CN110914267B - Pyrimidopyridone or pyridopyridone compound and application thereof - Google Patents

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 a pyridopyridone compound and an application thereof.

Background technique

Tumor molecular targeted therapy is a therapeutic method based on the selective killing of tumor cells by chemical or biological means for key molecules closely related to tumor growth. The characteristics of targeted therapy are: high specificity, strong selectivity, and mild side effects; when used in combination, it can enhance the efficacy of traditional chemotherapy and radiotherapy and reduce postoperative recurrence. 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), which has opened up a new era for tumor chemotherapy. Tumor-targeted therapy has developed rapidly in just a few years. The emergence of tumor-targeted therapy has had an impact on traditional drug delivery concepts and modes. For example, targeted drugs often fail to achieve dose-limiting toxicity and maximum tolerated doses in phase I clinical trials due to small toxic and side effects; Satisfactory efficacy can be achieved without the use of the maximum tolerated dose. Tumor targeted therapy is the hot spot 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 various tumor cells, such as lung, breast, and prostate cancer. About 62% of non-small cell lung cancer patients have EGFR overexpression, and inhibition of EGFR can significantly improve the survival of some patients. In addition, the EGFR small molecule inhibitor drugs Gefitinib and Erlotinib, which were launched in 2003-2004, have been used for the treatment of advanced non-small cell lung cancer, further confirming that EGFR is an effective target for the treatment of non-small cell lung cancer.

First-generation EGFR small-molecule inhibitors have achieved significant clinical efficacy in patients with EGFR-sensitizing mutations, extending their survival. However, after 10 to 12 months of use of the drug in the benefited patients, most patients will develop resistance. Among them, more than 50% of drug-resistant patients (carrying EGFR-sensitive mutations) are drug-resistant due to the secondary mutation of T790M in EGFR. Compared with the L858R-sensitive mutated EGFR, the L858R/T790M secondary mutated EGFR has a stronger affinity for ATP, and the first-generation drugs are all ATP-competitive inhibitors, thus leading to drug resistance.

Although the second-generation EGFR irreversible inhibitors have achieved good results in preclinical studies, they lack selectivity for wild-type EGFR (EGFRWT) and have high toxicity. Although Gilotrif, an irreversible EGFR inhibitor approved by the FDA in 2013, is effective for advanced NSCLC patients with activating EGFR mutations (L858R, del E746-A750), it still cannot resolve the EGFR T790M mutation at the clinical maximum tolerated dose (MTD). clinical resistance.

Osimertinib (AZD9291), the third-generation irreversible inhibitor that overcomes EGFRT790M resistance, received accelerated approval from the US FDA in November 2015 (Cancer discovery 2014, 4(9), 1046-1061), which is effective in clinical treatment Patients with advanced non-small cell lung cancer with epidermal growth factor receptor (EGFR) T790M mutation or resistance to other EGFR inhibitors. Although Osimertinib has achieved great success in the clinical treatment of EGFRT790M-mutated non-small cell lung cancer, some patients who benefited from treatment developed drug resistance after 9 to 14 months of treatment (Nature Medicine 2015, 21(6), 560 -2). The study found that up to 40% of resistant patients were resistant to Osimertinib due to the (EGFR) C797S point mutation. Further mechanistic studies showed that the point mutation of (EGFR) C797S changed the cysteine at position 797 to serine, resulting in the inability of Osimertinib to form covalent binding with the target protein, which eventually caused drug resistance. Currently, there is no effective EGFR inhibitor for the new mutation (C797S) alone. Therefore, new types of highly selective EGFR inhibitors are urgently needed to solve the problems of drug resistance caused by the (EGFR) C797S point mutation.

SUMMARY OF THE INVENTION

Based on this, the present invention provides a new class of pyrimidopyridone or pyridopyridone compounds, which can selectively inhibit the activity of mutant EGFR and can overcome the resistance of existing EGFR tyrosine kinase inhibitors Sexual issues.

The specific technical solutions are as follows:

Pyrimidopyridone or pyridopyridone compound having the structure of formula (I) or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule:

Wherein, X is optional from: CH or N;

W is optional from: H, D, _CH3 , _CD3 , _CF3 , _CH2F , _CHF2 , F, _Cl , Br, C2 _- C5alkyl, C3 _{- C6cycloalkyl} , substituted C ₃ -C ₆ cycloalkyl;

L can be selected from:

(1)-(CH ₂ ) _n NH-, wherein n is selected from an integer between 1-8;

其中n任选自0，1，2，3；(2)

Wherein n can be selected from 0, 1, 2, 3;

其中n任选自0，1，2，3；(3)

Wherein n can be selected from 0, 1, 2, 3;

(4) C ₅ -C ₁₀ monocycloalkyl, bridged cycloalkyl or cycloalkyl;

R ₁ is chosen from:

(1) H, C ₁ -C ₄ alkoxy;

其中R₄任选自C₁-C₆烷基，C₃-C₆环烷基；(2)

wherein R ₄ is optionally selected from C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl;

(3) (CH ₂ ) _n Y, n=0-6, Y is selected from halogen, hydroxyl, amino, (N-methyl)amino, (N,N-dimethyl)amino;

R ₂ is chosen from:

(1) H, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, substituted C ₃ -C ₆ cycloalkyl;

其中，n任选自0，1，2；A₁，A₂，A₃，A₄，A₅分别独立任选自：(2)

Wherein, n can be selected from 0, 1, 2; A ₁ , A ₂ , A ₃ , A ₄ , A ₅ can be independently selected from:

(a) hydrogen, halogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, substituted C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₆ containing Fluoroalkyl, C ₁ -C ₆ heteroatom-containing alkyl, NO ₂ , CN, COOH, CONH ₂ ;

其中，R₅，R₆分别独立选自C₁～C₅烷基，C₃～C₆环烷基，取代的C₃～C₆环烷基，R₅与R₆环合形成的含有1-3个杂原子的4-8元饱和杂环，R₅与R₆环合形成的含有1-3个杂原子的4-8元芳香杂环；(b)

Wherein, R ₅ and R ₆ are independently selected from C ₁ -C ₅ alkyl, C ₃ -C ₆ cycloalkyl, substituted C ₃ -C ₆ cycloalkyl, R ₅ and R ₆ are cyclized to form a compound containing 1 -4-8-membered saturated heterocycle with 3 heteroatoms, 4-8-membered aromatic heterocycle containing 1-3 heteroatoms formed by the cyclization of R ₅ and R ₆ ;

(c) a 5- or 6-membered aromatic group containing one or more nitrogen atoms and having 0-3 substituents selected from the group consisting of:

(d) A 5-12-membered saturated carbocycle or heterocycle containing 0-3 heteroatoms is formed between any two adjacent substituents in A ₁ , A ₂ , A ₃ , A ₄ , A ₅ ;

R ₃ is chosen from:

(1) C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl;

(2)

Wherein B ₁ , B ₂ , B ₃ , B ₄ , B ₅ are independently selected from:

(a) H, halogen, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted ethoxy, C ₁ -C ₄ alkoxy, C ₁ -C ₃ fluoroalkyl, substituted or unsubstituted C ₄ -C ₆ heteroatom-containing alkyl group, C ₄ -C ₉ heterocyclic group or amide formed by said heterocyclic group, nitro group, cyano group;

其中，R₅，R₆分别独立选自取代或未取代的C₁～C₅烷基，C₃～C₆环烷基，取代的C₃～C₆环烷基，R₅与R₆环合形成的含有1-3个杂原子的取代或未取代的4-8元饱和杂环，R₅与R₆环合形成的含有1-3个杂原子的取代或未取代的4-8元芳香杂环，R₅与R₆环合形成的含有1-3个杂原子的取代或未取代的8-12元饱和螺环，R₅与R₆环合形成的含有1-3个杂原子的取代或未取代的8-12元饱和稠环，R₅与R₆环合形成的含有1-3个杂原子的取代或未取代的8-12元饱和桥环；(b)

Wherein, R ₅ and R ₆ are independently selected from substituted or unsubstituted C ₁ -C ₅ alkyl, C ₃ -C ₆ cycloalkyl, substituted C ₃ -C ₆ cycloalkyl, R ₅ and R ₆ ring A substituted or unsubstituted 4-8-membered saturated heterocycle containing 1-3 heteroatoms formed by cyclization, and a substituted or unsubstituted 4-8-membered heterocyclic ring containing 1-3 heteroatoms formed by the cyclization of R ₅ and R ₆ Aromatic heterocycle, a substituted or unsubstituted 8-12-membered saturated spiro ring containing 1-3 heteroatoms formed by the cyclization of R ₅ and R ₆ , containing 1-3 heteroatoms formed by the cyclization of R ₅ and R ₆ A substituted or unsubstituted 8-12-membered saturated fused ring, a substituted or unsubstituted 8-12-membered saturated bridged ring containing 1-3 heteroatoms formed by the cyclization of R ₅ and R ₆ ;

(c) a 5- or 6-membered aromatic group containing one or more nitrogen atoms and having 0-3 substituents selected from the group consisting of:

(d) A 5-12-membered saturated carbocyclic or heterocyclic ring containing 0-3 heteroatoms is formed between any two adjacent substituents in B ₁ , B ₂ , B ₃ , B ₄ , and B ₅ .

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

In some of these embodiments, A ₁ , A ₂ , A ₃ , A ₄ , A ₅ are each independently selected from: A ₁ , A ₂ , A ₃ , A ₄ , A ₅ are each independently selected from: hydrogen, halogen , C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkoxy, N,N-dimethylaminoethoxy, N,N-dimethylaminopropoxy , 2-(N-methylpiperazinyl) ethoxy, 2-(N-acetylpiperazinyl) ethoxy, 2-morpholinyl ethoxy, 2-thiomorpholinyl ethoxy, 2-Piperidinylethoxy, 2-tetrahydropyrrolylethoxy, N-methylpiperazinyl, morpholinyl, thiomorpholine, piperidine, tetrahydropyrrole, imidazole, 3-N,N- Dimethyltetrahydropyrrole, 4-N,N-dimethylpiperidine, 4-acetylpiperazine, 1-methyl-4-(piperazine-4-substituted)piperidine, 4-(4-methylpiperidine) ylpiperazin-1-substituted) methyl, 1-methylpiperidin-4-amino, 4-piperazin-2-one, 1-methyl-4-piperazin-2-one, and the above groups form of esters, amides, sulfones, sulfoxides, ureas.

In some of these embodiments, A ₁ , A ₂ , A ₃ , A ₄ , and A ₅ are each independently selected from: hydrogen, halogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ ~ _C4alkoxy .

