WO2019057053A1 - Fused ring derivative used as fgfr4 inhibitor - Google Patents

Abstract

Provided are a compound of formula (I) having FGFR4 inhibitory activity, a preparation process therefor, and use thereof in the manufacture of a medicament for treating a disease associated with FGFR4.

Description

Fused ring derivatives used as FGFR4 inhibitors Technical field

The present invention provides fused ring derivative compounds for use in inhibiting the use of FGFR4 and methods of using the compounds to treat diseases.

Background technique

The fibroblast growth factor receptor (FGFR) belongs to the receptor protein tyrosine kinase family, and by binding to a ligand, many signaling pathways, including Ras-MAPK, AKT-PI3K, and phospholipase C, can be activated in cells. Growth, proliferation and survival all play an important role.

Alterations in FGFRs are associated with many human cancers, and abnormal activation of this pathway, whether overexpressing FGF ligands or FGFR or activated FGFR mutations, can lead to tumorigenesis, development, and resistance to traditional cancer treatment. Large-scale DNA sequencing of thousands of tumor samples reveals that the components of the FGFR pathway are the most common mutations in human cancers. FGFR4 is a tyrosine kinase receptor in humans encoded by the gene FGFR4 and is highly conserved in evolution and requires binding to its specific ligand FGF19. Its signaling pathway is roughly as follows: activated FGFR4 leads to FRS2 phosphorylation and Raising GRB2, and finally activating Ras-Raf-ERK1/2 (MAPK) and PI3K-Akt signaling pathways, increased cell proliferation and anti-apoptosis. More and more studies have shown that FGFR4 activation and FGF19 overexpression play an important role in the development of liver cancer. Inhibition of FGFR4 can effectively reduce the occurrence of liver cancer. About one-third of liver cancer patients have high expression of FGFR4, ligand FGF19 and coreceptor KLB. In addition, changes in the signal axis of FGFR4-FGF19 are also associated with the development of colorectal cancer, breast cancer, pancreatic cancer, prostate cancer, lung cancer, and thyroid cancer.

According to preliminary research, fibroblast growth factor receptor 4 (FGFR4) inhibitor has great potential for treating liver cancer, and it has better specificity and effectiveness than similar drugs. Liver cancer is the most common malignant and fatal disease after lung cancer, and China's liver cancer patients are the most in the world. As the only approved first-line drug for patients with advanced liver cancer, Sorafenib can only increase the patient's average survival of 3 months, and because of its multi-target tyrosine kinase inhibitor, it has strong side effects. Therefore, the development of more effective liver cancer drugs has become an urgent need around the world, and FGFR4 inhibitors offer a possibility for this breakthrough.

At present, FGFR4 inhibitors are a hot research direction in the field of liver cancer treatment research in the world, and also a market direction that the world's biopharmaceutical companies are competing for, but due to various limitations of experimental methods, research cycles, etc., there is currently no FGFR4 inhibitor drug. Put into the market. As the country with the highest incidence of liver cancer and the largest number of liver cancer patients in China, the breakthrough in this direction will have a strong clinical application significance. At present, there are no similar drugs in the country to enter clinical research, and the international are in the early stage of clinical research, so the breakthrough in this direction will greatly enhance the international competitiveness of new drug research and development in China.

Summary of the invention

The present invention provides fused ring derivatives as FGFR4 inhibitors, and their use in the treatment of diseases inhibited by FGFR4. The compound of the present invention has a structure represented by the formula (I) or a pharmaceutically acceptable salt thereof:

among them,

R _{1 is} selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, CH ₂ NR _1a R _1b or C(O)NR _1a R _1b ;

Each of R _1a and R _{1b is} independently selected from the group consisting of hydrogen, C _1-6 alkyl, C(O)CH ₂ OH, C(O)CH ₂ OCH ₃ , C(O)CH ₂ N(CH ₃ ) ₂ Or S(O) ₂ CH ₃ ;

or

R _1a and R _1b together with the N atom to which they are attached form a saturated substituted or unsubstituted 5-membered heterocyclic ring or 6-membered heterocyclic ring containing 1, 2, 3 or 4 a hetero atom independently selected from N or O, and may be substituted one or more times by R ₁₁ ;

R _{11 is} selected from the group consisting of hydrogen, halogen, amino, cyano, hydroxy, nitro, carboxy, C _1-6 alkyl, C _1-6 alkoxy or C(O)C _1-6 alkyl;

or

Two R ₁₁ attached to the same ring atom form an oxo group;

R _{2 is} selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, CH ₂ NR _2a R _2b or C(O)NR _2a R _2b ;

Each of R _2a and R _{2b is} independently selected from the group consisting of hydrogen, C _1-6 alkyl, C(O)CH ₂ OH, C(O)CH ₂ OCH ₃ , C(O)CH ₂ N(CH ₃ ) ₂ Or S(O) ₂ CH ₃ ;

or

R _2a and R _2b together with the N atom to which they are attached form a saturated substituted or unsubstituted 5-membered heterocyclic ring or 6-membered heterocyclic ring containing 1, 2, 3 or 4 a hetero atom independently selected from N or O, and may be substituted one or more times by R ₁₂ ;

R _{12 is} selected from the group consisting of hydrogen, halogen, amino, cyano, hydroxy, nitro, carboxy, C _1-6 alkyl, C _1-6 alkoxy or C(O)C _1-6 alkyl;

or

Two R ₁₂ attached to the same ring atom form an oxo group;

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

R _{4 is} selected from hydrogen, halogen, amino, cyano, hydroxy, nitro, carboxy, C _1-6 alkyl, C _1-6 alkoxy or NHR _4a , and each R ₄ may be optionally substituted with a substituent Or not substituted; the substituents are each independently selected from halogen, cyano, hydroxy, amino, C _1-6 alkyl or C _1-6 alkoxy;

R _{4a is} selected from the group consisting of hydrogen, C _1-6 alkyl, C _1-6 alkoxy, N(C _1-6 alkyl) ₂ or (CH ₂ ) _1-6 -C _1-6 alkoxy.

In some embodiments, R ₁ in formula (I) is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, C _1-3 alkyl, CH ₂ NR _1a R _1b or C(O)NR _1a R _1b .

In some embodiments, R ₁ in formula (I) is selected from the group consisting of hydrogen, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, CH ₂ NR _1a R _1b or C(O)NR _1a R _1b .

In some embodiments, each of R _1a and R _1b in formula (I) is independently selected from hydrogen, C _1-3 alkyl, C(O)CH ₂ OH, C(O)CH ₂ OCH ₃ or C, respectively. (O) CH ₂ N(CH ₃ ) ₂ .

In some embodiments, each of R _1a and R _1b in formula (I) is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl or C(O)CH ₂ OH.

In some embodiments, R _1a and R _1b in formula (I) are taken together with the N atom to which they are attached to form a saturated substituted or unsubstituted 5 membered heterocyclic or 6 membered heterocyclic ring, said 5 membered heterocyclic ring or 6 membered heterocyclic ring containing 1, 2 or 3 substituents each independently selected from N or O heteroatoms, and R ₁₁ may be substituted one or more times.

In some embodiments, R _1a and R _1b in formula (I) are taken together with the N atom to which they are attached to form a saturated substituted or unsubstituted 5 membered heterocyclic or 6 membered heterocyclic ring, said 5 membered heterocyclic ring or 6 membered heterocyclic ring containing 1 or 2 substituents each independently selected from N or O heteroatoms, and may be substituted once, twice or three times R _11.

In some embodiments, R ₁₁ in formula (I) is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, amino, cyano, hydroxy, nitro, carboxy, C _1-3 alkyl, C _1-3 alkoxy Or a C(O)C _1-3 alkyl group; or

Two R ₁₁ attached to the same ring atom form an oxo group.

Some embodiments of formula (I) R ₁₁ is selected from hydrogen, fluoro, chloro, bromo, amino, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy , isopropoxy, C(O)CH ₃ , C(O)CH ₂ CH ₃ , C(O)CH(CH ₃ ) ₂ or C(O)CH ₂ CH ₂ CH ₃ ;

Two R ₁₁ attached to the same ring atom form an oxo group.

In some embodiments, R _1a and R _1b in formula (I) are taken together with the N atom to which they are attached to form a substituted or unsubstituted 5-membered heterocyclic ring or 6-membered heterocyclic ring, said 5-membered heterocyclic ring or 6-membered heterocyclic ring. Ring selected

And may be substituted with one or more substituents R _11, R ₁₁ is selected from methyl, or both connected to the same ring atom R ₁₁ form an oxo.

In some embodiments, R _1a and R _1b in formula (I) are taken together with the N atom to which they are attached to form a substituted or unsubstituted 5-membered heterocyclic ring or 6-membered heterocyclic ring, said 5-membered heterocyclic ring or 6-membered heterocyclic ring. Ring selected

In some embodiments, R ₂ in formula (I) is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, C _1-3 alkyl, CH ₂ NR _2a R _2b or C(O)NR _2a R _2b .

In some embodiments, R ₂ in formula (I) is selected from the group consisting of hydrogen, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, CH ₂ NR _2a R _2b or C(O)NR _2a R _2b .

In some embodiments, each R _2a and R _2b in formula (I) are independently selected from hydrogen, C _1-3 alkyl, C(O)CH ₂ OH, C(O)CH ₂ OCH ₃ or C, respectively. (O) CH ₂ N(CH ₃ ) ₂ .

In some embodiments, each of R _2a and R _2b in formula (I) is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl or C(O)CH ₂ OH.

In some embodiments, R _2a and R _2b in formula (I) are taken together with the N atom to which they are attached to form a saturated substituted or unsubstituted 5 membered heterocyclic or 6 membered heterocyclic ring, said 5 membered heterocyclic ring or 6 membered heterocyclic ring containing 1, 2 or 3 substituents each independently selected from N or O heteroatoms, and R ₁₂ may be substituted one or more times.

