Cocrystalline forms of bruton's tyrosine kinase inhibitor

Abstract

To provide stable and low-hygroscopicity cocrystalline forms of (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide useful as a Bruton's Tyrosine Kinase-I (BTK-I) inhibitor.SOLUTION: The invention provides a cocrystalline form of (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide represented by the formula in the figure and a conformer selected from the group consisting of adipic acid and camphoric acid.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present disclosure relates to Bruton's Tyrosine Kinase (BTK) inhibitors. Novel co-crystal forms of, pharmaceutical compositions comprising the co-crystal forms, B-cell malignancies, B-cell lymphomas, Marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (diffuse large B-cell lymphoma, DLBCL), chronic lymphocytic leukemia (chronic lym leukemia (CLL), small lymphocytic lymphoma (small lymphocytic lymphoma, SLL), non-Hodgkin's lymphoma, Burkitt lymphoma, mantle cell lymphoma ell lymphoma, MCL), follicular lymphoma (FL), hair cell white Blood diseases, B-cell non-Hodgkin's lymphoma, B-cell prolymphocytic leukemia, Waldenstrom's disease Waldenstrom's macroglobulinemia (WM), multiple myeloma ple myeloma (MM), arthritis, especially rheumatoid arthritis (RA) and multiple sclerosis (MS), which can be treated by inhibiting BTK. and methods of using co-crystal forms to treat various conditions, as well as methods useful in the synthesis of co-crystal forms. Regarding useful processes. [Background technology]

[0002] BTK is a promising treatment for indolent and aggressive mature B-cell non-Hodgkin's lymphoma, including CLL and SLL. , WM, MCL, FL, DLBCL, B-cell prolymphocytic leukemia, hairy cell leukemia, It is a molecular target useful for the treatment of multiple B-cell leukemias and lymphomas, including MZL. B cells are responsible for chronic graft-versus-host disease (CRD), a life-threatening complication of allogeneic stem cell transplantation. It has been shown that vascular grafts play a prominent role in the development of cGVHD. This has prompted research into B cell-targeted therapies for the prevention and treatment of cGVHD. It is being done.

[0003] BTK inhibitors are known in the art, for example, in WO 2013 / 010136 No. 9090621, International Publication No. 2015 / 127310, International Publication No. 015 / 095099 and U.S. Patent Application Publication No. 2014 / 221333 It is knowledge.

[0004] Furthermore, in addition to cancer, certain BTK inhibitors are in clinical trials for RA and / or MS. It has been reported that research is being conducted in the field (for example, International Publication No. 2021 / 20282 5 and WO 2020 / 016850). The compound, (S)-5-amino-3-( 4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1 ,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide ( The BTK-I (herein referred to as "BTK-I") and pharmaceutically acceptable salts thereof are disclosed in International Publication No. This is disclosed in Patent Publication No. 2017 / 103611.

[0005] Furthermore, the spray-dried dispersion (SDD) formulation of BTK-I has been approved by international standards. This is disclosed in Publication No. 2020 / 028258.

[0006] BTK- provides solid-state and chemical stability for the preparation and manufacturing of pharmaceutical formulations. Novel forms of I are desired. Pharmaceutical compositions can be prepared by incorporating one or more polymers, e.g., polyvinyl Polyvinylpyrrolidone vinyl acetate (PVP-VA), Hydrogenated Hydroxypropylmethylcellulose (HPMC), or hydroxypropylmethylcellulose Hydroxypropyl methylcellulose acetate succinate se acetate succinate, HPMCAS), e.g. HPMCAS-L, HPMCAS-M , or HPMCAS-H. The pharmaceutical composition may also contain a pharmaceutically acceptable carrier , diluents, or excipients. Summary of the Invention [Problem to be solved by the invention]

[0007] An object of certain embodiments of the present disclosure is to provide a co-crystalline form that is stable and has low hygroscopicity. An objective of certain embodiments of the present disclosure is to provide formulations that require fewer manipulation steps than current formulations. The co-crystal form requires a processing step. Fewer operational process steps, including the advantage of simplified processing and fewer unit operations. Co-crystal forms can be obtained by incorporating the co-crystals into formulations such as tablets, capsules, and suspensions. The SDD formulation has little material transfer from different locations, such as moving it once to Manufacturing Active Pharmaceutical Ingredients (APIs) at the following locations: Starting from the first location, moving to a second location to incorporate the API into the SDD, then tablets, capsules, In a third location to incorporate the SDD with the API into formulations such as capsules and suspensions It is also an object of certain embodiments of the present disclosure to Utilizes a co-crystal form that requires less solvent than conventional formulations, resulting in a lower environmental impact. This is what we do.

