TWI580679B - Heteroaryl-pyrimidine derivatives, preparation process and pharmaceutical use thereof - Google Patents

Description

Heteroarylpyrimidine derivatives, preparation methods and uses thereof

The present invention relates to a novel heteroarylpyrimidine derivative, a pharmaceutically acceptable salt thereof, a process for the preparation thereof, and a pharmaceutical composition containing the same, and its use as a cancer therapeutic agent, particularly as an mTOR inhibitor.

In the past half century, research on cancer treatment has made many progress. With the deepening of research on tumor genetics and biology, a number of intracellular tumor-related key signaling pathways have been discovered. Tumor cells rely on these pathways to achieve intracellular transduction of extracellular signals, regulate their own sustained proliferation, invasion and metastasis, and anti-apoptosis activities, while maintaining their malignant phenotypic characteristics, on the other hand by regulating specific genes and their protein products. Tolerance to treatment. Among them, phospholipid inositol 3 kinase (PI3K)-AKT-mammalian rapamycin target (mToR) pathway as one of the most important signaling pathways has become a better target for tumor drug development.

As a key signaling pathway in the cell, PI3K-AKT-mTOR pathway is involved in the fine regulation of multiple processes such as cell cycle growth, protein synthesis, energy metabolism and survival and apoptosis after activation by various receptor signals.

Phosphatidylinositide 3-kinase (PI3K) belongs to the family of lipid kinases and can be classified into three classes according to its structural characteristics and substrate selectivity. Among them, the most in-depth study of Category 1 PI3K. This type of PI3K is a heterodimeric protein composed of p110 and p85 protein subunits, and each subunit has different subtypes, such as p110 α, p110 β, p85 α, p85 β and the like. P85-regulated subunit The interaction of the enzyme is initiated by phosphorylation, and the p110 catalytic subunit converts the phospholipid inositol diphosphate (PI2P) to the phospholipid inositol triphosphate (PI3P), which in turn can initiate multiple downstream signaling molecules to complete the cell. Continued conduction of the outer signal (Bader, 2005, Nature Rev., Cancer 5, 921-929; Engelman, 2006, Nature Rev. Genet. 7, 606-619.).

AKT, also known as protein kinase B, is a serine/threonine protein kinase and is a major downstream effector of PI3K. Phospholipid creatinine triphosphate produced by PI3K can induce intracellular AKT and phosphoinositide-dependent protein kinase 1 (PDK1) to be localized to and bound to the cell membrane. Activated PDK1 phosphorylates AKT and maximizes activity by interacting with mTOR complex 2. As the central link of the entire PI3K-AKT-mTOR signal, AKT relies on its kinase activity to regulate multiple downstream signals, completing the regulation of processes such as protein synthesis and cell proliferation, making it one of the important potential targets (Inoki, 2002, Nature Cell Biol, 4, 648-657; Hay, 2004, Genes Dev. 18, 1926-1945.).

Another key component of the PI3K-AKT-mTOR signal is the mammalian target of rapamycin (mTOR), which was discovered and named in 1990 when studying the mechanism of action of rapamycin. mTOR, which is an intracellular serine/threonine protein kinase, belongs to four classes of PI3k kinases and has a similar molecular structure to the p110 subunit of PI3K. mTOR exists in two different complexes, mTORC1 and mTORC2, by binding to different protein molecules. mTORC1 is located downstream of AKT; mTORC2 is initiated by other mechanisms and is involved in the regulation of AKT activity. AKT by phosphorus Acidizing the TSC protein (tuberous sclerosis) attenuates the inhibitory effect of the TSC protein on mTORC1, allowing mTORC1 to be activated by GTPase. The activated mTOR further transcribes and translates specific genes by ribosomal protein kinase p70S6K and transcriptional regulatory protein 4EBP1, thereby finally completing the conduction process and realizing the response of the cells to extracellular signals (Wullschleger, 2006, Cell 124, 471-484; Sabatini, 2006, Nature Rev. Cancer 6, 729-734.).

As a key regulatory pathway of cell function, PI3K-AKT-mTOR is closely related to the activation of proto-oncogenes and has a critical impact on the occurrence and development of tumors. As the most common abnormal signaling pathway in tumor cells, PI3K regulatory protein PTEN abnormality, AKT overexpression or overactivation can cause continuous activation of PI3K signal. These mutations are ubiquitous in a variety of solid tumors, such as breast, lung, colon, pancreatic, liver, and digestive tract tumors, and are closely associated with treatment tolerance and poor prognosis (Wood, 2007, Science 318, 1108-1113). ; Thomas, 2007, Nature Genet., 39, 347-351). Therefore, it is expected that the single or multiple inhibition of PI3K, AKT and mTOR by developing small molecule compounds has a good development prospect as a tumor therapeutic drug.

Currently, there are several compounds that inhibit PI3K, AKT, mTOR activity or PI3K/mTOR dual inhibition in development and clinical trials (Garcia, 2008, Oncogene 27, 5511-5526; Rhodes, 2008, Cancer Res. 68, 2366). -2374; Thoreen, 2009, J. Biol. Chem. 284, 8023-8032.). A series of mTOR kinases are currently disclosed Patent applications for inhibitors, including US20090099174 and WO2008023161.

Although a series of mTOR kinase inhibitors for cancer treatment have been published, it is still necessary to develop new drug compounds for better tumor treatment purposes to better meet market demand. The present invention provides a novel structure of an mTOR kinase inhibitor, and finds that a compound having such a structure also has good activity and exhibits excellent effects and effects.

The object of the present invention is to provide a novel heteroarylpyrimidine derivative represented by the formula (I) and a pharmaceutically acceptable salt thereof, Wherein: one or both of X ¹ , X ² or X ³ is an N atom, the others are CH; R ¹ and R ² together with the N atom to which they are attached form a heterocyclic group, wherein the heterocyclic group contains one or a plurality of heteroatoms selected from N, O or S(O) _m , and the heterocyclic group is further selected from one or more selected from the group consisting of alkyl, halogen, oxo, alkenyl, alkynyl, alkoxy, if desired , nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, -C(O)R ⁷ , -C(O)OR ⁷ , -S(O) _m R ⁷ , -NR ⁸ Substituted with a substituent of R ⁹ , —C(O)NR ⁸ R ⁹ , —NR ⁸ C(O)R ⁹ , —NR ⁸ S(O) _m R ⁹ or —S(O) _m NR ⁸ R ⁹ ; R ^{3 is} selected from aryl or heteroaryl, wherein the aryl or heteroaryl is further optionally one or more selected from the group consisting of alkyl, hydroxyalkyl, halogen, oxo, alkenyl, alkynyl, alkoxy. Base, nitro, cyano, cycloalkyl, haloalkoxy, heterocyclyl, aryl, heteroaryl, -C(O)R ⁷ , -C(O)OR ⁷ , -S(O) _m R ⁷ , -NR ⁸ R ⁹ , -C(O)NR ⁸ R ⁹ , -NR ⁸ C(O)R ⁹ , -NR ⁸ S(O) _m R ⁹ or -S(O) _m NR ⁸ R ⁹ substituents; R ⁴ is selected from cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl ^{, -OR 5, -SR 5, -NR} 5 R 6, -C (O) NR 8 R 9 , or -NHC (O) R ^7, wherein the heterocyclic group of the general formula (I) is connected pyrimidinyl The atom is a carbon atom, and the alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclic group is further optionally further selected from one or more selected from the group consisting of halogen, oxo, hydroxy, alkoxy, cyano, aryl, Substituted by a heterocyclic group, a heteroaryl group, a substituent of -C(O)OR ⁷ or -S(O) _m R ⁷ or -NR ⁸ R ⁹ ; R ^{5 is} selected from a heterocyclic group, wherein the heterocyclic group is Containing one or more heteroatoms selected from N, O or S(O) _m , and the heterocyclic group is further further selected from one or more selected from the group consisting of alkyl, halogen, oxo, alkenyl, alkynyl, Alkoxy, haloalkyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R ⁷ , -C(O)OR ⁷ , -S(O) _m R ⁷ , -NR ⁸ R ⁹ , -C(O)NR ⁸ R ⁹ , -NR ⁸ C(O)R ⁹ , -NR ⁸ S(O) _m R ⁹ or -S(O) _m NR ⁸ R ⁹ Substituted by a substituent; R ^{6 is} selected from a hydrogen atom, an alkyl group or a cycloalkyl group, wherein the alkyl group or the cycloalkyl group is further further selected from one or more selected from the group consisting of an alkyl group, an alkoxy group, a halogen group, and an oxo group. , nitro, cyano, cycloalkyl ^{Heterocyclyl, -C (O) R 7,} -C (O) OR 7, -S (O) m R 7, -NR 8 R 9, -C (O) NR 8 R 9, -NR 8 C ( O) R ⁹ , -NR ⁸ S(O) _m R ⁹ or -S(O) _m NR ⁸ R ⁹ substituted; R ⁷ , R ⁸ and R ⁹ are each independently selected from a hydrogen atom, an alkyl group a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is further further selected from one or more selected from the group consisting of alkyl, halogen, Substituent substitution of alkoxy, nitro, cyano, cycloalkyl, oxo, heterocyclyl, aryl or heteroaryl; m is 0, 1 or 2.

In a preferred embodiment of the invention, a compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein R ³ is an aryl group.

In another preferred embodiment of the present invention, a compound of the formula (I) or a pharmaceutically acceptable salt thereof, which is a compound of the formula (II) or a pharmaceutically acceptable salt thereof: Wherein: X ¹ to X ³ , R ³ to R ⁴ are as defined above for the definition of formula (I); and R ^{10 is} selected from a hydrogen atom or an alkyl group.

In another preferred embodiment of the present invention, a compound of the formula (II) or a pharmaceutically acceptable salt thereof, which is a compound of the formula (III) or a pharmaceutically acceptable salt thereof: Wherein: R ^{4 is} as defined above for the definition of formula (I); R ^{10 is} selected from a hydrogen atom or an alkyl group; and R ¹¹ or R ¹² are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a hydroxyl group. Or -C(O)NR ¹³ R ¹⁴ , wherein the alkyl or alkoxy group is further further selected from one or more selected from the group consisting of alkyl, hydroxyalkyl, hydroxy, alkoxy, halogen, nitro, cyano or Substituents of -NR ¹³ R ¹⁴ are substituted; and R ¹³ or R ¹⁴ are each independently selected from a hydrogen atom, an alkyl group or a cycloalkyl group.

In another preferred embodiment of the present invention, a compound of the formula (III) or a pharmaceutically acceptable salt thereof, which is a compound of the formula (IV) or a pharmaceutically acceptable salt thereof: Wherein: R ⁴ , R ¹¹ or R ¹² are as defined above for the definition of formula (III).

Further, in a preferred embodiment of the present invention, a compound of the formula (IV) or a pharmaceutically acceptable salt thereof, which is a compound represented by the formula (IV) i or the formula (IV) ii or Its pharmaceutically acceptable salt: Wherein: R ⁴ , R ¹¹ or R ¹² are as defined above for the definition of formula (IV).

Typical compounds of the invention include, but are not limited to: Or a pharmaceutically acceptable salt thereof.

The invention further relates to a process for the preparation of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, the process comprising:

The compound of the formula (IA) is subjected to a nucleophilic substitution reaction with R ⁴ H under basic conditions to give a compound of the formula (I); the conditions for providing basicity include an organic base and an inorganic base, the organic base including triethyl Amine, N,N-diisopropylethylamine, n-butyllithium, potassium t-butoxide, and the inorganic bases include sodium hydride, sodium carbonate, potassium carbonate or cesium carbonate.

Or catalyzing a compound of the formula (IA) with a R ⁴ B(OH) ₂ palladium catalyst, preferably tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride or [1, 1'-bis(diphenylphosphino)ferrocene]palladium dichloride is subjected to a Suzuki coupling reaction to give a compound of the formula (I).

Alternatively, a compound of the formula (IA) can be reacted with tributyl(R ⁴ )stannane in the presence of bis(triphenylphosphine)palladium dichloride and cuprous iodide to give a compound of the formula (I).

The solvent used includes dimethyl hydrazine, 1,4-dioxane or N,N-dimethylformamide.

In the formula (IA), X is selected from halogen; X ¹ to X ³ and R ¹ to R ³ are as defined above in the definition of the formula (I).

The invention further relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) according to the invention, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

The invention further relates to a compound of the formula (I) or a pharmaceutically acceptable compound thereof Use of a salt or a pharmaceutical composition comprising the same for the preparation of a medicament for inhibiting mTOR and/or PI3K kinase.

The present invention further relates to the use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the preparation of a medicament for treating a cancer or a tissue hyperplasia disease, wherein the cancer is selected from the group consisting of melanoma, Papillary thyroid tumor, cholangiocarcinoma, colon cancer, ovarian cancer, lung cancer, malignant lymphoma, liver cancer, kidney cancer, bladder cancer, prostate cancer, breast cancer and pancreatic cancer and sarcoma, and malignant glioma, skin cancer, colon cancer Primary and recurrent solid tumors or leukemias of thyroid cancer, lung cancer and ovarian cancer.

The present invention also relates to a method of inhibiting mTOR kinase activity comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

In other words, the present invention relates to a method for treating a cancer or a tissue hyperplasia comprising administering to a subject a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, The cancer is selected from the group consisting of melanoma, papillary thyroid tumor, cholangiocarcinoma, colon cancer, ovarian cancer, lung cancer, malignant lymphoma, liver, kidney, bladder, prostate, breast and pancreatic cancer and sarcoma, and skin, colon, Primary and recurrent solid tumors or leukemia of the thyroid, lungs and ovaries.

The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Tincture. Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions, such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavorings Agents, colorants and preservatives to provide a pleasing and palatable pharmaceutical preparation. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of a tablet for admixture. These excipients may be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn Starch or alginic acid; a binder such as starch, gelatin, polyvinylpyrrolidone or gum arabic and a lubricant such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or may be coated by a known technique which provides a sustained release effect over a longer period of time by masking the taste of the drug or delaying disintegration and absorption in the gastrointestinal tract. For example, water-soluble taste masking materials such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or extended-time materials such as ethylcellulose, cellulose acetate butyrate may be used.

It is also possible to use hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in which the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin or olive oil. Soft gelatin capsules provide oral preparations.

The aqueous suspension contains the active substance and excipients suitable for the preparation of the aqueous suspension for mixing. Such excipients are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and acacia; dispersing or wetting agents may be naturally occurring a phospholipid such as lecithin, or a condensation product of an alkylene oxide with a fatty acid such as polyoxyethylene stearate, or a condensation product of ethylene oxide with a long chain fatty alcohol, such as heptadecylethyleneoxy cetyl alcohol (heptadecaethyleneoxy cetanol), or ethylene oxide with partial esters derived from fatty acids and hexitols a condensation product, such as polyethylene oxide sorbitan monooleate, or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride, such as polyethylene oxide sorbitan monooleate . The aqueous suspensions may also contain one or more preservatives such as ethylparaben or n-propylparaben, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents such as sucrose, saccharin or arsenic. Spartan.

The oil suspension can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. The above sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of an anti-oxidant such as butylated hydroxyanisole or alpha-tocopherol.

Dispersible powders and granules suitable for use in the preparation of aqueous suspensions can be employed in the preparation of aqueous dispersions in the form of active ingredients and dispersions or wetting agents, suspending agents or one or more preservatives. Suitable dispersing or wetting agents and suspending agents can be used to illustrate the above examples. Other excipients such as sweetening, flavoring, and coloring agents may also be added. These compositions are preserved by the addition of an anti-oxidant such as ascorbic acid.

In the form of an oil-in-water emulsion, the oil phase may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids such as soy lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of the partial esters and ethylene oxide, for example Polyethylene oxide sorbitol monooleate. The emulsions may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.

The pharmaceutical composition of the invention may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oily phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. The oil solution is then added to a mixture of water and glycerin to form a microemulsion. The injection or microemulsion can be injected into the bloodstream of the patient by a local injection. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compound of the invention. To maintain this constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous pump.

The pharmaceutical composition of the present invention may be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration. The suspension may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension, such as a solution prepared in 1,3-butanediol, in a non-toxic parenterally acceptable diluent or solvent. In addition, sterile fixed oils may conveniently be employed as a solvent or suspension medium. For this purpose, any blended fixed oil including synthetic mono- or diglycerides can be used. In addition, fatty acids such as oleic acid can also be prepared as an injection.

The pharmaceutical composition of the present invention can be administered in the form of a suppository for rectal administration. A suitable non-irritating agent that releases the drug by melting the drug with a solid at normal temperature but in the rectum and thus melting in the rectum These agents are mixed to prepare these pharmaceutical compositions. Such materials include a mixture of cocoa butter, glycerin gelatin, hydrogenated vegetable oil, polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.

As is well known to those skilled in the art, the dosage of the drug to be administered depends on a variety of factors including, but not limited to, the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient, the patient's Diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc.; alternatively, the preferred mode of treatment, such as the mode of treatment, the daily amount of the compound of formula (I) or the type of pharmaceutically acceptable salt, may be Traditional treatment options to verify.

Detailed description of the invention

Terms used in the specification and patent claims have the following meanings unless stated to the contrary.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 12 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, t-butyl, n-pentyl, 1,1-dimethylpropyl 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl- 2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1 , 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl , 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-di Methylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl , 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4 -ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-decyl, 2-methyl-2-ethylhexyl, 2-methyl-3 -ethylhexyl 2,2-diethyl-pentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl group, and various branched chain isomers thereof. More preferred are lower alkyl groups having from 1 to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, Second butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methyl Butyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2 - dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4- Methyl amyl, 2,3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from the group consisting of alkane Base, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, -C(O)R ⁷ , -C(O)OR ⁷ , -S(O) _m R ⁷ -NR ⁸ R ⁹ , -C(O)NR ⁸ R ⁹ , -NR ⁸ C(O)R ⁹ , -NR ⁸ S(O) _m R ⁹ or -S(O) _m NR ⁸ R ⁹ .

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the cycloalkyl ring contains from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably 3 to 10 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene A polycycloalkyl group includes a spiro ring, a fused ring, and a cycloalkyl group.

The term "spirocycloalkyl" refers to a polycyclic group that shares a carbon atom (referred to as a spiro atom) between 5 to 20 members of a single ring, which may contain one or more double bonds, but none of the rings are fully conjugated π electronic system. It is preferably 6 to 14 members, more preferably 7 to 10 members. The spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group and a bispirocycloalkyl group, depending on the number of common spiro atoms between the ring and the ring. . More preferably, it is 4 members/4 members, 4 members/5 members, 4 members/6 members, 5 members/5 members or 5 members/6 members of the monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include:

The term "fused cycloalkyl" refers to 5 to 20 members, each ring of the system sharing an all-carbon polycyclic group of an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated π-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. The bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl group may be classified according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5 member/5 member or 5 member/6 member bicycloalkyl group. Non-limiting examples of fused cycloalkyl groups include:

The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms which are not directly bonded, which may contain one or more double bonds, but none of which has a complete Conjugate π-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring. Non-limiting examples of bridged cycloalkyl groups include:

The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthyl , benzocycloheptyl and the like. The cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, ring Alkylthio, heterocycloalkylthio, oxo, -NR ⁸ R ⁹ , -C(O)NR ⁸ R ⁹ , -NR ⁸ C(O)R ⁹ , -NR ⁸ S(O) _m R ⁹ , -S(O) _m NR ⁸ R ⁹ , -C(O)R ¹⁰ , -C(O)OR ¹⁰ or -S(O) _m R ¹⁰ .

The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or -butenyl and the like. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio. , alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, -C(O)R ⁷ , -C(O)OR ⁷ , -S(O) _m R ⁷ , -NR ⁸ R ⁹ , -C(O)NR ⁸ R ⁹ , -NR ⁸ C(O)R ⁹ , -NR ⁸ S(O) _m R ⁹ or -S(O) _m NR ⁸ R ⁹ .

The term "alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, 1-propynyl, 2-propynyl, 1-, 2- Or 3-butynyl and the like. The alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio. , alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, -C(O)R ⁷ , -C(O)OR ⁷ , -S(O) _m R ⁷ , -NR ⁸ R ⁹ , -C(O)NR ⁸ R ⁹ , -NR ⁸ C(O)R ⁹ , -NR ⁸ S(O) _m R ⁹ or -S(O) _m NR ⁸ R ⁹ .

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, that is, includes a monocyclic heterocyclic group and a polycyclic heterocyclic group, which contains 3 to 20 ring atoms, of which one or more The ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (where m is an integer from 0 to 2), but excluding the ring moiety of -OO-, -OS- or -SS-, the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are hetero atoms; more preferably, the cycloalkyl ring contains 3 to 10 ring atoms; more preferably, the cycloalkyl ring contains 5 to 7 ring atoms; Preferred cycloalkyl rings contain 5 or 6 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include:

The term "forming a heterocyclic group together with the N atom to be bonded" means a heterocyclic group containing at least one nitrogen ring atom, preferably 3 to 12 ring atoms, more preferably 3 to 8 ring atoms, more preferably The preferred cycloalkyl ring contains 5 to 7 ring atoms, and most preferably the cycloalkyl ring contains 5 or 6 ring atoms, wherein further one or more ring atoms are optionally selected from nitrogen, oxygen or S(O). a hetero atom wherein _m (wherein m is an integer of 0 to 2); "R ¹ and R ² together with the N atom to which they are bonded form a heterocyclic group" is used in the present invention to mean a heterocyclic group containing at least one nitrogen ring atom. Preferably, it contains from 3 to 12 ring atoms, more preferably from 3 to 8 ring atoms, more preferably the cycloalkyl ring contains from 5 to 7 ring atoms, and most preferably the cycloalkyl ring contains 5 or 6 ring atoms. It further contains one or more hetero atoms selected from N, O or S(O) _m as needed.

Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.

The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between 5 to 20 members of a single ring, wherein one or more ring atoms are selected from nitrogen, oxygen or S (O). ) _m (where m is an integer 0 to 2) heteroatoms, and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. The spiroheterocyclyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspirocyclic group, preferably a monospirocycloalkyl group and a bispirocycloalkyl group, depending on the number of common spiro atoms between the ring and the ring. . More preferably, it is 4 members/4 members, 4 members/5 members, 4 members/6 members, 5 members/5 members, or 5 members/6 members of a single spiro heterocyclic group. Non-limiting examples of spiroheterocyclyl groups include:

The term "fused heterocyclyl" refers to 5 to 20 members, each ring of the system sharing an adjacent pair of atomic polycyclic heterocyclic groups with other rings in the system, and one or more rings may contain one or more Double bond, but none of the rings have a fully conjugated π-electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (where m is an integer from 0 to 2), and the remaining rings The atom is carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. It may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group according to the number of constituent rings, preferably a bicyclic or tricyclic ring, more preferably a 5 member/5 member or a 5 member/6 member bicyclic fused heterocyclic ring. base. Non-limiting examples of fused heterocyclic groups include:

The term "bridge heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms which are not directly bonded, which may contain one or more double bonds, but none of the rings have a total A π-electron system of a yoke in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (where m is an integer from 0 to 2), the remaining ring atoms being carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring. Non-limiting examples of bridge heterocyclic groups include:

The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heterocyclic group, non-limiting examples of which include: Wait. The heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, ring Alkylthio, heterocycloalkylthio, oxo, -C(O)R ⁷ , -C(O)OR ⁷ , -S(O) _m R ⁷ , -NR ⁸ R ⁹ , -C(O) NR ⁸ R ⁹ , -NR ⁸ C(O)R ⁹ , -NR ⁸ S(O) _m R ⁹ or -S(O) _m NR ⁸ R ⁹ .

