Fgfr inhibitors, methods of making, pharmaceutical compositions, and uses thereof

Abstract

The application discloses a kind of FGFR inhibitors and preparation method, pharmaceutical composition and application thereof.The compound structure is as shown in formula I, also includes stereoisomer, pharmaceutically acceptable salt or their mixture thereof.The FGFR inhibitor and the pharmaceutical composition thereof have high efficient inhibiting effect on wild type and mutant FGFR, can be used to prepare the drug of FGFR related disease, the prepared drug can exert pharmacodynamic effect at molecular level and cell level, is widely applied, and has excellent liver microsomal stability, long half-life in vivo, high bioavailability, with good drug-like properties.In addition, the synthesis method of the compound is simple and easy to operate.

Description

Technical Field

[0001] This invention relates to an FGFR inhibitor, its preparation method, pharmaceutical composition, and application, and particularly to an inhibitor for drug-resistant FGFR mutants. V550L FGFR inhibitors with excellent specific inhibitory activity, their preparation methods, pharmaceutical compositions and applications. Background Technology

[0002] Fibroblast growth factor receptor (FGFR) belongs to the receptor tyrosine kinase (RTK) family. By binding to its ligand, fibroblast growth factor (FGF), FGFR can form a homodimer on the cell membrane. These dimers can induce phosphorylation of key intracellular tyrosine residues of FGFR, thereby activating several downstream signaling pathways within the cell. These intracellular signaling pathways play crucial roles in cell proliferation, survival, and differentiation. Disorders of FGFR signaling pathways, including increased expression of ligands and receptors, FGFR gene amplification, mutations, and deletions, can promote oncogenic transformation and play a significant role in tumor cell proliferation, drug resistance, and angiogenesis. For example, FGFR4 gene amplification has been found in 30% of liver cancers; FGFR2 gene fusion has been found in 10%-20% of cholangiocarcinomas; FGFR3 gene mutations have been found in 10%-60% of urothelial carcinomas; and FGFR1 gene amplification has been found in 10% of non-small cell lung cancers (NSCLC), among other alterations. Since FGFR plays a crucial role in the occurrence and development of tumors, developing new FGFR kinase inhibitors with high inhibitory activity and excellent pharmacokinetic properties has become key to the development of novel anti-tumor drugs.

[0003] To date, only three small molecule inhibitors targeting FGFR (Erdafitinib, Infigratinib, and Pemigatinib) are marketed, with several others in clinical trials (such as Futibatinib and Fisogatinib). Clinical trials have shown that the FGFR4 selective inhibitor Fisogatinib (BLU-554) has demonstrated clinical benefit and tumor regression in patients with FGF19 overexpression. Pemigatinib is approved by the FDA for previously treated patients with locally advanced or metastatic cholangiocarcinoma harboring FGFR2 fusions / rearrangements. Infigratinib is approved by the FDA for previously treated adult patients with unresectable locally advanced or metastatic cholangiocarcinoma harboring FGFR2 gene fusions or other rearrangements.

[0004] Although FGFR is a validated therapeutic target and biomarker for cancer drugs, a certain proportion of patients exhibit resistance to these drugs in clinical use. After 6 months of treatment with Fisogatinib inhibitors, 29% of patients showed resistance to these small molecule inhibitors. The frequency of FGFR4 resistance mutations is comparable to that of EGFR and ALK mutations in non-small cell lung cancer. The most prominent resistance mutations are gatekeeper residues V550L and V550M. These acquired mutations significantly reduce the affinity of drugs for the target, leading to resistance and causing tumor recurrence or disease progression. Similarly, Pemigatinib and Infigratinib also exhibit gatekeeper residue mutations, resulting in acquired resistance. Summary of the Invention

[0005] Purpose of the invention: Addressing the insufficient inhibitory activity of existing compounds against FGFR isoforms with mutated gatekeeper residues, this invention aims to provide a method targeting drug-resistant FGFR mutants. V550L FGFR inhibitors with significant specific inhibitory effects, their preparation methods, pharmaceutical compositions, and applications.

[0006] Technical solution: As a first aspect of the present invention, the FGFR inhibitor of the present invention has the structure of Formula I, wherein the FGFR inhibitor comprises its stereoisomer, a pharmaceutically acceptable salt, or a mixture thereof:

[0007]

[0008] Wherein, U is selected from CH or N;

[0009] V and W are each independently selected from C or N and are not the same;

[0010] X is selected from O, NH, NCH3, NCN, or NCF3;

[0011] Y is selected from N or C;

[0012] Z is selected from N or CH;

[0013] Ring A is selected from aryl or aromatic heterol; the aryl group is selected from phenyl, naphthyl, acenaphthyl or tetrahydronaphthyl; the aromatic heterol group is selected from piperidinyl, pyrroloyl, pyrazolyl, imidazolyl, furanyl, thiophene, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrazinyl, pyridazinyl, quinolinyl, quinazolinyl, indolyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzofuranyl, benzothiaphenyl, 2,3-dihydrobenzo[1,4]dioxacyclohexenyl or benzo[1,3]dioxacyclopentenyl;

[0014] R 1 R2 R 3 R 4 R 6 Each is independently selected from H, halogen, CH2OH, CF3, OCF3, CN, C 1-6 Alkyl or C 1-6 alkoxy; or R 2 R 3 They are linked together to form a 3-8 member heterocycle, which can optionally be C 1-6 Alkyl substitution;

[0015] R 5 Selected from -OR a -(CH2) m OR a -NR a R b -CONR a R b -SO2NR a R b -(SONH)NR a R b -(CH2) m -NR a R b -(CH2) m CON(CH3)2、-(CH2) m SO2N(CH3)2 or a 3-10 membered heterocycle, wherein the 3-10 membered heterocycle may optionally be composed of 1-3 R groups. 7 Substitution; m = 1, 2, or 3;

[0016] R a R b Each is independently selected from H and C. 1-6 Alkyl, -COC 1-5 Alkyl or -SO2C 1-5 Alkyl, the C 1-6 Alkyl, -COC 1-5 Alkyl, -SO2C 1-5 Alkyl optional -NR c R d -CONR c R d or -SO2C 1-5 Alkyl substitution;

[0017] R c R d Each is independently selected from H and C. 1-6 Alkyl or -COC 1-5 alkyl;

[0018] R 7Selected from C 1-6 Alkyl, C 3-8 Cycloalkyl, -CONH2, -SO2NH2, -CH2COOH, -CH2SO3H, -CH2CN, -(CH2)2NR c R d -NR c R d -(CH2) n OH, -COOC 1-6 Alkyl or 3-8 membered heterocycles, wherein the 3-8 membered heterocycle may optionally be C 1-6 Alkyl substitution; n = 1, 2 or 3.

[0019] Furthermore, the above-mentioned FGFR inhibitors have a structure of formula IA or IB:

[0020]

[0021] Where A, X, Y, Z, R 1 ~R 6 The definition is as described in claim 1.

