 Hz, 1H), 6.95-6.91 (m, 1H), 6.56 (s, 1H), 6.33 (s, 1H), 6.02 (s, 1H), 3.79 (s, 3H), 3.18-2.86 (m, 8H), 2.64-2.51 (m, 6H), 2.46 (s, 3H), 1.95-1.90 (m, 3H), 1.83 (s, 2H), 1.80-1.76 (m, 1H), 1.69-1.63 (m, 3H), 1.61-1.52 (m, 9H), 1.46-1.40 (m, 2H), 0.83-0.75 (m, 4H).

[0128] Example 53: N-(3-(2-((4-(4-(6-(2-((3R,5R,7R)-adamantan-1-yl)acetylamino)hexyl)piperazin-1-yl)-2-methoxyphenyl))amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX-HYT-53) JPEG0007756374000099.jpg52170 See Example 8 for the synthesis of compound ZX-HYT-53. HRMS (ESI) for C 47 H 60 N8O4[M+H] + : Calculated value, 801.4810; Measured value, 801.4823. 1H NMR (600 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.81 (s, 1H), 8.17 (s, 1H), 7.91 (s, 1H), 7.76 (s, 1H), 7.50‐7.45 (m, 2H), 7.19 (d, J = 8.8 Hz, 1H), 6.95-6.93 (m, 1H), 6.57 (s, 1H), 6.34 (s, 1H), 6.12 (s, 1H), 3.79 (s, 3H), 3.18-2.86 (m, 8H), 2.64-2.51 (m, 8H), 2.46 (s, 3H), 1.95-1.90 (m, 3H), 1.83 (s, 2H), 1.80-1.76 (m, 1H), 1.69-1.63 (m, 3H), 1.61-1.52 (m, 9H), 1.48-1.37 (m, 4H), 0.83-0.75 (m, 4H).

[0129] Example 54: N-(3-(2-((4-(4-(10-(2-((3R,5R,7R)-adamantan-1-yl)acetylamino)decyl)piperazin-1-yl)-2-methoxyphenyl))amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX-HYT-54) JPEG0007756374000100.jpg48170 See Example 8 for the synthesis of compound ZX-HYT-54. HRMS (ESI) for C 51 H 68 N8O4[M+H] + : Calculated value, 857.5436; Measured value, 857.5441. 1H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.80 (s, 1H), 8.11 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.62 (t, J = 5.7 Hz, 1H), 7.57‐7.41 (m, 2H), 7.28 (d, J = 8.9 Hz, 1H), 6.99-6.88 (m, 1H), 6.53 (d, J = 2.5 Hz, 1H), 6.32 (d, J = 1.4 Hz, 1H), 6.02 (s, 1H), 3.79 (s, 3H), 3.12-2.94 (m, 6H), 2.49-2.41 (m, 4H), 2.32 (q, J = 13.4, 7.5 Hz, 2H), 1.94-1.87 (m, 3H), 1.80 (s, 2H), 1.69-1.62 (m, 3H), 1.61-1.52 (m, 9H), 1.52-1.44 (m, 2H), 1.42-1.33 (m, 2H), 1.31-1.11 (m, 14H), 0.88-0.75 (m, 6H).

[0130] Example 55: N-(3-(2-((4-(4-(14-(2-((3R,5R,7R)-adamantan-1-yl)acetylamino)tetradecyl)piperazin-1-yl)-2-methoxyphenyl))amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX-HYT-55) JPEG0007756374000101.jpg46170 See Example 8 for the synthesis of compound ZX-HYT-55. HRMS (ESI) for C 55 H 76 N8O4[M+H] + : Calculated value, 913.6062; Measured value, 913.6062. 1H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.80 (s, 1H), 8.11 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.62 (t, J = 5.7 Hz, 1H), 7.55‐7.41 (m, 2H), 7.28 (d, J = 8.9 Hz, 1H), 6.99-6.88 (m, 1H), 6.53 (d, J = 2.5 Hz, 1H), 6.32 (d, J = 1.4 Hz, 1H), 6.02 (s, 1H), 3.79 (s, 3H), 3.12-2.94 (m, 6H), 2.49-2.41 (m, 4H), 2.32 (q, J = 13.4, 7.5 Hz, 2H), 1.94-1.87 (m, 3H), 1.80 (s, 2H), 1.69-1.62 (m, 3H), 1.61-1.52 (m, 9H), 1.52-1.44 (m, 2H), 1.42-1.33 (m, 2H), 1.32-1.12 (m, 22H), 0.88-0.75 (m, 6H).

[0131] Example 56: N-(3-(2-((4-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (ZX-HYT-56) JPEG0007756374000102.jpg57170 See Example 8 for the synthesis of compound ZX-HYT-56. HRMS (ESI) for C 40 H 45 N7O4[M+H] + : Calculated value, 688.3606; Measured value, 688.3673. 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.80 (s, 1H), 8.11 (s, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.62 (t, J = 5.6 Hz, 1H), 7.56 (t, J = 2.0 Hz, 1H), 7.51 (t, J = 8.1 Hz, 1H), 7.27 (d, J = 8.9 Hz, 1H), 6.98 (ddd, J = 7.8, 2.0, 1.0 Hz, 1H), 6.51 (d, J = 2.5 Hz, 1H), 6.48‐6.39 (m, 1H), 6.36-6.21 (m, 2H), 6.00 (s, 1H), 5.76 (dd, J = 10.1, 2.1 Hz, 1H), 3.78 (s, 3H), 3.06‐2.93 (m, 4H), 2.49‐2.40 (m, 4H), 2.41 (s, 3H), 2.30 - 2.12 (m, 2H), 1.79-1.61 (m, 3H), 1.42-1.20 (m, 12H).

[0132] Example 57: N-(3-(2-((4-(4-(2-(2-((3R,5R,7R)-adamantan-1-yl)acetylamino)ethyl)piperazin-1-yl)-2-methoxyphenyl))amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (ZX-HYT-57) JPEG0007756374000103.jpg55170 See Example 8 for the synthesis of compound ZX-HYT-57. HRMS (ESI) for C 42 H 50 N8O4[M+H] + : Calculated value, 731.4028; Measured value, 731.4031. 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.80 (s, 1H), 8.11 (s, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.62 (t, J = 5.6 Hz, 1H), 7.56 (t, J = 2.0 Hz, 1H), 7.51 (t, J = 8.1 Hz, 1H), 7.27 (d, J = 8.9 Hz, 1H), 6.98 (ddd, J = 7.8, 2.0, 1.0 Hz, 1H), 6.51 (d, J = 2.5 Hz, 1H), 6.48‐6.39 (m, 1H), 6.36-6.21 (m, 2H), 6.00 (s, 1H), 5.76 (dd, J = 10.1, 2.1 Hz, 1H), 3.78 (s, 3H), 3.06‐2.93 (m, 4H), 2.49‐2.40 (m, 4H), 2.41 (s, 3H), 2.30 - 2.12 (m, 4H), 1.69-1.61 (m, 3H), 1.60-1.53 ​​(m, 4H), 1.32-1.20 (m, 10H).

[0133] Example 58: N-(3-(2-((4-(4-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetylamino)butyl)piperazin-1-yl)-2-methoxyphenyl))amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (ZX-HYT-58) JPEG0007756374000104.jpg54170 See Example 8 for the synthesis of compound ZX-HYT-58. HRMS (ESI) for C 44 H 54 N8O4[M+H] + : Calculated value, 759.4341; Measured value, 759.4356. 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.80 (s, 1H), 8.11 (s, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.62 (t, J = 5.6 Hz, 1H), 7.56 (t, J = 2.0 Hz, 1H), 7.51 (t, J = 8.1 Hz, 1H), 7.27 (d, J = 8.9 Hz, 1H), 6.98 (ddd, J = 7.8, 2.0, 1.0 Hz, 1H), 6.51 (d, J = 2.5 Hz, 1H), 6.48‐6.39 (m, 1H), 6.36-6.21 (m, 2H), 6.00 (s, 1H), 5.76 (dd, J = 10.1, 2.1 Hz, 1H), 3.78 (s, 3H), 3.06‐2.93 (m, 6H), 2.49‐2.40 (m, 7H), 2.30 (t, J = 7.4 Hz, 2H), 1.90 (s, 3H), 1.69-1.61 (m, 3H), 1.60-1.53 ​​(m, 3H), 1.50-1.41 (m, 2H), 1.32-1.20 (m, 10H).

[0134] Example 59: N-(3-(2-((4-(4-(8-(2-((1S,3R,5S,7R)-3,5-dimethyladamantan-1-yl)acetylamino)octyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX-HYT-59) JPEG0007756374000105.jpg52170 See Example 32 for the synthesis of compound ZX-HYT-59. HRMS (ESI) for C 51 H 68 N8O4[M+H] + Calculated: 857.5442; Found: 857.5436. HPLC analysis: MeOH-HO (85:15), RT = 13.264 min, 96.02% purity. 1H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.79 (s, 1H), 8.14 (s, 1H), 7.81 (d, J = 7.9 Hz, 1H), 7.66 (t, J = 5.7 Hz, 1H), 7.50‐7.43 (m, 2H), 7.29 (d, J = 8.8 Hz, 1H), 6.92 (dd, J = 7.9, 2.0 Hz, 1H), 6.55 (d, J = 2.5 Hz, 1H), 6.32 (s, 1H), 6.04 (s, 1H), 3.78 (s, 3H), 3.12 (q, J = 7.4 Hz, 4H), 3.01 (q, J = 6.4 Hz, 2H), 2.82 (s, 2H), 2.52‐2.37 (m, 7H), 2.02‐1.95 (m, 1H), 1.83 (s, 1H), 1.77 (p, J = 6.2 Hz, 1H), 1.54 (s, 1H), 1.41‐1.34 (m, 3H), 1.28‐1.26 (m, 7H), 1.25‐1.23 (m, 8H), 1.20‐1.16 (m, 3H), 1.13‐1.07 (m, 2H), 1.03‐0.98 (m, 1H), 0.86‐0.62 (m, 10H). 13 C NMR (101 MHz, DMSO) δ 172.23, 170.21, 162.60, 157.03, 156.74, 147.36, 140.72, 137.48, 129.84, 123.89, 119.74, 118.84, 117.04, 106.89, 106.63, 100.37, 56.22, 54.03, 52.51, 51.10, 49.88, 48.94, 43.18, 42.29, 41.21, 38.62, 34.20, 31.32, 31.01, 29.63, 29.58, 29.32, 29.13, 27.05, 26.87, 18.53, 17.46, 17.23, 15.05, 12.99, 7.73, 7.63.

