WO2019029541A1

WO2019029541A1 - Fibroblast growth factor receptor inhibitor and use thereof

Info

Publication number: WO2019029541A1
Application number: PCT/CN2018/099242
Authority: WO
Inventors: 吴永谦
Original assignee: 南京药捷安康生物科技有限公司
Priority date: 2017-08-08
Filing date: 2018-08-07
Publication date: 2019-02-14
Also published as: CN109384790B; TWI750403B; TW201910331A; CN109384790A

Abstract

Provided are a fibroblast growth factor receptor (FGFR) irreversible inhibitor as represented by formula I, a pharmaceutically acceptable salt, a stereoisomer thereof, and pharmaceutical preparations, pharmaceutical compositions and uses of these compounds. Said compounds have an efficient and highly selective inhibitory effect on FGFR, and can be used for the treatment of related diseases mediated by FGF/FGFR abnormality, especially for the treatment of cancer diseases.

Description

Fibroblast growth factor receptor inhibitor and use thereof

This application claims the priority of the Chinese Patent Application entitled "Fibroblast Growth Factor Receptor Inhibitor and Its Use" by the Chinese Patent Office, Application No. 201710672089.X on August 08, 2017, the entire contents of which are hereby incorporated by reference. The citations are incorporated herein by reference.

Technical field

The invention belongs to the technical field of medicine and relates to an irreversible inhibitor of fibroblast growth factor receptor (FGFR), or a pharmaceutically acceptable salt thereof, a stereoisomer thereof and use thereof.

Background technique

Tyrosine kinase receptors play an important role in tumor angiogenesis, tumor cell proliferation, migration and infiltration. More than 100 tyrosine kinase inhibitor drugs have been marketed or entered clinical trials. These small molecule tyrosine kinase inhibitors (TKI) play a role in reversible inhibition, which brings some disadvantages: 1 the selectivity is not good enough, 2 the efficacy is not strong enough and lasting, 3 It is easy to cause drug resistance. Therefore, scientists are encouraged to focus their research on the development of irreversible TKI.

The irreversible TKI is usually modeled by the backbone structure of the reversible TKI, and an electrophilic functional group is attached at a suitable position, and the electrophilic functional group can be associated with a cysteine residue near the ATP binding domain of the tyrosine kinase. (Electron-rich nucleophilic structure) undergoes an electrophilic reaction to form a covalent bond, thereby irreversibly inhibiting kinase activity. Compared with reversible TKI, irreversible TKI has many unique advantages: 1 irreversible TKI works in a permanent inactivation manner, this way of inhibiting enzyme activity makes its effect stronger and longer, even drug molecules It is completely removed from the circulatory system and its efficacy is maintained. 2 Because its binding to the kinase does not exist ATP competition, it also reduces the possibility of kinase mutation and reduces or circumvents the emergence of drug resistance. 3 Because the electrophilic functional group on its molecular structure can selectively react with the thiol group on the cysteine residue, the selectivity of the irreversible TKI is very high. Based on the above characteristics, the development of irreversible TKI is gradually becoming a hot spot for research and development.

Fibroblast growth factor receptor (FGFR) is an important member of the tyrosine kinase receptor family. FGFR contains four members, namely FGFR-1, FGFR-2, FGFR-3 and FGFR. -4. They are mostly single-chain glycoprotein molecules with molecular masses ranging from 110 to 150 kd, and the structure is divided into extracellular regions, transmembrane regions and intracellular regions. Under normal physiological conditions, FGFR binds to its ligand fibroblast growth factor (FGF), which dimerizes FGFR and phosphorylates itself, activating downstream signaling pathways such as JAK/STAT pathway, phospholipase The C pathway, phosphatidylinositol-3-kinase PI3K and MAPK signaling pathways play an important role in tumor growth and angiogenesis. Abnormalities of FGFR are closely related to the occurrence of various tumors, such as bladder cancer (including urinary tract epithelial cancer, etc.), breast cancer, cholangiocarcinoma, gastric cancer, ovarian cancer, salivary gland cancer, colorectal cancer, non-small cell lung cancer, small Hepatocellular carcinoma, liver cancer, endometrial cancer, cervical cancer, pancreatic cancer, rhabdomyosarcoma, multiple myeloma, prostate cancer, esophageal cancer, glioma, myelodysplastic syndrome, dwarf syndrome, renal pelvic tumor, chondrosarcoma, Melanoma and the like.

Although a series of patent applications for irreversible inhibitors of FGFR have been disclosed, the compound PRN1371 is disclosed in the patent WO2015120049, which is currently in clinical phase I and has the following chemical structure:

There are currently no irreversible inhibitors of FGFR, especially irreversible inhibitors with high selectivity for pan-FGFR.

Summary of the invention

It is an object of the present invention to provide a novel class of irreversible inhibitors of pan-FGFR which have potent inhibitory activity against pan-FGFR and which offer the possibility of treatment of diseases mediated by pan-FGFR abnormalities. The invention also provides the use of the above FGFR inhibitors.

The technical solution adopted by the present invention is as follows:

An irreversible inhibitor of fibroblast growth factor receptor (FGFR) represented by the general formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof:

among them,

Warhead ₁ and warhead ₂ refer to the part capable of forming a covalent bond with a nucleophile, and warhead ₁ and warhead _{2 are} not present at the same time;

X is selected from C or N, when X is C,

Represents a double bond, when X is N,

Represents a single button;

When warhead _{1 is} present, R _{1 is} selected from C _1-6 alkylene, C _2-8 alkenylene, C _2-8 alkynylene, halo C _1-6 alkylene or —(L ₁ )n -Cy ₁ -(L ₂ )t-(Cy ₂ )p-; when warhead ₁ is absent, R _{1 is} selected from hydrogen, C _1-6 alkyl, C _2-8 alkenyl, C _2-8 alkynyl , halogenated C _1-6 alkyl or -(L ₁ )n-Cy ₁ -(L ₂ )t-(Cy ₂ )p;

When warhead _{2 is} present, R _{2 is} selected from C _1-6 alkylene, C _2-8 alkenylene, C _2-8 alkynylene, halo C _1-6 alkylene or —(L ₃ )q -Cy ₃ -; when warhead ₂ is absent, R _{2 is} selected from hydrogen, C _1-6 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, halo C _1-6 alkyl or -( L ₃ )q-Cy ₃ ;

Cy ₁ and Cy ₂ are each independently selected from the group consisting of one or more R _a substituted or unsubstituted 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3- a 12-membered heterocyclic group, an aryl group or a 5-10 membered heteroaryl group, the ring-forming carbon atom may be optionally oxidized to C(O), and the ring-forming sulfur atom may be optionally oxidized to S(O), S(O). ₂ or S(O)(N);

Cy _{3 is} selected from the group consisting of one or more R _b substituted or unsubstituted 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclic group. , aryl or 5-10 membered heteroaryl, the ring-forming carbon atom may be optionally oxidized to C(O), and the ring-forming sulfur atom may be optionally oxidized to S(O), S(O) ₂ or S ( O)(N);

R _a and R _b are each independently selected from:

(i) hydrogen;

(ii) a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen, a C _2-6 alkenylcarbonylamino group or =CH ₂ ;

(iii) optionally by hydroxy, amino, carboxy, cyano, nitro, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkoxy, C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, C _1-6 alkylcarbonylamino, C _1-6 alkylsulfonylamino group or a 3-8 membered heterocyclic group substituted with a C _1-6 Alkyl, C _1-6 alkoxy, C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, halo C _1-6 alkyl, halo C _1-6 alkoxy, C _{a 2-8} alkenyl group, a C _2-8 alkynyl group, a C _1-6 alkylsulfonyl group or a C _1-6 alkylthio group, and the 3-8 membered heterocyclic group may be optionally a hydroxyl group, an amino group or a carboxyl group. , cyano, nitro, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino or (C _1-6 alkyl) ₂ amino substituted;

(iv) optionally by hydroxy, amino, carboxy, cyano, nitro, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino or (C _1-6 alkyl a ₂ amino-substituted 3-8 membered cycloalkyl group, a 5-8 membered cycloalkenyl group or a 3-8 membered heterocyclic group;

or

(v) amino-carbonyl, cyano-carbonyl, C _1-6 alkyl-carbonyl, C _1-6 alkylamino-carbonyl, (C _1-6 alkyl) ₂ amino-carbonyl, C _1-6 alkoxy a carbonyl group, a 3-8 membered cycloalkyl-carbonyl group or a 3-8 membered heterocyclyl-carbonyl group;

R _{3 is} selected from the group consisting of hydrogen, C _1-6 alkyl, C _1-6 alkylamino C _1-6 alkyl, (C _1-6 alkyl) ₂ amino C _1-6 alkyl, halogenated C _1-6 An alkyl group, a halogenated C _2-8 alkenyl group, a C _2-8 alkynyl group, or a 3-12 membered cycloalkyl group optionally substituted by a substituent Q ₁ , a 3-12 membered cycloalkenyl group, a 3-12 membered hetero cycloalkyl group, an aryl group or a 5-10 membered heteroaryl, the substituents Q ₁ is selected from: hydroxy, amino, cyano, nitro, halogen, carboxyl, amide group, aminocarbonyl, aminosulfonyl, C _{1- 6} alkyl, C _1-6 alkoxy, C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _1-6 alkylsulfonyl, C _1-6 alkylcarbonylamino, (C _1-6 alkyl) ₂ carbonylamino, C _1-6 alkyl Aminocarbonyl, (C _1-6 alkyl) ₂ aminocarbonyl, C _1-6 alkylaminosulfonyl, (C _1-6 alkyl) ₂ aminosulfonyl or C _1-6 alkoxy C _1-6 alkane Oxylate

R _{4 is} selected from the group consisting of hydrogen, hydroxy, amino, cyano, nitro, halogen, carboxyl, amide, aminocarbonyl, aminosulfonyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkane Amino group, (C _1-6 alkyl) ₂ amino group, halogenated C _1-6 alkyl group, halogenated C _1-6 alkoxy group, C _2-8 alkenyl group, C _2-8 alkynyl group, C _{1- 6} alkylsulfonyl, C _1-6 alkylcarbonylamino, (C _1-6 alkyl) ₂ carbonylamino, C _1-6 alkylaminocarbonyl, (C _1-6 alkyl) ₂ aminocarbonyl, C _{1 -6} alkylaminosulfonyl, (C _1-6 alkyl) ₂ aminosulfonyl, C _1-6 alkoxy C _1-6 alkoxy, or 3-12 optionally substituted by substituent Q ₂ a cycloalkyl group, a 3-12 membered cycloalkenyl group, a 3-12 membered heterocyclic group, an aryl group or a 5-10 membered heteroaryl group, the substituent being selected from the group consisting of a hydroxyl group, an amino group, a cyano group, a nitro group, a halogen, Carboxy, amido, aminocarbonyl, aminosulfonyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, halogenated C _{1 -6} alkyl, halo C _1-6 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _1-6 alkylsulfonyl, C _1-6 alkylcarbonylamino, (C _{1 -6} _alkyl) amino carbonyl, C _1-6 alkylaminocarbonyl, (C _1-6 alkyl) ₂ amino Carbonyl, C _1-6 alkyl aminosulfonyl, (C _1-6 _alkyl) aminosulfonyl or C _1-6 alkoxy C _1-6 alkoxy; or two adjacent R ₄ and The atoms respectively attached thereto form a 3-8 membered cycloalkyl group, a 3-8 membered cycloalkenyl group, a 3-8 membered heterocyclic group, an aryl group or a 5-6 membered heteroaryl group;

L ₁ , L ₂ , and L ₃ are each independently a bond, -N(Rc)-, -O-, -S-, -S(O)-, -S(O) ₂ -, -S(O) ₂ NH-, -C(O)-, -NHC(O)-, -OC(O)-, C _1-6 alkylene, C _2-8 alkenylene or C _2-8 alkynylene, Rc selected From hydrogen or C _1-6 alkyl;

n, t, p, q are each independently 0 or 1;

m is an integer from 0 to 5, and when m ≥ 2, R ₄ may be selected from the same or different groups.

Another embodiment of the present invention relates to an irreversible inhibitor of fibroblast growth factor receptor represented by the general formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

Warhead ₁ and warhead ₂ are independently selected from

Warhead ₁ and warhead ₂ do not exist at the same time;

R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ , R ₁₅ are each independently selected from hydrogen, halogen, C _1-6 alkyl or halo C _1-6 alkyl;

Cy ₄ is a divalent group selected from the group consisting of a 3-12 membered cycloalkyl group, a 3-12 membered cycloalkenyl group, a 3-12 membered heterocyclic group, an aryl group or a 5-10 membered heteroaryl group;

z is an integer from 0-4;

X is selected from C or N, when X is C,

Represents a double bond, when X is N,

Represents a single button;

When warhead _{1 is} present, R _{1 is} selected from C _1-6 alkylene, halo C _1-6 alkylene or -(L ₁ )n-Cy ₁ -(L ₂ )t-(Cy ₂ )p- When warhead ₁ is absent, R _{1 is} selected from hydrogen, C _1-6 alkyl, halogenated C _1-4 alkyl or -(L ₁ )n-Cy ₁ -(L ₂ )t-(Cy ₂ ) p;

When warhead _{2 is} present, R _{2 is} selected from C _1-6 alkylene, halo C _1-6 alkylene or -(L ₃ )q-Cy ₃ -; when warhead ₂ is absent, R _{2 is} selected from Hydrogen, C _1-6 alkyl, halogenated C _1-6 alkyl or -(L ₃ )q-Cy ₃ ;

Cy1 and Cy2 are each independently selected from the group consisting of one or more Ra-substituted or unsubstituted 3-8 membered monoheterocyclic groups, 6-11-membered bridged heterocyclic groups, 7- a 12-membered spiroheterocyclyl group or a 6-11 membered heterocyclic group, an aryl group or a 5-10 membered heteroaryl group, the ring-forming carbon atom may be optionally oxidized to C(O), and the ring-forming sulfur atom may be optionally selected. Oxidized to S(O) or S(O)2;

Cy _{3 is} selected from the group consisting of one or more R _b -substituted or unsubstituted 3-8 membered monoheterocyclic groups, 6-11 membered bridged heterocyclic groups, 7-12 membered snails a heterocyclic group or a 6-11 membered heterocyclic group, an aryl group or a 5-10 membered heteroaryl group, the ring-forming carbon atom may be optionally oxidized to C(O), and the ring-forming sulfur atom may be optionally oxidized to S(O) or S(O) ₂ ;

R _a and R _b are each independently selected from:

(i) hydrogen, hydroxy, amino, carboxy, cyano, nitro, halogen, C _2-8 alkenylcarbonylamino or =CH ₂ ,

(ii) optionally selected by hydroxy, amino, carboxy, cyano, nitro, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkoxy, C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, C _1-6 alkylcarbonylamino, C _1-6 alkylsulfonylamino group or a 3-8 membered heterocyclic group substituted with a C _1-6 Alkyl, C _1-6 alkoxy, C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, halo C _1-6 alkyl, halo C _1-6 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _1-6 alkylsulfonyl or C _1-6 alkylthio,

(iii) optionally selected by hydroxy, amino, carboxy, cyano, nitro, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino or (C _1-6 alkyl a ₂ amino-substituted 3-8 membered cycloalkyl group or a 3-8 membered heterocyclic group,

or

(iv) amino-carbonyl, cyano-carbonyl, C _1-6 alkyl-carbonyl, C _1-6 alkylamino-carbonyl, (C _1-6 alkyl) ₂ amino-carbonyl, C _1-6 alkoxy a carbonyl group, a 3-8 membered cycloalkyl-carbonyl group or a 3-8 membered heterocyclyl-carbonyl group;

R _{3 is} selected from hydrogen or C _1-6 alkyl;

R _{4 is} selected from the group consisting of hydrogen, hydroxy, amino, cyano, nitro, halogen, carboxyl, amide, aminocarbonyl, aminosulfonyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkane Amino, (C _1-6 alkyl) ₂ amino, halo C _1-6 alkyl, halo C _1-6 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _{1- 6} alkylsulfonyl, C _1-6 alkylcarbonylamino, (C _1-6 alkyl) ₂ carbonylamino, C _1-6 alkylaminocarbonyl, (C _1-6 alkyl) ₂ aminocarbonyl, C _{1 -6} alkylaminosulfonyl, (C _1-6 alkyl) ₂ aminosulfonyl or C _1-6 alkoxy C _1-64 alkoxy;

L ₁ , L ₂ , and L ₃ are each independently a bond, -N(R _c )-, -O-, -S-, -S(O)-, -S(O) ₂ -, -C(O). -, -NHC(O)-, -OC(O)- or C _1-6 alkylene, R _{c is} selected from hydrogen or C _1-6 alkylene;

n, t, p, q are each independently 0 or 1;

m is an integer from 0 to 5, and when m ≥ 2, R ₄ may be selected from the same or different groups;

When R ₁ is -(L ₁ )n-Cy ₁ -(L ₂ )t-(Cy ₂ )p-, t and p are 0, and Cy ₁ is substituted by one to more R _a , or unsubstituted When a 3-8 membered monoheterocyclic group or a divalent group of a phenyl group, R ₂ is -(L ₃ )q-Cy ₃ , and Cy ₃ is substituted with one to more R _b or unsubstituted 7- 12-membered spiro heterocyclic group.

Warhead ₁ and warhead ₂ are independently selected from

Warhead ₁ and warhead ₂ do not exist at the same time;

R ₁₂ , R ₁₃ and R ₁₄ are each independently selected from hydrogen or C _1-4 alkyl;

X is selected from C or N, when X is C,

Represents a double bond, when X is N,

Represents a single button;

When warhead _{1 is} present, R _{1 is} selected from C _1-4 alkylene or -(L ₁ )n-Cy ₁ -(L ₂ )t-(Cy ₂ )p-; when warhead ₁ is absent, R ₁ Selected from hydrogen, C _1-4 alkyl or -(L ₁ )n-Cy ₁ -(L ₂ )t-(Cy ₂ )p;

When warhead _{2 is} present, R _{2 is} selected from C _1-4 alkylene, halo C _1-4 alkylene or -(L ₃ )q-Cy ₃ -; when warhead ₂ is absent, R _{2 is} selected from Hydrogen, C _1-4 alkyl or -(L ₃ )q-Cy ₃ ;

Cy _1, Cy ₂ are independently selected from the following group or a divalent group: substituted by one to the plurality of R _a, or unsubstituted 3-8 membered monocyclic heterocyclyl, 7-12 membered heterocyclyl spiro Or aryl;

Cy _{3 is} selected from the group consisting of one or more R _b substituted or unsubstituted 3-8 membered monoheterocyclyl or 7-12 membered spiroheterocyclyl;

R _a and R _b are each independently hydrogen, C _1-4 alkyl or hydroxy C _1-4 alkyl;

R _{3 is} selected from hydrogen or C _1-4 alkyl;

R _{4 is} selected from the group consisting of hydrogen, halogen, C _1-4 alkyl or C _1-4 alkoxy;

L ₁ , L ₂ , and L ₃ are each independently a bond or a C _1-4 alkylene group;

Warhead ₁ and warhead ₂ are independently selected from

Warhead ₁ and warhead ₂ do not exist at the same time;

X is selected from C or N, when X is C,

Represents a double bond, when X is N,

Represents a single button;

When warhead _{2 is} present, R _{2 is} selected from C _1-4 alkylene or -(L ₃ )q-Cy ₃ -; when warhead ₂ is absent, R _{2 is} selected from hydrogen, C _1-4 alkyl or - (L ₃ )q-Cy ₃ ;

Cy ₁ and Cy ₂ are each independently selected from the group consisting of one or more R _a substituted or unsubstituted 3-8 membered monoheterocyclic group, 6-11 membered bridged heterocyclic group. a 7-12 membered spiroheterocyclyl group or a 6-11 membered heterocyclic group;

Cy _{3 is} selected from the group consisting of one or more R _b -substituted or unsubstituted 3-8 membered monoheterocyclic groups, 6-11 membered bridged heterocyclic groups, 7-12 membered snails Heterocyclic group, 6-11 membered heterocyclic group;

R _a and R _b are each independently selected from:

(i) hydrogen, hydroxy, amino, cyano or halogen,

or

(ii) C _1-4 alkyl, C _1-4 alkylamino, (C _1-4 alkyl) ₂ amino, hydroxy C _1-4 alkyl, cyano C _1-4 alkyl or halogenated C _{1 -4} alkyl;

n, t, p, q are each independently 0 or 1;

R _{3 is} selected from hydrogen or C _1-4 alkyl;

When R ₁ is -(L ₁ )n-Cy ₁ -(L ₂ )t-(Cy ₂ )p-, t and p are 0, and Cy ₁ is substituted by one to more Ra, or unsubstituted When a divalent group of a 3-8 membered monoheterocyclic group, R ₂ is -(L ₃ )q-Cy ₃ , and Cy ₃ is substituted with one to more R _b or unsubstituted 7-12 membered spiro Ring base.

Warhead ₁ and warhead ₂ are independently selected from

Warhead ₁ and warhead ₂ do not exist at the same time;

X is selected from C or N, when X is C,

Represents a double bond, when X is N,

Represents a single button;

Cy _1, Cy ₂ are independently selected from the following groups or a divalent radical: by one to the plurality of R _a substituted or unsubstituted 3-8 membered monocyclic or 7-12 membered heterocyclyl spiro-heterocyclyl ;

R _a is hydrogen or C _1-4 alkylene;

R _b is hydrogen, C _1-4 alkylene or hydroxy C _1-4 alkyl;

n, t, p, q are each independently 0 or 1;

R _{3 is} selected from hydrogen or C _1-4 alkyl;

Warhead ₁ and warhead ₂ are independently selected from

Warhead ₁ and warhead ₂ do not exist at the same time;

X is selected from C or N, when X is C,

Represents a double bond, when X is N,

Represents a single button;

Cy ₁ and Cy ₂ are each independently selected from a monovalent or divalent group of the following structure: substituted with one to more R _a or unsubstituted

Cy _{3 is} selected from the group consisting of a monovalent or divalent group such as a structure: one or more R _b substituted or unsubstituted

R _a and R _b are each independently selected from hydrogen, C _1-4 alkyl or hydroxy C _1-4 alkyl;

n, t, p, q are each independently 0 or 1;

R _{3 is} selected from hydrogen or C _1-4 alkyl;

R _{4 is} selected from the group consisting of hydrogen, a halogen atom, a C _1-4 alkyl group or a C _1-4 alkoxy group;

When R ₁ is -(L ₁ )n-Cy ₁ -(L ₂ )t-(Cy ₂ )p-, t and p are 0, and Cy ₁ is substituted by one to more R _a , or unsubstituted of

In the case of a divalent group, R ₂ is -(L ₃ )q-Cy ₃ and Cy ₃ is substituted by one to more R _b or unsubstituted

One price base.

Warhead ₁ is

Warhead ₂ does not exist;

R ₁₂ and R ₁₃ are each independently selected from hydrogen or C _1-4 alkyl;

X is selected from C or N, when X is C,

Represents a double bond, when X is N,

Represents a single button;

R ₁ is -(L ₁ ) _n -Cy ₁ -;

Cy ₁ is a 7-12 membered spiroheterocyclyl group substituted by one to a plurality of R _a , preferably 7-12 members containing an N-spiroheterocyclic group, and any of warhead ₁ and Cy ₁ is looped. N heteroatoms are connected;

L ₁ is a bond or a C _1-4 alkylene group;

R _{a is} selected from hydrogen or C _1-4 alkyl;

R _{2 is} selected from hydrogen or C _1-4 alkyl;

R _{3 is} selected from hydrogen or C _1-4 alkyl;

n is 0 or 1;

Cy ₁ is a divalent group of the following structure: substituted by one to more R _a or unsubstituted

Warhead _{1 is} attached to any ring-forming N heteroatom in Cy ₁ .

Another embodiment of the present invention relates to the aforementioned fibroblast growth factor receptor irreversible inhibitor or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, the fibroblast growth factor receptor irreversible inhibitor such as a general formula (IA):

among them,

Warhead _{1 is} selected from

X is selected from C or N, when X is C,

Represents a double bond, when X is N,

Represents a single button;

R _{2 is} selected from the group consisting of hydrogen, C _1-4 alkyl, halo C _1-4 alkyl or -(L ₃ )q-Cy ₃ ;

Cy1 and Cy2 are each independently selected from a divalent group of a group: one to a plurality of Ra-substituted or unsubstituted 3-8 membered monoheterocyclic groups, 6-11-membered bridged heterocyclic groups, 7-12 a snail heterocyclic group or a 6-11 membered heterocyclic group;

Cy _{3 is} selected from the group consisting of one or more R _b substituted, or unsubstituted 3-8 membered monoheterocyclyl, 6-11 membered bridged heterocyclyl, 7-12 membered spiroheterocyclyl or 6 -11 membered heterocyclic group;

R _a and R _b are each independently selected from hydrogen, hydroxy, amino, carboxy, cyano, nitro, halogen, C _2-4 alkenylcarbonylamino, =CH ₂ or optionally hydroxy, amino, carboxy, cyano , nitro, halogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkoxy C _1-4 alkoxy, C _1-4 alkylamino, (C _1-4 alkyl ₂ amino, C _1-4 alkylcarbonylamino, C _1-4 alkylsulfonylamino or 3-8 membered heterocyclyl substituted C _1-4 alkyl, C _1-4 alkoxy, C _{1- 4} -alkylamino, (C _1-4 alkyl) ₂ amino, halo C _1-4 alkyl, halo C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkylsulfonyl or C _1-4 alkylthio;

R _{3 is} selected from hydrogen or C _1-4 alkyl;

R _{4 is} selected from the group consisting of hydrogen, hydroxy, amino, cyano, nitro, halogen, carboxyl, amide, aminocarbonyl, aminosulfonyl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkane Amino, (C _1-4 alkyl) ₂ amino, halo C _1-4 alkyl, halo C _1-4 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _{1- 4} -alkylsulfonyl, C _1-4 alkylcarbonylamino, (C _1-4 alkyl) ₂ carbonylamino, C _1-4 alkylaminocarbonyl, (C _1-4 alkyl) ₂ aminocarbonyl, C _{1 -4} alkylaminosulfonyl, (C _1-4 alkyl) ₂ aminosulfonyl or C _1-4 alkoxy C _1-4 alkoxy;

L ₁ , L ₂ , and L ₃ are each independently a bond, -N(R _c )-, -O-, -S- or C _1-4 alkylene, and R _{c is} selected from hydrogen or C _1-4 alkyl. ;

n, t, p, q are each independently 0 or 1;

When t and p are 0, and Cy ₁ is a divalent group of one or more R _a substituted or unsubstituted 3-8 membered monoheterocyclic groups, R ₂ is -(L ₃ )q-Cy ₃ and Cy ₃ is a 7-12 membered spiroheterocyclic group substituted with one to more R _b or unsubstituted.