[0022] Preferably, in the above structure:

[0023] X is selected from O or NH;

[0024] Y is selected from N or C;

[0025] Z is selected from N or CH;

[0026] Ring A is selected from aryl or aromatic heterol; the aryl group is selected from phenyl, naphthyl, acenaphthyl or tetrahydronaphthyl; the aromatic heterol group is selected from piperidinyl, pyrroloyl, pyrazolyl, imidazolyl, furanyl, thiophene, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrazinyl, quinolinyl, quinazolinyl, indolyl, benzimidazolyl, benzopyrazolyl, benziisooxazolyl, benzothiazolyl, benziisothiazolyl, benzofuranyl, benzothiaphenyl, 2,3-dihydrobenzo[1,4]dioxacyclohexenyl or benzo[1,3]dioxacyclopentenyl;

[0027] R 1 R 2 Each is independently selected from H, halogen, CN or C. 1-6 Alkoxy;

[0028] R 3 R 4 Each is independently selected from H, halogen, OCF3, or C. 1-6 alkoxy; or R 2 R 3They are linked together to form a 5-6 membered monocyclic alkyl group or a 5-6 membered monocyclic aromatic heterogroup; the 5-6 membered monocyclic alkyl group is selected from tetrahydrofuranyl, pyrrolylyl, 1,3-dioxopentyl, 1,3-oxazolylyl or piperidinyl; the 5-6 membered monocyclic aromatic heterogroup is selected from piperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrazinyl or pyridazinyl;

[0029] R 6 Selected from H, halogens, CH2OH, C 1-6 Alkyl or C 1-6 Alkoxy;

[0030] R 5 Selected from -OR a -(CH2) m OR a -NR a R b -CONR a R b -SO2NR a R b -(SONH)NR a R b -(CH2) m -NR a R b -(CH2) m CON(CH3)2、-(CH2) m SO2N(CH3)2 or a 3-10 membered heterocycle, wherein the 3-10 membered heterocycle may optionally be composed of 1-3 R groups. 7 Substitution; m = 1, 2, or 3;

[0031] R a R b Each is independently selected from H and C. 1-6 Alkyl, -COC 1-5 Alkyl or -SO2C 1-5 Alkyl, the C 1-6 Alkyl, -COC 1-5 Alkyl, -SO2C 1-5 Alkyl optional -NR c R d -CONR c R d or -SO2C 1-5 Alkyl substitution;

[0032] R c R d Each is independently selected from H and C. 1-6 Alkyl or -COC 1-5 alkyl;

[0033] R 7 Selected from C 1-6 Alkyl, C 3-8 Cycloalkyl, -CONH2, -SO2NH2, -CH2COOH, -CH2SO3H, -CH2CN, -(CH2)2NR c R d -NR c R d -(CH2) n OH, -COOC 1-6 Alkyl or 3-8 membered heterocycles, wherein the 3-8 membered heterocycle is optionally C 1-6 Alkyl substitution; n = 1, 2 or 3.

[0034] Further optimization, in the above structure:

[0035] X is selected from O;

[0036] Y is selected from N or C;

[0037] Z is selected from N or CH;

[0038] Ring A is selected from phenyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, benzimidazolyl, benzopyrazolyl, or benzisoxazolyl.

[0039] R 1 R 2 Each is independently selected from H, F, Cl, CN, or C. 1-3 Alkoxy;

[0040] R 3 R 4 Each is independently selected from H, F, Cl or C. 1-3 alkoxy; or R 2 R 3 They are linked together to form a 5-6 member monocyclic alkyl group or a 5-6 member monocyclic aromatic heterogroup; the 5-6 member monocyclic alkyl group is selected from 1,3-dioxopentyl, 1,3-oxazolyl or piperidinyl; the 5-6 member monocyclic aromatic heterogroup is selected from pyrazolyl, imidazolyl, isoxazolyl or thiazolyl.

[0041] R 6 Selected from H, F, Cl or C 1-3 Alkoxy;

[0042] R 5 Selected from -OR a -(CH2) m OR a -NR a R b -CONR a R b-SO2NR a R b -(SONH)NR a R b -(CH2) m -NR a R b -(CH2) m CON(CH3)2、-(CH2) m SO2N(CH3)2 or a 3-10 membered heterocycle, wherein the 3-10 membered heterocycle may optionally be composed of 1-3 R groups. 7 Substitution; m = 1, 2, or 3;

[0043] R a R b Each is independently selected from H and C. 1-6 Alkyl, -COC 1-5 Alkyl or -SO2C 1-5 Alkyl, the C 1-6 Alkyl, -COC 1-5 Alkyl, -SO2C 1-5 Alkyl optional -NR c R d -CONR c R d or -SO2C 1-5 Alkyl substitution;

[0044] R c R d Each is independently selected from H and C. 1-6 Alkyl or -COC 1-5 ;

[0045] R 7 Selected from C 1-6 Alkyl, C 3-8 Cycloalkyl, -CONH2, -SO2NH2, -CH2COOH, -CH2SO3H, -CH2CN, -(CH2)2NR c R d -NR c R d -(CH2) n OH, -COOC 1-6 Alkyl or 3-8 membered heterocycles, wherein the 3-8 membered heterocycle is optionally C 1-6 Alkyl substitution; n = 1, 2 or 3.

[0046] Furthermore, in the above structure:

[0047] X is selected from O;

[0048] Y is selected from N or C;

[0049] Z is selected from N or CH;

[0050] Ring A is selected from phenyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, benzimidazolyl, benzopyrazolyl, or benzisoxazolyl.

[0051] R 1 R 2 Each is independently selected from H, F, Cl, CN, or C. 1-3 Alkoxy;

[0052] R 3 R 4 Each is independently selected from H, F, Cl or C. 1-3 alkoxy; or R 2 R 3 They are linked together to form a 5-6 member monocyclic alkyl group or a 5-6 member monocyclic aromatic heterogroup; the 5-6 member monocyclic alkyl group is selected from 1,3-dioxopentyl, 1,3-oxazolyl or piperidinyl; the 5-6 member monocyclic aromatic heterogroup is selected from pyrazolyl, imidazolyl, isoxazolyl or thiazolyl.

[0053] R 6 Selected from H, F, Cl or C 1-3 Alkoxy;

[0054] R 5 Selected from

[0055] Preferably, the above-mentioned FGFR inhibitors are selected from any of the following compounds:

[0056]

[0057]

[0058]

[0059]

[0060]

[0061]

[0062]

[0063] Pharmaceutically acceptable salts of the aforementioned FGFR inhibitors include salts formed by compounds of general formula I with the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid or succinic acid, fumaric acid, salicylic acid, phenylacetic acid, and mandelic acid; and also include salts formed by compounds of general formula I with the following bases: basic metal cation salts, alkaline earth metal cation salts, or ammonium cation salts.

[0064] As a second aspect of the present invention, the method for preparing the above-mentioned FGFR inhibitor is selected from any of the following methods:

[0065] (1) When U and W are N and V is C, the general formula compound IA is prepared by substitution, halogenation and acylation reactions using bromobenzene or bromopyridine as starting materials.

[0066]

[0067] (2) When U and W are N and V is C, the general formula compound IA is prepared by using bromobenzene or bromopyridine as starting materials through substitution, halogenation, acylation, and substitution reactions.

