Co-crystalline form of a Bruton's tyrosine kinase inhibitor

Abstract

To provide cocrystalline forms comprising BTK-I, useful for the treatment and prevention of diseases that can be treated with a BTK inhibitor, as well as pharmaceutical compositions, and processes for preparing the cocrystals.SOLUTION: Provided is a crystalline form of (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide (BTK-I), comprising the following formula and having an X-ray powder diffraction (XRPD) pattern that includes an XRPD peak at a 2θ angle of 17.7° ±0.2°.SELECTED DRAWING: None

Description

Technical Field

[0001] The present disclosure relates to novel cocrystal forms of Bruton's Tyrosine Kinase (BTK) inhibitors, pharmaceutical compositions comprising the cocrystal forms, B cell malignancies, B cell lymphomas, marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), non-Hodgkin lymphoma, Burkitt lymphoma, mantle cell lymphoma (MCL), follicular lymphoma (FL), hairy cell leukemia, B cell non-Hodgkin lymphoma, B cell prolymphocytic leukemia, Waldenstrom's macroglobulinemia (WM), multiple myeloma (MM), arthritis, particularly rheumatoid arthritis (RA), and multiple sclerosis (MS), and methods of using the cocrystal forms for treating conditions treatable by inhibition of BTK, as well as processes useful in the synthesis of the cocrystal forms.

Background Art

[0002] BTK is involved in, for example, indolent and aggressive mature B cell non-Hodgkin lymphomas, CLL, SLL, WM, MCL, FL, DLBCL, B cell prolymphocytic leukemia, hairy cell leukemia,​​​​​​ A molecular target useful for the treatment of a number of B-cell leukemias and lymphomas, including MZL . B cells play a prominent role in the development of chronic graft-versus-host disease (cGVHD), a life-threatening complication of allogeneic stem cell transplantation . It has also been reported that research on B-cell targeted chemotherapy for the prevention and treatment of cGVHD has been promoted . .

[0003] BTK inhibitors are known in the art, for example, in International Publication No. WO 2013 / 010136 , U.S. Patent No. 9,090,621, International Publication No. WO 2015 / 127310, International Publication No. WO 2015 / 095099 , and U.S. Patent Application Publication No. US 2014 / 221333 .

[0004] Furthermore, in addition to cancer, it has been reported that certain BTK inhibitors are being studied in clinical trials for RA and / or MS (for example, International Publication Nos. WO 2021 / 202825 and WO 2020 / 016850). The compound, (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamide)methyl)phenyl)-1-(1,1 ,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide (referred to as "BTK-I" in this specification) and its pharmaceutically acceptable salts are disclosed in International Publication No. WO 2017 / 103611 . . . .

[0005] Furthermore, a spray dried dispersion (SDD) formulation of BTK-I is disclosed in International Publication No. WO 2020 / 028258 .

[0006] A novel form of BTK-I that provides solid-state and chemical stability for the preparation and manufacture of pharmaceutical formulations is desired. The pharmaceutical composition may comprise one or more polymers such as polyvinylpyrrolidone vinyl acetate (PVP-VA), hydroxypropylmethylcellulose (HPMC), or hydroxypropylmethylcellulose acetate succinate (HPMCAS), such as HPMCAS-L, HPMCAS-M, or HPMCAS-H. The pharmaceutical composition may also comprise a pharmaceutically acceptable carrier, diluent, or excipient. A novel form of BTK-I that provides solid-state and chemical stability for the preparation and manufacture of pharmaceutical formulations is desired. The pharmaceutical composition may comprise one or more polymers such as polyvinylpyrrolidone vinyl acetate (PVP-VA), hydroxypropylmethylcellulose (HPMC), or hydroxypropylmethylcellulose acetate succinate (HPMCAS), such as HPMCAS-L, HPMCAS-M, or HPMCAS-H. The pharmaceutical composition may also comprise a pharmaceutically acceptable carrier, diluent, or excipient. A novel form of BTK-I that provides solid-state and chemical stability for the preparation and manufacture of pharmaceutical formulations is desired. The pharmaceutical composition may comprise one or more polymers such as polyvinylpyrrolidone vinyl acetate (PVP-VA), hydroxypropylmethylcellulose (HPMC), or hydroxypropylmethylcellulose acetate succinate (HPMCAS), such as HPMCAS-L, HPMCAS-M, or HPMCAS-H. The pharmaceutical composition may also comprise a pharmaceutically acceptable carrier, diluent, or excipient. A novel form of BTK-I that provides solid-state and chemical stability for the preparation and manufacture of pharmaceutical formulations is desired. The pharmaceutical composition may comprise one or more polymers such as polyvinylpyrrolidone vinyl acetate (PVP-VA), hydroxypropylmethylcellulose (HPMC), or hydroxypropylmethylcellulose acetate succinate (HPMCAS), such as HPMCAS-L, HPMCAS-M, or HPMCAS-H. The pharmaceutical composition may also comprise a pharmaceutically acceptable carrier, diluent, or excipient. A novel form of BTK-I that provides solid-state and chemical stability for the preparation and manufacture of pharmaceutical formulations is desired. The pharmaceutical composition may comprise one or more polymers such as polyvinylpyrrolidone vinyl acetate (PVP-VA), hydroxypropylmethylcellulose (HPMC), or hydroxypropylmethylcellulose acetate succinate (HPMCAS), such as HPMCAS-L, HPMCAS-M, or HPMCAS-H. The pharmaceutical composition may also comprise a pharmaceutically acceptable carrier, diluent, or excipient. A novel form of BTK-I that provides solid-state and chemical stability for the preparation and manufacture of pharmaceutical formulations is desired. The pharmaceutical composition may comprise one or more polymers such as polyvinylpyrrolidone vinyl acetate (PVP-VA), hydroxypropylmethylcellulose (HPMC), or hydroxypropylmethylcellulose acetate succinate (HPMCAS), such as HPMCAS-L, HPMCAS-M, or HPMCAS-H. The pharmaceutical composition may also comprise a pharmaceutically acceptable carrier, diluent, or excipient. A novel form of BTK-I that provides solid-state and chemical stability for the preparation and manufacture of pharmaceutical formulations is desired. The pharmaceutical composition may comprise one or more polymers such as polyvinylpyrrolidone vinyl acetate (PVP-VA), hydroxypropylmethylcellulose (HPMC), or hydroxypropylmethylcellulose acetate succinate (HPMCAS), such as HPMCAS-L, HPMCAS-M, or HPMCAS-H. The pharmaceutical composition may also comprise a pharmaceutically acceptable carrier, diluent, or excipient. A novel form of BTK-I that provides solid-state and chemical stability for the preparation and manufacture of pharmaceutical formulations is desired. The pharmaceutical composition may comprise one or more polymers such as polyvinylpyrrolidone vinyl acetate (PVP-VA), hydroxypropylmethylcellulose (HPMC), or hydroxypropylmethylcellulose acetate succinate (HPMCAS), such as HPMCAS-L, HPMCAS-M, or HPMCAS-H. The pharmaceutical composition may also comprise a pharmaceutically acceptable carrier, diluent, or excipient. SUMMARY OF THE INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION

[0007] An object of certain embodiments of the present disclosure is to provide a stable and low hygroscopic cocrystal form. An object of certain embodiments of the present disclosure is to utilize a cocrystal form that requires fewer processing steps than current formulations. The cocrystal form can result in fewer processing steps, including advantages such as simplification of the supply chain and a smaller number of unit operations. The cocrystal form has less material movement from different locations, such as being moved once to incorporate the cocrystal into formulations such as tablets, capsules, and suspensions. SDD formulations start by manufacturing the active pharmaceutical ingredient (API) at a first location, move to a second location to incorporate the API into the SDD, and then An object of certain embodiments of the present disclosure is to provide a stable and low hygroscopic cocrystal form. An object of certain embodiments of the present disclosure is to utilize a cocrystal form that requires fewer processing steps than current formulations. The cocrystal form can result in fewer processing steps, including advantages such as simplification of the supply chain and a smaller number of unit operations. The cocrystal form has less material movement from different locations, such as being moved once to incorporate the cocrystal into formulations such as tablets, capsules, and suspensions. SDD formulations start by manufacturing the active pharmaceutical ingredient (API) at a first location, move to a second location to incorporate the API into the SDD, and then An object of certain embodiments of the present disclosure is to provide a stable and low hygroscopic cocrystal form. An object of certain embodiments of the present disclosure is to utilize a cocrystal form that requires fewer processing steps than current formulations. The cocrystal form can result in fewer processing steps, including advantages such as simplification of the supply chain and a smaller number of unit operations. The cocrystal form has less material movement from different locations, such as being moved once to incorporate the cocrystal into formulations such as tablets, capsules, and suspensions. SDD formulations start by manufacturing the active pharmaceutical ingredient (API) at a first location, move to a second location to incorporate the API into the SDD, and then An object of certain embodiments of the present disclosure is to provide a stable and low hygroscopic cocrystal form. An object of certain embodiments of the present disclosure is to utilize a cocrystal form that requires fewer processing steps than current formulations. The cocrystal form can result in fewer processing steps, including advantages such as simplification of the supply chain and a smaller number of unit operations. The cocrystal form has less material movement from different locations, such as being moved once to incorporate the cocrystal into formulations such as tablets, capsules, and suspensions. SDD formulations start by manufacturing the active pharmaceutical ingredient (API) at a first location, move to a second location to incorporate the API into the SDD, and then An object of certain embodiments of the present disclosure is to provide a stable and low hygroscopic cocrystal form. An object of certain embodiments of the present disclosure is to utilize a cocrystal form that requires fewer processing steps than current formulations. The cocrystal form can result in fewer processing steps, including advantages such as simplification of the supply chain and a smaller number of unit operations. The cocrystal form has less material movement from different locations, such as being moved once to incorporate the cocrystal into formulations such as tablets, capsules, and suspensions. SDD formulations start by manufacturing the active pharmaceutical ingredient (API) at a first location, move to a second location to incorporate the API into the SDD, and then An object of certain embodiments of the present disclosure is to provide a stable and low hygroscopic cocrystal form. An object of certain embodiments of the present disclosure is to utilize a cocrystal form that requires fewer processing steps than current formulations. The cocrystal form can result in fewer processing steps, including advantages such as simplification of the supply chain and a smaller number of unit operations. The cocrystal form has less material movement from different locations, such as being moved once to incorporate the cocrystal into formulations such as tablets, capsules, and suspensions. SDD formulations start by manufacturing the active pharmaceutical ingredient (API) at a first location, move to a second location to incorporate the API into the SDD, and then An object of certain embodiments of the present disclosure is to provide a stable and low hygroscopic cocrystal form. An object of certain embodiments of the present disclosure is to utilize a cocrystal form that requires fewer processing steps than current formulations. The cocrystal form can result in fewer processing steps, including advantages such as simplification of the supply chain and a smaller number of unit operations. The cocrystal form has less material movement from different locations, such as being moved once to incorporate the cocrystal into formulations such as tablets, capsules, and suspensions. SDD formulations start by manufacturing the active pharmaceutical ingredient (API) at a first location, move to a second location to incorporate the API into the SDD, and then An object of certain embodiments of the present disclosure is to provide a stable and low hygroscopic cocrystal form. An object of certain embodiments of the present disclosure is to utilize a cocrystal form that requires fewer processing steps than current formulations. The cocrystal form can result in fewer processing steps, including advantages such as simplification of the supply chain and a smaller number of unit operations. The cocrystal form has less material movement from different locations, such as being moved once to incorporate the cocrystal into formulations such as tablets, capsules, and suspensions. SDD formulations start by manufacturing the active pharmaceutical ingredient (API) at a first location, move to a second location to incorporate the API into the SDD, and then Moving to a third location to incorporate the SDD having the API in a formulation such as a cell and a suspension is generally recognized. The object of a particular embodiment of the present disclosure is also to utilize a co-crystal form that requires less solvent than the current formulation, resulting in less environmental impact. Accordingly, co-crystal forms of BTK-I and pharmaceutical compositions thereof are described herein. Particular embodiments of the present disclosure meet some or all of the above objectives. Means for Solving the Problems

[0008] In one aspect, co-crystal forms of BTK-I and a co-former selected from the group consisting of adipic acid and borneolic acid are disclosed herein. In an embodiment of this aspect, a co-crystal form comprising BTK-I and adipic acid is disclosed herein. In another embodiment of the aspect, a co-crystal form (referred to herein as the "BTK-I and hemi-adipic acid co-crystal form") in which the ratio of (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamide)methyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide to adipic acid is about 2:1 is disclosed herein. Means for Solving the Problems

[0009] In one aspect, co-crystal forms of BTK-I and a co-former selected from the group consisting of adipic acid and borneolic acid are disclosed herein. In an embodiment of this aspect, a co-crystal form comprising BTK-I and adipic acid is disclosed herein.

[0010] In another embodiment of the aspect, a co-crystal form (referred to herein as the "BTK-I and hemi-adipic acid co-crystal form") in which the ratio of (S)-5-amino-3-(4-((5-fluoro-2 -methoxybenzamide)methyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide to adipic acid is about 2:1 is disclosed herein. In another embodiment of the aspect, a co-crystal form (referred to herein as the "BTK-I and hemi-adipic acid co-crystal form") in which the ratio of (S)-5-amino-3-(4-((5-fluoro-2 -methoxybenzamide)methyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide to adipic acid is about 2:1 is disclosed herein.

[0011] In another embodiment of the aspect, peaks at 18.7°, and 8.1°, 10.4°, 11.7°, 12.1°, 14.2°, 15.1°, 17.0°, 17.3°, 18.1 °, 19.2°, 19.9°, 20.4°, 20.9°, 21.6°, 22.1°, 23 .7°, 24.3°, 24.8°, 25.5°, 26.1°, 27.2°, 27.4°, including one or more peaks at 28.3° or 29.8°, with an angular tolerance of the diffraction angle of ±0 .2 degrees, characterized by an X-ray powder diffraction (XRPD) pattern using CuKα radiation of the BTK-I and hemi-adipic acid co-crystalline form as disclosed herein. In another embodiment of the aspect, having a diffraction peak at a diffraction angle 2 theta of 18.7° in combination with one or more of the peaks selected from the group consisting of 10.4°, 14.2°, 15 .1°, 17.0°, and 21.6°, with an angular tolerance of the diffraction angle of ±0.2 degrees, characterized by an XRPD pattern using CuKα radiation of the BTK-I and hemi-adipic acid co-crystalline form as disclosed herein. In another embodiment of the aspect wherein, having a diffraction peak at a diffraction angle 2 theta of 18.7° in combination with one or more of the peaks selected from the group consisting of 14.2°, 17.0°, and 21.6°, with an angular tolerance of the diffraction angle of ±0.2 degrees, characterized by an XRPD pattern using CuKα radiation of the BTK-I and hemi-adipic acid co-crystalline form as disclosed herein. In another embodiment of the aspect wherein, having a diffraction peak at a diffraction angle 2 theta of 18.7° in combination with one or more of the peaks selected from the group consisting of 17.0° and 21.6°, with an angular tolerance of the diffraction angle of ±0.2 degrees, characterized by an XRPD pattern using CuKα radiation of the BTK-I and hemi-adipic acid co-crystalline form as disclosed herein. In another embodiment of the aspect wherein, having a diffraction peak at a diffraction angle 2 theta of 18.7° in combination with one or more of the peaks selected from the group consisting of 17.0° and 21.6°, with an angular tolerance of the diffraction angle of ±0.2 degrees, characterized by an XRPD pattern using CuKα radiation of the BTK-I and hemi-adipic acid co-crystalline form as disclosed herein. In another embodiment of the aspect wherein, a co-crystalline form having a diffraction peak at a diffraction angle 2 theta of 18.7° as disclosed herein is disclosed. It is disclosed in the book. In another embodiment of the aspect, one or more peaks at diffraction angle 2 theta A co-crystalline form selected from the group consisting of 17.0° and 21.6° is disclosed herein .

