3CLPRO inhibitor and method thereof

Abstract

This disclosure relates to a compound of formula (I) or a salt, solvate, stereoisomer, or prodrug thereof as a 3CLpro inhibitor. The compound may be used to treat coronavirus-related illnesses or conditions. TIFF2026518596000256.tif38149

Claims

1. Equation (I): 【Chemistry 1】 (In the formula, R １ The 'cyl' and 'cyano' are selected as optional replacements. R ２ It is selected from optionally substituted alkyls and optionally substituted alkenyls, X is N or CR ４ Selected from, R ３ The element is selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted amino, optionally substituted aryl, optionally substituted alkyloxy, optionally substituted cycloalkyloxy, optionally substituted oxyacylamino, optionally substituted aminoacyloxy, optionally substituted acylamino, optionally substituted aminoacyl, and optionally substituted sulfonylamino. R ４ is selected from H and optionally substituted alkyl groups, R ５ is independently selected from H and optionally substituted alkyl groups, R ６ is selected from H and optionally substituted alkyl groups, or R ２ and R ６ are linked to form an optionally substituted heterocycle, m is an integer selected from 1 to 4. n is an integer selected from 1 to 4. Compounds thereof or their salts, solvates, stereoisomers, or prodrugs.

2. R １ The compound according to claim 1, wherein is selected from HC(O)- and cyano.

3. R ２ C １ ~C ５ The compound according to claim 1 or 2, wherein it is alkyl.

4. R ２ The compound according to any one of claims 1 to 3, wherein is selected from butyl, iso-butyl, pentyl, iso-pentyl, neo-pentyl, halopentyl, haloiso-pentyl, halo-neo-pentyl, cyclopentylmethyl, and cyclopentyl.

5. R ３ H, optionally substituted with phenylmethyl, optionally substituted with halophenylmethyl, optionally substituted with trihalomethylphenylmethyl, optionally substituted with cyclopentyl, optionally substituted with cyclopentylmethyl, optionally substituted with tert-butyloxy, optionally substituted with cyclohexyloxy, optionally substituted with tetrahydropyranylacylamino, optionally substituted with tert-butylacylamino, optionally substituted with trihalo-tert-butylacylamino, optionally substituted with trihalometh Luacylamino, optionally substituted neo-pentylacylamino, optionally substituted dihalocyclobutylmethylacylamino, optionally substituted cyclopentylmethylacylamino, optionally substituted pyrimidinylacylamino, optionally substituted phenylacylamino, optionally substituted halophenylacylamino, optionally substituted dihalophenylacylamino, optionally substituted isoxazolylacylamino, optionally substituted methylisoxazolylacylamino, optionally substituted trihalo Methylisoxazolyl acylamino, optionally substituted thiazolyl acylamino, optionally substituted methylthiazolyl acylamino, optionally substituted oxazolyl acylamino, optionally substituted methyloxazolyl acylamino, optionally substituted phenyl acylamino, optionally substituted halophenyl acylamino, optionally substituted dihalophenyl acylamino, optionally substituted trihalomethylphenyl acylamino, optionally substituted halotrihalomethylphenyl acylamino, optionally placed Substituted halophenylpropyl acylamino, optionally substituted cyclopropyl acylamino, optionally substituted trihalomethylcyclopropyl acylamino, optionally substituted cyclobutyl acylamino, optionally substituted methylcyclobutyl acylamino, optionally substituted dihalocyclobutyl acylamino, optionally substituted bicyclo[1.1.1]pentyl acylamino, optionally substituted trihalomethylbicyclo[1.1.1]pentyl acylamino, optionally substituted oxetanyl acylamino,Optionally substituted methyloxetanylacylamino, optionally substituted bicyclo[2.1.1]hexylacylamino, optionally substituted cyclohexylacylamino, optionally substituted dihalocyclohexylacylamino, optionally substituted cyclohexylacylamino, optionally substituted spiro[3.3]heptylacylamino, optionally substituted tert-butyloxyacylamino (or Boc-NH or Boc-N(methyl)), optionally substituted cyclopentyloxyacylamino, optionally substituted neo-pentyloxyacylamino, optionally substituted cyclobutyloxyacylamino, optional A compound according to any one of claims 1 to 4, selected from trihalomethylcyclobutyloxyacylamino which is optionally substituted, phenylsulfonylamino which is optionally substituted, dihalophenylsulfonylamino which is optionally substituted, cyclopropylsulfonylamino which is optionally substituted, methylsulfonylamino which is optionally substituted, trihalomethylsulfonylamino which is optionally substituted, cyclobutylsulfonylamino which is optionally substituted, amino which is optionally substituted, pyrimidinylamino which is optionally substituted, trihalomethylpyrimidinylamino which is optionally substituted, and tert-butylaminoacyl which is optionally substituted.