[0068]

[0069] (3) When U and V are N and W is C, the general formula compound IB is prepared from halopyrrolo[2,1-f][1,2,4]triazine as the starting material through two steps of substitution, oxidation, and reaction.

[0070]

[0071] Among them, Y, Z, R 1 ~R 6 The definition is as stated above;

[0072] The compound IA or IB prepared by the above method is salted with the corresponding acid or base to obtain its pharmaceutically acceptable salt.

[0073] As a third aspect of the present invention, the above-mentioned FGFR inhibitor forms a pharmaceutical composition with a pharmaceutically acceptable carrier, in specific formulations such as tablets, capsules, syrups, suspensions or injections, and the formulation may contain commonly used pharmaceutical excipients such as flavorings, sweeteners, liquid / solid fillers, and diluents.

[0074] As a fourth aspect of the present invention, the above-mentioned FGFR inhibitors and pharmaceutical compositions thereof are used in the preparation of drugs for the prevention and / or treatment of FGFR-related diseases, specifically drugs for the prevention and / or treatment of liver cancer, non-small cell lung cancer, gastric cancer, bladder cancer, head and neck cancer, bile duct cancer, breast cancer, endometrial cancer, cervical cancer, esophageal cancer, kidney cancer, acute leukemia, prostate cancer, thyroid cancer, skin cancer, colorectal cancer, pancreatic cancer, ovarian cancer, myelodysplastic syndrome, or mesothelioma.

[0075] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0076] (1) This class of FGFR inhibitors and their drug compositions can effectively inhibit wild-type FGFR and mutant FGFR4. V550L And HUH7 cell proliferation, IC 50 The optimal values ​​are all below 50 nM;

[0077] (2) This class of FGFR inhibitors and their drug compositions have excellent liver microsomal stability, long in vivo half-life, low clearance rate, high bioavailability, and suitable AUC, and have good drug-like properties.

[0078] (3) This type of FGFR inhibitor and its drug composition have a wide range of applications and can be prepared as drugs for the treatment and / or prevention of FGFR-related diseases, especially suitable for various tumors resistant to conventional FGFR inhibitors; the drugs can exert their effects at both the molecular and cellular levels, and the therapeutic effect is even better, with the optimal concentration level reaching ten nanomolar levels.

[0079] (4) The compound preparation method is simple and easy to operate. Attached Figure Description

[0080] Figure 1 The results show the in vivo metabolism of compound I-63 in mice. Detailed Implementation

[0081] The technical solution of the present invention will be further described below with reference to the embodiments.

[0082] The starting materials and reaction reagents used in the specific embodiments of this invention are all commercially available. This invention can be prepared into a salt form using methods commonly used in the art, such as: dissolving the compound in hydrochloric acid-ethanol at room temperature to generate hydrochloride; or adding benzenesulfonic acid to generate benzenesulfonate.

[0083] Example 1: 4-Benzylthiobenzo[d][1,3]dioxonol (I-26-2)

[0084] 4-Bromobenzo[d][1,3]dioxane (I-26-1) (402 mg, 2 mmol), benzyl mercaptan (298 mg, 2.4 mmol), LiHMDS (1 M, 3 mL), and tBuBrettPhos Pd G3 (20 mg) were suspended in 1,4-dioxane (10 mL) and heated to 85 °C under a nitrogen atmosphere for 2 hours. The reaction mixture was evaporated to dryness, and column chromatography yielded 361 mg of a white solid. [M+H] + :245.3. 1 H NMR (300MHz, Chloroform-d) δ7.35–7.21(m,5H),6.81–6.73(m,3H),5.99(s,2H),4.13(s,2H).

[0085] The following compounds were prepared using a procedure similar to that in Example 1:

[0086]

[0087]

[0088] Example 2: Benzo[d][1,3]dioxono-4-sulfonyl chloride (I-26-3)

[0089] 4-Benzylthiobenzo[d][1,3]dioxonol (I-26-2) (488 mg, 2 mmol) was dissolved in a mixed solvent of acetonitrile and acetic acid (3:1), and NCS (1.07 g, 8 mmol) was slowly added. After stirring for 2 hours, an aqueous sodium bicarbonate solution was added. Extraction was performed with ethyl acetate, and column chromatography yielded 352 mg of a colorless liquid. [M+H] + 221.62

[0090] The following compounds were prepared using a similar procedure to that in Example 2:

[0091]

[0092] Example 3: N-(4-morpholinophenyl)-2-amino-7H-pyrrolo[2,3-d]pyrimidine (I-1-5)

[0093] 6-Chloro-1H-pyrrolo[3,2-c]pyridine (307 mg, 2 mmol), 4-morpholinoaniline (356 mg, 2 mmol), and p-toluenesulfonic acid (1.03 g, 6 mmol) were suspended in n-butanol (6 mL). The tube was sealed, and the reaction was carried out at 140 °C for 24 h. The reaction solution was cooled to room temperature, and dichloromethane (20 mL) and saturated sodium bicarbonate aqueous solution (20 mL) were added. The mixture was stirred, filtered, and the filter cake was dried to give 237 mg of a white solid. [M+H] + 296.35.1 H NMR(300MHz,Chloroform-d)δ9.71(d,J=8.3Hz,1H),8.92(dd,J=2.2,0.5Hz,1H),7.74–7.59(m,3H),7.03–6. 93(m,2H),6.62(dd,J=6.5,2.2Hz,1H),5.80(s,1H),3.86(dd,J=7.5,4.8Hz,4H),3.16(dd,J=7.6,4.9Hz,4H).

[0094] The following compounds were prepared using a procedure similar to that in Example 3:

[0095]

[0096] Example 4: N-(4-morpholinophenyl)-7-benzenesulfonyl-2-amino-7H-pyrrolo[2,3-d]pyrimidine (I-1)

[0097] N-(4-morpholinophenyl)-2-amino-7H-pyrrolo[2,3-d]pyrimidine (I-1-5) (295 mg, 1 mmol) was dissolved in DMF (3 mL), and sodium hydride (60%, 48 mg, 1.5 mmol) was added in portions under ice bath conditions. When no more bubbles were produced, benzenesulfonyl chloride (I-1-4) (265 mg, 1.5 mmol) was slowly added. After reacting for 2 hours, the reaction mixture was poured into ice water and stirred, then extracted with ethyl acetate. The ethyl acetate layer was purified by whole-cell chromatography to give 191 mg of a white solid. [M+H] + : 436.50. 1 H NMR(300MHz,DMSO)δ9.57(s,1H),8.70(s,1H),8.19–8.01(m,2H),7.77–7.66(m,3H),7.64–7.52(m ,3H),6.98(d,J=9.1Hz,2H),6.72(d,J=4.0Hz,1H),3.77(dd,J=6.0,3.6Hz,4H),3.14–3.03(m,4H).

[0098] The following compounds were prepared using a similar procedure to that in Example 4:

[0099]

[0100]

[0101]

[0102] Example 5: 3-(2-chloro-5-nitrophenoxy)tetrahydrofuran (I-41-8)

[0103] 2-Chloro-5-nitrophenol (347 mg, 2 mmol) was dissolved in DMF (4 mL). Sodium hydride (60%, 96 mg, 4 mmol) was slowly added under ice bath conditions. After stirring for 30 minutes, 3-iodotetrahydrofuran (594 mg, 3 mmol) was added. After the reaction was complete, the reaction was quenched with saturated ammonium chloride aqueous solution. The mixture was extracted with ethyl acetate and purified by column chromatography to give 428 mg of a yellow solid. [M+H] + : 244.64.

