5-aldehyde heterocyclic amide compounds and their applications

Abstract

The present invention relates to a 5-formyl heterocyclic amide compound and its application. The compound has a compound of formula (I) structure or a pharmaceutically acceptable salt, stereoisomer and prodrug molecule thereof. The compound of the present invention has FGFR4 inhibitory activity and can be used to prevent or treat diseases with abnormal FGFR4 activity such as fusion or overexpression, such as liver cancer, bile duct cancer, breast cancer, gastric cancer, prostate cancer, etc., and can also be used in combination with other drugs to be applied in anti-tumor and anti-cancer drugs.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical medicine, and particularly relates to a 5-aldehyde heterocyclic amide compound and application thereof. Technical Background

[0002] Fibroblast growth factor receptors (FGFRs) belong to the receptor tyrosine kinase family (RTKs) and include four receptor subtypes: FGFR1, FGFR2, FGFR3, and FGFR4. The structure of FGFRs primarily consists of three parts: an extracellular region composed of three immunoglobulin-like domains, a single transmembrane region, and an intracellular region containing the kinase domain. The activation mechanism of FGFR4 is similar to that of other receptor tyrosine kinases: ligands bind tightly to a complex formed by the receptor and co-receptors, inducing receptor dimerization and phosphorylating tyrosine residues in the receptor's intracellular region, thereby activating the receptor's kinase activity. Activated FGFR4 can phosphorylate downstream target proteins, triggering a signaling cascade. FGFR4 subtypes are primarily distributed in the liver, lung, lymphoid, and breast tissues. FGFR4 and its specific ligand, the fibroblast growth factor FGF19, play important physiological roles in these tissues. Studies have shown that FGF19 / FGFR4 is upregulated in 30-50% of liver cancers, and this upregulation is closely related to the poor prognosis of liver cancer, making it an effective new target for the treatment of liver cancer and other related tumors.

[0003] FGFR4 has become a hot target in current anti-tumor research, attracting the attention and R&D enthusiasm of numerous research institutions and pharmaceutical companies. Currently, several selective FGFR4 inhibitors have been reported. In 2015, Hagel et al., based on the differences in the key cysteine ​​residue at position 552 of FGFR4 from other members, developed the first selective inhibitor, BLU554, which entered clinical trials (NCT02508467), demonstrating promising therapeutic efficacy in patients with liver cancer and cholangiocarcinoma. H3 Biomedicine's selective FGFR4 inhibitor, H3B-6527, has also entered Phase I clinical trials (NCT03424577). However, recent studies have shown that FGFR4 protein can be rapidly resynthesized, with a synthesis rate of less than 2 hours. To address this issue, Novartis has developed a class of selective, reversible covalent FGFR4 inhibitors. A representative compound, FGF401, has entered Phase I / II clinical trials (NCT02325739) for the treatment of liver cancer with FGFR4 overexpression. Although many companies at home and abroad have also been researching FGFR4 selective inhibitors, no FGFR4 selective inhibitors have been approved for marketing, and more effective FGFR4 selective inhibitors are urgently needed in clinical practice. Summary of the Invention

[0004] In view of the deficiencies of the prior art, the present invention provides a 5-aldehyde heterocyclic amide compound or a pharmaceutically acceptable salt, stereoisomer and prodrug molecule thereof, which can highly selectively inhibit the activity of FGFR4 protein kinase.

[0005] The 5-aldehyde heterocyclic amide compound has a structure of formula (I) or a pharmaceutically acceptable salt, stereoisomer, or prodrug molecule thereof:

[0006]

[0007] In formula (I), n=0 or 1;

[0008] X is selected from NH, NR4, S or O; said R4 is optionally selected from CN, a 6-membered aromatic ring containing CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkanoyl, C 1-6 Sulfonic acid group, C 2-4 Alkynyl, C 1-6 alkyl;

[0009] W, Y and Z are independently selected from C or N;

[0010] R1 is optionally selected from hydrogen, halogen, cyano, trifluoromethyl, formamide, sulfonamide, C 1-3 Thio, C 1-6 Alkyl, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, C 1-3 an alkylthio group, a 6-membered aromatic ring thio group, a C 1-6 Alkyl, C 1-6 Alkanoyl, C 1-6 Cycloalkyl, C 1-6 Alkyl sulfide group, C 2-4 Alkenyl or C 2-4 Alkynyl;

[0011] R2 is optionally selected from hydrogen, halogen, amino, cyano, hydroxy, nitro, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, carboxyl substituted C 1-6 Alkyl, carboxyl substituted C 1-6 Alkoxy, OR5, NHR5 or NR5R6, wherein R5 and R6 are optionally selected from C 1-6 Alkyl, C 1-6 Alkoxy, 4- to 12-membered heterocyclic group containing heteroatoms selected from N, O and S, 6-membered aryl, 5- to 6-membered heteroaryl, C2-4 Alkenyl, C 2-4 Alkynyl or C 3-10 Cycloalkyl;

[0012] R3 is optionally selected from hydrogen, halogen, amino, cyano, hydroxy, nitro, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, carboxyl substituted C 1-6 Alkyl, carboxyl substituted C 1-6 Alkoxy, OR5, NHR5 or NR5R6, wherein R5 and R6 are optionally selected from C 1-6 Alkyl, C 1-6 Alkoxy, halogenated 6-membered aryl C 3-6 Cycloalkyl, 4- to 12-membered heterocyclic group containing heteroatoms selected from N, O and S, 6-membered aryl, 5-6-membered heteroaryl, halogenated 5-6-membered heteroaryl, alkoxy 6-membered aryl C 3-6 Cycloalkyl, C containing aromatic ring, monocyclic, spirocyclic or fused ring 3-6 Cycloalkyl, C 2-4 Alkenyl, C 2-4 Alkenyl C 3-6 Cycloalkyl, C 2-4 Alkynyl or C 3-10 Cycloalkyl.

[0013] Preferably, the compound is a compound having a structure of formula (II) or a pharmaceutically acceptable salt, stereoisomer, or prodrug molecule thereof:

[0014]

[0015] In formula (II), n=0 or 1;

[0016] R1 is optionally selected from hydrogen, halogen, cyano, trifluoromethyl, formamide, sulfonamide, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-4 Alkyl or halogenated C 1-4 Alkoxy, C 1-3 Thio, C 1-3 an alkylthio group, a 6-membered aromatic ring thio group, a C 1-6 alkyl;

[0017] Preferably, said R1 is selected from hydrogen, cyano, cyclopropyl or trifluoromethyl;

[0018] R2 is optionally selected from hydrogen, halogen, amino, cyano, hydroxy, nitro, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C1-6 Alkyl, carboxyl substituted C 1-6 Alkyl, carboxyl substituted C 1-6 Alkoxy, OR5, NHR5 or NR5R6, wherein R5 and R6 are optionally selected from C 1-6 Alkyl, C 1-6 Alkoxy, halogenated 6-membered aryl C 3-6 Cycloalkyl, 4- to 12-membered heterocyclic group containing heteroatoms selected from N, O and S, 6-membered aryl, 5-6-membered heteroaryl, halogenated 5-6-membered heteroaryl, alkoxy 6-membered aryl C 3-6 Cycloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl or C 3-10 Cycloalkyl;

[0019] Preferably, said R2 is selected from OR5, NHR5 or NR5R6, said R5 and R6 are optionally selected from C 1-6 Alkyl, C 1-6 Alkoxy, 4- to 12-membered heterocyclic group containing heteroatoms selected from N, O and S, 6-membered aryl, 5- to 6-membered heteroaryl, C 2-4 Alkenyl, C 2-4 Alkynyl or C 3-10 Cycloalkyl;

[0020] R3 is optionally selected from hydrogen, halogen, amino, cyano, hydroxy, nitro, carboxyl, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkoxy, amino substituted C 1-6 Alkyl, amino substituted C 1-6 Alkoxy, carboxyl substituted C 1-6 Alkyl, carboxyl substituted C 1-6 Alkoxy, N, O and S substituted 4- to 12-membered aromatic ring, monocyclic, spirocyclic or fused ring;

[0021] Preferably, when n=0, the R3 is selected from the following structures:

[0022] Br;

[0023] Preferably, when n=1, the R3 is selected from the following structures:

[0024]

[0025]

[0026] R4 is selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkyl;

[0027] Preferably, R4 is selected from C 1-6 alkyl.

[0028] The use of the 5-aldehyde heterocyclic amide compound or its pharmaceutically acceptable salt, stereoisomer and prodrug molecule in the preparation of anti-tumor and anti-cancer drugs for treating or preventing transitional proliferative diseases caused by abnormal FGFR4 signaling pathway, such as liver cancer, bile duct cancer, breast cancer, gastric cancer, prostate cancer, etc.

[0029] The pharmaceutical composition for treating or preventing a transient proliferative disease comprises an active ingredient and a pharmaceutically acceptable carrier, wherein the active ingredient comprises the above-mentioned 5-aldehyde heterocyclic amide compound or a pharmaceutically acceptable salt, stereoisomer, or prodrug molecule thereof.

[0030] The beneficial effects of the present invention are as follows:

[0031] (1) The present invention provides a novel 5-aldehyde heterocyclic amide compound or its pharmaceutically acceptable salt, stereoisomer, and prodrug molecule structure and preparation method, which can be used to treat or prevent transitional proliferative diseases caused by abnormal FGFR4 signaling pathway;

[0032] (2) The present invention provides a pharmaceutical composition for preventing and / or treating tumors, comprising an active ingredient and a pharmaceutically acceptable excipient. DETAILED DESCRIPTION

[0033] The experimental methods in the following examples of the present invention, where specific conditions are not specified, are generally carried out under conventional conditions or conditions recommended by the manufacturers. The various commonly used chemical reagents used in the examples are all commercially available products.

[0034] Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as those commonly understood by those skilled in the art. The terms used in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

[0035] The terms "comprise," "comprising," and "having," and any variations thereof, are intended to cover non-exclusive inclusions. For example, a process, method, apparatus, product, or device comprising a series of steps is not limited to the listed steps or modules but may optionally include steps not listed, or other steps inherent to the process, method, product, or device.

[0036] In this application, "plurality" refers to two or more. "And / or" describes the relationship between related objects, indicating that three possible relationships exist. For example, "A and / or B" can mean: A exists alone, A and B exist simultaneously, or B exists alone. The character " / " generally indicates that the related objects are in an "or" relationship.

