STAT3 inhibitor, preparation method, pharmaceutical composition and application of STAT3 inhibitor

Abstract

The invention belongs to the technical field of medicines, and particularly relates to an STAT3 inhibitor, a preparation method, a pharmaceutical composition and application of the STAT3 inhibitor. The compound is a compound as shown in a formula I or pharmaceutically acceptable salt, hydrate, solvate and isotope compound thereof. The compound provided by the invention can be used as a main component of a pharmaceutical composition, the aim of treating tumors is fulfilled by inhibiting the activity of STAT3, and the aim of treatment can be fulfilled by administering one or more compounds or pharmaceutical salts, stereoisomers or tautomers of the compounds of which the treatment or prevention is required to a patient. The structure of the formula I is shown in the specification.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a STAT3 inhibitor, its preparation method, pharmaceutical composition, and its uses. Background Technology

[0002] Signal transducer and activator of transcription 3 (STAT3) is aberrantly upregulated and activated in various cancers, including pancreatic cancer. It can regulate tumor cell proliferation, differentiation, apoptosis, and angiogenesis, thus serving as a promising target for anticancer therapy. STAT3 is transiently activated under physiological conditions but exhibits persistent activation in many cancers. Two amino acid residues of STAT3, Tyr705 and Ser727, are phosphorylated upon activation. Phosphorylation at the Tyr705 site of STAT3 (p-Tyr705) mediates the classical activation pathway of STAT3. Upon stimulation by cytokines or growth factors, Janus-activated kinase (JAK), Src kinase, and epidermal growth factor receptor (EGFR) can phosphorylate the Tyr705 residue of STAT3, further promoting STAT3 dimerization via the Srchomology 2 (SH2) domain. Subsequently, the STAT3 dimer is translocated to the nucleus to initiate downstream gene transcription. Unlike Tyr705 phosphorylation, phosphorylation of STAT3 at Ser727 (p-Ser727) mediates a non-canonical activation pathway for STAT3. Following phosphorylation by serine kinase mitogen-activated protein kinase (MAPK), extracellular regulatory protein kinases (ERK1 / 2), c-Jun N-terminal kinase (JNK), and p38, p-Ser727 enters the mitochondria via its interaction with GRIM-19 to regulate mitochondrial oxidative phosphorylation (OXPHOS). Mitochondrial STAT3 p-Ser727 enhances the activity of electron transport chain complexes (ETCs), leading to increased ATP production and oxygen consumption in cancer cells. Simultaneously, phosphorylation at STAT3 Ser727 also maximizes Tyr705 phosphorylation-mediated STAT3 transcriptional activity through interactions with other transcriptional cofactors. Notably, the synergistic effect of STAT3 phosphorylation at Tyr705 and Ser727 is essential for complete STAT3 activation, which promotes the formation and development of various cancers. Studies have shown that blocking Tyr705 phosphorylation-mediated aberrant STAT3 activation or blocking Ser727 phosphorylation can inhibit the proliferation and migration of pancreatic cancer cells. Furthermore, mounting evidence suggests that some pancreatic cells exhibit metabolic dependence on the OXPHOS pathway. For example, OXPHOS inhibitors targeting complex I, IACS-010759 and BAY87-224327, have entered clinical trials for the treatment of advanced pancreatic cancer, indicating that OXPHOS inhibition is emerging as a novel strategy for pancreatic cancer treatment. However, the clinical application of these OXPHOS inhibitors that directly target complex I is limited due to their toxicity.Therefore, inhibiting STAT3 Ser727 phosphorylation to indirectly block OXPHOS may be an alternative treatment strategy. Furthermore, some clinical studies have shown that high expression of p-Tyr705 and p-Ser727 is closely associated with poor prognosis in pancreatic cancer patients. Therefore, simultaneously blocking STAT3 Tyr705 and Ser727 phosphorylation may be a promising treatment strategy for pancreatic cancer. Summary of the Invention

[0003] The researchers of this invention have discovered that derivatives represented by structural formula I enhance antitumor activity by improving the immune system. Therefore, the object of this invention is to provide a STAT3 inhibitor, a method for its preparation, a pharmaceutical composition, and its uses. The compounds represented by formula I of this invention and their various derivatives possess antitumor pharmacological activity.

[0004] One objective of this invention is to provide compounds having the structure of Formula I, stereoisomers, or pharmaceutically acceptable salts, hydrates, solvates, or isotopic compounds thereof.

[0005]

[0006] R1 includes, but is not limited to, structures

[0007] X includes, but is not limited to, NH, NCH3, or (CH2). n Where n is 1 to 4;

[0008] Y and M represent N or C, and ring A is a substituted or unsubstituted benzene ring or an aromatic heterocycle;

[0009] When Z is CH2, there is no R2, W is N, and R3 includes, but is not limited to, the following structures:

[0010]

[0011]

[0012] When W- is CH2, there is no R3, Z is N, and R2 includes, but is not limited to, the following structures:

[0013]

[0014]

[0015] The compound having the structure of formula I can be, but is not limited to, compounds of the following formulas (1)-(40):

[0016]

[0017]

[0018]

[0019]

[0020] A second object of the present invention is to provide a pharmaceutical composition comprising a compound having the structure of Formula I, a stereoisomer thereof, and a nontoxic pharmaceutically acceptable salt, hydrate, solvate, or isotopic compound thereof.

[0021] The pharmaceutical composition further includes a pharmaceutical carrier and / or a diluent.

[0022] A third objective of this invention is to provide a compound having the structure of Formula I, its stereoisomers, and its non-toxic, pharmaceutically acceptable salts, hydrates, solvates, and pharmaceutical compositions containing these compounds as active ingredients as STAT3 inhibitors for the treatment of tumors.

[0023] The fourth objective of this invention is to treat tumors by inhibiting STAT3 activity. The compounds having Formula I, their stereoisomers, and their non-toxic, pharmaceutically acceptable salts, hydrates, solvates, and isotopic compounds are used for tumor treatment.

[0024] The tumors are selected from skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, rectal cancer, esophageal cancer, tongue cancer, stomach cancer, kidney cancer, renal parenchymal cancer, cervical cancer, uterine cancer, endometrial cancer, testicular cancer, urinary tract cancer, melanoma, astrocytoma, meningioma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, adult T-cell leukemia lymphoma, hepatocellular carcinoma, bronchial carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell tumor, seminoma, rhabdomyosarcoma, chondrosarcoma, sarcoma, and fibrosarcoma.

[0025] A fifth objective of this invention is to provide a method for preparing the compound having the structure of Formula I, its stereoisomer, or a pharmaceutically acceptable salt, hydrate, solvate, or isotopic compound thereof, characterized in that the preparation method comprises the following steps:

[0026]

[0027] (1) Synthesis of intermediate IV

[0028] Compound II reacts with Compound III at a temperature between 0°C and 80°C. The base is selected from triethylamine, diisopropylethylamine, pyridine, potassium carbonate, and cesium carbonate. The reaction solvent is dichloromethane, tetrahydrofuran, acetonitrile, or toluene.

[0029] (2) Synthesis of intermediate V

[0030] Compound VI reacts under the action of a base, and the reaction is carried out at a temperature of 20°C to 80°C. The base is selected from lithium hydroxide, sodium hydroxide, and potassium hydroxide, and the reaction solvent is methanol, ethanol, tetrahydrofuran / water, dioxane / water, or methanol / water.

[0031] (3) Synthesis of intermediate VII

[0032] Compound V reacts with compound VI under the action of a condensing agent. The reaction is carried out at a temperature of 20°C to 80°C. The condensing agent is selected from 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride / 1-hydroxybenzotriazole, and dicyclohexylcarbodiimide. The base is selected from triethylamine, diisopropylethylamine, and 4-dimethylaminopyridine. The reaction solvent is methanol, ethanol, tetrahydrofuran / water, dioxane / water, or methanol / water.

[0033] (4) Synthesis of Compound I

[0034] Intermediate VII undergoes a coupling reaction with compound VIII. The reaction is carried out at a temperature of 80°C to 120°C. The catalyst is selected from palladium acetate, tris(dibenzylacetone)palladium, or 1,1'-bis(diphenylphosphine)ferrocenepalladium dichloride. The ligand is selected from 1,1'-binaphthyl-2,2'-bisdiphenylphosphine, 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl, or 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene. The base is selected from cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, or potassium carbonate. The reaction solvent is dioxane, N,N-dimethylformamide, or toluene.