[0104] The following compounds were prepared using a procedure similar to that in Example 5:

[0105] compound raw material ESI-MS m / z 1-Chloro-2-isopropoxy-4-nitrobenzene (I-42-8) 2-Chloro-5-nitrophenol 216.63 4-(2-(2-chloro-5-nitrophenoxy)ethyl)morpholine (I-47-8) 2-Chloro-5-nitrophenol 287.71 N,N-Dimethyl-2-(5-nitro-1H-indazol-1-yl)ethylamine (I-48-8) 5-Nitro-2H-Indazole 235.11 N,N-Dimethyl-2-(6-nitro-1H-indazol-1-yl)ethylamine (I-49-8) 6-Nitro-2H-Indazole 235.11 N,N-Dimethyl-2-(4-nitro-1H-pyrazol-1-yl)ethylamine (I-57-8) 4-Nitro-1H-pyrazole 185.1 N,N-Dimethyl-3-(4-nitro-1H-pyrazol-1-yl)propylamine (I-58-8) 4-Nitro-1H-pyrazole 189.11

[0106] Example 6: N 1 -(2-(dimethylamino)ethyl)-N1-methyl-1,4-phenylenediamine (I-14-7)

[0107] In the first step, p-fluoronitrobenzene (282 mg, 2 mmol) and 3-methyl-1-(piperazinyl)azacyclobut-3-ol (1.7 g, 10 mmol) were dissolved in acetonitrile (10 mL), and the mixture was heated to 80 °C. After the reaction was complete, the reaction mixture was evaporated to dryness and purified by column chromatography to obtain a yellow solid intermediate. In the second step, the solid was dissolved in ethanol (10 mL), a palladium / carbon catalyst was added, and the mixture was hydrogenated at atmospheric pressure. After the reaction was complete, the mixture was filtered and evaporated to dryness to obtain 440 mg of a gray oily substance. [M+H] + : 263.35.

[0108] The following compounds were prepared using a procedure similar to that in Example 6:

[0109] compound ESI-MS m / z compound ESI-MS m / z I-17-7 275.41 I-57-7 155.21 I-37-7 262.36 I-58-7 169.24 I-38-7 262.36 I-61-7 218.31 I-39-7 275.41 I-63-7 206.3 I-41-7 278.36 I-66-7 318.43 I-42-7 250.35 I-72-7 290.37 I-43-7 206.30 I-75-7 206.26 I-44-7 206.3 I-78-7 304.4 I-47-7 321.43 I-86-7 318.43 I-48-7 205.27 I-88-7 192.23 I-49-7 205.27 I-90-7 206.3 I-56-7 207.28 I-92-7 231.31

[0110] Example 7: 7-(3-methoxybenzenesulfonyl)-N-(5-(4-methylpiperazine)pyridin-2-yl)-2-amino-7H-pyrrolo[2,3-d]pyrimidine (I-9)

[0111] 2-Chloro-7-(3-methoxybenzenesulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (I-2-6) (324 mg, 1 mmol), 1-methyl-4-(6-aminopyridin-3-yl)piperazine (193 mg, 1 mmol), and p-toluenesulfonic acid (1.03 g, 3 mmol) were suspended in isopropanol (3 mL). The tube was sealed, and the reaction mixture was reacted at 130 °C for 24 h. The reaction solution was cooled to room temperature, neutralized with saturated sodium bicarbonate, extracted with ethyl acetate, and evaporated to dryness before column chromatography to give 254 mg of a yellow solid. [M+H] + : 480.55.1 H NMR(300MHz,Chloroform-d)δ8.73(s,1H),8.68–8.64(m,1H),8.59(s,1H),8.16–8.08(m,1H),7. 72(dd,J=2.6,1.7Hz,1H),7.66(ddd,J=7.8,1.8,1.0Hz,1H),7.50(dd,J=9.2,3.0Hz,1H),7.44(d The following compounds were prepared using a similar procedure to that in Example 7: 7.34(t, J = 8.1 Hz, 1H), 7.08(ddd, J = 8.4, 2.6, 1.0 Hz, 1H), 6.55(d, J = 4.0 Hz, 1H), 3.59(s, 3H), 3.32–3.20(m, 4H), 2.67(dd, J = 6.2, 3.8 Hz, 4H), 2.41(s, 3H).

[0112]

[0113]

[0114]

[0115]

[0116] Example 8: N-(4-(2,7-diaza[3.5]nonen-7-yl)phenyl)-7-(3-methoxybenzenesulfonyl)-2-amino-7H-pyrrolo[2,3-d]pyrimidine (I-66)

[0117] 2-Chloro-7-(3-methoxybenzenesulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (I-2-6) (323 mg, 1 mmol), tert-butyl 7-(4-aminophenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (I-2-7) (380 mg, 1.2 mmol), cesium carbonate (538 mg, 1.5 mmol), and BrettPhos Pd G3 (20 mg) were suspended in 1,4-dioxane (8 mL) and heated to 90 °C under a nitrogen atmosphere for 2 hours. The reaction mixture was evaporated to dryness, and the coupling product was obtained by column chromatography. The solid was dissolved in hydrochloric acid solution (3 M methanol solution, 5 mL), stirred for 30 minutes, evaporated to dryness, dissolved in methanol (5 mL), and neutralized with potassium carbonate. The methanol solution was filtered and evaporated to dryness to obtain 252 mg of yellow solid. [M+H] + :505.6. 1H NMR(300MHz,Chloroform-d)δ9.70(s,1H),8.79(dd,J=2.2,0.5Hz,1H),8.32–8.24(m,1H),8.04(ddd,J= 8.3,1.9,1.2Hz,1H),7.86(dd,J=8.5,2.3Hz,1H),7.50(t,J=1.9Hz,1H),7.39(dd,J=8.4,7.8Hz,1H),7. 30–7.20(m,2H),6.99–6.85(m,3H),3.79(s,3H),3.47(dd,J=7.9,5.1Hz,2H),3.29(dd,J=7.9,5.2Hz,2H ), 2.87 (d, J = 5.4Hz, 2H), 2.73 (d, J = 5.5Hz, 2H), 2.28 (p, J = 5.4Hz, 1H), 1.81 (ddd, J = 9.7, 7.9, 5.1Hz, 4H).