The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (ie, a ring that shares a pair of adjacent carbon atoms) groups which are polycyclic rings having a conjugated π-electron system (ie, The ring group adjacent to a carbon atom is preferably 6 to 10 members, such as a phenyl group and a naphthyl group. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples of which include:

The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio. , alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, -C(O)R ⁷ , -C(O)OR ⁷ , -S(O) _m R ⁷ , -NR ⁸ R ⁹ , -C(O)NR ⁸ R ⁹ , -NR ⁸ C(O)R ⁹ , -NR ⁸ S(O) _m R ⁹ or -S(O) _m NR ⁸ R ⁹ .

The term "heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 10 members, more preferably 5 or 6 members, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl. , tetrazolyl and the like. The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples of which include:

The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, ring Alkylthio, heterocycloalkylthio, -C(O)R ⁷ , -C(O)OR ⁷ , -S(O) _m R ⁷ , -NR ⁸ R ⁹ , -C(O)NR ⁸ R ⁹ -NR ⁸ C(O)R ⁹ , -NR ⁸ S(O) _m R ⁹ or -S(O) _m NR ⁸ R ⁹ .

The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, ring Alkylthio, heterocycloalkylthio, -C(O)R ⁷ , -C(O)OR ⁷ , -S(O) _m R ⁷ , -NR ⁸ R ⁹ , -C(O)NR ⁸ R ⁹ -NR ⁸ C(O)R ⁹ , -NR ⁸ S(O) _m R ⁹ or -S(O) _m NR ⁸ R ⁹ .

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens.

The term "haloalkoxy" refers to an alkoxy group substituted on the alkyl group with one or more halogens.

The term "hydroxy" refers to an -OH group.

The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group.

The term "halogen" means fluoro, chloro, bromo or iodo.

The term "amino" refers to -NH _2.

The term "cyano" refers to -CN.

The term "nitro" refers to -NO ₂ .

The term "benzyl" refers to -CH ₂ - benzene.

The term "oxo" refers to =0.

The term "carboxy" refers to -C(O)OH.

The term "carboxylate group" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl, cycloalkyl are as defined above.

"As needed" or "as needed" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may be, but not necessarily, present, and the description includes a case where a heterocyclic group is substituted with an alkyl group and a case where a heterocyclic group is not substituted with an alkyl group. .

"Substituted" refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can do without too much effort. Determine (by experiment or theory) a substitution that may or may not be possible. For example, an amine group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.

"Pharmaceutical composition" means a mixture comprising one or more of the compounds herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers and excipient. The purpose of the pharmaceutical composition is to promote the administration of the organism, and to facilitate the absorption of the active ingredient to exert biological activity.

"Pharmaceutically acceptable salt" refers to a salt of a compound of the invention which is safe and effective for use in a mammal and which possesses the desired biological activity.

R ⁷ to R ⁹ are as defined in the compound of the formula (I), and m is 0, 1 or 2.

The invention is further described in the following examples, but these examples are not intended to limit the scope of the invention. The experimental methods in the examples of the present invention which do not specify the specific conditions are usually in accordance with conventional conditions or according to the conditions recommended by the raw material or the manufacturer of the commodity. Reagents without specific source are routine reagents purchased from the market.

The structure of the compound is determined by nuclear magnetic resonance ( ¹ H NMR) and/or mass spectrometry (MS). ^{The 1} H NMR shift (δ) is provided in units of parts per million (ppm). ^{The 1} H NMR measurement was carried out using a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated methanol (CD ₃ OD), deuterated chloroform (CDCl ₃ ), and deuterated dimethyl hydrazine (DMSO- d ₆ ). Marked as tetramethyl decane (TMS).

MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

The HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm chromatography column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm chromatography column).

The IC ₅₀ value was determined using a NovoStar plate reader (BMG, Germany).

The thin layer chromatography tantalum plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 tannin sheet, and the thin layer chromatography (TLC) detection of the tannin sheet used for the reaction is 0.15 mm to 0.2 mm. The thin layer chromatography is used to separate and purify the tannin sheet. The specifications used are from 0.4 mm to 0.5 mm.

The rubber hose column generally uses Yantai Huanghai Silicone 200 to 300 mesh silicone as a carrier.

The basic alumina column generally uses FCP 200 to 300 mesh basic alumina as a carrier for the chromatography of the national medicine.

The known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be used by ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc and Companies such as Rui Chemicals are buying.

Unless otherwise stated in the examples, the reactions were all carried out under a nitrogen or argon atmosphere.

An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.

The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon having a volume of about 1 L.

The pressurized hydrogenation reaction was carried out using a Parr Model 3916EKX hydrogenation apparatus and a clear blue QL-500 type hydrogen generator or a HC2-SS type hydrogenation apparatus.

The hydrogenation reaction is usually evacuated, charged with hydrogen, and the operation is repeated 3 times.

Unless otherwise stated in the examples, the solution means an aqueous solution.

There is no particular description in the examples, and the reaction temperature is room temperature and is 20 ° C to 30 ° C.

The progress of the reaction in the examples was monitored by thin layer chromatography (TLC). The systems used for the reaction were: dichloromethane and methanol systems, n-hexane and ethyl acetate systems, petroleum ether and ethyl acetate systems. In the acetone system, the volume ratio of the solvent is adjusted depending on the polarity of the compound.

The system of the eluent for column chromatography and the system for developing the thin layer chromatography of the purified compound include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: dichloromethane and In the acetone system, the volume ratio of the solvent is adjusted depending on the polarity of the compound, and a small amount of an alkaline reagent such as triethylamine or an acidic reagent such as acetic acid may be added for adjustment.

Example 1 7-[3-(Hydroxymethyl)-4-methoxy-phenyl]-4-morpholine-pyrido[2,3-d]pyrimidine-2-carbonitrile

The first step 7-chloro-1H-pyrido[2,3-d]pyrimidine-2,4-dione 2-amino-6-chloro-pyridine-carboxamide 1a (5.90 g, 34 mmol, The well-known method "prepared by the patent WO2007060404" was dissolved in 120 mL of toluene, and added with chloroform (5.6 mL, 68 mmol), and refluxed for 4 hours. Filtration, the filter cake was washed with toluene (20 mL×2) and dried in vacuo to give the title product crude 7-chloro-1H-pyrido[2,3-d]pyrimidine-2,4-dione 1b (6 g, milky white Solid), the product was directly subjected to the next step without purification. MS m/z (ESI): 198.2 [M+1].

The second step 2,4,7-trichloropyrido[2,3-d]pyrimidine will be crude 7-chloro-1H-pyrido[2,3-d]pyrimidine-2,4-dione 1b (6 g , 30.40 mmol) dissolved in 80 mL of toluene, added with N,N-diisopropylethylamine (11.80 g, 91.40 mmol), stirred at 70 ° C for 40 minutes, then Phosphorus oxychloride (15.50 g, 91.40 mmol) was added and the reaction was refluxed for 3 hours. The reaction mixture was concentrated under reduced pressure. EtOAc EtOAc (EtOAc m. The residue obtained was purified by column chromatography eluting with EtOAc (EtOAc) to ield: ield: ield: 2,4,7-trichloropyrido[2,3-d]pyrimidine 1c (5 g, white solid), yield: 69.4% . MS m/z (ESI): 234.1 [M+1].

The third step is 4-(2,7-dichloropyrido[2,3-d]pyrimidin-4-yl)morpholine 2,4,7-trichloropyrido[2,3-d]pyrimidine 1c ( 3 g, 12.80 mmol) was dissolved in 60 mL of dichloromethane, and morpholine (2.23 g, 25.60 mmol) was added dropwise to the solution, and the reaction was stirred for 19 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc)EtOAc. Concentration, the residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc) 2.90 g, white solid), yield: 79.7%. MS m/z (ESI): 285.1 [M+1].

The fourth step [5-(2-chloro-4-morpholine-pyrido[2,3-d]pyrimidin-7-yl)-2-methoxy-phenyl]methanol

Dissolve 4-(2,7-dichloropyrido[2,3-d]pyrimidin-4-yl)morpholine 1d (3.27 g, 11.50 mmol) in 100 mL of acetonitrile and water (V/V = 1:1 [2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl Methanol 1e (4.24 g, 13.80 mmol, prepared by the known method "Patent WO2007084786" Further, potassium carbonate (4.80 g, 34.50 mmol) and bis(triphenylphosphine)palladium dichloride (1.60 g, 2.30 mmol) were reacted at 90 ° C for 3 hours. After cooling, 400 mL of ethyl acetate was added, and the organic layer was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified to give the title product [5-(2-chloro-4-morpholine-pyrido[2,3-d]pyrimidin-7-yl)-2-methoxy-phenyl]methanol 1f (2 g, pale yellow solid), yield: 45.5%. MS m/z (ESI): 387.1 [M+1].

Step 5 7-[3-(Hydroxymethyl)-4-methoxy-phenyl]-4-morpholine-pyrido[2,3-d]pyrimidine-2-carbonitrile

[5-(2-Chloro-4-morpholine-pyrido[2,3-d]pyrimidin-7-yl)-2-methoxy-phenyl]methanol 1f (50 mg, 0.13 mmol) and cyanide Sodium (7 mg, 0.14 mmol) was dissolved in 2 mL of dimethyl hydrazine and reacted at 140 ° C for 2 hours. After cooling, 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL×2). The organic phase was combined, washed with water (40 mL×3) and saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue obtained was purified to purified crystals to afford to afford the title product 7-[3-(hydroxymethyl)-4-methoxy-phenyl]-4-morpholine-pyridine And [2,3-d]pyrimidine-2-carbonitrile 1 (10 mg, yellow solid), yield: 20.4%. MS m/z (ESI): 378.0 [M+1]. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.57 (d, 1H), 8.33 (s, 1H), 8.25 (d, 1H), 8.13 (d, 1H), 7.19 (d, 1H), 5.37 (s) , 1H), 4.75 (s, 2H), 4.13-4.09 (m, 4H), 3.98 (s, 3H), 3.89-3.88 (m, 4H).

Example 2 7-[3-(Hydroxymethyl)-4-methoxy-phenyl]-4-morpholine- Pyrido[2,3-d]pyrimidine-2-carboxamide

7-[3-(Hydroxymethyl)-4-methoxy-phenyl]-4-morpholine-pyrido[2,3-d]pyrimidine-2-carbonitrile 1 (130 mg, 0.33 mmol) Hydrogen peroxide solution (112 mg, 0.99 mmol) and potassium carbonate (92 mg, 0.66 mmol) were dissolved in 5 mL of dimethyl hydrazine and reacted for 12 hours. Add 20 mL of water, and extract with ethyl acetate (20 mL×3). The organic phase is combined, washed with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate The obtained residue was purified with eluent system A to give the title product 7-[3-(hydroxymethyl)-4-methoxy-phenyl]-4-morpholine-pyrido[2,3-d]pyrimidine. 2-carbamamine 2 (20 mg, yellow solid), yield 15.3. MS m/z (ESI): 396.2 [M + 1]. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.32 (s, 1H), 7.92-7.90 (m, 2H), 7.56 (d, 1H), 7.04 (d, 1H), 5.39 (s, 1H), 4.86 (s, 2H), 4.00 (s, 3H), 3.90-3.85 (m, 8H).

Embodiment Example 33 - {[7- [3- (hydroxymethyl) -4-methoxy - phenyl] -4 - [(3 S) -3- methyl-morpholin-4-yl] pyrido [ 2,3- d ]pyrimidin-2-yl]amino}azepine-2-one

[5-[2-Chloro-4-[(3 S )-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl]-2 was sequentially added to the sealed tube. -Methoxy-phenyl]methanol 3a (100 mg, 0.25 mmol, prepared by the known method "Patent WO2008023161"), 3-Aminoazetidine-2-one (47.36 mg, 0.37 mmol), N N-diisopropylethylamine (0.2 mL, 0.75 mmol) and 5 mL of 1,4-dioxane were reacted at 90 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAc mjjjjj 4-[(3 S )-3-methylmorpholin-4-yl]pyrido[2,3- d ]pyrimidin-2-yl]amino}azepine-2-one 3 (80 mg, yellow Solid), Yield: 65.0%. MS m/z (ESI): 49:21. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.23-8.01 (m, 3H), 7.56-7.49 (m, 1H), 7.01-6.91 (m, 1H), 5.37 (s, 1H), 4.82-4.79 (m) , 2H), 3.95 (s, 3H), 3.72-3.68 (m, 4H), 3.56-3.54 (m, 1H), 3.44-3.32 (m, 3H), 3.22-3.19 (m, 2H), 1.88-1.63 (m, 2H), 1.56-1.24 (m, 4H), 1.10 (d, 3H).

Example 4 {5- [2-cyclopropyl -4 - [(3 S) -3- methyl-morpholin-4-yl] pyrido [2,3- d] pyrimidin-7-yl] -2- Methoxy-phenyl}methanol

[5-[2-Chloro-4-[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl]-2- was added sequentially to the sealed tube. a mixed solvent of methoxy-phenyl]methanol 3a (30 mg, 0.07 mmol), 5 mL of 1,4-dioxane and water (V/V = 3:1), cyclopropylboronic acid (8 mg, 0.09) Methyl acetate (31 mg, 0.23 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (3 mg, 0.004 mmol) were reacted at 100 ° C for 18 hours. The reaction mixture was concentrated under reduced pressure, resulting in a thin layer chromatography developing solvent system A and the residue was purified to give the title product {5- [2-cyclopropyl -4 - [(3 S) -3- methylmorpholine - 4-yl]pyrido[2,3- d ]pyrimidin-7-yl]-2-methoxy-phenyl}methanol 4 (6 mg, white solid), yield: 20.0%. MS m/z (ESI): 407.2 [M+1]. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.27-8.25 (m, 2H), 8.15 (d, 1H), 7.75 (d, 1H), 7.03 (d, 1H), 4.82 (s, 2H), 4.51(s,1H),4.08(m,2H),3.98(s,3H),3.83-3.73(m,5H),1.55-1.53(m,3H),1.25-1.23(m,1H),1.13- 1.11 (m, 2H), 0.92-0.90 (m, 2H).

Example 5 2-{7-[3-(Hydroxymethyl)-4-methoxy-phenyl]-4-morpholine-pyrido[2,3- d ]pyrimidin-2-yl}propyl- 1,3-diol

First step, tert-butyl [[5-(2-chloro-4-morpholine-pyrido[2,3-d]pyrimidin-7-yl)-2-methoxy-phenyl]methanol]- Methyl decane

[5-(2-Chloro-4-morpholine-pyrido[2,3-d]pyrimidin-7-yl)-2-methoxy-phenyl]methanol 1f (300 mg, 0.78 mmol), Tributyldimethylchloromethane (140 mg, 0.93 mmol) and triethylamine (0.2 mL, 1.55 mmol) were dissolved in 10 mL of tetrahydrofuran and reacted at 60 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAc mjjjjjjjj 3-d]pyrimidin-7-yl)-2-methoxy-phenyl]methanol]-dimethyldecane 5a (150 mg, yellow solid), yield: 38.6%. MS m/z (ESI): 5021. [M+1].

The second step is 2-[7-[3-[(t-butyl(dimethyl)indolyl)oxymethyl]-4-methoxy-phenyl]-4-morpholine-pyrido[2, 3-d]pyrimidin-2-yl]malonic acid diethyl ester

Sodium hydride (28.80 mg, 1.20 mmol) and diethyl malonate (192 Mg, 1.20 mmol) was dissolved in 10 mL of acetonitrile, stirred for 30 minutes, and added to the tert-butyl [[5-(2-chloro-4-morpholine-pyrido[2,3-d]pyrimidin-7-yl) 2-methoxy-phenyl]methanol]-dimethyldecane 5a (300 mg, 0.60 mmol) was refluxed for 3 hours. The reaction mixture was poured into 30 mL of ice water and extracted with ethyl acetate (40 mL×3). The organic phase was combined and washed with saturated sodium chloride solution (50 mL×2), dried over anhydrous sodium sulfate Concentration, purification of the residue by HPLC to elute to afford the title product 2-[7-[3-[(t-butyl(dimethyl) decyl)oxymethyl]-4- Methoxy-phenyl]-4-morpholine-pyrido[2,3-d]pyrimidin-2-yl]malonate 5b (240 mg, reddish brown solid), yield: 64.2%. MS m/z (ESI): 625.1 [M+1].

The third step is 2-[7-[3-(hydroxymethyl)-4-methoxy-phenyl]-4-morpholine-pyrido[2,3-d]pyrimidin-2-yl]propyl- 1,3-diol

2-[7-[3-[(Third-butyl(dimethyl)indenyl)oxymethyl]-4-methoxy-phenyl]-4-morpholine-pyrido[2,3- d]pyrimidin-2-yl]diethyl malonate 5b (120 mg, 0.20 mmol) was dissolved in 10 mL of THF, and lithium borohydride (17 mg, 0.80 mmol) was added and reacted at 60 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure and purified tolululululululululululululululululululululululu 4-morpholine-pyrido[2,3- d ]pyrimidin-2-yl}propyl-1,3-diol 5 (8 mg, yellow solid), yield: 9.7%. MS m/z (ESI): 428.1 [M+1]. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.33 (s, 1H), 8.01-7.9 (m, 2H), 7.51 (d, 1H), 7.10 (d, 1H), 5.02 (s, 1H), 4.97 (s, 2H), 4.78 (s, 2H), 3.87-3.85 (m, 7H), 3.71-3.55 (m, 8H), 2.97-2.96 (m, 1H).

Example 6 {2-Methoxy-5-[4-morpholin-2-(4-piperidinylamino)pyrido[2,3- d ]pyrimidin-7-yl]phenyl}methanol

[5-(2-Chloro-4-morpholine-pyrido[2,3-d]pyrimidin-7-yl)-2-methoxy-phenyl]methanol 1f (150 mg, 0.39 mmol), 1 -Methylpiperidine-4-amine (53 mg, 0.46 mmol) and N,N-diisopropylethylamine (100 mg, 0.78 mmol) were dissolved in 5 mL of 1,4-dioxane, microwave 140 The reaction was carried out at ° C for 35 minutes. The reaction mixture was concentrated under reduced pressure and purified to purified crystals eluted elut elut elut elut elut elut elut elut elut elut elut elut Pyridyl[2,3- d ]pyrimidin-7-yl]phenyl}methanol 6 (10 mg, yellow solid), yield: 5.7%. MS m/z (ESI): 451.1 [M + 1]. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.32 (s, 1H), 8.21 (d, 1H), 8.08 (d, 1H), 7.62 (d, 1H), 7.10 (d, 1H), 5.26 ( s, 1H), 4.85 (s, 1H), 4.82 (s, 1H), 4.58 (s, 2H), 3.87 (s, 3H), 3.78-3.68 (m, 8H), 3.31-3.29 (m, 3H) , 3.04-2.98 (m, 2H), 2.03-2.00 (m, 2H), 1.51-1.48 (m, 2H).

Example 7 {5-[2-(Aminomethyl)-4-morpholine-pyrido[2,3- d ]pyrimidin-7-yl]-2-methoxy-phenyl}methanol

7-[3-(Hydroxymethyl)-4-methoxy-phenyl]-4-morpholine-pyrido[2,3-d]pyrimidine-2-carbonitrile 1 (6 mg, 0.02 mmol) Dissolved in 2 mL of methanol, added with 0.1 mL of amine water and palladium on carbon (3 mg, 10%), and replaced with hydrogen three times for 1 hour. The reaction solution was filtered, and the residue was evaporated to mjjjjjjjjjjjjjjjjjjjj 2,3- d ]pyrimidin-7-yl]-2-methoxy-phenyl}methanol 7 (5 mg, yellow solid), yield: 83.3%. MS m/z (ESI): 382.2 [M + 1]. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.32 (s, 1H), 7.99-7.97 (m, 2H), 7.56 (d, 1H), 7.04 (d, 1H), 5.39 (s, 2H), 4.85 (s, 1H), 4.72 (s, 2H), 4.04-3.93 (m, 4H), 3.89 (s, 3H), 3.77-3.72 (m, 4H), 2.28-2.26 (m, 2H).

Example 8 {5-[2-(3,6-Dihydro-2 H -pyran-4-yl)-4-morpholine-pyrido[2,3- d ]pyrimidin-7-yl]-2 -methoxy-phenyl}methanol

[5-(2-Chloro-4-morpholine-pyrido[2,3-d]pyrimidin-7-yl)-2-methoxy-phenyl]methanol 1f (100 mg, sequentially added to a microwave tube 0.26 mmol), tributyl (3,6-dihydro-2H-pyran-4-yl)stannane 8a (144 mg, 0.39 mmol, prepared by the known method "Patent WO2010014939"), double (three) Phenylphosphine) palladium dichloride (17 mg, 0.025 mmol), N,N-diisopropylethylamine (66 mg, 0.52 mmol), iodide iodide (4.70 mg, 0.025 mmol) and 5 mL N N-dimethylformamide was reacted at 130 ° C for 20 minutes. To the reaction mixture, 20 mL of ethyl acetate was added, and the mixture was evaporated, evaporated, evaporated, evaporated. in the resulting thin layer chromatography developing solvent system A and the residue was purified to give the title product {5- [2- (3,6-dihydro -2 H - pyran-4-yl) -4-morpholino - pyrido [2,3- d ]pyrimidin-7-yl]-2-methoxy-phenyl}methanol 8 (55 mg, yellow solid), yield: 49.1%. MS m/z (ESI): 435.2 [M + 1]. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.30 (m, 2H), 7.82 (d, 1H), 7.46 (d, 1H), 7.07 (d, 1H), 4.84 (s, 2H), 4.49 (s, 2H), 4.00 (s, 3H), 3.98-3.95 (m, 4H), 3.88-3.09 (m, 4H), 2.94 - 2.93 (m, 2H), 1.69-1.67 (m, 2H), 1.43-1.39 ( m, 2H).

Example 9 {2-Methoxy-5-[2-(methylsulfonylmethyl)-4-morpholine-pyrido[2,3- d ]pyrimidin-7-yl]phenyl}methanol

First step, tert-butyl-[[5-(2-chloro-4-morpholine-pyrido[2,3-d]pyrimidin-7-yl)-2-methoxy-phenyl]methyloxy Dimethyl-decane

[5-(2-Chloro-4-morpholine-pyrido[2,3-d]pyrimidin-7-yl)-2-methoxy-phenyl]methanol 1f (1 g, 2.58 mmol), Tributyldimethylchloromethane (779 mg, 5.16 mmol) and triethylamine (1 mL, 7.74 mmol) were dissolved in 10 mL of tetrahydrofuran, refluxed for 4 hours, and then reacted at 50 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure and purified to purified crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj , 3-d]pyrimidin-7-yl)-2-methoxy-phenyl]methoxy]-dimethyl-decane 9a (500 mg, white solid), yield 38.5%. MS m/z (ESI): 5021. [M+1].

