CN110914267B

CN110914267B - Pyrimidopyridone or pyridopyridone compound and application thereof

Info

Publication number: CN110914267B
Application number: CN201880047588.2A
Authority: CN
Inventors: 丁克; 丁健; 申佳奕; 耿美玉; 陆小云; 谢华; 孙敏; 宗在伟
Original assignee: Shanghai Institute of Materia Medica of CAS; Jinan University; Jiangsu Aosaikang Pharmaceutical Co Ltd
Current assignee: Shanghai Institute of Materia Medica of CAS; Jinan University; Jiangsu Aosaikang Pharmaceutical Co Ltd
Priority date: 2017-07-19
Filing date: 2018-07-17
Publication date: 2022-07-12
Anticipated expiration: 2038-07-17
Also published as: CN110914267A; WO2019015593A1

Abstract

A pyridopyrimidone or pyridopyridopyridopyridone compound having a structure of formula (i) or a pharmaceutically acceptable salt or a stereoisomer thereof or a prodrug molecule thereof. The compound can inhibit the 797 cysteine mutation of EGFR (epidermal growth factor receptor) into serine^C797S) The mutant has weak activity on wild EGFR, can effectively inhibit the growth of non-small cell lung cancer tumor cells, can be used for preparing antitumor drugs, is mainly used for clinical drug resistance of the 797 th cysteine mutated into serine (C797S) induced by the existing third-generation EGFR small molecule inhibitor anti-non-small cell lung cancer drugs such as Osimetinib (AZD9291), Olmutinib (HM6171) and Rociletinib (9, CO-1686), and has selectivity on wild non-small cell lung cancer.

Description

Pyrimidopyridone or pyridopyridone compound and application thereof

Technical Field

The invention relates to the field of chemical medicine, in particular to a pyrimidopyridone or pyridopyridone compound and application thereof.

Background

The tumor molecule targeted therapy is a therapeutic method based on selectively killing tumor cells by chemical or biological means through key molecules closely related to tumor growth. The targeted therapy is characterized in that: high specificity, strong selectivity and light toxic and side effects; when used in combination, it can enhance the curative effects of traditional chemotherapy and radiotherapy and reduce postoperative recurrence. Targeted drugs represented by imatinib mesylate (STI571) (Novartis, 2001), gefitinib (ZD1839) (AstraZeneca, 2003), erlotinib (OSI774) (Genentech and OSIP, 2004), sorafenib p-toluenesulfonate (Bay 43-9006) (Bayer and Onyx, 2005), sunitinib malate (SU11248) (Pfizer, 2006) and dasatinib (BMS-354825) (Bristol-Myers Squibb, 2006) opened a new era for tumor chemotherapy. Tumor-targeted therapy has developed rapidly in as few as a few years. The advent of tumor-targeted therapy has impacted traditional drug delivery concepts and modalities, e.g., targeted drugs often fail to reach dose-limiting toxicity and maximum tolerated dose in phase I clinical trials due to low toxic side effects; satisfactory efficacy can be achieved without the need for maximum tolerated doses with targeted therapeutic agents. Tumor-targeted therapy is a hotspot and development trend of tumor therapy.

Epidermal Growth Factor Receptor (EGFR), a receptor tyrosine protein kinase, regulates cell proliferation, survival, adhesion, migration and differentiation. EGFR is over-activated or persistently activated in a variety of tumor cells, such as lung cancer, breast cancer, prostate cancer, and the like. EGFR overexpression is present in about 62% of non-small cell lung cancer patients, and inhibition of EGFR significantly improves survival in a subset of patients. In addition, EGFR small-molecule inhibitor drugs Gefitinib and Erlotinib which are marketed in 2003-2004 are already used for treating advanced non-small cell lung cancer, and further define that EGFR is an effective target for treating non-small cell lung cancer.

The first generation of EGFR small molecule inhibitors have achieved significant clinical efficacy in patients carrying EGFR sensitive mutations, prolonging their survival. However, most of the benefited patients can develop drug resistance after using the drug for 10-12 months. Of these, more than 50% of drug resistant patients (carrying EGFR sensitive mutation) develop resistance due to the T790M secondary mutation in EGFR. The affinity of L858R/T790M secondarily mutated EGFR to ATP was stronger than that of L858R sensitive mutated EGFR, whereas the first generation drugs were ATP competitive inhibitors, thus leading to drug resistance.

Second generation irreversible EGFR inhibitors, although better results were obtained in preclinical studies, lack selectivity for wild-type EGFR (egfrwt) and are more toxic. Gilotrif, an EGFR irreversible inhibitor approved by the FDA in 2013, is effective in advanced NSCLC patients carrying activating EGFR mutation (L858R, del E746-A750), but still fails to address clinical resistance caused by the EGFRT790M mutation at the maximum clinically tolerated dose (MTD).

The third generation of an irreversible inhibitor, Osimertinib (AZD9291), which overcomes the resistance to EGFR T790M, was marketed under FDA accelerated approval in the us 11 months of 2015 (Cancer discovery 2014, 4(9), 1046-1061), which is clinically effective in treating advanced non-small cell lung Cancer patients with Epidermal Growth Factor Receptor (EGFR) T790M mutation or resistance to other EGFR inhibitors. Although the clinical treatment of the EGFRT790M mutant non-small cell lung cancer by the Osimetinib has great success, part of beneficial patients have drug resistance after 9-14 months of treatment (Nature Medicine 2015, 21(6), 560-2). It was found that up to 40% of resistant patients developed Osimertinib resistance due to the (EGFR) C797S point mutation. Further mechanistic studies have shown that point mutations in (EGFR) C797S convert the cysteine at position 797 to serine, resulting in the inability of Osimertinib to form covalent bonds with target proteins, ultimately leading to drug resistance. Currently, there is no clinically effective EGFR inhibitor against the new mutation (C797S) when administered alone. Therefore, a new type of highly selective EGFR inhibitor is urgently needed to solve the problems of drug resistance and the like caused by the point mutation of (EGFR) C797S.

Disclosure of Invention

Based on the above, the invention provides a novel pyrimidopyridone or pyridopyridone compound which can selectively inhibit the activity of the mutant EGFR and can overcome the drug resistance problem of the existing EGFR tyrosine kinase inhibitor.

The specific technical scheme is as follows:

a pyrimidopyridone or pyridopyridone compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof:

wherein, X is selected from: CH or N;

w is optionally selected from: h, D, CH₃，CD₃，CF₃，CH₂F，CHF₂，F，Cl，Br，C₂-C₅Alkyl radical, C₃-C₆Cycloalkyl, substituted C₃-C₆A cycloalkyl group;

l is optionally selected from:

(1)-(CH₂)_nNH-, wherein n is selected from an integer between 1 and 8;

(2)

wherein n is optionally selected from 0, 1, 2, 3;

(3)

wherein n is optionally selected from 0, 1, 2, 3;

(4)C₅-C₁₀mono-, bridged or cycloalkyls of (a);

R₁is optionally selected from:

(1)H，C₁～C₄an alkoxy group;

(2)

wherein R is₄Is optionally selected from C₁-C₆Alkyl radical, C₃-C₆A cycloalkyl group;

(3)(CH₂)_ny, N is 0 to 6, Y is selected from halogen, hydroxy, amino, (N-methyl) amino, (N, N-dimethyl) amino;

R₂is optionally selected from:

(1)H，C₁-C₃alkyl radical, C₃-C₆Cycloalkyl, substituted C₃-C₆A cycloalkyl group;

(2)

wherein n is selected from 0, 1 and 2; a. the₁，A₂，A₃，A₄，A₅Each independently selected from:

(a) hydrogen, halogen, C₁～C₄Alkyl radical, C₃～C₆Cycloalkyl, substituted C ₃～C₆Cycloalkyl radical, C₁～C₄Alkoxy radical, C₁～C₆Fluorine-containing alkyl group, C₁～C₆Containing hetero atom alkyl radicals, NO₂，CN，COOH，CONH₂；

(b)

Wherein R is₅，R₆Are each independently selected from C₁～C₅Alkyl radical, C₃～C₆Cycloalkyl, substituted C₃～C₆Cycloalkyl radical, R₅And R₆A 4-to 8-membered saturated heterocyclic ring containing 1 to 3 heteroatoms formed by ring closure, R₅And R₆4-8 membered aromatic heterocyclic ring containing 1-3 hetero atoms formed by cyclization;

(c) a 5-or 6-membered aromatic group containing one or more nitrogen atoms and bearing 0 to 3 substituents, selected from:

(d)A₁，A₂，A₃，A₄，A₅a 5-12 membered saturated carbocyclic or heterocyclic ring containing 0-3 heteroatoms is formed between any two adjacent substituents;

R₃is optionally selected from:

(1)C₁-C₆alkyl radical, C₃-C₆A cycloalkyl group;

(2)

wherein B is₁，B₂，B₃，B₄，B₅Each independently selected from:

(a) h, halogen, substituted or unsubstituted C₁～C₆Alkyl, substituted ethoxy, C₁～C₄Alkoxy radical, C₁～C₃Fluoroalkyl, substituted or unsubstituted C₄～C₆Containing hetero atom alkyl group, C₄～C₉Heterocyclic group or amide, nitro group, cyano group formed by the heterocyclic group;

(b)

wherein R is₅，R₆Each independently selected from substituted or unsubstituted C₁～C₅Alkyl radical, C₃～C₆Cycloalkyl, substituted C₃～C₆Cycloalkyl radical, R₅And R₆A ring closure forming a substituted or unsubstituted 4-to 8-membered saturated heterocyclic ring containing 1 to 3 heteroatoms, R₅And R₆A ring closure forming a substituted or unsubstituted 4-to 8-membered heteroaromatic ring containing 1 to 3 heteroatoms, R ₅And R₆A ring closure forming a substituted or unsubstituted 8-12 membered saturated spirocyclic ring containing 1-3 heteroatoms, R₅And R₆A ring closure forming a substituted or unsubstituted 8-12 membered saturated fused ring containing 1-3 heteroatoms, R₅And R₆A ring closure to form a substituted or unsubstituted 8-12 membered saturated bridged ring containing 1-3 heteroatoms;

(c) a 5-or 6-membered aromatic radical containing one or more nitrogen atoms and bearing 0 to 3 substituents, selected from:

(d)B₁，B₂，B₃，B₄，B₅any two adjacent substituents form a 5-12 membered saturated carbocyclic or heterocyclic ring containing 0-3 heteroatoms.

In some of these embodiments, the compound has the structure of formula (II):

in some of these embodiments, A₁，A₂，A₃，A₄，A₅Each independently selected from: a. the₁，A₂，A₃，A₄，A₅Each independently selected from: hydrogen, halogen, C₁～C₄Alkyl radical, C₃～C₆Cycloalkyl radical, C₁～C₄Alkoxy, N, N-dimethylaminoethoxy, N, N-dimethylaminopropoxy, 2- (N-methylpiperazinyl) ethoxy, 2- (N-acetylpiperazinyl) ethoxy, 2-morphinylethoxy, 2-thiomorpholinylethoxy, 2-piperidinylethoxy, 2-tetrahydropyrrolylethoxy, N-methylpiperazinyl, morphininyl, thiomorpholine, piperidine, tetrahydropyrrole, imidazole, 3-N, N-dimethyltetrahydropyrrole, 4-N, N-dimethylpiperidine, 4-acetylpiperazine, 1-methyl-4- (piperazine-4-substituted) piperidine, 4- (4-methylpiperazine-1-substituted) methyl, 1-methylpiperidin-4-amino, 4-piperazin-2-one, 1-methyl-4-piperazin-2-one, and esters, amides, sulfones, sulfoxides, ureas formed from the above groups.

In some of these embodiments, A₁，A₂，A₃，A₄，A₅Each independently selected from: hydrogen, halogen, C₁～C₄Alkyl radical, C₃～C₆Cycloalkyl radical, C₁～C₄An alkoxy group.

In some of these embodiments, A₁，A₂，A₃，A₄，A₅Each independently selected from:hydrogen, chlorine, fluorine, methyl, methoxy.

In some of these embodiments, W is selected from H, C₁-C₅An alkyl group.

In some of these embodiments, L is selected from:

in some of these embodiments, L is selected from:

in some of these embodiments, L is selected from:

in some of these embodiments, R₁Is optionally selected from:

wherein R is₄Optionally selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, neopentyl, cyclopentyl, cyclohexyl.

In some of these embodiments, R₁Is optionally selected from:

In some of these embodiments, the compound has the structure shown in formula III, formula IV, formula V, or VI:

in some of these embodiments, R₃Is optionally selected from:

in some of these embodiments, B₁，B₂，B₃，B₄，B₅Each independently selected from: h, substituted or unsubstituted C₁～C₆Alkyl, halogen, C ₁-C₄Alkoxy radical, C₁～C₃Fluoroalkyl, substituted ethoxy, substituted or unsubstituted C₄～C₉A heterocyclic group,

and esters, amides, sulfones, sulfoxides, ureas formed from the above groups;

wherein R is₅，R₆Each independently selected from substituted or unsubstituted C₁～C₅Alkyl radical, R₅And R₆A ring closure forming a substituted or unsubstituted 4-to 8-membered saturated heterocyclic ring containing 1 to 3 heteroatoms, R₅And R₆A ring closure forming a substituted or unsubstituted 4-to 8-membered heteroaromatic ring containing 1 to 3 heteroatoms, R₅And R₆A ring-closure forming a substituted or unsubstituted 8-12 membered saturated spirocyclic ring containing 1-3 heteroatoms, R₅And R₆A ring closure forming a substituted or unsubstituted 8-12 membered saturated fused ring containing 1-3 heteroatoms, R₅And R₆And (3) a ring closure to form a substituted or unsubstituted 8-12 membered saturated bridged ring containing 1-3 heteroatoms.

In some of these embodiments, B₁，B₂，B₃，B₄，B₅Each independently selected from: h, C₁～C₆Alkyl, halogen, C₁-C₄Alkoxy radical, C₁～C₃A fluoroalkyl group, an N, N-dimethylaminoethoxy group, an N, N-dimethylaminopropoxy group,2- (N-methylpiperazinyl) ethoxy, 2- (N-acetylpiperazinyl) ethoxy, 2-morphinylethoxy, 2-thiomorpholinylethoxy, 2-piperidinylethoxy, 2-tetrahydropyrrolylethoxy, N-methylpiperazinyl, N-ethylpiperazinyl, piperazinyl, (R) -3, 4-dimethylpiperazinyl, (S) -3, 4-dimethylpiperazinyl, 4-isopropylpiperazin-1-yl, (3S, 5R) -3, 4, 5-trimethylpiperazin-1-yl, morphininyl, thiomorpholine, piperidinyl, 4- (dimethylamino) piperidinyl, tetrahydropyrrolyl, imidazolyl, 3-N, N-dimethyltetrahydropyrrolyl, 4-N, n-dimethylpiperidinyl, 4-acetylpiperazine, 1-methyl-4- (piperazin-4-substituted) piperidinyl, 4- (4-methylpiperazin-1-yl) piperidinyl, 4- (4-methylpiperazin-1-substituted) methyl, 1-methylpiperidin-4-amino, 4-piperazin-2-one, 1-methyl-4-piperazin-2-one, 7-methyl-2, 7-diazaspiro [3.5 ]Nonan-2-yl, 9-methyl-3, 9-diazaspiro [5.5 ]]Undecane-3-yl, 3-methyl-1, 3-diazepan-1-yl, (1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1]Hept-2-yl, (2- (dimethylamino) ethyl) (methyl) amino, (3AR, 6AS) -5-methylhexahydropyrrolo [3, 4-c)]Pyrrol-2 (1H) -yl, 4- (oxetan-3-yl) piperazine, 4-ethylpiperazin-1-yl) methyl, piperazin-1-ylmethyl, as well as esters, amides, sulfones, sulfoxides, ureas of the foregoing.

In some of these embodiments, B₁，B₂，B₃，B₄，B₅Each independently selected from: h, C₁～C₃Alkyl, halogen, 4-methylpiperazin-1-yl, 4-isopropylpiperazin-1-yl, piperidinyl, 9-methyl-3, 9-diazaspiro [5.5]Undecane-3-yl, 3-methyl-1, 3-diazepan-1-yl, (1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1]Hept-2-yl, (2- (dimethylamino) ethyl) (methyl) amino, 4- (dimethylamino) piperidin-1-yl, 7-methyl-2, 7-diazaspiro [3.5 ]]Nonan-2-yl, (R) -3, 4-dimethylpiperazin-1-yl, (3S, 5R) -3, 4, 5-trimethylpiperazin-1-yl, (R) -3-methylpiperazin-1-yl, 4- (4-methylpiperazin-1-yl) piperidin-1-yl.

In some of these embodiments, B₁，B₂，B₄，B₅Each independently selected from: h, C ₁～C₃Alkyl, halogen; b is₃Selected from: 4-methylpiperazin-1-yl, 4-isopropylpiperazin-1-yl, piperidinyl, 9-methyl-3, 9-diazaspiro [5.5]Undecane-3-yl, 3-methyl-1, 3-diazepan-1-yl, (1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1]Hept-2-yl, (2- (dimethylamino) ethyl) (methyl) amino, 4- (dimethylamino) piperidin-1-yl, 7-methyl-2, 7-diazaspiro [3.5 ]]Nonan-2-yl, (R) -3, 4-dimethylpiperazin-1-yl, (3S, 5R) -3, 4, 5-trimethylpiperazin-1-yl, (R) -3-methylpiperazin-1-yl, 4- (4-methylpiperazin-1-yl) piperidin-1-yl.

In some of these embodiments, W is selected from: h, methyl; x is selected from N;

R₁selected from:

wherein R is₄Selected from the group consisting of: methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, neopentyl, cyclopentyl, cyclohexyl;

R₂selected from:

wherein n is 0; a. the₁，A₂，A₃，A₄，A₅Each independently selected from: hydrogen, chlorine, fluorine;

B₁，B₂，B₃，B₄，B₅each independently selected from: h, methyl, halogen, 4-methylpiperazin-1-yl, piperidinyl, 9-methyl-3, 9-diazaspiro [5.5]Undecane-3-yl, 3-methyl-1, 3-diazepan-1-yl, (1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1 ]Hept-2-yl, (2- (dimethylamino) ethyl) (methyl) amino, 4- (dimethylamino) piperidin-1-yl, 7-methyl-2, 7-diazaspiro [3.5 ]]Nonan-2-yl, (R) -3, 4-dimethylpiperazin-1-yl, (3S, 5R) -3, 4, 5-trimethylpiperazin-1-yl, (R) -3-methylpiperazin-1-yl, 4- (4-methylpiperazin-1-yl) piperidin-1-yl;

l is selected from:

in some of these embodiments, W is H; r₄Selected from: methyl, ethyl, n-propyl, isopropyl, cyclopropyl; a. the₁Is chlorine, A₂，A₃，A₄，A₅Are all hydrogen; b is₂Is methyl, B₃Is 4-methylpiperazin-1-yl, B₁，B₄，B₅Are all H; l is selected from:

in some of these embodiments, W is methyl; r₄Selected from: methyl, ethyl, n-propyl, isopropyl, cyclopropyl; a. the₁Is chlorine, A₂，A₃，A₄，A₅Are all hydrogen; b is₂Is methyl, B₃Is 4-methylpiperazin-1-yl, B₁，B₄，B₅Are all H; l is selected from:

in some of these embodiments, the compound is selected from:

6- (2-chlorophenyl) -8-cyclohexyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

6- (2-chlorophenyl) -8-cyclopentyl-5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7- (8H) -one,

N- ((1R, 4R) -4- (6- (2-chlorophenyl) -2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 13-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propanamide,

N- ((1R, 4R) -4- (6- (2-chlorophenyl) -2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) acetamide,

N- ((1R, 4R) -4- (6- (2-chlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propanamide,

N- ((1R, 4R) -4- (6- (2-chlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) acetamide,

N- ((1R, 4R) -4- (2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxo-6-phenylpyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) acetamide,

N- ((1R, 4R) -4- (2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxo-6-phenylpyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propanamide,

N- ((1R, 4R) -4- (6- (3-chlorophenyl) -2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) acetamide,

N- ((1R, 4R) -4- (6- (3-chlorophenyl) -2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 13-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propanamide,

6- (2-chlorophenyl) -2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -8- (1-acetylpiperidin-4-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

S) -8- (1-acetylpyrrol-3-yl) -6- (2-chlorophenyl) -2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one

6- (2-chlorophenyl) -2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -8- (1-propionylpiperidin-4-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -6- (2-chlorophenyl) -2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -8- (1-propionylpyrrolidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

6- (2-chlorophenyl) -8-cyclohexyl-5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7- (8H) -one,

6- (3-chlorophenyl) -8-cyclohexyl-5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7- (8H) -one,

8-cyclohexyl-5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -6-phenylpyrido [2, 3-d ] pyrimidin-7 (8H) -one,

8-cyclohexyl-6- (2-fluorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7- (8H) -one,

8-cyclohexyl-5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -6- (o-tolyl) pyrido [2, 3-d ] pyrimidin-7- (8H) -one,

8-cyclohexyl-6- (2-methoxyphenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7- (8H) -one,

6- (4-chlorophenyl) -8-cyclohexyl-5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7- (8H) -one,

8- ((3S, 5S, 7S) -adamantan-1-yl) -6- (2-chlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

8-cyclohexyl-5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

8-cyclopentyl-5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -6-phenylpyrido [2, 3-d ] pyrimidin-7 (8H) -one,

6- (3-chlorophenyl) -8-cyclopentyl-5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7- (8H) -one,

N- ((1R, 4R) -4- (6- (4-chlorophenyl) -2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) acetamide,

N- ((1R, 4R) -4- (6- (4-chlorophenyl) -2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propanamide,

(S) -8- (1-acetyl-3-yl) -6- (2-chlorophenyl) -2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -6- (2-chlorophenyl) -2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -8- (1-propionylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -8- (1-acetyl-3-yl) -6- (2-chlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -6- (2-chlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -8- (1-propionylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -8- (1-acetyl-3-yl) -6- (3-chlorophenyl) -2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -6- (3-chlorophenyl) -2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -8- (1-propionylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -8- (1-acetyl-3-yl) -6- (3-chlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -6- (3-chlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -8- (1-propionylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -8- (1-propionyl-3-yl) -6- (2-chlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

8- (1-acetylpiperidin-4-yl) -6- (2-chlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

6- (2-chlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -8- (1-propylpiperidin-4-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -8- (1-acetyl-3-yl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -6- (o-tolyl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -8- (1-propionyl-3-yl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -6- (o-tolyl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(R) -8- (1-acetylpyrrolidin-3-yl) -6- (2-chlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(R) -8- (1-propionylpyrrolidin-3-yl) -6- (2-chlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -8- (1-acetyl-3-yl) -6- (2, 5-dichlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -8- (1-propionyl-3-yl) -6- (2, 5-dichlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -8- (1-acetyl-3-yl) -6- (4-chlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -8- (1-propionyl-3-yl) -6- (4-chlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -8- (1-acetyl-3-yl) -6- (2, 4-dichlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -8- (1-propionyl-3-yl) -6- (2, 4-dichlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -6- (2-methoxyphenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -8- (1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -8- (1-acetyl-3-yl) -6- (2-fluorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -8- (1-propionyl-3-yl) -6- (2-fluorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -8- (1-acetyl-3-yl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -6-phenylpyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -8- (1-propionyl-3-yl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -6-phenylpyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -8- (1-acetyl-3-yl) -6- (3, 5-dichlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -8- (1-propionyl-3-yl) -6- (3, 5-dichlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

N- ((1S, 4S) -4- (6- (2-chlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) acetamide,

N- ((1S, 4S) -4- (6- (2-chlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propanamide,

(S) -8- (1-acetyl-3-yl) -6- (2-methoxypyrimidin-5-yl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -6- (2-methoxypyrimidin-5-yl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -8- (1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -8- (1-acetyl-3-yl) -6- (2-chloro-4-fluorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -8- (1-propionyl-3-yl) -6- (2-chloro-4-fluorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -8- (1-acetyl-3-yl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -6- (pyridin-4-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -8- (1-propionyl-3-yl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -6- (pyridin-4-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -8- (1-acetyl-3-yl) -6- (2-fluoropyridin-4-yl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -8- (1-propionyl-3-yl) -6- (2-fluoropyridin-4-yl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -8- (1-propionyl-3-yl) -6- (2-chloro-4-methoxyphenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -8- (1-acetyl-3-yl) -6- (3-chloropyridin-4-yl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -8- (1-propionyl-3-yl) -6- (3-chloropyridin-4-yl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -8- (1-acetyl-3-yl) -6- (furan-3-yl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -8- (1-propionyl-3-yl) -6- (furan-3-yl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -6- (2-chloro-3-fluorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -8- (1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -6- (2-chloro-4-fluorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -8- (1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

N- ((1S, 4S) -4- (6- (2-chloro-5-fluorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) acetamide,

N- ((1S, 4S) -4- (6- (2-chloro-5-fluorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propanamide,

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propanamide,

N- ((1S, 4S) -4- (6- (2-chloro-4-fluorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propanamide,

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) cyclopropanecarboxamide,

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) pivaloamide,

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -5-methyl-2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) cyclopentanecarboxamide,

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) cyclobutane,

N- ((1R, 4R) -4- (6- (2-chloro-3-fluorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) butanamide,

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) cyclohexanecarboxamide,

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) -3, 3-dimethylbutanamide,

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) acetamide,

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) pentanamide,

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) -3-methylbutanamide,

(S) -6- (2-chlorophenyl) -5-methyl-2- ((6-methyl-5- (4-methylpiperazin-1-yl) pyridin-2-yl) amino) -8- (1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -6- (2-chlorophenyl) -5-methyl-2- ((5- (4-methylpiperazin-1-yl) pyridin-2-yl) amino) -8- (1-propionylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -6- (2-chlorophenyl) -5-methyl-2- ((5- (piperazin-1-yl) pyridin-2-yl) amino) -8- (1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -6- (2-chlorophenyl) -2- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -3-methylphenyl) amino) -5-methyl-8- (1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one, pharmaceutically acceptable salts thereof, and pharmaceutically acceptable salts thereof,

