EP-3398939-B1 - ACRYLANILIDE DERIVATIVE, PREPARATION METHOD THEREFOR, AND APPLICATIONS THEREOF IN PHARMACY

Inventors

• SI, JUTONG
• WANG, GUAN
• YANG, Zhihe
• JIANG, Meifeng
• XU, Benpo
• ZHOU, Chentao

Dates

Publication Date

20260506

Application Date

20161230

Claims (9)

1. A compound of formula (I) or the pharmaceutically acceptable salts or solvates thereof: wherein: R 1 is -NR 5 R 6 , X is CR 4 and Y is N; R 2 is selected from the group consisting of (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylsulphanyl and NR 6 R 6 ; R 3 is selected from the group consisting of hydrogen, N(R y )(R z ), -N(R v )R u N(R y )(R z ), -OR u OR 6 , -OR u N(R y )(R z ), -SR 6 and -SR u N(R y )(R z ); R 4 and R' 4 are each selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl and cyano; R 5 is optionally substituted phenyl; when substituted, the substituent is selected from 1~5 R 7 groups; wherein each R 7 group is independently selected from the group consisting of halogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, aryl, aryl(C 1 -C 6 )alkyl, heterocyclyl; wherein the (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, is optionally substituted with 1-5 groups selected from halogen, hydroxyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylamino, pyrrolidinyl, phenyl, pyridinyl and halophenyl; R 6 is selected from hydrogen and (C 1 -C 6 )alkyl; R u is each independently selected from the group consisting of (C 1 -C 6 )alkylene, (C 2 -C 6 )alkenylene and (C 2 -C 6 )alkynylene; R v is selected from hydrogen and (C 1 -C 6 )alkyl; R y and R z are each independently selected from the following a) or b): a) R y and R z are each independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 10 )cycloalkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, hydroxyl(C 1 -C 6 )alkyl, pyrrolidinyl, (C 1 -C 6 )alkylamino and halo(C 1 -C 6 )alkyl; b) R y and R z form a 3- to 9-membered heterocyclyl together with the nitrogen atom attached to them, wherein the 3- to 9-membered heterocyclyl is optionally substituted with 1-4 groups selected from R 5 and R 7 .
2. The compound or the pharmaceutically acceptable salts or solvates thereof according to claim 1, which is characterized in that the compound of formula (I) is the compound of formula (IIc): R 2 is (C 1 -C 6 )alkoxy; R 3 is selected from the group consisting of hydrogen, N(R y )(R z ), -N(R v )R u N(R y )(R z ), -OR u OR 6 , and -OR u N(R y )(R z ); R 4 is hydrogen; R' 4 is selected from the group consisting of hydrogen, halogen, (C 1 -C 6 )alkyl and halo(C 1 -C 6 )alkyl; R 5 and R 6 are as defined in claim 1; R u is each independently (C 1 -C 6 )alkylene; R v is selected from hydrogen and (C 1 -C 6 )alkyl; Ry and Rz are each independently selected from the following a) or b): a) R y and R z are each selected from hydrogen, (C 1 -C 6 )alkyl and halo(C 1 -C 6 )alkyl; b) R y and R z form a 3- to 9-membered heterocyclyl together with the nitrogen atom attached to them, wherein the 3- to 9-membered heterocyclyl is optionally substituted with 1-4 groups selected from halogen, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylhydroxyl, NR 6 R 6 and heterocyclyl.