[0135] Example 60: (1S,2R,4S)—N-(8-(4-(4-((8-(3-(cyclopropanecarboxamido)phenyl)phenyl)-5-methyl-7-oxo-7,8-dihydropyridyl[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)octyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide (ZX-HYT-60) JPEG0007756374000106.jpg53170 See Example 32 for the synthesis of compound ZX-HYT-60. HRMS (ESI) for C 45 H 56 N8O4[M+H] + Calculated: 773.4503; Found: 773.4497. HPLC analysis: MeOH-HO (97:3), RT = 4.703 min, 98.47% purity. 1 H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 9.87 (s, 1H), 9.27 (s, 1H), 8.81 (s, 1H), 8.17 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.56 (t, J = 5.7 Hz, 1H), 7.48-7.44 (m, 1H), 7.32 (d, J = 8.8 Hz, 1H), 6.93 (d, J = 7.8 Hz, 1H), 6.61 (s, 1H), 6.33 (s, 1H), 6.10 (dd, J = 5.7, 3.0 Hz, 1H), 5.82-5.76 (m, 1H), 3.80 (s, 3H), 3.76-3.70 (m, 1H), 3.60-3.55 (m, 1H), 3.14-3.08 (m, 8H), 3.04-3.00 (m, 1H), 2.98-2.92 (m, 2H), 2.82-2.74 (m, 2H), 2.45 (s, 3H), 1.79 (t, J = 6.1 Hz, 1H), 1.73-1.67 (m, 2H), 1.38-1.35 (m, 1H), 1.32-1.29 (m, 3H), 1.27-1.24 (m, 3H), 1.20-1.16 (m, 7H), 0.83-0.74 (m, 4H).13 C NMR (101 MHz, DMSO) δ 173.07, 172.27, 162.57, 157.06, 156.73, 147.34, 140.71, 137.48, 137.28, 132.58, 129.81, 123.93, 119.82, 118.92, 117.12, 107.10, 106.70, 100.79, 56.30, 51.27, 49.85, 46.67, 46.15, 46.11, 43.77, 42.56, 38.91, 29.68, 28.93, 28.84, 26.73, 26.46, 17.47, 15.03, 9.04, 7.65.

[0136] Example 61: (1R,2R,4S)—N-(8-(4-(4-((8-(3-(cyclopropanecarboxamido)phenyl)phenyl)-5-methyl-7-oxo-7,8-dihydropyridyl[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)octyl)bicyclo[2.2.1]heptane-2-carboxamide (ZX-HYT-61) JPEG0007756374000107.jpg53170 See Example 32 for the synthesis of compound ZX-HYT-61. HRMS (ESI) for C 45 H 58 N8O4[M+H] + Calculated: 775.4659; Found: 775.4654. HPLC analysis: MeOH-H2O (95:5), 4.929 min, 96.20% purity. 1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.78 (s, 1H), 8.08 (s, 1H), 7.81 (d, J = 7.9 Hz, 1H), 7.70‐7.58 (m, 1H), 7.53‐7.42 (m, 2H), 7.27 (d, J = 8.9 Hz, 1H), 6.91 (d, J = 7.9 Hz, 1H), 6.52 (s, 1H), 6.30 (s, 1H), 6.02 (s, 1H), 3.78 (s, 3H), 3.11‐2.93 (m, 7H), 2.59‐2.53 (m, 1H), 2.49‐2.45 (m, 4H), 2.44‐2.40 (m, 4H), 2.29 (t, J = 7.4 Hz, 2H), 2.22‐2.09 (m, 2H), 1.85‐1.68 (m, 2H), 1.60‐1.53 (m, 1H), 1.49‐1.42 (m, 4H), 1.40‐1.35 (m, 3H), 1.29‐1.24 (m, 9H), 0.82‐0.75 (m, 4H). 13 C NMR (101 MHz, DMSO) δ 175.06, 173.17, 172.21, 162.60, 156.97, 156.73, 147.32, 140.79, 137.47, 130.11, 129.85, 123.82, 120.28, 119.68, 118.75, 116.98, 106.72, 106.56, 100.04, 58.37, 56.14, 53.27, 49.27, 46.87, 46.33, 41.94, 41.04, 38.98, 38.95, 37.06, 36.29, 35.86, 33.79, 31.13, 29.81, 29.73, 29.65, 29.44, 29.31, 29.21, 28.86, 27.39, 27.03, 26.82, 26.78, 24.32, 17.45, 15.04, 7.71, 7.63.

[0137] Example 62: N-(3-(2-((4-(4-(8-(cyclopropanecarboxamido)octyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d)]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX-HYT-62) JPEG0007756374000108.jpg50170 See Example 32 for the synthesis of compound ZX-HYT-62. HRMS (ESI) for C 41 H 52 N8O4[M+H] + : Calculated value, 721.4184; Measured value, 721.4192. 1 H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.80 (s, 1H), 8.11 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.62 (t, J = 5.7 Hz, 1H), 7.55‐7.41 (m, 2H), 7.28 (d, J = 8.9 Hz, 1H), 6.99-6.88 (m, 1H), 6.53 (d, J = 2.5 Hz, 1H), 6.32 (d, J = 1.4 Hz, 1H), 6.02 (s, 1H), 3.79 (s, 3H), 3.12-2.94 (m, 6H), 2.49-2.41 (m, 4H), 2.33 (s, 3H), 1.94-1.87 (m, 3H), 1.69-1.62 (m, 2H), 1.61-1.52 (m, 9H), 1.52-1.44 (m, 2H), 0.88-0.75 (m, 8H).

[0138] Example 63: N-(8-(4-(4-((8-(3-(cyclopropanecarboxamido)phenyl)-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)) amino)-3-methoxyphenyl)piperazin-1-yl)octyl)cyclohexanecarboxamide (ZX-HYT-63) JPEG0007756374000109.jpg52170 See Example 32 for the synthesis of compound ZX-HYT-63. HRMS (ESI) for C 44 H 58 N8O4[M+H] + : Calculated value, 763.4654; Measured value, 763.4661. 1 H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.80 (s, 1H), 8.11 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.62 (t, J = 5.7 Hz, 1H), 7.55‐7.41 (m, 2H), 7.28 (d, J = 8.9 Hz, 1H), 6.99-6.88 (m, 1H), 6.53 (d, J = 2.5 Hz, 1H), 6.32 (d, J = 1.4 Hz, 1H), 6.02 (s, 1H), 3.79 (s, 3H), 3.12-2.94 (m, 6H), 2.49-2.41 (m, 4H), 2.33 (s, 3H), 1.94-1.87 (m, 3H), 1.69-1.62 (m, 2H), 1.61-1.52 (m, 11H), 1.52-1.44 (m, 4H), 0.88-0.75 (m, 10H).

[0139] Example 64: N-((3S,5S,7S)-adamantan-1-yl)-4-(4-((8-(3-(cyclopropanecarboxamido)phenyl)-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxamide (ZX-HYT-64) Compound 29 (0.13 mg, 0.25 mmol), 1-isocyanoadamantane (44 mg, 0.25 mmol), and triethylamine (38 mg, 0.38 mmol) were added to anhydrous ethanol (5 mL) and stirred at 25 °C for 1 hour. After completion of the reaction was confirmed by TLC, the reaction mixture was evaporated to dryness. The resulting residue was purified by column chromatography (eluted with chloroform / methanol = 40:1) to obtain the target compound ZX-HYT-64 (0.17 g, 97% yield) as a yellow powder. HRMS (ESI) for C 40 H 46 N8O4[M+H] + : Calculated value, 703.3715; Measured value, 703.3721. 1 H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.80 (s, 1H), 8.11 (s, 1H), 7.87‐7.76 (m, 1H), 7.52‐7.42 (m, 2H), 7.28 (d, J = 8.9 Hz, 1H), 6.98-6.85 (m, 1H), 6.61-6.52 (m, 1H), 6.32 (s, 1H), 6.04 (s, 1H), 5.77 (s, 1H), 3.80 (s, 3H), 3.45-3.36 (m, 4H), 3.02-2.93 (m, 4H), 2.46 (s, 3H), 2.05-1.98 (m, 3H), 1.98-1.91 (m, 6H), 1.82-1.74 (m, 1H), 1.67-1.57 (m, 6H), 0.82-0.75 (m, 4H).

[0140] Example 65: N-(3-(2-((4-(4-((3R,5R,7R)-adamantane-1-carbonyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX-HYT-65) JPEG0007756374000111.jpg57170 See Example 32 for the synthesis of compound ZX-HYT-65. HRMS (ESI) for C 40 H 45 N7O4[M+H] + Calculated value: 688.3606; Measured value: 688.3611. HRMS (ESI) for C 40 H 46 N8O4[M+H] + : Calculated value, 703.3715; Measured value, 703.3723. 1 H NMR (600 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.81 (s, 1H), 8.13 (s, 1H), 7.81 (s, 1H), 7.53-7.43 (m, 2H), 7.29 (d, J = 8.8 Hz, 1H), 6.98-6.89 (m, 1H), 6.62-6.52 (m, 1H), 6.33 (s, 1H), 6.03 (s, 1H), 3.80 (s, 3H), 3.77-3.69 (m, 4H), 3.08-2.96 (m, 4H), 2.46 (s, 3H), 2.01 (s, 3H), 1.98‐1.90 (m, 6H), 1.78 (p, J = 6.2, 5.4 Hz, 1H), 1.76‐1.67 (m, 6H), 0.84‐0.75 (m, 4H).

[0141] Example 66: 2-((4-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-8-(3-(4-methyl-2-oxopiperazin-1-yl)phenyl)pyrido[2,3-d]pyrimidin-7(8H)-one (ZX-HYT-66) JPEG0007756374000112.jpg57170 See Example 18 for the synthesis of compound ZX-HYT-66. MS (ESI), m / z: 731.6 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 9.07 (s, 1H), 8.48 (s, 1H), 7.87 (t, J = 1.5 Hz, 1H), 7.53 (d, J = 7.5 Hz, 1H), 7.26 (t, J = 7.5 Hz, 1H), 7.09 (dd, J = 24.7, 7.5 Hz, 2H), 6.74 (dd, J = 7.5, 1.5 Hz, 1H), 6.58 (q, J = 0.9 Hz, 1H), 6.30 (d, J = 1.5 Hz, 1H), 3.94‐3.85 (m, 5H), 3.68 (t, J = 7.0 Hz, 4H), 3.51 (s, 2H), 3.32 (t, J = 7.1 Hz, 4H), 2.69 (t, J = 7.1 Hz, 2H), 2.47 (d, J = 1.1 Hz, 3H), 2.39 (s, 3H), 2.34 (s, 2H), 2.00 (p, J = 7.0 Hz, 3H), 1.69-1.58 (m, 12H).