(S) -6- (2-chlorophenyl) -2- ((5- ((4-ethylpiperazin-1-yl) methyl) pyridin-2-yl) amino) -5-methyl-8- (1-propionylpiperidin) pyridin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -6- (2-chlorophenyl) -5-methyl-2- ((3-methyl-4- (piperidin-4-yl) phenyl) amino) -8- (1-propionylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -6- (2-chlorophenyl) -2- ((2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) amino) -5-methyl-8- (1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -6- (2-chlorophenyl) -2- ((4- (4- (dimethylamino) piperidin-1-yl) -3-methylphenyl) amino) -5-methyl-8- (1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -6- (2-chlorophenyl) -5-methyl-2- ((3-methyl-4- (9-methyl-3, 9-diazaspiro [5.5] undecan-3-yl) phenyl) amino) -8- (1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -6- (2-chlorophenyl) -5-methyl-2- ((3-methyl-4- (7-methyl-2, 7-diazaspiro [3.5] non-2-yl) phenyl) amino) -8- (1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

6- (2-chlorophenyl) -5-methyl-2- ((3-methyl-4- ((3AR, 6AS) -5-methylhexahydropyrrolo [3, 4-c ] pyrrol-2 (1H) -yl) phenyl) amino) -8- ((S) -1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -6- (2-chlorophenyl) -5-methyl-2- ((3-methyl-4- (3-methyl-1, 3-diazepan-1-yl) phenyl) amino) -8- (1-propionylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

6- (2-chlorophenyl) -2- ((4- ((S) -3, 4-dimethylpiperazin-1-yl) -3-methylphenyl) amino) -5-methyl-8- ((S) -1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

6- (2-chlorophenyl) -2- ((4- ((R) -3, 4-dimethylpiperazin-1-yl) -3-methylphenyl) amino) -5-methyl-8- ((S) -1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

6- (2-chlorophenyl) -5-methyl-2- ((3-methyl-4- ((3S, 5R) -3, 4, 5-trimethylpiperazin-1-yl) phenyl) amino) -8- ((S) -1-propionylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -6- (2-chlorophenyl) -5-methyl-2- ((3-methyl-4- (4- (oxetan-3-yl) piperazin-1-yl) phenyl) amino) -8- (1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -8- (1-propionyl-3-yl) -6- (2-chlorophenyl) -5-methyl-2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -6- (2-chlorophenyl) -5-methyl-2- ((2-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -8- (1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -2- ((3-chloro-4- (4-methylpiperazin-1-yl) phenyl) amino) -6- (2-chlorophenyl) -5-methyl-8- (1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -6- (2-chlorophenyl) -5-methyl-2- ((4- (4-methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl) amino) -8- (1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -6- (2-chlorophenyl) -2- ((3-fluoro-4- (4-methylpiperazin-1-yl) phenyl) amino) -5-methyl-8- (1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -6- (2-chlorophenyl) -2- ((3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) -5-methyl-8- (1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -6- (2-chlorophenyl) -2- ((1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl) amino) -5-methyl-8- (1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -6- (2-chlorophenyl) -2- ((1- (2- (diethylamino) ethyl) -1H-pyrazol-4-yl) amino) -5-methyl-8- (1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt thereof,

(S) -6- (2-chlorophenyl) -5-methyl-2- ((5- ((4-methylpiperazin-1-yl) methyl) pyridin-2-yl) amino) -8- (1-propionylpiperidin) pyridin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -6- (2-chlorophenyl) -2- ((4- ((4-ethylpiperazin-1-yl) methyl) -3-methylphenyl) amino) -5-methyl-8- (1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -6- (2-chlorophenyl) -2- ((4- (4-ethylpiperazin-1-yl) -3-methylphenyl) amino) -5-methyl-8- (1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -6- (2-chlorophenyl) -5-methyl-2- ((3-methyl-4- (piperazin-1-yl) phenyl) amino) -8- (1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

(S) -6- (2-chlorophenyl) -5-methyl-2- ((5- (piperazin-1-ylmethyl) pyridin-2-yl) amino) -8- (1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

6- (2-chlorophenyl) -5-methyl-2- ((3-methyl-4- ((1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) phenyl) amino) -8- ((S) -1-propionylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

6- (2-chloro-3-fluorophenyl) -5-methyl-2- ((3-methyl-4- ((1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) phenyl) amino) -8- ((S) -1-propionylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one,

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -2- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -3-methylphenyl) amino) -5-methyl-7-oxopyrido [2, 3-d ] pyrimidin-8 (7H-yl) cyclohexyl) propanamide,

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -5-methyl-2- ((3-methyl-4- (piperidin-4-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propanamide,

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -2- ((4- (4- (dimethylamino) piperidin-1-yl) -3-methylphenyl) amino) -5-methyl-7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propanamide,

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -5-methyl-2- ((3-methyl-4- (9-methyl-3, 9-diazaspiro [5.5] undecan-3-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propanamide,

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -5-methyl-2- ((3-methyl-4- (7-methyl-2, 7-diazaspiro [3.5] nonan-2-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propanamide,

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -5-methyl-2- ((3-methyl-4- (3-methyl-1, 3-diazepan-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propanamide,

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -2- ((4- ((R) -3, 4-dimethylpiperazin-1-yl) -3-methylphenyl) amino) -5-methyl-7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propanamide,

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -5-methyl-2- ((3-methyl-4- ((3S, 5R) -3, 4, 5-trimethylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propanamide,

N- ((1S, 4S) -4- (6- (2-chlorophenyl) -5-methyl-2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 13-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propanamide,

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -2- ((3-chloro-4- (4-methylpiperazin-1-yl) phenyl) amino) -5-methyl-7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propanamide,

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -2- ((4- (4-ethylpiperazin-1-yl) -3-methylphenyl) amino) -5-methyl-7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propanamide,

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -5-methyl-2- ((3-methyl-4- ((1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propanamide,

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -2- ((3-chloro-4- ((R) -3-methylpiperazin-1-yl) phenyl) amino) -5-methyl-7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propanamide,

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -2- ((3-chloro-4- (3-methyl-1, 3-diazepan-1-yl) phenyl) amino) -5-methyl-7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propanamide,

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -2- ((3-chloro-4- ((R) -3, 4-dimethylpiperazin-1-yl) phenyl) amino) -5-methyl-7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propanamide,

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -5-methyl-2- ((3-methyl-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propanamide,

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -2- ((4- (4-isopropylpiperazin-1-yl) -3-methylphenyl) amino) -5-methyl-7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propanamide.

The invention also provides application of the pyridopyrimidone or pyridopyridopyridopyridone compound or pharmaceutically acceptable salt thereof or stereoisomer thereof or prodrug molecule thereof.

The specific technical scheme is as follows:

the pyridopyrimidone or pyridopyridopyridone compound or the pharmaceutically acceptable salt thereof or the stereoisomer thereof or the prodrug molecule thereof is applied to the preparation of the mutant EGFR inhibitor.

The pyridopyrimidone or pyridopyridopyridone compound or the pharmaceutically acceptable salt thereof or the stereoisomer thereof or the prodrug molecule thereof can be applied to the preparation of the drugs for preventing and treating tumors.

In some of these embodiments, the tumor is a malignant tumor in which the EGFR gene is mutated.

In some of these embodiments, the tumor comprises: non-small cell lung cancer, malignant melanoma, prostate cancer, renal 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.

In some of these embodiments, the tumor is EGFR^{L858R/T790MC797S}Mutant non-small cell lung cancer.

The invention also provides a pharmaceutical composition for preventing and treating tumors.

The technical scheme is as follows:

the active ingredient of the pharmaceutical composition for preventing and treating the tumors comprises the pyridopyrimidone or the pyridopyridopyridopyridone compound or the pharmaceutically acceptable salt or the stereoisomer or the prodrug molecule thereof.

The pyridopyrimidone or pyridopyridopyridone compound or the pharmaceutically acceptable salt thereof of the present invention has the following advantages and beneficial effects:

the compound of the invention can selectively inhibit the activity of mutant EGFR and inhibit other proteases in EGFR and Her families, and is a novel protein kinase inhibitor which can overcome the drug resistance of the existing EGFR tyrosine kinase inhibitor and has selectivity and good pharmacokinetic properties. The compound of the invention can effectively inhibit the growth of various tumor cells, and particularly can selectively inhibit EGFR^{L858R/T790MC797S}Lung cancer cells are partially preferred compounds that are more than 50-fold selective compared to wild-type cancer cells. The compound can be used for preparing antitumor drugs, can overcome the drug resistance problem induced by the existing drugs (such as gefitinib, erlotinib, especially AZD9291), and is mainly used for drug resistance of the 797 th cysteine mutated into serine (C797S) induced by the existing third-generation EGFR small-molecule inhibitor anti-non-small cell lung cancer drugs such as Osimetinib (AZD9291), Olmutitinib (HM6171), Rociletinib (9, CO-1686) and the like. The compound of the invention can be used for preventing postoperative recurrence of various tumors and further consolidation therapy, and achieves the purposes of prolonging the life cycle of tumor patients, improving the life quality of the tumor patients and inhibiting tumor deterioration.

Drawings

FIG. 1 shows the pair of the compound 560082 of the present invention against EGFR in tool cells^{L858R/T790M/C797S}And EGFR^{19D/T790M/C797S}A graph of the results of the phosphorylation effect of (a);

FIG. 2 shows the pair of the compound 580120 of the present invention against EGFR in tool cells^{L858R/T790M/C797S}And EGFR^{19D/T790M/C797S}Test results of the phosphorylation effect of (a).

Detailed Description

In the compounds of the invention, when any variable (e.g. R)₁R, etc.) occur more than one time in any constituent, then the definition of each occurrence is independent of the definition of each other occurrence. Also, combinations of substituents and variables are permissible only if such combinations result in stable compounds. The line drawn from a substituent into the ring system indicates that the indicated bond can be attached to any ring atom that can be substituted. If the ring system is polycyclic, it means that such a bond is only attached to any suitable carbon atom of the adjacent ring. To understand the artSubstituents and substitution patterns of the compounds of the invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and can be readily synthesized by those skilled in the art and methods set forth below from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms, so long as the structure is stable. The phrase "optionally substituted with one or more substituents" is considered equivalent to the phrase "optionally substituted with at least one substituent" and preferred embodiments in this case will have from 0 to 3 substituents.

The terms "alkyl" and "alkylene" as used herein are intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C₁-C₅Alkyl radical "middle" C₁-C₅The definition of "includes groups having 1, 2, 3, 4, or 5 carbon atoms in a straight or branched chain arrangement. For example, "C₁-C₅Alkyl "specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl. The term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms. For example, "cycloalkyl" includes cyclopropyl, methyl-cyclopropyl, 2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, and the like.

The term "heteroaryl" as used herein represents a stable monocyclic ring of up to 6 atoms in the ring or a bicyclic carbon ring of up to 6 atoms in each ring, wherein at least one ring is aromatic and contains 1-4 heteroatoms selected from O, N and S. Heteroaryl groups within the scope of this definition include, but are not limited to: imidazolyl, triazolyl, pyrazolyl, furyl, thienyl, oxazolyl, isoxazolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl. For the following definition of heteroaryl, "heteroaryl" is also understood to include any N-oxide derivative of a nitrogen-containing heteroaryl group. In the case where the heteroaryl substituent is bicyclic and contains one ring that is non-aromatic or contains no heteroatoms, it is understood that each is attached via an aromatic ring or via a heteroatom-containing ring.

The term "heterocycle" or "heterocyclyl" as used herein refers to a 5-to 6-membered aromatic or nonaromatic heterocycle containing 1 to 4 heteroatoms selected from O, N and S and includes bicyclic groups. "Heterocyclyl" thus includes the above-mentioned heteroaryl groups, as well as the dihydro and tetrahydro analogues thereof. Further examples of "heterocyclyl" include, but are not limited to: imidazolyl, indolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, oxetanyl (oxyethanyl), pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinoxalinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, l, 4-dioxanyl, pyrrolidinyl, dihydroimidazolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, tetrahydrofuryl and tetrahydrothienyl, and N-oxides thereof. Attachment of the heterocyclic substituent may be through a carbon atom or through a heteroatom. In one embodiment, the heterocycle is selected from the group consisting of imidazolyl, pyridyl, 1-pyrrolidone, 2-piperidone, 2-pyrimidone, 2-pyrrolidone, thienyl, oxazolyl, triazolyl, isoxazolyl.

As understood by those skilled in the art, "halo" or "halogen" as used herein is meant to include chloro, fluoro, bromo, and iodo.

Unless otherwise defined, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl substituents may be unsubstituted or substituted. For example, (C)₁-C₆) Alkyl groups may be substituted with one, two or three substituents selected from OH, halogen, alkoxy, dialkylamino or heterocyclyl, e.g. morpholinyl, piperidinyl and the like.

The invention includes the free forms of the compounds of formulae I-VI, as well as pharmaceutically acceptable salts and stereoisomers thereof. Some specific exemplary compounds herein are protonated salts of amine-based compounds. The term "free form" refers to the amine compound in a non-salt form. Included pharmaceutically acceptable salts include not only exemplary salts of the particular compounds described herein, but also all typical pharmaceutically acceptable salts of the free forms of the compounds of formulas I-VI. The free form of a particular salt of the compound may be isolated using techniques known in the art. For example, the free form can be regenerated by treating the salt with a dilute aqueous solution of a suitable base, such as a dilute aqueous NaOH solution, a dilute aqueous potassium carbonate solution, dilute aqueous ammonia, and a dilute aqueous sodium bicarbonate solution. The free forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of the invention such acid and base salts are otherwise pharmaceutically equivalent to their respective free forms.

Pharmaceutically acceptable salts of the invention can be synthesized from compounds of the invention containing a basic or acidic moiety by conventional chemical methods. In general, salts of basic compounds are prepared by ion exchange chromatography or by reaction of the free base with a stoichiometric amount or excess of an inorganic or organic acid in the form of the desired salt in an appropriate solvent or combination of solvents. Similarly, salts of acidic compounds are formed by reaction with suitable inorganic or organic bases.

Thus, pharmaceutically acceptable salts of the compounds of the present invention include the conventional non-toxic salts of the compounds of the present invention formed by the reaction of a basic compound of the present invention and an inorganic or organic acid. For example, conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, as well as those prepared 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, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxy-monobenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, and the like.

If a compound of the invention is acidic, an appropriate "pharmaceutically acceptable salt" refers to a salt prepared by a pharmaceutically acceptable non-toxic base including inorganic and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases including 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' -dibenzylethylenediamine, diethylamine, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, piperdine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

Berg et al, "Pharmaceutical Salts," j.pharm.sci.' 1977: 66: 1-19 describe in more detail the preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts.

Since acidic moieties such as carboxyl groups deprotonated in a compound under physiological conditions may be anionic and such charge may then be balanced out by a protonated or alkylated basic moiety such as a quaternary nitrogen atom bearing a cation internally, it should be noted that the compounds of the present invention are potential internal salts or zwitterions.

In addition to standard methods known in the literature or exemplified in experimental procedures, the compounds of the invention can be prepared using reactions as shown in the following schemes. The following illustrative schemes are therefore for illustrative purposes and are not limited to the compounds listed or any particular substituents. The number of substituents shown in the schemes does not necessarily correspond to the number used in the claims and for the sake of clarity a single substituent is shown attached to the compound allowing for multiple substituents under the definition of formula I above.

The compounds of the formulae I to VI according to the invention can be synthesized by the person skilled in the art, starting from 4-chloro-2-methylthiopyrimidine-5-carbonic acid ethyl ester or 2, 4-dichloro-5-bromopyrimidine, by means of several reaction steps, based on the prior art and the general knowledge available. (see examples 1, 9, 32, etc.)

The compounds of formulae I-VI and their pharmaceutically acceptable salts provided herein are useful for treating hyperproliferative diseases or conditions, such as tumors, in humans and other mammals.

In one embodiment, the compounds contemplated herein and pharmaceutically acceptable salts thereof can be used to treat or control non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, leukemia, histiocytic lymphoma, nasopharyngeal carcinoma, and other hyperproliferative diseases.

Drug metabolites and prodrugs

Metabolites of the compounds and pharmaceutically acceptable salts thereof to which this application relates, and prodrugs that can be converted in vivo to the structures of the compounds and pharmaceutically acceptable salts thereof to which this application relates, are also included in the claims of this application.

Combination drug

The compounds of formulae I-VI may be combined with other agents known to treat or ameliorate similar conditions. When administered in combination, the mode of administration & dosage of the original drug is maintained, while the compounds of formulae I-IV are administered simultaneously or subsequently. When the compounds of formulae I-IV are administered simultaneously with one or more other drugs, it is preferred to use pharmaceutical compositions containing both one or more known drugs and the compounds of formulae I-IV. The pharmaceutical combination may also comprise administering the compounds of formulae I-IV in overlapping time periods with one or more other known drugs. When the compounds of formulae I-VI are administered in combination with one or more other drugs, the dosages of the compounds of formulae I-IV or known drugs may be lower than the dosages when they are administered alone.

Drugs or active ingredients that may be used in combination with the compounds of formulas I-VI include, but are not limited to:

estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxins/cytostatics, antiproliferatives, protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protein kinase inhibitors, reverse transcriptase inhibitors, angiogenesis inhibitors, inhibitors of cell proliferation and survival signals, drugs that interfere with cell cycle checkpoints and apoptosis inducers, 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, histidine deacetylase inhibitors, proteasome inhibitors, CDK inhibitors, Bcl-2 family protein inhibitors, MDM2 family protein inhibitors, inhibitors of cytokines, inhibitors of the cell growth factor, inhibitors of cytokines, inhibitors of the cell growth factor, and/cell growth factors, IAP family protein inhibitors, STAT family protein inhibitors, PI3K inhibitors, AKT inhibitors, integrin blockers, interferon-alpha, interleukin-12, COX-2 inhibitors, p53, p53 activators, VEGF antibodies, EGF antibodies, and the like.

In one embodiment, drugs or active ingredients that may be used in pharmaceutical combination with the compounds of formulas I-VI include, but are not limited to: aldesleukin, alendronic acid, interferon, atrazine, allopurinol sodium, palonosetron hydrochloride, hexamethylmelamine, aminoglutethimide, amifostine, amrubicin, ambrolidine, anastrozole, dolasetron, aranesp, arglabin, arsenic trioxide, anoxin, 5-azacytidine, azathioprine, bacillus calmette or tide bacillus calmette, betadine, betamethasone acetate, betamethasone sodium phosphate preparation, bexarotene, bleomycin sulfate, bromouroxime, bortezomib, busulfan, calcitonin, alezomab injection, capecitabine, carboplatin, custard, cefesone, simon, daunorubicin, phenylbutyric acid azone, mustard, cladribine, clodronate, cyclophosphamide, alexanide, dacarbazine, actinomycin, dexamethasone, estramustin phosphate, estramustine, dexamethasone, estradiol phosphate, estradiol valerate phosphate, valproate, doxylamine, and mixtures thereof, Dinil interleukin 2, dibume, deslorelin, delazoxan, diethylstilbestrol, tolbutan, docetaxel, doxifluridine, doxorubicin, dronabinol, azulene-166-chitosan complex, eligard, labyrinase, epirubicin hydrochloride, aprepitant, epirubicin, alfafurtine, erythropoietin, eptaplatin, levamisole, estradiol formulations, 17-beta-estradiol, estramustine sodium phosphate, ethinylestradiol, amifostine, hydroxyphosphoric acid, pirimiphoside, etoposide, favuzole, tamoxifen formulations, filgrastim, phenastidine, floxuridine, fluconazole, fludarabine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil, flumetmesterone, flunomide, fulvestrant, 1-beta-D-arabinofuranosylcytisidine-5 '-stearoyl-5' -stearoyl phosphate, flutamide, fluvastatin, Fotemustine, fulvestrant, gamma globulin, gemcitabine, gemtuzumab ozogamicin, imatinib mesylate, carmustine wafer capsule, goserelin, glanesilong hydrochloride, histrelin, and meclizine, hydrocortisone, erythro-hydroxynonyladenine, hydroxyurea, temin bemomab, idarubicin, ifosfamide, interferon alpha 2A, interferon alpha 2B, interferon alpha nl, interferon alpha n3, interferon beta, interferon gamma la, interleukin 2, intron A, iressa, irinotecan, kateride, lentinan sulfate, letrozole, leucovorin, leuprolide, leuprorelin, levamisole acetate, levamisole, calcium levofolinate, sodium levothyroxine preparation, Lomustine, lonidamine, dronabinol, mechlorethamine, mecobalamin, medroxyprogesterone acetate, megestrol acetate, melphalan, esterified estrogen, 6-thionopurine, mesna, methotrexate, methyl aminolevulinate, miltefosine, medemycin, mitomycin C, mitotane, mitoxantrone, trilostane, doxorubicin citrate liposome, nedaplatin, pegylated filgrastim, alprenil interleukin, neupogen, nilutamide, tamoxifen, NSC-631570, recombinant human interleukin 1-beta, octreotide, ondansetron hydrochloride, hydrocortisone oral solution, oxaliplatin, paclitaxel, prednisone sodium phosphate formulation, pemetrexed, wintereprazole, pentostatin, streptolysin formulation, pilocarpine hydrochloride, porrubicin, plicamycin, porumycin, phenamacystin, prednimustine, pamoate, Spiprantelone, prednisone, pemetrexed, procarbazine, recombinant human erythropoietin, raltitrexed, ribi, rhenium-186 etidronate, merosal, dygulin-A, romopeptide, pilocarpine hydrochloride tablet, octreotide, samustine, semustine, Sizopyran, sobuzosin, Succinum methylprednisolone, Pafoscarnet, Stemonaccid, streptozocin, strontium chloride-89, levothyroxine sodium, tamoxifen, tamsulosin, tasolomide, Tastolactone, Tetharidin, Tecetithiozine, temozolomide, teniposide, testosterone propionate, megestrol, thioguanine, thiotepa, thyrotropine, Teluzole, topotecan, toremifene, tositumomab, Suzuzumab, Ottoepirubicin, Vavea tablet, methotrexate, trimetrexamine, triptorelin, trexate, troglib, troglitazone, trexate, trexaprop-A, tremulin, tremula, tremulin, tremula, tremulin, triptorelin pamoate, eucfordine, uridine, valrubicin, vesnarinone, vinblastine, vincristine, vinblastine amide, vinorelbine, vilaurizine, dexpropinimine, setastatin ester, pindoline, paclitaxel protein stabilizing formulation, acolbifene, interferon r-lb, affinitak, aminopterine, azoxifene, aspristil, atamestane, atrasentan, BAY43-9006, avastin, CCC-779, CDC-501, Ceprolegel, cetuximab, Clineralot, cyproterone acetate, decitabine, DN-101, adriamycin-MTC, dSLIM, dutasterin, eocharinin, eflornithine, irinotecan, camphene A dihydrochloride, histamine hydrogel, histrelin implant, TMP-166-DOholmium phosphonate, interferon gamma, endostatin gamma, PEG-containing loxapine, PEG-2-pore-forming protein, 1582, Lancet, lasofoxifene, libra, lonafamib, milbexifene, minodronate, MS-209, liposomal MTP-PE, MX-6, nafarelin, nemorubicin, neovastat, nolatrexed, Orimunoson, onco-TCS, osidmem, paclitaxel polyglutamate, sodium pamoate, PN-401, QS-21, quarta, R-1549, raloxifene, ranpirnase, 13-cis retinoic acid, satraplatin, seocalcitol, T-138067, tarceva, docosahexanoic acid paclitaxel, thymosin alpha l, Galfazolin, tipifarnib, tirapazamine, TLK-286, toremifene, trans MID-7R, vastada, pravastatin, vatalanib, valporopenpine, vinpocetine, Z-100, and lypocetine or combinations thereof.

The invention is further described in the following examples, which are not intended to limit the scope of the invention.

Example 1

Step 1.(S) -4- (1-tert-Butoxycarbonylpyrrolyl-3-amino) -2-methylmercaptopyrimidine-5-carbonic acid ethyl ester (2)

(S)-ethyl-4-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)amino)-2-(methylthio)pyrimidine-5-carboxylate

4-chloro-2-methylmercaptopyrimidine-5-carbonate ethyl ester (24.98g, 107.4mmol), (S) -1-tert-butoxycarbonyl-3-aminopyrrolidine (22.0g, 118.2mmol), K₂CO₃(29.64g, 214.8mmol) was dissolved in 50mL of anhydrous DMF and heated to 60 ℃ under argon and stirred overnight. After cooling to room temperature, 500mL of ice water was added with stirring, and a large amount of solid was precipitated. Filtration under reduced pressure and drying in vacuo afforded 6.0g of a white solid (74% yield).

¹H NMR(400MHz，CDCl₃)δ8.63(s，1H)，8.34(s，1H)，4.72(s，J＝2.4Hz，1H)，4.31(q，J＝7.2Hz，2H)，3.77-3.73(m，1H)，3.49-3.48(m，2H)，3.36-3.34(m，0.5H)，3.23-3.22(m，0.5H)，2.52(s，3H)，2.30-2.21(m，1H)，1.94-1.93(m，1H)，1.45(s，9H)，1.36(t，J＝7.2Hz，3H).

MS(ESI)m/z 383.2[M+H]⁺.

Step 2.(S) -tert-butyl-3- (5- (hydroxymethyl) -2-methylmercaptopyrimidine-4-amino) pyrrole-1-carbonate (3)

(S)-tert-butyl-3-((5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)pyrrolidine-1-carboxylate

(S) -4- (1-tert-Butoxycarbonylpyrrolyl-3-amino) -2-methylmercaptopyrimidine-5-carboxylic acid ethyl ester (2) (26.0g, 79.15mmol) was dissolved in 200mL tetrahydrofuran and cooledThe reaction was cooled to-40 ℃ and a suspension of lithium aluminum hydride (6.02g, 158.3mmol) in tetrahydrofuran was slowly added dropwise, stirred and slowly raised to 0 ℃ and the reaction was monitored on a dot-matrix plate. After the raw materials are reacted, the temperature is reduced to minus 40 ℃, 6mL of water, 6mL of 10 percent sodium hydroxide solution and 18mL of water are slowly dropped to react, and then dried MgSO ₄And (3) performing suction filtration and concentration on the powder. Extracting with dichloromethane and water, collecting organic phase, and extracting with anhydrous Na₂SO₄Drying, filtering, spin-drying, and separating by column chromatography (SiO)₂，CH₂Cl₂MeOH gradient elution, 40: 1 to 20: 1) gave 13g (48% yield) of a white oil.