[0118] The following compounds were prepared using a procedure similar to that in Example 8:

[0119]

[0120] Example 9: 7-(3-methoxybenzenesulfonyl)-N-(4-(2-methyl-2,7-diazaspiro[3.5]nonen-7-yl)phenyl)-2-amino-7H-pyrrolo[2,3-d]pyrimidine (I-68)

[0121] N-(4-(2,7-diaza[3.5]nonen-7-yl)phenyl)-7-(3-methoxybenzenesulfonyl)-2-amino-7H-pyrrolo[2,3-d]pyrimidine (I-66) (252 mg, 0.5 mmol) and potassium carbonate (138 mg, 1 mmol) were suspended in acetonitrile (3 mL), and iodomethane (142 mg, 1 mmol) was added and stirred. After the reaction was complete, the reaction solution was evaporated to dryness, and purified by column chromatography to obtain 217 mg of a yellow solid. [M+H] + : 519.63. 1H NMR(300MHz,Chloroform-d)δ9.70(s,1H),8.79(dd,J=2.2,0.5Hz,1H),8.32–8.24(m,1H),8.04(ddd ,J=8.3,1.9,1.2Hz,1H),7.88(dd,J=8.4,2.2Hz,1H),7.50(t,J=1.9Hz,1H),7.39(dd,J=8.5,7.8Hz,1 H),7.30–7.20(m,2H),7.01–6.85(m,3H),3.79(s,3H),3.47(dd,J=8.1,5.5Hz,2H),3.38(dd,J=8.1, 5.4Hz,2H),2.76(d,J=10.9Hz,2H),2.68(d,J=10.9Hz,2H),2.32(s,3H),1.79(dd,J=8.1,5.3Hz,4H).

[0122] The following compounds were prepared using a procedure similar to that in Example 9:

[0123]

[0124]

[0125] Example 10: 4-(4-nitrophenyl)thiomorpholine (I-94-13)

[0126] Using thiomorpholine as a raw material, and following the synthesis method in step one of Example 5, 316 mg of a yellow solid was obtained. [M+H] + : 225.28. 1 H NMR (300MHz, Chloroform-d) δ8.09–7.99(m,1H),7.06–6.96(m,1H),3.72(dd,J=7.3,4.6Hz,2H),2.95(dd,J=7.2,4.5Hz,2H).

[0127] Example 11: 1-Imine-4-(4-nitrophenyl)-1λ 6 -Thiomorpholine-1-oxide (I-94-14)

[0128]

[0129] 4-(4-nitrophenyl)thiomorpholine (I-94-13) (224 mg, 1 mmol) and ammonium carbonate (644 mg, 2 mmol) were dissolved in tetrahydrofuran (5 mL) and cooled to 0 °C. Iodophenylacetic acid (192 mg, 2 mmol) was then slowly added, and after reacting for 2 hours, the reaction mixture was evaporated to dryness. Column chromatography yielded 173 mg of a yellow solid. [M+H] + : 256.29. 1 H NMR (300MHz, Chloroform-d) δ8.09–7.99(m,1H),7.06–6.96(m,1H),3.23(ddd,J=10.2,7.6,0.6Hz,2H),2.80(ddd,J=10.2,7.4,0.6Hz,2H).

[0130] Example 12: (4-(4-aminophenyl)-1-oxo-1λ 6 1-Thiomorpholine-1-ylidene) tert-butyl carbamate (I-94-7)

[0131]

[0132] 1-Imin-4-(4-nitrophenyl)-1λ 6 1-Thiomorpholine-1-oxide (I-94-14) (225 mg, 1 mmol) was dissolved in tetrahydrofuran (5 mL) and cooled to -78 °C. LiHMDS (1 M, 2 mL) was then slowly added dropwise, and the mixture was stirred for 30 minutes. Di-tert-butyl dicarbonate (260 mg, 1.2 mmol) was then added. After reacting for 2 hours, the reaction mixture was brought to room temperature, and a saturated ammonium chloride solution was added. Extraction was performed with ethyl acetate, and column chromatography yielded a yellow solid. This solid was then added in the same proportion as in step 2 of Example 6 to obtain 300 mg of a gray oily substance. [M+H] + 356.41. 1 H NMR (300MHz, Chloroform-d) δ8.09–7.99(m,2H),7.06–6.96(m,2H),3.23(ddd,J=10.5,7.8,0.6Hz,4H),2.80(ddd,J=10.5,7.8,0.6Hz,4H),1.44(s,9H).

[0133] Example 13: 1-Imino-4-(4-((7-(3-methoxybenzenesulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)-1λ 6 -Thiomorpholine-1-oxide (I-94)

[0134] With (4-(4-aminophenyl)-1-oxo-1λ6 Using tert-butyl thiomorpholine-1-ylidene)carbamate (I-94-7) and 2-chloro-7-(3-methoxybenzenesulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (I-2-6) as starting materials, the materials were added in the same proportions according to the synthesis method of Example 8 to obtain 217 mg of a white solid. [M+H] + : 513.13. 1 H NMR(300MHz,Chloroform-d)δ9.49(s,1H),9.20(s,1H),8.79(dd,J=2.2,0.5Hz,1H) ,8.32–8.24(m,1H),8.01(ddd,J=8.5,1.9,1.1Hz,1H),7.86(dd,J=8.5,2.3Hz,1H), 7.51(t,J=1.9Hz,1H),7.39(dd,J=8.5,7.8Hz,1H),7.30–7.20(m,2H),7.04–6.90(m ,3H),3.79(s,3H),3.67(dd,J=10.3,7.6Hz,4H),2.82(ddd,J=10.1,7.6,2.4Hz,4H).

[0135] Example 14: 7-(3-methoxyphenylthio)-N-(4-(4-methylpiperazinphenyl))-2-aminopyrrolo[2,1-f][1,2,4]triazine (I-64-12)

[0136] 7-Bromo-2-amino-N-(4-(4-methylpiperazinphenyl))pyrrolo[2,1-f][1,2,4]triazine (I-64-10) (387 mg, 1 mmol), 3-methoxythiophenol (I-64-11) (280 mg, 2 mmol), cuprous iodide (20 mg, 0.1 mmol), ethylene glycol (0.3 mL), and potassium phosphate (637 mg, 3 mmol) were suspended in DMF (6 mL). The tube was sealed, and the reaction was carried out at 120 °C for 48 h. The reaction solution was cooled to room temperature, poured into water, extracted with ethyl acetate, and the ethyl acetate layer was evaporated to dryness. Column chromatography yielded 311 mg of a yellow solid. [M+H] + : 447.57. 1 H NMR (300MHz, CDCl3) δ8.68(s,1H),7.39–7.29(m,2H),7.17(t,J=8.0Hz,1H),6.93(d,J=4.6Hz,1 H),6.87–6.67(m,7H),3.74(s,3H),3.20(dd,J=6.7,3.5Hz,4H),2.77–2.57(m,4H),2.41(s,3H).

[0137] Example 15: 7-(3-methoxybenzenesulfonyl)-N-(4-(4-methylpiperazinphenyl))-2-aminopyrrolo[2,1-f][1,2,4]triazine (I-64)

[0138] 223 mg (0.5 mmol) of 7-(3-methoxyphenylthio)-N-(4-(4-methylpiperazinphenyl))-2-aminopyrrolo[2,1-f][1,2,4]triazine (I-64-12) was dissolved in methanol (5 mL). Hydrogen peroxide (30%, 1 mL) was added. After reacting for 2 hours, a saturated aqueous solution of sodium bicarbonate was added, followed by a saturated aqueous solution of sodium thiosulfate, and the mixture was stirred for 30 minutes. The reaction mixture was extracted with dichloromethane, the dichloromethane layer was evaporated to dryness, and column chromatography yielded 220 mg of a yellow solid. [M+H] + : 479.58. 1 HNMR(300MHz, CDCl3)δ8.77(s,1H),7.80–7.42(m,4H),7.34(d,J=4.9Hz,1H),7.27(s,1H),7.10–6.98(m, 3H), 6.91 (s, 1H), 6.72 (d, J = 4.9Hz, 1H), 3.50 (s, 3H), 3.32–3.24 (m, 4H), 2.87–2.57 (m, 4H), 2.43 (s, 3H).