Another embodiment of the present invention relates to the irreversible fibroblast growth factor receptor represented by the above formula (I-A)

An inhibitor or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, wherein:

among them,

Warhead _{1 is} selected from

X is selected from C or N, when X is C,

Represents a double bond, when X is N,

Represents a single button;

Cy1 and Cy2 are each independently selected from a divalent group of a group: one to a plurality of Ra-substituted or unsubstituted 3-8 membered monoheterocyclic groups or 7-12-membered spiroheterocyclic groups;

R _a , R _b are each independently selected from hydrogen, C _1-4 alkyl or hydroxy C _1-4 alkyl;

R _{3 is} selected from hydrogen or C _1-4 alkyl;

n, t, p, q are each independently 0 or 1;

Warhead _{1 is} selected from

X is selected from C or N, when X is C,

Represents a double bond, when X is N,

Represents a single button;

Cy ₁ and Cy ₂ are each independently a divalent group selected from the group consisting of one or more R _a substituted or unsubstituted 3-8 membered nitrogen-containing monoheterocyclic groups and a 6-11 membered nitrogen-containing bridge. a heterocyclic group or a 7-12 membered nitrogen-containing spiroheterocyclyl;

R _{2 is} selected from hydrogen, C _1-4 alkyl or -(L ₃ )q-Cy ₃ ;

Cy ₃ is a 7-12 membered spiroheterocyclic group substituted with one to more R _b or unsubstituted;

R _a , R _b , R ₃ are each independently selected from hydrogen or C _1-4 alkyl;

n, t, p, q are each independently 0 or 1;

When t and p are 0, and Cy ₁ is a divalent group of one or more R _a substituted or unsubstituted 3-8 membered nitrogen-containing monoheterocyclic groups, R ₂ is -(L ₃ )q -Cy ₃ and Cy ₃ is a 7-12 membered spiroheterocyclyl group substituted with one to more R _b or unsubstituted.

Another embodiment of the present invention relates to an irreversible inhibitor of fibroblast growth factor receptor represented by the above formula (I-A), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

Warhead _{1 is} selected from

X is selected from C or N, when X is C,

Represents a double bond, when X is N,

Represents a single button;

Cy ₁ and Cy ₂ are each independently selected from a divalent group of the following structure: one to a plurality of R _a substituted or unsubstituted

R _{2 is} selected from hydrogen, C _1-4 alkyl or -(L ₃ )q-Cy ₃ ;

R _a , R _b , and R ₃ are each independently selected from hydrogen, C _1-4 alkyl;

n, t, p, q are each independently 0 or 1;

When t and p are 0, and Cy ₁ is substituted by one to more R _a , or unsubstituted

In the case of a divalent group, R ₂ is -(L ₃ )q-Cy ₃ , and Cy ₃ is a 7-12 membered spiroheterocyclic group substituted with one to more R _b or unsubstituted.

Warhead ₁ is

Warhead _{1 is} attached to any ring-forming N hetero atom in Cy ₁ ;

t and p are respectively 0;

n is 0;

R _{a is} selected from hydrogen or C _1-4 alkyl;

R _{2 is} selected from hydrogen or C _1-4 alkyl;

R _{3 is} selected from hydrogen or C _1-4 alkyl;

Warhead ₁ is

Warhead _{1 is} attached to any ring-forming N hetero atom in Cy ₁ ;

t and p are respectively 0;

R _{2 is} selected from hydrogen, C _1-4 alkyl or is -(L ₃ )q-Cy ₃ -;

Cy ₃ is a monovalent group of the following structure: substituted with one to more R _b or unsubstituted

n, q are independently 0 or 1;

R _a , R _b are each independently selected from hydrogen or C _1-4 alkyl;

R _{3 is} selected from hydrogen or C _1-4 alkyl;

L ₁ , L ₃ are each independently a bond, -CH ₂ - or -CH ₂ -CH ₂ -;

Warhead ₁ is

Cy ₁ and Cy ₂ are each independently a divalent group of the following structure: optionally substituted by one to more R _a , or unsubstituted

Warhead _{1 is} attached to any of the N heteroatoms on the ring in Cy ₂ ;

n, t are respectively 0;

p is 1;

R _{a is} selected from hydrogen or C _1-4 alkyl;

R _{2 is} selected from hydrogen or C _1-4 alkyl;

R _{3 is} selected from hydrogen or C _1-4 alkyl;

Another embodiment of the present invention relates to the fibroblast growth factor receptor irreversible inhibitor represented by the above formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, which is affected by the fibroblast growth factor The irreversible inhibitor of the body is as shown in the general formula (IB):

among them,

Warhead _{2 is} selected from

R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ and R ₁₄ are each independently selected from hydrogen or C _1-4 alkyl;

X is selected from C or N, when X is C,

Represents a double bond, when X is N,

Represents a single button;

R _{1 is} selected from hydrogen or C _1-4 alkyl;

Cy ₃ is a 3-8 membered monomonoheterocyclic group substituted with one to more R _b or unsubstituted;

R _{b is} selected from:

(i) hydrogen, hydroxy, amino, carboxy, cyano, nitro, halogen, _C2-4 alkenylcarbonylamino or =CH ₂ ;

(ii) optionally by hydroxy, amino, carboxy, cyano, nitro, halogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkoxy C _1-4 alkoxy, C _1-4 alkylamino, (C _1-4 alkyl) ₂ amino, C _1-4 alkylcarbonylamino, C _1-4 alkylsulfonylamino or 3-8 membered heterocyclyl substituted C _1-4 Alkyl, C _1-4 alkoxy, C _1-4 alkylamino, (C _1-4 alkyl) ₂ amino, halogenated C _1-4 alkyl, halogenated C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkylsulfonyl or C _1-4 alkylthio;

(iii) optionally by hydroxy, amino, carboxy, cyano, nitro, halogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylamino or (C _1-4 alkyl a ₂ amino-substituted 3-8 membered cycloalkyl or 3-8 membered heterocyclic group;

or

(iv) amino-carbonyl, cyano-carbonyl, C _1-4 alkyl-carbonyl, C _1-4 alkylamino-carbonyl, (C _1-4 alkyl) ₂ amino-carbonyl, C _1-4 alkoxy a carbonyl group, a 3-8 membered cycloalkyl-carbonyl group or a 3-8 membered heterocyclyl-carbonyl group;

R _{3 is} selected from hydrogen or C _1-4 alkyl;

R _{4 is} selected from the group consisting of hydrogen, hydroxy, amino, cyano, nitro, halogen, carboxyl, amide, aminocarbonyl, aminosulfonyl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkane Amino, (C _1-4 alkyl) ₂ amino, halo C _1-4 alkyl, halo C _1-4 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _{1- 4} -alkylsulfonyl, C _1-4 alkylcarbonylamino, (C _1-4 alkyl) ₂ carbonylamino, C _1-4 alkylaminocarbonyl, (C ₁₄ alkyl) ₂ aminocarbonyl, C _1-4 An alkylaminosulfonyl group, a (C _1-4 alkyl) ₂ aminosulfonyl group or a C _1-4 alkoxy C _1-4 alkoxy group;

L _{3 is} each a bond, -N(R _c )-, -O-, -S- or C _1-4 alkyl, and R _{c is} selected from hydrogen or C _1-4 alkyl;

q is 0 or 1;

Another embodiment of the present invention relates to an irreversible inhibitor of fibroblast growth factor receptor represented by the above formula (I-B) or a pharmaceutically acceptable salt or stereoisomer thereof:

Warhead ₂ is

X is selected from C or N, when X is C,

Represents a double bond, when X is N,

Represents a single button;

R _{1 is} selected from hydrogen or C _1-4 alkyl;

Cy ₃ is a divalent group of the following structure: substituted by one to more R _b or unsubstituted

Optimal

Warhead _{2 is} connected to any ring-forming N hetero atom in Cy ₃ ;

q is 0;

R _{b is} selected from hydrogen, C _1-4 alkyl or hydroxy C _1-4 alkyl, preferably hydroxy C _1-4 alkyl;

R _{3 is} selected from hydrogen or C _1-4 alkyl;

In another preferred embodiment, the compound of the formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, the compound is selected from the compounds of Table 1:

Table 1

The present invention also provides a pharmaceutical preparation comprising the aforementioned irreversible inhibitor of fibroblast growth factor receptor, or a pharmaceutically acceptable salt or stereoisomer thereof.

In some embodiments of the invention, the pharmaceutical formulation comprises one or more pharmaceutically acceptable carriers.

The pharmaceutical carrier of the present invention may be one or more solid or liquid filler or gel materials suitable for human use. The pharmaceutically acceptable carrier preferably has sufficient purity and sufficiently low toxicity and is compatible with the active ingredient of the present invention (an irreversible inhibitor of fibroblast growth factor receptor or a pharmaceutically acceptable salt thereof, a stereoisomer thereof) Sexually and not significantly reduce the efficacy of the active ingredients. For example, the pharmaceutically acceptable carrier can be a filler, a binder, a disintegrant, a lubricant, an aqueous solvent or a non-aqueous solvent, and the like.

The pharmaceutical preparation of the present invention can be formulated into any pharmaceutically acceptable dosage form, and administered to any patient in need of such treatment by any suitable administration means, for example, by oral, parenteral, rectal or pulmonary administration. Or subject. For oral administration, it can be formulated into tablets, capsules, pills, granules and the like. For parenteral administration, it can be prepared as an injection solution, a sterile powder for injection, or the like.

In some embodiments of the present invention, the pharmaceutical preparation of the present invention further comprises one or more second therapeutically active agents, wherein the second therapeutically active agent is an antimetabolite, a growth factor inhibitor, Filament classification inhibitors, anti-tumor hormones, alkylating agents, metals, topoisomerase inhibitors, hormonal drugs, immunomodulators, tumor suppressor genes, cancer vaccines, immune checkpoints, or tumor immunotherapy-related antibodies And small molecule drugs.

The present invention also provides the aforementioned fibroblast growth factor receptor irreversible inhibitor or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, and the aforementioned pharmaceutical preparation for preparing an FGF (fibroblast growth factor)/FGFR abnormality The application of drugs that mediate diseases. The FGF/FGFR abnormality-mediated disease according to the present invention is cancer; the cancer includes lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer, breast ductal carcinoma, head and neck cancer, Endometrial cancer, uterine body cancer, rectal cancer, liver cancer, kidney cancer, renal pelvic cancer, esophageal cancer, esophageal adenocarcinoma, glioma, prostate cancer, thyroid cancer, female reproductive system cancer, carcinoma in situ, lymphoma, Neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, oral cancer, pharyngeal cancer, multiple myeloma, leukemia, non-Hodgkin's lymphoma, large intestine villus Tumor, melanoma, cell tumor and sarcoma and/or myelodysplastic syndrome.

The present invention also provides the aforementioned fibroblast growth factor receptor irreversible inhibitor or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, and the use of the aforementioned pharmaceutical preparation for treating a disease.

In some embodiments of the invention, the disease comprises a FGF/FGFR abnormally mediated disease, the FGF/FGFR abnormally mediated disease is cancer; the cancer comprises lung cancer, squamous cell carcinoma, Bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer, ductal carcinoma of the breast, head and neck cancer, endometrial cancer, uterine body cancer, rectal cancer, liver cancer, kidney cancer, renal pelvic cancer, esophageal cancer, esophageal adenocarcinoma, nerve glue Tumor, prostate, thyroid, female reproductive system cancer, carcinoma in situ, lymphoma, neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, oral cancer , pharyngeal cancer, multiple myeloma, leukemia, non-Hodgkin's lymphoma, large intestine villus adenoma, melanoma, cell tumor and sarcoma and / or myelodysplastic syndrome.

The present invention also provides a method of treating a disease comprising administering to a patient in need thereof a therapeutically effective amount of the aforementioned fibroblast growth factor receptor irreversible inhibitor or a pharmaceutically acceptable salt thereof, stereoisomerism Or a pharmaceutical preparation according to the above, wherein the disease comprises a disease mediated by FGF/FGFR abnormality, the disease mediated by the FGF/FGFR abnormality is cancer; the cancer comprises lung cancer, squamous cell carcinoma, Bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer, ductal carcinoma of the breast, head and neck cancer, endometrial cancer, uterine body cancer, rectal cancer, liver cancer, kidney cancer, renal pelvic cancer, esophageal cancer, esophageal adenocarcinoma, nerve glue Tumor, prostate, thyroid, female reproductive system cancer, carcinoma in situ, lymphoma, neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, oral cancer , pharyngeal cancer, multiple myeloma, leukemia, non-Hodgkin's lymphoma, large intestine villus adenoma, melanoma, cell tumor and sarcoma and / or myelodysplastic syndrome.

"Therapeutically effective amount" of the present invention refers to at least mitigate the symptoms of the disorder when administered to a patient is the fibroblast growth factor receptor irreversible inhibitor or a pharmaceutically acceptable salt, stereoisomer And the amount of the aforementioned pharmaceutical preparation. The actual amount comprising a "therapeutically effective amount" will vary depending on a variety of circumstances including, but not limited to, the particular condition being treated, the severity of the condition, the physique and health of the patient, and the route of administration. Skilled medical practitioners can readily determine the appropriate amount using methods known in the medical arts.

Detailed description of the invention

The "halogen" as used in the present invention means fluorine, chlorine, bromine, iodine or the like, preferably fluorine and chlorine.

As used herein, "halo" means that any of the hydrogen atoms in the substituent may be substituted by one or more of the same or different halogens. "Halogen" is as defined above.

The "monovalent group" and "divalent group" of the present specification refer to a group formed by the loss of one or two hydrogen atoms.

The "C _1-6 alkyl group" as used in the present invention means a straight or branched alkyl group derived from a hydrocarbon having 1 to 6 carbon atoms and removed by a hydrogen atom, such as a methyl group, an ethyl group, a n-propyl group, Isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, iso-hexyl Base, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl and 1-methyl Base-2-methylpropyl and the like. The "C _1-4 alkyl group" means the above examples containing from 1 to 4 carbon atoms.

The "C _1-6 alkylene group" as used in the present invention means that the aforementioned "C _1-6 alkyl group" further removes a linear or branched divalent alkyl group derived from a hydrogen atom.

The "C _2-8 alkenyl group" as used in the present invention means an olefin moiety having 2 to 8 carbon atoms containing a carbon-carbon double bond, and a linear or branched or cyclic alkene group derived from a hydrogen atom, such as a vinyl group. , 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 1,4-hexadienyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1, 4-cyclohexadienyl, cycloheptenyl, 1,4-cycloheptadienyl, cyclooctenyl, 1,5-cyclooctadienyl, and the like.

The "C _2-8 alkenylene group" as used in the present invention means that the aforementioned "C _2-8 alkenyl group" further removes a hydrogen atom-derived linear or branched divalent alkene group.

The "3-12 membered cycloalkenyl group" of the present invention includes, in the case where it is not particularly specified, all monocyclic rings, fused rings (including fused in the form of a snail, a snail, or a bridge) which may be formed, for example, 3-8-membered monocyclic olefin, 7-11-membered spirocycloolefin, 7-11-membered cycloalkenene, 6-11-membered bridged cycloolefin, and the like.

The "C _2-8 alkynyl group" as used in the present invention means an alkyne moiety having 2 to 8 carbon atoms containing a carbon-carbon oxime bond, and a straight or branched alkyne group derived by removing one hydrogen atom, such as ethynyl group, C. Alkynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 4-methyl-2-pentynyl, 2-hexynyl, 3-hexynyl, and the like.

The "C _2-8 alkynylene group" as used in the present invention means that the aforementioned "C _2-8 alkynyl group" further removes a hydrogen atom-derived linear or branched divalent alkyne group.

The "C _1-6 alkylamino group", "(C _1-6 alkyl) ₂ amino group", "C _1-6 alkylcarbonylamino group", and "C _1-6 alkylsulfonylamino group" according to the present invention "C _1-6 alkylaminocarbonyl"", "(C _1-6 alkyl) ₂ amino-carbonyl", "C _1-6 alkoxy-carbonyl", "C _1-6 alkylsulfonyl""","C _1-6 alkylthio", "C _1-6 alkyl-carbonyl", "3-8 membered cycloalkyl-carbonyl", "3-8 membered heterocyclyl-carbonyl", respectively C _1-6 alkyl-NH-, (C _1-6 alkyl)(C _1-6 alkyl)N-, C _1-6 alkyl-C(O)-NH-, C _1-6 alkyl -S(O) ₂ -NH ₂ -, C _1-6 alkyl-NH-C(O)-, (C _1-6 alkyl)(C _1-6 alkyl)NC(O)-, C _{1 -6-} alkyl-OC(O)-, C _1-6 alkyl-S(O) ₂ -, C _1-6 alkyl-S-, C _1-6 alkyl-C(O)-, 3- 8-membered cycloalkyl-C(O)-, 3-8 membered heterocyclyl-C(O)-; said "C _1-6 alkyl" is as defined above, preferably "C _1-4 alkyl"".

"C _1-6 alkoxy" refers to the present invention as hereinbefore defined "C _1-6 alkyl" group linked to the parent molecule through an oxygen atom, i.e., "C _1-6 alkyl -O- "Groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentyloxy, neopentyloxy and n-hexyloxy. The "C _1-4 alkoxy group" refers to the above-mentioned example having 1 to 4 carbon atoms, that is, a "C _1-4 alkyl-O-" group.

The "fused ring" as used in the present invention means a polycyclic ring structure formed by joining two, two or more cyclic structures in a snail, a snail, or a bridge. The parallel ring refers to a fused ring structure formed by two or more ring structures sharing two adjacent ring atoms with each other (ie, sharing one bond). The bridged ring refers to a fused ring structure formed by two or more ring-shaped structures sharing two non-adjacent ring atoms with each other. The spiro ring refers to a fused ring structure formed by two or more ring structures sharing one ring atom with each other.

As used herein, "cycloalkyl" refers to a 3-12 membered cycloalkyl group which may be a monocyclic, bicyclic, or polycyclic cycloalkyl system (also known as a fused ring system). Unless otherwise specified, all monocyclic, fused rings (including fused in the form of snails, snails, bridges) that may be formed are included.

Monocyclic systems are cyclic hydrocarbyl groups containing from 3 to 8 carbon atoms. Examples of 3-8 membered monocyclic alkyl groups include, but are not limited to, cyclopropyl, cyclobutane, cyclopentyl, cyclohexane, cycloheptyl, cyclooctyl, and the like. The fused ring cycloalkyl group includes a cyclocycloalkyl group, a bridged cycloalkyl group, a spirocycloalkyl group.

The cyclocycloalkyl group may be a 6-11 membered cyclocycloalkyl group, a 7-10 membered cyclocycloalkyl group, and representative examples thereof include, but are not limited to, bicyclo [3.1.1] heptane, bicyclo [2.2.1 Heptane, bicyclo [2.2.2] octane, bicyclo [3.2.2] decane, bicyclo [3.3.1] decane and bicyclo [4.2.1] decane.

The spiro group may be a 7-12 membered spiro group, a 7-11 membered spiro group, examples of which include, but are not limited to:

The bridged ring group may be a 6-11 membered bridged ring group and a 7-10 membered bridged ring group, and examples thereof include, but are not limited to:

The "3-12 membered heterocyclic group" as used in the present invention means a non-aromatic cyclic group in which at least one ring carbon atom is replaced by a hetero atom selected from O, S, N, preferably 1 to 3 hetero atoms. And including carbon atoms, nitrogen atoms and sulfur atoms can be substituted by oxo.

"Heterocyclyl" means a monocyclic heterocyclic ring, a bicyclic heterocyclic ring system or a polycyclic heterocyclic ring system (also known as a fused ring system), including saturated, partially saturated heterocyclic groups, but excluding aromatic rings. . Unless otherwise specified, all single rings, fused rings (including fused in the form of snails, snails, bridges), saturated, partially saturated, which may be formed, are included.

The term "submonoheterocyclic group" as used in the present invention means that the aforementioned "monoheterocyclic group" further removes a divalent single radical in which at least one ring carbon atom derived from one hydrogen atom is replaced by a hetero atom selected from O, S, N. A cyclic group. The monoheterocyclic group may be a 3-8 membered heterocyclic group, a 3-8 membered saturated heterocyclic group, a 3-6 membered heterocyclic group, a 4-7 membered heterocyclic group, a 5-7 membered heterocyclic group, 5- A 6-membered heterocyclic group, a 5-6 membered oxygen-containing heterocyclic group, a 3-8 membered nitrogen-containing heterocyclic group, a 5-6 membered nitrogen-containing heterocyclic group, a 5-6 membered saturated heterocyclic group or the like. "3-8"-membered saturated heterocyclic group, examples of which include, but are not limited to, aziridine, oxacyclopropane, thietyl, azetidinyl, oxetanyl, sulfur Heterocyclobutane, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiophenyl, imidazolidinyl, pyrazolidinyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl, 1,2- Thiazolidinyl, 1,3-thiazolidinyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, piperidinyl, piperazinyl, pyrrolyl, morpholinyl, 1,4-di An oxacyclohexyl group, a 1,4-oxothianyl group; a "3-8" member partially saturated heterocyclic group, and examples thereof include, but are not limited to, 4,5-dihydroisoxazolyl, 4, 5-Dihydrooxazolyl, 2,5-dihydrooxazolyl, 2,3-dihydrooxazolyl, 3,4-dihydro-2H-pyrrolyl, 2,3-dihydro-1H-pyrrole , 2,5-dihydro-1H-imidazolyl, 4,5-dihydro-1H-imidazolyl, 4,5-dihydro-1H-pyrazolyl, 4,5-dihydro-3H-pyrazole , 4,5-dihydrothiazolyl, 2,5-dihydrothiazolyl, 2H-pyranyl, 4H-pyranyl, 2H-thiopyranyl, 4H-thiopyranyl, 2,3,4, 5-tetrahydropyridyl, 1,2-isooxazinyl, 1,4-isooxazinyl or 6H-1,3-oxazinyl. The fused heterocyclic ring includes a heterocyclic group, a spiroheterocyclic group, a bridged heterocyclic group, and may be saturated, partially saturated or unsaturated, but not aromatic. The fused heterocyclic group is a monocyclic cycloalkyl group, a 5-6 membered monocyclic cycloalkenyl group, a 5-6 membered monocyclic heterocyclic group or a 5-6 membered monocyclic heteroaryl group fused to a benzene ring, 5-6 members. A 5-6 membered monocyclic heterocyclic ring of the group. The heterocyclic group may be 6-11 members and a cyclic group, a 7-10 membered ring group, a 6-10 membered ring group, a 6-12 membered saturated ring group, and representative examples include, but are not limited to: 3-azabicyclo[3.1.0]hexane, 3,6-diazabicyclo[3.2.0]heptyl, 3,8-diazabicyclo[4.2.0]octyl, 3, 7-diazabicyclo[4.2.0]octyl, octahydropyrrolo[3,4-c]pyrrolyl, octahydropyrrolo[3,4-b]pyrrolyl, octahydropyrrolo[3, 4-b][1,4]oxazinyl, octahydro-1H-pyrrolo[3,4-c]pyridyl, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydro Benzofuran-3-yl, indan-1-yl, indan-2-yl, indan-3-yl, 2,3-dihydrobenzothiophen-2-yl, octahydro- 1H-indenyl, octahydrobenzofuranyl.

The spiroheterocyclyl group may be a 6-12 membered spiroheterocyclyl group, a 7-12 membered spiroheterocyclyl group, a 7-12 membered N-containing spiroheterocyclyl group, a 6-12 membered saturated spirocyclic group, and examples thereof include But not limited to:

The term "spiroheterocyclyl" as used in the present invention means that the aforementioned "spiroheterocyclic group" further removes a divalent snail in which at least one ring carbon atom derived from a hydrogen atom is replaced by a hetero atom selected from O, S, and N. A cyclic group.

The bridged heterocyclic group may be a 6-11 membered bridged heterocyclic group, a 7-11 membered bridged heterocyclic group, and a 6-12 membered saturated bridged ring group, and examples thereof include, but are not limited to:

The "aryl group" as used in the present invention means a cyclic aromatic group having 6 to 14 carbon atoms, and includes a 6-8 membered monocyclic aryl group and an 8-14 membered fused ring aryl group, preferably 6-8 members. Monocyclic aryl. The 6-8 membered monocyclic aryl group may be a phenyl group, a pyrazole, a cyclooctadecenyl group or the like. The 8-14 membered fused ring aryl group may be naphthalene, phenanthrene or the like.