In some embodiments, R _2a and R _2b in formula (I) are taken together with the N atom to which they are attached to form a saturated substituted or unsubstituted 5 membered heterocyclic or 6 membered heterocyclic ring, said 5 membered heterocyclic ring or 6 The heterocyclic ring contains 1 or 2 heteroatoms independently selected from N or O, and may be substituted one or more times by R ₁₂ .

Some embodiments of formula (I) R ₁₂ is selected from hydrogen, fluoro, chloro, bromo, iodo, amino, cyano, hydroxyl, nitro, carboxyl, C _1-3 alkyl, C _1-3 alkoxy Or a C(O)C _1-3 alkyl group; or

Two R ₁₂ attached to the same ring atom form an oxo group.

Some embodiments of formula (I) R ₁₂ is selected from hydrogen, fluoro, chloro, bromo, amino, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy , isopropoxy, C(O)CH ₃ , C(O)CH ₂ CH ₃ , C(O)CH(CH ₃ ) ₂ or C(O)CH ₂ CH ₂ CH ₃ ;

Two R ₁₂ attached to the same ring atom form an oxo group.

In some embodiments, R _2a and R _2b in formula (I) are taken together with the N atom to which they are attached to form a substituted or unsubstituted 5-membered heterocyclic ring or 6-membered heterocyclic ring, said 5-membered heterocyclic ring or 6-membered heterocyclic ring. Ring selected

And may be substituted with one or more substituents R _12, R ₁₂ is selected from methyl, or both connected to the same ring atom R ₁₂ form an oxo.

In some embodiments, R _2a and R _2b in formula (I) are taken together with the N atom to which they are attached to form a substituted or unsubstituted 5-membered heterocyclic ring or 6-membered heterocyclic ring, said 5-membered heterocyclic ring or 6-membered heterocyclic ring. Ring selected

In some embodiments, R ₃ in formula (I) is selected from hydrogen, fluoro, chloro, bromo, iodo or C _1-3 alkyl.

In some embodiments, R ₃ in formula (I) is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl or isopropyl.

Some embodiments of formula (I) R ₄ is selected from hydrogen, fluoro, chloro, bromo, iodo, amino, cyano, hydroxy, C _1-3 alkyl, C _1-3 alkoxy or NHR _4a, And each R ₄ may be optionally substituted or unsubstituted with a substituent; the substituents are each independently selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, amino, C _1-3 alkyl or C _1-3 alkane Oxygen.

In some embodiments, R _4a in formula (I) is selected from the group consisting of hydrogen, C _1-3 alkyl, C _1-3 alkoxy, N(C _1-3 alkyl) ₂ or (CH ₂ ) _1-3 -C _1-3 alkoxy.

In some embodiments, R _4a in formula (I) is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, N (CH) ₃ ) ₂ , N(CH ₂ CH ₃ ) ₂ , CH ₂ OCH ₃ , CH(CH ₃ )OCH ₃ , CH ₂ CH ₂ OCH ₃ , CH ₂ CH ₂ CH ₂ OCH ₃ , CH ₂ OCH ₂ CH ₃ or C (CH ₃ ) ₂ OCH ₃ .

Some embodiments of formula (I) R ₄ is selected from hydrogen, fluoro, chloro, bromo, amino, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy , propoxy, isopropoxy, NHCH ₃ , NHCH ₂ CH ₃ , NHCH ₂ OCH ₃ , NHCH ₂ CH ₂ OCH ₃ or NHCH ₂ OCH ₂ CH ₃ , and each R ₄ may be optionally substituted with a substituent or Not substituted; the substituents are each independently selected from the group consisting of fluorine, chlorine, bromine, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropyl Oxygen.

Some embodiments of formula (I) R ₄ is selected from hydrogen, fluoro, chloro, amino, cyano, hydroxy, methyl, ethyl, isopropyl, methoxy, isopropoxy, NHCH _3, NHCH ₂ OCH ₃ or NHCH ₂ CH ₂ OCH ₃ , and each R _{4 is} optionally substituted or unsubstituted with a substituent; the substituents are each independently selected from the group consisting of fluorine, chlorine, hydroxyl, amino, methyl, ethyl , isopropyl, methoxy or isopropoxy.

In some embodiments, R ₄ in formula (I) is selected from the group consisting of hydrogen, fluoro, amino, cyano, methyl, isopropoxy, NHCH ₂ CH ₂ OCH ₃ or OCH(CH ₃ )CH ₂ OCH ₃ .

The invention further provides some particularly preferred technical solutions for the compounds of formula (I), said compounds being:

1) N-(5-Cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-2-formyl-3-((4-methyl-2-oxoper) Pyrazin-1-yl)methyl)quinoline-8-carboxamide;

2) N-(5-Cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-2-formyl-3-(4-methyl-2-oxopiperazine -1-carbonyl)quinoline-8-carboxamide;

3) N-(5-Cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-2-formyl-3-(4-methylpiperazine-1-carbonyl) Quinoline-8-carboxamide;

4) N-(5-Cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-2-formyl-quinoline-8-carboxamide;

5) N-(5-Cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-2-formyl-3-((2-oxopiperazine-1-yl) )methyl)quinoline-8-carboxamide;

6) N-(5-Cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-2-formyl-3-((3-oxomorpholine)methyl) Quinoline-8-carboxamide;

7) N-(5-Cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-2-formyl-3-((2-hydroxy-N-methylacetamide) Methyl)quinoline-8-carboxamide;

8) N-(5-Cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-2-formyl-3-((4-methyl-2-oxo) Azolidin-3-yl)methyl)quinoline-8-carboxamide;

9) N-(5-Cyano-4-((1-methoxypropan-2-yl)oxy)pyridin-2-yl)-2-formyl-3-((4-methyl-2) -oxopiperin-1-yl)methyl)quinoline-8-carboxamide;

10) N-(5-Cyano-4-((1-methoxypropan-2-yl)oxy)pyridin-2-yl)-2-formyl-3-((2-oxopiperazine) -1-yl)methyl)quinoline-8-carboxamide;

11) N-(5-Cyano-4-((1-methoxypropan-2-yl)oxy)pyridin-2-yl)-2-formyl-3-((3-oxomorpholine) )methyl)quinoline-8-carboxamide;

12) N-(5-Cyano-4-((1-methoxypropan-2-yl)oxy)pyridin-2-yl)-2-formyl-3-((2-hydroxy-N-) Methyl acetamido)methyl)quinoline-8-carboxamide;

13) N-(5-Cyano-4-((1-methoxypropan-2-yl)oxy)pyridin-2-yl)-2-formyl-3-((4-methyl-2) -oxooxazolidin-3-yl)methyl)quinoline-8-carboxamide;

14) N-(5-Cyano-4-isopropoxypyridin-2-yl)-2-formyl-3-((4-methyl-2-oxopiperin-1-yl)methyl Quinoline-8-carboxamide;

15) N-(5-Cyano-4-isopropoxypyridin-2-yl)-2-formyl-3-((2-oxopiperin-1-yl)methyl)quinoline-8 -formamide;

16) N-(5-Cyano-4-isopropoxypyridin-2-yl)-2-formyl-3-((3-oxomorpholine)methyl)quinoline-8-carboxamide;

17) N-(5-Cyano-4-isopropoxypyridin-2-yl)-2-formyl-3-((2-hydroxy-N-methylacetylamino)methyl)quinoline-8 -formamide;

18) N-(5-Cyano-4-isopropoxypyridin-2-yl)-2-formyl-3-((4-methyl-2-oxooxazol-3-yl)-methyl Base) quinoline-8-carboxamide.

The invention further provides some particularly preferred embodiments relating to the compound of formula (I), which means: N-(5-cyano-4-((2-methoxyethyl)amino)pyridine -2-yl)-2-formyl-3-((4-methyl-2-oxopiprazin-1-yl)methyl)quinoline-8-carboxamide.

The invention also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the above compounds and/or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant. In some compositions, the weight ratio of the compound and/or its pharmaceutically acceptable salt to the excipient is from 0.001:1 to 10:1.

Further, the present invention provides the compound of the above formula (I) or a pharmaceutically acceptable salt thereof, or the use of the pharmaceutical composition for the preparation of a medicament.

The invention further provides a preferred technical solution for said use.

In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition is used as an FGFR4 inhibitor.

In some embodiments, the FGFR4 inhibitor is used to treat, prevent, delay or prevent the onset or progression of cancer, cancer metastasis, cardiovascular disease, immunological disease.

In some embodiments, the cancer is selected from the group consisting of liver cancer, breast cancer, glioblastoma, prostate cancer, rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer, or colon cancer.

Furthermore, the present invention provides a method of treating a disease in a subject, which comprises administering to the subject a compound of formula (I) and/or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above.

The invention further provides a preferred embodiment of the above method.

In some embodiments, the method of treatment is for treating, preventing, delaying, or preventing the onset or progression of cancer, cancer metastasis, cardiovascular disease, immunological disease.

In some embodiments, the cancer is selected from the group consisting of liver cancer, breast cancer, glioblastoma, prostate cancer, rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer, or colon cancer.

In the present invention, the term "halogen" means fluorine, chlorine, bromine or iodine unless otherwise stated. Preferred halo groups refer to fluorine, chlorine and bromine.

In the present invention, unless otherwise indicated, the term "alkyl" means a straight or branched hydrocarbon group having a specific number of carbon atoms. For example, "C _1-6 alkyl" refers to a straight or branched alkyl group containing at least one, up to 6 carbon atoms, including, but not limited to, methyl, ethyl, propyl, n-butyl, positive Butyl, n-hexyl, isopropyl, isobutyl, tert-butyl and 1,1-dimethylpropyl.

In the present invention, unless otherwise indicated, the term "alkoxy" means a straight or branched alkoxy group having a specific number of carbon atoms. For example, "C _1-6 alkoxy" refers to a straight or branched alkoxy group containing at least one, up to 6 carbon atoms, including, but not limited to, methoxy, ethoxy, propoxy, Prop-2-oxy, butoxy, but-2-oxy, 2-methylprop-1-oxy, 2-methylprop-2-oxy, pentyloxy or hexyloxy.

