Granted Patent B2

US 12,577,233 · App. 18/001,371 · Granted Mar 17, 2026

Inventors: Kevin James Gagnon (Acton, MA); Jicong Li (Cambridge, MA); Ales Medek (Winchester, MA); Jack Raphael Minchom (Somerville, MA); Yi Shi (Natick, MA); Muna Shrestha (Belmont, MA); Faith Witkos (Attleboro, MA)

Assignee: Vertex Pharmaceuticals Incorporated

C07D403/12C07B2200/13

Abstract

Claims (74)

1 . A solid form of Compound I:

wherein the solid form is selected from:

(a) Ethanol solvate Form A;

(b) Ethanol solvate Form B;

(c) Citric acid cocrystal Form A; and

(d) Form B.

2 . The solid form of Compound I according to claim 1 , wherein the solid form is Ethanol solvate Form A, characterized by an X-ray powder diffractogram having a signal at 14.4±0.2 and/or 21.5±0.2 two-theta.

3 . The solid form of Compound I according to claim 1 , wherein the solid form is Ethanol solvate Form A, characterized by an X-ray powder diffractogram having (a) a signal at 14.4±0.2 and/or 21.5±0.2 two-theta; and (b) a signal at 23.5±0.2 and/or 24.8±0.2 two-theta.

4 . The solid form of Compound I according to claim 1 , wherein the solid form is Ethanol solvate Form A, characterized by an X-ray powder diffractogram substantially similar to that in FIG. 1 .

5 . The solid form of Compound I according to claim 1 , wherein the solid form is Ethanol solvate Form A, characterized by a 13 C NMR spectrum having one or more signals selected from 18.0±0.2 ppm, 57.5±0.2 ppm, 58.0±0.2 ppm, 116.7±0.2 ppm, and 128.0±0.2 ppm.

6 . The solid form of Compound I according to claim 1 , wherein the solid form is Ethanol solvate Form A, characterized by a 19 F NMR spectrum having a signal at one or more ppm values selected from −136.0±0.2 ppm, −131.2±0.2 ppm, −126.0±0.2 ppm, −122.9±0.2 ppm, −113.0±0.2 ppm, and −111.5±0.2 ppm.

7 . The solid form of Compound I according to claim 1 , wherein the solid form is Ethanol solvate Form B, characterized by an X-ray powder diffractogram having a signal at 11.4±0.2 and/or 15.3±0.2 two-theta.

8 . The solid form of Compound I according to claim 1 , wherein the solid form is Ethanol solvate Form B, characterized by an X-ray powder diffractogram having (a) a signal at 11.4±0.2 and/or 15.3±0.2 two-theta; and (b) a signal at 19.5±0.2 two-theta.

9 . The solid form of Compound I according to claim 1 , wherein the solid form is Ethanol solvate Form B, characterized by an X-ray powder diffractogram substantially similar to that in FIG. 4 .

10 . The solid form of Compound I according to claim 1 , wherein the solid form is Citric acid cocrystal Form A, characterized by an X-ray powder diffractogram having a signal at one or more two-theta values selected from 4.7±0.2, 18.8±0.2, 21.9±0.2, and 23.5±0.2.

11 . The solid form of Compound I according to claim 1 , wherein the solid form is Citric acid cocrystal Form A, characterized by an X-ray powder diffractogram having a signal at two or more two-theta values selected from 4.7±0.2, 18.8±0.2, 21.9±0.2, and 23.5±0.2.

12 . The solid form of Compound I according to claim 1 , wherein the solid form is Citric acid cocrystal Form A, characterized by an X-ray powder diffractogram substantially similar to that in FIG. 7 .

13 . The solid form of Compound I according to claim 1 , wherein the solid form is Form B, characterized by an X-ray powder diffractogram having a signal at two or more two-theta values selected from 11.8±0.2, 12.2±0.2, and 13.5±0.2.

14 . The solid form of Compound I according to claim 1 , wherein the solid form is Form B, characterized by an X-ray powder diffractogram substantially similar to that in FIG. 10 .