3. The compound or the pharmaceutically acceptable salts or solvates thereof according to claim 2, wherein the compound of formula (IIc) is the compound of formula (VII): wherein, R 7 a , R 7 b , R 7 c , R 7 d and R 7 e are identical or different from each other, and are each independently selected from the group consisting of halogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, aryl, aryl(C 1 -C 6 )alkyl, heterocyclyl; wherein the (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, is optionally substituted with 1-5 groups selected from the group consisting of halogen, (C 1 -C 6 )alkyl, and (C 1 -C 6 )alkoxy; R 2 and R 3 are as defined in claim 2.
4. The compound or the pharmaceutically acceptable salts, or solvates thereof according to claim 3 wherein in the compound of formula (VII): is selected from : R 3 is selected from:
5. The compound or the pharmaceutically acceptable salts thereof according to claim 1, wherein the compound is selected from the group consisting of: N-(5-(6-(3-bromo-phenylamino)-pyrimidin-4-ylamino)-2-((2-dimethylamino-ethyl)-met hyl-amino)-4-methoxyl-phenyl)-acrylamide; N-(2-((2-dimethylamino)-ethyl)-methyl-amino)-4-methoxyl-5-(6-(3-trifluoromethyl-phe nylamino)-pyrimidin-4-ylamino)-phenyl)-acrylamide; N-(5-(6-(3-alkynyl-phenylamino)-pyrimidin-4-ylamino)-2-((2-dimethylamino-ethyl)-m ethyl-amino)-4-methoxyl-phenyl)-acrylamide; N-(5-(6-(2,,4-dichloro-5-methoxyl-phenylamino)-pyrimidin-4-ylamino)-2-((2-dimethyl amino-ethyl)-methyl-amino)-4-methoxyl-phenyl)-acrylamide; N-(5-(6-(2-fluoro-3,4-dichloro-phenylamino)-pyrimidin-4-ylamino)-2-((2-dimethylamin o-ethyl)-methyl-amino)-4-methoxyl-phenyl)-acrylamide; N-(5-(6-(2-fluoro-3-chloro-phenylamino)-pyrimidin-4-ylamino)-2-((2-dimethylamino-et hyl)-methyl-amino)-4-methoxyl-phenyl)-acrylamide; N-(5-(6-(3-bromo-5-fluoro-phenylamino)-pyrimidin-4-ylamino)-2-((2-dimethylamino-e thyl)-methyl-amino)-4-methoxyl-phenyl)-acrylamide; N-(5-(6-(3-chloro-4-fluoro-phenylamino)-pyrimidin-4-ylamino)-2-((2-dimethylamino-et hyl)-methyl-amino)-4-methoxyl-phenyl)-acrylamide; N-(5-(6-(3-chloro-4-fluoro-phenylamino)-2-methyl-pyrimidin-4-ylamino)-2-((2-dimeth ylamino-ethyl)-methyl-amino)-4-methoxyl-phenyl)-acrylamide; N-(5-(6-(3-chloro-4-fluoro-phenylamino)-pyrimidin-4-ylamino)-2-[piperidin-1-yl]-4-me thoxyl-phenyl)-acrylamide; N-(5-(6-(3-chloro-4-fluoro-phenylamino)-pyrimidin-4-ylamino)-4-methoxyl-2-(4-morp holin-4-yl-piperidin-1-yl)-phenyl)-acrylamide; N-(5-(6-(3-chloro-4-fluoro-phenylamino)-pyrimidin-4-ylamino)-2-(4-methyl-[1,4]diaze pin-1-yl)-4-methoxyl-phenyl)-acrylamide; N-(5-(6-(3-chloro-4-fluoro-phenylamino)-pyrimidin-4-ylamino)-4-methoxyl-2-(4-meth yl-piperazin-1-yl)-phenyl)-acrylamide; N-(5-(6-(3-chloro-4-fluoro-phenylamino)-pyrimidin-4-ylamino)-4-methoxyl-2-(4-(1-me thylpiperidin-4-yl)-piperazin-1-yl)-phenyl)-acrylamide; N-(5-(6-(3-chloro-4-fluoro-phenylamino)-pyrimidin-4-ylamino)-2-(2-dimethylamino-et hoxyl)-4-methoxyl-phenyl)-acrylamide; N-(5-(6-(3-chloro-4-fluoro-phenylamino)-pyrimidin-4-ylamino)-4-methoxyl-2-(2-pyrrol idin-1-yl-ethoxyl)-phenyl)-acrylamide; N-(5-(6-(3-chloro-4-fluoro-phenylamino)-pyrimidin-4-ylamino)-2-(2-(4-methyl-piperaz