Imidazolyl derivatives that bind to dinitrophenyl, and their use

Abstract

The present invention relates to a compound represented by formula (I), its stereoisomer, deuterated derivative, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of its stereoisomer or a pharmaceutically acceptable salt of its deuterated derivative, and pharmaceutical compositions containing these compounds, as well as the use thereof. [Formula 1] TIFF2026520571000092.tif66164

Claims

【Request Item 1】 【Chemistry 1】 R １ In each occurrence, independently, -C １－３ Alkyl and -C ２－３ Selected from alkoxyalkyl groups; The aforementioned R １ This is 1, 2, 3, 4, 5, 6 or 7 R １１ It may be replaced by; Said R １１ is selected from deuterium, -C ２－３ alkoxyalkyl, and -O(C １－３ alkyl); When R １１ is -C ２－３ alkoxyalkyl or -O(C １－３ alkyl), said R １１ may be substituted by one or more deuteriums; R ４ In each occurrence, independently, -H, -D, halogen, and -C appear. １－３ Alkyl, halogenated C １－３ Alkyl, -C ２－３ Alkoxyalkyl, -C ２－３ Alkenyl, -C ２－３ Alkinyl, -CN, -NH ２ , -C(=O)OH, -NH(C １－３ Alkyl), -N(C １－３ Alkyl) ２ -OH, -O(C) １－３ Alkyl), -O (halogenated C １－３ Alkyl), -SH, -S(C １－３ Alkyl), -C (=O) (C １－３ Alkyl), -S (=O) (C １－３ Alkyl), and -S (=O) ２ (C １－３ Selected from alkyl; R ４ If is not -H, -D, halogen, or -CN, then R ４ may be substituted with one or more deuterium atoms; and, R ２ and R ３ These are independently -H, -D, halogen, and -C. １－３ Alkyl and halogenated C １－３ Selected from alkyl groups, R ２ or R ３ ga-C １－３ Alkyl or -halogenated C １－３ If it is alkyl, then R ２ or R ３ A compound represented by formula (I), wherein (I) may be substituted with one or more deuterium atoms; a deuterated derivative thereof; a stereoisomer thereof; a pharmaceutically acceptable salt thereof; a pharmaceutically acceptable salt of a stereoisomer; or a pharmaceutically acceptable salt of a deuterated derivative thereof.

2. R １ In each occurrence, independently, -C １－３ Selected from alkyl; the R １ may be substituted with 1, 2, 3, 4, 5, 6 or 7 deuterium atoms; and R １ ga-CH ３ In that case, the -CH ３ The compound represented by formula (I) according to claim 1, substituted with one, two, or three deuterium atoms, a deuterated derivative thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer, or a pharmaceutically acceptable salt of a deuterated derivative.

3. R １ In each occurrence, independently, -CD ３ ien-CH ２ CH ３ , 【Chemistry 2】 -CH ２ CH ２ CH ３ ien-CH ２ CH ２ CD ３ ien-CH ２ CD ２ CD ３ , -CD ２ CD ２ CD ３ , -CH(CH ３ ) ２ , -CD (CH ３ ) ２ , and -CD (CD ３ ) ２ A compound represented by formula (I) according to claim 1 or 2, selected from, a deuterated derivative thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer, or a pharmaceutically acceptable salt of a deuterated derivative.

4. R １ In each occurrence, independently, -CH ３ Selected from, and the -CH ３ A compound represented by formula (I) according to any one of claims 1 to 3, wherein is substituted with 1, 2, or 3 deuterium atoms; a deuterated derivative thereof; a stereoisomer thereof; a pharmaceutically acceptable salt thereof; a pharmaceutically acceptable salt of a stereoisomer; or a pharmaceutically acceptable salt of a deuterated derivative thereof.

5. R １ In each occurrence, independently, -CD ３ A compound represented by formula (I) according to any one of claims 1 to 4, selected from the above, a deuterated derivative thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer, or a pharmaceutically acceptable salt of a deuterated derivative.