The second step is the third butyl-[[2-methoxy-5-[2-(methylsulfonyl) 4-morpholine-pyrido[2,3-d]pyrimidin-7-yl]phenyl]methoxy]-dimethyl-decane

Dissolve sulfhydryl dimethane (282 mg, 3 mmol) in 5 mL of tetrahydrofuran, add n-butyllithium (0.18 mL, 0.45 mmol) dropwise, stir for 30 min, then add the third butyl-[[5-(2) -Chloro-4-morpholine-pyrido[2,3-d]pyrimidin-7-yl)-2-methoxy-phenyl]methoxy]-dimethyl-decane 9a (150 mg, 0.30 mmol ), the reaction was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure, and then purified to purified crystals eluted eluted elut elut elut elut elut elut elut elut elut elut elut elut 4-morpholine-pyrido[2,3-d]pyrimidin-7-yl]phenyl]methoxy]-dimethyl-decane 9b (10 mg, yellow solid), yield: 5.9%. MS m/z (ESI): 559.2.

The third step [2-methoxy-5-[2-(methylsulfonylmethyl)-4-morpholine-pyrido[2,3-d]pyrimidin-7-yl]phenyl]methanol

Tert-butyl-[[2-methoxy-5-[2-(methylsulfonylmethyl)-4-morpholine-pyrido[2,3-d]pyrimidin-7-yl]phenyl ]Methoxy]-dimethyl-decane 9b (10 mg, 0.02 mmol) and acetamidine chloride (5 mg, 0.05 mmol) were dissolved in 5 mL of methanol and reacted at 40 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate (20 mL), EtOAc (EtOAc) Concentration by pressure, purification of the residue by HPLC preparative chromatography eluting with eluent system A to give the title product {2-methoxy-5-[2-(methylsulfonylmethyl)-4-morpholine-pyridine [2,3- d ]pyrimidin-7-yl]phenyl}methanol 9 (5 mg, yellow solid), yield: 62.5%. MS m/z (ESI): 445.1 [M+1]. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.55 (s, 1H), 8.45 (d, 1H), 8.15 (d, 1H), 7.67 (d, 1H), 7.05 (d, 1H), 5.39 ( s, 1H), 4.86 (s, 2H), 4.83 (s, 2H), 4.14-4.10 (m, 4H), 3.97 (s, 3H), 3.88-3.83 (m, 4H), 3.15 (s, 3H) .

Example 10 {2-Methoxy-5-[4-[(3 S )-3-methylmorpholin-4-yl]-2-(tetrahydropyran-4-yl-amino)pyridine [2,3- d ]pyrimidin-7-yl}phenyl]methanol

[5-[2-Chloro-4-[(3 S )-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl]-2 was sequentially added to the sealed tube. -Methoxy-phenyl]methanol 3a (140 mg, 0.35 mmol), tetrahydropyran-4-amine (60 mg, 0.52 mmol), 3 mL 1,4-dioxane and N,N- Isopropylethylamine (225 mg, 1.75 mmol) was reacted at 90 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure, resulting in a thin layer chromatography developing solvent system A and the residue was purified to give the title product {2-methoxy -5- [4 - [(3 S ) -3- methylmorpholine - 4-yl]-2-(tetrahydropyran-4-yl-amino)pyrido[2,3- d ]pyrimidin-7-yl]phenyl}methanol 10 (17 mg, yellow solid) : 11.8%. MS m/z (ESI): 466.2 [M+1]. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.15 (d, 2H), 7.96 (d, 1H), 7.49 (s, 1H), 6.94 (d, 1H), 4.76 (s, 2H), 4.47-4.45 ( m, 1H), 4.02 (d, 3H), 3.92 (s, 3H), 3.81-3.80 (m, 3H), 3.75 (m, 3H), 3.71 (t, 2H), 2.90-2.80 (m, 2H) , 2.04-2.02 (m, 2H), 1.50-1.48 (m, 4H).

Example 11 {2-Methoxy-5-(4-morpholin-2-tetrahydropyran-4-yl-pyrido[2,3- d ]pyrimidin-7-yl)phenyl}methanol

[5-[2-(3,6-Dihydro-2 H -pyran-4-yl)-4-morpholine-pyrido[2,3-d]pyrimidin-7-yl]-2-yl Oxy-phenyl]methanol 8 (80 mg, 0.18 mmol) was dissolved in 5 mL of methanol, and then palladium/carbon (16 mg, 10%) and 0.2 mL of acetic acid were added, and the mixture was replaced with hydrogen three times, and the reaction was stirred for 12 hours. The reaction solution was filtered, and the filtrate was evaporated to dryness crystalljjjjjjjjjjjjjjjj 4-Base-pyrido[2,3- d ]pyrimidin-7-yl)phenyl}methanol 11 (23 mg, yellow solid), yield: 28.8%. MS m/z (ESI): 437.2 [M+1]. ¹ H NMR (400 MHz, CDCl ₃ ): 8.28 (d, 1H), 8.26 (s, 1H), 8.19 (d, 1H), 7.77 (d, 2H), 7.01 (d, 1H), 4.80 (s, 2H) ), 4.10 (d, 2H), 3.96 (s, 3H), 3.88-3.80 (m, 8H), 3.78 (s, 1H), 3.61 (t, 2H), 2.14-1.98 (m, 4H).

Example 12 3-{[7-[3-(Hydroxymethyl)-4-methoxy-phenyl]-4-morpholine-pyrido[2,3- d ]pyrimidin-2-yl]amino Aza-pyridin-2-one

[5-(2-Chloro-4-morpholine-pyrido[2,3-d]pyrimidin-7-yl)-2-methoxy-phenyl]methanol 1f (200 mg, 0.52 mmol), 3 -Aminothiazepin-2-one (100 mg, 0.62 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.37 mmol) dissolved in 5 mL 1,4-dioxane, reflux 7 hours. The reaction mixture was concentrated under reduced pressure and purified tolulululululululululululululululululululululululu 4-morpholine-pyrido[2,3- d ]pyrimidin-2-yl]amino}azepin-2-one 12 (80 mg, yellow solid), yield: 32.4%. MS m/z (ESI): 479.1 [M+1]. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.45 (s, 1H), 8.33 (d, 1H), 8.16-8.15 (m, 1H), 8.13 (d, 1H), 7.89 (d, 1H), 7.15 (d, 1H), 5.33 (s, 1H), 4.67 (s, 1H), 4.57 (s, 2H), 3.88 (s, 3H), 3.79-3.70 (m, 9H), 3.32-3.30 (m, 2H), 2.10-2.07 (m, 2H), 1.80-1.75 (m, 2H), 1.48-1.45 (m, 2H).

Example 13 Ethyl 2-{7-[3-(hydroxymethyl)-4-methoxy-phenyl]-4-morpholine-pyrido[2,3- d ]pyrimidin-2-yl}

First step 3-[(3-Aminoguanidin-6-chloro-2-pyridinyl)amino]-3-oxo-propionic acid methyl ester

2-Amino-6-chloro-pyridine-carboxamide 1a (500 mg, 2.91 mmol), N,N-diisopropylethylamine (537 mL, 2.91 mmol) and 4-dimethylaminopyridine ( 3.57 mg, 0.03 mmol) was dissolved in a mixed solvent of 16 mL of dichloromethane and N,N-dimethylformamide (V/V = 1:1), and 3-chloro-3-oxo was added dropwise at 0 °C. Methyl propionate (477 mg, 3.50 mmol) was stirred at room temperature for 18 h. 30 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL×2). The organic phase was combined and washed with water (50 mL×3) and saturated sodium chloride solution (50 mL×2), anhydrous sodium sulfate Dry, filter, and concentrate the filtrate under reduced pressure. The residue obtained was purified by eluent column chromatography eluting to afford the title product 3-[(3-aminocarbazin-6-chloro-2-pyridine)amino]-3-oxo-propionic acid Methyl ester 13a (420 mg, yellow solid), yield: 50.5%. MS m/z (ESI): 272.0 [M+1].

Step 2 2-(7-Chloro-4-oxo-3H-pyrido[2,3-d]pyrimidin-2-yl)acetate

3-[(3-Aminoguanidine-6-chloro-2-pyridine)amino]-3-oxo-propionic acid methyl ester 13a (30 mg, 0.11 mmol) and sodium carbonate (59 mg, 0.55 mmol The solution was dissolved in a mixed solvent of 2 mL of ethanol and water (V/V = 1:1), and the reaction was stirred for 34 hours. After adding 10 mL of water to the reaction mixture, the mixture was extracted with ethyl acetate (20 mL×3), and the organic phase was combined, washed with a saturated sodium chloride solution (40 mL×2), dried over anhydrous sodium sulfate The residue obtained was purified by eluent column chromatography using eluent column chromatography to afford the title product 2-(7-chloro-4-oxo-3H-pyrido[2,3-d]pyrimidin-2-yl)acetic acid Ethyl ester 13b (15 mg, white solid), yield: 53.6%. MS m/z (ESI): 268.1 [M+1].

Step 3 2-(4,7-Dichloropyrido[2,3-d]pyrimidin-2-yl)acetate

2-(7-Chloro-4-oxo-3H-pyrido[2,3-d]pyrimidin-2-yl)acetate 13b (340 mg, 1.27 mmol) and N,N-diisopropyl Ethylamine (493 mg, 3.82 mmol) was dissolved in 20 mL of toluene, and phosphorus oxychloride (52 mg, 0.34 mmol) was added at 0 ° C, and the reaction was stirred for 1 hour. The reaction mixture was concentrated under reduced vacuo. mjjjjjjjjjjjjjjjjj Purified directly for the next step of the reaction. MS m/z (ESI): 286.1 [M+1].

Step 4 2-(7-Chloro-4-morpholine-pyrido[2,3-d]pyrimidin-2-yl)acetate

The crude ethyl 2-(4,7-dichloropyrido[2,3-d]pyrimidin-2-yl)acetate 13c (160 mg, 0.56 mmol) and triethylamine (113 mg, 1.12 mmol) was dissolved in 10 To the methylene chloride, morpholine (55 mg, 0.62 mmol) was added at 0 ° C and allowed to react at room temperature for 18 hours. 20 mL of water was added to the reaction mixture, and the mixture was combined with ethyl acetate (20 mL × 3), and the organic phase was combined, washed with saturated sodium chloride solution (40 mL × 2), dried over anhydrous sodium sulfate The residue obtained was purified by eluent column chromatography using eluent column chromatography to afford ethyl 2-(7-chloro-4-morpholine-pyrido[2,3-d]pyrimidin-2-yl)acetate. 13d (160 mg, white solid), yield: 85.1%. MS m/z (ESI): 337.0 [M+1].

Step 5 2-[7-[3-(Hydroxymethyl)-4-methoxy-phenyl]-4-morpholine-pyrido[2,3-d]pyrimidin-2-yl]acetate

Ethyl 2-(7-chloro-4-morpholine-pyrido[2,3-d]pyrimidin-2-yl)acetate 13d (20 mg, 0.06 mmol), [2-methoxy-5- (4 ,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol 1e (17 mg, 0.06 mmol) and sodium bicarbonate (15 mg, 0.18 mmol) was dissolved in 2 mL of a mixed solvent of acetonitrile and water (V/V = 1:1), and tetrakis(triphenylphosphine)palladium (6.93 mg, 0.006 mmol) was added and reacted at 90 ° C for 3 hours. 10 mL of water was added to the reaction mixture, and the mixture was combined with EtOAc (EtOAc m. The residue obtained was purified by eluent column chromatography using eluent column chromatography to give the title product 2-{7-[3-(hydroxymethyl)-4-methoxy-phenyl]-4-morpholine- Pyrido[2,3- d ]pyrimidin-2-yl}acetate 13 (13 mg, yellow solid), yield: 50.0%. MS m/z (ESI): 439.1 [M+1]. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.28 (d, 1H), 8.26 (s, 1H), 8.19 (d, 1H), 7.77 (d, 2H), 7.01 (d, 1H), 4.80 ( s, 2H), 4.10 (d, 2H), 3.96 (s, 3H), 3.61 (m, 2H), 3.32-3.30 (m, 2H), 2.78 (s, 2H), 2.10-2.07 (m, 2H) , 1.80 - 1.75 (m, 2H), 1.35 (t, 3H).

Example 14 {5-[2-[(1,1-dioxothiopyran-4-yl)amino]-4-morpholine-pyrido[2,3- d ]pyrimidin-7-yl ]-2-methoxy-phenyl}methanol

First step 1,1-dioxothiopyran-4-amine

1,1-dioxothiopyran-4-one 14a (6.60 g, 44.70 mmol) and ammonium formate (28 g, 0.45 mmol) were dissolved in 70 mL of methanol and water (V/V = 6:1) Palladium on carbon (2.80 g, 10%) was added to the mixed solvent, and the mixture was replaced with hydrogen three times, and the reaction was stirred for 12 hours. The reaction mixture was filtered, and the filtrate was evaporated. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj White solid Body), yield: 63.6%. MS m/z (ESI): 149.1 [M+1].

The second step is 7-[3-[(t-butyl(dimethyl)decyl)oxymethyl]-4-methoxy-phenyl]-N-(1,1-dioxothio Pyran-4-yl)-4-morpholine-pyrido[2,3-d]pyrimidin-2-amine

Adding tert-butyl [[5-(2-chloro-4-morpholine-pyrido[2,3-d]pyrimidin-7-yl)-2-methoxy-phenyl]methanol to the sealed tube ]-Dimethyldecane 5a (100 mg, 0.20 mmol), 1,1-dioxothiopyran-4-amine 14b (60 mg, 0.40 mmol), N,N-diisopropylethylamine ( 80 mg, 0.60 mmol) and 15 mL of 1,4-dioxane were reacted at 120 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure and purified to purified crystals eluted elut elut elut elut elut elut elut elut elut elut elut elut 4-methoxy-phenyl]-N-(1,1-dioxothiopyran-4-yl)-4-morpholine-pyrido[2,3-d]pyrimidin-2-amine 14c ( 53 mg, yellow solid), yield: 43.4%. MS m/z (ESI): 61422.

The third step [5-[2-[(1,1-dioxothiopyran-4-yl)amino]-4-morpholine-pyrido[2,3-d]pyrimidin-7-yl ]-2-methoxy-phenyl]methanol

7-[3-[(T-butyl(dimethyl)decyl)oxymethyl]-4-methoxy-phenyl]-N-(1,1-dioxothiopyran) -4yl)-4-morpholine-pyrido[2,3-d]pyrimidin-2-amine 14c (122 mg, 0.20 mmol) was dissolved in 5 mL of methanol, and 10 mL hydrochloric acid methanol was added dropwise and stirred for 30 min. . The reaction mixture was concentrated under reduced vacuohyhyhyhyhyhyhyhyhyhyhyhyhyhyhyhyhyhyhyhyhyhyhyhyhyhyhyhyhyhyhyhyhyhyhyhyhyhyhyhyhyhyhyhy[[[[[[[1,1-dioxythiopyran-4-yl]amino] , 3- d ]pyrimidin-7-yl]-2-methoxy-phenyl}methanol 14 (6 mg, yellow solid), yield: 6.0%. MS m/z (ESI): 500.1 [M+1]. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.17 (s, 1H), 8.14 (s, 1H), 8.02 (d, 1H), 7.50 (d, 2H), 6.99 (d, 2H), 4.79 (s, 2H), 4.50 (br., 1H), 3.95 (s, 3H), 3.89-3.88 (m, 4H), 3.74 (s, 2H), 3.18-3.15 (m, 4H), 2.52-2.48 (m, 2H) ), 2.29-2.27 (m, 3H).

Example 15 {2-Methoxy-5-[4-morpholin-2-[(3 R )-tetrahydrofuran-3-yl]oxy-pyrido[2,3- d ]pyrimidin-7-yl] Phenyl}methanol

(3 R )-tetrahydrofuran-3-ol (45 mg, 0.51 mmol), 3 mL of N,N-dimethylformamide and sodium hydride (31 mg, 0.78 mmol) were added to the sealed tube and stirred at 50 °C. 1 hour, then [5-(2-chloro-4-morpholine-pyrido[2,3-d]pyrimidin-7-yl)-2-methoxy-phenyl]methanol 1f (100 mg, 0.26) Methyl), reacted at 50 ° C for 12 hours. 50 mL of ethyl acetate and 20 mL of water were added to the reaction mixture, and the organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by thin layer chromatography The residue obtained gave the title product {2-methoxy-5-[4-morpholin-2-[( 3R )-tetrahydrofuran-3-yl]oxy-pyrido[2,3- d ]pyrimidine- 7-yl]phenyl}methanol 15 (15 mg, yellow solid), yield: 13.3%. MS m/z (ESI): 439.1 [M+1]. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.11 (s, 1H), 7.91 (d, 1H), 7.78 (d, 1H), 7.05 (d, 1H), 6.86 (d, 1H), 4.80 (s, 2H), 4.07-4.00 (m, 8H), 3.95 (s, 3H), 3.89 (s, 4H), 2.31 (s, 3H).

Example 16 1-{4-[[7-[3-(Hydroxymethyl)-4-methoxy-phenyl]-4-morpholine-pyrido[2,3- d ]pyrimidin-2-yl Amino]-1-piperidinyl} ethyl ketone

[5-(2-Chloro-4-morpholine-pyrido[2,3-d]pyrimidin-7-yl)-2-methoxy-phenyl]methanol 1f (200 mg, 0.52 mmol), 1 -(4-Amino-1-piperidyl)ethanone (88 mg, 0.62 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.37 mmol) dissolved in 5 mL 1,4-dioxin The alkane was refluxed for 7 hours. The reaction mixture was concentrated under reduced pressure and purified tolulululululululululululululululululululululululululu 4- morpholine-pyrido[2,3- d ]pyrimidin-2-yl]amino]-1-piperidinyl}ethanone 16 (90 mg, yellow solid), yield: 35.1%. MS m/z (ESI): 49:21. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.30 (s, 1H), 8.17 (d, 1H), 8.07 (d, 1H), 7.72 (d, 1H), 7.09 (d, 1H), 5.21. t,1H), 4.56(d,2H), 4.33(br.,1H), 4.17(br.,2H),3.92(s,2H),3.87(s,3H),3.77(s,2H),3.65 (s, 3H), 3.24 - 3.21 (m, 2H), 2.03 (s, 3H), 1.99-1.87 (m, 4H), 1.48-1.30 (m, 2H).

Example 17 {2-Methoxy-5-(4-morpholin-2-tetrahydropyran-4-yl-oxy-pyrido[2,3- d ]pyrimidin-7-yl)phenyl} Methanol

Tetrahydropyran-4-ol (60 mg, 0.59 mmol), 3 mL of N,N-dimethylformamide and sodium hydride (10 mg, 0.26 mmol) were added to the sealed tube and stirred at 50 °C. After an hour, then [5-(2-chloro-4-morpholine-pyrido[2,3-d]pyrimidin-7-yl)-2-methoxy-phenyl]methanol 1f (100 mg, 0.26 mmol) ), reacted at 50 ° C for 12 hours. 50 mL of ethyl acetate and 20 mL of water were added to the reaction mixture, and the organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by thin layer chromatography The residue obtained gave the title product {2-methoxy-5-(4-morpholin-2-tetrahydropyran-4-yl-oxy-pyrido[2,3- d ]pyrimidin-7-yl Phenyl}methanol 17 (15 mg, yellow solid), yield: 12.8%. MS m/z (ESI): 453.1 [M + 1]. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.34 (d, 1H), 8.26 (s, 1H), 7.97 (d, 1H), 7.70 (d, 1H), 6.62 (d, 1H), 4.76 (s, 2H), 4.03-4.01 (m, 5H), 3.90-3.88 (m, 3H), 3.87 (s, 3H), 3.81-3.79 (m, 1H), 3.64-3.62 (m, 2H), 2.20-2.10 ( m, 2H), 2.00-1.85 (m, 4H).

Example 18 2-Methoxy-5-{4-morpholin-2-(4-piperidinyloxy)-pyrido[2,3- d ]pyrimidin-7-yl]phenyl}methanol

[5-(2-Chloro-4-morpholine-pyrido[2,3-d]pyrimidin-7-yl)-2-methoxy-phenyl]methanol 1f (100 mg, 0.25 mmol), 1-methylpiperidin-4-ol hydrochloride (76 mg, 0.50 mmol), cesium carbonate (82 mg, 0.25 mmol) and 5 mL 1,4-dioxane, reacted at 120 °C 4 hour. The reaction mixture was concentrated under reduced pressure. purified m.jjjjjjjj And [2,3- d ]pyrimidin-7-yl]phenyl}methanol 18 (25 mg, yellow solid), yield: 22.1%. MS m/z (ESI): 4521. [M+1]. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.30 (s, 1H), 8.18 (d, 1H), 8.05 (d, 1H), 7.56 (d, 1H), 7.07 (d, 1H), 5.19 (t, 1H), 4.72 (d, 1H), 4.56 (d, 2H), 4.38 (d, 2H), 3.86 (s, 3H), 3.77-3.70 (m, 4H), 3.67-3.66 (m, 4H), 3.36 -3.34 (m, 1H), 1.96-1.80 (m, 2H), 1.38-1.36 (m, 2H).

Example 19, 20 2-{7-[3-(Hydroxymethyl)-4-methoxy-phenyl]-4-morpholine-pyrido[2,3- d ]pyrimidin-2-yl}acetonitrile , 2-cyano-2-{7-[3-(hydroxymethyl)-4-methoxy-phenyl]-4-morpholine-pyrido[2,3- d ]pyrimidin-2-yl} Tert-butyl acetate

The first step is 2-[7-[3-[(t-butyl(dimethyl)indolyl)oxymethyl]-4-methoxy-phenyl]-4-morpholine-pyrido[2, 3-d]pyrimidin-2-yl]-2-cyano-acetic acid tert-butyl ester

Dissolve 2-cyano-acetic acid tert-butyl ester (140 mg, 1.00 mmol) in 5 mL of tetrahydrofuran, add potassium t-butoxide (40 mg, 0.35 mmol), stir for 30 minutes, then add the third butyl group. -[[5-(2-chloro-4-morpholine-pyrido[2,3-d]pyrimidin-7-yl)-2-methoxy-phenyl]methoxy]-dimethyl-decane 9a (50 mg, 0.10 mmol), reaction for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. [3-[(T-butyl(dimethyl)indenyl)oxymethyl]-4-methoxy-phenyl]-4-morpholine-pyrido[2,3-d]pyrimidin-2- 2-Chloro-acetic acid tert-butyl ester 19a (50 mg, yellow solid), product was used in the next step without purification. MS m/z (ESI): 606.2 [M + 1].

Second step 2-[7-[3-(hydroxymethyl)-4-methoxy-phenyl]-4-morpholine-pyrido[2,3-d]pyrimidin-2-yl]acetonitrile, 2 -Cyano-2-[7-[3-(hydroxymethyl)-4-methoxy-phenyl]-4-morpholine-pyrido[2,3-d]pyrimidin-2-yl]acetic acid Tributyl ester

The crude product is 2-[7-[3-[(t-butyl(dimethyl)indolyl)oxymethyl]-4-methoxy-phenyl]-4-morpholine-pyrido[2,3 -d]pyrimidin-2-yl]-2-cyano-acetic acid tert-butyl ester 19a (100 mg, 0.16 mmol) was dissolved in 5 mL of toluene and p-toluenesulfonic acid (10 mg, 0.03 mmol) was added. After an hour, the reaction was further carried out at 65 ° C for 3 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc)EtOAc. The obtained residue was purified to give the title product 2-{7-[3-(hydroxymethyl)-4-methoxy-phenyl]-4-morpholine-pyrido[2,3- d. Pyrimidine-2-yl}acetonitrile 19 (9 mg, yellow solid), yield: 10.0%. MS m/z (ESI): 3921. [M+1]. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.48 (s, 1H), 8.26 (d, 1H), 8.02 (d, 2H), 6.97 (d, 1H), 4.81 (s, 2H), 4.45 (s, 2H), 4.15 (s, 3H), 4.06 (s, 1H), 3.97 (s, 3H), 3.89 (s, 4H). 2-cyano-2-{7-[3-(hydroxymethyl)-4-methoxy-phenyl]-4-morpholine-pyrido[2,3- d ]pyrimidin-2-yl}acetic acid Third butyl ester 20 (10 mg, yellow solid), yield: 11.0%. MS m/z (ESI): 4921. [M+1]. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 12.62 (s, 1H), 8.09 (d, 2H), 7.90 (d, 1H), 7.54 (d, 1H), 6.98 (d, 1H), 4.80 ( s, 2H), 4.06 (s, 1H), 3.96 (s, 4H), 3.94 (s, 2H), 3.82 (s, 4H), 3.59 (s, 9H).

