Activating pyruvate kinase R

Patent metadata

Field	Value
Publication number	US-11071725-B2
Application number	US-202015929436-A
Country	US
Kind code	B2
Filing date	May 1, 2020
Priority date	Sep 19, 2018
Publication date	Jul 27, 2021
Grant date	Jul 27, 2021

Abstract

This disclosure provides compounds and compositions for activating pyruvate kinase R (PKR) and related methods of manufacturing and using these compounds and compositions.

First claim

We claim:

1. A process for preparing a compound of Formula I:

comprising coupling compound 5 with 3-hydroxy-2-phenylpropanoic acid to afford the compound of Formula I:

2. The process of claim 1 , wherein compound 5 is obtained by a process comprising deprotecting compound 4 to afford compound 5:

3. The process of claim 2 , wherein compound 4 is obtained by a process comprising coupling compound 3 with tert-butyl 1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-carboxylate to afford compound 4:

4. The process of claim 1 , wherein the compound of Formula I is Compound 1:

5. A compound selected from the group consisting of:

6. The compound of claim 5 , wherein the compound is:

7. The compound of claim 5 , wherein the compound is:

8. The process of claim 4 , comprising coupling compound 5 with (S)-3-hydroxy-2-phenylpropanoic acid to afford Compound 1:

9. A reaction mixture composition comprising:
2-[2H,3H-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole;
3-hydroxy-2-phenylpropanoic acid; and
1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluoro-phosphate (HATU).

10. The reaction mixture composition of claim 9 , wherein the 2-[2H,3H-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluoro-phosphate (HATU) are combined in a mole ratio of 1.0:2.0.

11. The reaction mixture composition of claim 9 , wherein the 2-[2H,3H-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole, 3-hydroxy-2-phenylpropanoic acid; and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluoro-phosphate (HATU) are combined in a mole ratio of 1.0:1.2:2.0.

12. The reaction mixture composition of claim 9 , further comprising (S)-1-(5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-hydroxy-2-phenylpropan-1-one (Compound 1).

13. A reaction mixture composition comprising:
7-((3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine;
(S)-3-hydroxy-2-phenylpropanoic acid; and
1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluoro-phosphate (HATU).

14. The reaction mixture composition of claim 13 , wherein the 7-((3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluoro-phosphate (HATU) are combined in a mole ratio of about 0.4:0.5.

15. The reaction mixture composition of claim 13 , wherein the 7-((3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine, (S)-3-hydroxy-2-phenylpropanoicacid, and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluoro-phosphate (HATU) are combined in a mole ratio of about 0.4:0.5:0.5.

16. The reaction mixture composition of claim 13 , further comprising (S)-1-(5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-hydroxy-2-phenylpropan-1-one (Compound 1).

17. A process comprising an amide coupling of Compound 5

and tropic acid in the presence of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluoro-phosphate (HATU) to generate a composition comprising (S)-1-(5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-hydroxy-2-phenylpropan-1-one (Compound 1).

18. A process of preparing a composition comprising (S)-1-(5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-hydroxy-2-phenylpropan-1-one (Compound 1), the process comprising the step of amide coupling of Compound 5

and tropic acid at a temperature of about 20 deg. C. in the presence of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluoro-phosphate (HATU) to generate a composition comprising (S)-1-(5-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-hydroxy-2-phenylpropan-1-one (Compound 1).

19. The process of claim 18 , further comprising the steps of:
a. treating 7-bromo-2H,3H-[1,4]dioxino[2,3-b]pyridine with a mixture of n-butyl lithium and dibutylmagnesium followed by sulfuryl chloride to give sulfonyl chloride 3:

b. treating sulfonyl chloride 3 with tert-butyl 1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-carboxylate in the presence of triethylamine (TEA) to obtain a Boc-protected monosulfonamide (Compound 4):

c. treating Compound 4 with trifluoroacetic acid (TFA) to obtain Compound 5

20. A process comprising the step of combining compound 5

with (S)-3-hydroxy-2-phenylpropanoic acid and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluoro-phosphate (HATU) in a reaction mixture to obtain a composition comprising a PKR Activating Compound characterized by 1H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J=2.0 Hz, 1H), 7.61 (d, J=2.0 Hz, 1H), 7.31-7.20 (m, 5H), 4.75 (t, J=5.2 Hz, 1H), 4.50-4.47 (m, 2H), 4.40-4.36 (m, 1H), 4.32-4.29 (m, 2H), 4.11-3.87 (m, 8H), 3.80-3.77 (m, 1H), 3.44-3.41 (m, 1H), LC-MS (ESI) m/z: calculated for C22H23N3O6S: 457.13; and 458.0 [M+H]+.

21. The process of claim 20 , wherein the reaction mixture is maintained at about 20 degrees C. to obtain the composition comprising the PKR Activating Compound.

Assignees

• Forma Therapeutics Inc

Inventors

• Ericsson Anna
• Green Neal
• Gustafson Gary
• Lancia Jr David R
• Marshall Gary
• Mitchell Lorna
• Richard David
• Wang Zhongguo

Classifications

• A61K9/2054

  Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose · CPC title

• A61P7/06

  Antianaemics · CPC title

• C07D491/056

  with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring · CPC title

• A61K31/436 Primary

  the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title