6. R １ In each occurrence, independently, -C １－３ Selected from alkyl, the R １ is R １１ Replaced by; the R １１ is, -C ２－３ Selected from alkoxyalkyl, and the R １１ The compound represented by formula (I) according to claim 1, which may be substituted with one or more deuterium atoms, a deuterated derivative thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer, or a pharmaceutically acceptable salt of a deuterated derivative thereof.

7. R １ is, independently at each occurrence, -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , and -CH(CH ３ ) ２ selected from; said R １ is substituted by R １１ ; said R １１ is -CH ２ -O-CH ３ , -CH ２ -O-CH ２ -CH ３ , -CH ２ -CH ２ -O-CH ３ , or -CH(CH ３ )-O-CH ３ selected from; and said R １１ may be substituted by 1, 2, 3, 4, 5, 6 or 7 deuteriums of deuterium, a compound represented by formula (I) according to claim 1 or 6, its deuterated derivative, stereoisomer, its pharmaceutically acceptable salt, pharmaceutically acceptable salt of a stereoisomer, or pharmaceutically acceptable salt of a deuterated derivative.

8. R １ In each appearance, independently, 【Transformation 3】 A compound represented by formula (I) according to claim 1, a deuterated derivative thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer, or a pharmaceutically acceptable salt of a deuterated derivative, selected from the above.

9. R １ In each appearance, independently, 【Chemistry 4】 A compound represented by formula (I) according to any one of claims 1 and 6 to 8, selected from the above, a deuterated derivative thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer, or a pharmaceutically acceptable salt of a deuterated derivative.

10. R ４ -H, -D, and -C １－３ Selected from alkyl groups; Preferably, R ４ is -H, -D, -Cl, -F, -Br, -CH ３ -, -CH ２ CH ３ -, -CH ２ CH ２ CH ３ -, -CH(CH ３ ) ２ -, -CH ２ F, -CHF ２ -, -CF ３ -, -CH ２ CH ２ F, -CH ２ CHF ２ -, -CH ２ CF ３ -, -CHFCH ３ -, -CF ２ CH ３ -, -CH ２ -O-CH ３ -, -CH ２ -O-CH ２ -CH ３ -, -CH ２ -CH ２ -O-CH ３ -, -CH(CH ３ )-O-CH ３ 、 【Transformation 5】 , -CN, -C(=O)OH, -NH ２ ,-NH(CH ３ ), -N(CH ３ ) ２ ,-NH(CH ２ CH ３ ), -OH, -O-CH ３ , -O-CH ２ -CH ３ , -O-CH ２ -CH ２ -CH ３ , -O-CH(CH ３ ) ２ , -O-CF ３ , -SH, -S-CH ３ , -S-CH ２ CH ３ , -S-CH ２ CH ２ CH ３ , -S-CH(CH ３ ) ２ , -C(=O)(CH ３ ), -C(=O)(CH ２ CH ３ ), -C(=O)(CH(CH ３ ) ２ ), -S(=O)(CH ３ ), -S(=O)(CH ２ CH ３ ), -S(=O)(CH(CH ３ ) ２ ), -S (=O) ２ (CH ３ ), -S (=O) ２ (CH ２ CH ３ ), and -S (=O) ２ (CH(CH ３ ) ２ ) selected from; R ４ If is not -H, -D, -Cl, -F, -Br, or -CN, then R ４ may be substituted with one or more deuterium atoms; More specifically, R ４ -H, -D, -CD ３ , and -CH ３ Selected from; and, More preferably, R ４ A compound represented by formula (I) according to any one of claims 1 to 9, wherein is -H; a deuterated derivative thereof; a stereoisomer thereof; a pharmaceutically acceptable salt thereof; a pharmaceutically acceptable salt of a stereoisomer; or a pharmaceutically acceptable salt of a deuterated derivative thereof.

11. R ４ A compound represented by formula (I) according to any one of claims 1 to 10, wherein is -H; a deuterated derivative thereof; a stereoisomer thereof; a pharmaceutically acceptable salt thereof; a pharmaceutically acceptable salt of a stereoisomer; or a pharmaceutically acceptable salt of a deuterated derivative thereof.