[0037] In the compounds described herein, when any variable (e.g., R5, R6, etc.) occurs more than once in any component, its definition at each occurrence is independent of its definition at every other occurrence. Similarly, combinations of substituents and variables are permitted so long as such combinations result in a stable compound. A line drawn from a substituent into the ring system indicates that the indicated bond may be attached to any substitutable ring atom. If the ring system is polycyclic, this means that such bonds are attached only to any suitable carbon atom of an adjacent ring. It will be understood that one of ordinary skill in the art can select substituents and substitution patterns in the compounds of the present invention to provide chemically stable compounds that can be readily synthesized from readily available raw materials using techniques in the art and the methods set forth below. If a substituent is itself substituted with more than one group, it will be understood that these groups may be on the same carbon atom or on different carbon atoms so long as the structure is stable.

[0038] As used herein, the term "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, the definition of "C1-C20 alkyl" includes groups having 1, 2, 3, 4, 5, or 20 carbon atoms in a straight or branched chain. The term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms. For example, "cycloalkyl" includes cyclopropyl, methylcyclopropyl, 2,2-dimethylcyclobutyl, 2-ethylcyclopentyl, cyclohexyl, and the like.

[0039] The term "alkoxy" as used herein represents an alkyl-oxy group wherein alkyl is as defined above.

[0040] As will be understood by those skilled in the art, "halogen" as used herein is meant to include chlorine, fluorine, bromine, and iodine.

[0041] The present invention includes the free form of the compound of formula (I), as well as its pharmaceutically acceptable salts, stereoisomers, and prodrug molecules. The term "free form" refers to the compound in a non-salt form. Pharmaceutically acceptable salts included include not only the exemplary salts of the specific compounds described herein, but also all typical pharmaceutically acceptable salts of the free form of the compound of formula (I). The free form of a specific salt of the compound can be isolated using techniques known in the art. For example, the free form can be regenerated by treating the salt with a suitable dilute aqueous base solution, such as a dilute aqueous solution of NaOH, a dilute aqueous solution of potassium carbonate, a dilute aqueous ammonia, and a dilute aqueous solution of sodium bicarbonate. The free form differs somewhat from its respective salt form in certain physical properties, such as solubility in polar solvents, but for the purposes of the invention, such acid and base salts are equivalent to their respective free forms in other pharmaceutical aspects.

[0042] Pharmaceutically acceptable salts of the present invention can be synthesized from compounds of the present invention containing a basic or acidic moiety by conventional chemical methods. Typically, salts of basic compounds are prepared by ion exchange chromatography or by reacting a free base with a stoichiometric amount or an excess of an inorganic or organic acid in the desired salt form in a suitable solvent or combination of solvents. Similarly, salts of acidic compounds are formed by reaction with a suitable inorganic or organic base.

[0043] Thus, the pharmaceutically acceptable salts of the compounds of the present invention include the conventional non-toxic salts of the compounds of the present invention formed by reacting a basic compound of the present invention with an inorganic or organic acid.

[0044] If the compound of the present invention is acidic, suitable "pharmaceutically acceptable salts" refer to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases.

[0045] In order to make the purpose, technical solutions and advantages of the present invention more clear, the present invention is further described in detail below in conjunction with specific embodiments. It should be understood that these descriptions are merely exemplary and are not intended to limit the scope of the present invention. In addition, in the following description, descriptions of well-known structures and technologies are omitted to avoid unnecessary confusion of the concept of the present invention.

[0046] The present invention is further described in the following examples, but these examples are not intended to limit the scope of protection of the present invention.

[0047] Example 1

[0048] Compound 1: N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

[0049]

[0050] Step a: Preparation of 2-chloro-3-nitro-6-pyridinecarboxaldehyde (Compound 1-1)

[0051] Selenium dioxide (12.86 g, 2.0 eq) was added to a solution of 2-chloro-3-nitro-6-methylpyridine (10.0 g, 1.0 eq) in dioxane (50 mL). The reaction was carried out at 120°C. After the system was monitored by TLC for completion of the reaction, the solution was cooled to room temperature and saturated sodium bicarbonate was slowly added with stirring to adjust the pH to 8.0. The solution was extracted with ethyl acetate, and the organic layer was concentrated under reduced pressure. The product (2.7 g) was separated by column chromatography with a yield of 25%.

[0052] 1 H NMR (400MHz, DMSO-d6) δ9.94 (d, J=0.8Hz, 1H), 8.78 (dd, J=8.1, 0.8Hz, 1H), 8.16 (d, J=8.1Hz, 1H). LC-MS (ESI) m / z 185.0 [M–H] - .

[0053] Step b: Preparation of 2-chloro-6-(1,3-dioxolane-2-yl)-3-nitropyridine (Compound 1-2)

[0054] Compound 1-1 (2.7 g, 1.0 eq), ethylene glycol (2.7 g, 3.0 eq), and p-toluenesulfonic acid monohydrate (1.38 g, 0.5 eq) were dissolved in 20 mL of toluene and reacted at 115°C for 1 h. After the reaction, ethyl acetate was added, and the organic phase was washed with water, concentrated under reduced pressure, and separated by column chromatography to obtain 2.8 g of the product in an 83.88% yield.

[0055] 1 H NMR (400MHz, DMSO-d6) δ8.63(d,J=8.2Hz,1H),7.81(d,J=8.2Hz,1H),5.85(s,1H),4.12–4.08(m,2H),4.04–4.00(m,2H).LC-MS(ESI)m / z 229.0[M–H] - .

[0056] Step c: Preparation of diethyl 2-(6-(1,3-dioxolane-2-yl)-3-nitropyridin-2-yl)malonate (Compound 1-3)

[0057] Compound 1-2 (2.8 g, 1.0 eq) and diethyl malonate (3.9 g, 2.0 eq) were dissolved in 20 mL of redistilled tetrahydrofuran solution. Sodium hydroxide (1.0 g, 2.0 eq) was slowly added at 0°C. After stirring for 10 min, the mixture was transferred to 70°C for reaction for 2 h. The mixture was cooled to room temperature, and the organic phase was washed with water and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure and separated by column chromatography to obtain 3.5 g of the product with a yield of 81.35%.

[0058] 1 H NMR (400MHz, DMSO-d6) δ8.68(d,J=8.5Hz,1H),7.83(d,J=8.5Hz,1H),5.82(s,1H),5.61(s,1H),4 .20(p,J=7.1Hz,4H),4.14–4.07(m,2H),4.07–4.00(m,2H),1.20(t,J=7.1Hz,6H).LC-MS(ESI)m / z 353.1[M–H] - .

[0059] Step d: Preparation of ethyl 2-(6-(1,3-dioxolane-2-yl)-3-nitropyridin-2-yl)acetate (Compound 1-4)

[0060] Compound 1-3 (3.5 g, 1.0 eq) and lithium chloride (0.63 g, 1.5 eq) were dissolved in 20 ml of a mixture of DMSO and H₂O (50:1) and reacted at 120°C for 8 h. After cooling to room temperature, the organic phase was washed with water and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure and separated by column chromatography to obtain 2.48 g of the product in an 88.95% yield.

[0061] 1 H NMR(400MHz,DMSO-d6)δ8.61(d,J=8.4Hz,1H),7.77(d,J=8.5Hz,1H),5.83(s,1H),4.25(s,2H), 4.15–4.12(m,2H),4.12–4.09(m,2H),4.04–4.01(m,2H),1.17(t,J=7.1Hz,3H).LC-MS(ESI)m / z 281.1[M–H] - .

[0062] Step e: Preparation of ethyl 2-(6-(1,3-dioxolane-2-yl)-3-nitropyridin-2-yl)-3-(dimethylamino)acrylate (Compound 1-5)

[0063] Compound 1-4 (2.48 g, 1.0 eq) and N,N-dimethylformamide dimethyl acetal (1.57 g, 1.5 eq) were dissolved in 20 mL of DMF and reacted at 80°C. After TLC monitoring of the complete reaction of the raw materials, the system was cooled to room temperature. The organic phase was washed with water and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure and separated by column chromatography to obtain 1.8 g of the product in a yield of 61.45%.

[0064] 1 H NMR (400MHz, DMSO-d6) δ8.34(d,J=8.3Hz,1H),7.70(s,1H),7.52(d,J=8.3Hz,1H),5.81(s,1H),4.09(d,J=7 .2Hz,2H),4.03–4.00(m,2H),3.94(m,2H),2.89(s,3H),2.73(s,3H),1.05(t,J=6.7Hz,3H).LC-MS(ESI)m / z 338.1[M+H] + .

[0065] Step f: Preparation of ethyl 5-(1,3-dioxolane-2-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylate (Compound 1-6)

[0066] Compound 1-5 (1.8 g, 1.0 eq) and iron powder (1.5 g, 5.0 eq) were dissolved in 20 mL of acetic acid and reacted at 50°C for 1 h. After cooling the system to room temperature, saturated sodium bicarbonate was slowly added to adjust the pH to 8.0. The mixture was extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The product (0.6 g) was isolated by column chromatography with a yield of 42.87%.

[0067] 1 H NMR (400MHz, CDCl3) δ11.18(s,1H),8.25(s,1H),7.88(d,J=8.5Hz,1H),7.47(d,J=8.5Hz,1H),5.94(s, 1H),4.35(q,J=7.0Hz,2H),4.20–4.13(m,2H),4.06–3.99(m,2H),1.35(t,J=7.1Hz,3H).LC-MS(ESI)m / z 263.1[M+H] + .

[0068] Step g: Preparation of ethyl 5-(1,3-dioxolane-2-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylate (Compound 1-7)

[0069] Compound 1-6 (200 mg, 1.0 eq), potassium carbonate (210 mg, 2.0 eq), and iodomethane (130 mg, 1.2 eq) were dissolved in 10 mL of anhydrous THF and reacted at room temperature. After the reaction of the raw materials was completed, the system was monitored by TLC. Ethyl acetate was added, and the organic phase was washed with water. The organic phase was concentrated under reduced pressure and separated by column chromatography to obtain 182 mg of the product with a yield of 86.38%.

