Benzamide derivative, preparation method therefor, and pharmaceutical composition comprising same as active ingredient for prevention or treatment of cancer

Patent metadata

Field	Value
Publication number	US-2022281817-A1
Application number	US-202017637044-A
Country	US
Kind code	A1
Filing date	Nov 19, 2020
Priority date	Nov 19, 2019
Publication date	Sep 8, 2022
Grant date	—

Abstract

The present invention relates to a benzamide derivative, a preparation method therefor, and a pharmaceutical composition comprising same as an active ingredient for prevention or treatment of cancer. The benzamide derivative provided in an aspect of the present invention can be used for preventing or treating cancer by suppressing EGFR mutation, and exhibits a remarkable synergy effect on anticancer activity when administered in combination with an EGFR antagonist such as Cetuximab, thus finding advantageous uses as an anticancer agent.

First claim

1 . A compound, or an optical isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, having a structure according to:

wherein:
R 1 is substituted C 6-12 aryl,
wherein, the substituted C 6-12 aryl is C 6-12 aryl substituted with unsubstituted or substituted 5˜10 membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O and S,
the substituted 5˜10 membered heterocycloalkyl is C 1-15 straight or branched alkylcarbonyl, —NR 4 R 5 , or 5˜10 membered heterocycloalkyl substituted with 5˜7 membered heterocycloalkyl unsubstituted or substituted with one or more C 1-5 straight or branched alkyl containing one or more heteroatoms selected from the group consisting of N, O and S, and R 4 and R 5 are independently hydrogen or C 1-15 straight or branched alkyl;
R 2 is halogen;
R 3 is —OH, or C 1-15 straight or branched alkoxy; and
X is ═CH—, or ═N—.

2 . The compound, the optical isomer thereof, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof according to claim 1 , wherein:
R 1 is substituted C 6-12 aryl, wherein, the substituted C 6-12 aryl is C 6-12 aryl substituted with unsubstituted or substituted 5˜10 membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O and S, the substituted 5˜10 membered heterocycloalkyl is C 1-10 straight or branched alkylcarbonyl, —NR 4 R 5 , or 5˜10 membered heterocycloalkyl substituted with 6 membered heterocycloalkyl unsubstituted or substituted with one or more C 1-3 straight or branched alkyl containing one or more heteroatoms selected from the group consisting of N, O and S, and R 4 and R 5 are independently hydrogen or C 1-10 straight or branched alkyl; R 2 is halogen; R 3 is —OH, or C 1-10 straight or branched alkoxy; and X is ═CH—, or ═N—.

3 . The compound, the optical isomer thereof, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof according to claim 1 , wherein:
R 1 is

R 2 is —F, or —Cl;
R 3 is —OH; and
X is ═CH—.

4 . The compound, the optical isomer thereof, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof according to claim 1 , having a structure according to:

