TW201605882A - Phosphorus-containing pyrido [2, 3-d] pyridine-7-ketone compound or pharmaceutically acceptable slat thereof, pharmaceutical composition and applications thereof - Google Patents

Abstract

The present invention provides a phosphorus-containing pyrido [2, 3-d] pyridine-7-ketone compound represented by formula (I) or a pharmaceutically acceptable slat thereof. This invention also discloses a preparation method of the compound, a pharmaceutical composition comprising the phosphorus-containing pyrido [2, 3-d] pyridine-7-ketone compound and applications thereof. The compound is a protein kinase (for example PI3K) inhibitor capable of treating diseases caused by abnormal activity of the protein kinase, such as a tumor.

Description

Phosphorous pyrido[2,3-d]pyrimidin-7-one compound or pharmaceutically acceptable salt thereof, pharmaceutical composition and use thereof

The present invention relates to the field of organic chemistry and medicinal chemistry, and in particular to a phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the same, and use thereof.

Protein kinase is a phosphotransferase that transfers the γ-phosphate group of ATP to a specific amino acid residue of a substrate to phosphorylate the protein and exert its physiological and biochemical functions. Protein kinase is an important kinase, and its main role in signal transduction is two aspects: one is to regulate the activity of protein through phosphorylation; the other is to gradually amplify the signal by step-by-step phosphorylation of the protein, causing the cell reaction.

Abnormal protein kinase activity is not only closely related to tumor proliferation, apoptosis, metastasis, etc., but also to a series of other human diseases related to inflammation or proliferative response. For example, rheumatoid arthritis, cardiovascular and nervous system diseases, asthma, psoriasis and the like. More than 400 human diseases are known to be directly or indirectly related to protein kinases, making protein kinases another important class of drug targets following G-protein coupled receptors.

The protein kinase family consists of more than 500 members and is usually classified into protein tyrosine kinases (PTKs) and serine-threonine kinases. According to the position of the kinase in the cell, it can be further divided into receptor kinases and non-receptor kinases, also known as intracellular kinases. Receptor kinases are generally tyrosine kinases, also known as receptor tyrosine kinases (RTKs), which are composed of extracellular, transmembrane, and intracytoplasmic, catalytically active kinases. Part of it is located in the cytoplasm. Most serine-threonine kinases are located in cells and are non-receptor kinases or cytosolic kinases.

Typical representatives of the RTKs family are growth factor receptors, with at least 19 subfamilies, and the following are several major subfamilies:

(a) HER family tyrosine receptor kinases, including EGFR (epithelial growth factor receptor), HER2, HER3 and HER4. EGFR is a target for the synthesis of small molecule drugs Tarceva ^® , Tykerb ^® and monoclonal antibody Erbitux ^® for non-small cell lung cancer.

(b) by insulin receptor (IR), insulin-like growth factor I receptor (IGF-1R) and insulin receptor-related receptor (insulin receptor-related) Composition of receptor or IRR). Among them, IGF-1R is a recognized anti-cancer target, but because it is too similar to IR, especially the intracellular kinase part, its amino acid sequence is 100% identical, inhibiting the activity of IGF-1R, usually inhibiting IR activity. . There is evidence that IR is also an effective anti-cancer target, but because IR inhibits the risk of elevated blood glucose, the use of IR inhibitors for anticancer needs to find a balance between benefits and safety risks.

(c) a family of platelet-derived growth factor receptors (PDGFRs), including PDGFR-α, PDGFR-β, CSF1R, c-KIT, and c-fms. Among them, c-KIT is also a molecular target of leukemia therapeutic drug Gleevec ^® for the treatment of gastrointestinal stromal tumors.

(d) a family of vascular endothelial growth factor receptors (VEGFRs), including FLT1 (Fms-like tyrosine kinase 1 or VEGFR1), KDR (or VEGFR-2), and FLT4 (or VEGFR3). Wherein the members Sutent ^® Naxavar ^® and molecular targets.

(e) a family of fibroblast growth factor receptors (FGFRs) including FGFR1, FGFR2, FGFR3 and FGFR4 and seven ligands FGF1, FGF2, FGF3, FGF4, FGF5, FGF6 and FGF7. Among them, members of the drug as molecular targets are still in clinical trials.

(f) MET family, including c-Met or human hepatocyte growth factor receptor (hHGFR) and RON. Among them, c-Met plays an important role in the growth and metastasis of initial tumors. Its molecular targets, Crizotinib and Cabozantinib, have been approved for the treatment of non-small cell lung cancer and medullary thyroid carcinoma, respectively.

(g) RET family, RET is a receptor for members of the GDNF family, and there are RET51, RET43 and RET9 isoforms. Its drug, Bobozantinib, has been approved for the treatment of medullary thyroid carcinoma.

(h) The Eph family is the largest family of tyrosine receptor kinases, consisting of 16 receptors (EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHA9, EPHA10, EPHB1, EPHB2, EPHB3, EPHB4 , EPHB5, EPHB6) and 9 ligands (EFNA1, EFNA2, EFNA3, EFNA4, EFNA5, EFNB1, EFNB2, EFNB3). These members play an important role in the development of animals, and some members play a role in the tumor.

Non-receptor kinases are absent from the extramembranous and transmembrane regions of the cell, and the entire kinase is in the cytoplasm. At least 24 non-receptor kinases are now known to be divided into 11 subfamilies, which are the Src, Frk, Btk, CsK, Abl, Zap70, Fes, Fps, Fak, Jak and AcK subfamilies. The Src subfamily is the largest, including Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, AUR1, AUR2, and Yrk kinase. For more detailed information, see Neet, K.; Hunter, T. Genes to Cells 1996, 1, 147-169 and the literature cited therein. Although several non-receptor kinases are tyrosine kinases, most non-receptor kinases are serine-threonine kinases. Several of these members are molecular targets for the leukemia therapeutics Gleevec ^® and Sprycel ^® .

PI3K (Phosphatidylinositide 3-kinase) is a family of lipid kinases involved in multiple cellular functions. These functions include cell growth, proliferation, differentiation, motility, survival, and intracellular trafficking (J. A. Engelman, Nat. Rev. Cancer 2009, 9, 550). The PI3K family is divided into three types based on primary structure, function, and specificity for lipid matrices: Type I, Type II, and Type III. Compared with type II and III, the most complete understanding of type I is currently available, and type I mainly plays a role in tumors. Type I PI3K is further divided into IA and IB subtypes according to the similarity of the amino acid sequence, and IA is a heterodimeric molecule comprising a regulatory subunit p85 (regulatory subunit) and a catalytic subunit p110 (catalytic subunit). The regulatory subunit p85 includes 5 variants, of which p85α is most expressed. There are three variants of the catalytic subunit p110, namely p110α, p110β and p110δ, which are expressed by the genes PIK3CA, PIK3CB and PIK3CD, respectively. Type IB PI3K consists of the regulatory subunit p101 and the catalytic subunit p110γ and is expressed by PIK3CAG. P110α and p110β are expressed in every cell, but p110δ is mainly expressed in leukocytes (CL Carpenter et al, J. Biol. Chem. 1990, 265, 19704. SJ Leevers et al, Curr. Opin. Cell Biol. 1999 , 11, 219. K. Okkenhaug, Ann. Rev. Immunol. 2013, 31, 675).

PI3K is initiated by receiving signals from tyrosine receptor kinases, G-protein coupled receptors (GPCRs), and activated RAS. P110 then interacts with phospholipid membranes to make inositol PIP2 in phospholipids. Phosphorylation produces PIP3. This process initiates a variety of downstream proteins that play a crucial role in tumors. The production and amount of PIP3 are strictly controlled by tumor suppressor proteins, phosphatases and PTEN (I. Brana and L. L. Siu BMC Med. 2012, 10, 161).

Many tumors are caused by the loss of control of the PI3K signaling pathway. A common mechanism is an increase in mutation or gene expression of PI3KCA, deletion of the tumor suppressor protein PTEN, hyperactivation by tyrosine receptor kinase or initiation of mutation. The PI3K-delta inhibitor Idelalisib has been approved by the FDA for the treatment of chronic lymphocytic leukemia (CLL), recurrent follicular B-cell non-Hodgkin's lymphoma and small lymphocytic lymphoma.

In addition to its role in tumors, PI3K also plays an important role in immune function. PI3K-γ and PI3K-δ subtypes are mainly expressed in immune cells and are associated with various inflammation, autoimmune and blood diseases. Blockade of PI3K-[gamma] and PI3K-[delta] activity will play a role in the treatment of diseases such as arthritis, bronchitis, lupus erythematosus (D. G. Winkler et al Chem. Biol. 2013, 20, 1364 and the literature cited therein).

mTOR is a serine/threonine kinase encoded by the human MTOR gene and belongs to the PI3K kinase family. mTOR plays a regulatory role in cell growth, proliferation, exercise, survival, protein synthesis, and transcription (N. Hay and N. Sonenberg, Genes Dev. 2004, 18, 1926.). mTOR is a catalytic subunit of two complexes with different structures, mTORC1 and mTORC2 (S. Wullschleger et al, Cell 2006, 124, 471.). Several mTOR inhibitors have been approved for clinical treatment of cancer (eg, temsirolimus, everolimus, etc.), anti-organ transplant rejection (ie, rapamycin), and the like.

WO2005113556A1 reports a series of quinazolinones as human PI3K-kinase inhibitors. WO2011146882A1 reports a series of isoquinolin-1-ones as PI3K kinase inhibitors. WO2007084786A1 reports a series of pyrimidine PI3K kinase inhibitors. WO2006122806A2 reports a series of imidazoquinolines as PI3K/mTOR kinase inhibitors. WO2008032162A1 reports a series of pyrido[2,3-d]pyrimidinones as PI3K/mTOR kinase inhibitors. WO2008144464A1 reports a series of quinoline compounds as PI3K/mTOR kinase inhibitors.

As mentioned above, receptor kinases and non-receptor kinases have been well documented in clinical and practical applications as anti-tumor targets, and several anti-tumor drugs have been approved for market treatment of patients. In addition to tumor therapy, inhibition of the aberrant activity of receptor kinases and non-receptor kinases can also be used to treat diseases including, but not limited to, psoriasis or psoriasis, cirrhosis, diabetes, bronchitis, lupus erythematosus, involving angiogenesis. Diseases, diseases involving restenosis, eye diseases, age-related macular degeneration, rheumatoid arthritis and other inflammations, immune system diseases such as autoimmune diseases, cardiovascular diseases such as atherosclerosis, kidney diseases, and the like. Therefore, it is necessary to continue to develop inhibitors of these kinases.

A first object of the present invention is to provide a phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound having a protein kinase (especially PI3K, mTOR, etc.) inhibitory activity or a pharmaceutically acceptable salt thereof , as well as its racemates or enantiomers.

A second object of the present invention is to provide a phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound or a pharmaceutically acceptable salt thereof, and a racemate or enantiomer thereof Pharmaceutical composition.

A third object of the present invention is to provide a phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound or a pharmaceutically acceptable salt thereof, and a racemate or an enantiomer thereof Use in the preparation of a medicament for the treatment of a disease caused by abnormal activity of a protein kinase.

To achieve the above object, the present invention adopts the following technical solutions:

A phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound or a pharmaceutically acceptable salt thereof, which has a molecular structural formula as shown in formula (I):

In the formula,

Ar is an aryl or heteroaryl group, and the hydrogen in Ar may be substituted by 1 to 5 identical or different G ¹ ;

X is CR ¹ or N;

A represents C _1-6 alkyl, C=O or a covalent bond, and when A is a C _1-6 alkyl group, the hydrogen therein may be substituted by 1 to 5 identical or different G ² ;

L represents O, NR ² , S(=O) _m or a covalent bond;

J represents a C _1-6 alkyl group or a covalent bond, and the hydrogen in J may be substituted by 1 to 5 identical or different G ³ ;

R and R' each independently represent H, OH, halogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-12 heteroalicyclic, C _1-6 alkoxy, C _{3-6 a cycloalkoxy group} or a C _3-12 heteroaliphatic epoxy group, and the hydrogen in R and R′ may be substituted by 1 to 5 identical or different G ⁴ , and R and R′ may also form together with the connected phosphorus atom. C _3-12 heterocycloaliphatic, C _3-12 said heteroalicyclic may additionally contain one or more O, N or S (= O) _m heteroatoms;

among them:

G ¹ , G ² , G ³ and G ⁴ each independently represent H, -CN, -CF ₃ , -OCF ₃ , -NO ₂ , halogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C ₆ aryl, C _5-6 heteroaryl, C _3-12 heteroalicyclic, R ³ O-, R ³ R ⁴ N-, R ³ S (=O) _m -, R ³ R ⁴ NS(=O) _m -, R ⁵ C(=O)-, R ³ R ⁴ NC(=O)-, R ³ OC(=O)-, R ⁵ C(=O)O-, R ³ R ⁴ NC(=O)O-, R ⁵ C(=O)NR ³ -, R ³ R ⁴ NC(=O)NR ⁶ -, R ³ OC(=O )NR ⁶ -, R ³ S(=O) _m NR ⁶ -, R ³ R ⁴ NS(=O) _m NR ⁶ -, R ³ R ⁴ NC(=NR ⁷ )NR ⁶ -, R ³ R ⁴ NC (=CHNO ₂ )NR ⁶ -, R ³ R ⁴ NC(=N-CN)NR ⁶ -, R ³ R ⁴ NC(=NR ⁷ )-, R ³ S(=O)(=NR ⁷ )NR ⁶ -or R ³ R ⁴ NS(=O)(=NR ⁷ )-;

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ each independently represent H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{3- a 6} cycloalkyl group, a C ₆ aryl group, a C _5-6 heteroaryl group or a C _3-12 heteroalicyclic group; when R ³ and R ^{4 are} bonded to the same nitrogen atom, a C may be formed together with the nitrogen atom _3-12 heterocycloaliphatic, C _3-12 heterocycloaliphatic this may additionally contain one or more O, N or S (= O) _m hetero atoms; and ^{R 1, R 2, R 3} , R 4, R ⁵ , the hydrogen in R ⁶ and R ⁷ may be substituted by 1 to 5 identical or different halogen, -CN, -OH, C _1-6 alkyl or C _3-6 cycloalkyl;

m is 0, 1, or 2.

Among them, it is preferred that the structure of the phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound is as shown in the formula (Ia) or (Ib):

As stated in the formula,

R ¹ represents hydrogen or C _1-6 alkyl;

A represents C _1-6 alkyl, C=O or a covalent bond, and when A is a C _1-6 alkyl group, the hydrogen therein may be substituted by 1 to 5 identical or different G ² ;

L represents O, NR ² or S(=O) _m or a covalent bond;

J represents a C _1-6 alkyl group or a covalent bond, and the hydrogen in J may be substituted by 1 to 5 identical or different G ³ ;

m, G ¹ , G ² , G ³ , R, R' and R ² are as defined above.

Or the structure of the phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound is as shown in formula (Ic) or (Id):

As stated in the formula,

G ¹¹ represents hydrogen, halogen, -OCF ₃ , -CF ₃ , -CN, -NMe ₂ , C _1-6 alkyl or C _1-6 alkoxy;

L represents O or NR ² ;

J represents a C _1-6 alkyl group, and the hydrogen in J may be substituted by 1 to 5 identical or different G ³ ;

RR and R'R' independently represent -OH, halogen, C _1-6 alkyl or C _1-6 alkoxy, respectively, and the hydrogens in RR and R'R' may be the same or different from 1 to 5 The G ⁴ substitution, RR and R'R' may also form a C _3-12 heteroalicyclic ring together with the associated phosphorus atom, and the C _3-12 heteroalicyclic ring may additionally comprise one or more O, N or S ( =O) _m heteroatom;

m, G ³ , G ⁴ and R ² are as defined above.

Or the structure of the phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound is as shown in the formula (Ie) or (If):

As stated in the formula,

G ¹¹ represents hydrogen, halogen, -OCF ₃ , -CF ₃ , -CN, -NMe ₂ , C _1-6 alkyl or C _1-6 alkoxy;

A represents C=O or C _1-6 alkyl, and when A is C _1-6 alkyl, the hydrogen therein may be substituted by 1 to 5 identical or different G ² ;

L represents O or NR ² ;

J represents a C _1-6 alkyl group, and the hydrogen in J may be substituted by 1 to 5 identical or different G ³ ;

RR and R'R' independently represent -OH, halogen, C _1-6 alkyl or C _1-6 alkoxy, respectively, and the hydrogens in RR and R'R' may be the same or different from 1 to 5 The G ⁴ substitution, RR and R'R' may also form a C _3-12 heteroalicyclic ring together with the associated phosphorus atom, and the C _3-12 heteroalicyclic ring may additionally comprise one or more O, N or S ( =O) _m heteroatom;

m, G ² , G ³ , G ⁴ and R ² are as defined above.

And or the structure of the phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound is as shown in the formula (Ig):

As stated in the formula,

G ¹¹ represents hydrogen, halogen, -OCF ₃ , -CF ₃ , -CN, -NMe ₂ , C _1-6 alkyl or C _1-6 alkoxy;

J represents a C _1-6 alkyl group, and the hydrogen in J may be substituted by 1 to 5 identical or different G ³ ;

RR and R'R' independently represent -OH, halogen, C _1-6 alkyl or C _1-6 alkoxy, respectively, and the hydrogens in RR and R'R' may be the same or different from 1 to 5 The G ⁴ substitution, RR and R'R' may also form a C _3-12 heteroalicyclic ring together with a linked phosphorus atom, and the C _3-12 heteroalicyclic ring may additionally contain one or more O, N or S (= O) _m heteroatom;

m, G ³ and G ⁴ are as defined above.

Wherein the pharmaceutically acceptable salt of the various compounds of the formula defined by the present invention is a phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound and an inorganic acid, an organic acid, an inorganic base or an organic base. a salt formed by a chemical reaction.