Example 21 {5- [2 - [(1,1-dioxo-thiopyran-4-yl) amino] -4 - [(3 S) -3- methyl-morpholin-4-yl] Pyrido[2,3- d ]pyrimidin-7-yl]-2-methoxy-phenyl}methanol

[5- [2-chloro -4 - [(3 S) -3- methyl-morpholin-4-yl] pyrido [2,3-d] pyrimidin-7-yl] -2-methoxy - Phenyl]methanol 3a (150 mg, 0.37 mmol) was dissolved in 5 mL of N,N-dimethylacetamide, and 1,1-dioxothiopyran-4-amine 14b (112 mg, 0.74) was added. Methyl) and N,N-diisopropylethylamine (143 mg, 1.11 mmol) were reacted at 90 ° C for 48 hours. The reaction mixture was poured into water (20 mL), EtOAc (EtOAc m. Chromatography by HPLC preparative purification of the residue obtained in eluent system A to give the title product {5-[2-[(1,1-dioxothiopyran-4-yl)amino]-4-[( 3 S )-3-methylmorpholin-4-yl]pyrido[2,3- d ]pyrimidin-7-yl]-2-methoxy-phenyl}methanol 21 (30 mg, yellow solid) Yield: 15.6%. MS m/z (ESI): 514.2 [M + 1]. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.30 (s, 1H), 8.16-8.07 (m, 2H), 7.62 (d, 1H), 7.11 (d, 1H), 4.57 (s, 2H), 4.30 (s, 1H), 3.87 (s, 3H), 3.73-3.11 (m, 13H), 2.22-2.11 (m, 4H), 1.30-1.27 (m, 3H).

Example 22 {5- [2- (cyclopropyl (tetrahydropyran-4-yl) amino) -4 - [(3 S) -3- methyl-morpholin-4-yl] pyrido [2 ,3- d ]pyrimidin-7-yl]-2-methoxy-phenyl}methanol

[5- [2-chloro -4 - [(3 S) -3- methyl-morpholin-4-yl] pyrido [2,3-d] pyrimidin-7-yl] -2-methoxy - Phenyl]methanol 3a (150 mg, 0.37 mmol) was dissolved in 5 mL of N,N-dimethylacetamide and N-cyclopropyltetrahydropyran-4-amine (80 mg, 0.56 mmol) and N,N-Diisopropylethylamine (13 mL, 0.74 mmol) was reacted at 90 ° C for 48 hours. The reaction mixture was poured into water (20 mL), EtOAc (EtOAc m. HPLC preparative chromatography purification of the obtained residue in eluent system A to give the title product {5-[2-(cyclopropyl(tetrahydropyran-4-yl)amino)-4-[( 3S )- 3-methylmorpholin-4-yl]pyrido[2,3- d ]pyrimidin-7-yl]-2-methoxy-phenyl}methanol 22 (10 mg, yellow solid), yield: 5.3 %. MS m/z (ESI): 506.2 [M + 1]. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.66-8.62 (m, 1H), 8.29-8.27 (m, 1H), 8.23-8.21 (m, 1H), 7.79-7.77 (m, 1H), 7.08-7.03 (m, 1H), 4.85 (s, 2H), 4.66-4.64 (m, 1H), 4.19-4.08 (m, 4H), 4.02 (s, 3H), 4.00-3.85 (m, 4H), 3.50-3.48 (m, 4H), 1.73-1.70 (m, 5H), 1.61-1.59 (m, 3H), 1.32-1.28 (m, 4H).

Example 23 {2-methoxy -5- [4 - [(3 S ) -3- methyl-morpholin-4-yl] -2-tetrahydropyran-4-yl - oxy - pyrido [ 2,3- d ]pyrimidin-7-yl]phenyl}methanol

Tetrahydropyran-4-ol (31 mg, 0.31 mmol) was dissolved in 5 mL of tetrahydrofuran, sodium hydride (13 mg, 0.34 mmol) was added with stirring, and stirred for 3 hr. [5-[2-chloro-4] -[(3 S )-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-phenyl]methanol 3a (150 mg, 0.37 Methyl), the reaction was stirred for 1 hour. The reaction solution was added to 10 mL of water, EtOAc (EtOAc m. concentrated and purified by thin-layer chromatography A purification to the resulting residue was developing solvent system, to give the title product {2-methoxy -5- [4 - [(3 S ) -3- methyl-morpholin-4-yl] - 2-Tetrahydropyran-4-yl-oxy-pyrido[2,3- d ]pyrimidin-7-yl]phenyl}methanol 23 (20 mg, yellow solid), yield: 12.5%. MS m/z (ESI): 467.1 [M + 1]. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.33 (s, 1H), 7.99-7.97 (m, 2H), 7.47 (d, 1H), 7.00 (d, 1H), 4.58 (s, 2H), 3.83 (s, 3H), 3.75-3.55 (m, 9H), 2.90-2.88 (m, 1H), 2.87-2.85 (m, 2H), 2.11-1.86 (m, 4H), 1.15 (d, 3H).

Example 24 {2-Methoxy-5-[4-[(3 S )-3-methylmorpholin-4-yl]-2-[(3 R )-tetrahydrofuran-3-yl]oxy- Pyrido[2,3- d ]pyrimidin-7-yl]phenyl}methanol

(3 R )-tetrahydrofuran-3-ol (88 mg, 1 mmol), 3 mL of N,N-dimethylformamide and sodium hydride (60 mg, 1.50 mmol) were added to the sealed tube at 50 ° C. stirred for 3 hours, followed by addition of [5- [2-chloro -4 - [(3 S) -3- methyl-morpholin-4-yl] pyrido [2,3-d] pyrimidin-7-yl] -2 -Methoxy-phenyl]methanol 3a (100 mg, 0.25 mmol) was reacted at 50 ° C for 12 hours. 50 mL of ethyl acetate and 15 mL of water were added to the reaction mixture, and the organic layer was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate and filtered. A resulting residue was purified developing solvent system, to give the title product {2-methoxy -5- [4 - [(3 S ) -3- methyl-morpholin-4-yl] -2 - [(3 R) - Tetrahydrofuran-3-yl]oxy-pyrido[2,3- d ]pyrimidin-7-yl]phenyl}methanol 24 (18 mg, yellow solid), yield: 16.4%. MS m/z (ESI): 453.2 [M + 1]. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.36 (s, 1H), 8.27 (d, 1H), 8.19-8.17 (m, 1H), 7.80 (d, 1H), 7.13 (d, 1H), 5.70-5.67 (m, 1H), 4.72 (s, 2H), 4.69-4.67 (m, 1H), 4.14 - 4.08 (m, 3H), 4.06-3.95 (m, 3H), 3.94 (s, 3H), 3.85-3.70 (m, 4H), 2.37-2.32 (m, 1H), 2.25-2.22 (m, 1H), 1.17-1.15 (m, 3H).

Example 25 4 - {[7- [3- (hydroxymethyl) -4-methoxy - phenyl] -4 - [(3 S) -3- methyl-morpholin-4-yl] - pyridine and [2,3- d ]pyrimidin-2-yl]amino}piperidine-2-carboxylic acid tert-butyl ester

[5-[2-Chloro-4-[(3 S )-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl]-2 was sequentially added to the sealed tube. -methoxy-phenyl]methanol 3a (100 mg, 0.25 mmol), 4-aminopiperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.50 mmol), cesium carbonate (98 mg, 0.30 mmol) and 5 mL of N,N-dimethylacetamide was reacted at 90 ° C for 12 hours. The reaction solution was added to 30 mL of water, filtered, and the filter cake was dried in vacuo to give the title product 4-{[7-[3-(hydroxymethyl)-4-methoxy-phenyl]-4-[( 3S ) 3-methylmorpholin-4-yl]-pyrido[2,3- d ]pyrimidin-2-yl]amino}piperidine-2-carboxylic acid tert-butyl ester 25 (100 mg, yellow solid) Yield: 71.4%. MS m/z (ESI): 565.3 [M+1]. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.21 (s, 1H), 8.16-8.10 (m, 2H), 7.56 (d, 1H), 7.10 (d, 1H), 5.49 (s, 1H), 4.70 (s, 2H), 4.60-4.30 (m, 1H), 4.07-3.90 (m, 5H), 3.85-3.69 (m, 6H), 2.99-2.84 (m, 2H), 2.82-2.80 (m, 4H) ), 2.20-2.03 (m, 1H), 1.89-1.85 (m, 2H), 1.32 (s, 9H).

Example 26 {2-Methoxy-5-[4-[(3 S )-3-methylmorpholin-4-yl]-2-(4-piperidinyl)pyridin[2,3 - d ] pyrimidin-7-yl]phenyl}methanol

4 - [[7- [3- (hydroxymethyl) -4-methoxy - phenyl] -4 - [(3 S) -3- methyl-morpholin-4-yl] - pyrido [2 , 3-d]pyrimidin-2-yl]amino]piperidine-2-carboxylic acid tert-butyl ester 25 (425 mg, 0.75 mmol) was dissolved in 20 mL of 1,4-dioxane hydrochloride for 12 hours. . The reaction mixture was concentrated under reduced pressure, by preparative HPLC chromatography to A resultant residue was purified eluent system, to give the title product {2-methoxy -5- [4 - [(3 S ) -3- methylmorpholine - 4-yl]-2-(4-piperidinylamino)pyrido[2,3- d ]pyrimidin-7-yl]phenyl}methanol 26 (300 mg, yellow solid), yield: 85.7%. MS m/z (ESI): 465.2 [M+]. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.32 (s, 1H), 8.21 (d, 1H), 8.08 (d, 1H), 7.62 (d, 1H), 7.10 (d, 1H), 5.26 ( s, 1H), 4.85 (s, 1H), 4.58 (s, 2H), 3.87 (s, 3H), 3.78-3.68 (m, 4H), 3.45-3.43 (m, 1H), 3.11-2.90 (m, 3H), 2.79-2.69 (m, 4H), 1.89-1.79 (m, 4H), 1.20 (d, 3H).

Example 27 {2-Methoxy-5-[4-[(3 S )-3-methylmorpholin-4-yl]-2-vinyl-pyrido[2,3- d ]pyrimidine-7 -yl]phenyl}methanol

In a microwave tube were added [5- [2-chloro -4 - [(3 S) -3- methyl-morpholin-4-yl] pyrido [2,3-d] pyrimidin-7-yl] -2 -methoxy-phenyl]methanol 3a (100 mg, 0.25 mmol), tributyl(vinyl)stannane (120 mg, 0.38 mmol), bis(triphenylphosphine)palladium dichloride (18 mg, 0.025 mmol), N,N-diisopropylethylamine (65 mg, 0.50 mmol), iodide (5 mg, 0.025 mmol) and 5 mL of N,N-dimethylformamide at 130 °C Reaction for 30 minutes. 20 mL of ethyl acetate was added to the reaction mixture, and the mixture was combined with EtOAc (EtOAc m. A layer chromatography to the resulting residue was purified by developing solvent system, to give the title product {2-methoxy -5- [4 - [(3 S ) -3- methyl-morpholin-4-yl] -2-vinyl- - Pyrido[2,3- d ]pyrimidin-7-yl]phenyl}methanol 27 (80 mg, yellow solid), yield: 81.6%. MS m/z (ESI): 393.2 [M + 1]. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.37-8.32 (m, 2H), 8.23 (d, 1H), 7.92 (d, 1H), 7.12 (d, 1H), 6.84-6.80 (m, 1H) ), 6.72-6.67 (m, 1H), 5.79-5.77 (m, 1H), 4.72-4.69 (m, 3H), 4.19-4.16 (m, 1H), 4.00-3.92 (m, 4H), 3.87-3.75 (m, 4H), 1.54-1.52 (m, 3H).

Example 28 {2-methoxy-5- [Embodiment 4 - [(3 S) -3- morpholin-4-yl-methyl] -2- [2- (3-pyridyl) ethynyl] pyrido [ 2,3- d ]pyrimidin-7-yl]phenyl}methanol

[5- [2-chloro -4 - [(3 S) -3- methyl-morpholin-4-yl] pyrido [2,3-d] pyrimidin-7-yl] -2-methoxy - Phenyl]methanol 3a (100 mg, 0.25 mmol) and 3-ethynylpyridine (30 mg, 0.30 mmol) were dissolved in 5 mL of N,N-dimethylformamide and bis(triphenylphosphine) Palladium chloride (10 mg, 0.015 mmol), iodide (10 mg, 0.05 mmol) and triethylamine (300 mg, 0.30 mmol) were reacted at 80 ° C for 4 hours. The reaction mixture was concentrated under reduced pressure, resulting in a thin layer chromatography developing solvent system A and the residue was purified to give the title product {2-methoxy -5- [4 - [(3 S ) -3- methylmorpholine -4 -yl]-2-[2-(3-pyridyl)ethynyl]pyrido[2,3- d ]pyrimidin-7-yl]phenyl}methanol 28 (20 mg, yellow solid), yield: 17.2 %. MS m/z (ESI): 468.2 [M + 1]. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.87 (s, 1H), 8.69-8.68 (m, 1H), 8.44-8.40 (m, 2H), 8.19-8.17 (m, 1H), 8.14 - 8.13 (m, 1H), 8.04-8.02 (d, 2H), 7.55-7.52 (m, 1H), 7.16 (d, 1H), 5.25-5.20 (m, 1H), 4.71-4.70 (m, 1H), 4.59 (s, 2H), 4.09-4.07 (m, 1H), 3.94-3.92 (m, 1H), 3.89 (s, 3H), 3.77-3.69 (m, 2H), 3.59-3.57 (m, 1H), 1.45 -1.43 (m, 3H).

Example 29 {4 - [[7- [3- (hydroxymethyl) -4-methoxy - phenyl] -4 - [(3 S) -3- methyl-morpholin-4-yl] pyridine and [2,3- d ]pyrimidin-2-yl]amino]-1-piperidinyl}-pyrrol-2-yl-methanone

First step 2-[4-(benzylamino)piperidin-1-carbonyl]pyrrole-1-carboxylic acid tert-butyl ester

2-(4-Oxopiperidin-1-carbonyl)pyrrole-1-carboxylic acid tert-butyl ester 29a (2.40 g, 8.11 mmol, prepared by the known method "Patent US2004134019"), benzylamine (870 mg) 8.13 mmol) and sodium tris(ethinyl)borohydride (4.30 g, 0.02 mmol) were dissolved in 30 mL of N,N-dimethylacetamide and the reaction was stirred for 12 hours. 50 mL of dichloromethane was added to the reaction solution, and the organic phase was washed successively with 2M sodium hydroxide solution (50 mL), saturated sodium carbonate solution (50 mL) and saturated sodium chloride solution (50 mL), anhydrous sulfuric acid The sodium was dried, filtered, and the filtrate was evaporated,jjjjjjjjjjjjjjjjjjjjjjjj The product was used in the next step without purification. MS m/z (ESI): 388.2 [M+1].

Second step 2-(4-Aminopiperidine-1-carbonyl)pyrrole-1-carboxylic acid tert-butyl ester

The crude 2-[4-(benzylamino)piperidine-1-carbonyl]pyrrole-1-carboxylic acid tert-butyl ester 29b (2 g, 5.20 mmol) was dissolved in 30 mL of methanol and then palladium/carbon (200) Mg, 10%), three times of hydrogen, and the reaction was stirred for 48 hours. The reaction solution was filtered, and the filtrate was evaporated tolulujjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Purified directly to the next step. MS m/z (ESI):

Step 2- [4 - [[7- [3- (hydroxymethyl) -4-methoxy - phenyl] -4 - [(3 S) -3- methyl-morpholin-4-yl] Pyridyl[2,3-d]pyrimidin-2-yl]amino]piperidin-1-carbonyl]pyrrole-1-carboxylic acid tert-butyl ester

[5-[2-Chloro-4-[(3 S )-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl]-2 was sequentially added to the sealed tube. -Methoxy-phenyl]methanol 3a (200 mg, 0.50 mmol), crude 2-(4-aminopiperidine-1-carbonyl)pyrrole-1-carboxylic acid tert-butyl ester 29c (225 mg, 0.75 mmol) Cesium carbonate (489 mg, 1.50 mmol) and 5 mL of N,N-dimethylacetamide were reacted at 120 ° C for 12 hours. After adding 20 mL of water to the reaction mixture, the mixture was extracted with dichloromethane (20 mL×3). Chromatography by HPLC to purify the residue obtained from eluent system A to give the title product 2-[4-[[7-[3-(hydroxymethyl)-4-methoxy-phenyl]-4-[( 3 S )-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-2-yl]amino]piperidin-1-carbonyl]pyrrole-1-carboxylic acid tert-butyl ester 29d (15 mg, yellow solid), yield: 5.0%. MS m/z (ESI): 662.3 [M+1].

The fourth step [4 - [[7- [3- (hydroxymethyl) -4-methoxy - phenyl] -4 - [(3 S) -3- methyl-morpholin-4-yl] pyridine and [2,3-d]pyrimidin-2-yl]amino]-1-piperidinyl]-pyrrol-2-yl-methanone

2- [4 - [[7- [3- (hydroxymethyl) -4-methoxy - phenyl] -4 - [(3 S) -3- methyl-morpholin-4-yl] pyridine and [2,3-d]pyrimidin-2-yl]amino]piperidine-1-carbonyl]pyrrole-1-carboxylic acid tert-butyl ester 29d (20 mg, 0.03 mmol) dissolved in 20 mL of 1,4-dihydrochloride The reaction was carried out for 12 hours in an oxane solvent. The reaction mixture was concentrated under reduced pressure. -4-[(3 S )-3-methylmorpholin-4-yl]pyrido[2,3- d ]pyrimidin-2-yl]amino]-1-piperidinyl}-pyrrole-2- Base-methanone 29 (10 mg, yellow solid), yield: 58.8%. MS m/z (ESI): 562.3 [M + 1]. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.21-8.11 (m, 2H), 8.07 (d, 1H), 7.90-7.87 (m, 1H), 6.94-6.81 (m, 1H), 4.57-4.46 (m, 1H), 4.45-4.40 (m, 3H), 4.06-3.69 (m, 8H), 3.66-3.36 (m, 7H), 3.10-3.01 (m, 5H), 3.00-2.40 (m, 1H) , 2.46-2.41 (m, 1H), 1.85-1.77 (m, 5H).

Example 30 {5- [2- (2,2-dimethoxyethyl) -4 - [(3 S) -3- methyl-morpholin-4-yl] pyrido [2,3- d] Pyrimidine-7-yl]-2-methoxy-phenyl}methanol

The first step [2-methoxy-5-[4-[(3 S )-3-methylmorpholin-4-yl]-2-(2-trimethyldecylethynyl)pyridin[2 ,3-d]pyrimidin-7-yl]phenyl]methanol

In a microwave tube were added [5- [2-chloro -4 - [(3 S) -3- methyl-morpholin-4-yl] pyrido [2,3-d] pyrimidin-7-yl] -2 -methoxy-phenyl]methanol 3a (150 mg, 0.37 mmol), ethynyl (trimethyl)decane (74 mg, 0.75 mmol), iodide (8 mg, 0.037 mmol), tetrakis Palladium (15 mg, 0.037 mmol), triethylamine (114 mg, 1.10 mmol) and 5 mL of N,N-dimethylformamide were reacted at 100 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure, resulting in a thin layer chromatography developing solvent system A and the residue was purified to give the title product [2-methoxy -5- [4 - [(3 S ) -3- methylmorpholine -4 -yl]-2-(2-trimethyldecylethynyl)pyrido[2,3-d]pyrimidin-7-yl]phenyl]methanol 30a (120 mg, yellow solid), yield: 70.0% . MS m/z (ESI): 463.2 [M+].

Step [5- [2- (2,2-dimethoxyethyl) -4 - [(3 S) -3- methyl-morpholin-4-yl] pyrido [2,3-d] Pyrimidine-7-yl]-2-methoxy-phenyl]methanol

[2-Methoxy-5-[4-[(3 S )-3-methylmorpholin-4-yl]-2-(2-trimethyldecylethynyl)pyridin[2,3 -d]pyrimidin-7-yl]phenyl]methanol 30b (100 mg, 0.21 mmol) and sodium hydroxide (17 mg, 0.42 mmol) were dissolved in 5 mL of methanol and reacted for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. A purified and the obtained residue was developing solvent system, to give the title product {5- [2- (2,2-dimethoxyethyl) -4 - [(3 S) -3- morpholin-4-yl-methyl Pyridine[2,3- d ]pyrimidin-7-yl]-2-methoxy-phenyl}methanol 30 (10 mg, yellow solid), yield: 12.5%. MS m/z (ESI): 455.2 [M+]. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 6.91 (d, 1H), 6.81 (s, 1H), 6.71 (d, 1H), 6.48 (d, 1H), 5.62 (d, 1H), 3.59- 3.56 (m, 1H), 3.18 (s, 3H), 3.17 (m, 1H), 2.77-2.73 (m, 1H), 2.48-2.46 (m, 1H), 2.32 (s, 3H), 2.28-2.17 ( m, 4H), 1.85 (s, 6H), 1.77 (m, 2H), 1.65 (m, 2H).

Example 31 {2-Methoxy-5-[4-[(3 S )-3-methylmorpholin-4-yl]-2-(methyl(tetrahydropyran-4-yl)amine Pyridine[2,3- d ]pyrimidin-7-yl]phenyl}methanol

[5-[2-Chloro-4-[(3 S )-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl]-2 was sequentially added to the sealed tube. -Methoxy-phenyl]methanol 3a (150 mg, 0.37 mmol), N-methyltetrahydropyran-4-amine (47 mg, 0.41 mmol), N,N-diisopropylethylamine (24 Mg, 0.19 mmol) and 5 mL of N,N-dimethylacetamide were reacted at 90 ° C for 12 hours. The reaction mixture was poured into 10 mL of water, filtered, and the filtered cake was dried in vacuo, and the residue was purified by HPLC to elute to afford the title product {2-methoxy-5-[4-[(3) S )-3-methylmorpholin-4-yl]-2-(methyl(tetrahydropyran-4-yl)amino)pyrido[2,3- d ]pyrimidin-7-yl]phenyl Methanol 31 (5 mg, yellow solid), yield: 3.0%. MS m/z (ESI): 480.2 [M+]. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.29 (s, 1H), 8.14 (d, 1H), 8.06 (d, 1H), 7.57 (d, 1H), 7.09 (d, 1H), 5.21. 5.19 (m, 1H), 4.58-4.56 (m, 2H), 4.40-4.39 (m, 1H), 4.02-3.97 (m, 2H), 3.91-3.85 (m, 2H), 3.86 (s, 3H), 3.75-3.74 (m, 1H), 3.66-3.63 (m, 2H), 3.52-3.42 (m, 3H), 3.07 (s, 3H), 2.53-2.52 (m, 1H), 2.01-1.83 (m, 4H) ), 1.37-1.36 (m, 3H).