[0070] 1 H NMR (400MHz, CDCl3) δ7.93(s,1H),7.65(d,J=8.6Hz,1H),7.46(d,J=8.6Hz,1H),6.05(s,1H),4.40(q,J =7.1Hz,2H),4.27–4.20(m,2H),4.14–4.07(m,2H),3.82(s,3H),1.42(t,J=7.1Hz,3H).LC-MS(ESI)m / z 277.1[M+H] + .

[0071] Step a1: Preparation of 2-amino-4-fluoro-5-iodopyridine (Compound 1-8)

[0072] 4-Fluoropyridine-2-amine (10.0 g, 1.0 eq), NIS (22.0 g, 1.1 eq), and TFA (4.0 g, 0.4 eq) were dissolved in 30 ml of MeCN. The mixture was reacted at room temperature overnight. Saturated aqueous Na2SO3 solution was added, followed by extraction with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain compound 1-8 (17.6 g, 82.84%).

[0073] 1 H NMR (400MHz, DMSO-d6) δ8.10 (d, J=9.8Hz, 1H), 6.41 (br, 2H), 6.29 (d, J=10.9Hz, 1H). LC-MS (ESI) m / z 239.0 [M+H] + .

[0074] Step b1: Preparation of 2-amino-4-fluoro-5-cyanopyridine (Compound 1-9)

[0075] The above compound 1-8 (17.6 g, 1.0 eq), Zn(CN)2 (9.1 g, 1.05 eq), Zn (1.0 g, 0.2 eq), 1,1'-bis(diphenylphosphino)ferrocene (8.2 g, 0.2 eq) and Pd2(dba)3 (2.7 g, 0.04 eq) were dissolved in 50 mL of DMA. After argon was replaced in the system, the temperature was raised to 110°C and the reaction temperature was raised to 5 h. The reaction was then cooled to room temperature, saturated NaHCO3 solution was added, and the mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure and separated by column chromatography to obtain 8.1 g of the product with a yield of 79.93%.

[0076] 1 H NMR (400MHz, DMSO-d6) δ7.95 (d, J = 10.2Hz, 1H), 6.50 (s, 2H), 6.25 (d, J = 5.7Hz, 1H). LC-MS (ESI) m / z 138.0 [M+H] + .

[0077] Step c1: Preparation of 6-amino-4-((2-methoxyethyl)amino)nicotinonitrile (Compound 1-10)

[0078] Compound 1-9 (2.0 g, 1.0 eq) and 2-methoxyethylamine (2.2 g, 2.0 eq) were dissolved in 20 mL of THF and reacted at 60°C overnight. Saturated aqueous NH4Cl solution was added, and the mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure and separated by column chromatography to obtain 2.4 g of the product in an 85.60% yield.

[0079] 1 H NMR (400MHz, DMSO-d6) δ7.90 (s, 1H), 6.39 (s, 2H), 6.14 (t, J = 5.7Hz, 1H), 5.62 (s, 1H), 3.4 7(t,J=5.9Hz,2H),3.27(s,3H),3.24(dd,J=6.0Hz,5.9Hz,2H).LC-MS(ESI)m / z192.1[M+H] + .

[0080] Step h: Preparation of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-(1,3-dioxolane-2-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 1-11)

[0081] Compound 1-7 (150.0 mg, 1.5 eq.) and compound 1-10 (70.0 mg, 1.0 eq.) were dissolved in 5 mL of toluene. Under argon, trimethylaluminum (0.36 mL, 2.0 eq, 2.0 M) was slowly added dropwise at 0°C and stirred for 10 min. The temperature was then slowly raised to 115°C and the reaction was allowed to proceed for 24 h. The system was cooled to room temperature and quenched with methanol. The system was then directly filtered under reduced pressure and separated by column chromatography to obtain 90.0 mg of the product in a 58.43% yield.

[0082] 1 H NMR (400MHz, CDCl3) δ11.09(s,1H),8.09(s,1H),8.04(s,1H),7.87(s,1H),7.77(d,J=8.0Hz,1H),7.53(d,J=8.0Hz,1H),6.17(s,1H),5.15(t,J= 4.0Hz,1H),4.38–4.36(s,2H),4.19–4.16(s,2H),3.93(s,3H),3.69(t,J=4.0Hz,2H),3.52(dd,J=4.0Hz,8.0Hz,2H),3.44(s,3H).LC-MS(ESI)m / z 423.2[M+H] + .

[0083] Step i Preparation of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-aldehyde-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 1)

[0084] Compound 1-11 (90.0 mg, 1.0 eq.) was dissolved in 5 ml of THF, and 1.0 ml of 2N hydrochloric acid was added. The reaction was allowed to react at room temperature. After completion of the reaction as monitored by TLC, saturated sodium bicarbonate was added to adjust the pH to 8.0. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The title compound (48.0 mg) was isolated by column chromatography in a yield of 59.54%.

[0085] 1 H NMR (400MHz, DMSO-d6) δ11.09(s,1H),10.08(s,1H),8.64(s,1H),8.32(d,J=9.2Hz,2H),7.95(d,J=8.5Hz,1H),7.77( s,1H),7.08(t,J=5.7Hz,1H),3.99(s,3H),3.56(t,J=5.8Hz,2H),3.42(q,J=5.7Hz,2H),3.34(s,3H).LC-MS(ESI)m / z 379.1[M+H] + .

[0086] Example 2 N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 2)

[0087]

[0088] Compound 1-6 and compound 1-10 were used as raw materials, and the synthesis method was the same as that in Example 1. 1 H NMR (400MHz, DMSO-d6) δ12.79(s,1H),11.19(s,1H),10.12(s,1H),8.65(d,J=3.1Hz,1H),8.37(s,1H),8.20(d,J=8.4Hz,1H) ,7.93(d,J=8.4Hz,1H),7.78(s,1H),7.24(d,J=5.8Hz,1H),3.55(s,2H),3.44(q,J=5.7Hz,2H),3.31(s,3H).LC-MS(ESI)m / z 365.1[M+H] + .

[0089] Example 3 N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-ethyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 3)

[0090]

[0091] The synthesis method is as in Example 1. 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 10.08 (s, 1H), 8.72 (s, 1H), 8.40 (d, J = 8.5 Hz, 1H), 8.31 (s, 1H), 7.94 (d, J = 8.5 Hz, 1H), 7.78 (s, 1H), 7.08 (t, J = 5.5 Hz, 1H), 4.42 (q, J = 7.2 Hz, 2H), 3.56 (t, J = 5.8 Hz, 2H), 3.42 (q, J = 5.7 Hz, 2H), 3.34 (s, 3H), 1.44 (t, J = 7.2 Hz, 3H). LC-MS (ESI) m / z 393.2 [M+H] + .

[0092] Example 4 N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-propyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 4)

[0093]

[0094] The synthesis method is as in Example 1. 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 10.08 (s, 1H), 8.71 (s, 1H), 8.42 (d, J = 8.5 Hz, 1H), 8.31 (s, 1H), 7.94 (d, J = 8.6 Hz, 1H), 7.78 (s, 1H), 7.09 (t, J = 5.5 Hz, 1H), 4.36 (t, J = 7.0 Hz, 2H), 3.56 (t, J = 5.8 Hz, 2H), 3.42 (q, J = 5.8 Hz, 2H), 3.31 (s, 3H), 1.85 (h, J = 7.3 Hz, 2H), 0.84 (t, J = 7.4 Hz, 3H). LC-MS (ESI) m / z 407.2 [M+H] + .

[0095] Example 5 N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-isopropyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 5)

[0096]

[0097] The synthesis method is as in Example 1. 1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 10.08 (s, 1H), 8.81 (s, 1H), 8.45 (d, J = 8.6 Hz, 1H), 8.31 (s, 1H), 7.94 (d, J = 8.6 Hz, 1H), 7.80 (s, 1H), 7.10 (t, J = 5.7 Hz, 1H), 4.98 (hept, J = 6.7 Hz, 1H), 3.55 (t, J = 5.8 Hz, 2H), 3.42 (q, J = 5.8 Hz, 2H), 3.31 (s, 3H), 1.55 (d, J = 6.7 Hz, 6H). LC-MS (ESI) m / z 407.2 [M+H] + .

[0098] Example 6 N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-isobutyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 6)

[0099]

[0100] The synthesis method is the same as in Example 1. 1H NMR (400MHz, DMSO-d6) δ11.10(s,1H),10.09(s,1H),8.68(s,1H),8.43(d,J= 8.6Hz,1H),8.32(s,1H),7.95(d,J=8.6Hz,1H),7.79(s,1H),7.09(t,J=5.7H z,1H),4.22(d,J=7.4Hz,2H),3.55(t,J=5.8Hz,2H),3.42(q,J=5.5Hz,2H),3 .31(s,3H),2.18(hept,J=6.9Hz,1H),0.86(d,J=6.6Hz,6H).LC-MS(ESI)m / z 421.2[M+H] + .

[0101] Example 7 N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-(cyclopropylmethyl)1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 7)

[0102]

[0103] The synthesis method is the same as in Example 1. 1 H NMR(400MHz,DMSO-d6)δ11.11(s,1H),10.11(s,1H),8.77(s,1H),8.46(d, J=8.0Hz,1H),8.32(s,1H),7.97(d,J=8.0Hz,1H),7.81(s,1H),7.09(t,J= 6.0Hz,1H),4.29(d,J=8.0Hz,2H),3.57(t,J=6.0Hz,2H),3.44(q,J=4.0Hz ,8.0Hz,2H),3.32(s,3H),1.38–1.34(m,1H).1.23(s,4H).LC-MS(ESI)m / z 419.2[M+H] + .

[0104] Example 8 N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-(2-methoxyethyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 8)

[0105]

[0106] The synthesis method is the same as in Example 1. 1H NMR (400MHz, DMSO-d6) δ11.09(s,1H),10.09(s,1H),8.64(s,1H),8.39(d,J=8.5Hz,1H),8.32(s,1H),7.95(d,J=8.5Hz,1H),7.79(s,1H),7.1 0(t,J=5.7Hz,1H),4.57(t,J=4.9Hz,2H),3.72(t,J=4.9Hz,2H),3.55(t,J=5.8Hz,2H),3.43(m,2H),3.31(s,3H),3.22(s,3H).LC-MS(ESI)m / z 423.2[M+H] + .