[0012] In another embodiment of the aspect, the 13 C solid The NMR spectrum has 174.6, 167.6, 166.1, 157.5, 155.5 , 152.7, 150.9, 150.3, 141.1, 140.4, 130.1, 129 .3, 127.7, 126.6, 123.6, 120.7, 120.2, 118.5, 1 16.5, 114.1, 112.8, 91.2, 63.6, 58.6, 56.8, 52. 2, 44.0, 34.5, 33.2, 25.1, 24.7, 13.8, 13.2 ppm Peaks based on the high-field resonance of adamantane at (δ = 29.5 ppm) are included, and the BTK-I and hemi-adipic acid co-crystalline form characterized by a tolerance of ±0.2 ppm is disclosed herein. In another embodiment of the aspect, 174.6, 91.2, 44 .0, 13.8, and 13.2 ppm based on the high-field resonance of adamantane Peaks are included, and the tolerance is ±0.2 ppm, A co-crystalline form characterized by a C solid NMR spectrum is disclosed herein. In another embodiment of the aspect, for example, as follows 13 A co-crystalline form characterized by a C solid NMR spectrum is disclosed herein. In another embodiment of the aspect, for example, a BTK-I and hemi-adipic acid co-crystalline form that can be represented by the following structure is disclosed herein : :

[0013]

Chemical formula

[0014] In an embodiment of this aspect, a co-crystalline form of BTK-I and shikimic acid is disclosed herein. In another embodiment of this aspect, a co-crystalline form (referred to herein as "BTK-I and shikimic acid co-crystalline form") comprising (S)-5-amino-3-(4-((5- fluoro-2-methoxybenzamide)methyl)phenyl)-1-(1,1,1-trifluoro propan-2-yl)-1H-pyrazole-4-carboxamide and shikimic acid is disclosed herein. In another embodiment of this aspect, a BTK-I and shikimic acid co-crystalline form (referred to herein as "BTK-I and mono-shikimic acid co-crystalline form") in which the ratio of (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamide)methyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide to shikimic acid is about 1:1 is disclosed herein. In another embodiment of this aspect, a BTK-I and mono-shikimic acid co-crystalline form having an XRPD pattern using CuKα radiation, which includes a peak at 17.7° and one or more peaks at 7.2°, 8.3°, 10.2°, 11.7°, 11.9°, 12.6°, 13.4°, 13.8°, 14.5°, 15.6°, 15.8°, 16.7°, 19.0°, 20.4°, 21.1°, 23.6°, 25.5°, 26.1°, or 27.2° with a tolerance of ±0.2 ppm is disclosed herein. In another embodiment of this aspect, having a diffraction peak at a diffraction angle 2 theta of 17.7° in combination with one or more of the peaks selected from the group consisting of 7.2°, 8.3°, 12.6°, 14.5°, and 16.7°, with a tolerance of the diffraction angle of ±0 ​​​​​​​​​​​​ .2 degrees, XRPD patterns using CuKα radiation, characterized by BTK-I and the mono-shikimic acid co-crystalline form are disclosed herein. In another embodiment of this aspect wherein, one of the peaks selected from the group consisting of 7.2°, 14.5°, and 16.7° in combination with one or more, having a diffraction peak at a diffraction angle 2 theta of 17.7°, with a tolerance of the diffraction angle of ±0.2 degrees, XRPD patterns using CuKα radiation, characterized by BTK-I and the mono-shikimic acid co-crystalline form are disclosed herein. Another embodiment of this aspect, one of the peaks selected from the group consisting of 7.2° and 14.5° in combination with one or more, having a diffraction peak at a diffraction angle 2 theta of 17.7°, with a tolerance of the diffraction angle of ±0.2 degrees, XRPD patterns using CuKα radiation, characterized by BTK-I and the mono-shikimic acid co-crystalline form are disclosed herein. Another embodiment of this aspect, the co-crystalline form having a diffraction peak at a diffraction angle 2 theta of 17.7° is disclosed herein. Another embodiment of this aspect, one or more peaks at a diffraction angle 2 theta selected from the group consisting of 7.2° and 14.5° of the co-crystalline form are disclosed herein In another embodiment of this aspect, for example, represented by the following structure BTK-I and the mono-shikimic acid co-crystalline form are disclosed herein:

[0015]

Chemical Formula

[0016] In another aspect, a pharmaceutical composition comprising the co-crystalline form and further comprising one or more polymers is Disclosed in this specification. In an embodiment of this aspect disclosed in this specification, PVP-V A, hydroxypropyl methylcellulose (HPMC), or HPMCAS, for example, H PMCAS-L, HPMCAS-M, or HPMCAS-H.

[0017] In another embodiment of this aspect disclosed in this specification, a pharmaceutical composition comprising a co-crystalline form may contain about 90 parts by weight of the co-crystalline form and about 10 parts by weight of the polymer, about 80 parts by weight of the co-crystalline form and about 20 parts by weight of the polymer, about 70 parts by weight of the co-crystalline form and about 30 parts by weight of the polymer , or about 50 parts by weight of the co-crystalline form and about 50 parts by weight of the polymer. In another embodiment of this aspect disclosed in this specification, the pharmaceutical composition contains about 80 parts by weight of the co-crystalline form and about 20 parts by weight of the polymer.

[0018] In another embodiment of this aspect disclosed in this specification, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, diluent, or excipient. In another embodiment of this aspect, a pharmaceutical composition, and a pharmaceutically acceptable carrier, diluent, or excipient are disclosed in this specification. In another embodiment of this aspect, a pharmaceutical composition is disclosed in this specification, and the composition contains less than about 20% by weight of other co-crystalline forms with conformers different from BTK-I. In another embodiment of this aspect, a pharmaceutical composition is disclosed in this specification, and the composition contains less than about 10% by weight of other co-crystalline forms with conformers different from BTK-I. In another embodiment of this aspect, a pharmaceutical composition is disclosed in this specification, and the composition contains less than about 5% by weight of other co-crystalline forms with conformers different from BTK-I.

[0019] In another aspect, a method of treating cancer in a patient in need thereof is disclosed, which comprises administering an effective amount of the cocrystal of the present invention or a pharmaceutical composition thereof. In an embodiment of this aspect, a method of treating BTK-related cancer in a patient in need thereof is disclosed, which comprises administering a BTK-I and hemi-adipic acid cocrystal form, and a BTK-I. In an embodiment of this aspect, a method of treating BTK-related cancer in a patient in need thereof is disclosed, which comprises administering a BTK-I and mono-camphoric acid cocrystal form. In another embodiment of this aspect, a method of treating BTK-related cancer in a patient in need thereof is disclosed, which comprises administering a BTK-I and mono-camphoric acid cocrystal form. In another embodiment of this aspect, a method of treating BTK-related cancer in a patient in need thereof is disclosed, which comprises administering a BTK-I and mono-camphoric acid cocrystal form. In another embodiment of this aspect, a method of treating BTK-related cancer in a patient in need thereof is disclosed, which comprises administering a BTK-I and mono-camphoric acid cocrystal form. In another embodiment of this aspect disclosed herein, the BTK-related cancer is selected from the group consisting of B-cell malignancies, B-cell lymphomas, MZL, DLBCL, CLL, SLL, non-Hodgkin lymphoma, Burkitt lymphoma, MCL, FL, hairy cell leukemia, B-cell non-Hodgkin lymphoma, WM, B-cell prolymphocytic leukemia, and MM. In another embodiment of this aspect disclosed herein, the BTK-related cancer is MCL. In another embodiment of this aspect disclosed herein, the BTK-related cancer is CLL. In another embodiment of this aspect disclosed herein, the BTK-related cancer is SLL. In another embodiment of this aspect disclosed herein, the BTK-related cancer is FL. In another embodiment of this aspect disclosed herein, the BTK-related cancer is MZL. In another embodiment of this aspect disclosed herein, MZL is splenic, nodal, or extranodal. In another embodiment of this aspect disclosed herein, the BTK-related cancer is DLBCL. In another embodiment of this aspect disclosed herein, the BTK-related cancer is B-cell non-Hodgkin lymphoma. In another embodiment of this aspect disclosed herein, the BTK-related cancer is B-cell non-Hodgkin lymphoma. In another embodiment of this aspect disclosed herein, MZL is splenic, nodal, or extranodal. In another embodiment of this aspect disclosed herein, the BTK-related cancer is DLBCL. In another embodiment of this aspect disclosed herein, the BTK-related cancer is B-cell non-Hodgkin lymphoma. , MCL, CLL, or SLL. In another embodiment of this aspect disclosed herein wherein the BTK-related cancer is selected from the group consisting of MCL, CLL, SLL, WM, FL, and MZL .

[0020] In another aspect, a method of inhibiting Bruton's tyrosine kinase in a patient in need thereof is disclosed herein, the method comprising administering to the patient an effective amount of a cocrystal of the invention or a pharmaceutical composition thereof . is disclosed herein.

[0021] In another aspect, a method of treating MS in a patient in need thereof is disclosed herein, the method comprising administering an effective amount of a cocrystal of the invention or a pharmaceutical composition thereof .

[0022] In another aspect, a method of treating arthritis, more specifically RA, in a patient in need thereof is disclosed herein, the method comprising administering an effective amount of a cocrystal of the invention or a pharmaceutical composition thereof . is disclosed herein.