Example 32 {2-methoxy-5- [Embodiment 4 - [(3 S) -3- methyl-morpholin-4-yl] -2 - [(3-methyl-tetrahydropyran-4-yl) Amino]pyrido[2,3- d ]pyrimidin-7-yl]phenyl}methanol

[5-[2-Chloro-4-[(3 S )-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl]-2 was sequentially added to the sealed tube. -Methoxy-phenyl]methanol 3a (150 mg, 0.37 mmol), 3-methyltetrahydropyran-4-amine (100 mg, 0.75 mmol), 0.1 mL N,N-diisopropylethylamine It was reacted with 5 mL of 1,4-dioxane at 100 ° C for 16 hours. The reaction mixture was concentrated under reduced pressure by preparative HPLC chromatography to A resultant residue was purified eluent system, to give the title product {2-methoxy -5- [4 - [(3 S ) -3- methylmorpholine 4-yl]-2-[(3-methyltetrahydropyran-4-yl)amino]pyrido[2,3- d ]pyrimidin-7-yl]phenyl}methanol 32 (5 mg, Yellow solid), Yield: 2.9%. MS m/z (ESI): 480.2 [M+]. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.20 (s, 1H), 8.15-8.13 (d, 1H), 7.54 (d, 1H), 7.35-7.33 (m, 1H), 7.08 (d, 1H) ), 4.71 (s, 2H), 4.50 (br., 2H), 3.93 (s, 6H), 3.92-3.90 (m, 1H), 3.85-3.83 (m, 2H), 3.77-3.75 (m, 8H) , 1.96 (br., 2H), 1.46 (d, 3H).

Example 33 {2-Methoxy-5-[4-[(3 S )-3-methylmorpholin-4-yl]-2-(tetrahydropyran-3-yl-amino)pyridine [2,3- d ]pyrimidin-7-yl]phenyl}methanol

[5-[2-Chloro-4-[(3 S )-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl]-2 was sequentially added to the sealed tube. -Methoxy-phenyl]methanol 3a (50 mg, 0.13 mmol), tetrahydropyran-3-amine (15 mg, 0.15 mmol), N,N-diisopropylethylamine (32 mg, 0.25 mmol And 5 mL of 1,4-dioxane were reacted at 100 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure by preparative HPLC chromatography to A resultant residue was purified eluent system, to give the title product {2-methoxy -5- [4 - [(3 S ) -3- methylmorpholine 4-yl]-2-(tetrahydropyran-3-yl-amino)pyrido[2,3- d ]pyrimidin-7-yl]phenyl}methanol 33 (10 mg, yellow solid) Rate: 17.2%. MS m/z (ESI): 466.2 [M+]. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.87 (s, 1H), 8.30 (s, 1H), 8.16-8.14 (m, 1H), 8.07-8.05 (m, 1H), 7.61-7.58 (m) , 1H), 5.27-5.24 (m, 1H), 4.96 (m, 1H), 4.75 (m, 1H), 4.57-4.56 (m, 1H), 4.41-4.39 (m, 2H), 4.14 - 4.12 (m , 1H), 3.87-3.86 (m, 3H), 3.74 (m, 2H), 3.66 (s, 2H), 3.60-3.54 (m, 3H), 1.37-1.33 (m, 2H), 1.29- 1.28 (m , 2H), 1.23 (s, 3H).

Example 34 {2-methoxy -5- [4 - [(3 S ) -3- methyl-morpholin-4-yl] -2- (tetrahydrofuran-3-yl -) pyrido [2, 3- d ]pyrimidin-7-yl]phenyl}methanol

[5- [2-chloro -4 - [(3 S) -3- methyl-morpholin-4-yl] pyrido [2,3-d] pyrimidin-7-yl] -2-methoxy - Phenyl]methanol 3a (150 mg, 0.37 mmol), tetrahydrofuran-3-amine (50 mg, 0.56 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.75 mmol) dissolved in 5 mL 1,4 In the dioxane, the reaction was carried out at 90 ° C for 12 hours. The reaction mixture was poured into water (20 mL), EtOAc (EtOAc m. A thin layer chromatography and the obtained residue was purified by developing solvent system, to give the title product {2-methoxy -5- [4 - [(3 S ) -3- methyl-morpholin-4-yl] -2- ( Tetrahydrofuran-3-yl-amino)pyrido[2,3- d ]pyrimidin-7-yl]phenyl}methanol 34 (10 mg, yellow solid), yield: 5.9%. MS m/z (ESI): 452.2 [M + 1]. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.32-8.31 (m, 2H), 8.10-8.09 (m, 1H), 7.84-7.74 (m, 1H), 7.14-7.13 (m, 1H), 5.24 (s, 1H), 4.58 (s, 2H), 3.88 (s, 3H), 3.93-3.65 (m, 12H), 2.24-2.20 (m, 1H), 1.96-1.94 (m, 1H), 1.28-1.24 (m, 3H).

Embodiment Example 353 - {[7- [3- (hydroxymethyl) -4-methoxyphenyl] -4 - [(3 S) -3- methyl-morpholin-4-yl] pyrido [2 ,3- d ]pyrimidin-2-yl]amino}piperidin-2-one

[5- [2-chloro -4 - [(3 S) -3- methyl-morpholin-4-yl] pyrido [2,3-d] pyrimidin-7-yl] -2-methoxy - Phenyl]methanol 3a (150 mg, 0.37 mmol), 3-aminopiperidin-2-one (50 mg, 0.41 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.56 mmol) The reaction was carried out at 90 ° C for 12 hours in 5 mL of 1,4-dioxane. The reaction mixture was poured into 20 mL of EtOAc (EtOAc)EtOAc. The residue obtained was purified by HPLC to give the titled product 3-{[7-[3-(hydroxymethyl)-4-methoxyphenyl]-4-[( 3S ) -3-methylmorpholin-4-yl]pyrido[2,3- d ]pyrimidin-2-yl]amino}piperidin-2-one 35 (10 mg, yellow solid), yield: 5.6% . MS m/z (ESI): 479.3 [M+1]. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.30 (s, 1H), 8.18-8.06 (m, 2H), 7.63 (d, 1H), 7.11 (d, 1H), 5.21-5.19 (m, 1H) ), 4.58 (d, 2H), 3.98-3.92 (m, 1H), 3.87 (s, 3H), 3.74-3.61 (m, 5H), 3.25-2.20 (m, 5H), 2.02-1.87 (m, 4H) ), 1.24 (s, 3H).

Example 36 N- {7- [3- (hydroxymethyl) -4-methoxyphenyl] -4 - [(3 S) -3- methyl-morpholin-4-yl] pyrido [2, 3- d ]pyrimidin-2-yl}cyclopropylcarboxamide

[5- [2-chloro -4 - [(3 S) -3- methyl-morpholin-4-yl] pyrido [2,3-d] pyrimidin-7-yl] -2-methoxy - Phenyl]methanol 3a (50 mg, 0.13 mmol) and N,N-diisopropylethylamine (33 mg, 0.26 mmol) were dissolved in 5 mL of dichloromethane. 20 mg, 0.19 mmol), reaction for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. The residue obtained was purified by HPLC to give the titled product N-{7-[3-(hydroxymethyl)-4-methoxyphenyl]-4-[( 3S )- 3-Methylmorpholin-4-yl]pyrido[2,3- d ]pyrimidin-2-yl}cyclopropylcarboxamide 36 (6 mg, milky white solid), yield: 10.3%. MS m/z (ESI): 450.2 [M + 1]. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.87 (s, 1H), 8.30 (s, 1H), 8.15-8.13 (m, 1H), 7.67-7.65 (m, 1H), 7.01 (d, 1H) ), 4.67 (s, 2H), 3.95-3.93 (m, 2H), 3.75-3.73 (m, 2H), 3.71-3.70 (m, 2H), 3.68 (s, 3H), 3.50-3.48 (m, 1H) ), 1.23 (s, 3H), 1.16-1.14 (m, 1H), 0.91 - 0.88 (m, 2H), 0.63-0.59 (m, 2H).

Example 37 (3 S) -3 - {[7- [3- (hydroxymethyl) -4-methoxy - phenyl] -4 - [(3 S) -3- methyl-morpholin-4 Pyridyl[2,3- d ]pyrimidin-2-yl]amino}azepine-2-one

[5- [2-chloro -4 - [(3 S) -3- methyl-morpholin-4-yl] pyrido [2,3-d] pyrimidin-7-yl] -2-methoxy - phenyl] methanol 3a (200 mg, 0.50 mmol) , (3 S) -3- amino azepin-2-one (70 mg, 0.55 mmol) and N, N- diisopropylethylamine (97 mg , 0.75 mol) was dissolved in 5 mL of N,N-dimethylacetamide and reacted at 90 ° C for 12 hours. The reaction mixture was poured into ice water, filtered, and the filter cake was washed with 5 mL of water, and the residue obtained was purified by HPLC to give the title product ( 3S )-3-{[7-[3- (hydroxymethyl)-4-methoxy-phenyl]-4-[(3 S )-3-methylmorpholin-4-yl]pyrido[2,3- d ]pyrimidin-2-yl] Amino} azeoxa-2-one 37 (30 mg, yellow solid), yield: 12.2%. MS m/z (ESI): 49:21. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.30 (s, 1H), 8.17-8.16 (m, 1H), 8.06-8.05 (m, 1H), 7.92-7.90 (m, 1H), 7.11-7.09 (d, 1H), 5.21-5.18 (m, 1H), 4.58 (d, 2H), 4.61-4.60 (m, 1H), 3.87 (s, 3H), 3.73-3.62 (m, 5H), 3.17-3.10 (m, 5H), 2.10 - 1.81 (m, 6H), 1.23 (s, 3H).

Example 38 {4 - [[7- [3- (hydroxymethyl) -4-methoxyphenyl] -4 - [(3 S) -3- methyl-morpholin-4-yl] pyrido [ 2,3- d ]pyrimidin-2-yl]amino]-1-piperidinyl}-(3-pyridyl)methanone

[5- [2-chloro -4 - [(3 S) -3- methyl-morpholin-4-yl] pyrido [2,3-d] pyrimidin-7-yl] -2-methoxy - Phenyl]methanol 3a (80 mg, 0.20 mmol), (4-amino-1-piperidinyl)-(3-pyridyl)methanone (58 mg, 0.24 mmol), N,N-diisopropyl Ethylamine (65 mg, 0.50 mol) and 5 mL of N,N-dimethylacetamide were reacted at 90 ° C for 4 hours. The reaction mixture was concentrated under reduced pressure and purified to purified crystals eluted elut elut elut elut elut eluting eluting 4-[(3 S )-3-methylmorpholin-4-yl]pyrido[2,3- d ]pyrimidin-2-yl]amino]-1-piperidinyl}-(3-pyridyl ) ketone 38 (20 mg, yellow solid), yield: 11.7%. MS m/z (ESI): 570.2 [M + 1]. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.87 (s, 1H), 8.72-8.70 (d, 1H), 8.32 (s, 1H), 8.23-8.19 (m, 1H), 8.09-7.96 (m) , 2H), 7.56-7.54 (m, 1H), 7.52-7.47 (m, 1H), 7.04-7.01 (m, 1H), 4.63 (s, 2H), 3.88 (s, 3H), 3.61-3.50 (m , 7H), 3.37-3.26 (m, 4H), 2.65-2.63 (m, 1H), 1.85-1.54 (m, 4H), 1.24 (s, 3H).

Example 39 {4 - [[7- [3- (hydroxymethyl) -4-methoxyphenyl] -4 - [(3 S) -3- methyl-morpholin-4-yl] pyrido [ 2,3- d ]pyrimidin-2-yl]amino}-N,N-dimethyl-piperidine-1-carboxamide

[5- [2-chloro -4 - [(3 S) -3- methyl-morpholin-4-yl] pyrido [2,3-d] pyrimidin-7-yl] -2-methoxy - Phenyl]methanol 3a (80 mg, 0.20 mmol), 4-amino-N,N-dimethyl-piperidine-1-carboxamide (40 mg, 0.24 mmol), N,N-diisopropyl Ethylamine (65 mg, 0.50 mmol) and 5 mL of N,N-dimethylacetamide were reacted at 90 ° C for 4 hours. The reaction mixture was concentrated under reduced pressure and purified to purified crystals eluted elut elut elut elut elut eluting eluting 4-[(3 S )-3-methylmorpholin-4-yl]pyrido[2,3- d ]pyrimidin-2-yl]amino}-N,N-dimethyl-piperidine-1 -Procarbamide 39 (30 mg, yellow solid), yield: 30.0%. MS m/z (ESI): 536.2 [M + 1]. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.26 (s, 1H), 8.12 (d, 1H), 7.94 (m, 1H), 7.56 (m, 1H), 7.09 (d, 1H), 4.57 ( s, 2H), 3.85-3.76 (m, 4H), 3.76-3.74 (m, 2H), 3.64-3.59 (m, 5H), 2.85 (s, 3H), 2.70 (s, 6H), 1.90 (m, 3H), 1.78-1.71 (m, 2H), 1.49 (s, 3H).

Example 40 (3 R )-3-{[7-[3-(Hydroxymethyl)-4-methoxy-phenyl]-4-[(3 S )-3-methylmorpholine-4- Pyridyl[2,3- d ]pyrimidin-2-yl]amino}azepine-2-one

[5- [2-chloro -4 - [(3 S) -3- methyl-morpholin-4-yl] pyrido [2,3-d] pyrimidin-7-yl] -2-methoxy - Phenyl]methanol 3a (200 mg, 0.50 mmol), ( 3R )-3-aminoazepine-2-one (77 mg, 0.60 mmol) and N,N-diisopropylethylamine (0.15 mL) , 1 mmol) was dissolved in 5 mL of N,N-dimethylacetamide and reacted at 90 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure by preparative HPLC chromatography to A resulting residue was purified by developing solvent system, to give the title product (3 R) -3 - {[ 7- [3- ( hydroxymethyl) -4-methoxy -phenyl]-4-[(3 S )-3-methylmorpholin-4-yl]pyrido[2,3- d ]pyrimidin-2-yl]amino}azepine-2-one 40 (10 mg, yellow solid), yield: 4.1%. MS m/z (ESI): 493, 3 [M + 1]. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.31 (s, 1H), 8.17-8.07 (m, 2H), 7.92-7.90 (m, 1H), 7.64 - 7.62 (m, 1H), 7.12 (d) , 1H), 6.62-6.59 (m, 1H), 5.22-5.19 (m, 1H), 4.19-4.17 (m, 2H), 3.87 (s, 3H), 3.75-3.62 (m, 5H), 3.20-3.14 (m, 3H), 2.11 - 1.82 (m, 4H), 1.45 - 1.34 (m, 2H), 1.24 (s, 3H).

Example 41 {2-Methoxy-5-[4-[(3 S )-3-methylmorpholin-4-yl]-2-(methyl(tetrahydrofuran-3-yl)amino)pyridine [2,3- d ]pyrimidin-7-yl]phenyl}methanol

[5- [2-chloro -4 - [(3 S) -3- methyl-morpholin-4-yl] pyrido [2,3-d] pyrimidin-7-yl] -2-methoxy - Phenyl]methanol 3a (80 mg, 0.20 mmol), N-methyltetrahydrofuran-3-amine (24 mg, 0.24 mmol) and N,N-diisopropylethylamine (65 mg, 0.40 mol) dissolved in 5 The reaction was carried out at 90 ° C for 12 hours in mL N,N-dimethylacetamide. The reaction mixture was concentrated under reduced pressure by preparative HPLC chromatography A purification to the resulting residue was developing solvent system, to give the title product {2-methoxy -5- [4 - [(3 S ) -3- methylmorpholine - 4-yl]-2-(methyl(tetrahydrofuran-3-yl)amino)pyrido[2,3- d ]pyrimidin-7-yl]phenyl}methanol 41 (5 mg, yellow solid) : 5.4%. MS m/z (ESI): 466.2 [M+]. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.32 (s, 1H), 8.17 (d, 1H), 8.08 (d, 1H), 7.61 (d, 1H), 7.01 (d, 1H), 4.58 ( d, 2H), 4.43-4.41 (m, 2H), 4.15-4.13 (m, 1H), 4.02-3.87 (m, 6H), 3.76-3.67 (m, 3H), 3.62-3.61 (m, 4H), 2.61-2.41 (m, 1H), 1.63 (s, 3H), 0.90-0.86 (m, 3H).

Embodiment Example 42 Cyclopropyl - {4 - [[7- [3- (hydroxymethyl) -4-methoxyphenyl] -4 - [(3 S) -3- morpholin-4-yl-methyl Pyridine[2,3- d ]pyrimidin-2-yl]-methyl-amino]-1-piperidinyl}methanone

First step cyclopropyl-(4-methylamino-1-piperidyl)methanone

1-(Cyclopropylcarbonyl)piperidin-4-one 42a (555 mg, 3.32 mmol, prepared by the known method "Patent US 4,312,876") was dissolved in 20 mL of methanol, and 3.3 mL of 2 M methylamine in tetrahydrofuran was added. The solution was stirred for 1 hour, then sodium triacetoxyborohydride (1.41 g, 6.64 mmol) was added and the mixture was reacted for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjj -piperidinyl)methanone 42b (250 mg, light yellow oil), product was used in the next step without purification. MS m/z (ESI): 183.1 [M+1].

Step cyclopropyl - [4 - [[7- [3- (hydroxymethyl) -4-methoxyphenyl] -4 - [(3 S) -3- morpholin-4-yl-methyl Pyridine[2,3-d]pyrimidin-2-yl]-methyl-amino]-1-piperidinyl]methanone

[5-[2-Chloro-4-[(3 S )-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl]-2 was sequentially added to the sealed tube. -Methoxy-phenyl]methanol 3a (150 mg, 0.37 mmol), crude cyclopropyl-(4-methylamino-1-piperidinyl)methanone 42b (82 mg, 0.45 mmol), N, N-Diisopropylethylamine (145 mg, 1.12 mol) and 5 mL of N,N-dimethylacetamide were reacted at 90 ° C for 12 hours. 10 mL of dichloromethane and 6 mL of water were added to the reaction mixture, the layers were separated, and the aqueous phase was extracted with methylene chloride (20 mL). The organic phase was combined and washed with saturated sodium chloride (20 mL) Filtration, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by HPLC to give the titled product of propyl propyl-{4-[[7-[3-(hydroxymethyl)-4-methoxy Phenyl]-4-[(3 S )-3-methylmorpholin-4-yl]pyrido[2,3- d ]pyrimidin-2-yl]-methyl-amino]-1-piperidyl Pyridyl}methanone 42 (2.5 mg, yellow solid), yield: 1.2%. MS m/z (ESI): 547.3 [M+]. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.22 (s, 2H), 8.11 (d, 1H), 7.51-7.41 (m, 1H), 7.10 (d, 1H), 4.73 (s, 2H), 3.82 (s, 3H), 3.80-3.60 (m, 10H), 2.81-2.61 (m, 4H), 2.21-2.11 (m, 5H), 1.53-1.45 (m, 1H), 1.35-1.26 (m, 3H) ), 1.12 - 0.91 (m, 2H), 0.95 - 0.90 (m, 1H), 0.82 - 0.74 (m, 2H).

Example 43 (3 R) -3 - { [7- [3- ( hydroxymethyl) -4-methoxy - phenyl] -4 - [(3 S) -3- methyl-morpholin-4 Pyridyl[2,3- d ]pyrimidin-2-yl]-methyl-amino}-1-methylazepin-2-one

[5-[2-Chloro-4-[(3 S )-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl]-2 was sequentially added to the sealed tube. -Methoxy-phenyl]methanol 3a (110 mg, 0.27 mmol), ( 3R )-1-methyl-3-methylamino-azaoxa-2-one (60 mg, 0.41 mmol), N,N-Diisopropylethylamine (106 mg, 0.82 mmol) and 5 mL of N,N-dimethylacetamide were reacted at 90 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure, by preparative HPLC chromatography to A resulting residue was purified by developing solvent system, to give the title product (3 R) -3 - {[ 7- [3- ( hydroxymethyl) -4-methoxy -phenyl]-4-[(3 S )-3-methylmorpholin-4-yl]pyrido[2,3- d ]pyrimidin-2-yl]-methyl-amino}-1-A Aza-oxa-2-one 43 (10 mg, yellow solid), yield: 7.2%. MS m/z (ESI): 5221. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.35 (s, 1H), 8.12 (d, 1H), 7.36 (d, 1H), 7.23 (d, 1H), 7.10 (d, 1H), 4.58 ( s, 2H), 3.88 (s, 3H), 3.90-3.63 (m, 8H), 3.52 (s, 3H), 3.25-3.16 (m, 3H), 2.89 (s, 3H), 2.02-1.75 (m, 6H), 1.26-1.24 (m, 3H).

Example 44 {4 - [[7- [3- (hydroxymethyl) -4-methoxyphenyl] -4- [(3 S) -3- methyl-morpholin-4-yl] pyrido [ 2,3- d ]pyrimidin-2-yl]-methyl-amino}piperidine-1-carboxylic acid isopropyl ester

[5-[2-Chloro-4-[(3 S )-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl]-2 was sequentially added to the sealed tube. -Methoxy-phenyl]methanol 3a (100 mg, 0.25 mmol), 4-methylaminopiperidine-1-carboxylic acid isopropyl ester (87 mg, 0,30 mmol), N,N-diisopropyl Ethylethylamine (130 mL, 0.75 mmol) and 5 mL of N,N-dimethylacetamide were reacted at 90 ° C for 12 hours. 20 mL of saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phase was combined, washed with saturated sodium chloride solution (15 mL×2), dried over anhydrous sodium sulfate, filtered The residue was purified by EtOAc (EtOAc) elut elut (3 S )-3-methylmorpholin-4-yl]pyrido[2,3- d ]pyrimidin-2-yl]-methyl-amino]piperidine-1-carboxylic acid isopropyl 44 (35 Mg, yellow solid), Yield: 24.8%. MS m/z (ESI): 566.2 [M + 1]. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.22 (s, 1H), 8.17 (d, 1H), 8.00 (d, 1H), 7.46 (d, 1H), 6.99 (d, 1H), 4.94-4.92 ( m, 2H), 4.78 (s, 2H), 3.98-3.96 (m, 1H), 3.87 (s, 3H), 3.86-3.84 (m, 4H), 3.77-3.76 (m, 4H), 3.08-3.02 ( m, 6H), 1.75 (s, 3H), 1.51 (d, 6H), 1.26 (s, 3H).