[0107] Example 9 N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-aldehyde-1-cyclopentyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 9)

[0108]

[0109] The synthesis method is the same as in Example 1. 1 H NMR (400MHz, DMSO-d6) δ11.05(s,1H),10.06(s,1H),8.67(s,1H),8.40(d,J=8.5Hz,1 H),8.28(s,1H),7.91(d,J=8.6Hz,1H),7.77(s,1H),7.08(t,J=5.7Hz,1H),5.06(p,J =7.4Hz,1H),3.55(t,J=5.9Hz,2H),3.41(q,J=5.9Hz,2H),3.31(s,3H),2.23(m,2H), 1.96(m,2H),1.88(t,J=6.3,2.3Hz,2H),1.73(dq,J=8.3,3.8Hz,2H).LC-MS(ESI)m / z 433.2[M+H] + .

[0110] Example 10 N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-(2-morpholinoethyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 10)

[0111]

[0112] The synthesis method is the same as in Example 1. 1H NMR(400MHz, CDCl3)δ11.30(s,1H),10.34(s,1H),8.37(s,1H),8.29(s,1H), 8.04(d,J=8.5Hz,1H),7.92(d,J=8.4Hz,1H),7.87(s,1H),5.38(t,J=5.1Hz,1 H),4.35(t,J=6.0Hz,2H),3.69(m,4H),3.68–3.66(m,2H),3.55(q,J=5.1Hz,2 H),3.44(s,3H),2.83(t,J=6.1Hz,2H),2.51(t,J=4.7Hz,4H).LC-MS(ESI)m / z 478.2[M+H] + .

[0113] Example 11 N-(5-cyano-4-((2-morpholinoethyl)amino)pyridin-2-yl)-5-aldehyde-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 11)

[0114]

[0115] The synthesis method is the same as in Example 1. 1 H NMR (400MHz, CDCl3) δ11.10(s,1H),10.09(s,1H),8.81(s,1H),8.45(d,J=8.6Hz,1H),8.31(s,1H),7.94(d,J=8.6Hz,1H), δ8.05(s,1H ),5.62(s,1H),4.76(s,2H),3.81–3.68(m,4H),3.20(dd,J=11.3,5.3Hz,2H),2.72–2.62(m,2H),2.51(d,J=4.0Hz,4H).LC-MS(ESI)m / z 434.2[M+H] + .

[0116] Example 12

[0117]

[0118] Step a: Preparation of 6-amino-4-isopropoxynicotinonitrile (Compound 12-2)

[0119]

[0120] Compound 12-1 (420.0 mg, 1.0 eq) was added to redistilled anhydrous DMF, and the mixture was heated to 0°C and stirred. NaH (550.0 mg, 2.0 eq) was slowly added and the reaction was continued for 30 minutes. Compound 1-9 (950.0 mg, 1.0 eq) was added and stirred for 10 minutes before being transferred to room temperature for reaction. After the reaction was complete as monitored by TLC, saturated ammonium chloride was added for quenching, and the mixture was extracted with ethyl acetate, dried by spin drying, and filtered to obtain 600.0 mg of the target product in a yield of 48.8%.

[0121] 1 H NMR(400MHz, DMSO-d6)δ8.10(s,1H),6.79(s,2H),6.04(s,1H),4.67–4.64(m,1H),1.29(d,J=7.1Hz,6H).LC-MS(ESI)m / z 178.1[M+H] + .

[0122] Step c1: Preparation of 6-amino-4-((2-methoxyethyl)amino)nicotinonitrile (Compound 1-10)

[0123] Step b and step c: Preparation of N-(5-cyano-4-(isopropoxy)pyridin-2-yl)-5-formyl-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 12)

[0124]

[0125] The synthesis method is the same as in Example 1.

[0126] 1 H NMR (400MHz, CDCl3) δ11.44(s,1H),10.33(s,1H),8.43(s,1H),8.24(s,1H),8.22(s,1H),8.05(d,J=8. 5Hz,1H),7.91(d,J=8.5Hz,1H),4.96–4.85(m,1H),4.01(s,3H),1.49(d,J=6.1Hz,6H).LC-MS(ESI)m / z 364.1[M+H] + .

[0127] Example 13 N-(5-cyano-4-((2-(dimethylamino)ethyl)amino)pyridin-2-yl)-5-formyl-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 13)

[0128]

[0129] The synthesis method is the same as in Example 1.1 H NMR (400MHz, CDCl3) δ11.10(s,1H),10.09(s,1H),8.81(s,1H),8.45(d,J=8.6Hz,1H),8.31(s,1H),8.05(s,1H),7.94(d, J=8.6Hz,1H),5.62(s,1H),3.14(dd,J=10.9,5.8Hz,2H),2.54(t,J=6.1Hz,2H),2.24(s,6H).LC-MS(ESI)m / z392.2[M+H] + .

[0130] Example 14 N-(5-cyano-4-((2-(4-methylpiperazin-1-yl)ethyl)amino)pyridin-2-yl)-5-formyl-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 14)

[0131]

[0132] The synthesis method is the same as in Example 1. 1 H NMR (400MHz, DMSO-d6) δ11.09(s,1H),10.11(s,1H),8.64(s,1H),8.35(s,1H),8.34(d,J=8.0Hz,1H),7.97(d,J=8 .0Hz,1H),7.77(s,1H),6.96(t,J=4.0Hz,1H),4.01(s,3H),2.99(s,6H),2.67(s,4H),2.62(s,3H).LC-MS(ESI)m / z 447.2[M+H] + .

[0133] Example 15 N-(5-chloro-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 15)

[0134]

[0135] The synthesis method was the same as compound 1, using 5-chloro-4-fluoropyridin-2-amine as the starting material.

[0136] 1H NMR (400MHz, DMSO-d6) δ11.88(s,1H),10.11(s,1H),8.61(s,1H),8.33(d,J=8.0Hz,1H),8.01(s,1H),7.97(d,J=8.0Hz,1H),7.8 0(s,1H),6.30(t,J=6.0Hz,1H),4.00(s,1H),3.58(t,J=6.0Hz,2H),3.41(q,J=8.0Hz,12.0Hz,2H),3.32(s,3H).LC-MS(ESI)m / z 388.1[M+H] + .

[0137] Example 16 N-(4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 16)

[0138]

[0139] The synthesis method is the same as that of Example 15. 1 H NMR (400MHz, CDCl3) δ11.10(s,1H),10.07(s,1H),8.60(s,1H),8.30(s,1H),8.45(d,J=8.0Hz,1H),7.92(d,J=8.0Hz,1H),7.75 (s,1H),7.02(t,J=4.0Hz,1H),3.98(s,1H),3.56(t,J=6.0Hz,2H),3.44–3.40(m,2H),3.32(s,3H).LC-MS(ESI)m / z354.1[M+H] + .

[0140] Example 17 N-(5-cyclopropylpyridin-2-yl)-5-aldehyde-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 17)

[0141]

[0142] The synthesis method was the same as compound 1, using 5-cyclopropylpyridin-2-amine as the starting material.

[0143] 1H NMR (400MHz, DMSO-d6) δ11.00(s,1H),10.12(s,1H),8.63(s,1H),8.31(d,J=8.0Hz,1H),8.22–8.20(m,2H),7.96(d,J=8.0H z,1H),7.50(dd,J=4.0Hz,8.0Hz,1H),3.99(s,3H),1.98–1.92(m,1H),1.01–0.96(m,2H),0.75–0.71(m,2H).LC-MS(ESI)m / z 394.2[M+H] + .

[0144] Example 18

[0145] The synthetic route of compound 18 is as follows:

[0146]

[0147] Step ah: Preparation of 6-bromo-N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-(1,3-dioxolane-2-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 18-2)

[0148] Compound 18-2 was obtained by using 2-chloro-3-nitro-5-bromo-6-methylpyridine (Compound 18-1) as the starting material and the same synthesis method as Example 1.

[0149]

[0150] 1 H NMR (400MHz, CDCl3) δ11.27(s,1H),8.24(s,1H),8.06(s,1H),7.95(s,1H),7.81(s,1H),6.65(s,1H),5.35–5.30(m,1H),4.63(t,J=6.8H z,2H),4.21(t,J=6.8Hz,2H),3.90(s,3H),3.67(t,J=5.0Hz,2H),3.52(dd,J=10.1,5.0Hz,2H),3.43(s,3H).LC-MS(ESI)m / z501.1[M+H] + .

[0151] Step i: Preparation of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-(1,3-dioxolane-2-yl)-1-methyl-6-(1-methyl-1H)-pyrazol-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 18-3)

[0152] Compound 18-2 (50 mg, 1.0 eq.), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (25.0 mg, 1.2 eq.), Pd2(dba)3 (9.0 mg, 0.1 eq.), XantPhos (6.0 mg, 0.1 eq.) and cesium carbonate (100.0 mg, 3.0 eq.) were dissolved in 8 ml of 1.4-dioxane, and 1 ml of water was added. After argon was replaced in the system, the mixture was reacted at 80°C. After the reaction was completed, the raw material was monitored by TLC plate and filtered. The organic layer was added with silica gel powder and dried. The product (35.0 mg) was separated by column chromatography with a yield of 69.7%

[0153]

[0154] 1 H NMR (400MHz, CDCl3) δ11.60(s,1H),8.25(s,1H),8.10(s,1H),7.85(s,1H),7.75(s,1H),7.67(s,1H),6.34(s,1H),5.34(s,1H),5.33(t,J=4.0Hz, 1H),4.69(t,J=6.0Hz,2H),4.19(t,J=8.0Hz,2H),4.03(s,3H),3.93(s,3 H),3.68(t,J=6.0Hz,2H),3.56–3.52(m,2H),3.44(s,3H).LC-MS(ESI)m / z 503.2[M+H] + .

[0155] Step j: Preparation of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-(1-methyl-1H-pyrazol-4-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 18)

[0156] The synthesis method is the same as compound 1.

[0157]

[0158] 1H NMR (400MHz, CDCl3) δ11.25(s,1H),10.39(s,1H),8.28(s,1H),8.20(s,1H),7.83(s,1H),7.82(s,1H),7.75(s,1H),7.7 2(s,1H),5.37(s,1H),4.03(s,3H),3.97(s,3H),3.68(t,J=8.0Hz,2H),3.55–3.53(m,2H),3.44(s,3H).LC-MS(ESI)m / z 459.2[M+H] + .