[0035] definition

[0036] "Pharmaceutically acceptable salts" refer to salts that retain the bioavailability and properties of the parent compound. These salts include: acid addition salts, obtained by the reaction of the free base of the parent compound with an inorganic acid or an organic acid; said inorganic acid includes hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, sulfuric acid, and perchloric acid; said organic acid includes acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, benzenesulfonic acid (benzenesulfonate), benzoic acid, camphorsulfonic acid, citric acid, fumaric acid, gluconic acid, glutamic acid, etc. Acids such as ethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, mucilage, dihydroxynaphthyl acid, pantothenic acid, succinic acid, tartaric acid, or malonic acid; preferably hydrochloric acid or (L)-malic acid; or forming a salt when the acid protons present in the parent compound are replaced by metal ions or coordinated with an organic base, said metal ions being such as alkali metal ions, alkaline earth ions, or aluminum ions; said organic bases being such as ethanolamine, diethanolamine, triethanolamine, thiocyanate, N-methylglucosamine, and the like.

[0037] "Pharmaceutical composition" means a mixture of one or more compounds described herein or their physiologically acceptable salts with other chemical components, such as physiologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate the delivery of the compound to a living organism.

[0038] When used in this article, "carrier" refers to a carrier or diluent that does not produce obvious irritation to an organism and does not eliminate the biological activity and properties of the given compound.

[0039] "Phenyl" refers to a group whose functional group is a benzene ring.

[0040] "Aryl" refers to an all-carbon monocyclic or fused-ring polycyclic group (i.e., a ring sharing adjacent carbon atom pairs) with a fully conjugated π-electron system. Preferably, the aryl group has 6 to 12 carbon atoms in the ring.

[0041] The compounds of the present invention may have one or more asymmetric centers; the compounds may therefore be prepared individually as (R)-stereoisomers or (S)-stereoisomers or mixtures thereof. Unless otherwise stated, the description or name of a particular compound in this specification and claims is intended to include individual enantiomers and their racemic mixtures or other mixtures. Methods for determining stereochemical configurations and separating stereoisomers are well known in the art (see discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition, J. March, John Wiley, and Sons, New York, 1992). Therefore, the present invention also covers any stereoisomer having STAT3-inhibiting activity, its corresponding enantiomers (d-isomers and l-isomers or (+) isomers and (-) isomers) and their diastereomers and mixtures thereof, and is not limited to any one stereoisomer. Detailed Implementation

[0042] The present invention can be further described through the following embodiments; however, the scope of the present invention is not limited to the following embodiments.

[0043] Example 1

[0044] 4-(3-((2-(methylsulfonyl)-2,3,4-5-tetrahydro-1H-benzo[c]azacycloheptane-7-yl)amino)piperidin-1-yl)methyl)benzamide

[0045]

[0046] first step:

[0047] Compounds 1a (40.0 g, 200.0 mmol), 1b (48.6 g, 200.0 mmol), and potassium carbonate (41.5 g, 300.0 mmol) were dissolved in acetonitrile (400 ml) and reacted at room temperature (25 °C) for 6 hours. The reaction was monitored by TLC. After the reaction was completed, water (400 ml) was added to quench the reaction. Ethyl acetate (400 ml) was added to the reaction mixture. The mixture was separated, the organic layer was dried, concentrated, and separated by column chromatography to obtain 1c as a white solid of 70.3 g, with a yield of 97%.

[0048] Step Two:

[0049] The compound 1c (70.0 g, 193 mmol) obtained above was dissolved in tetrahydrofuran (200 ml) and water (100 ml). Sodium hydroxide (38.6 g, 966 mmol) was added at room temperature, and the mixture was stirred for 8 hours. The reaction was monitored by TLC. After the reaction was completed, dilute hydrochloric acid was added to adjust the pH to 2-3. The mixture was extracted with ethyl acetate (500 ml x 2). The organic layer was concentrated to give 60.5 g of off-white solid 1d, with a yield of 94%.

[0050] Step 3:

[0051] Compound 1d (6.0 g, 17.9 mmol), ammonia (50 mL, 25–28%), cesium carbonate (3.0 g, 9.0 mmol), and tetrabutylammonium bromide (644 mg, 2 mmol) were reacted in a microwave at 120 W for 20 minutes. The reaction was repeated 5 times. The reaction mixtures were combined and extracted with ethyl acetate (2 × 500 mL). The organic layers were combined, concentrated, and separated by column chromatography to give 1e as an off-white solid of 26.2 g, with a yield of 87%.

[0052] Step 4:

[0053] Compound 1e (25.0 g, 150.0 mmol) was dissolved in tetrahydrofuran (150 ml) and concentrated hydrochloric acid water (90 ml). The mixture was stirred at room temperature (25 °C) for 4 hours. The reaction was monitored by TLC. After the reaction was complete, the pH was adjusted to 8-9 by dissolving the compound in 15% sodium hydroxide. The mixture was extracted with ethyl acetate (2 × 150 ml). The organic layers were combined, dried, concentrated, and separated by column chromatography to obtain 1f as an off-white solid of 16.3 g, with a yield of 93%.

[0054]

[0055] Step 5:

[0056] 1 g (26.2 g, 100.0 mmol) of the compound was dissolved in dichloromethane (250 ml), and tert-butyl nitrite (103.12 g, 1.0 mol) was added. Methylchlorosilane (54.3 g, 500.0 mmol) was added dropwise with stirring. After the addition was complete, the mixture was stirred at room temperature (25 °C) for 4 hours. The reaction was detected by TLC. After the reaction was complete, water (200 ml) was extracted with dichloromethane (2 × 100 ml). The organic layers were combined, dried, concentrated, and separated by column chromatography to obtain 21.7 g of off-white solid after 1 hour, with a yield of 77%.

[0057] Step 6:

[0058] Compound 1h (21.1 g, 75.0 mmol) was dissolved in tetrahydrofuran (100 ml) and concentrated hydrochloric acid water (50 ml). The mixture was stirred at room temperature (25 °C) for 4 hours. The reaction was monitored by TLC. After the reaction was complete, the pH was adjusted to 8-9 by dissolving the compound in 15% sodium hydroxide. The mixture was extracted with ethyl acetate (2 × 150 ml). The organic layers were combined, dried, concentrated, and separated by column chromatography to obtain 1i as an off-white solid, with a yield of 93%.

[0059] Step 7:

[0060] Compound 1i (9.1 g, 50 mmol) was dissolved in dichloromethane (100 ml), and triethylamine (7.6 g, 75 mmol) was added. The mixture was cooled to 0 °C, and methanesulfonyl chloride (6.3 g, 55 mmol) was added dropwise. After the addition was complete, the mixture was stirred at room temperature (25 °C) for 4 hours. The reaction was monitored by TLC. After the reaction was complete, the reaction solution was washed once with 100 ml of 0.2 N dilute hydrochloric acid, and then the pH was adjusted to 7-8 with saturated sodium bicarbonate aqueous solution. The solution was washed once, and the organic layer was collected, dried, concentrated, and separated by column chromatography to obtain 8.7 g of 1i as an off-white solid, with a yield of 67%.

[0061] Step 8:

[0062] Compound 1f (233 mg, 1.0 mmol) was dissolved in acetonitrile (10 mL), and compound 1j (260 mg, 1.0 mmol) and potassium carbonate (276 mg, 2.0 mmol) were added. The mixture was stirred at 50–55 °C for 4 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was extracted with water (20 mL) and ethyl acetate (2 × 20 mL). The organic layers were combined, dried, concentrated, and separated by column chromatography to give compound 1 as an off-white solid of 389 mg, with a yield of 85%. ESI(+) m / z = 457.2. 1 H-NMR (500MHz, d 6 -DMSO)δ9.80(d,J=1.7Hz,1H),8.74(d,J=1.6Hz,1H),8.46(dd,J=5.7,1.6Hz,1H), 8.31(d,J=5.7Hz,1H),8.05-7.98(m,1H),7.82(d,J=1.4Hz,1H),7.68(dq,J=4.8,2 .2Hz,2H),7.18(d,J=1.4Hz,1H),3.71(p,J=5.7Hz,1H),2.99(s,3H),0.92(dddd,J =10.2,8.4,5.7,1.8Hz,2H),0.82(dddd,J=10.6,9.0,5.7,1.8Hz,2H),0.71(s,1H).