In the present invention, unless otherwise indicated, the term "oxo" means that two hydrogen atoms on the same carbon are replaced together by an oxygen atom.

The term "composition" as used in the present invention is intended to include a product containing a particular amount of a particular component, as well as any product derived directly or indirectly from a particular quantity of the particular component. Therefore, a pharmaceutical composition comprising the compound of the present invention as an active ingredient and a method of preparing the same are also the contents of the present invention. Moreover, the crystalline forms of some of the compounds may exist in polymorphic form, and these are also included in the present invention. Further, some of the compounds form solvates with water (e.g., hydrates) or common organic solvents, and these solvates are also included in the present invention.

The compounds provided herein may also exist in the form of a pharmaceutically acceptable salt. In terms of pharmaceutical use, the salts of the compounds provided herein refer to non-toxic "pharmaceutically acceptable salts." The form of the pharmaceutically acceptable salt includes a pharmaceutically acceptable acid/anionic salt or a base/cationic salt. Pharmaceutically acceptable acid/anionic salts are generally present in the form of a basic nitrogen which is protonated by a mineral or organic acid. Typical organic or inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, lactic acid, succinic acid, maleic acid, fumaric acid, malic acid. , tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, isethionic acid, benzenesulfonic acid, oxalic acid, pamoic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfonic acid, salicyl Acid, saccharin acid or trifluoroacetic acid. Pharmaceutically acceptable base/cationic salts including, but not limited to, aluminum salts, calcium salts, chloroprocaine salts, choline, diethanolamine salts, ethylenediamine salts, lithium salts, magnesium salts, potassium salts, sodium Salt and zinc salts.

Prodrugs of the compounds of the invention are included within the scope of the invention. Generally, the prodrug refers to a functional derivative that is readily converted in vivo to the desired compound. Thus, the term "administering" in the methods of treatment provided by the present invention includes the administration of a compound disclosed herein, or, although not explicitly disclosed, can be converted in vivo to a compound disclosed in the present invention after administration to a subject. Various diseases. Conventional methods for the selection and preparation of suitable prodrug derivatives have been described, for example, in the book "Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985".

The compounds of the invention may contain one or more asymmetric centers and may thereby give rise to diastereomers and optical isomers. The invention includes all possible diastereomers and racemic mixtures thereof, substantially pure resolved enantiomers thereof, all possible geometric isomers, and pharmaceutically acceptable salts thereof.

The above formula (I) does not exactly define the stereostructure of a certain position of the compound. The present invention includes all stereoisomers of the compound of formula (I) and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers and isolated specific stereoisomers are also included in the present invention. In the course of the synthesis of such compounds, or in the course of racemization or epimerization processes well known to those skilled in the art, the resulting product may be a mixture of stereoisomers.

When a tautomer is present in the compound of formula (I), the invention includes any possible tautomer and pharmaceutically acceptable salts thereof, and mixtures thereof, unless otherwise stated.

When the compound of formula (I) and pharmaceutically acceptable salts thereof are in the form of a solvate or polymorph, the invention includes any possible solvates and polymorphs. The type of solvent forming the solvate is not particularly limited as long as the solvent is pharmacologically acceptable. For example, water, ethanol, propanol, acetone, and the like can be used.

The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid. When the compound provided by the present invention is an acid, the corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper (high and low), ferric iron, ferrous, lithium, magnesium, manganese (high and low), potassium, sodium, zinc and the like. Salts of ammonium, calcium, magnesium, potassium and sodium are particularly preferred. Non-toxic organic bases which can be derivatized into pharmaceutically acceptable salts include primary, secondary and tertiary amines, as well as cyclic amines and amines containing substituents such as naturally occurring and synthetic substituent-containing amines. Other pharmaceutically acceptable non-toxic organic bases capable of forming salts, including ion exchange resins and arginine, betaine, caffeine, choline, N', N'-dibenzylethylenediamine, diethylamine, 2 -diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, hexamine, isopropylamine Lysine, methyl glucosamine, morpholine, piperazine, piperidine, polyamine resin, procaine, guanidine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

When the compound provided by the present invention is a base, the corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid , lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid and p-toluenesulfonic acid. More preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid. More preferably, formic acid and hydrochloric acid. Since the compound of formula (I) will be used as a pharmaceutical, it is preferred to use a substantially pure form, for example, at least 60% purity, more suitably at least 75% purity, in particular at least 98% purity (% is weight ratio) ).

The pharmaceutical composition provided by the present invention comprises as an active ingredient a compound of the formula (I) (or a pharmaceutically acceptable salt thereof), a pharmaceutically acceptable excipient and other optional therapeutic components or Excipients. Although the most suitable form of administration of the active ingredient in any given case will depend on the particular subject being administered, the nature of the subject, and the severity of the condition, the pharmaceutical compositions of the present invention include those suitable for oral, rectal, topical and A pharmaceutical composition for parenteral administration, including subcutaneous administration, intramuscular injection, intravenous administration. The pharmaceutical compositions of the present invention may conveniently be prepared in unit dosage forms well known in the art and in any preparations known in the pharmaceutical art.

In fact, according to the conventional drug mixing technique, the compound of the formula (I), or a prodrug, or a metabolite, or a pharmaceutically acceptable salt of the present invention can be used as an active ingredient and mixed with a pharmaceutical carrier into a pharmaceutical combination. Things. The pharmaceutical carrier can take a wide variety of forms depending on the mode of administration desired to be employed, for example, orally or by injection (including intravenous injection). Accordingly, the pharmaceutical composition of the present invention may be in the form of a separate unit suitable for oral administration, such as a capsule, cachet or tablet containing a predetermined dose of the active ingredient. Further, the pharmaceutical composition of the present invention may be in the form of a powder, granule, solution, aqueous suspension, non-aqueous liquid, oil-in-water emulsion, or water-in-oil emulsion. Further, in addition to the above-mentioned common dosage forms, the compound of the formula (I) or a pharmaceutically acceptable salt thereof can also be administered by controlled release means and/or delivery means. The pharmaceutical composition of the present invention can be produced by any pharmaceutically effective method. In general, this method involves the step of bringing into association the active component with a carrier which comprises one or more of the essential ingredients. In general, the pharmaceutical compositions are prepared by uniformly intimately mixing the active ingredient with a liquid carrier or a finely divided solid carrier or a mixture of both. The product can then be conveniently prepared to the desired appearance.

Accordingly, the pharmaceutical composition of the present invention comprises a pharmaceutically acceptable carrier and a compound of the formula (I) or a pharmaceutically acceptable salt thereof. A compound of the formula (I) or a pharmaceutically acceptable salt thereof, in combination with one or more other therapeutically active compounds, is also included in the pharmaceutical composition of the present invention.

The pharmaceutical carrier employed in the present invention may be, for example, a solid carrier, a liquid carrier or a gas carrier. Solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid. Liquid carrier including syrup, peanut oil, olive oil and water. Gas carrier, including carbon dioxide and nitrogen. When preparing a pharmaceutical oral preparation, any convenient pharmaceutically acceptable medium can be used. For example, water, ethylene glycol, oils, alcohols, flavor enhancers, preservatives, colorants and the like can be used for oral liquid preparations such as suspensions, elixirs and solutions; and carriers such as starches, saccharides, Microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrators and the like can be used for oral solid preparations such as powders, capsules and tablets. Tablets and capsules are preferred for oral formulations in view of ease of administration. Alternatively, the tablet coating can be carried out using standard aqueous or non-aqueous formulation techniques.

Tablets containing a compound or pharmaceutical composition of the invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. The active ingredient is mixed in a free-flowing form such as a powder or granules with a lubricant, inert diluent, surfactant or dispersing agent, and in a suitable machine, compressed tablets can be prepared by compression. The powdered compound or pharmaceutical composition is wetted with an inert liquid diluent, and then molded into a molded article in a suitable machine. Preferably, each tablet contains from about 0.05 g to 0.5 g of active ingredient, and each cachet or capsule contains from about 0.05 g to 0.5 g of active ingredient. For example, a dosage form intended for oral administration to humans comprises from about 0.05 g to about 0.5 g of the active ingredient, complexed with a suitable and conveniently metered auxiliary material, which comprises from about 5% to 95% of the total amount of the pharmaceutical composition. . The unit dosage form will generally contain from about 5 mg to about 0.5 g of the active ingredient, typically 10 mg, 20 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg or 500 mg.

The pharmaceutical composition for parenteral administration provided by the present invention can be prepared by adding the active ingredient to water to prepare an aqueous solution or suspension. A suitable surfactant such as hydroxypropylcellulose can be included. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative may also be included in the pharmaceutical composition of the present invention for preventing the growth of harmful microorganisms.

The present invention provides pharmaceutical compositions suitable for injection, including sterile aqueous solutions or dispersions. Further, the above pharmaceutical composition can be prepared in the form of a sterile powder which can be used for the immediate preparation of a sterile injectable solution or dispersion. In any event, the final form of injection must be sterile and must be easy to flow for ease of injection. Furthermore, the pharmaceutical composition must be stable during preparation and storage. Therefore, preservation of antimicrobials such as bacterial and fungal contamination is preferred. The carrier can be a solvent or dispersion medium, for example, water, ethanol, polyol (such as glycerol, propylene glycol, liquid polyethylene glycol), vegetable oil, and suitable mixtures thereof.

The pharmaceutical composition provided by the present invention may be in a form suitable for topical administration, for example, an aerosol, an emulsion, an ointment, a lotion, dusting, or the like. Further, the pharmaceutical composition provided by the present invention may be in a form suitable for use in a transdermal administration device. These preparations can be produced by a conventional processing method using the compound of the formula (I) of the present invention, or a pharmaceutically acceptable salt thereof. As an example, an emulsion or ointment is prepared by adding a hydrophilic material and water to about 5 wt% to 10 wt% of the above compound to prepare an emulsion or ointment having the desired consistency.