in-1 yl)-ethoxyl)-4-methoxyl-phenyl)-acrylamide; N-(5-(6-(3-chloro-4-fluoro-phenylamino)-pyrimidin-4-ylamino)-4-methoxyl-2-(2-morp holin-4-yl-ethoxyl)-phenyl)-acrylamide; N-(5-(6-(3-chloro-4-fluoro-phenylamino)-pyrimidin-4-ylamino)-2-(2-methoxylethoxyl) -4-methoxyl-phenyl)-acrylamide; N-(5-(6-(3-chloro-4-(2-morpholin-4-yl-ethoxyl)-phenylamino)-pyrimidin-4-ylamino)-2-((2-dimethylaminoethyl)-methyl-amino)-4-methoxyphenyl)-acrylamide; N-(5-(6-(3-(1-(3-methylbutoxy)ethyl)-4-methoxylphenylamino)-pyrimidin-4-ylamino)-2-((2-dimethylaminoethyl)-methyl-amino)-4-methoxylphenylamino)-acrylamide; N-(5-(6-(3-chloro-4-methoxyl-phenylamino)-pyrimidin-4-ylamino)-2-(2-dimethylamino -ethoxyl)-4-methoxyl-phenyl)-acrylamide; N-(5-(6-(3-chloro-4-(3-methylbutoxy)-phenylamino)-pyrimidin-4-ylamino)-2-((2-dimet hylaminoethyl)-methyl-amino)-4-methoxyphenyl)-acrylamide; N-(5-(6-(4-methoxyl-3-trifluoromethyl-phenylamino)-pyrimidin-4-yl-amino)-2-((2-dim ethylamino-ethyl)-methyl-amino)-4-methoxyl-phenyl)-acrylamide; N-(5-(6-(4-methoxyl-3-bromo-phenylamino)-pyrimidin-4-yl-amino)-2-((2-dimethylami no-ethyl)-methyl-amino)-4-methoxyl-phenyl)-acrylamide; N-(5-(6-(4-methoxyl-3-chloro-phenylamino)-pyrimidin-4-yl-amino)-2-(2-(pyrrolidin-1-yl)-ethoxyl)-4-methoxyl-phenyl)-acrylamide; N-(5-(6-(4-fluoro-3-trifluoromethyl-phenylamino)-pyrimidin-4-yl-amino)-2-((2-dimeth ylamino-ethyl)-methyl-amino)-4-methoxyl-phenyl)-acrylamide; N-(5-(6-(3-chloro-4-methoxyl-phenylamino)-pyrimidin-4-ylamino)-2-(4-(1-methylpiper idin-4-yl)-piperazin-1-yl)-4-methoxyl-phenyl)-acrylamide; N-(5-(6-(4-chloro-3-trifluoromethyl-phenylamino)-pyrimidin-4-yl-amino)-2-((2-dimeth ylamino-ethyl)-methyl-amino)-4-methoxyl-phenyl)-acrylamide; N-(5-(6-(5-fluoro-3-trifluoromethyl-phenylamino)-pyrimidin-4-yl-amino)-2-((2-dimeth ylamino-ethyl)-methyl-amino)-4-methoxyl-phenyl)-acrylamide; N-(5-(6-(2-fluoro-5-trifluoromethyl-phenylamino)-pyrimidin-4-yl-amino)-2-((2-dimeth ylamino-ethyl)-methyl-amino)-4-methoxyl-phenyl)-acrylamide; N-(5-(6-(3-methoxyl-5-trifluoromethyl-phenylamino)-pyrimidin-4-yl-amino)-2-((2-dim ethylamino-ethyl)-methyl-amino)-4-methoxyl-phenyl)-acrylamide; N-(5-(6-(2-methoxyl-5-trifluoromethyl-phenylamino)-pyrimidin-4-yl-amino)-2-((2-dim ethylamino-ethyl)-methyl-amino)-4-methoxyl-phenyl)-acrylamide; N-(5-(6-(3-chloro-4-trifluoromethyl-phenylamino)-pyrimidin-4-yl-amino)-2-((2-dimeth ylamino-ethyl)-methyl-amino)-4-methoxyl-phenyl)-acrylamide; N-(5-(6-(3-chloro-5-fluoro-4-methoxyphenylamino)-pyrimidin-4-yl-amino)-2-((2-dimethylaminoethyl)-methyl-amino)-4-methoxyl-phenyl)-acrylamide N-(5-(6-(3-chloro-5-fluoro-4-(2-methoxyl-ethoxyl)-phenylamino)-pyrimidin-4-yl-amin o)-2-((2-dimethylamino-ethyl)-methyl-amino)-4-methoxyl-phenyl)-acrylamide; N-(5-(6-(2,4-dichloro-5-methoxyl-phenylamino)-pyrimidin-4-yl-amino)-2-(4-methyl-pi perazin-1-yl)-4-methoxyl-phenyl)-acrylamide; N-(5-(6-(2,4-dichloro-5-methoxyl-phenylamino)-pyrimidin-4-yl-amino)-2-(4-(morpholi n-1-yl)-piperidin-1-yl)-4-methoxyl-phenyl)-acrylamide; N-(5-(6-(2,4-dichloro-5-methoxyl-phenylamino)-pyrimidin-4-ylamino)-2-(2-dimethyla