The "heteroaryl" of the present invention may be a 5-10 membered heteroaryl group, and means an aromatic cyclic group in which at least one ring carbon atom is replaced by a hetero atom selected from O, S, N, preferably 1- 3 heteroatoms, including carbon atoms, sulfur atoms by oxo, such as carbon atoms replaced by C (O), sulfur atoms replaced by S (O), S (O) ₂ . The heteroaryl group includes a monoheteroaryl group and a fused heteroaryl group, and includes, unless otherwise specified, all monocyclic, fused ring, wholly aromatic, partially aromatic forms which may be formed. The monoheteroaryl group may be a 5-7 membered heteroaryl group, a 5-6 membered heteroaryl group, and examples thereof include, but are not limited to, furyl, imidazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl , oxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thienyl, triazolyl and triazinyl. And X. a 5- or 6-membered monocyclic heteroaryl ring of a 5- or 6-membered monocyclic heteroaryl group in which a fused cycloalkyl, cycloalkenyl and heterocyclic group is used as an independent oxo or thio group. One or two groups are optionally substituted. The fused heteroaryl group may be 8-12 membered heteroaryl, 9-10 membered heteroaryl, and examples include, but are not limited to, benzimidazolyl, benzofuranyl, benzothienyl, benzooxadiazolyl , benzothiadiazolyl, benzothiazolyl, porphyrinyl, 5,6-dihydroquinolin-2-yl, 5,6-dihydroisoquinolin-1-yl, furopyridinyl, anthracene Azyl, fluorenyl, isoquinolyl, naphthyridinyl, fluorenyl, quinolinyl, 5,6,7,8-tetrahydroquinolin-2-yl, 5,6,7,8-tetrahydro Quinolinyl, 5,6,7,8-tetrahydroquinolin-4-yl, 5,6,7,8-tetrahydroisoquinolin-1-yl, thienopyridinyl, 4,5,6, 7-Tetrahydro[c][1,2,5]oxadiazolyl and 6,7-dihydro[c][1,2,5]oxadiazol-4(5H)keto.

The "pharmaceutically acceptable salt" as used in the present invention means a pharmaceutically acceptable acid or base addition salt or a solvate thereof. Such pharmaceutically acceptable salts include salts of the following acids: hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, sulfurous acid, formic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, benzoic acid, citric acid, tartaric acid, maleic acid. Hydroiodic acid, alkanoic acid (such as acetic acid, HOOC-(CH ₂ ) n-COOH (where n is 0 to 4)), and the like. Salts of bases: sodium salts, potassium salts, calcium salts, ammonium salts, and the like. A variety of non-toxic pharmaceutically acceptable addition salts are known to those skilled in the art.

The "stereoisomer" of the compound of the formula (I) of the present invention means that when an asymmetric carbon atom is present in the compound of the formula (I), (IA), (IB), an enantiomer is produced; when the compound has carbon and carbon In the case of a double bond or a cyclic structure, a cis-trans isomer is produced; when a compound has a ketone or a oxime, a tautomer is produced, and all of the compounds of the formula (I), (IA), (IB) are enantiomerically Constructs, diastereomers, racemic isomers, cis-trans isomers, tautomers, geometric isomers, epimers, and mixtures thereof are included within the scope of the invention.

The "warhead" as used in the present invention refers to a moiety capable of forming a covalent bond with a nucleophile. A "nucleophile" is a substance that is directed to an electrophile to supply an electron pair to form a chemical bond in the reaction. In some embodiments, the nucleophile can be an oxygen nucleophile, eg, water or a hydroxyl group; a nitrogen nucleophile, eg, an amine; or a sulfur nucleophile, eg, a sulfhydryl group, such as a cystine residue Sulfhydryl groups in the side chain.

As used herein, "warhead" refers to a moiety that is reversibly or irreversibly involved in the reaction of a donor (eg, a protein) with a substrate. Warhead can, for example, form a covalent bond with a protein, or can form a stable transition state, or a reversible irreversible alkylating agent. For example, warhead can be a functional group on an inhibitor that can participate in a bond formation reaction, wherein a new covalent bond is formed between a portion of the warhead and a donor (eg, an amino acid residue of a protein). Warhead is an electrophile and the "donor" is a nucleophile, such as a side chain of a cysteine residue. Suitable for the warhead part include but are not limited to the following structure:

R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ and R ₁₅ are each independently selected from hydrogen, halogen, cyano, C _1-4 alkyl, halo C _1-4 alkyl, Cy ₄ or optionally substituted. a substituted C _1-4 alkyl group, a halogenated C _1-4 alkyl group, a Cy ₄ , a C _2-8 alkenyl group, a C _2-8 alkynyl group, the substituent being selected from the group consisting of a hydroxyl group, an amino group, a carboxyl group, and a cyano group. , nitro, halogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkoxy C _1-4 alkoxy, C _1-4 alkylamino, (C _1-4 alkyl a ₂ amino group, a C _1-4 alkylcarbonylamino group, a C _1-4 alkylsulfonylamino group, a 3-12 membered heterocyclic group;

Cy _{4 is} selected from a 3-12 membered cycloalkyl group, a 3-12 membered cycloalkenyl group, a 3-12 membered heterocyclic group, an aryl group or a 5-10 membered heteroaryl group.

z is an integer from 0-4.

More preferred specific examples are:

The fibroblast growth factor receptor (FGFR) irreversible inhibitor provided by the present invention, or a pharmaceutically acceptable salt thereof, stereoisomer thereof has an efficient and highly selective inhibitory effect on the fibroblast growth factor receptor, It can be applied to the treatment of related diseases mediated by FGF/FGFR abnormalities, especially in the treatment of cancer diseases.

Detailed ways

The abbreviation "NMP" as used herein refers to N-methylpyrrolidone; "DIPEA" means N,N-diisopropylethylamine; "TLC" means thin layer chromatography; "PE:EA" means petroleum ether Ethyl acetate; "TFA" means trifluoroacetic acid; "THF" means tetrahydrofuran; "EA" means ethyl acetate; "DCM: MeOH" means dichloromethane: methanol; "DCM" means dichloro Methane; "MTBE" means methyl tert-butyl ether; "TFAA" means trifluoroacetic anhydride; "TEA" means triethylamine; "LAN" means lithium tetrahydrogenate; "Boc" means uncle Butyloxycarbonyl; "MsCl" is succinyl chloride; "DEAD" means diethyl azodicarboxylate; "PPh ₃ " means triphenylphosphine; "mCPBA" means m-chloroperoxybenzoic acid; "LC -MS" means liquid chromatography-mass spectrometry.

The invention can be better understood from the following examples and experimental examples. However, those skilled in the art will understand that the description of the embodiments is only intended to illustrate the invention and should not be construed as limiting the invention as described in the claims. In addition, the materials, instruments, and the like involved in the following examples and experimental examples are commercially available unless otherwise specified.

Preparation Example 1: Synthesis of Intermediate 4-Amino-2-(methylthio)pyrimidine-5-carboxaldehyde

Step 1: Synthesis of ethyl 4-amino-2-(methylthio)pyrimidine-5-carboxylate

The starting material, ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (15 g, 64.4 mmol, 1.0 eq) was dissolved in THF (100 mL) and triethylamine (19.6 g, 193.4 mmol, 3.00 eq. ), the temperature was lowered to 0 ° C, ammonia water (7.8 g, 1288 mmol, 20.0 eq) was slowly added, and the reaction was allowed to rise to room temperature overnight, and the reaction was completed by LC-MS. The mixture was separated and the aqueous phase was extracted once with ethyl acetate. The organic phase was dried with EtOAc (EtOAc)EtOAc.

Step 2: Synthesis of (4-amino-2-(methylthio)pyrimidin-5-yl)methanol

The starting material ethyl 4-amino-2-(methylthio)pyrimidine-5-carboxylate (11.8 g, 55.3 mmol, 1.0 eq) was dissolved in tetrahydrofuran (100 mL), cooled to 0 ° C, Lithium (4.8g, 127.4mmol, 2.3eq), the reaction was allowed to rise to room temperature for 2 hours, and the reaction was completed by LC-MS. To the system was added tetrahydrofuran (100 mL), cooled to 0 ° C, and slowly added water (10 mL). And 15% NaOH (10 mL), EtOAc (EtOAc)

Step 3: Synthesis of 4-amino-2-(methylthio)pyrimidine-5-carboxaldehyde

The starting material (4-amino-2-(methylthio)pyrimidin-5-yl)methanol (10.0 g, crude, 1.0 eq) was dissolved in tetrahydrofuran (100 mL). Eq), the reaction was carried out at rt overnight, EtOAc (EtOAc:EtOAc)

Preparation 2: Synthesis of intermediate 6-((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

Step 1: Synthesis of 6-((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

The starting material, 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (1.1 g, 5 mmol, 1.0 eq) was dissolved in dichloromethane (15 mL) and triethylamine (1.5 g, 15 mmol, 3.0 eq) and methanesulfonyl chloride (573 mg, 5 mmol, 1.0 eq) were reacted at room temperature for 2 hours. The reaction was completed by LC-MS. EtOAc (EtOAc: EtOAc)

Preparation 3: Synthesis of intermediate 4-(3-((methylsulfonyl)oxy)propyl)piperazine-1-carboxylic acid tert-butyl ester

Step 1: Synthesis of 4-(3-hydroxypropyl)piperazine-1-carboxylic acid tert-butyl ester

The starting material tert-butylpiperazine-1-carboxylate (7 g, 0.0376 mol, 1.0 eq) was dissolved in acetonitrile (50 mL), 3-bromopropan-1-ol (5.2 g, 0.0376 mol, 1.0 eq. Potassium (15.5 g, 0.1127 mol, 3.0 eq). After four hours of reaction, the reaction was completed by EtOAc (EtOAc) (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Yield: 96%).

Step 2: Synthesis of 4-(3-((methylsulfonyl)oxy)propyl)piperazine-1-carboxylic acid tert-butyl ester

The starting material 4-(3-hydroxypropyl)piperazine-1-carboxylic acid tert-butyl ester (8.82 g, 0.0361 mol, 1.0 eq) was dissolved in dichloromethane (80 mL) and triethylamine (16.4 g, 0.1623 mol) A solution of methanesulfonyl chloride (6.28 g, 0.0541 mol, 1.5 eq) in dichloromethane (20 mL) was reacted for 12 hr. Water (100 mL) was added to the reaction mixture, and dichloromethane (100 mL×3) was evaporated. Liquid product (6.58 g, yield: 57%).

Example 1: 1-(1-(1-Aroylpiperidin-4-yl)azetidin-3-yl)-3-(2,6-dichloro-3,5-dimethoxy Synthesis of phenyl)-7-(methylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (Compound 1)

Step 1: Synthesis of ethyl 4-((1-(tert-butoxycarbonyl)azetidin-3-yl)amino)-2-(methylthio)pyrimidine-5-carboxylate

Ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (5.0 g, 21.5 mmol, 1.0 eq) was dissolved in 1,4-dioxane (30 mL). g, 75.3 mmol, 3.5 eq) and 3-aminoazetidine-1-carboxylic acid tert-butyl ester (4.4 g, 25.8 mmol, 1.2 eq), heated at 95 ° C for 10 h, the reaction was completely monitored by TLC, and the reaction mixture was cooled. The mixture was concentrated to EtOAc (EtOAc: EtOAc = EtOAc (EtOAc) ((1-(tert-Butoxycarbonyl)azetidin-3-yl)amino)-2-(methylthio)pyrimidine-5-carboxylic acid ethyl ester (7.5 g, yield: 95%).

Step 2: Synthesis of tert-butyl 3-((5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)azetidin-1-carboxylate

Lithium tetrahydroaluminum (1.2 g, 31.6 mmol, 1.5 eq) was dissolved in THF (50 mL), cooled to 0 ° C, and THF (20 mL) was added to dissolve 4-((1-(tert-butoxycarbonyl) aza Ethyl cyclobutane-3-yl)amino)-2-(methylthio)pyrimidine-5-carboxylate (7.5 g, 20.4 mmol, 1.0 eq), mp. Add water (1.2mL), stir for 10min, add 15% sodium hydroxide aqueous solution (1.2g), stir for 15min, add water (3.5mL), stir for 10min, suction filtration, filter cake washed with THF a small amount The filtrate was dried over anhydrous sodium sulfate, filtered, filtered, and then filtered,jjjjjjjjjjjjjjjjj (Methylthio)pyrimidin-4-yl)amino)azetidin-1-carboxylic acid tert-butyl ester (3.09 g, yield: 47%).

Step 3: Synthesis of tert-butyl 3-((5-formyl-2-(methylthio)pyrimidin-4-yl)amino)azetidin-1-carboxylate

3-((5-(Hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)azetidin-1-carboxylic acid tert-butyl ester (3.1 g, 9.5 mmol, 1.0 eq Dissolved in THF (60 mL), added manganese dioxide (6.6 g, 75.7 mmol, 8.0 eq), and stirred at 45 ° C for 12 h. The reaction was monitored by TLC, filtered over celite, and filtered. The filtrate was concentrated to give 3-((5-formyl-2-(methylthio)pyrimidin-4-yl)amino)azetidin-1-carboxylic acid tert-butyl ester (2.76 g, yield: 90%) ).

Step 4: 3-((5-((3,5-Dimethoxyphenyl)amino)methyl)-2-(methylthio)pyrimidin-4-yl)amino)azetidine- Synthesis of 1-tert-butyl carboxylate

Dissolving 3-((5-formyl-2-(methylthio)pyrimidin-4-yl)amino)azetidin-1-carboxylic acid tert-butyl ester (1.0 g, 3.1 mmol, 1.0 eq) In DCM (15 mL), acetic acid (0.5 mL) and 3,5-dimethoxyaniline (0.7 g, 4.6 mmol, 1.5 eq) were added, and the reaction was stirred for 15 min, and sodium triacetoxyborohydride (3.3 g, 15.4) was added. Ment, 5.0 eq), stirring for 8 h, the reaction was completed by TLC, EtOAc (EtOAc) EtOAc (EtOAc) The crude product was subjected to silica gel column chromatography (DCM: MeOH=100:1 to 60:1) to give 3-((5-((3,5-dimethoxyphenyl)amino)methyl)-2- (Methylthio)pyrimidin-4-yl)amino)azetidin-1-carboxylic acid tert-butyl ester (973 mg, yield: 70%).

Step 5: 3-(3-(3,5-Dimethoxyphenyl)-7-(methylthio)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidine Synthesis of -1(2H)-yl)azetidin-1-carboxylic acid tert-butyl ester

3-((5-((3,5-Dimethoxyphenyl)amino)methyl)-2-(methylthio)pyrimidin-4-yl)amino)azetidin-1- The tert-butyl carboxylic acid ester (1.0 g, 2.2 mmol, 1.0 eq) was dissolved in THF (20 mL), cooled to 0 ° C, triethylamine (657.5 mg, 6.5 mmol, 3.0 eq) and solid phosgene (771.5 mg, 2.6 mmol, 1.2 eq), the reaction was stirred at room temperature for 2 h, and the reaction was carried out at 75 ° C for 1.5 h. The reaction was completed by LC-MS, and then cooled to room temperature, and then a saturated aqueous solution of ammonium chloride (50 mL), DCM (3×50 mL) Drying with anhydrous sodium sulfate, filtration, EtOAc (EtOAc:EtOAc) 7-(Methylthio)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)azetidin-1-carboxylic acid tert-butyl ester ( 845 mg, yield: 80%).

Step 6: 3-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylthio)-2-oxo-3,4-dihydropyrimido[ Synthesis of 4,5-d]pyrimidine-1(2H)-yl)azetidin-1-carboxylic acid tert-butyl ester

3-(3-(3,5-Dimethoxyphenyl)-7-(methylthio)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidine-1 tert-Butyl (2H)-yl)azetidin-1-carboxylate (1.9 g, 3.9 mmol, 1.0 eq) was dissolved in DCM (20 mL). The mixture was stirred for 15 min. Filtration, concentration, and crude <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0> 7-(Methylthio)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)azetidin-1-carboxylic acid tert-butyl ester (1.67 g, yield: 61%).

Step 7: 3-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylsulfonyl)-2-oxo-3,4-dihydropyrimidine Synthesis of [4,5-d]pyrimidine-1(2H)-yl)azetidin-1-carboxylic acid tert-butyl ester

3-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylthio)-2-oxo-3,4-dihydropyrimido[4, 5-d]pyrimidin-1(2H)-yl)azetidin-1-carboxylic acid tert-butyl ester (800.0 mg, 1.4 mmol, 1.0 eq) was dissolved in DCM (20 mL). m-Chloroperoxybenzoic acid (496.2 mg, 2.8 mmol, 2.0 eq) was stirred at 0 ° C for 2 h, and the reaction was completed by LC-MS.

Step 8: 3-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-2-oxo-3,4-dihydropyrimido[ Synthesis of 4,5-d]pyrimidine-1(2H)-yl)azetidin-1-carboxylic acid tert-butyl ester

3-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylsulfonyl)-2-oxo-3,4-dihydropyrimido[4 , 5-d]pyrimidin-1 (2H)-yl)azetidin-1-carboxylic acid tert-butyl ester was added to the bee tube, and the methylamine aqueous solution (10 mL) was added, and the reaction was sealed at 45 ° C for 2 h. The reaction was completed by EtOAc (EtOAc: EtOAc: EtOAc (EtOAc). 60:1), 3-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-2-oxo-3,4-dihydrol was obtained. Pyrimido[4,5-d]pyrimidin-1(2H)-yl)azetidin-1-carboxylic acid tert-butyl ester (600 mg, two-step yield: 77%).

Step 9: 1-(Azetidin-3-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-3,4 Synthesis of dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

3-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-2-oxo-3,4-dihydropyrimido[4, 4-d]pyrimidin-1(2H)-yl)azetidin-1-carboxylic acid tert-butyl ester (600.0 mg, 1.1 mmol, 1.0 eq) was dissolved in EtOH (10 mL) %, 10 mL), the reaction was stirred at rt for 3 h, EtOAc EtOAc (EtOAc m. 1-(azetidin-3-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-3,4-dihydro Pyrimido[4,5-d]pyrimidine-2(1H)-one (460 mg, yield: 94%).

Step 10: 4-(3-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-2-oxo-3,4-dihydro Synthesis of pyrimido[4,5-d]pyrimidin-1(2H)-yl)azetidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester

tert-Butyl 1-(azetidin-3-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-3, 4-Dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (460.0 mg, 1.0 mmol, 1.0 eq) was dissolved in DCM (125 mL). Tert-butyl piperidine-1-carboxylate (330 mg, 1.6 mmol, 1.5 eq), stirred for 2 h, added sodium triacetoxyborohydride (665.7 mg, 3.1 mmol, 3.0 eq), stirred for 8 h, and the reaction was completely monitored by TLC. The pH of the solution was adjusted to 7-8 with a saturated aqueous solution of sodium bicarbonate, and the mixture was separated and evaporated, evaporated, evaporated, evaporated. =100:1 to 20:1) to give 4-(3-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-2-oxyl Generation of tert-butyl-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)azetidin-1-yl)piperidine-1-carboxylate (406.3 mg, Yield: 62%).

Step 11: 3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-1-(1-(piperidin-4-yl)azetidine Synthesis of alk-3-yl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one hydrochloride

4-(3-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-2-oxo-3,4-dihydropyrimidine [4,5-d]pyrimidine-1(2H)-yl)azetidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester (406.3 mg, 0.7 mmol, 1.0 eq) was dissolved in EtOH ( In 15 mL), a solution of hydrogen chloride in ethanol (10 mL) was added, and the reaction was stirred at room temperature for 3 h, and the reaction was completed by LC-MS and concentrated to give 3-(2,6-dichloro-3,5-dimethoxyphenyl)-7. -(methylamino)-1-(1-(piperidin-4-yl)azetidin-3-yl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2 ( 1H)-keto hydrochloride (364.8 mg, yield: 100%).

Step 12: 1-(1-(1-Anoylpiperidin-4-yl)azetidin-3-yl)-3-(2,6-dichloro-3,5-dimethoxybenzene Synthesis of 7-(methylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-1-(1-(piperidin-4-yl)azetidine- 3-yl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one hydrochloride (364.8 mg, 0.7 mmol, 1.0 eq), dissolved in THF (10 mL) Triethylamine (198.1 mg, 2.0 mmol, 3.0 eq) was added, and the reaction was stirred for 10 min. THF (2 mL) dissolved acryloyl chloride (70.9 mg, 0.8 mmol, 1.2 eq) was slowly added dropwise, and the reaction was stirred at room temperature for 2 h. , a saturated sodium hydrogencarbonate solution (20 mL), EtOAc (EtOAc (EtOAc) 1-(1-(1-acryloylpiperidin-4-yl)azetidin-3-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)- 7-(Methylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (200 mg, yield: 53%). Molecular formula: C ₂₆ H ₃₁ C _l2 N ₇ O ₄ Molecular weight: 576.48 LC-MS (m/z) = 576.18 [M+H ⁺ ].

: ¹ H NMR (400 MHz, DMSO) δ (ppm): 8.00 (s, 1H), 6.98-7.07 (m, 2H), 6.74-6.81 (m, 1H), 6.03-6.08 (m, 1H), 5.62-5.65 (m, 1H), 4.39 (m, 2H), 4.28 (s, 1H), 3.82-3.95 (m, 10H), 3.14-3.20 (m, 1H), 2.87-2.98 (m, 3H), 2.77-2.78 (s, 3H), 2.26 (m, 1H), 1.63 (m, 2H), 1.10 (m, 2H).

Example 2: 1-(7-acrylo-7-azaspiro[3.5]decane-2-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)- Synthesis of 7-(methylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (Compound 2)

Step 1: 2-((5-(Ethoxycarbonyl)-2-(methylthio)pyrimidin-4-yl)amino)-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester Synthesis

Ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (3.4 g, 14.55 mmol, 1.0 eq) was dissolved in 1,4-dioxane (30 mL). Add 2-amino-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester (4.2 g, 17.47 mmol, 1.2 eq) and triethylamine (4.4 g, 43.69 mmol, 3.0 eq). The mixture was stirred at reflux to 98 ° C overnight. The reaction was completed by TLC. After the reaction mixture was concentrated and evaporated, a saturated aqueous solution of ammonium chloride (100 mL) was added, and the mixture was stirred for 5 minutes, then extracted with dichloromethane (150 mL×3), the organic phase was dried over anhydrous sodium sulfate The crude product was separated by silica gel column chromatography (200-300 mesh silica gel; petroleum ether: ethyl acetate = 40:1) to give 2-((5-(ethoxycarbonyl)-2-(methylthio)pyrimidine-4 -Amino)amino-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester (6.49 g, yield: 100%).

Step 2: Synthesis of 2-((5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester

Lithium tetrahydroaluminum (842.5 mg, 22.2 mmol, 1.5 eq) was added to tetrahydrofuran (10 mL) at 0 ° C, and 2-((5-(ethoxycarbonyl))-2-methylsulfonate was slowly added dropwise with stirring. a solution of tert-butyl pyridyl-4-methyl)amino)-7-azaspiro[3.5]decane-7-carboxylate (6.49 g, 14.8 mmol, 1.0 eq) in tetrahydrofuran (30 mL) After 5 ° C or less, the mixture was slowly added to room temperature and stirred overnight. TLC showed the reaction was complete, the system was cooled to 0 ° C, water (842.4 mg) was added, and after stirring for 20 minutes, 15% aqueous sodium hydroxide solution (842.5 mg) was added dropwise at this temperature, stirred for 20 minutes, and again at 0. After adding dropwise water (2.5 g) at ° C for 40 minutes, suction filtration, the filtrate was dried over anhydrous sodium sulfate, filtered, filtered, and the filtrate was evaporated to silica gel column chromatography (200-300 mesh silica gel; 1 to 40:1) 2-((5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)-7-azaspiro[3.5]decane-7-carboxylic acid tert-Butyl ester (3.14 g, yield: 57.0%).

Step 3: Synthesis of 2-((5-formyl-2-(methylthio)pyrimidin-4-yl)amino)-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester

2-((5-(Hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester (3.12g) 7.9 mmol, 1.0 eq) was dissolved in tetrahydrofuran (20 mL). MgSO.sub.2 (6.8 g, 79 mmol, 10.0 eq. TLC showed the reaction was completed, the system was filtered through celite, dried over anhydrous sodium sulfate and filtered, and then filtered to give 2-((5-formyl-2-(methylthio)pyrimidin-4-yl)amino) -7-Azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester (3.56 g crude product, yield: 100%).

Step 4: 2-((5-((3,5-Dimethoxyphenyl)amino)methyl)-2-(methylthio)pyrimidin-4-yl)amino)-7-aza snail [3.5] Synthesis of tert-butyl decane-7-carboxylate

2-((5-Formyl-2-(methylthio)pyrimidin-4-yl)amino)-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester (3.56 g, 9.0 mmol) , 1.0 eq) and 3,5-dimethoxyaniline (2.06 g, 13.5 mmol, 1.5 eq) were dissolved in tetrahydrofuran (30 mL), and acetic acid (0.5 mL) was added dropwise, and stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (9.5 g, 45 mmol, 5.0 eq) was added and stirred at rt overnight. TLC showed the reaction was completed, the mixture was cooled to 0 ° C, EtOAc (EtOAc (EtOAc) (200-300 mesh silica gel; dichloromethane and methanol = 200:1) to give 2-((5-(((3,5-dimethoxyphenyl)amino)methyl)-2-)methylthio) Pyrimidin-4-yl)amino)-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester (2.89 g, yield: 61.4%).

