EP-4739658-A1 - SYNTHESIS OF PYRUVATE KINASE ACTIVATORS

Abstract

Provided herein are methods for preparing activators of Pyruvate Kinase (PK) or a salt or a hydrate thereof.

Inventors

• FANDRICK, Daniel, R.
• LEUNG, Chun Yuen
• CRANE, SHELDON
• LACHANCE, NICOLAS
• LE ROUX, Antoine
• PATEL, JIGNESH SURENDRABHAI
• VALAMALE, ASHALATHA BADIADKA

Assignees

• Agios Pharmaceuticals, Inc.

Dates

Publication Date

20260513

Application Date

20240705

Claims (1)

1. Listing of Claims: 1. A method of preparing a compound of Formula (A-1): or a salt thereof, wherein R 1 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 cyanoalkyl C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 3 -C 6 cycloalkyl, wherein said C 3 -C 6 cycloalkyl is optionally substituted with 1 to 3 groups selected from halo, hydroxyl, NH 2 , and CN; X is halo; L is a bond or C 1 -C 6 alkylene; and Q is C 3 -C 6 cycloalkyl, 5-14 membered heterocyclyl, 6-12 membered aryl, or 5-14 membered heteroaryl, each of which is optionally substituted with 1-3 groups selected from halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, hydroxyl, C 1 -C 6 aminoalkyl, -NH 2 , - NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , CN, and NO 2 ; the method comprising reacting a compound of Formula (A-2): (A-2) or a salt thereof, with a compound of Formula (A-3): to form the compound of Formula (A-1), or a salt thereof. 2. The method of claim 1, wherein R 1 is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. 3. The method of claim 1 or claim 2, wherein R 1 is methyl. 4. The method of any one of claims 1-3, wherein X is Cl. 5. The method of any one of claims 1-4, wherein L is C 1 -C 6 alkylene. 6. The method of any one of claims 1-5, wherein L is –CH 2 –. 7. The method of any one of claims 1-6, wherein Q is a 6-12 membered aryl, or 5-14 membered heteroaryl, each of which is optionally substituted with 1 to 3 groups selected from halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, hydroxyl, C 1 -C 6 aminoalkyl, NH 2 , -NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , CN, and NO 2. 8. The method of any one of claims 1-7, wherein Q is a 5-7 membered heteroaryl substituted with -NH 2. 9. The method of any one of claims 1-8, wherein the compound of Formula (A-1) is: 10. The method of any one of claims 1-9, wherein the compound of Formula (A-2) is: or a bis-acid salt thereof. 11. The method of any one of claims 1-9, wherein the compound of Formula (A-2) is: a tautomer or hydrate thereof. 12. The method of any one of claims 1-11, wherein the compound of Formula (A-3) is: . 13. The method of any one of claims 1-12, wherein the compound of Formula (A-2) or salt thereof is reacted with the compound of Formula (A-3) in the presence of an acid and one or more solvents. 14. The method of any of claims 1-13, wherein the compound of Formula (A-3) is reacted with a bis acid salt of the compound of Formula (A-2) in one or more solvents. 15. The method of claim 11 or 12, wherein the acid is selected from hydrochloric acid, acetic acid, phosphoric acid, sulfuric acid, citric acid, formic acid, methanesulfonic acid and p-toluenesulfonic acid. 16. The method of any one of claims 1-15, wherein at least one solvent is a polar protic solvent. 17. The method of claim 16, wherein at least one polar protic solvent is selected from water, methanol, ethanol, n-propanol, i-propanol, and t-butanol, or any combination thereof. 18. The method of claim 17, wherein at least one polar protic solvent is ethanol or n- propanol. 19. The method of claim 17, wherein the polar protic solvent is a mixture of ethanol and i-propanol. 