15 . The solid form of Compound I according to claim 1 , wherein the solid form is Form B, characterized by a 19 F NMR spectrum having a signal at three or more ppm values selected from −129.1±0.2 ppm, −128.4±0.2 ppm, −120.6±0.2 ppm, −115.3±0.2 ppm, and −107.9±0.2 ppm.

16 . The solid form of Compound I according to claim 1 , wherein the solid form is Form B, characterized by a 19 F NMR spectrum having signals at −129.1±0.2 ppm, −128.4±0.2 ppm, −120.6±0.2 ppm, −115.3±0.2 ppm, and −107.9±0.2 ppm.

17 . The solid form of Compound I according to claim 1 , wherein the solid form is Form B, characterized by a 19 F NMR spectrum substantially similar to that in FIG. 15 .

18 . A pharmaceutical composition comprising the solid form of Compound I according to claim 1 and a pharmaceutically acceptable carrier.

19 . A method of treating APOL1 mediated kidney disease comprising administering to a patient in need thereof the solid form of Compound I according to claim 1 .

20 . The method according to claim 19 , wherein the APOL1 mediated kidney disease is selected from ESKD, NDKD, FSGS, HIV-associated nephropathy, arterionephrosclerosis, lupus nephritis, microalbuminuria, and chronic kidney disease.

21 . The method according to claim 19 , wherein the APOL1 mediated kidney disease is associated with APOL1 genetic alleles selected from homozygous G1: S342G:I384M and homozygous G2: N388del:Y389del.

22 . The method according to claim 19 , wherein the APOL1 mediated kidney disease is associated with compound heterozygous G1: S342G:I384M and G2: N388del:Y389del APOL1 genetic alleles.

23 . A method of inhibiting APOL1 activity comprising contacting said APOL1 with the solid form of Compound I according to claim 1 .

24 . A method of preparing ethanol solvate Form A of Compound I:

comprising:

mixing Compound I Form A with anhydrous ethanol;

cooling to 5° C. and stirring for about 2 weeks; and

isolating ethanol solvate Form A of Compound I.

25 . A method of preparing ethanol solvate Form B of Compound I:

comprising:

mixing Compound I Form A with anhydrous ethanol;

cooling to 5° C. and stirring for about 2 weeks;

isolating a wet cake;

drying under vacuum at 45° C.; and

isolating ethanol solvate Form B of Compound I.

26 . A method of preparing citric acid cocrystal Form A of Compound I:

comprising:

combining Compound I Form A and citric acid in a ball mill vessel with propanol/water;

shaking at 15 Hz for about 30 minutes; and

isolating citric acid cocrystal Form A of Compound I.

27 . A method of preparing Form A of Compound I:

selected from:

(a) a method comprising:

repeated distillation of Compound I in 2-methyltetrahydrofuran;

heating to 62.5° C. in a solvent comprising methanol for about 35 minutes;

cooling to 25° C.; and

isolating Form A of Compound I;

(b) a method comprising:

mixing Compound I in 2-methyltetrahydrofuran and a solvent comprising methanol;

heating to 62.5° C. for about 20 minutes;

charging with heptane over about 1 hour;

adding seed crystals of Form A of Compound I;

holding at 62.5° C. for about 1 hour;

charging with heptane over about 5.5 hours;

cooling to 25° C.; and

isolating Form A of Compound I; or

(c) a method comprising:

mixing Compound I in 2-methyltetrahydrofuran and a solvent comprising ethanol;

heating to 62.5° C. for about 20 minutes;

charging with heptane over about 5 minutes;

adding seed crystals of Form A of Compound I;

holding at 62.5° C. for about 1 hour;

charging with heptane over about 12 hours;

cooling to 25° C.; and

isolating Form A of Compound I.

28 . A method of preparing Form B of Compound I:

comprising:

exposing Compound I Amorphous Form to heptane vapor at ambient temperature for about 1 month; and

isolating Form B of Compound I.

Assignments (1)

Continuity (2)

References Cited (172)