¹H NMR(400MHz，CDCl₃)δ7.74(s，1H)，6，02(s，1H)，4.68(d，J＝5.6Hz，1H)，4.52(s，2H)，3.72-3.71(m，1H)，3.46-3.45(m，2H)，3.27-3.21(m，1H)，2.50(s，3H)，2.25-2.23(m，1H)，1.92-1.91(m，1H)，1.46(s，9H).

MS(ESI)m/z 341.2[M+H]⁺.

Step 3.(S) -tert-butyl-3- (5-formyl-2-methylmercaptopyrimidine-4-amino) pyrrole-1-carbonate (4)

(S)-tert-butyl-3-((5-formyl-2-(methylthio)pyrimidin-4-yl)amino)pyrrolidine-1-carboxylate

(S) -tert-butyl-3- (5- (hydroxymethyl) -2-methylmercaptopyrimidine-4-amino) pyrrole-1-carbonate (3) (13g, 11.53mmol) was dissolved in 100mL of anhydrous dichloromethane, 3 equivalents of activated manganese dioxide (16.6g, 191.10mmol) were added in portions, and after completion of the reaction of the starting material, filtration was performed with celite by suction to remove solids, and spin-drying gave 11.2g of an oil (yield 87%).

¹H NMR(400MHz，CDCl₃)δ9.78(s，1H)，8.64(s，1H)，8.30(s，1H)，4.72(s，1H)，3.73-3.72(m，1H)，3.47-3.46(m，2H)，3.73-3.72(m，1H)，3.34-3.21(m，1H)，2.52(s，3H)，2.26-2.23(m，1H)，1.97-1.96(m，1H)，1.44(s，9H).

MS(ESI)m/z 339.2[M+H]⁺.

And 4, step 4: (S) -3- (6- (2-chlorophenyl) -2- (methylthio) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) -pyrrolidine-1-carboxylic acid tert-butyl ester (5)

(S)-tert-butyl-3-(6-(2-chlorophenyl)-2-(methylthio)-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)pyrrolidine-1-carboxylate

(S) -tert-butyl-3- (5-formyl-2-methylmercaptopyrimidine-4-amino) pyrrole-1-carbonate (4) (2.0g, 5.9mmol) was dissolved in 2mL DMF and ethyl o-chlorophenylacetate (1.4g, 7.0mmol), DBU (538.9mg, 7.08mmol) was added and the temperature was slowly raised to 85 ℃ and the reaction was monitored by a dot plate. Cooling to room temperature after the raw materials react, adding water to quench the reaction, extracting with dichloromethane and water, taking an organic phase, and adding anhydrous Na ₂SO₄Drying, filtering, spin-drying, and separating by column chromatography (SiO)₂PE/EA gradient elution, 10: 1 to 5: 1) gave 1.0g of a white oil (35% yield)

¹H NMR(400MHz，CDCl₃)δ8.11(s，1H)，7.50(d，J＝7.2Hz，1H)，7.27(s，1H)，7.36-7.31(m，3H)，4.56-4.51(m，1H)，3.88-3.83(m，1H)，3.72-3.67(m，2H)，3.44-3.39(m，1H)，2.77-2.71(m，1H)，2.54(s，3H)，2.15-2.14(m，1H)，1.45(s，9H).

MS(ESI)m/z 473.99[M+H]⁺.

Step 5 (S) -3- (6- (2-chlorophenyl) -2- (methylsulfonyl) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) -pyrrolidine-1-carboxylic acid tert-butyl ester (6)

(S)-tert-butyl-3-(6-(2-chlorophenyl)-2-(methylsulfonyl)-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)pyrrolidine-1-carboxylate

(S) -3- (6- (2-chlorophenyl) -2- (methylthio) -7-oxopyrido [2,3-d]pyrimidin-8 (7H) -yl) -pyrrolidine-1-carboxylic acid tert-butyl ester (5) (1.0g, 2.0mmol) was dissolved in 5mL of anhydrous dichloromethane, and m-chloroperoxybenzoic acid (1.2g, 6.0mmol) was added slowly at 0 ℃ in an ice bath, returned to room temperature, and stirred for 4 hours. The reaction mixture was diluted with dichloromethane and 50% Na₂S₂O₃/NaHCO₃The reaction was quenched with aqueous solution. The organic phase was washed twice with saturated brine and anhydrous Na₂SO₄Drying, filtering, spin-drying, and separating by column chromatography (SiO)₂PE/EA gradient elution, 4: 1 to 2: 1) to obtain 0.6g (60% yield)

¹H NMR(400MHz，CDCl₃)δ8.11(s，1H)，7.50(d，J＝7.2Hz，1H)，7.27(s，1H)，7.36-7.31(m，3H)，4.56-4.51(m，1H)，3.88-3.83(m，1H)，3.72-3.67(m，2H)，3.44-3.39(m，1H)，3.34(s，3H)，2.77-2.71(m，1H)，，2.15-2.14(m，1H)，1.45(s，9H).

MS(ESI)m/z 505.12[M+H]⁺.

Step 6 (S) -3- (6- (2-chlorophenyl) -2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) pyrrolidine-1-carboxylic acid tert-butyl ester (7)

(S)-tert-buty-3-(6-(2-chlorophenyl)-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)pyrrolidine-1-carboxylate

(S) -3- (6- (2-chlorophenyl) -2- (methylsulfonyl) -7-oxopyrido [2, 3-d]Pyrimidin-8 (7H) -yl) -pyrrolidine-1-carboxylic acid tert-butyl ester (6) (0.66g, 1.3mmol) was added to a closed bottle containing 10mL sec-butanol, followed by 3-methyl-4- (4-methylpiperazine-1-substituted) aniline (295mg, 1.44mmol) and TFA (110 μ L, 1.44 mmol). Heated to 110 ℃ and stirred for 18 hours. Cooled to room temperature and poured with 10% NaHCO ₃Extracting with dichloromethane twice in water solution, mixing organic phases, washing with saturated saline solution twice, and removing anhydrous Na₂SO₄Drying, filtering, spin-drying to obtain compound 7, and directly carrying outAnd (5) carrying out the next reaction.

And 7: (S) -6- (2-chlorophenyl) -2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -8- (pyrrolidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (8)

(S)-6-(2-chlorophenyl)-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8-(pyrrolidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

(S) -3- (6- (2-chlorophenyl) -2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d]Pyrimidin-8 (7H) -yl) pyrrolidine-1-carboxylic acid tert-butyl ester (7) was dissolved in 5mL of dichloromethane, TFA (0.5mL) was added, and the mixture was stirred at room temperature for 4H. The reaction was diluted with dichloromethane and saturated NaHCO₃Adjusting the pH value of the solution to 9, extracting the solution twice with dichloromethane, combining organic phases, and obtaining 10 percent NaHCO₃Washing with aqueous solution twice, washing with saturated saline solution twice, and removing anhydrous Na₂SO₄Drying, filtering, spin-drying, and separating by column chromatography (SiO)₂，CH₂Cl₂/MeOH/NH₄OH, 40: 1: to 20: 1) to give 300mg of solid (43% yield in two steps).

¹H NMR(400MHz，CDCl₃)δ7.98(s，1H)，7.51(d，J＝7.2Hz，1H)，7.42(s，1H)，7.37-7.31(m，4H)，7.10(s，1H)，7.04-7.02(m，1H)，5.49-5.47(m，1H)，4.73-4.66(m，1H)，4.50-4.45(m，1H)，3.30-3.47(m，2H)，3.09-3.04(m，1H)，2.94-2.92(m，4H)，2.74-2.69(m，1H)，2.67-2.65(m，4H)，2.36(s，3H)，2.32(s，3H)，1.89-1.88(m，2H).

MS(ESI)m/z 531.06[M+H]⁺.

And 8: (S) -8- (1-acetylpyrrol-3-yl) -6- (2-chlorophenyl) -2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (560123)

(S)-8-(1-acetylpyrrolidin-3-yl)-6-(2-chlorophenyl)-2-((3-methyl-4-(4-methylpiperazin-1-yl)ph enyl)amino)pyrido[2，3-d]pyrimidin-7(8H)-one

(S) -6- (2-chlorophenyl) -2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -8- (pyrrolidin-3-yl) pyrido [2, 3-d ]Pyrimidin-7 (8H) -one (8) (150mg, 0.28mmol) was dissolved in 10mL of anhydrous dichloromethane and Et was added at 0 ℃ in ice bath₃N (1.1mL, 0.84mmol), acetyl chloride (25. mu.L, 0.31mmol) was added slowly. Stir back to room temperature for 4 hours. After the reaction was complete, 10% NaHCO was added₃Extracting with water solution and dichloromethane twice, mixing organic phases, washing with saturated saline solution, and removing anhydrous Na₂SO₄Drying, filtering, spin-drying, and separating by column chromatography (SiO)₂，CH₂Cl₂/MeOH/NH₄OH, 40: 1: 0.4), and further purified by HPLC to obtain 130mg of a solid (yield 92%).

¹H NMR(400MHz，DMSO)δ10.01(s，1H)，8.80(s，1H)，7.86(s，1H)，7.73-7.30(m，5H)，7.10(d，J＝84.0Hz，1H)，6.18(s，1H)，3.77(dd，J＝123.0，102.3Hz，4H)，2.81(s，4H)，2.23(s，5H)，1.98(t，J＝35.0Hz，3H)，1.59-0.86(m，3H).

MS(ESI)m/z 573.06[M+H]⁺

Example 2

6- (2-chlorophenyl) -8-cyclohexyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (560069)

6-(2-chlorophenyl)-8-cyclohexyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrid o[2，3-d]pyrimidin-7(8H)-one

See example 1 for synthesis in 57% yield.

¹H NMR(300MHz，DMSO)δ9.90(s，1H)，8.74(s，1H)，7.77(s，1H)，7.65-7.19(m，6H)，7.01(d，J＝8.5Hz，1H)，5.38(s，1H)，2.82(s，4H)，2.28(s，3H)，2.23(s，3H)，1.82(s，2H)，1.60(d，J＝12.6Hz，3H)，1.29(t，J＝18.5Hz，3H)，1.17-0.82(m，2H)，0.82(t，J＝7.4Hz，1H).

MS(ESI)m/z 543.3[M+H]⁺。

Example 3

N- ((1R, 4R) -4- (6- (2-chlorophenyl) -2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 13-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propanamide (560080)

N-((1r，4r)-4-(6-(2-chlorophenyl)-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)cyclohexyl)propionamide

See example 1 for synthetic method, yield 79.6%.

¹H NMR(400MHz，DMSO)δ9.93(s，1H)，8.76(s，1H)，8.02(s，1H)，7.83(s，1H)，7.73(d，J＝1.8Hz，1H)，7.66-7.57(m，1H)，7.57-7.50(m，1H)，7.42(dd，J＝4.7，3.5Hz，2H)，7.09(s，1H)，5.56-5.11(m，2H)，2.86(d，J＝4.2Hz，4H)，2.57(s，2H)，2.30(s，3H)，2.28(s，3H)，2.02-1.89(m，2H)，1.79(d，J＝19.3Hz，2H)，1.71-1.52(m，2H)，1.39(s，1H)，1.35-1.25(m，1H)，1.16(t，J＝7.1Hz，1H).

MS(ESI)m/z 614.4[M+H]⁺。

Example 4

N- ((1R, 4R) -4- (6- (2-chlorophenyl) -2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) acetamide (560081)

N-((1R，4R)-4-(6-(2-chlorophenyl)-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)cyclohexyl)acetamide

See example 1 for synthesis in 73.3% yield.

MS(ESI)m/z 600.4[M+H]⁺。

Example 5

N- ((1R, 4R) -4- (2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxo-6-phenylpyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) acetamide (560105)

N-((1r，4r)-4-(2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxo-6-phenylpyrido[2，3-d]pyrimidin-8(7H)-yl)cyclohexyl)acetamide

See example 1 for synthetic methods, yield 59.6%

¹H NMR(400MHz，DMSO)δ9.81(d，J＝56.6Hz，1H)，8.76(s，1H)，7.90(d，J＝18.4Hz，1H)，7.66(dd，J＝20.1，18.6Hz，3H)，7.54(d，J＝8.0Hz，1H)，7.47-7.28(m，3H)，7.10(s，1H)，5.34(d，J＝43.0Hz，2H)，2.96-2.73(m，5H)，2.29(d，J＝9.5Hz，2H)，2.26(s，3H)，2.07(q，J＝7.6Hz，2H)，，1.62(s，2H)，1.43-1.13(m，3H)，1.00(q，J＝7.5Hz，3H).

Example 6

N- ((1R, 4R) -4- (2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxo-6-phenylpyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propanamide (560107)

N-((1R，4R)-4-(2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxo-6-phenylpyrido[2，3-d]pyrimidin-8(7H)-yl)cyclohexyl)propionamide

See example 1 for synthesis in 80.35% yield.

¹H NMR(400MHz，DMSO)δ9.81(d，J＝56.6Hz，1H)，8.76(s，1H)，7.90(d，J＝18.4Hz，1H)，7.66(dd，J＝20.1，18.6Hz，3H)，7.54(d，J＝8.0Hz，1H)，7.47-7.28(m，3H)，7.10(s，1H)，5.34(d，J＝43.0Hz，2H)，2.96-2.73(m，5H)，2.29(d，J＝9.5Hz，2H)，2.26(s，3H)，2.07(q，J＝7.6Hz，2H)，1.94(dd，J＝21.1，10.0Hz，2H)，1.62(s，2H)，1.43-1.13(m，3H)，1.00(q，J＝7.5Hz，3H).

MS(ESI)m/z 580.3[M+H]⁺。

Example 7

N- ((1R, 4R) -4- (6- (3-chlorophenyl) -2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) acetamide (560109)

N-((1r，4r)-4-(6-(3-chlorophenyl)-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)cyclohexyl)acetamide

See example 1 for synthetic method, yield 81.3%.

¹H NMR(400MHz，DMSO)δ9.93(s，1H)，8.76(s，1H)，8.02(s，1H)，7.83(s，1H)，7.73(d，J＝1.8Hz，1H)，7.66-7.57(m，1H)，7.57-7.50(m，1H)，7.42(dd，J＝4.7，3.5Hz，2H)，7.09(s，1H)，5.56-5.11(m，2H)，2.86(d，J＝4.2Hz，4H)，2.57(s，2H)，2.30(s，3H)，2.28(s，3H)，2.02-1.89(m，2H)，1.79(d，J＝19.3Hz，2H)，1.71-1.52(m，2H)，1.39(s，1H)，1.35-1.25(m，1H)，1.22(t，J＝7.2Hz，3H)，1.16(t，J＝7.1Hz，1H).

MS(ESI)m/z 600.4[M+H]⁺。

Example 8

N- ((1R, 4R) -4- (6- (3-chlorophenyl) -2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 13-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propanamide (560110)

N-((1r，4r)-4-(6-(3-chlorophenyl)-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)cyclohexyl)propionamide

See example 1 for synthesis in 78.9% yield.

¹H NMR(400MHz，DMSO)δ9.93(s，1H)，8.76(s，1H)，8.02(s，1H)，7.83(s，1H)，7.73(d，J＝1.8Hz，1H)，7.66-7.57(m，1H)，7.57-7.50(m，1H)，7.42(dd，J＝4.7，3.5Hz，2H)，7.09(s，1H)，5.56-5.11(m，2H)，2.86(d，J＝4.2Hz，4H)，2.57(s，2H)，2.30(s，3H)，2.28(s，3H)，2.02-1.89(m，2H)，1.79(t，J＝19.3Hz，2H)，1.71-1.52(m，2H)，1.39(s，1H)，1.35-1.25(m，1H)，1.22(t，J＝7.2Hz，3H)，1.16(t，J＝7.1Hz，1H).

MS(ESI)m/z 614.4[M+H]⁺。

Example 9

6- (2-chlorophenyl) -2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -8- (1-acetylpiperidin-4-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (560121)

8-(1-acetylpiperidin-4-yl)-6-(2-chlorophenyl)-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2，3-d]pyrimidin-7(8H)-one

See example 1 for synthetic method, yield 74.5%.

¹H NMR(400MHz，DMSO)δ9.95(s，1H)，8.76(s，1H)，7.80(s，1H)，7.60-7.47(m，3H)，7.46-7.27(m，3H)，7.00(d，J＝8.6Hz，1H)，5.60(s，1H)，4.58(d，J＝8.8Hz，1H)，3.99(d，J＝13.5Hz，2H)，3.17-2.93(m，2H)，2.79(d，J＝31.6Hz，4H)，2.55(s，4H)，2.28(s，3H)，2.27-2.15(m，3H)，2.10-1.96(m，3H)，1.73-1.58(m，2H).

MS(ESI)m/z 586.2[M+H]+。

Example 10

6- (2-chlorophenyl) -2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -8- (1-propionylpiperidin-4-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (560122)

6-(2-chlorophenyl)-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8-(1-propionylpiperidin-4-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

See example 1 for synthetic method, yield 72.7%.

¹H NMR(400MHz，DMSO)δ9.99(s，1H)，8.77(s，1H)，7.81(s，1H)，7.52(d，J＝4.1Hz，3H)，7.41(d，J＝10.1Hz，3H)，7.01(d，J＝8.3Hz，1H)，5.63(s，1H)，4.62(d，J＝8.2Hz，1H)，4.18-3.76(m，1H)，3.05(t，J＝11.7Hz，1H)，2.82(s，4H)，2.40-2.30(m，2H)，2.26(s，3H)，2.24(s，3H)，1.97(d，J＝11.0Hz，1H)，1.67(s，2H)，1.19(dd，J＝18.3，11.2Hz，2H)，1.00(t，J＝7.2Hz，3H).

MS(ESI)m/z 600.4[M+H]⁺。

Example 11

(S) -6- (2-chlorophenyl) -2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -8- (1-propionylpyrrolidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (560124)

(S)-6-(2-chlorophenyl)-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8-(1-propionylpyrrolidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

See example 1 for synthesis in 76.8% yield.

¹H NMR(400MHz，DMSO)δ10.00(s，1H)，8.80(d，J＝2.5Hz，1H)，7.85(d，J＝5.6Hz，1H)，7.61-7.27(m，6H)，6.97(t，J＝7.8Hz，1H)，6.47-5.98(m，1H)，2.81(s，5H)，2.24(s，3H)，2.22(s，3H)，1.99(s，1H)，1.17(t，J＝7.1Hz，1H)，0.98(ddd，J＝14.8，12.4，7.4Hz，4H).

MS(ESI)m/z 586.2[M+H]⁺。

Example 12

N- ((1R, 4R) -4- (6- (4-chlorophenyl) -2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) acetamide (570026)

N-((1R，4R)-4-(6-(4-chlorophenyl)-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)cyclohexyl)acetamide

See example 1 for synthesis in 78.7% yield.

¹H NMR(400MHz，DMSO)δ9.92(s，1H)，8.77(s，1H)，7.98(s，1H)，7.91-7.75(m，1H)，7.68(d，J＝8.5Hz，2H)，7.53(d，J＝7.4Hz，1H)，7.46(t，J＝8.4Hz，2H)，7.09(s，1H)，5.32(s，2H)，2.86(s，4H)，2.28(d，J＝2.3Hz，6H)，1.94(d，J＝11.3Hz，2H)，1.81(t，J＝5.9Hz，3H)，1.63(s，2H)，1.33(t，J＝17.8Hz，4H).

MS(ESI)m/z 600.4[M+H]⁺。

Example 13

N- ((1R, 4R) -4- (6- (4-chlorophenyl) -2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propanamide (570027)

N-((1R，4R)-4-(6-(4-chlorophenyl)-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)cyclohexyl)propionamide

See example 1 for synthetic method, yield 75.9%.

¹H NMR(400MHz，DMSO)δ9.92(s，1H)，8.77(s，1H)，7.98(s，1H)，7.91-7.75(m，1H)，7.68(d，J＝8.5Hz，2H)，7.53(d，J＝7.4Hz，1H)，7.46(t，J＝8.4Hz，2H)，7.09(s，1H)，5.32(s，2H)，2.86(s，4H)，2.28(d，J＝2.3Hz，6H)，1.94(d，J＝11.3Hz，2H)，1.81(t，J＝5.9Hz，3H)，1.33(t，J＝17.8Hz，4H).

MS(ESI)m/z 614.4[M+H]⁺。

Example 14

(S) -8- (1-acetyl-3-yl) -6- (2-chlorophenyl) -2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (570051)

(S)-8-(1-acetylpiperidin-3-yl)-6-(2-chlorophenyl)-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2，3-d]pyrimidin-7(8H)-one

See example 1 for synthetic method, yield 88.8%.

¹H NMR(400MHz，DMSO)δ10.01(s，1H)，8.79(s，1H)，7.84(d，J＝4.7Hz，1H)，7.47(d，J＝46.2Hz，5H)，7.00(s，1H)，5.36(d，J＝35.9Hz，1H)，4.42(s，1H)，3.85(dd，J＝94.2，53.4Hz，2H)，2.83(s，5H)，2.26(s，3H)，2.24(s，3H)，2.08(s，1H)，1.80(s，3H)，1.46(d，J＝13.6Hz，1H)，1.24(s，1H).

MS(ESI)m/z 586.2[M+H]⁺。

Example 15

(S) -6- (2-chlorophenyl) -2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -8- (1-propionylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (570052)

(S)-6-(2-chlorophenyl)-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8-(1-propionylpiperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

See example 1 for synthesis in 86% yield.

¹H NMR(400MHz，DMSO)δ10.02(s，1H)，8.78(s，1H)，7.85(t，J＝11.0Hz，1H)，7.53(d，J＝5.1Hz，2H)，7.41(s，4H)，6.97(s，1H)，5.34(d，J＝34.1Hz，1H)，4.44(s，1H)，4.17-3.86(m，1H)，3.75(d，J＝50.4Hz，1H)，2.81(s，4H)，2.25(s，3H)，2.21(d，J＝2.6Hz，3H)，2.05-1.55(m，3H)，1.46(s，1H)，1.20-0.85(m，2H)，0.80(s，1H).

MS(ESI)m/z 600.4[M+H]⁺。

Example 16

(S) -8- (1-acetyl-3-yl) -6- (3-chlorophenyl) -2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (570060)

(S)-8-(1-acetylpiperidin-3-yl)-6-(3-chlorophenyl)-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2，3-d]pyrimidin-7(8H)-one

See example 1,.

MS(ESI)m/z 586.2[M+H]⁺。

Example 17

(S) -6- (3-chlorophenyl) -2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -8- (1-propionylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (570061)

(S)-6-(3-chlorophenyl)-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8-(1-propionylpiperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

See example 1 for synthesis in 85.7% yield.

MS(ESI)m/z 600.4[M+H]⁺。

Example 18

N- ((1R, 4R) -4- (6- (2-chlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) acetamide (560083)

N-((1R，4R)-4-(6-(2-chlorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)cyclohexyl)propionamide

And step 9: ((1R, 4R) -4- ((5-bromo-2-chloropyrimidin-4-yl) amino) cyclohexyl) carbamic acid tert-butyl ester (10)

tert-butyl((1R，4R)-4-((5-bromo-2-chloropyrimidin-4-yl)amino)cyclohexyl)carbamate

5-bromo-2, 4-dichloropyrimidine (9) (5.8g, 25.45mmol), trans- (4-aminocyclohexyl) carbamic acid tert-butyl ester (5.0g, 23.23mmol) and K at room temperature₂CO₃(6.4g, 46.66mmol) was added to 70mL of MeCN. The mixed system was stirred at room temperature and the reaction was monitored by spotting. After the raw materials react, dichloromethane and water are used for extraction, and an organic phase is taken and anhydrous Na is added ₂SO₄Drying, filtering, spin-drying, and separating by column chromatography (SiO)₂PE/EA gradient elution, 15: 1to 10: 1) gave 4.6g (48% yield) of a white oil.

¹H NMR(400MHz，DMSO)δ8.88(s，1H)，5.34(s，1H)，2.84(s，5H)，2.30(d，J＝18.1Hz，3H)，2.11(s，3H)，2.06(q，J＝7.5Hz，2H)，1.92(d，J＝10.6Hz，2H)，1.59(t，2H)，1.38(s，9H)1.42-1.10(m，3H)，1.05(s，1H)，0.99(t，J＝7.5Hz，3H).

MS(ESI)m/z 406.4[M+H]⁺。

Step 10: ((1R, 4R) -4- (2-chloro-5-methyl-7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) carbamic acid tert-butyl ester (11)

tert-butyl((1R，4R)-4-(2-chloro-5-methyl-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)cyclohexyl)carhamate

Tert-butyl ((1R, 4R) -4- ((5-bromo-2-chloropyrimidin-4-yl) amino) cyclohexyl) carbamate (10) (3.25g, 8.00mmol) and trans crotonic acid (6.75.g, 80.0mmol) were added to THF (30mL) at room temperature,DIPEA (13mL) was slowly added to the system, the system was replaced with Ar three times, diphenylacetonitrile palladium dichloride (0.16g, 0.4mmol) and tris (o-methylphenyl) phosphine (125mg, 0.4mmol) were added to the mixed system, replaced with Ar three times again, the system was heated to 80 ℃ and stirred for reaction for 24h, then Ac2O (1.9mL) was added to the system, and heating and stirring were continued for reaction for 24 h. Stopping heating, cooling to room temperature, removing part of solvent by rotary evaporation under reduced pressure, adding DCM (50mL) into the system, washing the organic phase with HCl (1M, 100mL), washing the organic phase once with saturated saline (100mL), collecting the organic phase, and adding anhydrous Na₂SO₄Drying for 30min, filtering, concentrating under reduced pressure, and performing column chromatography to obtain light yellow solid, i.e. 0.71g, with yield of 30.0%.