20. A method of preparing a compound of Formula (A-3), wherein R 1 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 cyanoalkyl C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 3 -C 6 cycloalkyl, wherein said C 3 -C 6 cycloalkyl is optionally substituted with 1-3 groups selected from halo, hydroxyl, NH 2 , and CN; and X is halo; the method comprising: hydrolyzing a compound of Formula (A-6): wherein R 2 is C 1 -C 6 alkyl, to form compound of Formula (A-3). 21. The method of claim 20, wherein the compound of Formula (A-6) is hydrolyzed in the presence of a base and one or more solvents. 22. The method of claim 21, wherein the base is selected from lithium hydroxide (LiOH), calcium hydroxide (Ca(OH) 2 ), potassium hydroxide (KOH), sodium hydroxide (NaOH), and barium hydroxide (Ba(OH) 2 ). 23. The method of claim 22, wherein the base is sodium hydroxide (NaOH). 24. The method of any one of claims 20-23, wherein the compound of Formula (A-6) is hydrolyzed in the presence of water and one or more solvents. 25. The method of any one of claims 20-24, wherein the compound of Formula (A-6) is hydrolyzed in the presence of water and at least one solvent that is a polar aprotic solvent. 26. The method of claim 25, wherein at least one polar aprotic solvent is selected from dimethylacetamide (DMAC), 2-methyl tetrahydrofuran (2-Me THF), tetrahydrofuran (THF), acetone, dimethylformamide (DMF), acetonitrile (ACN), and dimethylsulfoxide (DMSO), or any combination thereof. 27. The method of claim 26, wherein at least one polar aprotic solvent is THF. 28. The method of any one of claims 20-27, wherein the compound of Formula (A-6) is prepared by reacting a compound of Formula (A-5): with phosphorus oxychloride (POCl 3 ), dimethylformamide (DMF), and one or more additional solvents to form the compound of Formula (A-6). 29. The method of claim 28, wherein one or more additional solvents is a non-polar solvent. 30. The method of claim 29, wherein the non-polar solvent is selected from dioxane, dichloroethane, benzene, toluene, chlorobenzene, dichlorobenzene, and xylene. 31. The method of claim 30, wherein the non-polar solvent is chlorobenzene. 32. The method of any one of claims 28-31, wherein the compound of Formula (A-5) is prepared by reacting a compound of Formula (A-4): with a halogenating agent, a base and at least one solvent to form the compound of Formula (A-5). 33. The method of claim 32, wherein the base is selected from, lithium diisopropylamide (LDA), sodium bis(trimethylsilyl)amide (NaHMDS), lithium bis(trimethylsilyl)amide (LiHMDS), potassium bis(trimethylsilyl)amide (KHMDS), and sodium hydride (NaH). 34. The method of claim 33, wherein the base is lithium bis(trimethylsilyl)amide (LiHMDS). 35. The method of any one of claims 31-34, wherein the halogenating reagent is selected from elemental halogen, carbon tetrachloride, hexachloroethane, carbon tetrabromide, n- bromosuccinmide (NBS), and n-chlorosuccinimide (NCS). 36. The method of claim 35, wherein the halogenating reagent is hexachloroethane. 37. The method of any one of claims 31-36, wherein at least one solvent is a polar aprotic solvent. 38. The method of claim 37, wherein the polar aprotic solvent is selected from dimethylacetamide (DMAC), 2-methyl tetrahydrofuran (2-Me THF), tetrahydrofuran (THF), acetonitrile (ACN), and dimethylsulfoxide (DMSO), or any combination thereof. 39. The method of claim 38, wherein the polar aprotic solvent is THF. 40. The method of any one of claims 22-39, wherein R 1 is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. 41. The method of any one of claims 20-40, wherein R 1 is C 1 -C 6 alkyl. 42. The method of any one of claims 20-41, wherein R 1 is methyl. 43. The method of any one of claims 20-42, wherein X is –Cl. 44. The method of any one of claims 20-43, wherein R 2 is ethyl. 