EA045554B1 - FGFR4 INHIBITOR AND ITS APPLICATION - Google Patents

Description

Field of invention

The present invention relates to a series of compounds that act as fibroblast growth factor receptor 4 (FGFR4) inhibitors, as well as a production method and a pharmaceutical composition thereof. The present invention further relates to the use of the above-described compounds or a pharmaceutical composition thereof in the treatment of FGFR4-mediated disorders.

Prior Art

Protein kinases are enzymes that catalyze the phosphorylation of proteins, in most cases this phosphorylation occurs on the serine (Ser), threonine (Thr) and tyrosine (Tyr) residues of the protein. Many aspects of cellular life processes (eg, cell growth, differentiation, proliferation, cell cycle, and survival) depend on protein kinase activity. In addition, many diseases (eg, cancer and inflammation) are associated with abnormal protein kinase activity.

It has been discovered that protein tyrosine kinase - PTK - now has more than 100 family members that play an important role in regulating cell differentiation, growth and proliferation. According to the structure of PTK, it can be divided into two types: receptor PTK, which is also called transmembrane PTK, and non-receptor PTK, which is also called intracellular PTK.

Fibroblast growth factor receptors (FGFRs) are members of the receptor tyrosine kinase (RTK) superfamily that regulate cell proliferation, differentiation and migration in various tissues through complex signal transduction pathways by combining with fibroblast growth factor (FGF) (Jouanneau J et al. Oncogene, 1999, 18:327-333). FGFR is a single-chain glycoprotein consisting of an extracellular region, a single transmembrane region, and a tyrosine kinase region in the cytoplasm. The extracellular region consists of a leader peptide and three immunoglobulin domains. The FGFR family contains FGFR1, FGFR2, FGFR3 and FGFR4. The FGFR4 gene, which is approximately 11.3 kb in length. with 18 exons, located on chromosome 5q35.1 (Kostrzewa M. Mammalian genome, 1998, 9(2):131-135). The FGFR4 protein is an important member of the FGFR family of tyrosine kinases, its 388th amino acid is located in the highly conserved transmembrane region of the RTK structure, and changes in the pathophysiological function of the FGFR4 protein caused by changes in this structure may enhance tyrosine kinase activity. The FGFR4 protein is a type of transmembrane tyrosine kinase receptor with autophosphorylation activity that plays an important role in embryonic development, tissue repair and angiogenesis (Eswarakumar V P et al. Cytokine Growth Factor Rev, 2005, 16(2): 139-149).

FGFR4 signaling pathway: When mediated by heparin or heparinoid, the ligand binds to FGFR4, causing dimerization of the FGFR4 monomer with tyrosine phosphorylation at the cytoplasmic C-terminus, kinase insertion region and membrane proximal region, with FGFR4 being activated by phosphorylation of the kinase domain A loop (activation loop). (Schlessinger J et al. Mol Cell, 2000, 6:743-750). Activated FGFR4 mainly has two intracellular agents, which are phospholipase C and FGF receptor substrate 2 (FRS2) (Dailey L et al. Cytokine Growth Factor Rev, 2005, 16:233-247).

When FGFR4 is activated, the Src homologous region 2 (SH2) domain of phospholipase C binds to its activated C-terminal tyrosine, causing PLC (phospholipase C) phosphorylation, and binds to the C-terminal tyrosine site. This activated PLC hydrolyzes its substrate phosphatidylinositol 4,5-bisphosphate (PIP2) to form diacylglycerol (DAG) and inositol triphosphate (IP3). IP3 binds to specific receptors in the cell to stimulate the intracellular calcium pool to release Ca ²⁺ , Ca ²⁺ binds to calmodulin to activate Ca ²⁺ /calmodulin-dependent protein kinase. In addition, both Ca ²⁺ and diacylglycerol can activate members of the protein kinase C family. In addition to activating transcription factors, the secondary signal generated by PIP2 hydrolysis can also activate a variety of intracellular reactions.

The SOS protein binds to the growth factor receptor-linked 2 (Grb2) Src homologous region 3 (SH3) domain to form the Grb2/SOS complex, which can bind to FGFR4 or FGFR substrate 2α (FRS2α), where FRS2α binds to the phosphotyrosine binding domain (RTB), stimulating the exchange of guanosine for Ras, causing Ras to become Ras-GTP with the initiation of the subsequent MAPK (mitogen-activated protein kinase) signaling pathway.

Autophosphorylation of FGFR4 activates JAK family factors (JAK), activated JAK causes phosphorylation of the adsorption site of a specific signaling protein on FGFR4, this site may represent a docking site for signal transducer and activator of transcription (STAT) and other signaling molecules. The C-terminal tyrosine residue of the STAT protein is phosphorylated by JAK upon uptake of the STAT protein by the FGFR4 docking site, and the phosphorylated STAT protein dissociates from the receptor to form a stable homodimer or heterodimer and is then translocated into the nucleus to interact with the interferon gamma activation site (GAS) of enhancer family members with activation transcription of target genes.

Small molecule FGFR4 inhibitors inhibit the FGFR4-mediated proliferation signal by blocking the combination of extracellular ligand molecules with receptors or intracellular kinase signaling. There are many types of FGFR4 inhibitors being developed

- 1 045554 currently, with the selective FGFR4 inhibitor AZ709, developed by AstraZeneca, showing a good inhibitory effect on cells expressing FGF19 or FGFR4 at high levels in in vitro experiments, but no obvious effect in in vivo experiments. The selective FGFR4 inhibitor FGF401, developed by Novartis, can specifically target FGFR4 to treat malignancies such as liver cancer caused by FGFR4 overexpression. The specific FGFR4 inhibitor H3B6527, developed by H3 Biomedicine, has potent antitumor activity on FGF19 gene-amplified cells and does not show any bile acid-related adverse reactions in murine and simian animal models. Blueprint Medicine has developed and characterized the FGFR4-specific inhibitor BLU554 for the treatment of FGFR4-overexpressing liver cancer and cholangiosarcoma.

With in-depth research on the structure and function of FGFR4 and the interaction with other genes, FGFR4 inhibitors with good specificity and therapeutic effect and mild adverse reactions will be developed, and the application of FGFR4 molecular targeted therapy against tumors will be very productive.

Summary of the invention

The present invention relates to compounds as an inhibitor of fibroblast growth factor receptor 4 (FGFR4) or pharmaceutically acceptable salts thereof. The compounds of the present invention have the general structure of formula (I):

Re

Formula I in which represents a single bond;

L is C, Q is N, T is selected from the group consisting of O, CH ₂ and CR ₁₇ ;

ring A is C ₆ - ₁₀ aryl, C ₅ - ₁₀ heteroaryl, C ₅ - ₁₀ heterocyclyl; where the indicated C ₅ - ₁₀ heteroaryl and C ₅ . ₁₀ heterocyclyls contain 1, 2 or 3 heteroatoms independently selected from N, O and S;

R1 represents hydrogen;

R2 is selected from the group consisting of C _{3_10 heterocyclyl} and C _{6_10} aryl, wherein _{said C 3_10 heterocyclyl contains} 1 or 2 heteroatoms selected from N and O;

R2 is optionally substituted with 1-2 R ₁₃ substituents;

R ₁₃ is selected from _the group consisting of hydroxyl _, halogen, _{C1_8} alkyl, _{C2_8} alkenyl _{, C2_8} alkynyl _{, C1_8} alkoxy, _{C6_10 aryl} , _{C3_10} cycloalkyl, _{C3_10} heterocyclyl, C ₅ - ₁₀ heteroaryl, -NR ₁₄ R ₁₅ and -CO-R16, where said C ₃ - ₁₀ heterocyclyl and C ₅ - ₁₀ heteroaryl contain 1, 2 or 3 heteroatoms selected from N and O;

R ₁₃ is optionally substituted with 0-1 substituent R ₁₈ ;

R ₁₈ is selected from the group consisting of hydroxyl, halogen, C _1-8 alkyl, C ₂ - ₈ alkenyl, C ₂ - ₈ alkynyl, C _1-8 alkoxy, C ₆ - ₁₀ aryl, C ₃ - ₁₀ cycloalkyl, C ₃ - ₁₀ heterocyclyl and C ₅ - ₁₀ heteroaryl, where said C ₃ - ₁₀ heterocyclyl and C ₅ - ₁₀ heteroaryl contain 1, 2 or 3 heteroatoms selected from N and O;

R ₅ , R 6 , R ₇ and R ₈ are independently selected from the group consisting of hydrogen, halogen and C1_ ₈ alkoxy;

R9 _is selected from the group consisting of H, halogen, amino, cyano, _{C1_8} alkyl, _{C1_8} alkoxy, _{C2_8} alkenyl, _{C2_8 alkynyl} , _{C6_10 aryl} , _{C3_8 cycloalkyl} , _{C3- 10} heterocyclyl and C ₅ _ ₁₀ heteroaryl, where said C ₃ _ ₁₀ heterocyclyl and C ₅ _ ₁₀ heteroaryl contain 1, 2 or 3 heteroatoms independently selected from N, O and S;

R9 is optionally substituted with 0-1 substituent R ₁₀ ;

R ₁₀ is selected from the group consisting of hydroxyl, halogen, _{C1_8} alkyl, _{C2_8} alkenyl _{, C2_8 alkynyl} ,

Λ

C _1-8 alkoxy, C ₆ _ ₁₀ aryl, C ₃ - ₈ cycloalkyl, C ₃ - ₁₀ heterocyclyl, substituted ¹¹ C ₃ - ₁₀ heterocyclyl, C ₅ _ ₁₀ heteroaryl, -CO-R16 and -(CH ₂ ) _n NR ₁₁ R ₁₂ , where the indicated C ₃ _ ₁₀ heterocyclyl and C ₅ . ₁₀ heteroaryl contain 1, 2 or 3 heteroatoms independently selected from N, O and S;

R11 and _R12 are independently selected from the group consisting of H and _{C1_8} alkyl;

R ₁₄ and R ₁₅ are independently selected from the group consisting of H, C ₂ - ₈ alkenyl, -CO-C ₂ - ₈ alkenyl and C ₂ - ₈ alkynyl;

R ₁₆ is selected from the group consisting of C _1-8 alkyl, C ₂ - ₈ alkenyl, C ₂ - ₈ alkynyl, C ₃ - ₁₀ cycloalkyl, C ₆ - ₁₀ aryl, C ₅ . ₁₀ heteroaryl, C ₃ - ₁₀ heterocyclyl and -NR11R12, wherein said C ₅ - ₁₀ heteroaryl and C ₃ - ₁₀ heterocyclyl contain 1, 2 or 3 heteroatoms independently selected from N, O and S;

R ₁₇ is _{C1_8} alkyl or R ₁₇ is _{C3_10} cycloalkyl and, taken together with the carbon atom _to which it is attached, forms a spiro ring;

m is 0 or 1;

- 2 045554 n is equal to 0, 1 or 2;

and provided that:

if ring A is a 5-membered heteroaryl containing 2 or 3 N atoms, then R ₂ is a vinylamide-substituted 6-membered heterocyclyl containing an oxygen heteroatom, wherein the vinylamide-substituted 6-membered heterocyclyl is optionally substituted with 0-1 R ₁₃ substituent;

In some embodiments, the compound of formula (I) is a compound of formula (II);

Formula (II) in which R1, R2, _R5 , R6, R7, _R8 , _R9 and m have the same definition as in formula (I).

