Imidazooxazole derivative having antitumor effect, and pharmaceutical composition including same

• US 10,570,155 B2
• Filed: 07/03/2017
• Issued: 02/25/2020
• Est. Priority Date: 07/05/2016
• Status: Active Grant

• Current Assignee: Korea Advanced Institute of Science and Technology
• Original Assignee: Korea Advanced Institute of Science and Technology
• Inventors: Mahmoud, Gamal El-din, Choi, Hong Seok, Yoo, Kyung Ho, Han, Dong Keun, Oh, Chang Hyun, Mohammed, Abdel-Maksoud, Mohammed, I. El-Gamal
• Primary Examiner(s): Pagano, Alexander R
• Application Number:
  US16/315,263
• Publication Number:
  US 20190211032A1
• Time in Patent Office: 967 Days
• CPC Class Codes: A61K 31/424 condensed with heterocyclic ring systems, e.g. clavulanic acid
• CPC Class Codes: A61K 31/429 condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/433 Thidiazoles
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 498/04 Ortho-condensed systems
• CPC Class Codes: C07D 513/04 Ortho-condensed systems

Abstract

Provided is a pharmaceutical composition for preventing and treating tumors, the pharmaceutical composition including an imidazooxazole derivative compound, a solvate, a stereoisomer, or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition is administered to an entity which has developed a tumor or is in danger of developing a tumor, and thus tumors can be prevented or treated.

Claims

1. A compound represented by the following Chemical Formula S or a solvate, stereoisomer, or pharmaceutically acceptable salt thereof:

2. The compound or the solvate, stereoisomer, or pharmaceutically acceptable salt thereof of claim 1, wherein,

when X is O, R¹ is hydrogen, fluoro, methoxy, or hydroxyl,

R², R³, and R⁴ are each independently hydrogen, tert-butyloxycarbonyl, ethyl, methyl, or benzyl, and

R⁵ is phenyl unsubstituted or substituted with one or more substituents, wherein the one or more substituents being selected from the group consisting of methyl, ethyl, fluoro, trifluoromethyl, hydroxyl, methoxy, nitro, amide, urea, and acetyl.

3. The compound or the solvate, stereoisomer, or pharmaceutically acceptable salt thereof of claim 1, wherein the Chemical Formula S is a compound represented by any one of the following Chemical Formulae I to IV:

4. The compound or the solvate, stereoisomer, or pharmaceutically acceptable salt thereof of claim 1, wherein the compound represented by Chemical Formula S is selected from the group consisting of:

2-(2-((4-(6-(4-fluorophenyl)imidazo[2,1-b]oxazol-5-yl)pyrimidin-2-yl)amino)ethyl)-5-methyl-1,2,5-thiadiazolidine 1,1-dioxide;

2-ethyl-5-(2-((4-(6-(4-fluorophenyl)imidazo[2,1-b]oxazol-5-yl)pyrimidin-2-yl)amino)ethyl)-1,2,5-thiadiazolidine 1,1-dioxide;

2-benzyl-5-(2-((4-(6-(4-fluorophenyl)imidazo[2,1-b]oxazol-5-yl)pyrimidin-2-yl)amino)ethyl)-1,2,5-thiadiazolidine 1,1-dioxide;

2-(2-((4-(6-(3-methoxyphenyl)imidazo[2,1-b]oxazol-5-yl)pyrimidin-2-yl)amino)ethyl)-5-methyl-1,2,5-thiadiazolidine 1,1-dioxide;

2-ethyl-5-(2-((4-(6-(3-methoxyphenyl)imidazo[2,1-b]oxazol-5-yl)pyrimidin-2-yl)amino)ethyl)-1,2,5-thiadiazolidine 1,1-dioxide;

2-benzyl-5-(2-((4-(6-(3-methoxyphenyl)imidazo[2,1-b]oxazol-5-yl)pyrimidin-2-yl)amino)ethyl)-1,2,5-thiadiazolidine 1,1-dioxide;