45. The method of any one of claims 20-44, wherein the compound of Formula (A-3) is . 46. The method of any one of claims 32-45, wherein the compound of Formula (A-4) is . 47. The method of any one of claims 20-46, wherein the compound of Formula (A-6) is . 48. The method of any one of claims 28-47, wherein the compound of Formula (A-5) is . \49. A method of preparing a compound of Formula (B-1): (B-1), wherein R 1 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 cyanoalkyl C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 3 -C 6 cycloalkyl, wherein said C 3 -C 6 cycloalkyl is optionally substituted with 1-3 groups selected from halo, hydroxyl, NH2, and CN; R 4 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 6-12 membered aryl, or 5-14 membered heteroaryl, wherein said 6-12 membered aryl or 5-14 membered heteroaryl is optionally substituted with 1 to 3 groups selected from halo or C 1 -C 6 alkyl; L is a bond or C 1 -C 6 alkylene; and Q is C 3 -C 6 cycloalkyl, 5-14 membered heterocyclyl, 6-12 membered aryl, or 5-14 membered heteroaryl, each of which is optionally substituted with 1-3 groups selected from halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, hydroxyl, C 1 -C 6 aminoalkyl, -NH 2 , - NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , CN, and NO 2 ; the method comprising: reacting a compound of Formula (A-2): (A-2) or a salt thereof, with a compound of Formula (B-5): to form the compound of Formula (B-1). 50. The method of claim 49, wherein the compound of Formula (A-2) or a salt thereof is reacted with the compound of Formula (B-5) in the presence of an acid and at least one solvent. 51. The method of claim 50, wherein the acid is selected from hydrochloric acid, trifluoroacetic acid, acetic acid, phosphoric acid, sulfuric acid, citric acid, formic acid, and carbonic acid. 52. The method of any one of claims 49-51, wherein at least one solvent is a polar protic solvent. 53. The method of claim 52 wherein the polar protic solvent is an alcohol. 54. The method of claim 53, wherein at least one polar protic solvent is selected from methanol, ethanol, n-propanol, i-propanol, sec- butanol, and t-butanol, or any combination thereof. 55. The method of claim 54, wherein at least one polar protic solvent is ethanol, i- propanol or n-propanol or a mixture thereof. 56. The method of any one of claims 49-55, wherein the compound of Formula (B-5) is prepared by hydrolyzing a compound of the Formula (B-4): wherein R 2 is C 1 -C 6 alkyl. 57. The method of claim 56, wherein the compound of Formula (B-4) is hydrolized in the presence of a base and one or more solvents. 58. The method of claim 57, wherein the base is selected from lithium hydroxide (LiOH), calcium hydroxide (Ca(OH) 2 ), potassium hydroxide (KOH), sodium hydroxide (NaOH), and barium hydroxide (Ba(OH) 2 ). 59. The method of claim 58, wherein the base is lithium hydroxide (LiOH) or sodium hydroxide (NaOH). 60. The method of any one of claims 56-59, wherein at least one solvent is water. 61. The method of any one of claims 56-60, wherein the compound of Formula (B-4) is hydrolyzed in water and a polar aprotic solvent. 62. The method of claim 61, wherein the polar aprotic solvent is selected from dimethylacetamide (DMAC), 2-methyl tetrahydrofuran (2-Me THF), tetrahydrofuran (THF), dimethylformamide (DMF), acetonitrile (ACN), and dimethylsulfoxide (DMSO), or any combination thereof. 63. The method of claim 62, wherein the polar aprotic solvent is THF. 64. The method of any one of claims 56-63, wherein the compound of Formula (B-4) is prepared by reacting a compound of Formula (B-3): with an oxidizing agent in at least one solvent to form a compound of Formula (B-4). 