[0023] In another aspect, a cocrystal of the invention or a pharmaceutical composition thereof for use in therapy is disclosed herein. In an embodiment of this aspect, a cocrystal of the invention or a pharmaceutical composition thereof for use in the treatment of cancer is disclosed herein. In another embodiment of this aspect a BTK-I and hemi-adipic acid cocrystal form for use in the treatment of BTK-related cancer is disclosed herein. In another embodiment of this aspect, a BTK-I and mono-camphoric acid cocrystal form for use in the treatment of BTK-related cancer is disclosed herein. In another embodiment of this aspect disclosed herein, the BTK-related cancer is is disclosed herein. In another embodiment of this aspect a BTK-I and hemi-adipic acid cocrystal form for use in the treatment of BTK-related cancer is disclosed herein. In another embodiment of this aspect, a BTK-I and mono-camphoric acid cocrystal form for use in the treatment of BTK-related cancer is disclosed herein. In another embodiment of this aspect disclosed herein, the BTK-related cancer is is disclosed herein. In another embodiment of this aspect, a BTK-I and mono-camphoric acid cocrystal form for use in the treatment of BTK-related cancer is disclosed herein. In another embodiment of this aspect disclosed herein, the BTK-related cancer is a BTK-I and mono-camphoric acid cocrystal form for use in the treatment of BTK-related cancer is disclosed herein. In another embodiment of this aspect disclosed herein, the BTK-related cancer is disclosed herein. In another embodiment of this aspect disclosed herein, the BTK-related cancer is , B cell malignancies, B cell lymphomas, MZL, DLBCL, CLL, SLL, non-Hodgkin lymphoma, Burkitt lymphoma, MCL, FL, hairy cell leukemia, B cell non-Hodgkin lymph oma, WM, B cell prolymphocytic leukemia, and MM, selected from the group consisting of. This specification In another embodiment of this aspect disclosed herein, the BTK-related cancer is MCL. This spec In another embodiment of this aspect disclosed herein, the BTK-related cancer is CLL. In another embodiment of this aspect disclosed herein, the BTK-related cancer is SLL In another embodiment of this aspect disclosed herein, the BTK-related cancer is FL In another embodiment of this aspect disclosed herein, the BTK-related cancer is MZ L. In another embodiment of this aspect disclosed herein, MZL is splenic, nodal, or extranodal. In another embodiment of this aspect disclosed herein, BTK related cancer is DLBCL. In another embodiment of this aspect disclosed herein , the BTK-related cancer is B cell non-Hodgkin lymphoma, MCL, CLL, or SLL. In another embodiment of this aspect disclosed herein, the BTK-related cancer is MCL, C LL, SLL, WM, FL, and MZL, selected from the group consisting of.

[0024] In another aspect, a co-crystal of the invention for use in the inhibition of Bruton's tyrosine kinase or a pharmaceutical composition thereof is disclosed herein. In another aspect, a co-crystal for use in the treatment of MS or a pharmaceutical composition thereof is disclosed herein.

[0025] In another aspect, a co-crystal for use in the treatment of MS or a pharmaceutical composition thereof is disclosed herein. In another aspect, a co-crystal for use in the treatment of MS or a pharmaceutical composition thereof is disclosed herein.

[0026] In another aspect, a co-crystal or a pharmaceutical composition thereof for use in the treatment of arthritis, particularly RA, is disclosed herein.

[0027] In another aspect, the use of the co-crystal of the present invention or a pharmaceutical composition thereof in the manufacture of a medicament for the treatment of cancer is disclosed herein. In an embodiment of this aspect, the use of the BTK-I and hemi-adipic acid co-crystal form in the manufacture of a medicament for the treatment of BTK-related cancer is disclosed herein. In another embodiment of this aspect, the use of the BTK-I and mono-camphoric acid co-crystal form in the manufacture of a medicament for the treatment of BTK-related cancer is disclosed herein. In another embodiment of this aspect, the BTK-related cancer is selected from the group consisting of B cell malignancies, B cell lymphomas, MZL, DLBCL, CLL, SLL, non-Hodgkin lymphoma, Burkitt lymphoma, MCL, FL, hairy cell leukemia, B cell non-Hodgkin lymphoma, WM, B cell prolymphocytic leukemia, and MM, as disclosed herein. In another embodiment of this aspect, the BTK-related cancer is MCL, as disclosed herein. In another embodiment of this aspect, the BTK-related cancer is CLL. In another embodiment of this aspect, the BTK-related cancer is SLL. In another embodiment of this aspect, the BTK-related cancer is FL. In another embodiment of this aspect, the BTK-related cancer is MZL. In another embodiment of this aspect, MZL is splenic, nodal, or extranodal. In another embodiment of this aspect, the BTK-related cancer is DLBCL, as disclosed herein. In another embodiment of this aspect disclosed herein, the BTK-related cancer is FL. In another embodiment of this aspect disclosed herein, the BTK-related cancer is MZL. In another embodiment of this aspect disclosed herein, MZL is splenic, nodal, or extranodal. In another embodiment of this aspect disclosed herein, the BTK-related cancer is DLBCL. In another embodiment of this aspect disclosed herein, wherein the BTK-related cancer is B-cell non-Hodgkin lymphoma, MCL, CLL, or SLL . In another embodiment of this aspect disclosed herein, the BTK-related cancer is MCL, CLL, SLL, WM, FL, and MZL selected from the group consisting of.

[0028] In another aspect, the use of the cocrystal of the present invention or its pharmaceutical composition in the manufacture of an agent for inhibiting Bruton's tyrosine kinase is disclosed herein.

[0029] In another aspect, the use of the cocrystal or its pharmaceutical composition in the manufacture of an agent for the treatment of MS is disclosed herein.

[0030] In another aspect, the use of the cocrystal or its pharmaceutical composition in the manufacture of an agent for the treatment of arthritis, particularly RA, is disclosed herein.

[0031] In another aspect, a process for preparing the BTK-I and hemi-adipic acid cocrystal form is disclosed herein, comprising suspending and partially dissolving adipic acid in a BTK-I and hemi-adipic acid cocrystal form solvent, adding BTK-I, and stirring while heating, and isolating the BTK-I and hemi-adipic acid cocrystal form. In an embodiment of this aspect, the isolation step is by filtration under vacuum followed by drying under a nitrogen stream. A process is disclosed herein. In another embodiment of this aspect, a process is disclosed herein where the heat is about 55 °C. In another embodiment of this aspect, a process is disclosed herein where the stirring step is about 500 rpm. In another embodiment of this aspect, a process is disclosed herein where the stirring while heating occurs for about 1 hour. ​ It is disclosed in the book. In another embodiment of this aspect, BTK-I and hemi-adipic acid co- crystalline form solvents are disclosed herein as a process selected from the group consisting of ethyl acetate, cyclopentyl methyl ether, isopropyl alcohol , and acetonitrile. In another embodiment of this aspect, a process in which the BTK-I and hemi-adipic acid co-crystalline form solvent is ethyl acetate is disclosed herein.

[0032] In another aspect, a process for preparing a co-crystalline form of BTK-I and mono-thiourea is disclosed herein, which includes suspending BTK-I in a co-crystalline solvent of BTK-I saturated with thiourea and mono-thiourea , stirring while heating, and then stirring without heating , and isolating the co-crystalline form of BTK-I and mono-thiourea. In an embodiment of this aspect, a process in which the isolating step is by filtration under vacuum is disclosed herein. In another embodiment of this aspect, a process in which the heat is about 5 0 °C is disclosed herein. In another embodiment of this aspect, a process in which the stirring step is about 800 rpm is disclosed herein. In another embodiment of this aspect, a process in which the stirring step while heating occurs for about 2 hours is disclosed herein. In another embodiment of this aspect, a process in which the stirring step without heating occurs for more than 2 hours is disclosed herein. In another embodiment of this aspect, a process in which the co-crystalline solvent of BTK-I and mono-thiourea is cyclopentyl methyl ether is disclosed herein. is disclosed herein.

[0033] In another aspect, the co-crystalline forms of BTK-I obtainable by any of the processes of the present invention are disclosed herein.

Brief Description of the Drawings

[0034]

Figure 1

Modes for Carrying Out the Invention

[0035] Definitions Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this disclosure belongs. When used herein, the following terms have the meanings ascribed to them below, unless otherwise specified.

