CRYSTALLINE FORM OF (S)-7-(1-ACRYLOYLPIPERIDIN-4-YL)-2-(4-PHENOXYPHENYL)-4,5,6,7-TETRA-HYDROPYRAZOLO[1,5-a]PYRIMIDINE-3-CARBOXAMIDE, PREPARATION, AND USES THEREOF
The present invention relates to a crystalline form of (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide for inhibiting Btk, methods of preparation thereof and pharmaceutical compositions, and use of the crystalline form above in the treatment of a disease, or in the manufacturing of a medicament for the treatment of a disease.
1 .- 13 . (canceled)
14 . A method of preparing the compound of Formula Ia, comprising asymmetrically reducing the compound of Formula I in the presence of the catalyst and/or reductant to produce the compound of Formula Ia,
wherein the R 1 is hydrogen or an amino protecting group.
15 . The method of claim 14 , where in the amino protecting group is selected from acetyl, propionyl, butyryl, phenylacetyl, benzoyl, toluyl, phenoxyacetyl, methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, tert-butyloxycarbonyl, 2-iodoethoxycarbonyl, carbobenzoxy, 4-methoxybenzyloxycarbonyl, (fluoren-9-ylmethoxy)carbonyl, 4-methoxy-2,3,6-trimethylbenzenesulphonyl, benzyl, methyl or 4-methoxybenzyl.
16 . The method of claim 14 , wherein the catalyst is a neutral catalyst system, or a cationic catalyst system.
17 .- 21 . (canceled)
22 . A method of preparing a crystalline form of Compound 1,
wherein the crystalline form is an anhydrate and the crystalline form exhibits an X-ray powder diffraction pattern comprising diffraction peaks having 2θ angle values at 14.8±0.2°, 15.6±0.2°, 16.4±0.2° and 21.4±0.2°, comprising the steps of dissolving Compound 1 in DCM (dichloromethane), replacing DCM with EtOAc (ethyl acetate), and recrystallizing from EtOAc/MTBE (methyl tertiary butyl ether) mixture, to obtain the crystalline form of Compound 1.
23 .- 29 . (canceled)
30 . The method of claim 22 , wherein the crystalline form of Compound 1 has ee value of more than 90%.
31 .- 35 . (canceled)
36 . A method of treating a disease associated with undesirable Btk activity in a subject by administering to the subject a crystalline form of Compound 1,
wherein the crystalline form exhibits an X-ray powder diffraction pattern comprising diffraction peaks having 2θ angle values at 14.8±0.2°, 15.6±0.2°, 16.4±0.2° and 21.4±0.2°.
37 . The method of claim 36 , wherein the disease is selected from an allergic disease, an autoimmune disease, an inflammatory disease, a cancer, a B-cell proliferative disease, or a combination of two or more thereof.
38 . The method of claim 37 , wherein the B-cell proliferative disease is a B-cell malignancy.
39 . The method of claim 38 , wherein the B-cell malignancy is lymphoma, non-Hodgkin's lymphoma (NHL), diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), waldenstrom macroglobulinemia (WM), marginal zone lymphoma (MZL), Hairy cell leukemia (HCL), Burkitt's-like leukemia (BL), or a combination of two or more thereof.
40 . The method of claim 38 , wherein the B-cell malignancy is relapsed/refractory B-cell malignancy selected from relapsed/refractory mantle cell lymphoma (R/R MCL), relapsed/refractory chronic lymphocytic leukemia (R/R CLL), relapsed/refractory small lymphocytic lymphoma (R/R SLL), relapsed/refractory Waldenstrom macroglobulinemia (R/R WM), or a combination of two or more thereof.
41 . The method of claim 38 , wherein the crystalline form of Compound 1 is administrated at a dose of 40 mg-320 mg/day.
42 . The method of claim 38 , wherein the crystalline form of Compound 1 is administered at a dose of 160 mg twice a day (BID) or 320 mg once a day (QD).
43 . The method of claim 38 , wherein the crystalline form is an anhydrate.
44 . The method of claim 22 , wherein the crystalline form of Compound 1 has ee value of more than 97%.