6. R ４ The compound according to any one of claims 1 to 5, wherein is H or methyl.

7. R ５ The compound according to any one of claims 1 to 6, wherein is H or methyl.

8. Equation (Ia): 【Chemistry 2】 (In the formula, R １ The 'cyl' and 'cyano' are selected as optional replacements. Ht is a heterocycline that is optionally substituted, X is N or CR ４ Selected from, R ３ The element is selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted amino, optionally substituted aryl, optionally substituted alkyloxy, optionally substituted cycloalkyloxy, optionally substituted oxyacylamino, optionally substituted aminoacyloxy, optionally substituted acylamino, optionally substituted aminoacyl, and optionally substituted sulfonylamino. R ４ is selected from H and optionally substituted alkyl groups, R ５ is independently selected from H and optionally substituted alkyl groups, m is an integer selected from 1 to 4. n is an integer selected from 1 to 4. A compound according to any one of claims 1 to 7, which is a compound of the above.

9. R ２ and R ６ The compound according to any one of claims 1 to 8, wherein when the members are linked to form a heterocycline that is optionally substituted or is Ht, the heterocycline is an optionally substituted 5- to 7-membered heterocycline.

10. The compound according to any one of claims 1 to 9, wherein the optionally selected substituent on the heterocyclyl is selected from halo, methyl, methoxy, ethoxy, cyclopropyl, condensed dimethylcyclopropyl, condensed cyclopentyl, crosslinked methylene, and crosslinked ethylene.

11. The compound according to any one of claims 1 to 10, wherein m is an integer selected from 1 to 3.

12. The compound according to any one of claims 1 to 11, wherein n is an integer selected from 1 to 2.

13. A compound of formula (I) or its salt, solvate, stereoisomer, or prodrug is of formula (I ｉｉｘ b): 【Transformation 3】 The compound according to any one of claims 1 to 12, as represented by [the specified expression].

14. A compound of formula (Ia) or its salt, solvate, stereoisomer, or prodrug is a compound of formula (Ia ｉｉｘ b): 【Chemistry 4】 The compound according to any one of claims 1 to 12, as represented by [the specified expression].

15. below: Table 1 A compound according to any one of claims 1 to 14, selected from one of the following.

16. A pharmaceutical composition comprising an effective amount of a compound of formula (I) described in any one of claims 1 to 15, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, in combination with an optionally pharmaceutically acceptable carrier, excipient, or diluent.

17. A method for treating a coronavirus-related illness or condition in a patient who requires treatment for such illness or condition, comprising the step of administering to the patient a therapeutically effective amount of a compound of formula (I) described in any one of claims 1 to 15 or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

18. Use of a compound of formula (I) according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, in the manufacture of a pharmaceutical product for treating a coronavirus-related disease or condition.

19. A compound of formula (I) according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, for use in the treatment of coronavirus-related illnesses or conditions.

20. The method, use, or compound for use according to any one of claims 17 to 19, wherein the compound of formula (I) is a 3CLpro inhibitor.

21. The method, use, or compound for use according to any one of claims 17 to 20, wherein the coronavirus-related illness or condition is caused by a virus selected from SARS-CoV-1, SARS-CoV-2, MERS-CoV, CoV-229E, and HCoV-OC43.

22. Protease inhibition assay IC with compound of formula (I) less than 20 μM ５０ A compound for use, a method according to any one of claims 17 to 21, characterized by a value.

23. Viral cytopathic effect assay EC with compound (I) at a concentration of less than 20 μM ５０ A method, use, or compound for use according to any one of claims 17 to 22, characterized by a value.

24. i) A step of reacting a compound of formula (II) with a compound of formula (III) under dehydration conditions to form an amide bond, 【Transformation 5】 ii) Perform the ring-closing olefin metathesis reaction to produce formula (IV): 【Transformation 6】 The step of forming the compound, iii) The alkyloxyacyl portion in formula (IV) is R １ The steps of converting to a part to form the compound of formula (I) and A method for producing a compound of formula (I) containing [the specified compound].

25. The method according to claim 24, further comprising step ii) a hydrogenation reaction after the olefin metathesis reaction.

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