mino-ethoxyl)-4-methoxyl-phenyl)-acrylamide; N-(5-(6-(2,4-dichloro-5-methoxyl-phenylamino)-pyrimidin-4-yl-amino)-2-(2-(morpholi n-4-yl)-ethoxyl-4-methoxyl-phenyl)-acrylamide; N-(5-(6-(2,4-dichloro-5-methoxyl-phenylamino)-pyrimidin-4-yl-amino)-2-(2-(pyrrolidi n-1-yl)-ethoxyl)-4-methoxyl-phenyl)-acrylamide; N-(5-(6-(2,4-dichloro-5-methoxyl-phenylamino)-pyrimidin-4-yl-amino)-2-(2-(4-methyl -piperazin-1-yl)-ethoxyl)-4-methoxyl-phenyl)-acrylamide; N-(5-(6-(2,4-dichloro-5-methoxyl-phenylamino)-pyrimidin-4-yl-amino)-2-(3-(pyrrolidi n-1-yl)-propyl)-4-methoxyl-phenyl)-acrylamide; N-(5-(6-(2,4-dichloro-5-methoxyl-phenylamino)-pyrimidin-4-yl-amino)-2-(2-(piperidin -1-yl)-ethoxyl-4-methoxyl-phenyl)-acrylamide; N-(5-(6-(2,4-dichloro-5-methoxyl-phenylamino)-pyrimidin-4-yl-amino)-2-(3-(4-methyl -piperazin-1-yl)- propyl)-4-methoxyl-phenyl)-acrylamide; N-(5-(6-((2,4-dichloro-5-methoxyl-phenyl)-methyl-amino)-pyrimidin-4-ylamino)-2-((2-dimethylamino-ethyl)-methyl-amino)-4-methoxyl-phenyl)-acrylamide; N-(5-(6-(3-chloro-4-tert-butoxy-phenylamino)-pyrimidin-4-yl-amino)-2-((2-dimethylam ino-ethyl)-methyl-amino)-4-methoxyl-phenyl)-acrylamide; N-(5-(6-(3-acetenyl-4-methoxyl-phenylamino)-pyrimidin-4-yl-amino)-2-((2-dimethyla mino-ethyl)-methyl-amino)-4-methoxyl-phenyl)-acrylamide.
6. A compound or a pharmaceutically acceptable salt thereof, which is selected from: N-(2-(4-acetyl-piperazin-1-yl)-5-(6-(3-chloro-4-fluoro-phenylamino)-pyrimidin-4-yl-amino)-4-methoxyl-phenyl)-acrylamide; N-(5-(6-(3-chloro-4-(3-fluoro-benzyloxy)-phenylamino)-pyrimidin-4-ylamino)-2-((2-dimethylamino-ethyl)-methyl-amino)-4-methoxyl-phenyl)-acrylamide; N-(5-(6-(3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino)-pyrimidin-4-ylamino)-2-((2-dimethylamino-ethyl)-methyl-amino)-4-methoxyl-phenyl)-acrylamide; N-(5-(6-(3-chloro-4-(tetrahydropyran-4-yl-methoxyl)-phenylamino)-pyrimidin-4-yl-amino)-2-((2-dimethylaminoethyl)-methyl-amino)-4-methoxyphenyl)-acrylamide; 5-(6-(5-acrylamido-4-((2-methoxyphenyl)-methyl-amino)-2-methoxylphenylamino)-pyrimidin-4-yl)-2-methoxybenzamide; 5-(6-(5-acrylamido-4-((2-methoxyphenyl)-methyl-amino)-2-methoxylphenylamino)-pyrimidin-4-yl)-2-methoxyl-N-methylbenzamide; N-(5-(6-(3-chloro-4-(thiazol-2-ylmethoxy)-phenylamino)-pyrimidin-4-ylamino)-2-((2-dimethylamino-ethyl)-methyl-amino)-4-methoxyl-phenyl)-acrylamide; N-(5-(6-(3-cyano-phenylamino)-pyrimidin-4-yl-amino)-2-((2-dimethylamino-ethyl)-methyl-amino)-4-methoxyl-phenyl)-acrylamide; N-(5-(6-(3-methanesulfonamido-4-methoxyl-phenylamino)-pyrimidin-4-yl-amino)-2-((2-dimethylamino-ethyl)-methyl-amino)-4-methoxyl-phenyl)-acrylamide; N-(5-(6-(2,4-dichloro-5-methoxyl-phenylamino)-pyrimidin-4-yl-amino)-2-(methyl-(2-(4-methyl-piperazin-1-yl)- 2-oxoethyl)-amino)-4-methoxyl-phenyl)-acrylamide; and N-(5-(6-(3-chloro-4-(3-methyl-oxetan-3-yl-methoxyl)-phenylamino)-pyrimidin-4-yl-amino)-2-((2-dimethylamino-ethyl)-methyl-amino)-4-methoxyl-phenyl)-acrylamide.
7. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 as active ingredient.
8. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 for use in the prevention or treatment of cancers.
9. A pharmaceutical composition according to claim 7 for use in the prevention or treatment of cancers.