The above salts retain the biological activity of the compounds described herein. The inorganic or organic acid may be: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, perchloric acid, acetic acid, citric acid, oxalic acid, lactic acid, malic acid, salicylic acid, tartaric acid. , methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, substituted benzenesulfonic acid (for example, p-toluenesulfonic acid), isonicotinic acid, oleic acid, capric acid, pantothenic acid, ascorbic acid , succinic acid, maleic acid, gentisic acid, fumaric acid, gluconic acid, uronic acid, gluconic acid or sucrose, formic acid, benzoic acid, glutamic acid, pamoic acid, sorbic acid, etc.; The inorganic or organic base may be: sodium hydroxide, potassium hydroxide, lithium hydroxide, iron hydroxide, calcium hydroxide, barium hydroxide, aluminum hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, and hydroxide. Organic quaternary ammonium salt, sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate, barium carbonate, magnesium carbonate, carbonated organic quaternary ammonium salt, sodium hydrogencarbonate, potassium hydrogencarbonate, lithium hydrogencarbonate, calcium hydrogencarbonate, barium hydrogencarbonate, Magnesium bicarbonate, hydrogenated organic quaternary ammonium salt, methylamine, dimethylamine, trimethylamine, ethylamine , diethylamine, triethylamine, trishydroxymethylaminomethane, and the like.

A more preferred phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound or a pharmaceutically acceptable salt thereof is any one of the following compounds: trans-2-amino-8-[4-(two Ethoxyphosphonylmethoxy)cyclohexyl]-6-(6-methoxy-3-pyridyl)-4-methylpyridine[2,3-d]pyrimidin-7-one; cis- 2-amino-8-[4-(diethoxyphosphonylmethoxy)cyclohexyl]-6-(6-methoxy-3-pyridyl)-4-methylpyridine [2,3- d]pyrimidin-7-one; trans-2-amino-8-[4-(diethoxyphosphonylmethylamino)cyclohexyl]-6-(6-methoxy-3-pyridyl)- 4-methylpyridine [2,3-d]pyrimidin-7-one; cis-2-amino-8-[4-(diethoxyphosphoniummethylamino)cyclohexyl]-6-(6- Methoxy-3-pyridyl)-4-methylpyridine[2,3-d]pyrimidin-7-one; trans-4-[2-amino-6-(6-methoxy-3-pyridine yl) -4-methyl-7-yloxy pyridine [2,3-d] pyrimidin-8-yl] - N - (diethoxyphosphoryl acyl methyl) cyclohexyl methyl Amides; cis-4 - [2-amino-6- (6-methoxy-3-pyridyl) methyl-7-yloxy pyridine [2,3-d] pyrimidin-8-yl] - N - (diethylamino Oxyphosphorylmethyl)cyclohexylcarbamide; trans-2-amino-8-[4-(diethoxyphosphonylmethoxymethyl)cyclohexane ] -6- (6-methoxy-3-pyridyl) -4-methyl-pyridine [2,3- d] pyrimidin-7-one; cis-2-amino-8- [4- (diethylamino Oxylphosphonium methoxymethyl)cyclohexyl]-6-(6-methoxy-3-pyridyl)-4-methylpyridine [2,3- d ]pyrimidin-7-one; 2- Amino-8-[1-(diethoxyphosphoniummethyl)-4-oxaridinyl]-6-(6-methoxy-3-pyridyl)-4-methylpyridine [2,3 - d ] pyrimidin-7-one; trans-2-amino-8-[4-(diethoxyphosphonylmethoxy)cyclohexyl]-6-(6-dimethylamino-3-pyridyl -4-methylpyridine [2,3-d]pyrimidin-7-one; cis-2-amino-8-[4-(diethoxyphosphonylmethoxy)cyclohexyl]-6- (6-dimethylamino-3-pyridyl)-4-methylpyridine [2,3-d]pyrimidin-7-one; trans-2-amino-8-[4-(diethoxyphosphonium) Methylamino)cyclohexyl]-6-(6-dimethylamino-3-pyridyl)-4-methylpyridine[2,3-d]pyrimidin-7-one; cis-2-amino-8- [4-(Diethoxyphosphoniummethylamino)cyclohexyl]-6-(6-dimethylamino-3-pyridyl)-4-methylpyridine [2,3-d]pyrimidin-7-one Trans-4-[2-amino-6-(6-dimethylamino-3-pyridyl)-4-methyl-7-oxypyridine [2,3-d]pyrimidin-8-yl]- N - (diethoxyphosphoryl acyl methyl) cyclohexyl group A Amine; cis-4-[2-amino-6-(6-dimethylamino-3-pyridyl)-4-methyl-7-oxypyridine [2,3-d]pyrimidin-8-yl] - N- (diethoxyphosphonylmethyl)cyclohexylcarbamide; trans-2-amino-8-[4-(diethoxyphosphonylmethoxymethyl)cyclohexyl]- 6-(6-Dimethylamino-3-pyridyl)-4-methylpyridine [2,3- d ]pyrimidin-7-one; cis-2-amino-8-[4-(diethoxy) Phosphonylmethoxymethyl)cyclohexyl]-6-(6-dimethylamino-3-pyridyl)-4-methylpyridine [2,3- d ]pyrimidin-7-one; 2-amino- 8-[1-(Diethoxyphosphonylmethyl)-4-oxaridinyl]-6-(6-dimethylamino-3-pyridyl)-4-methylpyridine [2,3- d Pyrimidine-7-one; trans-2-amino-8-[4-(diethoxyphosphonylmethoxy)cyclohexyl]-6-(6-ethyl-3-pyridyl)-4 -methylpyridine [2,3-d]pyrimidin-7-one; cis-2-amino-8-[4-(diethoxyphosphoniummethoxy)cyclohexyl]-6-(6- Ethyl-3-pyridyl)-4-methylpyridine[2,3-d]pyrimidin-7-one; trans-2-amino-8-[4-(diethoxyphosphonylmethylamino) Cyclohexyl]-6-(6-ethyl-3-pyridyl)-4-methylpyridine[2,3-d]pyrimidin-7-one; cis-2-amino-8-[4-(two Ethoxyphosphonium methylamino) ring 6-(6-ethyl-3-pyridyl)-4-methylpyridine [2,3-d]pyrimidin-7-one; trans-2-amino-8-[4-(di-B Oxylphosphonium methoxy)cyclohexyl]-6-(6-methylamino-3-pyridyl)-4-methylpyridine[2,3-d]pyrimidin-7-one; cis-2- Amino-8-[4-(diethoxyphosphonylmethoxy)cyclohexyl]-6-(6-methylamino-3-pyridyl)-4-methylpyridine [2,3-d]pyrimidine -7-ketone; trans-2-amino-8-[4-(diethoxyphosphoniummethylamino)cyclohexyl]-6-(6-methylamino-3-pyridyl)-4-methyl Pyridine [2,3-d]pyrimidin-7-one; cis-2-amino-8-[4-(diethoxyphosphonylmethylamino)cyclohexyl]-6-(6-methylamino-3 -pyridyl)-4-methylpyridine[2,3-d]pyrimidin-7-one; trans-2-amino-8-[4-(diethoxyphosphonylmethyl(methyl)amino Cyclohexyl]-6-(6-methoxy-3-pyridyl)-4-methylpyridine[2,3-d]pyrimidin-7-one; cis-2-amino-8-[4- (Diethoxyphosphonylmethyl(methyl)amino)cyclohexyl]-6-(6-methoxy-3-pyridyl)-4-methylpyridine [2,3-d]pyrimidin-7 -ketone; trans-2-amino-8-[4-(diethoxyphosphonylmethyl(ethyl)amino)cyclohexyl]-6-(6-methoxy-3-pyridyl)- 4-methylpyridine [2,3-d]pyrimidin-7-one ; cis-2-amino-8-[4-(diethoxyphosphonylmethyl(ethyl)amino)cyclohexyl]-6-(6-methoxy-3-pyridyl)-4- Methylpyridine [2,3-d]pyrimidin-7-one; trans-2-amino-8-[4-(diethoxyphosphonylmethyl(n-propyl)amino)cyclohexyl]-6 -(6-methoxy-3-pyridyl)-4-methylpyridine[2,3-d]pyrimidin-7-one; cis-2-amino-8-[4-(diethoxyphosphorus) Mercaptomethyl (n-propyl)amino)cyclohexyl]-6-(6-methoxy-3-pyridyl)-4-methylpyridine[2,3-d]pyrimidin-7-one; trans -2-amino-8-[4-(diethoxyphosphonylmethyl(isopropyl)amino)cyclohexyl]-6-(6-methoxy-3-pyridyl)-4-methyl Pyridine [2,3-d]pyrimidin-7-one; cis-2-amino-8-[4-(diethoxyphosphonylmethyl(isopropyl)amino)cyclohexyl]-6-( 6-methoxy-3-pyridyl)-4-methylpyridine [2,3-d]pyrimidin-7-one; trans-2-amino-8-[4-(diethoxyphosphonium) Methyl(cyclopropyl)amino)cyclohexyl]-6-(6-methoxy-3-pyridyl)-4-methylpyridine[2,3-d]pyrimidin-7-one; cis-2 -amino-8-[4-(diethoxyphosphonylmethyl(cyclopropyl)amino)cyclohexyl]-6-(6-methoxy-3-pyridyl)-4-methylpyridine [ 2,3-d]pyrimidin-7-one Trans-8-[4-(diethoxyphosphonylmethoxy)cyclohexyl]-2-(2,5-dimethylpyrrol-1-yl)-6-(6-methoxy- 3-pyridyl)-4-methylpyridine [2,3-d]pyrimidin-7-one; cis-8-[4-(diethoxyphosphonylmethoxy)cyclohexyl]-2- (2,5-Dimethylpyrrol-1-yl)-6-(6-methoxy-3-pyridyl)-4-methylpyridine[2,3-d]pyrimidin-7-one; trans 8-(4-(diethoxyphosphoniummethylamino)cyclohexyl]-2-(2,5-dimethylpyrrol-1-yl)-6-(6-methoxy-3-pyridine 4-methylpyridine [2,3-d]pyrimidin-7-one; trans-[4-[2-amino-6-(6-methoxy-3-pyridyl)-4-methyl -7-oxy-pyrido[2,3-d]pyrimidin-8-yl]cyclohexyloxy]methyl-ethoxy-phosphoric acid; cis-[4-[2-amino-6-( 6-methoxy-3-pyridyl)-4-methyl-7-oxy-pyrido[2,3-d]pyrimidin-8-yl]cyclohexyloxy]methyl-ethoxy-phosphoric acid Trans-[4-[2-Amino-6-(6-methoxy-3-pyridyl)-4-methyl-7-oxy-pyrido[2,3-d]pyrimidine-8- Cyclohexyloxy]methyl-phosphoric acid; cis-[4-[2-amino-6-(6-methoxy-3-pyridyl)-4-methyl-7-oxy-pyridine [2,3-d]pyrimidin-8-yl]cyclohexyloxy]methyl-phosphoric acid; trans-[[4-[2-amino-6-(6- Oxy-3-pyridyl)-4-methyl-7-oxy-pyrido[2,3-d]pyrimidin-8-yl]cyclohexyl]amino]methyl-ethoxy-phosphoric acid; cis -[[4-[2-amino-6-(6-methoxy-3-pyridyl)-4-methyl-7-oxy-pyrido[2,3-d]pyrimidin-8-yl] Cyclohexyl]amino]methyl-ethoxy-phosphoric acid; trans-[[4-[2-amino-6-(6-methoxy-3-pyridyl)-4-methyl-7-oxyl -pyrido[2,3-d]pyrimidin-8-yl]cyclohexyl]amino]methyl-phosphoric acid or cis-[[4-[2-amino-6-(6-methoxy-3-pyridine) 4-methyl-7-oxy-pyrido[2,3-d]pyrimidin-8-yl]cyclohexyl]amino]methyl-phosphoric acid.

Any of the above-mentioned phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compounds or their racemates or enantiomers of pharmaceutically acceptable salts is also a technical solution of the present invention.

The cis or trans isomer of any of the above-mentioned phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compounds or their pharmaceutically acceptable salts is also a technical solution of the present invention.

The present invention also claims the above-mentioned phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound or a racemate or enantiomer thereof in a pharmaceutically acceptable salt, wherein Preparing a phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound or a pharmaceutically acceptable salt thereof, the racemate and the corresponding isomer thereof can be obtained by a conventional technique, It is also foreseen by those skilled in the art that the racemates and corresponding isomers also have the same/similar activity.

The present invention also protects the above synthetic intermediate (IIa), (IIb) or (IIc) of the phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound:

In the formula,

Ar 'is an aryl or heteroaryl group and Ar' is hydrogen may be 1-5 identical or different substituents R ^8;

R ² represents H, C _1-6 alkyl, C _3-6 cycloalkyl or C _3-12 heteroalicyclic; and the hydrogen in R ² may be 1 to 5 identical or different halogen, -CN, -OH, C _1-6 alkyl or C _3-6 cycloalkyl substituted;

R and R' each independently represent H, OH, halogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-12 heteroalicyclic, C _1-6 alkoxy, C _{3-6 cycloalkoxy,} or C _3-12 heteroaliphatic epoxy group, and R and R 'are hydrogen may be 1-5 identical or different substituents R ^9, R and R' may form together with the phosphorus atom of the C _3-12 heterocycloaliphatic, C _3-12 said heteroalicyclic may additionally contain one or more O, N or S (= O) _m heteroatoms;

among them:

R ⁸ and R ⁹ each independently represent H, -CN, -CF ₃ , -OCF ₃ , -NO ₂ , halogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-12 heteroalicyclic ring a group, a C _1-6 alkoxy group, a C _{1-6 cycloalkoxy group} , a C _3-12 heteroaliphatic group or R ¹⁰ R ¹¹ N-. Wherein R ¹⁰ and R ¹¹ each independently represent H, C _1-6 alkyl, C _3-6 cycloalkyl or C _3-12 heteroalicyclic. When R ¹⁰ and R ^{11 are} bonded to the same nitrogen atom, a C _3-12 heteroalicyclic ring may be formed together with the nitrogen atom, and the C _3-12 heteroalicyclic ring may additionally contain one or more O, N or S(=O) _m heteroatom;

m is 0, 1, or 2.

Or a synthetic intermediate as shown by structural formula (IIaa), (IIbb) or (IIcc):

As stated in the formula,

R ² represents hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl or C _3-12 heteroalicyclic, preferably hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, anthracene Pyridyl, pyridazinyl or morpholinyl, further preferably hydrogen, methyl, ethyl, n-propyl, ethylpropyl, cyclopropyl, oxetanyl, tetrahydrofuranyl or tetrahydropyranyl, Further preferred are hydrogen, methyl, ethyl, isopropyl, cyclopropyl, and these groups may be substituted by 1 to 5 halogens, -CN, -OH or C _1-6 alkyl;

R ⁸⁸ represents hydrogen, halogen, -OCF ₃ , -CF ₃ , -CN, -NMe ₂ , C _1-6 alkyl or C _1-6 alkoxy, preferably halogen, -OCF ₃ , -OCH ₃ , - OCH ₂ CH ₃ or -NMe ₂ , further preferably -OCH ₃ or -NMe ₂ ;

R ¹² and R ¹³ each independently represent -OH, halogen, C _1-6 alkyl or C _1-6 alkoxy, preferably -OH or C _1-6 alkoxy, further preferably C _1-6 alkane The oxy group is still more preferably a methoxy group, an ethoxy group, a n-propoxy group or an isopropoxy group.

The present invention provides a method for preparing the above phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound and a synthetic intermediate thereof. As an embodiment, the method can be carried out by the reaction scheme 1A and/or the reaction scheme. The composition of the steps shown in 1B (for example, the reaction scheme 1A illustrates the preparation method of the partially synthesized intermediate, and the reaction scheme 1A + the reaction scheme 1B shows a part of the phosphorus-containing pyrido[2,3-d]pyrimidin-7-one The preparation method of the compound, the reaction scheme 1B shows the method for preparing the phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound directly from the above synthetic intermediate, the same as below:

Wherein, Ar, R and R' have the same meanings as defined above (see the definition of each substituent in the compound of the formula (I)). M includes, but is not limited to, Li, Zn, ZnCl, ZnBr, ZnI, MgCl, MgBr, MgI, B(OH) ₂ , B(OMe) ₂ , B(OEt) ₂ , B (bipinol borate) )), BF ₃ K, Sn(Bu- n ) ₄ , SnMe _4, and the like. LG represents a leaving group including, but not limited to, F, Cl, Br, I, MsO, p- TsO, TfO, PhSO _3, and the like. The meaning of Pd catalysts, bases and solvents is described in the "Definition of Terms" section. Compound A-1 can be prepared according to WO2008032162.

A process for the preparation of a phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound consisting of the steps shown in Reaction Scheme 2A and/or Reaction Scheme 2B:

Wherein, Ar, R ² , R and R' have the same meanings as defined above (see the definition of each substituent in the compound of the formula (I)). W represents an amino group or a 2,5-dimethylpyrrol-1-yl group. The meanings of oxidizing agents, reducing agents, bases and solvents are given in the "Definition of Terms" section.

A process for the preparation of a phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound consisting of the steps shown in Reaction Scheme 3A and/or Reaction Scheme 3B:

Wherein, Ar, R ² , R and R' have the same meanings as defined above (see the definition of each substituent in the compound of the formula (I)). M includes, but is not limited to, Li, Zn, ZnCl, ZnBr, ZnI, MgCl, MgBr, MgI, B(OH) ₂ , B(OMe) ₂ , B(OEt) ₂ , B (bi-fractional borate), BF ₃ K, Sn(Bu- n ) ₄ , SnMe _4, and the like. The meaning of Pd catalysts, coupling reagents, bases and solvents is described in the "Definition of Terms" section.

A process for the preparation of a phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound consisting of the steps shown in Reaction Scheme 4A and/or Reaction Scheme 4B:

Wherein, Ar, R and R' have the same meanings as defined above (see the definition of each substituent in the compound of the formula (I)). M includes, but is not limited to, Li, Zn, ZnCl, ZnBr, ZnI, MgCl, MgBr, MgI, B(OH) ₂ , B(OMe) ₂ , B(OEt) ₂ , B (bi-fractional borate), BF ₃ K, Sn(Bu- n ) ₄ , SnMe _4, and the like. LG represents a leaving group including, but not limited to, F, Cl, Br, I, MsO, p- TsO, TfO, PhSO _3, and the like. The meaning of Pd catalysts, bases and solvents is described in the "Definition of Terms" section.

A process for the preparation of a phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound consisting of the steps shown in Reaction Scheme 5A and/or Reaction Scheme 5B:

Wherein, Ar, R and R' have the same meanings as defined above (see the definition of each substituent in the compound of the formula (I)). M includes, but is not limited to, Li, Zn, ZnCl, ZnBr, ZnI, MgCl, MgBr, MgI, B(OH) ₂ , B(OMe) ₂ , B(OEt) ₂ , B (bi-fractional borate), BF ₃ K, Sn(Bu- n ) ₄ , SnMe _4, and the like. LG represents a leaving group including, but not limited to, F, Cl, Br, I, MsO, p- TsO, TfO, PhSO _3, and the like. The meaning of Pd catalysts, acids, bases and solvents is described in the "Definition of Terms" section.