In some embodiments, ring A of formula (I) is phenyl, C ₅ - ₆ heteroaryl, or C ₁₀ heterocyclyl, wherein C ₅ - ₆ heteroaryl optionally contains 1, 2 or 3 heteroatoms selected from N and S, wherein C ₁₀ heterocyclyl is a fused bicycle that has two N atoms and one O atom in the ring.

In some embodiments, ring A is _C6 heteroaryl.

In some embodiments, R9 is selected from the group consisting of H, halogen, _cyano , _{C1_6} alkyl, _{C1_6} alkyl substituted with _halogen , -( _CH2 ) _nNR11R12 substituted amino, _C1 . ₆ alkoxy which is substituted with oA substituted II C ₆ heterocyclyl, wherein said C ₆ heterocyclyl contains 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein R11 and R ₁₂ are each selected from C1_ ₆ alkyl.

formula (I) is

In some incarnations

In some embodiments, R1 of formula (I) is H, R2 is selected from the group consisting of _{C5_7heterocyclyl} and phenyl, wherein _{C5_7heterocyclyl} contains 1 or 2 heteroatoms selected from N and O.

In some embodiments, R2 is substituted with 1 or 2 _R13 substituents, wherein _R13 is selected from the group consisting of _C5 . ₆ heterocyclyl, -NR ₁₄ R ₁₅ and -CO-R16; R ₁₄ represents _H , R ₁₅ represents -CO-C _{2_4} alkenyl, R ₁₆ represents C ₁ . ₃ αlkyl, where the indicated C ₅ . ₆ heterocyclyl contains 1, 2 or 3 heteroatoms, independently selected from N and O.

In some embodiments, R ₁₃ of formula (I) is substituted with 0-1 R ₁₈ substituent, wherein R ₁₈ is selected from the group consisting of C 1_ ₆ alkyl and C ₅ _ ₆ heterocyclyl, wherein C ₅ _ ₆ heterocyclyl contains 1 or 2 heteroatoms selected from N and O.

In some embodiments, R2 of formula (I) is

- 3 045554

In certain embodiments, R5, _R6 , R7, and R8 of formula (I) are each independently selected from the group consisting of hydrogen, halogen, and _C1-3 alkoxy.

In some embodiments, R5 and R8 of formula (I) are selected from the following groups:

(i) both _R5 and R8 are chlorine;

(ii) both _R5 and R8 are hydrogen;

(iii) _R5 is hydrogen, R8 is chlorine; or (iv) R ₅ is chlorine, R8 is hydrogen.

In some embodiments, R ₆ and R 7 of formula (I) are selected from the following groups:

(i) both _R6 and R7 are methoxy;

(ii) R ₆ is methoxy, R 7 is H; or (iii) R ₆ is H, R7 is methoxy.

In some embodiments, m of formula (I) is 0 or 1.

In some embodiments, n of formula (I) is 2.

The present invention further provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of the following:

(1) N-(2-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dihydropyrimido[5,4-c][1,8]nαphthyridin-2-yl)αmino )5-(4-morpholinopiperidin-1-yl)phenyl)acrylamide;

(2) N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dihydronirimido[5,4-c][1,8]naphthyridine2 -yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide;

(4) N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-5-methyl-5,6-dihydropyrimido[5,4-c][1 ,8]nαphthyridin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide;

(6) N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dihydropyrimido[5,4-c]quinolin-2yl)amino) tetrahydro-2H-pyran-4-yl)acrylamide;

(7) N-((3R,4S)-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dihydropyrimido[5,4-c][1,8]naphthyridine -2-yl)amino)tetrahydrofuran-3-yl)acrylamide;

(8) N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dihydronirimido[5,4-с][1,5]nαphthyridine2 -yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide;

(9) N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dihydropyrido[2,3-d:4,5-d] dipyrimidin2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide;

(10) N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dihydropyrazino[2',3':5,6]pyrido[ 4.3-

d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide;

(11) N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-9-fluoro-5,6-dihydropyrimido[5,4-с][1 ,8]naphthyridin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide;

(12) N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-10-methyl-5,6-dihydropyrimido[5,4-c][1 ,8]naphthyridin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide;

(13) N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-9-methyl-5,6-dihydropyrimido[5,4-c][1 ,8]naphthyridin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide;

(14) N-((3S,4S)-3-((6-(2-chloro-3,5-dimethoxyphenyl)-9-methyl-5,6-dihydropyrimido[5,4-c][1,8 ]naphthyridin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide;

(15) N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-methyl-5,6-dihydropyrimido[5,4-c][1 ,8]naphthyridin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide;

(16) N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-9-(trifluoromethyl)-5,6-dihydropyrimido[5,4с][1 ,8]naphthyridin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide;

(17) N-((3S,4S)-3-((6'-(2,6-dichloro-3,5-dimethoxyphenyl)-6Ή-spiro[cyclopropane-1,5'-pyrimido[5,4с] [1,8]naphthyridin]-2'-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide;

(19) N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-5-methyl-5,6-dihydrothieno[3',4':5, 6]pyrido[4,3-

d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide;

(20) N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-6H-pyrido[3',2':4,5]pyrano[3, 2-d]pyrimidin-2yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide;

(21) N-((3S,4S)-3-((6-(2-chloro-5-methoxyphenyl)-5,6-dihydropyrimido[5,4-c][1,8]naphthyridin-2yl)amino )tetrahydro-2H-pyran-4-yl)acrylamide;

(22) N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-6,9,10,11-terαhydro-5H-[1,4]oxαzino [2,3-

b]pyrimido[4,5-f][1,8]naphthyridin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide;

(23) N-((3R,4S)-4-((10-(2-(4-acryloylpiperazin-1-yl)ethoxy)-6-(2,6-dichloro-3,5-dimethoxyphenyl)5, 6-dihydropyrimido[5,4-c][1,8]naphthyridin-2-yl)amino)tetrahydrofuran-3-yl)acrylamide;

- 4 045554 (24) N-((3R,4S)-1-acetyl-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dihydropyrimido[5,4-c ][1,8]naphthyridin-2-yl)amino)piperidin-4-yl)acrylamide;

(25) N-((3S,4S)-3-((4-(2,6-dichloro-3,5-dimethoxyphenyl)-5-methyl-4,5-dihydrothiazolo[5',4':5, 6]pyrido[4,3d]pyrimidin-8-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide;

(26) N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-9-((2-(dimethylamino)ethyl)amino)-5,6dihydropyrimido[ 5,4-c][1,8]naphthyridin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide;

(27) N-((3S,4R)-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dihydropyrimido[5,4-c][1,8]naphthyridine -2yl)amino)-1-(1-methylpiperidin-4-yl)pyrrolidin-3-yl)acrylamide;

(28) N-((3S,4S)-3-((9-chloro-6-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dihydropyrimido[5,4-с][1 ,8]naphthyridin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide;

(29) N-((3S,4S)-3-((9-cyano-6-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dihydropyrimido[5,4-c][1 ,8]naphthyridin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide;

(30) P-((38.48)-3-((6-(2-chloro-5-methoxyphenyl)-9-methyl-5,6-dihydropyrimido[5,4-c][1,8]naphthyridine -2yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide;

(31) N-((3S,4S)-3-((6-(2-chloro-3-methoxyphenyl)-9-methyl-5,6-dihydropyrimido[5,4-c][1,8]naphthyridine -2yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide;

(32) N-((3S,4S)-3-((6-(2,6-dichloro-3-methoxyphenyl)-9-methyl-5,6-dihydropyrimido[5,4-c][1,8 ]naphthyridin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide.

The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of at least any of the compounds of formula (I) and at least one pharmaceutically acceptable excipient.

According to the present invention, there is further provided a pharmaceutical composition in which the weight ratio of the compound of formula (I) and the specified excipient is 0.0001-10.

The present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof in the manufacture of a medicinal product.

The present invention further provides a preferred technical solution for such an application.

Preferably, this use is for the treatment, prevention or delay of the onset or progression of cancer or metastasis of cancer.

Preferably, this use is for the manufacture of a medicament for use in the treatment of a disease mediated by FGFR4.

Preferably the disease is cancer.

Preferably, the cancer is selected from the group consisting of the following: breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatocellular carcinoma, head and neck tumors, hepatobiliary cell carcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Schwann cell tumor, squamous cell carcinoma of the lung, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer or liposarcoma.

A preferred use is as an FGFR4 inhibitor.

The present invention also provides a method of treating or preventing a disease mediated by FGFR4, comprising administering to a subject a therapeutically effective amount of at least one of the compounds of formula (I) or a pharmaceutically acceptable salt thereof.

Preferably, in the above method, the FGFR4-mediated disease is cancer.

Preferably, in the above-described method, the cancer is selected from the group consisting of breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatic cell carcinoma, head and neck tumors, hepatobiliary cell carcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Schwann cell tumor, squamous cell carcinoma of the lung, lichenoid keratosis, synovial sarcoma, skin cancer , pancreatic cancer, testicular cancer or liposarcoma.

Unless otherwise stated, the terms used in the present invention have the following meanings.

The term alkyl includes saturated hydrocarbon groups having straight and branched chains or cyclic groups. For example, the alkyl group includes methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2- methylbutyl, neopentyl, cyclopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and cyclohexyl, but not limited to. Likewise, _C1-8 , as in _C1-8 alkyl, is defined for identification

- 5 045554 groups having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms in a linear, branched or cyclic configuration.

Alkenyl and alkynyl groups include straight-chain, branched-chain and cyclic alkenes and alkynes. Likewise, C _2-8 alkenyl and C _2-8 alkynyl mean an alkenyl or alkynyl group having 2, 3, 4, 5, 6, 7 or 8 carbon atoms in a linear or branched or cyclic configuration.

Alkoxy refers to the oxygen ether form of the previously described straight-chain, branched-chain, or cyclic alkyl groups.

The term aryl as used herein, unless otherwise noted, refers to an unsubstituted or substituted mono- or polycyclic ring system containing carbon atoms. Preferred aryls are 6-10 membered mono- or bicyclic aromatic ring systems. Phenyl and naphthyl are preferred aryls. The most preferred aryl is phenyl.