2-(2-((4-(6-(3-methoxyphenyl)imidazo[2,1-b]oxazol-5-yl)pyrimidin-2-yl)amino)ethyl)-1,2,5-thiadiazolidine 1,1-dioxide;

2-(2-((4-(6-(3-methoxyphenyl)imidazo[2,1-b]oxazol-5-yl)pyrimidin-2-yl)amino)ethyl)-4,4-dimethyl-1,2,5-thiadiazolidine 1,1-dioxide;

2-(2-((4-(6-(3-methoxyphenyl)imidazo[2,1-b]oxazol-5-yl)pyrimidin-2-yl)amino)ethyl)-6-methyl-1,2,6-thiadiazinane 1,1-dioxide;

2-(2-((4-(6-(3-methoxyphenyl)imidazo[2,1-b]oxazol-5-yl)pyrimidin-2-yl)amino)ethyl)-1,2,6-thiadiazinane 1,1-dioxide;

2-(2-((4-(6-(3-hydroxylphenyl)imidazo[2,1-b]oxazol-5-yl)pyrimidin-2-yl)amino)ethyl)-5-methyl-1,2,5-thiadiazolidine 1,1-dioxide;

2-ethyl-5-(2-((4-(6-(3-hydroxylphenyl)imidazo[2,1-b]oxazol-5-yl)pyrimidin-2-yl)amino)ethyl)-1,2,5-thiadiazolidine 1,1-dioxide;

2-benzyl-5-(2-((4-(6-(3-hydroxylphenyl)imidazo[2,1-b]oxazol-5-yl)pyrimidin-2-yl)amino)ethyl)-1,2,5-thiadiazolidine 1,1-dioxide;

2-(2-((4-(6-(3-hydroxylphenyl)imidazo[2,1-b]oxazol-5-yl)pyrimidin-2-yl)amino)ethyl)-1,2,5-thiadiazolidine 1,1-dioxide;

2-(2-((4-(6-(3-hydroxylphenyl)imidazo[2,1-b]oxazol-5-yl)pyrimidin-2-yl)amino)ethyl)-4,4-dimethyl-1,2,5-thiadiazolidine 1,1-dioxide;

2-(2-((4-(6-(3-hydroxylphenyl)imidazo[2,1-b]oxazol-5-yl)pyrimidin-2-yl)amino)ethyl)-6-methyl-1,2,6-thiadiazinane 1,1-dioxide;

tert-butyl-6-(2-((4-(6-(3-hydroxylphenyl)imidazo[2,1-b]oxazol-5-yl)pyrimidin-2-yl)amino)ethyl)-1,2,6-thiadiazinane-2-carboxylate 1,1-dioxide;

2-(2-((4-(6-(3-hydroxylphenyl)imidazo[2,1-b]oxazol-5-yl)pyrimidin-2-yl)amino)ethyl)-1,2,6-thiadiazinane 1,1-dioxide;

4-fluoro-N-(2-((4-(6-phenylimidazo[2,1-b]thiazol-5-yl)pyrimidin-2-yl)amino)ethyl)benzenesulfonamide;

4-methoxy-N-(2-((4-(6-phenylimidazo[2,1-b]thiazol-5-yl)pyrimidin-2-yl)amino)ethyl)benzenesulfonamide;

4-methyl-N-(2-((4-(6-phenylimidazo[2,1-b]thiazol-5-yl)pyrimidin-2-yl)amino)ethyl)benzenesulfonamide;

N-(2-((4-(6-(4-fluorophenyl)imidazo[2,1-b]oxazol-5-yl)pyrimidin-2-yl)amino)ethyl)benzenesulfonamide;

3-fluoro-N-(2-((4-(6-(4-fluorophenyl)imidazo[2,1-b]oxazol-5-yl)pyrimidin-2-yl)amino)ethyl)benzenesulfonamide;