The present invention also contemplates a pharmaceutical composition comprising the above phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound or a pharmaceutically acceptable salt thereof, or a racemate or enantiomer thereof .

The pharmaceutical composition of the present invention can be used for the treatment of diseases caused by abnormal activities of protein kinases. In addition to the above active ingredients, the pharmaceutical compositions of the present invention also include one or more carriers or diluents which are pharmaceutically acceptable.

Formulation forms of the pharmaceutical compositions of the present invention include, but are not limited to, oral, injection, anal sputum, nasal inhalation, eye drops or skin patches.

The pharmaceutical composition consisting of the compound of the present invention is useful for treating a disease caused by abnormal activity of a protein kinase in a mammal, such as a human patient.

The compounds of the invention (including racemates, enantiomers, cis-trans isomers and other stereoisomers) or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof A formulation process, prepared with a suitable pharmaceutically acceptable carrier and a pharmaceutically acceptable adjuvant, is a pharmaceutical composition that facilitates administration.

Specifically, the drug administration route composed of the compound of the present invention may be: (1) oral: such as tablets, capsules, etc.; (2) injection: for example, intravenous injection, subcutaneous injection, intramuscular injection, eye injection, intraperitoneal injection (3) anal plug: for example, suppository, gel, etc.; (4) nostril inhalation: for example, spray, aerosol, etc.; (5) eye drops; (6) skin patch. Drug release systems, such as liposomes, sustained release techniques, and the like, may also be used, with the preferred methods being oral and injectable, with the preferred method being oral.

The various dosage forms of the pharmaceutical compositions of the present invention consisting of the compounds can be prepared by methods commonly used in the pharmaceutical industry, for example, mixing, dissolving, granulating, grinding, emulsifying, capsule, sugar coating, freeze drying, reconstituted spray, and the like.

The content of the compound of the present invention in the aforementioned pharmaceutical composition ranges from 0.001 to 100%. The pharmaceutical composition is administered to a mammal, including a human, at an effective dose of from 0.1 to 500 mg per kilogram of body weight per day, and an optimized dose of from 1 to 100 mg per kilogram of body weight per day. Within this effective dosage range, the compounds of the invention exert their pharmacological effects of inhibiting protein kinase activity and treating diseases (e.g., cancer) caused by abnormal protein kinase activity.

The frequency of use of the medicament of the present invention varies depending on the compound to be used or a pharmaceutical composition thereof and the use thereof, and the pharmaceutical composition of the present invention is usually administered 1-6 times a day, and the optimized administration frequency is daily. 1-3 times.

The packaging and preservation of the medicament of the invention are similar to the general medicament. For example, the solid dosage form of the medicament can be directly loaded into a glass, a plastic, a paper or a metal bottle, and a desiccant or the like is preferably placed in the bottle to maintain the quality of the drug; the liquid dosage form The drug is usually placed in a glass, plastic or metal bottle or hose; the aerosol-type drug is generally placed in a metal or plastic container with a pressure-resistant device such as a pressure reducing valve.

The present invention further provides the phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound or a pharmaceutically acceptable salt thereof, or a racemate or enantiomer thereof, or a A pharmaceutical composition comprising a phosphorus pyrido[2,3-d]pyrimidin-7-one compound or a pharmaceutically acceptable salt thereof, or a racemate or an enantiomer thereof, for treating a protein kinase abnormality Use in diseases caused by activity.

In the above use, the protein kinase is PI3K or mTOR, and preferably the protein kinase is PI3K, and further preferably PI3K-a, PI3K-β, PI3K-g and PI3K-d.

The diseases described in the use of the pharmaceutical composition comprising the compound of the present invention are psoriasis, cirrhosis, bronchitis, rheumatoid arthritis, lupus erythematosus, diabetes, diseases involving angiogenesis, eye diseases, immune system diseases, heart Vascular disease, epilepsy, neurodegenerative disease, Alzheimer's disease, Huntington's disease or Parkinson's disease.

The diseases caused by the abnormal activity of the protein kinase of the present invention are tumors, and specifically include solid tumors and liquid tumors, and more specifically: lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or intraocular melanoma, Uterine cancer, ovarian cancer, rectal cancer, anal cancer, gastric cancer, colon cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulva cancer, Hodgkin's disease, esophageal cancer, small bowel cancer, Endocrine system cancer, thyroid cancer, parathyroid carcinoma, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, bladder cancer, kidney or ureteral cancer, kidney cancer, central nervous system (CNS) neoplasm A combination of any one or any combination of a spinal axis tumor, a pituitary adenoma, a gastrointestinal stromal tumor, a colorectal cancer, a non-small cell lung cancer, a small cell lung cancer, a mastocytosis, a glioma, a sarcoma, a lymphoma.

Through a series of experiments, the phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound of the present invention or a pharmaceutically acceptable salt thereof has the following beneficial effects: (1) screening by inhibiting kinase activity In the experiment, it can be seen that the compound of the present invention has a strong inhibitory effect on a series of protein kinases, especially PI3K and mTOR; (2) it can be seen by the tumor inhibition test on animals that the phosphorus-containing pyridine is [2,3- d] pyrimidine-7-one compound or a pharmaceutically acceptable salt thereof can significantly inhibit tumor without obvious toxicity; (3) the compound of the present invention can be used together with other antitumor drugs to cooperate (synergistic) or additive effect; (4) The compound of the present invention can be used together with other tumor therapies such as radiation therapy, interventional therapy and the like. Thus, a phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound or a pharmaceutically acceptable salt thereof can be used as a medicament for effectively treating diseases caused by abnormal activities of protein kinases. .

The compound of the present invention is used for treating the above-mentioned diseases caused by abnormal protein kinase activity, wherein the kidney cancer is adrenal cancer, renal cell carcinoma, renal pelvic cancer; glioma is brain stem glioma, neuroendocrine glial tumor, nerve Glioma.

The compound of the present invention may treat psoriasis (or psoriasis), cirrhosis, bronchitis, rheumatoid arthritis, lupus erythematosus, diabetes, in addition to tumors in the treatment of diseases caused by abnormal protein kinase activity. Angiogenesis diseases, diseases involving restenosis, eye diseases such as AMD, rheumatoid arthritis and other inflammations, immune system diseases such as autoimmune diseases (eg, AIDS, etc.), cardiovascular diseases such as atherosclerosis, kidney diseases , epilepsy, neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, Parkinson's disease, etc. Definition of term

The following is a definition of the terms involved in the present invention. The variable groups used in the present invention, such as R ^a , R ^b , m, etc., are only applicable to this subsection (ie, the "Definition of Terms" section).

According to the general knowledge of one of ordinary skill in the art, chemical reactions need to be carried out in a solvent in many cases, and Solvents commonly used in the preparation of the compounds of the present invention include, but are not limited to, water, methanol, ethanol, isopropanol, n-propanol, n-Butanol, isobutanol, tert-butanol, 2-methoxyethanol, 2,2,2-trifluoroethanol, dichloromethane, 1,2-dichloroethane, chloroform, THF, dioxane , DME, ethyl acetate, diethyl ether, methyl tert-butyl ether, hexane, cyclohexane, toluene, acetonitrile, DMF, DMSO or a mixture of two or more of these solvents, and the like.

The chemical reaction sometimes needs to occur in the presence of an acid or a base. Bases commonly used in the preparation of the compounds of the present invention include, but are not limited to, Et ₃ N, Me ₃ N, i -Pr ₂ NEt , pyridine, DBU, DABCO, tetramethylguanidine, NaOH, KOH, Cs ₂ CO ₃ , Na ₂ CO ₃ , K ₂ CO ₃ , NaHCO ₃ , KF, CsF, K ₃ PO ₃ , K ₂ HPO ₄ , KH ₂ PO ₄ , NaH, n -BuLi, s -BuLi, t -BuLi, NaN(SiMe ₃ ) ₂ , LiN(SiMe ₃ ) ₂ , KN(SiMe ₃ ) ₂ or a mixture of two or more of these bases; Commonly used acids include, but are not limited to, HCO ₂ H, AcOH, TFA (trifluoroacetic acid), HCl (hydrochloric acid), H ₂ SO ₄ , HNO ₃ , H ₃ PO ₄ , p- TsOH, PhSO ₃ H, CSA. , MsOH or the like or Lewis acid ZnCl ₂ , AlCl ₃ , BF ₃ .OEt ₂ and the like.

The chemical reaction sometimes needs to occur in the presence of a coupling reagent (Coupling Reagent). Coupling Reagents commonly used in the preparation of the compounds of the present invention include, but are not limited to, DCC, EDC, HATU, TBTU, PyBOP, HCTU, BOP, T3P, DIC, HOBt, HOAt, CDI, DEPBT, etc.

Some steps in the preparation of the compounds of the invention require the use of reduction and reductant reagents including, but not limited to, H ₂ + Pd/C, H ₂ + Pd(OH) ₂ , H ₂ + PtO ₂ , H ₂ +Raney® Ni, Ti(OPr- i ) ₄ +NaBH ₄ , Ti(OPr- i ) ₄ +NaB(OAc) ₃ H, Ti(OPr- i ) ₄ +NaBH ₃ (CN), Ti( OPr- i ) ₄ +H ₂ , H ₂ NNH ₂ +Raney® Ni, Mg+MeOH, Fe+AcOH, Fe+HCl, Zn+AcOH, Zn+HCl, Zn+NH ₄ OAc, SnCl ₂ , LiAlH ₄ , NaBH ₄ , NaBH ₃ (CN), NaB(OAc) ₃ H, BH ₃ and the like.

The preparation of the compounds of the present invention requires the use of an oxidation reaction (Oxidation) and an oxidizing reagent (Oxidant) including, but not limited to, PCC (PyH.ClCrO ₃ ), PDC (2Py.Cr ₂ O ₇ ), K ₂ Cr. _{2 O 7, Na 2 Cr 2} O 7, H 2 Cr 2 O 7, CrO 3, CrO 3 .2Py, O 2, H 2 O 2, mCPBA, DMSO + (COCl) 2, NaClO 2, NaClO, Dess-Martin Reagent, KMnO ₄ , OsO ₄ , MnO _{2 ,} etc.

Some steps in the preparation of the compounds of the invention require the use of a pd catalyst, including but not limited to Pd/C, Pd(PPh ₃ ) ₄ , Pd ₂ (dba) ₃ , PdCl ₂ , Pd(OAc) ₂ Pd(O ₂ CCF ₃ ) ₂ , PdCl ₂ (dppf), PdCl ₂ (dppp), Pd(PPh ₃ ) ₂ Cl ₂ , Pd(PhCN) ₂ Cl ₂ , Pd(OH) ₂ and the like.

Some steps in the preparation of the compounds of the present invention require deprotection. When the protecting group is Boc (or -CO ₂ Bu- t ), commonly used deprotecting agents include, but are not limited to, HCl, TFA, H ₂ SO _{4 ,} and the like. When the protecting group is CBZ (or -CO ₂ CH ₂ Ph), commonly used deprotecting reagents include, but are not limited to, concentrated HCl, H ₂ + Pd/C, etc., when the protecting group is Bn (or -CH ₂ Ph), Common deprotection reagents include, but are not limited to, H ₂ + Pd/C, H ₂ + Pd(OH) ₂ , H ₂ + Pd/C + HCl, and the like.

The reaction for preparing the compound of the present invention is usually carried out at room temperature, but sometimes it is required to be lowered to -78 ° C or heated to 200 ° C; the reaction is usually carried out under the aforementioned solvent and temperature under ordinary stirring conditions, but sometimes in a microwave oven When the base, reagent, or catalyst used is sensitive to water or oxygen, the reaction is carried out under anhydrous and anaerobic conditions. In this case, a protic solvent cannot be used.

"Solvate" means a stable substance formed by a compound of the present invention and a chemically used solvent by covalent bond, hydrogen bond, ionic bond, van der Waals force, complexation, inclusion, etc., and the solvent may be : methanol, ethanol, propanol, butanol, ethylene glycol, propylene glycol, polyethylene glycol, acetone, acetonitrile, diethyl ether, methyl tert-butyl ether, and the like.

"Hydrate" means a solvate wherein the solvent is water.

"Prodrug" means the conversion of a compound of the invention to another compound by chemical synthesis or physical means, and after administration of the compound to a mammal, is converted in the animal to the compound of the invention. The "prodrug" method is generally used to overcome the poor or poor physicochemical properties or drug-forming properties of the drug compound itself.

"Di race, enantiomer, cis-trans isomer and other stereoisomers" means that the compounds have the same molecular formula and molecular weight, but differ in the manner of different bonding modes and spatial arrangement between the atoms. Compounds, such compounds are called isomers or stereoisomers. When these stereoisomers are mirror images of each other, they look alike, but they do not completely coincide, as with the left and right hands. These compounds are called enantiomers. The absolute configuration of the enantiomers is usually indicated by ( R )- and ( S )- or R- and S- . See particularly Chapter 4 of determining the absolute configuration of the enantiomers of the rule ^{"Advanced Organic Chemistry," 4 th} edition (by J. March, John Wiley and Sons, New York, 1992). The ( R )- and ( S )-enantiomers have opposite rotational effects on polarized light, namely left-handed and right-handed. When the ( R )- and ( S )-enantiomers are mixed or present in a ratio of 1:1, the mixture has no rotation effect on the polarized light, and the mixture is referred to as a racemate.

There may also be a compound of the present invention tautomer (Tautomers), rotational isomers (rotamers), cis and trans isomers, and the like, these concepts can be in J. March in ^{"Advanced Organic Chemistry," 4 th} edition of Find and get to know. These isomers are also encompassed by the present invention as long as these isomers have the same or similar effects of inhibiting protein kinase activity as the compounds of the present invention.

After administration of a compound of the present invention to a mammal (e.g., a human), it is possible in the art to be metabolized by various enzymes into various metabolites in an animal as long as these metabolites have similar inhibition to the compounds of the present invention. The role of protein kinase activity, these metabolites are also encompassed by the present invention.

"Pharmaceutical composition" refers to one or more, pharmaceutically acceptable salts or solvates or hydrates or prodrugs of the compounds described herein, and other chemical ingredients (eg, pharmaceutically acceptable carriers or dilutions) (mixture) prepared by mixing the preparation. The purpose of the pharmaceutical composition is to facilitate the administration of the animal. The above pharmaceutical composition may include, in addition to a pharmaceutically acceptable carrier, an adjuvant commonly used in medicine, such as an antibacterial agent, an antifungal agent, an antimicrobial agent, a shelf life agent, A toner, a solubilizer, a thickener, a surfactant, a complexing agent, a protein, an amino acid, a fat, a saccharide, a vitamin, a mineral, a trace element, a sweetener, a coloring matter, a flavor, or a combination thereof.

"Pharmaceutically acceptable carrier" or "diluent" refers to an inactive ingredient in a pharmaceutical composition which may be, but is not limited to, calcium carbonate, calcium phosphate, various sugars (eg, lactose, mannitol, etc.), starch, cyclodextrin. Fine, magnesium stearate, cellulose, magnesium carbonate, acrylic polymer, methacrylic acid polymer, gel, water, polyethylene glycol, propylene glycol, ethylene glycol, castor oil, hydrogenated castor oil, polyethoxylate Hydrogenated castor oil, sesame oil, corn oil, peanut oil, and the like.

"Alkyl" means a straight or branched saturated hydrocarbon group having the indicated number of carbon atoms, for example, _C1-6 alkyl means a straight or branched chain group containing at least 1 and up to 6 carbon atoms. . C ₀ alkyl represents a covalent single bond. The alkyl groups described in the present invention include, but are not limited to, methyl, ethyl, propyl, butyl, isopropyl, neopentyl, 2-methyl-1-hexyl and the like. The alkyl group of the present invention sometimes also refers to an alkylene group, that is, a group in which an alkyl group loses one hydrogen atom. One or all of the hydrogen atoms in the alkyl or alkylene group may be substituted by a cycloalkyl group, an aryl group, a heteroaryl group, a heteroalicyclic ring, a halogen, an amino group, a hydroxyl group, a cyano group, a nitro group, a carboxyl group, a fluorenyl group. , oxo, alkoxy, aryloxy, alkyl fluorenyl, aryl fluorenyl, carbonyl, thiocarbonyl, C -decylamine, N -nonylamino, O -aminocarbonyloxy, N -ammonia a carbonyloxy group, an O -thioaminocarbonyloxy group, an N -thioaminocarbonyloxy group, a C -ester group, an O -ester group, and -NR ^a R ^b , wherein R ^a and R ^b are each selected from the group consisting of: hydrogen An alkyl group, a cycloalkyl group, an aryl group, an ethyl fluorenyl group, a carbonyl group, a sulfonyl group, a trifluoromethanesulfonyl group or the like, and R ^a and R ^b together with a nitrogen atom may form a 5- or 6-membered heteroalicyclic ring.

"Cycloalkyl" or "cycloalkane" refers to a mono-, di- or polycyclic hydrocarbon group having the indicated number of carbon atoms, which may be fused when bicyclic or polycyclic (two rings or multiple rings share two) a combination of an adjacent carbon atom or a splicing (two or more rings sharing a carbon atom), for example, a C _1-6 cycloalkyl group containing a minimum of one and a maximum of six single, double or multiple a hydrocarbon group of the ring. The C ₀ cycloalkyl group represents a covalent single bond. The cycloalkyl group may contain an unsaturated double or triple bond, but does not have a fully conjugated p-electron system. The cycloalkyl group of the present invention sometimes also refers to a cycloalkylene group, that is, a group in which a cycloalkyl group loses one hydrogen atom. The cycloalkyl group of the present invention includes, but is not limited to, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentenyl, cycloheptatrienyl, adamantane, etc. (for example, Table A):

One or all of the hydrogen atoms in the cycloalkyl or cycloalkane may be substituted by an alkyl group, an aryl group, a heteroaryl group, a heteroalicyclic ring, a halogen, an amino group, a hydroxyl group, a cyano group, a nitro group, a carboxyl group, a fluorenyl group, Oxy (oxo), alkoxy, aryloxy, alkyl fluorenyl, aryl fluorenyl, carbonyl, thiocarbonyl, C -nonylamino, N -nonylamino, O -aminocarbonyloxy, N -aminocarbonyl An oxy group, an O -thioaminocarbonyloxy group, an N -thioaminocarbonyloxy group, a C -ester group, an O -ester group, and -NR ^a R ^b , wherein R ^a and R ^b are each selected from the group consisting of hydrogen, An alkyl group, a cycloalkyl group, an aryl group, an ethyl fluorenyl group, a carbonyl group, a sulfonyl group, a trifluoromethanesulfonyl group or the like, and R ^a and R ^b together with a nitrogen atom may form a 5- or 6-membered heteroalicyclic ring.