The term heteroaryl refers to a monovalent heteroatom group formed by the removal of one hydrogen atom from the carbon atom of the parent heteroaromatic ring system. This heteroaryl group includes a 5-7 membered aromatic monocyclic ring containing at least one heteroatom selected from N, O or S, for example 1-4 heteroatoms or preferably 1-3 heteroatoms, and the other atom on the ring is carbon; the polyheteroaryl ring includes at least one heteroatom selected from N, O or S, for example 1-4 heteroatoms or preferably 1-3 heteroatoms, and the other atoms on the ring are carbon and at least one of the heteroatoms is on an aromatic ring . Particularly preferred heteroaryl groups are C ₃ - ₁₀ heteroaryl groups including pyrrolyl, furyl, thienyl, pyridyl, pyranyl, pyrazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, indolyl, benzofuranyl, benzothiazolyl, benzimidazolyl, benzopyrazolyl , benzotriazolyl, carbazolyl, quinolyl, isoquinolinyl, purinyl and similar groups.

However, in any case, the heteroaryl group and the aryl group do not overlap or contain each other. Thus, according to the definition described above, when at least one aromatic ring containing only carbon atoms is condensed with a heterocyclic group, a heteroaryl group is obtained instead of an aryl group.

The term cycloalkyl refers to a saturated or unsaturated cyclic group without aromaticity. According to the specific level of saturation, the terms cycloalkyl, cycloalkenyl or cycloalkynyl are used, respectively. Exemplary cycloalkyl groups include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane or cyclohexene and the like. In particular, the cycloalkyl group may be _{a C 3_10 cycloalkyl} group such as _a C _{3_6} cycloalkyl group.

Heterocyclyl refers to a saturated or unsaturated cyclic group without aromaticity, and where one or more than one carbon atom (and attached hydrogen atoms) may be replaced by the same or different heteroatoms and corresponding hydrogen atoms, respectively. Typical heteroatoms that replace carbon atoms include, but are not limited to, N, P, O, S, and Si. The terms heterocycloalkyl or heterocyclenyl are used, respectively, when it is necessary to describe a particular degree of saturation. Suitable heterocyclyl groups include, but are not limited to, epoxy compounds, imidazolidines, morpholine, piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine, tetrahydrofuran or tetrahydropyran and the like. A substituted heterocyclyl group also includes a ring system substituted with at least one oxygen (=O) or oxide (-O-)-containing substituent, such as piperidine nitrogen oxide, morpholinyl nitrogen oxide, 1-oxo-1-thiomorpholinyl And 1-dioxy-1-thiomorpholinyl.

However, in any case, the heterocycloalkyl group and the cycloalkyl group do not overlap or contain each other. Thus, according to the above definition, if at least one carbocyclic ring is fused with a heterocycloalkyl group to form a di-, poly-, or spiro ring, it will still be defined as a heterocycloalkyl group.

In addition, when a heteroaryl condenses with a heterocyclyl to form a di-, poly-, or spiro ring, it will be identified as heterocyclyl instead of heteroaryl.

The term halogen refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). Preferred halogens include fluorine, chlorine and bromine.

The term halogen- refers to the group fluorine-, chlorine-, bromo- or iodine-. Preferred halogens are fluoro- and chloro-.

The term substituted refers to the fact that each one or more hydrogen atoms in a group are replaced by the same or different substituents. Typical substituents include, but are not limited to, halogen, amino, hydroxy, oxo, carbonyl, cyano, alkyl, alkoxy, aryl, cycloalkyl, heterocyclyl, heteroaryl, alkylpiperazine, morpholinyl. In some embodiments, these substituents include F, Cl, CN, amino, hydroxyl, cyano, methyl, trifluoromethyl, cyclopropyl, phenyl, dimethylamino,

but are not limited to them.

Whenever the term alkyl or aryl or its prefix root appears in the name of a substituent (such as an aralkyl group or a dialkylamino group), these substituents should be defined according to the above-mentioned terms alkyl and aryl. A precisely defined number of carbon atoms (e.g., _C1-6 ) will independently represent the number of carbon atoms in an alkyl group or an alkyl group in a larger substituent (where the alkyl group is at the prefix root).

The term compound as used herein includes the compound of formula (I) and all pharmaceutically acceptable forms thereof. These pharmaceutically acceptable forms include salts, solvates, non-covalent complexes, chelates or prodrugs thereof, or any mixture of all of the above.

The phrase pharmaceutically acceptable means that it is well known for use in animals, in particular for use in humans.

The term composition as used in the present invention includes products containing a precisely defined amount of a particular component, as well as any product derived directly or indirectly from a specified amount of a particular component. Therefore, a pharmaceutical composition containing the compound of the present invention as an active ingredient and a method for its preparation constitute the contents of the present invention.

The phrase "therapeutically effective amount" means that when a compound is administered to a subject for the treatment and prevention and/or inhibition of at least one clinical condition, disease, condition, symptom, indication and/or discomfort, a sufficient dose is administered to produce a specified effect in treating the disease, condition , symptom, indication or discomfort. The specific effective therapeutic amount may vary depending on the compound, route of administration, age of the patient, weight of the patient, type of disease or discomfort being treated, symptoms and severity, and the like. In any circumstances where possible, a suitable dosage will be apparent to those skilled in the art and can be determined by conventional experimentation.

The compounds of the present invention may also be present in the form of pharmaceutically acceptable salts. For medical use, the salts of the compounds of this invention are non-toxic pharmaceutically acceptable salts. Pharmaceutically acceptable salt forms include pharmaceutically acceptable acid/anionic or basic/cationic salts. The pharmaceutically acceptable acid/anionic salt typically takes a form in which a basic nitrogen is protonated with an inorganic or organic acid. Representative organic or inorganic acids include hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic acid, pamoic acid, 2-naphthalene sulfonic acid, p-toluene sulfonic acid, cyclohexane sulfonic acid, salicylic acid, saccharic acid or trifluoroacetic acid. Pharmaceutically acceptable basic/cationic salts include, but are not limited to, aluminum, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium, magnesium, potassium, sodium and zinc salts.

The present invention includes, within its scope, prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of compounds that are readily convertible in vivo into the desired compound. Thus, in the methods of treatment of the present invention, the term administration should encompass the treatment of various described disorders using a specifically disclosed compound or using a compound that may not be specifically disclosed but which is converted to a specific compound in vivo upon administration to a subject. Traditional techniques for selecting and preparing suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.

What is meant is that the definition of any substituent or variable at a particular position in a molecule is independent of its definitions elsewhere in the molecule. It is understood that the substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be easily synthesized by techniques known in the art, as well as the methods set forth herein. document.

While the compound of formula I and its pharmaceutically acceptable salts exist as solvates or polymorphic forms, the present invention includes any possible solvates and polymorphic forms. The type of solvent that forms the solvate is not particularly limited as long as the solvent is pharmacologically acceptable. For example, water, ethanol, propanol, acetone or the like can be used.

The term pharmaceutically acceptable salts refers to salts derived from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper ((II) and (I)), iron (III), iron (II), lithium, magnesium, manganese ((IV) and (II) salts ), potassium, sodium, zinc and similar salts. Particularly preferred are the ammonium, calcium, manganese, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, as well as cyclic amines and substituted amines, such as naturally occurring and synthesized substituted amines. Other pharmaceutically acceptable organic non-toxic bases from which salts can be formed include ion exchange salts such as, for example, arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine , N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, formic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucinic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acids and the like. Preferred acids are citric, hydrobromic, formic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids. Particularly preferred acids are formic and hydrochloric acid. Since the compounds of formula I are intended for pharmaceutical use, they are preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure, especially at least 98% pure ( % are expressed on a w/w basis).

The pharmaceutical compositions of the present invention include the compound represented by Formula I (or a pharmaceutically acceptable salt thereof) as the active ingredient, a pharmaceutically acceptable carrier, and optionally other therapeutic ingredients or adjuvants. These compositions include compositions suitable for oral, rectal, topical and parenteral (including subcutaneous, intramuscular and intravenous) administration, although the most suitable route in any given case will depend on the particular host, nature and severity of the conditions against which the active ingredient is administered. The pharmaceutical compositions may conveniently be presented in unit dosage form and prepared by any of the methods well known in the pharmaceutical field.

In practice, the compounds represented by Formula I, or the prodrug or metabolite, or pharmaceutically acceptable salts thereof of this invention may be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical formulation techniques. This carrier can take a wide variety of forms, depending on the desired form of the drug for administration, for example, oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present invention may be presented in discrete units suitable for oral administration, such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient. In addition, the compositions may be presented as a powder, as a granule, as a solution or suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion, or as a liquid water-in-oil emulsion. In addition to the conventional dosage forms set forth above, the compound represented by Formula I or a pharmaceutically acceptable salt thereof can also be administered by controlled release agents and/or delivery devices. These compositions can be prepared by any of the pharmaceutical methods. In general, such methods include the step of bringing the active ingredient into association with a carrier that contains one or more of the desired ingredients. In general, these compositions are prepared by uniformly and thoroughly mixing the active ingredient with liquid carriers or finely divided solid carriers, or both. This product can then be conveniently molded into the desired presentation form.

Thus, the pharmaceutical compositions of this invention may include a pharmaceutically acceptable carrier and a compound or pharmaceutically acceptable salt of Formula I. Compounds of Formula I or pharmaceutically acceptable salts thereof may also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.

The pharmaceutical carrier used may be, for example, a solid, liquid or gas. Examples of solid carriers include lactose, gypsum powder, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, mannitol, sorbitol, microcrystalline cellulose, inorganic salts, starch, pregelatinized starch, powdered sugar and the like . Examples of liquid carriers are sugar syrup, peanut butter, olive oil and water. Examples of gaseous carriers include carbon dioxide and nitrogen. In preparing the compositions for oral dosage form, any convenient pharmaceutical media may be used. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, dyes and the like can be used to form liquid oral preparations such as suspensions, elixirs and solutions; whereas for the formation of solid oral preparations such as powders, capsules and tablets, carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants and the like can be used. Because of their ease of administration, tablets and capsules are the preferred oral dosage forms, using solid pharmaceutical carriers. Optionally, tablets can be coated using standard aqueous or non-aqueous techniques.

A tablet containing the compounds or composition of this invention may be prepared by compression or casting, optionally with one or more one auxiliary ingredient or adjuvant. Compressed tablets can be prepared by compressing in a suitable apparatus the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a lubricant, an inert diluent, a surfactant or a dispersant. Cast tablets may be prepared by casting in a suitable apparatus a mixture of the powder compound or composition moistened with an inert liquid diluent. Each tablet preferably contains from about 0.01 mg to about 5 g of the active ingredient, and each cachet or capsule preferably contains from about 0.1 mg to about 0.5 g of the active ingredient. For example, a formulation intended for oral administration to a human may contain from about 0.1 mg to about 0.5 g of active agent formulated with a suitable and convenient amount of carrier material, which may range from about 5 to about 99.99 percent of the active agent. the entire composition. Unit dosage forms will typically contain from about 0.1 mg to about 0.5 g of active ingredient, typically 0.1 mg, 0.2 mg, 0.5 mg, 1 mg, 2 mg, 2.5 mg, 5 mg , 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg or 500 mg.