12. R ２ and R ３ These are independently -H, -D, and -C １－３ Selected from alkyl groups; Preferably, R ２ and R ３ These are, independently, -H, -D, -Cl, -F, -Br, and -CH ３ ien-CH ２ CH ３ ien-CH ２ CH ２ CH ３ , -CH(CH ３ ) ２ ien-CH ２ F, -CHF ２ , -CF ３ ien-CH ２ CH ２ F, -CH ２ CHF ２ ien-CH ２ CF ３ yan-CHFCH ３ and -CF ２ CH ３ A group consisting of R is selected, where R ２ or R ３ If is not -H, -D, -Cl, -F, or -Br, then R ２ or R ３ may be substituted with one or more deuterium atoms; More specifically, R ２ and R ３ These are independently -H, -D, and -CD. ３ , and -CH ３ Selected from the group consisting of; and More preferably, R ２ and R ３ Each of the following is independently -H: a compound represented by formula (I) according to any one of claims 1 to 11, a deuterated derivative thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer, or a pharmaceutically acceptable salt of a deuterated derivative.

13. R ２ A compound represented by formula (I) according to any one of claims 1 to 12, wherein is -H; a deuterated derivative thereof; a stereoisomer thereof; a pharmaceutically acceptable salt thereof; a pharmaceutically acceptable salt of a stereoisomer; or a pharmaceutically acceptable salt of a deuterated derivative thereof.

14. R ３ A compound represented by formula (I) according to any one of claims 1 to 13, wherein is -H; a deuterated derivative thereof; a stereoisomer thereof; a pharmaceutically acceptable salt thereof; a pharmaceutically acceptable salt of a stereoisomer; or a pharmaceutically acceptable salt of a deuterated derivative thereof.

15. R ２ is -H; and R ３ A compound represented by formula (I) according to any one of claims 1 to 14, wherein is -H; a deuterated derivative thereof; a stereoisomer thereof; a pharmaceutically acceptable salt thereof; a pharmaceutically acceptable salt of a stereoisomer; or a pharmaceutically acceptable salt of a deuterated derivative thereof. 【Request Item 16】 【Chemistry 6】 R １ In each occurrence, independently, -C １－３ Selected from alkyl; the R １ is 1, 2, or 3 R １１ It may be replaced by; The aforementioned R １１ is deuterium, -C ２－３ Alkoxyalkyls, and -O(C) １－３ Selected from alkyl; R １１ ga-C ２－３ Alkoxyalkyl or -O(C) １－３ If it is alkyl, then R １１ may be substituted with one or more deuterium atoms; R ４ These are independently -H, -D, and -C １－３ Selected from alkyl; and, R ２ and R ３ These are independently -H, -D, and -C １－３ A compound represented by formula (I), selected from alkyl groups, its deuterated derivative, stereoisomer, pharmaceutically acceptable salt thereof, pharmaceutically acceptable salt of a stereoisomer, or pharmaceutically acceptable salt of a deuterated derivative. 【Request Item 17】 【Chemistry 7】 R １ In each occurrence, independently, -C １－３ Selected from alkyl; the R １ This may be substituted with 1, 2, 3, 4, 5, 6, or 7 deuterium atoms; R ４ These are independently -H, -D, and -C １－３ Selected from alkyl; and, R ２ and R ３ These are independently -H, -D, and -C １－３ A compound represented by formula (I), selected from alkyl groups, its deuterated derivative, stereoisomer, pharmaceutically acceptable salt thereof, pharmaceutically acceptable salt of a stereoisomer, or pharmaceutically acceptable salt of a deuterated derivative. 【Request Item 18】 【Chemistry 8】 R １ In each occurrence, independently, -C １－３ Selected from alkyl, the R １ is R １１ Replaced by; the R １１ Ha-C ２－３ Selected from alkoxyalkyls, the R １１ may be substituted with one or more deuterium atoms; R ４ These are independently -H, -D, and -C １－３ Selected from alkyl; and R ２ and R ３ These are independently -H, -D, and -C １－３ A compound represented by formula (I), selected from alkyl groups, its deuterated derivative, stereoisomer, pharmaceutically acceptable salt thereof, pharmaceutically acceptable salt of a stereoisomer, or pharmaceutically acceptable salt of a deuterated derivative. 【Request Item 19】 【Chemistry 9】 R ４ These are independently -H, -D, and -C １－３ Selected from alkyl; and, R ２ and R ３ These are independently -H, -D, and -C １－３ A compound represented by formula (I-1), selected from alkyl groups; a deuterated derivative thereof; a stereoisomer thereof; a pharmaceutically acceptable salt thereof; a pharmaceutically acceptable salt of a stereoisomer; or a pharmaceutically acceptable salt of a deuterated derivative thereof. 【Request Item 20】 【Chemistry 10】 R ４ These are independently -H, -D, and -C １－３ Selected from alkyl; and R ２ and R ３ These are independently -H, -D, and -C １－３ Compounds represented by formula (I-2), selected from alkyl groups, deuterated derivatives thereof, stereoisomers thereof, pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts of stereoisomers, or pharmaceutically acceptable salts of deuterated derivatives.