Example 45 {2-methoxy embodiment -5- [4 - [(3 S ) -3- morpholin-4-yl-methyl] -2- [methyl - [(3 R) - tetrahydrofuran-3-yl Amino]pyrido[2,3- d ]pyrimidin-7-yl]phenyl}methanol

[5-[2-Chloro-4-[(3 S )-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl]-2 was sequentially added to the sealed tube. -Methoxy-phenyl]methanol 3a (150 mg, 0.37 mmol), ( 3R )-N-methyltetrahydrofuran-3-amine (91 mg, 0.45 mmol), N,N-diisopropylethylamine (195 mL, 1.12 mmol) and 5 mL of N,N-dimethylacetamide were reacted at 90 ° C for 12 hours. 15 mL of saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL×3). The organic phase was combined, washed with saturated sodium chloride solution (15 mL×2), dried over anhydrous sodium sulfate, filtered concentrated under reduced pressure, resulting in a thin layer chromatography developing solvent system A and the residue was purified to give the title product {2-methoxy -5- [4 - [(3 S ) -3- morpholin-4-yl-methyl ]-2-[Methyl-[(3 R )-tetrahydrofuran-3-yl]amino]pyrido[2,3- d ]pyrimidin-7-yl]phenyl}methanol 45 (31 mg, yellow solid) , Yield: 17.8%. MS m/z (ESI): 466.2 [M+]. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.18 (s, 1H), 8.15 (d, 1H), 7.78 (d, 1H), 7.43 (d, 1H), 7.00 (d, 1H), 4.78 (s, 2H), 4.40 (s, 1H), 4.12-4.10 (m, 1H), 3.94-3.92 (m, 1H), 3.90 (s, 3H), 3.88-3.86 (m, 2H), 3.72-3.70 (m, 3H), 3.23 (s, 3H), 2.37 (s, 1H), 1.95 (br., 5H), 1.50 (d, 3H).

Example 46 [5-[2-Terbutyl-4-[(3S)-3-methylmorpholine]pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy- Phenyl]methanol

First step 2-(t-butyl)-7-chloro-2,3-dihydropyrido[2,3-d] Pyrimidine-4(1H)-one

2-Amino-6-chloro-pyridine-carboxamide 1a (500 mg, 2.90 mmol), trimethylacetaldehyde (754 mg, 8.80 mmol), copper chloride (1.20 g, 8.80) were added to the reaction flask. Ment) and 5 mL of ethanol, reacted at 75 ° C for 12 hours, the reaction solution was filtered, and the filter cake was washed with dichloromethane (5 mL × 2), and the filtrate was concentrated under reduced pressure, and the residue was purified by a solvent column chromatography using a solvent system A. The title product 2-(t-butyl)-7-chloro-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one 46a (96 mg, white solid) Yield: 13.9%.

The second step 2-(t-butyl)-7-chloro-pyrido[2,3-d]pyrimidin-4(3H)-one

Dissolving 2-(t-butyl)-7-chloro-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one 46a (110 mg, 0.46 mmol) in 5 mL To methyl chloride, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (210 mg, 0.92 mmol) was added for 1 hour, 10 mL of water was added and extracted with dichloromethane (10) </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> The title product 2-(t-butyl)-7-chloro-pyrido[2,3-d]pyrimidin-4(3H)-one 46b (80 mg, m. MS m/z (ESI): 238.2 [M+1]

The third step (S)-4-(2-t-butyl)-7-chloro-pyrido[2,3-d]pyrimidin-4-yl)-3-methylmorpholine

Add 2-(t-butyl)-7-chloro-pyridine in sequence to the reaction flask and [2,3-d]pyrimidin-4(3H)-one 46b (80 mg, 0.33 mmol) and 2 mL of phosphorus oxychloride, refluxed for 30 minutes, concentrated under reduced pressure, dried in vacuo, 5 mL Methane and (S)-3-methylmorpholine (100 mg, 1.00 mmol) were stirred for 1 hour. The reaction was concentrated under reduced pressure. (S)-4-(2-t-butyl)-7-chloro-pyrido[2,3-d]pyrimidin-4-yl)-3-methylmorpholine 46c (70 mg, yellow oil ), yield: 66.6%.

The fourth step [5-[2-t-butyl-4-[(3S)-3-methylmorpholine]pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy- Phenyl]methanol

(S)-4-(2-Tert-butyl)-7-chloro-pyrido[2,3-d]pyrimidin-4-yl)-3-methylmorpholine 46c (60) was sequentially added to the reaction flask. Mg, 0.19 mmol), [2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol 1e (59 mg, 0.22 mmol), tetratriphenylphosphine palladium (6 mg, 10%), potassium carbonate (78 mg, 0.56 mmol) and 1.25 mL of 1,4-dioxane and water (V/V=4 :1) The mixed solvent was reacted at 80 ° C for 12 hours, and the reaction mixture was concentrated under reduced pressure. (3S)-3-Methylmorpholine]pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-phenyl]methanol 46 (51 mg, pale yellow solid). 64.5%. MS m/z (ESI): 423.2 [M + 1] ¹ H NMR (400 MHz, CDCl3): δ 8.27-8.25 (m, 1H), 8.23 - 8.22 (m, 1H), 8.18-8.16 (m, 1H) , 7.77-7.75 (m, 1H), 7.03-7.01 (m, 1H), 4.80 (s, 2H), 4.47-4.45 (m, 1H) 4.06-4.98 (m, 2H), 3.96 (s, 3H), 3.84-3.69(m,4H),1.66- 1.64(m,3H), 1.49(s,9H)

Example 47 Cyclopropyl - {4- [7- [3- (hydroxymethyl) -4-methoxyphenyl] -4 - [(3 S) -3- methyl-morpholin-4-yl] Pyrido[2,3- d ]pyrimidin-2-yl]oxy-1-piperidinyl}methanone

Dissolve cyclopropyl-(4-hydroxy-1-piperidyl)methanone (95 mg, 0.56 mmol) in 5 mL of N,N-dimethylformamide and add sodium hydride (41 mg). , 1.12 mmol), stirred for 30 minutes, [5- [2-chloro -4 - [(3 S) -3- methyl-morpholin-4-yl] pyrido [2,3-d] pyrimidin-7 2-[2-methoxy-phenyl]methanol 3a (150 mg, 0.37 mmol) was reacted for 12 hours at room temperature. The reaction mixture was poured into 20 mL of EtOAc (EtOAc)EtOAc. The residue obtained was purified by HPLC to give the titled product of cyclopropyl-{4-[7-[3-(hydroxymethyl)-4-methoxyphenyl]-4-[( 3 S )-3-methylmorpholin-4-yl]pyrido[2,3- d ]pyrimidin-2-yl]oxy-1-piperidinyl}methanone 47 (5 mg, yellow solid) Yield: 2.5%. MS m/z (ESI): 434.2 [M + 1]. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.35-8.33 (m, 2H), 8.12 (d, 1H), 7.83 (d, 1H), 7.13 (d, 1H), 4.70 (s, 2H), 3.88(s,3H),3.73-3.56(m,10H), 3.00-2.94(m,3H),2.12-2.00(m,4H),1.54-1.52(m,1H),1.42-1.39(m,3H) ), 1.24-1.23 (m, 4H).

Example 48 {2-methoxy-5- [Embodiment 4 - [(3 S) -3- methyl-morpholin-4-yl] -2-tetrahydropyran-4-thio - pyrido [2 ,3- d ]pyrimidin-7-yl]phenyl}methanol

[5-[2-Chloro-4-[(3 S )-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl]-2 was sequentially added to the sealed tube. -Methoxy-phenyl]methanol 3a (130 mg, 0.32 mmol), tetrahydropyran-4-thiol (56 mg, 0.39 mmol), N,N-diisopropylethylamine (126 mg, 0.92 Methyl), potassium carbonate (100 mg, 0.72 mmol) and 5 mL of N,N-dimethylacetamide, reacted at 110 ° C for 12 hours. 20 mL of a saturated ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phase was combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate concentrated under pressure, resulting in a thin layer chromatography developing solvent system A and the residue was purified to give the title product {2-methoxy -5- [4 - [(3 S ) -3- methyl-morpholin-4-yl] 2-Tetrahydropyran-4-ylthio-pyrido[2,3- d ]pyrimidin-7-yl]phenyl}methanol 48 (20 mg, yellow solid), yield: 12.8%. MS m/z (ESI): 483.2 [M + 1]. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.22 (s, 1H), 8.18 (d, 1H), 7.99 (d, 1H), 7.46 (d, 1H), 6.78 (d, 1H), 4.80 ( s, 2H), 4.43 (s, 1H), 4.02-4.00 (m, 1H), 3.95 (s, 3H), 3.85-3.83 (m, 2H), 3.75-3.73 (m, 3H), 3.35 (s, 4H), 1.71 (br., 6H), 1.48 (d, 2H).

Example 49 {4 - [[7- [3- (hydroxymethyl) -4-methoxyphenyl] -4 - [(3 S) -3- methyl-morpholin-4-yl] pyrido [ 2,3- d ]pyrimidin-2-yl]-methyl-amino]-1-piperidinyl}-(3-pyridyl)methanone

[5-[2-Chloro-4-[(3 S )-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl]-2 was sequentially added to the sealed tube. -Methoxy-phenyl]methanol 3a (100 mg, 0.25 mmol), (4-methylamino-1-piperidinyl)-(3-pyridyl)methanone (60 mg, 0.27 mmol), N N-diisopropylethylamine (64 mg, 0.49 mmol) and 5 mL of N,N-dimethylacetamide were reacted at 90 ° C for 4 hours. The reaction mixture was concentrated under reduced pressure and purified to purified crystals eluted elut elut elut elut elut elut elut elut eluting 4-[(3 S )-3-methylmorpholin-4-yl]pyrido[2,3- d ]pyrimidin-2-yl]-methyl-amino]-1-piperidinyl}-( 3-pyridyl)methanone 49 (20 mg, yellow solid), yield: 13.8%. MS m/z (ESI): 58422. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.67-8.63 (m, 3H), 8.29-8.28 (m, 1H), 8.14 - 8.13 (m, 1H), 7.57 (d, 1H), 7.51 - 7.48 (m, 2H), 7.09-7.07 (m, 1H), 4.55 (d, 2H), 3.76 (s, 3H), 3.65-3.63 (m, 2H), 3.60-3.40 (m, 5H), 3.39-3.31 (m, 1H), 3.20 (s, 3H), 3.08 (m, 2H), 1.79-1.60 (m, 6H), 1.22 (m, 3H).

Example 50 {2-Methoxy-5-[4-[(3 S )-3-methylmorpholin-4-yl]-2-(tetrahydropyran-4-yl-methyl)pyridine [2,3- d ]pyrimidin-7-yl]phenyl}methanol

The first step is 2-methoxy-5-[4-oxo-2-(tetrahydropyran-4-yl-methyl)-3H-pyrido[2,3-d]pyrimidin-7-yl]benzene Methyl carbamate

2-Methoxy-5-[4-oxo-2-(tetrahydropyran-4-yl-methyl)-3H-pyrido[2,3-d]pyrimidin-7-yl]phenylcarboxylic acid 50a (395 mg, 1 mmol, prepared by the known method "patent CN101983199A") dissolved in 5 mL of methanol, added with 3 mL of hydrazine chloride, refluxed for 3 hours, concentrated under reduced pressure, and thin layer chromatography The residue obtained was purified to give the title product 2-methoxy-5-[4-oxo-2-(tetrahydropyran-4-yl-methyl)-3H-pyridine and [2,3- d]pyrimidin-7-yl]methyl benzoate 50b (180 mg, yellow solid), yield: 44.0%. MS m/z (ESI): 410.1 [M + 1].

The second step is 2-methoxy-5-[4-[(3 S )-3-methylmorpholin-4-yl]-2-(tetrahydropyran-4-yl-methyl)pyridino[ Methyl 2,3-d]pyrimidin-7-yl]phenylcarboxylate

2-Methoxy-5-[4-oxo-2-(tetrahydropyran-4-yl-methyl)-3H-pyrido[2,3-d]pyrimidin-7-yl]phenylcarboxylic acid methyl ester 50b (50 mg, 0.13 mmol) and (3 S) -3- methylmorpholine hydrochloride was dissolved in 1.5 mL of phosphorus oxychloride was added N, N- diisopropylethylamine (82 mg, 0.63 mmol), reacted at 90 ° C for 3 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc (EtOAc) concentrated under reduced pressure, resulting in a thin layer chromatography developing solvent system A and the residue was purified to give the title product 2-methoxy -5- [4 - [(3 S ) -3- methyl-morpholin-4-yl] Methyl 2-(tetrahydropyran-4-yl-methyl)pyrido[2,3-d]pyrimidin-7-yl]phenylcarboxylate 50b (18 mg, yellow solid), yield: 29.0% . MS m/z (ESI): 49:21.

The third step is [2-methoxy-5-[4-[(3 S )-3-methylmorpholin-4-yl]-2-(tetrahydropyran-4-yl-methyl)pyridine [2,3-d]pyrimidin-7-yl]phenyl]methanol

2-methoxy-5-[4-[(3 S )-3-methylmorpholin-4-yl]-2-(tetrahydropyran-4-yl-methyl)pyridino[2, Methyl 3-d]pyrimidin-7-yl]phenylcarboxylate 50b (18 mg, 0.04 mmol) and 0.5 mL of ethanol were dissolved in 0.5 mL of tetrahydrofuran, and sodium borohydride (2 mg, 0.05 mmol) was added and reacted for 12 hours. The reaction mixture was concentrated under reduced pressure, resulting in a thin layer chromatography developing solvent system A and the residue was purified to give the title product {2-methoxy -5- [4 - [(3 S ) -3- methylmorpholine - 4-yl]-2-(tetrahydropyran-4-yl-methyl)pyrido[2,3- d ]pyrimidin-7-yl]phenyl}methanol 50 (11 mg, yellow solid) : 64.7%. MS m/z (ESI): 465.1 [M + 1]. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.32 (s, 1H), 7.97-7.92 (m, 2H), 7.47 (s, 1H), 7.01 (s, 1H), 4.61 (s, 2H), 3.65 (s, 3H), 3.57-3.40 (m, 8H), 3.01-3.00 (m, 1H), 2.75-2.70 (m, 2H), 2.51-2.48 (m, 2H), 1.98-1.96 (s, 1H) ), 1.69-1.67 (m, 2H), 1.44-1.42 (m, 2H), 1.12 (s, 3H).

Example 51 {5- [2- (3,6-dihydro -2 H - pyran-4-yl) -4 - [(3 S) -3- methyl-morpholin-4-yl] pyrido [ 2,3- d ]pyrimidin-7-yl]-2-methoxy-phenyl}methanol

In a microwave tube were added [5- [2-chloro -4 - [(3 S) -3- methyl-morpholin-4-yl] pyrido [2,3-d] pyrimidin-7-yl] -2 -Methoxy-phenyl]methanol 3a (250 mg, 0.67 mmol), tributyl(3,6-dihydro-2H-pyran-4-yl)stannane 8a (300 mg, 0.80 mmol), double (triphenylphosphine)palladium dichloride (47 mg, 0.067 mmol), N,N-diisopropylethylamine (233 mL, 1.34 mmol), iodide (15 mg, 0.07 mmol) and 0.5 mL N,N-dimethylformamide was reacted at 130 ° C for 20 minutes. After adding 25 mL of water to the reaction mixture, the mixture was extracted with ethyl acetate (30 mL×2). A thin-layer chromatography to the resulting residue was purified by developing solvent system, to give the title product {5- [2- (3,6-dihydro -2 H - pyran-4-yl) -4 - [(3 S) - 3-methylmorpholin-4-yl]pyrido[2,3- d ]pyrimidin-7-yl]-2-methoxy-phenyl}methanol 51 (28 mg, yellow solid), yield: 9.3 %. MS m/z (ESI): 449.2. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.27-8.26 (m, 2H), 8.22-8.20 (d, 1H), 7.80 (d, 1H), 7.07-7.05 (d, 1H), 5.96-5.94 (m, 1H), 4.86 (s, 2H), 4.56-4.54 (m, 1H), 4.48-4.46 (m, 2H), 4.06-4.04 (m, 2H), 4.00 (s, 3H), 3.98-3.96 (m, 1H), 3.83-3.80 (m, 3H), 3.78-3.76 (m, 1H), 2.92-2.90 (m, 2H), 2.35 (s, 2H), 1.52 (d, 2H).

Example 52 {2-Methoxy-5-[4-[(3 S )-3-methylmorpholin-4-yl]-2-[methyl-[1-(3-pyridylmethyl) 4-piperidinyl]amino]pyrido[2,3- d ]pyrimidin-7-yl]phenyl}methanol

[5-[2-Chloro-4-[(3 S )-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl]-2 was sequentially added to the sealed tube. -Methoxy-phenyl]methanol 3a (100 mg, 0.25 mmol), N-methyl-1-(3-pyridylmethyl)piperidin-4-amine (100 mg, 0.49 mmol), 0.5 mL N-diisopropylethylamine and 2 mL of N,N-dimethylacetamide were reacted at 110 ° C for 12 hours. 10 mL of ethyl acetate and 6 mL of water were added to the reaction mixture, and the organic layer was washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, The residue obtained was purified by EtOAc EtOAc ( EtOAc ) [1-(3-Pyridylmethyl)-4-piperidinyl]amino]pyrido[2,3- d ]pyrimidin-7-yl]phenyl}methanol 52 (68 mg, yellow solid) Rate: 47.9%. MS m/z (ESI): 570.6 [M + 1]. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.61-8.51 (m, 2H), 8.25-8.11 (m, 2H), 7.97 (d, 1H), 7.82 (d, 1H), 7.41 (d, 1H) ), 7.33-7.31 (m, 1H), 6.99 (d, 1H), 4.61 (s, 2H), 4.36 (br., 1H), 4.03-3.61 (m, 9H), 3.42-2.90 (m, 8H) , 2.25 - 1.76 (m, 4H), 1.48 (d, 3H), 1.26 (s, 3H).

Example 53 {2-Methoxy-5-[4-[(3 S )-3-methylmorpholin-4-yl]-2-tetrahydropyran-4-yl-pyrido[2,3 - d ] pyrimidin-7-yl]phenyl}methanol

[5-[2-(3,6-Dihydro-2 H -pyran-4-yl)-4-[(3 S )-3-methylmorpholin-4-yl]pyridine[2, 3-d]pyrimidin-7-yl]-2-methoxy-phenyl]methanol 54 (25 mg, 0.05 mmol) was dissolved in 20 mL of methanol, then palladium/carbon (10 mg, 10%) Three times, the reaction was stirred for 3 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, the resulting thin layer chromatography in a developing solvent system A and the residue was purified to give the title product {2-methoxy -5- [4 - [(3 S ) -3- methyl Morpholin-4-yl]-2-tetrahydropyran-4-yl-pyrido[2,3- d ]pyrimidin-7-yl]phenyl}methanol 53 (15 mg, pale yellow solid), yield : 60.0%. MS m/z (ESI): 4521. [M+]. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.29 (d, 1H), 8.25 (d, 1H), 8.18 (d, 1H), 7.78 (d, 1H), 7.04 (d, 1H), 4.80 ( s, 2H), 4.56-4.54 (m, 1H), 4.17 (d, 2H), 3.99 (d, 1H), 3.96 (s, 3H), 3.82-3.80 (m, 1H), 3.75 (d, 3H) , 3.58-3.56 (m, 2H), 3.22 (s, 1H), 2.14 - 2.12 (m, 3H), 2.02 - 2.00 (m, 2H), 1.56 (d, 3H).

Example 54 4-{[7-[3-(Hydroxymethyl)-4-methoxy-phenyl]-4-[(3S)-3-methylmorpholin-4-yl]pyridin[2 ,3- d ]pyrimidin-2-yl]-methyl-amino}piperidin-1-carboxylic acid methyl ester

[5-[2-Chloro-4-[(3 S )-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl]-2 was sequentially added to the sealed tube. -Methoxy-phenyl]methanol 3a (100 mg, 0.25 mmol), methyl 4-methylaminopiperidine-1-carboxylate (50 mg, 0.30 mmol), N,N-diisopropylethylamine (96 mg, 0.75 mmol) and 5 mL of N,N-dimethylacetamide, reacted at 90 ° C for 4 hours, concentrated under reduced pressure, and purified by HPLC to give the titled product 4 -{[7-[3-(hydroxymethyl)-4-methoxy-phenyl]-4-[(3 S )-3-methylmorpholin-4-yl]pyrido[2,3- d ]pyrimidin-2-yl]-methyl-amino}piperidine-1-carboxylic acid methyl ester 54 (20 mg, yellow solid), yield: 15.3%. MS m/z (ESI): 537.2 [M+1]. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.28 (s, 1H), 8.13 (d, 1H), 8.04 (d, 1H), 7.56 (d, 1H), 7.08 (d, 1H), 4.56 ( d, 2H), 4.24-4.05 (m, 3H), 3.82 (s, 3H), 3.74-3.72 (m, 2H), 3.64 (s, 3H), 3.03 (s, 3H), 3.02-2.68 (m, 4H), 2.40-2.31 (m, 3H), 1.76-1.60 (m, 4H), 1.36 (d, 3H).

Example 55 {5-[2-[[1-(2-Fluoro-2-methyl-propyl)-4-piperidinyl]-methyl-amino]-4-[( 3S )-3 -methylmorpholin-4-yl]pyrido[2,3- d ]pyrimidin-7-yl]-2-methoxy-phenyl}methanol

[5-[2-Chloro-4-[(3 S )-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl]-2 was sequentially added to the sealed tube. -methoxy-phenyl]methanol 3a (100 mg, 0.25 mmol), 1-(2-fluoro-2-methyl-propyl)-N-methyl-piperidinyl-4-amine (300 mg, 1.60 mmol), N,N-diisopropylethylamine (370 mg, 2.88 mmol) and 3 mL of N,N-dimethylacetamide, reacted at 110 ° C for 12 hours. 10 mL of ethyl acetate and 6 mL of water were added to the reaction mixture, and the organic layer was washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, The residue obtained was purified by the titled solvent system A to give the title product <5-[2-[[1-(2-fluoro-2-methyl-propyl)-4-piperidinyl]-methyl-amine ]-4-[(3 S )-3-methylmorpholin-4-yl]pyrido[2,3- d ]pyrimidin-7-yl]-2-methoxy-phenyl}methanol 55 (35 Mg, yellow solid), yield: 7.2%. MS m/z (ESI): 551.3. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.23 (s, 1H), 8.15 (d, 1H), 8.02 (d, 1H), 7.46 (d, 1H), 7.03 (d, 1H), 4. s, 2H), 4.10-3.71 (m, 6H), 3.21 (s, 3H), 2.51-1.55 (m, 12H), 1.53-1.37 (m, 4H), 1.29 (s, 9H).

Example 56 {2-methoxy-5- [2-methyl -4 - [(3 S) -3- methyl-morpholin-4-yl] pyrido [2,3- d] pyrimidin-7 Phenyl]methanol

First step 2-[7-[3-(2,2-dimethylpropoxymethyl)-4-methoxy-phenyl]-4-[(3 S )-3-methyl? Diphenyl-4-yl]pyrido[2,3-d]pyrimidin-2-yl]malonate diethyl ester

Sodium hydride (133 mg, 3.27 mmol) was dissolved in 35 mL of tetrahydrofuran, diethyl malonate (525 mg, 3.27 mmol) was added dropwise to the solution, stirred for 30 minutes, then 20 mL [5-[2 - chloro -4 - [(3 S) -3- methyl-morpholin-4-yl] pyrido [2,3-d] pyrimidin-7-yl] -2-methoxy - phenyl] - methyl -2,2-Dimethylpropionate 56a (700 mg, 1.49 mmol, prepared by a known method "Patent US20090318434A1") in tetrahydrofuran, refluxed for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc)EtOAc. The residue obtained was purified by chromatography EtOAc (EtOAc) -[(3 S )-3-Methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-2-yl]malonate 56b (860 mg, yellow solid), yield : 97.8%. MS m/z (ESI): 609.2 [M+1].