4-fluoro-N-(2-((4-(6-(4-fluorophenyl)imidazo[2,1-b]oxazol-5-yl)pyrimidin-2-yl)amino)ethyl)benzenesulfonamide;

N-(2-((4-(6-(4-fluorophenyl)imidazo[2,1-b]oxazol-5-yl)pyrimidin-2-yl)amino)ethyl)-4-iodobenzenesulfonamide;

N-(2-((4-(6-(4-fluorophenyl)imidazo[2,1-b]oxazol-5-yl)pyrimidin-2-yl)amino)ethyl)-4-methoxybenzenesulfonamide;

N-(2-((4-(6-(4-fluorophenyl)imidazo[2,1-b]oxazol-5-yl)pyrimidin-2-yl)amino)ethyl)-4-methyl benzenesulfonamide;

N-(2-((4-(6-(4-fluorophenyl)imidazo[2,1-b]oxazol-5-yl)pyrimidin-2-yl)amino)ethyl)-4-(trifluoromethyl)benzenesulfonamide;

N-(2-((4-(6-(4-fluorophenyl)imidazo[2,1-b]oxazol-5-yl)pyrimidin-2-yl)amino)ethyl)-3,4-dimethoxybenzenesulfonamide;

N-(2-((4-(6-(4-fluorophenyl)imidazo[2,1-b]oxazol-5-yl)pyrimidin-2-yl)amino)ethyl)-3,4-dimethylbenzenesulfonamide;

N-(2-((4-(6-(4-fluorophenyl)imidazo[2,1-b]oxazol-5-yl)pyrimidin-2-yl)amino)ethyl)naphthalene-2-sulfonamide;

N-(2-((4-(6-(3-methoxyphenyl)imidazo[2,1-b]thiazol-5-yl)pyrimidin-2-yl) amino)ethyl)benzenesulfonamide;

4-fluoro-N-(2-((4-(6-(3-methoxyphenyl)imidazo[2,1-b]thiazol-5-yl)pyrimidin-2-yl)amino)ethyl)benzenesulfonamide;

4-methoxy-N-(2-((4-(6-(3-methoxyphenyl)imidazo[2,1-b]thiazol-5-yl)pyrimidin-2-yl)amino)ethyl)benzenesulfonamide;

N-(2-((4-(6-(3-methoxyphenyl)imidazo[2,1-b]thiazol-5-yl)pyrimidin-2-yl)amino)ethyl)-4-methylbenzenesulfonamide;

N-(2-((4-(6-(3-methoxyphenyl)imidazo[2,1-b]thiazol-5-yl)pyrimidin-2-yl)amino)ethyl)-4-(trifluoromethyl)benzenesulfonamide;

3-fluoro-N-(2-((4-(6-(3-methoxyphenyl)imidazo[2,1-b]thiazol-5-yl)pyrimidin-2-yl)amino)ethyl)benzenesulfonamide;

N-(2-((4-(6-(3-methoxyphenyl)imidazo[2,1-b]thiazol-5-yl)pyrimidin-2-yl)amino)ethyl)naphthalene-2-sulfonamide;

4-fluoro-N-(2-((4-(6-(4-methoxyphenyl)imidazo[2,1-b]thiazol-5-yl)pyrimidin-2-yl)amino)ethyl)benzenesulfonamide;

4-methoxy-N-(2-((4-(6-(4-methoxyphenyl)imidazo[2,1b]thiazol-5-yl)pyrimidin-2-yl)amino)ethyl)benzenesulfonamide;

N-(2-((4-(6-(4-methoxyphenyl)imidazo[2,1-b]thiazol-5-yl)pyrimidin-2-yl)amino)ethyl)-4-methylbenzenesulfonamide;

N-(2-((4-(6-(4-methoxyphenyl)imidazo[2,1-b]thiazol-5-yl)pyrimidin-2-yl)amino)ethyl)naphthalene-2-sulfonamide;

