Salts and processes of preparing a PI3K inhibitor
The present application provides processes for preparing (R)-4-(3-((S)-1-(4-amino-3-methyl-1H-pyrazolo [3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one, which is useful as an inhibitor phosphoinositide 3-kinase-delta (PI3Kδ), as well as a salt form and intermediates related thereto.
1. A method of inhibiting an activity of a PI3Kδ kinase, comprising contacting the kinase with a salt which is crystalline (R)-4-(3-((S)-1-(4-amino-3-methyl-1H-pyrazolo [3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one hydrochloric acid salt, wherein the crystalline (R)-4-(3-((S)-1-(4-amino-3-methyl-1H-pyrazolo [3, 4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one hydrochloric acid salt has at least four XRPD peaks, in terms of 2-theta, selected from about 11.3°, about 16.4°, about 21.0°, about 23.0°, about 28.1°, about 31.2°, and about 32.8°.
2. The method of claim 1 , wherein said salt is a selective inhibitor for PI3Kδ over one or more of PI3Kα, PI3Kβ, or PI3Kγ.
3. A method of treating a disease selected from idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, vasculitis, pemphigus, autoimmune hemolytic anemia, membranous nephropathy, chronic lymphocytic leukemia, Non-Hodgkin lymphoma, hairy cell leukemia, acute myeloblastic leukemia, chronic myeloid leukemia, Mantle cell lymphoma, Burkitt lymphoma, small lymphocytic lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma, Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, prolymphocytic leukemia, acute lymphoblastic leukemia, myelofibrosis, mucosa-associated lymphatic tissue lymphoma, B-cell lymphoma, mediastinal large B-cell lymphoma, lymphomatoid granulomatosis, splenic marginal zone lymphoma, primary effusion lymphoma, intravascular large B-cell lymphoma, plasma cell leukemia, extramedullary plasmacytoma, smouldering myeloma, monoclonal gammopathy of undetermined significance, B cell lymphoma, osteoarthritis, restenosis, atherosclerosis, bone disorders, arthritis, diabetic retinopathy, psoriasis, benign prostatic hypertrophy, inflammation, angiogenesis, pancreatitis, kidney disease, inflammatory bowel disease, myasthenia gravis, multiple sclerosis, Sjögren's syndrome, rheumatoid arthritis, allergy, asthma, glomerulonephritis, lupus, inflammation related to rheumatoid arthritis, inflammation related to allergy, inflammation related to asthma, inflammation related to glomerulonephritis, inflammation related to lupus, breast cancer, prostate cancer, colon cancer, endometrial cancer, brain cancer, bladder cancer, skin cancer, cancer of the uterus, cancer of the ovary, lung cancer, pancreatic cancer, renal cancer, gastric cancer, acute lung injury, and adult respiratory distress syndrome in a patient, wherein said disease is associated with abnormal expression or activity of a PI3Kδ kinase, comprising administering to said patient a therapeutically effective amount of crystalline (R)-4-(3-((S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one hydrochloric acid salt, wherein the crystalline (R)-4-(3-((S)-1-(4-amino-3-methyl-1H-pyrazolo [3, 4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one hydrochloric acid salt has at least four XRPD peaks, in terms of 2-theta, selected from about 11.3°, about 16.4°, about 21.0°, about 23.0°, about 28.1°, about 31.2°, and about 32.8°.
4. The method of claim 3 , wherein the disease is selected from idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, vasculitis, systemic lupus erythematosus, lupus nephritis, pemphigus, autoimmune hemolytic anemia, membranous nephropathy, chronic lymphocytic leukemia, Non-Hodgkin lymphoma, hairy cell leukemia, Mantle cell lymphoma, Burkitt lymphoma, small lymphocytic lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma, Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, prolymphocytic leukemia, acute lymphoblastic leukemia, myelofibrosis, mucosa-associated lymphatic tissue lymphoma, B-cell lymphoma, mediastinal large B-cell lymphoma, lymphomatoid granulomatosis, splenic marginal zone lymphoma, primary effusion lymphoma, intravascular large B-cell lymphoma, plasma cell leukemia, extramedullary plasmacytoma, smouldering myeloma, monoclonal gammopathy of undetermined significance and B cell lymphoma.
5. The method of claim 3 , wherein said disease is idiopathic thrombocytopenic purpura selected from relapsed idiopathic thrombocytopenic purpura and refractory idiopathic thrombocytopenic purpura.