"Heteroalicyclic or heteroalicyclic" means a monocyclic, bicyclic or polycyclic ring system consisting of 3 to 12 non-hydrogen ring atoms, wherein at least one ring atom is a hetero atom selected from O, N, S or P, The remaining ring atoms are carbon atoms. For example, a C ₈ heteroalicyclic group refers to a monocyclic, bicyclic or polycyclic group composed of 8 non-hydrogen ring atoms, wherein at least one ring atom is selected from O, N, S or P. Such a ring may contain a double bond or a triple bond in addition to a single bond, but these double bonds or triple bonds do not constitute all conjugated aromatic structures. These monocyclic, bicyclic or polycyclic systems may exist in the form of fused rings, bridged rings or spiro rings. The heteroalicyclic group of the present invention sometimes also refers to a heteroalicyclic group, that is, a group in which a heteroalicyclic group loses one hydrogen atom. The heteroalicyclic or heteroalicyclic ring in the present invention includes, but is not limited to, acridine, morpholine, pyridazine, pyrrolidine, porphyrin, tetrahydropyridine, tetrahydrofuran, tropinol, etc. (for example, Table B):

One or all of the hydrogen atoms in the heteroalicyclic or heteroalicyclic ring may be substituted by an alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, a heteroalicyclic ring, a halogen, an amino group, a hydroxyl group, a cyano group, a nitrate Base, carboxyl, sulfhydryl, oxo, alkoxy, aryloxy, alkyl fluorenyl, aryl fluorenyl, carbonyl, thiocarbonyl, C -nonylamino, N -nonylamino, O -aminocarbonyl a group, N -aminocarbonyloxy, O -thioaminocarbonyloxy, N -thioaminocarbonyloxy, C -ester, O -ester and -NR ^a R ^b , wherein R ^a and R ^b They are respectively selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, ethyl carbonyl, carbonyl, sulfonyl, trifluoromethanesulfonyl, etc., and R ^a and R ^b together with a nitrogen atom can form 5- or 6- A person with a grease ring.

"Alkenyl" means a straight or branched hydrocarbon group containing at least two carbon atoms and one double bond, for example, C _2-6 alkenyl means a straight or branched chain containing at least 2 and up to 6 carbon atoms. An unsaturated group having at least one double bond in the chain. The alkenyl group in the present invention includes, but is not limited to, a vinyl group, a 2-propenyl group, a 1-pentenyl group, and the like.

"Alkynyl" means a straight or branched hydrocarbon group containing at least two carbon atoms and a triple bond, for example, C _2-6 alkynyl refers to a straight or branched chain containing at least 2 and up to 6 carbon atoms. The chain contains at least one triple bond of an unsaturated group. The alkynyl group in the present invention includes, but is not limited to, an ethynyl group, a 2-propynyl group, a 1-pentynyl group and the like.

"Halogen" means fluoro, chloro, bromo or iodo.

"Alkoxy" means an alkyl group having the indicated number of carbon atoms attached to the other group through an oxygen atom. Alkoxy groups in the present invention include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopentyloxy, cyclohexyloxy, isopropoxy, neopentyloxy, 2- Methyl-1-hexyloxy and the like.

"Cycloalkoxy" means a cycloalkyl group having the indicated number of carbon atoms attached to the other group through an oxygen atom. The cycloalkoxy group in the present invention includes, but is not limited to, a cyclopropoxy group, a cyclobutoxy group, a cyclohexaneoxy group, and the like.

"Heteroaliphatic" means that a heteroalicyclic group is attached to another group through an oxygen atom. The heteroaliphatic epoxy group in the present invention includes, but is not limited to, an acridine-4-yloxy group, an oxetane-3-yloxy group, and the like.

"Aryl" means a monocyclic, bicyclic or polycyclic group consisting of a specified number of carbon atoms, wherein at least one of the rings has a fully conjugated p-electron system and conforms to the N+2 rule, ie is aromatic, but the entire group Not necessarily all conjugates. For example, C ₆ aryl refers to phenyl. The aryl group may also be present in the form of an arylene group, that is, two or more points of attachment to other groups in the aryl structure. The aryl group in the present invention includes, but is not limited to, a phenyl group, a naphthyl group, an anthracenyl group, an indanyl group, a tetrahydronaphthalene or the like. One or all of the hydrogen atoms in the aryl group may be substituted with an alkyl group, a cycloalkyl group, a heteroaryl group, a heteroalicyclic ring, a halogen, an amino group, a hydroxyl group, a cyano group, a nitro group, a carboxyl group, a decyl group, an oxy group ( Oxo), alkoxy, aryloxy, alkyl fluorenyl, aryl fluorenyl, carbonyl, thiocarbonyl, C -nonylamino, N -nonylamino, O -aminocarbonyloxy, N -aminocarbonyloxy, O -thioaminocarbonyloxy, N -thioaminocarbonyloxy, C -ester, O -ester and -NR ^a R ^b , wherein R ^a and R ^b are each selected from the group consisting of hydrogen, alkyl, A cycloalkyl group, an aryl group, an ethyl fluorenyl group, a carbonyl group, a sulfonyl group, a trifluoromethanesulfonyl group or the like, and R ^a and R ^b together with a nitrogen atom may form a 5- or 6-membered heteroalicyclic ring.

"Heteroaryl" means a monocyclic, bicyclic or polycyclic group consisting of a specified number of non-hydrogen ring atoms, wherein at least one of the ring atoms is a heteroatom selected from O, N, S or P, and the remaining ring atoms are carbon atoms. And wherein at least one of the rings has a fully conjugated p-electron system and conforms to the N+2 rule, ie, has aromaticity, but the entire group does not have to be fully conjugated, for example, C ₅ heteroaryl refers to 5 non- An aromatic ring group composed of a hydrogen ring atom, wherein at least one ring atom is selected from O, N, S or P. The heteroaryl group may also be present in the form of a heteroarylene group having two or more points of attachment to other groups in the heteroaryl structure. The heteroaryl group in the present invention includes, but is not limited to, acridine, anthrone, tetrahydrofurfurone, imidazole, pyrazine, pyridazine, imidazole, thiazole, thiophene, furan, anthracene, azaindole, Benzimidazole, porphyrin, fluorenone, quinine, etc. (for example, Table C):

One or all of the hydrogen atoms in the heteroaryl group may be substituted with an alkyl group, a cycloalkyl group, an aryl group, a heteroalicyclic ring, a halogen, an amino group, a hydroxyl group, a cyano group, a nitro group, a carboxyl group, a decyl group, an oxy group ( Oxo), alkoxy, aryloxy, alkyl fluorenyl, aryl fluorenyl, carbonyl, thiocarbonyl, C -nonylamino, N -nonylamino, O -aminocarbonyloxy, N -aminocarbonyloxy, O -thioaminocarbonyloxy, N -thioaminocarbonyloxy, C -ester, O -ester and -NR ^a R ^b , wherein R ^a and R ^b are each selected from the group consisting of hydrogen, alkyl and ring An alkyl group, an aryl group, an ethyl fluorenyl group, a carbonyl group, a sulfonyl group, a trifluoromethanesulfonyl group or the like, and R ^a and R ^b together with a nitrogen atom may form a 5- or 6-membered heteroalicyclic ring.

"Aryloxy" means that the aryl group is attached to the other group through an oxygen atom. The aryloxy group in the present invention includes, but is not limited to, a phenoxy group, a naphthyloxy group and the like.

"Heteroaryloxy" means a heteroaryl group attached to another group through an oxygen atom. The heteroaryloxy group in the present invention includes, but is not limited to, 4-acridinyloxy group, 2-thienyloxy group and the like.

"Amino" refers to H ₂ N- wherein a hydrogen atom or a substituted H ₂ N-, i.e., R ^a HN- and R ^a R ^b N-.

"oxo" or "oxy" means =0, that is, an oxygen atom is bonded to a carbon or a hetero atom such as N, S or P through a double bond. Examples of substitution by an oxy group include, but are not limited to, those shown in Table D: "Hydroxy" means -OH. "Nitro" means -NO ₂ . "Carboxyl" means -CO ₂ H. "巯基" means -SH. "Alkyl fluorenyl" means alkyl-S-. "Aryl indenyl" refers to aryl-S-. "Carbonyl" means -C(=O)-. "Thiocarbonyl" means -C(=S)-. " C -Amidino" refers to -C(=O)NR ^a R ^b . " N -Amidino" refers to C(=O)NR ^a -. " O -Aminocarbonyloxy" means -OC(=O)NR ^a R ^b . " N -Aminocarbonyloxy" means OC(=O)NR ^a -. " O -thioaminocarbonyloxy" means -OC(=S)NR ^a R ^b . " N -thioaminocarbonyloxy" means OC(=S)NR ^a -. " C -ester group" means -C(=O)OR ^a . " N -ester group" means C(=O)O-. "Ethylene" means CH ₃ C(=O)-. "Sulfo" refers to -SO ₂ R ^a . "Trifluoromethanesulfonyl" refers to CF ₃ SO ₂ -.

The present invention will be further described in detail below in conjunction with the specific examples, in order to further understand the present invention, the preparation method and the beneficial effects thereof, but the specific embodiments of the present invention do not limit the contents claimed in the present invention.

The English abbreviations appearing in the examples and the corresponding Chinese meanings are listed below. If an abbreviation not listed herein appears in the examples, it represents a generally accepted meaning. DMSO: dimethyl hydrazine DMSO- d ₆ : hexamethylene dimethyl hydrazine TMS: tetramethyl decane DCM: dichloromethane CDCl ₃ : deuterated chloroform CD ₃ OD: deuterated methanol THF: tetrahydrofuran EtOAc: acetic acid Ethyl acetate MeOH: methanol EtOH: ethanol HCl: hydrogen chloride or hydrochloric acid TLC: thin layer chromatography LC-MS: liquid chromatography-mass spectrometry g: g mg: mg mol: molar mmol: millimoles mM: micromoles L : liter mL: microliter nM: nanomolar [M+H] ⁺ : molecular ion peak in mass spectrum N: equivalent concentration m/z : mass to charge ratio d: chemical shift DMAP: 4-dimethylaminopyridine DIPEA: Diisopropylethylamine DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene PCC: pyridinium chlorochromate Ti(OPr- i ) ₄ : tetraisopropyl Titanate Pd(PPh ₃ ) ₄ : Tetrakis(triphenylphosphine)palladium(0) Pd(PPh ₃ ) ₂ Cl ₂ : bis-(triphenylphosphine)palladium(II) chloride NBS: N -bromo Amber quinone imine LiHMDS: lithium bis-(trimethylsulfonyl)amine LiAlH ₄ : lithium tetrahydrogen aluminum DMA: dimethyl acetamide General experimental conditions:

Nuclear magnetic resonance spectra and carbon spectra were obtained on a Varian 400 MHz or Bruker 400 MHz instrument (deuterated DMSO, deuterated chloroform, deuterated methanol, etc., TMS as internal standard). Mass spectrometry was obtained by liquid chromatography-mass spectrometry (using ESI or APCI ion source ZQ4000, Waters, USA). The ultraviolet spectrum was measured by a UV-3010 ultraviolet spectrophotometer from Hitachi, Japan. Infrared spectroscopy was performed using a NICOLET 6700 infrared spectrum analyzer (KBr pellet). High performance liquid chromatography was performed using a Waters 2695 ZORBAX high performance liquid chromatograph (Bx-C ₈ 5μ 150 x 4.6 mm column). The melting point was determined using an Electrothermal digital melting point apparatus IA9100 and was uncorrected.

Starting materials, reagents and solvents were purchased from the following suppliers: Beta-Pharma; Shanghai PI Chemicals; AndaChem; Taiyuan; Shanghai FWD Chemicals; Sigma-Aldrich, Milwaukee, WI, USA; Acros, Morris Plains, NJ, USA; Frontier Scientific , Logan, Utah, USA; Alfa Aesar, Ward Hill, MA, USA, etc. or synthesized by methods reported in the literature. Unless otherwise indicated, the solvent is generally not dried and is used directly from the supplier's product or dried through molecular sieves. Example 1A

Trans-8-[4-(diethoxyphosphonylmethoxy)cyclohexyl]-2-(2,5-dimethylpyrrol-1-yl)-6-(6-methoxy- Preparation of 3-pyridyl)-4-methylpyridine [2,3-d]pyrimidin-7-one ( 1-15 ), the specific reaction formula is as follows:

First step: bromine (134 g, 0.84 mol) was added dropwise to a solution of 4-chloro-6-methylpyrimidin-2-amine ( 1-1 , 100 g, 0.70 mol) in dichloromethane (4 L). The resulting suspension was stirred at room temperature for 2 hours, diluted with dichloromethane (5 L), washed with saturated sodium bicarbonate (2×3 L) and brine (3 L) Concentration gave the product 5-bromo-4-chloro-6-methylpyrimidin-2-amine ( 1-2 ) as a white solid (120 g, yield: 79%).

The second step: 5-bromo 4-chloro-6-methylpyrimidin-2-amine ( 1-2 , 120 g, 0.54 mol), trans-4-aminocyclohexanol ( 1-3 , 58 g, 0.5 A solution of mol and diisopropylethylamine (110 g, 0.84 mol) in dimethylacetamide (4 L) was heated at 120 ° C for 16 hours. The reaction mixture was diluted with methyl tert-butyl ether (2.0 L), washed with a saturated aqueous solution of ammonium chloride (2 x 3.0 L) and brine, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness Purification, dichloromethane/methanol mixture (95/5) as eluent to give the product trans-4-[(2-amino-5-bromo-6-methylpyrimidin-4-yl)amino] ring Hexanol ( 1-4 ) was a light red solid (100 g, yield: 61%). NMR analysis results: ¹ H-NMR (CD ₃ OD, 400 MHz): δ 3.90 (m, 1 H), 3.56 (m, 1 H), 3.25 (s, 3 H), 1.99-1.94 (m, 4 H), 1.42-1.30 (m, 4 H).

The third step: trans-4-[(2-amino-5-bromo-6-methylpyrimidin-4-yl)amino]cyclohexanol ( 1-4 , 50 g, 0.166 mol), ethyl acrylate ( A solution of 1-5 , 83 g, 0.83 mol), triethylamine (84 g, 0.83 mol) and Pd(PPh ₃ ) ₄ (10 g, 8.65 mmol) in DMF (500 mL) was heated at 130 ° C for 16 hours. The reaction mixture was cooled to room temperature and concentrated, the~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Ethylamino-6-methylpyrimidin-5-yl]-2-propenoic acid ( 1-6 ) as a white solid (25 g, yield: 46%). Mass spectrometry results: m/z : 321.20 [M+H] ⁺ .

The fourth step: trans-(E)-3-[2-amino-4-[(4-hydroxycyclohexyl)amino]-6-methylpyrimidin-5-yl]-2-propenoic acid ethyl ester ( 1- 6 , 40 g, 0.125 mol), thiophenol (14 g, 0.13 mol), sodium thiophenolate (33 g, 0.25 mol), DBU ( 1-7 , 76 g, 0.5 mol) and diisopropyl B The solution of the amine (97 g, 0.75 mol) in DMF (400 mL) was heated at 120 ° C for 16 hours. The reaction mixture was concentrated to dryness. EtOAc mjjjjjjjjjj -4-methylpyridine [2,3-d]pyrimidin-7-one as a yellow solid ( 1-8 , 29 g, yield: 85%). Mass spectrometry results: m/z : 275.20 [M+H] ⁺ .

Step 5: trans-(2-Amino-8-(4-hydroxycyclohexyl)-4-methylpyridine[2,3-d]pyrimidin-7-one ( 1-8 , 29 g, 0.106 mol) NBS (23 g, 0.13 mol) was added to a solution of EtOAc (EtOAc) /5) as an eluent, the product trans-2-amino-6-bromo-8-(4-hydroxycyclohexyl)-4-methylpyridine[2,3-d]pyrimidin-7-one ( 1 -9 ), as a yellow solid (27 g, yield: 71%). Mass. mp .: 353.00 [M+H, ⁷⁹ Br] ⁺ , 355.00 [M+H, ⁸¹ Br] ⁺ .

Step 6: trans-2-amino-6-bromo-8-(4-hydroxycyclohexyl)-4-methylpyridine [2,3-d]pyrimidin-7-one ( 1-9 , 11 g , 31.1 mmol), potassium carbonate (13 g, 93 mmol) and 2-methoxypyridin-3-ylboronic acid ( 1-10 , 6.8 g, 56 mmol) in DMF/H ₂ O (5:1, 24 mL The mixture was filled with nitrogen for 5 minutes, and Pd(PPh ₃ ) ₂ Cl ₂ (3 g, 4.28 mmol) was added to the mixture. The resulting mixture was stirred with heating at 100 ° C for 2 hours in a microwave oven. The reaction mixture was concentrated to dryness. EtOAc mjjjjjjjjjj -6-(6-Methoxy-3-pyridyl)-4-methylpyridine[2,3-d]pyrimidin-7-one ( 1-11 ) as a yellow solid (6.64 g, yield: 56%). Mass spectrometry results: m/z : 382.30 [M+H] ⁺ .

Step 7: trans-2-amino-8-(4-hydroxycyclohexyl)-6-(6-methoxy-3-pyridyl)-4-methylpyridine [2,3-d]pyrimidine- 7-ketone ( 1-11 , 1.5 g, 3.93 mmol), 2,5-dihexanone ( 1-12 , 2.7 g, 24 mmol) and p-toluenesulfonic acid (0.15 g, 0.87 mmol) in toluene (100 mL) The solution was heated to reflux overnight. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by column chromatography eluting with petroleum ether / ethyl acetate (yield: 80/20) to afford product trans-2-(2,5-dimethylpyrrol-1-yl)-8 -(4-hydroxycyclohexyl)-6-(6-methoxy-3-pyridyl)-4-methylpyridine[2,3-d]pyrimidin-7-one ( 1-13 ) as a white solid (1 g, yield: 55%).