[0142] Example 67: N-(3-(2-((6-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)piperazin-1-yl)-2-methoxypyridin-3-yl))amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX-HYT-67) JPEG0007756374000113.jpg57170 See Example 32 for the synthesis of compound ZX-HYT-67. HRMS (ESI) for C 40 H 46 N8O4[M+H] + : Calculated value, 703.3715; Measured value, 703.3723. 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.79 (s, 1H), 8.34 (s, 1H), 7.77‐7.66 (m, 1H), 7.50‐7.40 (m, 3H), 6.90 (d, J = 7.8 Hz, 1H), 6.30 (s, 1H), 5.86 (s, 1H), 3.80 (s, 3H), 3.66‐3.53 (m, 4H), 3.42‐3.36 (m, 4H), 2.45 (s, 3H), 2.16 (s, 2H), 1.97‐1.89 (m, 3H), 1.82-1.73 (m, 1H), 1.70-1.57 (m, 12H), 0.83-0.70 (m, 4H).

[0143] Example 68: N-((3S,5S,7S)-adamantan-1-yl)-4-(5-((8-(3-(cyclopropanecarboxamido)phenyl)-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-6-methoxypyridin-2-yl)piperazine-1-carboxamide (ZX-HYT-68) JPEG0007756374000114.jpg58170 See Example 65 for the synthesis of compound ZX-HYT-68. HRMS (ESI) for C 39 H 45 NO4[M+H] + : Calculated value, 704.3667; Measured value, 704.3653. 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.79 (s, 1H), 8.32 (s, 1H), 7.78‐7.70 (m, 1H), 7.50‐7.40 (m, 3H), 6.90 (d, J = 7.8 Hz, 1H), 6.30 (s, 1H), 5.83 (s, 1H), 5.76 (s, 1H), 3.80 (s, 3H), 3.45‐3.35 (m, 8H), 2.45 (s, 3H), 2.05‐1.98 (m, 3H), 1.98‐1.90 (m, 6H), 1.82-1.74 (m, 1H), 1.68-1.56 (m, 6H), 0.83-0.73 (m, 4H).

[0144] Example 69: N-(3-(2-((6-(4-((3R,5R,7R)-adamantane-1-carbonyl)piperazin-1-yl)-2-methoxypyridin-3-yl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX-HYT-69) JPEG0007756374000115.jpg53170 See Example 32 for the synthesis of compound ZX-HYT-69. HRMS (ESI) for C 39 H 44 N8O4[M+H] + : Calculated value, 689.3558; Measured value, 689.3562. 1 H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.79 (s, 1H), 8.33 (s, 1H), 7.81‐7.66 (m, 1H), 7.50‐7.40 (m, 3H), 6.91 (d, J = 7.8 Hz, 1H), 6.31 (s, 1H), 5.86 (s, 1H), 3.81 (s, 3H), 3.75-3.65 (m, 4H), 3.33-3.33 (m, 4H), 2.45 (s, 3H), 2.05-1.98 (m, 3H), 1.98-1.91 (m, 6H), 1.81-1.63 (m, 7H), 0.84‐0.71 (m, 4H).

[0145] Example 70: N-(3-(2-((6-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)piperazin-1-yl)-4-methoxypyridin-3-yl))amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX-HYT-70) JPEG0007756374000116.jpg57170 See Example 32 for the synthesis of compound ZX-HYT-70. HRMS (ESI) for C 40 H 46 N8O4[M+H] + : Calculated value, 703.3715; Measured value, 703.3723. 1 H NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.72 (s, 1H), 8.52 (s, 1H), 7.83 (s, 1H), 7.66‐7.56 (m, 1H), 7.46 (s, 1H), 7.36 (s, 1H), 6.91-6.74 (m, 1H), 6.40-6.20 (m, 2H), 3.73 (s, 3H), 3.64-3.55 (m, 4H), 3.51-3.39 (m, 4H), 2.42 (s, 3H), 2.21-2.12 (m, 2H), 1.93 (s, 3H), 1.81-1.73 (m, 1H), 1.72-1.54 (m, 12H), 0.83-0.72 (m, 4H).

[0146] Example 71: N-((3S,5S,7S)-adamantan-1-yl)-4-(5-((8-(3-(cyclopropanecarboxamido)phenyl)-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-4-methoxypyridin-2-yl)piperazine-1-carboxamide (ZX-HYT-71) JPEG0007756374000117.jpg58170 See Example 65 for the synthesis of compound ZX-HYT-71. HRMS (ESI) for C39 H 45 NO4[M+H] + : Calculated value, 704.3667; Measured value, 704.3653. 1 H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 8.72 (s, 1H), 8.50 (s, 1H), 7.82 (s, 1H), 7.63‐7.55 (m, 1H), 7.47 (s, 1H), 7.37 (s, 1H), 6.85 (s, 1H), 6.30 (s, 1H), 6.27 (s, 1H), 5.74 (s, 1H), 3.73 (s, 3H), 3.45-3.35 (m, 8H), 2.42 (s, 3H), 2.06-1.99 (m, 3H), 1.99-1.93 (m, 6H), 1.82-1.74 (m, 1H), 1.65-1.58 (m, 6H), 0.84-0.74 (m, 4H).

[0147] Example 72: N-(3-(2-((6-(4-((3R,5R,7R)-adamantane-1-carbonyl)piperazin-1-yl)-4-methoxypyridin-3-yl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX-HYT-72) JPEG0007756374000118.jpg53170 See Example 32 for the synthesis of compound ZX-HYT-72. HRMS (ESI) for C 39 H 44 N8O4[M+H] + : Calculated value, 689.3558; Measured value, 689.3562. 1H NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.72 (s, 1H), 8.52 (s, 1H), 7.84 (s, 1H), 7.66‐7.54 (m, 1H), 7.46 (s, 1H), 7.37 (s, 1H), 6.84 (s, 1H), 6.34-6.24 (m, 2H), 3.78-3.65 (m, 7H), 3.49-3.39 (m, 4H), 2.42 (s, 3H), 2.05-1.88 (m, 9H), 1.80-1.63 (m, 7H), 0.82-0.73 (m, 4H).

[0148] Example 73: N-(3-(2-((4-((2-(2-((3R,5R,7R)-adamantan-1-yl)-N-methylacetylamino)ethyl)(methyl)amino)-2-methoxyphenyl))amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX-HYT-73) JPEG0007756374000119.jpg57170 See Example 32 for the synthesis of compound ZX-HYT-73. HRMS (ESI) for C 41 H 49 N7O4[M+H] + : Calculated value, 704.3919; Measured value, 704.3923. 1 H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.79 (s, 1H), 8.34 (s, 1H), 7.77‐7.66 (m, 1H), 7.50‐7.40 (m, 3H), 6.90 (d, J = 7.8 Hz, 1H), 6.30 (s, 1H), 5.86 (s, 1H), 3.80 (s, 3H), 3.67 (s, 3H), 3.42‐3.36 (m, 4H), 3.16 (s, 3H), 2.45 (s, 3H), 2.16 (s, 2H), 1.97-1.89 (m, 3H), 1.82-1.72 (m, 1H), 1.71-1.58 (m, 12H), 0.85-0.73 (m, 4H).

[0149] Example 74: 2-((4-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-8-(3-((4-methylpiperazin-1-yl)methyl)phenyl)pyrido[2,3-d]pyrimidin-7(8H)-one (ZX-HYT-74) JPEG0007756374000120.jpg58170 See Example 18 for the synthesis of compound ZX-HYT-74. MS (ESI), m / z: 730.9 [M+H] + . 1 H NMR (500 MHz, Chloroform-d) δ 9.07 (s, 1H), 8.49 (s, 1H), 7.81 (p, J = 1.3 Hz, 1H), 7.42 (dt, J = 7.5, 1.5 Hz, 1H), 7.34 (t, J = 7.5 Hz, 1H), 7.13 (dddd, J = 7.5, 2.6, 1.7, 1.1 Hz, 1H), 7.07 (d, J = 7.5 Hz, 1H), 6.74 (dd, J = 7.5, 1.5 Hz, 1H), 6.58 (q, J = 0.9 Hz, 1H), 6.30 (d, J = 1.5 Hz, 1H), 3.87 (s, 3H), 3.68 (t, J = 7.0 Hz, 4H), 3.54 (t, J = 1.0 Hz, 2H), 3.32 (t, J = 7.1 Hz, 4H), 3.02 (t, J = 7.1 Hz, 4H), 2.49‐2.43 (m, 7H), 2.33 (d, J = 8.8 Hz, 5H), 2.00 (s, 3H), 1.67‐1.57 (m, 12H).

[0150] Example 75: 2-((4-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)piperazin-1-yl)-2-methoxyphenyl)amino)-8-(4-fluoro-3-((4-methylpiperazin-1-yl)methyl)phenyl)-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (ZX-HYT-75) JPEG0007756374000121.jpg59170 See Example 18 for the synthesis of compound ZX-HYT-75. MS (ESI), m / z: 748.9 [M+H] + . 1 H NMR (500 MHz, Chloroform-d) δ 9.07 (s, 1H), 8.78 (s, 1H), 7.85 (dq, J = 4.9, 1.1 Hz, 1H), 7.41(ddd, J = 7.5, 4.9, 1.5 Hz, 1H), 7.27‐7.18 (m, 1H), 7.07 (d, J = 7.5 Hz, 1H), 6.74 (dd, J = 7.5, 1.5 Hz, 1H), 6.58 (q, J = 0.9 Hz, 1H), 6.30 (d, J = 1.5 Hz, 1H), 3.89 (s, 3H), 3.67 (t, J = 7.0 Hz, 4H), 3.61 (d, J = 1.1 Hz, 2H), 3.31 (t, J = 7.1 Hz, 4H), 2.59 (td, J = 6.9, 0.8 Hz, 4H), 2.48‐2.42 (m, 7H), 2.33 (d, J = 9.0 Hz, 5H), 2.10 (s, 3H), 1.69-1.51 (m, 12H).