The pharmaceutical composition provided by the present invention can be prepared in a form which is solid as a carrier and is suitable for rectal administration. A preferred dosage form is a mixture to form a unit dose of a suppository. Suitable excipients include cocoa butter and other materials commonly used in the art. Suppositories can be conveniently prepared by first mixing the pharmaceutical composition with softened or melted excipients, followed by cooling and molding.

In addition to the carrier components mentioned above, the above pharmaceutical preparations may also include, as appropriate, one or more additional excipient components, such as diluents, buffers, flavoring agents, binders, surfactants, and additions. Thickeners, lubricants, preservatives (including antioxidants), etc. In addition, other adjuvants may also include penetration enhancers that modulate the osmotic pressure of the drug and blood. A pharmaceutical composition comprising a compound of the formula (I), or a pharmaceutically acceptable salt thereof, may also be prepared in the form of a powder or a concentrate.

In general, in the treatment of the conditions or discomforts indicated above, the dosage level of the drug is from about 0.01 mg/kg body weight to 150 mg/kg body weight per day, or from 0.5 mg to 7 g per patient per day. For example, inflammation, cancer, psoriasis, allergies/asthma, diseases and discomforts of the immune system, diseases and discomforts of the central nervous system (CNS), effective therapeutic doses ranging from 0.01 mg/kg body weight to 50 mg/kg body weight per day, or Each patient is 0.5 mg to 3.5 g per day.

However, it will be appreciated that the specific dosage level for any particular patient will depend on a number of factors, including age, weight, general health, sex, diet, time of administration, route of administration, rate of excretion, combination of drugs, and acceptance. The severity of the particular disease being treated.

In order to make the above content clearer and clearer, the present invention will be further explained below.

DRAWINGS

Figure 1 is a graph showing the relationship between the number of days of inoculation and the tumor volume in the in vivo pharmacodynamic test of the compound of Example 1 and the control group.

Figure 2 is a graph showing the relationship between the number of days of inoculation and body weight in the in vivo pharmacodynamic test of the compound of Example 1 and the control group.

Detailed ways

The following examples are presented to better understand the present invention. Unless otherwise stated, all parts and percentages are by weight and all temperatures are in degrees Celsius. The following abbreviations are used in the examples:

DCM: dichloromethane; DIPEA: N,N-diisopropylethylamine; DMF: N,N-dimethylformamide; DPPF: 1,1'-bis(diphenylphosphino)ferrocene; EtOAc Ethyl acetate; EtOH: ethanol; HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; MeOH:methanol;min: Minute; Pd ₂ (dba) ₃ : tris(dibenzylideneacetone) dipalladium; Pd(OAc) ₂ : palladium acetate; rt or RT: room temperature; THF: tetrahydrofuran; TLC: thin layer chromatography; XantPhos: 4, 5 - bisdiphenylphosphino-9,9-dimethyloxaxime.

Example 1: Synthesis of Compound 1

Methyl dimethoxyacetate (147.59 g, 1.00 mol) was dissolved in EtOAc (150.23 g), and Na (33.42 g, 1.45 mol). It was cooled to room temperature, diluted with EtOAc EtOAc EtOAc.

2-(Methylamino)ethylcarbamic acid tert-butyl ester (69.54 g, 0.40 mol) and DIPEA (156.21 g, 1.21 mol) were dissolved in DCM (500 mL), and ethyl 2-bromoacetate (0. g, 0.41 mol), stirred at room temperature for 6.5 hours. Concentrated under reduced pressure, EtOAc (EtOAc (EtOAc)EtOAc. . MS: 261 (M+H) ⁺ .

Compound 1-2 (3.35 g, 12.87 mmol) was dissolved in DCM (10 mL), EtOAc (EtOAc m. Concentration under reduced pressure gave Compound 1-3 (2.93 g, 12. MS: 161 (M+H) ⁺ .

Compound 1-4 (30.02 g, 0.14 mol) was dissolved in THF (250 mL), and BH ₃ (1 mol/L THF solution, 350 mL, 0.35 mol) was added dropwise at 0 ° C, and stirred at 60 ° C overnight. After cooling to room temperature, water (50 mL) was evaporated. MS: 202, 204 (M+H) ⁺ .

Compound 1-5 (25.68g, 0.13mol) was dissolved in DCM (250mL), was added MnO ₂ (151.47g, 1.74mol), stirred at room temperature overnight. Filtration, DCM (300 mL) was evaporated. MS: 200, 202 (M+H) ⁺ .

Compound 1-6 (187.38 g, 0.94 mol), compound 1-1 (214.68 g, 1.13 mol) and L-valine (108.15 g, 0.94 mol) were dissolved in anhydrous EtOH (1300 mL) and stirred at 90 ° C for 5 hours. . It was cooled to room temperature, EtOAc (EtOAc) (EtOAcjjjjjjjjjjjj Mol). MS: 354, 356 (M+H) ⁺ .

Compound 1-7 (11.63g, 0.03mol) was dissolved in anhydrous EtOH (150mL), sequentially added _{CaCl 2 (3.66g, 0.03mol),} NaBH 4 (3.12g, 0.08mol), stirred at room temperature overnight. Concentrated under reduced pressure, was added 300mL of water, EtOAc and extracted (300mL × 2), the organic phase was dried over anhydrous Na ₂ SO _4, concentrated under reduced pressure, silica gel column chromatography to give a yellow oily compound 1-8 (4.20g, 0.01mol) . MS: 312, 314 (M+H) ⁺ .

Compound 1-8 (131.52g, 0.42mol) was dissolved in DCM (1000mL), was added MnO ₂ (205.71g, 2.37mol), stirred at room temperature for 4 hours. Filtration, DCM rinsing (500 mL), EtOAc (EtOAc:EtOAc: MS: 310, 312 (M+H) ⁺ .

Compound 1-3 (18.54 g, 0.80 mol) was dissolved in DCM (150 mL), triethylamine (24.59 g, 0.24 mol) was added dropwise and stirred for 10 min. Compounds 1-9 (14.02 g, 0.05 mol) and sodium triacetoxyborohydride (54.32 g, 0.26 mol) were added sequentially and stirred at room temperature overnight. Water (100 mL) quenched, DCM and extracted (500mL × 2), organic phases were combined, dried over anhydrous Na ₂ SO _4, concentrated under reduced pressure, silica gel column chromatography to obtain a colorless oily compound 1-10 (18.45g, 0.05mol ). MS: 408, 410 (M+H) ⁺ .

Compound 1-10 (18.45 g, 45.19 mmol), Zn(CN) ₂ (6.27 g, 53.40 mmol), Pd ₂ (dba) ₃ (4.31 g, 4.71 mmol), DPPF (4.85 g, 8.75 mmol) and iodide Cuprous (5.72 g, 30.03 mmol) was dissolved in N,N-dimethylacetamide (200 mL). Cooled to room temperature, EtOAc (1000mL) was diluted, washed with saturated aqueous NaCl (1000mL × 6), the organic phase was dried over anhydrous Na ₂ SO _4, concentrated under reduced pressure, silica gel column chromatography, to give a brown solid compound 1-11 (8.41g, 23.73 mmol). MS: 355 (M+H) ⁺ .

Compound 1-11 (9.93g, 28.02mmol), acetaldehyde oxime (10mL) and copper oxide (II) (10.24g, 128.72mmol) was dissolved in _{H 2 O / MeOH (1:} 5,600mL), stirred overnight at 85 ℃. It was cooled to room temperature, filtered, EtOAc (150 mL)EtOAc. MS: 373 (M+H) ⁺ .

Compound 1-12 (9.32 g, 25.02 mmol), 4,6-dichloronicotinonitrile (5.14 g, 29.71 mmol), Pd ₂ (dba) ₃ (2.45 g, 2.68 mmol), XantPhos (2.93 g, 5.88 mmol) The cesium carbonate (24.59 g, 75.47 mmol) was dissolved in 1,4-dioxane (130 mL), and the mixture was stirred under nitrogen for 3.5 hours. The mixture was cooled to room temperature, filtered, EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj MS: 509, 511 (M+H) ⁺ .

Compound 1-13 (5.54 g, 10.88 mmol), 2-methoxyethylamine (8 mL), DIPEA (1 mL) was dissolved in N,N-dimethylacetamide (100 mL) and stirred at 70 ° C for 3 hours. Cooled to room temperature, water (400 mL) quenched, EtOAc and extracted (1000mL × 2), organic phases were combined, washed with saturated aqueous NaCl (1000mL × 4), dried over anhydrous Na ₂ SO _4, concentrated under reduced pressure, the residue was added n-hexane /EtOAc/DCM (20 mL/5 mL / 1 mL), stirred for 10 min. Filtration gave the off-white solid compound 1-14 (4.59 g, 8.38 mmol). MS: 548 (M+H) ⁺ .

Compound 1-14 (2.01g, 3.67mmol) was dissolved in _{H 2 O / CH 3 CN (} 1: 2,15mL), was added dropwise concentrated hydrochloric acid (9mL), was stirred at room temperature for 8 hours. Concentrated residue was added CH ₃ CN (16mL) and water (4 mL), stirred for 10 minutes under reduced pressure. Filtration gave Compound 1 (935 mg, 1.74 mmol). MS: 502 (M+H) ⁺ .

¹ H-NMR (D ₂ O, 400 MHz): 8.53 (d, 1H), 8.32 (s, 1H), 8.19 (d, 1H), 8.1 (s, 1H), 7.74 (t, 1H), 6. , 1H), 6.42 (s, 1H), 5.05 (s, 2H), 4.28 (m, 2H), 3.86 (m, 4H), 3.68 (t, 2H), 3.43 (s, 3H), 3.31 (t, 2H), 3.15 (s, 3H).

Example 2: Synthesis of Compound 2

Compound 1-14 (0.42g, 0.77mmol) was dissolved in DCM (20mL), was added MnO ₂ (1.49g, 17.14mmol), stirred at room temperature overnight. Filtration, DCM (50 mL), EtOAc (EtOAc)EtOAc. MS: 562 (M+H) ⁺ .