The pharmaceutical compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant may be included, such as, for example, sodium lauryl sulfate, polysorbate-80 (Tween-80), polyoxyethylene, hydrogenated castor oil, poloxamer. Dispersions can also be prepared in glycerin, liquid polyethylene glycols and mixtures thereof in oils. In addition, a preservative may be included to prevent harmful microbial growth.

Suitable injectable pharmaceutical compositions of the present invention include sterile aqueous solutions or dispersions. In addition, these compositions may be in the form of sterile powders for immediate preparation before administration of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and flow efficiently for easy syringe collection. These pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, they should preferably be protected against the contaminating action of microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersing medium containing, for example, water, ethanol, polyol (eg, glycerin, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

The pharmaceutical compositions of the present invention may be in a suitable form for topical use, such as, for example, an aerosol, cream, ointment, lotion, powder or the like. In addition, these compositions may be in a suitable form for use in transdermal devices. These preparations can be prepared using the compound represented by Formula I of this invention, or a pharmaceutically acceptable salt thereof, through conventional processing methods. As an example, a cream or ointment is prepared by mixing a hydrophilic

- 9 045554 substances and water together with from about 5% by weight to about 50% by weight of the compound to obtain a cream or ointment having the desired consistency.

The pharmaceutical compositions of this invention may be in a suitable form for rectal administration, wherein the carrier is a solid. It is preferred that the mixture forms single-dose suppositories. Suitable carriers include cocoa butter and other substances commonly used in the art. These suppositories can be conveniently formed by initially mixing the composition with softened or melted carriers, followed by cooling and molding.

In addition to the above-mentioned carrier ingredients, the pharmaceutical preparations described above may include, as appropriate, one or more additional carrier ingredients, such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants) etc. In addition, other adjuvants may be included to make the drug isotonic with the blood of the intended recipient. Compositions containing a compound described in Formula I, or pharmaceutically acceptable salts thereof, may also be prepared as a powder or liquid concentrate.

Examples

To be clearer, the present invention is further illustrated by the following examples. The following examples are intended to illustrate specific embodiments of the present invention to enable those skilled in the art to understand the present invention, but not to limit the scope of patent protection of the present invention. In the examples of the present invention, the techniques or methods, unless expressly stated otherwise, are conventional techniques or methods in the art.

Unless otherwise stated, all parts and percentages of the invention are by weight and temperatures are in degrees Celsius (°C).

In these examples the following abbreviations were used:

ATP: adenine nucleoside triphosphate;

(Boc)2O: di-tert-butyl dicarbonate;

DCM: dichloromethane;

DIPEA: K,K-diisopropylethylamine;

DMAP: 4-dimethylaminopyridine;

DMF: K,K-dimethylformamide;

DMSO: dimethyl sulfoxide;

EA: ethyl acetate;

HCOOEt: ethyl formate;

NOAc: acetic acid;

COAs: potassium acetate;

LC-MS: liquid chromatograph - mass spectrometer;

m-CPBA or mCPBA: m-chloroperbenzoic acid;

MeMgBr: methyl magnesium bromide;

MeOH: methanol;

PdCl ₂ (dppf)CH2Cl ₂ : [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex;

Pd(OAc)2: palladium(P) acetate;

Pd(PPh ₃ ) ₄ : tetra(triphenylphosphine) palladium;

Room temp.: room temperature;

h: hour;

TEA: triethylamine;

THF: tetrahydrofuran;

TCX: thin layer chromatography;

Xant-phos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.

Example 1: preparation of K-(2-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dihydropyrimido[5,4-c][1,8]naphthyridin-2-yl) amino)-5-(4-morpholinopiperidin-1-yl)phenyl)acrylamide.

- 10 045554

Stage 1: Receiving connection 1-1.

M1 (0.85 g), M2 (0.91 g), Cs ₂ CO ₃ (2.49 g), Pd(OAc)2 (0.09 g), Xant-phos (0.44 g) were dissolved in toluene (40 ml) and reacted at 115°C for 5 h under N2 protection. LC-MS showed that the reaction was complete. Concentration was carried out under reduced pressure, the residue was dissolved in water, extracted with DCM, the organic layer was washed successively with water, saturated brine, concentrated, the residue was purified by column chromatography, eluting with hexane:dichloromethane (1:5), to obtain 1.28 g of compound 1-1 as a yellow solid.

LC-MS [M+H+] 376.9.

Stage 2: receiving connection 1-2.

Compound 1-1 (1.25 g), pinacola diborate (0.91 g), KOAc (1.20 g) and PdCl ₂ (dppf)CH ₂ Cl ₂ (0.14 g) were dissolved in 1,4-dioxane (40 ml) and reacted at 100°C for 15 hours under N2 protection. LC-MS showed that the reaction was complete. Concentration was carried out under reduced pressure, the residue was dissolved in water, extracted with EA, the organic layer was washed successively with water, saturated brine, concentrated, the residue was purified by column chromatography, eluting with dichloromethane:methanol (30:1), to obtain 1.07 g of compound 1-2 as a brown solid.

LC-MS [M+H+] 343.0.

Stage 3: obtaining connection 1 -3.

Compound 1-2 (1.03 g), M3 (0.57 g), K ₂ CO ₃ (0.83 g) and Pd(PPh ₃ ) ₄ (0.35 g) were dissolved in 35 ml of acetonitrile/12 ml water and reacted at 85°C for 4.5 hours under N2 protection. LC-MS showed that the reaction was complete. Concentration was carried out under reduced pressure, the residue was dissolved in water, extracted with DCM, the organic layer was washed successively with water, saturated brine, concentrated, the residue was purified by column chromatography, eluting with dichloromethane:methanol (200:1), to obtain compound 1-3 (0.93 d) as a yellow solid.

LC-MS [M+H+] 451.0.

Stage 4: obtaining connection 1-4.

Compound 1-3 (0.92 g), acetic acid (0.19 g) and sodium cyano borohydride (0.20 g) were dissolved in methanol (25 ml) and reacted at room temperature for 14 h under N2 protection. LC-MS showed that the reaction was complete. Concentration was carried out under reduced pressure, the residue was dissolved in water, a saturated aqueous solution of Na ₂ CO ₃ and DCM, extracted twice with DCM, the organic layer was combined and washed successively with water and saturated brine, concentrated, the residue was purified by column chromatography, eluting with DCM:CH ₃ OH ( 100:1) to give compound 1-4 (0.39 g) as a yellow solid.

LC-MS [M+H+] 434.9.

Stage 5: obtaining connection 1-5.

Compound 1-4 (0.35 g) was dissolved in DCM (25 ml), mCPBA (85%) (0.36 g) was added slowly at

- 11 045554 conditions of an ice water bath, after the addition was naturally warmed to room temperature and reacted for 7 hours. LC-MS indicated that the reaction was complete. The reaction solution was washed twice with saturated aqueous NaHCO ₃ solution, the organic layers were combined, washed with water and saturated brine, dried over anhydrous Na ₂ SO ₄ for 1 hour, filtered and concentrated under reduced pressure to give compound 1-5 (0.39 g) as an orange-yellow solid.

LC-MS [M+H+] 451.0.

Stage 6: obtaining connection 1-6.

To a solution of compound M4 (10.85 g) was slowly added with stirring DMAP (1.22 g), triethylamine (17.4 ml) in tetrahydrofuran (250 ml), (Boc) ₂ O (24.01 g) dissolved in tetrahydrofuran (40 ml), after addition, this reaction mixture was refluxed for 16 hours under N2 protection. The TCX indicated that the reaction was almost complete. Concentrated under reduced pressure, the residue was dissolved in water, extracted with DCM, the organic layer was washed successively with water, saturated brine, concentrated, the residue was purified by column chromatography eluting with hexane:ethyl acetate (5:1) to give compound 1-6 (20.18 g ) as a yellow solid.

LC-MS [M+H+] 417.1.

Stage 7: obtaining connection 1-7.

Compound 1-6 (3.02 g), M5 (1.13 g), Cs ₂ CO ₃ (5.36 g), Pd ₂ dba ₃ (0.60 g), Xant-phos (0.76 g) dissolved in toluene (50 ml) and reacted at 110°C for 14 h under N2 protection. LC-MS showed that the reaction was complete. Concentration was carried out under reduced pressure, the residue was dissolved in water, extracted with DCM, the organic layer was washed successively with water, saturated brine, concentrated, the residue was purified by column chromatography, eluting with DCM:MeOH (40:1), to obtain compound 1-7 (2.20 d) in the form of a red-brown sticky substance.

LC-MS [M+H+] 507.1.

Stage 8: Receiving connection 1-8.

Trifluoroacetate (20 ml) was slowly added to a solution of compound 1-7 (2.20 g) in DCM (30 ml), reacted at room temperature for 2 hours, and the pH of the residue was adjusted to 8~9 using a saturated aqueous solution of NaHCO ₃ , extracted with DCM, washed with water and saturated brine, the organic layer was dried over anhydrous Na ₂ SO ₄ for 1 hour, filtered and concentrated under reduced pressure to obtain the crude product (1.20 g) as a red-brown solid, which was directly used for next stage without cleaning.

LC-MS [M+H+] 307.1.

Stage 9: Receiving connection 1-9.

Compound 1-8 (307 mg), compound 1-5 (451 mg) were dissolved in anhydrous DMF (10 ml), potassium tert-butoxide (169 mg) was slowly added at -10°C, after addition, this mixture was reacted for 2 hours after natural warming to room temperature. LC-MS showed that the reaction was complete. The reaction was quenched with water, extracted with EA, the organic layer was washed successively with water and saturated brine, concentrated, and the residue was purified by column chromatography eluting with dichloromethane:methanol (40:1) to give compound 1-9 (200 mg) as a yellow solid.

LC-MS [M+H+] 693.1.

Stage 10: Receiving connection 1-10.

A solution of compound 1-9 (0.20 g), reduced iron powder (0.13 g), ammonium chloride (0.13 g) in ethanol (30 ml) and water (6 ml) was refluxed for 3 hours under the protection of N2. LC-MS showed completion of the reaction. The reaction mixture was filtered without cooling, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography eluting with DCM:MeOH (9:1) to give compound 1-10 (0.16 g) as an orange-yellow solid.

LC-MS [M+H+] 663.1.

Stage 11: Receive Connection 1.

To a solution of compound 1-10 (100 mg) in DCM (8 ml), trimethylamine (0.1 ml) was added, and then acrylic chloride was slowly added at -10° C., the reaction mixture was reacted at this temperature for 1 hour LC-MS showed that the reaction was almost complete, the mixture was quenched with saturated aqueous NaHCO3, the DCM layer was washed successively with water and saturated brine, concentrated under reduced pressure, the residue was purified by preparative TLC, eluting with DCM:MeOH (10:1), to obtain compound 1 (43 mg) as an orange-yellow solid.