In some of these embodiments, A ₁ , A ₂ , A ₃ , A ₄ , A ₅ are each independently selected from: hydrogen, chlorine, fluorine, methyl, methoxy.

In some of these embodiments, W is selected from H, C ₁ -C ₅ alkyl.

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, R ₁ is optionally selected from:

其中R₄任选自甲基，乙基，正丙基，异丙基，环丙基，正丁基，异丁基，叔丁基，环丁基，新戊基，环戊基，环己基。

wherein R4 is optionally selected from methyl, ethyl, n _- propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, neopentyl, cyclopentyl, cyclohexyl .

In some of these embodiments, R ₁ is optionally selected from:

其中R₄任选自甲基，乙基，正丙基，异丙基，环丙基，正丁基，异丁基，叔丁基，环丁基，新戊基，环戊基，环己基。

wherein R4 is optionally selected from methyl, ethyl, n _- propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, neopentyl, cyclopentyl, cyclohexyl .

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

In some of these embodiments, _R is optionally selected from:

以及上述基团形成的酯，酰胺，砜，亚砜，脲；In some of these embodiments, B ₁ , B ₂ , B ₃ , B ₄ , B ₅ are each independently optionally selected from: H, substituted or unsubstituted C ₁ -C ₆ alkyl, halogen, C ₁ -C ₄ alkane Oxy group, C ₁ -C ₃ fluorine-containing alkyl group, substituted ethoxy group, substituted or unsubstituted C ₄ -C ₉ heterocyclic group,

And esters, amides, sulfones, sulfoxides, ureas formed by the above groups;

Wherein, R ₅ and R ₆ are independently selected from substituted or unsubstituted C ₁ -C ₅ alkyl groups, and R ₅ and R ₆ are cyclized to form a substituted or unsubstituted 4-8-membered substituted or unsubstituted 4-8 membered group containing 1-3 heteroatoms. Saturated heterocycle, substituted or unsubstituted 4-8-membered aromatic heterocycle containing 1-3 heteroatoms formed by the cyclization of R ₅ and R ₆ , containing 1-3 heteroatoms formed by the cyclization of R ₅ and R ₆ A substituted or unsubstituted 8-12-membered saturated spiro ring, a substituted or unsubstituted 8-12-membered saturated fused ring containing 1-3 heteroatoms formed by the cyclization of R _{5 and R 6 , R 5 and R 6} ring A substituted or unsubstituted 8-12-membered saturated bridged ring containing 1-3 heteroatoms.

In some of these embodiments, B ₁ , B ₂ , B ₃ , B ₄ , and B ₅ are each independently optionally selected from: H, C ₁ -C ₆ alkyl, halogen, C ₁ -C ₄ alkoxy, C ₁ ~C ₃ fluoroalkyl, N,N-dimethylaminoethoxy, N,N-dimethylaminopropoxy, 2-(N-methylpiperazinyl)ethoxy, 2-( N-Acetylpiperazinyl)ethoxy, 2-morpholinylethoxy, 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, morpholinyl, thiomorpholine, piperidinyl, 4-(bis Methylamino) piperidinyl, tetrahydropyrrolyl, imidazolyl, 3-N,N-dimethyltetrahydropyrrolyl, 4-N,N-dimethylpiperidinyl, 4-acetylpiperazine, 1-Methyl-4-(piperazine-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-diazepine Spiro[3.5]nonan-2-yl, 9-methyl-3,9-diazaspiro[5.5]undecan-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, and esters, amides, sulfones, sulfoxides, ureas formed by the above groups.

In some of these embodiments, B ₁ , B ₂ , B ₃ , B ₄ , B ₅ are each independently optionally selected from: H, C ₁ -C ₃ alkyl, halogen, 4-methylpiperazin-1-yl, 4-Isopropylpiperazin-1-yl, piperidinyl, 9-methyl-3,9-diazaspiro[5.5]undecan-3-yl, 3-methyl-1,3-di Azacycloheptan-1-yl, (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl, (2-(dimethylamino)ethyl yl)(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 the embodiments, B ₁ , B ₂ , B ₄ , and B ₅ are independently selected from: H, C ₁ -C ₃ alkyl, halogen; B ₃ is selected from: 4-methylpiperazine-1- base, 4-isopropylpiperazin-1-yl, piperidinyl, 9-methyl-3,9-diazaspiro[5.5]undecan-3-yl, 3-methyl-1,3 -Diazepan-1-yl, (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-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;

其中，R₄选自：甲基，乙基，正丙基，异丙基，环丙基，正丁基，异丁基，叔丁基，环丁基，新戊基，环戊基，环己基；R1 is selected from _:

Wherein, R4 is selected from: methyl, ethyl, n _- propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, neopentyl, cyclopentyl, cyclopentyl Hexyl;

其中，n为0；A₁，A₂，A₃，A₄，A₅分别独立任选自：氢，氯，氟；R ₂ is selected from:

wherein, n is 0; A ₁ , A ₂ , A ₃ , A ₄ , and A ₅ are independently selected from: hydrogen, chlorine, and fluorine;

B ₁ , B ₂ , B ₃ , B ₄ , B ₅ are each independently selected from: H, methyl, halogen, 4-methylpiperazin-1-yl, piperidinyl, 9-methyl-3,9 - Diazaspiro[5.5]undecan-3-yl, 3-methyl-1,3-diazacycloheptan-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; R ₄ is selected from: methyl, ethyl, n-propyl, isopropyl, cyclopropyl; A ₁ is chlorine, A ₂ , A ₃ , A ₄ , A ₅ All are hydrogen; B ₂ is methyl, B ₃ is 4-methylpiperazin-1-yl, B ₁ , B ₄ , and B ₅ are all H; L is selected from:

In some of these embodiments, W is methyl; R ₄ is selected from: methyl, ethyl, n-propyl, isopropyl, cyclopropyl; A ₁ is chlorine, A ₂ , A ₃ , A ₄ , A ₅ is hydrogen; B ₂ is methyl, B ₃ is 4-methylpiperazin-1-yl, B ₁ , B ₄ , and B ₅ are 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)pyridine and [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)propionamide,

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-phenyl Pyrido[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-phenyl Pyrido[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-acetylpiperidine-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-propionylpiperidine-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-propionyl Pyrrolidin-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-methyl) piperazin-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]pyrimidine-7 (8H)-ketone,

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)pyridine and [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-propionyl piperidin-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-methylpiperazine) -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-propionyl piperidin-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-methylpiperazine) -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-methylpiperazine) -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-methylpiperazine-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-propane) piperidin-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-methylpiperin) oxazin-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-methyl) piperazin-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-methyl) ylpiperazin-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-methyl) ylpiperazin-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-methylpiperazine) -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-methylpiperazine) -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-methyl) ylpiperazin-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-methyl) ylpiperazin-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-Proppiperidin-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-methylpiperazine) -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-methylpiperazine) -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-methyl) ylpiperazin-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-methyl) ylpiperazin-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)propionamide,

(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-propiperidin-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-methyl) ylpiperazin-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-methyl) ylpiperazin-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-methyl) ylpiperazin-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-methyl) ylpiperazin-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-methylpiperazine) -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-methylpiperazine) -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-propiperidin-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)-6-(2-Chloro-4-fluorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino )-8-(1-propiperidin-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-methylpiperazine- 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-methylpiperazine- 1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)cyclohexyl)propionamide,

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

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

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

N-((1S,4S)-4-(6-(2-Chloro-3-fluorophenyl)-5-methyl-2-((4-(4-methylpiperazin-1-yl)benzene yl)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-methylpiperazine- 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-methylpiperazine- 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-methylpiperazine- 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-methylpiperazine- 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-methylpiperazine- 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-methylpiperazine- 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-methylpiperazine- 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-Proppiperidin-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)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-proppiperidine -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-proppiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one,

(S)-6-(2-Chlorophenyl)-2-((5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)amino)-5-methyl- 8-(1-Propionylpiperidine)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-propane) acylpiperidin-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-Proppiperidin-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 yl-8-(1-propiperidin-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]undecane) -3-yl)phenyl)amino)-8-(1-proppiperidin-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]nonan-2 -yl)phenyl)amino)-8-(1-proppiperidin-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]pyrrole- 2(1H)-yl)phenyl)amino)-8-((S)-1-propiperidin-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-Propiperidin-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-Propiperidin-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)benzene yl)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-proppiperidin-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-Proppiperidin-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-Proppiperidin-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-propiperidin-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-Proppiperidin-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-Proppiperidin-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-Proppiperidin-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-Proppiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one,

(S)-6-(2-Chlorophenyl)-5-methyl-2-((5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)amino)- 8-(1-Propionylpiperidine)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 yl-8-(1-propiperidin-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-Proppiperidin-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-propane) piperidin-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-propane) piperidin-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]pyrimidine-7(8H) -ketone,

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,

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,

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,

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 ,

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)propionamide,

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,

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)propionamide,

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

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,

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

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

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

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

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

The present invention also provides the application of the above-mentioned pyridopyrimidinone or pyridopyridone compound or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule.

The specific technical solutions are as follows:

Use of the above-mentioned pyridopyrimidinone or pyridopyridone compound or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule in the preparation of mutant EGFR inhibitor.

The use of the above-mentioned pyridopyrimidinone or pyridopyridone compound or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule in the preparation of a medicament for preventing and treating tumors.

In some of these embodiments, the tumor is an EGFR gene-mutated malignancy.

In some of these embodiments, the tumor comprises: non-small cell lung cancer, malignant melanoma, prostate cancer, kidney cancer, bladder cancer, ovarian cancer, colon cancer, rectal cancer, breast cancer, cervical cancer, lung cancer, throat cancer, Nasopharyngeal cancer, pancreatic cancer, multiple myeloma, B lymphoma, leukemia.

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

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

The technical solutions are as follows:

A pharmaceutical composition for preventing and treating tumors, the active ingredients of which include the above-mentioned pyridopyrimidinone or pyridopyridone compounds or their pharmaceutically acceptable salts or their stereoisomers or their prodrug molecules.

In some of these embodiments, the tumor is an EGFR gene-mutated malignancy.

In some of these embodiments, the tumor comprises: non-small cell lung cancer, malignant melanoma, prostate cancer, kidney cancer, bladder cancer, ovarian cancer, colon cancer, rectal cancer, breast cancer, cervical cancer, lung cancer, throat cancer, Nasopharyngeal cancer, pancreatic cancer, multiple myeloma, B lymphoma, leukemia.