Step 5: 2-(3-(3,5-Dimethoxyphenyl)-7-(methylthio)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidine Synthesis of -1(2H)-yl)-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester

2-((5-((3,5-Dimethoxyphenyl)amino)methyl)-2-(methylthio)pyrimidin-4-yl)amino)-7-azaspiro[3.5 tert-Butyl-7-carboxylic acid tert-butyl ester (2.89 g, 5.45 mmol, 1.0 eq) was dissolved in tetrahydrofuran (20 mL), stirred and warmed to 0 ° C, triethylamine (1.65 g, 16.35 mmol, 3.0 eq) ). After the dropwise addition, the mixture was stirred at this temperature for 10 minutes, and a solution of triphosgene (1.46 g, 7.08 mmol, 1.3 eq) in tetrahydrofuran (5 mL) was added dropwise, and the mixture was slowly stirred at room temperature for 1 hour, then warmed to 72 ° C for 2 hours. . LC-MS showed no starting material. The mixture was cooled to room temperature. EtOAc (50 mL) , the crude product was separated by silica gel column chromatography (200-300 mesh silica gel; dichloromethane and methanol = 200:1) to give 2-(3-(3,5-dimethoxyphenyl)-7-(methylthio) 2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester (1.76 g, yield 58.6%).

Step 6: 2-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylthio)-2-oxo-3,4-dihydropyrimido[ Synthesis of 4,5-d]pyrimidine-1(2H)-yl)-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester

2-(3-(3,5-Dimethoxyphenyl)-7-(methylthio)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidine-1 (2H)-yl)-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester (1.76 g, 3.16 mmol, 1.0 eq) was dissolved in dichloromethane (15 mL). A solution of sulfonyl chloride (1.06 g, 7.9 mmol, 2.5 eq) in dichloromethane (10 mL) was evaporated. After the dropwise addition, the mixture was stirred at this temperature for 15 minutes, and the reaction solution was added dropwise to a saturated aqueous solution of sodium hydrogencarbonate (50 mL), and the organic layer was dried over anhydrous sodium sulfate and evaporated to give 2-(3-(2,6- Chloro-3,5-dimethoxyphenyl)-7-(methylthio)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl 7-Azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester (1.71 g crude product, yield: 89.4%).

Step 7: 2-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylsulfonyl)-2-oxo-3,4-dihydropyrimidine Synthesis of [4,5-d]pyrimidine-1(2H)-yl)-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester

2-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylthio)-2-oxo-3,4-dihydropyrimido[4, 5-d]pyrimidin-1(2H)-yl)-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester (1.71 g, 2.73 mmol, 1.0 eq) dissolved in dichloromethane (15 mL) The mixture was stirred to a temperature of 0 ° C for 30 minutes, and a suspension of m-chloroperoxybenzoic acid (1.17 g, 6.82 mmol, 2.5 eq) in dichloromethane (10 mL) was added portionwise, and the mixture was stirred at this temperature for 15 minutes. The system was added dropwise to a saturated aqueous solution of sodium hydrogencarbonate (50 mL), and then evaporated. -dimethoxyphenyl)-7-(methylsulfonyl)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)-7- Azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester (1.52 g, yield: 84.9%).

Step 8: 2-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-2-oxo-3,4-dihydropyrimido[ Synthesis of 4,5-d]pyrimidine-1(2H)-yl)-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester

2-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylsulfonyl)-2-oxo-3,4-dihydropyrimido[4 , 5-d]pyrimidin-1(2H)-yl)-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester (1.52 g, 2.31 mmol, 1.0 eq) was added to aqueous methylamine (30 mL) In the case, it was heated at 45 ° C for 3 hours. TLC showed that the reaction was completed, cooled to room temperature, extracted with dichloromethane (150 mL×3), dried over anhydrous sodium sulfate, filtered, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (200-300 mesh silica gel; Methane and methanol = 200:1 to 80:1) 2-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-2-oxo -3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester (574.1 mg, yield 41.3%).

Step 9: 3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-1-(7-azaspiro[3.5]decane-2-yl Synthesis of-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-one hydrochloride

2-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-2-oxo-3,4-dihydropyrimido[4, 5-d]pyrimidin-1(2H)-yl)-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester (574.1 mg, 0.94 mmol, 1.0 eq) was added to ethanol (4 mL). The temperature was lowered to 0 ° C, and a solution of hydrogen chloride in ethanol (15 mL) was added dropwise. After the addition was completed, the mixture was stirred at room temperature overnight. TLC showed the reaction was complete and the system was concentrated to give 3-(2,6-dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-1-(7-azaspiro[3.5] Cycloalkyl-2-yl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one hydrochloride (569.8 mg crude, yield 100%).

Step 10: 1-(7-Acyryl-7-azaspiro[3.5]decane-2-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-7 Synthesis of -(methylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-1-(7-azaspiro[3.5]indol-2-yl)-3 , 4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one hydrochloride (569.8mg crude, 0.94mmol) was added to tetrahydrofuran (15mL), cooled to 0 ° C, then added dropwise Amine (339.9 mg, 3.36 mmol) and acryloyl chloride (121.6 mg, 1.34 mmol) were added and stirred at room temperature for 2 hr. TLC showed that the reaction was completed. EtOAc (EtOAc) (EtOAc) Separation (200-300 mesh silica gel; dichloromethane and methanol = 200:1 to 80:1) gave 1-(7-acrylo-7-azaspiro[3.5]decane-2-yl)-3-( 2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (180.75 mg, 24.2 yield in 2 steps).

Molecular formula: C ₂₆ H ₃₀ Cl ₂ N ₆ O ₄ Molecular weight: 561.46 LC-MS (Pos, m/z) = 562.2 [M+H ⁺ ].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 7.98 (s, 1H), 6.97-7.01 (m, 1H), 6.73-6.83 (m, 1H), 6.03-6.07 (m, 2H), 5.62 -5.75 (s, 1H), 4.81-4.85 (m, 1H), 4.37 (s, 2H), 3.95 (s, 6H), 3.31-3.50 (m, 4H), 2.78-2.79 (s, 3H), 2.25 -2.35 (m, 4H), 1.51-1.58 (m, 4H).

Example 3: 8-(7-acryloyl-7-azaspiro[3.5]decane-2-yl)-6-(2-chloro-3,5-dimethoxyphenyl)-2-( Synthesis of methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound 3)

Step 1: 2-(6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidine-8 ( Synthesis of 7H)-yl)-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester

6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (726 mg, 2 mmol, 1.0 Eq), tert-butyl 2-hydroxy-7-azaspiro[3.5]decane-7-carboxylate (483 mg, 2 mmol, 1.0 eq) and triphenylphosphine (787 mg, 3 mmol, 1.5 eq) dissolved in tetrahydrofuran ( In 10 mL), diethyl azodicarboxylate (522 mg, 3 mmol, 1.5 eq) was slowly added, and reacted at 25 ° C for 4 h. The reaction was completely monitored by TLC. The reaction mixture was poured into water, extracted with EA, and the organic phase was combined and concentrated. The crude product was purified by silica gel column chromatography (PE: EA=2:1) to give 2-(6-(2-chloro-3). 5-dimethoxyphenyl)-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)-7-azaspiro[3.5]壬Alkyl-7-carboxylic acid tert-butyl ester (1.1 g, yield 93%).

Step 2: 2-(6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylsulfonyl)-7-oxopyrido[2,3-d]pyrimidine-8 Synthesis of (7H)-yl)-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester

2-(6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidine-8 (7H) -yl)-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester (587 mg, 1 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL) and m-chloroperoxybenzoic acid (246 mg, 1 mmol, 1.0 eq, mass fraction 70%), reacted at 25 ° C for 2 h, the reaction was completely monitored by TLC, and the reaction mixture was used in the next step without being treated.

Step 3: 2-(6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidine-8 ( Synthesis of 7H)-yl)-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester

The reaction solution obtained in the above step was directly added to a methylamine aqueous solution (10 mL), and reacted at 25 ° C for 4 h. The reaction was completed by LC-MS. The reaction mixture was separated, the organic phase was dried and concentrated. The crude product was purified by silica gel column chromatography (PE: EA=1:1) to give 2-(6-(2-chloro-3,5- Methoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidine-8(7H)-yl)-7-azaspiro[3.5]decane-7 - tert-butyl carboxylate (230 mg, yield 40%).

Step 4: 6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylamino)-8-(7-azaspiro[3.5]decane-2-yl)pyridine Synthesis of [2,3-d]pyrimidine-8(7H)-one

2-(6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidine-8 (7H) -Based - 7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester (230 mg, 0.40 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL), 25 °C reaction for 2h. The reaction was monitored by TLC, EtOAc (EtOAc: EtOAc (EtOAc) 8-(7-Azaspiro[3.5]decane-2-yl)pyrido[2,3-d]pyrimidine-8(7H)-one (100 mg, yield 53%).

Step 5: 8-(7-acryloyl-7-azaspiro[3.5]decane-2-yl)-6-(2-chloro-3,5-dimethoxyphenyl)-2-(A Synthesis of pyridyl[2,3-d]pyrimidin-7(8H)-one

6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylamino)-8-(7-azaspiro[3.5]decane-2-yl)pyridin[2] , 3-d]pyrimidin-8(7H)-one (100 mg, 0.213 mmol, 1.0 eq) was dissolved in dichloromethane (2 mL), triethylamine (65 mg, 0.639 mmol) and acryloyl chloride (19.2 mg, 0.213) Mm). The reaction was carried out at 25 ° C for 2 h, and the reaction was completed by TLC. The reaction mixture was poured into water, and extracted with dichloromethane. The organic phase was combined and concentrated. The crude product was purified by silica gel column chromatography (EA eluting) to give 8-(7-acryloyl-7- Azaspiro[3.5]decane-2-yl)-6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)pyrido[2,3-d]pyrimidine -7(8H)-one (60 mg, yield 54%).

Molecular formula: C ₂₇ H ₃₀ ClN ₅ O ₄ Molecular weight: 524.02 LC-MS (Pos, m/z) = 524.2 [M+H ⁺ ]

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.92 (s, 1H), 7.96 (s, 1H), 7.60 (s, 1H), 6.76 (s, 1H), 6.59-6.60 (m, 1H), 6.04-6.08(m,2H),5.62-5.65(d,1H),5.37(s,1H),3.89(s,3H),3.80(s,3H),3.50(s,2H), 3.40(s, 2H), 2.91-2.92 (m, 3H), 2.43 (m, 2H), 1.75-1.79 (m, 2H), 1.59 (s, 2H), 1.47 (s, 2H).

Example 4 8-(2-Aroyl-2-azaspiro[3.3]heptan-6-yl)-6-(2-chloro-3,5-dimethoxyphenyl)-2-(A Synthesis of pyridyl[2,3-d]pyrimidin-7-(8H)-one (Compound 4)

Step 1: 6-(6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidine-8 ( Synthesis of 7H)-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

The starting material 6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (300 mg, 0.825 mmol) , 1.2 eq) was dissolved in THF (7.5 mL), and tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (49 mg, 0.229 mmol, 1 eq) and triphenylphosphine ( 180 mg, 0.687 mmol, 3 eq), cooled to 0 ° C, EtOAc (EtOAc, EtOAc) The reaction was completed by TLC, and water (5 mL) was added to the reaction mixture, and the mixture was stirred for 10 min, extracted with DCM, and concentrated. The crude product was purified by silica gel column chromatography (PE: EA = 10:1 to 5:1) to give a white solid product ( 603mg crude).

Step 2: 6-(6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylsulfonyl)-7-oxopyrido[2,3-d]pyrimidine-8 Synthesis of (7H)-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

The intermediate 6-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidine-8 ( tert-Butyl 7H)-yl)-2-azaspiro[3.3]heptane-2-carboxylate (603 mg, crude, EtOAc, EtOAc, EtOAc) mCPBA (263 mg, 1.068 mg, 1.1 eq) was reacted at 0 ° C for 1 hour, and the reaction was completely monitored by TLC, and the reaction mixture was directly subjected to a step reaction without being treated.

Step 3: 6-(6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidine-8 (7H Synthesis of tert-butyl ester of 2-aminopyridyl[3.3]heptane-2-carboxylic acid:

The reaction solution obtained in the above step was added to a methylamine solution (20 mL), and the mixture was reacted at 50 ° C overnight, and then extracted with DCM (20 mL × 3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Chromatography (PE: EA = 5:1 to 1:1) gave product (yield: 187 mg).

Step 4: 6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylamino)-8-(2-azaspiro[3.3]heptan-6-yl)pyridine Synthesis of [2,3-d]pyrimidin-7(8H)-one trifluoroacetate:

The intermediate 6-(6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidine-8 (7H Tert-butyl 2-aminospiro[3.3]heptane-2-carboxylate (187 mg) was dissolved in DCM (3 mL), cooled to 0 ° C, TFA (3 mL) After 2 hours, the reaction was completely monitored by TLC, and concentrated under reduced pressure to give the product (yield: 109 mg).

Step 5: 8-(2-Acryloyl-2-azaspiro[3.3]heptane-6-yl)-6-(2-chloro-3,5-dimethoxyphenyl)-2-(A Synthesis of pyridyl[2,3-d]pyrimidin-7-(8H)-one:

The intermediate 6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylamino)-8-(2-azaspiro[3.3]heptan-6-yl)pyridine [2,3-d]pyrimidin-7(8H)-one trifluoroacetate (109 mg crude) was dissolved in THF (5 mL), triethylamine (124 mg, 1.23 mmol, 5 eq) , a solution of acryloyl chloride (26.6 mg, 0.296 mmol, 1.2 eq) in DCM (5 mL) was slowly added, and the reaction was stirred for 1 hr, and the reaction was completed by TLC, saturated sodium bicarbonate solution was added, stirred, DCM (20 mL×3), combined The organic phase was dried over anhydrous sodium sulfate (MgSO4).

Molecular formula: C ₂₅ H ₂₆ ClN ₅ O ₄ Molecular weight: 495.96 LC-MS (Pos, m/z) = 496.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.93 (s, 1H), 7.78 (s, 1H), 7.63 (s, 1H), 6.77 (s, 1H), 6.60 (s, 1H), 6.20-6.28(m,1H),6.05-6.10(d,1H),5.64-5.67(d,1H),5.33(s,1H),4.31(s,1H),4.16(s,1H),4.02( s, 1H), 3.81-3.90 (m, 7H), 2.92 (s, 3H), 2.72 (s, 3H), 2.16-2.21 (t, 1H).

Example 5: 7-(((3S,5S)-1-acryloyl-5-(hydroxymethyl)pyrrolidin-3-yl)amino)-3-(2,6-dichloro-3,5- Synthesis of dimethoxyphenyl)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (Compound 5)

Step 1: Synthesis of ethyl 4-(methylamino)-2-(methylthio)pyrimidine-5-carboxylate

Ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (22.0 g, 94.55 mmol, 1.0 eq) was dissolved in THF (100 mL). Aqueous methylamine solution (100 mL) was added dropwise slowly, the temperature did not exceed 30 ° C, and the reaction was completed at room temperature (25 ° C) overnight and monitored by TLC. The reaction was completely monitored by TLC. The reaction mixture was dried under reduced pressure. Water (50 mL) was added, and the mixture was stirred at room temperature (25 ° C) for 10 min. The reaction mixture was filtered with suction. The filter cake was washed with water (several washings) and the filter cake was dried to give a solid 4 Ethyl (methylamino)-2-(methylthio)pyrimidine-5-carboxylate (16.98 g crude).

Step 2: Synthesis of (4-(methylamino)-2-(methylthio)pyrimidin-5-yl)methanol

Lithium tetrahydroaluminum (4.01 g, 105.47 mmol, 1.5 eq) was dissolved in THF (500 mL), cooled to -10 ° C to -5 ° C in an ice salt bath, and 4-(methylamino)-2- was slowly added dropwise. A solution of ethyl methylthio)pyrimidine-5-carboxylate (15.98 mg of crude product, 70.31 mmol, 1.0 eq) in THF (120 mL), and the temperature is controlled from -10 ° C to -5 ° C during the dropwise addition. The reaction was stirred at room temperature (25 ° C), rt (25 ° C) overnight (12h) The reaction was completely monitored by TLC. EtOAc (4 mL), 10% aqueous sodium hydroxide (4mL) and water (12mL) were successively quenched with lithium hydride, filtered, filtered, washed with THF, and the filtrate was combined and dried over anhydrous magnesium sulfate , concentrated, crude product was separated by silica gel column chromatography (eluent PE: EA = 5:1, 2:1) to give (4-(methylamino)-2-(methylthio)pyrimidin-5-yl)methanol (11.24 g, yield: 86.33%).

Step 3: Synthesis of 4-(methylamino)-2-(methylthio)pyrimidine-5-carboxaldehyde

(4-(Methylamino)-2-(methylthio)pyrimidin-5-yl)methanol (11.24 g, 60.67 mmol, 1.0 eq) was dissolved in DCM (582 mL). 485.36 mmol, 8.0 eq), stirred at rt overnight (25 ° C The reaction was completely monitored by TLC, and the reaction mixture was filtered with Celite, and filtrate was concentrated to give 4-(methylamino)-2-(methylthio)pyrimidine-5-carbaldehyde (10.68 g, yield: 96.04%).

Step 4: Synthesis of 5-((3,5-dimethoxyphenyl)amino)methyl)-N-methyl-2-(methylthio)pyrimidine-4-amine

4-(Methylamino)-2-(methylthio)pyrimidine-5-carboxaldehyde (5.18 g, 28.27 mmol, 1.0 eq) was dissolved in DCM (173 mL). 5.20 g, 33.92 mmol, 1.2 eq), EtOAc (EtOAc) (EtOAc) The reaction was completed by TLC. The mixture was stirred and evaporated to dryness. EtOAc EtOAc EtOAc EtOAc. Column chromatography (eluent PE: EA = 10:1 to 4:1) gave 5-((3,5-dimethoxyphenyl)amino)methyl)-N-methyl-2 -(Methylthio)pyrimidine-4-amine (5.44 g, yield: 60.0%).

Step 5: 3-(3,5-Dimethoxyphenyl)-1-methyl-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidine-2 ( 1H)-ketone synthesis

5-(((3,5-Dimethoxyphenyl)amino)methyl)-N-methyl-2-(methylthio)pyrimidin-4-amine (3.84 g, 12.0 mmol, 1.0 eq) Dissolved in THF (40.0 mL), cooled to 0 ° C in an ice-water bath, then added to TEA (3.64 g, 18.0 mmol, 1.5 eq) and stirred for 5 min, slowly added to phosgene (5.64 g, 36.0 mmol) at 0 ° C under nitrogen. , 3.0 eq) of THF (20.0 mL) was added, and the mixture was slowly warmed to room temperature (25 ° C) and stirred for 2 h, then warmed to 70 ° C and refluxed overnight (12 h). The reaction was completely monitored by TLC. The mixture was washed with saturated aqueous ammonium chloride (20 mL), and a solid product was precipitated, filtered, and the filter cake was washed with ice water (10mL×3), and the filter cake was dried to give 3-(3,5) -dimethoxyphenyl)-1-methyl-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (2.80 g, Rate: 67.5%).

Step 6: 3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-methyl-7-(methylthio)-3,4-dihydropyrimido[4,5 Synthesis of -d]pyrimidine-2(1H)-one

3-(3,5-Dimethoxyphenyl)-1-methyl-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidine-2 (1H) The ketone (2.16 g, 6.24 mmol, 1.0 eq) was dissolved in EtOAc EtOAc (EtOAc) After the addition was completed, the mixture was stirred at 0 ° C for 15 min, and the reaction was monitored by TLC. The organic layer was combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude was purified by silica gel column chromatography (eluent MeOH: DCM = 0 to 1:30) To give 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methyl-7-(methylthio)-3,4-dihydropyrimido[4,5- d] Pyrimidine-2(1H)-one (620.00 mg, yield: 18.5%).

Step 7: 3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-methyl-7-(methylsulfonyl)-3,4-dihydropyrimido[4, Synthesis of 5-d]pyrimidine-2(1H)-one

3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-methyl-7-(methylthio)-3,4-dihydropyrimido[4,5-d Pyrimidine-2(1H)-one (620.00 mg, 1.49 mmol, 1.0 eq) was dissolved in DCM (18 mL), cooled in ice ice bath to 0 ° C, and slowly added chloro-perbenzoic acid (70%) (737.70 mg) , 2.98 mmol, 2.0 eq), after completion, slowly warmed to room temperature (25 ° C) and stirred overnight (12 h). The reaction was completely monitored by TLC. A saturated aqueous solution of sodium thiosulfate (5 mL) was added, and saturated aqueous sodium hydrogen carbonate solution was added to adjust pH=7-8, and the aqueous phase was extracted with DCM (10 mL×3). The sodium was dried, filtered, and the filtrate was concentrated. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjj 1-methyl-7-(methylsulfonyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (280.00 mg, yield: 42.0%) .

Step 8: (2S,4S)-4-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-methyl-7-oxo-5,6,7 Synthesis of 8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-methyl-7-(methylsulfonyl)-3,4-dihydropyrimido[4,5- d]pyrimidine-2(1H)-one (280.00 mg, 0.63 mmol, 1.0 eq) was dissolved in N-methyl-2-pyrrolidone (10 mL) and (2S,4S)-4-amino-2-(hydroxy) tert-Butyl methylpyrrolidine-l-carboxylate (545.00 mg, 2.52 mmol, 4.0 eq), EtOAc (318.40 mg, 3. The reaction was completed by TLC. EtOAc (EtOAc) (EtOAc (EtOAc) (eluent MeOH: DCM = 0 to 1:50) to give (2S,4S)-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-8- Methyl-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid Tert-butyl ester (83.70 mg, yield: 22.8%).

Step 9: 3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(((3S,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)amino Synthesis of 1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one hydrochloride

(2S,4S)-4-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-methyl-7-oxo-5,6,7,8 - tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (83.00 mg, 0.142 mmol, 1.0 eq) was dissolved. A solution of hydrogen chloride/ethanol (5 mL) was added to ethanol (2.0 mL) and stirred at room temperature (25 ° C) overnight (12 h). The reaction was completely monitored by TLC and concentrated under reduced pressure to give 3-(2,6-dichloro-3,5-dimethoxyphenyl)-7-(((3S,5S)-5-(hydroxymethyl)pyrrole. Alkyl-3-yl)amino)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one hydrochloride (84.88 mg, crude).

Step 10: 7-(((3S,5S)-1-acryloyl-5-(hydroxymethyl)pyrrolidin-3-yl)amino)-3-(2,6-dichloro-3,5-di Synthesis of methoxyphenyl)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(((3S,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)amino)- 1-Methyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one hydrochloride (84.88 mg crude, 0.142 mmol) was dissolved in THF (18 mL). 49.48mg, 0.489mmol), stirred at room temperature (25 ° C) for 15min, cooled to 0 ° C in ice salt bath, slowly added acryloyl chloride (14.75mg, 0.163mmol) in THF (1mL), add, slowly rise to room temperature (25 °C) Stir for 30 min. The reaction was completed by TLC. EtOAc (EtOAc)EtOAc. MeOH: DCM = 0 to 3: 100) gave 7-(((3S,5S)-1-acryloyl-5-(hydroxymethyl)pyrrolidin-3-yl)amino)-3-(2,6- Dichloro-3,5-dimethoxyphenyl)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (34.00 mg, two-step production The rate is 44.6%).

Molecular formula: C ₂₃ H ₂₆ Cl ₂ N ₆ O ₅ , molecular weight: 537.40, LC-MS (Pos, m/z) = 538.9 [M+H ⁺ ].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.01 (s, 1H), 7.40-7.52 (d, 1H), 6.99 (s, 1H), 6.55-6.69 (m, 1H), 6.10-6. (m, 1H), 5.64-5.67 (m, 1H), 5.00-5.07 (m, 1H), 4.46 (s, 2H), 4.35-4.36 (m, 2H), 4.28-4.29 (m, 3H), 3.83 -3.87 (m, 6H), 3.57-3.69 (m, 3H), 3.25-3.26 (m, 3H).

Example 6: 2-(((3S,5S)-1-acryloyl-5-(hydroxymethyl)pyrrolidin-3-yl)amino)-6-(2-chloro-3,5-dimethoxy Synthesis of phenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (Compound 6)

Step 1: 6-(2-Chloro-3,5-dimethoxyphenyl)-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)- Ketone synthesis

6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (600 mg, 1.65 mmol, The mixture was stirred at rt. EtOAc (EtOAc (EtOAc)EtOAc. The reaction was completed by LC-MS. The reaction mixture was poured into water, extracted with dichloromethane, and the organic phase was combined, dried, concentrated, and the crude was added to dichloromethane to give 6-(2-chloro-3,5-dimethoxyphenyl) 8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (400 mg, yield 60%).

Step 2: 6-(2-Chloro-3,5-dimethoxyphenyl)-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7 (8H) -ketone synthesis

6-(2-Chloro-3,5-dimethoxyphenyl)-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one ( 400 mg, 1.06 mmol, 1.0 eq) was dissolved in DMF (6 mL), m.m. (m.

Step 3: (2S,4S)-4-((6-(2-Chloro-3,5-dimethoxyphenyl)-8-methyl-7-oxo-7,8-dihydropyridine Synthesis of [2,3-d]pyrimidin-2-yl)amino)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

The reaction solution of the above step was added to (2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (230 mg, 1.06 mmol, 1.0 eq) previously dissolved in DMF (5 mL). Triethylamine (537 mg, 5.30 mmol, 3.0 eq) was added and reacted at 50 ° C for 4 h. The reaction was completely monitored by TLC. The reaction mixture was poured into water, extracted with EA, and the organic phases were combined, washed once with water and brine, and dried. Concentrated and crude by silica gel column chromatography (PE: EA=1:1) (2S, 4S)-4-((6-(2-chloro-3,5-dimethoxyphenyl)-8-methyl -7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (140 mg, Yield 25%).