[0008] Accordingly, co-crystalline 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 problem]

[0009] In one embodiment, BTK-I and a compound selected from the group consisting of adipic acid and camphoric acid are used. Disclosed herein are co-crystalline forms with coformers such as B Disclosed herein is a co-crystalline form comprising TK-I and adipic acid.

[0010] In another embodiment of the aspect, (S)-5-amino-3-(4-((5-fluoro-2 -Methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane The ratio of (benzo-2-yl)-1H-pyrazole-4-carboxamide to adipic acid was approximately 2:1. A co-crystal form (referred to herein as the "BTK-I and hemi-adipic acid co-crystal form") ) are disclosed herein.

[0011] In another embodiment of the aspect, the peak at 18.7° and the peaks at 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°, 28.3° or 29.8° and one or more peaks at the diffraction angle tolerance of ±0. X-ray powder diffraction (X) using CuKα radiation, which is 0.2 degrees. BTK-I and hemi-adipic acid co-crystal morphology characterized by a RPD pattern In another embodiment of the aspect, 10.4°, 14.2°, 15 one or more peaks selected from the group consisting of 0.1°, 17.0°, and 21.6° In combination with this, it has a diffraction peak at a diffraction angle 2 theta of 18.7°, and the diffraction angle tolerance BTK characterized by an XRPD pattern using CuKα radiation with a deviation of ±0.2 degrees In another embodiment of the present invention, a co-crystalline form of hydroxybenzoates of hydroxybenzoates containing hydroxybenzoates of hydroxybenzoates is disclosed. Among the peaks selected from the group consisting of 14.2°, 17.0°, and 21.6° and having a diffraction peak at a diffraction angle 2-theta of 18.7° in combination with one or more of XRPD patterns were characterized using CuKα radiation with a tolerance of ±0.2 degrees. Disclosed herein are BTK-I and hemi-adipic acid co-crystal forms. In an embodiment, one of the peaks selected from the group consisting of 17.0° and 21.6° and a diffraction peak at a diffraction angle 2-theta of 18.7° in combination with one or more Characterized by XRPD patterns using CuKα radiation with a tolerance of ±0.2 degrees BTK-I and hemi-adipic acid co-crystalline forms are disclosed herein. In this embodiment, a co-crystal form having a diffraction peak at a diffraction angle 2 theta of 18.7° is described in the present specification. In another embodiment of the invention, one or more peaks in the diffraction angle 2 theta are Disclosed herein are co-crystal forms in which the angle is selected from the group consisting of 17.0° and 21.6°. can be.

[0012] In another embodiment of the aspect, BTK-I and hemi-adipic acid co-crystal form 13 C hard The NMR spectrum of the compound is 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 The peaks are based on the upfield resonance of adamantane (δ = 29.5 ppm) in the BTK-I and Hemi-Adipic Acid Co-Crystal Form Characterized by a Tolerance of ±0.2 ppm In another embodiment of the aspect disclosed herein, 174.6, 91.2, 44 Peaks referenced to the upfield resonances of adamantane at 0.0, 13.8, and 13.2 ppm The tolerance is ±0.2 ppm. 13 Characterized by C solid-state NMR spectrum Co-crystal forms are disclosed herein. In another embodiment of the aspect, for example, Described herein are BTK-I and hemi-adipic acid co-crystalline forms that can be represented by various structures. Shown:

[0013] [ka]