Compound 2-1 (206mg, 0.37mmol) was dissolved in _{H 2 O / CH 3 CN (} 1: 2,9mL), was added dropwise concentrated hydrochloric acid (4mL), was stirred at room temperature for 7 hours. Concentrated under reduced pressure, the residue was added CH ₃ CN (2mL) and water (0.5 mL), stirred for 10 minutes and filtered to give a purple solid compound 2 (156mg, 0.28mmol). MS: 516 (M+H) ⁺ , 534 (M+H) ⁺ + H ₂ O

¹ H-NMR (DMSO-d ₆ , 400 MHz): 13.66 (s, 1H), 10.30 (s, 1H), 8.78 (d, 1H), 8.70 (s, 1H), 8.47 (d, 1H), 8.38 ( s, 1H), 8.00 (t, 1H), 7.85 (s, 1H), 7.12 (t, 1H), 5.14 (s, 2H), 3.69 (m, 4H), 3.58 (t, 2H), 3.47 (m) , 2H), 3.30 (s, 3H), 3.01 (s, 3H), 2.50 (m, 2H).

Example 3: Synthesis of Compound 3

Compound 1-7 (5.15g, 14.54mmol) was dissolved in _{THF / H 2 O / MeOH (} v: v: v = 1: 1: 1,60mL), was added NaOH (1.63g, 40.75mmol), stirred at room temperature overnight. Concentration under reduced pressure gave a yellow solid compound 3-1 (5.61 g, 16.11 mmol). MS: 326, 328 (M+H) ⁺ .

Compound 3-1 (5.61 g, 16.11 mmol), 1-methylpiperazine (5 mL) and DIPEA (3 mL) was dissolved in DMF (40 mL). Water (500 mL) quenched, EtOAc and extracted (200mL × 3), washed with saturated aqueous NaCl (300mL × 2), dried over anhydrous Na ₂ SO _4, concentrated under reduced pressure, silica gel column chromatography to give compound 3-2 as a yellow oil ( 6.90 g, 16.90 mol). MS: 408, 410 (M+H) ⁺ .

Compound 3-2 (6.41 g, 15.70 mmol), Zn(CN) ₂ (3.11 g, 26.49 mmol), Pd ₂ (dba) ₃ (1.46 g, 1.59 mmol), DPPF (1.75 g, 3.16 mmol) and iodide Cuprous (0.31 g, 1.63 mmol) was dissolved in N,N-dimethylacetamide (50 mL). Cooled to room temperature, EtOAc (300mL) was diluted with saturated aqueous NaCl solution (100mL × 3), the organic phase was dried over anhydrous Na ₂ SO _4, concentrated under reduced pressure, silica gel column chromatography to obtain a yellow oil compound 3-3 (2.70g, 7.62 mmol). MS: 355 (M+H) ⁺ .

Compound 3-3 (2.65g, 7.48mmol) was dissolved in _{H 2 O / MeOH (1:} 1,30mL), was added NaOH (0.57g, 14.25mmol), stirred overnight at 85 ℃. The mixture was cooled to rt. MS: 373 (M+H) ⁺ .

Compound 3-4 (1.21 g, 3.25 mmol), 4,6-dichloronicotinonitrile (0.87 g, 5.03 mmol), Pd ₂ (dba) ₃ (0.31 g, 0.34 mmol), XantPhos (0.40 g, 0.80 mmol) The cesium carbonate (2.86 g, 8.78 mmol) was dissolved in 1,4-dioxane (15 mL), and the mixture was stirred under nitrogen for 7 hours. Cooled to room temperature, water (50mL) quenched, DCM and extracted (50mL × 3), combined organic phases were dried over anhydrous Na ₂ SO _4, concentrated under reduced pressure, silica gel column chromatography, to obtain a red solid compound 3-5 (860mg, 1.69 mmol). MS: 509, 511 (M+H) ⁺ .

Compound 3-5 (860 mg, 1.69 mmol), 2-methoxyethylamine (2 mL), EtOAc (EtOAc) It was cooled to room temperature and purified by reverse phase chromatography to yield Compound 3-6 (420 mg, MS: 548 (M+H) ⁺ .

Compound 3-6 (125mg, 0.23mmol) was dissolved in _{H 2 O / CH 3 CN (} 1: 2,6mL), was added dropwise concentrated hydrochloric acid (2mL), stirred at room temperature for 2.5 hours. Concentration under reduced pressure gave a yellow solid compound 3-7 (148 mg, 0.35 mol). MS: 420 (M+H) ⁺ .

Compound 3-7 (148 mg, 0.35 mmol), 1-methylpiperazine (0.3 mL), EtOAc (3 mL) Purified by reverse phase chromatography, EtOAc (EtOAc)EtOAc. Filtration gave yellow solid compound 3 (67 mg, 0.13 mmol). MS: 502 (M+H) ⁺ .

¹ H-NMR (DMSO-d ₆ , 400 MHz): 13.29 (s, 1H), 10.19 (s, 1H), 8.79 (d, 1H), 8.77 (s, 1H), 8.43 (d, 1H), 8.37 ( s, 1H), 8.04 (t, 1H), 7.86 (s, 1H), 7.12 (t, 1H), 3.71 (t, 2H), 3.58 (m, 2H), 3.48 (m, 2H), 3.32 (s) , 3H), 3.14 (t, 2H), 2.50 (t, 2H), 2.47 (t, 2H), 2.21 (s, 3H).

Example 4: Synthesis of Compound 4

Compound 4-1 (1.14g, 6.82mmol), Pd / C (0.24g) was dissolved in MeOH (60mL), H ₂ protection was stirred at room temperature for 2 hours. Filtration and concentration under reduced pressure gave Compound 4-2 (0.84 g, 6.

Compound 4-2 (0.84 g, 6.13 mmol) was dissolved in EtOAc (EtOAc (EtOAc)EtOAc. Cooled to room temperature, DCM and extracted (20mL × 2), organic phases were combined, washed with saturated aqueous NaCl (50 mL), dried over anhydrous Na ₂ SO _4, concentrated under reduced pressure, silica gel column chromatography to give compound 4-3 (557mg, 2.98 Mm). MS: 188 (M + H) +, 186 (MH) -.

Compound 4-3 (405mg, 2.16mmol), SeO 2 (507mg, 4.57mmol) was dissolved in 1,4-dioxane (20 mL), nitrogen, stirring 110 ℃ 1 hour. It was cooled to rt, EtOAc (EtOAc m. MS: 202 (M+H) ⁺ , 200 (MH) ^- .

Compound 4-4 (270 mg, 1.34 mmol), trimethyl orthoformate (8 mL, 73.12 mmol) and TsOH. H ₂ O (42 mg, 0.22 mmol) was dissolved in MeOH (20 mL). It was cooled to room temperature, concentrated under reduced pressure and purified silicagelgelgel. MS: 248 (M + H) +, 246 (MH) -.

Compound 4-5 (120mg, 0.49mmol), NH 4 Cl (119mg, 2.22mmol) and DIPEA (0.5mL) was dissolved in DMF (3mL), was added HATU (174mg, 0.46mmol), stirred at room temperature for 1 hour. Water (30mL) was quenched, EtOAc and extracted (20mL × 2), organic phases were combined, washed with saturated aqueous NaCl solution (50mL × 3), dried over anhydrous Na ₂ SO _4, and concentrated under reduced pressure, to give compound 4-6 (110mg, 0.45 Mm). MS: 247 (M+H) ⁺ .

Compound 4-6 (110 mg, 0.45 mmol), 4,6-dichloronicotinonitrile (89 mg, 0.51 mmol), Pd(OAc) ₂ (10 mg, 0.04 mmol), XantPhos (54 mg, 0.10 mmol) and K ₂ CO ₃ (157 mg, 1.14 mmol) was dissolved in THF (5 mL). Cooled to room temperature, (30 mL) and diluted with water, EtOAc and extracted (100mL × 2), organic phases were combined, washed with saturated aqueous NaCl (100 mL), dried over anhydrous Na ₂ SO _4, concentrated under reduced pressure, the residue was added EtOAc (10mL), Stir for 10 min and filter to give compound 4-7 (117 mg, <RTIgt; MS: 383, 385 (M+H) ⁺ .

Compound 4-7 (117 mg, 0.31 mmol), 2-methoxyethylamine (183 mg, 2.44 mmol), DIPEA (158 mg, 1.22 mmol) dissolved in N,N-dimethylacetamide (5 mL), stirred at 75 ° C 16 hours. It was cooled to room temperature, concentrated under reduced pressure and purified silicagelgelgel. MS: 422 (M+H) ⁺ .

Compound 4-8 (104 mg, 0.25 mmol) was dissolved in THF (10 mL). Water (30mL) was quenched with saturated aqueous sodium carbonate solution adjusted pH = 9, EtOAc extraction (10mL × 3), combined organic phases were washed with saturated aqueous NaCl solution (20 mL), dried over anhydrous Na ₂ SO _4, and concentrated under reduced pressure, to give compound 4 (45 mg, 0.11 mmol). MS: 376 (M+H) ⁺ .

¹ H-NMR (DMSO-d ₆ , 400 MHz): 13.57 (s, 1H), 10.20 (s, 1H), 8.86 (d, 1H), 8.80 (d, 1H), 8.45 (d, 1H), 8.36 ( s,1H), 8.17(d,1H), 8.00(t,1H),7.86(s,1H),7.12(t,1H),3.58(m,2H),3.47(m,2H),3.32(s , 3H).

Referring to the above method, the compounds shown in Table 1 below were prepared using different raw materials:

Table 1

The compounds provided by the present invention are preferably pharmaceutical compositions having a plurality of modes of administration. Most preferably, the pharmaceutical composition is administered orally. Such pharmaceutical compositions and their preparation are well known in the art, for example, REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY, A. Gennaro, et al, eds., 19th ed., Mack Publishing Co., 1995). The compounds of formula (I) are effective over a wide range of dosages.