[0063] Example 2

[0064] N-Methyl-4-(3-((2-(methanesulfonyl)-2,3,4-5-tetrahydro-1H-benzo[c]azacycloheptane-7-yl)amino)piperidin-1-yl)methyl)benzamide

[0065]

[0066] first step:

[0067] Compound 1d (6.0 g, 17.9 mmol), methylamine hydrochloride (1.8 g, 26.85 mmol), cesium carbonate (11.7 g, 53.8 mmol), and tetrabutylammonium bromide (644 mg, 2 mmol) were added to 50 mL of water and reacted at 120 W microwave power for 20 min. The reaction was repeated 5 times. The reaction solutions were combined and extracted with ethyl acetate (2 × 500 mL). The organic layers were combined, concentrated, and separated by column chromatography to give 2e as an off-white solid of 28.6 g, with a yield of 92%.

[0068] Step Two:

[0069] The specific operation is the same as step four in Example 1, and compound 2f is obtained as 18.9 g of off-white solid, with a yield of 93%.

[0070] Step 3:

[0071] Compound 2f (247 mg, 1.0 mmol) was dissolved in acetonitrile (10 mL), and compound 1j (260 mg, 1.0 mmol) and potassium carbonate (276 mg, 2.0 mmol) were added. The mixture was stirred at 50–55 °C for 4 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was extracted with water (20 mL) and ethyl acetate (2 × 20 mL). The organic layers were combined, dried, concentrated, and separated by column chromatography to give compound 2 as an off-white solid of 405 mg, with a yield of 86%. ESI(+) m / z = 471.2. 1 H-NMR (500MHz, d 6 -DMSO) δ9.80(d,J=2.1Hz,1H),8.74(d,J=1.6Hz,1H),8.46(dd,J=5.6,1.5Hz,1H),8.31(d,J=5.6Hz,1H),8.04-7.98(m,1H),7.82(d,J=1 .4Hz,1H),7.68(dq,J=4.9,2.2Hz,2H),7.09(d,J=1.4Hz,1H),4.55(hept,J=6.3Hz,1H),2.99(s,3H),1.33(d,J=6.4Hz,6H),0.70(s,1H).

[0072] Example 3

[0073] 2-(Methylsulfonyl)-N-(1-(4-(2,2,2-trifluoroethoxy)benzyl)piperidin-3-yl)-2,3,4-5-tetrahydro-1H-benzo[c]azacycloheptane-7-amine

[0074]

[0075] Compound 1e (420 mg, 1.0 mmol), compound 3a (126 mg, 1.0 mmol), tetraphenylphosphine palladium (115 mg, 0.1 mmol), and potassium carbonate (276 mg, 2.0 mmol) were dissolved in tetrahydrofuran (10 ml) and water (5 ml). The mixture was heated to 80 °C (oil bath temperature) and stirred for 10 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was extracted with ethyl acetate (2 × 50 ml). The organic layers were combined, dried, concentrated, and separated by column chromatography to give 285 mg of an off-white solid, with a yield of 67.4% and ESI(+) m / z = 424.1. 1 H-NMR (500MHz, d 6 -DMSO) δ9.80(d,J=2.2Hz,1H),8.73(d,J=1.6Hz,1H),8.47(dd,J=5.7,1.6Hz,1H),8.28(d,J=5.7Hz,1H),8.00(dd,J=8 .4,1.7Hz,1H),7.79(d,J=1.4Hz,1H),7.74-7.66(m,2H),7.09(d,J=1.4Hz,1H),3.97(s,3H),2.99(s,3H),1.09(s,1H).

[0076] Example 4

[0077] 2-(methylsulfonyl)-N-(1-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)piperidin-3-yl)-2,3,4-5-tetrahydro-1H-benzo[c]azacycloheptane-7-amine

[0078]

[0079] Compound 1e (420 mg, 1.0 mmol), compound 4a (125 mg, 1.0 mmol), tetraphenylphosphine palladium (115 mg, 0.1 mmol), and potassium carbonate (276 mg, 2.0 mmol) were dissolved in tetrahydrofuran (10 ml) and water (5 ml). The mixture was heated to 80 °C (oil bath temperature) and stirred for 10 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was extracted with ethyl acetate (2 × 50 ml). The organic layers were combined, dried, concentrated, and separated by column chromatography to give 294 mg of an off-white solid, with a yield of 69.7% and ESI(+) m / z = 423.1. 1H-NMR (500MHz, d 6 -DMSO) δ9.80(d,J=1.8Hz,1H),8.67(d,J=1.6Hz,1H),8.46(dd,J=5.7,1.6Hz,1H),8.19(d,J=5.6Hz,1H),8.01(dd,J=8.4,1.7Hz,1H) ,7.74-7.66(m,2H),7.02(d,J=4.3Hz,1H),6.80(d,J=1.4Hz,1H),6.03(dd,J=4.2,1.5Hz,1H),3.68(s,3H),2.99(s,3H),1.07(s,1H).

[0080] Example 5

[0081] 2-(methylsulfonyl)-N-(1-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)piperidin-3-yl)-2,3,4-5-tetrahydro-1H-benzo[c]azacycloheptane-7-amine

[0082]

[0083] Compound 1e (420 mg, 1.0 mmol), compound 5a (126 mg, 1.0 mmol), tetraphenylphosphine palladium (115 mg, 0.1 mmol), and potassium carbonate (276 mg, 2.0 mmol) were dissolved in tetrahydrofuran (10 ml) and water (5 ml). The mixture was heated to 80 °C (oil bath temperature) and stirred for 10 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was extracted with acetate (2 × 50 ml). The organic layers were combined, dried, concentrated, and separated by column chromatography to obtain 247 mg of an off-white solid, with a yield of 58.4% and ESI(+) m / z = 424.1. 1 H-NMR (500MHz, d 6 -DMSO) δ10.00(s,1H),9.80(d,J=2.1Hz,1H),8.82(d,J=1.6Hz,1H),8.46(dd,J=5.6,1.5Hz,1H),8.01(dd,J=8.4,1. 8Hz,1H),7.86(d,J=5.6Hz,1H),7.78(s,1H),7.74-7.66(m,2H),7.15(s,1H),3.71(s,3H),2.99(s,3H),1.07(s,1H).

[0084] Example 6

[0085] 2-Fluoro-N-methyl-4-(3-((2-(methanesulfonyl)-2,3,4-5-tetrahydro-1H-benzo[c]azacycloheptane-7-yl)amino)piperidin-1-yl)methyl)benzamide

[0086]

[0087] Compound 1e (420 mg, 1.0 mmol), compound 6a (140 mg, 1.0 mmol), tetraphenylphosphine palladium (115 mg, 0.1 mmol), and potassium carbonate (276 mg, 2.0 mmol) were dissolved in tetrahydrofuran (10 ml) and water (5 ml). The mixture was heated to 80 °C (oil bath temperature) and stirred for 10 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was extracted with acetate (2 × 50 ml). The organic layers were combined, dried, concentrated, and separated by column chromatography to obtain 258 mg of an off-white solid. The yield was 59.0%, and the ESI (+) m / z = 438.1. 1 H-NMR (500MHz, d 6 -DMSO) δ9.81(s,1H),9.73(d,J=2.2Hz,1H),8.73(d,J=1.6Hz,1H),8.46(dd,J=5.7,1.6Hz,1H),8.25(d,J=5.7Hz,1 H),8.02-7.95(m,1H),7.68(dq,J=4.5,2.2Hz,2H),7.56-7.49(m,2H),7.21-7.13(m,2H),2.99(s,3H),0.78(s,1H).

[0088] Example 7

[0089] N-(3-(4-chlorophenyl)pyridin-4-yl)-7-(methylsulfonylamino)quinazolin-2-carboxamide

[0090]

[0091] Compound 1e (420 mg, 1.0 mmol), compound 7a (156 mg, 1.0 mmol), tetraphenylphosphine palladium (115 mg, 0.1 mmol), and potassium carbonate (276 mg, 2.0 mmol) were dissolved in tetrahydrofuran (10 ml) and water (5 ml). The mixture was heated to 80 °C (oil bath temperature) and stirred for 10 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was extracted with acetate (2 × 50 ml). The organic layers were combined, dried, concentrated, and separated by column chromatography to give 258 mg of an off-white solid, with a yield of 59.0% and ESI(+) m / z = 454.1. 1 H-NMR (500MHz, d 6-DMSO) δ9.86(s,1H),9.73(d,J=2.2Hz,1H),8.77(d,J=1.5Hz,1H),8.46(dd,J=5.6,1.5Hz,1H),8.25(d,J=5.7Hz,1 H),8.01-7.95(m,1H),7.68(dq,J=4.5,2.2Hz,2H),7.53-7.47(m,2H),7.36-7.30(m,2H),2.99(s,3H),0.78(s,1H).