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

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

The compounds of the present invention can selectively inhibit the activity of mutant EGFR, and have inhibitory effects on other proteases of EGFR and Her family. Protein kinase inhibitor with good pharmacokinetic properties. The compounds of the present invention can effectively inhibit the growth of various tumor cells, especially can selectively inhibit EGFR ^{L858R/T790MC797S} lung cancer cells. Compared with wild-type cancer cells, some of the preferred compounds have a selectivity greater than 50 times. The compound of the present invention can be used to prepare antitumor drugs, and can overcome the drug resistance problem induced by existing drugs (such as gefitinib, erlotinib, especially osimertinib (AZD9291)), and is mainly used for existing drugs. The third-generation EGFR small molecule inhibitor class of anti-non-small cell lung cancer drugs Osimertinib (AZD9291), Olmutinib (HM6171), Rociletinib (9, CO-1686), etc. induced mutation of cysteine 797 to serine (C797S) Resistant. The compounds of the present invention can be used for preventing postoperative recurrence of various tumors and further consolidating treatment, so as to achieve the purpose of prolonging the survival period of tumor patients, improving their quality of life and inhibiting tumor deterioration.

Description of drawings

Figure 1 is a graph showing the test results of the effect of the compound 560082 of the present invention on the phosphorylation of EGFR ^{L858R/T790M/C797S} and EGFR ^{19D/T790M/C797S} in tool cells;

Figure 2 is a graph showing the test results of the effect of the compound 580120 of the present invention on the phosphorylation of EGFR ^{L858R/T790M/C797S} and EGFR ^{19D/T790M/C797S} in tool cells.

Detailed ways

In the compounds of the present invention, when any variable (eg, R1, R, etc.) occurs more _than once in any component, the definition of each occurrence is independent of the definition of each other occurrence. Likewise, combinations of substituents and variables are permissible so long as such combinations stabilize the compound. A line drawn into a ring system from a substituent indicates that the indicated bond may be attached to any substitutable ring atom. If the ring system is polycyclic, it means that such bonds are only attached to any suitable carbon atoms adjacent to the ring. It will be appreciated that one of ordinary skill in the art can select substituents and substitution patterns for the compounds of the present invention to provide compounds that are chemically stable and readily synthesized from readily available starting materials by the skill of the art and the methods set forth below. 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 stabilized. The phrase "optionally substituted with one or more substituents" is considered equivalent to the phrase "optionally substituted with at least one substituent" and in this case preferred embodiments will have 0-3 substituents.

The terms "alkyl" and "alkylene" as used herein are meant to include branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, the definition of "C ₁ -C ₅ " in "C ₁ -C ₅ alkyl" includes groups having 1, 2, 3, 4, or 5 carbon atoms arranged in a straight or branched chain. For example, " _C1 - _C5 alkyl" 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, 2,2-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 carbocyclic ring of up to 6 atoms in each ring, wherein at least one ring is aromatic and contains 1-4 optional rings Heteroatoms 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, Pyrimidyl, pyrrolyl. For the following definition of heteroaryl, "heteroaryl" is also understood to include the N-oxide derivative of any nitrogen-containing heteroaryl. In instances where the heteroaryl substituents are bicyclic and contain 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 non-aromatic heterocycle containing 1-4 heteroatoms selected from O, N, and S, and includes bicyclyl group. "Heterocyclyl" thus includes the above-mentioned heteroaryl groups, as well as their dihydro and tetrahydro analogs. Further examples of "heterocyclyl" include, but are not limited to, imidazolyl, indolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, oxetanyl, pyridine pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinoxolinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, l, 4-dioxanyl, pyrrolidinyl, dihydroimidazolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydro Pyrazolyl, dihydropyridyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydro Azetidine, tetrahydrofuranyl and tetrahydrothienyl, and their N-oxides. Attachment of heterocyclic substituents can be through carbon atoms or through heteroatoms. In one embodiment, the heterocycle is selected from the group consisting of imidazolyl, pyridyl, 1-pyrrolidone, 2-piperidone, 2-pyrimidinone, 2-pyrrolidone, thienyl, oxazolyl, triazolyl, isoxazole base.

As understood by those skilled in the art, "halo" ("halo") or "halogen" as used herein is meant to include chlorine, fluorine, bromine and iodine.

Unless otherwise defined, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl substituents can be unsubstituted or substituted. For example, (C ₁ -C ₆ )alkyl may be substituted with one, two or three substituents selected from OH, halogen, alkoxy, dialkylamino, or heterocyclyl such as morpholinyl, piperidinyl, and the like replace.

The present invention includes the free forms of the compounds of formulae I-VI, as well as the pharmaceutically acceptable salts and stereoisomers thereof. Some of the specific exemplary compounds herein are protonated salts of amine compounds. The term "free form" refers to the amine compound in non-salt form. Included pharmaceutically acceptable salts include not only exemplary salts of the particular compounds described herein, but also typical pharmaceutically acceptable salts of all compounds of formulae I-VI in free form. The free forms of specific salts of the compounds can be isolated using techniques known in the art. For example, the free form can be regenerated by treating the salt with a suitable dilute aqueous base, such as dilute aqueous NaOH, dilute aqueous potassium carbonate, dilute aqueous ammonia, and dilute aqueous sodium bicarbonate. 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.

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

Accordingly, pharmaceutically acceptable salts of the compounds of the present invention include conventional non-toxic salts of the compounds of the present invention formed by reacting a basic compound of the present invention with 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 derived from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, hard Fatty 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, p-aminobenzenesulfonic acid, 2-acetyl Salts prepared from oxymonobenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, etc.

If the compound of the present invention is acidic, appropriate "pharmaceutically acceptable salts" refer to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganous, potassium, sodium, zinc, and the like. Ammonium, calcium, magnesium, potassium and sodium salts are particularly preferred. 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 Amino acid, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethyl Diamine, N-ethylmorpholine, N-ethylpiperidine, Glucosamine, Glucosamine, Histidine, Hydroxocobalamin, Isopropylamine, Lysine, Methylglucamine, Morpholine, Piperazine , piperidine, quack, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

Berg et al., "Pharmaceutical Salts," J. Pharm. Sci. '1977:66:1-19 describes the preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts in more detail.

Since deprotonated acidic moieties such as carboxyl groups in compounds can be anionic under physiological conditions, such charged charges can then be replaced by internally cationic protonated or alkylated basic moieties such as tetravalent The nitrogen atoms balance out, so it should be noted that the compounds of the present invention are potential inner salts or zwitterions.

In addition to standard methods known in the literature or exemplified in experimental procedures, the compounds of this invention can be prepared using reactions as shown in the following schemes. Accordingly, the following illustrative schemes are for illustrative purposes and are not limited to the listed compounds or any particular substituents. The numbers of substituents shown in the schemes do not necessarily correspond to those used in the claims, and for clarity, mono-substituents are shown attached to compounds that allow for multi-substituents under the definition of formula I above.

As described in the invention, the compounds of formula I-VI can be prepared by those skilled in the art according to the prior art and common knowledge, from 4-chloro-2-methylthiopyrimidine-5-ethyl carbonate or 2,4-dichloro -5-Bromopyrimidine was used as the starting material to synthesize through several steps. (see embodiment 1,9,32 etc. for specific synthesis steps)

The compounds of formulas I-VI and pharmaceutically acceptable salts thereof provided in this application can be used for the treatment of overproliferative diseases or symptoms such as tumors in humans or other mammals.

In one embodiment, the compounds designed in the present application and their pharmaceutically acceptable salts can be used for the treatment or control of non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer , liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, leukemia, histiocytic lymphoma, nasopharyngeal carcinoma and other transitional proliferative diseases.

Drug Metabolites and Prodrugs

The metabolites of the compounds involved in the present application and their pharmaceutically acceptable salts, as well as prodrugs that can be converted into the structures of the compounds involved in the present application and their pharmaceutically acceptable salts in vivo, are also included in the claims of the present application middle.

Combination medication

The compounds of formulae I-VI can be used in combination with other drugs known to treat or ameliorate similar conditions. When co-administered, the mode of administration & dosage of the original drug remains unchanged, while the compound of formula I-IV is administered concurrently or subsequently. When the compound of formulae I-IV is administered concomitantly with one or more other drugs, it is preferred to use a pharmaceutical composition containing one or more known drugs and the compound of formulae I-IV at the same time. Drug combinations also include administration of a compound of formulae I-IV with one or more other known drugs at overlapping time periods. When the compounds of formulae I-VI are administered in combination with one or more other drugs, the doses of compounds of formulae I-IV or known drugs may be lower than when they are administered alone.

Drugs or active ingredients that can be used in pharmaceutical combinations with compounds of formulae I-VI include, but are not limited to:

Estrogen receptor modulators, androgen receptor modulators, retinal-like receptor modulators, cytotoxic/cytostatics, antiproliferative agents, protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protein kinase inhibitors agents, reverse transcriptase inhibitors, angiogenesis inhibitors, cell proliferation and survival signal inhibitors, drugs that interfere with cell cycle checkpoints and apoptosis inducers, cytotoxic drugs, tyrosine protein inhibitors, EGFR inhibitors, VEGFR inhibitor, serine/threonine protein inhibitor, Bcr-Abl inhibitor, c-Kit inhibitor, Met inhibitor, Raf inhibitor, MEK inhibitor, MMP inhibitor, topoisomerase inhibitor, histidine Acid deacetylase inhibitors, proteasome inhibitors, CDK inhibitors, Bcl-2 family protein inhibitors, MDM2 family protein inhibitors, IAP family protein inhibitors, STAT family protein inhibitors, PI3K inhibitors, AKT inhibitors , Integrin blocker, interferon-α, interleukin-12, COX-2 inhibitor, p53, p53 activator, VEGF antibody, EGF antibody, etc.