[0139] Example 16: Biological Activity

[0140] 1. Kinase IC 50 Test Experiment Method

[0141] Reaction phase: Prepare assay buffer and dilute the compound; prepare 5× kinase (final concentration 0.3 ng / μL, working concentration 1.5 ng / μL) with assay buffer, 2 μL per well; prepare 2.5× TK-Substrate-biotin / ATP with assay buffer, final ATP concentration 100 μM, final substrate concentration 500 nM, 4 μL per well; add 4 μL of the compound with 2.5% DMSO to the well, add 4 μL of assay buffer with 2.5% DMSO to the positive control well; add 4 μL of 2.5× TK-Substrate-biotin / ATP and 2 μL of 5× FGFR4 to the compound well and positive control well, add 4 μL of 2.5× TK-Substrate-biotin / ATP and 6 μL of assay buffer to the enzyme-free negative control well; incubate at room temperature for 1.0 h.

[0142] Assay: Dilute Sa-XL665 (store concentration 16.67 μM) to 500 nM with detection buffer, add 5 μL to each well; add 5 μL of TK Antibody-Cryptate to each well; incubate for 1 h; read the plate. Calculate the IC50 of each compound using GraphPad Prism 5.0 software. 50 value.

[0143] 2. Cellular IC 50 Test Experiment Method

[0144] Cell Culture: Thaw cells in a 37°C water bath. Spray the surface of cryovials with 75% ethanol and transfer the cells to 15mL centrifuge tubes pre-filled with 10mL of culture medium. Centrifuge at 1000rpm for 5min. Remove the supernatant and resuspend the cells in 1mL of culture medium. Transfer the cell suspension to culture dishes containing an appropriate amount of culture medium and incubate at 37°C in a 5% CO2 incubator. When the cell confluence reaches 90%, passage the cells. Remove the culture medium from the culture dishes, add an appropriate amount of 0.25% trypsin, and incubate at 37°C. Once the cells become rounded, remove them from the incubator, resuspend the cells in culture medium, and transfer the resuspended cells to 15mL centrifuge tubes. Centrifuge at 1000rpm for 5min. Resuspend the centrifuged cells in culture medium and passage at a ratio of 1:3 to 1:5. Incubate at 37°C in a 5% CO2 incubator. Digest the cells with 90% confluence using 0.25% trypsin and count the resulting cell suspension. Seed 20 μL (800 cells / well) of cells into each 384 plate, and then incubate the cell plate overnight at 37°C in a 5% CO2 incubator.

[0145] Compound preparation: Dilute the 10 mM compound stock solution with DMSO to prepare a 2 mM compound solution. Then, starting from the 2 mM concentration, perform a three-fold serial dilution with DMSO, resulting in a total of 12 concentration points.

[0146] Add the compound: Add 1 μL of serially diluted DMSO solution to 99 μL of complete culture medium to prepare a working solution with an initial concentration of 10 μM and a DMSO concentration of 1%. After culturing cells overnight, add 20 μL of the prepared working solution to each well of the cell plate and continue culturing for 72 h.

[0147] Plate reading: Add 20 μL / well of Cell Titer-Glo reagent to the cell plate, react at room temperature in the dark for 15 min, and then read the plate using a microplate reader. Process the data using Prism, and calculate the IC50 of the compounds. 50 value.

[0148] 3. Experimental Results

[0149] Table 1 shows the in vitro FGFR kinase activity and in vitro cancer cell activity results of some compounds. A represents IC50. 50 Values ​​less than 50 nM, B represents IC 50 Values ​​range from 50nM to 200nM, where C represents IC. 50 The value is greater than 200 nM.

[0150] Table 1. In vitro activities of the compounds

[0151]

[0152]

[0153] As shown in Table 1, the 2-amino-7H-pyrrolo[2,3-d]pyrimidine compounds of the present invention have effects on wild-type FGFR and mutant FGFR. V550L Both HUH7 and IC50 cells showed inhibitory effects on cell proliferation. 50 The optimal values ​​are all below 50 nM, and it has excellent activity at both the molecular and cellular levels, which can provide a basis for the preparation of drugs to prevent and / or treat FGFR-related diseases and for the treatment of resistance to other FGFR inhibitory therapies.

[0154] Example 17: Pharmacokinetic Experiment

[0155] 1. Liver microsomal stability test

[0156] Metabolic stability of the test compound was determined using various liver microsomes, including RLM (rat liver microsomes), DLM (canine liver microsomes), CLM (monkey liver microsomes), and HLM (human liver microsomes). The test compound solution or control solution was added to each well (T0, T5, T15, T30, T60, and NCF60). After adding 80 μL of microsome solution to each well, the mixture was incubated at 37°C for 10 min. In NCF60, 10 μL of 100 mM potassium phosphate buffer was added to each well, and the mixture was incubated at 37°C for 1.0 h. After preheating, the reaction was terminated using a 1:1 mixture of tosylate and labetalol at 5, 15, 30, and 60 min after incubation. The mixture was vortexed for 5 min, centrifuged at 4000 rpm for 20 min at 4°C, and the supernatant was analyzed by LC-MS. The Tg ratio was calculated using first-order kinetic analysis data. 1 / 2 " and "CL".

[0157] 2. In vivo metabolic analysis experiment in mice

[0158] Thirty normal mice and thirty tumor-bearing mice were randomly divided into six time groups (2, 4, 10, 15, 30, and 60 min). Mice were fasted for 12 hours and administered the drug via tail vein. Blood samples were collected from each group at predetermined time points after drug administration and processed into plasma for later use. Mice were then sacrificed, and liver and tumor tissues were removed, homogenized, centrifuged, and the supernatant was collected for later use. The plasma and homogenate supernatant were analyzed using LC-MS to determine the drug and its related metabolites in the tissues. Drug-time curves (AUC) were plotted, and pharmacokinetic software was used to process the data and determine the major pharmacokinetic parameters. The half-life, pharmacokinetic parameters, and tissue distribution of the drug in both groups of mice were investigated to evaluate the drug's drug-likeness and its targeting in tumor tissues.

[0159] Six approximately 8-week-old male Sprague-Dawley mice were fasted overnight before intravenous and oral pharmacokinetic studies of the drug were conducted. To determine oral bioavailability, the test compound was administered via a single intravenous (IV) rapid bolus or gavage at doses of 1 and 10 mg / kg, respectively. Injection formulation: (DMSO:PEG200:saline = 20:20:60, v / v / v, concentration 0.2 mg / mL). Alternatively, the compound was suspended in physiological saline containing 0.5% CMC-Na and 0.2% Tween 80 to obtain an oral formulation (concentration 1 mg / mL). For plasma samples: 30 μL aliquots of the sample were added to 150 μL of LCN containing 5 ng / mL verapamil and 50 ng / mL glibenclamide for protein precipitation. The mixture was vortexed for 10 min and centrifuged at 3700 rpm for 10 min. Then, 70 μL of water was added to 70 μL of the supernatant and vortexed for 10 min. Equal 15 μL portions of the mixture were injected into the system and analyzed by LC-MS / MS using an Agilent Technologies 6430 LC-MS system.