[0092] Example 8

[0093] N-(3-(4-methoxyphenyl)pyridin-4-yl)-7-(methylsulfonylamino)quinazolin-2-carboxamide

[0094] Compound 1e (420 mg, 1.0 mmol), compound 8a (152 mg, 1.0 mmol), tetraphenylphosphine palladium (115 mg, 0.1 mmol), and potassium carbonate (276 mg, 2.0 mmol) were dissolved in tetrahydrofuran (10 ml) and water (5 ml). The mixture was heated to 80 °C (oil bath temperature) and stirred for 10 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was extracted with acetate (2 × 50 ml). The organic layers were combined, dried, concentrated, and separated by column chromatography to obtain 258 mg of an off-white solid. The yield was 59.0%, and the ESI (+) m / z = 450.1. 1 H-NMR (500MHz, d 6 -DMSO) δ9.86(s,1H),9.73(d,J=2.2Hz,1H),8.74(d,J=1.6Hz,1H),8.45(dd,J=5.7,1.6Hz,1H),8.23(d,J=5.7Hz,1H),8.0 0-7.94(m,1H),7.68(dq,J=4.9,2.2Hz,2H),7.26-7.20(m,2H),6.95-6.89(m,2H),3.80(s,3H),2.99(s,3H),0.61(s,1H).

[0095] Example 9

[0096] N-(3-(4-cyanophenyl)pyridin-4-yl)-7-(methylsulfonylamino)quinazolin-2-carboxamide

[0097]

[0098] Compound 1e (420 mg, 1.0 mmol), compound 9a (147 mg, 1.0 mmol), tetraphenylphosphine palladium (115 mg, 0.1 mmol), and potassium carbonate (276 mg, 2.0 mmol) were dissolved in tetrahydrofuran (10 ml) and water (5 ml). The mixture was heated to 80 °C (oil bath temperature) and stirred for 10 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was extracted with acetate (2 × 50 ml). The organic layers were combined, dried, concentrated, and separated by column chromatography to give 293 mg of an off-white solid, with a yield of 66.0% and ESI(+) m / z = 445.1. 1 H-NMR (500MHz, d 6 -DMSO) δ9.81(s,1H),9.73(d,J=1.7Hz,1H),8.81(d,J=1.6Hz,1H),8.46(dd,J=5.7,1.6Hz,1H),8.28(d,J=5.6Hz,1 H),8.02-7.96(m,1H),7.93-7.87(m,2H),7.78-7.72(m,2H),7.68(dq,J=4.9,2.2Hz,2H),2.99(s,3H),0.76(s,1H).

[0099] Example 10

[0100] N-(3-(4-aminocarbonylphenyl)pyridin-4-yl)-7-(methylsulfonylamino)quinazolin-2-carboxamide

[0101] Compound 1e (420 mg, 1.0 mmol), compound 10a (165 mg, 1.0 mmol), tetraphenylphosphine palladium (115 mg, 0.1 mmol), and potassium carbonate (276 mg, 2.0 mmol) were dissolved in tetrahydrofuran (10 ml) and water (5 ml). The mixture was heated to 80 °C (oil bath temperature) and stirred for 10 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was extracted with acetate (2 × 50 ml). The organic layers were combined, dried, concentrated, and separated by column chromatography to give 301 mg of an off-white solid, with a yield of 65.2% and ESI(+) m / z = 463.1. 1 H-NMR (500MHz, d 6-DMSO) δ9.87(s,1H),9.74(d,J=1.7Hz,1H),8.84(d,J=1.6Hz,1H),8.46(dd,J=5.6,1.5Hz,1H),8.27(d,J=5.7Hz ,1H),8.03-7.96(m,3H),7.68(dq,J=4.1,2.2Hz,2H),7.64-7.58(m,2H),7.10(s,2H),2.99(s,3H),0.76(s,1H).

[0102] Example 11

[0103] N-(3'-Fluoro-[3,4'-Bipyridin]-4-yl)-7-(Methylsulfonylamino)quinazolin-2-carboxamide

[0104]

[0105] Compound 1e (420 mg, 1.0 mmol), compound 11a (141 mg, 1.0 mmol), tetraphenylphosphine palladium (115 mg, 0.1 mmol), and potassium carbonate (276 mg, 2.0 mmol) were dissolved in tetrahydrofuran (10 ml) and water (5 ml). The mixture was heated to 80 °C (oil bath temperature) and stirred for 10 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was extracted with acetate (2 × 50 ml). The organic layers were combined, dried, concentrated, and separated by column chromatography to give 310 mg of an off-white solid, with a yield of 70.8% and ESI(+) m / z = 439.1. 1 H-NMR (500MHz, d 6 -DMSO) δ9.97(s,1H),9.76(d,J=1.8Hz,1H),8.79(t,J=1.8Hz,1H),8.72(dd,J=5.7,1.7Hz,1H),8.57(dd,J=8.1,1.6Hz, 1H),8.45(dd,J=5.6,1.5Hz,1H),8.26(d,J=5.7Hz,1H),8.03-7.97(m,1H),7.71-7.61(m,3H),2.99(s,3H),0.71(s,1H).

[0106] Example 12

[0107] N-(2',6'-Dichloro-[3,4'-bipyridin]-4-yl)-7-(methylsulfonylamino)quinazolin-2-carboxamide

[0108]

[0109] Compound 1e (420 mg, 1.0 mmol), compound 12a (191 mg, 1.0 mmol), tetraphenylphosphine palladium (115 mg, 0.1 mmol), and potassium carbonate (276 mg, 2.0 mmol) were dissolved in tetrahydrofuran (10 ml) and water (5 ml). The mixture was heated to 80 °C (oil bath temperature) and stirred for 10 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was extracted with acetate (2 × 50 ml). The organic layers were combined, dried, concentrated, and separated by column chromatography to give 393 mg of an off-white solid, with a yield of 80.5% and ESI(+) m / z = 489.1. 1 H-NMR (500MHz, d 6 -DMSO) δ9.78-9.73(m,2H),8.82(d,J=1.6Hz,1H),8.44(dd,J=5.7,1.6Hz,1H),8.31(d,J=5.6H z,1H),8.02-7.95(m,1H),7.81(s,2H),7.68(dq,J=4.8,2.2Hz,2H),2.99(s,3H),0.54(s,1H).

[0110] Example 13

[0111] N-(3-(2-fluoro-4-methoxyphenyl)pyridin-4-yl)-7-(methylsulfonylamino)quinazolin-2-carboxamide

[0112]

[0113] Compound 1e (420 mg, 1.0 mmol), compound 13a (170 mg, 1.0 mmol), tetraphenylphosphine palladium (115 mg, 0.1 mmol), and potassium carbonate (276 mg, 2.0 mmol) were dissolved in tetrahydrofuran (10 ml) and water (5 ml). The mixture was heated to 80 °C (oil bath temperature) and stirred for 10 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was extracted with acetate (2 × 50 ml). The organic layers were combined, dried, concentrated, and separated by column chromatography to give 367 mg of an off-white solid, with a yield of 78.6% and ESI(+) m / z = 468.1. 1 H-NMR (500MHz, d 6-DMSO)δ9.96(s,1H),9.73(d,J=1.8Hz,1H),8.72(t,J=1.8Hz,1H),8.45(dd,J=5.7,1.6Hz,1H),8.24(d,J=5.7Hz,1H),8.02-7.96(m,1H),7.68(dq ,J=4.1,2.2Hz,2H),7.55(dd,J=8.4,5.0Hz,1H),6.98(dd,J=8.4,2.0Hz,1H),6.47(dd,J=7.9,1.9Hz,1H),3.82(s,3H),2.99(s,3H),0.71(s,1H).

[0114] Example 14

[0115] N-(2'-methoxy-[3,4'-bipyridine]-4-yl)-7-(methylsulfonylamino)quinazolin-2-carboxamide

[0116]

[0117] Compound 1e (420 mg, 1.0 mmol), compound 14a (153 mg, 1.0 mmol), tetraphenylphosphine palladium (115 mg, 0.1 mmol), and potassium carbonate (276 mg, 2.0 mmol) were dissolved in tetrahydrofuran (10 ml) and water (5 ml). The mixture was heated to 80 °C (oil bath temperature) and stirred for 10 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was extracted with acetate (2 × 50 ml). The organic layers were combined, dried, concentrated, and separated by column chromatography to give 344 mg of an off-white solid, with a yield of 76.4% and ESI(+) m / z = 451.1. 1 H-NMR (500MHz, d 6 -DMSO)δ9.78-9.72(m,2H),8.80(d,J=1.6Hz,1H),8.47-8.41(m,2H),8.24(d,J=5.7Hz,1H),8.02-7.96(m,1H),7 .68(h,J=2.2Hz,2H),7.36(d,J=2.0Hz,1H),7.19(dd,J=5.7,1.8Hz,1H),3.97(s,3H),2.99(s,3H),0.71(s,1H).