In one embodiment, drugs or active ingredients that can be used in pharmaceutical combination with compounds of formulae I-VI include, but are not limited to: aldesleukin, alendronic acid, interferon, atranoin, allopurinol, allopurinol, Sodium purinol, Palonosetron hydrochloride, Hexamethylmelamine, Aminoglutide, Amifostine, Amrubicin, Amridine, Anastrozole, Dolassetron, aranesp, arglabin, Arsenic trioxide, Arsenic, 5-azacytidine, azathioprine, BCG or tice BCG, betadine, betamethasone acetate, betamethasone sodium phosphate preparation, bexarotene, bleomycin sulfate, bromuria Gan, bortezomib, busulfan, calcitonin, alezolizumab injection, capecitabine, carboplatin, casodex, cefesone, simoleukin, daunorubicin, chlorambucil, cisplatin, Cladribine, Cladribine, Clodronate, Cyclophosphamide, Cytarabine, Dacarbazine, Actinomycin D, Daunorubicin Liposome, Dexamethasone, Dexamethasone Phosphate, Valeric Acid Estradiol, Denisole-2, Dipomet, Deslorelin, Delazoxan, Diethylstilbestrol, Diflucan, Docetaxel, Deoxyfluridine, Doxorubicin, Dronabinol, Chin-166 -Chitosan complex, eligard, rasburicase, epirubicin hydrochloride, aprepitant, epirubicin, epoetin alfa, erythropoietin, eplatin, levamisole tablets, estradiol Preparation, 17-beta-estradiol, estramustine sodium phosphate, ethinyl estradiol, amifostine, hydroxyphosphate, fenbifur, etoposide, fadrozole, tamoxifen preparation, filgrastim , finasteride, feleastide, floxuridine, fluconazole, fludarabine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil, fluoxymesterone, flutamide, formin Stan, 1-β-D-arabinofuranosyl cytidine-5'-stearoyl phosphate, fomustine, fulvestrant, gamma globulin, gemcitabine, gemtuzumab, imabyl mesylate Matinib, Carzapine Wax Paper Capsules, Goserelin, Granisirone Hydrochloride, Histrelin, and Methionine, Hydrocortisone, Erythro-hydroxynonyladenine, Hydroxyurea, Titan Isobemumab, idarubicin, ifosfamide, interferon alpha, interferon-alpha2, interferon alpha-2A, interferon alpha-2B, interferon alpha-nl, interferon alpha-n3, interferon Interleukin β, Interferon γ-la, Interleukin-2, Intron A, Iressa, Irinotecan, Kaiteri, Lentinan sulfate, Letrozole, Leucovorin, Leuprolide, Leuprolide acetate, levothyroxine, levofolinate calcium salt, levothyroxine sodium, levothyroxine sodium preparations, lomustine, lonidamine, dronabinol, nitrogen mustard, methylcobalamin, Medroxyprogesterone acetate, megestrol acetate, melphalan, esterified estrogens, 6-mercaptopurine, mesna, methotrexate, methyl aminolevulinate, miltefosine, Meiman Amycin, mitomycin C, mitotane, mitosodium quinone, trilostane, doxorubicin citrate liposome, nedaplatin, pegylated filgrastim, oppreleukin, neupogen, nilutamide, tamoxifen, NSC-63 1570. Recombinant human interleukin-1-beta, octreotide, ondansetron hydrochloride, dehydrocortisone oral solution, oxaliplatin, paclitaxel, prednisone sodium phosphate preparation, pegmatase, perol Xin, pentostatin, streptolytic preparations, pilocarpine hydrochloride, pirorubicin, prukamycin, porfim sodium, prednimustine, steprednisolone, prednisone, Premarin, Procarba, Recombinant Human Erythropoietin, Raltitrexed, Ribbi, Etidronate, Rhenium-186, Rituxan, Rituxan-A, Romotide, Pilocarpine Hydrochloride Tablets, Octreotide, Shamo Krastim, Semustine, Sizoran, Sobuzoxan, Methylprednisolone, Paphos Acid, Stem Cell Therapy, Streptozocin, Strontium Chloride-89, Levothyroxine Sodium, Tamoxifen, tamsulosin, tasonamin, tastolactone, taxotere, tesetiazine, temozolomide, teniposide, testosterone propionate, methyltestosterone, thioguanine, thiotepa, thyrotropin, tiludosine acid, topotecan, toremifene, tosilimumab, trastuzumab, triosulfan, tretinoin, methotrexate tablets, trimethylmelamine, trimetrexate, acetic acid Triptorelin, Triptorelin pamoate, Eufodine, Uridine, Valrubicin, Vesrinone, Vinblastine, Vincristine, Vincamide, Vinorelbine, Velulizine, Dextropropimide, net statin, zofenin, paclitaxel protein stabilizer, acolbifene, interferon r-lb, affinitak, aminopterin, azoxifene, asoprisnil, atametan, atraxen Tan, BAY43-9006, Avastin, CCI-779, CDC-501, Celebrex, Cetuximab, Crinator, Cyproterone Acetate, Decitabine, DN-101, Doxorubicin -MTC, dSLIM, dutasteride, edotecarin, eflunomine, ixitecan, fenretinide, histamine dihydrochloride, histrelin hydrogel implant, holmium-166DOTMP, ibandronic acid, interferon gamma, intron-PEG, ixabepilone, keyhole limpet hemocyanin, L-651582, lanreotide, lasoxifene, libra, lonafamib, milepoxifene, minodex Ester, MS-209, liposomal MTP-PE, MX-6, nafarelin, naimrubicin, novarestat, nolatrexide, olimerson, onco-TCS, osidem, paclitaxel Polyglutamic acid ester, sodium bromide, PN-401, QS-21, quasiyang, R-1549, raloxifene, leopard enzyme, 13-cis-retinoic acid, saplatin, theocalcidol , T-138067, tarceva, docosahexaenoate paclitaxel, thymosin alfa, gazofurin, tipifarnib, tirapazamine, TLK-286, toremifene, trans MID-lo7R, valspro Dalta, vapretide, vatalanib, verteporfin, vinflunine, Z-100, and zolelinic acid or a combination thereof.

The following examples further describe the present invention, but the examples are not intended to limit the protection scope of the present invention.

Example 1

Step 1. (S)-ethyl 4-(1-tert-butoxycarbonylpyrrolyl-3-amino)-2-methylmercaptopyrimidine-5-carbonate (2)

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

4-Chloro-2-methylmercaptopyrimidine-5-ethyl carbonate (24.98 g, 107.4 mmol), (S)-1-tert-butoxycarbonyl-3-aminopyrrolidine (22.0 g, 118.2 mmol), K ₂ CO ₃ (29.64 g, 214.8 mmol) was dissolved in 50 mL of anhydrous DMF, heated to 60°C under argon protection, and stirred overnight. Cooled to room temperature, 500 mL of ice water was added with stirring, and a large amount of solid was precipitated. Filtration under reduced pressure and vacuum drying gave 6.0 g of white solid (yield 74%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.63 (s, 1H), 8.34 (s, 1H), 4.72 (s, J=2.4 Hz, 1H), 4.31 (q, J=7.2 Hz, 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)-ethyl 4-(1-tert-butoxycarbonylpyrrolyl-3-amino)-2-methylmercaptopyrimidine-5-carbonate (2) (26.0 g, 79.15 mmol) was dissolved in 200 mL of tetrahydrofuran, cooled to -40 °C, slowly dropwise add lithium aluminum tetrahydrogen (6.02 g, 158.3 mmol) in tetrahydrofuran suspension, stir and slowly raise to 0 °C, and monitor the reaction by spotting. After the raw materials were reacted, the temperature was lowered to -40°C, and 6 mL of water, 6 mL of 10% sodium hydroxide solution and 18 mL of water were slowly added dropwise to quench the reaction, followed by addition of dry MgSO ₄ powder, suction filtration, and concentration. Then extract with dichloromethane and water, take the organic phase, dry with anhydrous Na ₂ SO ₄ , then filter and spin dry, and separate by column chromatography (SiO ₂ , CH ₂ Cl ₂ /MeOH gradient elution, 40:1 to 20 : 1) to obtain 13 g of white oil (yield 48%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.74 (s, 1H), 6,02 (s, 1H), 4.68 (d, J=5.6 Hz, 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) (13 g, 11.53 mmol) was dissolved in 100 mL of anhydrous bismuth In the methyl chloride, 3 equivalents of active manganese dioxide (16.6g, 191.10mmol) were added in batches, after the reaction of the raw materials, suction filtration with diatomaceous earth was used to remove the solid, and spin-dried to obtain 11.2g of oil (yield 87%) .

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.78(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] ⁺ .

Step 4: (S)-3-(6-(2-Chlorophenyl)-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl) - tert-butyl pyrrolidine-1-carboxylate (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) (2.0 g, 5.9 mmol) was dissolved in 2 mL of DMF, added Ethyl o-chlorophenylacetate (1.4 g, 7.0 mmol), DBU (538.9 mg, 7.08 mmol) were slowly heated to 85°C, and the reaction was monitored by spot plate. After the reaction of the raw materials, the temperature was cooled to room temperature, water was added to quench the reaction, and then extracted with dichloromethane and water, the organic phase was taken, dried over anhydrous Na ₂ SO ₄ , then filtered and rotated to dryness, and separated by column chromatography (SiO ₂ , PE /EA gradient elution, 10:1 to 5:1) to obtain 1.0 g of white oil (yield 35%)

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.11 (s, 1H), 7.50 (d, J=7.2 Hz, 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-carboxylate 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 tert-Butyl-1-carboxylate (5) (1.0 g, 2.0 mmol) was dissolved in 5 mL of anhydrous dichloromethane, and m-chloroperoxybenzoic acid (1.2 g, 6.0 mmol) was slowly added under an ice bath at 0 °C, and the to room temperature and stirred for 4 hours. Dichloromethane was added to dilute the reaction and quenched with 50 _% aqueous _{Na2S2O3 / NaHCO3} . The organic phase was washed twice with saturated brine, dried over anhydrous Na ₂ SO ₄ , filtered and spin-dried, and separated by column chromatography (SiO ₂ , PE/EA gradient elution, 4:1 to 2:1) to obtain 0.6 g ( Yield 60%)

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.11 (s, 1H), 7.50 (d, J=7.2 Hz, 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-carboxylate 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)-pyrrole Alkane-1-carboxylate tert-butyl ester (6) (0.66g, 1.3mmol) was added to a sealed bottle containing 10mL of sec-butanol, followed by 3-methyl-4-(4-methylpiperazine-1-substituted ) aniline (295 mg, 1.44 mmol) and TFA (110 μL, 1.44 mmol). Heat to 110°C and stir for 18 hours. Cooled to room temperature, poured into 10% NaHCO ₃ aqueous solution, extracted twice with dichloromethane, combined the organic phases, washed twice with saturated brine, dried over anhydrous Na ₂ SO ₄ , filtered, and spin-dried to obtain compound 7. one-step reaction.