Step 8: trans-2-(2,5-dimethylpyrrol-1-yl)-8-(4-hydroxycyclohexyl)-6-(6-methoxy-3) at 0 oC To a THF solution (20 mL) of -pyridyl)-4-methylpyridine[2,3-d]pyrimidin-7-one ( 1-13 , 1.1 g, 2.39 mmol) in THF (1 N in THF, 4 mL, 4 mmol). The resulting mixture was stirred at room temperature for 1 hour, cooled to 0 ° C, and diethoxyphosphonylmethyl trifluoromethanesulfonate ( 1-14 , 1.1 g, 3.6 mmol). The mixture was stirred at room temperature for 5 hours, a saturated solution was quenched with NH ₄ Cl and extracted with dichloromethane. The organic layer was dried and concentrated, and the residue was purified by preparative TLC to afford compound -8-[4-(diethoxyphosphonylmethoxy)cyclohexyl]-2-(2,5-dimethylpyrrole- 1-yl)-6-(6-methoxy-3-pyridyl)-4-methylpyridine[2,3-d]pyrimidin-7-one ( 1-15 , 0.61 g, yield: 42% ). Mass spectrometry results: m/z : 610.20 [M+H] ⁺ .

Example 1

Trans-2-amino-8-[4-(diethoxyphosphonylmethoxy)cyclohexyl]-6-(6-methoxy-3-pyridyl)-4-methylpyridine [2 , 3-d] pyrimidine-7-one ( 1-16 ), the specific reaction formula is as follows:

Trans-8-[4-(diethoxyphosphonylmethoxy)cyclohexyl]-2-(2,5-dimethylpyrrol-1-yl)-6-(6-methoxy- 3-pyridyl)-4-methylpyridine [2,3-d]pyrimidin-7-one ( 1-15 , 0.61 g, 1 mmol, prepared according to Example 1A) and hydroxylamine hydrochloride (0.35 g, 5 mmol) Dissolved in ethanol/water (10:1, 22 mL) and heated to reflux overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative EtOAc EtOAc EtOAc -3-pyridyl)-4-methylpyridine [2,3-d]pyrimidin-7-one ( 1-16 , 210 mg, yield: 40%) as a yellow solid. NMR analysis results: ¹ H-NMR (CDCl ₃ , 400 MHz): δ 8.31 (d, J = 2.8 Hz, 1 H), 7.96 (dd, J = 2.4, 8.4 Hz, 1 H), 7.74 (s, 1 H), 6.80 (d, J = 8.4 Hz, 1 H), 5.52 (m, 1 H), 5.31 (s, 2 H), 4.24-4.17 (m, 4 H), 3.98 (s, 3 H) , 3.85 (d, J = 9.2 Hz, 2 H), 3.51 (m, 1 H), 2.82 (m, 1 H), 2.60 (s, 3 H), 2.23-2.20 (m, 2 H), 1.73- 1.70 (m, 2 H), 1.54-1.43 (m, 2 H), 1.37 (t, J = 7.2 Hz, 6 H). Mass spectrometry results: m/z : 532.20 [M+H] ⁺ .

The following compounds, but not limited to these compounds, can be synthesized according to the same or similar methods as described in Example 1A and Example 1:

Example 2A

Cis/trans-8-[4-(diethoxyphosphoniummethylamino)cyclohexyl]-2-(2,5-dimethylpyrrol-1-yl)-6-(6-methoxy Preparation of benzyl-3-pyridyl)-4-methylpyridine [2,3-d]pyrimidin-7-one ( 2A ), the specific reaction formula is as follows:

First step: trans-2-(2,5-dimethylpyrrol-1-yl)-8-(4-hydroxycyclohexyl)-6-(6-methoxy- at 0 °C 3-pyridyl)-4-methylpyridine [2,3-d]pyrimidin-7-one ( 1-13 , 0.179 g, 0.39 mmol, synthesized according to the seventh step of Example 1A) and sodium acetate (64 mg) PCC (0.11 g, 0.47 mmol) was added to a solution of dichloromethane (5 mL), and the mixture was stirred at room temperature for 4 hr then filtered and concentrated under reduced pressure. Ether/ethyl acetate mixture (70/30) as eluent to give the compound 2-(2,5-dimethylpyrrol-1-yl)-6-(6-methoxy-3-pyridyl)- 4-Methyl-8-(4-oxocyclohexyl)pyridine [2,3-d]pyrimidin-7-one ( 2A-1 , 0.093 g, yield: 52%). Mass spectrometry results: m/z : 458.32 [M+H] ⁺ .

Second step: 2-(2,5-dimethylpyrrol-1-yl)-6-(6-methoxy-3-pyridyl)-4-methyl-8-(4-oxocyclohexyl a solution of pyridine [2,3-d]pyrimidin-7-one ( 2A-1 , 0.092 g, 0.2 mmol) and triethylamine (0.060 g, 0.59 mmol) in THF (5 mL) Ti(OPr- i ) ₄ (0.25 mL) and diethoxyphosphonylmethylamine ( 2-2 , 0.075 g, 0.30 mmol) were added, and the mixture was stirred at room temperature for 2 hr. After stirring at 0.038 g, 1.0 mmol). The reaction mixture was quenched with aq. EtOAc EtOAc (EtOAc) Ethoxyphosphonylmethylamino)cyclohexyl]-2-(2,5-dimethylpyrrol-1-yl)-6-(6-methoxy-3-pyridyl)-4-methylpyridine [2,3-d]pyrimidin-7-one ( 2A , 38 mg, yield: 31%) as a trans/cis mixture. Mass spectrometry results: m/z : 609.32 [M+H] ⁺ .

Example 2

Cis-2-amino-8-[4-(diethoxyphosphoniummethylamino)cyclohexyl]-6-(6-methoxy-3-pyridyl)-4-methylpyridine [2, 3-d]pyrimidin-7-one ( 2-4a ) and trans-2-amino-8-[4-(diethoxyphosphoniummethylamino)cyclohexyl]-6-(6-methoxy Preparation of -3-pyridyl)-4-methylpyridine [2,3-d]pyrimidin-7-one ( 2-4b ), the specific reaction formula is as follows:

First step: trans-2-amino-8-(4-hydroxycyclohexyl)-6-(6-methoxy-3-pyridyl)-4-methylpyridine at 0 °C [2] , 3-d]pyrimidin-7-one ( 1-11 , 1.5 g, 3.93 mmol, synthesized according to the sixth step in Example 1) and sodium acetate (640 mg, 7.8 mmol) in dichloromethane (15 mL) PCC (1.1 g, 4.7 mmol) was added, and the mixture was stirred at room temperature for 4 hr, then filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography, petroleum ether / ethyl acetate mixture (70/30) Deprotection to give the compound 2-amino-6-(6-methoxy-3-pyridyl)-4-methyl-8-(4-oxocyclohexyl)pyridine [2,3-d]pyrimidine-7 - one (2-1, 1 g, yield: 67%). Mass spectrometry results: m/z : 380.30 [M+H] ⁺ .

Second step: 2-amino-6-(6-methoxy-3-pyridyl)-4-methyl-8-(4-oxocyclohexyl)pyridine [2,3-d]pyrimidine-7- A solution of the ketone ( 2-1 , 1.5 g, 4.0 mmol) and triethylamine (1.2 g, 11.8 mmol) in THF (15 mL) was stirred at room temperature for 1 hour, then Ti(OPr- i ) ₄ (5 mL) And diethoxyphosphonium methylamine ( 2-2 , 1.5 g, 5.9 mmol), the mixture was stirred at room temperature for 2 hr, and sodium borohydride (0.75 g, 19.8 mmol) was added and stirred overnight. The reaction mixture was quenched with aq. EtOAc EtOAc (EtOAc) 4-(Diethoxyphosphoniummethylamino)cyclohexyl]-6-(6-methoxy-3-pyridyl)-4-methylpyridine[2,3-d]pyrimidin-7-one ( 2-3 , 400 mg, yield: 19%), a trans/cis mixture, further separated by supercritical fluid chromatography (SFC) to give 226 mg of cis and 50 mg of the trans product.

Cis-product ( 2-4a ): NMR analysis: ¹ H-NMR (CDCl ₃ , 400 MHz): δ 8.32 (t, J = 2.0 Hz, 1 H), 7.99 (dd, J = 2.4, 8.4 Hz , 1 H), 7.75 (s, 1 H), 6.81 (d, J = 8.4 Hz, 1 H), 5.51 (m, 1 H), 5.21 (s, 2 H), 4.24-4.14 (m, 4 H ), 3.99 (s, 3 H), 3.06 (d, J = 13.6 Hz, 2 H), 2.88 (s, 2 H), 2.84-2.58 (m, 4 H), 2.10-2.07 (m, 2 H) , 1.72-1.61 (m, 3 H), 1.39-1.34 (m, 8 H). Mass spectrometry results: m/z : 531.30 [M+H] ⁺ .

Trans product ( 2-4b ): NMR analysis results: ¹ H-NMR (CDCl ₃ , 400 MHz): δ 8.35 (d, J = 2.8 Hz, 1 H), 8.00 (dd, J = 2.4, 8.4 Hz , 1 H), 7.75 (s, 1 H), 6.81 (d, J = 8.4 Hz, 1 H), 5.44 (m, 1 H), 4.29-4.19 (m, 4 H), 3.99 (s, 3 H ), 3.12-3.06 (m, 2 H), 3.01 (d, J = 14.4 Hz, 2 H), 2.90 (s, 1 H), 2.58 (s, 3 H), 2.02-1.99 (m, 2 H) , 1.88 (m, 1 H), 1.61-1.51 (m, 4 H), 1.41-1.37 (m, 6 H). Mass spectrometry results: m/z : 531.30 [M+H] ⁺ .

The following compounds, but not limited to these compounds, can be synthesized according to the same or similar methods as described in Example 2:

Example 3A

Trans-4-[2-amino-6-(6-methoxy-3-pyridyl)-4-methyl-7-oxypyridine[2,3-d]pyrimidin-8-yl]cyclohexyl Preparation of formic acid ( 3-7 ), the specific reaction formula is as follows:

First step: 5-bromo-4-chloro-6-methylpyrimidin-2-amine ( 1-2 , 109 g, 0.49 mol), trans-4-aminocyclohexylcarboxylic acid ethyl ester ( 3-1 , 102 A solution of g, 0.5 mol) and diisopropylethylamine (194 g, 1.5 mol) in dimethylacetamide (1 L) was refluxed at 130 °C for 12 hours. The mixture was concentrated under reduced pressure and the residue was crystallisjjjjjjjjjjjjj The organic phase was dried over sodium sulfate, filtered and concentrated to ethylamine <RTI ID=0.0>########################################################### It was used in the next reaction without purification.

The second step: trans-4-[(2-amino-5-bromo-6-methylpyrimidin-4-yl)amino]cyclohexylcarboxylate ( 3-2 , 90 g, 251.9 mmol), acrylic acid B Mixture of ester ( 1-5 , 126 g, 1.26 mol), Pd(PPh ₃ ) ₄ (30 g) and triethylamine (127 g, 1.26 mol) in DMF (1.5 L) at 130 ° C with heating and stirring 12 hours. The mixture was concentrated under reduced pressure. EtOAc EtOAc m. The organic phase was dried over sodium sulfate, filtered, and concentrated to give the crude product trans-4 - [[2-amino -5 - [(E) -3- ethoxy-3-oxo-prop-1-enyl] -6 Ethyl-methylpyrimidin-4-yl]amino]cyclohexylcarboxylate ( 3-3 ) was used in the next reaction without purification.

The third step: trans-4-[[2-amino-5-[( E )-3-ethoxy-3-oxyprop-1-enyl]-6-methylpyrimidin-4-yl] Amino]ethyl cyclohexylcarboxylate ( 3-3 , 80 g, 212.51 mmol), thiophenol (23 g, 213 mmol), sodium thiophenolate (34 g, 255 mmol), DBU ( 1-7 , 130 g) A mixture of 852 mmol) and diisopropylethylamine (165 g, 12.8 mol) in DMF (1.2 L) was stirred and stirred at 130 ° C for 8 hours. The mixture was concentrated under reduced pressure. EtOAc m. The organic phase was dried over sodium sulfate, filtered and evaporated tolulululululululululululu Ethyloxypyridine [2,3-d]pyrimidin-8-yl)cyclohexylcarboxylic acid ethyl ester ( 3-4 , 25 g, 3 step total yield: 35%).

Step 4: To trans-4-(2-amino-4-methyl-7-oxypyridine [2,3-d]pyrimidin-8-yl)cyclohexylcarboxylate ( 3-4 , 25 g NBS (12.8 g, 72 mmol) was added to a solution of &lt;RTI ID=0.0&gt;&gt; The mixture was concentrated under reduced pressure. EtOAc m. The organic phase is dried over sodium sulfate, filtered and evaporated tolululululululululululu Ethyl methyl-7-oxypyridine [2,3-d]pyrimidin-8-yl)cyclohexylcarboxylate ( 3-5 , 15 g, yield: 48%).

The fifth step: trans-4-(2-amino-6-bromo-4-methyl-7-oxypyridine [2,3-d]pyrimidin-8-yl)cyclohexylcarboxylic acid ethyl ester ( 3-5 , 22 g, 53.75 mmol), potassium carbonate (14.9 g, 108 mmol), 2-methoxypyrid-3-ylboronic acid ( 1-10 , 12.4 g, 81 mmol) and Pd(PPh ₃ ) ₄ (4 g The mixture in DMF/H ₂ O (5:1, 260 ml) was stirred at 100 ° C for 2 hours. The mixture was concentrated under reduced pressure. EtOAc m. The organic phase was dried over sodium sulfate, filtered and evaporated tolulululululululululululululu Ethyloxy-3-pyridyl)-4-methyl-7-oxypyridine [2,3-d]pyrimidin-8-yl]cyclohexylcarboxylate ( 3-6 , 3.5 g, yield: 15% ).

Step 6: trans-4-[2-amino-6-(6-methoxy-3-pyridyl)-4-methyl-7-oxypyridine [2,3-d]pyrimidine-8- Ethyl cyclohexylcarboxylate ( 3-6 , 1.1 g, 2.5 mmol) and lithium hydroxide (210 mg, 5 mmol) in a mixture of H ₂ O (10 mL) and EtOH (10 mL) at room temperature after stirring for 3 hours, concentrated, and diluted with H ₂ O (10 mL), extracted with ethyl acetate (2 x 20 mL). The aqueous layer was adjusted to pH 5 with 1N EtOAc. EtOAc (EtOAc m. -Methoxy-3-pyridyl)-4-methyl-7-oxypyridine [2,3-d]pyrimidin-8-yl]cyclohexylcarboxylic acid ( 3-7 ), used directly without purification One step reaction. Mass spectrometry results: m/z : 411.20 [M+H] ⁺ .

Example 3

Trans-4-[2-amino-6-(6-methoxy-3-pyridyl)-4-methyl-7-oxypyridine[2,3-d]pyrimidin-8-yl] -N Preparation of (diethoxyphosphonylmethyl)cyclohexylcarbamide ( 3-8 ), the specific reaction formula is as follows:

Trans-4-[2-amino-6-(6-methoxy-3-pyridyl)-4-methyl-7-oxypyridine[2,3-d]pyrimidin-8-yl]cyclohexyl Formic acid ( 3-7 , 1 g, 2.44 mmol), crude product synthesized according to the sixth step of Example 3A), diethoxyphosphonylmethylamine ( 2-2 , 720 mg, 2.8 mmol), hydroxybenzene Triazole (HOBT, 513 mg, 3.8 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbenium diimide) (EDCI, 730 mg, 3.8 mmol) and N -methyl A solution of morpholine (NMM, 2 g, 20 mmol) in dichloromethane was stirred at room temperature for 8 h. The reaction mixture was concentrated under reduced vacuo. EtOAc m. The organic phase is dried over sodium sulfate, filtered and concentrated to give crystals crystals of of of of of of of of of of of of of of of of of of of of of of oxypyridine [2,3-d] pyrimidin-8-yl] - N - (diethoxyphosphoryl acyl methyl) cyclohexyl methyl Amides (3-8, 203 mg, 15% ). ¹ H-NMR (CDCl ₃ , 400 MHz): δ 8.23 (d, J = 2.4 Hz, 1 H), 7.88 (dd, J = 2.4, 8.8 Hz, 1 H), 7.66 (s, 1 H), 6.73 (d, J = 8.8 Hz, 1 H), 5.93 (s, 1 H), 5.52 (m, 1 H), 5.24 (s, 2 H), 4.12-4.04 (m, 4 H), 3.90 (s, 3 H), 3.66 (dd, J = 6.0, 12.0 Hz, 2 H), 2.75-2.69 (m, 2 H), 2.53 (s, 3 H), 2.24 (m, 1 H), 1.97-1.94 (m , 2 H), 1.71-1.62 (m, 4 H), 1.27 (t, J = 6.8 Hz, 6 H). Mass spectrometry results: m/z : 559.30 [M+H] ⁺ .

The following compounds, but not limited to these compounds, can be synthesized according to the same or similar methods as described in Example 3A and Example 3:

Example 4A

Trans-2-(2,5-Dimethylpyrrol-1-yl)-8-[4-(hydroxymethyl)cyclohexyl]-6-(6-methoxy-3-pyridyl)-4 -Preparation of -methylpyridine [2,3- d ]pyrimidin-7-one ( 4-9 ), the specific reaction formula is as follows:

Step: trans-4-aminocyclohexyl-carboxylic acid hydrochloride (4-1, 50 g, 0.28 mol ) in ethanol (500 mL) was added SOCl ₂ (100 mL), the resulting mixture was stirred at 100 ^o C Stir for 8 hours. The solvent was removed under reduced pressure to give trans-4-aminocyclohexyl carboxylic acid ethyl ester hydrochloride (4-2, 58 g, yield: 100%).

Step Two: In 0 ^o C, to trans-4-aminocyclohexyl carboxylic acid ethyl ester hydrochloride (4-2, 53.3 g, 257 mmol ) in THF (1 L) was carefully added portionwise LiAlH ₄ (11.4 g, 309 mmol), the mixture was stirred at room temperature for 3 hr. The reaction mixture was carefully quenched with EtOAc (EtOAc) EtOAc.EtOAc .