LC-MS [M+H+] 717.2.

Example 2: Preparation of N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dihydropyrimido[5,4c][1,8]naphthyridine- 2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide.

- 12 045554

Stage 1: Receive connection 2-1.

M6 (3.57 g), TEA (6.2 ml) and formic acid (88%) (2.09 g) were dissolved in ethyl formate (100 ml), this reaction mixture was refluxed for 4 hours. TLC showed completion of the reaction. Concentration was carried out under reduced pressure, the residue was dissolved in ethyl acetate, the organic layer was washed successively with a small amount of water and saturated brine, concentrated to give compound 2-1 (3.49 g) as an off-white solid, which was directly used in the next reaction without purification.

Stage 2: Receiving connection 2-2.

To a solution of compound 2-1 (90 mg) in anhydrous DMF (2 ml), NaH (60%) (42 mg) was slowly added under ice-salt bath conditions, the reaction mixture was reacted at this temperature for 40 min, and then compound 1-5 (239 mg) was added, after addition this reaction mixture was warmed to room. pace. and interacted for 40 minutes. LC-MS showed completion of the reaction. This reaction mixture was quenched with water, the organic layer was washed successively with water and saturated brine, concentrated, and the residue was purified by column chromatography eluting with DCM:CH ₃ OH (40:1) to give compound 2-2 (139 mg) as an orange-yellow sticky substance. LC-MS [M+H+] 529.1.

Stage 3: obtaining connection 2-3.

A mixture of compound 2-2 (135 mg) and 10% Pd/C (50 mg) in EA/CH3OH (15 ml/10 ml) was reacted at 30°C for 2 hours under H ₂ conditions. Filtration was carried out, concentrated under reduced pressure to obtain the crude product - compound 2-3 (132 mg) - as an orange-yellow sticky substance, which was used directly in the next reaction without purification.

LC-MS [M+H+] 503.1.

Stage 4: Receive connection 2.

To a solution of compound 2-3 (130 mg) in DCM (8 ml) was added trimethylamine (0.12 ml), acrylic chloride (23 mg) was slowly added at -20°C, the reaction mixture was reacted at this temperature for 1 h. LC-MS showed the reaction was complete, quenched with saturated aqueous NaHCO3, the DCM layer was washed successively with water and saturated brine, concentrated under reduced pressure, the residue was purified by thick preparative TLC, eluting with DCM/MeOH (40:1), to obtain the compound 2 (41 mg) as a light yellow solid.

LC-MS [M+H+] 557.1.

Example 3: Preparation of N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-5-oxo-5,6-dihydropyrimido[5,4-c][ 1,8]naphthyridin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide.

Stage 1: Receive connection 3-1.

Compound 3-1 was prepared using a method similar to that shown in Step 3 of Example 1, with 4-chloro-2-methylthiopyrimidine-5-ethylcarboxylate (M7) replacing M3 as the starting material to prepare Compound 3-1.

LC-MS [M+H+] 449.0.

Stage 2: obtaining connection 3-2.

Compound 3-2 was prepared using a method similar to that described in step 5 of Example 1. LC-MS [M+H+] 464.9.

Stage 3: obtaining connection 3-3.

- 13 045554

Compound 3-2 (780 mg), M6 (300 mg), DIPEA (1.26 ml) and DMF (8 ml) were sequentially added to a sealed tube and reacted at 80°C for 2 hours. Quenched with water, extracted EA, washed four times with saturated brine, concentrated and purified by column chromatography, eluting with DCM/MeOH (100:1) to give compound 3-3 as an orange-yellow solid.

LC-MS [M+H+] 543.0.

Stage 4: obtaining connection 3-4.

Compound 3-4 was prepared using a method similar to that described in step 3 of example 2. LC-MS [M+H+] 517.1.

Stage 5: Receive connection 3.

Compound 3 was prepared using a method similar to that described in step 4 of example 2. LC-MS [M+H+] 571.5.

Example 4: Preparation of N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-5-methyl-5,6-dihydropyrimido[5,4-c][ 1,8]naphthyridin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide.

Stage 1: Receiving Connection 4-1.

M3 (3.77 g) was dissolved in anhydrous THF (100 ml), methylmagnesium bromide (1M in THF) (1.2 ml) was slowly added under ice water bath conditions (less than 5°C) and the reaction was continued for 1 hour at the same temperature. LC-MS showed completion of the reaction. This reaction was quenched with aqueous ammonium chloride, extracted with DCM, the organic layer was washed successively with water and saturated brine, concentrated, and the residue was purified by column chromatography eluting with DCM:CH ₃ OH (50:1) to give compound 4-1 (3.72 g ) in the form of a yellow liquid.

LC-MS [M+H+] 205.4.

Stage 2: Receiving connection 4-2.

Compound 4-1 (2.05 g) was dissolved in dichloromethane (20 ml), thionyl chloride (3.63 ml) was added slowly under ice water bath conditions (less than 5° C.), after addition, the reaction was continued for 2 hours at the same temperature. LC-MS showed completion of the reaction. The reaction solution was added to stirred ice-water (1 L), extracted twice with dichloromethane, the organic layers were combined, washed successively with water and saturated brine, and the residue was purified by column chromatography eluting with hexane:dichloromethane (3:1) to give compound 4-2 in the form of a light yellow liquid. LC-MS [M+H+] 223.3.

Stage 3: obtaining connection 4-3.

Compound 4-3 was prepared using a method similar to that described in Step 3 of Example 1, with Compound 4-2 replacing M3 as the starting material.

LC-MS [M+H+] 449.0.

Stage 4: Receiving connection 4-4.

Compound 4-4 was prepared using a method similar to that described in step 5 of Example 1. LC-MS [M+H+] 465.0.

Stage 5: obtaining connection 4-5.

Compound 4-5 was prepared using a method similar to that described in step 2 of example 2. LC-MS [M+H+] 543.0.

Stage 6: obtaining connection 4-6.

Compound 4-6 was prepared using a method similar to that described in step 3 of example 2. LC-MS [M+H+] 517.1.

Stage 7: receiving connection 4.

Compound 4 was prepared using a method similar to that described in step 4 of example 2.

LC-MS [M+H+] 571.1.

Connections in the table. 1 can be obtained using a method similar to that described in

- 14 045554 the above examples with other starting materials and suitable reagents. For example, when replacing M2 in example 1 with

Compound 12, 13, 15, 16, 28 or 29 can be prepared with reference to the preparation method of Example 2.

Table 1

No. note Chemical structure Chemical name LC-MS [M+H ⁺ ] 5 Z—ς o Ж o—°\ °\ L/-((35.48)-3-((6-(2,6-dichloro-3,5dimethoxyphenyl)-5,6dihydropyrimido[5,4e][1,2,4]triazolo[4,3-a ]pyrimidin2-yl)amino)tetrahydro-2H-pyran-4yl)acrylamide 547.1 6 3 ΖΖ Ζ y - O \ L/-((35.45)-3-((6-(2,6-dichloro-3,5dimethoxyphenyl)-5,6dihydropyrimido[5,4-c]quinolin-2yl)amino)tetrahydro-2/7- pyran-4yl)acrylamide 556.1 7 Ζ^/^Ο Ιξ / ΖΖ Ζ y ^Ω o—O )=/ \ o \ L/-((ZY48)-4-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-5,6dihydropyrimido[5,4c][1,8]naphthyridin-2yl)amino)tetrahydrofuran-3yl)acrylamide 543.7 8 3 3 ABOUT- O \ /\/-((35.48)-3-((6-(2,6-dichloro-3,5dimethoxyphenyl)-5,6dihydropyrimido[5,4c][1,5]naphthyridin-2yl)amino)tetrahydro- 2H-pyran-4yl)acrylamide 557.1 9 Jo ΖΖ g L/-((35.48)-3-((6-(2,6-dichloro-3,5dimethoxyphenyl)-5,6dihydroprido[2,3-с/:4,5сУ]dipyrimidin-2yl)amino)tetrahydro -2/7-pyran-4yl)acrylamide 558.0 10 θ' ^H O /\/-((35.48)-3-((6-(2,6-dichloro-3,5dimethoxyphenyl)-5,6dihydropyrazino[2',3':5,6]pyrido[4, 3-phpyrimidine -2yl)amino)tetrahydro-2/7-pian-4yl)acrylamide 558.0 eleven _A . ^{s| n} ψ O F /\/-((35.48)-3-((6-(2,6-dichloro-3,5dimethoxyphenyl)-9-fluoro-5,6dihydropyrimido[5,4c][1,8]naphthyridin-2yl) amino)tetrahydro-2/7-pyran-4yl)acrylamide 575.7

- 15 045554

12 ^CI \J\ o /^XJU Г Ί ^N if ν о ^NH ^H JU 0 L/-((38.48)-3-((6-(2,6-dichloro-3,5dimethoxyphenyl)-10-methyl-5,6dihydropyrimido[5,4c][1,8]naphthyridin-2yl)amino )tetrahydro-2/-/-pyran-4yl)acrylamide 571.7 13 CI^J\ o ____JUU JJn ^{cl h} u 0 I L/-((38.48)-3-((6-(2,6-dichloro-3,5dimethoxyphenyl)-9-methyl-5,6dihydropyrimido[5,4c][1,8]naphthyridin-2yl)amino )tetrahydro-2/-/-pyran-4yl)acrylamide 571.7 14 □ 4 Z ZI / \I O >—z G /V-((3S,4S)-3-((6-(2-xnop-3,5dimethoxyphenyl)-9-methyl-5,6dihydropyrimido[5,4c][1,8]naphthyridin-2yl)amino)tetrahydro -2/-/-pyran-4yl)acrylamide 537.7 15 Cl^x^ o XI / Г Ί ^N if n o Χ4 ^Λ ν\Λν ^Cl ^An ^h uj 0 L/-((38.48)-3-((6-(2,6-dichloro-3,5dimethoxyphenyl)-8-methyl-5,6dihydropyrimido[5,4c][1,8]naphthyridin-2yl)amino )tetrahydro-2/-/-pyran-4yl)acrylamide 571.7 16 \ about y—ll? S 4 ζ ζζ / \ I Ο >-ζ Γ L/-((38.45)-3-((6-(2,6-dichloro-3,5- dimethoxyphenyl)-9(trifluoromethyl)-5,6dihydropyrimido[5,4c][1,8]naphthyridin-2yl)amino)tetrahydro-2H-pyran-4yl)acrylamide 625.6 17 Jo ^χ °-Ο- ^σ _ζ _ ⁵ i>/ ^z_ w ά Ζ and ζτ o \-ζ g L/-((38.48)-3-((6'-(2,6-dichloro-3,5dimethoxyphenyl)-6'/-/spiro[cyclopropane-1,5'pyrimido[5,4-c] [1,8]naphthyridin]-2'yl)amino)tetrahydro-2/-/-pyran-4yl)acrylamide 583.1 18 сХ Cl^x f "·J <> ^N if 0 kJ'N^N^'J'N θ' ^γΑ _Η ^H U 0 /V-((3S,4S)-3-((6-(2,6-dichloro-3,5dimethoxyphenyl)pyrimido[4,5f][1,7]naphthyridin-2yl)amino)tetrahydro-2/-/ -pyran-4yl)acrylamide 555.1 19 0^ ^C| u^i CX jc « M 0 L/-((38.48)-3-((6-(2,6-dichloro-3,5dimethoxyphenyl)-5-methyl-5,6dihydrothieno[3',4':5,6]pyrido[4, 3c(]pyrimidin-2yl)amino)tetrahydro-2/-/-pyran-4yl)acrylamide 576.2