Step 7: (S)-6-(2-Chlorophenyl)-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8-(pyrrole Alk-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-oxo Pyrido[2,3-d]pyrimidin-8(7H)-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (7) was dissolved in 5 mL of dichloromethane, TFA (0.5 mL) was added, and the mixture was stirred at room temperature for 4 h. The reaction solution was diluted with dichloromethane, adjusted to pH 9 with saturated NaHCO ₃ solution, extracted twice with dichloromethane, the organic phases were combined, washed twice with 10% NaHCO ₃ aqueous solution, twice with saturated brine, and anhydrous Na ₂ SO _4. Dry, filter and spin dry, and separate by column chromatography (SiO ₂ , CH ₂ Cl ₂ /MeOH/NH ₄ OH, 40:1: to 20:.1) to obtain 300 mg of solid (2-step yield 43%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98 (s, 1H), 7.51 (d, J=7.2 Hz, 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] ⁺ .

Step 8: (S)-8-(1-Acetylpyrrol-3-yl)-6-(2-chlorophenyl)-2-((3-methyl-4-(4-methylpiperazine- 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-(pyrrolidine-3 -yl)pyrido[2,3-d]pyrimidin-7(8H)-one (8) (150 mg, 0.28 mmol) was dissolved in 10 mL of anhydrous dichloromethane, and Et ₃ N (1.1 mL, 0.84 mmol), and acetyl chloride (25 μL, 0.31 mmol) was added slowly. Return to room temperature and stir for 4 hours. After the reaction, 10% NaHCO ₃ aqueous solution was added, extracted twice with dichloromethane, the organic phases were combined, washed once with saturated brine, dried over anhydrous Na ₂ SO ₄ , filtered and spin-dried, separated by column chromatography (SiO ₂ , CH ₂ Cl ₂ /MeOH/NH ₄ OH, 40:1:0.4), and further purified by high performance liquid chromatography to obtain 130 mg of solid (yield 92%).

¹ H NMR (400MHz, DMSO) δ 10.01 (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] Pyrimidine-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

The synthetic method is shown in Example 1, and the yield is 57%.

¹ H NMR (300MHz, DMSO) δ 9.90 (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

The synthetic method is shown in Example 1, and the yield is 79.6%.

¹ H NMR (400MHz, DMSO) δ 9.93(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

The synthetic method is shown in Example 1, and the yield is 73.3%.

¹ H NMR (400MHz, DMSO) δ 9.93(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 600.4 [M+H] ⁺ .

Example 5

N-((1R,4R)-4-(2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxo-6-phenyl Pyrido[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 the synthesis method, the yield is 59.6%

¹ H NMR (400MHz, DMSO) δ 9.81 (d, J=56.6Hz, 1H), 8.76 (s, 1H), 7.90 (d, J=18.4Hz, 1H), 7.66 (dd, J=20.1, 18.6 Hz, 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-phenyl Pyrido[2,3-d]pyrimidin-8(7H)-yl)cyclohexyl)propionamide (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

The synthetic method is shown in Example 1, and the yield is 80.35%.

¹ H NMR (400MHz, DMSO) δ 9.81 (d, J=56.6Hz, 1H), 8.76 (s, 1H), 7.90 (d, J=18.4Hz, 1H), 7.66 (dd, J=20.1, 18.6 Hz, 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

The synthetic method is shown in Example 1, and the yield is 81.3%.

¹ H NMR (400MHz, DMSO) δ 9.93(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)propionamide (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

The synthetic method is shown in Example 1, and the yield is 78.9%.

¹ H NMR (400MHz, DMSO) δ 9.93(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-acetylpiperidine-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

The synthetic method is shown in Example 1, and the yield is 74.5%.

¹ H NMR (400MHz, DMSO) δ 9.95(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-propionylpiperidine-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

The synthetic method is shown in Example 1, and the yield is 72.7%.

¹ H NMR (400 MHz, DMSO) δ 9.99 (s, 1H), 8.77 (s, 1H), 7.81 (s, 1H), 7.52 (d, J=4.1 Hz, 3H), 7.41 (d, J=10.1 Hz, 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-propionyl Pyrrolidin-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

The synthetic method is shown in Example 1, and the yield is 76.8%.

¹ H NMR (400MHz, DMSO) δ 10.00 (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

The synthetic method is shown in Example 1, and the yield is 78.7%.

¹ H NMR (400MHz, DMSO) δ 9.92(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

The synthetic method is shown in Example 1, and the yield is 75.9%.

¹ H NMR (400MHz, DMSO) δ 9.92(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

The synthetic method is shown in Example 1, and the yield is 88.8%.

¹ H NMR (400MHz, DMSO) δ 10.01 (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-propionyl Piperidin-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

The synthetic method is shown in Example 1, and the yield is 86%.

¹ H NMR (400 MHz, DMSO) δ 10.02 (s, 1H), 8.78 (s, 1H), 7.85 (t, J=11.0 Hz, 1H), 7.53 (d, J=5.1 Hz, 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 for the synthesis method.

¹ H NMR (400MHz, DMSO) δ 10.01 (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 17

(S)-6-(3-Chlorophenyl)-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-8-(1-propionyl Piperidin-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

The synthetic method is shown in Example 1, and the yield is 85.7%.

¹ H NMR (400 MHz, DMSO) δ 10.02 (s, 1H), 8.78 (s, 1H), 7.85 (t, J=11.0 Hz, 1H), 7.53 (d, J=5.1 Hz, 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 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

Step 9: tert-Butyl ((1R,4R)-4-((5-bromo-2-chloropyrimidin-4-yl)amino)cyclohexyl)carbamate (10)

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

5-Bromo-2,4-dichloropyrimidine (9) (5.8 g, 25.45 mmol), tert-butyl trans-(4-aminocyclohexyl)carbamate (5.0 g, 23.23 mmol) _were combined with K at room temperature _CO3 (6.4 g, 46.66 mmol) was added to 70 mL of MeCN. The mixed system continued to be stirred at room temperature, and the reaction was monitored by spotting. After the reaction of the raw materials, it was extracted with dichloromethane and water, the organic phase was taken, dried over anhydrous Na ₂ SO ₄ , then filtered and spin-dried, and separated by column chromatography (SiO ₂ , PE/EA gradient elution, 15:1 to 10:1 ) to obtain 4.6 g of white oil (yield 48%).

¹ H NMR (400MHz, DMSO) δ 8.88 (s, 1H), 5.34 (s, 1H), 2.84 (s, 5H), 2.30 (d, J=18.1 Hz, 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: tert ((1R,4R)-4-(2-chloro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)cyclohexyl)carbamate Butyl ester (11)

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

Compound ((1R,4R)-4-((5-bromo-2-chloropyrimidin-4-yl)amino)cyclohexyl)carbamic acid tert-butyl ester (10) (3.25 g, 8.00 mmol) was mixed with trans at room temperature. Crotonic acid (6.75.g, 80.0 mmol) was added to THF (30 mL), then DIPEA (13 mL) was slowly added to the system, the system was replaced with Ar three times, and then diphenylacetonitrile palladium dichloride (0.16 g, 0.4 mmol) and tris(o-methylphenyl) phosphine (125 mg, 0.4 mmol) were added to the mixed system, replaced with Ar again three times, the system was heated to 80 °C and stirred for 24 h, and then Ac2O (1.9 mL) was added to the system , continue to heat and stir the reaction for 24h. Heating was stopped, and when the temperature of the system dropped to room temperature, part of the solvent was removed by rotary evaporation under reduced pressure, then DCM (50 mL) was added to the system, and the organic phase was washed with HCl (1 M, 100 mL), and then washed once with saturated brine (100 mL). The organic phase was collected, dried with anhydrous Na ₂ SO ₄ for 30 min, filtered, concentrated under reduced pressure, and subjected to column chromatography to obtain 0.71 g of a light yellow solid, the product, with a yield of 30.0%.

¹ H NMR (400MHz, DMSO) δ 8.88(s, 1H), 6.41(s=1H), 7.27(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 ) tert-butyl carbamate (12)

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

Compound ((1R,4R)-4-(2-chloro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)cyclohexyl)carbamic acid at room temperature Tert-butyl ester (11) (383 mg, 0.97 mmol) was dissolved in AcOH (1.6 mL), sodium acetate (320 mg 3.88 mmol) was added, liquid bromine (0.013 mL, 2.7 mmol) was slowly added dropwise, the temperature was raised to 55°C, and stirred overnight , add saturated Na ₂ S ₂ O ₃ solution, stir until the red color of the system disappears, extract the separated organic phase, wash once with water (5 mL) and saturated brine (5 mL) in turn, collect the organic phase, and dry it with anhydrous Na ₂ SO ₄ 30min, filtered, concentrated under reduced pressure, and column chromatography gave 282 mg of white solid with a yield of 58.9%.

¹ H NMR (400MHz, DMSO) δ 8.88(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) tert-Butyl -7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)cyclohexyl)carbamate (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 a sealed bottle containing 7mL of sec-butanol, followed by 3-methyl-4-(4-methylpiperazine-1-substituted)aniline (160mg, 0.78 mmol) and TFA (50 μL, 0.71 mmol). Heat to 110°C and stir for 18 hours. Cooled to room temperature, poured into 10% NaHCO ₃ aqueous solution, extracted twice with dichloromethane, combined the organic phases, washed twice with saturated brine, dried over anhydrous Na ₂ SO ₄ , and column chromatography gave a yellow solid 300 mg, yield: 66%.

¹ H NMR (400MHz, DMSO) δ 9.86 (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)carbamate 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

Compound ((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 (13) (336 mg, 0.5 mmol), 2-chlorophenylboronic acid (410 mg, 2.6 mmol), bistriphenylphosphonium palladium dichloride (18.4 mg, 0.026 mmol), Na ₂ CO ₃ (167 mg, 1.56 mmol) was added to 1,4-dioxane (6 mL) and H ₂ O (2 mL) ) in the mixed solvent of ), replace the air with Ar, heat the system to 110°C and stir the reaction for 24h, stop heating, wait for the system to drop to room temperature, add DCM (10mL) and saturated NaHCO ₃ (5mL) solution, extract and separate to obtain an organic phase, Washed once with saturated brine (5 mL), collected the organic phase, dried over anhydrous Na ₂ SO ₄ for 30 min, filtered, concentrated under reduced pressure, and column chromatography gave 280.mg of yellow solid with a yield of 83.0%.

¹ H NMR (400MHz, DMSO) δ 9.86 (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-methyl) Piperazin-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-oxopyridin[2,3-d]pyrimidin-8(7H)-yl)cyclohexyl)carbamate (14) 280 mg was dissolved in 5 mL of dichloromethane, TFA (0.5 mL) was added ) and stirred at room temperature for 4h. The reaction was diluted with dichloromethane, adjusted to pH 9 with saturated NaHCO ₃ solution, extracted twice with dichloromethane, the organic phases were combined, washed twice with 10% NaHCO ₃ aqueous solution, twice with saturated brine, and anhydrous Na ₂ SO ₄ Dry, filter and spin dry, and separate by column chromatography to obtain 200 mg of yellow solid (yield 84%).