¹H NMR(400MHz，DMSO)δ8.88(s，1H)，6.41(s＝1H)，7.27，5.75(s，1H)，2.84(s，3H)，2.24(s，3H)，2.11(s，3H)，2.06(q，J＝7.5Hz，2H)，1.92(d，J＝10.6Hz，2H)，1.59(s，9H)。

MS(ESI)m/z 393.6[M+H]⁺。

Step 11: ((1R, 4R) -4- (6-bromo-2-chloro-5-methyl-7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) carbamic acid tert-butyl ester (12)

tert-butyl((1R，4R)-4-(6-bromo-2-chloro-5-methyl-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)cyclohexyl)carbamate

The compound ((1R, 4R) -4- (2-chloro-5-methyl-7-oxopyrido [2, 3-d) was reacted at room temperature]Pyrimidin-8 (7H) -yl) cyclohexyl) carbamic acid tert-butyl ester (11) (383mg, 0.97mmol) was dissolved in AcOH (1.6mL), sodium acetate (320mg, 3.88mmol) was added, liquid bromine (0.013mL, 2.7mmol) was slowly added dropwise, temperature was raised to 55 deg.C, stirring was continued overnight, saturated Na was added₂S₂O₃Stirring the solution until the red color disappears, extracting the separated organic phase, washing with water (5mL) and saturated saline solution (5mL) in sequence, collecting the organic phase, and adding anhydrous Na₂SO₄Drying for 30min, and filteringConcentrating under reduced pressure, and performing column chromatography to obtain white solid 282mg with yield 58.9%.

¹H NMR(400MHz，DMSO)δ8.88(s，1H)，，5.75(s，1H)，2.84(s，3H)，2.24(s，3H)，2.11(s，3H)，2.06(q，J＝7.5Hz，2H)，1.92(d，J＝10.6Hz，2H)，1.59(s，9H)。

MS(ESI)m/z 472.6[M+H]⁺。

Step 12: ((1R, 4R) -4- (6-bromo-5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) carbamic acid tert-butyl ester (13)

tert-butyl((1R，4R)-4-(6-bromo-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)cyclohexyl)carbamate

((1R, 4R) -4- (6-bromo-2-chloro-5-methyl-7-oxopyrido [2, 3-d)]Pyrimidin-8 (7H) -yl) cyclohexyl) carbamic acid tert-butyl ester (12) (4.55mg, 0.71mmol) was added to an enclosed bottle containing 7mL sec-butanol, followed by the addition of 3-methyl-4- (4-methylpiperazine-1-substituted) aniline (160mg, 0.78mmol) and TFA (50 μ L, 0.71 mmol). Heated to 110 ℃ and stirred for 18 hours. Cooled to room temperature and poured with 10% NaHCO ₃Extracting with dichloromethane twice in water solution, mixing organic phases, washing twice with saturated saline solution, and removing anhydrous Na₂SO₄Drying and column chromatography gave 300mg of yellow solid, yield: 66 percent.

¹H NMR(400MHz，DMSO)δ9.86(s，1H)，8.88(s，1H)，7.41(dd，J＝5.1，2.6Hz，2H)，7.27(d，J＝4.5Hz，1H)，5.75(s，1H)，5.34(s，1H)，2.84(s，4H)，2.30(d，J＝18.1Hz，3H)，2.24(s，3H)，2.11(s，3H)，2.06(q，J＝7.5Hz，2H)，1.92(d，J＝10.6Hz，2H)，1.59(s，9H)，1.42-110(m，3H)，1.05(s，1H)，0.99(t，J＝7.5Hz，3H).

MS(ESI)m/z 641.2[M+H]⁺。

Step 13: ((1R, 4R) -4- (6- (2-chlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) carbamic acid tert-butyl ester (14)

tert-butyl((1R，4R)-4-(6-(2-chlorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)cyclohexyl)carbamate

The compound ((1R, 4R) -4- (6-bromo-5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d) was reacted at room temperature]Pyrimidin-8 (7H) -yl) cyclohexyl) carbamic acid tert-butyl ester (13) (336mg, 0.5mmol), 2-chlorobenzeneboronic acid (410mg, 2.6mmol), bis triphenylphosphonium dichloropalladium (18.4mg, 0.026mmol), Na₂CO₃(167mg, 1.56mmol) was added to 1, 4-dioxane (6mL) and H₂O (2mL) in a mixed solvent, replacing air with Ar, heating to 110 ℃, stirring for 24 hours, stopping heating, cooling to room temperature, adding DCM (10mL) and saturated NaHCO₃(5mL) solution, extracting and separating to obtain an organic phase, washing with saturated saline (5mL) once, collecting the organic phase, and adding anhydrous Na₂SO₄Drying for 30min, filtering, concentrating under reduced pressure, and performing column chromatography to obtain yellow solid 280.mg with yield 83.0%.

¹H NMR(400MHz，DMSO)δ9.86(s，1H)，8.88(s，1H)，7.68(s，1H)，7.54(t，J＝7.9Hz，3H)，7.41(dd，J＝5.1，2.6Hz，2H)，7.27(d，J＝4.5Hz，1H)，7.09(s，1H)，5.75(s，1H)，5.34(s，lH)，2.84(s，4H)，2.30(d，J＝18.1Hz，3H)，2.24(s，3H)，2.11(s，3H)，2.06(q，J＝7.5Hz，2H)，1.92(d，J＝10.6Hz，2H)，1.59(s，9H)，1.42-110(m，3H)，1.05(s，1H)，0.99(t，J＝7.5Hz，3H).

MS(ESI)m/z 673.2[M+H]⁺。

Step 14: 8- ((1R, 4R) -4-aminocyclohexyl) -6- (2-chlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (15)

8-((1R，4R)-4-aminocyclohexyl)-6-(2-chlorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2，3-d]pyrimidin-7(8H)-one

((1R, 4R) -4- (6- (2-chlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyridine [2, 3-d)]Pyrimidin-8 (7H) -yl) cyclohexyl) carbamic acid tert-butyl ester (14)280mg was dissolved in 5mL of dichloromethane, added TFA (0.5mL), and stirred at room temperature for 4H. The reaction was diluted with dichloromethane and saturated NaHCO₃Adjusting the pH of the solution to 9, extracting with dichloromethane twice, combining the organic phases, and 10% NaHCO₃Washing with aqueous solution twice, washing with saturated saline solution twice, and removing anhydrous Na₂SO₄Drying, filtration and spin-drying, column chromatography gave 200mg (84% yield) of a yellow solid.

¹H NMR(400MHz，DMSO)δ9.86(s，1H)，8.88(s，1H)，7.68(s，1H)，7.54(t，J＝7.9Hz，3H)，7.41(dd，J＝5.1，2.6Hz，2H)，7.27(d，J＝4.5Hz，1H)，7.09(s，1H)，5.75(s，1H)，5.34(s，1H)，2.84(s，5H)，2.30(d，J＝18.1Hz，3H)，2.24(s，3H)，2.11(s，3H)，2.06(q，J＝7.5Hz，2H)，1.92(d，J＝10.6Hz，2H)，1.42-1.10(m，2H)，1.05(s，1H)，0.99(t，J＝7.5Hz，3H).

MS(ESI)m/z 573.2[M+H]⁺。

Step 15: n- ((1R, 4R) -4- (6- (2-chlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) acetamide (560083)

N-((1R，4R)-4-(6-(2-chlorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)cyclohexyl)acetamide

8- ((1R, 4R) -4-aminocyclohexyl) -6- (2-chlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d]Pyrimidin-7 (8H) -one (15) (150mg, 0.28mmol) was dissolved in 10mL of anhydrous dichloromethane and Et was added at 0 ℃ in ice bath ₃N (1.1mL, 0.84mmol), acetyl chloride (25. mu.L, 0.31mmol) was added slowly. Stir back to room temperature for 4 hours. After the reaction is finished, 10% NaHCO is added₃Extracting with water solution and dichloromethane twice, mixing organic phases, washing with saturated saline solution, and removing anhydrous Na₂SO₄Drying, filtering, spin-drying, and separating by column chromatography (SiO)₂，CH₂Cl₂/MeOH/NH₄OH, 40: 1: 0.4), and further purified by HPLC to obtain 130mg of a solid (yield 92%).

¹H NMR(400MHz，DMSO)δ9.86(s，1H)，8.88(s，1H)，7.68(s，1H)，7.54(t，J＝7.9Hz，3H)，7.41(dd，J＝5.1，2.6Hz，2H)，7.27(d，J＝4.5Hz，1H)，7.09(s，1H)，5.75(s，1H)，5.34(s，1H)，2.84(s，5H)，2.30(d，J＝18.1Hz，3H)，2.24(s，3H)，2.11(s，3H)，2.06(q，J＝7.5Hz，2H)，1.92(d，J＝10.6Hz，2H)，1.59(t，2H)，1.42-1.10(m，3H)，1.05(s，1H)，0.99(t，J＝7.5Hz，3H)。

MS(ESI)m/z 600.4[M+H]⁺。

Example 19

6- (2-chlorophenyl) -8-cyclopentyl-5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7- (8H) -one (560070)

6-(2-chlorophenyl)-8-cyclopentyl-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2，3-d]pyrimidin-7(8H)-one

See example 18 for synthesis in 47.4% yield.

¹H NMR(400MHz，CDCl₃)δ8.71(s，1H)，7.57(s，1H)，7.48(d，J＝7.2Hz，1H)，7.33(t，J＝9.0Hz，3H)，7.27-7.20(m，3H)，7.05(d，J＝8.5Hz，1H)，6.12-5.85(m，1H)，2.96(d，J＝3.9Hz，4H)，2.63(s，4H)，2.39(s，4H)，2.37-2.26(m，5H)，2.16(s，3H)，2.01(dd，J＝37.8，11.7Hz，4H)，1.89(d，J＝5.9Hz，3H)，1.63(t，J＝15.7Hz，3H)，1.38-1.14(m，3H)，0.86(d，J＝9.3Hz，1H).

MS(ESI)m/z 543.3[M+H]⁺。

Example 20

N- ((1R, 4R) -4- (6- (2-chlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propanamide (560082)

See example 18 for synthesis in 92% yield.

¹H NMR(400MHz，DMSO)δ9.86(s，1H)，8.88(s，1H)，7.68(s，1H)，7.54(t，J＝7.9Hz，3H)，7.41(dd，J＝5.1，2.6Hz，2H)，7.27(d，J＝4.5Hz，1H)，7.09(s，1H)，5.75(s，1H)，5.34(s，1H)，2.84(s，5H)，2.30(d，J＝18.1Hz，3H)，2.24(s，3H)，2.11(s，3H)，2.06(q，J＝7.5Hz，2H)，1.92(d，J＝10.6Hz，2H)，1.59(t，2H)，1.42-1.10(m，3H)，1.05(s，1H)，0.99(t，J＝7.5Hz，3H).

MS(ESI)m/z 629.3[M+H]⁺。

Example 21

6- (2-chlorophenyl) -8-cyclohexyl-5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7- (8H) -one (560132)

6-(2-chlorophenyl)-8-cyclohexyl-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2，3-d]pyrimidin-7(8H)-one

See example 18 for synthesis in 47.6% yield.

¹H NMR(400MHz，CDCl₃)δ8.71(s，1H)，7.57(s，1H)，7.48(d，J＝7.2Hz，1H)，7.33(t，J＝9.0Hz，3H)，7.27-7.20(m，3H)，7.05(d，J＝8.5Hz，1H)，6.12-5.85(m，1H)，2.96(d，J＝3.9Hz，4H)，2.63(s，4H)，2.39(s，4H)，2.37-2.26(m，5H)，2.16(s，3H)，2.01(dd，J＝37.8，11.7Hz，4H)，1.89(d，J＝5.9Hz，3H)，1.63(t，J＝15.7Hz，3H)，1.38-1.14(m，3H)，0.86(d，J＝9.3Hz，2H).

MS(ESI)m/z 557.3[M+H]⁺。

Example 22

6- (3-chlorophenyl) -8-cyclohexyl-5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7- (8H) -one (560133)

6-(3-chlorophenyl)-8-cyclohexyl-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2，3-d]pyrimidin-7(8H)-one

See example 18 for synthesis in 78.3% yield.

¹H NMR(400MHz，DMSO)δ9.86(s，1H)，8.86(s，1H)，7.43(d，J＝5.7Hz，4H)，7.23(d，J＝39.4Hz，2H)，7.00(d，J＝8.0Hz，1H)，5.36(d，J＝47.1Hz，1H)，3.17-2.91(m，1H)，2.81(s，4H)，2.27(s，3H)，2.23(s，3H)，2.20(s，3H)，1.84(d，J＝54.6Hz，3H)，1.57(s，3H)，1.26(d，J＝36.6Hz，3H)，1.13-0.91(m，2H).

MS(ESI)m/z 557.3[M+H]⁺。

Example 23

8-cyclohexyl-5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -6-phenylpyrido [2, 3-d ] pyrimidin-7 (8H) -one (560134)

8-cyclohexyl-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-6-phenylpyrido[2，3-d]pyrimidin-7(8H)-one

See example 18 for synthesis in 89% yield.

¹H NMR(400MHz，DMSO)δ9.81(s，1H)，8.85(s，1H)，7.41(t，J＝19.3Hz，5H)，7.11(d，J＝76.4Hz，2H)，5.36(d，J＝40.5Hz，1H)，2.81(s，4H)，2.27(s，3H)，2.23(s，3H)，2.19(s，3H)，1.79(d，J＝11.8Hz，2H)，1.58(s，3H)，1.27(d，J＝36.7Hz，3H).

MS(ESI)m/z 523.3[M+H]⁺。

Example 24

8-cyclohexyl-6- (2-fluorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7- (8H) -one (560135)

8-cyclohexyl-6-(2-fluorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2，3-d]pyrimidin-7(8H)-one

See example 18 for synthesis in 47.3% yield.

¹H NMR(400MHz，DMSO)δ9.85(s，1H)，8.87(s，1H)，7.68-7.36(m，3H)，7.25(td，J＝8.5，4.9Hz，3H)，7.01(d，J＝8.6Hz，1H)，5.33(dd，J＝23.8，19.1Hz，1H)，4.37(s，1H)，2.82(t，J＝4.4Hz，4H)，2.27(s，3H)，2.24(s，3H)，2.19(s，3H)，1.86-1.66(m，3H)，1.58(s，3H)，1.44-1.10(m，5H).

MS(ESI)m/z 541.3[M+H]⁺。

Example 25

8-cyclohexyl-5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -6- (o-tolyl) pyrido [2, 3-d ] pyrimidin-7- (8H) -one (560136)

8-cyclohexyl-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-6-(o-tolyl)pyrido[2，3-d]pyrimidin-7(8H)-one

See example 18 for synthesis in 49.2% yield.

¹H NMR(400MHz，DMSO)δ9.85(s，1H)，8.87(s，1H)，7.68-7.36(m，3H)，7.25(td，J＝8.5，4.9Hz，3H)，7.01(d，J＝8.6Hz，1H)，5.33(dd，J＝23.8，19.1Hz，1H)，4.37(s，1H)，2.82(t，J＝4.4Hz，4H)，2.47(s，3H)2.27(s，3H)，2.24(s，3H)，2.19(s，3H)，1.86-1.66(m，3H)，1.58(s，3H)，1.44-1.10(m，5H).

MS(ESI)m/z 537.4[M+H]⁺。

Example 26

8-cyclohexyl-6- (2-methoxyphenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7- (8H) -one (560138)

8-cyclohexyl-6-(2-methoxyphenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2，3-d]pyrimidin-7(8H)-one

See example 18 for synthesis in 42% yield.

¹H NMR(400MHz，DMSO)δ9.76(s，1H)，8.79(d，J＝24.7Hz，1H)，7.79(s，1H)，7.71-7.40(m，2H)，7.35(t，J＝7.2Hz，1H)，7.20-6.91(m，3H)，5.37(s，1H)，3.85-3.58(m，3H)，3.03(dt，J＝13.9，7.1Hz，1H)，2.82(s，3H)，2.31(d，J＝27.8Hz，3H)，2.25(s，3H)，2.09(s，2H)，1.89-1.70(m，3H)，1.60(d，J＝24.8Hz，3H)，1.27(dd，J＝47.3，13.7Hz，3H)，1.18-1.00(m，1H)，0.98(d，J＝7.2Hz，1H).

MS(ESI)m/z 553.4[M+H]⁺。

Example 27

6- (4-chlorophenyl) -8-cyclohexyl-5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7- (8H) -one (560140)

6-(4-chlorophenyl)-8-cyclohexyl-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2，3-d]pyrimidin-7(8H)-one

See example 18 for synthesis in 86% yield.

1H NMR(400MHz，DMSO)δ9.76(s，1H)，8.79(d，J＝24.7Hz，1H)，7.79(s，1H)，7.71-7.40(m，2H)，7.35(t，J＝7.2Hz，1H)，7.20-6.91(m，3H)，5.37(s，1H)，3.85-3.58(m，3H)，3.03(dt，J＝13.9，7.1Hz，1H)，2.82(s，3H)，2.31(d，J＝27.8Hz，3H)，2.09(s，2H)，1.89-1.70(m，3H)，1.60(d，J＝24.8Hz，3H)，1.27(dd，J＝47.3，13.7Hz，3H)，1.18-1.00(m，1H)，0.98(d，J＝7.2Hz，1H).

MS(ESI)m/z 557.3[M+H]⁺。

Example 28

8- ((3S, 5S, 7S) -adamantan-1-yl) -6- (2-chlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (560145)

8-((3S，5S，7S)-adamantan-1-yl)-6-(2-chlorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2，3-d]pyrimidin-7(8H)-one

See example 18 for synthesis in 47.9% yield.

¹H NMR(400MHz，DMSO)δ9.56(s，1H)，8.75(s，1H)，7.56-7.46(m，1H)，7.46-7.27(m，4H)，7.27-7.18(m，1H)，7.00(d，J＝8.0Hz，1H)，3.03(td，J＝12.8，7.2Hz，1H)，2.80(d，J＝3.6Hz，5H)，2.56(s，6H)，2.31-2.17(m，7H)，2.07(d，J＝11.2Hz，3H)，1.97(d，J＝10.7Hz，5H)，1.77(s，1H)，1.54(s，7H)，1.21(d，J＝29.3，7.2Hz，4H)，1.05-0.93(m，2H).

MS(ESI)m/z 610.1[M+H]⁺。

Example 29

8-cyclohexyl-5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (560150)

8-cyclohexyl-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2，3-d]pyrimidin-7(8H)-one

See example 18 for synthesis in 59.2% yield.

¹H NMR(400MHz，DMSO)δ9.81(s，1H)，8.76(s，1H)，7.82-7.30(m，2H)，7.01(d，J＝8.6Hz，1H)，6.15(s，1H)，5.33(dd，J＝12.4，7.7Hz，1H)，2.82(d，J＝4.2Hz，4H)，2.40(d，J＝35.7Hz，3H)，2.27(s，3H)，2.24(d，J＝15.9Hz，3H)，2.04-1.93(m，1H)，1.80(d，J＝20.0Hz，2H)，1.65(s，1H)，1.60-1.42(m，2H)，1.41-1.28(m，2H).

MS(ESI)m/z 447.3[M+H]⁺。

Example 30

8-cyclopentyl-5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -6-phenylpyrido [2, 3-d ] pyrimidin-7 (8H) -one (570008)

8-cyclopentyl-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-6-phenylpyrido[2，3-d]pyrimidin-7(8H)-one

See example 18 for synthesis in 42% yield.

¹H NMR(400MHz，DMSO)δ9.83(s，1H)，8.88(s，1H)，7.68(s，1H)，7.53-7.29(m，3H)，7.29-7.12(m，2H)，7.00(d，J＝8.6Hz，1H)，6.20-5.51(m，1H)，2.82(t，J＝4.3Hz，3H)，2.25(s，4H)，2.20(s，3H)，1.85(d，J＝16.1Hz，2H)，1.84-1.72(m，2H)，1.64-1.48(m，2H).

MS(ESI)m/z 509.4[M+H]⁺。

Example 31

6- (3-chlorophenyl) -8-cyclopentyl-5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7- (8H) -one (570012)

6-(3-chlorophenyl)-8-cyclopentyl-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2，3-d]pyrimidin-7(8H)-one

See example 18 for synthesis in 79.8% yield.

¹H NMR(400MHz，DMSO)δ9.88(s，1H)，8.89(s，1H)，7.77-7.60(m，1H)，7.56-7.35(m，3H)，7.30(d，J＝1.8Hz，1H)，7.19(dt，J＝6.8，1.7Hz，1H)，7.00(d，J＝8.6Hz，1H)，6.06-5.77(m，1H)，2.81(t，J＝4.4Hz，4H)，2.48(d，J＝12.4Hz，4H)，2.25(s，3H)，2.23(s，3H)，2.21(s，3H)，1.87(s，2H)，1.80(dd，J＝12.3，7.1Hz，2H)，1.57(dd，J＝11.3，5.1Hz，3H).

MS(ESI)m/z 543.3[M+H]⁺。

Example 32

(S) -8- (1-acetyl-3-yl) -6- (2-chlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (570056)

(S)-8-(1-acetylpiperidin-3-yl)-6-(2-chlorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2，3-d]pyrimidin-7(8H)-one

See example 18 for synthesis in 78.9% yield.

¹H NMR(400MHz，DMSO)δ9.95(s，1H)，8.91(d，J＝3.8Hz，1H)，7.72-7.48(m，2H)，7.41(dd，J＝4.8，2.7Hz，3H)，7.36-7.20(m，1H)，6.98(d，J＝6.5Hz，1H)，5.34(dd，J＝21.8，17.0Hz，1H)，4.40(s，1H)，3.90(dd，J＝97.8，35.0Hz，3H)，2.81(s，5H)，2.14(d，J＝2.9Hz，3H)，2.04(d，J＝16.1Hz，1H)，1.76(s，3H)，1.45(s，1H)，1.23(s，2H).

MS(ESI)m/z 600.3[M+H]⁺。

Example 33

(S) -6- (2-chlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -8- (1-propionylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (560057)

(S)-6-(2-chlorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8-(1-propionylpiperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

See example 18 for synthesis in 82.6% yield.

¹H NMR(400MHz，DMSO)δ9.98(s，1H)，8.91(s，1H)，7.67-7.49(m，2H)，7.49-7.33(m，3H)，7.28(dd，J＝7.9，4.0Hz，1H)，6.96(s，1H)，5.91-5.01(m，1H)，4.43(s，1H)，4.25-3.79(m，1H)，3.79-3.46(m，1H)，2.80(s，4H)，2.23(s，3H)，2.21(d，J＝2.9Hz，3H)，2.13(s，3H)，1.77(s，3H)，1.44(s，2H)，0.98(d，J＝21.7Hz，2H)，0.81(s，2H).

MS(ESI)m/z 614.3[M+H]⁺。

Example 34

(S) -8- (1-acetyl-3-yl) -6- (3-chlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (570063)

(S)-8-(1-acetylpiperidin-3-yl)-6-(3-chlorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2，3-d]pyrimidin-7(8H)-one

See example 18 for synthesis in 77.16% yield.

¹H NMR(400MHz，DMSO)δ9.95(s，1H)，8.91(d，J＝3.8Hz，1H)，7.72-7.48(m，2H)，7.41(dd，J＝4.8，2.7Hz，3H)，7.36-7.20(m，1H)，7.05(s，1H)，6.98(d，J＝6.5Hz，1H)，5.34(dd，J＝21.8，17.0Hz，1H)，4.40(s，1H)，3.90(dd，J＝97.8，35.0Hz，3H)，2.81(s，5H)，2.14(d，J＝2.9Hz，3H)，2.04(d，J＝16.1Hz，1H)，1.76(s，3H)，1.45(s，1H)，1.23(s，2H).

MS(ESI)m/z 600.4[M+H]⁺。

Example 35

(S) -6- (3-chlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -8- (1-propionylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (570064)

(S)-6-(3-chlorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8-(1-propionylpiperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

See example 18 for synthesis in 81.8% yield.

¹H NMR(400MHz，DMSO)δ9.98(s，1H)，8.91(s，1H)，7.67-7.49(m，2H)，7.49-7.33(m，3H)，7.28(dd，J＝7.9，4.0Hz，1H)，7.05(s，1H)，6.96(s，1H)，5.91-5.01(m，1H)，4.43(s，1H)，4.25-3.79(m，1H)，3.79-3.46(m，1H)，2.80(s，4H)，2.23(s，3H)，2.21(d，J＝2.9Hz，3H)，2.13(s，3H)，1.77(s，3H)，1.44(s，2H)，0.98(d，J＝21.7Hz，2H)，0.81(s，2H).

MS(ESI)m/z 614.4[M+H]⁺。

Example 36

(S) -8- (1-propionyl-3-yl) -6- (2-chlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (570089)

The synthesis was as in example 18, with a yield of 76.9%.

¹H NMR(400MHz，DMSO)δ9.99(s，1H)，8.77(s，1H)，7.81(s，1H)，7.52(d，J＝4.1Hz，3H)，7.41(d，J＝10.1Hz，3H)，7.01(d，J＝8.3Hz，1H)5.63(s，1H)，4.62(d，J＝8.2Hz，1H)，4.25-3.81(m，1H)，3.05(t，J＝11.7Hz，1H)，2.92-2.67(m，4H)，2.57(d，J＝9.0Hz，2H)，2.51(s，3H)，2.41-2.35(m，2H)，2.26(s，3H)，2.24(s，3H)，1.72(q，J＝37.9Hz，2H)，1.00(t，J＝7.2Hz，3H).

MS(ESI)m/z 614.3[M+H]⁺。

Example 37

8- (1-acetylpiperidin-4-yl) -6- (2-chlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (570104)

8-(1-acetylpiperidin-4-yl)-6-(2-chlorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, with a yield of 86.8%.

¹H NMR(400MHz，DMSO)δ9.95(s，1H)，8.91(s，1H)，7.72-7.48(m，2H)，7.41(dd，J＝2.7Hz，3H)，7.36-7.20(m，1H)，6.98(s，1H)，5.34(dd，J＝21.8Hz，1H)，4.40(s，1H)，3.90(dd，J＝35.0，11.2Hz，3H)，3.6(t，J＝8.7Hz，1H)，2.92-2.67(m，4H)，2.14(s，3H)，2.04(d，J＝16.1Hz，2H)，1.85(s，3H)1.76(s，3H)，1.45(s，1H)，1.23(s，3H).

MS(ESI)m/z 600.3[M+H]⁺。

Example 38

6- (2-chlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -8- (1-propylpiperidin-4-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (570105)

6-(2-chlorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8-(1-propionylpiperidin-4-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, 75.2% yield.

¹H NMR(400MHz，DMSO)δ9.98(s，1H)，8.91(s，1H)，7.67-7.49(m，2H)，7.49-7.33(m，3H)，7.28(dd，J＝7.9，4.0Hz，1H)，6.96(s，1H)，5.91-5.01(m，1H)，4.62(d，J＝8.2Hz，1H)，4.25-3.81(m，1H)，3.05(t，J＝11.7Hz，1H)，2.92-2.67(m，4H)，2.57(d，J＝9.0Hz，2H)，2.51(s，3H)，2.41-2.35(m，2H)，2.26(s，3H)，2.24(s，3H)，1.72(q，J＝37.9Hz，2H)，1.00(t，J＝7.2Hz，3H).

