AT2R Agonist

Abstract

The present disclosure relates to the field of medicine, specifically, the present disclosure provides a compound represented by formula I, its tautomers, stereoisomers, hydrates, solvates, pharma- ceutically acceptable salts or prodrugs, which can be used as agonists of the AT2 receptor. JPEG2025511239000238.jpg59170I

Claims

1. A compound represented by formula I, or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 I Ring B is a benzene ring, R is hydrogen, m is selected from 1, 2, 3, or 4, and L is unsubstituted or substituted with one or more substituents. １ -C ６ It is an alkyl group, and each substituent can independently be a halogen or C １ -C ６ If selected from alkyl groups and having multiple substituents, the substituents may be the same or different. Alternatively, if R6 is hydrogen and m is selected from 0, then L is a C substituted with one or more substituents. １ -C ６ It is an alkyl group, and each substituent can independently be a halogen or C １ -C ６ If selected from alkyl groups and having multiple substituents, the substituents may be the same or different. Alternatively, when R6 is halogen, a hydroxyl group, a cyano group, an amino group, or an unsubstituted C １ -C ６ alkyl group, m is selected from 0, 1, 2, 3 or 4, and L is an unsubstituted or C １ -C ６ alkyl group substituted with one or more substituents, and each substituent is independently halogen, C １ -C ６ alkyl group, C １ -C ６ halogenated alkyl group, oxo (=O), R 1 is C １ -C ６ Selected from alkyl groups, R ３ is a cyano group, or C １ -C ６ Selected from alkyl groups, The aforementioned R １ and R ３ Each of these is independently a halogen, a hydroxyl group, an amino group, a cyano group, and C １ -C ６ alkyl group, C ３ -C ７ Substituting with 0, 1, 2, 3, or 4 substituents selected from cycloalkyl groups, and if there are multiple substituents, the substituents may be the same or different. R ２ C １ -C ６ Selected from alkyl groups, The aforementioned R ２ is halogen, hydroxyl group, amino group, cyano group, C １ -C ６ alkyl group, C ３ -C ７ Substituted with 0, 1, 2, 3, or 4 substituents selected from a cycloalkyl group, a 5-6 membered aryl group, or a 5-6 membered heteroaryl group containing 1 to 3 heteroatoms independently selected from N, O, and S, and if there are multiple substituents, the substituents may be the same or different. Z is -O- or -NR ４ - Selected from, R ４ is C １ -C ３ It is an alkyl group or H, Ring A is imidazole, n is selected from 1, 2, 3, 4, or 5, and substituent R ５ If there are multiple substituents, the substituents may be the same or different. R ５ H, halogen, or C １ -C ６ Selected from alkyl groups, The aforementioned R ５ C １ -C ６ If it is an alkyl group, then C １ -C ６ Alkyl groups can independently be halogens, hydroxyl groups, and C １ -C ６ alkyl group, C ３ -C ７ A compound represented by formula I, or a pharmaceutically acceptable salt thereof, substituted with 0, 1, 2, 3, or 4 substituents selected from cycloalkyl groups, wherein, if there are multiple substituents, the substituents may be the same or different.

2. The aforementioned compounds are selected from the following structures: 【Chemistry 2】 II L is unsubstituted or C is substituted with one or more substituents. １ -C ６ It is an alkyl group, and each substituent can independently be a halogen or C １ -C ６ Selected from alkyl groups, Ring B is a benzene ring, m is selected from 1, 2, 3 or 4. R １ is C １ -C ６ Selected from alkyl groups, R ３ is a cyano group, or C １ -C ６ Selected from alkyl groups, The aforementioned R １ and R ３ Each of these is independently a halogen, a hydroxyl group, an amino group, a cyano group, and C １ -C ６ alkyl group, C ３ -C ７ Substituting with 0, 1, 2, 3, or 4 substituents selected from cycloalkyl groups, and if there are multiple substituents, the substituents may be the same or different. R ２ C １ -C ６ Selected from alkyl groups, The aforementioned R ２ is halogen, hydroxyl group, amino group, cyano group, C １ -C ６ alkyl group, C ３ -C ７ Substituted with 0, 1, 2, 3, or 4 substituents selected from a cycloalkyl group, a 5-6 membered aryl group, or a 5-6 membered heteroaryl group containing 1 to 3 heteroatoms independently selected from N, O, and S, and if there are multiple substituents, the substituents may be the same or different. Z is -O- or -NR ４ - Selected from, R ４ is C １ -C ３ It is an alkyl group or H, Ring A is imidazole, n is selected from 1, 2, 3, 4, or 5, and substituent R ５ If there are multiple substituents, the substituents may be the same or different. R ５ H, halogen, or C １ -C ６ Selected from alkyl groups, The foregoing R ５ is C １ -C ６ When it is an alkyl group, the C １ -C ６ alkyl group is independently substituted with 0, 1, 2, 3 or 4 substituents selected from halogen, hydroxyl group, C １ -C ６ alkyl group, C ３ -C ７ cycloalkyl group, and when there are a plurality of substituents, the substituents are the same or different, a compound represented by formula I according to claim 1, or a pharmaceutically acceptable salt thereof.

3. The aforementioned compounds are selected from the following structures: 【Transformation 3】 III L is a C substituted with one or more substituents １ -C ６ is an alkyl group, and each substituent is independently halogen, or C １ -C ６ selected from alkyl groups, m is a compound represented by formula I as described in claim 1, or a pharmaceutically acceptable salt thereof, selected from 0.