[0036] Adipic acid, also known as hexanedioic acid, has a structure exemplified by the following formula:

[0037]

Chemical formula

[0038] rel-(1R,3S)-1,2,2-Trimethylcyclopentane-1,3-dicarboxylic acid or borneolic acid, also known as (1R,3S)-rel-1,2,2-trimethylcyclopentane-1,3-di carboxylic acid, has a structure exemplified by the following formula:

[0039]

Chemical formula

[0040] 5-Amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]meth yl]phenyl]-1-[(1S)-2,2,2-trifluoro-1-methyl-ethyl] pyrazole-4-carboxamide or (S)-5-amino-3-(4-((5-fluoro -2-methoxybenzamide)methyl)phenyl)-1-(1,1,1-trifluorop ropan-2-yl)-1H-pyrazole-4-carboxamide, also known as compound BT K-I, has the structure exemplified below:

[0041]

Chemical formula

[0042] BTK-I can be prepared as described in U.S. Patent No. 10,342,780 as follows.

[0043] The terms "treatment", "treating", "treatment", etc. mean including delaying the progression of a disorder , stopping, or reversing it. These terms also include alleviating, remitting, attenuating, eliminating, or reducing one or more symptoms of a disorder or condition, even if the disorder or condition is not actually eliminated and even if the progression of the disorder or condition itself is not delayed or reversed.

[0044] The term "effective amount" means an amount of a compound that can provide a therapeutic benefit to a patient in need thereof . The effective amount in a particular patient depends on whether the compound or its salt is administered ; the size, age, gender, and general health of the patient; the stage and / or severity of the cancer, disease, or disorder ; the responsiveness of the individual patient to previous therapies; whether the patient has had previous therapies Whether there is a recurrence of a disease, illness, or cancer later; mode of administration; bio availability characteristics; selected dosing regimen; and factors such as the use of other concomitant medications that can be affected thereby.

[0045] The term "therapeutic benefit" means an improvement in survival, a reduction in symptoms, a restoration of functional ability, or a decrease in the chance of developing a chronic condition. Measurement of such therapeutic benefit includes overall survival, progression-free survival, time to progression, disease-free survival, event-free survival, time to treatment failure, time to next treatment, duration of clinical benefit, duration of response, objective response rate, complete response, pathologic complete response, disease control rate, clinical benefit rate, health-related quality of life, and increase in milestone survival. See the following: A. Delgado and A. K. Guddati, Clinical Endpoints in Oncology -a Primer, Am J Cancer Res, 2021;11(4):112

[0046] As used herein, the term "patient" refers to a human.

[0047] To make the description more concise, some of the quantitative expressions in this specification are listed as a range of about amount X to about amount Y. When a range is listed, the range is not limited to its listed upper and lower limits, but rather includes the entire range of about amount X to about amount Y, or any range therein, as understood.

[0048] "Room temperature" or "RT (Room temperature)" refers to the ambient temperature of a typical laboratory, which is usually about 25°C.

[0049] As used herein, the term "excipient" refers to any substance necessary to formulate a composition into the desired form. For example, suitable excipients include, but are not limited to, diluents or fillers, binders or granulating agents or adhesives, disintegrants, lubricants, anti-adhesion agents, flow promoters, dispersants or wetting agents, dissolution retardants or accelerators, adsorbents, buffers, chelating agents, preservatives, coloring agents, flavoring agents, and sweetening agents. "Pharmaceutically acceptable carrier, diluent, or excipient" is a medium generally acceptable in the art for the delivery of biologically active agents to humans. The terms "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" include any and all solvents, co-solvents, complexing agents, dispersion media, coatings, films, antibacterial and antifungal agents, isotonic agents, and absorption delaying agents, etc., that are not biologically or otherwise undesirable. The use of such media and agents for pharmaceutically active substances is well known in the art. The use thereof in therapeutic formulations is contemplated, except where any conventional medium or agent is incompatible with the active ingredient. Auxiliary active ingredients can also be incorporated into the formulations. In addition, various excipients such as those commonly used in the art may be included. These and other such compounds are described in the literature, for example, Merck Index, Merck & Company, Rahway, N.J. Considerations for including various components in pharmaceutical compositions are described, for example, in Gilman et al. (Eds.). 2010, Goodman and Gilman’s: The Pharmacologic "Pharmaceutically acceptable carrier, diluent, or excipient" is a medium generally acceptable in the art for the delivery of biologically active agents to humans. The terms "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" include any and all solvents, co-solvents, complexing agents, dispersion media, coatings, films, antibacterial and antifungal agents, isotonic agents, and absorption delaying agents, etc., that are not biologically or otherwise undesirable. The use of such media and agents for pharmaceutically active substances is well known in the art. The use thereof in therapeutic formulations is contemplated, except where any conventional medium or agent is incompatible with the active ingredient. Auxiliary active ingredients can also be incorporated into the formulations. "Pharmaceutically acceptable carrier, diluent, or excipient" is a medium generally acceptable in the art for the delivery of biologically active agents to humans. The terms "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" include any and all solvents, co-solvents, complexing agents, dispersion media, coatings, films, antibacterial and antifungal agents, isotonic agents, and absorption delaying agents, etc., that are not biologically or otherwise undesirable. The use of such media and agents for pharmaceutically active substances is well known in the art. The use thereof in therapeutic formulations is contemplated, except where any conventional medium or agent is incompatible with the active ingredient. Auxiliary active ingredients can also be incorporated into the formulations.

[0050] "Pharmaceutically acceptable carrier, diluent, or excipient" is a medium generally acceptable in the art for the delivery of biologically active agents to humans. The terms "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" include any and all solvents, co-solvents, complexing agents, dispersion media, coatings, films, antibacterial and antifungal agents, isotonic agents, and absorption delaying agents, etc., that are not biologically or otherwise undesirable. The use of such media and agents for pharmaceutically active substances is well known in the art. The use thereof in therapeutic formulations is contemplated, except where any conventional medium or agent is incompatible with the active ingredient. Auxiliary active ingredients can also be incorporated into the formulations. "Pharmaceutically acceptable carrier, diluent, or excipient" is a medium generally acceptable in the art for the delivery of biologically active agents to humans. The terms "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" include any and all solvents, co-solvents, complexing agents, dispersion media, coatings, films, antibacterial and antifungal agents, isotonic agents, and absorption delaying agents, etc., that are not biologically or otherwise undesirable. The use of such media and agents for pharmaceutically active substances is well known in the art. The use thereof in therapeutic formulations is contemplated, except where any conventional medium or agent is incompatible with the active ingredient. Auxiliary active ingredients can also be incorporated into the formulations. "Pharmaceutically acceptable carrier, diluent, or excipient" is a medium generally acceptable in the art for the delivery of biologically active agents to humans. The terms "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" include any and all solvents, co-solvents, complexing agents, dispersion media, coatings, films, antibacterial and antifungal agents, isotonic agents, and absorption delaying agents, etc., that are not biologically or otherwise undesirable. The use of such media and agents for pharmaceutically active substances is well known in the art. The use thereof in therapeutic formulations is contemplated, except where any conventional medium or agent is incompatible with the active ingredient. Auxiliary active ingredients can also be incorporated into the formulations. "Pharmaceutically acceptable carrier, diluent, or excipient" is a medium generally acceptable in the art for the delivery of biologically active agents to humans. The terms "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" include any and all solvents, co-solvents, complexing agents, dispersion media, coatings, films, antibacterial and antifungal agents, isotonic agents, and absorption delaying agents, etc., that are not biologically or otherwise undesirable. The use of such media and agents for pharmaceutically active substances is well known in the art. The use thereof in therapeutic formulations is contemplated, except where any conventional medium or agent is incompatible with the active ingredient. Auxiliary active ingredients can also be incorporated into the formulations. "Pharmaceutically acceptable carrier, diluent, or excipient" is a medium generally acceptable in the art for the delivery of biologically active agents to humans. The terms "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" include any and all solvents, co-solvents, complexing agents, dispersion media, coatings, films, antibacterial and antifungal agents, isotonic agents, and absorption delaying agents, etc., that are not biologically or otherwise undesirable. The use of such media and agents for pharmaceutically active substances is well known in the art. The use thereof in therapeutic formulations is contemplated, except where any conventional medium or agent is incompatible with the active ingredient. Auxiliary active ingredients can also be incorporated into the formulations. "Pharmaceutically acceptable carrier, diluent, or excipient" is a medium generally acceptable in the art for the delivery of biologically active agents to humans. The terms "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" include any and all solvents, co-solvents, complexing agents, dispersion media, coatings, films, antibacterial and antifungal agents, isotonic agents, and absorption delaying agents, etc., that are not biologically or otherwise undesirable. The use of such media and agents for pharmaceutically active substances is well known in the art. The use thereof in therapeutic formulations is contemplated, except where any conventional medium or agent is incompatible with the active ingredient. Auxiliary active ingredients can also be incorporated into the formulations. "Pharmaceutically acceptable carrier, diluent, or excipient" is a medium generally acceptable in the art for the delivery of biologically active agents to humans. The terms "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" include any and all solvents, co-solvents, complexing agents, dispersion media, coatings, films, antibacterial and antifungal agents, isotonic agents, and absorption delaying agents, etc., that are not biologically or otherwise undesirable. The use of such media and agents for pharmaceutically active substances is well known in the art. The use thereof in therapeutic formulations is contemplated, except where any conventional medium or agent is incompatible with the active ingredient. Auxiliary active ingredients can also be incorporated into the formulations. "Pharmaceutically acceptable carrier, diluent, or excipient" is a medium generally acceptable in the art for the delivery of biologically active agents to humans. The terms "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" include any and all solvents, co-solvents, complexing agents, dispersion media, coatings, films, antibacterial and antifungal agents, isotonic agents, and absorption delaying agents, etc., that are not biologically or otherwise undesirable. The use of such media and agents for pharmaceutically active substances is well known in the art. The use thereof in therapeutic formulations is contemplated, except where any conventional medium or agent is incompatible with the active ingredient. Auxiliary active ingredients can also be incorporated into the formulations. In addition, various excipients such as those commonly used in the art may be included. These and other such compounds are described in the literature, for example, Merck Index, Merck & Company, Rahway, N.J. Considerations for including various components in pharmaceutical compositions are described, for example, in Gilman et al. (Eds.). 2010, Goodman and Gilman’s: The Pharmacologic In addition, various excipients such as those commonly used in the art may be included. These and other such compounds are described in the literature, for example, Merck Index, Merck & Company, Rahway, N.J. Considerations for including various components in pharmaceutical compositions are described, for example, in Gilman et al. (Eds.). 2010, Goodman and Gilman’s: The Pharmacologic In addition, various excipients such as those commonly used in the art may be included. These and other such compounds are described in the literature, for example, Merck Index, Merck & Company, Rahway, N.J. Considerations for including various components in pharmaceutical compositions are described, for example, in Gilman et al. (Eds.). 2010, Goodman and Gilman’s: The Pharmacologic In addition, various excipients such as those commonly used in the art may be included. These and other such compounds are described in the literature, for example, Merck Index, Merck & Company, Rahway, N.J. Considerations for including various components in pharmaceutical compositions are described, for example, in Gilman et al. (Eds.). 2010, Goodman and Gilman’s: The Pharmacologic In addition, various excipients such as those commonly used in the art may be included. These and other such compounds are described in the literature, for example, Merck Index, Merck & Company, Rahway, N.J. Considerations for including various components in pharmaceutical compositions are described, for example, in Gilman et al. (Eds.). 2010, Goodman and Gilman’s: The Pharmacologic al Basis of Therapeutics, 12th Ed., The Mc is described in the McGraw-Hill Companies.