[0118] Example 15

[0119] N-(3-(3-aminocarbonylphenyl)pyridin-4-yl)-7-(methylsulfonylamino)quinazolin-2-carboxamide

[0120]

[0121] Compound 1e (420 mg, 1.0 mmol), compound 15a (165 mg, 1.0 mmol), tetraphenylphosphine palladium (115 mg, 0.1 mmol), and potassium carbonate (276 mg, 2.0 mmol) were dissolved in tetrahydrofuran (10 ml) and water (5 ml). The mixture was heated to 80 °C (oil bath temperature) and stirred for 10 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was extracted with acetate (2 × 50 ml). The organic layers were combined, dried, concentrated, and separated by column chromatography to give 329 mg of an off-white solid, with a yield of 71.2% and ESI(+) m / z = 463.1. 1 H-NMR (500MHz, d 6 -DMSO) δ9.89(s,1H),9.74(d,J=2.3Hz,1H),8.75(d,J=1.6Hz,1H),8.47(dd,J=5.6,1.5Hz,1H),8.28(d,J=5.6Hz,1H),8.06-7.96(m,2H),7.9 2-7.86(m,1H),7.78(ddd,J=7.7,1.8,1.1Hz,1H),7.71-7.60(m,3H),7.51(d,J=7.9Hz,1H),7.45(d,J=7.9Hz,1H),2.99(s,3H),0.79(s,1H).

[0122] Example 16

[0123] N-(5'-chloro-[3,3'-bipyridin]-4-yl)-7-(methylsulfonylamino)quinazolin-2-carboxamide

[0124]

[0125] Compound 1e (420 mg, 1.0 mmol), compound 16a (157 mg, 1.0 mmol), tetraphenylphosphine palladium (115 mg, 0.1 mmol), and potassium carbonate (276 mg, 2.0 mmol) were dissolved in tetrahydrofuran (10 ml) and water (5 ml). The mixture was heated to 80 °C (oil bath temperature) and stirred for 10 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was extracted with acetate (2 × 50 ml). The organic layers were combined, dried, concentrated, and separated by column chromatography to obtain 366 mg of an off-white solid, with a yield of 80.6% and ESI(+) m / z = 455.1. 1 H-NMR (500MHz, d 6-DMSO) δ9.93(s,1H),9.74(d,J=2.2Hz,1H),8.80(dd,J=10.8,1.6Hz,2H),8.62(d,J=1.4Hz,1H),8.48(dd,J=5. 7,1.6Hz,1H),8.33(d,J=5.5Hz,1H),8.02-7.95(m,2H),7.68(dq,J=4.4,2.2Hz,2H),2.99(s,3H),0.81(s,1H).

[0126] Example 17

[0127] 7-(Methylsulfonylamino)-N-(3-(pyrimidin-4-yl)pyridin-4-yl)quinazoline-2-carboxamide

[0128]

[0129] Compound 1e (420 mg, 1.0 mmol), compound 17a (124 mg, 1.0 mmol), tetraphenylphosphine palladium (115 mg, 0.1 mmol), and potassium carbonate (276 mg, 2.0 mmol) were dissolved in tetrahydrofuran (10 ml) and water (5 ml). The mixture was heated to 80 °C (oil bath temperature) and stirred for 10 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was extracted with acetate (2 × 50 ml). The organic layers were combined, dried, concentrated, and separated by column chromatography to obtain 348 mg of an off-white solid, with a yield of 82.7% and ESI(+) m / z = 422.1. 1 H-NMR (500MHz, d 6 -DMSO)δ9.92(s,1H),9.80(d,J=1.8Hz,1H),9.48(d,J=1.4Hz,1H),9.16(d,J=5.5Hz,1H),9.01(d,J=1.5Hz,1H),8 .49(dd,J=5.7,1.6Hz,1H),8.35(d,J=5.7Hz,1H),8.04-7.98(m,2H),7.74-7.66(m,2H),2.99(s,3H),1.24(s,1H).

[0130] Example 18

[0131] N-(2'-aminocarbonyl-[3,4'-bipyridine]-4-yl)-7-(methylsulfonylamino)quinazolin-2-carboxamide

[0132]

[0133] Compound 1e (420 mg, 1.0 mmol), compound 18a (166 mg, 1.0 mmol), tetraphenylphosphine palladium (115 mg, 0.1 mmol), and potassium carbonate (276 mg, 2.0 mmol) were dissolved in tetrahydrofuran (10 ml) and water (5 ml). The mixture was heated to 80 °C (oil bath temperature) and stirred for 10 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was extracted with acetate (2 × 50 ml). The organic layers were combined, dried, concentrated, and separated by column chromatography to give 360 ​​mg of an off-white solid, with a yield of 77.8% and ESI(+) m / z = 464.1. 1 H-NMR (500MHz, d 6 -DMSO) δ9.87(s,1H),9.81(d,J=2.1Hz,1H),9.06(d,J=5.6Hz,1H),8.81(d,J=1.6Hz,1H),8.47(dd,J=5.7,1.6Hz,1H),8.34(d,J=5.7Hz,1H) ,8.23(d,J=1.9Hz,1H),8.04-7.98(m,1H),7.83(dd,J=5.6,1.9Hz,1H),7.75-7.65(m,3H),7.57(d,J=7.9Hz,1H),2.99(s,3H),0.68(s,1H).

[0134] Example 19

[0135] 7-(cyclopropylsulfonylamino)-N-(3-(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-4-yl)quinazolin-2-carboxamide

[0136] first step:

[0137] Compound 1a (20.3 g, 100.0 mmol) and triethylamine (1.5 g, 150.0 mmol) were dissolved in dichloromethane (300 ml), cooled to 0 °C, and cyclopropylsulfonyl chloride (14.0 g, 100.0 mmol) was added dropwise. After the addition was complete, the temperature was raised to 25 °C and the reaction was maintained for 6 hours. The reaction was detected by TLC. After the reaction was complete, water (100 ml) was added to quench the reaction. The organic layer was dried, concentrated, and separated by column chromatography to obtain 20.7 g of yellow solid, with a yield of 67.4%.

[0138] Step Two:

[0139] The compound 19a (20.0 g, 65.1 mmol) obtained above was dissolved in tetrahydrofuran (200 ml) and water (100 ml). Lithium hydroxide (3.1 g, 130.2 mmol) was added at room temperature, and the mixture was stirred for 8 hours. The reaction was detected by TLC. After the reaction was completed, the reaction was quenched with dilute hydrochloric acid. The mixture was extracted with ethyl acetate (500 ml x 2), the organic layer was concentrated, and the product was separated by column chromatography to obtain 15.1 g of off-white solid, with a yield of 79.1%.

[0140] Step 3:

[0141] Compound 19b (15.0 g, 51.2 mmol), compound 1d (9.6 g, 51.2 mmol), and DIPEA (9.9 mg, 76.8 mmol) were dissolved in DMF (100 ml). HATU (29.2 g, 76.8 mmol) was added at room temperature, and the mixture was stirred for 4 hours. The reaction was monitored by TLC. After the reaction was complete, water (100 ml) was added to quench the reaction. The mixture was extracted with ethyl acetate (2 × 500 ml), and the organic layers were combined, dried, concentrated, and separated by column chromatography to give 18.2 g of an off-white solid, with a yield of 79.5%.

[0142] Step 4:

[0143] Compound 19c (447 mg, 1.0 mmol), compound 1f (152 mg, 1.0 mmol), tetraphenylphosphine palladium (115 mg, 0.1 mmol), and potassium carbonate (276 mg, 2.0 mmol) were dissolved in tetrahydrofuran (10 ml) and water (5 ml). The mixture was heated to 80 °C (oil bath temperature) and stirred for 10 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was extracted with ethyl acetate (2 × 50 ml). The organic layers were combined, dried, concentrated, and separated by column chromatography to give 299 mg of an off-white solid, with a yield of 62.9% and ESI(+) m / z = 476.1. 1 H-NMR (500MHz, d 6 -DMSO)δ9.79(d,J=1.7Hz,1H),9.28(s,1H),8.74(d,J=1.6Hz,1H),8.46(dd,J=5.7, 1.5Hz,1H),8.31(d,J=5.7Hz,1H),8.00(dd,J=8.4,1.9Hz,1H),7.82(d,J=1.5Hz,1H) ,7.75-7.67(m,2H),7.19(d,J=1.5Hz,1H),3.71(p,J=5.7Hz,1H),1.84(p,J=5.5Hz, 1H),1.11(dddd,J=10.1,8.6,5.5,1.3Hz,2H),1.02-0.87(m,4H),0.87-0.78(m,2H).