[0151] Example 76: 2-((4-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-8-(3-((4-methylpiperazin-1-yl)methyl)-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyrimidin-7(8H)-one (ZX-HYT-76) JPEG0007756374000122.jpg59170 See Example 18 for the synthesis of compound ZX-HYT-76. MS (ESI), m / z: 798.9 [M+H] + . 1H NMR (500 MHz, Chloroform-d) δ 9.07 (s, 1H), 8.49 (s, 1H), 7.60-7.54 (m, 2H), 7.42 (dd, J = 7.4, 1.5 Hz, 1H), 7.07 (d, J = 7.5 Hz, 1H), 6.74 (dd, J = 7.5, 1.5 Hz, 1H), 6.58 (q, J = 0.9 Hz, 1H), 6.30 (d, J = 1.5 Hz, 1H), 3.89 (s, 2H), 3.81‐3.64 (m, 6H), 3.31 (t, J = 7.1 Hz, 4H), 2.67 (td, J = 7.0, 0.8 Hz, 4H), 2.49‐2.42 (m, 7H), 2.34 (d, J = 10.2 Hz, 4H), 2.16 (s, 3H), 1.67‐1.57 (m, 12H).

[0152] Example 77: 3-(2-((4-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)-N-(1-methylazetidin-3-yl)benzamide (ZX-HYT-77) JPEG0007756374000123.jpg54170 See Example 18 for the synthesis of compound ZX-HYT-77. MS (ESI), m / z: 730.9 [M+H] + . 1H NMR (500 MHz, Chloroform-d) δ 9.09 (s, 1H), 8.68 (s, 1H), 8.29 (t, J = 1.5 Hz, 1H), 7.79 (d, J = 9.5 Hz, 1H), 7.71 (dt, J = 7.3, 1.5 Hz, 1H), 7.52 (dt, J = 7.5, 1.5 Hz, 1H), 7.41 (t, J = 7.5 Hz, 1H), 7.07 (d, J = 7.5 Hz, 1H), 6.74 (dd, J = 7.5, 1.5 Hz, 1H), 6.59 (q, J = 1.0 Hz, 1H), 6.30 (d, J = 1.5 Hz, 1H), 4.14 (dp, J = 9.5, 7.0 Hz, 1H), 3.87 (s, 3H), 3.68 (t, J = 7.0 Hz, 4H), 3.32 (t, J = 7.1 Hz, 4H), 3.16 (dd, J = 12.4, 7.0 Hz, 2H), 2.94 (dd, J = 12.4, 7.1 Hz, 2H), 2.47 (d, J = 1.1 Hz, 3H), 2.34 (s, 2H), 2.24 (s, 3H), 1.98 (s, 3H), 1.69-1.50 (m, 12H).

[0153] Example 78: 4-(2-((4-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)-N-(1-methylazetidin-3-yl)pyridineamide (ZX-HYT-106) JPEG0007756374000124.jpg55170 See Example 18 for the synthesis of compound ZX-HYT-78. MS (ESI), m / z: 732.3 [M+H] + . 1H NMR (500 MHz, Chloroform-d) δ 9.07 (s, 1H), 8.75 (d, J = 1.5 Hz, 1H), 8.48 (s, 1H), 8.43 (d, J = 7.5 Hz, 1H), 8.33 (dd, J = 7.4, 1.5 Hz, 1H), 7.99 (d, J = 10.3 Hz, 1H), 7.07 (d, J = 7.5 Hz, 1H), 6.74 (dd, J = 7.5, 1.5 Hz, 1H), 6.58 (q, J = 1.0 Hz, 1H), 6.30 (d, J = 1.5 Hz, 1H), 4.14 (dp, J = 9.5, 7.0 Hz, 1H), 3.87 (s, 3H), 3.68 (t, J = 7.0 Hz, 4H), 3.32 (t, J = 7.1 Hz, 4H), 3.16 (dd, J = 12.4, 7.0 Hz, 2H), 2.94 (dd, J = 12.4, 7.1 Hz, 2H), 2.47 (d, J = 1.1 Hz, 3H), 2.34 (s, 2H), 2.24 (s, 3H), 1.98 (s, 3H), 1.69‐1.50 (m, 12H).

[0154] Example 79: 5-(2-((4-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)-2-fluoro-N-(1-methylazetidin-3-yl)benzamide (ZX-HYT-79) JPEG0007756374000125.jpg56170 See Example 18 for the synthesis of compound ZX-HYT-79. MS (ESI), m / z: 749.3 [M+H] + . 1H NMR (600 MHz, Chloroform-d) δ 8.65 (s, 1H), 8.01 (dd, J = 6.9, 2.7 Hz, 1H), 7.76 (s, 1H), 7.45‐7.27 (m, 3H), 6.81 (dd, J = 12.2, 3.2 Hz, 1H), 6.44 (s, 1H), 6.37 (s, 1H), 6.05 (s, 1H), 3.84 (s, 3H), 3.82-3.78 (m, 4H), 3.72-3.67 (m, 4H), 3.51 - 3.16 (m, 4H), 2.93 (tq, J = 7.2, 3.6 Hz, 1H), 2.62 (s, 3H), 2.46 (s, 3H), 2.20 (s, 2H), 2.00‐1.97 (m, 3H), 1.72‐1.65 (m, 12H).

[0155] Example 80: 5-(2-((4-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)-N-(1-methylazetidin-3-yl)-2-(trifluoromethyl)benzamide (ZX-HYT-80) JPEG0007756374000126.jpg58170 See Example 18 for the synthesis of compound ZX-HYT-80. MS (ESI), m / z: 799.3 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 9.07 (s, 1H), 8.48 (s, 1H), 8.02 (d, J = 1.5 Hz, 1H), 7.67 (d, J = 7.4 Hz, 1H), 7.56 (dd, J = 7.5, 1.6 Hz, 1H), 7.32 (d, J = 9.7 Hz, 1H), 7.07 (d, J = 7.5 Hz, 1H), 6.74 (dd, J = 7.5, 1.5 Hz, 1H), 6.57 (q, J = 0.9 Hz, 1H), 6.30 (d, J = 1.5 Hz, 1H), 4.31 - 4.14 (m, 1H), 3.86 (s, 2H), 3.68 (t, J = 7.0 Hz, 4H), 3.32 (t, J = 7.1 Hz, 4H), 3.17 (dd, J = 12.5, 7.0 Hz, 2H), 2.95 (dd, J = 12.4, 7.0 Hz, 2H), 2.47 (d, J = 1.1 Hz, 3H), 2.34 -2.25 (m, 4H), 2.12 (s, 3H), 1.7‐1.57 (m, 12H).

[0156] Example 81: N-(3-(2-((4-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)-1-aminocyclopropane-1-carboxamide (ZX-HYT-81) JPEG0007756374000127.jpg57170 See Example 18 for the synthesis of compound ZX-HYT-81. MS (ESI), m / z: 717.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.80 (s, 1H), 8.13 (s, 1H), 7.87 (s, 1H), 7.60 (s, 1H), 7.48 (t, J = 8.1 Hz, 1H), 7.28 (d, J = 8.8 Hz, 1H), 6.95 (d, J = 7.8 Hz, 1H), 6.57 (s, 1H), 6.32 (s, 1H), 6.06 (s, 1H), 3.79 (s, 3H), 3.70‐3.55 (m, 4H), 3.11‐2.92 (m, 4H), 2.46 (s, 3H), 2.16 (s, 2H), 1.93 (s, 3H), 1.74-1.50 (m, 12H), 1.21-1.09 (m, 2H), 0.93-0.80 (m, 2H).

[0157] Example 82: N-(3-(2-((4-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)-2-aminoacetamide (ZX-HYT-82) JPEG0007756374000128.jpg57170 See Example 18 for the synthesis of compound ZX-HYT-82. MS (ESI), m / z: 691.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.81 (s, 1H), 8.11 (s, 1H), 7.87 (s, 1H), 7.60 (s, 1H), 7.48 (t, J = 8.1 Hz, 1H), 7.28 (d, J = 8.8 Hz, 1H), 6.95 (d, J = 7.8 Hz, 1H), 6.57 (s, 1H), 6.32 (s, 1H), 6.06 (s, 1H), 4.12 (s, 2H), 3.79 (s, 3H), 3.70-3.55 (m, 4H), 3.11-2.92 (m, 4H), 2.46 (s, 3H), 2.16 (s, 2H), 1.93 (s, 3H), 1.74-1.50 (m, 12H).

[0158] Example 83: N-(3-(2-((4-(4-(((3R,5R,7R)-adamantan-1-yl)methyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX-HYT-83) Compound 29 (0.13 g, 0.25 mmol), 1-adamantaneformaldehyde (0.041 g, 0.025 mmol), and sodium cyanoborohydride (0.032 g, 0.5 mmol) were added sequentially to 10 mL of dichloromethane. The mixture was stirred at room temperature for 2 h. After completion of the reaction was confirmed by TLC, the reaction mixture was evaporated to dryness. The remaining solid residue was purified by column chromatography (eluted with chloroform / methanol = 40:1) to obtain the target compound ZX-HYT-83 (0.11 g, 65% yield) as a yellow powder. HRMS (ESI) for C 40 H 47 N7O3[M+H] + : Calculated value, 674.3813; Measured value, 674.3824. 1H NMR (400 MHz, DMSO-d6) δ 10.49 (s, 1H), 8.82 (s, 1H), 8.24 (s, 1H), 7.81 (s, 1H), 7.64-7.43 (m, 2H), 7.29 (d, J = 8.8 Hz, 1H), 6.98-6.87 (m, 1H), 6.66-6.50 (m, 1H), 6.33 (s, 1H), 6.03 (s, 1H), 3.80 (s, 3H), 3.70-3.57 (m, 4H), 3.09-2.94 (m, 4H), 2.46 (s, 3H), 2.16 (s, 2H), 1.94 (s, 3H), 1.79 (p, J = 6.3 Hz, 1H), 1.72‐1.61 (m, 12H), 0.87‐0.71 (m, 4H).

[0159] Example 84: N-(3-(2-((4-(4-(2-((3R,5R,7R)-adamantan-1-yl)ethyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX-HYT-84) JPEG0007756374000130.jpg58170 See Example 83 for the synthesis of compound ZX-HYT-84. HRMS (ESI) for C 41 H 49 N7O3[M+H] + : Calculated value, 688.3970; Measured value, 688.3981. 1H NMR (400 MHz, DMSO-d6) δ 10.49 (s, 1H), 8.82 (s, 1H), 8.24 (s, 1H), 7.81 (s, 1H), 7.64-7.43 (m, 2H), 7.29 (d, J = 8.8 Hz, 1H), 6.98-6.87 (m, 1H), 6.66-6.50 (m, 1H), 6.33 (s, 1H), 6.03 (s, 1H), 3.80 (s, 3H), 3.70-3.57 (m, 4H), 3.09-2.94 (m, 4H), 2.46 (s, 3H), 2.26 (s, 2H), 1.95 (s, 3H), 1.79 (p, J = 6.4 Hz, 1H), 1.72‐1.63 (m, 14H), 0.88‐0.70 (m, 4H).