The third step: 5-bromo-4-chloro-6-methylpyrimidin-2-amine ( 1-2 , 57 g, 256.2 mmol), trans-(4-aminocyclohexyl)methanol ( 4-3 , 33 A mixture of g, 257 mmol) and DIPEA (66 g, 514 mmol) in DMA (l. The mixture was concentrated under reduced pressure and diluted with DCM (500 mL). The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated. mjjjjjjjjjjj Methylpyrimidin-4-yl)amino]cyclohexyl]methanol ( 4-4 , 58 g, yield: 72%).

The fourth step: trans-[4-[(2-amino-5-bromo-6-methylpyrimidin-4-yl)amino]cyclohexyl]methanol ( 4-4 , 70 g, 222 mmol), acrylic acid B A mixture of ester ( 1-5 , 111.5 g, 1.12 mol), Pd(PPh ₃ ) ₄ (20 g) and triethylamine (112 g, 1.12 mol) in DMF (1 L) was stirred and stirred at 130 ° C for 12 hours. The mixture was concentrated under reduced pressure and diluted with DCM (300 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel to give trans column chromatography (dichloromethane to 5% methanol) with - (E) -3- [2- amino-4 - [[ Ethyl 4-(hydroxymethyl)cyclohexyl]amino]-6-methylpyrimidin-5-yl]prop-2-enoate ( 4-5 , 48 g, yield: 65%).

The fifth step: trans-( E )-3-[2-amino-4-[[4-(hydroxymethyl)cyclohexyl]amino]-6-methylpyrimidin-5-yl]prop-2-ene Ethyl acetate ( 4-5 , 48 g, 143.5 mmol), thiophenol (15.8 g, 143 mmol), sodium thiophenolate (22.7 g, 172 mmol), DBU ( 1-7 , 43 g, 286 mmol) ) and diisopropylethyl amine (55 g, 429 mmol) in DMF (1 L) was heated at 130 ^o C for 8 hours. The mixture was concentrated under reduced pressure and diluted with DCM (300 mL). The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated. mjjjjjjjjjj Hexyl]-4-methylpyridine [2,3- d ]pyrimidin-7-one ( 4-6 , 8.6 g, yield: 21%).

Step 6: trans-2-amino-8-[4-(hydroxymethyl)cyclohexyl]-4-methylpyridine [2,3- d ]pyrimidin-7-one ( 4-6 , 8.6 g, NBS (5.3 g, 30 mmol) was added to a solution of EtOAc (EtOAc) (EtOAc). Wash with saline (50 mL). The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated. mjjjjjjjjjj Methyl)cyclohexyl]-4-methylpyridine [2,3- d ]pyrimidin-7-one ( 4-7 , 9.0 g, yield: 82%).

Step 7: trans-2-amino-6-bromo-8-[4-(hydroxymethyl)cyclohexyl]-4-methylpyridine [2,3- d ]pyrimidin-7-one ( 4-7 , 9 g, 24.5 mmol), potassium carbonate (6.9 g, 50 mmol) and 2-methoxypyridin-3-ylboronic acid ( 1-10 , 3.7 g, 30 mmol) in DMF/H ₂ O (5:1) The mixture in 100 mL) was purged with nitrogen for 5 minutes, and Pd(PPh ₃ ) ₄ (2 g) was added to the mixture. The resulting mixture was stirred with heating at 100 ° C for 2 hours. The reaction mixture was concentrated with EtOAc (EtOAc)EtOAc. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated. mjjjjjjjj Hexyl]-6-(6-methoxy-3-pyridyl)-4-methylpyridine [2,3- d ]pyrimidin-7-one ( 4-8 , 4.0 g, yield: 41%).

Step 8: trans-2-amino-8-[4-(hydroxymethyl)cyclohexyl]-6-(6-methoxy-3-pyridyl)-4-methylpyridine [2,3- d ] pyrimidine-7-one ( 4-8 , 4.8 g, 12.1 mmol), 2,5-dihexanone ( 1-12 , 7 g, 61 mmol) and p-toluenesulfonic acid (0.46 g) in toluene (100) The mL) solution was heated to reflux overnight. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by column chromatography eluting EtOAc EtOAc (EtOAc) [4-(Hydroxymethyl)cyclohexyl]-6-(6-methoxy-3-pyridyl)-4-methylpyridine [2,3- d ]pyrimidin-7-one ( 4-9 ), It was a white solid (2.5 g, yield: 43%). Mass spectrometry results: m/z : 474.32 [M+H] ⁺ .

Example 4

Trans-2-amino-8-[4-(diethoxyphosphonylmethoxymethyl)cyclohexyl]-6-(6-methoxy-3-pyridyl)-4-methylpyridine Preparation of [2,3- d ]pyrimidin-7-one ( 4-11 ), the specific reaction formula is as follows:

First step: trans-(2-(2,5-dimethylpyrrol-1-yl)-8-[4-(hydroxymethyl)cyclohexyl]-6-(6-A) at -78 oC Oxy-3-pyridyl)-4-methylpyridine [2,3- d ]pyrimidin-7-one ( 4-9 , 1.3 g, 2.7 mmol, prepared according to the seventh step of Example 4A) and A solution of 1 M LiHMDS in THF (5.6 mL, 5.6 mmol) was added dropwise to a solution of fluoromethanesulfonic acid (diethoxyphosphonylmethyl) ester ( 1-14 , 1.7 g, 5.6 mmol) in THF (50 mL) . The resulting mixture was stirred at -78 °C for 0.5 h, then warmed to room temperature and stirred for 0.5 h. The reaction mixture was quenched with EtOAc EtOAc (EtOAc) The organic layer was combined, dried over anhydrous sodium sulfate, filtered and evaporated (2,5-Dimethylpyrrol-1-yl)-6-(6-methoxy-3-pyridyl)-4-methylpyridine[2,3- d ]pyrimidin-7-one ( 4- 10 , 100 mg, yield: 5.8%).

The second step: trans-8-[4-(diethoxyphosphonium methoxymethyl)cyclohexyl]-2-(2,5-dimethylpyrrol-1-yl)-6-( 6-Methoxy-3-pyridyl)-4-methylpyridine [2,3- d ]pyrimidin-7-one ( 4-10 , 100 mg, 0.16 mmol) and hydroxylamine hydrochloride (35 mg, 0.5 Methyl) was heated to reflux in a mixture of ethanol/water (10:1, 5 mL). The reaction mixture was concentrated and the residue was purified by preparative HPLC to afford trans-2-amino-8-[4-(diethoxyphosphonylmethoxymethyl)cyclohexyl]-6-(6-methoxy -3-pyridyl)-4-methylpyridine [2,3- d ]pyrimidin-7-one ( 4-11 , 8 mg, yield: 9%). NMR analysis results: ¹ H-NMR (CDCl ₃ , 400 MHz): δ 8.32 (d, J = 2.0 Hz, 1 H), 7.99 (dd, J = 2.4, 8.4 Hz, 1 H), 7.75 (s, 1 H), 6.81 (d, J = 8.4 Hz, 1 H), 5.48 (m, 1 H), 5.27 (s, 2 H), 4.24-4.17 (m, 4 H), 3.99 (s, 3 H) , 3.81 (d, J = 8.4 Hz, 2 H), 3.46 (d, J = 6.0 Hz, 1 H), 2.81-2.77 (m, 2 H), 2.62 (s, 3 H), 2.03-1.97 (m , 2 H), 1.72-1.70 (m, 2 H), 1.38 (t, J = 6.8 Hz, 6 H), 1.30-1.12 (m, 3 H). Mass spectrometry results: m/z : 546.20 [M+H] ⁺ .

The following compounds, but not limited to these compounds, can be synthesized according to the same or similar methods as described in Example 4 and Example 4A:

Example 5

2-amino-8-[1-(diethoxyphosphonylmethyl)-4-oxaridinyl]-6-(6-methoxy-3-pyridyl)-4-methylpyridine [2 , 3- d ] pyrimidine-7-one ( 5-9 ), the specific reaction formula is as follows:

First step: 5-bromo-4-chloro-6-methylpyrimidin-2-amine ( 1-2 , 200 g, 0.9 mol), 4-aminoacridine-1-carboxylic acid tert-butyl ester ( 5-1 , A solution of 217 g, 1.08 mol) and diisopropylethylamine (232.6 g, 1.8 mol) in dimethylacetamide (1 L) was heated at 120 ° C overnight. The reaction mixture was concentrated with EtOAc EtOAc EtOAc m. 4-[(2-Amino-5-bromo-6-methylpyrimidin-4-yl)amino]acridine-1-carboxylic acid tert-butyl ester ( 5-2 , 250 g, yield: 70%). Mass analysis: m / z: 386.20 [M + H, 79 Br] +, 388.20 [M + H, 81 Br] +. TLC thin layer chromatography: R _f = 0.4 (DCM / MeOH = 20:1).

Step 2: 4-[(2-Amino-5-bromo-6-methylpyrimidin-4-yl)amino]acridine-1-carboxylic acid tert-butyl ester ( 5-2 , 150 g, 0.39 mol under nitrogen) a mixture of ethyl acrylate ( 1-5 , 194 g, 1.94 mol), triethylamine (300 mL) and Pd(PPh ₃ ) ₄ (45 g, 38 mmol) in DMF (500 mL) at 120 °C The reaction was heated for 48 hours. The reaction mixture was cooled to room temperature and concentrated, the residue was purified by column chromatography, dichloromethane / methanol as eluent to give the product 4 - [[2-amino -5 - [(E) -3- B -3-oxo-l-enyl] -6-methyl-pyrimidin-4-yl] amino] piperidine-1-carboxylate (5-3) as a yellow solid (50 g, yield Rate: 30%). Mass spectrometry results: m/z : 406.30 [M+H] ⁺ . Silicone thin layer chromatography: _Rf = 0.35 (DCM / MeOH = 20:1).

The third step: 4-[[2-amino-5-[( E )-3-ethoxy-3-oxoprop-1-enyl]-6-methylpyrimidin-4-yl]amino]indole Tert-butyl-1-carboxylic acid ( 5-3 , 115 g, 0.28 mol), thiophenol (31.23 g, 0.28 mol), sodium thiophenolate (37.48 g, 0.28 mol), DBU ( 1-7 , 172.6 g, 1.13 mol) and diisopropylethylamine (219.78 g, 1.7 mol) in DMF (1 L) were heated at 110 ° C overnight. The reaction mixture was concentrated, and DCM (500 mL) The organic phase was separated and concentrated to give the crude product, ethyl acetate (200 mL), the product was collected as a white 4- (2-methyl-7- oxopyrido [2,3- d] pyrimidin-filter -8- Base) acridine-1-carboxylic acid tert-butyl ester ( 5-4 , 56 g, yield: 56%). Mass spectrometry results: m/z : 360.20 [M+H] ⁺ . Silicone _{TLC: R f = 0.45 (DCM /} MeOH = 20: 1).

Step IV: 4- (2-pyridin-4-methyl-7-oxo [2,3- d] pyrimidin-8-yl) piperidine-1-carboxylate (5-4, 20 g After adding NBS (11.83 g, 66 mmol) to a solution of EtOAc (EtOAc) (EtOAc) Sodium hydrogen solution (300 mL). The organic phase is separated and concentrated to give the crude 4-(2-amino-6-bromo-4-methyl-7-oxopyridine [2,3- d ]pyrimidin-8-yl)acridine-1-carboxylic acid tert-butyl The ester ( 5-5 , 19 g) was obtained as a brown solid which was used in the next step without purification. Mass analysis: m / z: 438.20 [M + H, 79 Br] +, 440.20 [M + H, 81 Br] +. TLC thin layer chromatography: R _f = 0.5 (DCM / MeOH = 20:1).

Step 5: 4-(2-Amino-6-bromo-4-methyl-7-oxopyridine [2,3- d ]pyrimidin-8-yl)acridine-1-carboxylic acid tert-butyl ester ( 5- 5 , 19 g, 43 mmol), potassium carbonate (18 g, 130 mmol) and 2-methoxypyrid-3-ylboronic acid ( 1-10 , 9.98 g, 66 mmol) in DMF/H ₂ O (5: The mixture in 1,240 mL) was purged with nitrogen for 5 minutes, and Pd(PPh ₃ ) ₂ Cl ₂ (3.00 g) was added to the mixture. The resulting mixture was stirred with heating at 100 ° C overnight. The reaction mixture was concentrated to dryness. EtOAc mjjjjjjjjjj -3-pyridyl)-4-methyl-7-oxopyridine [2,3- d ]pyrimidin-8-yl)acridine-1-carboxylic acid tert-butyl ester ( 5-6 ) as a brown solid (8 g, yield: 40%). Mass spectrometry results: m/z : 467.30 [M+H] ⁺ . TLC thin layer chromatography: R _f = 0.4 (DCM / MeOH = 20:1).

Step 6: 4-(2-Amino-6-(6-methoxy-3-pyridyl)-4-methyl-7-oxopyridine [2,3- d ]pyrimidin-8-yl)indole The pyridine-l-carboxylic acid tert-butyl ester ( 5-6 , 4.5 g, 9.6 mmol) was dissolved in EtOAc EtOAc m. Wash with water and wash with ethyl acetate and discard the organic layer. The aqueous layer was adjusted to pH = 8-9 with a sodium bicarbonate solution and then extracted three times with DCM. The organic layers were combined, dried over sodium sulfate and concentrated to give the product 2-amino-6-(6-methoxy-3-pyridyl)-4-methyl-8-(4-oxadinyl)pyridine [2 , 3- d ]pyrimidin-7-one ( 5-7 , 4 g, yield: 90%), as a yellow-green solid. Silicone thin layer chromatography: _Rf = 0.1 (DCM / MeOH = 5:1).

Step 7: To 2-amino-6-(6-methoxy-3-pyridyl)-4-methyl-8-(4-oxaridinyl)pyridine [2,3- d ]pyrimidine-7- To a solution of ketone ( 5-7 , 2.5 g, 6.82 mmol) in dioxane (200 mL) was added diethyl phosphite (HPO(OEt) ₂ , 5-8 , 1.9 g, 13.66 mmol), paraformaldehyde ( 0.2 g, 6.83 mmol) and acetic acid (0.41 g, 6.83 mmol). After the resulting mixture was stirred under reflux for 5 hours, the solution was concentrated, and the crude product was purified by preparative HPLC to give the product 2-amino-8-[1-(diethoxyphosphonylmethyl)-4-pyridinyl]-6- (6-methoxy-3-pyridyl)-4-methylpyridine [2,3- d ]pyrimidin-7-one ( 5-9 , 1.0 g, yield: 28%, purity 95%), Yellow solid. Further purification by SFC afforded 220 mg of pure product with a purity of 99% as a yellow solid. TLC thin layer chromatography: R _f = 0.6 (DCM / MeOH = 20:1). ¹ H-NMR (CDCl ₃ , 400 MHz): δ 8.32 (dd, J = 0.4, 2.4 Hz, 1 H), 7.98 (dd, J = 2.4, 8.8 Hz, 1 H), 7.75 (s, 1 H) , 6.82 (dd, J = 0.4, 8.4 Hz, 1 H), 5.47 (s, br, 2 H), 4.23-4.18 (m, 4 H), 3.99 (s, 3 H), 3.25-3.23 (m, 3 H), 2.89 (d, J = 11.6 Hz, 2 H), 2.60 (s, 3 H), 2.47-2.41 (m, 2 H), 1.92 (s, 2 H), 1.61-1.59 (m, 2 H), 1.38 (t, J = 6.4 Hz, 6 H). Mass spectrometry results: m/z : 517.30 [M+H] ⁺ .

The following compounds, but not limited to these compounds, can be synthesized in the same or similar manner as described in Example 5:

Example 6 Screening experiments for inhibition of kinases:

This example is the compound prepared in Example 2, cis-2-amino-8-[4-(diethoxyphosphoniummethylamino)cyclohexyl]-6-(6-methoxy-3-pyridyl) ) -4-methyl-pyridine [2,3-d] pyrimidin-7-one (2-4a) in DiscoveRx Corporation (4215 Sorrento Valley Blvd, San Diego , CA 92121) the KinomeScan ^TM (www.kinomescan.com) of The inhibition results for 98 kinases at 100 nM compound concentration in the system are shown in Table 1:

Details of this screening technique can be found in Fabian, MA et al, Nat., Biotechnol. 2005 , 23 , 329 and Karaman, MW et al, Nat., Biotechnol. 2008 , 26 , 127. From the above representative results, the compounds of the present invention have a significant inhibitory effect on kinases including mTOR, PIK3C2B, PIK3CA, PIK3CG, TYK2, DYRK1B and the like and mutants thereof.

Example 7

Biochemical inhibitory activity against several kinases and their subtypes: This example is the compound prepared in Example 2, cis-2-amino-8-[4-(diethoxyphosphoniummethylamino)cyclohexyl]-6 -(6-methoxy-3-pyridyl)-4-methylpyridine [2,3-d]pyrimidin-7-one ( 2-4a ) by Reaction Biology Corporation (Reaction Biology Corp., One Great Valley Parkway, Suite 2, Malvern, PA 19355, USA . http://www.reactionbiology.com/webapps/main/pages/kinase.aspx) Determination of mTOR, PI3K-a, PI3K-β, PI3K-g, PI3K- d, inhibition of DYRK1B, TYK2 kinase and its subtype activity. Specific steps are as follows:

The compound of the present invention was dissolved in dimethyl hydrazine (DMSO) to prepare a 10 mM stock solution, and 10 different doses were prepared by 10-fold serial dilution from 10 mM. When the inhibitory activities of the four PI3K isoforms were determined, the ATP concentration was 10 μM using the HTRF assay. When the other three kinases (mTOR, DYRK1B, TYK2) were measured, their ATP concentrations were their corresponding Km values. The measurement results

The IC ₅₀ values of the compounds 2-4a prepared in Example 2 of the present invention for inhibiting seven kinases and subtype enzymes are shown in Table 2:

As can be seen from the above data, the compound examples 2-4a of the present invention have strong inhibitory activity against the four subtypes of PI3K, and the IC ₅₀ values are respectively below 100 nM. Compound 2a also showed significant inhibition of mTOR with an IC ₅₀ value of 670 nM. The inhibitory activity of this compound against DYRK1B and TYK2 was weak.