[0159] Example 19 N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-(1,3-dimethyl-1H-pyrazol-4-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 19)

[0160]

[0161] The synthesis method is the same as that of Example 18.

[0162] 1 H NMR (400MHz, CDCl3) δ11.37(s,1H),10.34(s,1H),8.32(s,1H),8.25(s,1H),7.86(s,1H),7.67(s,1H),7.46(s,1H) ,5.41(s,1H),3.98(s,3H),3.97(s,3H),3.68(s,2H),3.58–3.55(m,2H),3.45(s,3H),2.18(s,3H).LC-MS(ESI)m / z 473.2[M+H] + .

[0163] Example 20 N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-aldehyde-6-(1-methyl-1H-pyrazol-5-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 20)

[0164]

[0165] The synthesis method is the same as Example 18.

[0166] 1H NMR (400MHz, DMSO-d6) δ11.10(s,1H),10.07(s,1H),8.76(s,1H),8.36(s,1H),8.35(s,1H),7.81(s,1H),7.55(d,J=1.2Hz,1H),6.40(d,J=1 .2Hz,1H),5.77(s,1H),5.32(t,J=3.2Hz,1H),4.02(s,2H),3.60(s,2H),3.31(s,3H),3.17(s,3H),3.16(s,3H).LC-MS(ESI)m / z458.2[M+H] + .

[0167] Example 21 N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-aldehyde-6-(pyridin-3-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 21)

[0168]

[0169] The synthesis method is the same as that of Example 18.

[0170] 1 H NMR(400MHz,DMSO-d6)δ11.14(s,1H),10.10(s,1H),8.71–8.71(m,2H),8. 65(dd,J1=0.8Hz,3.2Hz,1H),8.34(s,1H),8.33(s,1H),7.97–7.95(m,1H), 7.80(s,1H),7.53(dd,J=1.2Hz,5.2Hz,1H),7.14(t,J=3.2Hz,1H),4.02(s, 3H),3.56(t,J=4.0Hz,2H),3.45–3.43(m,2H),3.32(s,3H).LC-MS(ESI)m / z 456.2[M+H] + .

[0171] Example 22 N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-(thiophen-2-yl))-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 22)

[0172]

[0173] The synthesis method is the same as that of Example 18.

[0174] 1H NMR (400MHz, DMSO-d6) δ11.03(s,1H),10.14(s,1H),8.66(s,1H),8.33(s,1H),8.32(s,1H),7.79(d,J=4.0Hz,1H),7.78(s,1H),7.33(d,J=1. 6Hz,1H),7.24(t,J=3.2Hz,1H),7.10(s,1H),4.00(s,3H),3.56(t,J=3.6Hz,2H),3.55(dd,J=4.0Hz,8.0Hz,2H),3.31(s,3H).LC-MS(ESI)m / z 461.1[M+H] + .

[0175] Example 23 N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-(furan-2-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 23)

[0176]

[0177] The synthesis method is the same as that of Example 18.

[0178] 1 H NMR (400MHz, DMSO-d6) δ11.04(s,1H),10.14(s,1H),8.66(s,1H),8.32(s,1H),7.92(s,1H),7.76(d,J=4.0Hz,1H),7.66(s,1H),7.35(d,J=1. 6Hz,1H),7.27(t,J=3.8Hz,1H),7.14(s,1H),4.06(s,3H),3.55(t,J=3.6Hz,2H),3.50(dd,J=4.0Hz,8.0Hz,2H),3.31(s,3H).LC-MS(ESI)m / z 445.1[M+H] + .

[0179] Example 24 N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-(2-methylthiazol-5-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 24)

[0180]

[0181] The synthesis method is the same as that of Example 18.

[0182] 1H NMR (400MHz, DMSO-d6) δ11.04(s,1H),10.15(s,1H),8.71(s,1H),8.36(s,1H),8.33(s,1H),7.80(s,1H),7.78(s,1H),7.07(t,J=4 .0Hz,1H),3.99(s,3H),3.57(t,J=6.0Hz,2H),3.44(dd,J=4.0Hz,8.0Hz,2H),3.32(s,3H),2.75(s,3H).LC-MS(ESI)m / z476.1[M+H] + .

[0183] Example 25 N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-(2-fluoro-6-methoxyphenyl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 25)

[0184]

[0185] The synthesis method is the same as that of Example 18.

[0186] 1 H NMR(400MHz,DMSO-d6)δ11.10(s,1H),11.03(s,1H),8.68(s,1H),8.33(s,1H),8.26(s ,1H),7.81(s,1H),7.58–7.54(m.1H),7.48(d,J=8.0Hz,1H),7.07(t,J=4.0Hz,1H),7.0 1(dd,J=8.0Hz,16.0Hz,1H),5.32(t,J=4.0Hz,1H)),3.99(s,3H),3.05(s,3H),3.57(t, J=6.0Hz,2H),3.45(dd,J=4.0Hz,8.0Hz,2H),3.32(s,3H),2.75(s,3H).LC-MS(ESI)m / z 503.2[M+H] + .

[0187] Example 26 N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-(2-methoxyphenyl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 26)

[0188]

[0189] The synthesis method is the same as that of Example 18.

[0190] 1 H NMR(400MHz,DMSO-d6)δ11.11(s,1H),9.95(s,1H),8.61(s,1H),8.32(s,1 H),8.14(s,1H),7.80(s,1H),7.47(t,J=8.0Hz,1H),7.40(t,J=8.0Hz,1H) ,7.13(t,J=6.0Hz,1H),7.04(t,J=4.0Hz,1H)),3.99(s,3H),3.68(s,3H), 3.57(t,J=6.0Hz,2H),3.32(s,3H),3.17(d,J=8.0Hz,2H).LC-MS(ESI)m / z 485.2[M+H] + .

[0191] Example 27

[0192] 6-Bromo-N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 27)

[0193]

[0194] Compound 18-10 was used as the starting material and the synthesis method was the same as that of compound 1.

[0195] 1 H NMR (400MHz, DMSO-d6) δ10.82(s,1H),10.20(s,1H),8.67(s,1H),8.64(s,1H),8.31(s,1H),7.75( s,1H),7.05(s,1H),3.97(s,3H),3.56(t,J=4.0Hz,2H),3.56(br,2H),3.31(s,3H).LC-MS(ESI)m / z 457.1[M+H] + .

[0196] Example 28

[0197]

[0198] Step a: Preparation of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-(1,3-dioxolane-2-yl)-6-((4-methylpiperazin-1-yl)methyl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 28-1)

[0199] Compound 18-2 (200.0 mg, 1.0 eq), 1-methyl-4-(methylenetrifluoropiperazine) potassium salt (166.0 mg, 2.0 eq), palladium acetate (8.5 mg, 0.1 eq), X-Phos (18.0 mg, 0.1 eq.), and cesium carbonate (370.0 mg, 3.0 eq.) were dissolved in 10 mL of tetrahydrofuran. 1 ml of H2O was added, and the system was replaced with argon. The temperature was raised to 80°C and the reaction was allowed to react overnight. The reaction was then concentrated under reduced pressure and separated by column chromatography to obtain 50.0 mg of the target product containing a small amount of impurities in a yield of 37.5%.

[0200] 1 H NMR(400MHz, CDCl3)δ11.06(s,1H),10.23(s,1H),8.58(s,1H),8.33(s,1H),8.21 (s,1H),7.83(s,1H),7.00(t,J=4.0Hz,1H),6.20–6.11(m,1H),5.72–5.67(m,2H) ,5.57–5.48(m,2H),4.09(s,2H),3.96(s,3H),3.59(t,J=6.0Hz,2H),3.46(q,J=4 .0Hz,12.0Hz,2H),3.28(s,3H),2.72–2.61(m,4H),2.46(br,4H).LC-MS(ESI)m / z 535.3[M+H] + .

[0201] Step b: Preparation of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-((4-methylpiperazin-1-yl)methyl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 28)

[0202] The synthesis method is the same as compound 1.

[0203]

[0204] 1 H NMR (400MHz, CDCl3) δ11.06(s,1H),10.24(s,1H),8.61(s,1H),8.32(s,1H),8.26(s,1H),7.8(s,1H),7.05(t,J=4.0Hz,1H),4.07(s, 2H),3.99(s,3H),3.56(t,J=6.0Hz,2H),3.44(q,J=4.0Hz,12.0Hz,2H),3.31(s,3H),2.72–2.61(m,4H),2.45(br,4H).LC-MS(ESI)m / z

[0205] 491.2[M+H] + .

[0206] Example 29

[0207]

[0208] Step a: Preparation of ethyl 6-bromo-5-(1,3-dioxolane-2-yl)-1-isopropyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylate (Compound 29-1)

[0209] The synthesis method is the same as compound 1-7. 1 H NMR (400MHz, CDCl3) δ8.12(s,1H),7.89(s,1H),6.53(s,1H),4.59–4.57(m,1H),4.47–4.43(m,2H),4.3 8(q,J=7.1Hz,2H),4.15–4.11(m,2H),1.54(s,3H),1.55(s,3H),1.42(t,J=7.1Hz,3H).LC-MS(ESI)m / z 383.1[M+H] + .

[0210] Step b: Preparation of 6-bromo-N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-(1,3-dioxolane-2-yl)-1-isopropyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 29-2)

[0211] The synthesis method is the same as compound 1-11. 1 H NMR(400MHz,DMSO-d6)δ11.10(s,1H),8.66(s,1H),8.64(s,1H),8.29(s,1 H),7.77(s,1H),7.09(t,J=5.7Hz,1H),6.40(s,1H),4.93(p,J=6.6Hz,1H) ,4.47–4.41(m,2H),4.11–4.05(m,2H),3.54(t,J=5.8Hz,2H),3.44(dd,J= 6.0Hz,12.0Hz,2H),3.30(s,3H),1.52(s,3H),1.52(s,3H).LC-MS(ESI)m / z 529.1[M+H] + .

[0212] Step c: N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-(1,3-dioxolane-2-yl)-6-((4-methylpiperazin-1-yl)methyl)-1-isopropyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 29-3)

[0213] The synthesis method is the same as compound 26-1.