[0014] In an embodiment of this aspect, a co-crystalline form of BTK-I and camphoric acid is described herein. In another embodiment of this aspect, (S)-5-amino-3-(4-((5 -fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-tri Fluoropropan-2-yl)-1H-pyrazole-4-carboxamide and camphor A co-crystal form containing camphoric acid (referred to herein as the "BTK-I and camphoric acid co-crystal form") In another embodiment of this aspect, (S)-5-aminobenzoates are disclosed herein. 3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1 -(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide BTK-I and camphoric acid co-crystal form (this product) with a camphoric acid to camphoric acid ratio of approximately 1:1. The BTK-I and mono-camphoric acid co-crystal form (referred to herein as the "BTK-I and mono-camphoric acid co-crystal form") is In another embodiment of this aspect, the peak at 17.7° and the peak 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°, One or more of the following angles: 21.1°, 23.6°, 25.5°, 26.1°, or 27.2° XRPD patterns using CuKα radiation, including peaks 1 and 2, with a tolerance of ±0.2 ppm. BTK-I and mono-camphoric acid co-crystal forms characterized by having a turn are described herein. In another embodiment of this aspect, the angle is 7.2°, 8.3°, 12.6°, 14.5°, and 16.7°. In addition, it has a diffraction peak at a diffraction angle 2 theta of 17.7°, and the diffraction angle tolerance is ±0. BTK-I and BTK-II characterized by an XRPD pattern using CuKα radiation at 0.2 degrees Celsius. Disclosed herein is a mono-camphoric acid co-crystalline form. In another embodiment of this aspect and one of the peaks selected from the group consisting of 7.2°, 14.5°, and 16.7°. and a diffraction peak at a diffraction angle 2-theta of 17.7° in combination with one or more Characterized by XRPD patterns using CuKα radiation with a tolerance of ±0.2 degrees BTK-I and mono-camphoric acid co-crystalline forms are disclosed herein. In an embodiment, one of the peaks selected from the group consisting of 7.2° and 14.5° and a diffraction peak at a diffraction angle 2-theta of 17.7° in combination with one or more Characterized by XRPD patterns using CuKα radiation with a tolerance of ±0.2 degrees BTK-I and mono-camphoric acid co-crystalline forms are disclosed herein. In an embodiment, a co-crystal form having a diffraction peak at a diffraction angle 2 theta of 17.7° is In another embodiment of this aspect, one in the diffraction angle 2 theta is The co-crystal form in which the above peak is selected from the group consisting of 7.2° and 14.5° is described herein. In another embodiment of this aspect, the compound is represented by the structure: Disclosed herein is a BTK-I and mono-camphoric acid co-crystalline form that can be obtained by:

[0015] [ka]

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

[0017] In another embodiment of this aspect disclosed herein, a pharmaceutical composition comprising a co-crystalline form The composition comprises 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 about 20 parts by weight of the co-crystalline form and about 70 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 shown, the pharmaceutical composition comprises about 80 parts by weight of the co-crystalline form and about 20 parts by weight of polymer.

[0018] In another embodiment of this aspect disclosed herein, the pharmaceutical composition is a pharmaceutically acceptable In another embodiment of this aspect, the pharmaceutical Disclosed herein are compositions and pharmaceutically acceptable carriers, diluents, or excipients. In another embodiment of this aspect, a pharmaceutical composition is disclosed herein, the composition comprising about Contains less than 20% by weight of other co-crystal forms of BTK-I with different coformers. In another embodiment, a pharmaceutical composition is disclosed herein, the composition comprising about 10 fold % of other co-crystal forms of BTK-I with different coformers. In embodiments, pharmaceutical compositions are disclosed herein, wherein the composition comprises less than about 5% by weight It contains other co-crystal forms of BTK-I with different coformers.