6. The method of claim 3 , wherein said disease is vasculitis selected from Behcet's disease, Cogan's syndrome, giant cell arteritis, polymyalgia rheumatica, Takayasu's arteritis, Buerger's disease, central nervous system vasculitis, Kawasaki disease, polyarteritis nodosa, Churg-Strauss syndrome, mixed cryoglobulinemia vasculitis, essential mixed cryoglobulinemia vasculitis of hepatitis C virus induced mixed cryoglobulinemia vasculitis, Henoch-Schnlein purpura, hypersensitivity vasculitis, microscopic polyangiitis, Wegener's granulomatosis, and anti-neutrophil cytoplasm antibody associated systemic vasculitis.
7. The method of claim 3 , wherein said disease is non-Hodgkin lymphoma selected from relapsed non-Hodgkin lymphoma, refractory non-Hodgkin lymphoma, and recurrent follicular non-Hodgkin lymphoma.
8. The method of claim 3 , wherein said disease is B cell lymphoma.
9. The method of claim 8 , wherein said B cell lymphoma is activated B-cell like diffuse large B cell lymphoma or germinal center B cell diffuse large B cell lymphoma.
10. The method of claim 3 , wherein said disease is selected from osteoarthritis, restenosis, atherosclerosis, bone disorders, arthritis, diabetic retinopathy, psoriasis, benign prostatic hypertrophy, inflammation, angiogenesis, pancreatitis, kidney disease, inflammatory bowel disease, myasthenia gravis, multiple sclerosis, and Sjögren's syndrome.
11. The method of claim 3 , wherein said disease is selected from rheumatoid arthritis, allergy, asthma, glomerulonephritis, lupus, inflammation related to rheumatoid arthritis, inflammation related to allergy, inflammation related to asthma, inflammation related to glomerulonephritis, and inflammation related to lupus.
12. The method of claim 11 , wherein said disease is lupus.
13. The method of claim 3 , wherein said disease is breast cancer, prostate cancer, colon cancer, endometrial cancer, brain cancer, bladder cancer, skin cancer, cancer of the uterus, cancer of the ovary, lung cancer, pancreatic cancer, renal cancer, gastric cancer.
14. The method of claim 3 , wherein said disease is selected from acute myeloblastic leukemia and chronic myeloid leukemia.
15. The method of claim 3 , wherein said disease is selected from acute lung injury and adult respiratory distress syndrome.
16. The method of claim 3 , wherein said disease is chronic lymphocytic leukemia.
17. The method of claim 3 , wherein said disease is hairy cell leukemia.
18. The method of claim 3 , wherein said disease is Mantle cell lymphoma.
19. The method of claim 3 , wherein said disease is small lymphocytic lymphoma.
20. The method of claim 3 , wherein said disease is follicular lymphoma.
21. The method of claim 3 , wherein said disease is lymphoplasmacytic lymphoma.
22. The method of claim 3 , wherein said disease is extranodal marginal zone lymphoma.
23. The method of claim 3 , wherein said disease is myelofibrosis.
24. The method of claim 3 , wherein said disease is B cell lymphoma, wherein said B cell lymphoma is diffuse large B cell lymphoma.
25. The method of claim 24 , wherein said diffuse large B cell lymphoma is activated B-cell like diffuse large B cell lymphoma.
26. The method of claim 24 , wherein said diffuse large B cell lymphoma is germinal center B cell diffuse large B cell lymphoma.
27. The method of claim 3 , wherein said disease is Non-Hodgkin lymphoma.
28. The method of claim 3 , wherein said disease is Hodgkin's lymphoma.
29. The method of claim 12 , wherein said lupus is lupus nephritis.
30. The method of claim 12 , wherein said lupus is systemic lupus erythematosus.
31. The method of claim 3 , wherein said disease is pemphigus.
32. The method of claim 3 , wherein said disease is autoimmune hemolytic anemia.
33. The method of claim 3 , wherein said disease is Sjögren's syndrome.
34. The method of claim 3 , wherein said crystalline (R)-4-(3-((S)-1-(4-amino-3-methyl-1H-pyrazolo [3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one hydrochloric acid salt is further characterized by a DSC thermogram having an endothermic peak at about 207° C.
35. The method of claim 3 , wherein said crystalline (R)-4-(3-((S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d] pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one hydrochloric acid salt is further characterized by having a TGA thermogram as shown in FIG. 2 .
36. The method of claim 3 , wherein said crystalline (R)-4-(3-((S)-1-(4-amino-3-methyl-1H-pyrazolo [3, 4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one hydrochloric acid salt has at least five XRPD peaks, in terms of 2-theta, selected from about 11.3°, about 16.4°, about 21.0°, about 23.0°, about 28.1°, about 31.2°, and about 32.8°.
37. The method of claim 3 , wherein said crystalline (R)-4-(3-((S)-1-(4-amino-3-methyl-1H-pyrazolo [3, 4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one hydrochloric acid salt has an XRPD profile as shown in FIG. 3 .