MS(ESI)m/z 614.3[M+H]⁺。

Example 39

(S) -8- (1-acetyl-3-yl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -6- (o-tolyl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (570111)

(S)-8-(1-acetylpiperidin-3-yl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-6-(o-tolyl)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, with a yield of 79.5%.

¹H NMR(400MHz，DMSO)δ9.68(s，1H)，8.94(s，1H)，8.41(s，2H)，7.85-7.20(m，3H)，6.87(m，2H)，5.68-5.00(m，1H)，4.28(d，J＝105.3Hz，1H)，3.96(s，3H)，2.81(s，4H)，2.38(s，3H)，2.30(d，J＝5.0Hz，1H)，2.32-2.27(m，2H)，2.23(d，J＝4.6Hz，2H)，2.24-2.17(m，1H)，2.19-1.85(m，2H)，1.80(s，3H)，1.62-1.29(m，2H)，1.28(s，3H).

MS(ESI)m/z 580.2[M+H]⁺

Example 40

(S) -8- (1-propionyl-3-yl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -6- (o-tolyl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (570112)

(S)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8-(1-propionylpiperidin-3-yl)-6-(o-tolyl)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, 68% yield.

¹H NMR(400MHz，DMSO)δ9.99(s，1H)，8.77(s，1H)，7.81(s，1H)，7.52(d，J＝4.1Hz，2H)，7.41(d，J＝10.1Hz，3H)，7.01(d，J＝8.3Hz，1H)，5.63(s，1H)，4.62(d，J＝8.2Hz，1H)，4.18-3.76(m，2H)，3.05(t，J＝11.7Hz，1H)，2.82(s，4H)，2.40-2.30(m，2H)，2.26(s，3H)，2.24(s，3H)，1.97(d，J＝11.0Hz，1H)，1.67(s，3H)，1.19(dd，J＝18.3，11.2Hz，2H)，1.00(t，J＝7.2Hz，3H).

MS(ESI)m/z 594.4[M+H]⁺。

EXAMPLE 41

(R) -8- (1-acetylpyrrolidin-3-yl) -6- (2-chlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (570118)

(R)-8-(1-acetylpyrrolidin-3-yl)-6-(2-chlorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, 67.7% yield.

¹H NMR(400MHz，DMSO)δ9.95(s，1H)，8.91(s，1H)，7.72-7.48(m，2H)，7.41(dd，J＝2.7Hz，3H)，7.36-7.20(m，1H)，6.98(s，1H)，5.34(dd，J＝21.8Hz，1H)，4.40(s，1H)，3.90(dd，J＝35.0，11.2Hz，3H)，3.6(t，J＝8.7Hz，1H)，2.92-2.67(m，4H)，2.14(s，3H)，1.85(s，3H)1.76(s，3H)，1.45(s，1H)，1.23(s，3H).

MS(ESI)m/z 587.0[M+H]+。

Example 42

(R) -8- (1-propionylpyrrolidin-3-yl) -6- (2-chlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (570119)

(R)-6-(2-chlorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8-(1-propionylpyrrolidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was carried out as in example 18, with a yield of 66.5%,

¹H NMR(400MHz，DMSO)δ9.98(s，1H)，8.91(s，1H)，7.67-7.49(m，2H)，7.49-7.33(m，3H)，7.28(dd，J＝7.9，4.0Hz，1H)，6.96(s，1H)，5.91-5.01(m，1H)，4.62(d，J＝8.2Hz，1H)，4.25-3.81(m，1H)，3.05(t，J＝11.7Hz，1H)，2.92-2.67(m，4H)，2.57(d，J＝9.0Hz，2H)，2.51(s，3H)，2.26(s，3H)，2.24(s，3H)，1.72(q，J＝37.9Hz，2H)，1.00(t，J＝7.2Hz，3H).

MS(ESI)m/z 600.1[M+H]⁺。

example 43

(S) -8- (1-acetyl-3-yl) -6- (2, 5-dichlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (570144)

(S)-8-(1-acetylpiperidin-3-yl)-6-(2，5-dichlorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, 75% yield.

¹H NMR(400MHz，DMSO)δ9.94(s，1H)，8.90(s，1H)，7.48(dd，J＝8.4，2.8Hz，2H)，7.43(d，J＝29.2Hz，2H)，7.25(s，1H)，6.93(s，1H)，4.40(s，1H)，4.26-3.49(m，2H)，2.75(s，4H)，2.23(s，3H)，2.22(d，J＝2.9Hz，2H)，2.21(s，3H)，2.13-1.94(m，2H)，1.82(t，J＝29.3Hz，4H)，1.60-1.30(m，2H)，1.32(s，3H).

MS(ESI)m/z 634.3[M+H]⁺。

Example 44

(S) -8- (1-propionyl-3-yl) -6- (2, 5-dichlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (570145)

(S)-6-(2，5-dichlorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8-(1-propionylpiperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, with a yield of 60.8%.

¹H NMR(400MHz，DMSO)δ9.94(s，1H)，8.90(s，1H)，7.48(dd，J＝8.4，2.8Hz，3H)，7.43(d，J＝29.2Hz，1H)，7.25(s，1H)，6.97(s，1H)，4.40(s，1H)，4.26-3.49(m，2H)，2.75(s，4H)，2.23(s，3H)，2.22(d，J＝2.9Hz，2H)，2.21(q，2H)，2.13-1.94(m，1H)，1.82(t，J＝29.3Hz，2H)，1.60-1.30(m，2H)，1.10(t，J＝20.8，3H).

MS(ESI)m/z 648.1[M+H]⁺。

Example 45

(S) -8- (1-acetyl-3-yl) -6- (4-chlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (570149)

(S)-8-(1-acetylpiperidin-3-yl)-6-(4-chlorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, 85.4% yield.

¹H NMR(400MHz，DMSO)δ9.96(s，1H)，8.90(s，1H)，7.48(d，J＝2.3Hz，1H)，7.46(d，J＝2.4Hz，1H)，7.38(t，J＝15.4Hz，1H)，7.26(t，J＝3.5Hz，1H)，7.23(d，J＝9.4Hz，1H)，6.95(s，1H)，5.82-5.03(m，1H)，4.40(s，1H)，4.26-3.49(m，2H)，2.75(s，4H)，2.23(s，3H)，2.22(d，J＝2.9Hz，2H)，2.21(s，3H)，2.13-1.94(m，2H)，1.82(t，J＝29.3Hz，4H)，1.60-1.30(m，2H)，1.32(s，3H).

MS(ESI)m/z 600.2[M+H]⁺。

Example 46

(S) -8- (1-propionyl-3-yl) -6- (4-chlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (570150)

(S)-6-(4-chlorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8-(1-propionylpiperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, with a yield of 79.6%.

¹H NMR(400MHz，DMSO)δ9.96(s，1H)，8.90(s，1H)，7.48(d，J＝2.3Hz，1H)，7.46(d，J＝2.4Hz，1H)，7.38(t，J＝15.4Hz，1H)，7.26(t，J＝3.5Hz，1H)，7.23(d，J＝9.4Hz，1H)，6.95(s，1H)，5.82-5.03(m，1H)，4.43(s，1H)，4.22-3.54(m，2H)，2.80(s，3H)，2.23(d，J＝3.1Hz，3H)，2.22(d，J＝4.2Hz，3H)，2.21(s，3H)，2.00-1.60(m，2H)，1.40(t，J＝48.0，Hz，2H)，1.37-1.12(m，3H)，1.01(s，1H)，0.84(t，J＝8.8Hz，3H).

MS(ESI)m/z 614.4[M+H]⁺。

Example 47

(S) -8- (1-acetyl-3-yl) -6- (2, 4-dichlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (570157)

(S)-8-(1-acetylpiperidin-3-yl)-6-(2，4-dichlorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiper azin-1-yl)phenyl)amino)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, 69.4% yield.

¹H NMR(400MHz，DMSO)δ9.99(s，1H)，9.32(s，1H)，7.71(s，1H)，7.49(d，J＝10.8Hz，2H)，7.47-7.23(m，2H)，6.88(s，1H)，5.54-5.14(m，1H)，4.43(t，J＝83.0Hz，1H)，3.72(dd，J＝66.7Hz，2H)，2.87(s，3H)，2.22(s，3H)，2.23-2.18(m，4H)，2.15(s，3H)，1.82(t，J＝29.3Hz，2H)，1.60-1.30(m，2H)，1.32(s，3H)

MS(ESI)m/z 634.3[M+H]⁺。

Example 48

(S) -8- (1-propionyl-3-yl) -6- (2, 4-dichlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (570158)

(S)-6-(2，4-dichlorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8-(1-propionylpiperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18 with a yield of 55%.

¹H NMR(400MHz，DMSO)δ9.99(s，1H)，9.32(s，1H)，7.71(s，1H)，7.49(d，J＝10.8Hz，2H)，7.47-7.23(m，2H)，6.88(s，1H)，5.54-5.14(m，1H)，4.43(t，J＝83.0Hz，1H)，3.72(dd，J＝118.4，66.7Hz，2H)，2.87(d，J＝53.7Hz，2H)，2.22(s，3H)，2.23-2.18(m，3H)，2.15(s，3H)，1.74(t，J＝52.9Hz，2H)，1.55-1.30(m，2H)，，1.13(q，J＝53.7，2H)，0.93(t，J＝20.8，3H).

MS(ESI)m/z 649.3[M+H]⁺。

Example 49

(S) -6- (2-methoxyphenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -8- (1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (580011)

(S)-6-(2-methoxyphenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8-(1-propionylpiperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, yield 79.5%.

¹H NMR(400MHz，DMSO)δ9.69(s，1H)，8.94(s，1H)，8.51(d，J＝2.8Hz，3H)，7.65-7.23(m，3H)，6.86(d，J＝68.6Hz，1H)，5.82-5.08(m，1H)，4.76-4.09(m，1H)，3.96(s，3H)，2.80(s，3H)，2.49-2.37(m，4H)，2.30(d，J＝5.1Hz，3H)，2.32-2.26(m，2H)，2.22(d，J＝9.6Hz，2H)，2.18(q，J＝19.8Hz，2H)，1.76(s，3H)，1.59-1.33(m，2H)，1.36-1.13(m，2H)，0.86(t，3H).

MS(ESI)m/z 610.2[M+H]⁺。

Example 50

(S) -8- (1-acetyl-3-yl) -6- (2-fluorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (580013)

(S)-8-(1-acetylpiperidin-3-yl)-6-(2-fluorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, 62% yield.

MS(ESI)m/z 584.1[M+H]⁺。

Example 51

(S) -8- (1-propionyl-3-yl) -6- (2-fluorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (580014)

(S)-6-(2-fluorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8-(1-propionylpiperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, with a yield of 60.6%.

MS(ESI)m/z 598.1[M+H]⁺。

Example 52

(S) -8- (1-acetyl-3-yl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -6-phenylpyrido [2, 3-d ] pyrimidin-7 (8H) -one (580018)

(S)-8-(1-acetylpiperidin-3-yl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-6-phenylpyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18 with a yield of 80.8%.

¹H NMR(400MHz，DMSO)δ9.95(s，1H)，8.91(s，1H)，7.72-7.48(m，2H)，7.41(dd，J＝2.7Hz，3H)，7.36-7.20(m，2H)，6.98(s，1H)，5.34(dd，J＝21.8Hz，1H)，4.40(s，1H)，3.90(dd，J＝35.0，11.2Hz，3H)，3.6(t，J＝8.7Hz，1H)，2.92-2.67(m，4H)，2.14(s，3H)，2.04(d，J＝16.1Hz，2H)，1.85(s，3H)1.76(s，3H)，1.45(s，1H)，1.23(s，3H).

MS(ESI)m/z 588.1[M+Na]⁺。

Example 53

(S) -8- (1-propionyl-3-yl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -6-phenylpyrido [2, 3-d ] pyrimidin-7 (8H) -one (580019)

(S)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-6-phenyl-8-(1-propionylpiperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, yield 72.44%.

¹H NMR(400MHz，DMSO)δ9.98(s，1H)，8.91(s，1H)，7.67-7.49(m，2H)，7.49-7.33(m，3H)，7.28(dd，J＝7.9，4.0Hz，2H)，6.96(s，1H)，5.91-5.01(m，1H)，4.62(d，J＝8.2Hz，1H)，4.25-3.81(m，1H)，3.05(t，J＝11.7Hz，1H)，2.92-2.67(m，4H)，2.57(d，J＝9.0Hz，2H)，2.51(s，3H)，2.41-2.35(m，2H)，2.26(s，3H)，2.24(s，3H)，1.72(q，J＝37.9Hz，2H)，1.00(t，J＝7.2Hz，3H).

MS(ESI)m/z 580.2[M+H]⁺。

Example 54

(S) -8- (1-acetyl-3-yl) -6- (3, 5-dichlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (580023)

(S)-8-(1-acetylpiperidin-3-yl)-6-(3，5-dichlorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18 with a yield of 75.9%.

¹H NMR(400MHz，DMSO)δ9.99(s，1H)，9.32(s，1H)，7.71(s，1H)，7.49(s，2H)，7.47-7.23(m，2H)，6.88(s，1H)，5.54-5.14(m，1H)，4.43(t，J＝83.0Hz，1H)，3.72(dd，J＝66.7Hz，2H)，2.87(s，3H)，2.22(s，3H)，2.23-2.18(m，4H)，2.15(s，3H)，1.82(t，J＝29.3Hz，2H)，1.60-1.30(m，2H)，1.06(s，3H).

MS(ESI)m/z 634.0[M+H]⁺。

Example 55

(S) -8- (1-propionyl-3-yl) -6- (3, 5-dichlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (580024)

(S)-6-(3，5-dichlorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8-(1-propionylpiperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, 85.4% yield.

¹H NMR(400MHz，DMSO)δ9.99(s，1H)，9.32(s，1H)，7.71(s，1H)，7.49(s，2H)，7.47-7.23(m，2H)，6.88(s，1H)，5.54-5.14(m，1H)，4.43(t，J＝83.0Hz，1H)，3.72(dd，J＝118.4，66.7Hz，2H)，2.87(d，J＝53.7Hz，2H)，2.22(s，3H)，2.23-2.18(m，3H)，2.15(s，3H)，1.74(t，J＝52.9Hz，2H)，1.55-1.30(m，2H)，，1.13(q，J＝53.7，2H)，0.93(t，J＝20.8，3H).

MS(ESI)m/z 648.1[M+H]⁺。

Example 56

N- ((1S, 4S) -4- (6- (2-chlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) acetamide (580043)

N-((1s，4s)-4-(6-(2-chlorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)cyclohexyl)acetamide

The synthesis was as in example 18, 81.96% yield.

¹H NMR(400MHz，DMSO)δ9.86(s，1H)，8.88(s，1H)，7.68(s，1H)，7.54(t，J＝7.9Hz，2H)，7.41(dd，J＝5.1，2.6Hz，2H)，7.27(d，J＝4.5Hz，1H)，7.09(s，1H)，5.75(s，1H)，5.34(s，1H)，2.84(s，5H)，2.30(d，J＝18.1Hz，3H)，2.24(s，3H)，2.11(s，3H)，2.06(q，J＝7.5Hz，2H)，1.92(d，J＝10.6Hz，2H)，.159(t，2H)，1.42-1.10(m，3H)，1.05(s，1H)，0.99(t，J＝7.5Hz，3H).

MS(ESI)m/z 614.0[M+H]⁺。

Example 57

N- ((1S, 4S) -4- (6- (2-chlorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propanamide (580044)

N-((1s，4s)-4-(6-(2-chlorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)cyclohexyl)propionamide

The synthesis was as in example 18, 81.6% yield.

MS(ESI)m/z 628.1[M+H]⁺。

Example 58

(S) -8- (1-acetyl-3-yl) -6- (2-methoxypyrimidin-5-yl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (580053)

(S)-8-(1-acetylpiperidin-3-yl)-6-(2-methoxypyrimidin-5-yl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, with a yield of 77.5%.

¹H NMR(400MHz，DMSO)δ9.68(s，1H)，8.94(s，1H)，8.41(s，2H)，7.85-7.20(m，2H)，6.87(s，1H)，5.68-5.00(m，1H)，4.28(d，J＝105.3Hz，1H)，3.96(s，3H)，2.81(s，4H)，2.38(s，3H)，2.30(d，J＝5.0Hz，1H)，2.32-2.27(m，2H)，2.23(d，J＝4.6Hz，2H)，2.24-2.17(m，1H)，2.19-1.85(m，2H)，1.80(s，3H)，1.62-1.29(m，2H)，1.28(s，3H).

MS(ESI)m/z 598.2[M+H]⁺。

Example 59

(S) -6- (2-methoxypyrimidin-5-yl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -8- (1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (580054)

(S)-6-(2-methoxypyrimidin-5-yl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8-(1-propionylpiperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, yield 79.5%.

¹H NMR(400MHz，DMSO)δ9.69(s，1H)，8.94(s，1H)，8.51(d，J＝2.8Hz，2H)，7.65-7.23(m，2H)，6.86(d，J＝68.6Hz，1H)，5.82-5.08(m，1H)，4.76-4.09(m，1H)，3.96(s，3H)，2.80(s，3H)，2.49-2.37(m，4H)，2.30(d，J＝5.1Hz，3H)，2.32-2.26(m，2H)，2.22(d，J＝9.6Hz，2H)，2.18(q，J＝19.8Hz，2H)，1.76(s，3H)，1.59-1.33(m，2H)，1.36-1.13(m，2H)，0.86(t，3H).

MS(ESI)m/z 612.2[M+H]⁺。

Example 60

(S) -8- (1-acetyl-3-yl) -6- (2-chloro-4-fluorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (580058)

(S)-8-(1-acetylpiperidin-3-yl)-6-(2-chloro-4-fluorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, 80.9% yield.

¹H NMR(400MHz，DMSO)δ9.99(s，1H)，9.32(s，1H)，7.71(s，1H)，7.49(d，J＝10.8Hz，2H)，7.47-7.23(m，2H)，6.88(s，1H)，5.54-5.14(m，1H)，4.43(t，J＝83.0Hz，1H)，3.72(dd，J＝66.7Hz，2H)，2.87(s，3H)，2.22(s，3H)，2.23-2.18(m，4H)，2.15(s，3H)，1.82(t，J＝29.3Hz，2H)，1.60-1.30(m，2H)，1.32(s，3H).

MS(ESI)m/z 618.1[M+H]⁺。

Example 61

(S) -8- (1-propionyl-3-yl) -6- (2-chloro-4-fluorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (580061)

(S)-6-(2-chloro-4-fluorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8-(1-propionylpiperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, with 87.5% yield.

MS(ESI)m/z 632.0[M+H]⁺。

Example 62

(S) -8- (1-acetyl-3-yl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -6- (pyridin-4-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (580067)

(S)-8-(1-acetylpiperidin-3-yl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-6-(pyridin-4-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, with a yield of 79.4%.

MS(ESI)m/z 567.2[M+H]⁺

Example 63

(S) -8- (1-propionyl-3-yl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -6- (pyridin-4-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (580068)

(S)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8-(1-propionylpiperidin-3-yl)-6-(pyridin-4-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

Synthesis procedure as in example 18

¹H NMR (400MHz, DMSO) δ 9.99(s, 1H), 9.32(s, 1H), 7.71(s, 1H), 7.49(d, J ═ 10.8Hz, 2H), 7.47-7.23(m, 2H), 6.88(s, 1H), 5.54-5.14(m, 1H), 4.43(t, J ═ 83.0Hz, 1H), 3.72(dd, J ═ 66.7Hz, 2H), 2.87(s, 3H), 2.22(s, 3H), 2.23-2.18(m, 4H), 2.15(s, 3H), 1.82(t, J ═ 29.3Hz, 2H), 1.60-1.30(m, 2H), 1.32(s, 3H) (yield 79.6%)

MS(ESI)m/z 581.2[M+H]⁺。

Example 64

(S) -8- (1-acetyl-3-yl) -6- (2-fluoropyridin-4-yl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (580073)

(S)-8-(1-acetylpiperidin-3-yl)-6-(2-fluoropyridin-4-yl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, with a yield of 76.9%.

MS(ESI)m/z 585.2[M+H]⁺。

Example 65

(S) -8- (1-propionyl-3-yl) -6- (2-fluoropyridin-4-yl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (580074)

(S)-6-(2-fluoropyridin-4-yl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8-(1-propionylpiperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18 with a yield of 79.85%.

¹H NMR(400MHz，DMSO)δ10.05(s，1H)，8.96(s，1H)，8.29(dd，J＝4.9，2.7Hz，1H)，7.78-7.30(m，2H)，7.38-7.19(m，1H)，7.19-7.00(m，1H)，7.05-6.59(m，1H)，5.34(d，J＝150.9，142.3Hz，1H)，4.97-4.11(m，1H)，4.27-3.46(m，2H)，3.00-2.68(m，4H)，2.26(s，1H)，2.23(d，J＝5.7Hz，3H)，2.21(d，J＝2.8Hz，3H)，1.94-1.59(m，2H)，1.52-1.32(m，2H)，1.36-1.18(m，3H)，1.09-0.90(m，2H)，0.91-0.78(m，2H).

MS(ESI)m/z 599.2[M+H]⁺。

Example 66

(S) -8- (1-propionyl-3-yl) -6- (2-chloro-4-methoxyphenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (580082)

(S)-6-(2-chloro-4-methoxyphenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8-(1-propionylpiperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, with a yield of 76.4%.

¹H NMR(400MHz，DMSO)δ9.99(s，1H)，8.77(s，1H)，7.81(s，1H)，7.52(d，J＝4.1Hz，2H)，7.41(d，J＝10.1Hz，1H)，7.01(d，J＝8.3Hz，1H)，5.82-5.08(m，1H)，4.76-4.09(m，1H)，3.96(s，3H)，2.80(s，3H)，2.49-2.37(m，4H)，2.30(d，J＝5.1Hz，3H)，2.32-2.26(m，2H)，2.22(d，J＝9.6Hz，2H)，2.18(q，J＝19.8Hz，2H)，1.76(s，3H)，1.59-1.33(m，2H)，1.36-1.13(m，2H)，0.86(t，3H).

MS(ESI)m/z 644.2[M+H]⁺。

Example 67

(S) -8- (1-acetyl-3-yl) -6- (3-chloropyridin-4-yl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (580097)

(S)-8-(1-acetylpiperidin-3-yl)-6-(3-chloropyridin-4-yl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, 74.1% yield.

MS(ESI)m/z 601.0[M+H]⁺。

Example 68

(S) -8- (1-propionyl-3-yl) -6- (3-chloropyridin-4-yl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (580098)

(S)-6-(3-chloropyridin-4-yl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8-(1-propionylpiperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, 73% yield.

MS(ESI)m/z 614.9[M+H]⁺。

Example 69

(S) -8- (1-acetyl-3-yl) -6- (furan-3-yl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (580112)

(S)-8-(1-acetylpiperidin-3-yl)-6-(furan-3-yl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, 68.9% yield.

¹H NMR(400MHz，DMSO)δ9.99(s，1H)，9.32(s，1H)，8.25(s，1H)，7.71(s，1H)，7.49(d，J＝10.8Hz，2H)，7.23(d，J＝13.7Hz，1H)，6.88(d，J＝14.0Hz，1H)，5.54-5.14(m，1H)，4.43(t，J＝83.0Hz，1H)，3.72(dd，J＝66.7Hz，2H)，2.87(s，3H)，2.22(s，3H)，2.23-2.18(m，4H)，2.15(s，3H)，1.82(t，J＝29.3Hz，2H)，1.60-1.30(m，2H)，1.32(s，3H).

MS(ESI)m/z 556.0[M+H]⁺。

Example 70

(S) -8- (1-propionyl-3-yl) -6- (furan-3-yl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (580113)

(S)-6-(furan-3-yl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8-(1-propionylpiperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, 58.5% yield.

¹H NMR(400MHz，DMSO)δ9.99(s，1H)，9.32(s，1H)，8.25(s，1H)，7.71(s，1H)，7.49(d，J＝10.8Hz，2H)，7.23(d，J＝13.7Hz，1H)，6.88(d，J＝14.0Hz，1H)，5.34(d，J＝150.9，142.3Hz，1H)，4.97-4.11(m，1H)，4.27-3.46(m，2H)，3.00-2.68(m，4H)，2.26(s，1H)，2.23(d，J＝5.7Hz，3H)，2.21(d，J＝2.8Hz，3H)，1.94-1.59(m，2H)，1.52-1.32(m，2H)，1.36-1.18(m，3H)，1.09-0.90(m，2H)，0.91-0.78(m，2H).

MS(ESI)m/z 570.4[M+H]⁺。

Example 71

(S) -6- (2-chloro-3-fluorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -8- (1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (580120)

(S)-6-(2-chloro-3-fluorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8-(1-propionylpiperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, with a yield of 63.7%.

MS(ESI)m/z 632.4[M+H]⁺。

Example 72

(S) -8- (1-acetyl-3-yl) -6- (2-chloro-4-fluorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (580123)

The synthesis was as in example 18, 63.3% yield.

MS(ESI)m/z 618.4[M+H]⁺。

Example 73

(S) -6- (2-chloro-4-fluorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -8- (1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (580124)

The synthesis was as in example 18, 61.8% yield.

MS(ESI)m/z 632.3[M+H]⁺。

Example 74

N- ((1S, 4S) -4- (6- (2-chloro-5-fluorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) acetamide (580145)

N-((1s，4s)-4-(6-(2-chloro-5-fluorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)cyclohexyl)acetamide

The synthesis was as in example 18, with a yield of 72.9%.

¹H NMR(400MHz，DMSO)δ9.94(s，1H)，8.85(s，1H)，7.79-7.56(m，2H)，7.51(s，1H)，7.43(dd，J＝17.3，10.5，6.7Hz，2H)，7.22-7.05(m，1H)，7.02(t，J＝7.3Hz，1H)，5.37(d，J＝39.8Hz，1H)，4.35(t，J＝5.0Hz，1H)，4.30-4.12(m，1H)，4.01(dt，J＝12.1，6.9Hz，1H)，3.88(s，4H)，3.55-3.35(m，2H)，2.93-2.71(m，2H)，2.37(s，3H)，2.28(s，3H)，2.21(d，J＝24.3Hz，2H)，2.12(d，J＝12.2Hz，3H)，2.03-1.73(m，2H)，1.93(s，3H)，1.70-1.34(m，2H)，0.86(s，3H).