[0144] Example 20

[0145] 7-(cyclopropylsulfonylamino)-N-(3-(1-isopropyl-1H-pyrazol-4-yl)pyridin-4-yl)quinazolin-2-carboxamide

[0146]

[0147] Compound 19c (447 mg, 1.0 mmol), compound 2a (154 mg, 1.0 mmol), tetraphenylphosphine palladium (115 mg, 0.1 mmol), and potassium carbonate (276 mg, 2.0 mmol) were dissolved in tetrahydrofuran (10 ml) and water (5 ml). The mixture was heated to 80 °C (oil bath temperature) and stirred for 10 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was extracted with ethyl acetate (2 × 50 ml). The organic layers were combined, dried, concentrated, and separated by column chromatography to give 319 mg of an off-white solid, with a yield of 66.9% and ESI(+) m / z = 478.1. 1 H-NMR (500MHz, d 6 -DMSO) δ9.81(d,J=1.8Hz,1H),9.28(s,1H),8.74(d,J=1.5Hz,1H),8.47(dd,J=5.6,1.5H z,1H),8.31(d,J=5.7Hz,1H),8.05-7.99(m,1H),7.81(d,J=1.4Hz,1H),7.74-7.67(m,2H) ,7.10(d,J=1.4Hz,1H),4.55(hept,J=6.4Hz,1H),1.84(p,J=5.6Hz,1H),1.33(d,J=6.4H z,6H),1.10(dddd,J=9.9,8.4,5.6,1.7Hz,2H),1.00(dddd,J=10.6,8.8,5.5,1.8Hz,2H).

[0148] Example 21

[0149] 7-(cyclopropylsulfonylamino)-N-(3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)quinazolin-2-carboxamide

[0150]

[0151] Compound 19c (447 mg, 1.0 mmol), compound 3a (126 mg, 1.0 mmol), tetraphenylphosphine palladium (115 mg, 0.1 mmol), and potassium carbonate (276 mg, 2.0 mmol) were dissolved in tetrahydrofuran (10 ml) and water (5 ml). The mixture was heated to 80 °C (oil bath temperature) and stirred for 10 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was extracted with ethyl acetate (2 × 50 ml). The organic layers were combined, dried, concentrated, and separated by column chromatography to give 281 mg of an off-white solid, with a yield of 62.6% and ESI(+) m / z = 450.1. 1 H-NMR (500MHz, d 6 -DMSO)δ9.80(d,J=1.7Hz,1H),9.19(s,1H),8.73(d,J=1.6Hz,1H),8.46(dd,J=5 .7,1.5Hz,1H),8.28(d,J=5.6Hz,1H),8.03-7.96(m,1H),7.79(d,J=1.5Hz,1H), 7.72-7.66(m,2H),7.10(d,J=1.5Hz,1H),3.98(s,3H),1.84(p,J=5.5Hz,1H),1. 12(dddd,J=10.1,8.4,5.5,1.6Hz,2H), 1.01(dddd,J=10.4,9.0,5.5,1.6Hz,2H).

[0152] Example 22

[0153] 7-(cyclopropylsulfonylamino)-N-(3-(1-methyl-1H-pyrrolo-3-yl)pyridin-4-yl)quinazolin-2-carboxamide

[0154]

[0155] Compound 19c (447 mg, 1.0 mmol), compound 4a (125 mg, 1.0 mmol), tetraphenylphosphine palladium (115 mg, 0.1 mmol), and potassium carbonate (276 mg, 2.0 mmol) were dissolved in tetrahydrofuran (10 ml) and water (5 ml). The mixture was heated to 80 °C (oil bath temperature) and stirred for 10 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was extracted with ethyl acetate (2 × 50 ml). The organic layers were combined, dried, concentrated, and separated by column chromatography to give 268 mg of an off-white solid, with a yield of 59.8% and ESI(+) m / z = 449.1. 1 H-NMR (500MHz, d 6-DMSO) δ9.79(d,J=2.0Hz,1H),9.19(s,1H),8.67(d,J=1.6Hz,1H),8.45(dd,J=5.6,1.6 Hz,1H),8.19(d,J=5.6Hz,1H),8.05-7.98(m,1H),7.72-7.66(m,2H),7.02(d,J=4.3Hz, 1H),6.79(d,J=1.6Hz,1H),6.03(dd,J=4.2,1.5Hz,1H),3.69(s,3H),1.84(p,J=5.5Hz, 1H), 1.09 (dddd, J=10.1, 8.5, 5.5, 1.7Hz, 2H), 0.99 (dddd, J=10.5, 8.8, 5.6, 1.7Hz, 2H).

[0156] Example 23

[0157] 7-(cyclopropylsulfonylamino)-N-(3-(1-methyl1H-imidazol-4-yl)pyridin-4-yl)quinazolin-2-carboxamide

[0158]

[0159] Compound 19c (447 mg, 1.0 mmol), compound 5a (126 mg, 1.0 mmol), tetraphenylphosphine palladium (115 mg, 0.1 mmol), and potassium carbonate (276 mg, 2.0 mmol) were dissolved in tetrahydrofuran (10 ml) and water (5 ml). The mixture was heated to 80 °C (oil bath temperature) and stirred for 10 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was extracted with ethyl acetate (2 × 50 ml). The organic layers were combined, dried, concentrated, and separated by column chromatography to give 245 mg of an off-white solid, with a yield of 54.6% and ESI(+) m / z = 450.1. 1 H-NMR (500MHz, d 6 -DMSO)δ9.98(s,1H),9.79(d,J=1.7Hz,1H),9.19(s,1H),8.80(d,J=1.6Hz,1H) ,8.46(dd,J=5.7,1.6Hz,1H),8.03-7.96(m,1H),7.86(d,J=5.7Hz,1H),7.74(s ,1H),7.72-7.66(m,2H),7.23(s,1H),3.71(s,3H),1.84(p,J=5.5Hz,1H),1.12 (dddd,J=10.1,8.4,5.5,1.6Hz,2H),1.01(dddd,J=10.4,9.0,5.5,1.6Hz,2H).

[0160] Example 24

[0161] 7-(cyclopropylsulfonylamino)-N-(3-(4-fluorophenyl)pyridin-4-yl)quinazolin-2-carboxamide

[0162]

[0163] Compound 19c (447 mg, 1.0 mmol), compound 6a (140 mg, 1.0 mmol), tetraphenylphosphine palladium (115 mg, 0.1 mmol), and potassium carbonate (276 mg, 2.0 mmol) were dissolved in tetrahydrofuran (10 ml) and water (5 ml). The mixture was heated to 80 °C (oil bath temperature) and stirred for 10 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was extracted with ethyl acetate (2 × 50 ml). The organic layers were combined, dried, concentrated, and separated by column chromatography to give 297 mg of an off-white solid, with a yield of 64.1% and ESI(+) m / z = 464.1. 1 H-NMR (500MHz, d 6 -DMSO) δ9.83-9.75(m,2H),9.28(s,1H),8.74(d,J=1.6Hz,1H),8.47(dd,J=5.6,1.6Hz,1H),8.24(d,J=5.7Hz,1H),8.04-7.98(m,1H),7.7 2-7.66(m,2H),7.57-7.49(m,2H),7.21-7.13(m,2H),1.84(p,J=5.5Hz,1H),1.14(dddd,J=10.1,8.6,5.5,1.2Hz,2H),1.04-0.95(m,2H).

[0164] Example 25

[0165] N-(3-(4-chlorophenyl)pyridin-4-yl)-7-(cyclopropylsulfonylamino)quinazolin-2-carboxamide

[0166]

[0167] Compound 19c (447 mg, 1.0 mmol), compound 7a (156 mg, 1.0 mmol), tetraphenylphosphine palladium (115 mg, 0.1 mmol), and potassium carbonate (276 mg, 2.0 mmol) were dissolved in tetrahydrofuran (10 ml) and water (5 ml). The mixture was heated to 80 °C (oil bath temperature) and stirred for 10 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was extracted with ethyl acetate (2 × 50 ml). The organic layers were combined, dried, concentrated, and separated by column chromatography to give 297 mg of an off-white solid, with a yield of 64.1% and ESI(+) m / z = 480.1. 1H-NMR (500MHz, d 6 -DMSO) δ9.85(s,1H),9.73(d,J=2.0Hz,1H),9.28(s,1H),8.77(d,J=1.5Hz,1H),8.46(dd,J=5.7,1.6Hz,1H),8.25(d,J=5.7H z,1H),8.00-7.94(m,1H),7.72-7.66(m,2H),7.54-7.48(m,2H),7.36-7.31(m,2H),1.84(p,J=5.5Hz,1H),1.25-1.07(m,4H).

