Granted Patent B2

US 12,365,669 · App. 19/052,553 · Granted Jul 22, 2025

Inventors: Shanghai Yu (Kun Shan, CN); Ben Li (Kun Shan, CN)

Assignee: Terns, Inc.

C07D403/12

Abstract

Claims (80)

1. A method of preparing a compound of Formula (I):

or a pharmaceutically acceptable salt thereof;

wherein:

Ring A is a C 5-10 aliphatic ring or a C 5-10 aromatic ring, each optionally substituted with one or more substituents independently selected from the group consisting of hydrogen, halogen atoms, hydroxy, —OCF 3 , —NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 , —CONH 2 , —CONHC 1-4 alkyl, —CON(C 1-4 alkyl) 2 , —NHCOC 1-4 alkyl, C 1-6 alkyl, C 1-6 alkoxy, and C 3-6 cycloalkyl, and when two substituents are contained, the two substituents can form a ring structure together with the carbon connected thereto; and the halogen atoms are selected from the group consisting of F, Cl, and Br;

R 2 and R 3 are each independently selected from the group consisting of halogen atoms and substituted or unsubstituted C 1-6 alkyl, the substituent being selected from the group consisting of halogen atoms, hydroxy, and C 1-6 alkoxy; and

R 1 is selected from the group consisting of hydrogen, cyano, substituted or unsubstituted C 1-6 alkyl, and substituted or unsubstituted C 3-6 cycloalkyl, the substituent being selected from the group consisting of halogen atoms, hydroxy, and C 1-6 alkoxy;

the method comprising contacting a compound of Formula (I-f):

or a salt thereof, with a compound of Formula (I-g):

or a salt thereof, to produce the compound of Formula (I).

2. The method of claim 1 , wherein the contacting occurs in the presence of a nitrite.

3. The method of claim 1 , wherein the contacting occurs in an acidic aqueous solution.

4. The method of claim 1 , wherein the contacting occurs in the presence of sodium nitrite.

5. The method of claim 1 , wherein the contacting occurs in the presence of hydrochloric acid.

6. The method of claim 1 , wherein the contacting occurs in the presence of acetic acid and sodium acetate.

7. The method of claim 1 , wherein Ring A is a C 6 aromatic ring substituted with hydrogen.

8. The method of claim 7 , wherein R 2 and R 3 are Cl.

9. The method of claim 1 , wherein Ring A is a C 5 aliphatic ring, optionally substituted with one or more substituents independently selected from the group consisting of hydrogen and C 1 alkyl.

10. The method of claim 9 , wherein R 2 and R 3 are Cl.

11. A method of preparing a compound of Formula (I):

or a pharmaceutically acceptable salt thereof;

wherein:

Ring A is a C 5-10 aliphatic ring or a C 5-10 aromatic ring, each optionally substituted with one or more substituents independently selected from the group consisting of hydrogen, halogen atoms, hydroxy, —OCF 3 , —NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 , —CONH 2 , —CONHC 1-4 alkyl, —CON(C 1-4 alkyl) 2 , —NHCOC 1-4 alkyl, C 1-6 alkyl, C 1-6 alkoxy, and C 3-6 cycloalkyl, and when two substituents are contained, the two substituents can form a ring structure together with the carbon connected thereto; and the halogen atoms are selected from the group consisting of F, Cl, and Br;

R 2 and R 3 are each independently selected from the group consisting of halogen atoms and substituted or unsubstituted C 1-6 alkyl, the substituent being selected from the group consisting of halogen atoms, hydroxy, and C 1-6 alkoxy; and

R 1 is selected from the group consisting of hydrogen, cyano, substituted or unsubstituted C 1-6 alkyl, and substituted or unsubstituted C 3-6 cycloalkyl, the substituent being selected from the group consisting of halogen atoms, hydroxy, and C 1-6 alkoxy;

comprising subjecting a compound of Formula (I-c):

or a salt thereof, to a series of steps comprising a coupling reaction at a first temperature, and a hydrolysis reaction in an alkaline or acidic environment at a second temperature to produce a compound of Formula (I-f):

or a salt thereof.

12. The method of claim 11 , wherein the coupling reaction takes place in the presence of a catalyst.

13. The method of claim 12 , wherein the catalyst is cuprous iodide.

14. The method of claim 11 , wherein the first temperature is greater than about 100° C.

15. The method of claim 11 , wherein the alkaline or acidic environment comprises acetic acid and sodium acetate.

16. The method of claim 11 , wherein the second temperature is about 120° C.

17. The method of claim 11 , wherein Ring A is a C 5-10 aromatic ring, optionally substituted with one or more substituents independently selected from the group consisting of hydrogen, halogen atoms, hydroxy, —OCF 3 , —NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 , —CONH 2 , —CONHC 1-4 alkyl, —CON(C 1-4 alkyl) 2 , —NHCOC 1-4 alkyl, C 1-6 alkyl, C 1-6 alkoxy, and C 3-6 cycloalkyl, and when two substituents are contained, the two substituents can form a ring structure together with the carbon connected thereto; and the halogen atoms are selected from the group consisting of F, Cl, and Br.