¹ H NMR (400MHz, DMSO) δ 9.86 (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-methylpiperazine-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-methylpiperazine- 1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (15) (150 mg, 0.28 mmol) was dissolved in 10 mL of anhydrous dichloromethane, ice bath at 0 °C _Et3N (1.1 mL, 0.84 mmol) was added at the bottom and acetyl chloride (25 [mu]L, 0.31 mmol) was added slowly. Return to room temperature and stir for 4 hours. After the reaction, 10% NaHCO ₃ aqueous solution was added, extracted twice with dichloromethane, the organic phases were combined, washed once with saturated brine, dried over anhydrous Na ₂ SO ₄ , filtered and spin-dried, separated by column chromatography (SiO ₂ , CH ₂ Cl ₂ /MeOH/NH ₄ OH, 40:1:0.4), and further purified by high performance liquid chromatography to obtain 130 mg of solid (yield 92%).

¹ H NMR (400MHz, DMSO) δ 9.86 (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)pyridine Hepo[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

The synthetic method is shown in Example 18, and the yield is 47.4%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.71 (s, 1H), 7.57 (s, 1H), 7.48 (d, J=7.2 Hz, 1H), 7.33 (t, J=9.0 Hz, 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)propionamide (560082)

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

The synthetic method is shown in Example 18, and the yield is 92%.

¹ H NMR (400MHz, DMSO) δ 9.86 (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

The synthetic method is shown in Example 18, and the yield is 47.6%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.71 (s, 1H), 7.57 (s, 1H), 7.48 (d, J=7.2 Hz, 1H), 7.33 (t, J=9.0 Hz, 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

The synthetic method is shown in Example 18, and the yield is 78.3%.

¹ H NMR (400MHz, DMSO) δ 9.86(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] Pyrimidine-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

The synthetic method is shown in Example 18, and the yield is 89%.

¹ H NMR (400MHz, DMSO) δ 9.81(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

The synthetic method is shown in Example 18, and the yield is 47.3%.

¹ H NMR (400MHz, DMSO) δ 9.85 (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

The synthetic method is shown in Example 18, and the yield is 49.2%.

¹ H NMR (400MHz, DMSO) δ 9.85 (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

The synthetic method is shown in Example 18, and the yield is 42%.

¹ H NMR (400MHz, DMSO) δ 9.76(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

The synthetic method is shown in Example 18, and the yield is 86%.

1H NMR (400MHz, DMSO) δ 9.76(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-methyl) Piperazin-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

The synthetic method is shown in Example 18, and the yield is 47.9%.

¹ H NMR (400MHz, DMSO) δ 9.56 (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]pyrimidine-7 (8H)-ketone (560150)

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

The synthetic method is shown in Example 18, and the yield is 59.2%.

¹ H NMR (400MHz, DMSO) δ 9.81 (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

The synthetic method is shown in Example 18, and the yield is 42%.

¹ H NMR (400MHz, DMSO) δ 9.83(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)pyridine Ipo[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

The synthetic method is shown in Example 18, and the yield is 79.8%.

¹ H NMR (400MHz, DMSO) δ 9.88 (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, 7.1 Hz, 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-methylpiperazine) -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

The synthetic method is shown in Example 18, and the yield is 78.9%.

¹ H NMR (400MHz, DMSO) δ 9.95 (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

The synthetic method is shown in Example 18, and the yield is 82.6%.

¹ H NMR (400MHz, DMSO) δ 9.98 (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-methylpiperazine) -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

The synthetic method is shown in Example 18, and the yield is 77.16%.

¹ H NMR (400MHz, DMSO) δ 9.95 (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

The synthetic method is shown in Example 18, and the yield is 81.8%.

¹ H NMR (400MHz, DMSO) δ 9.98 (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-methylpiperazine) -1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (570089)

(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

The synthetic method is as in Example 18, and the yield is 76.9%.

¹ H NMR (400 MHz, DMSO) δ 9.99 (s, 1H), 8.77 (s, 1H), 7.81 (s, 1H), 7.52 (d, J=4.1 Hz, 3H), 7.41 (d, J=10.1 Hz, 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-methylpiperazine-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 synthetic method is as in Example 18, and the yield is 86.8%.

¹ H NMR (400MHz, DMSO) δ 9.95 (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-propane) Piperidin-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 synthetic method was as in Example 18, and the yield was 75.2%.

¹ H NMR (400MHz, DMSO) δ 9.98 (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=11.7 Hz, 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 synthetic method is as in Example 18, and the yield is 79.5%.

¹ H NMR (400MHz, DMSO) δ 9.68 (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 synthetic method is as in Example 18, and the yield is 68%.

¹ H NMR (400 MHz, DMSO) δ 9.99 (s, 1H), 8.77 (s, 1H), 7.81 (s, 1H), 7.52 (d, J=4.1 Hz, 2H), 7.41 (d, J=10.1 Hz, 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-methylpiperin) Azin-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 synthetic method is as in Example 18, and the yield is 67.7%.

¹ H NMR (400MHz, DMSO) δ 9.95 (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-methyl) Piperazin-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 synthetic method is as in Example 18, the yield is 66.5%,

¹ H NMR (400MHz, DMSO) δ 9.98 (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=11.7 Hz, 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-methyl) ylpiperazin-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 synthetic method is as in Example 18, and the yield is 75%.

¹ H NMR (400MHz, DMSO) δ 9.94 (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-methyl) ylpiperazin-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 synthetic method is as in Example 18, and the yield is 60.8%.

¹ H NMR (400MHz, DMSO) δ 9.94 (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-methylpiperazine) -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 synthetic method is as in Example 18, and the yield is 85.4%.

¹ H NMR (400MHz, DMSO) δ 9.96(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-methylpiperazine) -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 synthetic method is as in Example 18, and the yield is 79.6%.

¹ H NMR (400MHz, DMSO) δ 9.96(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-methyl) ylpiperazin-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 synthetic method is as in Example 18, and the yield is 69.4%.

¹ H 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)

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-methyl) ylpiperazin-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 synthetic method is as in Example 18, and the yield is 55%.

¹ H 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=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-Proppiperidin-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 synthetic method is as in Example 18, and the yield is 79.5%.

¹ H NMR (400MHz, DMSO) δ 9.69(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-methylpiperazine) -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 synthetic method is as in Example 18, and the yield is 62%.

¹ H NMR (400MHz, DMSO) δ 9.95 (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 584.1 [M+H] ⁺ .

Example 51

(S)-8-(1-Propionyl-3-yl)-6-(2-fluorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazine) -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 synthetic method is as in Example 18, and the yield is 60.6%.

¹ H NMR (400MHz, DMSO) δ 9.98 (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=11.7 Hz, 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 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 synthetic method is as in Example 18, and the yield is 80.8%.

¹ H NMR (400MHz, DMSO) δ 9.95 (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 synthetic method is as in Example 18, and the yield is 72.44%.

¹ H NMR (400MHz, DMSO) δ 9.98 (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=11.7 Hz, 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-methyl) ylpiperazin-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 synthetic method was as in Example 18, and the yield was 75.9%.

¹ H NMR (400MHz, DMSO) δ 9.99(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-methyl) ylpiperazin-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 synthetic method is as in Example 18, and the yield is 85.4%.

¹ H NMR (400MHz, DMSO) δ 9.99(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 synthetic method is as in Example 18, and the yield is 81.96%.

¹ H NMR (400MHz, DMSO) δ 9.86 (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)propionamide (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 synthetic method is as in Example 18, and the yield is 81.6%.

¹ H NMR (400MHz, DMSO) δ 9.86 (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 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 synthetic method was as in Example 18, and the yield was 77.5%.

¹ H NMR (400MHz, DMSO) δ 9.68 (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-Proppiperidin-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 synthetic method is as in Example 18, and the yield is 79.5%.

¹ H NMR (400MHz, DMSO) δ 9.69(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 synthetic method is as in Example 18, and the yield is 80.9%.

¹ H 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).

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 synthetic method is as in Example 18, and the yield is 87.5%.

¹ H 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=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 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 synthetic method is as in Example 18, and the yield is 79.4%.

¹ H NMR (400MHz, DMSO) δ 9.96(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 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

The synthetic method is as in Example 18

¹ H 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). (79.6% yield)

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-methyl) ylpiperazin-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 synthetic method is as in Example 18, and the yield is 76.9%.

¹ H 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).

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-methyl) ylpiperazin-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 synthetic method is as in Example 18, and the yield is 79.85%.

¹ H NMR (400MHz, DMSO) δ 10.05 (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 synthetic method was as in Example 18, and the yield was 76.4%.

¹ H NMR (400 MHz, DMSO) δ 9.99 (s, 1H), 8.77 (s, 1H), 7.81 (s, 1H), 7.52 (d, J=4.1 Hz, 2H), 7.41 (d, J=10.1 Hz, 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-methyl) ylpiperazin-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 synthetic method was as in Example 18, and the yield was 74.1%.

¹ H 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).

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-methyl) ylpiperazin-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 synthetic method was as in Example 18, and the yield was 73%.

¹ H NMR (400MHz, DMSO) δ 10.05 (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 614.9 [M+H] ⁺ .

Example 69

(S)-8-(1-Acetyl-3-yl)-6-(furan-3-yl)-5-methyl-2-((3-methyl-4-(4-methylpiperazine) -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 synthetic method is as in Example 18, and the yield is 68.9%.

¹ H NMR (400MHz, DMSO) δ 9.99(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-methylpiperazine) -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 synthetic method is as in Example 18, and the yield is 58.5%.

¹ H NMR (400MHz, DMSO) δ 9.99(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-Propiperidin-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 synthetic method is as in Example 18, and the yield is 63.7%.

¹ H 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=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 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)

(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 synthetic method is as in Example 18, and the yield is 63.3%.

¹ H 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).

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-Proppiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (580124)

(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 synthetic method is as in Example 18, and the yield is 61.8%.

¹ H 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=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 632.3 [M+H] ⁺ .

Example 74

N-((1S,4S)-4-(6-(2-Chloro-5-fluorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazine- 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 synthetic method was as in Example 18, and the yield was 72.9%.

¹ H NMR (400MHz, DMSO) δ 9.94 (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-methylpiperazine- 1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)cyclohexyl)propionamide (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 synthetic method was as in Example 18, and the yield was 73.4%.

¹ H NMR (400MHz, DMSO) δ 9.94 (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-methylpiperazine- 1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)cyclohexyl)propionamide (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 synthetic method was as in Example 18, and the yield was 70.3%.