4-fluoro-N-(3-((4-(6-phenylimidazo[2,1-b]thiazol-5-yl)pyrimidin-2-yl)amino)propyl)benzenesulfonamide;

4-methoxy-N-(3-((4-(6-phenylimidazo[2,1-b]thiazol-5-yl)pyrimidin-2-yl)amino)propyl)benzenesulfonamide;

4-methyl-N-(3-((4-(6-phenylimidazo[2,1-b]thiazol-5-yl)pyrimidin-2-yl)amino)propyl)benzenesulfonamide;

N-(3-((4-(6-(4-fluorophenyl)imidazo[2,1-b]oxazol-5-yl)pyrimidin-2-yl)amino)propyl)benzenesulfonamide;

4-fluoro-N-(3-((4-(6-(4-fluorophenyl)imidazo[2,1-b]oxazol-5-yl)pyrimidin-2-yl)amino)propyl)benzenesulfonamide;

N-(3-((4-(6-(4-fluorophenyl)imidazo[2,1-b]oxazol-5-yl)pyrimidin-2-yl)amino)propyl)-4-iodobenzenesulfonamide;

N-(3-((4-(6-(4-fluorophenyl)imidazo[2,1-b]oxazol-5-yl)pyrimidin-2-yl)amino)propyl)-4-methoxybenzenesulfonamide;

N-(3-((4-(6-(4-fluorophenyl)imidazo[2,1-b]oxazol-5-yl)pyrimidin-2-yl)amino)propyl)-4-methylbenzenesulfonamide;

N-(3-((4-(6-(4-fluorophenyl)imidazo[2,1-b]oxazol-5-yl)pyrimidin-2-yl)amino)propyl)-4-(trifluoromethyl)benzenesulfonamide;

3-fluoro-N-(3-((4-(6-(4-fluorophenyl)imidazo[2,1-b]oxazol-5-yl)pyrimidin-2-yl)amino)propyl)benzenesulfonamide;

N-(3-((4-(6-(4-fluorophenyl)imidazo[2,1-b]oxazol-5-yl)pyrimidin-2-yl)amino)propyl)-3,4-dimethoxybenzenesulfonamide;

N-(3-((4-(6-(4-fluorophenyl)imidazo[2,1-b]oxazol-5-yl)pyrimidin-2-yl)amino)propyl)-3,4-dimethylbenzenesulfonamide;

N-(3-((4-(6-(4-fluorophenyl)imidazo[2,1-b]oxazol-5-yl)pyrimidin-2-yl)amino)propyl)naphthalene-2-sulfonamide;

N-(3-((4-(6-(3-methoxyphenyl)imidazo[2,1-b]thiazol-5-yl) pyrimidin-2-yl)amino)propyl)benzenesulfonamide;

3-fluoro-N-(3-((4-(6-(3-methoxyphenyl)imidazo[2,1-b]thiazol-5-yl)pyrimidin-2-yl)amino)propyl)benzenesulfonamide;

4-fluoro-N-(3-((4-(6-(3-methoxyphenyl)imidazo[2,1-b]thiazol-5-yl)pyrimidin-2-yl)amino)propyl)benzenesulfonamide;

4-methoxy-N-(3-((4-(6-(3-methoxyphenyl)imidazo[2,1-b]thiazol-5-yl)pyrimidin-2-yl)amino)propyl)benzenesulfonamide;

N-(3-((4-(6-(3-methoxyphenyl)imidazo[2,1-b]thiazol-5-yl)pyrimidin-2-yl)amino)propyl)-4-methylbenzenesulfonamide;

N-(3-((4-(6-(3-methoxyphenyl)imidazo[2,1-b]thiazol-5-yl)pyrimidin-2-yl)amino)propyl)naphthalene-2-sulfonamide;

4-hydroxyl-N-(2-((4-(6-phenylimidazo[2,1-b]thiazol-5-yl)pyrimidin-2-yl)amino)ethyl)benzenesulfonamide;