The second step [2-methoxy-5- [2-methyl -4 - [(3 S) -3- methyl-morpholin-4-yl] pyrido [2,3-d] pyrimidin-7 Phenyl]methyl-2,2-dimethylpropionate

2- [7- [3- (2,2-dimethyl-propoxy acyl oxymethyl) -4-methoxy - phenyl] -4 - [(3 S) -3- methylmorpholine - Diethyl 4-pyrido[2,3-d]pyrimidin-2-yl]malonate 56b (860 mg, 1.41 mmol) was dissolved in 15 mL of dimethyl hydrazine and added with lithium chloride (60 Mg, 1.41 mmol), reacted at 150 ° C for 2 hours. 30 mL of ethyl acetate and 30 mL of water were added to the reaction mixture, and the mixture was evaporated. layer chromatography using a developing solvent system, the resulting residue was purified by C, to give the title product [2-methoxy-5- [2-methyl -4 - [(3 S) -3- methyl-morpholin-4-yl] Pyrido[2,3-d]pyrimidin-7-yl]phenyl]methyl-2,2-dimethylpropanoate 56c (430 mg, pale yellow oil), yield: 65.5%. MS m/z (ESI): 465.2 [M+].

The third step [2-methoxy-5- [2-methyl -4 - [(3 S) -3- methyl-morpholin-4-yl] pyrido [2,3-d] pyrimidin-7 Phenyl]methanol

The [2-methoxy-5- [2-methyl -4 - [(3 S) -3- methyl-morpholin-4-yl] pyrido [2,3-d] pyrimidin-7-yl] Phenyl]methyl-2,2-dimethylpropionate 56c (30 mg, 0.06 mmol) was dissolved in 6 mL of a mixture of tetrahydrofuran and water (V/V = 5:1), and lithium hydroxide (28) was added. Mg, 0.65 mmol), mp. (3 S) -3- methyl-morpholin-4-yl] pyrido [2,3- d] pyrimidin-7-yl] phenyl} methanol 56 (19 mg, pale yellow solid), yield: 76.9% . MS m/z (ESI): 381.2 [M+1]. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.29 (d, 1H), 8.26 (s, 1H), 8.17 (d, 1H), 7.77 (d, 1H), 7.03 (d, 1H), 4.79 ( s, 2H), 4.56-4.55 (m, 1H), 4.09-4.06 (m, 1H), 4.01-3.99 (m, 1H), 3.96 (s, 3H), 3.86-3.83 (m, 1H), 3.76- 3.73 (m, 3H), 2.71 (s, 3H), 1.52 (d, 3H).

Example 57 [2-Methoxy-5-[4-[(3 S )-3-methylmorpholin-4-yl]-2-[methyl-[1-(2,2,2-tri) Fluoroethyl)-4-piperidinyl]amino]pyrido[2,3-d]pyrimidin-7-yl]phenyl]methanol

[5- [2-chloro -4 - [(3 S) -3- methyl-morpholin-4-yl] pyrido [2,3-d] pyrimidin-7-yl] -2-methoxy - Phenyl]methanol 3a (150 mg, 0.37 mmol), N-methyl-1-(2,2,2-trifluoroethyl)piperidin-4-amine (110 mg, 0.56 mmol) and N,N- Diisopropylethylamine (0.2 mL, 1.12 mmol) was dissolved in 5 mL of N,N-dimethylacetamide, and reacted at 90 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure. A resulting residue was purified to give the title product [2-methoxy -5- [4 - [(3 S ) -3- morpholin-4-yl-methyl] -2- [methyl - [1- (2 ,2,2-trifluoroethyl)-4-piperidinyl]amino]pyrido[2,3-d]pyrimidin-7-yl]phenyl]methanol 57 (15 mg, yellow solid) : 7.2%. MS m/z (ESI): 561.6 [M+1]. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.30 (s, 1H), 8.15 (d, 1H), 8.07 (d, 1H), 7.57 (d, 1H), 7.10 (d, 1H), 5.23 5.20 (m, 1H), 4.59-4.57 (m, 2H), 3.90-3.89 (m, 2H), 3.87 (s, 3H), 3.75-3.59 (m, 4H), 3.30-3.28 (m, 4H), 3.27-2.21 (m, 2H), 3.07 (s, 3H), 3.06-3.03 (m, 2H), 1.85-1.82 (m, 2H), 1.63-1.61 (m, 2H), 1.58-1.37 (m, 3H) ).

Example 58 [2-Methoxy-5-[4-[(3 S )-3-methylmorpholin-4-yl]-2-[methyl-(1-tetrahydropyran-4-yl) 4-piperidinyl)amino]pyrido[2,3-d]pyrimidin-7-yl]phenyl]methanol

The N- tetrahydropyran-4-methyl-1 - piperidin-4-amine (60 mg, 0.30 mmol), [5- [2- chloro -4 - [(3 S) -3- methyl Methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-phenyl]methanol 3a (100 mg, 0.25 mmol) and N,N-diisopropyl Ethylethylamine (78 mg, 0.60 mmol) was dissolved in 5 mL of N,N-dimethylacetamide, and reacted at 90 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure and purified by thin layer chromatography. The residue, to give the title product [2-methoxy -5- [4 - [(3 S ) -3- morpholin-4-yl-methyl] -2- [methyl - (l-tetrahydropyran - 4-yl-4-piperidinyl)amino]pyrido[2,3-d]pyrimidin-7-yl]phenyl]methanol 58 (15 mg, yellow solid), yield: 10.7%. MS m/z (ESI): 563.2 [M + 1]. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.30 (d, 1H), 8.15 (d, 1H), 8.05 (d, 1H), 7.58 (d, 1H), 7.09 (d, 1H), 4.58 ( d, 1H), 4, 48-4.45 (m, 2H), 3.95-3.89 (m, 4H), 3.87-3.81 (m, 3H), 3.82-3.74 (m, 1H), 3.72-3.54 (m, 4H) ), 3.31-3.27 (m, 2H), 3.17 (d, 1H), 3.07 (s, 3H), 2.54-2.52 (m, 4H), 1.96-1.56 (m, 6H), 1.38 (d, 3H), 1.30-1.27 (m, 1H).

Example 59 [2-Methoxy-5-[2-(methyl(tetrahydropyran-4-yl)) Amino)-4-(8-oxa-3-azabicyclo[3.2.1]octane-3-yl)pyrido[2,3-d]pyrimidin-7-yl]phenyl]methanol

First step 3-(2,7-Dichloropyrido[2,3-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane

2,4,7-Trichloropyrido[2,3-d]pyrimidine 1c (235 mg, 1 mmol), 8-oxa-3-azabicyclo[3.2.1]octane (150 mg, 1 mmol) and N,N-diisopropylethylamine (258 mg, 2 mmol) were dissolved in 10 mL of tetrahydrofuran, reacted for 12 hours, concentrated under reduced pressure, and then added with 25 mL of water and 25 mL of ethyl acetate. The aqueous phase was extracted with ethyl acetate (30 mL×2), EtOAcjjjjjjjjj ,7-Dichloropyrido[2,3-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane 59a (320 mg, pale yellow solid), product It was used in the next step without purification. MS m/z (ESI): 3121. [M+1].

The second step [5-[2-chloro-4-(8-oxa-3-azabicyclo[3.2.1]octane-3-yl)pyrido[2,3-d]pyrimidine-7- 2-methoxyphenyl]methanol

The crude 3-(2,7-dichloropyrido[2,3-d]pyrimidin-4-yl)-8-oxygen Hetero-3-azabicyclo[3.2.1]octane 59a (311 mg, 1 mmol), [2-methoxy-5-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)phenyl]methanol 1e (396 mg, 1.50 mmol), bis(triphenylphosphine)palladium dichloride (115 mg, 0.10 mmol) and sodium carbonate (212 mg, 2 mmol) dissolved in 10 mL of 1,4-dioxane and water (V/V=2:1) mixed solvent, reacted at 90 ° C for 4 hours, concentrated under reduced pressure, added with 20 mL of water, with two Methyl chloride extraction (30 mL × 2), combined organic phase, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue gave the title product [5-[2-chloro-4-(8-oxa-3-azabicyclo[3.2.1]octane-3-yl)pyrido[2,3-d]pyrimidine -7-yl]-2-methoxyphenyl]methanol 59b (300 mg, yellow solid), yield: 72.7%. MS m/z (ESI): 413.4 [M + 1].

The third step [2-methoxy-5-[2-(methyl(tetrahydropyran-4-yl)amino)-4-(8-oxa-3-azabicyclo[3.2.1] Octane-3-yl)pyrido[2,3-d]pyrimidin-7-yl]phenyl]methanol

[5-[2-Chloro-4-(8-oxa-3-azabicyclo[3.2.1]octane-3-yl)pyrido[2,3-d]pyrimidin-7-yl] 2-methoxyphenyl]methanol 59b (300 mg, 0.73 mmol), N-methyltetrahydropyran-4-amine (167 mg, 1.45 mmol) and N,N-diisopropylethylamine ( 0.4 mL, 2.20 mmol) was dissolved in 5 mL of N,N-dimethylacetamide, and reacted at 90 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure. The title product [2-methoxy-5-[2-(methyl(tetrahydropyran-4-yl)amino)-4-(8-oxa-3-azabicyclo[3.2.1] Octane-3-yl)pyrido[2,3-d]pyrimidin-7-yl]phenyl]methanol 59 (10 mg, yellow solid), yield: 5.5%. MS m/z (ESI): 492.6 [M + 1]. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.29 (s, 1H), 8.18 (d, 1H), 8.07 (d, 1H), 7.57 (d, 1H), 7.11 (d, 1H), 5.22-5.19 ( m,1H), 4.59-4.57 (m, 2H), 4.42 (s, 2H), 4.13-4.10 (m, 2H), 3.99-3.98 (m, 2H), 3.93 (s, 1H), 3.87 (s, 3H), 3.53-3.46 (m, 4H), 3.07 (s, 3H), 1.89-1.75 (m, 6H), 1.61-1.59 (m, 2H).

Example 60 6-[4-[(3 S )-3-methylmorpholin-4-yl)-2-(methyl(tetrahydropyran-4-yl)amino)pyridin[2,3 -d]pyrimidin-7-yl]chroman-4-ol

First step (3 S )-4-(2,7-dichloropyrido[2,3-d]pyrimidin-4-yl)-3-methyl-morpholine

2,4,7-Trichloropyrido[2,3-d]pyrimidine 1c (1.50 g, 6.41 mmol) was dissolved in 10 mL of dichloromethane, and N,N-diisopropylethylamine was added at 0 °C. 827 mg, 6.41 mmol) and (3 S) -3- methylmorpholine (647 mg, 6.41 mmol), at room temperature for 1 hour, 20 mL of water and 40 mL ethyl acetate layers were separated, the organic phase was washed with saturated washed with sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, by silica gel column chromatography to B the resulting residue was purified by developing solvent system, to give the title product (3 S) -4- (2 , 7-Dichloropyrido[2,3-d]pyrimidin-4-yl)-3-methyl-morpholine 60a (1.80 g, yellow solid), yield: 94.2%. MS m/z (ESI): 299.0 [M+1].

Step 7-chloro -N- methyl -4 - [(3 S) -3- methyl-morpholin-4-yl] -N- tetrahydropyran-4-yl - pyrido [2,3- d]pyrimidine-2-amine

Dissolve (3 S )-4-(2,7-dichloropyrido[2,3-d]pyrimidin-4-yl)-3-methyl-morpholine 60a (329 mg, 1.10 mmol) in 2 mL N,N-Diisopropylethylamine (142 mg, 1.10 mmol) and N-methyltetrahydropyran-4-amine (126 mg, 1.10 mmol) were added to N,N-dimethylacetamide. The reaction was carried out at 90 ° C for 12 hours, 5 mL of water and 20 mL of ethyl acetate were added, the layers were separated, and the organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and evaporated. The resulting column chromatography developing solvent system B and the residue was purified to give the title product 7-chloro -N- methyl -4 - [(3 S) -3- methyl-morpholin-4-yl] -N- tetrahydro-pyridine M--4-yl-pyrido[2,3-d]pyrimidin-2-amine 60b (70 mg, yellow solid), yield: 16.8%. MS m/z (ESI): 378.1 [M+1].

The third step is 6-[4-[(3 S -3-methylmorpholin-4-yl)-2-(methyl(tetrahydropyran-4-yl)amino)pyridin[2,3- d]pyrimidin-7-yl]chroman-4-one

6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-4-one 60c (101 mg, 0.37 mmol, using known methods "patent WO2007084786" preparation derived) and 7-chloro -N- methyl -4 - [(3 S) -3- methyl-morpholin-4-yl] -N- tetrahydropyran-4 Base-pyrido[2,3-d]pyrimidin-2-amine 60b (70 mg, 0.18 mmol) was dissolved in 2 mL of a mixture of 1,4-dioxane and water (V/V=4:1). Add tetrakis(triphenylphosphine)palladium (20.70 mg, 0.018 mmol) and potassium carbonate (46 mg, 0.32 mmol), stir for 10 minutes, microwave reaction at 100 °C for 20 minutes, filter, add 2 mL water and 10 mL to the filtrate. The organic layer was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The title product 6-[4-[(3 S -3-methylmorpholin-4-yl)-2-(methyl(tetrahydropyran-4-yl)amino)pyrido[2,3-d Pyrimidine-7-yl]chroman-4-one 60d (80 mg, yellow solid), yield: 88.5%. MS m/z (ESI):495.

The fourth step is 6-[4-[(3 S -3-methylmorpholin-4-yl)-2-(methyl(tetrahydropyran-4-yl)amino)pyridin[2,3- d]pyrimidin-7-yl]chroman-4-ol

6-[4-[(3 S -3-methylmorpholin-4-yl)-2-(methyl(tetrahydropyran-4-yl)amino)pyrido[2,3-d] Pyrimidine-7-yl]chroman-4-one 60d (75 mg, 0.19 mmol) was dissolved in 2 mL of methanol, sodium borohydride (21.30 mg, 0.56 mmol) was added and reacted for 2 hours, 2 mL water and 5 mL were added. The organic layer was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The product 6- [4- [(3 S -3- methyl-morpholin-4-yl) -2- (methyl (tetrahydropyran-4-yl) amino) pyrido [2,3-d] Pyrimidine-7-yl]chroman-4-ol 60 (36 mg, pale yellow solid), yield: 39.0%. MS m/z (ESI):495. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.31 (s, 1H), 7.95 (d, 2H), 7.36 (d, 1H), 6.92 (d, 1H), 4.91 (s, 1H), 4.36-4.31 ( m, 4H), 4.08-3.67 (m, 11H), 3.15 (s, 2H), 2.11 (m, 2H), 1.94-1.90 (m, 2H), 1.69 (m, 2H), 1.46 (d, 3H) .

Example 61 (2-Methoxy-5-(2-(methyl(1-(pyrimidin-2-yl)piperidin-4-yl)amino)-4-((3S)-3-methyl) Morpholine) pyrido[2,3-d]pyrimidin-7-yl)phenyl)methanol

First step 1-(pyrimidin-2-yl)piperidin-4-one

2-Chloropyrimidine 61a (100 mg, 0.87 mmol), piperidin-4-one 61b (140 mg, 1.05 mmol), triethylamine (435 mg, 4.35 mmol) and 5 mL 1,4 were added to the sealed tube. - Dioxane, the reaction was carried out at 90 ° C for 12 hours, the reaction mixture was filtered, and the filtrate was evaporated. The product was used in the next step without purification. MS m/z (ESI): 178.2 [M+1]

Second step N-methyl-1-(pyrimidin-2-yl)piperidin-4-amine

The crude 1-(pyrimidin-2-yl)piperidin-4-one 61c (400 mg, 2.26 mmol) and methylamine hydrochloride (305 mg, 4.52 mmol) were dissolved in 20 mL 1,2-dichloroethane The reaction was stirred for 1 hour, sodium borohydride triacetate (1.40 g, 6.78 mmol) was added, and the reaction was carried out for 12 hours, 30 mL of dichloromethane was added, and the organic phase was separated with saturated sodium hydrogen carbonate solution (30 mL×3). Washed with a saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate 61d (210 mg, white oil), product was used in the next step without purification. MS m/z (ESI): 193.2 [M+1]

The third step (2-methoxy-5-(2-(methyl(1-(pyrimidin-2-yl)piperidin-4-yl)amino)-4-((3S)-3-methyl) Morpholine) pyrido[2,3-d]pyrimidin-7-yl)phenyl)methanol

[5-[2-Chloro-4-[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl]-2- was added sequentially to the sealed tube. Methoxy-phenyl]methanol 3a (100 mg, 0.25 mmol), crude N-methyl-1-(pyrimidin-2-yl)piperidin-4-amine 61d (87 mg, 0.30 mmol), N, N -Diisopropylethylamine (0.3 mL, 0.75 mmol) and 4 mL of N,N-dimethylacetamide, reacted at 90 ° C for 12 hours, added 15 mL of water and extracted with ethyl acetate (15 mL × 2) The organic phase was combined, washed with a saturated sodium chloride solution (10 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. (2-Methoxy-5-(2-(methyl(1-(pyrimidin-2-yl)piperidin-4-yl)amino)-4-((3S)-3-methylmorpholine) Pyrido[2,3-d]pyrimidin-7-yl)phenyl)methanol 61 (21 mg, yellow solid), yield: 19.1%. MS m/z (ESI): 557.5 [M+1] ¹ H NMR (400 MHz, DMSO-d6): δ 8.37 (d, 2H), 8.36 (s, 1H), 8.24 (s, 1H), 8.08 (d) , 1H), 7.71 (s, 1H), 7.12 (d, 1H), 6.62 (t, 1H), 5.31 (s, 1H), 4.84 (d, 2H), 4.56 (s, 2H), 3.90 (d, 1H), 3.86 (s, 3H), 3.58-3.75 (m, 4H), 3.06 (s, 4H), 1.92-2.08 (m, 2H), 1.75 (s, 3H), 1.41 (d, 3H), 0.84 (t, 2H)

Example 62 [2-Methoxy-5-[4-[(3 S )-3-methylmorpholin-4-yl]-2-[methyl(tetrahydropyran-4-yl)amine Pyridine[2,3-d]pyrimidin-7-yl]phenyl]methanol

[5-(2-Chloro-4-morpholine-pyrido[2,3-d]pyrimidin-7-yl)-2-methoxy-phenyl]methanol 1f (100 mg, 0.26 mmol), N -Methyltetrahydropyran-4-amine (29 mg, 0.26 mmol) and N,N-diisopropylethylamine (66 mg, 0.51 mmol) dissolved in 5 mL of N,N-dimethylacetamide in reaction 90 ℃ 12 hours, the reaction mixture was concentrated under reduced pressure, resulting in a thin layer chromatography developing solvent system A and the residue was purified to give the title product [2-methoxy -5- [4 - [(3 S ) - 3-methylmorpholin-4-yl]-2-[methyl(tetrahydropyran-4-yl)amino]pyrido[2,3-d]pyrimidin-7-yl]phenyl]methanol 62 (10 mg, yellow solid), yield: 8.3%. MS m/z (ESI): 563.2 [M + 1]. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.29 (s, 1H), 8.19 (d, 1H), 8.06 (d, 1H), 7.58 (d, 1H), 7.09 (d, 1H), 4.57 ( s, 2H), 4.01-3.82 (m, 2H), 3.86 (s, 3H), 3.78-3.50 (m, 4H), 3.49-3.40 (m, 2H), 3.39-3.18 (m, 6H), 3.07 ( s, 3H), 1.85-1.78 (m, 3H).

Example 63 [2-(Difluoromethoxy)-5-[4-[(3 S )-3-methylmorpholin-4-yl]-2-(methyl(tetrahydropyran-4-) Amino)pyrido[2,3-d]pyrimidin-7-yl]phenyl]methanol

First step [5-[2-chloro-4-[(3 S )-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl]-2-(di) Fluoromethoxy)phenyl]methanol

(3 S )-4-(2,7-Dichloropyrido[2,3-d]pyrimidin-4-yl)-3-methyl-morpholine 60a (380 mg, 1.67 mmol), [2- (difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (500 mg, 1.67 mmol, prepared by the well-known method "patent WO2007084786", [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (61 mg, 0.083 mmol) and sodium carbonate (530) Mg, 5 mmol) was dissolved in 6 mL of 1,4-dioxane and water (V/V = 5:1) in a mixed solvent. The reaction was carried out at 90 ° C for 12 hours. The reaction was concentrated under reduced pressure. 10 mL of water, EtOAc, EtOAc (EtOAc m. A thin-layer chromatography to the resulting residue was purified by developing solvent system, to give the title product [5- [2-chloro -4 - [(3 S) -3- methyl-morpholin-4-yl] pyridine [2,3- -d]pyrimidin-7-yl]-2-(difluoromethoxy)phenyl]methanol 63a (80 mg, mp.). MS m/z (ESI): 437.1 [M+1].

The second step [2-(difluoromethoxy)-5-[4-[(3 S )-3-methylmorpholin-4-yl]-2-(methyl(tetrahydropyran-4-) Amino)pyrido[2,3-d]pyrimidin-7-yl]phenyl]methanol

[5-[2-Chloro-4-[(3 S )-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl]-2 was sequentially added to the sealed tube. -(Difluoromethoxy)phenyl]methanol 63a (80 mg, 0.18 mmol), N-methylmorpholin-4-amine (100 mg, 0.87 mmol), N,N-diisopropylethylamine ( 70 mg, 0.54 mmol) and 3 mL of N,N-dimethylacetamide, reacted at 110 ° C for 12 hours, added 9 mL of water and 15 mL of ethyl acetate, layered, and the organic phase was washed with saturated sodium chloride solution (5 mL × 2), dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated. [4-[(3 S )-3-methylmorpholin-4-yl]-2-(methyl(tetrahydropyran-4-yl)amino)pyrido[2,3-d]pyrimidine- 7-yl]phenyl]methanol 63 (7 mg, light brown solid), yield: 7.4%. MS m/z (ESI): 516.2 [M + 1]. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.85 (d, 1H), 7.75-7.65 (br., 1H), 7.38 (t, 1H), 7.25 (d, 1H), 6.62-6.52 (m, 1H), 5.75-5.65 (m, 1H), 5.34 (s, 2H), 4.40-4.25 (m, 1H), 4.15-3.98 (m, 2H), 3.91-3.50 (m, 8H), 3.30-3.10 ( m, 1H), 2.21 (s, 3H), 2.13-1.90 (m, 2H), 1.56-1.46 (m, 2H), 1.29 (s, 3H).

Example 64 [2-Fluoro-5-[4-[(3 S )-3-methylmorpholin-4-yl]-2-(methyl(tetrahydropyran-4-yl)amino)pyridine And [2,3-d]pyrimidin-7-yl]phenyl]methanol

First step [5-[2-chloro-4-[(3 S )-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl]-2-fluoro- Phenyl]methanol

The [4-fluoro-3- (hydroxymethyl) phenyl] boronic acid (293 mg, 1.72 mmol, using well-known methods "patent WO2004000814" preparation derived), (3 S) -4- ( 2,7- two Chloropyrido[2,3-d]pyrimidin-4-yl)-3-methyl-morpholine 60a (430 mg, 1.44 mmol), [1,1'-bis(diphenylphosphino)ferrocene Palladium dichloride (104 mg, 0.144 mmol) and sodium carbonate (305 mg, 2.88 mmol) were dissolved in 10 mL of a mixture of 1,4-dioxane and water (V/V = 5:1) at 90 After reacting for 12 hours at ° C, the reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc)EtOAc. (30 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, resulting in a thin layer chromatography developing solvent system A and the residue was purified to give the title product [5- [2-chloro -4 - [(3 S) 3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl]-2-fluoro-phenyl]methanol 64a (110 mg, yellow solid), yield: 19.6% . MS m/z (ESI): 390.1 [M+1].