¹ H NMR (400MHz, DMSO) δ 9.94 (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 646.2 [M+H] ⁺ .

Example 77

N-((1S,4S)-4-(6-(2-Chloro-4-fluorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazine- 1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)cyclohexyl)propionamide (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 synthetic method is as in Example 18, and the yield is 70%.

¹ H NMR (400MHz, DMSO) δ 9.94 (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 646.3 [M+H] ⁺ .

Example 78

N-((1S,4S)-4-(6-(2-Chloro-3-fluorophenyl)-5-methyl-2-((3-methyl-4-(4-methylpiperazine- 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 synthetic method is as in Example 18, and the yield is 67.4%.

¹ H NMR (400MHz, DMSO) δ 9.94 (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=14.7 Hz, 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-methylpiperazine- 1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)cyclohexyl)pivalamide (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 synthetic method is as in Example 18, and the yield is 69.8%.

¹ H NMR (400MHz, DMSO) δ 9.94 (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)benzene yl)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 synthetic method was as in Example 18, and the yield was 73.3%.

¹ H NMR (400MHz, DMSO) δ 9.95 (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-methylpiperazine- 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 synthetic method is as in Example 18, and the yield is 70%.

¹ H NMR (400MHz, DMSO) δ 9.95 (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-methylpiperazine- 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 synthetic method is as in Example 18, and the yield is 64.1%.

¹ H NMR (400MHz, DMSO) δ 9.94 (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-methylpiperazine- 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 synthetic method is as in Example 18, and the yield is 71.4%.

¹ H NMR (400MHz, DMSO) δ 9.95 (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-methylpiperazine- 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 synthetic method is as in Example 18, and the yield is 67.5%.

¹ H 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), 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-methylpiperazine- 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 synthetic method is as in Example 18, and the yield is 65.2%.

¹ H 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), 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-methylpiperazine- 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 synthetic method is as in Example 18, and the yield is 67%.

¹ H NMR (400MHz, DMSO) δ 9.94 (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-methylpiperazine- 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 synthetic method is as in Example 18, and the yield is 66.48%.

¹ H NMR (400MHz, DMSO) δ 9.94 (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-Proppiperidin-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 synthetic method is as in Example 18, and the yield is 85.4%.

¹ H NMR (400 MHz, Chloroform-d) δ 8.83 (d, J=11.0 Hz, 1H), 8.04 (dd, J=20.7, 10.7 Hz, 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=13.4 Hz, 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)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 synthetic method is as in Example 18, and the yield is 67%.

¹ H NMR (400MHz, DMSO-d6) δ 10.22(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-proppiperidine -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 synthetic method is as in Example 18, and the yield is 87.2%.

¹ H NMR (400 MHz, DMSO-d6) δ 10.21 (d, J=18.1 Hz, 1H), 8.94 (d, J=2.9 Hz, 1H), 8.04 (d, J=2.9 Hz, 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-proppiperidin-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 synthetic method is as in Example 18, and the yield is 77.3%.

¹ H NMR (400MHz, DMSO-d6) δ 9.96 (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-Propionylpiperidine)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 synthetic method is as in Example 18, and the yield is 56.7%.

¹ H NMR (400MHz, DMSO-d6) δ 10.50 (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-propane) Acylpiperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (10901B)

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

The synthetic method was as in Example 18, and the yield was 81.2%.

¹ H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.93 (d, J=4.1 Hz, 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-Proppiperidin-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 synthetic method is as in Example 18, and the yield is 74.3%.

¹ H NMR (400MHz, DMSO-d6) δ 8.89 (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 yl-8-(1-propiperidin-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 synthetic method is as in Example 18, and the yield is 79.7%.

¹ H NMR (400MHz, DMSO-d6) δ 9.97 (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]undecane) -3-yl)phenyl)amino)-8-(1-proppiperidin-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-propionylpipidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one

The synthetic method is as in Example 18, and the yield is 76.7%.

¹ H NMR (400MHz, DMSO-d6) δ 9.98(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]nonan-2 -yl)phenyl)amino)-8-(1-proppiperidin-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-propionylpipidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one

The synthetic method is as in Example 18, and the yield is 66.9%.

¹ H NMR (400 MHz, DMSO-d6) δ 9.76 (s, 1H), 8.85 (d, J=3.2 Hz, 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=4.2 Hz, 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]pyrrole- 2(1H)-yl)phenyl)amino)-8-((S)-1-propiperidin-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 synthetic method is as in Example 18, the yield is 76.2%

¹ H NMR (400MHz, DMSO-d6) δ 10.05 (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 synthetic method is as in Example 18, and the yield is 57.8%.

¹ H NMR (400MHz, DMSO-d6) δ 9.95 (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=5.4 Hz, 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-Propiperidin-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 synthetic method is as in Example 18, and the yield is 53.9%.

¹ H NMR (400 MHz, DMSO-d6) δ 10.05 (d, J=60.9 Hz, 1H), 8.90 (d, J=5.1 Hz, 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-Propiperidin-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 synthetic method is as in Example 18, and the yield is 66.7%.

¹ H NMR (400MHz, DMSO-d6) δ 9.96 (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, 12.5 Hz, 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)benzene yl)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 synthetic method is as in Example 18, and the yield is 86.7%.

¹ H NMR (400 MHz, DMSO-d6) δ 9.99 (s, 1H), 8.91 (d, J=3.0 Hz, 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-propiperidin-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 synthetic method is as in Example 18, and the yield is 68.9%.

¹ H NMR (400 MHz, DMSO-d6) δ 10.05 (d, J=48.1 Hz, 1H), 8.91 (d, J=4.6 Hz, 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 synthetic method is as in Example 18, and the yield is 87%.

¹ H NMR (400MHz, DMSO-d6) δ 10.04 (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=5.6 Hz, 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-Proppiperidin-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 synthetic method was as in Example 18, and the yield was 73.4%.

¹ H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 9.28 (d, J=12.4 Hz, 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-Proppiperidin-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 synthetic method is as in Example 18, and the yield is 76.7%.

¹ H NMR (400MHz, DMSO-d6) δ 10.15 (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-Propiperidin-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 synthetic method is as in Example 18, and the yield is 86.7%.

¹ H NMR (400MHz, DMSO-d6) δ 10.26 (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-Proppiperidin-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 synthetic method is as in Example 18, and the yield is 63.7%.

¹ H NMR (400MHz, DMSO-d6) δ 10.12 (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-Proppiperidin-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 synthetic method is as in Example 18, and the yield is 84%.

1H NMR (400MHz, DMSO-d6) δ 9.92 (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-Proppiperidin-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 synthetic method is as in Example 18, and the yield is 68%.

¹ H NMR (400MHz, DMSO-d6) δ 10.15 (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-Proppiperidin-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 synthetic method is as in Example 18, and the yield is 56.7%.

¹ H NMR (400MHz, DMSO-d6) δ 9.97 (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-Propionylpiperidine)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 synthetic method is as in Example 18, and the yield is 69%.

¹ H NMR (400MHz, DMSO-d6) δ 10.51 (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 yl-8-(1-propiperidin-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 synthetic method is as in Example 18, and the yield is 58%.

¹ H NMR (400MHz, DMSO-d6) δ 10.06 (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-Proppiperidin-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 synthetic method is as in Example 18, and the yield is 64%.

¹ H NMR (400MHz, DMSO-d6) δ 9.98 (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-propane) Piperidin-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 synthetic method is as in Example 18, and the yield is 86%.

¹ H NMR (400 MHz, Chloroform-d) δ 8.69 (d, J=11.3 Hz, 1H), 7.54-7.46 (m, 1H), 7.34 (dq, J=8.5, 5.1, 3.2 Hz, 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, 13.4 Hz, 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-propane) Piperidin-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 synthetic method is as in Example 18, and the yield is 87%.

¹ H NMR (400MHz, DMSO-d6) δ 10.52 (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 synthetic method is as in Example 18, and the yield is 84.3%.

¹ H NMR (400 MHz, DMSO-d6) δ 9.72 (d, J=110.7 Hz, 1H), 8.88 (d, J=4.3 Hz, 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]pyrimidine-7(8H) - Ketone (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 synthetic method is as in Example 18, and the yield is 76%.

¹ H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 8.90 (d, J=3.6 Hz, 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 synthetic method was as in Example 18, and the yield was 77%.

¹ H NMR (400 MHz, DMSO-d6) δ 9.93 (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-(pipidin-4-yl)phenyl)amino)- 7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)cyclohexyl)propionamide

The synthetic method is as in Example 18, and the yield is 69%.

¹ H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.93 (s, 1H), 8.65 (d, J=11.2 Hz, 1H), 8.37 (d, J=11.7 Hz, 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)propionamide (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 synthetic method was as in Example 18, and the yield was 71%.

¹ H NMR (400MHz, DMSO-d6) δ 9.92 (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)propionamide (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 synthetic method is as in Example 18, and the yield is 65%.

1H NMR (400MHz, DMSO-d6) δ 10.13 (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)propionamide ( 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 synthetic method is as in Example 18, and the yield is 85%.

¹ H NMR (400MHz, DMSO-d6) δ 9.77(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 synthetic method was as in Example 18, and the yield was 83%.

¹ H NMR (400 MHz, DMSO-d6) δ 9.91 (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)propionamide (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 synthetic method was as in Example 18, and the yield was 82%.

¹ H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.91 (s, 1H), 7.60 (d, J=2.8 Hz, 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 synthetic method was as in Example 18, and the yield was 73%.

¹ H NMR (400MHz, DMSO-d6) δ 9.91 (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)propionamide (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 synthetic method was as in Example 18, and the yield was 81%.

¹ H NMR (400MHz, DMSO-d6) δ 9.87(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)propionamide (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 synthetic method was as in Example 18, and the yield was 79%.

¹ H NMR (400MHz, DMSO-d6) δ 10.18 (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=7.5 Hz, 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-methylbenzene yl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)cyclohexyl)propionamide (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 synthetic method was as in Example 18, and the yield was 77%.

¹ H NMR (400MHz, DMSO-d6) δ 9.92 (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 synthetic method was as in Example 18, and the yield was 82%.

¹ H NMR (400MHz, DMSO-d6) δ 9.85(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-methylpiperazine-1- yl)phenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)cyclohexyl)propionamide (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 synthetic method is as in Example 18, and the yield is 75%.

¹ H NMR (400MHz, DMSO-d6) δ 10.15 (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-diazacycle Hept-1-yl)phenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)cyclohexyl)propionamide (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 synthetic method is as in Example 18, the yield is 67%

¹ H NMR (400MHz, DMSO-d6) δ 10.13 (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-dimethylpiperazine -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 synthetic method was as in Example 18, and the yield was 74%.