[0160] Example 85: N-(3-(2-((4-(((3S,5S,7S)-adamantan-1-yl)amino)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d)]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX-HYT-85) JPEG0007756374000131.jpg49170 See Example 25 for the synthesis of compound ZX-HYT-85. HRMS (ESI) for C 35 H 38 N6O3[M+H] + : Calculated value, 591.7355; Measured value, 591.9362. 1H NMR (400 MHz, DMSO-d6) δ 10.49 (s, 1H), 8.82 (s, 1H), 8.24 (s, 1H), 7.81 (s, 1H), 7.64-7.43 (m, 2H), 7.29 (d, J = 8.8 Hz, 1H), 6.98-6.87 (m, 1H), 6.66-6.50 (m, 1H), 6.33 (s, 1H), 6.03 (s, 1H), 5.83 (s, 1H), 3.80 (s, 3H), 2.46 (s, 3H), 1.95 (s, 3H), 1.79 (p, J = 6.4 Hz, 1H), 1.74‐1.63 (m, 12H), 0.88‐0.71 (m, 4H).

[0161] Example 86: N-(3-(2-((4-((3R,5R,7R)-adamantan-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin)-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX-HYT-86) JPEG0007756374000132.jpg45170 See Example 25 for the synthesis of compound ZX-HYT-86. HRMS (ESI) for C 35 H 37 N5O3[M+H] + : Calculated value, 576.2969; Measured value, 576.2971. 1 H NMR (400 MHz, DMSO-d6) δ 10.49 (s, 1H), 8.82 (s, 1H), 8.24 (s, 1H), 7.81 (s, 1H), 7.64-7.43 (m, 2H), 7.29 (d, J = 8.8 Hz, 1H), 6.98-6.87 (m, 1H), 6.66-6.50 (m, 1H), 6.33 (s, 1H), 6.03 (s, 1H), 3.80 (s, 3H), 2.46 (s, 3H), 1.95 (s, 3H), 1.79 (p, J = 6.4 Hz, 1H), 1.74-1.63 (m, 12H), 0.88‐0.71 (m, 4H).

[0162] Example 87: N-((3S,5S,7S)-adamantan-1-yl)-1-(4-((8-(3-(cyclopropanecarboxamido)phenyl)-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)azetidine-3-carboxamide (ZX-HYT-87) JPEG0007756374000133.jpg52170 See Example 25 for the synthesis of compound ZX-HYT-87. HRMS (ESI) for C 39 H 43 N7O4[M+H] + : Calculated value, 674.3449; Measured value, 674.3452. 1 H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.77 (s, 1H), 8.02 (s, 1H), 7.79‐7.65 (m, 1H), 7.53‐7.47 (m, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.16 (d, J = 8.7 Hz, 1H), 6.93 (d, J = 7.8 Hz, 1H), 6.31-6.26 (m, 2H), 5.93 (s, 1H), 5.62 (s, 1H), 3.97 (s, 3H), 3.77-3.59 (m, 4H), 2.44 (s, 3H), 1.93-1.86 (m, 3H), 1.81-1.73 (m, 2H), 1.68-1.49 (m, 12H), 0.83-0.70 (m, 4H).

[0163] Example 88: N-(5-(2-((4-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)-2-fluorophenyl)-2-aminoacetamide (ZX-HYT-88) JPEG0007756374000134.jpg53170 For the synthesis of compound ZX-HYT-88, see Example 18. MS (ESI), m / z: 709.8 [M+H]+ . 1 H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.91 (s, 1H), 8.18 (s, 1H), 7.87 (s, 1H), 7.60 (s, 1H), 7.4 (d, J = 7.8 Hz, 1H), 6.98 (d, J = 7.8 Hz, 1H), 6.57 (s, 1H), 6.32 (s, 1H), 6.06 (s, 1H), 4.12 (s, 2H), 3.79 (s, 3H), 3.70-3.55 (m, 4H), 3.11-2.92 (m, 4H), 2.46 (s, 3H), 2.16 (s, 2H), 1.93 (s, 3H), 1.74-1.50 (m, 12H).

[0164] Example 89: N-(((3R,5R,7R)-adamantan-1-yl)methyl)-1-(4-((8-(3-(cyclopropanecarboxamido)phenyl)-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidine-4-carboxamide (ZX-HYT-89) JPEG0007756374000135.jpg56170 See Example 25 for the synthesis of compound ZX-HYT-89. HRMS (ESI) for C 42 H 49 N7O4[M+H] + : Calculated value, 716.3919; Measured value, 716.3921. 1H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.80 (s, 1H), 8.10 (s, 1H), 7.84-7.75 (m, 1H), 7.70-7.63 (m, 1H), 7.51-7.42 (m, 2H), 7.26 (d, J = 8.8 Hz, 1H), 6.92 (d, J = 7.9 Hz, 1H), 6.53 (s, 1H), 6.31 (s, 1H), 6.03 (s, 1H), 3.78 (s, 3H), 3.67-3.56 (m, 2H), 2.81-2.75 (m, 2H), 2.64-2.54 (m, 2H), 2.45 (s, 3H), 2.37-2.28 (m, 1H), 1.97-1.87 (m, 3H), 1.82-1.53 ​​(m, 11H), 1.49-1.37 (m, 6H), 0.83-0.71 (m, 4H).

[0165] Example 90: N-(3-(2-((4-(5-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)-2,5-azabicyclo[2.2.2]octan-2-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX-HYT-90) JPEG0007756374000136.jpg55170 See Example 25 for the synthesis of compound ZX-HYT-90. HRMS (ESI) for C 43 H 49 N7O4[M+H] + : Calculated value, 728.9175; Measured value, 728.9182. 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.76 (s, 1H), 8.02 (s, 1H), 7.79‐7.65 (m, 1H), 7.53‐7.47 (m, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.16 (d, J = 8.7 Hz, 1H), 6.93 (d, J = 7.8 Hz, 1H), 6.32-6.22 (m, 2H), 5.62 (s, 1H), 3.98-3.87 (m, 4H), 3.77-3.59 (m, 5H), 3.29-3.22 (m, 2H), 2.44 (s, 3H), 1.93-1.86 (m, 3H), 1.85-1.73 (m, 5H), 1.68-1.49 (m, 12H), 0.83-0.70 (m, 4H).

[0166] Example 91: N-(3-(2-((4-(6-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)-2,6-diazaspiro[3.3]hept-2-yl))-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX-HYT-91) JPEG0007756374000137.jpg58170 See Example 25 for the synthesis of compound ZX-HYT-91. HRMS (ESI) for C 42 H 47 N7O4[M+H] + : Calculated value, 714.3762; Measured value, 714.3774. 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.76 (s, 1H), 8.02 (s, 1H), 7.79‐7.65 (m, 1H), 7.53‐7.47 (m, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.16 (d, J = 8.7 Hz, 1H), 6.93 (d, J = 7.8 Hz, 1H), 6.32-6.22 (m, 2H), 5.62 (s, 1H), 3.98-3.87 (m, 4H), 3.77-3.59 (m, 5H), 3.29-3.22 (m, 2H), 2.44 (s, 3H), 1.93-1.86 (m, 3H), 1.85-1.73 (m, 3H), 1.68-1.49 (m, 12H), 0.83-0.70 (m, 4H).

[0167] Example 92: N-(3-(2-((4-(2-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)-2,7-diazaspiro[3.5]-7-yl))-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX-HYT-92) JPEG0007756374000138.jpg60170 See Example 25 for the synthesis of compound ZX-HYT-92. HRMS (ESI) for C 44 H 51 N7O4[M+H] + : Calculated value, 742.4075; Measured value, 742.4082. 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.76 (s, 1H), 8.02 (s, 1H), 7.79‐7.65 (m, 1H), 7.53‐7.47 (m, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.16 (d, J = 8.7 Hz, 1H), 6.93 (d, J = 7.8 Hz, 1H), 6.32-6.22 (m, 2H), 5.62 (s, 1H), 3.98-3.87 (m, 7H), 3.77-3.59 (m, 4H), 3.29-3.22 (m, 2H), 2.44 (s, 3H), 1.93-1.86 (m, 3H), 1.85-1.73 (m, 5H), 1.68-1.49 (m, 12H), 0.83-0.70 (m, 4H).

[0168] Example 93: N-(3-(2-((4-(5-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX-HYT-93) JPEG0007756374000139.jpg57170 See Example 25 for the synthesis of compound ZX-HYT-93. HRMS (ESI) for C 43 H 49 N7O4[M+H] + : Calculated value, 728.3919; Measured value, 728.3919. 1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.81 (s, 1H), 8.14 (s, 1H), 7.80 (s, 1H), 7.54-7.41 (m, 2H), 7.29 (d, J = 8.8 Hz, 1H), 6.98-6.87 (m, 1H), 6.66-6.50 (m, 1H), 6.33 (s, 1H), 6.03 (s, 1H), 3.80 (s, 3H), 3.70-3.57 (m, 4H), 3.09-2.94 (m, 4H), 2.46 (s, 3H), 2.16 (s, 2H), 1.94 (s, 3H), 1.81-1.74 (m, 1H), 1.69-1.53 ​​(m, 14H), 0.82-0.73 (m, 4H).

[0169] Example 94: N-(5-(2-((4-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)-2-fluorophenyl)cyclopropanecarboxamide (ZX-HYT-94) JPEG0007756374000140.jpg57170 See Example 20 for the synthesis of compound ZX-HYT-94. HRMS (ESI) for C 41 H 46 FN7O4[M+H] + : Calculated value, 720.3668; Measured value, 720.3673. 1H NMR (400 MHz, DMSO-d6) δ 10.49 (s, 1H), 8.82 (s, 1H), 8.51 (s, 1H), 7.83 (s, 1H), 7.67‐7.56 (m, 1H), 7.42 (s, 1H), 7.31 (s, 1H), 6.91-6.74 (m, 1H), 6.40-6.20 (m, 2H), 3.73 (s, 3H), 3.64-3.55 (m, 4H), 3.51-3.39 (m, 4H), 2.42 (s, 3H), 2.21-2.12 (m, 2H), 1.93 (s, 3H), 1.81-1.73 (m, 1H), 1.72-1.54 (m, 12H), 0.83-0.72 (m, 4H).