[0051] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0052] As used herein, ranges and amounts may be expressed as "about" a particular value or range, and in particular, "about" means within 5% or 10% of the numerical value. "About" also includes the exact amount. Thus, "about 5 grams" also means "about 5 grams" and "5 grams." It is also understood that ranges recited herein include integers and fractions within that range. For example, a range of 5 grams to 20 grams includes integer values such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, and 22 grams, as well as fractions within the range, including, but not limited to, 4.5, 4.75, 5.25, 6.5, 8.75, 11.95, and 21.95 grams.

[0053] As used herein, "optionally" or "optionally" means that the subsequently recited event or circumstance may or may not occur, and the description includes examples where the event or circumstance occurs and examples where it does not occur. For example, a reaction mixture "optionally containing a catalyst" means that the reaction mixture may or may not contain a catalyst.

[0054] As used herein, "relative intensity" is the highest peak in the relevant spectrum. ​​​​​​​Means the percentage of any peak relative to the peak.

[0055] Certain features of the present disclosure that are described in the context of separate embodiments for clarity may also be provided in combination in a single embodiment. Conversely, various features of the disclosure that are described in the context of a single embodiment for brevity may also be provided separately or in any suitable partial combination. It is understood that they may be provided in combination in a single embodiment. Conversely, for the sake of brevity, various features of the disclosure described in the context of a single embodiment may also be provided separately or in any suitable partial combination. For the sake of brevity, various features of the disclosure described in the context of a single embodiment may also be provided separately or in any suitable partial combination. It can be provided as a combination.