MS(ESI)m/z 632.3[M+H]⁺。

Example 75

N- ((1S, 4S) -4- (6- (2-chloro-5-fluorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propanamide (580146)

N-((1s，4s)-4-(6-(2-chloro-5-fluorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)cyclohexyl)propionamide

The synthesis was as in example 18, 73.4% yield.

¹H NMR(400MHz，DMSO)δ9.94(s，1H)，8.85(s，1H)，7.79-7.56(m，2H)，7.51(s，1H)，7.43(dd，J＝17.3，10.5，6.7Hz，2H)，7.22-7.05(m，1H)，7.02(t，J＝7.3Hz，1H)，5.37(d，J＝39.8Hz，1H)，4.35(t，J＝5.0Hz，1H)，4.30-4.12(m，1H)，4.01(dt，J＝12.1，6.9Hz，1H)，3.88(s，4H)，3.55-3.35(m，2H)，2.93-2.71(m，2H)，2.37(s，3H)，2.28(s，3H)，2.21(d，J＝24.3Hz，2H)，2.12(d，J＝12.2Hz，3H)，2.03-1.73(t，2H)，1.93(s，3H)，1.70-1.34(m，2H)，0.86(q，J＝5.3Hz，3H).

MS(ESI)m/z 646.8[M+H]⁺。

Example 76

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propanamide (580152)

N-((1s，4s)-4-(6-(2-chloro-3-fluorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)cyclohexyl)propionamide

The synthesis was as in example 18, with a yield of 70.3%.

MS(ESI)m/z 646.2[M+H]⁺。

Example 77

N- ((1S, 4S) -4- (6- (2-chloro-4-fluorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propanamide (590011)

N-((1s，4s)-4-(6-(2-chloro-4-fluorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)cyclohexyl)propionamide

The synthesis was as in example 18, with a yield of 70%.

MS(ESI)m/z 646.3[M+H]⁺。

Example 78

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) cyclopropanecarboxamide (590024)

N-((1s，4s)-4-(6-(2-chloro-3-fluorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)cyclohexyl)cyclopropanecarboxamide

The synthesis was as in example 18, 67.4% yield.

¹H NMR(400MHz，DMSO)δ9.94(s，1H)，8.85(s，1H)，7.79-7.56(m，2H)，7.51(s，1H)，7.43(dd，J＝17.3，10.5，6.7Hz，2H)，7.22-7.05(m，1H)，7.02(t，J＝7.3Hz，1H)，5.37(d，J＝39.8Hz，1H)，4.35(t，J＝5.0Hz，1H)，4.30-4.12(m，1H)，4.01(dt，J＝12.1，6.9Hz，1H)，3.88(s，4H)，3.55-3.35(m，2H)，2.93-2.71(m，2H)，2.37(s，3H)，2.28(s，3H)，2.21(d，J＝24.3Hz，2H)，2.12(d，J＝12.2Hz，3H)，2.03-1.73(m，2H)，1.93(s，3H)，1.70-1.34(m，2H)，1.18-0.91(m，2H)，1.13-0.93(m，2H)，0.86(t，J＝14.7Hz，3H)。

MS(ESI)m/z 658.3[M+H]⁺。

Example 79

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) pivaloamide (590030)

N-((1s，4s)-4-(6-(2-chloro-3-fluorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)cyclohexyl)pivalamide

The synthesis was as in example 18 with 69.8% yield.

¹H NMR(400MHz，DMSO)δ9.94(s，1H)，8.85(s，1H)，7.79-7.56(m，2H)，7.51(s，1H)，7.43(dd，J＝17.3，10.5，6.7Hz，2H)，7.22-7.05(m，1H)，7.02(t，J＝7.3Hz，1H)，5.37(d，J＝39.8Hz，1H)，4.35(t，J＝5.0Hz，1H)，4.30-4.12(m，1H)，4.01(dt，J＝12.1，6.9Hz，1H)，3.88(s，4H)，3.55-3.35(m，2H)，2.93-2.71(m，2H)，2.37(s，3H)，2.28(s，3H)，2.21(d，J＝24.3Hz，2H)，2.12(d，J＝12.2Hz，3H)，2.03-1.73(m，2H)，1.93(s，3H)，1.34(s，9H).

MS(ESI)m/z 674.4[M+H]⁺。

Example 80

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -5-methyl-2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) cyclopentanecarboxamide (590031)

N-((1s，4s)-4-(6-(2-chloro-3-fluorophenyl)-5-methyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)cyclohexyl)cyclopentanecarboxamide

The synthesis was as in example 18, 73.3% yield.

¹H NMR(400MHz，DMSO)δ9.95(s，1H)，9.13-8.70(m，1H)，7.66-7.48(m，2H)，7.49-7.40(m，2H)，7.22-7.12(m，1H)，7.00(dd，J＝16.3，10.3Hz，1H)，5.76(s，1H)，5.42(s，1H)，3.52-3.36(m，2H)，2.82(s，4H)，2.32(s，3H)，2.26(d，J＝10.1Hz，3H)，2.21(d，J＝18.7Hz，3H)，2.14(s，3H)，2.00(m，2H)，1.93(s，3H)1.64(t，J＝13.7Hz，4H)，1.62-1.47(m，3H)，1.40(t，J＝14.0Hz，2H)，1.23(dd，J＝13.3，6.7Hz，3H)，1.19-1.10(m，2H)，1.04(dd，J＝15.5，8.5Hz，2H).

MS(ESI)m/z 686.5[M+H]⁺

Example 81

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) cyclobutane (590034)

N-((1s，4s)-4-(6-(2-chloro-3-fluorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)cyclohexyl)cyclobutanecarboxamide

The synthesis was as in example 18, with a yield of 70%.

¹H NMR(400MHz，DMSO)δ9.95(s，1H)，9.13-8.70(m，1H)，7.66-7.48(m，2H)，7.49-7.40(m，2H)，7.22-7.12(m，1H)，7.00(dd，J＝16.3，10.3Hz，1H)，5.76(s，1H)，5.42(s，1H)，3.52-3.36(m，2H)，2.82(s，4H)，2.32(s，3H)，2.26(d，J＝10.1Hz，3H)，2.21(d，J＝18.7Hz，3H)，2.14(s，3H)，2.00(m，2H)，1.93(s，3H)1.64(t，J＝13.7Hz，4H)，1.62-1.47(m，3H)，1.40(t，J＝14.0Hz，2H)，1.23(dd，J＝13.3，6.7Hz，3H)，1.04(dd，J＝15.5，8.5Hz，2H).

MS(ESI)m/z 672.4[M+H]⁺。

Example 82

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) butanamide (590037)

N-((1s，4s)-4-(6-(2-chloro-3-fluorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)cyclohexyl)butyramide

The synthesis was as in example 18, with a yield of 64.1%.

¹H NMR(400MHz，DMSO)δ9.94(s，1H)，8.85(s，1H)，7.79-7.56(m，2H)，7.51(s，1H)，7.43(dd，J＝17.3，10.5，6.7Hz，2H)，7.22-7.05(m，1H)，7.02(t，J＝7.3Hz，1H)，5.37(d，J＝39.8Hz，1H)，4.35(t，J＝5.0Hz，1H)，4.30-4.12(m，1H)，4.01(dt，J＝12.1，6.9Hz，1H)，3.88(s，4H)，3.55-3.35(m，2H)，2.93-2.71(m，2H)，2.37(s，3H)，2.28(s，3H)，2.21(d，J＝24.3Hz，2H)，2.12(d，J＝12.2Hz，3H)，2.03-1.73(m，2H)，1.93(s，3H)，1.70-1.34(m，2H)，1.18-0.91(m，2H)，1.13-0.93(m，2H)，0.86(t，J＝14.7Hz，3H).

MS(ESI)m/z 660.4[M+H]⁺。

Example 83

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) cyclohexanecarboxamide (590039)

N-((1s，4s)-4-(6-(2-chloro-3-fluorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)cyclohexyl)cyclohexanecarboxamide

The synthesis was as in example 18, 71.4% yield.

¹H NMR(400MHz，DMSO)δ9.95(s，1H)，9.13-8.70(m，1H)，7.66-7.48(m，2H)，7.49-7.40(m，2H)，7.22-7.12(m，1H)，7.00(dd，J＝16.3，10.3Hz，1H)，5.76(s，1H)，5.42(s，1H)，3.52-3.36(m，2H)，2.82(s，4H)，2.32(s，3H)，2.26(d，J＝10.1Hz，3H)，2.21(d，J＝18.7Hz，3H)，2.14(s，3H)，2.00(m，2H)，1.93(s，3H)1.64(t，J＝13.7Hz，4H)，1.62-1.47(m，3H)，1.40(t，J＝14.0Hz，2H)，1.36-1.27(m，2H)，1.23(dd，J＝13.3，6.7Hz，3H)，1.19-1.10(m，2H)，1.04(dd，J＝15.5，8.5Hz，2H).

MS(ESI)m/z 700.5[M+H]⁺。

Example 84

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) -3, 3-dimethylbutanamide (590040)

N-((1s，4s)-4-(6-(2-chloro-3-fluorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)cyclohexyl)-3，3-dimethylbutanamide

The synthesis was as in example 18, 67.5% yield.

¹H NMR(400MHz，DMSO)δ9.99(s，1H)，9.32(s，1H)，7.71(s，1H)，7.49(d，J＝10.8Hz，2H)，7.47-7.23(m，2H)，6.88(s，1H)，5.54-5.14(m，1H)，4.43(t，J＝83.0Hz，1H)，3.72(dd，J＝66.7Hz，2H)，3.69-3.37(m，2H)2.87(s，3H)，2.22(s，3H)，2.23-2.18(m，4H)，2.15(s，3H)，1.82(t，J＝29.3Hz，2H)，1.60-1.30(m，2H)，1.32(s，9H).

MS(ESI)m/z 688.4[M+H]⁺。

Example 85

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) acetamide (590041)

N-((1s，4s)-4-(6-(2-chloro-3-fluorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)cyclohexyl)acetamide

The synthesis was as in example 18 with a yield of 65.2%.

¹H NMR(400MHz，DMSO)δ9.99(s，1H)，9.32(s，1H)，7.71(s，1H)，7.49(d，J＝10.8Hz，2H)，7.47-7.23(m，2H)，6.88(s，1H)，5.54-5.14(m，1H)，4.43(t，J＝83.0Hz，1H)，3.72(dd，J＝66.7Hz，2H)，3.69-3.37(m，2H)2.87(s，3H)，2.22(s，3H)，2.23-2.18(m，4H)，2.15(s，3H)，1.82(t，J＝29.3Hz，2H)，1.60-1.30(m，2H)，1.32(s，3H).

MS(ESI)m/z 632.3[M+H]⁺。

Example 86

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) pentanamide (590047)

N-((1s，4s)-4-(6-(2-chloro-3-fluorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)cyclohexyl)pentanamide

The synthesis was as in example 18, 67% yield.

¹H NMR(400MHz，DMSO)δ9.94(s，1H)，8.85(s，1H)，7.79-7.56(m，2H)，7.51(s，1H)，7.43(dd，J＝17.3，10.5，6.7Hz，2H)，7.22-7.05(m，1H)，7.02(t，J＝7.3Hz，1H)，5.41(s，1H)，4.28(dt，J＝13.2，5.8Hz，1H)，4.18-3.71(m，2H)，3.69-3.37(m，2H)，2.79(s，4H)，2.39-2.26(m，3H)，2.32(s，3H)，2.24(s，3H)，2.19-2.07(t，J＝7.0Hz，1H)，1.93(s，3H)，1.99-1.81(m，1H)，1.68-1.50(m，2H)，1.50-1.35(m，3H)，1.37-1.14(m，2H)，1.14-0.95(m，2H)，0.87(t，J＝17.0，3H).

MS(ESI)m/z 674.4[M+H]⁺。

Example 87

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -5-methyl-2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) -3-methylbutanamide (590048)

N-((1s，4s)-4-(6-(2-chloro-3-fluorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)cyclohexyl)-3-methylbutanamide

The synthesis was as in example 18, yield 66.48%.

¹H NMR(400MHz，DMSO)δ9.94(s，1H)，8.85(s，1H)，7.79-7.56(m，2H)，7.51(s，1H)，7.43(dd，J＝17.3，10.5，6.7Hz，2H)，7.22-7.05(m，1H)，7.02(t，J＝7.3Hz，1H)，5.41(s，1H)，4.28(dt，J＝13.2，5.8Hz，1H)，4.18-3.71(m，1H)，3.69-3.37(m，1H)，2.79(s，4H)，2.39-2.26(m，3H)，2.32(s，3H)，2.24(s，3H)，2.19-2.07(t，J＝7.0Hz，1H)，1.93(s，3H)，1.99-1.81(m，1H)，1.68-1.50(m，2H)，1.50-1.35(m，3H)，1.37-1.14(m，2H)，1.14-0.95(m，2H)，0.87(dd，J＝17.0，4.9Hz，2H)，0.85-0.77(m，6H).

MS(ESI)m/z 674.4[M+H]⁺。

Example 88

(S) -6- (2-chlorophenyl) -5-methyl-2- ((6-methyl-5- (4-methylpiperazin-1-yl) pyridin-2-yl) amino) -8- (1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (10201B)

(S)-6-(2-chlorophenyl)-5-methyl-2-((6-methyl-5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-8-(1-propionyl piperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, 85.4% yield.

¹H NMR(400MHz，Chloroform-d)δ8.83(d，J＝11.0Hz，1H)，8.04(dd，J＝20.7，10.7Hz，2H)，7.55-7.46(m，1H)，7.46-7.32(m，3H)，7.25-7.19(m，1H)，5.50(s，1H)，4.70(d，J＝12.6Hz，1H)，4.00-3.71(m，2H)，3.06(d，J＝13.4Hz，1H)，2.97(d，J＝6.2Hz，3H)，2.88(d，J＝11.4Hz，1H)，2.63(d，J＝25.4Hz，3H)，2.49(d，J＝3.7Hz，2H)，2.43(dd，J＝12.3，6.1Hz，3H)，2.30(p，J＝7.3Hz，1H)，2.25-2.17(m，3H)，1.91(d，J＝23.1Hz，3H)，1.61(d，J＝10.0Hz，2H)，1.07(td，J＝7.4，3.6Hz，2H)，0.87(dd，J＝15.5，8.4Hz，2H).

MS(ESI)m/z 615.3[M+H]⁺。

Example 89

(S) -6- (2-chlorophenyl) -5-methyl-2- ((5- (4-methylpiperazin-1-yl) pyridin-2-yl) amino) -8- (1-propionylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (10301B)

(S)-6-(2-chlorophenyl)-5-methyl-2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-8-(1-propionyl piperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, 67% yield.

¹H NMR(400MHz，DMSO-d6)δ10.22(d，J＝18.0Hz，1H)，8.95(s，1H)，8.07(s，1H)，7.88(s，1H)，7.60-7.52(m，1H)，7.45-7.40(m，2H)，7.37-7.26(m，2H)，4.49-3.67(m，1H)，3.30(s，2H)，3.16(s，3H)，2.31(d，J＝15.9Hz，7H)，2.15(d，J＝2.9Hz，4H)，2.04-1.96(m，1H)，1.76(d，J＝39.0Hz，3H)，1.45(s，2H)，1.02(t，J＝7.3Hz，2H)，0.93-0.78(m，3H).

MS(ESI)m/z 601.2[M+H]⁺。

Example 90

(S) -6- (2-chlorophenyl) -5-methyl-2- ((5- (piperazin-1-yl) pyridin-2-yl) amino) -8- (1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (10401B)

(S)-6-(2-chlorophenyl)-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-8-(1-propionylpiperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, with 87.2% yield.

¹H NMR(400MHz，DMSO-d6)δ10.21(d，J＝18.1Hz，1H)，8.94(d，J＝2.9Hz，1H)，8.04(d，J＝2.9Hz，1H)，7.87(s，1H)，7.68-7.51(m，1H)，7.36(ddt，J＝49.1，9.1，5.4Hz，4H)，5.33(s，1H)，4.58-3.60(m，2H)，3.06(t，J＝3.5Hz，5H)，2.87(dt，J＝6.7，3.4Hz，4H)，2.64(s，1H)，2.40(s，1H)，2.33-2.22(m，1H)，2.15(d，J＝2.9Hz，3H)，2.02-1.34(m，4H)，1.09-0.78(m，4H).

MS(ESI)m/z 588.2[M+H]⁺。

Example 91

(S) -6- (2-chlorophenyl) -2- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -3-methylphenyl) amino) -5-methyl-8- (1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (10501B)

(S)-6-(2-chlorophenyl)-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-3-methylphenyl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18 with a yield of 77.3%.

¹H NMR(400MHz，DMSO-d6)δ9.96(s，1H)，8.91(d，J＝3.6Hz，1H)，7.63-7.25(m，6H)，7.01(d，J＝8.6Hz，1H)，5.41(d，J＝8.9Hz，1H)，4.43(s，1H)，4.12-3.55(m，2H)，3.26-3.07(m，1H)，2.92(td，J＝7.0，2.4Hz，3H)，2.50(p，J＝1.8Hz，1H)，2.38(q，J＝6.8Hz，3H)，2.21(d，J＝2.8Hz，4H)，2.18-2.10(m，9H)，1.76(s，2H)，1.46(d，J＝14.3Hz，1H)，1.02(t，J＝7.3Hz，2H)，0.83(d，J＝9.4Hz，2H).

MS(ESI)m/z 616.9[M+H]⁺。

Example 92

(S) -6- (2-chlorophenyl) -2- ((5- ((4-ethylpiperazin-1-yl) methyl) pyridin-2-yl) amino) -5-methyl-8- (1-propionylpiperidin) pyridin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (10801B)

(S)-6-(2-chlorophenyl)-2-((5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)amino)-5-methyl-8-(1-propionyl piperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one(10801B)

The synthesis was as in example 18 with a yield of 56.7%.

¹H NMR(400MHz，DMSO-d6)δ10.50(d，J＝21.6Hz，1H)，9.00(d，J＝3.9Hz，1H)，8.23(d，J＝2.8Hz，1H)，8.13-7.93(m，1H)，7.88-7.53(m，2H)，7.47-7.14(m，3H)，5.62-4.94(m，1H)，4.14(dd，J＝245.0，24.4Hz，2H)，3.45(d，J＝2.8Hz，3H)，2.82(d，J＝125.1Hz，1H)，2.46-2.21(m，10H)，2.16(d，J＝3.5Hz，3H)，2.10-1.94(m，1H)，1.92-1.32(m，4H)，1.11-1.01(m，2H)，0.98(t，J＝7.2Hz，3H)，0.87(dq，J＝14.1，6.7Hz，2H).

MS(ESI)m/z 629.30[M+H]⁺。

Example 93

(S) -6- (2-chlorophenyl) -5-methyl-2- ((3-methyl-4- (piperidin-4-yl) phenyl) amino) -8- (1-propionylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (10901B)

(S)-6-(2-chlorophenyl)-5-methyl-2-((3-methyl-4-(piperidin-4-yl)phenyl)amino)-8-(1-propionyl piperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, 81.2% yield.

¹H NMR(400MHz，DMSO-d6)δ10.03(s，1H)，8.93(d，J＝4.1Hz，1H)，7.70-7.37(m，5H)，7.36-7.24(m，1H)，7.10(s，1H)，5.47(d，J＝46.2Hz，1H)，4.44(s，1H)，3.85(dd，J＝95.6，42.7Hz，2H)，3.13(t，J＝10.8Hz，2H)，3.01-2.59(m，4H)，2.27(d，J＝3.0Hz，5H)，2.14(t，J＝2.7Hz，4H)，1.71(d，J＝48.4Hz，4H)，1.61-1.36(m，3H)，1.01(s，2H)，0.82(d，J＝20.5Hz，2H).

MS(ESI)m/z 599.6[M+H]⁺。

Example 94

(S) -6- (2-chlorophenyl) -2- ((2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) amino) -5-methyl-8- (1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (11001B)

(S)-6-(2-chlorophenyl)-2-((2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, 74.3% yield.

¹H NMR(400MHz，DMSO-d6)δ8.89(d，J＝5.8Hz，1H)，7.62-7.50(m，1H)，7.47-7.15(m，4H)，6.87(d，J＝21.1Hz，1H)，5.63-4.69(m，1H)，4.62-3.85(m，3H)，3.62(s，2H)，3.31-2.62(m，6H)，2.22(d，J＝4.2Hz，3H)，2.16-2.10(m，3H)，2.02(dd，J＝30.1，16.3Hz，2H)，1.71(d，J＝25.3Hz，6H)，1.18(s，6H)，0.96(t，J＝7.4Hz，2H)，0.88-0.77(m，3H).

MS(ESI)m/z 658.3[M+H]⁺。

Example 95

(S) -6- (2-chlorophenyl) -2- ((4- (4- (dimethylamino) piperidin-1-yl) -3-methylphenyl) amino) -5-methyl-8- (1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (11101B)

(S)-6-(2-chlorophenyl)-2-((4-(4-(dimethylamino)piperidin-1-yl)-3-methylphenyl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, with a yield of 79.7%.

¹H NMR(400MHz，DMSO-d6)δ9.97(s，1H)，8.91(d，J＝3.6Hz，1H)，7.67-7.19(m，6H)，6.94(d，J＝8.3Hz，1H)，5.59-5.28(m，1H)，4.58-3.58(m，2H)，3.11(d，J＝35.6Hz，2H)，2.78-2.53(m，3H)，2.42-2.25(m，8H)，2.21(d，J＝3.4Hz，3H)，2.14(t，J＝2.6Hz，4H)，1.93-1.70(m，4H)，1.67-1.36(m，4H)，1.01(s，2H)，0.82(d，J＝21.3Hz，2H).

MS(ESI)m/z 642.4[M+H]⁺。

Example 96

(S) -6- (2-chlorophenyl) -5-methyl-2- ((3-methyl-4- (9-methyl-3, 9-diazaspiro [5.5] undecan-3-yl) phenyl) amino) -8- (1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (11201B)

(S)-6-(2-chlorophenyl)-5-methyl-2-((3-methyl-4-(9-methyl-3，9-diazaspiro[5.5]undecan-3-yl)phenyl)amino)-8-(1-propionylpiperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, with a yield of 76.7%.

¹H NMR(400MHz，DMSO-d6)δ9.98(s，1H)，8.91(d，J＝4.1Hz，1H)，7.75-7.21(m，6H)，6.98(s，1H)，5.45(d，J＝32.9Hz，1H)，4.43(s，1H)，3.84(dd，J＝101.7，37.8Hz，2H)，2.75(q，J＝7.0，5.7Hz，4H)，2.31(s，5H)，2.23-1.97(m，9H)，1.93-1.66(m，2H)，1.53(dt，J＝21.3，5.2Hz，9H)，1.09-0.64(m，4H).

MS(ESI)m/z 683.2[M+H]⁺。

Example 97

(S) -6- (2-chlorophenyl) -5-methyl-2- ((3-methyl-4- (7-methyl-2, 7-diazaspiro [3.5] non-2-yl) phenyl) amino) -8- (1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (11301B)

(S)-6-(2-chlorophenyl)-5-methyl-2-((3-methyl-4-(7-methyl-2，7-diazaspiro[3.5]nonan-2-yl)phenyl)amino)-8-(1-propionylpiperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, 66.9% yield.

¹H NMR(400MHz，DMSO-d6)δ9.76(s，1H)，8.85(d，J＝3.2Hz，1H)，7.62-7.51(m，1H)，7.47-7.18(m，5H)，6.52(s，1H)，5.58-4.88(m，2H)，4.23(d，J＝155.3Hz，1H)，3.62(s，2H)，3.55-3.38(m，4H)，3.30(d，J＝4.2Hz，2H)，3.14(d，J＝2.7Hz，3H)，2.80-2.56(m，1H)，2.35-2.20(m，1H)，2.16-2.05(m，9H)，1.76(d，J＝47.2Hz，5H)，1.42(d，J＝23.7Hz，1H)，1.01(t，J＝7.3Hz，2H)，0.84(d，J＝6.9Hz，2H).

MS(ESI)m/z 654.3[M+H]⁺。

Example 98

6- (2-chlorophenyl) -5-methyl-2- ((3-methyl-4- ((3AR, 6AS) -5-methylhexahydropyrrolo [3, 4-c ] pyrrol-2 (1H) -yl) phenyl) amino) -8- ((S) -1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (11401B)

6-(2-chlorophenyl)-5-methyl-2-((3-methyl-4-((3aR，6aS)-5-methylhexahydropyrrolo[3，4-c]pyrrol-2(1H)-yl)phenyl)amino)-8-((S)-1-propionylpiperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, 76.2% yield

¹H NMR(400MHz，DMSO-d6)δ10.05(d，J＝60.4Hz，1H)，8.90(d，J＝3.7Hz，1H)，7.60-7.24(m，6H)，7.00-6.84(m，1H)，5.38(s，1H)，4.60-3.54(m，1H)，3.27-2.57(m，8H)，2.33(d，J＝9.4Hz，6H)，2.23(d，J＝2.5Hz，3H)，2.13(t，J＝2.7Hz，4H)，2.06-1.26(m，6H)，0.93(d，J＝62.9Hz，4H).

MS(ESI)m/z 640.7[M+H]⁺。

Example 99

(S) -6- (2-chlorophenyl) -5-methyl-2- ((3-methyl-4- (3-methyl-1, 3-diazepan-1-yl) phenyl) amino) -8- (1-propionylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (11501B)

(S)-6-(2-chlorophenyl)-5-methyl-2-((3-methyl-4-(3-methyl-1，3-diazepan-1-yl)phenyl)amino)-8-(1-propionylpiperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, 57.8% yield.

¹H NMR(400MHz，DMSO-d6)δ9.95(s，1H)，8.90(d，J＝4.8Hz，1H)，7.59-7.24(m，6H)，7.04-6.93(m，1H)，5.45(d，J＝42.1Hz，1H)，4.58-3.57(m，2H)，3.16-2.88(m，4H)，2.69(q，J＝8.9，7.4Hz，4H)，2.34(d，J＝5.4Hz，4H)，2.22(d，J＝2.9Hz，3H)，2.13(t，J＝3.0Hz，3H)，2.00(dd，J＝14.6，7.1Hz，1H)，1.94-1.61(m，5H)，1.42(d，J＝22.0Hz，2H)，1.08-0.65(m，4H).

