IRAK4 degraders and uses thereof
The present invention relates to a method of treating autoimmune/autoinflammatory diseases and hematological malignancies in a subject.
1. A method of treating an autoimmune/autoinflammatory disease and/or a hematological malignancy, comprising administering to a patient in need thereof a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and/or composition thereof,
wherein a C max of up to about 561 ng/mL of Compound A in plasma is achieved, and
wherein Compound A is 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.
2. The method of claim 1 , wherein the C max of Compound A in plasma is 500 ng/mL to 561 ng/mL.
3. The method of claim 1 , wherein the C max of Compound A in plasma is 450 ng/mL to 550 ng/mL.
4. The method of claim 1 , wherein a C max of up to 288 ng/mL of Compound B in plasma is achieved,
wherein Compound B is 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-((3-(1-((S)-2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.
5. The method of claim 4 , wherein the C max of Compound B in plasma is 260 ng/mL to 288 ng/mL.
6. The method of claim 4 , wherein the C max of Compound B in plasma is 240 ng/mL to 260 ng/mL.
7. The method of claim 1 , wherein a C max of up to 265 ng/mL of Compound C in plasma is achieved,
wherein Compound C is 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-((3-(1-((R)-2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.
8. The method of claim 7 , wherein the C max of Compound C in plasma is 240 ng/mL to 265 ng/mL.
9. The method of claim 7 , wherein the C max of Compound C in plasma is 220 ng/mL to 240 ng/mL.
10. The method of claim 1 , wherein the Compound A is administered at a dose of 10 mg/kg to 200 mg/kg.
11. The method of claim 10 , wherein the Compound A is administered at a dose selected from the group consisting of about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85 mg/kg, and about 90 mg/kg.
12. A method of treating an autoimmune/autoinflammatory disease and/or a hematological malignancy, comprising administering to a patient in need thereof a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt and/or composition thereof,
wherein an AUC 0-24 of up to 11700 ng*hr/mL of Compound A in plasma is achieved, and
wherein Compound A is 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.
13. The method of claim 12 , wherein the AUC 0-24 of Compound A in plasma is 11,000 ng*h/mL to 11,700 ng*h/mL.
14. The method of claim 12 , wherein the AUC 0-24 of Compound A in plasma is 10,000 ng*h/mL to 11,000 ng*h/mL.
15. The method of claim 12 , wherein an AUC 0-24 of up to about 6090 ng*h/mL of Compound B in plasma is achieved, and
wherein Compound B is 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-((3-(1-((S)-2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.
16. The method of claim 15 , wherein the AUC 0-24 of Compound B in plasma is 5500 ng*h/mL to 6090 ng*h/mL.
17. The method of claim 15 , wherein the AUC 0-24 of Compound B in plasma is 5,000 ng*h/mL to 5500 ng*h/mL.
18. The method of claim 12 , wherein an AUC 0-24 of up to 5620 ng*h/mL of Compound C in plasma is achieved, and
wherein Compound B is 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-((3-(1-((R)-2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.
19. The method of claim 18 , wherein the AUC 0-24 of Compound C in plasma is 5000 ng*h/mL to 5620 ng*h/mL.
20. The method of claim 18 , wherein the AUC 0-24 of Compound C in plasma is 4500 ng*h/mL to 5,000 ng*h/mL.
21. The method of claim 12 , wherein Compound A is administered at a dose of 10 mg/kg to 200 mg/kg.
22. The method of claim 12 , wherein Compound A is administered at a dose selected from about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85 mg/kg, and about 90 mg/kg.
23. The method of claim 1 , wherein the T max of Compound A is achieved in 4 hrs to 12 hrs.
24. The method of claim 1 , wherein the autoimmune/autoinflammatory disease is selected from a cutaneous, rheumatic, and gastrointestinal autoimmune/autoinflammatory disease.
25. The method of claim 1 , wherein the autoimmune/autoinflammatory disease is a cutaneous autoimmune/autoinflammatory disease selected from atopic dermatitis (AD) and hidradenitis suppurativa (HS).