Example 8

Anti-tumor experiment: In this example, trans-2-amino-8-[4-(diethoxyphosphonylmethoxy)cyclohexyl]-6-(6-methoxy-) prepared in Example 1 was used. The method and results of anti-tumor experiments in 3-549 human lung cancer cell xenograft nude mouse model of 3-pyridyl)-4-methylpyridine [2,3-d]pyrimidin-7-one are as follows: Experimental materials

4 to 5 weeks old SPF female BALB/c-nu/nu mice weighing 16-20 g were purchased from Guangdong Experimental Animal Center, certificate number: NO: 0072659. A549 lung cancer cells were purchased from the Cell Resource Center of the Shanghai Institute of Biological Sciences. DMEM cell culture medium, fetal bovine serum (FBS) and trypsin digest were from Gibco. Various antibiotics were purchased from Sigma. experimental method

First culture of A549 lung cancer cells: A549 cells were inoculated in DMEM medium containing 10% FBS, 100 U/ml penicillin, 100 U/ml streptomycin at 37 ° C, 5% CO ₂ , 100% humidity. The cells were cultured in a carbon dioxide incubator, and the cells were overgrown at about 48 h after inoculation. Then, 80% of A549 cells that had been overgrown at the bottom of the culture flask were digested, centrifuged at 1000 r/min for 3 min, and the cell pellet was collected. The cells were diluted to 1×10 ⁸ /mL, and 0.1 mL/negative was inoculated into the right front of the nude mouse. . On the 12th day after inoculation of the tumor cells, the tumor-bearing nude mice were weighed, the tumor size was measured, and the mice with the tumor size in the range of 150-200 mm ³ were randomly divided into a solvent group (Vehicle), aqueous hydrochloric acid solution, pH was 3) and one of the pyridine [2,3-d]pyrimidin-7-one compounds trans-2-amino-8-[4-(diethoxyphosphonylmethoxy)cyclohexyl]-6- (6-methoxy-3-pyridyl)-4-methylpyridine [2,3-d]pyrimidin-7-one ( 1-16 ) (dissolved in a carrier at a concentration of 1.0 mg/mL), per Group 4 mice; thereafter, nude mice were weighed daily and orally administered by intragastric administration (10 mg/kg qd via po) at 0.1 mL/10 g body weight, and the tumor size of each animal was measured every two days. After 18 days, the tumor-bearing mice were sacrificed by cervical dislocation and the tumor was removed and weighed. Tumor Growth Inhibition (TGI) calculation method: experimental data expressed as mean±SD; tumor inhibition rate (TGI) = [(V _{solvent group} - V _{treatment group} ) ÷V _{solvent group} ] × 100%. The V _{solvent group} was the solvent group mouse tumor volume; the V _{treatment group} was the treatment group mouse tumor volume. Experimental result

The antitumor effect of the therapeutic group of the present invention on the tumor of the mouse in the treatment group of the present invention: after the solvent and the drug solution were respectively administered to the solvent group and the treatment group for 18 days, the average tumor volume of the solvent group and the treatment group was 1179.7±420.6 mm, respectively. ³ (n=4) and 550.8±76.2 (n=4); therefore, the tumor inhibition rate (TGI) of the treatment group was 53%. There was a significant reduction in tumors in the treatment group compared to the initial tumor volume. The experimental curve is shown in Figure 1.

From the results of the above tumor inhibition experiments, the representative compounds of the present invention showed significant tumor inhibition effects in an xenograft nude mouse animal model, orally administered, 10 mg/kg once daily, and tumor suppression rate after 18 days. Up to 53%. Animals in the treatment group had little change in body weight, indicating that the drug had no significant toxicity.

Example 9

Antitumor experiment: The same procedure as in Example 8 was employed. The compound used in this example was the trans-2-amino-8-[4-(diethoxyphosphoniummethylamino) ring prepared in Example 2-4b. Hexyl]-6-(6-methoxy-3-pyridyl)-4-methylpyridine [2,3-d]pyrimidin-7-one. The tumor model was an A549 human lung cancer cell xenograft nude mouse model. Experimental result

The antitumor effect of the therapeutic group of the present invention in the treatment group of the present invention described in Example 2-4b on the tumor of the mouse is shown in Fig. 2. From the results of the above tumor inhibition experiments, representative compounds of the present invention showed tumor suppressive effects in an xenograft nude mouse animal model.

Example 10

Anti-tumor experiment: In the same manner as in Example 8, the compound used in this example was trans-4-[2-amino-6-(6-methoxy-3-pyridyl)-4 prepared in Example 3. - methyl-7-yloxy pyridine [2,3-d] pyrimidin-8-yl] - N - (diethoxyphosphoryl acyl methyl) cyclohexyl methyl Amides. The tumor model was an A549 human lung cancer cell xenograft nude mouse model. Experimental result

The antitumor effect of the therapeutic group of the compound of the present invention on the tumor of the mouse described in Example 3 is shown in Fig. 3. From the results of the above tumor inhibition experiments, representative compounds of the present invention showed tumor suppressive effects in an xenograft nude mouse animal model.

Example 11

Antitumor experiment: In the same manner as in Example 8, the compound used in this example was 2-amino-8-[1-(diethoxyphosphonylmethyl)-4-indolyl group prepared in Example 5. -6-(6-Methoxy-3-pyridyl)-4-methylpyridine [2,3- d ]pyrimidin-7-one. The tumor model was an A549 human lung cancer cell xenograft nude mouse model. Experimental result

The antitumor effect of the therapeutic group of the present invention in the treatment group of the present invention as described in Example 5 is shown in Fig. 4. After 18 days of the experiment, the tumor was removed after the animals were sacrificed, and Figure 4 shows the tumor weight of the drug-administered group and the vehicle control group. From the results of the above tumor inhibition experiments, representative compounds of the present invention showed tumor suppressive effects in an xenograft nude mouse animal model.

Example 12

Anti-tumor experiment: Using a method similar to that of Example 8, the compound used in this example is the cis-2-amino-8-[4-(diethoxyphosphoniummethylamino) ring prepared in Example 2-4a. Hexyl]-6-(6-methoxy-3-pyridyl)-4-methylpyridine [2,3-d]pyrimidin-7-one. The tumor model was an animal model of PC3 human prostate cancer cell xenograft nude mice. Experimental result

The antitumor effect of the therapeutic group of the present invention in the treatment group of the present invention described in Example 2-4a on the tumor of mice is shown in Fig. 5. From the results of the above tumor inhibition experiments, the representative compounds of the present invention showed significant tumor inhibition in the xenograft nude mouse animal model, orally administered, 10 mg/kg once daily, and the tumor inhibition rate after 21 days. Up to 73%. Animals in the treatment group had little change in body weight, indicating that the drug had no significant toxicity.

Example 13

Anti-tumor experiment: Using a method similar to that of Example 8, the compound used in this example is the cis-2-amino-8-[4-(diethoxyphosphoniummethylamino) ring prepared in Example 2-4a. Hexyl]-6-(6-methoxy-3-pyridyl)-4-methylpyridine [2,3-d]pyrimidin-7-one. The tumor model was a U87MG human glioblastoma cell xenograft nude mouse model. Experimental result

The antitumor effect of the therapeutic group of the present invention in the treatment group of the present invention described in Example 2-4a on the tumor of the mouse is shown in Fig. 6. From the results of the above tumor inhibition experiments, the representative compounds of the present invention showed significant tumor inhibition in the xenograft nude mouse animal model, orally administered, 2.5 mg/kg once daily, and the tumor inhibition rate after 14 days. Up to 64%. Animals in the treatment group had little change in body weight, indicating that the drug had no significant toxicity.

Example 14: Tablets (mg/tablet) Compound prepared in Example 1 : 100; lactose, Ph EUR: 182.75; sodium carboxymethylcellulose: 12.0; corn starch slurry (5 w/v%): 2.25; Magnesium citrate: 3.0.

Example 15: Tablets (mg/tablet) The compound prepared in Example 5: 100, the content of other substances was the same as in Example 14.

Example 16: Tablets (mg/tablet) Compound prepared in Example 2-4a: 50; lactose, Ph EUR: 223.75; sodium carboxymethylcellulose: 6.0; corn starch: 15.0; polyvinylpyrrolidone (5 w/ v%): 2.25; magnesium stearate: 3.0.

Example 17: Tablets (mg/tablet) The compound prepared in Example 2-4a: 50, the other substance content was the same as in Example 16.

Example 18: Tablets (mg/tablet) Compound prepared in Example 3: 1.0; lactose, Ph EUR: 93.25; sodium carboxymethylcellulose: 4.0; corn starch slurry (5 w/v%): 0.75; Magnesium citrate: 76.

Example 19: Tablets (mg/tablet) The compound prepared in Example 3: 1.0, the other substance content was the same as in Example 18.

Example 20: Capsules (mg/capsule) Compound prepared in Example 2-4a: 10.0; lactose, Ph EUR: 488.5; Magnesium: 1.5.

Example 21: Pharmaceutical composition and preparation Capsule (mg/capsule) The compound prepared in Example 2-4a: 10.0, the other substance content was the same as in Example 20.

Example 22: Pharmaceutical composition and preparation Injection (50 mg/ml) Compound prepared in Example 4: 5%; 1 M sodium hydroxide solution: 15%; 0.1 M hydrochloric acid solution (adjusted pH = 7.6); polyethylene glycol 400:5%; water for injection is adjusted to 100%.

Example 23: Pharmaceutical composition and preparation Injection (50 mg/ml) The compound prepared in Example 2-4b: 5%, the other substance content was the same as in Example 22, and finally adjusted to 100% with water for injection.

Example 24: Pharmaceutical composition and preparation Injection (10 mg/ml) Compound prepared in Example 2-4a: 1%; disodium hydrogen phosphate BP: 3.6%; 0.1 M sodium hydroxide solution: 15%; water for injection was adjusted to 100%.

Example 25: Pharmaceutical composition and preparation Injection (10 mg/ml) The compound prepared in Example 5: 1%, the other substance content was the same as in Example 32, and the water for injection was adjusted to 100%.

Example 26: Pharmaceutical composition and preparation Injection (1 mg/ml) (pH adjusted to 6) Compound prepared in Example 1: 0.1%; disodium hydrogen phosphate BP: 2.26%; citric acid: 0.38%; polyethylene glycol 400:3.5%; water for injection is adjusted to 100%;

Example 27: Pharmaceutical composition and preparation Injection (1 mg/ml) (pH adjusted to 6) The compound prepared in Example 2-4a: 0.1%, the content of other substances was the same as in Example 26, and finally adjusted to 100 with water for injection. %.

Example 28: Pharmaceutical composition and formulation Aerosol (mg/ml) Compound prepared in Example 1 : 10; sorbitan oleate: 13.5; trichlorofluoromethane: 910.0; dichlorodifluoromethane: 490.0.

Example 29: Pharmaceutical composition and formulation Aerosol (mg/ml) The compound prepared in Example 3: 10, the other substance content was the same as in Example 28.

Example 30: Pharmaceutical Composition and Formulation Aerosol (mg/ml) Compound prepared in Example 2-4a: 0.2; sorbitan oleate: 0.27; trichlorofluoromethane: 70.0; dichlorodifluoromethane: 280.0; Dichlorotetrafluoroethane: 1094.0.

Example 31: Pharmaceutical composition and formulation Aerosol (mg/ml) The compound prepared in Example 2-4a: 0.2, the other substance content was the same as in Example 30.

Example 32: Pharmaceutical composition and formulation aerosol (mg/ml) Compound prepared in Example 5: 2.5; sorbitan oleate: 3.38; trichlorofluoromethane: 67.5; dichlorodifluoromethane: 1086.0; Dichlorotetrafluoroethane: 191.60.

Example 33: Pharmaceutical composition and formulation Aerosol (mg/ml) The compound prepared in Example 2-4b: 2.5, the other substance content was the same as in Example 32.

Example 34: Pharmaceutical Composition and Formulation Aerosol (mg/ml) Compound prepared in Example 2-4a: 2.5; Soy lecithin: 2.7; Trichlorofluoromethane: 67.5; Dichlorodifluoromethane: 1086.0; Dichloro Tetrafluoroethane: 191.60.

Example 35: Pharmaceutical composition and formulation Aerosol (mg/ml) The compound prepared in Example 2-4a: 2.5, the other substance content was the same as in Example 34.

Example 36: Pharmaceutical composition and preparation ointment (/ml) Compound prepared in Example 2-4a: 40 mg; ethanol: 300 μl; water: 300 μl; 1 - dodecyl azacycloheptanone: 50 Microliter; propylene glycol: to 1 ml.

Example 37: Ointment (/ml) Compound prepared in Example 2-4a: 40 mg, the same as in Example 36.

The above is only a specific embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art can easily think of changes or substitutions within the technical scope of the present invention. All should be covered by the scope of the present invention. Therefore, the scope of the invention should be determined by the scope of the appended claims.

no.

Figure 1 is a comparison chart of the anti-tumor effect of the compound of the present invention described in Example 1 on a mouse A549 tumor;

Figure 2 is a graph showing the anti-tumor effect of the compound of the present invention described in Example 2-4b on a mouse A549 tumor;

Figure 3 is a comparison chart of the anti-tumor effect of the compound of the present invention on the tumor of mouse A549 described in Example 3;

Figure 4 is a graph showing the tumor weight of the compound of the present invention as described in Example 5 for tumor suppressor effect on mouse A549 tumor;

Figure 5 is a graph showing the anti-tumor effect of the compound of the present invention on the tumor of mouse PC3 as described in Example 2-4a;

Figure 6 is a graph showing the anti-tumor effect of the compound of the present invention described in Example 2-4a on mouse U87MG tumor.

no.

Claims (18)