[0019] In another embodiment, a method for treating a rheumatoid arthritis comprises administering an effective amount of a cocrystal of the present invention or a pharmaceutical composition thereof. Disclosed herein are methods for treating cancer, including the treatment of cancer, in a patient in need thereof. In an embodiment of this aspect, BTK-I and hemi-adipic acid co-crystal forms, and BTK- and administering to a patient in need thereof a BTK-associated cancer. In another embodiment of this aspect, a method is disclosed herein in which BTK-I and mono- A method for treating a BTK-associated cancer, comprising administering a camphoric acid co-crystal form to a patient in need thereof. Disclosed herein are methods for performing the same in a patient with the same disease. In some embodiments, the BTK-associated cancer is a B-cell malignancy, B-cell lymphoma, MZL, D LBCL, CLL, SLL, non-Hodgkin's lymphoma, Burkitt lymphoma, MCL, FL, Hairy cell leukemia, B-cell non-Hodgkin's lymphoma, WM, B-cell prolymphocytic leukemia, and M In another embodiment of this aspect disclosed herein, The BTK-associated cancer is MCL. In another embodiment of this aspect disclosed herein In another embodiment of this aspect disclosed herein, the BTK-associated cancer is CLL. In another embodiment, the BTK-associated cancer is SLL. In one embodiment, the BTK-associated cancer is FL. In one embodiment, the BTK-associated cancer is MZL. In embodiments, the MZL is splenic, nodal, or extranodal. In another embodiment of this aspect, the BTK-associated cancer is DLBCL. In another embodiment of this aspect, the BTK-associated cancer is B-cell non-Hodgkin's lymphoma. In another embodiment of this aspect disclosed herein, In this study, BTK-associated cancers consist of MCL, CLL, SLL, WM, FL, and MZL. is selected from the group.

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

[0021] In another embodiment, a method for treating a rheumatoid arthritis comprises administering an effective amount of a cocrystal of the present invention or a pharmaceutical composition thereof. Disclosed herein are methods for treating MS, including steroid therapy, in a patient in need thereof.

[0022] In another embodiment, a method for treating a rheumatoid arthritis comprises administering an effective amount of a cocrystal of the present invention or a pharmaceutical composition thereof. The present invention provides a method for treating arthritis, more specifically RA, in a patient in need thereof. Disclosed in the specification.

[0023] In another embodiment, a cocrystal of the invention or a pharmaceutical composition thereof for use in therapy is provided. In an embodiment of this aspect, a method for treating cancer is disclosed. Disclosed herein are cocrystals of the present invention or pharmaceutical compositions thereof. BTK-I and hemi-adipic acid for use in the treatment of BTK-associated cancers Co-crystal forms are disclosed herein. In another embodiment of this aspect, a BTK-associated cancer Described herein are BTK-I and mono-camphoric acid co-crystalline forms for use in the treatment of In another embodiment of this aspect disclosed herein, the BTK-associated cancer is , B-cell malignancies, B-cell lymphoma, MZL, DLBCL, CLL, SLL, Non-Hodgkin's Lymphoma, Burkitt's lymphoma, MCL, FL, hairy cell leukemia, B-cell non-Hodgkin's lymphoma The present invention relates to a method for treating leukemia, the method comprising administering to a patient a therapeutically effective amount of ... In another embodiment of this aspect disclosed in, the BTK-associated cancer is MCL. In another embodiment of this aspect disclosed herein, the BTK-associated cancer is CLL. In another embodiment of this aspect disclosed herein, the BTK-associated cancer is SLL. In another embodiment of this aspect disclosed herein, the BTK-associated cancer is FL. In another embodiment of this aspect disclosed herein, the BTK-associated cancer is MZ In another embodiment of this aspect disclosed herein, the MZL is L. In another embodiment of this aspect disclosed herein, BTK In another embodiment of this aspect disclosed herein, the associated cancer is DLBCL. The BTK-associated cancer is B-cell non-Hodgkin's lymphoma, MCL, CLL, or SLL. In another embodiment of this aspect disclosed herein, the BTK-associated cancer is MCL, C LL, SLL, WM, FL, and MZL.

[0024] In another embodiment, a compound of the present invention for use in inhibiting Bruton's tyrosine kinase. Disclosed herein are cocrystals or pharmaceutical compositions thereof.

[0025] In another aspect, a cocrystal or a pharmaceutical composition thereof for use in the treatment of MS is provided herein. Disclosed in the specification.