- 16 045554

20 Ell z—< o t \ / ZZ A ^Z A /=( o / \__/ o ^{4 ζ} ΖΗ_ _ο - \=/ \ °\ L/-((38.48)-3-((6-(2,6-dichloro-3,5dimethoxyphenyl)-6/7pyrido[3',2':4,5]pyrano[3,2c(]pyrimidine -2yl)amino)tetrahydro-2/7-pyran-4yl)acrylamide 558.1 21 ^C| \^\ η lllll XI / L i l 1 A ^NH ^H U 0 /V-((3S,4S)-3-((6-(2-xnop-5methoxyphenyl)-5,6dihydropyrimido[5,4c][1,8]naphthyridin-2yl)amino)tetrahydro-2H-pyran-4yl )acrylamide 493.1 22 3 °H ZZ У\ Z р WHAT? Z _o oZu - o o \ L/-((38.48)-3-((6-(2,6-dichloro-3,5dimethoxyphenyl)-6,9,10,11tetrahydro-5/7-[1,4]oxazino[2,3b ]pyrimido[4,5-/][1,8]naphthyridin2-yl)amino)tetrahydro-2/7-pyran-4yl)acrylamide 614.1 23 A, 0-, \ A. A A. A- CI γ Ν Ν Ν Αί» d> ⁰ / 0 A /V-((3R,4S)-4-((10-(2-(4- acryloylpiperazin-1-yl)ethoxy)-6(2,6-dichloro-3,5-dimethoxyphenyl)5,6-dihydropyrimido[5,4- c][1,8]naphthyridine-2- yl)amino)terahydrofuran-3yl)acrylamide 725.2 24 An ΙΖ^_ her? ^ζ _ο χΧ _ο o \ L/-((3,48)-1-acetyl-3-((6-(2,6dichloro-3,5-dimethoxyphenyl)-5,6dihydropyrimido[5,4c][1,8]naphthyridin-2yl)amino )piperidin-4yl)acrylamide 598.1 25 > \ /A ^oH Ur° __/ y-ω he to ZI O >—Z g L/-((38.48)-3-((4-(2,6-dichloro-3,5dimethoxyphenyl)-5-methyl-4,5dihydrothiazolo[5',4':5,6]pyrido[4, 3 -c(]pyrimidin-8yl)amino)tetrahydro-2/7-pyran-4yl)acrylamide 577.1 26 a ggA CHAAHA ^{S| n} X O ΗΝ. X ^x \ L/-((38.48)-3-((6-(2,6-dichloro-3,5dimethoxyphenyl)-9-((2(dimethylamino)ethyl)amino)-5,6dihydropyrimido[5,4c][ 1,8]naphthyridin-2yl)amino)tetrahydro-2/7-pyran-4yl)acrylamide 643.2 27 \ o A ΖΖ -A L/-((38.4R)-4-((6-(2,6-dichloro-3,5dimethoxyphenyl)-5,6dihydropyrimido[5,4c][1,8]naphthyridin-2-yl)amino)- 1(1-methylpiperidin-4yl)pyrrolidin-3-yl)acrylamide 639.2

- 17 045554

28 J π ZZ z у о—p “ ^Ζ ο^Η^ο _χ ο' \ L/-((38.48)-3-((9-chloro-6-(2,6-dichloro3,5-dimethoxyphenyl)-5,6dihydropyrimido[5,4c][1,8]naphthyridin-2yl)amino )tetrahydro-2/7-pyran-4yl)acrylamide 591.6 29 3 ΙΖ ζ у О—/у— ^ζ р ^Ζ “ ^Ζ „^Η_ο ₄ ο \ L/-((38.48)-3-((9-cyano-6-(2,6dichloro-3,5-dimethoxyphenyl)-5,6dihydropyrimido[5,4c][1,8]naphthyridin-2yl)amino )tetrahydro-2/7-pyran-4yl)acrylamide 582.8 thirty 3 Ή ΙΖ ζ y °\ /V-((3S,4S)-3-((6-(2-xnop-5methoxyphenyl)-9-methyl-5,6dihydropyrmido[5,4c][1,8]naphthyridin-2yl)amino)tetrahydro-2 /7-pyran-4yl)acrylamide 507.2 31 3 ^ο= \ιζ ζ y /V-((3S,4S)-3-((6-(2-xnop-3methoxyphenyl)-9-methyl-5,6dihydropyrimido[5,4c][1,8]naphthyridin-2yl)amino)tetrahydro-2 /7-pyran-4yl)acrylamide 507.2 32 ζ—< ο ι\/ ΙΖ ζ у о Q^^O L/-((38.48)-3-((6-(2,6-dichloro-3methoxyphenyl)-9-methyl-5,6dihydropyrimido[5,4c][1,8]naphthyridin-2yl)amino)tetrahydro -2/7-pyran-4yl)acrylamide 541.1 33 3 ^ζι O 3-Z G L/-((38.48)-3-((6-(2,6-dichloro-3,5dimethoxyphenyl)- [1,2,4]triazolo[4',3': 1,6]pyrido[2,3с(]pyrimidine-2- yl)amino)tetrahydro-2/7-pyran-4yl)acrylamide 543.1 34 IZ m 0^^0^ o \ L/-(3-((9-chloro-6-(2,6-dichloro-3,5dimethoxyphenyl)-5-oxo-5,6dihydropyrimido[5,4c][1,8]naphthyridin-2yl)amino)tetrahydro -2/7-pyran-4yl)acrylamide 605.9

NMR (nuclear magnetic resonance) data for compounds 13, 14, 16, 28 and 32 are as follows: 1H NMR (DMSO- _d6 , 500 MHz) δ ( ^ppm ) 8.14 (s, 1H), 8.12 (s, 1H) , 7.99 (d, J=7.8 Hz, 1H), 7.78 (s, 1H), 6.96 (s, 1H), 6.57 (d, J=7.5 Hz, 1H), 6.19 (br, 1H), 6.05-6.01 (m, 1H), 5.49 (br, 1H), 4.76 (d, J=14.0 Hz, 1H), 4.71 (d, J=14.0 Hz, 1H), 4.43 (br, 1H) , 4.27-4.20 (m, 1H), 3.95 (s, 6H), 3.91-3.72 (m, 2H), 3.68-3.57 (m, 1H), 3.56-3.44 (m, 1H), 2.17 (s, 3H) , 2.02-1.85 (m, 1H), 1.71-1.54 (m, 1H). (compound 13);

1H NMR (CDCls, 500 MHz) δ ( ^ppm ) 8.14 (s, 1H), 8.03 (s, 1H), 7.96 (s, 1H), 7.04 (d, J=5.0 Hz, 1H), 6.53 (s, 1H), 6.51 (s, 1H), 6.18 (d, J=17.1 Hz, 1H), 5.90 (dd, J=16.7, 10.9 Hz, 1H), 5.80 (d, J =8.0 Hz, 1H), 5.49 (d, J=10.1 Hz, 1H), 4.81 (s, 2H), 4.45 (s, 1H), 4.30-4.25 (m, 1H), 4.07-4.01 ( m, 1H), 3.98 (d, J=11.7 Hz, 1H), 3.90 (s, 3H), 3.80 (s, 3H), 3.73 (d, J=11.8 Hz, 1H), 3.61 (t , J=12.0 Hz, 1H), 2.21 (s, 3H), 2.08 (d, J=12.4 Hz, 1H), 1.87 (tt, J=12.3, 6.3 Hz, 1H). (compound 14);

1H NMR (CDCl ₃ , 500 MHz) δ ( ^ppm ) 8.51 (s, 1H), 8.26 (s, 1H), 8.06 (s, 1H), 6.64 (s, 2H), 6.17 (d, J=17 ,0 Hz, 1H), 5.91 (t, J=10.9 Hz, 2H), 5.51 (d, J=10.1 Hz, 1H), 4.87 (d, J=15.9 Hz, 2H), 4.49 (br, 1H), 4.30-4.24(m, 2H), 4.01-3.95 (m, 1H), 3.97 (s, 6H), 3.73 (d, J=11.7 Hz, 1H), 3.60 (t, J =11.7 Hz, 1H), 2.14-1.96 (m, 1H), 1.901.80 (m, 1H). (compound 16);

1H NMR (CDCl ₃ , 500 MHz) δ ( ^ppm ) 8.27 (s, 1H), 8.04 (s, 1H), 7.94 (s, 1H), 6.72 (br, 1H), 6.62 (s, 1H), 5.91 (dd, J=16.6 Hz, 10.5 Hz, 1H), 5.11 (d, J=8.5 Hz, 1H), 5.53 (d, J=10.0 Hz, 1H), 4.87 (s , 2H), 4.47 (br, 1H), 4.31-4.24(m, 1H), 4.01-3.93(m, 2H), 3.96 (s, 6H), 3.72 (d, J=12.0 Hz, 1H), 3.60 (t, J=12.0 Hz, 1H), 2.07-2.01 (m, 1H), 1.87-1.82 (m, 1H). (compound 28);

1H NMR (CDCl ₃ , 500 MHz) δ ( ^ppm ) 9.49 (s, 1H), 8.16 (s, 1H), 8.06 (s, 1H), 7.73 (s, 1H), 7.41 (d, J=9 ,0 Hz, 1H), 6.95 (d, J=8.9 Hz, 2H), 6.22 (d, J=17.0 Hz, 1H), 6.06 (dd, J=17.0, 10.4 Hz, 1H), 5.61 (d, J=10.3 Hz, 1H), 4.88-4.72 (m, 2H), 4.60-4.45 (m, 2H), 4.31 (d, J=11.5 Hz, 1H), 4.20 -4.00 (m, 1H), 3.98 (s, 3H), 3.69 (d,

- 18 045554

J=12.3 Hz, 1H), 3.58 (t, J=11.3 Hz, 1H), 2.29 (s, 3H), 2.26-1.95(m, 1H), 1.84-1.77 (m, 1H). (compound 32).

Pharmacological analysis.

Example A: Kinase Assay.