[0214] 1 H NMR (400MHz, CDCl3) δ11.08(s,1H),10.22(s,1H),8.56(s,1H),8.32(s,1H),8.20(s,1H),7. 85(s,1H),7.00(t,J=4.0Hz,1H),6.22-6.01(m,1H),6.20–6.11(m,1H),5.72–5.67(m,2H),5. 57–5.48(m,2H),4.12(s,2H),3.98(s,3H),3.62(t,J=6.0Hz,2H),3.45(q,J=4.0Hz,12.0Hz, 2H),3.28(s,3H),2.72–2.61(m,4H),2.46(br,4H),1.62(s,3H),1.62(s,3H).LC-MS(ESI)m / z 563.3[M+H] + .

[0215] Step d: Preparation of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-((4-methylpiperazin-1-yl)methyl)-1-isopropyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 29)

[0216] The synthesis method is the same as compound 1. 1 H NMR (400MHz, CDCl3) δ11.22(s,1H),10.38(s,1H),8.37(s,1H),8.23(s,1H),8.08(s,1H),7.83(s,1H),5.35(t,J=5.2Hz,1H),4.76(hept,J=6.8Hz,1 H),4.17(s,2H),3.64(t,J=5.1Hz,2H),3.50(q,J=5.2Hz,2H),3.40(s,3H) ,2.72–2.70(m,8H),2.42(s,3H),1.63(s,3H),1.62(s,3H).LC-MS(ESI)m / z 519.3[M+H] + .

[0217] Example 30 N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-(morpholinomethyl)-1-isopropyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 30)

[0218]

[0219] The synthesis method is the same as Example 27. 1 H NMR (400MHz, CDCl3) δ11.22(s,1H),10.38(s,1H),8.37(s,1H),8.23(s,1H),8.08(s,1H),7.83(s,1H),5.35(t,J=5.2Hz,1H),4.76(hept,J=6. 8Hz,1H),4.17(s,2H),3.64(t,J=5.1Hz,2H),3.50(q,J=5.2Hz,2H),3.40(s,3H),2.61–2.58(m,8H),1.62(s,3H),1.61(s,3H).LC-MS(ESI)m / z 506.2[M+H] + .

[0220] Example 31 N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-6-((((3S,5R)-3,5-dimethylpiperazin-1-yl)methyl)-5-formyl-1-isopropyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 31)

[0221]

[0222] The synthesis method is the same as Example 27. 1 H NMR (400MHz, CDCl3) δ11.29(s,1H),10.41(s,1H),8.37(s,1H),8.26(s,1H),8.14(s,1H), 7.85(s,1H),6.98(d,J=0.7Hz,1H),5.34(t,J=4.4Hz,1H),4.77(dt,J=13.4,6.7Hz,1H),4. 11(s,2H),3.66(dd,J=5.6,4.6Hz,2H),3.53(t,J=5.1Hz,2H),3.42(s,2H),3.02–2.95(m,2 H),2.27(s,2H),1.63(d,J=6.7Hz,6H),1.37(s,2H),1.06(d,J=6.5Hz,6H).LC-MS(ESI)m / z 533.3[M+H] + .

[0223] Example 326-Bromo-N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-isopropyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 32)

[0224]

[0225] Using compound 29-2 as the starting material, the deprotection and synthesis methods were the same as those of compound 1.

[0226] 1 H NMR(400MHz,DMSO-d6)δ10.87(s,1H),10.21(s,1H),8.83(s,1H),8.78(s,1H),8.31(s,1H),7.78(s,1H),7.09(d ,J=4.0Hz,1H),5.01–4.97(m,1H),3.55(t,J=4.0Hz,2H),2.31(s,3H),1.54(s,3H),1.53(s,3H).LC-MS(ESI)m / z 485.1[M+H] + .

[0227] Example 33

[0228] The synthetic route of compound 33 is as follows:

[0229]

[0230] Step a: Preparation of 6-amino-4-((2-morpholinoethyl)amino)nicotinonitrile (Compound 33-1)

[0231] The synthesis method is the same as compound 1-10. 1 H NMR (400MHz, CDCl3) δ8.25 (s, 1H), 7.92 (s, 1H), 5.86 (t, J = 4.0Hz, 1H), 3.76–3.74 (m, 4H), 3.40(dd,J=8.0Hz,12.0Hz,2H),2.71(t,J=6.0Hz,2H),2.56–2.53(m,4H).LC-MS(ESI)m / z 248.1[M+H] + .

[0232] Step b: Preparation of 6-bromo-N-(5-cyano-4-((2-morpholinoethyl)amino)pyridin-2-yl)-5-(1,3-dioxolane-2-yl)-1-isopropyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 33-2)

[0233] The synthesis method is the same as compound 1-11.1 H NMR (400MHz, CDCl3) δ11.31(s,1H),8.26(s,1H),8.25(s,1H),8.01(s,1H),6.65(s,1H),5.86(t,J=4.0Hz,1H),4.69–4.61(m,3H),4.23–4.20( m,2H),3.79–3.77(m,4H),3.40(dd,J=8.0Hz,12.0Hz,2H),2.73(t,J=6.0Hz,2H),2.56–2.54(m,4H),1.63(s,3H),1.62(s,3H).LC-MS(ESI)m / z 584.1[M+H] + .

[0234] Step c: Preparation of 6-bromo-N-(5-cyano-4-((2-morpholinoethyl)amino)pyridin-2-yl)-5-formyl-1-isopropyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 33)

[0235] The synthesis method is the same as compound 1. 1 H NMR (400MHz, DMSO-d6) δ10.88(s,1H),10.26(s,1H),8.82(s,1H),8.77(s,1H),8.30(s,1H),7.74(s,1H),6.96(t,J=4.0Hz,1H),5.0 1–4.96(m,1H),3.61–3.59(m,4H),3.38–3.35(m,2H),2.57(t,J=4.0Hz,2H),2.47(br,2H),1.54(s,3H),1.53(s,3H).LC-MS(ESI)m / z 540.1[M+H] + .

[0236] Example 34

[0237] Compound 34: 6-Bromo-N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-(2-morpholinoethyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

[0238]

[0239] The synthesis method is the same as Example 25. 1H NMR (400MHz, DMSO-d6) δ10.88(s,1H),10.21(s,1H),8.76(s,1H),8.70(s,1H),8.33(s,1H),7.77(s,1H),7.07(t,J=4.0Hz,1H),4.49(t,J=4.0Hz,1 H),3.56(t,J=6.0Hz,2H),3.51–3.49(m,4H),3.43(dd,J=6.0Hz,9.0Hz,2H),3.31(s,3H),2.72(t,J=6.0Hz,2H),2.46–2.44(m,4H).LC-MS(ESI)m / z 556.1[M+H] + .

[0240] Example 35

[0241] The synthetic route of compound 35 is as follows:

[0242]

[0243] Step a: Preparation of N-(2-(((tert-Butoxycarbonyl)amino)ethyl)-N-methylglycine ethyl ester (Compound 35-1)

[0244] Dissolve tert-butyl 2-(methylamino)ethylcarbamate (1.0 g, 1.0 eq.), ethyl bromoacetate (958.0 mg, 1.0 eq.), and triethylamine (608 mg, 1.05 eq.) in 10 mL of THF and react at room temperature for 6 h. Concentrate the organic phase under reduced pressure and separate by column chromatography to obtain 1.3 g of the product in an 87% yield.

[0245] 1 H NMR (400MHz, CDCl3) δ5.59 (s, 1H), 4.11 (q, J = 8.0Hz, 20.0Hz, 2H), 3.21 (s, 1H), 3.14 (dd, J = 8.0Hz, 1 2.0Hz,2H),2.57(t,J=6.0Hz,2H),2.32(s,3H),1.39(s,9H),1.22(t,J=6.0Hz,2H).LC-MS(ESI)m / z 261.1[M+H] + .

[0246] Step b: Preparation of N-(2-aminoethyl)-N-methylglycine ethyl ester (Compound 35-2)

[0247] Compound 35-1 (1.3 g, 1.0 eq.) and trifluoroacetic acid (1.14 g, 2.0 eq.) were dissolved in 10 mL of DCM and reacted at room temperature for 3 h. The system was dried and then saturated sodium bicarbonate was added to adjust the pH to 8.0. The system was extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The product (680 mg) was separated by column chromatography with a yield of 85%.

[0248] 1 H NMR (400MHz, CDCl3) δ4.16(q,J=7.0Hz,2H),3.29(s,2H),3.20(d,J=5.2Hz,2H),2.65(t,J =5.6Hz,2H),2.39(s,3H),1.40(s,2H),1.26(t,J=7.1Hz,3H).LC-MS(ESI)m / z161.1[M+H] + .

[0249] Step c: Preparation of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-(1,3-dioxolane-2-yl)-6-vinyl-1-isopropyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 35-3)

[0250] Compound 18-2 (100.0 mg, 1.0 eq), Pd(dppf)Cl2 (15.0 mg, 0.1 eq), cesium carbonate (195.0 mg, 3.0 eq), 5 ml of 1.4-dioxane, and 1 ml of water were added to a Schlenk flask. After argon was replaced in the system, vinylboronic acid pinacol ester (310.0 mg, 10.0 eq) was added. The reaction was heated to 110°C for 2 h. The system was directly concentrated and column chromatography was performed to obtain 50.0 mg of the target compound in a yield of 55.6%.

[0251] 1 H NMR (400MHz, CDCl3) δ11.49(s,1H),8.27(s,1H),7.87(s,1H),7.36(dd,J=10.0Hz,20.0 Hz.1H),6.39(s,1H),5.73(d,J=20.0Hz,1H),5.46(d,J=12.0Hz,1H),5.33(d,J=6.0Hz, 1H),4.77–4.71(m,1H),4.51–4.47(m,2H),4.21–4.17(m,2H),3.67(t,J=4.0Hz,2H),3. 54(t,J=6.0Hz,2H),3.44(s,3H),1.63(s,3H),1.62(s,3H).LC-MS(ESI)m / z477.2[M+H] + .

[0252] Step d: Preparation of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-(1,3-dioxolane-2-yl)-6-formyl-1-isopropyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 35-4)

[0253] Compound 35-3 (50.0 mg, 1.0 eq), potassium osmate dihydrate (5.2 mg, 0.15 eq), 1.4-dioxane (10 ml) and water (1 ml) were added to a single-necked flask respectively. After stirring for 5 min, sodium periodate (82.0 mg, 4.0 eq) was added and the reaction was continued for 2 h. After the reaction was completed, the raw material was directly concentrated by column chromatography after monitoring by TLC to obtain 25.0 mg of compound (yield: 50.0%).