18. The method of claim 11 , wherein Ring A is a C 5-10 aliphatic ring, optionally substituted with one or more substituents independently selected from the group consisting of hydrogen, halogen atoms, hydroxy, —OCF 3 , —NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 , —CONH 2 , —CONHC 1-4 alkyl, —CON(C 1-4 alkyl) 2 , —NHCOC 1-4 alkyl, C 1-6 alkyl, C 1-6 alkoxy, and C 3-6 cycloalkyl, and when two substituents are contained, the two substituents can form a ring structure together with the carbon connected thereto; and the halogen atoms are selected from the group consisting of F, Cl, and Br.

19. The method of claim 11 , wherein the compound of Formula (I) is a compound of Formula (II):

or a pharmaceutically acceptable salt thereof;

wherein:

R 2 and R 3 are each independently selected from the group consisting of halogen atoms and substituted or unsubstituted C 1-6 alkyl, the substituent being selected from the group consisting of halogen atoms, hydroxy, and C 1-6 alkoxy;

R 1 is selected from the group consisting of hydrogen, cyano, substituted or unsubstituted C 1-6 alkyl, and substituted or unsubstituted C 3-6 cycloalkyl, the substituent being selected from the group consisting of halogen atoms, hydroxy, and C 1-6 alkoxy;

L is not present or is selected from the group consisting of —CH 2 — and —CH 2 CH 2 —;

R 4 is selected from the group consisting of hydrogen, halogen atoms, hydroxy, —OCF 3 , —NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 , C 1-6 alkyl, C 1-6 alkoxy, and C 3-6 cycloalkyl;

n is an integer from the range 1 to 4;

m is an integer from the range 1 to 4; and

the halogen atoms are selected from the group consisting of F, Cl, and Br.

20. The method of claim 19 , wherein:

R 4 is selected from the group consisting of hydrogen, halogen atoms, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, and C 3-6 cycloalkyl;

L is not present or is selected from the group consisting of —CH 2 — and —CH 2 CH 2 —;

n is 1, 2 or 3.

21. The method of claim 19 , wherein:

R 4 is selected from the group consisting of hydrogen and C 1-3 alkyl;

L is not present;

n is 1, 2 or 3.

22. The method of claim 19 , wherein R 2 and R 3 are each independently selected from the group consisting of F, Cl, and Br.

23. The method of claim 19 , wherein R 2 and R 3 are Cl.

24. The method of claim 17 , wherein the compound of Formula (I) is a compound of Formula (III):

or a pharmaceutically acceptable salt thereof;

wherein,

R 2 and R 3 are each independently selected from the group consisting of halogen atoms and substituted or unsubstituted C 1-6 alkyl, the substituent being selected from the group consisting of halogen atoms, hydroxy, and C 1-6 alkoxy;

R 1 is selected from the group consisting of hydrogen, cyano, substituted or unsubstituted C 1-6 alkyl, and substituted or unsubstituted C 3-6 cycloalkyl, the substituent being selected from the group consisting of halogen atoms, hydroxy, and C 1-6 alkoxy;

R 4 is selected from the group consisting of hydrogen, halogen atoms, hydroxy, —OCF 3 , —NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 , —CONH 2 , —CONHC 1-4 alkyl, —CON(C 1-4 alkyl) 2 , —NHCOC 1-4 alkyl, C 1-6 alkyl, C 1-6 alkoxy, and C 3-6 cycloalkyl;

m is an integer from the range 1 to 4; and

the halogen atoms are selected from the group consisting of F, Cl, and Br.

25. The method of claim 24 , wherein:

R 4 is selected from the group consisting of hydrogen, halogen atoms, hydroxy, —OCF 3 , C 1-6 alkyl, C 1-6 alkoxy, and C 3-6 cycloalkyl.

26. The method of claim 24 , wherein:

R 4 is selected from the group consisting of hydrogen, halogen atoms, and C 1-3 alkyl.

27. The method of claim 24 , wherein R 2 and R 3 are each independently selected from the group consisting of F, Cl, and Br.

28. The method of claim 24 , wherein R 2 and R 3 are Cl.

29. The method of claim 1 , wherein the compound of Formula (I) is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

30. The method of claim 1 , wherein the compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.

31. The method of claim 1 , wherein the compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.

32. The method of claim 11 , wherein the compound of Formula (I) is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

33. The method of claim 11 , wherein the compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.

34. The method of claim 11 , wherein the compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.

Assignments (4)

Priority Claims (1)

Continuity (6)

References Cited (240)

Cited By (3)

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