The effect of the compounds of the present invention on the activity of FGFR4 tyrosine kinase was assessed using an in vitro kinase detection experiment. In this experiment, a mobility shift assay was used and a fluorescently labeled polypeptide was used as a substrate, the substrate being converted to product by the enzyme in the reaction system and its charge also changing accordingly. This method can use the difference between the charge of the substrate and the product to separate them and then detect them separately.

Experimental procedure.

(1) Obtaining a connection.

A solution of compound in DMSO (300 µM) was diluted to 100 times the final concentration of the solution in DMSO in a 384-well plate, with a 3-fold dilution, 250 nl of compound with 100 times the final concentration was transferred to the OptiPlate-384F target plate using an Echo 550 dispenser The final concentration of the compound was 3000 nM, 1000 nM, 333.3 nM, 111.1 nM, 37.04 nM, 12.35 nM, 4.115 nM, 1.372 nM, 0.4572 nM, 0.1524 nM, and the compound and the enzyme was incubated for 60 min;

(2) Kinase reaction.

1x kinase buffer was prepared, this 1x kinase buffer was used to obtain 2.5 times the final concentration of the kinase solution, 10 µl of the 2.5 times the final concentration of the kinase solution was added to the compound well and the positive control well, respectively, and 10 µl of 1x kinase buffers were added to the negative control well. After centrifugation, the reaction plate was shaken, mixed and incubated at room temperature for 60 minutes, and a mixture of 25/15 times the final concentration of adenosine triphosphate (ATP) and kinase substrate 22 with 1x kinase buffer was prepared. Add 15 µl of 25/15 times the final concentration of ATP and substrate mixed solution to start the reaction, the 384-well plate is centrifuged, mixed and then incubated at room temperature for 30 min, 30 µl of stop detection solution is added to stop the kinase reaction, and conversion was read using a Caliper EZ reader after centrifugation and mixing;

(3) Data analysis.

Calculation formula:

Iinhibition index% = ^{% p} R ^{eev %} conversion sample. _w q % conversion max - % conversion_min where % conversion_sample was the conversion rate of the sample; %conversion_min was the average of the negative control well, which represents the conversion of a well without enzymatic activity; %conversion_max was the average of the positive control well, which represents the conversion of the well without compound inhibition.

Take log concentration as the abscissa, percent inhibition as the ordinate, and apply the following GraphPad Prism analysis function: log(inhibitor) vs. response-variable slope (four parameters) to fit a dose-response curve to obtain the IC ₅₀ value of each compound on an enzyme. The formula is: Y = smallest value + (largest value - smallest value)/(1+10 ^Λ ((LogIC ₅₀ -X)*slope)).

The IC ₅₀ data for some examples and BLU554 are shown in Table 1. 2.

table 2

Connection number 1C ₅₀ (nM) compounds FGFR1 FGFR4 Connection 1 /® 9.4 Connection 2 912 10 Connection 11 1531 1.8 Connection 13 367 1.0 Connection 14 1435 2.6 Connection 15 1001 5.2 Connection 16 166 3.6 Connection 28 741 1.8 BLU554® 1480 13

Note:

1/ indicates that they were not tested;

2BLU554 is Compound No. 40, which is disclosed by Blueprint Medicines Corporation in WO 2015061572

The compound of the present invention has a great inhibitory effect on FGFR4 kinase,

- 19 045554 and such compounds have a significantly stronger inhibitory effect on FGFR4 than on FGFR1, which represents greater selectivity.

Example B: Cell Proliferation Assay.

An in vitro cell assay was used to measure the effects of a compound of the present invention on the proliferation of Hep3B human liver cancer cells. In this assay, the CELL TITER-GLO luminescent assay (CTG) was used as a detection method, which can detect the number of live cells through the quantification of ATP. Since ATP is involved in many enzymatic reactions in the body, it is an indicator of the metabolism of living cells, and its content directly reflects the number and cellular state of cells during the experiment, when CellTiter-Glo™ reagent is added to the cell culture medium to measure luminescence, the luminescence value is directly proportional amount of ATP, and ATP is positively related to the number of living cells, so cell viability can be checked by detecting ATP content.

Experimental technique.

(1) Planting cells on a plate.

A bottle with Hep3B cells in the logarithmic growth phase was taken, these cells were counted after splitting and resuspension, then the cell density was adjusted and they were seeded in a volume of 180 μl per well (1500 cells/well) in a 96-well plate, this plate was incubated for 24 hours at 37°C in an incubator with 5% CO ₂ .

(2) Delivery of the drug into the cell.

600 µM of the experimental substance dissolved in DMSO was diluted with DMSO in a ratio of 1:3 to 200 times the final concentration of the solution, then the cell culture medium was diluted 20 times (10 x), and 20 µl of the compound solution was added to 96 wells on the plate containing cells, wherein the final high to low concentration of the compound was 3000 nM, 1000 nM, 333.3 nM, 111.1 nM, 37.04 nM, 12.35 nM, 4.115 nM, 1.372 nM, 0.4572 nM, and the well plate was placed for 96 hours in an incubator at 37°C with 5% CO2;

(3) Detection of CTG.

After 96 h of incubation, 60 μl of CellTiter-Glo® Luminescence Cell Viability Assay Solution was added to each well, gently vortexed for 2 min, incubation continued for 10 min at room temperature, and the luminescence value of each well was read on a multifunctional microplate reader.

(4) Data analysis.

The inhibition index was calculated based on the light emission value:

Inhibition rate in % = (blank group value - injection group value)/(blank group value - apoptosis group value) * 100.

The log concentration value was used as the abscissa, and the percentage inhibition value was used as the ordinate. Log(inhibitor) vs. response-variable slope (four parameters) GraphPad Prism was used to fit the dose-response curve, and the IC ₅₀ of the compound for inhibiting cell proliferation was calculated. The experimental data were shown in Table. 3.

Table 3

Connection number 1C ₅ o(nM) compounds on NerZV cells BLU554 62.7 Connection 1 6.9 Connection 3 >3000 Connection 11 10.6 Connection 13 5.1 Connection 14 18.7 Connection 16 14.5 Connection 28 9.9 Connection 33 524.4 Connection 34 1027.0

The preferred compound of the present invention has a good inhibitory effect on the proliferation of Hep3B cells.

Example C: Tumor xenograft models.

Female BALB/c nu/nu mice were subcutaneously inoculated into the right anterior scapula with 5 x ^{10 6} human hepatocarcinoma Hep3B cells, and the cell suspension to Matrigel volume ratio was 1:1 (0.2/ml/mouse). Mice were grouped according to tumor size until the average tumor volume was 158 mm ³ . The treatment group was given a solution of the test compound prepared with a suitable solvent, and the solvent control group was given blank solvent. During the formation

Claims (29)