65. The method of claim 64, wherein the oxidizing agent is hydrogen peroxide and sodium tungstate (Na 2 WO 4 ). 66. The method of claim 63-65, wherein at least one solvent is a non-polar solvent. 67. The method of claim 66, wherein at least one non-polar solvent is selected from dichloromethane, toluene, chlorobenzene, dichlorobenzene, and xylene, or any combination thereof. 68. The method of claim 67, wherein the non-polar solvent is chlorobenzene. 69. The method of any one of claims 63-68, wherein the method further comprises at least one phase transfer catalyst. 70. The method of claim 69, wherein the phase transfer catalyst is methyl tri- octylammonium hydrogen sulfate. 71. The method of any one of claims 63-70, wherein the method further comprises at least one acid. 72. The method of claim 71, wherein the acid is phenyl phosphonic acid. 73. The method of any one of claims 63-72, wherein the compound of Formula (B-3) is prepared by reacting a compound of Formula (B-2): with phosphorus oxychloride (POCl 3 ), dimethylformamide (DMF), and one or more solvent(s) to form the compound of Formula (B-3). 74. The method of claim 73, wherein one solvent is a non-polar solvent. 75. The method of claim 74, wherein the non-polar solvent is selected from toluene, chlorobenzene, dichlorobenzene, and xylene, or any combination thereof. 76. The method of claim 75, wherein the non-polar solvent is chlorobenzene. 77. The method of any one of claims 47-76, wherein R 1 is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. 78. The method of any one of claims 47-77, wherein R 1 is C 1 -C 6 alkyl. 79. The method of any one of claims 47-78, wherein R 1 is methyl. 80. The method of any one of claims 56-79, wherein R 2 is ethyl. 81. The method of any one of claims 56-80, wherein R 4 is 6-12 membered aryl optionally substituted with 1 to 3 groups selected from halo and C 1 -C 6 alkyl. 82. The method of any one of claims 56-81, wherein R 4 is 4-methyl benzene. 83. The method of any one of claims 49-82, wherein L is C 1 -C 6 alkylene. 84. The method of any one of claims 49-83, wherein L is –CH 2 –. 85. The method of any one of claims 49-84, wherein Q is a 6-12 membered aryl, or 5-14 membered heteroaryl, each of which is optionally substituted with 1-3 groups selected from halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, hydroxyl, C 1 -C 6 aminoalkyl, -NH 2 , - NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , -CN, and –NO 2 . 86. The method of any one of claims 49-85, wherein Q is a 5-7 membered heteroaryl substituted with -NH 2 . 87. The method of any one of claims 49-86, wherein the compound of Formula (B-1) is . 88. The method of any one of claims 73-87, wherein the compound of Formula (B-2) is . 89. The method of any one of claims 64-88, wherein the compound of Formula (B-3) is . 90. The method of any one of claims 56-89, wherein the compound of Formula (B-4) is . 91. The method of any one of claims 49-90, wherein the compound of Formula (B-5) is . 92. The method of any one of claims 49-91, wherein the compound of Formula (A-2) is: . 93. A compound having the structure: or a salt, tautomer or hydrate thereof. 94. A compound having the structure: or a salt, tautomer or hydrate thereof. 95. A compound having the structure: or a salt, tautomer or hydrate thereof. 96. A compound having the structure: or a salt, tautomer or hydrate thereof. 97. A compound having the structure: or a salt, tautomer or hydrate thereof. 98. A compound having the structure: or a salt, tautomer or hydrate thereof. 99. A compound having the structure: or a salt, tautomer or hydrate thereof. 100. A compound having the structure: bis acid salt thereof. 101. A compound having the structure: or a tautomer or hydrate thereof.

