Patent Application

App. No. 18/255,402

Abstract

Claims (130)

1 . A compound of Formula (I):

or a salt thereof.

2 . The compound of claim 1 , wherein the compound is a compound of Formula (Ia):

or a salt thereof.

3 . The compound of claim 1 , wherein the compound is a compound of Formula (Ib):

or a salt thereof.

4 . A compound of Formula (II):

or a salt thereof.

5 . The compound of claim 4 , wherein the compound is a compound of Formula (IIa):

or a salt thereof.

6 . The compound of claim 4 , wherein the compound is a compound of Formula (IIb):

or a salt thereof.

7 . A compound of Formula (III):

or a salt thereof.

8 . The compound of claim 7 , wherein the compound is a compound of Formula (IIIa):

or a salt thereof.

9 . The compound of claim 7 , wherein the compound is a compound of Formula (IIIb):

or a salt thereof.

10 . An isomeric mixture of cis and trans isomers of a compound of Formula (III):

or a salt thereof, wherein the cis isomer is a compound of Formula (IIIa):

or a salt thereof, and the trans isomer is a compound of Formula (IIIb):

or a salt thereof, wherein the ratio of the cis isomer to the trans isomer is greater than or equal to about 4 to 1.

11 . A compound of Formula (IVa):

or a salt thereof.

12 . A compound of Formula (IVb):

or a salt thereof.

13 . An isomeric mixture of cis and trans isomers of a compound of Formula (IV):

or a salt thereof, wherein the cis isomer is a compound of Formula (IVa):

and the trans isomer is a compound of Formula (IVb):

or a salt thereof, wherein the ratio of the cis isomer to the trans isomer is greater than or equal to about 4 to 1.

14 . A compound of Formula V-1:

or a salt thereof, wherein R is an activating group.

15 . The compound of claim 14 , wherein the compound is a compound of Formula V:

or a salt thereof.

16 . The compound of claim 15 , wherein the compound is a compound of Formula (Va):

or a salt thereof.

17 . The compound of claim 15 , wherein the compound is a compound of Formula (Vb):

or a salt thereof.

18 . An isomeric mixture of cis and trans isomers of a compound of Formula (V):

or a salt thereof, wherein the cis isomer is a compound of Formula (Va):

or a salt thereof, and the trans isomer is a compound of Formula (Vb):

or a salt thereof, wherein the ratio of the cis isomer to the trans isomer is greater than or equal to about 4 to 1.

19 . A composition comprising a compound of Formula VI:

or a salt thereof, wherein the composition is substantially free of a compound of Formula (VIa):

or a salt thereof.

20 . The composition of claim 19 , wherein the ratio of the compound of Formula (VI) or a salt thereof and the compound of Formula (VIa) or a salt thereof is greater than or equal to about 97 to 3.

21 . The composition of claim 18 or 19 , wherein the ratio of the compound of Formula (VI) or a salt thereof and the compound of Formula (VIa) or a salt thereof is detected using HPLC.

22 . The composition of any one of claims 18 - 20 , wherein the composition comprises less than 0.1% a compound of Formula (VIa) or a salt thereof by weight of a compound of Formula (VI) or a salt thereof.

23 . A composition comprising a compound of Formula (VII):

or a salt thereof, wherein the composition is substantially free of the compound of Formula (VIIa):

or a salt thereof.

24 . The composition of claim 23 , wherein the ratio of the compound of Formula (VII) or a salt thereof and the compound of Formula (VIIa) or a salt thereof is greater than or equal to about 97 to 3.

25 . A process of preparing a composition comprising a mixture of cis and trans isomers of a compound of Formula (IV):

or a salt thereof, wherein the process comprises:

(a) reacting a compound of Formula (II):

or a salt thereof with an ammonium source in the presence of a solvent, thereby producing a compound of Formula (III):

or a salt thereof; and

(b) reacting a compound of Formula (III) with alkyl acetoacetate, thereby producing a composition comprising a mixture of cis and trans isomers of a compound of Formula (IV) having a greater amount of the cis isomer, Formula (IVa):

or a salt thereof, as compared to the trans isomer, Formula (IVb):

or a salt thereof.

26 . A process of preparing a composition comprising a mixture of cis and trans isomers of a compound of Formula (III) or a salt thereof with an increased ratio of the cis isomer to the trans isomer:

wherein the cis isomer is a compound of Formula (IIIa):

or a salt thereof and the trans isomer is a compound of Formula (IIIb):

or a salt thereof, comprising reacting a compound of Formula (II):

or a salt thereof with an ammonium source in the presence of a solvent, thereby producing a composition comprising a mixture of cis and trans isomers of a compound of Formula (III) or a salt thereof with increased ratio of the cis isomer to the trans isomer.

27 . A process of preparing a compound of Formula (X):

or a salt thereof, comprising the steps of:

(a) reacting a compound of Formula (II):

or a salt thereof with an ammonium source in the presence of a solvent, thereby producing a compound of Formula (III):

or a salt thereof;

(b) reacting a compound of Formula (III) with alkyl acetoacetate, thereby producing an isomeric mixture of a compound of Formula (IV):

or a salt thereof, wherein the isomeric mixture of the compound of Formula (IV) has a greater amount of the cis isomer, Formula (IVa):

or a salt thereof, as compared to the trans isomer, Formula (IVb):

or a salt thereof:

(c) purifying the isomeric mixture of the compound of Formula (IV) or a salt thereof to obtain the compound of Formula (IVa) or a salt thereof;

(d) reacting the compound of Formula (IVa) or a salt thereof with an activating agent, thereby providing a compound of Formula (V-1a):

or a salt thereof,

(e) reacting the compound of Formula (V-1a) or a salt thereof with 5-methyl-3-pyrazolamine, thereby providing a compound of Formula (VI):

or a salt thereof;

(f) reacting the compound of Formula (VI) or a salt thereof with a base, thereby providing a compound of Formula (VII):

or a salt thereof;

(g) reacting the compound of Formula (VII) or a salt thereof with a compound of Formula (VIII):

or a salt thereof, thereby providing the compound of Formula (X) or a salt thereof.