A phosphorus-containing pyrido[2,3- d ]pyrimidin-7-one compound or a pharmaceutically acceptable salt thereof, which has a molecular structural formula as shown in formula (I): Wherein Ar is an aryl or heteroaryl group, and the hydrogen in Ar may be substituted by 1 to 5 identical or different G ¹ ; X is CR ¹ or N; A represents C _1-6 alkyl, C=O Or a covalent bond, and when A is a C _1-6 alkyl group, the hydrogen therein may be substituted with 1-5 identical or different G ² ; L represents O, NR ² , S(=O) _m or one Covalent bond; J represents a C _1-6 alkyl group or a covalent bond, and the hydrogen in J may be substituted by 1 to 5 identical or different G ³ ; R and R' each independently represent H, OH, halogen , C _1-6 alkyl, C _3-6 cycloalkyl, C _3-12 heteroalicyclic, C _1-6 alkoxy, C _3-6 cycloalkoxy or C _3-12 heterolipid epoxy a group, and the hydrogen in R and R' may be substituted by 1 to 5 identical or different G ⁴ , and R and R' may together with the linked phosphorus atom form a C _3-12 heteroalicyclic ring, said C _{3 - The 12} heteroalicyclic ring may additionally comprise one or more O, N or S(=O) _m heteroatoms; wherein: G ¹ , G ² , G ³ and G ⁴ independently represent H, -CN, -CF ₃ , -OCF ₃ , -NO ₂ , halogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C ₆ aryl, C _5-6 heteroaryl Base, C _3-12 heteroalicyclic group, R ³ O-, R ³ R ⁴ N-, R ³ S(=O) _m -, R ³ R ⁴ NS(=O _m -, R ⁵ C(=O)-, R ³ R ⁴ NC(=O)-, R ³ OC(=O)-, R ⁵ C(=O)O-, R ³ R ⁴ NC(= O)O-, R ⁵ C(=O)NR ³ -, R ³ R ⁴ NC(=O)NR ⁶ -, R ³ OC(=O)NR ⁶ -, R ³ S(=O) _m NR ⁶ -, R ³ R ⁴ NS(=O) _m NR ⁶ -, R ³ R ⁴ NC(=NR ⁷ )NR ⁶ -, R ³ R ⁴ NC(=CHNO ₂ )NR ⁶ -, R ³ R ⁴ NC( =N-CN)NR ⁶ -, R ³ R ⁴ NC(=NR ⁷ )-, R ³ S(=O)(=NR ⁷ )NR ⁶ - or R ³ R ⁴ NS(=O)(=NR ⁷ And R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ each independently represent H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, a C _3-6 cycloalkyl group, a C ₆ aryl group, a C _5-6 heteroaryl group or a C _3-12 heteroalicyclic group; when R ³ and R ^{4 are} bonded to the same nitrogen atom, together with the nitrogen atom forming a C _3-12 heterocycloaliphatic, C _3-12 heterocycloaliphatic this may additionally contain one or more O, N or S (= O) _m hetero atoms; and ^{R 1, R 2, R 3} , R ⁴ , the hydrogen in R ⁵ , R ⁶ and R ⁷ may be substituted by 1 to 5 identical or different halogen, -CN, -OH, C _1-6 alkyl or C _3-6 cycloalkyl; m is 0 , 1 or 2. The phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein when Ar is a substituted pyridyl group, X is When CR ¹ or N, the structure of the compound is as shown in formula (Ia) or (Ib): In the formula, R ¹ represents hydrogen or C _1-6 alkyl; A represents C _1-6 alkyl, C=O or a covalent bond, and when A is a C _1-6 alkyl group, hydrogen therein It may be substituted by 1 to 5 identical or different G ² ; L represents O, NR ² or S(=O) _m or a covalent bond; J represents a C _1-6 alkyl group or a covalent bond, and J The hydrogen may be substituted by 1 to 5 identical or different G ³ ; the definitions of m, G ¹ , G ² , G ³ , R, R' and R ² are the same as those described in claim 1 of the scope of the patent application. The phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound (Ia) or a pharmaceutically acceptable salt thereof according to claim 2, wherein the substituted pyridyl group is pyridine-3 a group wherein the substituent G ¹ is G ¹¹ , R ¹ is hydrogen, R is RR, and R ' is R'R'. When A is a covalent bond, the structure of the compound is as defined in formula (Ic) or (Id ) shown: In the formula, G ¹¹ represents hydrogen, halogen, -OCF ₃ , -CF ₃ , -CN, -NMe ₂ , C _1-6 alkyl or C _1-6 alkoxy; L represents O or NR ² ; Represents a C _1-6 alkyl group, and the hydrogen in J may be substituted with 1-5 identical or different G ³ ; RR and R'R' each independently represent -OH, halogen, C _1-6 alkyl or C _1-6 alkoxy, and the hydrogen in RR and R'R' may be substituted by 1 to 5 identical or different G ⁴ , and RR and R'R' may together with the linked phosphorus atom form C _3-12 a heteroalicyclic ring, the C _3-12 heteroalicyclic ring may additionally comprise one or more O, N or S(=O) _m heteroatoms; m, G ³ , G ⁴ and R ² are defined and claimed The same as described in item 1. The phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound (Ia) or a pharmaceutically acceptable salt thereof according to claim 2, wherein the substituted pyridyl group is pyridine-3 a group wherein the substituent G ¹ is G ¹¹ , R ¹ is hydrogen, R is RR, and R' is R'R', the structure of the compound is as shown in formula (Ie) or (If): In the formula, G ¹¹ represents hydrogen, halogen, -OCF ₃ , -CF ₃ , -CN, -NMe ₂ , C _1-6 alkyl or C _1-6 alkoxy; A represents C=O or C _{1 -6} alkyl, and when A is a C _1-6 alkyl group, the hydrogen therein may be substituted with 1 to 5 identical or different G ² ; L represents O or NR ² ; J represents a C _1-6 alkyl group, And the hydrogen in J may be substituted by 1 to 5 identical or different G ³ ; RR and R'R' each independently represent -OH, halogen, C _1-6 alkyl or C _1-6 alkoxy, and The hydrogen in RR and R'R' may be substituted by 1 to 5 identical or different G ⁴ , and RR and R'R' may together with the linked phosphorus atom form a C _3-12 heteroalicyclic ring, said C _{3 The -12} heteroalicyclic ring may additionally comprise one or more O, N or S(=O) _m heteroatoms; m, G ² , G ³ , G ⁴ and R ² are as defined in claim 1 The same. The phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound (Ib) or a pharmaceutically acceptable salt thereof according to claim 2, wherein the substituted pyridyl group is pyridine-3 a group wherein the substituent G ¹ is G ¹¹ and R is RR, and when R' is R'R', the structure of the compound is as shown in the formula (Ig): In the formula, G ¹¹ represents hydrogen, halogen, -OCF ₃ , -CF ₃ , -CN, -NMe ₂ , C _1-6 alkyl or C _1-6 alkoxy; J represents C _1-6 alkyl And the hydrogen in J may be substituted by 1 to 5 identical or different G ³ ; RR and R'R' each independently represent -OH, halogen, C _1-6 alkyl or C _1-6 alkoxy, And the hydrogen in RR and R'R' may be substituted by 1 to 5 identical or different G ⁴ , and RR and R'R' may together with the linked phosphorus atom form a C _3-12 heteroalicyclic ring, said C _{The 3-12} heteroalicyclic ring may additionally contain one or more O, N or S(=O) _m heteroatoms; the definitions of m, G ³ and G ⁴ are the same as those described in claim 1 of the scope of the patent application. The phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound or a pharmaceutically acceptable salt thereof, according to the invention of claim 1, wherein the compound or a pharmaceutically acceptable salt thereof Is any one of the following compounds: trans-2-amino-8-[4-(diethoxyphosphonylmethoxy)cyclohexyl]-6-(6-methoxy-3-pyridyl)-4 -methylpyridine [2,3-d]pyrimidin-7-one; cis-2-amino-8-[4-(diethoxyphosphoniummethoxy)cyclohexyl]-6-(6- Methoxy-3-pyridyl)-4-methylpyridine[2,3-d]pyrimidin-7-one; trans-2-amino-8-[4-(diethoxyphosphoniummethylamino) Cyclohexyl]-6-(6-methoxy-3-pyridyl)-4-methylpyridine[2,3-d]pyrimidin-7-one; cis-2-amino-8-[4- (diethoxyphosphoniummethylamino)cyclohexyl]-6-(6-methoxy-3-pyridyl)-4-methylpyridine [2,3-d]pyrimidin-7-one; trans -4-[2-Amino-6-(6-methoxy-3-pyridyl)-4-methyl-7-oxypyridine [2,3-d]pyrimidin-8-yl]-N-( Diethoxyphosphonylmethyl)cyclohexylcarbamide; cis-4-[2-amino-6-(6-methoxy-3-pyridyl)-4-methyl-7-oxyl Pyridine [2,3-d]pyrimidin-8-yl]-N-(diethoxyphosphonylmethyl)cyclohexyl Amine; trans-2-amino-8-[4-(diethoxyphosphonylmethoxymethyl)cyclohexyl]-6-(6-methoxy-3-pyridyl)-4-methyl Pyridine [2,3-d]pyrimidin-7-one; cis-2-amino-8-[4-(diethoxyphosphonylmethoxymethyl)cyclohexyl]-6-(6- Methoxy-3-pyridyl)-4-methylpyridine[2,3-d]pyrimidin-7-one; 2-amino-8-[1-(diethoxyphosphonylmethyl)-4 -acridinyl]-6-(6-methoxy-3-pyridyl)-4-methylpyridine[2,3-d]pyrimidin-7-one; trans-2-amino-8-[4 -(diethoxyphosphonium methoxy)cyclohexyl]-6-(6-dimethylamino-3-pyridyl)-4-methylpyridine [2,3-d]pyrimidin-7-one; Cis-2-amino-8-[4-(diethoxyphosphonylmethoxy)cyclohexyl]-6-(6-dimethylamino-3-pyridyl)-4-methylpyridine [2 ,3-d]pyrimidin-7-one; trans-2-amino-8-[4-(diethoxyphosphoniummethylamino)cyclohexyl]-6-(6-dimethylamino-3-pyridine -4-methylpyridine [2,3-d]pyrimidin-7-one; cis-2-amino-8-[4-(diethoxyphosphoniummethylamino)cyclohexyl]-6- (6-dimethylamino-3-pyridyl)-4-methylpyridine [2,3-d]pyrimidin-7-one; trans-4-[2-amino-6-(6-dimethylamino- 3-pyridyl)-4-methyl-7-oxypyridyl [2,3-d]pyrimidin-8-yl]-N-(diethoxyphosphonylmethyl)cyclohexylcarbamide; cis-4-[2-amino-6-(6-dimethyl Amino-3-pyridyl)-4-methyl-7-oxypyridine[2,3-d]pyrimidin-8-yl]-N-(diethoxyphosphonylmethyl)cyclohexylcarbamide ; trans-2-amino-8-[4-(diethoxyphosphonylmethoxymethyl)cyclohexyl]-6-(6-dimethylamino-3-pyridyl)-4-methyl Pyridine [2,3-d]pyrimidin-7-one; cis-2-amino-8-[4-(diethoxyphosphonylmethoxymethyl)cyclohexyl]-6-(6-di Methylamino-3-pyridyl)-4-methylpyridine[2,3-d]pyrimidin-7-one; 2-amino-8-[1-(diethoxyphosphonylmethyl)-4- Acridinyl]-6-(6-dimethylamino-3-pyridyl)-4-methylpyridine[2,3-d]pyrimidin-7-one; trans-2-amino-8-[4- (diethoxyphosphonium methoxy)cyclohexyl]-6-(6-ethyl-3-pyridyl)-4-methylpyridine [2,3-d]pyrimidin-7-one; cis -2-amino-8-[4-(diethoxyphosphonylmethoxy)cyclohexyl]-6-(6-ethyl-3-pyridyl)-4-methylpyridine [2,3- d]pyrimidin-7-one; trans-2-amino-8-[4-(diethoxyphosphoniummethylamino)cyclohexyl]-6-(6-ethyl-3-pyridyl)-4 -methylpyridine [2,3-d]pyrimidin-7-one; Cis-2-amino-8-[4-(diethoxyphosphoniummethylamino)cyclohexyl]-6-(6-ethyl-3-pyridyl)-4-methylpyridine [2,3 -d]pyrimidin-7-one; trans-2-amino-8-[4-(diethoxyphosphonylmethoxy)cyclohexyl]-6-(6-methylamino-3-pyridyl) -4-methylpyridine [2,3-d]pyrimidin-7-one; cis-2-amino-8-[4-(diethoxyphosphonium methoxy)cyclohexyl]-6-( 6-methylamino-3-pyridyl)-4-methylpyridine [2,3-d]pyrimidin-7-one; trans-2-amino-8-[4-(diethoxyphosphonyl) Amino)cyclohexyl]-6-(6-methylamino-3-pyridyl)-4-methylpyridine[2,3-d]pyrimidin-7-one; cis-2-amino-8-[4- (diethoxyphosphoniummethylamino)cyclohexyl]-6-(6-methylamino-3-pyridyl)-4-methylpyridine[2,3-d]pyrimidin-7-one; trans- 2-amino-8-[4-(diethoxyphosphonylmethyl(methyl)amino)cyclohexyl]-6-(6-methoxy-3-pyridyl)-4-methylpyridine [ 2,3-d]pyrimidin-7-one; cis-2-amino-8-[4-(diethoxyphosphonylmethyl(methyl)amino)cyclohexyl]-6-(6-A Oxy-3-pyridyl)-4-methylpyridine [2,3-d]pyrimidin-7-one; trans-2-amino-8-[4-(diethoxyphosphonylmethyl) Ethyl)amino)cyclohexyl]-6- (6-methoxy-3-pyridyl)-4-methylpyridine [2,3-d]pyrimidin-7-one; cis-2-amino-8-[4-(diethoxyphosphonium) Methyl(ethyl)amino)cyclohexyl]-6-(6-methoxy-3-pyridyl)-4-methylpyridine[2,3-d]pyrimidin-7-one; trans-2 -amino-8-[4-(diethoxyphosphonylmethyl(n-propyl)amino)cyclohexyl]-6-(6-methoxy-3-pyridyl)-4-methylpyridine [ 2,3-d]pyrimidin-7-one; cis-2-amino-8-[4-(diethoxyphosphonylmethyl(n-propyl)amino)cyclohexyl]-6-(6- Methoxy-3-pyridyl)-4-methylpyridine[2,3-d]pyrimidin-7-one; trans-2-amino-8-[4-(diethoxyphosphonylmethyl) (isopropyl)amino)cyclohexyl]-6-(6-methoxy-3-pyridyl)-4-methylpyridine[2,3-d]pyrimidin-7-one; cis-2-amino 8-(4-(diethoxyphosphonylmethyl(isopropyl)amino)cyclohexyl]-6-(6-methoxy-3-pyridyl)-4-methylpyridine [2, 3-d]pyrimidin-7-one; trans-2-amino-8-[4-(diethoxyphosphonylmethyl(cyclopropyl)amino)cyclohexyl]-6-(6-methoxy Benzyl-3-pyridyl)-4-methylpyridine[2,3-d]pyrimidin-7-one; cis-2-amino-8-[4-(diethoxyphosphonylmethyl) Propyl)amino)cyclohexyl]-6-(6 -methoxy-3-pyridyl)-4-methylpyridine [2,3-d]pyrimidin-7-one; trans-8-[4-(diethoxyphosphonium methoxy) ring Hexyl]-2-(2,5-dimethylpyrrol-1-yl)-6-(6-methoxy-3-pyridyl)-4-methylpyridine[2,3-d]pyrimidin-7 -ketone; cis-8-[4-(diethoxyphosphoniummethoxy)cyclohexyl]-2-(2,5-dimethylpyrrol-1-yl)-6-(6-A Oxy-3-pyridyl)-4-methylpyridine [2,3-d]pyrimidin-7-one; trans-8-[4-(diethoxyphosphoniummethylamino)cyclohexyl]- 2-(2,5-dimethylpyrrol-1-yl)-6-(6-methoxy-3-pyridyl)-4-methylpyridine[2,3-d]pyrimidin-7-one; Trans-[4-[2-Amino-6-(6-methoxy-3-pyridyl)-4-methyl-7-oxy-pyrido[2,3-d]pyrimidin-8-yl Cyclohexyloxy]methyl-ethoxy-phosphoric acid; cis-[4-[2-amino-6-(6-methoxy-3-pyridyl)-4-methyl-7-oxyl -pyrido[2,3-d]pyrimidin-8-yl]cyclohexyloxy]methyl-ethoxy-phosphoric acid; trans-[4-[2-amino-6-(6-methoxy-) 3-pyridyl)-4-methyl-7-oxy-pyrido[2,3-d]pyrimidin-8-yl]cyclohexyloxy]methyl-phosphate; cis-[4-[2- Amino-6-(6-methoxy-3-pyridyl)-4-methyl-7-oxy-pyrido[2,3-d]pyrimidin-8-yl Cyclohexyloxy]methyl-phosphoric acid; trans-[[4-[2-amino-6-(6-methoxy-3-pyridyl)-4-methyl-7-oxy-pyridine [2,3-d]pyrimidin-8-yl]cyclohexyl]amino]methyl-ethoxy-phosphoric acid; cis-[[4-[2-amino-6-(6-methoxy-3- Pyridyl)-4-methyl-7-oxy-pyrido[2,3-d]pyrimidin-8-yl]cyclohexyl]amino]methyl-ethoxy-phosphoric acid; trans-[[4- [2-Amino-6-(6-methoxy-3-pyridyl)-4-methyl-7-oxy-pyrido[2,3-d]pyrimidin-8-yl]cyclohexyl]amino] Methyl-phosphoric acid or cis-[[4-[2-amino-6-(6-methoxy-3-pyridyl)-4-methyl-7-oxy-pyrido[2,3-d Pyrimidine-8-yl]cyclohexyl]amino]methyl-phosphoric acid. The phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein the pharmaceutically The above acceptable salt is a salt formed by chemical reaction of the phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound with an inorganic acid, an organic acid, an inorganic base or an organic base. A racemic solution of a phosphorus-containing pyrido[2,3-d]pyrimidin-7-one or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7 Or enantiomer. A phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound having a molecular structural formula of formula (IIa), (IIb) or (IIc): Wherein Ar' is aryl or heteroaryl, and the hydrogen in Ar' may be substituted by 1 to 5 identical or different R ⁸ ; R ² represents H, C _1-6 alkyl, C _3-6 ring An alkyl or C _3-12 heteroalicyclic group, and the hydrogen in R ² may be 1 to 5 identical or different halogen, -CN, -OH, C _1-6 alkyl or C _3-6 cycloalkyl Substituting; R and R' independently represent H, OH, halogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-12 heteroalicyclic, C _1-6 alkoxy, C _{3 a -6} cycloalkoxy group or a C _3-12 heteroaliphatic epoxy group, and the hydrogen in R and R′ may be substituted by 1 to 5 identical or different R ⁹ , and R and R′ may also be bonded to a phosphorus atom. Forming a C _3-12 heteroalicyclic ring together, the C _3-12 heteroalicyclic ring may additionally comprise one or more O, N or S(=O) _m heteroatoms; wherein: R ⁸ and R ⁹ independently represent H, -CN, -CF ₃ , -OCF ₃ , -NO ₂ , halogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-12 heteroalicyclic, C _1-6 alkoxy, C _{a 1-6} cycloalkoxy group, a C _3-12 heteroaliphatic epoxy group or R ¹⁰ R ¹¹ N-; wherein R ¹⁰ and R ¹¹ each independently represent H, C _1-6 alkyl, C _3-6 ring alkyl or C _3-12 heterocycloaliphatic group; when R ¹⁰ and R ^{11 are} attached to the same nitrogen atom, the nitrogen atom may be a Forming a C _3-12 heterocycloaliphatic, C _3-12 heterocycloaliphatic this may additionally contain one or more O, N or S (= O) _m hetero atoms; m is 0, 1 or 2. The phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound (IIa), (IIb) or (IIc) as described in claim 9 wherein Ar' is pyridin-3-yl When the substituent R ⁸ is R ⁸⁸ and R is RR, and R' is R'R', the structure of the compound is as shown in formula (IIaa), (IIbb) or (IIcc): In the formula, R ² represents hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl or C _3-12 heteroalicyclic, preferably hydrogen, methyl, ethyl, n-propyl, isopropyl Base, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrogen Pyranyl, acridinyl, pyridazinyl or morpholinyl, further preferably hydrogen, methyl, ethyl, n-propyl, ethylpropyl, cyclopropyl, oxetanyl, tetrahydrofuranyl or tetrahydrogen a pyranyl group, still more preferably hydrogen, methyl, ethyl, isopropyl, cyclopropyl, and these groups may be substituted by 1 to 5 halogens, -CN, -OH or C _1-6 alkyl; R ⁸⁸ represents hydrogen, halogen, -OCF ₃ , -CF ₃ , -CN, -NMe ₂ , C _1-6 alkyl or C _1-6 alkoxy, preferably halogen, -OCF ₃ , -OCH ₃ , - OCH ₂ CH ₃ or -NMe ₂ , further preferably -OCH ₃ or -NMe ₂ ; R ¹² and R ¹³ each independently represent -OH, halogen, C _1-6 alkyl or C _1-6 alkoxy group, preferably is -OH or C _1-6 alkoxy group, more preferably a C _1-6 alkoxy group, even more preferably methoxy, ethoxy, Propoxy or isopropoxy. A pharmaceutical composition comprising a phosphorus pyrido[2,3-d]pyrimidin-7-one compound according to any one of claims 1 to 7 or a pharmaceutically acceptable composition thereof Accepted salt, or a racemic or enantiomer of a phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound or a pharmaceutically acceptable salt thereof according to claim 8. The pharmaceutical composition of claim 11, wherein the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers or diluents. The pharmaceutical composition according to claim 11 or 12, wherein the pharmaceutical composition is in the form of an oral preparation, an injection, an anal preparation, a nostril inhalation, an eye drop or a skin patch. A phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or a phosphorus-containing pyridinium according to claim 8 a 2,3-d]pyrimidin-7-one compound or a racemate or enantiomer thereof in a pharmaceutically acceptable salt, or a pharmaceutical composition according to any one of claims 11 to 13 in the treatment of Use in diseases caused by abnormal activities of protein kinases. The use according to claim 14, wherein the protein kinase is PI3K or mTOR, preferably PI3K, and even more preferably PI3K-a, PI3K-β, PI3K-g and PI3K-d. The use according to claim 14, wherein the diseases are psoriasis, cirrhosis, bronchitis, rheumatoid arthritis, lupus erythematosus, diabetes, diseases involving angiogenesis, eye diseases, immune system diseases, cardiovascular diseases. Disease, epilepsy, neurodegenerative disease, Alzheimer's disease, Huntington's disease or Parkinson's disease. The use of claim 14, wherein the disease is a tumor, the tumor comprising a solid tumor and a liquid tumor. The use of the invention as claimed in claim 17, wherein the tumor comprises: lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer , gastric cancer, colon cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulva cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid carcinoma , soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, bladder cancer, kidney or ureteral cancer, kidney cancer, central nervous system neoplasm, spinal axis tumor, pituitary adenoma, gastrointestinal stromal tumor, colon A combination of one or any combination of rectal cancer, non-small cell lung cancer, small cell lung cancer, mastocytosis, glioma, sarcoma, and lymphoma.