[0160] 3. Experimental Results

[0161] See Tables 2-3 and Figure 1 .

[0162] Table 2 Liver microsomal stability

[0163]

[0164] Table 3. Metabolic analysis experiments in mice.

[0165]

[0166] From Tables 2 to 3 and Figure 1As can be seen, the representative compound I-63 exhibits excellent liver microsomal stability; it has a long half-life and low clearance rate in mice. The representative compound I-63 also has high bioavailability and an AUC within a suitable range, demonstrating good drug-like properties.

[0167] The compounds designed in this invention and their pharmaceutically acceptable salts have FGFR inhibitory activity and can be used as active ingredients in drugs. The pharmaceutical compositions prepared from them can be used to prepare drugs for the prevention and / or treatment of clinical conditions related to FGFR, such as liver cancer, non-small cell lung cancer, gastric cancer, bladder cancer, head and neck cancer, bile duct cancer, breast cancer, endometrial cancer, cervical cancer, esophageal cancer, kidney cancer, acute leukemia, prostate cancer, thyroid cancer, skin cancer, colorectal cancer, pancreatic cancer, ovarian cancer, myelodysplastic syndrome, mesothelioma, etc.

Claims

1. An FGFR inhibitor, characterized in that, Selected from any of the following compounds, or pharmaceutically acceptable salts thereof: 7-(3-Methoxybenzenesulfonyl)-N-(4-morpholinophenyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, N-(4-(4-methylpiperazine)phenyl)-7-(pyridine-3-sulfonyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, 7-(2-Methoxybenzenesulfonyl)-N-(4-(4-methylpiperazine)phenyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, 7-(3-Fluorobenzenesulfonyl)-N-(4-(4-methylpiperazine)phenyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, N-(4-(4-methylpiperazine)phenyl)-7-(3-trifluoromethylbenzenesulfonyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, 7-(3-methoxybenzenesulfonyl)-N-(5-(4-methylpiperazine)pyridin-2-yl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, N-(3-methoxy-4-(4-methylpiperazine)phenyl)-7-(3-methoxybenzenesulfonyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, 2-(4-(3-methoxybenzenesulfonyl)-7 H -pyrrolo[2,3- d ]pyrimidin-2-yl)amino)-1H-pyrazolyl)ethanol, 7-(2-fluoro-5-methoxybenzenesulfonyl)-N-(4-(4-methylpiperazine)phenyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, 7-(3-methoxybenzenesulfonyl)-N-(6-(4-methylpiperazine)pyridin-3-yl)-7 H -pyrrole(2,3- d Pyrimidine-2-amine 1-(1-(4-((7-(3-methoxybenzenesulfonyl)-7 H -pyrrole[2,3- d Pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)-3-methylazacyclobut-3-ol, N-(4-(4-isopropylpiperazinyl)phenyl)-7-(3-methoxybenzenesulfonyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, 7-(3-methoxybenzenesulfonyl)-N-(4-(1-methylpiperidin-4-yl)phenyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, 7-(3-methoxybenzenesulfonyl)-N-(4-(4-(4-(4-(4-methylpiperazine)piperidinyl)phenyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, 7-(2-methoxybenzenesulfonyl)-N-(4-(2-(pyrrolidinyl)ethoxy)phenyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, 7-(2,5-Dimethoxybenzenesulfonyl)-N-(4-(4-methylpiperazine)phenyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, 7-(2-Chlorobenzenesulfonyl)-N-(4-(4-methylpiperazine)phenyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, 7-(2,6-dichlorobenzenesulfonyl)-N-(4-(4-methylpiperazine)phenyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, N-(4-(4-methylpiperazine)phenyl)-7-(2-trifluoromethoxybenzenesulfonyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, 2-(2-(4-(4-(4-methylpiperazine)phenyl)amino)-7 H -pyrrolo[2,3- d Pyrimidine-7-sulfonyl)benzonitrile, 7-(5-chloro-2-methoxybenzenesulfonyl)-N-(4-methylpiperazine)phenyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, 7-(benzo[ d [1,3]dioxotropine-4-sulfonyl)-N-(4-(4-methylpiperazine)phenyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, 7-(2,5-Dichlorobenzenesulfonyl)-N-(4-(4-methylpiperazine)phenyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, N-(4-(4-methylpiperazine)phenyl)-7-benzenesulfonyl-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, 7-(3-methoxybenzenesulfonyl)-N-(4-((1R)-8-methyl-3,8-diazabicyclo[3.2.1]octyl-3-yl)phenyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, 7-(2,4-Dichloropyridine-3-sulfonyl)-N-(4-methylpiperazine)phenyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, N-(3-fluoro-4-(4-methylpiperazine)phenyl)-7-(3-methoxybenzenesulfonyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, 7-(3-methoxybenzenesulfonyl)-N-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-7 H -Pyrroloyl[2,3- d Pyrimidine-2-amine 5-(7-methoxybenzenesulfonyl)-7 H -pyrrolo[2,3- d ]pyrimidin-2-yl)amino)-2-(4-methylpiperazine)phenol, (5-(((3-methoxybenzenesulfonyl)-7 H -pyrrolidine-2-yl)amino)-2-(4-methylpiperazine)phenyl)methanol, 1-(3-methoxybenzenesulfonyl)-N-4-(4-methylpiperazinphenyl)-6-amino-1H-pyrrolo[3,2- c ]Pyridine, 7-(3-methoxybenzenesulfonyl)-N-(4-(4-(tetrahydroxy-2H-pyran-4-yl)piperazinyl)phenyl)-7 H -pyrrole(2,3- d Pyrimidine-2-amine 7-(3-methoxybenzenesulfonyl)-N-(4-(4-thiopiperidinyl)phenyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, 7-(3-methoxybenzenesulfonyl)-N-(4-(4-(1-(1-methylpiperidin-4-yl)piperazinyl)phenyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, 7-(3-methoxybenzenesulfonyl)-N-(4-((1S4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-yl)phenyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, 7-(3-methoxybenzenesulfonyl)-N-(4-methylpiperazine)-3-((tetrahydrofuran-3-yl)oxy)phenyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, N-(3-Isopropoxy-4-(4-methylpiperazine)phenyl)-7-(3-methoxybenzenesulfonyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, N-(4-((3R,5R)-3,5-dimethylpiperazinyl)phenyl)-7-(3-methoxybenzenesulfonyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, N-(4-(dimethylamino)pyrrolidinyl)phenyl)-7-(3-methoxybenzenesulfonyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, N-(4-(dimethylamino)piperidinyl)phenyl)-7-(3-methoxybenzenesulfonyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, 7-(3-methoxybenzenesulfonyl)-N-(4-methylpiperazine)-3-(2-morpholinoethoxy)phenyl)-7 H -pyrrolopyrimidine-2-amine, N-(2-(dimethylamino)ethyl)-1H-indazol-5-yl)-7-(3-methoxybenzenesulfonyl)-7 H -pyrrole((3-methoxyphenyl)[2,3- d Pyrimidine-2-amine 7-(3,5-difluorobenzenesulfonyl)-N-(4-methylpiperazine)phenyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, 