Step 4: 6-(2-Chloro-3,5-dimethoxyphenyl)-2-(((3S,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)amino)-8 Synthesis of -methylpyrido[2,3-d]pyrimidin-7(8H)-one

(2S,4S)-4-((6-(2-Chloro-3,5-dimethoxyphenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2] , 3-d]pyrimidin-2-yl)amino)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (140 mg, 0.26 mmol, 1.0 eq) was dissolved in dichloromethane (2 mL). Trifluoroacetic acid (0.5 mL) was added and the mixture was reacted at room temperature for two hours. After the completion of the reaction by LC-MS, the reaction mixture was concentrated. EtOAcjjjjjjjjjjj ((3S,5S)-5-(Hydroxymethyl)pyrrolidin-3-yl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (80 mg, yield 70%).

Step 5: 2-(((3S,5S)-1-acryloyl-5-(hydroxymethyl)pyrrolidin-3-yl)amino)-6-(2-chloro-3,5-dimethoxy Synthesis of Phenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

6-(2-Chloro-3,5-dimethoxyphenyl)-2-(((3S,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)amino)-8-A Pyridyl[2,3-d]pyrimidin-7(8H)-one (80 mg, 0.18 mmol, 1.0 eq) was dissolved in a mixture of DMF (1 mL) and THF (2 mL) and triethylamine (55 mg, 0.54) Methyl, 3.0 eq) and acryloyl chloride (16 mg, 0.18 mmol, 1.0 eq) were reacted at room temperature for 2 h. The reaction was completed by TLC, and the reaction mixture was poured into water, extracted with EA, and the organic phase was combined, washed with water and brine, dried and concentrated, and the crude product was obtained by silica gel column chromatography (EA) to give 2-(((3S,5S) )-1-acryloyl-5-(hydroxymethyl)pyrrolidin-3-yl)amino)-6-(2-chloro-3,5-dimethoxyphenyl)-8-methylpyridino[ 2,3-d]pyrimidine-7(8H)-one (34 mg, yield 38%).

Molecular formula: C ₂₄ H ₂₆ ClN ₅ O ₅ Molecular weight: 499.95 LC-MS (Pos, m/z) = 500.1 [M+H ⁺ ].

^{_{1 HNMR (400MHz, CDCl 3)}} δ (ppm): 8.47 (s, 1H), 7.53 (s, 1H), 6.85 (s, 1H), 6.57 (s, 1H), 6.50-6.51 (d, 1H), 6.43-6.45 (m, 2H), 5.74-5.77 (m, 1H), 4.72-4.77 (m, 1H), 4.42 (s, 1H), 4.13-4.17 (m, 2H), 4.10 (s, 3H), 3.92 (s, 3H), 3.73-3.82 (m, 3H), 3.58 (s, 1H), 2.59-2.64 (m, 1H), 1.90 (s, 1H).

Example 7: 2-(((3S,5S)-1-acryloyl-5-(hydroxymethyl)pyrrolidin-3-yl)amino)-6-(2-chloro-3,5-dimethoxy Synthesis of phenyl)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound 7)

Step 1: Synthesis of 6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one

The starting material 6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (300 mg, 0.825 mmol) , 1.0 eq) was added to THF and dissolved by heating. The temperature was lowered to 0 ° C, and THF dissolved mCPBA (318.8 mg, 0.907 mmol, 1.1 eq) was added dropwise. After stirring for 2 h, the reaction was completed by TLC. EtOAc (EtOAc m.) Phenyl)-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (390 mg).

Step 2: (2S,4S)-4-((6-(2-Chloro-3,5-dimethoxyphenyl)-7-oxo-7,8-dihydropyrido[2,3- Synthesis of d]pyrimidin-2-yl)amino)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (270 mg, 0.682 mmol) , 1.0 eq), (2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (295 mg, 1.364 mmol, 2.0 eq) and DIPEA (176.3 mg, 1.364 mmol, 2.0 eq) was dissolved in NMP (5 mL) and reacted at 90 ° C for 5 h. The reaction was completed by TLC. The reaction mixture was poured into water (30 mL), DCM (30 mL) was added, and the mixture was stirred. The aqueous phase was extracted with DCM (20 mL). The organic phase was combined and washed with saturated sodium chloride solution (20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated, and the crude was purified by silica gel column chromatography (PE: EA=10:1 to 5:1) (2S,4S)-4-((6-(2-chloro-3,5) -dimethoxyphenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-2-(hydroxymethyl)pyrrolidine-1- Tert-butyl carboxylate (76 mg, yield: 21%).

Step 3: 6-(2-Chloro-3,5-dimethoxyphenyl)-2-(((3S,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)amino)pyridine Synthesis of [2,3-d]pyrimidine-7(8H)-one hydrochloride

(2S,4S)-4-((6-(2-Chloro-3,5-dimethoxyphenyl)-7-oxo-7,8-dihydropyrido[2,3-d] Pyrimidin-2-yl)amino)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (76 mg, 0.143 mmol, 1.0 eq) was dissolved in ethanol (5 mL), cooled to 0 ° C, dropwise Hydrogen chloride in ethanol (5 mL), after 6 h of reaction, the reaction was completed by TLC, concentrated, and the crude material was dissolved in THF, and concentrated three times.

Step 4: 2-(((3S,5S)-1-acryloyl-5-(hydroxymethyl)pyrrolidin-3-yl)amino)-6-(2-chloro-3,5-dimethoxy Synthesis of Phenyl)pyrido[2,3-d]pyrimidin-7(8H)-one

6-(2-Chloro-3,5-dimethoxyphenyl)-2-(((3S,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)amino)pyridin[2] , 3-d]pyrimidin-7(8H)-one hydrochloride (crude, 0.143 mmol, 1.0 eq) was dissolved in THF (10 mL), and then triethylamine (72.35 mg, 0.715 mmol, 5.0 eq). At ° C, acryloyl chloride (12.94 mg, 0.143 mmol, 1.0 eq) was slowly added. After 1 h of reaction, TLC monitored a little residue of the starting material, and added acryloyl chloride (12.94 mg, 0.143 mmol, 1.0 eq). After 2 h of reaction, TLC showed a small amount of starting material. Add saturated sodium bicarbonate solution (10 mL) and DCM (10 mL), EtOAc (EtOAc)EtOAc. 2-(((3S,5S)-1-acryloyl-5-(hydroxymethyl)pyrrolidin-3-yl)amino)-6-(2-chloro-3,5-dimethoxyphenyl) Pyrido[2,3-d]pyrimidin-7(8H)-one (32 mg, yield: 46%).

Molecular formula: C ₂₃ H ₂₄ ClN ₅ O ₅ Molecular weight: 485.93 LC-MS (Pos, m/z) = 486.2 [M+H ⁺ ].

^{1 HNMR (400MHz, DMSO-d} 6) δ (ppm): 12.12 (m, 1H), 8.61 (s, 1H), 7.91-8.13 (m, 1H), 7.70-7.74 (s, 1H), 6.58-6.68 (m, 1H), 6.53-6.54 (m, 1H), 6.23-6.24 (m, 1H), 6.05-6.10 (s, 1H), 5.05-5.12 (m, 1H), 4.10 (m, 1H), 4.09 (m, 1H), 4.02 (m, 2H), 3.87 (m, 3H), 3.79 (m, 3H), 3.18 (m, 1H), 3.16 (m, 1H), 2.32 (m, 1H), 2.05 ( s, 2H).

Example 8: 1-(2-acryloyl-2-azaspiro[3.3]heptan-6-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)- Synthesis of 7-(methylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (Compound 9)

Step 1: 6-((5-(ethoxycarbonyl)-2-(methylthio)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester Synthesis

The starting material, 6-amino-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (5.0 g, 23.55 mmol, 1.0 eq) was dissolved in tetrahydrofuran (100 mL). Ethyl 2-(methylthio)pyrimidine-5-carboxylate (8.2 g, 35.32 mmol, 1.5 eq) and triethylamine (7.1 g, 70.65 mmol, 3.0 eq). The reaction was completely monitored by TLC. EtOAc (EtOAc) (EtOAc)EtOAc. Purification (silica gel size: 200-300 mesh, methylene chloride:methanol = 200:1 to 90:1) afforded product (8.15 g, yield: 84.8%).

Step 2: Synthesis of 6-((5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

Lithium tetrahydrogen aluminum (2.26 g, 59.7 mmol, 3.0 eq) was added to tetrahydrofuran (50 mL), stirred, cooled to 0 ° C, and 6-((5-(ethoxycarbonyl))-2-(methylsulfonate) was slowly added dropwise with stirring. a solution of tert-butyl pyridyl-4-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate (8.15 g, 19.9 mmol, 1.0 eq) in tetrahydrofuran (30 mL). The reaction was carried out at ° C for 6 hours. TLC showed the reaction was complete. After stirring at 0 ° C, water (2.26 g) was added for 20 min, then 15% aqueous sodium hydroxide solution (2.26 g) was added dropwise, stirred for 20 minutes, water (6.78 g) was added dropwise, stirred for 2 hours, suction filtration The filtrate was dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (silica gel: 200-300 mesh, petroleum ether: ethyl acetate = 10:1 to 3:1) , yield: 30.5%).

Step 3: Synthesis of 6-((5-formyl-2-(methylthio)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

6-((5-(Hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (3.03 g, 8.26 mmol, 1.0 eq) was dissolved in tetrahydrofuran (60 mL). EtOAc (EtOAc·········· TLC showed that the reaction was completed, filtered through celite, dried over anhydrous sodium sulfate, filtered, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography ( silica gel: 200-300 mesh, petroleum ether: ethyl acetate = 20:1 5:1) The product was isolated (2.70 g, yield: 90.0%).

Step 4: 6-((5-((3,5-Dimethoxyphenyl)amino)methyl)-2-(methylthio)pyrimidin-4-yl)amino)-2-azaspiro [3.3] Synthesis of tert-butyl heptane-2-carboxylate

6-((5-Formyl-2-(methylthio)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (2.6 g, 7.13 mmol, 1.0 eq) dissolved in dichloromethane (50 mL), stirred and dissolved, added 3,5-dimethoxyaniline (1.63 g, 10.69 mmol, 1.5 eq) and acetic acid (0.6 mL). Sodium triacetoxyborohydride (7.55 g, 35.65 mmol, 5.0 eq) was added portionwise under ice-water bath, and then stirred at room temperature overnight. TLC showed the reaction was completed. EtOAc EtOAc (EtOAc) The product was obtained from petroleum ether: ethyl acetate = 10:1 (2.68 g, yield: 72.4%).

Step 5: 6-(3-(3,5-Dimethoxyphenyl)-7-(methylthio)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidine Synthesis of tert-butyl ester of -1(2H)-yl)-2-azaspiro[3.3]heptane-2-carboxylate

6-((5-((3,5-Dimethoxyphenyl)amino)methyl)-2-(methylthio)pyrimidin-4-yl)amino)-2-azaspiro[3.3 tert-Butyl-butane-2-carboxylate (2.68 g, 5.34 mmol, 1.0 eq) was dissolved in THF (3 mL), EtOAc (EtOAc) After the dropwise addition, the mixture was stirred for 10 minutes, and a solution of triphosgene (2.06 g, 6.94 mmol, 1.3 eq) in tetrahydrofuran (10 mL) was added dropwise, and the mixture was slowly stirred to room temperature and stirred for 1 hour, and heated to 70 ° C for 3.5 hours. LC-MS showed no starting material, cooled to room temperature, EtOAc (EtOAc) (EtOAc) Chromatography (silica gel: 200-300 mesh, petroleum ether: ethyl acetate = 10:1 to 5:1) gave product (1.69 g, yield: 60.3%).

Step 6: 6-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylthio)-2-oxo-3,4-dihydropyrimido[ Synthesis of 4,5-d]pyrimidine-1(2H)-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

6-(3-(3,5-Dimethoxyphenyl)-7-(methylthio)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidine-1 tert-Butyl (2H)-yl)-2-azaspiro[3.3]heptane-2-carboxylate (1.69 g, 3.2 mmol, 1.0 eq) was dissolved in dichloromethane (12 mL). After 30 minutes, a solution of sulfonyl chloride (1.08 g, 8.0 mmol, 2.5 eq) in dichloromethane (5 mL) was added dropwise, and the mixture was stirred at this temperature for 15 minutes, and the TLC reaction was completed. The system was added dropwise to a saturated aqueous solution of sodium hydrogencarbonate (50 mL), and the mixture was evaporated. Methanol = 200:1) The product was obtained (702.3 mg, yield: 36.9%).

Step 7: 6-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylsulfonyl)-2-oxo-3,4-dihydropyrimidine Synthesis of [4,5-d]pyrimidine-1(2H)-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

6-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylthio)-2-oxo-3,4-dihydropyrimido[4, 5-d]pyrimidin-1(2H)yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (448.1 mg, 0.75 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL) The temperature was lowered to 0 ° C, stirred for 30 minutes, and m-chloroperoxybenzoic acid (323.9 mg, 1.87 mmol, 2.5 eq) was added portionwise, and the mixture was stirred for 3 hours, and the reaction was completely monitored by TLC. The reaction mixture was poured into a saturated aqueous solution of sodium thiosulfate (20 mL), and the organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give product (yield: 589.6mg, yield: 100.0%).

Step 8: 6-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-2-oxo-3,4-dihydropyrimido[ Synthesis of 4,5-d]pyrimidine-1(2H)-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

6-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylsulfonyl)-2-oxo-3,4-dihydropyrimido[4 , 5-d]pyrimidin-1(2H)-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (335.7 mg crude, 0.42 mmol, 1.0 eq) was added to aqueous methylamine ( In 15 mL), the mixture was heated and stirred at 45 ° C for 4 hours, and TLC showed the reaction was completed. The mixture was cooled to room temperature, extracted with methylene chloride (150 mL×3), dried over anhydrous sodium sulfate, filtered, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (silica gel: 200-300 mesh, dichloromethane: methanol =200:1 to 100:1) The product was obtained (105.5 mg, yield: 43.3%).

Step 9: 3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-1-(2-azaspiro[3.3]heptane-6-yl Synthesis of-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-one hydrochloride

6-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-2-oxo-3,4-dihydropyrimido[4, 5-d]pyrimidin-1(2H)-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (105.5 mg, 0.182 mmol, 1.0 eq) was added to ethanol (3 mL). The mixture was cooled to 0 ° C, and a solution of hydrogen chloride in ethanol (3 mL) was added dropwise, and the mixture was stirred at room temperature and stirred for 2 hours. TLC showed that the reaction was completed, and the reaction mixture was concentrated to give product (128.6 mg, crude product, yield: 100.0%).

Step 10: 1-(2-Aroyl-2-azaspiro[3.3]heptan-6-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-7 Synthesis of -(methylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-1-(2-azaspiro[3.3]heptane-6-yl)- 3,4-Dihydropyrimido[4,5-d]pyrimidin-2(1H)-one hydrochloride (128.6 mg crude, 0.18 mmol, 1.0 eq) was added to tetrahydrofuran (4 mL), cooled to 0 ° C, Triethylamine (81.3 mg, 0.804 mmol, 4.4 eq) and acryloyl chloride (29.1 mg, 0.321 mmol, 1.7 eq) were added dropwise, and the mixture was stirred at room temperature for 2 hr. A saturated aqueous solution of ammonium chloride (10 mL) was added to the mixture, which was extracted with dichloromethane (30mL×3), dried over anhydrous sodium sulfate, filtered and filtered. 30:1) The product was obtained (11.1 mg, yield: 11.5%).

Molecular formula: C ₂₄ H ₂₆ Cl ₂ N ₆ O ₄ Molecular weight: 533.41 LC-MS (m/z) = 533.0 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 7.98 (s, 1H), 6.97 (s, 1H), 6.24-6.28 (m, 1H), 6.08-6.09 (m, 1H), 5.63 (m) , 1H), 5.31 (m, 1H), 4.37 (s, 2H), 4.29 (s, 1H), 4.16 (s, 1H), 3.95 (s, 6H), 3.86 (s, 1H), 2.79-2.80 ( m, 3H), 2.66-2.68 (m, 2H), 1.98-2.03 (m, 2H), 1.10 (s, 1H), 0.83-0.86 (m, 1H).

Example 9: 1-(1'-acrylo[1,3'-biazetidine]-3-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl) Synthesis of -7-(methylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (Compound 10)

Step 1: 3-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylsulfonyl)-2-oxo-3,4-dihydropyrimidine Synthesis of [4,5-d]pyrimidine-1(2H)-yl)azetidin-1-carboxylic acid tert-butyl ester

3-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylthio)-2-oxo-3,4-dihydropyrimido[4, 4-d]pyrimidin-1(2H)-yl)azetidin-1-carboxylic acid tert-butyl ester (700.0 mg, 1.3 mmol, 1.0 eq) was dissolved in DCM (20 mL). Chloroperoxybenzoic acid (434.2 mg, 2.5 mmol, 2.0 eq) was stirred at 0 ° C for 2 h, and the reaction was completed by LC-MS.

Step 2: 3-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-2-oxo-3,4-dihydropyrimido[ Synthesis of 4,5-d]pyrimidine-1(2H)-yl)azetidin-1-carboxylic acid tert-butyl ester

The reaction liquid of the previous step was added to a sealed tube, and the aqueous solution of methylamine (10 mL) was added, and the reaction was carried out at 45 ° C for 2 h. The reaction was completed by LC-MS. Drying over anhydrous sodium sulfate, filtration, EtOAc (EtOAc:EtOAc:EtOAc Oxyphenyl)-7-(methylamino)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)azetidin-1 - tert-butyl carboxylate (470 mg, two-step yield: 69%).

Step 3: 1-(Azetidin-3-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-3,4 Synthesis of dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

3-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-2-oxo-3,4-dihydropyrimido[4, 5-d]pyrimidin-1(2H)-yl)azetidin-1-carboxylic acid tert-butyl ester (470.0 mg, 0.9 mmol, 1.0 eq) was dissolved in EtOH (10 mL). The reaction was stirred at room temperature for 3 h. EtOAc (EtOAc) (EtOAc m. Cyclobutane-3-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-3,4-dihydropyrimido[4, 5-d]pyrimidine-2(1H)-one (340 mg, yield: 89%).

Step 4: 3-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-2-oxo-3,4-dihydropyrimido[ Synthesis of 4,5-d]pyrimidine-1(2H)-yl)-[-1,3'-biazetidine]-1'-carboxylic acid tert-butyl ester

1-(Azetidin-3-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-3,4-di Hydropyrimido[4,5-d]pyrimidin-2(1H)-one (340.0 mg, 0.8 mmol, 1.0 eq) was dissolved in DCM (125 mL). Butane-1-carboxylic acid tert-butyl ester (198.7 mg, 1.2 mmol, 1.5 eq), stirred for 2 h, added sodium triacetoxyborohydride (492.1 mg, 2.3 mmol, 3.0 eq), stirred for 8 h, TLC monitoring The reaction was completed, the pH of the solution was adjusted to 7-8 with a saturated aqueous solution of sodium bicarbonate, and the mixture was separated, and then extracted with DCM (2×50mL). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated. : MeOH = 100:1 to 20:1) to give 3-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-2-oxo -3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)-[-1,3'-biazetidine]-1'-carboxylic acid tert-butyl ester (240 mg, Yield: 52%).

Step 5: 1-([1,3'-biazetidine]-3-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-7-(methyl Synthesis of amino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one hydrochloride

3-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-2-oxo-3,4-dihydropyrimido[4, 5-d]pyrimidin-1(2H)-yl)-[-1,3'-biazetidine]-1'-carboxylic acid tert-butyl ester (240.0 mg, 0.4 mmol, 1.0 eq) was dissolved in EtOH (15 mL) To the solution, a solution of hydrogen chloride in ethanol (10 mL) was added, and the reaction was stirred at room temperature for 3 h, and the reaction was completed by LC-MS and concentrated to give 1-([1,3'-biazetidine]-3-yl)-3-(2) ,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one salt Acid salt (320 mg, yield: 100%).

Step 6: 1-(1'-acrylo[-1,3'-biazetidine]-3-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl) Synthesis of -7-(methylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

1-([1,3'-biazetidine]-3-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-7-(methylamino) -3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one hydrochloride (320.0 mg, 0.6 mmol, 1.0 eq), dissolved in THF (15 mL), triethylamine (244.1 mg, 2.4 mmol, 4.0 eq), stirring for 10 min, THF (1 mL) dissolved acryloyl chloride (81.8 mg, 0.9 mmol, 1.5 eq) was slowly added dropwise, and the mixture was stirred at room temperature for 2 h, and the reaction was completely monitored by TLC. Sodium hydride solution (20 mL), EtOAc (EtOAc (EtOAc) (EtOAcjjjjjj -acrylo[-1,3'-biazetidine]-3-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-7-(methylamino) -3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-one (100 mg, yield: 30%).

Molecular formula: C ₂₄ H ₂₇ Cl ₂ N ₇ O ₄ Molecular weight: 548.43 LC-MS (m/z) = 548.1 [M+H ⁺ ].

¹ H NMR (400 MHz, DMSO) δ (ppm): 8.00 (s, 1H), 7.05 (m, 1H), 6.97 (m, 1H), 6.25-6.29 (m, 1H), 6.05-6.09 (m, 1H) , 5.63-5.67 (m, 1H), 4.39 (m, 3H), 4.16-4.18 (m, 1H), 3.86-3.95 (m, 10H), 3.62-3.64 (m, 2H), 3.01 (m, 2H) , 2.77-2.78(s, 3H).

Example 10: 2-((2-oxaspiro[3.3]heptan-6-yl)amino)-8-(3-(4-acryloylpiperazin-1-yl)propyl)-6-( Synthesis of 2-chloro-3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound 12)

Step 1: Synthesis of 6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one

6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (580 mg, 1.754 mmol, The mixture was dissolved in tetrahydrofuran (15 mL), cooled to 0 ° C, and a solution of 70% of mCPBA (616.3 mg, 1.754 mmol, 1.1 eq) in tetrahydrofuran (2 mL) was added dropwise, and the mixture was stirred at 0 ° C - 5 ° C for 3 h. The reaction was completed by TLC. A saturated sodium carbonate solution (10 mL), saturated brine (10 mL), sodium thiosulfate solution (10 mL), and stirred for 10 min, and extracted with dichloromethane (50 mL×3), and combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and then evaporated. 3-d]pyrimidin-7(8H)-one (605.7 mg, yield: 100%).

Step 2: 2-((2-oxaspiro[3.3]heptan-6-yl)amino)-6-(2-chloro-3,5-dimethoxyphenyl)pyrido[2,3- Synthesis of d]pyrimidin-7(8H)-one

6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one (605.7 mg, 1.594 mmol, 1.0 eq), 2-oxaspiro[3.3]heptane-6-amine hydrochloride (475.5 mg, 3.188 mmol, 2.0 eq) and triethylamine (806 mg, 7.770 mmol, 5.0 eq) dissolved in 1 In 4-dioxane (10 mL), the reaction was heated to 95 ° C for 2 h. TLC monitored no raw materials, concentrated under reduced pressure, crude product was added with water (10 mL×1) for 10 min, filter cake was beaten with ethyl acetate (50 mL×2), filtered, and the filter cake was dried at 60 ° C to obtain 2-((2-oxaspiro) [3.3]heptane-6-yl)amino)-6-(2-chloro-3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7(8H)-one (220 mg , yield: 32%).

Step 3: 4-(3-(2-((2-oxaspiro[3.3]heptan-6-yl)amino)-6-(2-chloro-3,5-dimethoxyphenyl)- Synthesis of tert-butyl 7-oxopyrido[2,3-d]pyrimidine-8(7H)-yl)propyl)piperazine-1-carboxylate

2-((2-oxaspiro[3.3]heptan-6-yl)amino)-6-(2-chloro-3,5-dimethoxyphenyl)pyrido[2,3-d] Pyrimidine-7(8H)-one (220 mg, 0.5129 mmol, 1.0 eq) was dissolved in DMF (5 mL) and 4-(3-((methylsulfonyl)oxy)propyl)piperazine-1-carboxylic acid was added. tert-Butyl ester (248 mg, 0.769 mmol, 1.5 eq) and potassium carbonate (212.3 mg, 1.539 mmol, 3.0 eq). After the addition, the temperature was raised at 90 ° C and stirred for 0.5 h. TLC was monitored without the starting material, and the mixture was cooled to 30 ° C. The reaction mixture was poured into ice water and extracted with dichloromethane (50 mL×2). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, Column chromatography purification (EA: PE = 1:2, MeOH: DCM = 1: 30) gave 4-(3-(2-(2-oxaspiro[3.3]heptane-6-yl)amino)- 6-(2-Chloro-3,5-dimethoxyphenyl)-7-oxopyrido[2,3-d]pyrimidine-8(7H)-yl)propyl)piperazine-1-carboxylate Tert-butyl acid ester (288 mg, yield: 78.6%).