Both tumor volume was measured twice a week, and tumor weight was measured after the last dose to determine compound activity. Tumor growth inhibition index (%, TGI) was calculated by comparing the tumor volume and weight of the treatment group and the vehicle control group. Measuring body weight as a traditional determination of toxicity has the same frequency as measuring tumor volume. In this model, the compound of Example 13 showed good antitumor activity. For example, when the doses were 50 mg/kg, 100 mg/kg and 200 mg/kg (BID x 14), the inhibition rate of the compound of Example 13 on Hep3B tumor volume growth was 73.02%, 86.26% and 90.26%, respectively, the inhibition rate of tumor mass growth of NerB was 84.76%, 92.27% and 98.15%, respectively, indicating that the compound of Example 13 exhibited a dose-dependent effect in inhibiting tumor volume and mass. The compound of Example 16 also showed good antitumor activity in this model, when the dose was 50 mg/kg (BID x14), the inhibition rates of tumor volume and tumor weight were 78.37% and 83.85%, respectively. In addition, throughout the experiment, animals given the compounds of Example 13 and Example 16 showed no apparent weight loss, indicating that these two compounds were well tolerated under treatment dosage conditions. Although the present invention has been fully described by way of its embodiments, it is worth noting that various changes and modifications will be apparent to those skilled in the art. Such changes and modifications are intended to come within the scope of the appended claims. CLAIM 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, Re Formula I where - represents a single bond; L is C, Q is N, T is selected from the group consisting of O, CH ₂ and CR ₁₇ ; ring A is C ₆ - ₁₀ aryl, C ₅ - ₁₀ heteroaryl, C ₅ . ₁₀ heterocyclyl; where said C ₅ - ₁₀ heteroaryl and C ₅ - ₁₀ heterocyclyl contain 1, 2 or 3 heteroatoms independently selected from N, O and S; R1 represents hydrogen; R2 is selected from the group consisting of C ₃ - ₁₀ heterocyclyl and C ₆ - ₁₀ aryl, wherein said C ₃ - ₁₀ heterocyclyl contains 1 or 2 heteroatoms selected from N and O; R2 is optionally substituted with 1-2 R ₁₃ substituents; R ₁₃ is selected from _the group consisting of hydroxyl _, halogen, _{C1_8} alkyl, _{C2_8} alkenyl _{, C2_8} alkynyl _{, C1_8} alkoxy, _{C6_10 aryl} , _{C3_10} cycloalkyl, _{C3_10} heterocyclyl, C ₅ _ ₁₀ heteroaryl, -NR ₁₄ R ₁₅ and -CO-R16, where said C ₃ _ ₁₀ heterocyclyl and C ₅ _ ₁₀ heteroaryl contain 1, 2 or 3 heteroatoms selected from N and O; R ₁₃ is optionally substituted with 0-1 substituent R ₁₈ ; R ₁₈ is selected _from the group consisting of hydroxyl, halogen, _{C1_8} alkyl, _{C2_8} alkenyl, _{C2_8 alkynyl} , C1. ₈ alkoxy, C ₆ - ₁₀ aryl, C ₃ - ₁₀ cycloalkyl, C ₃ - ₁₀ heterocyclyl and C ₅ - ₁₀ heteroaryl, where said C ₃ - ₁₀ heterocyclyl and C ₅ - ₁₀ heteroaryl contain 1, 2 or 3 heteroatoms selected from N and O; R ₅ , R 6 , R ₇ and R 8 are independently selected from the group consisting of hydrogen, halogen and C1_ ₈ alkoxy; R9 is selected from the group consisting of H, halogen, amino, cyano, C1. ₈ alkyl, C ₁ . ₈ alkoxy, C ₂ _ ₈ alkenyl, C ₂ - ₈ alkynyl, C ₆ - ₁₀ aryl, C ₃ - ₈ cycloalkyl, C ₃ - ₁₀ heterocyclyl and C ₅ _ ₁₀ heteroaryl, where the indicated C ₃ _ ₁₀ heterocyclyl and C ₅ _ ₁₀ heteroaryl contain 1, 2 or 3 heteroatoms independently selected from N, O and S; R9 is optionally substituted with 0-1 substituent R ₁₀ ; R ₁₀ is selected from the group consisting of hydroxyl, halogen, _{C1_8} alkyl, _{C2_8} alkenyl _{, C2_8 alkynyl} , °A C1. ₈ alkoxy, C ₆ _ ₁₀ aryl, C ₃ - ₈ cycloalkyl, C ₃ - ₁₀ heterocyclyl, substituted ¹¹ C ₃ - ₁₀ heterocyclyl, C ₅ _ ₁₀ heteroaryl, -CO-R16 and -(CH ₂ ) _n NR ₁₁ R ₁₂ , where the indicated C ₃ _ ₁₀ heterocyclyl and C ₅ . ₁₀ heteroaryl contain 1, 2 or 3 heteroatoms independently selected from N, O and S; R11 and _R12 are independently selected from the group consisting of H and _{C1_8} alkyl; R ₁₄ and R ₁₅ are independently selected from the group consisting of H, C ₂ - ₈ alkenyl, -CO-C ₂ - ₈ alkenyl and C ₂ - ₈ alkynyl; R ₁₆ is selected from the group consisting of C1. ₈ alkyl, C ₂ - ₈ alkenyl, C ₂ - ₈ alkynyl, C ₃ - ₁₀ cycloalkyl, - 21 045554 C _6-10 aryl, C _5-10 heteroaryl, C _3-10 heterocyclyl and -NR11R12, where said C _5-10 heteroaryl and C _3-10 heterocyclyl contain 1,2 or 3 heteroatoms independently selected from N, O and S ; R ₁₇ is C _1-8 alkyl or R ₁₇ is C _3-10 cycloalkyl and, taken together with the carbon atom to which it is attached, forms a spiro ring; m is 0 or 1; n is 0, 1 or 2; and provided that: if ring A is a 5-membered heteroaryl containing 2 or 3 N atoms, then R2 is a vinylamide-substituted 6-membered heterocyclyl containing an oxygen heteroatom, wherein the vinylamide-substituted 6-membered heterocyclyl is optionally substituted with 0-1 R ₁₃ substituent. 2. A compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is represented by formula (II): ^r -n R R ₇ Formula (II). 3. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1, 2, in which ring A represents phenyl, C _5-6 heteroaryl or C ₁₀ heterocyclyl, wherein said C _5-6 heteroaryl contains 1, 2 or 3 heteroatoms, selected from N and S, and said C ₁₀ heterocyclyl is a fused bicycle that has two N atoms and one O atom in the ring. 4. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1, 2, wherein ring A is C ₆ heteroaryl. 5. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1, 2, wherein R ₉ is selected from the group consisting of H, halogen, cyano, C _1-6 alkyl, C _1-6 alkyl substituted with halogen, A -(CH ₂ ) _n NR ₁₁ R ₁₂ substituted with amino, C _1-6 alkoxy which is substituted with substituted ¹¹ C ₆ heterocyclyl, where said C ₆ heterocyclyl contains 1, 2 or 3 heteroatoms independently selected from N, O and S, where each R ₁₁ and R ₁₂ is selected from C _1-6 alkyl. 6. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1, 2, in which 7. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1, 2, in which R ₁ represents H, R2 is selected from the group consisting of C _5-7 heterocyclyl and phenyl, wherein said C 5-7 heterocyclyl contains 1 or 2 heteroatoms , selected from N and O. 8. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1, 2, in which R2 is substituted with 1 or 2 _R13 substituents, and _R13 is selected from the group consisting of C _5-6 heterocyclyl, -NR ₁₄ R ₁₅ and - CO-R ₁₆ ; R ₁₄ represents H, R ₁₅ represents -CO-C _2-4 alkenyl, R ₁₆ represents Q. ₃ alkyl, wherein said C _5-6 heterocyclyl contains 1, 2 or 3 heteroatoms independently selected from N and O. 9. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1, 2, in which R ₁₃ is substituted with 0-1 R ₁₈ substituent, and R ₁₈ is selected from the group consisting of C _1-6 alkyl and C _5-6 heterocyclyl, where said C5-6 heterocyclyl contains 1 or 2 heteroatoms selected from N and O. 10. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1, 2, in which R2 represents - 22 045554 11. The compound or its pharmaceutically acceptable salt according to any one of paragraphs. 1, 2, in which each R ₅ , R ₆ , R 7 and R ₈ are independently selected from the group consisting of hydrogen, halogen and C1_ ₃ alkoxy. 12. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein R ₅ and R ₈ are selected from the following groups: (i) both R ₅ and R ₈ are chlorine; (ii) R ₅ and R ₈ are both hydrogen; (iii) R ₅ is hydrogen, R ₈ is chlorine; or (iv) R ₅ is chlorine, R ₈ is hydrogen. 13. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein _R6 and R7 are selected from the following groups: (i) R6 and R7 are both methoxy; (ii) R ₆ is methoxy, R 7 is H; or (iii) R ₆ is H, R7 is methoxy. 14. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein m is 0 or 1. 15. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein n is 2. 16. The compound or pharmaceutically acceptable salt according to claim 1, where the compound is selected from the following: (1) K-(2-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dihydropyrimido[5,4-c][1,8]naphthyridin-2-yl)amino )5-(4-morpholinopiperidin-1-yl)phenyl)acrylamide; (2) N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dihydropyrimido[5,4-c][1,8]naphthyridine -2ul)amino)tetrahydro-2H-pyran-4-yl)acrylamide; (4) N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-5-methyl-5,6-dihydropyrimido[5,4-c][1 ,8]naphthyridin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide; (6) N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dihydropyrimido[5,4-c]quinoline-2ul)amino) tetrahydro-2H-pyran-4-yl)acrylamide; (7) N-((3R,4S)-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dihydropyrimido[5,4-c][1,8]naphthyridine2 -yl)amino)tetrahydrofuran-3-yl)acrylamide; (8) N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dihydropyrimido[5,4-c][1,5]naphthyridine2 -yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide; (9) N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dihydropyrido[2,3-d:4,5-d' ]dipyrimidin-2ul)amino)tetrahydro-2H-pyran-4-yl)acrylamide; (10) N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dihydropyrazino[2',3':5,6]pyrido[ 4.3- d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide; (11) N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-9-fluoro-5,6-dihydropyrimido[5,4с] [1,8 ]naphthyridin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide; (12) N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-10-methyl-5,6-dihydropyrimido[5,4с] [1,8 ]naphthyridin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide; (13) N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-9-methyl-5,6-dihydropyrimido[5,4с] [1,8 ]naphthyridin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide; (14) N-((3S,4S)-3-((6-(2-chloro-3,5-dimethoxyphenyl)-9-methyl-5,6-dihydropyrimido[5,4-c][1,8 ]naphthyridin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide; (15) N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-methyl-5,6-dihydropyrimido[5,4-c][1 ,8]naphthyridin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide; (16) N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-9-(trifluoromethyl)-5,6-dihydropyrimido[5,4с] [1 ,8]naphthyridin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide; (17) N-((3S,4S)-3-((6'-(2,6-dichloro-3,5-dimethoxyphenyl)-6Ή-spiro[cyclopropane-1,5'-pyrimido[5,4с] [1,8]naphthyridin]-2'-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide; (19) N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-5-methyl-5,6-dihydrothieno[3',4':5, 6]pyrido[4,3- d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide; (20) N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-6H-pyrido[3',2':4,5]pyrano[3, 2-d]pyrimidin-2ul)amino)tetrahydro-2H-pyran-4-yl)acrylamide; (21) N-((3S,4S)-3-((6-(2-chloro-5-methoxyphenyl)-5,6-dihydropyrimido[5,4-c][1,8]naphthyridin-2ul)amino )tetrahydro-2H-pyran-4-yl)acrylamide; - 23 045554 (22) N-((3S,48)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-6,9,10,11-tetrahydro-5H-[1,4]oxazino [2,3b]pyrimido[4,5-1][1,8]naphthyridin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide; (23) N-((3R,48)-4-(( 10-(2-(4-acryloylpiperazin-1-yl)ethoxy)-6-(2,6-dichloro-3,5-dimethoxyphenyl)5, 6-dihydropyrimido[5,4-c][1,8]naphthyridin-2-yl)amino)tetrahydrofuran-3-yl)acrylamide; (24) N-((3R,4S)-1-acetyl-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dihydropyr imido[5,4c] [1,8]naphthyridin-2-yl)amino)piperidin-4-yl)acrylamide; (25) N-((3S,48)-3-((4-(2,6-dichloro-3,5-dimethoxyphenyl)-5-methyl-4,5-dihydrothiazolo[5',4':5, 6]pyrido[4,3<3]pyrimidin-8-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide; (26) N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-9-((2-(dimethylamino)ethyl)amino)-5,6dihydropyrimido [5,4-c][1,8]naphthyridin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide; (27) N-((3S,4R)-4-((6-(2,6-dichloro-3,5-dimethoκciphenyl)-5,6-dihydropyrimido[5,4-c][l,8]naφτyridine -2yl)amino)-1-(1-methylpiperidin-4-yl)pyrrolidin-3-yl)acrylamide; (28) M-((38.48)-3-((9-chloro-6-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dihydropyrimido[5,4-c][1 ,8]naphthyridin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide; (29) M-((38.48)-3-((9-cyano-6-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dihydropyrimido[5,4-c][1 ,8]naphthyridin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide; (30) N-((3S, 48)-3-((6-(2-chloro-5-methoxyphenyl)-9-methyl-5,6-dihydropyrimido[5,4-c][1,8]naphthyridine -2yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide; (31) N-((3S, 48)-3-((6-(2-chloro-3-methoxyphenyl)-9-methyl-5,6-dihydropyrimido[5,4-c][1,8]naphthyridine -2yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide; (32) N-((3S, 48)-3-((6-(2,6-dichloro-3-methoxyphenyl)-9-methyl-5,6-dihydropyrimido[5,4-c][1,8 ]naphthyridin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide. 17. A pharmaceutical composition containing a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16 and at least one pharmaceutically acceptable excipient. 18. The pharmaceutical composition according to claim 17, wherein the weight ratio of said compound and pharmaceutically acceptable excipient is 0.0001:1-10. 19. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16 in the manufacture of a medicinal product, wherein said medicinal product is used in the treatment, prevention or delay of the onset or progression of cancer or cancer metastases. 20. Use of a pharmaceutical composition according to claim 17 or 18 in the manufacture of a medicinal product, wherein said medicinal product is used in the treatment, prevention or delay of the onset or progression of cancer or cancer metastases. 21. A method of treating or preventing a disease mediated by FGFR4, comprising administering to a subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16. 22. The method of claim 21, wherein the FGFR4-mediated disease is cancer. 23. The method of claim 22, wherein the cancer is selected from the group consisting of the following: breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatocellular carcinoma, head and neck tumors, hepatobiliary cell carcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Schwann cell tumor, squamous cell carcinoma of the lung, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer or liposarcoma. About the Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky lane, 2