MS(ESI)m/z 628.7[M+H]⁺。

Example 100

6- (2-chlorophenyl) -2- ((4- ((S) -3, 4-dimethylpiperazin-1-yl) -3-methylphenyl) amino) -5-methyl-8- ((S) -1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (11601B)

6-(2-chlorophenyl)-2-((4-((S)-3，4-dimethylpiperazin-1-yl)-3-methylphenyl)amino)-5-methyl-8-((S)-1-propionylpiperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, 53.9% yield.

¹H NMR(400MHz，DMSO-d6)δ10.05(d，J＝60.9Hz，1H)，8.90(d，J＝5.1Hz，1H)，7.66-7.21(m，6H)，7.06-6.83(m，1H)，5.41(s，1H)，4.44(s，1H)，3.84(dd，J＝101.7，39.7Hz，2H)，3.10-2.57(m，5H)，2.47-2.27(m，4H)，2.26-2.17(m，7H)，2.13(t，J＝2.9Hz，3H)，1.76(s，3H)，1.45(d，J＝14.2Hz，1H)，1.07-0.98(m，4H)，0.82(d，J＝18.0Hz，2H).

MS(ESI)m/z 628.3[M+H]⁺。

Example 101

6- (2-chlorophenyl) -2- ((4- ((R) -3, 4-dimethylpiperazin-1-yl) -3-methylphenyl) amino) -5-methyl-8- ((S) -1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (11701B)

6-(2-chlorophenyl)-2-((4-((R)-3，4-dimethylpiperazin-1-yl)-3-methylphenyl)amino)-5-methyl-8-((S)-1-propionylpiperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, 66.7% yield.

¹H NMR(400MHz，DMSO-d6)δ9.96(s，1H)，8.90(d，J＝6.7Hz，1H)，7.62-7.22(m，6H)，6.93(d，J＝9.9Hz，1H)，5.41(s，1H)，4.57-4.25(m，1H)，3.84(dd，J＝103.1，40.2Hz，2H)，2.94-2.66(m，5H)，2.38(dt，J＝29.3，12.5Hz，4H)，2.22(d，J＝5.6Hz，7H)，2.13(d，J＝4.5Hz，3H)，1.76(s，2H)，1.44(t，J＝13.9Hz，1H)，1.10-0.95(m，5H)，0.89-0.71(m，2H).

MS(ESI)m/z 628.3[M+H]⁺。

Example 102

6- (2-chlorophenyl) -5-methyl-2- ((3-methyl-4- ((3S, 5R) -3, 4, 5-trimethylpiperazin-1-yl) phenyl) amino) -8- ((S) -1-propionylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (11801B)

6-(2-chlorophenyl)-5-methyl-2-((3-methyl-4-((3S，5R)-3，4，5-trimethylpiperazin-1-yl)phenyl)amino)-8-((S)-1-propionylpiperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, with a yield of 86.7%.

¹H NMR(400MHz，DMSO-d6)δ9.99(s，1H)，8.91(d，J＝3.0Hz，1H)，7.66-7.51(m，2H)，7.48-7.34(m，3H)，7.34-7.24(m，1H)，6.91(s，1H)，5.66-5.28(m，1H)，4.42(d，J＝28.0Hz，1H)，3.84(dd，J＝106.4，39.1Hz，2H)，3.06-2.59(m，3H)，2.46-2.28(m，5H)，2.22(d，J＝4.5Hz，6H)，2.14(d，J＝3.0Hz，3H)，2.04-1.63(m，3H)，1.61-1.31(m，2H)，1.11-0.99(m，7H)，0.85(td，J＝15.5，13.1，7.9Hz，2H).

MS(ESI)m/z 642.3[M+H]⁺。

Example 103

(S) -6- (2-chlorophenyl) -5-methyl-2- ((3-methyl-4- (4- (oxetan-3-yl) piperazin-1-yl) phenyl) amino) -8- (1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (12102B)

(S)-6-(2-chlorophenyl)-5-methyl-2-((3-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-8-(1-propionylpiperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, 68.9% yield.

¹H NMR(400MHz，DMSO-d6)δ10.05(d，J＝48.1Hz，1H)，8.91(d，J＝4.6Hz，1H)，7.67-7.35(m，5H)，7.37-7.18(m，1H)，7.07-6.90(m，1H)，5.47(d，J＝43.9Hz，1H)，4.82-4.20(m，5H)，4.15-3.40(m，2H)，3.10-2.56(m，5H)，2.41(s，5H)，2.21(d，J＝2.7Hz，3H)，2.18-2.09(m，3H)，2.08-1.93(m，1H)，1.91-1.32(m，4H)，1.06-0.66(m，4H).

MS(ESI)m/z 656.3[M+H]⁺。

Example 104

(S) -8- (1-propionyl-3-yl) -6- (2-chlorophenyl) -5-methyl-2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrido [2, 3-d ] pyrimidin-7 (8H) -one

(S)-6-(2-chlorophenyl)-5-methyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-8-(1-propionylpiperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one(12201B)

The synthesis was as in example 18, 87% yield.

¹H NMR(400MHz，DMSO-d6)δ10.04(d，J＝59.8Hz，1H)，8.89(d，J＝3.0Hz，1H)，7.69-7.47(m，3H)，7.47-7.37(m，2H)，7.37-7.25(m，1H)，7.00-6.76(m，2H)，5.46(d，J＝56.8Hz，1H)，4.64-3.49(m，3H)，3.08(d，J＝5.6Hz，4H)，2.67(d，J＝2.6Hz，2H)，2.34(d，J＝88.4Hz，7H)，2.13(d，J＝2.7Hz，4H)，1.95-1.31(m，4H)，0.93(d，J＝67.2Hz，3H).

MS(ESI)m/z 600.3[M+H]⁺。

Example 105

(S) -6- (2-chlorophenyl) -5-methyl-2- ((2-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -8- (1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (12301B)

(S)-6-(2-chlorophenyl)-5-methyl-2-((2-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8-(1-propionylpiperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, 73.4% yield.

¹H NMR(400MHz，DMSO-d6)δ10.11(s，1H)，9.28(d，J＝12.4Hz，1H)，8.83(s，1H)，7.62-7.49(m，1H)，7.40(dq，J＝7.1，3.9，3.1Hz，2H)，7.35-7.21(m，2H)，7.13(td，J＝7.8，1.7Hz，1H)，7.02-6.72(m，3H)，5.03-3.44(m，2H)，3.12(s，4H)，2.33(s，2H)，2.26(d，J＝4.8Hz，4H)，2.15(d，J＝3.4Hz，3H)，2.12-2.05(m，4H)，2.04-1.87(m，1H)，1.86-1.28(m，4H)，1.05-0.77(m，4H).

MS(ESI)m/z 614.4[M+H]⁺。

Example 106

(S) -2- ((3-chloro-4- (4-methylpiperazin-1-yl) phenyl) amino) -6- (2-chlorophenyl) -5-methyl-8- (1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (12401B)

(S)-2-((3-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-6-(2-chlorophenyl)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one(12401B)

The synthesis was as in example 18, with a yield of 76.7%.

¹H NMR(400MHz，DMSO-d6)δ10.15(d，J＝28.8Hz，1H)，8.96(d，J＝3.4Hz，1H)，7.90(d，J＝36.5Hz，1H)，7.68-7.38(m，4H)，7.38-7.26(m，1H)，7.11(s，1H)，5.44(d，J＝96.5Hz，1H)，4.61-3.56(m，2H)，3.30(t，J＝7.0Hz，4H)，2.94(s，4H)，2.69(s，3H)，2.35(d，J＝20.5Hz，2H)，2.26(d，J＝3.0Hz，3H)，2.21-2.09(m，5H)，2.01-1.43(m，7H)，0.92(dt，J＝61.2，7.8Hz，4H).

MS(ESI)m/z 634.4[M+H]⁺。

Example 107

(S) -6- (2-chlorophenyl) -5-methyl-2- ((4- (4-methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl) amino) -8- (1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (12601B)

(S)-6-(2-chlorophenyl)-5-methyl-2-((4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)-8-(1-propionylpiperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, with a yield of 86.7%.

¹H NMR(400MHz，DMSO-d6)δ10.26(s，1H)，8.97(d，J＝6.7Hz，1H)，8.02-7.91(m，1H)，7.67-7.58(m，3H)，7.54(ddd，J＝8.7，4.9，2.2Hz，3H)，7.46-7.37(m，2H)，7.33-7.25(m，1H)，5.35(s，1H)，4.44(d，J＝13.0Hz，1H)，4.21-3.51(m，2H)，2.83(q，J＝4.7Hz，4H)，2.42(d，J＝27.8Hz，4H)，2.23(d，J＝2.1Hz，3H)，2.15(t，J＝2.8Hz，3H)，1.78(d，J＝24.5Hz，2H)，1.56-1.39(m，1H)，1.02(t，J＝7.4Hz，2H)，0.90-0.72(m，2H).

MS(ESI)m/z 668.3[M+H]⁺。

Example 108

(S) -6- (2-chlorophenyl) -2- ((3-fluoro-4- (4-methylpiperazin-1-yl) phenyl) amino) -5-methyl-8- (1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (12701B)

(S)-6-(2-chlorophenyl)-2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, 63.7% yield.

¹H NMR(400MHz，DMSO-d6)δ10.12(s，1H)，8.94(d，J＝5.2Hz，1H)，7.77-7.51(m，2H)，7.50-7.20(m，4H)，7.09-6.87(m，1H)，5.35(s，1H)，4.58-4.29(m，1H)，4.14-3.59(m，2H)，3.10-2.88(m，4H)，2.78-2.59(m，1H)，2.47(s，3H)，2.42-2.28(m，2H)，2.22(s，3H)，2.14(d，J＝2.8Hz，3H)，2.09-1.32(m，4H)，0.92(dt，J＝63.4，7.8Hz，4H).

MS(ESI)m/z 618.3[M+H]⁺。

Example 109

(S) -6- (2-chlorophenyl) -2- ((3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) -5-methyl-8- (1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (12801B)

(S)-6-(2-chlorophenyl)-2-((3-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18 with 84% yield.

1H NMR(400MHz，DMSO-d6)δ9.92(s，1H)，8.91(s，1H)，7.55(d，J＝6.3Hz，1H)，7.41(d，J＝6.8Hz，3H)，7.36-6.67(m，4H)，5.39(s，1H)，4.16(d，J＝210.3Hz，2H)，3.58(s，1H)，3.36(s，3H)，2.93(s，4H)，2.80-2.58(m，1H)，2.38(s，2H)，2.23(s，3H)，2.13(s，3H)，1.59(d，J＝116.5Hz，5H)，1.10-0.67(m，4H).

MS(ESI)m/z 630.3[M+H]⁺。

Example 110

(S) -6- (2-chlorophenyl) -2- ((1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl) amino) -5-methyl-8- (1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (12901B)

(S)-6-(2-chlorophenyl)-2-((1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, 68% yield.

¹H NMR(400MHz，DMSO-d6)δ10.15(s，1H)，8.90(d，J＝5.8Hz，1H)，8.15-7.98(m，1H)，7.86(q，J＝15.6，11.6Hz，2H)，7.77-7.50(m，3H)，5.41(s，1H)，4.34(d，J＝26.9Hz，3H)，3.80(s，2H)，3.15(s，2H)，2.56(s，3H)，2.39(s，3H)，2.19-2.09(m，3H)，1.79(d，J＝46.8Hz，3H)，1.48(s，2H)，1.02(d，J＝10.0Hz，3H)，0.83(s，2H).

MS(ESI)m/z 563.1[M+H]⁺。

Example 111

(S) -6- (2-chlorophenyl) -2- ((1- (2- (diethylamino) ethyl) -1H-pyrazol-4-yl) amino) -5-methyl-8- (1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (13001B)

(S)-6-(2-chlorophenyl)-2-((1-(2-(diethylamino)ethyl)-1H-pyrazol-4-yl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, 56.7% yield.

¹H NMR(400MHz，DMSO-d6)δ9.97(d，J＝104.5Hz，1H)，8.89(t，J＝7.5Hz，1H)，8.31(s，1H)，7.68-7.50(m，2H)，7.29(dp，J＝28.8，8.5，7.3Hz，4H)，5.39(s，1H)，4.60-4.29(m，1H)，4.26-3.99(m，3H)，3.99-3.61(m，2H)，2.77(d，J＝45.7Hz，3H)，2.33(d，J＝40.3Hz，2H)，2.13(s，4H)，1.92-1.41(m，4H)，0.99(d，J＝34.2Hz，10H).

MS(ESI)m/z 590.2[M+H]⁺。

Example 112

(S) -6- (2-chlorophenyl) -5-methyl-2- ((5- ((4-methylpiperazin-1-yl) methyl) pyridin-2-yl) amino) -8- (1-propionylpiperidin) pyridin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (13201B)

(S)-6-(2-chlorophenyl)-5-methyl-2-((5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)amino)-8-(1-propionylpiperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, 69% yield.

¹H NMR(400MHz，DMSO-d6)δ10.51(s，1H)，9.08-8.94(m，1H)，8.23(s，1H)，8.05(t，J＝9.8Hz，1H)，7.73-7.53(m，2H)，7.43(dt，J＝6.6，1.8Hz，2H)，7.29(q，J＝5.2，4.0Hz，1H)，5.33(d，J＝4.9Hz，1H)，4.54-4.35(m，1H)，3.84(d，J＝39.7Hz，1H)，3.45(s，2H)，2.77-2.61(m，1H)，2.47-2.25(m，7H)，2.25-2.10(m，6H)，2.04-1.66(m，4H)，1.55-1.31(m，2H)，1.05(s，2H)，0.86(q，J＝7.1，6.3Hz，3H).

MS(ESI)m/z 615.7[M+H]⁺。

Example 113

(S) -6- (2-chlorophenyl) -2- ((4- ((4-ethylpiperazin-1-yl) methyl) -3-methylphenyl) amino) -5-methyl-8- (1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (13301B)

(S)-6-(2-chlorophenyl)-2-((4-((4-ethylpiperazin-1-yl)methyl)-3-methylphenyl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, 58% yield.

¹H NMR(400MHz，DMSO-d6)δ10.06(s，1H)，8.93(d，J＝4.7Hz，1H)，7.59-7.52(m，1H)，7.46-7.37(m，3H)，7.37-7.22(m，2H)，7.17-7.02(m，1H)，5.41(s，1H)，4.40(d，J＝32.8Hz，1H)，4.18-3.43(m，3H)，3.09-2.56(m，2H)，2.47-2.21(m，13H)，2.14(t，J＝2.9Hz，4H)，1.94-1.34(m，4H)，1.01(dt，J＝24.8，7.0Hz，5H)，0.82(s，2H).

MS(ESI)m/z 642.4[M+H]⁺。

Example 114

(S) -6- (2-chlorophenyl) -2- ((4- (4-ethylpiperazin-1-yl) -3-methylphenyl) amino) -5-methyl-8- (1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (14101B)

(S)-6-(2-chlorophenyl)-2-((4-(4-ethylpiperazin-1-yl)-3-methylphenyl)amino)-5-methyl-8-(1-propionylpiperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, 64% yield.

¹H NMR(400MHz，DMSO-d6)δ9.98(s，1H)，8.91(d，J＝4.2Hz，1H)，7.61-7.37(m，5H)，7.29(dtd，J＝12.6，7.2，6.2，3.5Hz，1H)，7.03-6.90(m，1H)，5.47(d，J＝48.1Hz，1H)，4.51-3.60(m，2H)，2.81(t，J＝5.0Hz，5H)，2.54(s，3H)，2.41(s，4H)，2.21(d，J＝2.9Hz，4H)，2.13(t，J＝2.7Hz，3H)，1.92-1.32(m，4H)，1.04(td，J＝7.2，2.6Hz，5H)，0.90-0.70(m，2H).

MS(ESI)m/z 628.3[M+H]⁺。

Example 115

(S) -6- (2-chlorophenyl) -5-methyl-2- ((3-methyl-4- (piperazin-1-yl) phenyl) amino) -8- (1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (14201B)

(S)-6-(2-chlorophenyl)-5-methyl-2-((3-methyl-4-(piperazin-1-yl)phenyl)amino)-8-(1-propionylpiperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, with a yield of 86%.

¹H NMR(400MHz，Chloroform-d)δ8.69(d，J＝11.3Hz，1H)，7.54-7.46(m，1H)，7.34(dq，J＝8.5，5.1，3.2Hz，2H)，7.22(q，J＝5.4Hz，1H)，6.87(dd，J＝14.3，8.3Hz，1H)，6.60(d，J＝2.9Hz，1H)，6.52(dd，J＝8.5，2.6Hz，1H)，5.43(d，J＝34.5Hz，1H)，4.65(dd，J＝23.9，12.6Hz，1H)，4.33(s，1H)，4.02(s，3H)，3.80(dd，J＝34.7，13.4Hz，2H)，3.50(s，2H)，2.90(t，J＝5.0Hz，5H)，2.53(t，J＝12.8Hz，1H)，2.37(t，J＝7.2Hz，2H)，2.31(s，3H)，2.16(d，J＝7.4Hz，3H)，1.84(d，J＝12.3Hz，2H)，1.14(t，J＝7.5Hz，3H).

MS(ESI)m/z 600.3[M+H]⁺。

Example 116

(S) -6- (2-chlorophenyl) -5-methyl-2- ((5- (piperazin-1-ylmethyl) pyridin-2-yl) amino) -8- (1-propylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (14401B)

(S)-6-(2-chlorophenyl)-5-methyl-2-((5-(piperazin-1-ylmethyl)pyridin-2-yl)amino)-8-(1-propionylpiperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, 87% yield.

¹H NMR(400MHz，DMSO-d6)δ10.52(s，1H)，9.00(d，J＝3.6Hz，1H)，8.24(d，J＝2.7Hz，1H)，8.05(dt，J＝9.0，4.6Hz，1H)，7.72-7.52(m，2H)，7.42(td，J＝7.0，5.9，4.0Hz，2H)，7.35-7.21(m，1H)，5.32(d，J＝5.0Hz，1H)，4.14(dd，J＝243.6，25.0Hz，4H)，3.01(s，1H)，2.88-2.75(m，4H)，2.49-2.32(m，6H)，2.31-2.19(m，1H)，2.18-2.12(m，3H)，2.07-1.65(m，3H)，1.50-1.38(m，1H)，1.12-0.97(m，2H)，0.95-0.77(m，2H).

MS(ESI)m/z 601.2[M+H]⁺。

Example 117

6- (2-chlorophenyl) -5-methyl-2- ((3-methyl-4- ((1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) phenyl) amino) -8- ((S) -1-propionylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (14601B)

6-(2-chlorophenyl)-5-methyl-2-((3-methyl-4-((1S，4S)-5-methyl-2，5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-8-((S)-1-propionylpiperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, 84.3% yield.

¹H NMR(400MHz，DMSO-d6)δ9.72(d，J＝110.7Hz，1H)，8.88(d，J＝4.3Hz，1H)，7.59-7.51(m，1H)，7.48-7.21(m，5H)，6.73(d，J＝8.9Hz，1H)，5.61-5.22(m，1H)，4.42(s，1H)，3.85(d，J＝72.6Hz，3H)，3.38(d，J＝7.0Hz，2H)，3.27-3.15(m，2H)，2.75(h，J＝9.6，8.4Hz，3H)，2.31(d，J＝5.3Hz，4H)，2.18(d，J＝2.3Hz，3H)，2.13(t，J＝2.7Hz，3H)，1.89-1.64(m，4H)，1.43(q，J＝17.4，13.6Hz，1H)，1.00(t，J＝7.4Hz，2H)，0.85(t，J＝5.7Hz，2H).

MS(ESI)m/z 626.6[M+H]⁺。

Example 118

6- (2-chloro-3-fluorophenyl) -5-methyl-2- ((3-methyl-4- ((1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) phenyl) amino) -8- ((S) -1-propionylpiperidin-3-yl) pyrido [2, 3-d ] pyrimidin-7 (8H) -one (14602B)

6-(2-chloro-3-fluorophenyl)-5-methyl-2-((3-methyl-4-((1S，4S)-5-methyl-2，5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-8-((S)-1-propionylpiperidin-3-yl)pyrido[2，3-d]pyrimidin-7(8H)-one

The synthesis was as in example 18, 76% yield.

¹H NMR(400MHz，DMSO-d6)δ9.91(s，1H)，8.90(d，J＝3.6Hz，1H)，7.51-7.24(m，4H)，7.20-7.12(m，1H)，6.73(d，J＝9.1Hz，1H)，5.58-5.32(m，1H)，4.42(s，1H)，3.85(d，J＝72.4Hz，4H)，3.37(s，1H)，3.21(d，J＝15.1Hz，2H)，2.83-2.65(m，3H)，2.30(d，J＝5.6Hz，3H)，2.18(d，J＝2.6Hz，3H)，2.14(t，J＝2.7Hz，3H)，2.04-1.95(m，1H)，1.87-1.68(m，4H)，1.45(s，1H)，1.00(s，2H)，0.88-0.80(m，2H).

MS(ESI)m/z 644.6[M+H]⁺。

Example 119

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -2- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -3-methylphenyl) amino) -5-methyl-7-oxopyrido [2, 3-d ] pyrimidin-8 (7H-yl) cyclohexyl) propanamide (20502B)

N-((1s，4s)-4-(6-(2-chloro-3-fluorophenyl)-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-3-methylphenyl)amino)-5-methyl-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)cyclohexyl)propionamide

The synthesis was as in example 18, with a yield of 77%.

¹H NMR(400MHz，DMSO-d6)δ9.93(s，1H)，8.91(s，1H)，7.64-7.54(m，2H)，7.52-7.43(m，3H)，7.15(dd，J＝5.8，3.3Hz，1H)，7.08(d，J＝8.7Hz，1H)，5.42(s，1H)，3.85(s，1H)，3.04-2.90(m，2H)，2.88-2.70(m，2H)，2.63(s，3H)，2.36(q，J＝7.7Hz，2H)，2.28(s，3H)，2.14(s，9H)，2.07-1.84(m，3H)，1.48(dd，J＝43.5，12.4Hz，4H)，0.97(t，J＝7.6Hz，3H)，0.90-0.75(m，1H).

MS(ESI)m/z 648.2[M+H]⁺。

Example 120

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -5-methyl-2- ((3-methyl-4- (piperidin-4-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propionamide (20902B)

N-((1s，4s)-4-(6-(2-chloro-3-fluorophenyl)-5-methyl-2-((3-methyl-4-(piperidin-4-yl)phenyl)amino)-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)cyclohexyl)propionamide

The synthesis was as in example 18, 69% yield.

¹H NMR(400MHz，DMSO-d6)δ10.02(s，1H)，8.93(s，1H)，8.65(d，J＝11.2Hz，1H)，8.37(d，J＝11.7Hz，1H)，7.64(dd，J＝8.5，2.5Hz，2H)，7.52(d，J＝2.3Hz，1H)，7.48-7.42(m，2H)，7.19-7.10(m，2H)，5.43(s，1H)，3.86(d，J＝4.9Hz，1H)，3.39(d，J＝12.2Hz，2H)，3.14-2.98(m，3H)，2.91-2.65(m，2H)，2.36(s，3H)，2.15(s，3H)，2.12(d，J＝7.6Hz，1H)，1.99-1.75(m，6H)，1.49(dd，J＝39.1，12.8Hz，4H)，0.97(t，J＝7.6Hz，3H).

MS(ESI)m/z 631.2[M+H]⁺。

Example 121

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -2- ((4- (4- (dimethylamino) piperidin-1-yl) -3-methylphenyl) amino) -5-methyl-7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propanamide (21102B)

N-((1s，4s)-4-(6-(2-chloro-3-fluorophenyl)-2-((4-(4-(dimethylamino)piperidin-1-yl)-3-methylphenyl)amino)-5-methyl-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)cyclohexyl)propionamide

The synthesis was as in example 18 with 71% yield.

¹H NMR(400MHz，DMSO-d6)δ9.92(s，1H)，8.90(s，1H)，7.69-7.55(m，2H)，7.52-7.38(m，3H)，7.14(dd，J＝5.8，3.4Hz，1H)，7.00(d，J＝8.7Hz，1H)，5.43(d，J＝8.3Hz，1H)，3.87(dt，J＝6.1，3.2Hz，1H)，3.05(d，J＝11.0Hz，2H)，2.79(dd，J＝28.6，13.4Hz，2H)，2.64-2.53(m，2H)，2.27(s，3H)，2.23(s，6H)，2.19(dd，J＝4.4，3.0Hz，1H)，2.14(d，J＝3.2Hz，5H)，1.97-1.88(m，2H)，1.87-1.80(m，2H)，1.54(qd，J＝11.7，3.7Hz，4H)，1.47-1.38(m，2H)，0.97(t，J＝7.6Hz，3H).

MS(ESI)m/z 675.2[M+H]⁺。

Example 122

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -5-methyl-2- ((3-methyl-4- (9-methyl-3, 9-diazaspiro [5.5] undecan-3-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propanamide (21202B)

N-((1s，4s)-4-(6-(2-chloro-3-fluorophenyl)-5-methyl-2-((3-methyl-4-(9-methyl-3，9-diazaspiro[5.5]undecan-3-yl)phenyl)amino)-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)cyclohexyl)propionamide

The synthesis was as in example 18 with a yield of 65%.

1H NMR(400MHz，DMSO-d6)δ10.13(s，1H)，8.94(s，1H)，8.06(d，J＝2.5Hz，1H)，7.64-7.55(m，1H)，7.51-7.41(m，3H)，7.19(d，J＝8.8Hz，1H)，7.17-7.12(m，1H)，5.42(t，J＝10.0Hz，1H)，3.86(dt，J＝6.2，3.1Hz，1H)，3.21(dq，J＝6.0，3.9，2.8Hz，4H)，2.84-2.63(m，6H)，2.32(s，3H)，2.14(d，J＝9.3Hz，5H)，1.95-1.85(m，4H)，1.76-1.57(m，2H)，1.49-1.37(m，2H)，0.97(t，J＝7.6Hz，3H).