Step 4: 2-((2-oxaspiro[3.3]heptan-6-yl)amino)-6-(2-chloro-3,5-dimethoxyphenyl)-8-(3-( Synthesis of piperazin-1-yl)propyl)pyrido[2,3-d]pyrimidin-7(8H)one

4-(3-(2-(2-oxaspiro[3.3]heptan-6-yl)amino)-6-(2-chloro-3,5-dimethoxyphenyl)-7- Oxypyrido[2,3-d]pyrimidin-8(7H)-yl)propyl)piperazine-1-carboxylic acid tert-butyl ester (288 mg, 0.440 mmol, 1.0 eq) dissolved in dichloromethane (5 mL) The mixture was cooled to 0 ° C, trifluoroacetic acid (1.5 mL) was added dropwise, and the mixture was added dropwise, and the mixture was reacted at 0 ° C for 3 h. The solvent was concentrated under reduced pressure. The crude material was dissolved in tetrahydrofuran (50 mL), and concentrated three times to give an oily liquid. It was extracted with ethyl acetate (20 mL×2), the aqueous phase was adjusted to pH=8-9 with sodium carbonate solution, extracted with dichloromethane (50mL×3), the organic phase was combined, dried, filtered and concentrated to give 2-((2) -oxaspiro[3.3]heptane-6-yl)amino)-6-(2-chloro-3,5-dimethoxyphenyl)-8-(3-(piperazin-1-yl)propane Pyridyl[2,3-d]pyrimidin-7(8H)one (129 mg, yield: 52.8%).

Step 5: 2-((2-oxaspiro[3.3]heptan-6-yl)amino)-8-(3-(4-acryloylpiperazin-1-yl)propyl)-6-(2 Synthesis of -Chloro-3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7(8H)-one

2-((2-oxaspiro[3.3]heptan-6-yl)amino)-6-(2-chloro-3,5-dimethoxyphenyl)-8-(3-(piperazine) -1-yl)propyl)pyrido[2,3-d]pyrimidin-7(8H)one (129 mg, 0.2323 mmol, 1.0 eq) was dissolved in tetrahydrofuran (5 mL) and triethylamine (117.5 mg, 1.162) Methyl acetate (5.0 eq) was cooled to 0 ° C and acryloyl chloride (21 mg, 0.232 mmol, 1.0 eq). Stir at 0 ° C for 1 h. The reaction was completely monitored by TLC. EtOAc (EtOAc) (EtOAc)EtOAc. Purification by chromatography gave 2-((2-oxaspiro[3.3]heptan-6-yl)amino)-8-(3-(4-acryloylpiperazin-1-yl)propyl)-6-(2 -Chloro-3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7(8H)-one (56 mg, yield: 39.6%).

Molecular formula: C ₃₁ H ₃₇ ClN ₆ O ₅ Molecular weight: 609.13 LC-MS (Pos, m/z) = 609.3 [M+H ⁺ ].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.62 (s, 1H), 8.16-8.17 (s, 1H), 7.72-7.73 (m, 1H), 7.68-7.70 (m, 2H), 6.73 -6.78(s,1H),6.06-6.10(m,1H),5.64-5.67(m,1H),4.63(m,2H),4.53(m,2H), 4.32(m,2H), 4.23(m , 1H), 3.87 (s, 3H), 3.78 (s, 3H), 3.31-3.50 (m, 4H), 2.67 (m, 2H), 2.31-2.51 (m, 6H), 1.26 (m, 2H), 1.24 (m, 1H), 0.92 (m, 1H).

Example 11: 8-(2-acryloyl-2-azaspiro[3.3]heptan-6-yl)-6-(2,6-dichloro-3,5-dimethoxyphenyl) Synthesis of -2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound 15)

Step 1: Synthesis of methyl 2-(3,5-dimethoxyphenyl)acetate

2-(3,5-Dimethoxyphenyl)acetic acid (25 g, 0.13 mol, 1.0 eq) was dissolved in methanol (250 mL), DMF (0.5 mL) and thionyl chloride (5 mL). </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt;

Step 2: Synthesis of 6-(3,5-dimethoxyphenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one

Methyl 2-(3,5-dimethoxyphenyl)acetate (14.3 g, 68.25 mmol, 1.5 eq) and 4-amino-2(methylthio)pyrimidine-5-carbaldehyde (7.7 g, 45.5 mmol , 1.0 eq) dissolved in DMF (50 mL), added potassium carbonate (12.5 g, 91 mmol, 3.0 eq), warmed to 70 ° C for 5 hours, LC-MS detection reaction was completed, the reaction solution was poured into water, ethyl acetate extraction The organic layer was washed twice with EtOAc EtOAc (EtOAc)

Step 3: Synthesis of 6-(3,5-dimethoxyphenyl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one

6-(3,5-Dimethoxyphenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (3.8 g, 11.54 mmol, 1.0 eq) Dissolved in DMF (30 mL), cooled to 0 ° C, then added 70% m-chloroperoxybenzoic acid (2.84 g, 11.54 mmol, 1.0 eq). After 2 hours of reaction, the reaction solution was added to aqueous methylamine (30 mL) The mixture was heated to 50 ° C for 1 hour, and solids were precipitated in the reaction system, filtered, and the filter cake was washed twice with dichloromethane, and dried to give a product (1.9 g, yield: 53%).

Step 4: 6-(6-(3,5-Dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl Synthesis of 2-Azaspiro[33]heptane-2-carboxylic acid tert-butyl ester

6-(3,5-Dimethoxyphenyl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (313 mg, 1 mmol) and 6-(( Methylsulfonyloxy)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (437 mg, 1.5 mmol, 1.5 eq) was dissolved in DMF (15 mL). 3 mmol, 3.0 eq), and the mixture was heated to 100 ° C for 12 hours. The reaction was completed by LC-MS. The reaction mixture was poured into water, ethyl acetate was evaporated, and the mixture was washed with EtOAc EtOAc EtOAc EtOAc. Product as a yellow solid (230 mg, yield: 45%).

Step 5: (6-(2,6-Dichloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidine-8 Synthesis of (7H)-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

6-(6-(3,5-Dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidine-8(7H)-yl)- 2-Azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (230 mg, 0.45 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL), cooled to 0 ° C, sulfonyl chloride (135 mg, 1 mmol) The reaction was carried out at room temperature for 2 hours, and the reaction was completed by LC-MS. The reaction mixture was poured into water, extracted with dichloromethane, and washed twice with saturated brine. The organic phase was combined, dried and concentrated. 1:1) The product was obtained as a pale yellow solid (110 mg, yield: 42.4%).

Step 6: 6-(2,6-Dichloro-3,5-dimethoxyphenyl)-2-(methylamino)-8-(2-aza-spiro[3.3]hept-6-yl Synthesis of pyrido[2,3-d]pyrimidin-7(8H)one

(6-(2,6-Dichloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidine-8 (7H tert-Butyl 2-aminospiro[3.3]heptane-2-carboxylate (110 mg, 0.19 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (0.5 mL) After the reaction was completed by LC-MS, the product was purified to give a pale yellow oil (yield: 100%, yield: 100%).

Step 7: 8-(2-Acryloyl-2-azaspiro[3.3]heptan-6-yl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)- Synthesis of 2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one

6-(2,6-Dichloro-3,5-dimethoxyphenyl)-2-(methylamino)-8-(2-aza-spiro[3.3]hept-6-yl)pyridine And [2,3-d]pyrimidin-7(8H)one (150 mg, 0.19 mmol, 1.0 eq) was dissolved in dichloromethane (3 mL), triethylamine (160 mg, 1.57 mmol, 8.0 eq) and acryloyl chloride (28.5mg, 0.31mmol, 1.6eq), reacted at 25 °C for 2h, the reaction was completed by TLC, the reaction mixture was poured into water, extracted with methylene chloride, the organic phase was combined, concentrated, and the crude was purified by silica gel column chromatography (EA) Product as light yellow solid (40 mg, yield: 40%).

^{_{1 HNMR (400MHz, CDCl 3)}} δ (ppm): 8.94 (s, 1H), 7.94 (s, 1H), 7.67 (s, 1H), 7.00 (s, 1H), 6.18-6.29 (m, 1H), 6.04-6.09(d,1H),5.63-5.66(d,1H),5.33(s,1H), 4.29(s,1H), 4.12(s,1H),3.98(s,7H),3.84(s, 1H), 2.92 (s, 3H), 2.70 (m, 2H), 2.01-2.12 (m, 2H).

Molecular formula: C ₂₅ H ₂₅ Cl ₂ N ₅ O ₄ Molecular weight: 530.41 LC-MS (Pos, m/z) = 530.9 [M+H] ⁺ .

Example: 12: N-(4-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-((2-methyl-2-azaspiro[3.3]) Synthesis of heptane-6-yl)amino)-7-oxopyrido[2,3-d]pyrimidine-8(7H)-yl)ethyl)phenyl)acrylamide (Compound 17)

Step 1: 6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylthio)-8-(4-nitrophenyl)pyrido[2,3-d]pyrimidine- Synthesis of 7(8H)-one

6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (3.0 g, 8.25 mmol) 4, 4-Nitrophenylethyl methanesulfonate (5.67 g, 23.1 mmol) and K ₂ CO ₃ (2.28 g, 16.5 mmol) were added to DMF (40 mL) successively. The reaction solution was cooled, poured into water (60 mL), and then EA (10 mL) was added, and the mixture was stirred for 2 min, then filtered and filtered to give a white solid (3.2 g, yield: 75.6%).

Step 2: 6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylsulfonyl)-8-(4-nitrophenethyl)pyrido[2,3-d] Synthesis of pyrimidine-7(8H)-one

6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylthio)-8-(4-nitrophenyl)pyrido[2,3-d]pyrimidin-7 ( 8H)-one (400 mg, 0.78 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL). Add 70% of mCPBA (301.4 mg, 0.86 mmol, 1.1 eq) to dichloromethane (3 mL), The reaction was completed by TLC. Toluene sodium hydrogen carbonate solution (10 mL), brine (10 mL), and stirred for 10 min, and extracted with dichloromethane (50 mL×3). Dry, filter, and concentrate the filtrate under reduced pressure. EtOAc (EtOAc: EtOAc = 8-(4-Nitrophenylethyl)pyrido[2,3-d]pyrimidin-7(8H)-one (397 mg, yield: 93.6%).

Step 2: 6-((6-(2-Chloro-3,5-dimethoxyphenyl)-8-(4-nitrophenethyl)-7-oxo-7,8-dihydropyridine Synthesis of [2,3-d]pyrimidin-2-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylsulfonyl)-8-(4-nitrophenyl)pyrido[2,3-d]pyrimidine-7 ( 8H)-ketone (397 mg, 0.73 mmol, 1.0 eq), 6-amino-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (618.5 mg, 2.91 mmol, 4.0 eq) and triethylamine (368.5 mg, 3.64 mmol, 5.0 eq) was dissolved in 1,4-dioxane (5 mL) and warmed to 95 ° C overnight. TLC was monitored without a mixture. A saturated aqueous solution of ammonium chloride (10 mL) was added and extracted with dichloromethane (50mL×3). The organic phase was combined, dried over anhydrous sulfuric acid, filtered, and concentrated to give 6-((6-( 2-chloro-3,5-dimethoxyphenyl)-8-(4-nitrophenethyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine- Tert-butyl 2-amino)-2-azaspiro[3.3]heptane-2-carboxylate (280 mg, yield: 56.7%).

Step 3: 2-((2-Azaspiro[3.3]heptan-6-yl)amino)-6-(2-chloro-3,5-dimethoxyphenyl)-8-(4-nitro Synthesis of pyridyl[2,3-d]pyrimidin-7(8H)-one trifluoroacetate

6-((6-(2-Chloro-3,5-dimethoxyphenyl)-8-(4-nitrophenethyl)-7-oxo-7,8-dihydropyridyl[ 2,3-d]pyrimidin-2-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (280 mg, 0.41 mmol, 1.0 eq) dissolved in dichloromethane (5 mL) The temperature was lowered to 0 ° C, and a solution of trifluoroacetic acid (5 mL) was added dropwise and stirred at room temperature for 2 h. TLC was monitored for the title compound, EtOAc (EtOAc) (EtOAc) -3,5-dimethoxyphenyl)-8-(4-nitrophenethyl)pyrido[2,3-d]pyrimidin-7(8H)-one trifluoroacetate, theoretical quantity Put it to the next step.

Step 4: 6-(2-Chloro-3,5-dimethoxyphenyl)-2-((2-methyl-2-azaspiro[3.3]heptan-6-yl)amino)-8 Synthesis of (4-nitrophenethyl)pyrido[2,3-d]pyrimidin-7(8H)-one

The crude product obtained in the above step was dissolved in methanol (10 mL), and then added to a solution of 37% aqueous formaldehyde (83.8 mg, 1.03 mmol, 2.5 eq), and stirred at room temperature under nitrogen for 1 h. The temperature was lowered to 0 ° C, and sodium triacetoxyborohydride (318.8 mg, 1.24 mmol, 3.0 eq) was added portionwise. The reaction was completed by TLC. EtOAc (EtOAc) (EtOAc (EtOAc) (2-Chloro-3,5-dimethoxyphenyl)-2-((2-methyl-2-azaspiro[3.3]heptan-6-yl)amino)-8-(4-nitro Phenylethyl)pyrido[2,3-d]pyrimidin-7(8H)-one (200 mg, yield: 80%).

Step 5: 8-(4-Aminophenethyl)-6-(2-chloro-3,5-dimethoxyphenyl)-2-((2-methyl-2-azaspiro[3.3] Synthesis of heptane-6-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one

6-(2-Chloro-3,5-dimethoxyphenyl)-2-((2-methyl-2-azaspiro[3.3]heptan-6-yl)amino)-8-( 4-Nitrophenylethyl)pyrido[2,3-d]pyrimidin-7(8H)-one (200 mg, 0.338 mmol, 1.0 eq) was dissolved in methanol (10 mL). ), iron powder (378.9 mg, 6.766 mmol, 20 eq) was added, and the mixture was stirred under reflux for 2 h. The reaction was completed by TLC, and filtered, and filtered, and filtered, and the filtrate was washed with methanol, and the filtrate was concentrated under reduced pressure to give a solid, which was purified with methylene chloride (100 mL × 3), filtered, and concentrated under reduced pressure to give 8-(4-aminophenethylethyl) - 6-(2-Chloro-3,5-dimethoxyphenyl)-2-((2-methyl-2-azaspiro[3.3]heptan-6-yl)amino)pyridin[ 2,3-d]pyrimidine-7(8H)-one (142 mg, yield: 75%).

Step 6: N-(4-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-((2-methyl-2-azaspiro[3.3]heptane-) Synthesis of 6-yl)amino)-7-oxopyrido[2,3-d]pyrimidine-8(7H)-yl)ethyl)phenyl)acrylamide

8-(4-Aminophenethyl)-6-(2-chloro-3,5-dimethoxyphenyl)-2-((2-methyl-2-azaspiro[3.3]heptane -6-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (142mg, 0.253mmol, 1.0eq) was dissolved in dichloromethane (5mL), cooled to 0 ° C, dropwise Acryloyl chloride (22.8 mg, 0.253 mmol, 1.0 eq) was stirred at 0 ° C for 2 h. After the reaction was completed by TLC, a saturated sodium carbonate solution (10 mL) was added, and the mixture was stirred for 20 min, and the mixture was separated, and the aqueous phase was extracted with dichloromethane (50 mL×2). The crude product was purified by preparative thin-layer chromatography to give N-(4-(6-(2-chloro-3,5-dimethoxyphenyl)-2-((2-methyl-2-a) [3.3]Heptane-6-yl)amino)-7-oxopyrido[2,3-d]pyrimidine-8(7H)-yl)ethyl)phenyl)acrylamide (5 mg, yield: 3 %).

Molecular formula: C ₃₃ H ₃₅ ClN ₆ O ₄ Molecular weight: 615.13 LC-MS (Pos, m/z) = 615.21 [M+H ⁺ ]. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.78 (s) , 1H), 7.70-7.75 (s, 1H), 7.65-7.68 (d, 1H), 7.60 (s, 1H), 7.15-7.20 (m, 2H), 6.70-6.75 (m, 1H), 6.50 (m) , 1H), 6.20-6.25 (m, 1H), 5.73-5.75 (m, 1H), 5.30 (m, 1H), 4.30-4.45 (m, 4H), 4.25 (m, 1H), 3.80-3.85 (s , 3H), 3.75-3.78 (s, 3H), 3.10 (m, 1H), 2.80-2.85 (s, 3H), 2.65-2.68 (m, 2H), 2.20-2.50 (m, 1H), 1.90-2.00 (m, 2H), 1.40-1.45 (m, 2H).

Example 13: 1-(2-acryloyl-2-azaspiro[3.3]hept-6-yl)-7-amino-3-(2,6-dichloro-3,5-dimethoxybenzene Synthesis of 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (Compound 18)

Step 1: 6-(7-Amino-3-(2,6-dichloro-3,5-dimethoxyphenyl)-2-oxo-3,4-dihydropyrimido[4,5- Synthesis of d]pyrimidine-1(2H)-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

6-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylsulfonyl)-2-oxo-3,4-dihydropyrimido[4 , 5-d]pyrimidin-1(2H)-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (169.8 mg, 0.21 mmol, 1.0 eq) was added to aqueous amine (10 mL) The mixture was heated at 60 ° C for 5 hours, and TLC showed the reaction was completed. The system was cooled to room temperature and then extracted with dichloromethane (30 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (silica gel: 200-300 mesh, dichloromethane: Methanol = 200:1 to 30:1) The product was obtained (59.2 mg, yield: 49.8%).

Step 2: 7-Amino-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(2-azaspiro[3.3]heptan-6-yl)-3, Synthesis of 4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-one hydrochloride

6-(7-Amino-3-(2,6-dichloro-3,5-dimethoxyphenyl)-2-oxo-3,4-dihydropyrimido[4,5-d] Pyrimidine-1(2H)-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (59.2 mg, 0.10 mmol, 1.0 eq) was added to ethanol (1 mL). °C, a solution of hydrogen chloride in ethanol (2 mL) was added dropwise, and the mixture was stirred at room temperature for 2 hours. TLC showed that the reaction was completed, and the system was concentrated to give the product (57.2 mg of crude product, yield: 100.0%).

Step 3: 1-(2-Aroyl-2-azaspiro[3.3]hept-6-yl)-7-amino-3-(2,6-dichloro-3,5-dimethoxyphenyl Synthesis of-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

7-Amino-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(2-azaspiro[3.3]heptan-6-yl)-3,4- Dihydropyrimido[4,5-d]pyrimidin-2(1H)-one hydrochloride (57.2 mg of crude product, 0.10 mmol, 1.0 eq) was added to tetrahydrofuran (3 mL), cooled to 0 ° C, and then added dropwise Amine (37.3 mg, 0.36 mmol, 3.6 eq) and acryloyl chloride (13.6 mg, 0.13 mmol, 1.3 eq). A saturated aqueous solution of ammonium chloride (10 mL) was added to the mixture, and the mixture was evaporated to methylene chloride (30mL×3). :1) A product (1.8 mg, yield: 3.4%) was obtained.

Molecular formula: C ₂₃ H ₂₄ Cl ₂ N ₆ O ₄ Molecular weight: 519.38 LC-MS (m/z) = 520.08 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 7.72 (s, 1H), 7.22 (s, 1H), 6.99 (m, 1H), 6.64-6.99 (s, 1H), 6.21-6.30 (m) , 1H), 6.04-6.08 (m, 1H), 5.55-5.65 (m, 1H), 5.31-5.33 (m, 1H), 4.28-4.31 (m, 2H), 4.15 (m, 1H), 3.94-3.98 (s, 6H), 3.84-3.86 (m, 1H), 2.63-2.66 (m, 2H), 1.98-2.02 (m, 2H), 0.83-0.86 (m, 2H).

Example 14: N-(4-(2-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-2-oxo-3, Synthesis of 4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)ethyl)phenyl)acrylamide (Compound 19)

Step 1: Synthesis of ethyl 2-(methylthio)-4-((4-nitrophenethyl)amino)pyrimidine-5-carboxylate

Ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (20.0 g, 86.2 mmol, 1.0 eq), 2-(4-nitrophenyl)ethyl-1-amine hydrochloride (20.9 g, 103.4 mmol, 1.2 eq) and triethylamine (26.2 g, 258.6 mmol, 3.0 eq) were dissolved in tetrahydrofuran (200.0 mL). Filtration and concentration of the filtrate under reduced pressure gave ethyl 2-(methylthio)-4-((4-nitrophenethyl)amino)pyrimidine-5-carboxylate (33.0 g).

Step 2: Synthesis of 2-(methylthio)-4-((4-nitrophenethyl)amino)pyrimidin-5-yl)methanol

Lithium tetrahydroaluminum (4.9 g, 129.3 mmol, 1.5 eq) was dissolved in tetrahydrofuran (200.0 mL), and 2-(methylthio)-4-((4-nitrophenethyl) was slowly added dropwise at 0 °C. A solution of ethylaminopyrimidine-5-carboxylate (33.0 g) in tetrahydrofuran (100.0 mL) was stirred at 0 ° C for 1 h. Water (4.9 mL) was added to the ice bath, stirred for 2 min, 10% aqueous sodium hydroxide solution (4.9 mL) was added to the ice bath, stirred for 2 min, then water (15.0 mL) was added, stirred for 15 min, filtered through celite, and filtrate was evaporated. The product was purified by EtOAc EtOAcjjjjjjjj

Step 3: Synthesis of 2-(methylthio)-4-((4-nitrophenethyl)amino)pyrimidine-5-carboxaldehyde

2-(Methylthio)-4-((4-nitrophenethyl)amino)pyrimidin-5-yl)methanol (3.56 g, 11.122 mmol, 1.0 eq) was dissolved in dichloromethane (70.0 mL) Manganese dioxide (7.74 g, 88.975 mmol, 8.0 eq) was added to a mixed solvent of tetrahydrofuran (10.0 mL), and stirred at room temperature overnight. The reaction was completed by TLC, EtOAc (EtOAc) (EtOAc (EtOAc). ).

Step 4: Synthesis of 5-(((3,5-dimethoxyphenyl)amino)methyl)-2-(methylthio)-N-(4-nitrophenyl)pyrimidine-4-amine

2-(Methylthio)-4-((4-nitrophenethyl)amino)pyrimidine-5-carboxaldehyde (2.78 g, 8.732 mmol, 1.0 eq) was dissolved in dichloromethane (50 mL). 5-Dimethoxyaniline (1.604 g, 10.478 mmol, 1.2 eq) and sodium triacetoxyborohydride (4.627 g, 21.830 mmol, 2.5 eq) were stirred at room temperature overnight. The reaction was completed by TLC, EtOAc (EtOAc) (EtOAc). The product was purified as a yellow solid (2.68 g, yield: 70%).

Step 5: 3-(3,5-Dimethoxyphenyl)-7-(methylthio)-1-(4-nitrophenyl)-3,4-dihydropyrimido[4,5- Synthesis of d]pyrimidine-2(1H)-one

5-(((3,5-Dimethoxyphenyl)amino)methyl)-2-(methylthio)-N-(4-nitrophenyl)pyrimidine-4-amine (2.68 g, 5.883 mmol, 1.0 eq) was dissolved in tetrahydrofuran (50.0 mL). Toluene (1.89 g, 6.471 mmol, 1.1 eq) was added at 0 ° C, stirred at room temperature for 1 h, cooled to 0 ° C, then added triethylamine (1.79 g, 17.649 mmol) , 3.0 eq), the temperature was raised to 70 ° C for 1.5 h, and the reaction was complete by TLC. The reaction mixture was quenched with saturated EtOAc (EtOAc)EtOAc.EtOAc. The product was obtained as a white solid (2.42 g, yield: 90.3%).

Step 6: 3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylthio)-1-(4-nitrophenyl)-3,4-dihydro Synthesis of pyrimido[4,5-d]pyrimidin-2(1H)-one

3-(3,5-Dimethoxyphenyl)-7-(methylthio)-1-(4-nitrophenyl)-3,4-dihydropyrimido[4,5-d] Pyrimidine-2(1H)-one (500.0 mg, 1.038 mmol, 1.0 eq) was dissolved in dichloromethane (10.0 mL), cooled to 0 ° C, and dichloromethane (349.1 mg) diluted with dichloromethane (2.0 mL). After the reaction was carried out for 15 min, EtOAc EtOAc (EtOAc m. The product (478.0 mg, yield: 83.62%).

Step 7: 3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylsulfonyl)-1-(4-nitrophenyl)-3,4-di Synthesis of Hydropyrimido[4,5-d]pyrimidin-2(1H)-one

3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylthio)-1-(4-nitrophenyl)-3,4-dihydropyrimidine [4,5-d]pyrimidin-2(1H)-one (478.0 mg, 0.868 mmol, 1.0 eq), dissolved in dichloromethane (15.0 mL), cooled to 0 ° C, and added m-chloroperoxybenzoic acid (470.9) Mg, 1.910 mmol, 2.2 eq), 1 h, TLC showed the reaction was completed. The mixture was quenched with EtOAc EtOAc (EtOAc m.hhhhHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Yield: 75.7%).

Step 8: 3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-1-(4-nitrophenyl)-3,4-dihydro Synthesis of pyrimido[4,5-d]pyrimidin-2(1H)-one

3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylsulfonyl)-1-(4-nitrophenyl)-3,4-dihydropyrimidine And [4,5-d]pyrimidine-2(1H)-one (336.0 mg, 0.6546 mmol, 1.0 eq), methylamine solution (286.7 mg, 2.308 mmol, 4.0 eq) and triethylamine (350.3 mg, 3.462 mmol) , 6.0 eq) was dissolved in dioxane (5.0 mL) and tetrahydrofuran (2.0 mL) and refluxed at 80 ° C for 3 h. After adding water, the organic layer is combined with EtOAc (EtOAc m. Mg, yield: 55.4%).