28 . A process of preparing a compound of Formula (X):

or a salt thereof, comprising the steps of:

(a) reacting a compound of Formula (IVa):

or a salt thereof with an activating agent, thereby providing a compound of Formula (V-1a):

or a salt thereof, wherein R is an activating group;

(b) reacting the compound of Formula (V-1a) or a salt thereof with 5-methyl-3-pyrazolamine, thereby providing a compound of Formula (VI):

or a salt thereof;

(c) reacting the compound of Formula (VI) or a salt thereof with a base, thereby providing a compound of Formula (VII):

or a salt thereof; and

(d) reacting a compound of Formula (VII) or a salt thereof with a compound of Formula (VIII):

or a salt thereof, thereby providing a salt of a compound of Formula (X).

29 . The process of claim 27 or 28 , wherein the last step of the process further comprises reacting a salt of a compound of Formula (X) with a base, thereby providing a compound of Formula (X).

30 . The process of claim 29 , wherein the salt of a compound of Formula (X) is an HCl salt.

31 . The process of any one of claims 25 - 27 , 29 , and 30 , wherein the ratio of the cis isomer to the trans isomer of a compound of Formula (III) is at least 4 to 1.

32 . The process of any one of claims 25 , 27 , and 29 - 31 , wherein the ratio of the cis isomer to the trans isomer of a compound of Formula (IV) is at least 4 to 1.

33 . The process of any one of claims 25 , 27 , and 29 - 32 , wherein step (a) further comprises heating the solvent.

34 . The process of claim 26 and 30 - 33 , further comprising heating the solvent to reflux.

35 . The process of claim 25 , 27 , and 29 - 32 , wherein step (a) further comprises heating the solvent to about 40° C. or higher, or to about 50° C. or higher.

36 . The process of claim 26 and 30 - 32 , further comprising heating the solvent to about 50° C. or higher.

37 . The process of any one of claims 25 - 36 , wherein the solvent is a polar organic solvent.

38 . The process of claim 25 - 37 , wherein the solvent is an alcohol.

39 . The process of claim 25 - 38 , wherein the solvent is methanol.

40 . The process of any one of claims 25 , 27 , and 29 - 39 , wherein the alkyl acetoacetate is methyl acetoacetate.

41 . The process of any one of claims 27 - 40 , wherein the activating agent is a methanesulfonyl agent or methanesulfonyl chloride and R is-OMs.

42 . The process of any one of claims 27 - 41 , wherein the base is a metal hydroxide.

43 . The process of any one of claims 27 - 42 , wherein the metal hydroxide is sodium hydroxide.

44 . The process of any one of claims 27 - 43 , wherein the ammonium source is NH 3 or NH 4 Cl.

45 . A process of preparing a composition comprising a mixture of cis and trans isomers of a compound of Formula (X) having a majority of the cis isomer configuration:

the process comprising:

reacting a compound of Formula (VII):

or a salt thereof, with a compound of Formula (VIII):

or a salt thereof, thereby providing a composition comprising a mixture of cis and trans isomers of the compound of Formula (X) having a majority of a cis isomer configuration.

46 . The process of claim 45 , wherein the composition) having a majority of the cis isomer configuration has a cis:trans molar ratio of from 4:1 to about 99:1.

47 . The process of claim 45 or 46 , wherein the composition having a majority of the cis isomer configuration has a cis:trans molar ratio of from about 97:3 to about 99:3.

48 . The process of any one of claims 45 - 47 , further comprising a process of preparing the compound of Formula (VII) or a salt thereof comprising:

(a) reacting a compound of Formula (IVa):

or a salt thereof with an activating agent, thereby providing a compound of Formula (V-1a):

or a salt thereof, wherein R is an activating group;

(b) reacting the compound of Formula (V-1a) or a salt thereof with 5-methyl-3-pyrazolamine, thereby providing a compound of Formula (VI):

or a salt thereof,

(c) reacting the compound of Formula (VI) or a salt thereof with a base, thereby providing the compound of Formula (VII) or a salt thereof.

49 . The process of claim 48 , wherein the activating agent is a methanesulfonyl agent and R is —OMs.

50 . A geometric isomeric mixture comprising a compound of Formula (X):

prepared with a process of claim 45 or 46 , wherein the geometric isomer mixture has a cis:trans molar ratio of from about 4:1 to about 99:1.

51 . The geometric isomeric mixture of claim 50 , wherein the geometric isomer mixture has a cis:trans molar ratio of from about 4:1 to about 99:3.

52 . The geometric isomeric mixture of claim 50 , wherein the geometric isomer mixture has a cis:trans molar ratio of from about 90:10 to about 99:1.

53 . The geometric isomeric mixture of claim 50 , wherein the geometric isomer mixture has a cis:trans molar ratio of from about 90:3 to about 99:3.

Assignments (8)