[0168] Example 26

[0169] 7-(cyclopropylsulfonylamino)-N-(3-(4-methoxyphenyl)pyridin-4-yl)quinazolin-2-carboxamide

[0170]

[0171] Compound 19c (447 mg, 1.0 mmol), compound 8a (152 mg, 1.0 mmol), tetraphenylphosphine palladium (115 mg, 0.1 mmol), and potassium carbonate (276 mg, 2.0 mmol) were dissolved in tetrahydrofuran (10 ml) and water (5 ml). The mixture was heated to 80 °C (oil bath temperature) and stirred for 10 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was extracted with ethyl acetate (2 × 50 ml). The organic layers were combined, dried, concentrated, and separated by column chromatography to give 297 mg of an off-white solid, with a yield of 63.4% and ESI(+) m / z = 476.1. 1 H-NMR (500MHz, d 6 -DMSO)δ9.86(s,1H),9.73(d,J=1.7Hz,1H),9.28(s,1H),8.74(d,J=1.5Hz, 1H),8.45(dd,J=5.7,1.6Hz,1H),8.23(d,J=5.7Hz,1H),7.98(dd,J=8.4,1.9 Hz,1H),7.84(d,J=2.2Hz,1H),7.71(dd,J=8.4,2.2Hz,1H),7.24-7.18(m,2H ),6.95-6.89(m,2H),3.79(s,3H),1.84(p,J=5.6Hz,1H),1.13-0.94(m,4H).

[0172] Example 27

[0173] N-(3-(4-cyanophenyl)pyridin-4-yl)-7-(cyclopropylsulfonylamino)quinazolin-2-carboxamide

[0174]

[0175] Compound 19c (447 mg, 1.0 mmol), compound 9a (147 mg, 1.0 mmol), tetraphenylphosphine palladium (115 mg, 0.1 mmol), and potassium carbonate (276 mg, 2.0 mmol) were dissolved in tetrahydrofuran (10 ml) and water (5 ml). The mixture was heated to 80 °C (oil bath temperature) and stirred for 10 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was extracted with ethyl acetate (2 × 50 ml). The organic layers were combined, dried, concentrated, and separated by column chromatography to obtain 277 mg of an off-white solid, with a yield of 58.9% and ESI(+) m / z = 471.1. 1 H-NMR (500MHz, d 6 -DMSO)δ9.75-9.69(m,2H),9.28(s,1H),8.80(d,J=1.5Hz,1H),8.47(dd,J=5.7,1.6Hz,1H),8.28(d,J=5.6Hz,1H),8.00(dd,J=8.4,1.9Hz,1H), 7.93-7.87(m,2H),7.78-7.67(m,4H),1.84(p,J=5.6Hz,1H),1.11(dddd,J=9.9,8.4,5.5,1.8Hz,2H),1.01(dddd,J=10.6,8.8,5.5,1.8Hz,2H).

[0176] Example 28

[0177] N-(3-(4-aminocarbonylphenyl)pyridin-4-yl)-7-(cyclopropylsulfonylamino)quinazolin-2-carboxamide

[0178]

[0179] Compound 19c (447 mg, 1.0 mmol), compound 10a (165 mg, 1.0 mmol), tetraphenylphosphine palladium (115 mg, 0.1 mmol), and potassium carbonate (276 mg, 2.0 mmol) were dissolved in tetrahydrofuran (10 ml) and water (5 ml). The mixture was heated to 80 °C (oil bath temperature) and stirred for 10 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was extracted with ethyl acetate (2 × 50 ml). The organic layers were combined, dried, concentrated, and separated by column chromatography to give 289 mg of an off-white solid, with a yield of 59.2% and ESI(+) m / z = 489.1. 1 H-NMR (500MHz, d6 -DMSO) δ9.88(s,1H),9.73(d,J=1.6Hz,1H),9.28(s,1H),8.83(d,J=1.6Hz,1H ),8.46(dd,J=5.6,1.5Hz,1H),8.28(d,J=5.7Hz,1H),8.02-7.95(m,3H),7.74-

[0180] 7.67(m,2H),7.64-7.58(m,2H),7.13(s,2H),1.84(p,J=5.6Hz,1H),1.11(d dddd,J=10.1,8.4,5.5,1.6Hz,2H),1.01(dddd,J=10.6,9.0,5.6,1.8Hz,2H).

[0181] Example 29

[0182] 7-(cyclopropylsulfonylamino)-N-(3'-fluoro-[3,4'-bipyridine]-4-yl)quinazolin-2-carboxamide

[0183]

[0184] Compound 19c (447 mg, 1.0 mmol), compound 11a (141 mg, 1.0 mmol), tetraphenylphosphine palladium (115 mg, 0.1 mmol), and potassium carbonate (276 mg, 2.0 mmol) were dissolved in tetrahydrofuran (10 ml) and water (5 ml). The mixture was heated to 80 °C (oil bath temperature) and stirred for 10 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was extracted with ethyl acetate (2 × 50 ml). The organic layers were combined, dried, concentrated, and separated by column chromatography to give 311 mg of an off-white solid, with a yield of 67.0% and ESI(+) m / z = 465.1. 1 H-NMR (500MHz, d 6 -DMSO) δ9.92(s,1H),9.78(d,J=1.7Hz,1H),9.28(s,1H),8.80(t,J=1.8Hz,1H),8.72(dd,J=5.6,1.6Hz,1H),8.58(dd,J=8.0,1.6Hz,1 H),8.45(dd,J=5.6,1.6Hz,1H),8.28(d,J=5.7Hz,1H),8.04-7.98(m,1H),7.72-7.62(m,3H),1.84(p,J=5.5Hz,1H),1.18-1.00(m,4H).

[0185] Example 30

[0186] 7-(cyclopropylsulfonylamino)-N-(2',6'-dichloro-[3,4'-bipyridine]-4-yl)quinazolin-2-carboxamide

[0187]

[0188] Compound 19c (447 mg, 1.0 mmol), compound 12a (191 mg, 1.0 mmol), tetraphenylphosphine palladium (115 mg, 0.1 mmol), and potassium carbonate (276 mg, 2.0 mmol) were dissolved in tetrahydrofuran (10 ml) and water (5 ml). The mixture was heated to 80 °C (oil bath temperature) and stirred for 10 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was extracted with ethyl acetate (2 × 50 ml). The organic layers were combined, dried, concentrated, and separated by column chromatography to give 315 mg of an off-white solid, with a yield of 61.3% and ESI(+) m / z = 515.1. 1 H-NMR (500MHz, d 6 -DMSO) δ9.79-9.74(m,2H),9.28(s,1H),8.82(d,J=1.6Hz,1H),8.45(dd,J=5.6,1.5Hz,1H),8.25(d,J=5 .6Hz,1H),8.01-7.95(m,1H),7.82(s,2H),7.71-7.66(m,2H),1.84(p,J=5.5Hz,1H),1.24-1.08(m,4H).

[0189] Example 31

[0190] 7-(cyclopropylsulfonylamino)-N-(3-(2-fluoro-4-methoxyphenyl)pyridin-4-yl)quinazolin-2-carboxamide

[0191]

[0192] Compound 19c (447 mg, 1.0 mmol), compound 13a (170 mg, 1.0 mmol), tetraphenylphosphine palladium (115 mg, 0.1 mmol), and potassium carbonate (276 mg, 2.0 mmol) were dissolved in tetrahydrofuran (10 ml) and water (5 ml). The mixture was heated to 80 °C (oil bath temperature) and stirred for 10 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was extracted with ethyl acetate (2 × 50 ml). The organic layers were combined, dried, concentrated, and separated by column chromatography to obtain 302 mg of an off-white solid, with a yield of 61.3% and ESI(+) m / z = 494.1. 1 H-NMR (500MHz, d 6-DMSO) δ9.89(s,1H),9.73(d,J=1.7Hz,1H),9.28(s,1H),8.72(t,J=1.8Hz,1H),8.45(dd,J=5.6 ,1.5Hz,1H),8.24(d,J=5.7Hz,1H),7.98(dd,J=8.3,1.9Hz,1H),7.74-7.67(m,2H),7.53(dd,J=8 .4,4.9Hz,1H),7.01(dd,J=8.5,1.9Hz,1H),6.42(dd,J=7.9,1.9Hz,1H),3.81(s,3H),1.84(p,J =5.6Hz,1H),1.12(dddd,J=10.1,8.6,5.5,1.5Hz,2H),1.01(dddd,J=10.4,9.0,5.5,1.6Hz,2H).