Step 9: 1-(4-Aminophenethyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-3,4-dihydro Synthesis of pyrimido[4,5-d]pyrimidin-2(1H)-one

3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-1-(4-nitrophenyl)-3,4-dihydropyrimidine [4,5-d]pyrimidine-2(1H)-one (194.0 mg, 0.364 mmol, 1.0 eq) was dissolved in ethanol (5.0 mmol), iron powder (814.7 mg, 14.549 mmol, 40.0 eq) and saturated chlorination The ammonium solution (2.5 mL) was refluxed at 80 ° C for 1.5 h. TLC showed that the reaction was completed, filtered, and the filtrate was evaporated to dryness. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

Step 10: N-(4-(2-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-2-oxo-3,4 Synthesis of dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)ethyl)phenyl)acrylamide

1-(4-Aminophenethyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-3,4-dihydropyrimidine [4,5-d]pyrimidine-2(1H)-one (20.0 mg, 0.0377 mmol, 1.0 eq) was dissolved in tetrahydrofuran (1.0 mL), triethylamine (11.4 mg, 0.113 mmol, 3.0 eq), 0 ° C Add acryloyl chloride (5.1 mg, 0.0566 mmol, 1.5 eq) and slowly warm to room temperature. After 1 h, TLC showed the reaction was completed. The mixture was quenched with EtOAc EtOAc (EtOAc)EtOAc. :1) Purified white solid N-(4-(2-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-2-oxo) -3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)ethyl)phenyl)acrylamide (6.0 mg, yield: 30%).

Molecular formula: C ₂₆ H ₂₆ Cl ₂ N ₆ O ₄ Molecular weight: 557.43 LC-MS (Pos, m/z) = 558.4 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 10.07 (s, 1H), 7.99 (s, 1H), 7.59-7.57 (d, 2H), 7.20-7.18 (d, 2H), 6.99 (s) , 1H), 6.46-6.39 (m, 1H), 6.27-6.22 (d, 1H), 5.76-5.73 (d, 1H), 4.42 (s, 2H), 4.14 - 4.13 (m, 2H), 3.97 (s , 6H), 2.90-2.86 (m, 5H), 2.02-1.99 (m, 1H).

Comparative Example 1: 8-(3-(4-Acrylopiperazin-1-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-( Synthesis of methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (PRN1371, abbreviated as compound A)

Step 1: Synthesis of methyl 2-(3,5-dimethoxyphenyl)acetate

The starting material 2-(3,5-dimethoxyphenyl)acetic acid (50 g, 0.26 mol, 1.0 eq) was dissolved in methanol (500 mL), DMF (0.5 mL) and thionyl chloride (10 mL) After 12 hours, the reaction was completed by LC-MS, EtOAc (EtOAc). :100%).

Methyl 2-(3,5-dimethoxyphenyl)acetate (19.6 g, 0.0931 mol, 1.5 eq) and 4-amino-2-(methylthio)pyrimidine-5-carbaldehyde (10.5 g, 0.0621) Mol, 1.0 eq) was dissolved in NMP (20 mL), potassium carbonate (17.1 g, 0.124 mol, 3.0 eq) was added, and the mixture was heated to 100 ° C for 12 hours. The reaction was completed by LC-MS and the reaction mixture was poured into water. The ethyl ester was extracted and washed twice with saturated brine. EtOAc was evaporated.

Step 3: Synthesis of 6-(3,5-dimethoxyphenyl)-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one

6-(3,5-Dimethoxyphenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (4.0 g, 0.0121 mol, 1.0 eq) Dissolved in DMF (50 mL), cooled to 0 ° C, added 70% m-chloroperoxybenzoic acid (3.5 g, 0.0134 mol, 1.1 eq), reacted for 2 hours, LC-MS detection reaction was complete, the reaction solution was used directly under Step reaction.

Step 4: Synthesis of 6-(3,5-dimethoxyphenyl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one

6-(3,5-Dimethoxyphenyl)-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (4.178 g, 0.0121 mol, 1.0 eq Dissolve in methylamine methanol solution (300mL), after 12 hours at 50 °C, LC-MS detection reaction is complete, add water (200mL), stir for 10min, filter, filter cake washed twice with dichloromethane, bake The product was obtained after drying (2.75 g, yield: 72.7%).

Step 5: 4-(3-(6-(3,5-Dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidine-8 (7H) Synthesis of tert-butyl ester of propyl)piperazine-1-carboxylate

6-(3,5-Dimethoxyphenyl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (2.75 g, 0.00888 mol, 1.0 eq) And tert-butyl 4-(3-((methylsulfonyl)oxy)propyl)piperazine-1-carboxylate (4.256 mg, 0.0132 mol, 1.5 eq) was mixed in DMF (50 mL) (3.645g, 0.0264mol, 3.0eq), the temperature was raised to 90 ° C for 3 hours, the reaction was completed by LC-MS, the reaction solution was poured into water, extracted with dichloromethane, washed twice with saturated brine, and the organic phase was combined and dried. The product was obtained as a pale yellow oil (yield: </RTI> <RTIgt;

Step 5: 4-(3-(6-(2,6-Dichloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyridine[2,3-d Synthesis of pyrimidine-8(7H)-yl)propyl)piperazine-1-carboxylic acid tert-butyl ester

4-(3-(6-(3,5-Dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidine-8(7H)-yl Propyl) piperazine-1-carboxylic acid tert-butyl ester (4.738 g, 0.0088 mol, 1.0 eq) was dissolved in dichloromethane (100 mL), cooled to 0 ° C, sulfonyl chloride (2.969 g, 0.022 mol, 2.5 eq) ), reacted at room temperature for 2 hours. After the reaction was completed by LC-MS, the reaction mixture was poured into water, and the mixture was evaporated to dichloromethane. Product as a pale yellow solid (5.432 g, yield: 100%). Directly invest in the next reaction according to the theoretical amount.

Step 6: 6-(2,6-Dichloro-3,5-dimethoxyphenyl)-2-(methylamino)-8-(3-(piperazin-1-yl)propyl)pyridine And [2,3-d]pyrimidin-7(8H)-one trifluoroacetate

4-(3-(6-(2,6-Dichloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidine -8(7H)-yl)propyl)piperazine-1-carboxylic acid tert-butyl ester (5.346 g, 0.00888 mol, 1.0 eq) was dissolved in dichloromethane (50 mL), trifluoroacetic acid (50 mL) After the reaction was completed by LC-MS, the product was concentrated (4.465 g, crude), and was directly applied to the next reaction.

Step 7: 8-(3-(4-Acrylopiperazin-1-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(A Synthesis of pyridyl[2,3-d]pyrimidin-7(8H)-one

6-(2,6-Dichloro-3,5-dimethoxyphenyl)-2-(methylamino)-8-(3-(piperazin-1-yl)propyl)pyridinium[ 2,3-d]pyrimidin-7(8H)-one trifluoroacetate (4.465 g, 0.00888 mol, 1.0 eq) was dissolved in tetrahydrofuran (50 mL), then added triethylamine (4.452 g, 0.044 mol, 5.0 Eq), acryloyl chloride (1.5 g, 0.0088 mol, 1.0 eq) was added at 0 ° C, and reacted at 0 to 5 ° C for 2 h. The reaction was completed by LC-MS. The reaction mixture was poured into saturated aqueous sodium carbonate (50 mL) and stirred for 20 min. The mixture was extracted with methylene chloride (100 mL×3). The organic phase was combined, dried and concentrated. The crude product was purified by silica gel column chromatography (MeOH:DCM=1:150). The product was obtained as a yellow solid (600 mg, 3 step yield: 13%).

Molecular formula: C ₂₆ H ₃₀ Cl ₂ N ₆ O ₄ Molecular weight: 561.46 LC-MS (Pos, m/z) = 561.11 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.618 (s, 1H), 7.892 (s, 1H), 7.675 (s, 1H), 6.976 (s, 1H), 6.732-6.800 (m, 1H) ), 6.054-6.101 (m, 1H), 5.633-5.665 (m, 1H), 4.282-4.368 (d, 2H), 3.951 (s, 6H), 3.445-3.462 (d, 4H), 2.910-2.921 (d , 3H), 2.301-2.389 (d, 6H), 1.837 (s, 2H).

Compared with the prior art, the compounds of the present invention have the following innovations: 1 The compound has stronger enzymatic inhibitory activity against each subtype of FGFR, and the cancer cell killing activity due to abnormal FGFR gene is more excellent. 2 The compound is more medicinal in the PK of animals and humans in vivo and in vivo, and can ensure better exposure of animals and humans after administration, thereby facilitating the anti-cancer effect of the drug. 3 The compound exhibited a superior inhibitory effect on the animal pharmacodynamic model, so it was predicted to have a better clinical application effect in the human body.

The present invention can be better understood from the following experimental examples. However, those skilled in the art will understand that the description of the present invention is intended to be illustrative only and not to limit the invention as described in the claims.

Experimental Example 1 Cell viability test of the compound of the present invention

Hep3B is an abnormal cell of hepatocellular carcinoma FGFR, derived from ATCC

RT112/84 is an abnormal cell of bladder cancer FGFR, derived from ECACC

SNU-16 is an abnormal cell of gastric cancer FGFR, derived from ATCC

Test substance: The compound of the present invention, the structure of which is shown above.

Test equipment: EnSpire ^TM or EnVision ^TM multifunctional microplate reader.

experiment method:

Each strain of cells was inoculated in a 96-well plate and cultured overnight. Different concentrations of compounds (12 dose groups, 3 fold gradient DMSO dilution) were added to give a final concentration of 0.17-30000 nM, and the final DMSO content was 5 ‰ (v). /v). The negative control wells contained only medium containing 5 DMSO, and the positive control wells were medium containing cells and 5 DMSO. It was tested after incubation at 37 ° C, 5% CO ₂ , 95% humidity for 72 h. 30 μL of Cell titer-Glo ^TM reagent was added to each well, and after incubation for 30 min at room temperature, the plate reader was used to read the chemiluminescence final data.

The cell viability inhibition rate is calculated according to the following formula:

Among them, the maximum luminescence value was obtained from the positive control well, and the minimum luminescence value was obtained from the negative control well. The IC50 value was obtained by XLFit regression, and the regression curve was fit=(A+((BA)/(1+((x/C)^D) )))), where A is the minimum inhibition rate of the compound, B is the maximum inhibition rate of the compound, C is the IC50, and D is the slope.

The test results are shown in Table 2-3:

Table 2 Inhibitory activity of the compound of the present invention on cell viability (IC50)

化合物Compound	Hep3B(nM)Hep3B(nM)	RT112/84(nM)RT112/84(nM)	SNU-16(nM)SNU-16(nM)
22	7474	1919	1313
33	--	123123	--
44	110110	--	--
55	--	6969	9292
66	--	--	149149
1212	6666	22twenty two	77
1717	--	8484	--

Table 3 Inhibitory activity of the compounds of the present invention on cell viability (IC50)

化合物Compound	Hep3B(nM)Hep3B(nM)	RT112/84(nM)RT112/84(nM)	SNU-16(nM)SNU-16(nM)
99	2626	88	22
1414	--	123123	5050
1515	2929	2525	22
1919	22twenty two	1111	--

- Indicates that it has not been tested.

As can be seen from the results of Table 2-3, the compound of the present invention has a good inhibitory activity against the abnormal cell viability of FGFR such as Hep3B, RT112/84, SNU-16, etc., indicating that the compound of the present invention can be used for the treatment of abnormality mediated by FGF/FGFR. Cancers such as liver cancer, stomach cancer, and bladder cancer have very good clinical value.

Experimental Example 2 Enzymatic activity test of the compound of the present invention

The FAM-labeled peptide substrate P22 is derived from GL Biochem

Tester: Use Caliper EZ Reader ^TM Ⅱ drug screening platform.

experiment method:

1. Compound plate preparation

a) 10 dose groups of the compound were placed in a 96-well plate, DMSO was added to each well, and diluted in 3-fold gradient DMSO to obtain a dilution of each compound; the highest concentration of the compound was 500 μM;

b) Transfer each compound dilution prepared in step a) to a 384-well plate and dilute with 1×kinase buffer (50 mM HEPES, Ph 7.5; 0.0015% Brij-35; 2 mM DTT) to give 5 μL of 10% DMSO per well. (v/v) Dissolved 5 x compound solution such that the highest final concentration was 10 μM. The negative control wells were 5 [mu]L of 1X Kinase Buffer containing 10% DMSO.

2. Experimental steps

Add 10 μL of 2.5× enzyme solution to the 5× compound solution in step 1b), and after reacting for 10 min at room temperature, add a total volume of 10 μL of FAM-labeled peptide substrate previously dissolved in 1×kinase buffer, and ATP. After the initiation of the reaction, incubation was carried out for 30 minutes by adding 25 μL of stop solution (100 mM HEPES, pH 7.5; 0.015% Brij-35; 0.2% Coating Reagent #3; 50 mM EDTA) to terminate the reaction Caliper reading final data.

The test results are shown in Table 4:

Table 4 Inhibitory activity of the compound of the present invention on FGFR (IC50)

- Indicates that it has not been tested.

It can be seen from the experimental results in Table 4 that the compound of the present invention has a good inhibitory activity against FGFR, indicating that the compound of the present invention has a good clinical application potential in the treatment of diseases mediated by FGF/FGFR abnormality.

Experimental Example 3 Evaluation of Mouse Pharmacokinetics of Compounds of the Invention

1. Purpose:

The pharmacokinetic parameters of the compounds of the present invention in BalbC female nude mice (Nanjing University-Nanjing Institute of Biomedicine) were evaluated, and their bioavailability was examined.

2. Animal administration and sample collection:

Compound 9 was prepared by dispersing 0.5% CMC-Na aqueous solution (containing 0.5% Tween-80) to prepare a suspension. Compound 9 suspension was administered to BalbC nude mice at a dose of 10.0 mg/kg (9 in total, 3 points) The group, 3 in each group, was intragastrically administered (suspension of compound 9), and the time of blood collection was after administration: 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 24 h, 30 h.

Compound 9 was treated with dimethylacetamide (DMA): polyoxyethylene castor oil (EL): 10% hydroxypropyl-β-cyclodextrin (HP-β-CD) physiological saline: 1 M HCl = 5:5: 89.5: 0.5 (v/v/v/v) dissolved preparation solution, the solution of compound 9 was administered to BalbC nude mice at a dose of 4.0 mg/kg (9 in total, 3 in groups, 3 in each group) to give a bolus The time of blood collection was after administration (3 time points per collection): 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 24 h.

About 100 μL of blood was collected through the posterior orbital venous plexus, and the blood was collected and placed in an EDTA-K ₂ anticoagulant tube. Blood samples were centrifuged at 8000 rpm for 6 min at 4 ° C to obtain plasma samples. The plasma must be prepared within 30 min after blood collection and stored in a -80 ° C refrigerator before plasma testing.

3. Sample analysis method:

The samples from 9 mouse individuals were taken out from the -80 °C refrigerator and vortexed at room temperature for 5 min. The 10 μL plasma samples from different individual mice at each time point were precisely aspirated into a 1.5 mL centrifuge tube (precision extraction). Standard curve plasma 30 μL); add 200 μL of 100 ng/mL toluene butyrate in methanol (internal standard working solution), mix; vortex 5 min, centrifuge at 12000 rpm for 5 min; precision soak 50 μL of supernatant to pre-added 150 μL per well of water in 96-well plates; vortexed for 5 min for LC-MS/MS measurement with an injection volume of 10 μL.

4, data processing methods:

The compound concentration was measured using AB's Analyst 1.6.3. Microsoft Excel calculates the mean, standard deviation, coefficient of variation and other parameters (Analyst 1.6.3 direct output is not calculated), and the pharmacokinetic parameters are calculated using Pharsight Phoenix 6.1 software NCA.

The results are shown in Table 5:

Table 5 PK parameters of Compound 9 in BalbC nude mice (iv: 4 mg/kg, po: 10 mg/kg, n=9)

Note T _max po: peak time, AUC _inf iv/po: area under the drug-time curve, F%: bioavailability

Conclusion: The compounds of the invention have better in vivo exposure and bioavailability.

Experimental Example 4 Evaluation of Human Liver Microsome Stability of Compounds of the Invention

OBJECTIVE: To evaluate the stability of human liver microsomes of compounds of the invention.

Table 6 Composition of the incubation system

experiment procedure:

(1). The liver microsomes (20 mg protein/mL) were taken out from the -80 °C refrigerator, placed in a 37 ° C water bath thermostat shaker for 3 min, and thawed for use.

(2) Prepare a mixed solution of the incubation system (without compound and β-NADPH) according to the ratio of "constitution of the incubation system" in Table 6 above, and pre-incubate for 2 min on a 37 ° C water bath thermostat.

(3). Control group (excluding β-NADPH): 30 μL of water and 30 μL of compound working solution (10 μM) were added to 240 μL of the incubation solution of step (2), vortexed for 30 s, mixed, and reacted. The total volume was 300 μL and the sample was duplicated. Incubate into a 37 ° C water bath thermostat and start timing. The sampling time points are 0 min and 60 min.

(4). Sample group: 70 μL β-NADPH solution (10 mM) and 70 μL of compound working solution (10 μM) were added to 560 μL of the mixed solution in step (2), the total volume of the reaction was 700 μL, vortexed for 30 s, mixed, and duplicated. . Incubate into a 37 ° C water bath thermostat shaker, and start timing. The sampling time point is 0 min, 5 min, 10 min, 20 min, 30 min, 60 min after timing.

(5). After vortexing for 3 min, centrifuge at 12000 rpm for 5 min.

(6). Take 50 μL of the supernatant and add 150 μL of water, vortex and mix, and analyze by LC/MS/MS.

data analysis:

The half-life (t _1/2 ) and clearance (Cl) were calculated using the following first-order kinetic formula:

Ct=C0*e ^–kt

t _1/2 =ln2/k=0.693/k

Cl _int =Vd*k

Vd=1/protein content in liver microsomes

Note: k is the slope of the logarithm of the remaining amount of the compound versus time, and Vd is the apparent volume of distribution.

The results are shown in Table 7:

Table 7

Note: R ² : coefficient of determination; t _1/2 : elimination half-life; Cl _int : intrinsic clearance; E _h : liver extraction rate.

From the above results, it can be seen that our compound has a compound A disclosed in the human liver microsomes compared to the prior art.

Lower clearance rate.

Experimental Example 5 Evaluation of canine plasma stability of the compound of the present invention

Objective: To evaluate the stability of the dog plasma of the compounds of the invention.

Working solution preparation:

Test substance: Take about 2 mg of the compound, first prepare a 5 mM stock solution with DMSO, dilute it with DMSO to a 1 mM solution, and finally dilute with water to 50 μM of the test compound working solution, and set aside.

Stop solution: Take about 2 mg of the compound tolbutamide, first prepare a 1 mg/mL stock solution with DMSO, and finally dilute to 100 ng/mL stop solution with acetonitrile, and store at 4 ° C until use.

experiment procedure:

1). The frozen Beagle dog plasma (purchased from Reid Liver Disease Research (Shanghai) Co., Ltd.) was pre-incubated and thawed in a 37 ° C water bath thermostat.

2). 10 μL of the test compound working solution (50 μM) was added to 490 μL of Beagle dog plasma, and the final concentration of the test substance was 1 μM, and two replicates were used.

3). Vortex and mix and incubate in a 37 ° C water bath thermostat.

4). At the corresponding time point (T=0h, 0.5h, 1h, 2h, 4h; 0h sample is not incubated), take 40μL of the reaction solution, add 400μL of stop solution (100ng/mL tolbutamide acetonitrile) Solution), mix and freeze at -80 °C. .

6). After the incubation experiment is completed, the sample tube at each time point is thawed, mixed, and centrifuged at 12000 rpm for 5 min in a 4 °C centrifuge. .

7). Add 96 μL of water to the 96-well sample plate, take 50 μL of the supernatant after centrifugation in step 6) into the sample well, mix and analyze the sample.

data analysis:

The stability of the compound in plasma was evaluated by the percentage retention of the compound after incubation at each time point, and the concentration of the sample was expressed as the ratio of the peak area of the test compound to the internal standard peak area.

The calculation formula is as follows: retention rate (%) = C _Tn / C _T0

Wherein, C _Tn is the concentration of the final solution of the compound after each incubation time point, n=0.5 h, 1 h, 2 h,

4h; C _T0 is the concentration of the final solution of the compound at the initial incubation.

The results are shown in Table 8:

Table 8

Conclusion: From the above results, it can be seen that our compound has better canine plasma stability than the compound A disclosed in the prior art.

The above is only the preferred embodiment of the present invention, and is not intended to limit the present invention. Any modifications, equivalents, improvements, etc., which are made within the spirit and principles of the present invention, should be included in the present invention. Within the scope of protection.

Claims

An irreversible inhibitor of fibroblast growth factor receptor (FGFR) represented by the general formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof:

among them,

Warhead 1 and warhead 2 refer to the part capable of forming a covalent bond with a nucleophile, and warhead 1 and warhead 2 are not present at the same time;

X is selected from C or N, when X is C,
Represents a double bond, when X is N,
Represents a single button;

When warhead 1 is present, R 1 is selected from C 1-6 alkylene, C 2-8 alkenylene, C 2-8 alkynylene, halo C 1-6 alkylene or —(L 1 )n -Cy 1 -(L 2 )t-(Cy 2 )p-; when warhead 1 is absent, R 1 is selected from hydrogen, C 1-6 alkyl, C 2-8 alkenyl, C 2-8 alkynyl , halogenated C 1-6 alkyl or -(L 1 )n-Cy 1 -(L 2 )t-(Cy 2 )p;

When warhead 2 is present, R 2 is selected from C 1-6 alkylene, C 2-8 alkenylene, C 2-8 alkynylene, halo C 1-6 alkylene or —(L 3 )q -Cy 3 -; when warhead 2 is absent, R 2 is selected from hydrogen, C 1-6 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halo C 1-6 alkyl or -( L 3 )q-Cy 3 ;

Cy 1 and Cy 2 are each independently selected from the group consisting of one or more R a substituted or unsubstituted 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3- a 12-membered heterocyclic group, an aryl group or a 5-10 membered heteroaryl group, the ring-forming carbon atom may be optionally oxidized to C(O), and the ring-forming sulfur atom may be optionally oxidized to S(O), S(O). 2 or S(O)(N);

Cy 3 is selected from the group consisting of one or more R b substituted or unsubstituted 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclic group. , aryl or 5-10 membered heteroaryl, the ring-forming carbon atom may be optionally oxidized to C(O), and the ring-forming sulfur atom may be optionally oxidized to S(O), S(O) 2 or S ( O)(N);

R a and R b are each independently selected from:

(i) hydrogen;

(ii) a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen, a C 2-6 alkenylcarbonylamino group or =CH 2 ;

(iii) optionally by hydroxy, amino, carboxy, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino group or a 3-8 membered heterocyclic group substituted with a C 1-6 Alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, halo C 1-6 alkyl, halo C 1-6 alkoxy, C a 2-8 alkenyl group, a C 2-8 alkynyl group, a C 1-6 alkylsulfonyl group or a C 1-6 alkylthio group, and the 3-8 membered heterocyclic group may be optionally a hydroxyl group, an amino group or a carboxyl group. , cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino or (C 1-6 alkyl) 2 amino substituted;

(iv) optionally by hydroxy, amino, carboxy, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino or (C 1-6 alkyl a 2 amino-substituted 3-8 membered cycloalkyl, 5-8 membered cycloalkenyl or 3-8 membered heterocyclyl;

(v) amino-carbonyl, cyano-carbonyl, C 1-6 alkyl-carbonyl, C 1-6 alkylamino-carbonyl, (C 1-6 alkyl) 2 amino-carbonyl, C 1-6 alkoxy a carbonyl group, a 3-8 membered cycloalkyl-carbonyl group or a 3-8 membered heterocyclyl-carbonyl group;

R 3 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkylamino C 1-6 alkyl, (C 1-6 alkyl) 2 amino C 1-6 alkyl, halogenated C 1-6 An alkyl group, a halogenated C 2-8 alkenyl group, a C 2-8 alkynyl group, or a 3-12 membered cycloalkyl group optionally substituted by a substituent Q 1 , a 3-12 membered cycloalkenyl group, a 3-12 membered hetero cycloalkyl group, an aryl group or a 5-10 membered heteroaryl, the substituents Q 1 is selected from: hydroxy, amino, cyano, nitro, halogen, carboxyl, amide group, aminocarbonyl, aminosulfonyl, C 1- 6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylsulfonyl, C 1-6 alkylcarbonylamino, (C 1-6 alkyl) 2 carbonylamino, C 1-6 alkyl Aminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, C 1-6 alkylaminosulfonyl, (C 1-6 alkyl) 2 aminosulfonyl or C 1-6 alkoxy C 1-6 alkane Oxylate

R 4 is selected from the group consisting of hydrogen, hydroxy, amino, cyano, nitro, halogen, carboxyl, amide, aminocarbonyl, aminosulfonyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkane Amino group, (C 1-6 alkyl) 2 amino group, halogenated C 1-6 alkyl group, halogenated C 1-6 alkoxy group, C 2-8 alkenyl group, C 2-8 alkynyl group, C 1- 6 alkylsulfonyl, C 1-6 alkylcarbonylamino, (C 1-6 alkyl) 2 carbonylamino, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, C 1 -6 alkylaminosulfonyl, (C 1-6 alkyl) 2 aminosulfonyl, C 1-6 alkoxy C 1-6 alkoxy, or 3-12 optionally substituted by substituent Q 2 a cycloalkyl group, a 3-12 membered cycloalkenyl group, a 3-12 membered heterocyclic group, an aryl group or a 5-10 membered heteroaryl group, the substituent being selected from the group consisting of a hydroxyl group, an amino group, a cyano group, a nitro group, a halogen, Carboxy, amido, aminocarbonyl, aminosulfonyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, halogenated C 1 -6 alkyl, halo C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylsulfonyl, C 1-6 alkylcarbonylamino, (C 1 -6 alkyl) amino carbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 amino Carbonyl, C 1-6 alkyl aminosulfonyl, (C 1-6 alkyl) aminosulfonyl or C 1-6 alkoxy C 1-6 alkoxy; or two adjacent R 4 and The atoms respectively attached thereto form a 3-8 membered cycloalkyl group, a 3-8 membered cycloalkenyl group, a 3-8 membered heterocyclic group, an aryl group or a 5-6 membered heteroaryl group;