7-(2-chloro-5-methoxybenzenesulfonyl)-N-(4-(4-methylpiperazine)phenyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, 7-(3,5-difluoro-2-methoxybenzenesulfonyl)-N-(4-(4-methylpiperazine)phenyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, 7-(3-Methoxybenzenesulfonyl)-N-(3-methyl-4-(4-methylpiperazine)phenyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, N-(4-ethylpiperazinyl)phenyl)-7-(3-methoxybenzenesulfonyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, N-(3-chloro-4-(4-methylpiperazine)phenyl)-7-(3-methoxybenzenesulfonyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, 7-(3-methoxybenzenesulfonyl)-N-(4-((((1-methylpiperidin-4-yl)oxy)phenyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, N-(2-(dimethylamino)ethyl)-1H-pyrazole-4-yl)-7-(3-methoxybenzenesulfonyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, N-(1-(dimethylamino)propyl)-1H-pyrazole-4-yl)-7-(3-methoxybenzenesulfonyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, 2-(4-(4-((7-(3-methoxybenzenesulfonyl)-7 H -pyrrolo[2,3- d ]pyrimidin-2-yl)amino)phenyl)piperazinyl)ethanol, (4-((7-(3-methoxybenzenesulfonyl)-7 H -pyrrolo[2,3- d ]pyrimidin-2-yl)amino)phenyl)(4-methylpiperazin-1) methyl ketone, 7-(3-methoxybenzenesulfonyl)-N-(4-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)phenyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, 7-(3-methoxybenzenesulfonyl)-N-(4-((4-methylpiperazine)methyl)phenyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, N-(4-((3S,5R)-3,5-dimethylpiperazinyl)phenyl)-7-(3-methoxybenzenesulfonyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, 7-(3-methoxybenzenesulfonyl)-N-(4-(4-methylpiperazinphenyl))-2-aminopyrrolo[2,1- f [1,2,4]triazine, 7-(3-methoxybenzenesulfonyl)-N-(4-methylpiperazine)phenyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, N-(4-(2,7-diaza[3.5]nonen-7-yl)phenyl)-7-(3-methoxybenzenesulfonyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, 7-(5-isopropylpyridine-3-sulfonyl)-N-(4-(4-methylpiperazine)phenyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, 7-(3-methoxybenzenesulfonyl)-N-(4-(2-methyl-2,7-diazaspiro[3.5]nonen-7-yl)phenyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, 7-(5-methoxypyridine-3-sulfonyl)-N-(4-(4-methylpiperazine)phenyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, N-(4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)phenyl)-7-(3-methoxybenzenesulfonyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, 7-(5-Fluoropyridine-3-sulfonyl)-N-(4-methylpiperazine)phenyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, N-(((1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-yl)phenyl)-7-(3-methoxybenzenesulfonyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, 7-(4-methoxypyridine-3-sulfonyl)-N-(4-(4-methylpiperazine)phenyl)-7 H -pyrrolo[2,3- d Pyrimidine-2-amine 7-(3-methoxybenzenesulfonyl)-N-(4-((1R4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-yl)phenyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, 1-(4-((7-(3-methoxybenzenesulfonyl)-7 H -pyrrolo[2,3- d ]pyrimidin-2-yl)amino)phenyl)-4-methyl-2-piperazinone, 7-(3-methoxybenzenesulfonyl)-N-(4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-yl)phenyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, 7-(2-chloro-3-methoxybenzenesulfonyl)-N-(4-methylpiperazine)phenyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, N-(4-((1R)-3,8-diazabicyclo[3.2.1]octane-3-yl)phenyl)-7-(3-methoxybenzenesulfonyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, 7-(3-fluoro-5-methoxybenzenesulfonyl)-N-(4-(4-methylpiperazine)phenyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, 1-(4-(4-((7-(3-methoxybenzenesulfonyl)-7 H -pyrrolo[2,3- d ]pyrimidin-2-yl)amino)phenyl)piperazinyl)acetone, 7-(2,6-dichloro-3-fluoro-5-methoxybenzenesulfonyl)-N-(4-methylpiperazine)phenyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, N-(4-Cyclopropylpiperazinyl)phenyl)-7-(3-Methoxybenzenesulfonyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, 7-(2,6-dichloro-3-methoxybenzenesulfonyl)-N-(4-(4-methylpiperazine)phenyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, 7-(3-methoxybenzenesulfonyl)-N-(4-methyl-2,7-diazaspiro[3.5]azeloyl-2-yl)phenyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, 7-(2,4-dichloro-5-methoxypyridine-3-sulfonyl)-N-(4-(4-methylpiperazine)phenyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, N-(4-(2,7-diazaspiro[3.5]nonen-2-yl)phenyl)-7-(3-methoxybenzenesulfonyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, 7-(2,4-dichloro-5-fluoropyridine-3-sulfonyl)-N-(4-methylpiperazine)phenyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, 4-(4-(3-methoxybenzenesulfonyl)-7 H -pyrrolo[2,3- d ]pyrimidin-2-yl)amino)phenyl)-2-piperazinone, 7-(2-Methoxypyridine-3-sulfonyl)-N-(4-(4-methylpiperazine)phenyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, N-(4-((3S,5S)-3,5-dimethylpiperazinyl)phenyl)-7-(3-methoxybenzenesulfonyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, 7-(4-chloropyridine-3-sulfonyl)-N-(4-methylpiperazine)phenyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, 7-(2-chloropyridine-3-sulfonyl)-N-(4-methylpiperazine)phenyl)-2-amino-7 H -pyrrolo[2,3- d Pyrimidine, 1-Imine-4-(4-((7-(3-methoxybenzenesulfonyl)-7 H -pyrrolo[2,3- d ]Pyrimidin-2-yl)amino)phenyl)-thiomorpholine-1-oxide.

2. The FGFR inhibitor according to claim 1, characterized in that, The pharmaceutically acceptable salt is a salt formed by the compound with the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid or succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid; or a salt selected from the compound formed with the following bases: basic metal cation salts, alkaline earth metal cation salts, or ammonium cation salts.

3. A pharmaceutical composition, characterized in that, This includes the FGFR inhibitors as described in any one of claims 1 to 2 and pharmaceutically acceptable carriers.

4. The use of an FGFR inhibitor according to any one of claims 1 to 2 or a pharmaceutical composition according to claim 3 in the preparation of a medicament for the prevention and / or treatment of FGFR-related diseases, wherein the FGFR-related diseases are selected from liver cancer, non-small cell lung cancer, gastric cancer, bladder cancer, head and neck cancer, bile duct cancer, breast cancer, endometrial cancer, cervical cancer, esophageal cancer, kidney cancer, acute leukemia, prostate cancer, thyroid cancer, skin cancer, colorectal cancer, pancreatic cancer, ovarian cancer, myelodysplastic syndrome, or mesothelioma.

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