[0193] Example 32

[0194] 7-(cyclopropylsulfonylamino)-N-(2'-methoxy-[3,4'-bipyridine]-4-yl)quinazolin-2-carboxamide

[0195]

[0196] Compound 19c (447 mg, 1.0 mmol), compound 14a (153 mg, 1.0 mmol), tetraphenylphosphine palladium (115 mg, 0.1 mmol), and potassium carbonate (276 mg, 2.0 mmol) were dissolved in tetrahydrofuran (10 ml) and water (5 ml). The mixture was heated to 80 °C (oil bath temperature) and stirred for 10 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was extracted with ethyl acetate (2 × 50 ml). The organic layers were combined, dried, concentrated, and separated by column chromatography to give 321 mg of an off-white solid, with a yield of 67.4% and ESI(+) m / z = 477.1. 1 H-NMR (500MHz, d 6 -DMSO) δ9.76(d,J=1.7Hz,1H),9.68(s,1H),9.28(s,1H),8.80(d,J=1.6Hz,1 H),8.47-8.41(m,2H),8.24(d,J=5.6Hz,1H),8.00(dd,J=8.4,1.9Hz,1H),7.8 4(d,J=2.2Hz,1H),7.71(dd,J=8.4,2.2Hz,1H),7.36(d,J=1.9Hz,1H),7.21( dd,J=5.6,1.9Hz,1H),3.97(s,3H),1.84(p,J=5.6Hz,1H),1.15-0.97(m,4H).

[0197] Example 33

[0198] N-(3-(3-aminocarbonylphenyl)pyridin-4-yl)-7-(cyclopropylsulfonylamino)quinazolin-2-carboxamide

[0199]

[0200] Compound 19c (447 mg, 1.0 mmol), compound 15a (165 mg, 1.0 mmol), tetraphenylphosphine palladium (115 mg, 0.1 mmol), and potassium carbonate (276 mg, 2.0 mmol) were dissolved in tetrahydrofuran (10 ml) and water (5 ml). The mixture was heated to 80 °C (oil bath temperature) and stirred for 10 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was extracted with ethyl acetate (2 × 50 ml). The organic layers were combined, dried, concentrated, and separated by column chromatography to give 321 mg of an off-white solid, with a yield of 67.4% and ESI(+) m / z = 489.1. 1 H-NMR (500MHz, d 6 -DMSO)δ9.88(s,1H),9.74(d,J=2.2Hz,1H),9.28(s,1H),8.75(d,J=1.6Hz,1H),8.47(dd,J=5.7,1.6Hz,1H), 8.28(d,J=5.7Hz,1H),8.04(t,J=1.9Hz,1H),8.01-7.95(m,1H),7.90(ddd,J=7.7,1.8,1.1Hz,1H),7.77(ddd ,J=7.8,1.9,1.2Hz,1H),7.74-7.67(m,2H),7.63(t,J=7.8Hz,1H),7.51(d,J=7.9Hz,1H),7.45(d,J=7.9Hz,1 H), 1.84 (p, J = 5.6Hz, 1H), 1.12 (dddd, J = 10.1, 8.5, 5.5, 1.5Hz, 2H), 1.01 (dddd, J = 10.4, 9.0, 5.5, 1.6Hz, 2H).

[0201] Example 34

[0202] Biological evaluation

[0203] Example: Determination of kinase activity

[0204] Compound solution and FGFR4 kinase solution were added to a 384-well assay plate, mixed thoroughly, and incubated at room temperature for 30 minutes. Substrate reaction solution was then added, and the reaction mixture was incubated at room temperature for 60 minutes. An equal volume of assay solution was then added, mixed thoroughly, and incubated at room temperature. After 60 minutes, the enzyme reaction was terminated with EDTA, and Envision assays were performed to obtain FGFR4 activity (the group without FGFR4 protein served as a negative control, and the group with FGFR4 protein but without the compound served as a positive control). The IC50 of the compound was calculated using software.

[0205] Kinase test results: A < 100 nM, 100 nM ≤ B ≤ 1000 nM, 1000 nM ≤ C

[0206] compound IC50(FGFR4) compound IC50(FGFR4) 1 B 14 B 2 B 15 B 3 C 16 C 4 A 17 A 5 A 18 A 6 C 19 B 7 C 20 B 8 A 21 C 9 B 22 C 10 B 23 A 11 B 24 B 12 A 25 B 13 C

[0207] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A class of compounds having the structure of Formula I, stereoisomers, or pharmaceutically acceptable salts, hydrates, solvates, or isotopes thereof: in, R1 includes, but is not limited to, structures. X includes, but is not limited to, NH, NCH3, or (CH2). n Where n is 1 to 4; Y and M represent N or C, and ring A is a substituted or unsubstituted benzene ring or an aromatic heterocycle; When Z is CH2, there is no R2, W is N, and R3 includes, but is not limited to, the following structures: When W is CH2, there is no R3, Z is N, and R2 includes, but is not limited to, the following structures:

2. The method for preparing compounds, stereoisomers, or pharmaceutically acceptable salts, hydrates, solvates, or isotopic compounds having the structure of Formula I according to claim 1, characterized in that, The preparation method includes the following steps: (1) Synthesis of intermediate III: Compound II reacts with compound III at a temperature of 0°C to 80°C. The base is selected from triethylamine, diisopropylethylamine, pyridine, potassium carbonate, and cesium carbonate. The reaction solvent is dichloromethane, tetrahydrofuran, acetonitrile, or toluene. (2) Synthesis of intermediate V: Compound VI is reacted under the action of a base. The reaction is carried out at a temperature of 20°C to 80°C. The base is selected from lithium hydroxide, sodium hydroxide, and potassium hydroxide. The reaction solvent is methanol, ethanol, tetrahydrofuran / water, dioxane / water, and methanol / water. (3) Synthesis of intermediate VII: Compound V reacts with compound VI in the presence of a condensing agent. The reaction is carried out at a temperature of 20°C to 80°C. The condensing agent is selected from 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride / 1-hydroxybenzotriazole, and dicyclohexylcarbodiimide. The base is selected from triethylamine, diisopropylethylamine, and 4-dimethylaminopyridine. The reaction solvent is methanol, ethanol, tetrahydrofuran / water, dioxane / water, and methanol / water. (4) Synthesis of Compound I: Intermediate VII undergoes a coupling reaction with Compound VIII. The reaction is carried out at a temperature of 80°C to 120°C. The catalyst is selected from palladium acetate, tris(dibenzylacetone)palladium, and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride. The ligand is selected from 1,1'-binaphthyl-2,2'-bisdiphenylphosphine, 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl, and 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene. The base is selected from cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, and potassium carbonate. The reaction solvent is dioxane, N,N-dimethylformamide, and toluene.

3. A pharmaceutical composition, characterized in that, Includes compounds, stereoisomers, and their non-toxic, pharmaceutically acceptable salts, hydrates, solvates, and isotopic compounds as described in claim 1; The pharmaceutical composition further includes a pharmaceutical carrier and / or a diluent.

4. The compounds having the structure of Formula I according to claim 1, their stereoisomers, and their non-toxic pharmaceutically acceptable salts, hydrates, solvates, and pharmaceutical compositions containing these compounds as active ingredients are used as STAT3 inhibitors for the treatment of tumors.

5. A compound having the structure of Formula I as described in claim 1, its stereoisomers, and its non-toxic, pharmaceutically acceptable salts, hydrates, solvates, and isotopic compounds for the treatment of tumors.

6. The use as described in claim 3 or 4, characterized in that, The tumors are selected from skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, rectal cancer, esophageal cancer, tongue cancer, stomach cancer, kidney cancer, renal parenchymal cancer, cervical cancer, uterine cancer, endometrial cancer, testicular cancer, urinary tract cancer, melanoma, astrocytoma, meningioma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, adult T-cell leukemia lymphoma, hepatocellular carcinoma, bronchial carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell tumor, seminoma, rhabdomyosarcoma, chondrosarcoma, sarcoma, and fibrosarcoma.

7. The compound having the structure of Formula I, its stereoisomers, and its non-toxic, pharmaceutically acceptable salts, hydrates, solvates, and isotopic compounds according to claim 1, characterized in that, The compounds having the structure of Formula I are selected from the compounds of the following formulas (1)-(40):

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