MS(ESI)m/z 714.5[M+H]⁺。

Example 123

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -5-methyl-2- ((3-methyl-4- (7-methyl-2, 7-diazaspiro [3.5] nonan-2-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propanamide (21302B)

N-((1s，4s)-4-(6-(2-chloro-3-fluorophenyl)-5-methyl-2-((3-methyl-4-(7-methyl-2，7-diazaspiro[3.5]nonan-2-yl)phenyl)amino)-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)cyclohexyl)propionamide

The synthesis was as in example 18, 85% yield.

¹H NMR(400MHz，DMSO-d6)δ9.77(s，1H)，8.85(s，1H)，7.62(s，1H)，7.49-7.41(m，2H)，7.41-7.34(m，2H)，7.14(dd，J＝5.8，3.3Hz，1H)，6.60(d，J＝9.3Hz，1H)，5.42(s，1H)，5.04(t，J＝6.5Hz，1H)，3.85(s，1H)，3.61(q，J＝9.3，8.5Hz，2H)，3.47(dd，J＝14.7，8.8Hz，4H)，3.30(s，2H)，3.14(s，3H)，2.90-2.64(m，2H)，2.14(d，J＝12.9Hz，9H)，1.90(s，2H)，1.82(s，2H)，1.52(d，J＝14.9Hz，2H)，1.41(d，J＝12.2Hz，2H)，0.97(t，J＝7.6Hz，3H).

MS(ESI)m/z 686.3[M+H]⁺。

Example 124

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -5-methyl-2- ((3-methyl-4- (3-methyl-1, 3-diazepan-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propanamide (21502B)

N-((1s，4s)-4-(6-(2-chloro-3-fluorophenyl)-5-methyl-2-((3-methyl-4-(3-methyl-1，3-diazepan-1-yl)phenyl)amino)-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)cyclohexyl)propionamide

The synthesis was as in example 18 with 83% yield.

¹H NMR(400MHz，DMSO-d6)δ9.91(s，1H)，8.91(s，1H)，7.65-7.55(m，2H)，7.51-7.41(m，3H)，7.15(dd，J＝5.8，3.3Hz，1H)，7.06(d，J＝8.7Hz，1H)，5.42(s，1H)，3.86(s，1H)，3.16-3.04(m，4H)，2.71(q，J＝7.6，6.5Hz，6H)，2.35(s，3H)，2.29(s，3H)，2.14(s，5H)，1.87(p，J＝5.9Hz，4H)，1.61-1.49(m，2H)，1.42(d，J＝12.3Hz，2H)，0.97(t，J＝7.6Hz，3H).

MS(ESI)m/z 660.3[M+H]⁺。

Example 125

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -2- ((4- ((R) -3, 4-dimethylpiperazin-1-yl) -3-methylphenyl) amino) -5-methyl-7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propanamide (21702B)

N-((1s，4s)-4-(6-(2-chloro-3-fluorophenyl)-2-((4-((R)-3，4-dimethylpiperazin-1-yl)-3-methylphenyl)amino)-5-methyl-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)cyclohexyl)propionamide

The synthesis was as in example 18, with a yield of 82%.

¹H NMR(400MHz，DMSO-d6)δ9.93(s，1H)，8.91(s，1H)，7.60(d，J＝2.8Hz，2H)，7.53-7.42(m，3H)，7.15(dd，J＝5.8，3.4Hz，1H)，7.01(d，J＝8.7Hz，1H)，5.42(s，1H)，3.86(s，1H)，2.94-2.69(m，6H)，2.41(t，J＝10.3Hz，1H)，2.35-2.31(m，1H)，2.28(s，3H)，2.22(s，3H)，2.14(s，5H)，1.91(s，2H)，1.42(d，J＝12.1Hz，5H)，1.02(d，J＝6.1Hz，3H)，0.97(t，J＝7.6Hz，3H).

MS(ESI)m/z 660.3[M+H]⁺。

Example 126

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -5-methyl-2- ((3-methyl-4- ((3S, 5R) -3, 4, 5-trimethylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propanamide (21802B)

N-((1s，4s)-4-(6-(2-chloro-3-fluorophenyl)-5-methyl-2-((3-methyl-4-((3S，5R)-3，4，5-trimethylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)cyclohexyl)propionamide

The synthesis was as in example 18, 73% yield.

¹H NMR(400MHz，DMSO-d6)δ9.91(s，1H)，8.91(s，1H)，7.60(d，J＝2.6Hz，2H)，7.47(ddd，J＝15.8，7.9，2.8Hz，3H)，7.15(t，J＝4.6Hz，1H)，6.98(d，J＝8.6Hz，1H)，5.42(s，1H)，3.87(s，1H)，2.87(d，J＝10.8Hz，4H)，2.43(t，J＝10.7Hz，2H)，2.36-2.29(m，2H)，2.28(s，3H)，2.21(s，3H)，2.14(s，5H)，1.91(d，J＝9.5Hz，2H)，1.63-1.49(m，2H)，1.42(d，J＝12.2Hz，2H)，1.04(d，J＝6.0Hz，6H)，0.97(t，J＝7.6Hz，3H).

MS(ESI)m/z 674.3[M+H]⁺。

Example 127

N- ((1S, 4S) -4- (6- (2-chlorophenyl) -5-methyl-2- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -7-oxopyrido [2, 13-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propanamide (22201B)

N-((1s，4s)-4-(6-(2-chlorophenyl)-5-methyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)cyclohexyl)propionamide

The synthesis was as in example 18, 81% yield.

¹H NMR(400MHz，DMSO-d6)δ9.87(s，1H)，8.87(s，1H)，7.68-7.51(m，4H)，7.48-7.37(m，2H)，7.32-7.24(m，1H)，6.99-6.89(m，2H)，5.36(d，J＝36.2Hz，1H)，3.89(p，J＝3.0Hz，1H)，3.10(t，J＝4.9Hz，4H)，2.93-2.66(m，2H)，2.47(t，J＝4.9Hz，4H)，2.23(s，3H)，2.18-2.13(m，2H)，2.12(s，3H)，1.96-1.85(m，2H)，1.62-1.48(m，2H)，1.43(d，J＝11.2Hz，2H)，0.98(t，J＝7.6Hz，3H).

MS(ESI)m/z 614.2[M+H]⁺。

Example 128

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -2- ((3-chloro-4- (4-methylpiperazin-1-yl) phenyl) amino) -5-methyl-7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propanamide (22402B)

N-((1s，4s)-4-(6-(2-chloro-3-fluorophenyl)-2-((3-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)cyclohexyl)propionamid

The synthesis was as in example 18, 79% yield.

¹H NMR(400MHz，DMSO-d6)δ10.18(s，1H)，8.96(s，1H)，8.10(d，J＝2.5Hz，1H)，7.60(d，J＝5.1Hz，1H)，7.55-7.40(m，3H)，7.24-7.10(m，2H)，5.54-5.29(m，1H)，2.96(s，4H)，2.80(s，3H)，2.25(s，3H)，2.16(s，3H)，2.12(t，J＝7.6Hz，2H)，1.94(d，J＝25.0Hz，3H)，1.65(s，3H)，1.45(s，3H)，0.97(t，J＝7.5Hz，3H)，0.85(t，J＝6.6Hz，1H).

MS(ESI)m/z 666.8[M+H]⁺。

Example 129

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -2- ((4- (4-ethylpiperazin-1-yl) -3-methylphenyl) amino) -5-methyl-7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propanamide (24102B)

N-((1s，4s)-4-(6-(2-chloro-3-fluorophenyl)-2-((4-(4-ethylpiperazin-1-yl)-3-methylphenyl)amino)-5-methyl-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)cyclohexyl)propionamide

The synthesis was as in example 18, with a yield of 77%.

¹H NMR(400MHz，DMSO-d6)δ9.92(s，1H)，8.91(s，1H)，7.59(d，J＝2.6Hz，2H)，7.50(dd，J＝8.6，2.6Hz，1H)，7.48-7.42(m，2H)，7.20-7.12(m，1H)，7.03(d，J＝8.7Hz，1H)，5.42(s，1H)，3.86(s，1H)，2.83(t，J＝4.8Hz，6H)，2.53(s，3H)，2.40(d，J＝7.6Hz，2H)，2.28(s，3H)，2.14(s，5H)，1.91(s，2H)，1.48(dd，J＝49.7，11.7Hz，5H)，1.04(t，J＝7.2Hz，3H)，0.97(t，J＝7.6Hz，3H).

MS(ESI)m/z 660.3[M+H]⁺。

Example 130

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -5-methyl-2- ((3-methyl-4- ((1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propionamide (24602B)

N-((1s，4s)-4-(6-(2-chloro-3-fluorophenyl)-5-methyl-2-((3-methyl-4-((1S，4S)-5-methyl-2，5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)cyclohexyl)propionamide

The synthesis was as in example 18, 82% yield.

¹H NMR(400MHz，DMSO-d6)δ9.85(s，1H)，8.88(s，1H)，7.59(s，1H)，7.49-7.41(m，3H)，7.37(dt，J＝8.7，2.5Hz，1H)，7.19-7.11(m，1H)，6.76(d，J＝8.8Hz，1H)，5.42(s，1H)，3.90(d，J＝43.2Hz，2H)，3.29-3.19(m，2H)，2.91-2.61(m，4H)，2.29(s，3H)，2.24(s，3H)，2.13(s，5H)，1.89(s，2H)，1.84-1.66(m，2H)，1.53(d，J＝14.7Hz，2H)，1.41(d，J＝12.4Hz，2H)，0.97(t，J＝7.6Hz，3H).

MS(ESI)m/z 658.4[M+H]⁺。

Example 131

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -2- ((3-chloro-4- ((R) -3-methylpiperazin-1-yl) phenyl) amino) -5-methyl-7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propanamide (24802B)

N-((1s，4s)-4-(6-(2-chloro-3-fluorophenyl)-2-((3-chloro-4-((R)-3-methylpiperazin-1-yl)phenyl)amino)-5-methyl-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)cyclohexyl)propionamide

The synthesis was as in example 18, 75% yield.

¹H NMR(400MHz，DMSO-d6)δ10.15(s，1H)，8.96(s，1H)，8.09(d，J＝2.4Hz，1H)，7.59(d，J＝5.8Hz，1H)，7.54-7.39(m，3H)，7.26-7.09(m，2H)，5.42(s，1H)，3.97-3.76(m，1H)，3.13-3.02(m，2H)，2.99-2.65(m，5H)，2.59(td，J＝10.8，3.1Hz，1H)，2.28(t，J＝10.3Hz，1H)，2.15(s，3H)，2.12(t，J＝7.6Hz，2H)，1.91(s，2H)，1.74-1.58(m，2H)，1.49-1.38(m，2H)，1.02-0.94(m，6H).

MS(ESI)m/z 666.8[M+H]⁺。

Example 132

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -2- ((3-chloro-4- (3-methyl-1, 3-diazepan-1-yl) phenyl) amino) -5-methyl-7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propanamide (24902B)

N-((1s，4s)-4-(6-(2-chloro-3-fluorophenyl)-2-((3-chloro-4-(3-methyl-1，3-diazepan-1-yl)phenyl)amino)-5-methyl-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)cyclohexyl)propionamide

The synthesis was as in example 18, 67% yield

¹H NMR(400MHz，DMSO-d6)δ10.13(s，1H)，8.94(s，1H)，8.06(d，J＝2.5Hz，1H)，7.64-7.55(m，1H)，7.51-7.41(m，3H)，7.19(d，J＝8.8Hz，1H)，7.17-7.12(m，1H)，5.42(t，J＝10.0Hz，1H)，3.86(dt，J＝6.2，3.1Hz，1H)，3.21(dq，J＝6.0，3.9，2.8Hz，4H)，2.84-2.63(m，6H)，2.32(s，3H)，2.14(d，J＝9.3Hz，5H)，1.95-1.85(m，4H)，1.76-1.57(m，2H)，1.49-1.37(m，2H)，0.97(t，J＝7.6Hz，3H).

MS(ESI)m/z 680.6[M+H]⁺。

Example 133

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -2- ((3-chloro-4- ((R) -3, 4-dimethylpiperazin-1-yl) phenyl) amino) -5-methyl-7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propanamide (25002B)

N-((1s，4s)-4-(6-(2-chloro-3-fluorophenyl)-2-((3-chloro-4-((R)-3，4-dimethylpiperazin-1-yl)phenyl)amino)-5-methyl-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)cyclohexyl)propionamide

The synthesis was as in example 18, 74% yield.

¹H NMR(400MHz，DMSO-d6)δ10.10(d，J＝32.1Hz，0H)，8.95(s，1H)，8.15-8.01(m，1H)，7.60(d，J＝5.8Hz，1H)，7.52-7.41(m，3H)，7.19-7.10(m，2H)，5.42(s，1H)，3.86(s，1H)，3.09(ddt，J＝21.3，11.0，2.6Hz，3H)，2.87-2.73(m，4H)，2.45(t，J＝10.2Hz，1H)，2.33(td，J＝11.6，2.9Hz，1H)，2.22(s，4H)，2.15(s，3H)，2.12(t，J＝7.5Hz，2H)，1.89(s，2H)，1.65(s，2H)，1.43(d，J＝12.4Hz，2H)，1.02(d，J＝6.2Hz，3H)，0.97(t，J＝7.6Hz，3H).

MS(ESI)m/z 680.6[M+H]⁺。

Example 134

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -5-methyl-2- ((3-methyl-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) -7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propanamide (25102B)

N-((1s，4s)-4-(6-(2-chloro-3-fluorophenyl)-5-methyl-2-((3-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)cyclohexyl)propionamide

The synthesis was as in example 18, with a yield of 86%.

¹H NMR(400MHz，DMSO-d6)δ9.92(s，1H)，8.91(s，1H)，7.59(t，J＝3.9Hz，2H)，7.52-7.41(m，3H)，7.18-7.12(m，1H)，7.01(d，J＝8.7Hz，1H)，5.42(s，1H)，3.86(s，1H)，3.06(d，J＝11.3Hz，2H)，2.78(d，J＝27.5Hz，2H)，2.59(t，J＝11.5Hz，5H)，2.37(d，J＝37.3Hz，4H)，2.27(s，3H)，2.22(s，3H)，2.14(s，5H)，1.98-1.79(m，5H)，1.62-1.51(m，4H)，1.42(d，J＝12.3Hz，3H)，0.97(t，J＝7.6Hz，3H).

MS(ESI)m/z 729.6[M+H]⁺。

Example 135

N- ((1S, 4S) -4- (6- (2-chloro-3-fluorophenyl) -2- ((4- (4-isopropylpiperazin-1-yl) -3-methylphenyl) amino) -5-methyl-7-oxopyrido [2, 3-d ] pyrimidin-8 (7H) -yl) cyclohexyl) propionamide (25202B)

N-((1s，4s)-4-(6-(2-chloro-3-fluorophenyl)-2-((4-(4-isopropylpiperazin-1-yl)-3-methylphenyl)amino)-5-methyl-7-oxopyrido[2，3-d]pyrimidin-8(7H)-yl)cyclohexyl)propionamide

The synthesis was as in example 18, 67% yield.

¹H NMR(400MHz，DMSO-d6)δ9.92(s，1H)，8.90(s，1H)，7.66-7.52(m，2H)，7.50(dd，J＝8.6，2.6Hz，1H)，7.49-7.39(m，2H)，7.19-7.09(m，1H)，7.02(d，J＝8.7Hz，1H)，5.42(s，1H)，3.87(dt，J＝6.5，3.1Hz，1H)，2.90-2.55(m，11H)，2.28(s，3H)，2.14(s，5H)，1.91(t，J＝10.6Hz，2H)，1.55(h，J＝10.6，10.0Hz，2H)，1.47-1.38(m，2H)，1.01(d，J＝6.5Hz，6H)，0.97(t，J＝7.6Hz，3H).

MS(ESI)m/z 674.3[M+H]⁺。

Example 136

The compound has the effect on EGFR wild type, EGFR-L858R/T790M, EGFR-L858R/T790M/C797S mutant kinase EC₅₀Testing

EGFR (WT) is a wild-type epidermal growth factor receptor, EGFR (T790M) is an epidermal growth factor receptor with the 790 th amino acid mutated from threonine to methionine, EGFR (L858R) is an epidermal growth factor receptor with the 858 th amino acid mutated from leucine to arginine, EGFR (L861Q) is an epidermal growth factor receptor with the 861 th amino acid mutated from leucine to glutamine, EGFR (L858R/T790M) is an epidermal growth factor receptor with the 858 th amino acid mutated from leucine to glutamine, and 790 th amino acid mutated from threonine to methionine double mutation. EGFR (L858R/T790M/C797S) is a triple mutant epidermal growth factor receptor with the 858 th amino acid mutated from leucine to glutamine, the 790 th amino acid mutated from threonine to methionine, and the 797 th amino acid mutated from cysteine to serine.

And (3) kinase activity detection: use of Z' -LYTE^TMThe technique (detection by fluorescence, enzyme coupling, based on the difference in the sensitivity of phosphorylated and non-phosphorylated polypeptides to proteolytic cleavage) employs the principle of Fluorescence Resonance Energy Transfer (FRET) using Z' LYTE^TM FRET peptide substrate, and secondary reaction for detecting the kinase activity of the compound. (Invitrogen, Z' -LYTE)^TMKINASE ASSAY KIT-TYR 2 PEPTIDE, PV3191) EGFR-T790M kinase (invitrogen, PV4803) is diluted step by step, FRET PEPTIDE and ATP are added, compounds with different concentrations are added, after reaction for 1h, site-specific protease is added, non-phosphorylated FRET PEPTIDE is identified and cleaved, reaction for 1h is carried out, excitation wavelength of 400nm is used, and absorption at 445nm and 520nm is detected.

IC₅₀Values were calculated by fitting the inhibition curve with four parameters.

Obtaining positive correlation between inhibition rate and drug concentration, making relation curve of kinase activity and concentration, and calculating IC₅₀The value is obtained.

Compound numbers and stress enzyme activity results are listed in table 1.

TABLE 1 Compound kinase inhibitory Activity

Example 137

In vitro proliferation inhibition effect of compound on BaF3 EGFRL858R/T790M/C797S tool cell strain

Cell line: BaF3 EGFRL858R/T790M/C797S tool cell strain.

The method comprises the following steps: the sulfonylurea B (SRB) method is as follows: inoculating a certain number of different tumor cells in a logarithmic growth phase to a 96-well culture plate, culturing for 24h, adding the tested compound of the invention with different concentrations, setting three or more wells for each concentration, and setting DMSO solution control and cell-free zeroing wells with corresponding concentrations. After treating the cells with the drug for 72h, the culture medium was decanted, 100. mu.L of ice-pre-cooled 10% trichloroacetic acid solution was added to fix the cells, the cells were left at 4 ℃ for 1h, washed 5 times with distilled water, and air-dried. Then 100. mu.L of SRB (4mg/mL) (Sigma, St Louis, MO, USA) solution was added, stained at room temperature for 15min, destained, washed 5 times with 1% glacial acetic acid, and air dried. Finally, 150. mu.L of 10mM Tris solution (pH 10.5) and an adjustable wavelength microplate reader (VERSAmax) are added^TM，Molecular Device Corporation, Sunnyvale, Calif., USA) at a wavelength of 515 nm. The inhibition rate of the drug on cell growth was calculated by the following formula: inhibition (%) ═ OD control-OD dosing)/OD control × 100%.

Based on the growth inhibitory effect of the compounds on these cells, we calculated the median Inhibitory Concentration (IC) of the compounds₅₀) The values are described in table 2.

TABLE 2 Compound cellular Activity

The result shows that (see table 2), the pyrimidopyrimidinone or pyridopyrimidinone compound can obviously inhibit the proliferation of BaF3EGFRL858R/T790M/C797S cells, and the inhibition rate is in positive correlation with the drug concentration.

Example 138

The pyrimidopyridone or pyridopyridone compound of the invention has good effect on EGFR^{L858R/T790M/C797S}And EGFR^{19D/T790M/C797S}The activation of target in tool cell has obvious inhibiting effect.

Detection was performed using a conventional Western Blot (immunoblotting), as follows: separately subjecting BaF3-EGFR in logarithmic growth phase^{L858R/T790M/C797S}Cells and BaF3-EGFR^{19D/T790M/C797S}The cells are planted on a 6-pore plate according to a certain quantity, after the cells are cultured in an incubator in a wall-mounted manner overnight, the cells are starved for 24 hours by changing a serum-free culture solution, a compound with a certain concentration is added for action for 2 hours, EGF stimulation factors are added, the action is carried out for 10 minutes at a concentration of 50ng/mL, and the cells are cracked by using a lysate for sampling. Then taking a proper amount of sample to carry out SDS-PAGE electrophoresis, transferring the protein to a nitrocellulose membrane by using a semi-dry electrotransfer system after the electrophoresis is finished, sealing the nitrocellulose membrane in a sealing solution (5 percent of skimmed milk powder is diluted in TBS containing 0.1 percent of Tween 20) at room temperature for 2h, and then respectively putting the membranes in a primary antibody solution (1: 500 is diluted in TBS containing 0.1 percent of Tween 20) to incubate at 4 ℃ overnight. Three washes with TBS containing 0.1% Tween 20, 15min each. The membrane was placed in a secondary antibody solution (horseradish peroxidase-labeled goat anti-rabbit IgG, diluted 1: 2000 in TBS with 0.1% Tween 20) and reacted for 1h at room temperature. After washing the membrane three times as above, it was developed with ECL plus reagent and photographed with Image Quant LAS 4000. The results are shown in FIGS. 1-2.

As can be seen from the a plot in FIG. 1, the concentration of compound 560082 dependently inhibited EGFR in tool cells^L858R ^/T790M/C797SPhosphorylation of (2). As can be seen from the b-plot in FIG. 1, the concentration of compound 560082 dependently inhibited EGFR in tool cells^{19D/T790M/C797S}Phosphorylation of (2).

As can be seen from the a-plot in FIG. 2, the concentration-dependent inhibition of EGFR in tool cells by compound 580120^L858R ^/T790M/C797SPhosphorylation of (3) As can be seen from the b plot in FIG. 2, the concentration of compound 580120 dependently inhibited EGFR in tool cells^{19D/T790M/C797S}Phosphorylation of (2).

The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.

The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent should be subject to the appended claims.

Claims

1. A pyrimidopyridone compound having the structure of formula (i) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof:

wherein, X is selected from: n;

w is optionally selected from: h, CH₃，C₂-C₅An alkyl group;

l is optionally selected from:

and R is₁Is optionally selected from:

wherein R is₄Optionally selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

l is optionally selected from:

and R is₁Is optionally selected from: h or

Wherein R is₄Optionally selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, neopentyl, cyclopentyl, cyclohexyl;

R₂is optionally selected from:

R₃is optionally selected from:

wherein, the first and the second end of the pipe are connected with each other,

B₁,B₂,B₄,B₅each independently selected from: h, chlorine, C₁～C₃An alkyl group, a carboxyl group,

B₃selected from: 4-methylpiperazin-1-yl, N-ethylpiperazinyl, 4-isopropylpiperazin-1-yl, piperidinyl, 9-methyl-3, 9-diazaspiro [5.5]Undecane-3-yl, 3-methyl-1, 3-diazepan-1-yl,(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1]Hept-2-yl, (2- (dimethylamino) ethyl) (methyl) amino, 4- (dimethylamino) piperidin-1-yl, 7-methyl-2, 7-diazaspiro [3.5 ]]Nonan-2-yl, (R) -3, 4-dimethylpiperazin-1-yl, (S) -3, 4-dimethylpiperazin-1-yl, (3S, 5R) -3,4, 5-trimethylpiperazin-1-yl, (R) -3-methylpiperazin-1-yl, 4- (4-methylpiperazin-1-yl) piperidin-1-yl.

2. A pyrimidopyridone compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to claim 1, wherein L is selected from:

3. a pyrimidopyridinone compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any of claims 1-2, wherein the compound has a structure represented by formula III, formula IV, formula V or VI:

4. the pyrimidopyridinone compound or the pharmaceutically acceptable salt thereof or the stereoisomer thereof according to any one of claims 1 to 2, wherein B is₃Selected from: 4-methylpiperazin-1-yl.

5. A pyrimidopyridinone compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of claims 1 to 2, wherein W is selected from: the group consisting of H, methyl,

B₁,B₂,B₄,B₅each independently selected from: h, a methyl group,

B₃each independently selected from: 4-methylpiperazines-1-yl, piperidinyl, 9-methyl-3, 9-diazaspiro [5.5]Undecane-3-yl, 3-methyl-1, 3-diazepan-1-yl, (1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1]Hept-2-yl, (2- (dimethylamino) ethyl) (methyl) amino, 4- (dimethylamino) piperidin-1-yl, 7-methyl-2, 7-diazaspiro [3.5 ] ]Nonan-2-yl, (R) -3, 4-dimethylpiperazin-1-yl, (3S, 5R) -3,4, 5-trimethylpiperazin-1-yl, (R) -3-methylpiperazin-1-yl, 4- (4-methylpiperazin-1-yl) piperidin-1-yl.

6. A pyrimidopyridone compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein the compound is selected from the group consisting of:

7. use of the pyrimidopyridinone compound or the pharmaceutically acceptable salt thereof or the stereoisomer thereof according to any one of claims 1 to 6 for preparing a mutant EGFR inhibitor^L858R/T790MOr EGFR^{L858R/T790M/C797S}。

8. Use of a pyrimidopyridinone compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of claims 1 to 6 for the preparation of a medicament for the prevention and treatment of tumors.

9. The use of claim 8, wherein the tumor is a malignant tumor having a mutation in the EGFR gene.

10. The use according to claim 8, wherein the tumor is selected from the group consisting of: non-small cell lung cancer, malignant melanoma, prostate cancer, renal cancer, bladder cancer, ovarian cancer, colon cancer, rectal cancer, breast cancer, cervical cancer, lung cancer, larynx cancer, nasopharyngeal carcinoma, pancreatic cancer, multiple myeloma, B lymphoma, leukemia.

11. The use of claim 10, wherein the tumor is EGFR^{L858R/T790MC797S}Mutant non-small cell lung cancer.

12. A pharmaceutical composition for the prevention and treatment of tumors, characterized in that the active ingredient thereof comprises the pyrimidopyridinone compound or the pharmaceutically acceptable salt thereof or the stereoisomer thereof according to any one of claims 1 to 6.