[0026] In another embodiment, a cocrystal or a pharmaceutical composition thereof for use in the treatment of arthritis, particularly RA. Disclosed herein are compositions for treating rheumatoid arthritis.

[0027] In another aspect, a cocrystal of the invention or a medicament thereof in the manufacture of a medicament for the treatment of cancer. Disclosed herein are uses of biological compositions. In an embodiment of this aspect, BTK-associated Use of BTK-I and Hemi-Adipic Acid Co-Crystal Forms in the Manufacture of Medicaments for the Treatment of Cancer Disclosed herein are methods for treating BTK-associated cancers. The use of BTK-I and mono-camphoric acid co-crystalline forms in the manufacture of medicaments for In another embodiment of this aspect disclosed herein, a BTK-associated cancer B-cell malignancies, B-cell lymphoma, MZL, DLBCL, CLL, SLL, non-Hodgkin lymphoma Lymphoma, Burkitt's lymphoma, MCL, FL, hairy cell leukemia, B-cell non-Hodgkin's lymphoma The present invention relates to a method for treating leukemia, including the treatment of leukemia, leukemia, and leukemia-associated lymphoma, including leukemia, WM, B-cell prolymphocytic leukemia, and MM. In another embodiment of this aspect disclosed herein, the BTK-associated cancer is MCL. In another embodiment of this aspect disclosed herein, the BTK-associated cancer is CLL. In another embodiment of this aspect disclosed herein, the BTK-associated cancer is SLL. In another embodiment of this aspect disclosed herein, the BTK-associated cancer is FL In another embodiment of this aspect disclosed herein, the BTK-associated cancer is M In another embodiment of this aspect disclosed herein, the MZL is a spleen, In another embodiment of this aspect disclosed herein, the BT The K-associated cancer is DLBCL. In another embodiment of this aspect disclosed herein The BTK-associated cancer is B-cell non-Hodgkin's lymphoma, MCL, CLL, or SLL. In another embodiment of this aspect disclosed herein, the BTK-associated cancer is MCL, Selected from the group consisting of CLL, SLL, WM, FL, and MZL.

[0028] In another embodiment, in the manufacture of a medicament for inhibiting Bruton's tyrosine kinase, Disclosed herein are uses of the cocrystals of the present invention or pharmaceutical compositions thereof.

[0029] In another aspect, a cocrystal or pharmaceutical composition thereof in the manufacture of a medicament for the treatment of MS. Uses of the articles are disclosed herein.

[0030] In another aspect, the use of a cocrystal or a method thereof in the manufacture of a medicament for the treatment of arthritis, particularly RA. Disclosed herein are uses of the pharmaceutical compositions of

[0031] In another embodiment, adipic acid is added to a solvent containing BTK-I and hemi-adipic acid to form a co-crystal. suspending and partially dissolving the BTK-I; adding the BTK-I and stirring with heating; and isolating the BTK-I and hemi-adipic acid co-crystalline form. Disclosed herein is a process for the preparation of a co-crystalline form of benzophenone and hemi-adipic acid. In certain embodiments, the isolating step comprises filtering under vacuum followed by drying under a stream of nitrogen. Disclosed herein is a process that is based on the Disclosed herein is a process in which the heat is about 55°C. Disclosed herein is a process in which the stirring step is at about 500 rpm. In another embodiment, the process described herein is characterized in that the step of stirring while heating occurs for about 1 hour. In another embodiment of this aspect, BTK-I and hemi-adipic acid co-receptors are disclosed. Crystalline form solvents: ethyl acetate, cyclopentyl methyl ether, isopropyl alcohol and acetonitrile. In another embodiment of the present invention, the BTK-I and hemi-adipic acid co-crystal formation solvent is ethyl acetate. Disclosed herein is a process for chilling.