[0170] Example 95: N-(5-(2-((4-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)-2-(trifluoromethyl)phenyl)cyclopropanecarboxamide (ZX-HYT-95) JPEG0007756374000141.jpg57170 See Example 20 for the synthesis of compound ZX-HYT-95. HRMS (ESI) for C 42 H 46 F3N7O4[M+H] + : Calculated value, 770.3636; Measured value, 770.3641. 1H NMR (600 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.77 (s, 1H), 8.51 (s, 1H), 7.88 (s, 1H), 7.68‐7.55 (m, 1H), 7.41 (s, 1H), 7.30 (s, 1H), 6.91-6.74 (m, 1H), 6.40-6.20 (m, 2H), 3.73 (s, 3H), 3.64-3.55 (m, 4H), 3.51-3.39 (m, 4H), 2.42 (s, 3H), 2.21-2.12 (m, 2H), 1.93 (s, 3H), 1.81-1.73 (m, 1H), 1.72-1.54 (m, 12H), 0.83-0.72 (m, 4H).

[0171] Example 96: N-(4-(2-((4-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)pyridin-2-yl)cyclopropanecarboxamide (ZX-HYT-96) JPEG0007756374000142.jpg57170 See Example 20 for the synthesis of compound ZX-HYT-96. HRMS (ESI) for C 40 H 46 N8O4[M+H] + : Calculated value, 703.3715; Measured value, 703.3723. 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.77 (s, 1H), 8.51 (s, 1H), 7.88 (s, 1H), 7.68‐7.59 (m, 1H), 7.31 (s, 1H), 7.21 (s, 1H), 6.91-6.74 (m, 1H), 6.40-6.20 (m, 2H), 3.73 (s, 3H), 3.64-3.55 (m, 4H), 3.51-3.39 (m, 4H), 2.42 (s, 3H), 2.21-2.12 (m, 2H), 1.93 (s, 3H), 1.81-1.73 (m, 1H), 1.72-1.54 (m, 12H), 0.83-0.72 (m, 4H).

[0172] Example 97: 2-((4-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)piperazin-1-yl)-2-methoxyphenyl)amino)-8-(3-((cyclopropylmethyl)amino)phenyl)-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (ZX-HYT-97) JPEG0007756374000143.jpg57170 See Example 18 for the synthesis of compound ZX-HYT-97. HRMS (ESI) for C 41 H 49 N7O3[M+H] + : Calculated value, 688.3970; Measured value, 688.3965. 1H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.81 (s, 1H), 8.14 (s, 1H), 7.80 (s, 1H), 7.54-7.41 (m, 2H), 7.29 (d, J = 8.8 Hz, 1H), 6.98-6.87 (m, 1H), 6.66-6.50 (m, 1H), 6.33 (s, 1H), 6.03 (s, 1H), 3.80 (s, 3H), 3.70-3.57 (m, 4H), 3.24 (dd, J = 7.0, 5.9 Hz, 2H), 3.09-2.94 (m, 4H), 2.46 (s, 3H), 2.16 (s, 2H), 1.94 (s, 3H), 1.71-1.60 (m, 1H), 1.69-1.60 (m, 12H), 0.82-0.73 (m, 4H).

[0173] Example 98: 2-((4-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-8-(3-morpholinophenyl)pyrido[2,3-d]pyrimidin-7(8H)-one (ZX-HYT-98) JPEG0007756374000144.jpg57170 See Example 18 for the synthesis of compound ZX-HYT-98. HRMS (ESI) for C 43 H 54 N8O3[M+H] + : Calculated value, 731.4392; Measured value, 731.4395. 1H NMR (500 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.09 (s, 1H), 7.37 (t, J = 8.0 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 7.07 (d, J = 8.5 Hz, 1H), 6.85 (d, J = 2.3 Hz, 1H), 6.69‐6.63 (m, 1H), 6.57 (d, J = 2.5 Hz, 1H), 6.29 (s, 1H), 5.99 (s, 1H), 3.77 (s, 3H), 3.68 (t, J = 4.9 Hz, 4H), 3.62 (dq, J = 11.0, 5.4, 5.0 Hz, 4H), 3.10 (q, J = 5.0 Hz, 4H), 3.04-2.94 (m, 4H), 2.43 (s, 3H), 2.14 (t, J = 4.5 Hz, 2H), 1.91 (s, 3H), 1.67-1.54 (m, 12H).

[0174] Example 99: N-(3-(2-((4-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)-5-(trifluoromethyl)phenyl)-2-aminoacetamide (ZX-HYT-99) JPEG0007756374000145.jpg49170 See Example 18 for the synthesis of compound ZX-HYT-99. MS (ESI), m / z: 759.8 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.91 (s, 1H), 8.18 (s, 1H), 7.90 (s, 1H), 7.78 (s, 1H), 7.4 (d, J = 7.8 Hz, 1H), 6.98 (d, J = 7.8 Hz, 1H), 6.57 (s, 1H), 6.32 (s, 1H), 6.06 (s, 1H), 4.12 (s, 2H), 3.79 (s, 3H), 3.70-3.55 (m, 4H), 3.11-2.92 (m, 4H), 2.46 (s, 3H), 2.16 (s, 2H), 1.93 (s, 3H), 1.74-1.50 (m, 12H).

[0175] Example 100: 5-(2-((4-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)-N-cyclopropyl-2-fluorobenzamide (ZX-HYT-100) JPEG0007756374000146.jpg54170 For the synthesis of compound ZX-HYT-100, see Example 18. MS (ESI), m / z: 720.4 [M+H] + . 1H NMR (600 MHz, Chloroform-d) δ 8.65 (s, 1H), 8.01 (dd, J = 6.9, 2.7 Hz, 1H), 7.76 (s, 1H), 7.45‐7.27 (m, 3H), 6.81 (dd, J = 12.2, 3.2 Hz, 1H), 6.44 (s, 1H), 6.37 (s, 1H), 6.05 (s, 1H), 3.84 (s, 3H), 3.82‐3.78 (m, 2H), 3.72‐3.67 (m, 2H), 3.06 (dt, J = 14.9, 4.9 Hz, 4H), 2.93 (tq, J = 7.2, 3.6 Hz, 1H), 2.46 (s, 3H), 2.20 (s, 2H), 2.00-1.97 (m, 3H), 1.72-1.65 (m, 12H), 0.91-0.86 (m, 2H), 0.65-0.61 (m, 2H).

[0176] Example 101: 8-(3-(1H-imidazol-1-yl)phenyl)-2-((4-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (ZX-HYT-101) JPEG0007756374000147.jpg57170 For the synthesis of compound ZX-HYT-101, see Example 18. MS (ESI), m / z: 685.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.91 (s, 1H), 8.18 (s, 1H), 7.87 (s, 1H), 7.72 (s, 1H), 7.46‐7.59 (m, 2H),7.4 (d, J = 7.8 Hz, 1H), 7.18 (s, 1H), 6.98 (d, J = 7.8 Hz, 1H), 6.57 (s, 1H), 6.32 (s, 1H), 6.06 (s, 1H), 3.79 (s, 3H), 3.70-3.55 (m, 4H), 3.11-2.92 (m, 4H), 2.46 (s, 3H), 2.16 (s, 2H), 1.93 (s, 3H), 1.74‐1.50 (m, 12H).

[0177] Example 102: 4-(2-((4-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)-N-cyclopropylpyridineamide (ZX-HYT-102) JPEG0007756374000148.jpg57170 See Example 18 for the synthesis of compound ZX-HYT-102. MS (ESI), m / z: 703.3 [M+H] + . 1H NMR (600 MHz, Chloroform-d) δ 8.72 (d, J = 5.1 Hz, 1H), 8.68 (s, 1H), 8.20 (s, 1H), 8.11 (d, J = 3.9 Hz, 1H), 7.42 (dd, J = 6.1, 4.3 Hz, 1H), 7.26 (s, 1H), 6.43 (s, 1H), 6.37 (s, 1H), 3.84 (s, 3H), 3.81 (t, J = 5.2 Hz, 2H), 3.68 (t, J = 5.1 Hz, 2H), 3.05 (s, 4H), 2.98 (dq, J = 7.2, 3.6 Hz, 1H), 2.48 (s, 3H), 2.20 (s, 2H), 1.99 (s, 3H), 1.73-1.65 (m, 12H), 0.94-0.89 (m, 2H), 0.72-0.67 (m, 2H).

[0178] Example 103: 3-(2-((4-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)-N-cyclopropylbenzamide (ZX-HYT-103) JPEG0007756374000149.jpg57170 See Example 18 for the synthesis of compound ZX-HYT-103. MS (ESI), m / z: 702.4 [M+H] + . 1H NMR (500 MHz, Chloroform-d) δ 8.63 (s, 1H), 8.10‐7.97 (m, 1H), 7.83 (s, 1H), 7.64 (t, J = 7.8 Hz, 1H), 7.58 (t, J = 1.9 Hz, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.26 (s, 1H), 6.50 (d, J = 3.2 Hz, 1H), 6.41 (d, J = 2.6 Hz, 1H), 6.35 (d, J = 1.4 Hz, 1H), 6.02 (s, 1H), 3.83 (s, 3H), 3.82-3.76 (m, 2H), 3.73-3.64 (m, 2H), 3.12-2.99 (m, 4H), 2.84 (tq, J = 7.2, 3.7 Hz, 1H), 2.45 (s, 3H), 2.21 (s, 2H), 2.03-1.90 (m, 3H), 1.77-1.54 (m, 12H), 0.85-0.74 (m, 2H), 0.59-0.45 (m, 2H).

[0179] Example 104: 5-(2-((4-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)-N-cyclopropyl-2-(trifluoromethyl)benzamide (ZX-HYT-104) JPEG0007756374000150.jpg58170 See Example 18 for the synthesis of compound ZX-HYT-104. MS (ESI), m / z: 770.2 [M+H] + . 1H NMR (600 MHz, Chloroform-d) δ 8.66 (s, 1H), 7.90 (d, J = 8.2 Hz, 1H), 7.80 (s, 1H), 7.52‐7.45 (m, 2H), 7.21 (s, 1H), 6.49‐6.40 (m, 1H), 6.37 (s, 1H), 6.15 (s, 1H), 5.90 (s, 1H), 3.85 (s, 3H), 3.83‐3.74 (m, 2H), 3.71‐3.64 (m, 2H), 3.13‐3.04 (m, 4H), 2.83 (q, J = 3.6 Hz, 1H), 2.48 (s, 3H), 2.24-2.19 (m, 2H), 1.99 (s, 3H), 1.75-1.63 (m, 12H), 0.84-0.78 (m, 2H), 0.56-0.47 (m, 2H).