For example, the normal daily dose will generally range from about 1 mg to about 500 mg per day (total total daily dose), preferably, the total daily dose is from 1 mg to 200 mg, such as from 1 mg to 150 mg, more preferably, day. The total dose is from 1 mg to 50 mg. In some cases, a dose level below the lower end of the above range may also be sufficient, while in other cases, a large dose is still available. The above dosage ranges do not limit the scope of protection of the invention in any way. It is to be understood that the actual dosage of the compound provided by the present invention will be determined by the physician according to the relevant circumstances, including the conditions of the treatment, the choice of the route of administration, the compound and compound actually administered, the age, the body weight, and the individual patient. The response and the severity of the patient's symptoms.

Biological test evaluation

1.FGFR4 enzymatic experiment

This experiment employed a method of changing the mobility (mobility shift assay) test compound inhibition of FGFR4 kinase activity, and inhibition rate of the compound obtained FGFR4 kinase activity or on the half maximal inhibitory concentration IC _50.

(1) The test compound was placed in a concentration gradient in 100% DMSO and buffered (pH of buffer 7.5 containing 50 mM HEPES (N-(2-hydroxyethyl) piperazine-N'-2 sulfonic acid) ), 0.00015% (ml/ml) Brij-35 (dodecyl polyethylene glycol ether) and the balance of water) were diluted into 10% DMSO and added to a 384-well plate. For example, when the initial concentration of the compound is 10 μM, it is made into 500 μM with 100% DMSO, and diluted in 10 concentrations, and diluted 10-fold with buffer to prepare an intermediate dilution of the compound containing 10% DMSO, and transferred 5 μl to 384-well plate. ;

(2) FGFR4 enzyme buffer (the pH of the buffer is 7.5, which contains 50 mM HEPES, 0.00015% (ml/ml) Brij-35, 2 mM DTT (dithiothreitol) and the balance of water) is diluted to the most Good concentration (final concentration 12.5 nM). Transfer 10 μl to a 384-well plate and incubate with the test compound for 10-15 minutes;

(3) Substrate (Peptide FAM-P22, GL Biochem, Cat. No. 112393, Lot. No. P180116-MJ112393) with buffer (the pH of the buffer is 7.5, which contains 50 mM HEPES, 0.00015% (ml/ml) Brij-35, 10 mM MgCl ₂ , adenosine triphosphate 66 μM at Km and the balance of water) was diluted to an optimum concentration of 10 nM. The reaction was initiated by adding 10 μl to a 384-well plate and reacted at 28 ° C for 1 hour;

(4) Read the conversion rate with Caliper Reader and calculate the inhibition rate as the average of the two tests;

(5) The IC ₅₀ value was fitted by XL-fit software, and the results are shown in Table 2 below:

Table 2

Compound number	Inhibition rate	FGFR4 IC 50 (nM)
Example 1	100%@20nM	3.9
Example 2	93.0%@20nM	/
Example 3	/	/
Example 4	97.3%@50nM	/

Note: “@” in Table 2 indicates the concentration of the compound.

2. Hepatoma cell proliferation inhibition experiment

The method of the present study, test compounds were MTS hepatoma cells Hep3B, HUH7 JHH7 and proliferation inhibition, the compounds inhibit cell proliferation and obtain half maximal inhibitory concentration IC ₅₀ activity.

(1) 100 μl of liver cancer cell suspension was seeded in a 96-well cell culture plate at a density of 2.0×10 ⁴ cells/ml, and the culture plate was cultured in a cell culture incubator for 16-24 hours (37° C., 5% CO ₂ );

(2) adding gradient dilutions of different concentrations of the test compound solution to the culture plate cells, incubating the culture plate in an incubator for 120 h (37 ° C, 5% CO ₂ );

(3) Add MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, 3-(4,5-di) to each well Methylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-benzenesulfonate)-2H-tetrazole/PMS (phenazine methosulfate, methyl piperazine sulfate The mixture was developed with color, MTS/PMS was mixed at 20:1 (ml: ml), 30 μl was added to each well, and incubated for 2-3 hours in an incubator;

(4) measuring the chemiluminescence signal value of each plate at a wavelength of 492 nm by a microplate reader;

(5) calculating the inhibition rate by the value of the chemiluminescence signal;

(6) The IC _{50 of the} compound was obtained by curve fitting according to the inhibition rate of different concentrations, and the measured results are shown in Table 3 below:

table 3

Compound number	Hep3B IC 50 (μM)	JHH7 IC 50 (μM)	HUH7 IC 50 (μM)
Example 1	0.022	0.029	0.027

Example 2	0.131	/	/
Example 3	1.393	/	/
Example 4	6.552	/	4.111

From the cell activity data of the specific example compounds, the present Example 1 has a good inhibitory effect on the proliferative activity of Hep3B, JHH7 and HUH7 hepatoma cells (high expression of FGF19 and FGFR4) which are highly expressed by FGFR4 and FGF19.

3. Western blot analysis of the inhibition rate of compounds on p-FRS2 protein

In this experiment, the inhibition rate of p-FRS2 in Hep3B cells was tested by Western blot, and the inhibition of FGFR4 molecular pathway by compounds was evaluated.

(1) Cell seeding - Hep3B cells were seeded at a suitable density in a 6-well plate at 3.0-4.0 × 10 ⁵ cells/well (different depending on the growth rate and size of different cells), and incubated overnight in an incubator;

(2) Administration - adding a medium with a final concentration of 50 nM, and incubating the drug overnight (about 16 h);

(3) Extract the protein - discard the original liquid, wash with PBS 2-3 times, if the cells are adherent cells, use a scraper to hang the cells to the centrifuge tube, if it is a suspension cell, directly centrifuge, add appropriate amount of 1 × cell lysis Cell lysis buffer (10× cell lysate diluted 10 times with ultrapure water, containing 1 mM PMSF, 1×Phosphatase inhibitor, 2 mM Na ₃ VO ₄ ), cleavage on ice for 15-20 min;

(4) 13000 rpm, 10 min, centrifuged at 4 ° C, and the supernatant was collected;

(5) take appropriate amount of volume protein, add loading buffer (loading buffer), 100 ° C metal bath for 5 min, -20 ° C;

(6) preparing an SDS-PAGE gel;

(7) Loading, electrophoresis - 100V, run 20-30min in concentrated gel; 120V separation gel.

(8) Electro-rotation - transfer film at a current of 400 mA for 120-130 min, transfer to an ice-cold bath, and PVDF membrane before activation is activated with methanol for 1-2 min;

(9) closed - 5% BSA / TBST closed;

(10) Primary antibody incubation - Primary antibody (p-FRS2 antibody) was diluted with 5% BSA/TBST and incubated overnight at 4 °C;

(11) 1 × TBST wash 3 times, 10min / time;

(12) secondary antibody incubation - secondary antibody (anti-rabbit IgG) diluted with 5% BSA / TBST, room temperature 1h;

(13) 1 × TBST wash 3 times, 10min / time;

(14) ECL luminescence and exposure—add the same volume of ECL A and B reagents, drop on the membrane, illuminate for 2 min, and expose;

(15) Save pictures and data analysis. The measured results are shown in Table 4 below:

Table 4

Compound number	p-FRS2 inhibition rate%
Example 1	100
Example 2	81
Example 3	70
Example 4	0

4. PK analysis of rats

In the present invention, rat pharmacokinetic experiments were carried out on the compounds of Example 1 and Example 2 using SD rats (Vitronius).

(1) Mode of administration: single intragastric administration and intravenous administration;

(2) Dosage: 10 mg/kg by intragastric administration and 3 mg/kg by intravenous injection;

(3) Sampling point:

Administration by intragastric administration: before administration, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 24 h;

Intravenous injection: before administration, 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 24h;

(4) Sample processing: The blood volume of the eyelids was 200 μL/time point. After anticoagulation with heparin, the blood was centrifuged at 5500 rpm for 10 min, and the supernatant was taken to be ≥ 60 μL, and placed in a refrigerator at -80 ° C for examination.

Chromatographic separation conditions and mass spectrometric conditions of the compound of Example 1

Column: Agilent ZORBAX SB C8 3.5μ (50 x 2.1mm)

Mobile phase: A: 5% acetonitrile (Acetonitrile) and 95% water (Water) (0.04% NH ₃ .H ₂ O)

B: 95% acetonitrile (Acetonitrile) and 5% water (Water) (0.04% NH ₃ .H ₂ O)

Flow rate: 0.6 mL/min; elution time: 3.80 min; injection amount: 10 μL.

The elution gradient is shown in Table 5 below:

table 5

Time	Mobile phase A (%)	Mobile phase B (%)
0.00	90	10
0.20	90	10
1.50	0	100
1.60	0	100
2.60	90	10
3.80	90	10

The mass spectrometer setting conditions in mass spectrometry are shown in Table 6 below:

Table 6

Compound	Q1	Q3	DP	EP	CE	CXP
Example 1	502.195	310.100	126	10	37	8
Verapamil	449.122	409.000	101	10	29	12

Note: Q1, Q3, DP, EP, CE and CXP in Table 6 represent Q1: parent ion; Q3: daughter ion; DP: de-clustered voltage; EP: inlet voltage; CE: collision energy; CXP: collision cell exit voltage .

Chromatographic separation conditions and mass spectrometric conditions of the compound of Example 2

Column: Agilent ZORBAX SB C8 3.5μ (50 x 2.1mm)

Mobile phase: A: 5% acetonitrile (Acetonitrile) and 95% water (Water) (0.04% NH ₃ .H ₂ O);

B: 95% acetonitrile (Acetonitrile) and 5% water (Water) (0.04% NH ₃ .H ₂ O)

Flow rate: 0.6 mL/min; elution time: 3.80 min; injection amount: 10 μL.