5 . The compound, the optical isomer thereof, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound is selected from the group consisting of the following:
(1) (R)-N-((5-fluoro-2-hydroxyphenyl)(1H-indole-2-yl)methyl)-4′-(piperazine-1-yl)-[1,1′-biphenyl]-3-carboxamide; (2) (R)-4′-(4-acetylpiperazine-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indole-2-yl)methyl)-[1,1′-biphenyl]-3-carboxamide; (3) (R)-4′-(4-aminopiperidine-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indole-2-yl)methyl)-[1,1′-biphenyl]-3-carboxamide; (4) (R)-4′-(4-aminopiperidine-1-yl)-N-((5-chloro-2-hydroxyphenyl)(1H-indole-2-yl)methyl)-[1,1′-biphenyl]-3-carboxamide; (5) (R)-N-((5-fluoro-2-hydroxyphenyl)(1H-indole-2-yl)methyl)-4′-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)-[1,1′-biphenyl]-3-carboxamide; (6) (R)-N-((5-fluoro-2-hydroxyphenyl)(1H-indole-2-yl)methyl)-4′-(4-(piperazine-1-yl)piperidine-1-yl)-[1,1′-biphenyl]-3-carboxamide; (7) (R)-4′-(4-(dimethylamino)piperidine-1-yl)-N-((5-fluoro-2-hydroxyphenyl)(1H-indole-2-yl)methyl)-[1,1′-biphenyl]-3-carboxamide; (8) (R)-N-((5-fluoro-2-hydroxyphenyl)(1H-indole-2-yl)methyl)-4′-(4-(piperidine-4-yl)piperazine-1-yl)-[1,1′-biphenyl]-3-carboxamide; (9) (R)-N-((5-fluoro-2-hydroxyphenyl)(1H-indole-2-yl)methyl)-4′-(4-(1-methylpiperidine-4-yl)piperazine-1-yl)-[1,1′-biphenyl]-3-carboxamide; (10) (R)-N-((5-fluoro-2-hydroxyphenyl)(1H-indole-2-yl)methyl)-4′-(pyrrolidine-1-yl)-[1,1′-biphenyl]-3-carboxamide; (11) 4′-((R)-3-aminopyrrolidine-1-yl)-N-((R)-(5-fluoro-2-hydroxyphenyl)(1H-indole-2-yl)methyl)-[1,1′-biphenyl]-3-carboxamide; (12) 4′-((S)-3-aminopyrrolidine-1-yl)-N-((R)-(5-fluoro-2-hydroxyphenyl)(1H-indole-2-yl)methyl)-[1,1′-biphenyl]-3-carboxamide; and (13) 4′-((S)-3-aminopyrrolidine-1-yl)-N-((R)-(5-chloro-2-hydroxyphenyl)(1H-indole-2-yl)methyl)-[1,1′-biphenyl]-3-carboxamide.

6 . A pharmaceutical composition comprising the compound of claim 1 , or an optical isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, as an active ingredient for use in preventing or treating cancer.

7 . The pharmaceutical composition according to claim 6 , wherein the compound inhibits EGFR (epidermal growth factor receptor) mutation to prevent or treat cancer.

8 . The pharmaceutical composition according to claim 7 , wherein the EGFR (epidermal growth factor receptor) mutation is at least one selected from the group consisting of EGFR L858R/T790M and EGFR L858R/T790M/C797S.

9 . The pharmaceutical composition according to claim 6 , wherein the cancer is at least one selected from the group consisting of pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testis cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycelia, acute myelogenous leukemia, acute lymphocytic leukemia, basal cell cancer, ovarian epithelial carcinoma, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampullar of vater cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, nasal cavity cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain cancer, pediatric lymphoma, pediatric leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvic cancer, renal cell carcinoma, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, primary site unknown cancer, gastric lymphoma, stomach cancer, gastric carcinoid tumor, gastrointestinal stromal tumor, Wilms cancer, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoma, vaginal cancer, spinal cord cancer, acoustic tumor, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleura cancer and thymus cancer.

10 . A health functional food composition comprising a compound represented by formula 1, an optical isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient for the prevention or amelioration of cancer.

11 . A combination preparation comprising a compound represented by formula 1, an optical isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt ther

Assignees

• Korea Res Inst Chemical Tech

Inventors

• Lee Kwangho
• Kim Jiwon
• Cho Byoung Chul
• Choi Gildon
• Yun Jiyeon
• Park Chae Won
• Duggirala Krishna Babu
• Chae Chong Hak
• Lee Seo Young
• Go A Reum

Classifications

• A61K9/0019

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title

• A61K9/1623

  Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules · CPC title

• A61K9/2018

  Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates · CPC title

• A61K9/0095

  Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches (A61K9/0007 takes precedence; eatable gels or foams A61K9/0056; oral mucosa adhesive forms A61K9/006) · CPC title

• A61P35/00

  Antineoplastic agents · CPC title