Second step [2-Fluoro-5-[4-[(3 S )-3-methylmorpholin-4-yl]-2-(methyl(tetrahydropyran-4-yl)amino)pyridine And [2,3-d]pyrimidin-7-yl]phenyl]methanol

[5- [2-chloro -4 - [(3 S) -3- methyl-morpholin-4-yl] pyrido [2,3-d] pyrimidin-7-yl] -2-fluoro - phenyl Methanol 64a (100 mg, 0.26 mmol), N-methylmorpholin-4-amine (44.40 mg, 0.39 mmol) and N,N-diisopropylethylamine (100 mg, 0.77 mmol) dissolved in 5 mL The N,N-dimethylacetamide was reacted at 90 ° C for 12 hours, and the reaction mixture was concentrated under reduced pressure. [4-[(3 S )-3-methylmorpholin-4-yl]-2-(methyl(tetrahydropyran-4-yl)amino)pyrido[2,3-d]pyrimidine- 7-yl]phenyl]methanol 64 (4 mg, yellow solid), yield: 3.3%. MS m/z (ESI): 468.2 [M + 1]. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.41 (s, 1H), 8.09 (d, 1H), 7.67-7.44 (m, 2H), 7.17 (d, 1H), 5.41-5.39 (m, 1H), 4.89 (s, 2H), 4.17-3.70 (m, 8H), 3.53 (s, 3H), 3.28-3.21 (m, 4H), 2.01-1.98 (m, 2H), 1.56-1.52 (m, 2H), 1.35-1.30 (m, 3H).

Example 65 [4 - [[7- [3- (hydroxymethyl) -4-methoxy - phenyl] -4 - [(3 S) -3- methyl-morpholin-4-yl] pyridine and [2,3-d]pyrimidin-2-yl]-methyl-amino]-1-piperidinyl]-(2-pyridyl)methanone

(4-dimethylamino-1-piperidinyl) - (2-pyridyl) methanone (60 mg, 0.27 mmol), [5- [2- chloro -4 - [(3 S) -3- Methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-phenyl]methanol 3a (100 mg, 0.25 mmol) and N,N-diiso Propylethylamine (64 mg, 0.49 mmol) was dissolved in 3 mL of N,N-dimethylacetamide, and reacted at 90 ° C for 12 hours. The reaction was concentrated under reduced pressure and purified by HPLC. The resulting residue was the title product [4 - [[7- [3- (hydroxymethyl) -4-methoxy - phenyl] -4 - [(3 S) -3- methyl-morpholin-4 Pyridyl[2,3-d]pyrimidin-2-yl]-methyl-amino]-1-piperidinyl]-(2-pyridyl)methanone 65 (30 mg, yellow solid) Rate: 20.6%. MS m/z (ESI): 468.2 [M + 1]. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.68 (s, 1H), 8.22 (s, 1H), 8.11 - 7.93 (m, 3H), 7.66-7.60 (m, 2H), 7.52-7, 47 (m, 1H), 6.91 (d, 1H), 4.85-4.75 (m, 2H), 4.08-4.05 (m, 1H), 3.88 (s, 3H), 3.84-3.65 (m, 5H), 3.48-3.25 (m, 2H), 3.20-2.75 (m, 3H), 2.67-2.65 (m, 1H), 2.10 - 1.76 (m, 7H), 1.63-1.61 (m, 3H).

Example 66 [4 - [[7- [3- (hydroxymethyl) -4-methoxy - phenyl] -4 - [(3 S) -3- methyl-morpholin-4-yl] pyridine and [2,3-d]pyrimidin-2-yl]-methyl-amino]-1-piperidinyl]-phenyl ketone

(4-dimethylamino-1-piperidinyl) - phenyl-methanone (60 mg, 0.28 mmol), [5- [2- chloro -4 - [(3 S) -3- methylmorpholine 4-yl]pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-phenyl]methanol 3a (100 mg, 0.25 mmol) and N,N-diisopropylethylamine (64 mg, 0.49 mmol) was dissolved in 3 mL of N,N-dimethylacetamide, and reacted at 90 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue obtained was purified by HPLC. The title product [4-[[7-[3-(hydroxymethyl)-4-methoxy-phenyl]-4-[(3S)-3-methylmorpholin-4-yl]pyridine) was obtained. 2,3-d]pyrimidin-2-yl]-methyl-amino]-1-piperidinyl]-phenylmethanone 66 (40 mg, yellow solid), yield: 27.5%. MS m/z (ESI): 468.2 [M + 1]. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.29 (s, 1H), 8.15 (d, 1H), 8.05 (d, 1H), 7.57-7.55 (d, 1H), 7.49-7.32 (m, 4H) ), 7.09-7.07 (m, 1H), 4.56 (s, 2H), 4.47-4.43 (m, 1H), 3.86 (s, 3H), 3.76-3.59 (m, 5H), 3.08 (s, 3H), 1.77-1.56 (m, 4H), 1.66-1.62 (m, 6H), 1.37-1.35 (m, 2H), 1.25-1.20 (m, 2H).

Example 67 [5-[2-Isopropyl-4-[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl]-2-A Oxy-phenyl]methanol

First step 5-(2-Isopropyl-4-oxo-3H-pyrido[2,3-d]pyrimidin-7-yl)-2-methoxy-phenylcarboxylic acid methyl ester

5-(2-Isopropyl-4-oxo-3H-pyrido[2,3-d]pyrimidin-7-yl)-2-methoxy-phenylcarboxylic acid 67a (200 mg, 0.60 mmol, It was prepared by a known method "Journal of Medicinal chemistry, 2009 (25): 7946-7949") and 1 mL of dichloromethane was dissolved in 5 mL of methanol, refluxed for 12 hours, concentrated under reduced pressure, and added to 5 mL. Water and 5 mL of dichloromethane, layered, and the aqueous phase was extracted with dichloromethane (10 mL×2). The organic phase was combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate Concentration by pressure gave the title product crude 5-(2-isopropyl-4-oxo-3H-pyrido[2,3-d]pyrimidin-7-yl)-2-methoxy-phenylcarboxylic acid methyl ester 67b (120 mg, yellow solid), product was used directly without purification Step reaction. MS m/z (ESI): 354.2 [M + 1].

Step 5- [2-Isopropyl--4 - [(3 S) -3- methyl-morpholin-4-yl] pyrido [2,3-d] pyrimidin-7-yl] -2- Methyl oxy-phenylcarboxylate

Add 5-(2-isopropyl-4-oxo-3H-pyrido[2,3-d]pyrimidin-7-yl)-2-methoxy-phenylcarboxylic acid methyl ester 67b to the reaction flask (120 mg, 0.34 mmol) and 2 mL of phosphorous oxychloride was refluxed for 6 hours, concentrated under reduced pressure, added 5 mL N, N- dimethylacetamide, (3 S) -3- methylmorpholine ( 100 mg, 1 mmol) and 1 mL of N,N-diisopropylethylamine, reacted at 120 ° C for 12 hours, added 20 mL of water, extracted with ethyl acetate (10 mL × 3), combined organic phase with saturated chlorine washed with a solution of sodium (20 mL × 2), dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the crude title product 5- [2-isopropyl--4 - [(3 S) -3- methylmorpholine 4-methyl]pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-phenylcarboxylate 67 c (40 mg, yellow solid). Step reaction. MS m/z (ESI): 437.2 [M+1].

The third step [5- [2-Isopropyl--4 - [(3 S) -3- methyl-morpholin-4-yl] pyrido [2,3-d] pyrimidin-7-yl] -2- Methoxy-phenyl]methanol

The crude 5- [2-Isopropyl--4 - [(3 S) -3- methyl-morpholin-4-yl] pyrido [2,3-d] pyrimidin-7-yl] -2-methoxy Methyl phenylcarboxylate 67c (40 mg, 0.09 mmol) was dissolved in 2 mL of THF. EtOAc (5 mg, 0.11 mmol). A purified and the obtained residue was developing solvent system, to give the title product [5- [2-isopropyl--4 - [(3 S) -3- methyl-morpholin-4-yl] pyrido [2,3-d Pyrimidine-7-yl]-2-methoxy-phenyl]methanol 67 (7 mg, yellow solid), yield: 18.9%. MS m/z (ESI): 408.2 [M + 1]. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.30-8.25 (m, 2H), 8.17 (d, 1H), 7.78 (d, 1H), 7.03 (d, 1H), 4.79 (s, 2H), 4.52-4.50 (m, 1H), 4.10-4.02 (m, 1H), 3.96 (s, 3H), 3.78-3.73 (m, 2H), 3.44-3.38 (m, 2H), 2.91-2.89 (m, 2H) ), 1.69 (s, 6H), 1.53-1.51 (m, 3H).

Example 68 ( S )-3-(2-Tert-butyl)-4-(3-methylmorpholine)pyrido[2,3-d]pyrimidin-7-yl) -N -methylbenzamide

( S )-4-(2-Tertibutyl)-7-chloro-pyrido[2,3- d ]pyrimidin-4-yl)-3-methylmorpholine 46c (1.3 g, 4.15 mmol) , N -methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine 68a (1.3 g, 5 mmol) , tetrakistriphenylphosphine palladium (0.48 g, 0.42 mmol), potassium carbonate (1.7 g, 12.45 mmol) dissolved in 25 mL of dioxane and water (V / V = 4:1) mixed solvent, 80 ° C reaction 5 The reaction mixture was concentrated under reduced pressure. The residue obtained was purified eluted eluted eluted eluted eluted S )-3-(2-t-butyl)-4-(3-methylmorpholine)pyrido[2,3-d]pyrimidin-7-yl) -N -methylbenzamide 68 (420 Mg, white solid), Yield: 24.1%. MS m/z (ESI): 420.4 [M+1] ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.80 (s, 1H), 8.27-8.22 (m, 2H), 8.03-8.01 (m, 1H), 7.86-7.84 (m, 1H), 7.59-7.55 (m, 1H), 6.55 (s, 1H), 4.57-4.56 (m, 1H), 4.30-4.20 (m, 1H), 4.05-4.01 (m, 1H) ), 3.85-3.77 (m, 4H), 3.09-3.08 (m, 3H), 1.60-1.56 (m, 3H), 1.51 (s, 9H)

Test case: Biological evaluation Test Example 1 Determination of inhibition of mTOR kinase activity by a compound of the present invention

Inhibition of in vitro mTOR kinase activity was tested by the following method.

In this experiment, K-LISA ^TM mTOR (recombinant) activity kit (Activity Kit), NO: CBA104, commercially available from MERCK.

The in vitro cell assay described below can determine the inhibitory activity of the test compound on mTOR kinase, and the test compound is dissolved in dimethyl sulfoxide according to the concentration required for the experiment. ATP and DTT were diluted with 1x buffer to give 200 μM ATP and 2000 μM DTT solution with a final concentration of mTOR enzyme of 2 ng/μL. 50 μL of ATP and DTT solution were added to the microplate, 1 μL of test compound DMSO solution (only 1 μl of pure DMSO was added to the control and blank) and 50 μL of the above enzyme solution (only 50 μL of 1× buffer was added to the control). After thoroughly mixing the tubes, the cells were incubated at 30 ° C for 45 minutes, washed three times with a washing solution, and primary antibodies were added and incubated for 1 hour. Wash 3 times with washing solution, add secondary antibody, and bred for 1 hour. Add TMB and develop for 5 to 15 minutes. The reaction was terminated by the addition of a stop solution. The absorbance was measured at a wavelength of 450 nm on a NOVOstar plate reader. IC ₅₀ values for compounds may be obtained by calculating the test compound at various concentrations for inhibition of mTOR activity value.

Activity of the compounds of the invention

The biochemical activity of the compounds of the present invention was determined by the above test, and the measured TC ₅₀ values are shown in Table 1 below.

Conclusion: The compounds of the examples of the present invention have a significant inhibitory effect on the proliferation of mTOR kinase.

Test Example 2 Inhibition of proliferation of cell MCF-7 by the compound of the present invention

The following in vitro assay was used to determine the proliferation inhibitory activity of the compounds of the invention against the cell line -MCF-7 (breast cancer cells).

The in vitro cell assay described below can determine the proliferation inhibitory activity of a test compound against tumor cells that highly express mTOR/PI3k, and the activity can be expressed by an IC ₅₀ value. The general protocol for such an experiment is as follows: First, MCF-7 cells (purchased in Institute of biochemistry and cell biology) are seeded on a 96-well culture plate at a suitable cell concentration of 4000 cells/mL, and then the cells are placed in a carbon dioxide incubator. Incubate at 37 ° C, allow them to grow overnight, and change the medium to a medium supplemented with a series of concentration (1000, 1000, 100, 10, 1, 0.1 nm) test compound solution, and put the plate back into the incubator. Continuous culture for 72 hours. After 72 hours, the test compound was assayed for inhibition of cell proliferation activity using CCK8 (Cell Counting Kit-8, Cat. No.: CK04, purchased from Dojindo). The IC ₅₀ value can be calculated from the inhibition values of the test compound for the cells by a series of different concentrations.

Compound activity of the present invention

The biological activity of the compounds of the present invention was obtained from the above analysis, and the calculated IC ₅₀ values are shown in Table 2 below:

Conclusion: The compounds of the present invention all have significant proliferation inhibitory activity against MCF-7 cells.

Test Example 3 Determination of Proliferation Inhibition of Cellular PC-3 by Compounds of the Invention

The following in vitro assay was used to determine the proliferation inhibitory activity of the compounds of the invention against the cell line - PC-3 (human prostate cancer cells).

The in vitro cell assay described below can determine the proliferation inhibitory activity of a test compound on tumor cells, and the inhibitory activity of the compound can be expressed by an IC ₅₀ value. The experimental protocol is briefly described as follows: firstly, DMEM-F12 is supplemented with 10% FBS (purchased from Gibco) as a complete medium for PC-3 cells (purchased in Institute of biochemistry and cell biology) at a suitable cell concentration of 2000 cells/mL medium. The cells were seeded on a 96-well culture plate, and then cultured overnight in a constant temperature incubator at 37 ° C under 5% CO ₂ . After the cells were attached, the medium was changed to fresh medium containing a gradient of the test compound (10000, 1000, 100, 10, 1, 0.1 nm). Thereafter, the cell culture plate was continuously cultured for 72 hours under the aforementioned conditions. After 72 hours, the inhibitory activity of the compound against cell proliferation was measured by the CCK8 method. IC ₅₀ values for compounds may be obtained by calculating the test compound at various concentrations for inhibition of cell proliferation values.

Compound activity of the present invention

The biological activity of the compounds of the present invention was obtained from the above analysis, and the calculated IC ₅₀ values are shown in Table 3 below:

Conclusion: The compounds of the present invention all have significant proliferation inhibitory activity against PC-3 cells.

Pharmacokinetic evaluation Test Example 4, Pharmacokinetic Testing of Compounds of the Invention 1. Summary

Rats were used as test animals, and the drug concentration in plasma at different times after administration of the compound of Example 4, the compound of Example 31, the compound of Example 46 and the compound of Example 57 by intragastric administration was determined by LC/MS/MS method. The pharmacokinetic behavior of the compounds of the invention in rats was investigated and their pharmacokinetic characteristics were evaluated.

2, the test plan 2.1 test drugs

The compound of Example 4, the compound of Example 31, the compound of Example 46 and the compound of Example 57.

2.2 Test animals

Healthy adult SD rats, 16 males and females, were divided into 4 groups, 4 in each group, purchased from Shanghai Xipuer-Beikai Experimental Animal Co., Ltd., animal production license number: SCXK (Shanghai) 2008-0016.

2.3 drug preparation

An appropriate amount of the sample was weighed, 0.5% CMC-Na was added, and a 0.5 mg/ml suspension was prepared by ultrasonication.

2.4 administration

Sixteen SD rats, half male and half female, were divided into 4 groups. After fasting overnight, they were intragastrically administered at a dose of 5.0 mg/kg or 10.0 mg/kg and a dose of 10 ml/kg.

3, operation

The compound of Example 4, the compound of Example 31, the compound of Example 46 and the compound of Example 57 were administered by gavage to rats 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 11.0 before and after administration. 0.1 ml of blood was collected at 24.0 hours, placed in a heparinized test tube, and the plasma was separated by centrifugation at 3500 rpm for 5 min, and stored at 20 °C. Eat 2 hours after administration.

The content of the test compound in the plasma of rats after intragastric administration of different concentrations of the drug was determined by LC/MS/MS method. The linear range of the method was 1.00 to 2000 ng/ml; plasma samples were analyzed by methanol precipitation protein analysis.

4, pharmacokinetic parameters results

The pharmacokinetic parameters of the compounds of the invention are as follows:

Conclusion: The compounds of the present invention have good drug metabolism absorption and have obvious pharmacokinetic advantages.

Claims (13)

a compound of the formula (I) or a pharmaceutically acceptable salt thereof, Wherein: X ¹ is an N atom, X ² and X ³ are CH; and R ¹ and R ² together with the N atom to which they are bonded form a heterocyclic group, which is further selected from one or more selected from C _1- Substituted with a ₆ alkyl substituent; R ^{3 is} selected from a C _6-10 aryl group, wherein the C _6-10 aryl group is further further selected from one or more selected from C _1-6 alkyl, C _1-6 hydroxyalkyl as needed Substituted by a substituent of a halogen, an oxo group, a C _1-6 alkoxy group, a C _1-6 haloalkoxy group, a -C(O)NR ⁸ R ⁹ group; R ^{4 is} selected from a cyano group, C _1-6 An alkyl group, an alkenyl group, an alkynyl group, a C _3-10 cycloalkyl group, -NR ⁵ R ⁶ or -C(O)NR ⁸ R ⁹ , wherein the C _1-6 alkyl group, alkenyl group, alkynyl group, C _{3 The -10} cycloalkyl group is further optionally one or more selected from the group consisting of halogen, oxo, hydroxy, C _3-10 alkoxy, cyano, aryl, heterocyclic, C _6-10 heteroaryl, - Substituted by a substituent of C(O)OR ⁷ or -S(O) _m R ⁷ or -NR ⁸ R ⁹ ; R ^{5 is} selected from heterocyclic group, wherein the heterocyclic group is further selected from one or more as needed C _1-6 alkyl, oxo, C _1-6 haloalkyl, C _1-6 alkoxy, heterocyclic, C _6-10 aryl, heteroaryl, -C(O)R ⁷ , - ^{C (O) oR 7, -S} (O) m R 7 or -C (O) NR ⁸ R ⁹ substituents Generation; R ⁶ is selected from hydrogen, C _1-6 alkyl or C _3-10 cycloalkyl; R ^7, R ⁸ and R ⁹ are each independently selected from hydrogen atom, C _1-6 alkyl, C _{3- a 10-} cycloalkyl group, a heterocyclic group, a C _6-10 aryl group or a heteroaryl group; the heterocyclic group is composed of 3 to 12 ring atoms, of which 1 to 4 are optionally N, O or S(O) _m Heteroatom; the heteroaryl group is a heteroaromatic group containing 5 to 10 ring atoms, and contains 1 to 4 hetero atoms which are optionally N or O; m is 0, 1, or 2. A compound of the formula (I) or a pharmaceutically acceptable salt thereof, according to the invention of claim 1, wherein the R ³ is a phenyl group. A compound of the formula (I), or a pharmaceutically acceptable salt thereof, according to the invention of claim 1, which is a compound of the formula (II) or a pharmaceutically acceptable salt thereof: Wherein: X ¹ to X ³ , R ³ to R ⁴ are as defined in the first item of the patent application; R ^{10 is} selected from a hydrogen atom or a C _1-6 alkyl group. A compound of the formula (I), or a pharmaceutically acceptable salt thereof, according to claim 3, which is a compound of the formula (III) or a pharmaceutically acceptable salt thereof: Wherein: R ^{4 is} as defined in claim 1; R ^{10 is} selected from a hydrogen atom or a C _1-6 alkyl group; and R ¹¹ or R ¹² are each independently selected from a hydrogen atom, a C _1-6 alkyl group. , C _1-6 alkoxy, hydroxy or -C(O)NR ¹³ R ¹⁴ , wherein the C _1-6 alkyl or C _1-6 alkoxy group is further selected from one or more selected from C _1- Substituted with a substituent of a ₆ alkyl group, a C _1-6 hydroxyalkyl group, a hydroxyl group, a C _1-6 alkoxy group or a halogen; and R ¹³ or R ¹⁴ are each independently selected from a hydrogen atom, a C _1-6 alkyl group or C _3-10 cycloalkyl. A compound of the formula (I) or a pharmaceutically acceptable salt thereof according to the fourth aspect of the invention, which is a compound of the formula (IV) or a pharmaceutically acceptable salt thereof: Wherein: R ⁴ , R ¹¹ or R ¹² are as defined in claim 4 of the scope of the patent application. a compound of the formula (I) or a pharmaceutically acceptable salt thereof according to claim 5, which is a compound represented by the formula (IV) i or the formula (IV) ii or a pharmaceutically acceptable compound thereof salt: Wherein: R ⁴ , R ¹¹ or R ¹² are as defined in item 4 of the scope of the patent application. A compound of the formula (I) or a pharmaceutically acceptable salt thereof, according to claim 1, wherein the compound is selected from the group consisting of: A process for the preparation of a compound of the formula (I) or a pharmaceutically acceptable salt thereof according to the first aspect of the invention, which comprises reacting a compound of the formula (IA) with R ⁴ H under basic conditions, a step of obtaining a compound of the formula (I), Wherein, X is selected from halogen; ^X-1 to X ^3, R ¹ to R ⁴ as defined in the patent application range item 1. A process for the preparation of a compound of the formula (I) or a pharmaceutically acceptable salt thereof according to the first aspect of the patent application, which comprises Suzuki coupling of a compound of the formula (IA) with R ⁴ B(OH) ₂ a reaction to obtain a compound of the formula (I), Wherein X is selected from halogen; X ¹ to X ³ and R ¹ to R ⁴ are as defined in the first item of the patent application. A process for the preparation of a compound of the formula (I) or a pharmaceutically acceptable salt thereof according to the first aspect of the invention, which comprises reacting a compound of the formula (IA) with tributyl(R ⁴ )stannane a step of obtaining a compound of the formula (I), Wherein, X is selected from halogen; ^X-1 to X ^3, R ¹ to R ⁴ as defined in the patent application range item 1. A pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as described in claim 1 of the patent application, and one or more pharmaceutically acceptable carriers or excipient. A use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof according to the first aspect of the invention, or a pharmaceutical composition according to claim 11 for use in the preparation of a mTOR inhibiting / or PI3K kinase drugs. A compound represented by the formula (I) according to the first aspect of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11 for the preparation of a medicament for treating cancer or tissue hyperplasia Use in which the cancer is selected from the group consisting of melanoma, papillary thyroid tumor, cholangiocarcinoma, colon cancer, ovarian cancer, lung cancer, malignant lymphoma, liver cancer, kidney cancer, bladder cancer, prostate cancer, breast cancer, and pancreatic cancer. Sarcoma, as well as primary and recurrent solid tumors or leukemia of malignant glioma, skin cancer, colon cancer, thyroid cancer, lung cancer and ovarian cancer.