[0180] Example 105: Effect of compounds on the levels of AKT3 protein in H1975OR cells Cell line: Non-small cell lung cancer H1975-OR cell line. This cell line is an osimertinib-resistant H1975 cell line, obtained by culturing using a gradual increase method starting from a low dose. Specifically, H1975 cells were seeded in 10 cm dishes at 60-70% confluence, and 50 nM osimertinib was added to the medium. After the cell state stabilized, the osimertinib concentration was gradually doubled to 3 μM. Genetic testing revealed that the resulting drug-resistant cell line (H1975-OR) showed significantly higher expression of AKT3 compared to the original H1975 cell line. Detection was performed using standard Western blot (immunoblotting) techniques. Specifically, H1975-OR cells were seeded at a fixed number in a 96-well plate and cultured overnight in an incubator. After incubation, a fixed concentration of compounds was added and allowed to react for 24 hours. Cells were lysed using 1x SDS lysis buffer containing protease and phosphatase inhibitors. The cell lysates were separated by SDS-PAGE and transferred to a PVDF membrane. The PVDF membrane was then removed and immersed in blocking solution (5% BSA in TBS containing 0.5% Tween-20) at room temperature for 1 hour, followed by incubation with specific primary antibodies overnight at 4°C. The blot was washed with TBST and incubated with horseradish peroxidase (HRP)-conjugated secondary antibodies at room temperature for 2 hours. Finally, proteins were developed using ECL plus fluorescent detection reagent (Thermo Scientific, Waltham, MA) and imaged using an Amersham Imager 600 system (GE, USA). The detection results were each processed using ImageJ software to obtain a density (G) value, and the maximum protein degradation rate (Dmax) was calculated using the following formula: Dmax = 1 - (Gmax - Gmin) / Gmax × 100%, where Gmax = density of the blank control group. (目的タンパク質バンド) / Density (GAPDHに対応) Gmin is the density at which the maximum degradation of the target protein is observed in the compound-treated group. (目的タンパク質バンド) / Density (GAPDHに対応) The results are shown in Table 1 as Dmax (%).

[0181] Table 1. Induction ability of compounds on AKT1, AKT2, and AKT3 protein degradation in H1975-OR cells JPEG0007756374000151.jpg119150

[0182] Example 106: Effect of compound ZX-HYT-11 on AKT1 / 2 / 3 proteins in other tumor cells Tumor cells (H1975, PC-9, H1299, and A549) were incubated with different concentrations of compound ZX-HYT-11 for 24 hours, and then the protein levels of AKT1 / 2 / 3 were analyzed using the Western blotting method described in Example 105. The results (Figure 1) showed that compound ZX-HYT-11 could selectively degrade AKT3 protein in the above cells, without affecting AKT1 / 2, further demonstrating the effectiveness and versatility of this compound in degrading AKT3 protein.

[0183] Example 107: Inhibitory activity of compounds against tumor cell proliferation Tumor cells (see Tables 2 to 5) were seeded in 96-well plates (2,000–3,000 cells / well) in complete medium. After overnight incubation, the cells were treated separately with different concentrations (0.000508–10 μM) of compounds for 72 h. Cell proliferation was assessed using CCK-8 (Cell Counting Kit 8, Dojindo Laboratories, Kumamoto, Japan) experiments. The half-maximal inhibitory concentrations (IC) were calculated by concentration-response curve fitting using GraphPad Prism 5.0 software (GraphPad Software, La Jolla, CA). 50 ) values ​​were calculated. 50 The values ​​are expressed as mean ± SD. The results are shown in Tables 2 to 5.

[0184] Table 2. Growth inhibitory activity of compounds against multiple types of tumor cells JPEG0007756374000152.jpg114147

[0185] Table 3 Growth inhibitory activity of compounds against tumor cells such as PC-9 JPEG0007756374000153.jpg86170

[0186] Table 4. Growth inhibitory activity of compounds against tumor cells such as MDA-MB-231 JPEG0007756374000154.jpg77170

[0187] Table 5. Growth inhibitory activity of compounds against tumor cells such as A549 JPEG0007756374000155.jpg31170

[0188] The technical features of the above-described embodiments may be combined in any manner. For the sake of brevity, not all possible combinations of the technical features in the following embodiments are described. However, as long as there is no contradiction in the combinations of these technical features, they should all be considered to be within the scope described in this specification.

[0189] The above examples merely illustrate some embodiments of the present invention, and although the descriptions are more specific and detailed, they should not be understood as limiting the scope of the patent of the present invention. It should be noted that a person skilled in the art can make some modifications and improvements without departing from the concept of the present invention, which fall within the scope of protection of the present invention. Therefore, the scope of protection of the patent of the present invention shall be determined by the scope of the attached claims.

Claims

1. A pyridopyrimidine compound having a structure represented by formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. (where, ~C １２ Cycloalkyl group, C １ ~C ３ Alkyl-substituted C ３ ~C １２ Cycloalkyl and halogen-substituted C ３ ~C １２ cycloalkyl groups, R ６ is a halogen, C １ ~C ６ Alkyl group and halogen-substituted C １ ~C ６ alkyl groups, L is absent or is a linking unit consisting of one or more of an alkylene group, an ether group, a thioether group, an ester group, an amino group, an amide group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, and an -N=N- group; Y is absent or is —O—, —NH—, —NHCO—, or —CH ２ -, -S-, and -CO-; Z is absent or is —O—, —NH—, —N(C １ ~C ６ alkyl group)-, -NHCO-, -CH ２ selected from —, —S—, —CO— and —SO—; R １ is C １ ~C ６ Alkyl groups, halogens, and halogen-substituted C １ ~C ６ alkyl groups, R ２ is C ３ ~C １５ Cycloalkyl group, substituted C ３ ~C １５ Cycloalkyl groups, 3- to 15-membered heterocycloalkyl groups, substituted 3- to 15-membered heterocycloalkyl groups, C ６ ~C １０ Aryl group, substituted C ６ ~C １０ selected from an aryl group, a 5- to 10-membered heteroaryl group, and a substituted 5- to 10-membered heteroaryl group; A is selected from -NH- and -NHR-, R is a phenylene group, R ７ Substituted phenylene groups, 6-membered heteroarylene groups, and R ７ substituted 6-membered heteroarylene groups; R ７ is C １ ~C ６ Alkyl group, C ３ ~C ６ Cycloalkyl group, halogen, C １ ~C ６ Alkoxy group, halogen-substituted C １ ~C ６ Alkoxy group, deuterated C １ ~C ６ Alkoxy group, halogen-substituted C １ ~C ６ Alkyl group, cyano-substituted C １ ~C ６ Alkyl groups, deuterated C １ ~C ６ Alkyl group, trifluoromethyl-substituted C ３ ~C ６ Cycloalkyl group, C １ ~C ６ Alkyl-substituted C ３ ~C ６ Cycloalkyl groups, hydroxy groups, amino groups, -SO(C １ ~C ６ alkyl group), -S(O) ２ (C １ ~C ６ alkyl group), and C １ ~C ６ alkylthio groups; B does not exist or C ３ ~C １２ Cycloalkyl group, R ８ Substitution C ３ ~C １２ cycloalkyl group, 3- to 12-membered heterocycloalkyl group, R ８ substituted 3- to 12-membered heterocycloalkyl group, 3- to 12-membered heterocycloalkanone group, R ８ Substituted 3- to 12-membered heterocycloalkanone group, C ３ ~C １２ cycloalkyl-substituted amino groups, and 3- to 12-membered heterocycloalkyl-substituted amino groups, or a group of the formula: is selected from R ８ is C １ ~C ６ Alkyl group, C ３ ~C １２ Cycloalkyl group, 3- to 12-membered heterocycloalkyl group, amino group, cyano-substituted C １ ~C ６ Alkyl group, halogen, C １ ~C ６ Alkoxy group, halogen-substituted C １ ~C ６ selected from alkyl groups, hydroxy groups, and amino groups

2. E is R ５ Substitution C １ ~C ６ Alkyl group, C ３ ~C １０ a cycloalkyl group and R ６ Substitution C ３ ~C １０ cycloalkyl groups, R ５ is C ６ ~C １０ Cycloalkyl group, methyl-substituted C ６ ~C １０ Cycloalkyl groups and halogen-substituted C ６ ~C １０ cycloalkyl groups, R ６ is a halogen and C １ ~C ３ 2. The pyridopyrimidine compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to claim 1, wherein the aryl group is selected from the group consisting of aryl, arylsulfonyl ...

3. E is a cyclopropyl group or a group of the formula: wherein x is an integer of 0 to 3, and y is an integer of 0 to 3. The pyridopyrimidine compound, its pharmaceutically acceptable salt, or its stereoisomer according to claim 1,

4. L is a group of the formula: wherein n and m are each independently an integer of 0 to 14. The pyridopyrimidine compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to claim 1,

5. L is a group of the formula: wherein n is an integer of 0 to 7, and m is an integer of 0 to 3. The pyridopyrimidine compound, its pharmaceutically acceptable salt, or its stereoisomer according to claim 4,

6. L is a group of the formula: The pyridopyrimidine compound or its pharmaceutically acceptable salt or its stereoisomer according to claim 1, characterized in that n is selected from the group consisting of:

7. Y is -CH ２ The pyridopyrimidine compound or its pharmaceutically acceptable salt or stereoisomer according to claim 1, wherein Z is selected from -, -CO-, and -O-, or is absent, and Z is selected from -NHCO- and -NH-, or is absent.

8. R １ is a halogen and C １ ~C ３ 2. The pyridopyrimidine compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to claim 1, wherein the aryl group is selected from the group consisting of aryl, arylsulfonyl ...