[0254] 1 H NMR (400MHz, CDCl3) δ11.27(s,1H),10.69(s,1H),8.48(s,1H),8.45(s,1H),8.29(s,1H),7.87(s,1H),6.41(s,1H),5.36(t,J=4.0Hz,1H),4.85–4 .79(m,1H),4.44–4.40(m,2H),4.25–4.22(m,2H),3.68(t,J=6.0Hz,2H), 3.54(q,J=6.0Hz,10.0Hz,2H),3.44(s,3H),1.66(s,6H).LC-MS(ESI)m / z 479.2[M+H] + .

[0255] Step e: Preparation of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-(1,3-dioxolane-2-yl)-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-1-isopropyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 35-5)

[0256] Compound 35-4 (25.0 mg, 1.0 eq.), compound 35-2 (22.0 mg, 1.5 eq.), and sodium triacetylborohydride (30.0 mg, 5.0 eq.) were dissolved in 5 mL of anhydrous dichloromethane and reacted at room temperature for 24 h. The pH was adjusted to 8.0 with saturated sodium bicarbonate, and the mixture was extracted with dichloromethane. The organic phase was concentrated under reduced pressure and separated by column chromatography to obtain 14.0 mg of the product in a 45.7% yield.

[0257] 1H NMR (400MHz, CDCl3) δ11.41(s,1H),8.27(s,1H),8.26(s,1H),6.28(s,1H),5.35–5.27( m,1H),5.02(s,3H),4.73–4.67(m,1H),4.43–4.41(m,2H),4.24–4.16(m,2H),3.67(t,J =8.0Hz,2H),3.53(t,J=6.0Hz,2H),3.44(s,3H),3.32(t,J=6.0Hz,2H),3.25(s,3H),2. 62(t,J=4.0Hz,2H),2.36(s,3H),1.59(s,3H),1.58(s,3H).LC-MS(ESI)m / z577.28[M+H] + .

[0258] Step f: Preparation of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-1-isopropyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 35)

[0259] The synthesis method is the same as compound 1.

[0260] H NMR(400MHz,DMSO-d6)δ11.09(s,1H),10.22(s,1H),8.79(s,1H),8.31(s,1H), 7.92(s,1H),7.80(s,1H),7.08(t,J=6.0Hz,1H),5.10(s,2H),5.01–4.94(m,1H) ,3.56(t,J=6.0Hz,2H),3.45–3.41(m,2H),3.32(s,3H),3.28(s,2H),3.12(s,2H ),2.66(t,J=6.0Hz,2H),2.27(s,3H),1.56(s,3H),1.54(s,3H).LC-MS(ESI)m / z 533.3[M+H] + .

[0261] Example 36

[0262]

[0263] Step a: Preparation of 2-chloro-N-(2-methoxyethyl)-5-(trifluoromethyl)pyridin-4-amine (Compound 36-2)

[0264] Compound 36-1 (2.0 g, 1.0 eq) was added to 50 mL of toluene along with 2-methoxyethylamine (510.0 mg, 1.05 eq), Pd2dba3 (300.0 mg, 0.05 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 190.0 mg, 0.05 eq), and cesium carbonate (6.4 g, 3.0 eq). The system was purged of argon and heated to 80° C. to react overnight. The system was then directly concentrated under reduced pressure and separated by column chromatography to obtain 400.0 mg of the target product in a yield of 24.2%.

[0265] 1 H NMR (400MHz, CDCl3) δ8.24 (s, 1H), 6.62 (s, 1H), 5.32 (br, 1H), 3.65 (t, J = 4.0Hz, 2H), 3.34 (s, 3H), 3.40–3.36 (m, 2H). LC-MS (ESI) m / z 255.1[M+H] + .

[0266] Step b: Preparation of N-(2,4-dimethoxybenzyl)-N-(2-methoxyethyl)-5-(trifluoromethyl)pyridine-2,4-diamine (Compound 36-3)

[0267] Compound 36-2 (400.0 mg, 1.0 eq), 2.4-dimethoxyaniline (2.6 g, 10.0 eq), Pd2dba3 (72.0 mg, 0.05 eq), Xantphos (45.0 mg, 0.05 eq), and cesium carbonate (1.54 g, 3.0 eq) were added to 10 mL of toluene. After argon was replaced in the system, the temperature was raised to 100°C and the reaction was allowed to proceed overnight. The system was then directly concentrated under reduced pressure and separated by column chromatography to obtain 250.0 mg of the target product in a yield of 41.2%.

[0268] 1 H NMR (400MHz, CDCl3) δ8.62(s,1H),8.20(s,1H),7.24–7.18(m,3H),6.58(s,1H),5.40(s,2H),5. 28(br,1H),3.78(s,6H),3.64(t,J=4.0Hz,2H),3.32(s,3H),3.41–3.35(m,2H).LC-MS(ESI)m / z 386.2[M+H] + .

[0269] Step c: Preparation of N-(2-methoxyethyl)-5-(trifluoromethyl)pyridine-2,4-diamine (Compound 36-4)

[0270] Compound 36-3 (250.0 mg, 1.0 eq) was added to 10.0 ml of dichloromethane, and 3.0 ml of trifluoroacetic acid was slowly added to the system. After TLC monitoring, the system was completely reacted with the raw materials. After thorough spin drying, 160.0 mg of the product was obtained with a yield of 104.6% (as trifluoroacetate salt), which was directly used in the next step. LC-MS (ESI) m / z 236.1 [M+H] + .

[0271] Step d and step e: Preparation of N-(5-trifluoromethyl-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 36)

[0272] The synthesis method is the same as that of Example 1

[0273] Result analysis: 1 H NMR (400MHz, DMSO-d6) δ11.05(s,1H),10.12(s,1H),8.66(s,1H),8.35(d,J=8.0Hz,1H),7.98(d,J=8.0Hz,1H ),7.87(s,1H),5.32(t,J=4.0Hz,1H),4.01(s,2H),3.58(t,J=6.0Hz,2H),3.47–3.44(m,2H).LC-MS(ESI)m / z 422.2[M+H] + .

[0274] Example 37

[0275] The synthetic route of compound 37 is as follows:

[0276]

[0277] Step a: Preparation of 5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (Compound 37-1)

[0278] Ethyl 3-amino-1H-pyrazole-4-carboxylate (10 g, 1.0 eq.) and 4,4-dimethoxy-2-butanone (12.3 g, 1.3 eq.) were dissolved in 50 ml of toluene and reacted at 100°C for 5 h. The organic phase was concentrated under reduced pressure and separated by column chromatography to obtain 10 g of the product with a yield of 75.8%.

[0279] 1H NMR(400MHz, DMSO-d6)δ9.11(d,J=7.1Hz,1H),8.52(s,1H),7.17(d,J=7.1Hz, 1H),4.28(q,J=7.1Hz,2H),2.62(s,3H),1.30(t,J=7.1Hz,3H).LC-MS(ESI)m / z 206.1[M+H] + .

[0280] Step b: Preparation of ethyl 5-formylpyrazolo[1,5-a]pyrimidine-3-carboxylate (Compound 37-2)

[0281] The synthesis method is the same as compound 1-1. 1 H NMR(400MHz,DMSO-d6)δ9.98(d,J=0.7Hz,1H),9.47(dd,J=7.1,0.8Hz,1H),8.82(s,1H ),7.60(d,J=7.1Hz,1H),4.36(q,J=7.1Hz,2H),1.35(t,J=7.1Hz,3H).LC-MS(ESI)m / z 220.0[M+H] + .

[0282] Step c: Preparation of ethyl 5-(1,3-dioxolane-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (Compound 37-3)

[0283] The synthesis method is the same as compound 1-2. 1 H NMR (400MHz, DMSO-d6) δ9.32(d,J=7.2Hz,1H),8.66(s,1H),7.33(d,J=7.2Hz,1H),5.80(s,1H),4 .30(q,J=7.1Hz,2H),4.22–4.15(m,2H),4.10–4.03(m,2H),1.31(t,J=7.1Hz,3H).LC-MS(ESI)m / z 264.1[M+H] + .

[0284] Step d: Preparation of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-(1,3-dioxolane-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 37-4)

[0285] The synthesis method is the same as compound 1-11. 1H NMR (400MHz, DMSO-d6) δ10.34(s,1H),8.86(d,J=8.0Hz,1H),8.76(s,1H),8.25(s,1H),7.85(s,1H),7.28(d,J=8.0Hz,1H),6.02(s,1H),5.3 8(t,J=4.0Hz,1H),4.34–4.27(m,2H),4.22–4.18(m,2H),3.68(t,J=6.0Hz,2H),3.54(q,J=4.0Hz,12.0Hz,2H),3.44(s,3H).LC-MS(ESI)m / z 410.1[M+H] + .

[0286] Step e: Preparation of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1H-pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 37)

[0287] The synthesis method is the same as compound 1. 1 H NMR (400MHz, DMSO-d6) δ10.30(s,1H),10.03(s,1H),9.59(d,J=7.1Hz,1H),8.97(s,1H),7.68( d,J=7.1Hz,1H),5.64(s,2H),3.68(br,2H),3.56(d,J=2.5Hz,2H),3.31(s,3H).LC-MS(ESI)m / z 366.1[M+H] + .

[0288] Example 38: N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-methyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 38)

[0289]

[0290] The synthesis method is the same as compound 35.

[0291] H NMR(400MHz,DMSO-d6)δ11.06(s,1H),10.23(s,1H),8.65(s,1H),8.32(s,1H),7.82(s,1H),7.78(s,1H),7.07(s,1H),5.10(s,2H),3.99(s,2 H),3.57–3.54(m,2H),3.44–3.42(m,2H),3.35(s,3H),3.32(s,3H),3.12(s,2H),2.68–2.66(m,2H),2.27(s,3H).LC-MS(ESI)m / z505.2[M+H] + .