Description

SYNTHESIS OF PYRUVATE KINASE ACTIVATORS RELATED APPLICATIONS [0001] This application claims priority to U.S. Provisional Application No.63/525,079, filed July 05, 2023, the entirety of which is incorporated herein by reference. BACKGROUND [0002] Pyruvate kinase (PK) is a metabolic enzyme that converts phosphoenolpyruvate to pyruvate during glycolysis. Four PK isoforms exist in mammals: the L and R isoforms are expressed in liver and red blood cells, the M1 isoform is expressed in most adult tissues, and the M2 isoform is a splice variant of M1 expressed during embryonic development. A well- known difference between the M1 and M2 isoforms of PK is that M2 is a low-activity enzyme that relies on allosteric activation by the upstream glycowlytic intermediate, fructose- 1,6-bisphosphate (FBP), whereas M1 is a constitutively active enzyme. PK activators can be used to treat a number of different disorders including PKD (Pyruvate Kinase Deficiency), thalassemia (e.g., alpha and beta-thalassemia), hereditary elliptocytosis, abetalipoproteinemia or Bassen-Kornzweig syndrome, sickle cell disease, paroxysmal nocturnal hemoglobinuria, and various anemias which include congenital anemias (e.g., enzymopathies) and hemolytic anemias (e.g. hereditary and/or congenital hemolytic anemia, acquired hemolytic anemia, chronic hemolytic anemia caused by phosphoglycerate kinase deficiency, anemia due to MDS (myelodysplastic syndromes), non-spherocytic hemolytic anemia and hereditary spherocytosis). SUMMARY [0003] Provided herein are synthetic methods for preparing pyruvate kinase (PK) activators, or a salt or a hydrate thereof. Such activators may be prepared using compounds having the Formula (A-1) and/or Formula (B-1): wherein X, R1, R4, and Q are as defined herein. [0004] Specific PK activators and various intermediates prepared by and/or used in the synthetic methods described herein are also disclosed. BRIEF DESCRIPTION OF THE FIGURES [0005] FIG.1 depicts a Nuclear Magnetic Resonance (NMR) spectrum for tert-butyl 2- (6-((6-aminopyridin-2-yl)methyl)-4-methyl-5-oxo-5,6-dihydro-4H- thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-2-yl)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol- 3-yl)acetate. [0006] FIG.2 depicts a Nuclear Magnetic Resonance (NMR) spectrum for 2-chloro-6- formyl-4-methyl-4H-pyrrolo[2,3-d]thiazole-5-carboxylic acid. DETAILED DESCRIPTION [0007] In one embodiment, provided is a method of preparing a compound of Formula (A-1): or a salt thereof, wherein R1 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl, wherein said C3-C6 cycloalkyl is optionally substituted with 1 to 3 groups selected from halo, hydroxyl, NH2, and CN; X is halo; L is a bond or C1-C6 alkylene; and Q is C3-C6 cycloalkyl, 5-14 membered heterocyclyl, 6-12 membered aryl, or 5-14 membered heteroaryl, each of which is optionally substituted with 1-3 groups selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxyl, C1-C6 aminoalkyl, -NH2, - NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, CN, and NO2; the method comprising reacting a compound of Formula (A-2): with a compound of Formula (A-3): to form the compound of Formula (A-1), or a salt thereof. [0008] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. The terminology used in the description is for describing particular embodiments only and is not intended to be limiting of the disclosure. [0009] The use of any and all examples or exemplary language (e.g., “such as” and “e.g.”) as provided herein, is intended to better illustrate the disclosure and is not a limitation on the scope of the disclosure unless expressly claimed otherwise. Phrases such as “in one aspect” or “in one embodiment” or “in some embodiments” or “in certain embodiments” or “in further embodiments” and the like should not be construed as indicating that such elements occur or exist in isolation or that such elements are not shared by other aspects or embodiments of the disclosure. Rather, it should be understood that all aspects and embodiments may be freely combined with any and all other aspects and embodiments of the disclosure as described herein. No language in the specification should be construed as indicating that any non-claimed element is essential to the practice of the disclosure. [0010] The terms “C1-C6 alkyl” refers to a straight- or branched-chain hydrocarbon group having from 1 to 6 carbon atoms. Examples of C1-C6 alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, iso- butyl), pentyl (C5) (e.g., n-pentyl, 3-pentyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C6) (e.g., n-hexyl). [0011] The term “C1-C6 alkylene” refers to a bivalent radical of a saturated, str