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US 2026/0306462 A1Published application
Treatment of clonal hematopoietic disorders using kinase inhibitors
OwnerRicardo Macarrón Larumbe, Ekaterine Asatiani +13inventors
InventorsRicardo Macarrón Larumbe, Ekaterine Asatiani, Hang Thi Dang, Brent Douty, Xin Li, Michael Liang, Patrick Mayes, Minh Nguyen, Evan Styduhar, Oleg Vechorkin, Anlai Wang, Xiaozhao Wang, Hai Fen Ye, Eddy W. Yue, Peng Zhao
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Abstract
The present application provides methods for the treatment of clonal hematopoietic disorders using compounds that modulate kinase activity or antibodies that binds to human mutant calreticulin (CALR).
Claims22
A method of treating clonal hematopoiesis of indeterminate potential in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound selected from:
- methyl ((1R,3R)-3-(7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-3-(methyl-d3)-8-(1-(methyl-d3)-1H-indazol-5-yl)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate;
- methyl ((1R,3R)-3-(7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-8-(4-fluorophenyl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate;
- methyl ((1R,3R)-3-(8-(1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl)-7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate;
- methyl ((3R)-3-(6-((1-(1-carbamoylcyclopropyl)-4-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)-3-(methyl-d3)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclopentyl-1-d)carbamate;
- methyl ((3R)-3-(6-((1-(1-carbamoylcyclobutyl)-4-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)-3-(methyl-d3)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclopentyl-1-d)carbamate;
- methyl ((1R,3R)-3-(6-((1-(1-carbamoylcyclobutyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)-3-(methyl-d3)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclopentyl-1-d)carbamate;
- methyl ((3R)-3-(6-((1-(1-carbamoylcyclobutyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)-3-(methyl-d3)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclopentyl-1-d)carbamate;
- methyl ((1R,3R)-3-(6-((7-(1-carbamoyl-3-fluorocyclobutyl)imidazo[1,5-b]pyridazin-2-yl)amino)-3-(methyl-d3)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclopentyl-1-d)carbamate;
- methyl ((1R,3R)-3-(6-((7-(1-carbamoyl-2-methylcyclopropyl)imidazo[1,5-b]pyridazin-2-yl)amino)-3-(methyl-d3)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclopentyl-1-d)carbamate;
- methyl ((1R,3R)-3-(6-((7-(1-carbamoyl-3-fluorocyclobutyl)-5-cyclopropylimidazo[1,5-b]pyridazin-2-yl)amino)-3-(methyl-d3)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclopentyl-1-d)carbamate;
- methyl ((1R,3R)-3-(6-((7-(1-carbamoyl-3-fluorocyclobutyl)-5-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-b]pyridazin-2-yl)amino)-3-(methyl-d3)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclopentyl-1-d)carbamate;
- methyl ((1R,3R)-3-(6-((7-(1-carbamoyl-3-fluorocyclobutyl)-5-cyclobutylimidazo[1,5-b]pyridazin-2-yl)amino)-3-(methyl-d3)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclopentyl-1-d)carbamate;
- methyl ((1R,3R)-3-(6-((7-(1-carbamoyl-3-fluorocyclobutyl)imidazo[1,5-b]pyridazin-2-yl-5-d)amino)-3-(methyl-d3)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclopentyl-1-d)carbamate;
- methyl ((1R,3R)-3-(6-((7-(1-carbamoyl-3-fluorocyclobutyl)-5-(2-hydroxypropan-2-yl)imidazo[1,5-b]pyridazin-2-yl)amino)-3-(methyl-d3)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclopentyl-1-d)carbamate;
- methyl ((1R,3R)-3-(6-((1-(1-carbamoylcyclobutyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)-3-(methyl-d3)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclopentyl-1,2,2,5,5-d5)carbamate;
- methyl ((1R,3R)-3-(6-((1-(1-carbamoylcyclobutyl)-4-(trans-4-hydroxycyclohexyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)-3-(methyl-d3)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclopentyl-1-d)carbamate;