[0292] Example 39: IC of Compounds for FGFR1-4 Kinases 50 Test results

[0293] FGFR1-4 kinase inhibition assay: Compound inhibitory activity against FGFR1-4 was determined using the FRET-based Z'-Lyte assay system according to the manufacturer's instructions (Life Technologies, Carlsbad, CA, USA). Reactions were performed in 384-well plates in 5 μL reaction volumes in 50 mM HEPES (pH 7.5), 10 mM MgCl2, 1 mM EGTA, and 0.01% Brij-35 with the appropriate amount of kinase. Reactions were incubated for 1.5 hours at room temperature in the presence of 2 μM substrate and the corresponding ATP concentration for each kinase (FGFR1: 25 μM, FGFR2: 5 μM, FGFR3: 75 μM, FGFR4: 150 μM) and various concentrations of compound. 2.5 μL of developer was then added and incubated for another hour at room temperature, followed by the addition of 2.5 μL of stop solution. The fluorescence signal ratio of 445 nm (coumarin) / 520 nm (fluorescein) was detected using EnVision Multilabel Reader (Perkin Elmer, Inc.). 50 Data were analyzed using Graphpad Prism 5 (Graphpad Software, Inc).

[0294] Calculation: The inhibition rate of each well is calculated by the fully active wells and the control signal wells. The data analysis method is as follows:

[0295] Phosphorylation ratio = 1–{(emission ratio × F100%–C100%) / [C0%–C100% + emission ratio × (F100%–F0%)]} × 100;

[0296] Inhibition rate = 100 × (1 - phosphorylation ratio of compound / phosphorylation ratio of negative control).

[0297] IC 50 The values ​​were calculated using medical graphics software (GraphPad Prism 5.0).

[0298] Table 1: FGFR4 kinase activity test results of some compounds (IC50: nM)

[0299]

[0300]

[0301] NT=Not Test

[0302] It can be seen from the data in Table 1 that some of the 5-aldehyde heterocyclic amide compounds of the present invention have strong inhibitory activity against FGFR4 kinase, and have excellent selectivity against the other three subtypes of the FGFR family, FGFR1-3.

[0303] Example 40: Results of cell proliferation inhibition activity based on BaF3-FGFR4 stable strain

[0304] The Ba / F3 cells (mouse pre-B cells) used in this experiment were purchased from ThermoFisher. The wild-type Ba / F3-TEL-FGFR4 and the stable strains of drug-resistant mutants Ba / F3-TEL-FGFR4 (V550L) and Ba / F3-TEL-FGFR4 (V550M) were all constructed in our laboratory and verified to be completely correct through positive drug activity, protein expression, and gene sequencing experiments.

[0305] The brief steps for stable strain construction are as follows:

[0306] 1. The kinase domain gene of human FGFR4 (NM_002011.5) was fused to the N-terminus of ETV6 (NM_001987.4), and the fusion gene TEL-FGFR4 was cloned into the pMSCV vector. Positive clones were picked and verified by sequencing.

[0307] 2. Using the recombinant plasmid TEL-FGFR4-pMSCV as a template, the FGFR4 gatekeeper mutant plasmids TEL-FGFR4(V550L)-pMSCV and TEL-FGFR4(V550M)-pMSCV were constructed.

[0308] 3. Transfect 293T cells with the three successfully constructed plasmids and the empty plasmid without the target gene, and collect and preserve the virus-containing supernatant culture medium.

[0309] 4. Use this supernatant medium to infect Ba / F3 cells for three days, change to normal medium containing puromycin for recovery for one day, and then select positive cell lines under the conditions of no interleukin-3 and added puromycin.

[0310] 5. The positive stable cell lines screened were verified by western-blot.

[0311] Cell proliferation inhibitory activity study:

[0312] 1. Add 2000 positive stable cell lines obtained by screening into 96-well cell culture plates, and use the Ba / F3 cell line transfected with an empty plasmid without the target gene as a control.

[0313] 2. After 6-12 hours, add an equal volume of pre-diluted small molecule inhibitor (3-fold dilution).

[0314] 3. After 72 h, CCK-8 reagent was added to detect cell viability.

[0315] 4. Calculate IC of small molecule inhibition using GraphPad Prism software 50 .

[0316] Table 2: Activity test results of some compounds on Ba / F3-FGFR4 cells (IC 50 :nM)

[0317] Compound number Ba / F3-FGFR4 Compound number Ba / F3-FGFR4 Example 8 6.4 Example 25 312.0 Example 9 67.0 Example 26 519.0 Example 10 27.0 Example 27 27.0 Example 18 47.0 Example 28 117.0 Example 19 >3000 Example 29 15.0 Example 20 38.0 Example 30 35.0 Example 21 29.0 Example 31 20.0 Example 22 10.0 Example 38 7.0 Example 23 11.0 FGFR401 4.0 Example 24 12.8

[0318] From the data in Table 2, it can be seen that some of the 5-aldehyde heterocyclic amide compounds of the present invention have strong inhibitory activity on the cell proliferation of the Ba / F3-FGFR4 stable strain.

[0319] Table 3. Complementary activity of representative compounds on drug-resistant cells

[0320]

[0321] From the data in Table 3, it can be seen that some of the 5-aldehyde heterocyclic amide compounds of the present invention have good proliferation inhibition activity against the stable cell lines of Ba / F3-FGFR4 with mutations to V550L or V550M.

[0322] It should be noted that the specific features, structures, materials or characteristics described in this specification can be combined arbitrarily. In order to make the description concise, not all possible combinations of the various technical features in the above embodiments are described. Unless there is any contradiction, those skilled in the art can combine and combine the different embodiments and features of different embodiments described in this specification.

[0323] The above-described embodiments merely represent several implementation methods of the present invention. While the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the patent. It should be noted that a person skilled in the art would be able to make various modifications and improvements without departing from the spirit of the present invention, all of which fall within the scope of protection of the present invention. Therefore, the scope of protection of the patent for this invention shall be determined by the appended claims.

Claims

1. 5-aldehyde heterocyclic amide compounds, characterized in that The compound is a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof: （I） In formula (I), n=0 or 1; X is selected from NH, NR4; said R4 is selected from C 1-6 alkyl; W is selected from C or N, Y and Z are independently selected from C; R1 is optionally selected from hydrogen, cyano, cyclopropyl or trifluoromethyl; R2 is optionally selected from hydrogen, OR5; said R5 is selected from C 1-6 alkyl; When n=0, R3 is selected from hydrogen, halogen, , , , , , , , , ; When n=1, R3 can be selected from , , , .

2. The 5-aldehyde heterocyclic amide compound according to claim 1, characterized in that: The compound is a compound having a structure of formula (II) or a pharmaceutically acceptable salt thereof: (II) In formula (II), n=0 or 1; R1 is optionally selected from hydrogen, cyano, cyclopropyl or trifluoromethyl; R2 is optionally selected from hydrogen, OR5; said R5 is selected from C 1-6 alkyl; When n=0, R3 is selected from hydrogen, halogen, , , , , , , , , ; When n=1, R3 can be selected from , , , ; R4 is selected from C 1-6 alkyl.

3. The 5-aldehyde heterocyclic amide compound according to any one of claims 1 to 2, characterized in that: When n=0, the R3 is selected from the following structures: Br； ； ； ； ； ； ； ； When n=1, the R3 is selected from the following structures: ； ； ； 。 4. A 5-aldehyde heterocyclic amide compound, characterized in that: The compound is selected from any one of the following: N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-ethyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-propyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-isopropyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-isobutyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-(cyclopropylmethyl)1H-pyrrolo[3,2-b]pyridine-3-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-(2-methoxyethyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-aldehyde-1-cyclopentyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-(2-morpholinoethyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide; N-(5-cyano-4-((2-morpholinoethyl)amino)pyridin-2-yl)-5-formyl-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide; N-(5-cyano-4-(isopropoxy)pyridin-2-yl)-5-formyl-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide; N-(5-cyano-4-((2-(dimethylamino)ethyl)amino)pyridin-2-yl)-5-formyl-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide; N-(5-cyano-4-((2-(4-methylpiperazin-1-yl)ethyl)amino)pyridin-2-yl)-5-formyl-1-methyl-1H-pyrrolo[3,2-b ]pyridine-3-carboxamide; N-(5-chloro-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide; N-(4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide; N-(5-cyclopropylpyridin-2-yl)-5-formyl-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-(1-methyl-1H-pyrazol-4-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-(1,3-dimethyl-1H-pyrazol-4-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-(1-methyl-1H-pyrazol-5-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-(pyridin-3-yl)-1-methyl-1H-pyrrolo[3,2- b ]pyridine-3-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-(thien-2-yl))-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-(furan-2-yl)-1-methyl-1H-pyrrolo[3,2- b ]pyridine-3-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-(2-methylthiazol-5-yl)-1-methyl-1H-pyrrolo[3, 2-b]pyridine-3-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-(2-fluoro-6-methoxyphenyl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-(2-methoxyphenyl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide; 6-Bromo-N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-((4-methylpiperazin-1-yl)methyl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-((4-methylpiperazin-1-yl)methyl)-1-isopropyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-(morpholinomethyl)-1-isopropyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-6-(((3S,5R)-3,5-dimethylpiperazin-1-yl)methyl)-5-formyl-1-isopropyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide; 6-Bromo-N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-isopropyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide; 6-Bromo-N-(5-cyano-4-((2-morpholinoethyl)amino)pyridin-2-yl)-5-formyl-1-isopropyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide; 6-Bromo-N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-(2-morpholinoethyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-1-isopropyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide; N-(5-trifluoromethyl-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1H-pyrazolo[1,5-a]pyrimidine-3-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-methyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide.

5. Use of the 5-aldehyde heterocyclic amide compound or a pharmaceutically acceptable salt thereof according to claim 4 in the preparation of a medicament for treating or preventing a transient proliferative disease caused by abnormal FGFR4 signaling pathway.

6. The use according to claim 5, characterized in that: The transitional proliferative disease is a tumor, the tumor is a solid tumor or a fluid tumor, and the solid tumor is liver cancer, bile duct cancer, breast cancer, gastric cancer, prostate cancer, lung cancer, nasopharyngeal cancer, oral cancer, and intestinal cancer.

7. A pharmaceutical composition for treating or preventing a transient proliferative disease, characterized in that: The composition consists of an active ingredient and a pharmaceutically acceptable carrier, and the active ingredient consists of the 5-aldehyde heterocyclic amide compound according to claim 5 or a pharmaceutically acceptable salt thereof.

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