The elution gradient is shown in Table 7 below:

Table 7

Time	Mobile phase A (%)	Mobile phase B (%)
0.00	70	30
0.20	70	30
1.50	0	100
1.60	0	100
2.60	70	30
3.80	70	30

The mass spectrometer setting conditions in mass spectrometry are shown in Table 8 below:

Table 8

Compound	Q1	Q3	DP	EP	CE	CXP
Example 2	516.218	324.000	121	10	37	8
Verapamil	449.122	409.000	101	10	29	12

Note: Q1, Q3, DP, EP, CE and CXP in Table 8 represent Q1: parent ion; Q3: daughter ion; DP: de-clustered voltage; EP: inlet voltage; CE: collision energy; CXP: collision cell outlet voltage .

The results measured according to the above experimental steps are shown in Table 9 below:

Table 9

From the results of the rat pharmacokinetic experiments in Table 9, it can be seen that the compound of Example 1 of the present experiment exhibited good metabolic properties, and both the exposure AUC and the maximum blood concentration _Cmax performed well.

5. In vivo pharmacodynamic experiment of the compound of Example 1

5.1 Reagents and materials

Hep3B cell strain was purchased from ATCC, MEM cell culture medium, fetal bovine serum, trypsin was purchased from Gibco, cell culture flask was purchased from Greiner, disposable cell counting plate, trypan blue solution was purchased from Bio-Rad. One-time sterile syringes were purchased from Changzhou Jinlong Medical Plastics Co., Ltd., ophthalmic surgical scissors and ophthalmic surgery were purchased from Shanghai Medical Devices (Group) Co., Ltd. surgical instrument factory, NOD-SCID mice 6-8 weeks, female, purchased from Victoria Lihua.

5.2 Cell culture and cell suspension preparation

a. Remove one Hep3B cell from the cell bank, resuscitate the cells with MEM medium (MEM + 10% FBS + 10% PS), and resuscitate the cells in a cell culture flask (mark the cell types on the bottle wall, Date, culture name, etc.) were placed in a CO ₂ incubator (incubator temperature 37 ° C, CO ₂ concentration 5%);

b. After the cells are covered with about 90% of the bottom of the culture flask, the cells are passaged, and after passage, the cells are continuously cultured in a CO ₂ incubator. Repeat the process until the number of cells meets the in vivo efficacy requirements;

c. Collect the cultured cells, count them with a BIO-Rad TC20 cytometer, and resuspend the cells with PBS and Matrigel (1:1) according to the counting results to prepare a cell suspension (density 5×10 ⁷ /ml). Place in an ice box for use.

5.3 cell inoculation, tumor

a. Mix the cells before inoculation, take 0.5 ml of the cell suspension with a 1 ml syringe, remove the air bubbles, and place the syringe on the ice bag for use.

b. Left-handed Baoding NOD-SCID mice, disinfected the right back skin of the mice with 75% alcohol, and started inoculation 30 seconds later.

c. Holding a 1 mL syringe in the right hand, inoculate 0.1 mL of cell suspension subcutaneously in the right shoulder position of the right side of the mouse; inoculate the gap, place the syringe on the ice bag, and inoculate the test mice in turn.

d. According to tumor growth, tumors were dosed on days 14-16 after inoculation and tumor size was calculated.

Tumor volume calculation: tumor volume (mm ³ ) = length (mm) × width (mm) × width (mm) / 2

e. When the tumor grows to an average volume of 100-150 mm ³ , it is randomly divided into two groups according to tumor size and mouse body weight, with 6 rats in each group, one of which is a control group and the other is a drug-administered group.

f. The administration method is intragastric administration once a day, the control group is given 10% DMSO + 10% castor oil + 10% PEG 400 + 70% physiological saline, and the administration group is administered with a dose of 100 mg/kg, and weekly administration is started. The tumor was weighed and weighed twice.

g. The tumor volume of the control group was about 1200 mm ³ and the experiment was terminated.

h. Process data using software such as Excel. The experimental results are shown in FIG. 1 and FIG. 2. As can be seen from FIG. 1 and FIG. 2, the anti-tumor effect of the embodiment 1 is obvious, and the cachexia of the model can be effectively alleviated.

Claims (40)

1. a compound of formula I or a pharmaceutically acceptable salt thereof:

   

   among them,

   R _{1 is} selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, CH ₂ NR _1a R _1b or C(O)NR _1a R _1b ;

   Each of R _1a and R _{1b is} independently selected from the group consisting of hydrogen, C _1-6 alkyl, C(O)CH ₂ OH, C(O)CH ₂ OCH ₃ , C(O)CH ₂ N(CH ₃ ) ₂ Or S(O) ₂ CH ₃ ; or

   R _1a and R _1b together with the N atom to which they are attached form a saturated substituted or unsubstituted 5-membered heterocyclic ring or 6-membered heterocyclic ring containing 1, 2, 3 or 4 a hetero atom independently selected from N or O, and may be substituted one or more times by R ₁₁ ;

   R _{11 is} selected from the group consisting of hydrogen, halogen, amino, cyano, hydroxy, nitro, carboxy, C _1-6 alkyl, C _1-6 alkoxy or C(O)C _1-6 alkyl;

   Two R ₁₁ attached to the same ring atom form an oxo group;

   R _{2 is} selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, CH ₂ NR _2a R _2b or C(O)NR _2a R _2b ;

   Each of R _2a and R _{2b is} independently selected from the group consisting of hydrogen, C _1-6 alkyl, C(O)CH ₂ OH, C(O)CH ₂ OCH ₃ , C(O)CH ₂ N(CH ₃ ) ₂ Or S(O) ₂ CH ₃ ; or

   R _2a and R _2b together with the N atom to which they are attached form a saturated substituted or unsubstituted 5-membered heterocyclic ring or 6-membered heterocyclic ring containing 1, 2, 3 or 4 a hetero atom independently selected from N or O, and may be substituted one or more times by R ₁₂ ;

   R _{12 is} selected from the group consisting of hydrogen, halogen, amino, cyano, hydroxy, nitro, carboxy, C _1-6 alkyl, C _1-6 alkoxy or C(O)C _1-6 alkyl;

   Two R ₁₂ attached to the same ring atom form an oxo group;

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

   R _{4 is} selected from hydrogen, halogen, amino, cyano, hydroxy, nitro, carboxy, C _1-6 alkyl, C _1-6 alkoxy or NHR _4a , and each R ₄ may be optionally substituted with a substituent Or not substituted; the substituents are each independently selected from halogen, cyano, hydroxy, amino, C _1-6 alkyl or C _1-6 alkoxy;

   R _{4a is} selected from the group consisting of hydrogen, C _1-6 alkyl, C _1-6 alkoxy, N(C _1-6 alkyl) ₂ or (CH ₂ ) _1-6 -C _1-6 alkoxy.
2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R _{1 is} selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, C _1-3 alkyl, CH ₂ NR _1a R _1b or C (O) NR _1a R _1b .
3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R _{1 is} selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, CH ₂ NR _1a R _1b or C(O)NR _1a R _1b .
4. The compound according to any one of claims 1 to 3, wherein each of R _1a and R _{1b is} independently selected from the group consisting of hydrogen, C _1-3 alkyl, C (O), or a pharmaceutically acceptable salt thereof. CH ₂ OH, C(O)CH ₂ OCH ₃ or C(O)CH ₂ N(CH ₃ ) ₂ .
5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein each of R _1a and R _{1b is} independently selected from the group consisting of hydrogen, methyl, ethyl, propyl and iso Propyl or C(O)CH ₂ OH.
6. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R _1a and R _1b together with the N atom to which they are attached form a saturated substituted or unsubstituted 5 -membered impurity. A cyclic or 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from N or O, and may be substituted one or more times by R ₁₁ .
7. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R _1a and R _1b together with the N atom to which they are attached form a saturated substituted or unsubstituted 5 membered heterocyclic ring or 6-membered heterocyclic ring, said 5-membered heterocyclic ring or 6-membered heterocyclic ring containing 1 or 2 substituents each independently selected from N or O heteroatoms, and may be substituted once, twice or three times R _11.
8. The compound according to any one of claims 1 to 3, 6 or 7 or a pharmaceutically acceptable salt thereof, wherein R _{11 is} selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, amino, cyano, hydroxy , nitro, carboxy, C _1-3 alkyl, C _1-3 alkoxy or C(O)C _1-3 alkyl; or

   Two R ₁₁ attached to the same ring atom form an oxo group.
9. The compound of any one of claims 1-3, 6-8, or a pharmaceutically acceptable salt thereof, wherein R _{11 is} selected from the group consisting of hydrogen, fluorine, chlorine, bromine, amino, hydroxy, methyl, and B. Base, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, C(O)CH ₃ , C(O)CH ₂ CH ₃ , C(O)CH(CH _{3 2} or C(O)CH ₂ CH ₂ CH ₃ ; or

   Two R ₁₁ attached to the same ring atom form an oxo group.
10. A compound according to any one of claims 1-3, 6-9, or a pharmaceutically acceptable salt thereof, wherein R _1a and R _1b together with the N atom to which they are attached form a substituted or unsubstituted 5 a heterocyclic ring or a 6-membered heterocyclic ring, the 5-membered heterocyclic ring or 6-membered heterocyclic ring being selected from

    

    And may be substituted with one or more substituents R _11, R ₁₁ is selected from methyl, or both connected to the same ring atom R ₁₁ form an oxo.
11. The compound of any one of claims 1-3, 6-10, or a pharmaceutically acceptable salt thereof, wherein R _1a and R _1b together with the N atom to which they are attached form a substituted or unsubstituted 5 a heterocyclic ring or a 6-membered heterocyclic ring, the 5-membered heterocyclic ring or 6-membered heterocyclic ring being selected from