N-(2-((4-(6-(4-fluorophenyl)imidazo[2,1-b]oxazol-5-yl)pyrimidin-2-yl)amino)ethyl)-4-hydroxylbenzenesulfonamide;

4-fluoro-N-(2-((4-(6-(3-hydroxylphenyl)imidazo[2,1-b]thiazol-5-yl)pyrimidin-2-yl)amino)ethyl)benzenesulfonamide;

4-hydroxyl-N-(2-((4-(6-(3-hydroxylphenyl)imidazo[2,1-b]thiazol-5-yl)pyrimidin-2-yl)amino)ethyl)benzenesulfonamide;

N-(2-((4-(6-(3-hydroxylphenyl)imidazo[2,1-b]thiazol-5-yl)pyrimidin-2-yl)amino)ethyl)-4-methylbenzenesulfonamide;

4-hydroxyl-N-(2-((4-(6-(4-hydroxylphenyl)imidazo[2,1-b]thiazol-5-yl)pyrimidin-2-yl)amino)ethyl)benzenesulfonamide;

N-(2-((4-(6-(4-hydroxylphenyl)imidazo[2,1-b]thiazol-5-yl)pyrimidin-2-yl)amino)ethylbenzenesulfonamide;

N-(3-((4-(6-(4-fluorophenyl)imidazo[2,1-b]oxazol-5-yl)pyrimidin-2-yl)amino)propyl)-4-hydroxylbenzenesulfonamide;

N-(3-((4-(6-(3-hydroxylphenyl)imidazo[2,1-b]thiazol-5-yl)pyrimidin-2-yl)amino)propyl)benzenesulfonamide; and

4-fluoro-N-(3-((4-(6-(3-hydroxylphenyl)imidazo[2,1-b]thiazol-5-yl)pyrimidin-2-yl)amino)propyl)benzenesulfonamide.

5. A method of preparing the compound or the solvate, stereoisomer, or pharmaceutically acceptable salt thereof of claim 1, the method comprising:

cyclizing a compound of Chemical Formula 1 and a compound of Chemical Formula 2 to prepare a compound of Chemical Formula 3;

reacting the compound of Chemical Formula 3 with 4-chloro-2-(methylthio)pyrimidine to prepare a compound of Chemical Formula 4;

oxidizing the compound of Chemical Formula 4 to prepare a compound of Chemical Formula 5; and

reacting the compound of Chemical Formula 5 with an N-aminoethylcyclic sulfonamide derivative or an N-(2-aminoethyl)benzenesulfonamide derivative in the presence of a base to prepare the compound of Chemical Formula S;

6. A pharmaceutical composition for preventing and treating a tumor, the pharmaceutical composition comprising the compound or the solvate, stereoisomer, or pharmaceutically acceptable salt thereof of claim 1 as an active ingredient.

7. The pharmaceutical composition of claim 6, wherein the compound or the solvate, stereoisomer, or pharmaceutically acceptable salt thereof inhibits protein kinase to inhibit proliferation of tumor cells.

8. The pharmaceutical composition of claim 7, wherein the protein kinase is selected from the group consisting of V600E RAF, B-RAF, C-RAF, mitogen-activated protein kinase 14 (MAPK14), Fms-like tyrosine kinase 3 (FLT3), and glycogen synthase kinase 3 beta (GSK313).

9. The pharmaceutical composition of claim 6, wherein the tumor is selected from the group consisting of lung cancer, liver cancer, esophageal cancer, stomach cancer, colorectal cancer, small intestine cancer, pancreatic cancer, melanoma, breast cancer, oral cancer, brain tumor, thyroid cancer, parathyroid cancer, renal cancer, cervical cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer, testicular cancer, hematological malignancy, lymphoma, skin cancer, psoriasis, and fibroadenoma.

10. A method of preventing or treating a tumor, the method comprising administering the pharmaceutical composition of claim 6 to a subject having or at risk of developing a tumor.