[0032] In another embodiment, BTK-I is prepared by the addition of camphoric acid saturated BTK-I and mono- suspending the ammonium hydroxide cocrystal in a solvent, stirring with heating, and then stirring without heating. and isolating the BTK-I and mono-camphoric acid co-crystalline form. Disclosed herein is a process for the preparation of BTK-I and mono-camphoric acid co-crystalline forms. In an embodiment of this aspect, the isolating step is by filtering under vacuum. In another embodiment of this aspect, the heat is about 5 Disclosed herein is a process in which the temperature is 0°C. Disclosed herein is a process in which the rotating speed is about 800 rpm. In one embodiment, the process disclosed herein involves stirring while heating for about 2 hours. In another embodiment of this aspect, the step of stirring without heating occurs for more than 2 hours. In another embodiment of this aspect, a process is disclosed herein. The process described herein is one in which the camphoric acid co-crystallization solvent is cyclopentyl methyl ether. will be disclosed.

[0033] In another embodiment, BTK-I obtainable by any of the processes of the present invention Disclosed herein is a co-crystalline form of [Brief explanation of the drawings]

[0034] [Figure 1] X-ray powder diffraction overlay of BTK-I crystalline free form (bottom), BTK-I and hemi-adipic acid co-crystal form (middle), and BTK-I and camphoric acid co-crystal form (top). DETAILED DESCRIPTION OF THE INVENTION

[0035] definition Unless otherwise defined, all technical and scientific terms used herein are within the meaning of the present disclosure. As used herein, the terms "antibody" and "antibody" have the meaning commonly understood by those skilled in the art to which they pertain. When used herein, the following terms have the meanings ascribed to them unless otherwise specified.

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

[0037] [ka]

[0038] rel-(1R,3S)-1,2,2-trimethylcyclopentane-1,3-dicarboxamide Phosphoric acid or (1R,3S)-rel-1,2,2-trimethylcyclopentane-1,3-diamine Camphoric acid, also known as carboxylic acid, has the structure illustrated by the following formula:

[0039] [ka]

[0040] 5-amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl ethyl]phenyl]-1-[(1S)-2,2,2-trifluoro-1-methyl-ethyl] Pyrazole-4-carboxamide or (S)-5-amino-3-(4-((5-fluoro -2-Methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane The compound BT, also known as propan-2-yl)-1H-pyrazole-4-carboxamide KI has the structure exemplified below:

[0041] [ka]

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

[0043] The terms "treatment," "treat," "treating," and similar terms refer to the treatment of a disorder, including the slowing of progression of the disorder. These terms also include: Even if the disability or condition is not actually eliminated and the progression of the disability or condition itself is delayed or reversed, alleviating, ameliorating, attenuating, eliminating, or reducing one or more symptoms of a disorder or condition, even if the disorder or condition is not transformed This includes reducing or mitigating the damage.

[0044] The term "effective amount" refers to an amount of a compound that provides a therapeutic benefit to a patient in need thereof. The effective amount in a particular patient is the amount at which the compound or salt thereof is administered. whether the patient is a cancer, disease, or illness; the patient's size, age, sex, and general health; the stage and / or severity of the disease; the individual patient's response to previous therapy; whether the patient has had any adverse events or changes in the course of previous therapy; whether the patient subsequently has a recurrence of the disease, illness, or cancer; the mode of administration; the biologics of the administered formulation; availability characteristics; selected dosing regimen; and use of other concomitant medications. This can be affected.

[0045] The term "therapeutic benefit" refers to improved survival, reduced symptoms, restored functional capacity, or chronic It refers to a reduction in the chance of developing a condition. Such measures of therapeutic benefit include overall survival, Progression-free survival, time to progression, disease-free survival, event-free survival, time to treatment failure, time to treatment, duration of clinical benefit, duration of response, objective response rate, complete response, disease Physical complete response, disease control rate, clinical benefit rate, health-related quality of life, and milestones See A. Delgado and A. K.Guddati,Clinical Endpoints in Oncology -a Primer,Am J Cancer Res,2021;11(4):112 1-1131.

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

[0047] For the sake of brevity, some of the quantitative expressions herein are expressed as about X to about The amount Y is recited as a range. When a range is recited, the range is limited to the recited upper and lower limits. It is not limited to a lower limit, but rather includes the entire range of about X to about Y, or any range therein. It is understood that:

[0048] "Room temperature" or "RT (Room temperature)" refers to the ambient temperature in a typical laboratory. It is usually around 25°C.