¹ H NMR (400 MHz, DMSO-d6) δ 10.10 (d, J=32.1 Hz, 0H), 8.95 (s, 1H), 8.15-8.01 (m, 1H), 7.60 (d, J=5.8 Hz, 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-methyl) Piperazin-1-yl)piperidin-1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)cyclohexyl)propionamide (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 synthetic method is as in Example 18, and the yield is 86%.

¹ H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 8.91 (s, 1H), 7.59 (t, J=3.9 Hz, 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-methyl Phenyl)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 synthetic method is as in Example 18, and the yield is 67%.

¹ H NMR (400MHz, DMSO-d6) δ 9.92 (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

Kinase EC ₅₀ testing of compounds against EGFR wild-type, EGFR-L858R/T790M, EGFR-L858R/T790M/C797S mutations

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

Kinase activity detection: Z'-LYTE ^TM technology (detection by fluorescence, enzyme-coupled form, based on the difference in sensitivity of phosphorylated and non-phosphorylated polypeptides to proteolytic cleavage), using fluorescence resonance energy transfer (FRET) In principle, the kinase activity of the compound is detected by a secondary reaction using the ^Z'LYTE ™ FRET peptide substrate. (invitrogen, Z'-LYTE ^TM KINASE ASSAY KIT-TYR 2 PEPTIDE, PV3191) The EGFR-T790M kinase (invitrogen, PV4803) was diluted step by step, then FRET peptide, ATP were added, and then different concentrations of compounds were added. The site-specific protease recognizes and cleaves non-phosphorylated FRET peptides, reacts for 1 h, and detects absorption at 445 nm and 520 nm using an excitation wavelength of 400 nm.

_IC50 values were calculated by four-parameter fit of inhibition curves.

The inhibition rate was positively correlated with the drug concentration, and the relationship curve between the kinase activity and the concentration was drawn, and the IC ₅₀ value was calculated.

The compound numbers and corresponding kinase activity results are listed in Table 1.

Table 1 Compound kinase inhibitory activity

Example 137

In vitro proliferation inhibitory effects of compounds on BaF3 EGFRL858R/T790M/C797S tool cell lines

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

Method: sulforhodamine B (SRB) method, as follows: a certain number of different tumor cells in the logarithmic growth phase are inoculated in a 96-well culture plate, and after culturing the cells for 24 hours, different concentrations of the present invention are added. For test compounds, three replicate wells were set for each concentration, and DMSO solution control and cell-free zero-adjustment wells were set at corresponding concentrations. After the cells were treated with drugs for 72 h, the culture medium was poured out, 100 μL of ice-cold 10% trichloroacetic acid solution was added to fix the cells, placed at 4°C for 1 h, washed with distilled water for 5 times, and air-dried naturally. Then 100 μL of SRB (4 mg/mL) (Sigma, St Louis, MO, USA) solution was added, stained for 15 min at room temperature, removed the staining solution, washed with 1% glacial acetic acid for 5 times, and air-dried. Finally, 150 μL of 10 mM Tris solution (pH 10.5) was added, and the OD value was measured at a wavelength of 515 nm by a tunable wavelength microplate reader (VERSAmax ^™ , Molecular Device Corporation, Sunnyvale, CA, USA). The inhibition rate of drug on cell growth was calculated by the following formula: inhibition rate (%)=(OD control-OD added drug)/OD control×100%.

Based on the growth inhibitory effect of the compounds on these cells, we calculated the median inhibitory concentration (IC ₅₀ ) values as described in Table 2.

Table 2 Compound cell activity

The results showed that (see Table 2), the pyrimidopyridone or pyridopyrimidinone compounds of the present invention can significantly inhibit the proliferation of BaF3EGFRL858R/T790M/C797S cells, and the inhibition rate is positively correlated with the drug concentration.

Example 138

The pyrimidopyridone or the pyridopyridone compound of the present invention has a significant inhibitory effect on the activation of targets in EGFR ^{L858R/T790M/C797S} and EGFR ^{19D/T790M/C797S} tool cells.

Use conventional Western Blot (immunoblotting) for detection, as follows: BaF3-EGFR ^{L858R/T790M/C797S} cells and BaF3-EGFR ^{19D/T790M/C797S} cells in logarithmic growth phase are respectively seeded in 6-well plates in a certain number After culturing overnight in the incubator, change the serum-free medium to starvation for 24 hours, add a certain concentration of compounds for 2 hours, add EGF stimulating factor, 50ng/mL for 10 minutes, and lyse the cells with lysis buffer to collect samples. Then take an appropriate amount of samples for SDS-PAGE electrophoresis. After electrophoresis, the protein is transferred to a nitrocellulose membrane using a semi-dry electrotransfer system, and the nitrocellulose membrane is placed in a blocking solution (5% skimmed milk powder diluted in 0.1% Tween 20). TBS) was blocked at room temperature for 2 h, and then the membranes were respectively placed in primary antibody solution (1:500 diluted in TBS containing 0.1% Tween 20) and incubated overnight at 4°C. Wash three times with 0.1% Tween 20 in TBS for 15 min each. The membrane was placed in a secondary antibody solution (horseradish peroxidase-labeled goat anti-rabbit IgG, diluted 1:2000 in TBS containing 0.1% Tween 20) for 1 h at room temperature. After washing the membrane three times as above, the color was developed with ECL plus reagent and photographed with Image QuantLAS 4000. The results are shown in Figures 1-2.

It can be found from panel a in Figure 1 that compound 560082 inhibits the phosphorylation of EGFR ^{L858R /T790M/C797S} in the tool cells in a concentration-dependent manner. It can be found from panel b in Figure 1 that compound 560082 inhibits the phosphorylation of EGFR ^{19D/T790M/C797S} in the tool cells in a concentration-dependent manner.

It can be found from panel a in Figure 2 that compound 580120 concentration-dependently inhibits the phosphorylation of EGFR ^{L858R /T790M/C797S} in tool cells. From panel b in Figure 2, it can be found that compound 580120 concentration-dependently inhibits EGFR ^19D/ C797S in tool cells. Phosphorylation of ^T790M/C797S .

The technical features of the above-described embodiments can be combined arbitrarily. For the sake of brevity, all possible combinations of the technical features in the above-described embodiments are not described. However, as long as there is no contradiction between the combinations of these technical features, All should be regarded as the scope described in this specification.

The above-mentioned embodiments only represent several embodiments of the present invention, and the descriptions thereof are more specific and detailed, but should not be construed as a limitation on the scope of the invention patent. It should be pointed out that for those skilled in the art, without departing from the concept of the present invention, several modifications and improvements can be made, which all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the appended claims.

Claims (12)

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

Wherein, X can be selected from: N; W is optionally selected from: H, CH ₃ , C ₂ -C ₅ alkyl; L can be selected from:

and R ₁ is chosen from:

wherein, R ₄ is optionally selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; L can be selected from:

and R ₁ is optionally selected from: H or

wherein, R4 is optionally selected from methyl, ethyl, n _- propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, neopentyl, cyclopentyl, cyclopentyl Hexyl; R ₂ is chosen from:

wherein, n is 0; A ₁ , A ₂ , A ₃ , A ₄ , and A ₅ are independently selected from: hydrogen, chlorine, and fluorine; R ₃ is chosen from:

in, B ₁ , B ₂ , B ₄ , and B ₅ are independently selected from: H, chlorine, C ₁ -C ₃ alkyl, B ₃ is selected from: 4-methylpiperazin-1-yl, N-ethylpiperazinyl, 4-isopropylpiperazin-1-yl, piperidinyl, 9-methyl-3,9-di Azaspiro[5.5]undecan-3-yl, 3-methyl-1,3-diazepan-1-yl, (1S,4S)-5-methyl-2,5-di Azabicyclo[2.2.1]heptan-2-yl, (2-(dimethylamino)ethyl)(methyl)amino, 4-(dimethylamino)piperidin-1-yl, 7-methyl yl-2,7-diazaspiro[3.5]nonan-2-yl, (R)-3,4-dimethylpiperazin-1-yl, (S)-3,4-dimethylpiperyl Azin-1-yl, (3S,5R)-3,4,5-trimethylpiperazin-1-yl, (R)-3-methylpiperazin-1-yl, 4-(4-methyl piperazin-1-yl) piperidin-1-yl. 2. The pyrimidopyridone compound according to claim 1 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein L is selected from:

3. The pyrimidopyridone compound according to any one of claims 1-2 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein the compound has formula III, formula IV, formula Structure shown in V or VI:

4. The pyrimidopyridone compound according to any one of claims 1-2, or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein B is selected from: ₄ -methylpiperazine -1-base. 5. The pyrimidopyridone compound according to any one of claims 1-2 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein W is selected from: H, methyl, B ₁ , B ₂ , B ₄ , B ₅ are independently selected from: H, methyl, B ₃ are each independently optionally selected from: 4-methylpiperazin-1-yl, piperidinyl, 9-methyl-3,9-diazaspiro[5.5]undecan-3-yl, 3-methyl Alkyl-1,3-diazacycloheptan-1-yl, (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl, (2- (Dimethylamino)ethyl)(methyl)amino, 4-(dimethylamino)piperidin-1-yl, 7-methyl-2,7-diazaspiro[3.5]nonane-2 -yl, (R)-3,4-dimethylpiperazin-1-yl, (3S,5R)-3,4,5-trimethylpiperazin-1-yl, (R)-3-methyl piperazin-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:

7. Use of the pyrimidopyridone compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt or stereoisomer thereof in the preparation of a mutant EGFR inhibitor, wherein the mutant EGFR is EGFR ^L858R/T790M or EGFR ^{L858R/T790M/C797S} . 8 . Use of the pyrimidopyridone compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof in the preparation of a medicament for preventing and treating tumors. 9 . 9 . The use according to claim 8 , wherein the tumor is a malignant tumor with EGFR gene mutation. 10 . 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, kidney cancer, bladder cancer, ovarian cancer, colon cancer, rectal cancer, breast cancer , cervical cancer, lung cancer, laryngeal cancer, nasopharyngeal cancer, pancreatic cancer, multiple myeloma, B lymphoma, leukemia. The use according to claim 10, wherein the tumor is non-small cell lung cancer with EGFR ^{L858R/T790MC797S} mutation. 12. A pharmaceutical composition for preventing and treating tumors, wherein the active ingredient comprises the pyrimidopyridone compound according to any one of claims 1-6 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof body.

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