    
12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R _{2 is} selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, C _1-3 alkyl, CH ₂ NR _2a R _2b or C(O)NR _2a R _2b .
13. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R _{2 is} selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl , CH ₂ NR _2a R _2b or C(O)NR _2a R _2b .
14. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein each of R _2a and R _{2b is} independently selected from the group consisting of hydrogen, C _1-3 alkyl, C (O) CH ₂ OH, C(O)CH ₂ OCH ₃ or C(O)CH ₂ N(CH ₃ ) ₂ .
15. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein each of R _2a and R _{2b is} independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, and iso Propyl or C(O)CH ₂ OH.
16. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R _2a and R _2b together with the N atom to which they are attached form a saturated substituted or unsubstituted 5-membered A cyclic or 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from N or O, and may be substituted one or more times by R ₁₂ .
17. A compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, wherein R _2a and R _2b together with the N atom to which they are attached form a saturated substituted or unsubstituted 5 A heterocyclic ring or a 6-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from N or O, and may be substituted one or more times by R ₁₂ .
18. The compound according to any one of claims 1 to 13, 16 or 17, or a pharmaceutically acceptable salt thereof, wherein R _{12 is} selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, amino, cyano, hydroxy , nitro, carboxy, C _1-3 alkyl, C _1-3 alkoxy or C(O)C _1-3 alkyl; or

    Two R ₁₂ attached to the same ring atom form an oxo group.
19. A compound according to any one of claims 1 to 13 or 16 to ₁₈ , wherein R _{12 is} selected from the group consisting of hydrogen, fluorine, chlorine, bromine, amino, hydroxy, methyl, and Base, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, C(O)CH ₃ , C(O)CH ₂ CH ₃ , C(O)CH(CH _{3 2} or C(O)CH ₂ CH ₂ CH ₃ ; or

    Two R ₁₂ attached to the same ring atom form an oxo group.
20. A compound according to any one of claims 1 to 13 or 16 to 19, wherein R _2a and R _2b together with the N atom to which they are attached form a substituted or unsubstituted 5 a heterocyclic ring or a 6-membered heterocyclic ring, the 5-membered heterocyclic ring or 6-membered heterocyclic ring being selected from

    

    And may be substituted with one or more substituents R _12, R ₁₂ is selected from methyl, or both connected to the same ring atom R ₁₂ form an oxo.
21. The compound according to any one of claims 1 to 13, 16 or 20, wherein R _2a and R _2b together with the N atom to which they are attached form a substituted or unsubstituted 5 a heterocyclic ring or a 6-membered heterocyclic ring, the 5-membered heterocyclic ring or 6-membered heterocyclic ring being selected from

    
22. The compound according to any one of claims 1 to 21, wherein R _{3 is} selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine or C _1-3 alkyl.
23. The compound according to any one of claims 1 to 2, wherein R _{3 is} selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl or isopropyl, or a pharmaceutically acceptable salt thereof .
24. The compound according to any one of claims 1 to ₂₃ , or a pharmaceutically acceptable salt thereof, wherein R _{4 is} selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, amino, cyano, hydroxy, C _{1- a 3} alkyl group, a C _1-3 alkoxy group or NHR _4a , and each R ₄ may be optionally substituted or unsubstituted with a substituent; the substituents are each independently selected from the group consisting of fluorine, chlorine, bromine, iodine, and hydroxyl groups. Amino, C _1-3 alkyl or C _1-3 alkoxy.
25. The compound according to any one of claims 1 to 24, wherein R _{4a is} selected from the group consisting of hydrogen, C _1-3 alkyl, C _1-3 alkoxy, N (C), or a pharmaceutically acceptable salt thereof _1-3 alkyl) ₂ or (CH ₂ ) _1-3 -C _1-3 alkoxy.
26. The compound according to any one of claims 1 to 25, wherein R _{4a is} selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy and iso Propyloxy, N(CH ₃ ) ₂ , N(CH ₂ CH ₃ ) ₂ , CH ₂ OCH ₃ , CH(CH ₃ )OCH ₃ , CH ₂ CH ₂ OCH ₃ , CH ₂ CH ₂ CH ₂ OCH ₃ , CH ₂ OCH ₂ CH ₃ or C(CH ₃ ) ₂ OCH ₃ .
27. A compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein R _{4 is} selected from the group consisting of hydrogen, fluorine, chlorine, bromine, amino, cyano, hydroxy, methyl, ethyl , propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, NHCH ₃ , NHCH ₂ CH ₃ , NHCH ₂ OCH ₃ , NHCH ₂ CH ₂ OCH ₃ or NHCH ₂ OCH ₂ CH ₃ , and each R ₄ may be optionally substituted or unsubstituted with a substituent; the substituents are each independently selected from the group consisting of fluorine, chlorine, bromine, hydroxyl, amino, methyl, ethyl, propyl, isopropyl , methoxy, ethoxy, propoxy or isopropoxy.
28. The compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein R _{4 is} selected from the group consisting of hydrogen, fluorine, chlorine, amino, cyano, hydroxy, methyl, ethyl, iso a propyl group, a methoxy group, an isopropoxy group, NHCH ₃ , NHCH ₂ OCH ₃ or NHCH ₂ CH ₂ OCH ₃ , and each R ₄ may be optionally substituted or unsubstituted with a substituent; the substituents are each independently It is selected from the group consisting of fluorine, chlorine, hydroxyl, amino, methyl, ethyl, isopropyl, methoxy or isopropoxy.
29. A compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein R _{4 is} selected from the group consisting of hydrogen, fluorine, amino, cyano, methyl, isopropoxy, NHCH ₂ CH ₂ OCH ₃ or OCH(CH ₃ )CH ₂ OCH ₃ .
30. A compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of:

    1) N-(5-Cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-2-formyl-3-((4-methyl-2-oxoper) Pyrazin-1-yl)methyl)quinoline-8-carboxamide;

    2) N-(5-Cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-2-formyl-3-(4-methyl-2-oxopiperazine -1-carbonyl)quinoline-8-carboxamide;

    3) N-(5-Cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-2-formyl-3-(4-methylpiperazine-1-carbonyl) Quinoline-8-carboxamide;

    4) N-(5-Cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-2-formyl-quinoline-8-carboxamide;

    5) N-(5-Cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-2-formyl-3-((2-oxopiperazine-1-yl) )methyl)quinoline-8-carboxamide;

    6) N-(5-Cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-2-formyl-3-((3-oxomorpholine)methyl) Quinoline-8-carboxamide;

    7) N-(5-Cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-2-formyl-3-((2-hydroxy-N-methylacetamide) Methyl)quinoline-8-carboxamide;

    8) N-(5-Cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-2-formyl-3-((4-methyl-2-oxo) Azolidin-3-yl)methyl)quinoline-8-carboxamide;

    9) N-(5-Cyano-4-((1-methoxypropan-2-yl)oxy)pyridin-2-yl)-2-formyl-3-((4-methyl-2) -oxopiperin-1-yl)methyl)quinoline-8-carboxamide;

    10) N-(5-Cyano-4-((1-methoxypropan-2-yl)oxy)pyridin-2-yl)-2-formyl-3-((2-oxopiperazine) -1-yl)methyl)quinoline-8-carboxamide;

    11) N-(5-Cyano-4-((1-methoxypropan-2-yl)oxy)pyridin-2-yl)-2-formyl-3-((3-oxomorpholine) )methyl)quinoline-8-carboxamide;

    12) N-(5-Cyano-4-((1-methoxypropan-2-yl)oxy)pyridin-2-yl)-2-formyl-3-((2-hydroxy-N-) Methyl acetamido)methyl)quinoline-8-carboxamide;

    13) N-(5-Cyano-4-((1-methoxypropan-2-yl)oxy)pyridin-2-yl)-2-formyl-3-((4-methyl-2) -oxooxazolidin-3-yl)methyl)quinoline-8-carboxamide;

    14) N-(5-Cyano-4-isopropoxypyridin-2-yl)-2-formyl-3-((4-methyl-2-oxopiperin-1-yl)methyl Quinoline-8-carboxamide;

    15) N-(5-Cyano-4-isopropoxypyridin-2-yl)-2-formyl-3-((2-oxopiperin-1-yl)methyl)quinoline-8 -formamide;

    16) N-(5-Cyano-4-isopropoxypyridin-2-yl)-2-formyl-3-((3-oxomorpholine)methyl)quinoline-8-carboxamide;

    17) N-(5-Cyano-4-isopropoxypyridin-2-yl)-2-formyl-3-((2-hydroxy-N-methylacetylamino)methyl)quinoline-8 -formamide;

    18) N-(5-Cyano-4-isopropoxypyridin-2-yl)-2-formyl-3-((4-methyl-2-oxooxazol-3-yl)-methyl Base) quinoline-8-carboxamide.
31. The compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: N-(5-cyano-4-((2-methoxy) Amino)pyridin-2-yl)-2-formyl-3-((4-methyl-2-oxopipyrazin-1-yl)methyl)quinoline-8-carboxamide.
32. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any of claims 1-31 and/or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.
33. The pharmaceutical composition according to claim 31, wherein the weight ratio of the compound and/or its pharmaceutically acceptable salt to the adjuvant is from 0.001:1 to 10:1.
34. Use of the compound according to any one of claims 1 to 31 and/or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 32 or 33 for the preparation of a medicament.
35. The use according to claim 34, characterized in that the compound and/or its pharmaceutically acceptable salt or the pharmaceutical composition is used as an FGFR4 inhibitor.
36. The use according to claim 35, wherein the FGFR4 inhibitor is for treating, preventing, delaying or preventing the onset or progression of cancer, cancer metastasis, cardiovascular disease, immunological disease.
37. The use according to claim 36, wherein the cancer is selected from the group consisting of liver cancer, breast cancer, glioblastoma, prostate cancer, rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer or colon cancer.
38. A therapeutic method for inhibiting the activity of FGFR4, which comprises administering the compound according to any one of claims 1-31 and/or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 32 or 33, as needed Therapeutic target of treatment.
39. The method of treatment according to claim 38, for use in treating, preventing, delaying or preventing the onset or progression of cancer, cancer metastasis, cardiovascular disease, immunological disease.
40. The method of treatment according to claim 39, wherein the cancer is selected from the group consisting of liver cancer, breast cancer, glioblastoma, prostate cancer, rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer or colon cancer.

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