[0049] As used herein, the term "excipient" refers to an agent that formulates a composition into a desired form. For example, suitable excipients include diluents or fillers, binders, or a granulating or adhesive agent, a disintegrant, a lubricant, an anti-adherent, a glidant, a dispersing or wetting agent; Dissolution retarders or enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavors, and sweeteners These include, but are not limited to, flavorings.

[0050] A "pharmaceutically acceptable carrier, diluent, or excipient" is a substance that is capable of delivering a biologically active agent to a human. "Pharmaceutically acceptable" is a vehicle generally accepted in the art for the delivery of The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to a substance that is biologically or otherwise Any and all solvents, co-solvents, complexing agents, dispersing media, coatings, etc., which are not undesirable, may be used. These include coatings, films, antibacterial and antifungal agents, isotonic agents, and absorption delaying agents. The use of such media and agents for therapeutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, it may be used in therapeutic formulations. Supplementary active ingredients can also be incorporated into the formulations. Additionally, various excipients may be included as commonly used in the art. and other such compounds can be found in the literature, e.g., Merck Index, Merck & Co. Company, Rahway, NJ. Considerations for inclusion are discussed, for example, in Gilman et al. (Eds.). 201 0, Goodman and Gilman's: The Pharmacologic al Basis of Therapeutics,12th Ed.,The Mc Listed in Graw-Hill Companies.

[0051] As used herein, the singular forms "a," "an," and "the" are used interchangeably, particularly where the context requires. Thus, unless expressly indicated otherwise, it includes multiple referents.

[0052] As used herein, ranges and amounts may be expressed as "about" a particular value or range. In particular, "about" means within 5% or 10% of a numerical value. About also includes the exact amount. Therefore, "about 5 grams" also means "about 5 grams" and "5 grams." It is also understood that ranges expressed in writing include whole numbers and fractions thereof within that range. For example, The range of 5 grams to 20 grams is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, Integer values ​​such as 15, 16, 17, 18, 19, 20, 21, and 22 grams, as well as 4. Includes 5, 4.75, 5.25, 6.5, 8.75, 11.95, and 21.95 grams This includes, but is not limited to, fractions within the range.

[0053] As used herein, "as needed" or "as needed" refers to the Any events or circumstances described may or may not occur, and any statements made may not be accurate or implied. This is meant to include examples of when it happens and examples of when it doesn't happen. The term "reaction mixture optionally containing a catalyst" refers to whether the reaction mixture contains a catalyst or does not contain a catalyst. means.

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

[0055] Certain features of the present disclosure, which are, for clarity, described in the context of separate embodiments, may also be used interchangeably. It is understood that they may be provided in combination in one embodiment. Various features of the disclosure that are described in the context of a single embodiment may also be used separately or in any suitable manner. It may be provided as a subcombination.

[0056] All combinations of embodiments relating to aspects described herein are to be construed as being within the scope of the present invention. To the extent that it encompasses all possible aspects, it is as if every possible combination were individually and explicitly enumerated. In addition, the aspects described herein are specifically encompassed by the present disclosure as if fully set forth herein. All subcombinations of the embodiments included in this application, and all other aspects described herein. All subcombinations of the included embodiments are also included as if each and every embodiment were included. All such subcombinations are expressly incorporated herein by this disclosure as if they were expressly recited herein. Specifically included.

[0057] The following examples further illustrate the present disclosure.

[0058] XRPD patterns were obtained on the instruments described in Examples 1 and 2. For each, The dry powder is packed into a quartz sample holder and the surface is smoothed using a glass slide. The crystalline form diffraction pattern is collected at ambient temperature and relative humidity. The position is an internal NIST 675 standard with peaks at 8.853 and 26.774 2θ°. After the overall pattern shift based on this, it is determined by MDI-Jade.