Description

FIELD OF THE INVENTION The present invention relates to epidermal growth factor receptor (EGFR) protein tyrosine kinase (PTK) family inhibitors and the pharmaceutical applications thereof. BACKGROUND OF THE INVENTION Tumor, including leukemia, is one of the major diseases causing human clinical death. The mortality rate of malignant tumors is extremely high in lung cancer, gastric cancer, breast cancer, pancreatic cancer, liver cancer, intestinal cancer and esophagus cancer. So far, there are still no effective therapeutic drugs or methods that can completely eradicate or cure cancer. There is an urgent need for high-quality anticancer drugs with good specificity, high activity, low toxicity and none drug resistance in clinical applications. The incidence, development, metastasis and deterioration of cancer are related to many factors. The abnormality of signal transduction cascades in normal cells, especially that of the multi-functional signal transduction pathways mediated by transmembrane receptor, is one of the major factors leading to cell transformation and cancerization. Protein tyrosine kinases (PTKs) are enzymes that catalyze the phosphorylation of tyrosine residues of proteins and are necessary for multi-physiological functions of cells such as growth, development, differentiation, metabolism, aging and apoptosis. In general, PTKs can be classified into two categories: membrane receptor and cytoplasmic PTKs. PTK abnormalities can directly lead to different clinical diseases, for example, cancers, inflammations, autoimmune diseases, neurological or cardiovascular diseases. After decades of continuous efforts, people have identified many PTKs, such as EGFR, HER2/3/4, VEGFR, PDGFR, Met, IGF-1R, FGFR, CSF-1R, Trk receptor, Ephrin receptor, TAM receptor, Tie-2, FLT-3, RET, ALK, BCR-ABL, JAKs, SRC, FAK, BTK, SYK and BLK , that can be as drugable molecules for different diseases clinically. Some of such PTK inhibitors have been successfully applied in clinical practice and have demonstrated good therapeutic effects. EGFR is a member of the EGFR family that includes four transmermbrane receptor protein tyrosine kinases: EGFR (HER1/ErbB1), HER2/ErbB2, BER3/ErbB3 and BER4/ErbB4. EGFR family kinases mediate important multiple signaling pathways in cells. They can control and regulate many physiological functions of cells. Basic science researches, big genomic and clinical data indicate that genetic abnormalities of EGFR, HER2, HER3 and HER4, such as point mutation, deletion, amplification and overexpression may not only directly lead to cell malignant transformation and tumorigenesis, but also they are closely related to the proliferation, invasion, survival, metastasis, infiltration, angiogenesis and drug resistance of tumor cells. In clinical practice, EGFR abnormal genetic variations (overexpression, point mutation, deletion, insertion, etc.) often present in patients with different cancers, especially lung cancer. Lung cancer is a kind of malignant solid tumor with extremely high death rate. Non-small-cell lung carcinoma (NSCLC), mainly including adenocarcinoma, squamous-cell carcinoma and large cell carcinoma, accounts for about 80% of the entire lung cancer family, and high-frequency variation of EGFR often occurs in NSCLC, leading to the constitutive activation of the signaling pathways mediated by it and cell cancerization. Similarly, the genetic abnormalities of HER2/ErbB2 (such as mutation, amplification and overexpression) occur in patients with NSCLC, especially the patients showing amplification and/or overexpression of HER2/ErbB2. Besides NSCLC, the aberrations of HER2/ErbB2 frequently occur in many other cancers, some of which are even up to over 30%, such as breast cancer (20%), gastric cancer (22~25%), esophagus cancer (10~25%), pancreatic cancer (2~30%), bladder carcinoma (5~ 15%), salivary duct carcinoma (15~37%), cervical cancer (1~21%), malignant glioma (7~15%), followed by NSCLC (5%), colorectal cancer (2~3%), ovarian cancer (6~ 7%), head and neck cancer (3%), hepatocellular carcinoma (2.4%) and melanoma (0-5%). In addition, HER2 amplification and /or overexpression degree is not only positively correlated with the malignancy grade of the tumor, but also associated with acquired drug resistance of many chemotherapeutics, such as Paclitaxel/Oxaliplatin. EGFR and HER2 have been used as drugable targets for the development of anti-cancer drugs. Up to now, a variety of new anti-cancer drugs have been successfully developed or developing, such as macromolecular monoclonal antibodies, including Cetuximab, Panitumumab and Herceptin, which target on the extracellular domain of EGFR/HER2 protein molecules, and small molecule inhibitors, such as Gefitinib, Erlotinib and Lapatinib, which work on the intracellular kinase domain of EGFR/HER2 protein molecules. They have been applied clinically for years, and have achieved good therapeutic effects. Like many other anti-cancer drugs, however, EGFR dr