- methyl ((1R,3R)-3-(6-((1-(1-carbamoyl-3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)-3-(methyl-d3)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclopentyl-1-d)carbamate;
- methyl ((1R,3R)-3-(6-((1-(1-carbamoyl-3-methoxycyclobutyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)-3-(methyl-d3)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclopentyl-1-d)carbamate;
- methyl ((1R,3R)-3-(6-((1-(1-carbamoyl-2-methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)-3-(methyl-d3)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclopentyl-1-d)carbamate;
- methyl ((1R,3R)-3-(6-((1-(1-carbamoylcyclobutyl)-3-(1-hydroxyethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)-3-(methyl-d3)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclopentyl-1-d)carbamate;
- methyl ((1R,3R)-3-(6-((1-(1-carbamoylcyclobutyl)-3-(2-hydroxyethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)-3-(methyl-d3)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclopentyl-1-d)carbamate;
- methyl ((1R,3R)-3-(6-((1-(1-carbamoylcyclobutyl)-3-(2-hydroxypropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)-3-(methyl-d3)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclopentyl-1-d)carbamate;
- methyl ((1R,3R)-3-(6-((1-(1-carbamoyl-3-fluorocyclobutyl)-3-(2-hydroxypropan-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)-3-(methyl-d3)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclopentyl-1-d)carbamate;
- methyl ((1R,3R)-3-(6-((3-(1-carbamoyl-3-fluorocyclobutyl)-7-methyl-2-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-5-yl)amino)-3-(methyl-d3)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclopentyl-1-d)carbamate;
- methyl ((1R,3R)-3-(6-((3-(1-carbamoyl-3-fluorocyclobutyl)-2-(difluoromethyl)-7-methyl-3H-imidazo[4,5-b]pyridin-5-yl)amino)-3-(methyl-d3)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclopentyl-1-d)carbamate;
- methyl ((1R,3R)-3-(6-((3-(1-amino-2-cyclopropyl-1-oxopropan-2-yl)-7-methyl-3H-imidazo[4,5-b]pyridin-5-yl)amino)-3-(methyl-d3)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclopentyl-1-d)carbamate;
- methyl ((1R,3R)-3-(6-((1-(1-carbamoyl-3-fluorocyclobutyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)-3-(methyl-d3)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclopentyl-1-d)carbamate;
- methyl ((1R,3R)-3-(6-((1-((1r,3R)-1-carbamoyl-3-fluorocyclobutyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)-3-(methyl-d3)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclopentyl-1-d)carbamate;
- methyl ((1R,3R)-3-(6-((1-((1s,3S)-1-carbamoyl-3-fluorocyclobutyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)-3-(methyl-d3)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclopentyl-1-d)carbamate;
- methyl ((1R,3R)-3-(6-((7-((1s,3S)-1-carbamoyl-3-fluorocyclobutyl)imidazo[1,5-b]pyridazin-2-yl)amino)-3-(methyl-d3)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclopentyl-1-d)carbamate;
- and
- methyl ((1R,3R)-3-(6-((7-((1r,3R)-1-carbamoyl-3-fluorocyclobutyl)imidazo[1,5-b]pyridazin-2-yl)amino)-3-(methyl-d3)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclopentyl-1-d)carbamate;
- or a pharmaceutically acceptable salt of any of the aforementioned.
30 more elements
3-4. (canceled)
7-15. (canceled)
A method of treating a clonal hematopoietic disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of an antibody that binds to human mutant calreticulin (CALR).
17-33. (canceled)
A method of treating clonal hematopoiesis of indeterminate potential in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula I:
- or a pharmaceutically acceptable salt thereof, wherein:
- R1 is selected from phenyl, indazolyl, and dihydroisobenzofuranyl, each of which is optionally substituted by 1, 2, or 3 substituents independently selected from halo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 hydroxyalkyl;
- R2 is C1-6 alkyl or C1-6 haloalkyl;
- R3 is selected from halo, C1-6 alkyl, and C1-6 alkoxy;
- and
- R4 is C1-6 alkyl.
3 more elements
(canceled)
Dependencies are inferred from the claim text.