[0056] All combinations of embodiments related to the aspects described herein are specifically encompassed by the present disclosure to the extent that such combinations are possible, as if every possible combination was explicitly enumerated individually. In addition, all partial combinations of embodiments included in the aspects described herein, and all partial combinations of embodiments included in all other aspects described herein, are also specifically encompassed by the present disclosure as if every possible partial combination of all embodiments was explicitly enumerated herein. The present invention includes the following aspects. Item 1. (S)-5-Amino-3-(4-((5-fluoro-2-methoxybenzamide)methyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide and a coformer selected from the group consisting of adipic acid and camphoric acid, a co-crystalline form. Item 2. (S)-5-Amino-3-(4-((5-fluoro-2-methoxybenzamide)methyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide and adipic acid, the co-crystalline form according to Item 1. Item 3. The cocrystal form according to item 2, wherein the ratio of (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamide)methyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide to adipic acid is about 2:1. Item 4. The cocrystal form according to item 3, characterized by an X-ray powder diffraction pattern using CuKα radiation, having a diffraction peak at a diffraction angle 2 theta of 18.7°, in combination with one or more of the peaks selected from the group consisting of 10.4°, 14.2°, 15.1°, 17.0°, and 21.6°, and the tolerance of the diffraction angle being ±0.2 degrees. Item 5. The cocrystal form according to any one of items 1 to 3, characterized by an X-ray powder diffraction pattern using CuKα radiation, having a diffraction peak at a diffraction angle 2 theta of 18.7°, in combination with one or more of the peaks selected from the group consisting of 14.2°, 17.0°, and 21.6°, and the tolerance of the diffraction angle being ±0.2 degrees. Item 6. The cocrystal form according to any one of items 1 to 3, characterized by an X-ray powder diffraction pattern using CuKα radiation, having a diffraction peak at a diffraction angle 2 theta of 18.7°, in combination with one or more of the peaks selected from the group consisting of 17.0° and 21.6°, and the tolerance of the diffraction angle being ±0.2 degrees. Item 7. Including peaks based on the high-field resonance of adamantane at 174.6, 167.6, 166.1, 157.5, 155.5, 152.7, 150.9, 150.3, 141.1, 140.4, 130.1, 129.3, 127.7, 126.6, 123.6, 120.7, 120.2, 118.5, 116.5, 114.1, 112.8, 91.2, 63.6, 58.6, 56.8, 52.2, 44.0, 34.5, 33.2, 25.1, 24.7, 13.8, and 13.2 ppm, with a tolerance of ±0.2 ppm. 13 The cocrystal form according to any one of items 1 to 3, characterized by a 13C solid NMR spectrum. Item 8. Peaks based on the high-field resonance of adamantane at 174.6, 91.2, 44.0, 13.8, and 13.2 ppm, with a tolerance of ±0.2 ppm, 13 The cocrystal form according to any one of items 1 to 3, characterized by a 13 C solid NMR spectrum. Item 9. The cocrystal form according to item 1, comprising (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamide)methyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide and borneol acid. Item 10. The cocrystal form according to item 9, wherein the ratio of (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamide)methyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide to borneol acid is about 1:1. Item 11. The cocrystal form according to item 10, having a diffraction peak at a diffraction angle 2 theta of 17.7°, in combination with one or more of the peaks selected from the group consisting of 7.2°, 8.3°, 12.6°, 14.5°, and 16.7°, with a tolerance of ±0.2° for the diffraction angle, and characterized by an X-ray powder diffraction pattern using CuKα radiation. Item 12. The cocrystal form according to item 1 or 9 or 10, having a diffraction peak at a diffraction angle 2 theta of 17.7°, in combination with one or more of the peaks selected from the group consisting of 7.2°, 14.5°, and 16.7°, with a tolerance of ±0.2° for the diffraction angle, and characterized by an X-ray powder diffraction pattern using CuKα radiation. Item 13. The cocrystal form according to item 1 or 9 or 10, having a diffraction peak at a diffraction angle 2 theta of 17.7°, in combination with one or more of the peaks selected from the group consisting of 7.2° and 14.5°, with a tolerance of ±0.2° for the diffraction angle, and characterized by an X-ray powder diffraction pattern using CuKα radiation. Item 14. A pharmaceutical composition comprising the cocrystal form according to any one of items 1 to 13, and further comprising one or more polymers and a pharmaceutically acceptable carrier, diluent, or excipient. Item 15. The pharmaceutical composition according to item 14, wherein the one or more polymers are selected from PVP-VA, HPMC, and HPMCAS. Item 16. The pharmaceutical composition according to item 15, wherein the HPMCAS is HPMCAS-L, HPMCAS-M, or HPMCAS-H. Item 17. The pharmaceutical composition according to item 16, wherein the HPMCAS is HPMCAS-M. Item 18. The pharmaceutical composition according to any one of items 14 to 17, wherein the pharmaceutical composition comprises about 90 parts by weight of polymer and about 10 parts by weight of cocrystal form, about 80 parts by weight of polymer and about 20 parts by weight of cocrystal form, about 70 parts by weight of polymer and about 30 parts by weight of cocrystal form, or about 50 parts by weight of cocrystal form and about 50 parts by weight of polymer. Item 19. The pharmaceutical composition according to any one of items 14 to 17, wherein the cocrystal form constitutes about 20 parts by weight and the one or more polymers constitute about 80 parts by weight. Item 20. The pharmaceutical composition according to any one of items 14 to 17, wherein the composition contains less than about 20% by weight of other cocrystal forms with conformers different from BTK-I. Item 21. The pharmaceutical composition according to any one of items 14 to 17, wherein the composition contains less than about 10% by weight of other cocrystal forms with conformers different from BTK-I. Item 22. A method for treating BTK-related cancer in a patient in need thereof, the method comprising administering to the patient an effective amount of the cocrystal form according to any one of items 1 to 13 or the pharmaceutical composition according to any one of items 14 to 21. Item 23. The method according to item 22, wherein the BTK-related cancer is selected from the group consisting of B-cell malignancies, B-cell lymphomas, marginal zone lymphomas, diffuse large B-cell lymphomas, chronic lymphocytic leukemia, small lymphocytic lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia, B-cell non-Hodgkin lymphoma, B-cell prolymphocytic leukemia, Waldenström macroglobulinemia, and multiple myeloma. Item 24. The method according to item 23, wherein the BTK-related cancer is selected from the group consisting of mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenström macroglobulinemia, follicular lymphoma, and marginal zone lymphoma. Item 25. A method for treating multiple sclerosis in a patient in need thereof, comprising administering to the patient an effective amount of the cocrystal form according to any one of items 1 to 13 or the pharmaceutical composition according to any one of items 14 to 21. Item 26. A method for treating arthritis in a patient in need thereof, comprising administering to the patient an effective amount of the cocrystal form according to any one of items 1 to 13 or the pharmaceutical composition according to any one of items 14 to 21. Item 27. The method according to item 26, wherein the arthritis is rheumatoid arthritis. Item 28. The cocrystal form according to any one of items 1 to 13 or the pharmaceutical composition according to any one of items 14 to 21 for use in therapy. Item 29. The cocrystal form according to any one of items 1 to 13 or the pharmaceutical composition according to any one of items 14 to 21 for use in the treatment of BTK-related cancer. Item 30. The cocrystalline form or pharmaceutical composition for use according to item 29, wherein the BTK-related cancer is selected from the group consisting of B-cell malignancies, B-cell lymphomas, marginal zone lymphomas, diffuse large B-cell lymphomas, chronic lymphocytic leukemia, small lymphocytic lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia, B-cell non-Hodgkin lymphoma, B-cell prolymphocytic leukemia, Waldenström macroglobulinemia, and multiple myeloma. Item 31. The cocrystalline form or pharmaceutical composition for use according to item 30, wherein the BTK-related cancer is selected from the group consisting of mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenström macroglobulinemia, follicular lymphoma, and marginal zone lymphoma. Item 32. The cocrystalline form according to any one of items 1 to 13 or the pharmaceutical composition according to any one of items 14 to 21 for use in the treatment of multiple sclerosis. Item 33. The cocrystalline form according to any one of items 1 to 13 or the pharmaceutical composition according to any one of items 14 to 21 for use in the treatment of arthritis. Item 34. The cocrystalline form or pharmaceutical composition for use according to item 33, wherein the arthritis is rheumatoid arthritis.

[0057] The present disclosure will be further described by the following examples.

[0058] The XRPD pattern is obtained with the equipment described in Example 1 and Example 2. For each, The dry powder is filled into a quartz sample holder, and the smooth surface is obtained using a glass slide The crystalline form diffraction pattern is collected at ambient temperature and relative humidity. The crystal peak positions Are determined with MDI-Jade after overall pattern shifting based on the internal NIST 675 standard having peaks at 8.853 and 26.774 2θ°. Based on the internal NIST 675 standard having peaks at 8.853 and 26.774 2θ°, the crystal peak positions are determined with MDI-Jade after overall pattern shifting.

[0059] For any given crystalline form, it is well known in the field of crystallography that the relative intensities of diffraction peaks can vary due to preferred orientation resulting from factors such as crystal morphology and crystal habit. When the effect of preferred orientation is present, the peak intensities are modified, but the characteristic peak positions of the form remain unchanged. For example, see The United States Pharmacop eia #23, National Formulary #18, pages 1843 - 1844, 1995. Further, it is also well known in the field of crystallography that the angular peak positions can vary slightly for any given crystalline form. For example, the peak positions can be shifted by variations in the temperature at which the sample is analyzed, sample displacement, or the presence or absence of an internal standard. In this case, it is estimated that peak position variability of ±0.2 2θ° takes into account these potential variations without preventing clear identification of the indicated crystalline form. Confirmation of the crystalline form can be made based on any unique combination of characteristic peaks. Solid state NMR was obtained on a Bruker Avance III HD equipped with a Bruker UltraShield 400 WB Plus magnet operating at a frequency of 100.6 MHz. The probe used was a Bruker MAS 4 BL CP BB D VT N - P / H. The acquisition parameters were as follows: 31104 scans, an acquisition time of 34 milliseconds, a pulse delay of 4.6 seconds, a MAS frequency of 10 kHz, a contact time of 1.5 milliseconds, and a SPINAL64 decoupling scheme. The data was referenced to adamantane at 29.5 ppm ± 0.2 ppm as an external reference. EXAMPLE

[0060] Solid state NMR was obtained on a Bruker Avance III HD equipped with a Bruker UltraShield 400 WB Plus magnet operating at a frequency of 100.6 MHz. The probe used was a Bruker MAS 4 BL CP BB D VT N - P / H. The acquisition parameters were as follows: 31104 scans, an acquisition time of 34 milliseconds, a pulse delay of 4.6 seconds, a MAS frequency of 10 kHz, a contact time of 1.5 milliseconds, and a SPINAL64 decoupling scheme. The data was referenced to adamantane at 29.5 ppm ± 0.2 ppm as an external reference. Solid state NMR was obtained on a Bruker Avance III HD equipped with a Bruker UltraShield 400 WB Plus magnet operating at a frequency of 100.6 MHz. The probe used was a Bruker MAS 4 BL CP BB D VT N - P / H. The acquisition parameters were as follows: 31104 scans, an acquisition time of 34 milliseconds, a pulse delay of 4.6 seconds, a MAS frequency of 10 kHz, a contact time of 1.5 milliseconds, and a SPINAL64 decoupling scheme. The data was referenced to adamantane at 29.5 ppm ± 0.2 ppm as an external reference. Solid state NMR was obtained on a Bruker Avance III HD equipped with a Bruker UltraShield 400 WB Plus magnet operating at a frequency of 100.6 MHz. The probe used was a Bruker MAS 4 BL CP BB D EXAMPLE

[0061] (S)-5-Amino-3-(4-((5-fluoro-2-methoxybenzamide)methyl phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyraz ole-4-carboxamide (「BTK-I」), hemi-adipic acid cocrystal form (「BTK -I and hemi-adipic acid cocrystal form」)

[0062]

Chemical formula

[0063] Suspend adipic acid (2.42 g, 16.56 mmol) in ethyl acetate (60 mL) , partially dissolve it, and heat the mixture to 55 °C. (S)-5-Amino-3-(4-(( 5-fluoro-2-methoxybenzamide)methyl)phenyl)-1-(1,1,1-tr ifluoropropan-2-yl)-1H-pyrazole-4-carboxamide (15.08 g, 31.45 mmol) is added, and the mixture is stirred at 500 rpm and 55 °C. The solid never completely dissolves, but within the next few minutes the slurry changes from light yellowish brown to light white. Stir the reaction for 1 hour and remove the heat source. Isolate the white solid on a nylon filter under vacuum and dry it under a nitrogen stream for 15 minutes. Dry the solid in a vacuum oven at 65 °C for 48 hours to obtain the title compound (16.3 g, 94.3%). The solid-state NMR (101 MHz) of the BTK-I and hemi-adip ic acid cocrystal form shows δ 174.6, 167.6, 13 C solid NMR (101 MHz) is δ 174.6, 167.6, 166.8, 166.1, 157.5, 155.5, 152.7, 150.9, 150. 3, 141.1, 140.4, 132.1, 130.1, 129.3, 127.7, 12 6.6, 123.6, 120.7, 120.2, 118.5, 116.5, 114.1, 112.8, 91.2, 63.6, 58.6, 56.8, 52.2, 44.0, 34.5 including peaks at 33.2, 25.1, 24.7, 13.8, 13.2.