9. R ２ is C ５ ~C １０ Cycloalkyl group, R ９ Substitution C ５ ~C １０ Cycloalkyl group, 5- to 10-membered heterocycloalkyl group, R ９ Substituted 5- to 10-membered heterocycloalkyl groups, C ６ ~C １０ aryl group, R ９ Substitution C ６ ~C １０ aryl group, 5- to 10-membered heteroaryl group, R ９ Substituted 5- to 10-membered heteroaryl groups, 5- to 10-membered heteroaryl ketone groups, and R ９ substituted 5- to 10-membered heteroaryl ketone groups; R ９ is an amino group, -N(C １ ~C ６ alkyl group) ２ , halogen, C １ ~C ６ Alkyl group, C １ ~C ６ Alkoxy group, halogen-substituted C １ ~C ６ Alkyl group, halogen-substituted C １ ~C ６ Alkoxy group, —NH(R ４ ), -N(R ４ ) ２ , -O(R ４ ), -C=O-NH(R ４ ), -C=O-NH(C ３ ~C ６ cycloalkyl group), R １０ Substitution C １ ~C ６ Alkyl group, C ３ ~C １０ Cycloalkyl group, 3- to 10-membered heterocycloalkyl group, R １０ Substitution C ３ ~C １０ Cycloalkyl group, R １０ substituted 3- to 10-membered heterocycloalkyl group, —NH(R ４ ) a substituted 3- to 10-membered heterocycloalkyl group, a 5- to 10-membered heteroaryl group, and —COR １１ is selected from R ４ represents hydrogen, an amino group, an ester group, a carboxy group, a hydroxy group, a mercapto group, a sulfone group, a sulfoxide group, C １ ~C １５ alkyl group, R １０ Substitution C １ ~C １５ Alkyl group, C ３ ~C １５ cycloalkyl group, 3- to 15-membered heterocycloalkyl group, R １０ Substitution C ３ ~C １５ Cycloalkyl group, R １０ a substituted 3- to 15-membered heterocycloalkyl group, and —COR １１ is selected from R １０ is C １ ~C ６ Alkyl group, amino-substituted C １ ~C ６ Alkyl group, C ３ ~C ６ Cycloalkyl group, dimethylamino-substituted C １ ~C ６ alkyl group, 3- to 6-membered heterocycloalkyl group, dimethylamino group, C １ ~C ３ Alkoxy-substituted C １ ~C ６ Alkyl group, hydroxy-substituted C １ ~C ６ Alkyl group, C １ ~C ６ Alkyl-substituted 3- to 6-membered heterocycloalkyl groups, C １ ~C ６ Alkyl acyl group, hydroxy group, C １ ~C ６ Alkyl-substituted C ３ ~C ６ cycloalkyl groups, dimethylaminoethyl-substituted 5- to 6-membered heterocycloalkyl groups, and C １ ~C ６ alkoxy groups, R １１ is a vinyl group, C １ ~C ６ Alkyl group, amino-substituted C １ ~C ６ Alkyl group, C ３ ~C ６ Cycloalkyl group, amino-substituted C ３ ~C ６ Cycloalkyl group, halogen-substituted C ３ ~C ６ Cycloalkyl groups, 3- to 6-membered heterocycloalkyl groups, C １ ~C ６ Alkyl-substituted 3- to 6-membered heterocycloalkyl group, dimethylamino-substituted C １ ~C ６ 2. The pyridopyrimidine compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, according to claim 1, wherein the aryl group is selected from the group consisting of an alkyl group and a dimethylaminoethyl-substituted 5- to 6-membered heterocycloalkyl group.

10. R ２ is a phenyl group or a group of the formula: is selected from Here, R ４ is a group of the following formula: The pyridopyrimidine compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to claim 1, wherein the compound is selected from the group consisting of:

11. R ２ is C ５ ~C ８ Cycloalkyl group, R ９ Substitution C ５ ~C ８ Cycloalkyl group, 5- to 8-membered heterocycloalkyl group, R ９ substituted 5- to 8-membered heterocycloalkyl group, phenyl group, R ９ Substituted phenyl groups, 5- to 6-membered heteroaryl groups, and R ９ substituted 5-6 membered heteroaryl groups; R ９ is H, dimethylamino group, amino group, halogen, C １ ~C ３ Alkyl group, C １ ~C ３ Alkoxy group, halogen-substituted C １ ~C ３ Alkyl group, halogen-substituted C １ ~C ３ Alkoxy group, —NH(R ４ ), -N(R ４ ) ２ , -OR ４ , —C═O—NH (cyclopropyl group), R １０ Substitution C １ ~C ３ Alkyl group, C ３ ~C ６ Cycloalkyl group, 3- to 6-membered heterocycloalkyl group, R １０ Substitution C ３ ~C ６ Cycloalkyl group, R １０ substituted 3- to 6-membered heterocycloalkyl group, —NH(R ４ ) a substituted 3- to 6-membered heterocycloalkyl group, and —COR １１ is selected from R ４ is H, C １ ~C ６ alkyl group, R １０ Substitution C １ ~C ６ Alkyl group, C ３ ~C ６ Cycloalkyl group, 3- to 6-membered heterocycloalkyl group, R １０ Substitution C ３ ~C ６ Cycloalkyl group, R １０ substituted 3- to 6-membered heterocycloalkyl group, —CH ２ R １１ , and -COR １１ is selected from R １０ is C １ ~C ３ Alkyl group, dimethylamino group, C ３ ~C ６ Cycloalkyl groups, 3- to 6-membered heterocycloalkyl groups, C １ ~C ３ Alkyl-substituted 3- to 6-membered heterocycloalkyl groups, and C １ ~C ３ Alkyl-substituted C ３ ~C ６ cycloalkyl groups, R １１ is a vinyl group, C １ ~C ４ Alkyl group, C ３ ~C ６ Cycloalkyl groups and halogen-substituted C ３ ~C ６ 2. The pyridopyrimidine compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to claim 1, wherein the cycloalkyl group is selected from the group consisting of cycloalkyl groups.

12. R ２ is C ５ ~C ６ Cycloalkyl group, R ９ Substitution C ５ ~C ６ Cycloalkyl group, 5- to 6-membered heterocycloalkyl group, R ９ a substituted 5- to 6-membered heterocycloalkyl group, a phenyl group, and R ９ substituted phenyl groups; R ９ is H, dimethylamino group, amino group, C １ ~C ３ alkyl group, —NH(R ４ ), -OR ４ , —C═O—NH (cyclopropyl group), R １０ Substitution C １ ~C ３ Alkyl group, C ３ ~C ６ Cycloalkyl group, 5- to 6-membered heterocycloalkyl group, R １０ Substitution C ３ ~C ６ Cycloalkyl group, R １０ Substituted 5- to 6-membered heterocycloalkyl groups, and —COR １１ is selected from R ４ is H, C １ ~C ３ alkyl group, R １０ Substitution C １ ~C ３ Alkyl group, C ３ ~C ６ Cycloalkyl group, 5- to 6-membered heterocycloalkyl group, R １０ Substitution C ３ ~C ６ Cycloalkyl group, R １０ substituted 5- to 6-membered heterocycloalkyl group, —CH ２ R １１ , and -COR １１ is selected from R １０ is C １ ~C ３ Alkyl groups and C ３ ~C ６ cycloalkyl groups, R １１ is a vinyl group, C １ ~C ４ Alkyl groups and C ３ ~C ６ 12. The pyridopyrimidine compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, according to claim 11, wherein the cycloalkyl group is selected from the group consisting of cycloalkyl groups.

13. R ２ is a group of the following formula: is selected from Here, R ９ is H, dimethylamino group, C １ ~C ３ alkyl group, —NH(R ４ ), -OR ４ , and -COR １１ is selected from R ４ is H, a methylpiperidinyl group, -CH ２ R １１ , and -COR １１ and R １１ is a vinyl group, C １ ~C ４ 12. The pyridopyrimidine compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, according to claim 11, wherein the group is selected from the group consisting of an alkyl group, a cyclopropyl group, a cyclobutyl group, and a cyclopentyl group.

14. A is a group of the formula: is selected from B is absent or a group of the formula: The pyridopyrimidine compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to claim 1, wherein the compound is selected from the group consisting of:

15. A is selected from -NH- and -NHR-, R is a phenylene group, a 6-membered heteroarylene group, R ７ a substituted phenylene group, and R ７ substituted 6-membered heteroarylene groups; R ７ is C １ ~C ３ Alkyl group, halogen, C １ ~C ３ Alkoxy group, halogen-substituted C １ ~C ３ Alkoxy group, halogen-substituted C １ ~C ３ Alkyl groups and cyano-substituted C １ ~C ３ alkyl groups, B does not exist or C ４ ~C １２ Cycloalkyl group, R ８ Substitution C ４ ~C １２ a cycloalkyl group, a 4- to 12-membered heterocycloalkyl group, or R ８ a substituted 4- to 12-membered heterocycloalkyl group, or a group of the formula: is selected from R ８ is C １ ~C ３ Alkyl group, C ４ ~C ６ Cycloalkyl groups, 4- to 6-membered heterocycloalkyl groups, cyano-substituted C １ ~C ３ Alkyl group, halogen, C １ ~C ３ Alkoxy group and halogen-substituted C １ ~C ３ 2. The pyridopyrimidine compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to claim 1, wherein the aryl group is selected from the group consisting of aryl, arylsulfonyl ...

16. A is selected from -NH- and -NHR-, R is a phenylene group, a 6-membered nitrogen-containing heteroarylene group, R ７ Substituted phenylene groups, and R ７ substituted 6-membered nitrogen-containing heteroarylene groups; R ７ is C １ ~C ３ alkoxy groups, B does not exist or C ４ ~C ８ Cycloalkyl group, R ８ Substitution C ４ ~C １０ Cycloalkyl groups, 4- to 10-membered heterocycloalkyl groups, and R ８ substituted 4-10 membered heterocycloalkyl groups or groups of the formula: is selected from R ８ is C １ ~C ３ Alkyl groups and C １ ~C ３ 16. The pyridopyrimidine compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to claim 15, wherein the aryl group is selected from the group consisting of aryl, aryl, aryl ...

17. R ３ is a group of the following formula: The pyridopyrimidine compound or its pharmaceutically acceptable salt or its stereoisomer according to claim 16, wherein the compound is selected from the group consisting of:

18. A pyridopyrimidine compound selected from the following compounds ZX-HYT-01 to ZX-HYT-123 and ZX-HYT-124, or a pharmaceutically acceptable salt or stereoisomer thereof.

19. Use of the pyridopyrimidine compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in the manufacture of an agent for degrading AKT3 protein.

20. Use of the pyridopyrimidine compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in the manufacture of a drug for preventing and / or treating a disease associated with the abnormal expression of AKT3 protein, wherein the disease associated with the abnormal expression of AKT3 protein is tumor, cardiovascular disease, diabetes, hypertension, muscular dystrophy, Parkinson's disease, or Alzheimer's disease.

21. Use of the pyridopyrimidine compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in the manufacture of a drug for preventing and / or treating a tumor, or for preventing tumor recurrence after surgery.

22. 22. The use of claim 21, wherein the tumor is non-small cell lung cancer, malignant melanoma, prostate cancer, kidney cancer, liver cancer, bladder cancer, ovarian cancer, colon cancer, rectal cancer, breast cancer, cervical cancer, lung cancer, laryngeal cancer, nasopharyngeal cancer, pancreatic cancer, multiple myeloma, B lymphoma, leukemia, or cutaneous squamous cell carcinoma.

23. 20. An AKT3 protein degrading agent, comprising the pyridopyrimidine compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, as an active ingredient.

24. A pharmaceutical composition for treating and / or preventing a tumor or preventing postoperative recurrence of a tumor, comprising: A pharmaceutical composition prepared using an active ingredient and a pharmaceutically acceptable carrier or excipient, wherein the active ingredient comprises a pyridopyrimidine compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

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