4. The aforementioned compounds are selected from the following structures: 【Chemistry 4】 IV R ６ C is a halogen, hydroxyl group, cyano group, amino group, or unsubstituted C １ -C ６ If selected from alkyl groups, m is selected from 0, 1, 2, 3 or 4. L is unsubstituted or C is substituted with one or more substituents. １ -C ６ It is an alkyl group, and each substituent can independently be a halogen, C １ -C ６ alkyl group, C １ -C ６ A compound represented by formula I as described in claim 1, selected from an alkyl halogenate and an oxo (=O), or a pharmaceutically acceptable salt thereof.

5. L is C １ -C ３ It is an alkyl group, The aforementioned L is a halogen or C １ -C ６ A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, optionally substituted with an alkyl group.

6. R ３ is a cyano group, or C １ -C ３ Selected from alkyl groups, The aforementioned R ３ These are independently halogen, hydroxyl group, amino group, cyano group, and C １ -C ６ alkyl group, C ３ -C ７ A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, substituted with 0, 1, 2, 3, or 4 substituents selected from cycloalkyl groups, wherein, if there are multiple substituents, the substituents are the same or different.

7. Ring B is a benzene ring, and the benzene ring has 1, 2, 3 or 4 R ３ Replaced by, R ３ is a cyano group, or C １ -C ３ A compound selected from alkyl groups according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

8. R １ The compound according to any one of claims 1 to 4, wherein is an isobutyl group, or a pharmaceutically acceptable salt thereof.

9. R ２ C １ -C ６ Alkyl alkyl group, or C １ -C ６ Selected from halogenated alkyl groups, The aforementioned R ２ C １ -C ６ If it is an alkyl group, then R ２ is halogen, hydroxyl group, amino group, cyano group, C １ -C ６ alkyl group, C ３ -C ７ A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, substituted with 0, 1, 2, 3, or 4 substituents selected from a cycloalkyl group, a 5-6 membered aryl group, or a 5-6 membered heteroaryl group, wherein, if there are multiple substituents, the substituents may be the same or different.

10. n is 1, 2, 3, 4, or 5. R ５ is selected from H, halogen, methyl group, ethyl group, or t-butyl group. 【Transformation 5】 teeth, 【Transformation 6】 A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

11. R ６ is H, halogen, hydroxyl group, or C １ -C ３ Selected from alkyl groups, The aforementioned R ６ These are independently halogen, hydroxyl group, amino group, cyano group, and C １ -C ６ alkyl group, C ３ -C ７ A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, substituted with 0, 1, 2, 3, or 4 substituents selected from cycloalkyl groups, wherein, if there are multiple substituents, the substituents are the same or different.

12. Ring B is a benzene ring, R ６ H is H, m is selected from 1, 2, 3 or 4, and L is C １ -C ３ alkyl group, C １ -C ６ C substituted with alkyl group １ -C ３ It is an alkyl group 【Transformation 7】 teeth, 【Transformation 8】 It has, R １ It is selected from the isobutyl group, R ３ The group is selected from the cyano group and the methyl group. Z is selected from -O- or -NH-. R ２ C １ -C ６ Selected from alkyl groups, The aforementioned R ２ It is substituted with 0, 1, 2, or 3 substituents selected from a 5-6 membered heteroaryl group containing 1 to 3 heteroatoms independently selected from halogens, hydroxyl groups, N, O, and S. L is -CH ２ - or -CH(CH ３ ) - the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

13. Ring B is a benzene ring, R ６ If H and m is 0, then L is C １ -C ６ C substituted with alkyl group １ -C ３ It is an alkyl group, 【Chemistry 9】 teeth, 【Chemistry 10】 It has, R １ It is selected from the isobutyl group, R ３ The group is selected from the cyano group and the methyl group. Z is selected from -O-, R ２ C １ -C ６ Selected from alkyl groups, L is -CH(CH ３ ) - the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

14. Ring B is a benzene ring, R ６ It is not hydrogen, and is not a halogen or C １ -C ３ Selected from alkyl groups, where m is 0 or 1, L is C １ -C ３ alkyl group, C １ -C ６ C substituted with alkyl group １ -C ３ It is an alkyl group, 【Chemistry 11】 teeth, 【Chemistry 12】 It has, R １ It is selected from the isobutyl group, R ３ It is selected from the methyl group, Z is selected from -O-, R ２ C １ -C ６ Selected from alkyl groups, R ６ is the compound according to claim 1, selected from a fluorine or methyl group, or a pharmaceutically acceptable salt thereof.

15. The aforementioned compound is as follows: 【Chemistry 13】 【change】 【change】 A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

17. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, Use in the preparation of drugs, pharmaceutical compositions, or formulations as AT2 receptor agonists, or use in the preparation of drugs, pharmaceutical compositions, or formulations that prevent or treat diseases in which AT2 receptors are expressed and stimulation is expected or required.

18. A therapeutic agent comprising a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, used to prevent or treat diseases in which an endogenous deficiency of AngII occurs, or in which an increase in AngII activity is expected or necessary, or in which AT2 receptors are expressed and the occurrence of stimulation is expected or necessary, The aforementioned diseases are disorders of the gastrointestinal tract, cardiovascular system, respiratory tract, kidneys, eyes, female reproductive system, or central nervous system; therapies for which the above-mentioned diseases are treated.

19. The therapeutic agent according to claim 18, wherein the disease is asthma, obstructive pulmonary disease, pneumonia, pulmonary hypertension, adult respiratory distress syndrome, or idiopathic pulmonary fibrosis.

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