[0064] XRPD of BTK-I and hemi-adipic acid cocrystal form The XRPD patterns of the BTK-I and hemi-adipic acid cocrystal form solids were obtained with a Bruker D4 Endeavor X-ray powder diffractometer operating at 35 kV and 50 mA with a CuKα(1 .5418 Å) source and a Vantec detector. The BTK-I and hemi-adipic acid cocrystal form samples were scanned at 2θ° from 4 to 40 with a step size of 0.008 2θ° and a scan rate of 0.5 s / step, using a 1.0 mm divergence slit, a 6.6 mm fixed anti-scatter slit, and an 11.3 mm detector slit.

[0065] XRPD of BTK-I and hemi-adipic acid cocrystal form The prepared samples of the BTK-I and hemi-adipic acid cocrystal form are characterized by an XRPD pattern using CuKα radiation, having diffraction peaks (2-theta values) as set forth in Table 1 below, in particular, in combination with one or more of the peaks selected from the group consisting of 14.2, 17.0, and 21 .6, having a peak at 18.7, with an angular tolerance of the diffraction angle of ±0.2 degrees.

[0066]

Table 1

[0067] Alternative Example 1 BTK-I and hemi-adipic acid co-crystalline form Alternatively, the BTK-I and hemi-adipic acid co-crystalline form can be prepared using a solvent other than ethyl acetate. For example, isopropyl alcohol as a solvent can be used as follows: (S)-5-amino-3-(4-((5-fluoro-2-methoxy benzamide)methyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide (1.75 g, 3.65 mmol) and adipic acid (0.266 g, 1.82 mmol) are suspended in isopropyl alcohol (20 mL). The slurry is heated to 80 °C. All solids dissolve. The solution is cooled to 65 °C and then seeded with 1 wt% co-crystal. Using a linear cooling gradient, the mixture is cooled to 55 °C over 8 hours. Stirring is maintained at 200 rpm. The solid is isolated on a Whatman® #1 filter to obtain the title compound (1.37 g, 6 8.3%).

Example

[0068] (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamide)methyl phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide, (1R,3S)-1,2,2-trimethylcyclopentane- 1,3-dicarboxylic acid (「camphoric acid」) (「BTK-I and mono-camphoric acid co-crystalline form」)

[0069]

[0070] ​​​​​​​​​(S)-5-Amino-3-(4-((5-fluoro-2-methoxybenzamide)methyl phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyraz ole-4-carboxamide (466 mg, 0.97 mmol) was suspended in cyclopentylmethyl ether (20 mL) saturated with camphorsulfonic acid and stirred at 50 °C and 800 rpm. The reaction mixture becomes a slurry of white solid (initially slightly yellowish brown). The mixture was stirred as a slurry at 50 °C for 2 hours. The heat source was removed and the mixture was stirred at room temperature overnight. The white solid was isolated by filtration under vacuum to give the title compound (564 mg, 87.4% yield).

[0071] XRPD of the co-crystalline form of BTK-I and mono-camphorsulfonic acid The XRPD patterns of the co-crystalline form of BTK-I and mono-camphorsulfonic acid solids were obtained using a Bruker D8 Endeavor X-ray powder diffractometer operating at 40 kV and 40 mA with a CuKα (1.5418 Å) source and a Linxeye detector. The samples of the co-crystalline form of BTK-I and mono-camphorsulfonic acid were scanned at 4 - 42 2θ° with a step size of 0.009 2θ° and a scan speed of 0.5 seconds / step, using a primary slit aperture of 0.3° and a position sensitive detector (PSD) aperture of 3.9°.

[0072] XRPD of BTK-I, (1R,3S)-1,2,2-trimethylcyclopentane-1,3-dicar boxylic acid The prepared samples of BTK-I, (1R,3S)-1,2,2-trimethylcyclopentane-1,3-dicar boxylic acid have the diffraction peaks (2-theta values) listed in Table 2. Specifically, among the peaks selected from the group consisting of 7.2, 14.5, and 16.7, in combination with one or more, those having a peak at 17.7, with CuKα radiation is used to characterize the XRPD pattern, and the tolerance of the diffraction angle is ±0.2 degrees.

[0073] [Table 2]

Claims

1. A crystalline form of (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide having the following formula and an X-ray powder diffraction (XRPD) pattern including an XRPD peak at a 2-theta angle of 17.7°±0.2°: 【Chemistry 2】

2. 2. The crystal of claim 1, having an X-ray powder diffraction (XRPD) pattern further comprising one or more XRPD peaks at 2-theta angles of 7.2°±0.2°, 8.3°±0.2°, 10.2°±0.2°, 11.7°±0.2°, 11.9°±0.2°, 12.6°±0.2°, 13.4°±0.2°, 13.8°±0.2°, 14.5°±0.2°, 15.6°±0.2°, 15.8°±0.2°, 16.7°±0.2°, 19.0°±0.2°, 20.4°±0.2°, 21.1°±0.2°, 23.6°±0.2°, 25.5°±0.2°, 26.1°±0.2°, or 27.2°±0.2°.

3. 2. The crystal of claim 1, having an X-ray powder diffraction (XRPD) pattern comprising XRPD peaks at 2-theta angles of 7.2°±0.2°, 14.5°±0.2°, 16.7°±0.2°, and 17.7°±0.2°.

4. 2. The crystal of claim 1, having an X-ray powder diffraction (XRPD) pattern comprising XRPD peaks at 2-theta angles of 7.2°±0.2°, 14.5±0.2°, and 17.7°±0.2°.

5. A pharmaceutical composition comprising the crystal described in claim 1 and a pharma- ceutically acceptable carrier, diluent, and / or excipient.

6. 6. The pharmaceutical composition of claim 5, comprising one or more polymers selected from the group consisting of polyvinylpyrrolidone vinyl acetate (PVP-VA), hydroxypropyl methylcellulose (HPMC), or hydroxypropyl methylcellulose acetate succinate (HPMCAS).

7. 7. The pharmaceutical composition of claim 6, wherein the HPMCAS is selected from the group consisting of HPMCAS-L, HPMCAS-M, and HPMCAS-H.

8. 2. The crystal of claim 1 for use in the treatment of Bruton's tyrosine kinase (BTK) associated cancer.

9. 9. The crystal for use of claim 8, wherein the BTK associated cancer is selected from B cell malignancies, B cell lymphoma, marginal zone lymphoma, diffuse large B cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia, B cell non-Hodgkin's lymphoma, B cell prolymphocytic leukemia, Waldenstrom's macroglobulinemia, and multiple myeloma.

10. 10. The method of claim 9, wherein the BTK-associated cancer is chronic lymphocytic leukemia.

11. 10. The method of claim 9, wherein the BTK-associated cancer is small lymphocytic lymphoma.

12. 10. The method of claim 9, wherein the BTK-associated cancer is mantle cell lymphoma.

13. 2. The crystal of claim 1 for use in the treatment of multiple sclerosis.

14. 13. The crystal of claim 1 for use in the treatment of arthritis.

15. The method of claim 14, wherein the arthritis is rheumatoid arthritis.

16. A process for preparing the crystal of claim 1, comprising: mixing (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide and camphoric acid in a solvent; and heating the mixture to 45-55°C.

17. 17. The process of claim 16, wherein the solvent is selected from the group consisting of ethyl acetate, cyclopentyl methyl ether, isopropyl alcohol, and acetonitrile.

18. 17. The process of claim 16, wherein the mixture is stirred at 720 to 880 rpm.

19. The process of claim 17, further comprising isolating the crystals of claim 1.

20. The process of claim 18, further comprising isolating the crystals of claim 1.

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