L 1 , L 2 , and L 3 are each independently a bond, -N(Rc)-, -O-, -S-, -S(O)-, -S(O) 2 -, -S(O) 2 NH-, -C(O)-, -NHC(O)-, -OC(O)-, C 1-6 alkylene, C 2-8 alkenylene or C 2-8 alkynylene, Rc selected From hydrogen or C 1-6 alkyl;

n, t, p, q are each independently 0 or 1;

m is an integer from 0 to 5, and when m ≥ 2, R 4 may be selected from the same or different groups.
The irreversible inhibitor of fibroblast growth factor receptor according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

Warhead 1 and warhead 2 are independently selected from

Warhead 1 and warhead 2 do not exist at the same time;

R 10 , R 11 , R 12 , R 13 , R 14 , R 15 are each independently selected from hydrogen, halogen, C 1-6 alkyl or halo C 1-6 alkyl;

Cy 4 is a divalent group selected from the group consisting of a 3-12 membered cycloalkyl group, a 3-12 membered cycloalkenyl group, a 3-12 membered heterocyclic group, an aryl group or a 5-10 membered heteroaryl group;

z is an integer from 0-4;

X is selected from C or N, when X is C,
Represents a double bond, when X is N,
Represents a single button;

When warhead 1 is present, R 1 is selected from C 1-6 alkylene, halo C 1-6 alkylene or -(L 1 )n-Cy 1 -(L 2 )t-(Cy 2 )p- When warhead 1 is absent, R 1 is selected from hydrogen, C 1-6 alkyl, halogenated C 1-4 alkyl or -(L 1 )n-Cy 1 -(L 2 )t-(Cy 2 ) p;

When warhead 2 is present, R 2 is selected from C 1-6 alkylene, halo C 1-6 alkylene or -(L 3 )q-Cy 3 -; when warhead 2 is absent, R 2 is selected from Hydrogen, C 1-6 alkyl, halogenated C 1-6 alkyl or -(L 3 )q-Cy 3 ;

Cy 1 and Cy 2 are each independently selected from the group consisting of one or more R a substituted or unsubstituted 3-8 membered monoheterocyclic group, 6-11 membered bridged heterocyclic group. a 7-12 membered spiroheterocyclyl group or a 6-11 membered heterocyclic group, an aryl group or a 5-10 membered heteroaryl group, the ring-forming carbon atom may be optionally oxidized to C(O), a ring-forming sulfur atom Optionally optionally oxidized to S(O) or S(O) 2 ;

Cy 3 is selected from the group consisting of one or more R b -substituted or unsubstituted 3-8 membered monoheterocyclic groups, 6-11 membered bridged heterocyclic groups, 7-12 membered snails a heterocyclic group or a 6-11 membered heterocyclic group, an aryl group or a 5-10 membered heteroaryl group, the ring-forming carbon atom may be optionally oxidized to C(O), and the ring-forming sulfur atom may be optionally oxidized to S(O) or S(O) 2 ;

R a and R b are each independently selected from:

(i) hydrogen, hydroxy, amino, carboxy, cyano, nitro, halogen, C 2-8 alkenylcarbonylamino or =CH 2 ,

(ii) optionally selected by hydroxy, amino, carboxy, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino group or a 3-8 membered heterocyclic group substituted with a C 1-6 Alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylsulfonyl or C 1-6 alkylthio,

(iii) optionally selected by hydroxy, amino, carboxy, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino or (C 1-6 alkyl a 2 amino-substituted 3-8 membered cycloalkyl group or a 3-8 membered heterocyclic group,

or

(iv) amino-carbonyl, cyano-carbonyl, C 1-6 alkyl-carbonyl, C 1-6 alkylamino-carbonyl, (C 1-6 alkyl) 2 amino-carbonyl, C 1-6 alkoxy a carbonyl group, a 3-8 membered cycloalkyl-carbonyl group or a 3-8 membered heterocyclyl-carbonyl group;

R 3 is selected from hydrogen or C 1-6 alkyl;

R 4 is selected from the group consisting of hydrogen, hydroxy, amino, cyano, nitro, halogen, carboxyl, amide, aminocarbonyl, aminosulfonyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkane Amino group, (C 1-6 alkyl) 2 amino group, halogenated C 1-6 alkyl group, halogenated C 1-6 alkoxy group, C 2-8 alkenyl group, C 2-8 alkynyl group, C 1- 6 alkylsulfonyl, C 1-6 alkylcarbonylamino, (C 1-6 alkyl) 2 carbonylamino, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, C 1 -6 alkylaminosulfonyl, (C 1-6 alkyl) 2 aminosulfonyl or C 1-6 alkoxy C 1-64 alkoxy;

L 1 , L 2 , and L 3 are each independently a bond, -N(R c )-, -O-, -S-, -S(O)-, -S(O) 2 -, -C(O). -, -NHC(O)-, -OC(O)- or C 1-6 alkylene, R c is selected from hydrogen or C 1-6 alkylene;

n, t, p, q are each independently 0 or 1;

m is an integer from 0 to 5, and when m ≥ 2, R 4 may be selected from the same or different groups;

When R 1 is -(L 1 )n-Cy 1 -(L 2 )t-(Cy 2 )p-, t and p are 0, and Cy 1 is substituted by one to more R a , or unsubstituted When a 3-8 membered monoheterocyclic group or a divalent group of a phenyl group, R 2 is -(L 3 )q-Cy 3 , and Cy 3 is substituted with one to more R b or unsubstituted 7- 12-membered spiro heterocyclic group.
The irreversible inhibitor of fibroblast growth factor receptor according to claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

Warhead 1 and warhead 2 are independently selected from

Warhead 1 and warhead 2 do not exist at the same time;

R 12 , R 13 and R 14 are each independently selected from hydrogen or C 1-4 alkyl;

X is selected from C or N, when X is C,
Represents a double bond, when X is N,
Represents a single button;

When warhead 1 is present, R 1 is selected from C 1-4 alkylene or -(L 1 )n-Cy 1 -(L 2 )t-(Cy 2 )p-; when warhead 1 is absent, R 1 Selected from hydrogen, C 1-4 alkyl or -(L 1 )n-Cy 1 -(L 2 )t-(Cy 2 )p;

When warhead 2 is present, R 2 is selected from C 1-4 alkylene or -(L 3 )q-Cy 3 -; when warhead 2 is absent, R 2 is selected from hydrogen, C 1-4 alkyl or - (L 3 )q-Cy 3 ;

Cy 1 and Cy 2 are each independently selected from the group consisting of one or more R a substituted or unsubstituted 3-8 membered monoheterocyclic group, 6-11 membered bridged heterocyclic group. a 7-12 membered spiroheterocyclyl group or a 6-11 membered heterocyclic group;

Cy 3 is selected from the group consisting of one or more R b -substituted or unsubstituted 3-8 membered monoheterocyclic groups, 6-11 membered bridged heterocyclic groups, 7-12 membered snails Heterocyclic group, 6-11 membered heterocyclic group;

R a and R b are each independently selected from:

(i) hydrogen, hydroxy, amino, cyano or halogen,

or

(ii) C 1-4 alkyl, C 1-4 alkylamino, (C 1-4 alkyl) 2 amino, hydroxy C 1-4 alkyl, cyano C 1-4 alkyl or halogenated C 1 -4 alkyl;

L 1 , L 2 , and L 3 are each independently a bond or a C 1-4 alkylene group;

n, t, p, q are each independently 0 or 1;

R 3 is selected from hydrogen or C 1-4 alkyl;

R 4 is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl or C 1-4 alkoxy;

m is an integer from 0 to 5, and when m ≥ 2, R 4 may be selected from the same or different groups;

When R 1 is -(L 1 )n-Cy 1 -(L 2 )t-(Cy 2 )p-, t and p are 0, and Cy 1 is substituted by one to more Ra, or unsubstituted When a divalent group of a 3-8 membered monoheterocyclic group, R 2 is -(L 3 )q-Cy 3 , and Cy 3 is substituted with one to more R b or unsubstituted 7-12 membered spiro Ring base.
The irreversible inhibitor of fibroblast growth factor receptor according to any one of claims 1 to 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

Warhead 1 and warhead 2 are independently selected from

Warhead 1 and warhead 2 do not exist at the same time;

R 12 , R 13 and R 14 are each independently selected from hydrogen or C 1-4 alkyl;

X is selected from C or N, when X is C,
Represents a double bond, when X is N,
Represents a single button;

When warhead 1 is present, R 1 is selected from C 1-4 alkylene or -(L 1 )n-Cy 1 -(L 2 )t-(Cy 2 )p-; when warhead 1 is absent, R 1 Selected from hydrogen, C 1-4 alkyl or -(L 1 )n-Cy 1 -(L 2 )t-(Cy 2 )p;

When warhead 2 is present, R 2 is selected from C 1-4 alkylene or -(L 3 )q-Cy 3 -; when warhead 2 is absent, R 2 is selected from hydrogen, C 1-4 alkyl or - (L 3 )q-Cy 3 ;

Cy 1 and Cy 2 are each independently a monovalent or divalent group selected from the group consisting of one or more R a substituted or unsubstituted

Cy 3 is selected from a monovalent or divalent group of the following structure: substituted with one to more R b or unsubstituted

R a and R b are each independently selected from hydrogen, C 1-4 alkyl or hydroxy C 1-4 alkyl;

L 1 , L 2 , and L 3 are each independently a bond or a C 1-4 alkylene group;

n, t, p, q are each independently 0 or 1;

R 3 is selected from hydrogen or C 1-4 alkyl;

R 4 is selected from the group consisting of hydrogen, a halogen atom, a C 1-4 alkyl group or a C 1-4 alkoxy group;

m is an integer from 0 to 5, and when m ≥ 2, R 4 may be selected from the same or different groups;

When R 1 is -(L 1 )n-Cy 1 -(L 2 )t-(Cy 2 )p-, t and p are 0, and Cy 1 is substituted by one to more R a , or unsubstituted of
In the case of a divalent group, R 2 is -(L 3 )q-Cy 3 and Cy 3 is substituted by one to more R b or unsubstituted
or
One price base.
The irreversible inhibitor of fibroblast growth factor receptor according to claim 3, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

Warhead 1 is
Warhead 2 does not exist;

R 12 and R 13 are each independently selected from hydrogen or C 1-4 alkyl;

X is selected from C or N, when X is C,
Represents a double bond, when X is N,
Represents a single button;

R 1 is -(L 1 ) n -Cy 1 -;

Cy 1 is a 7-12 membered spiroheterocyclyl group substituted by one to a plurality of R a , preferably 7-12 members containing an N-spiroheterocyclic group, and any of warhead 1 and Cy 1 is looped. N heteroatoms are connected;

L 1 is a bond or a C 1-4 alkylene group;

R a is selected from hydrogen or C 1-4 alkyl;

R 2 is selected from hydrogen or C 1-4 alkyl;

R 3 is selected from hydrogen or C 1-4 alkyl;

R 4 is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl or C 1-4 alkoxy;

n is 0 or 1;

m is an integer from 0 to 5, and when m ≥ 2, R 4 may be selected from the same or different groups.
The irreversible inhibitor of fibroblast growth factor receptor according to claim 5, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

Cy 1 is a divalent group of the following structure: substituted by one to more R a or unsubstituted

Warhead 1 is attached to any ring-forming N heteroatom in Cy 1 .
The irreversible inhibitor of fibroblast growth factor receptor according to claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof, said fibroblast growth factor receptor irreversible inhibitor such as IA):

among them,

Warhead 1 is selected from

R 12 , R 13 and R 14 are each independently selected from hydrogen or C 1-4 alkyl;

X is selected from C or N, when X is C,
Represents a double bond, when X is N,
Represents a single button;

R 2 is selected from the group consisting of hydrogen, C 1-4 alkyl, halo C 1-4 alkyl or -(L 3 )q-Cy 3 ;

Cy 1 and Cy 2 are each independently selected from a divalent group of a group: one or more R a substituted, or unsubstituted 3-8 membered monoheterocyclic group, 6-11 membered bridged heterocyclic group, a 7-12 membered spiroheterocyclyl group or a 6-11 membered heterocyclic group;

Cy 3 is selected from the group consisting of one or more R b substituted, or unsubstituted 3-8 membered monoheterocyclyl, 6-11 membered bridged heterocyclyl, 7-12 membered spiroheterocyclyl or 6 -11 membered heterocyclic group;

R a and R b are each independently selected from hydrogen, hydroxy, amino, carboxy, cyano, nitro, halogen, C 2-4 alkenylcarbonylamino, =CH 2 or optionally hydroxy, amino, carboxy, cyano , nitro, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxy C 1-4 alkoxy, C 1-4 alkylamino, (C 1-4 alkyl 2 amino, C 1-4 alkylcarbonylamino, C 1-4 alkylsulfonylamino or 3-8 membered heterocyclyl substituted C 1-4 alkyl, C 1-4 alkoxy, C 1- 4 -alkylamino, (C 1-4 alkyl) 2 amino, halo C 1-4 alkyl, halo C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkylsulfonyl or C 1-4 alkylthio;

R 3 is selected from hydrogen or C 1-4 alkyl;

R 4 is selected from the group consisting of hydrogen, hydroxy, amino, cyano, nitro, halogen, carboxyl, amide, aminocarbonyl, aminosulfonyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkane Amino, (C 1-4 alkyl) 2 amino, halo C 1-4 alkyl, halo C 1-4 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 1- 4 -alkylsulfonyl, C 1-4 alkylcarbonylamino, (C 1-4 alkyl) 2 carbonylamino, C 1-4 alkylaminocarbonyl, (C 1-4 alkyl) 2 aminocarbonyl, C 1 -4 alkylaminosulfonyl, (C 1-4 alkyl) 2 aminosulfonyl or C 1-4 alkoxy C 1-4 alkoxy;

L 1 , L 2 , and L 3 are each independently a bond, -N(R c )-, -O-, -S- or C 1-4 alkylene, and R c is selected from hydrogen or C 1-4 alkyl. ;

n, t, p, q are each independently 0 or 1;

m is an integer from 0 to 5, and when m ≥ 2, R 4 may be selected from the same or different groups;

When t and p are 0, and Cy 1 is a divalent group of one or more R a substituted or unsubstituted 3-8 membered monoheterocyclic groups, R 2 is -(L 3 )q-Cy 3 and Cy 3 is a 7-12 membered spiroheterocyclic group substituted with one to more R b or unsubstituted.
The irreversible inhibitor of fibroblast growth factor receptor according to claim 7, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

Warhead 1 is selected from

R 12 , R 13 and R 14 are each independently selected from hydrogen or C 1-4 alkyl;

X is selected from C or N, when X is C,
Represents a double bond, when X is N,
Represents a single button;

Cy 1 and Cy 2 are each independently a divalent group selected from the group consisting of one or more R a substituted or unsubstituted 3-8 membered nitrogen-containing monoheterocyclic groups and a 6-11 membered nitrogen-containing bridge. a heterocyclic group or a 7-12 membered nitrogen-containing spiroheterocyclyl;

R 2 is selected from hydrogen, C 1-4 alkyl or -(L 3 )q-Cy 3 ;

Cy 3 is a 7-12 membered spiroheterocyclic group substituted with one to more R b or unsubstituted;

R a , R b , R 3 are each independently selected from hydrogen or C 1-4 alkyl;

R 4 is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl or C 1-4 alkoxy;

L 1 , L 2 , and L 3 are each independently a bond or a C 1-4 alkylene group;

n, t, p, q are each independently 0 or 1;

m is an integer from 0 to 5, and when m ≥ 2, R 4 may be selected from the same or different groups;

When t and p are 0, and Cy 1 is a divalent group of one or more R a substituted or unsubstituted 3-8 membered nitrogen-containing monoheterocyclic groups, R 2 is -(L 3 )q -Cy 3 and Cy 3 is a 7-12 membered spiroheterocyclyl group substituted with one to more R b or unsubstituted.
The irreversible inhibitor of fibroblast growth factor receptor according to claim 8, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

Warhead 1 is selected from

R 12 , R 13 and R 14 are each independently selected from hydrogen or C 1-4 alkyl;

X is selected from C or N, when X is C,
Represents a double bond, when X is N,
Represents a single button;

Cy 1 and Cy 2 are each independently selected from a divalent group of the following structure: one to a plurality of R a substituted or unsubstituted

R 2 is selected from hydrogen, C 1-4 alkyl or -(L 3 )q-Cy 3 ;

Cy 3 is a 7-12 membered spiroheterocyclic group substituted with one to more R b or unsubstituted;

R a , R b , and R 3 are each independently selected from hydrogen, C 1-4 alkyl;

R 4 is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl or C 1-4 alkoxy;

L 1 , L 2 , and L 3 are each independently a bond or a C 1-4 alkylene group;

n, t, p, q are each independently 0 or 1;

m is an integer from 0 to 5, and when m ≥ 2, R 4 may be selected from the same or different groups;

When t and p are 0, and Cy 1 is substituted by one to more R a , or unsubstituted

In the case of a divalent group, R 2 is -(L 3 )q-Cy 3 , and Cy 3 is a 7-12 membered spiroheterocyclic group substituted with one to more R b or unsubstituted.
The irreversible inhibitor of fibroblast growth factor receptor according to any one of claims 7 to 9, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

Warhead 1 is

R 12 and R 13 are each independently selected from hydrogen or C 1-4 alkyl;

Cy 1 is a divalent group of the following structure: substituted by one to more R a or unsubstituted

Warhead 1 is attached to any ring-forming N hetero atom in Cy 1 ;

t and p are respectively 0;

n is 0;

R a is selected from hydrogen or C 1-4 alkyl;

R 2 is selected from hydrogen or C 1-4 alkyl;

R 3 is selected from hydrogen or C 1-4 alkyl;

R 4 is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl or C 1-4 alkoxy;

m is an integer from 0 to 5, and when m ≥ 2, R 4 may be selected from the same or different groups.
The irreversible inhibitor of fibroblast growth factor receptor according to any one of claims 7 to 9, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

Warhead 1 is

R 12 , R 13 and R 14 are each independently selected from hydrogen or C 1-4 alkyl;

Cy 1 is a divalent group of the following structure: substituted by one to more R a or unsubstituted

Warhead 1 is attached to any ring-forming N hetero atom in Cy 1 ;

t and p are respectively 0;

R 2 is selected from hydrogen, C 1-4 alkyl or is -(L 3 )q-Cy 3 ;

Cy 3 is a monovalent group of the following structure: substituted with one to more R b or unsubstituted
n, q are independently 0 or 1;

R a , R b are each independently selected from hydrogen or C 1-4 alkyl;

R 3 is selected from hydrogen or C 1-4 alkyl;

R 4 is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl or C 1-4 alkoxy;

L 1 and L 3 are each independently a bond, a C 1-4 alkyl group;

m is an integer from 0 to 5, and when m ≥ 2, R 4 may be selected from the same or different groups.
The irreversible inhibitor of fibroblast growth factor receptor according to any one of claims 7 to 9, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

Warhead 1 is

R 12 and R 13 are each independently selected from hydrogen or C 1-4 alkyl;

Cy 1 and Cy 2 are each independently a divalent group of the following structure: optionally substituted by one to more R a , or unsubstituted

Warhead 1 is attached to any ring-forming N hetero atom in Cy 2 ;

n, t are respectively 0;

p is 1;

R a is selected from hydrogen or C 1-4 alkyl;

R 2 is selected from hydrogen or C 1-4 alkyl;

R 3 is selected from hydrogen or C 1-4 alkyl;

R 4 is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl or C 1-4 alkoxy;

m is an integer from 0 to 5, and when m ≥ 2, R 4 may be selected from the same or different groups.
The irreversible inhibitor of fibroblast growth factor receptor according to claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof, the fibroblast growth factor receptor irreversible inhibitor such as the formula (IB) ) shown:

among them,

Warhead 2 is selected from

R 10 , R 11 , R 12 , R 13 and R 14 are each independently selected from hydrogen or C 1-4 alkyl;

X is selected from C or N, when X is C,
Represents a double bond, when X is N,
Represents a single button;

R 1 is selected from hydrogen or C 1-4 alkyl;

Cy 3 is a 3-8 membered monomonoheterocyclic group substituted with one to more R b or unsubstituted;

R b is selected from:

(i) hydrogen, hydroxy, amino, carboxy, cyano, nitro, halogen, C2-4 alkenylcarbonylamino or =CH 2 ;

(ii) optionally by hydroxy, amino, carboxy, cyano, nitro, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxy C 1-4 alkoxy, C 1-4 alkylamino, (C 1-4 alkyl) 2 amino, C 1-4 alkylcarbonylamino, C 1-4 alkylsulfonylamino or 3-8 membered heterocyclyl substituted C 1-4 Alkyl, C 1-4 alkoxy, C 1-4 alkylamino, (C 1-4 alkyl) 2 amino, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkylsulfonyl or C 1-4 alkylthio;

(iii) optionally by hydroxy, amino, carboxy, cyano, nitro, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino or (C 1-4 alkyl a 2 amino-substituted 3-8 membered cycloalkyl or 3-8 membered heterocyclic group;

or

(iv) amino-carbonyl, cyano-carbonyl, C 1-4 alkyl-carbonyl, C 1-4 alkylamino-carbonyl, (C 1-4 alkyl) 2 amino-carbonyl, C 1-4 alkoxy a carbonyl group, a 3-8 membered cycloalkyl-carbonyl group or a 3-8 membered heterocyclyl-carbonyl group;

R 3 is selected from hydrogen or C 1-4 alkyl;

R 4 is selected from the group consisting of hydrogen, hydroxy, amino, cyano, nitro, halogen, carboxyl, amide, aminocarbonyl, aminosulfonyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkane Amino, (C 1-4 alkyl) 2 amino, halo C 1-4 alkyl, halo C 1-4 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 1- 4 -alkylsulfonyl, C 1-4 alkylcarbonylamino, (C 1-4 alkyl) 2 carbonylamino, C 1-4 alkylaminocarbonyl, (C 14 alkyl) 2 aminocarbonyl, C 1-4 An alkylaminosulfonyl group, a (C 1-4 alkyl) 2 aminosulfonyl group or a C 1-4 alkoxy C 1-4 alkoxy group;

L 3 is each a bond, -N(R c )-, -O-, -S- or C 1-4 alkyl, and R c is selected from hydrogen or C 1-4 alkyl;

q is 0 or 1;

m is an integer from 0 to 5, and when m ≥ 2, R 4 may be selected from the same or different groups.
The fibroblast growth factor receptor irreversible inhibitor according to claim 13, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

Warhead 2 is

R 12 and R 13 are each independently selected from hydrogen or C 1-4 alkyl;

X is selected from C or N, when X is C,
Represents a double bond, when X is N,
Represents a single button;

R 1 is selected from hydrogen or C 1-4 alkyl;

Cy 3 is a divalent group of the following structure: substituted by one to more R b or unsubstituted

Warhead 2 is connected to any ring-forming N hetero atom in Cy 3 ;

q is 0;

R b is selected from hydrogen, C 1-4 alkyl or hydroxy C 1-4 alkyl;

R 3 is selected from hydrogen or C 1-4 alkyl;

R 4 is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl or C 1-4 alkoxy;

m is an integer from 0 to 5, and when m ≥ 2, R 4 may be selected from the same or different groups.
The irreversible inhibitor of fibroblast growth factor receptor according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the fibroblast growth factor receptor irreversible inhibitor A compound selected from the following structures:
A pharmaceutical preparation comprising the irreversible inhibitor of fibroblast growth factor receptor according to any one of claims 1 to 15, or a pharmaceutically acceptable salt or stereoisomer thereof, preferably, the pharmaceutical preparation comprises one or a plurality of pharmaceutically acceptable carriers, and preferably, the pharmaceutical preparation comprises one or more second therapeutically active agents, the second therapeutically active agent being an antimetabolite, a growth factor inhibitor, a silk classification inhibitor, Anti-tumor hormones, alkylating agents, metals, topoisomerase inhibitors, hormonal drugs, immunomodulators, tumor suppressor genes, cancer vaccines, immunological checkpoints or tumor immunotherapy-related antibodies and small molecule drugs.
The fibroblast growth factor receptor irreversible inhibitor according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, a stereoisomer or the pharmaceutical preparation according to any one of claims 16 to prepare a therapeutic FGF /FGFR Abnormally Mediated Use of Drugs in Diseases

Preferably, the FGF/FGFR abnormally mediated disease is cancer; the cancer includes lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer, breast ductal carcinoma, head and neck cancer , endometrial cancer, uterine body cancer, rectal cancer, liver cancer, kidney cancer, renal pelvic cancer, esophageal cancer, esophageal adenocarcinoma, glioma, prostate cancer, thyroid cancer, female reproductive system cancer, carcinoma in situ, lymphoma , neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, oral cancer, pharyngeal cancer, multiple myeloma, leukemia, non-Hodgkin's lymphoma, large intestine villi Adenoma, melanoma, cell tumor and sarcoma and / or myelodysplastic syndrome.