21. The aforementioned compound has the following formula: 【Chemistry 11】 A compound represented by formula (I) according to any one of claims 1 to 18, a deuterated derivative thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer, or a pharmaceutically acceptable salt of a deuterated derivative.

22. The aforementioned compound has the following formula: 【Chemistry 12】 A compound represented by formula (I) according to any one of claims 1 to 18 and 21, a deuterated derivative thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer, or a pharmaceutically acceptable salt of a deuterated derivative, or a compound represented by formula (I-1) according to claim 19, a deuterated derivative thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer, or a pharmaceutically acceptable salt of a deuterated derivative.

23. The aforementioned compound has the following formula: 【Chemistry 13】 A compound represented by formula (I) according to any one of claims 1 to 18 and 21, a deuterated derivative thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer, or a pharmaceutically acceptable salt of a deuterated derivative, or a compound represented by formula (I-2) according to claim 20, a deuterated derivative thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer, or a pharmaceutically acceptable salt of a deuterated derivative.

24. A pharmaceutical composition comprising a compound according to any one of claims 1 to 23, a deuterated derivative thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer, or a pharmaceutically acceptable salt of a deuterated derivative, and at least one pharmaceutically acceptable excipient.

25. A method for treating a subject having a mitochondrial-related disease or symptom, The method comprises administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 23, a deuterated derivative thereof, a stereoisomer, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer, or a pharmaceutically acceptable salt of a deuterated derivative, or the pharmaceutical composition according to claim 24. The aforementioned disease or symptom is obesity, excess body fat, diabetes, insulin resistance or intolerance, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), fatty liver, type 2 diabetes mellitus (T2DM), dyslipidemia, cardiovascular disease, heart disease, or arteriosclerosis, and the method is as follows.

26. The use of a compound according to any one of claims 1 to 23, a deuterated derivative thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer, or a pharmaceutically acceptable salt of a deuterated derivative, or the pharmaceutical composition according to claim 24, in the manufacture of a pharmaceutical for treating a mitochondrial-related disease or symptom, The aforementioned diseases or symptoms include obesity, excess body fat, diabetes, insulin resistance or intolerance, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), fatty liver, type 2 diabetes mellitus (T2DM), dyslipidemia, cardiovascular disease, heart disease, or arteriosclerosis.

27. A compound according to any one of claims 1 to 23, a deuterated derivative thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer, or a pharmaceutically acceptable salt of a deuterated derivative thereof, used for the treatment of mitochondrial-related diseases or conditions, wherein the disease or condition is obesity, excess body fat, diabetes, insulin resistance or intolerance, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), fatty liver, type 2 diabetes mellitus (T2DM), dyslipidemia, cardiovascular disease, heart disease, or arteriosclerosis, or a pharmaceutical composition according to claim 24.

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