[0059] For any given crystalline form, the relative intensities of the diffraction peaks are indicative of the crystalline morphology and habit. It is well known in the field of crystallography that the orientation of the crystals can vary depending on the preferred orientation due to factors such as: When the effect of preferred orientation is present, the peak intensity is modified, but the characteristic peaks of the morphology are still visible. The location is immutable. For example, The United States Pharmacop eia#23,National Formulary #18,pages1843- 1844, 1995. Furthermore, for any given crystalline form, the angular peak positions It is also well known in the field of crystallography that the positions of the peaks may vary slightly. may vary due to variations in the temperature at which the sample is analyzed, sample displacement, or the presence or absence of an internal standard. In this case, the peak position variability of ±0.2 2θ° is It is assumed that these potential variations can be taken into account without precluding unambiguous identification of the crystalline form. Confirmation of crystalline form can be based on any unique combination of characteristic peaks. can.

[0060] Solid-state NMR was performed on a Bruker Ultrasonic NMR system operating at a frequency of 100.6 MHz. Bruker Avance III HD with eld 400WB Plus magnet The probe used was Bruker MAS 4 BL CP BB D VT NP / H. Acquisition parameters were: 31104 scans, 34 mm. ns acquisition time, 4.6 s interpulse delay, 10 kHz MAS frequency, 1.5 ms contact time, and SPINAL64 decoupling scheme. Data are 29.5 ppm ± Adamantane at 0.2 ppm is used as the external standard. [Example]

[0061] (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl) (phenyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazo BTK-I, a hemi-adipic acid co-crystal form (BTK -I and hemi-adipic acid co-crystal form)

[0062] [ka]

[0063] Suspend adipic acid (2.42 g, 16.56 mmol) in ethyl acetate (60 mL). , partially dissolve, and the mixture is heated to 55°C. (S)-5-amino-3-(4-(( 5-Fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trimethylphenyl) Trifluoropropan-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. Although it never completely dissolves, over the next few minutes the slurry changes from a light tan to a bright white color. The reaction is stirred for 1 hour, the heat is removed, and the white solid is filtered under vacuum through a nylon filter. The solid was isolated on a sieve and dried under a stream of nitrogen for 15 minutes. The solid was then placed in a vacuum oven at 65°C for 48 hours. Dry to obtain the title compound (16.3 g, 94.3%). Pinic acid cocrystal form 13 C solid-state NMR (101 MHz) shows 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, and 13.2.

[0064] XRPD of BTK-I and hemi-adipic acid co-crystal forms The XRPD pattern of the BTK-I and hemi-adipic acid co-crystal solid was CuKα(1 It was equipped with a 0.5418Å (0.5418Å) source and a Vantec detector, operating at 35 kV and 50 mA. The data were obtained using a Bruker D4 Endeavor X-ray powder diffractometer. The hemi-adipic acid co-crystal morphology sample was analyzed using a step size of 0.008° 2θ and 0.5 seconds / step. With a scanning speed of 1.0 mm, a divergence slit, and a fixed anti-scatter slit of 6.6 mm, and scanned from 4 to 40 2θ° using an 11.3 mm detector slit.

[0065] XRPD of BTK-I and hemi-adipic acid co-crystal forms The prepared samples of BTK-I and hemi-adipic acid co-crystal forms are listed in Table 1 below. Diffraction peaks (2-theta values) of 14.2, 17.0, and 21 18.7 in combination with one or more peaks selected from the group consisting of characterized by an XRPD pattern using CuKα radiation as having peaks The diffraction angle tolerance is ±0.2 degrees.

[0066] [Table 1]

[0067] Alternative Example 1 BTK-I and hemi-adipic acid co-crystal morphology Alternatively, BTK-I and hemi-adipic acid co-crystal forms can be prepared using solvents other than ethyl acetate. For example, isopropyl alcohol as a solvent can be used as follows: This can be done as follows: (S)-5-amino-3-(4-((5-fluoro-2-methoxy) (Cibenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropane-2- (yl)-1H-pyrazole-4-carboxamide (1.75 g, 3.65 mmol) and Adipic acid (0.266 g, 1.82 mmol) in isopropyl alcohol (20 mL) Heat the slurry to 80°C until all solids are dissolved. Heat the solution to 65°C. The mixture is cooled and then seeded with 1 wt. % co-crystals. A linear cooling gradient is used to cool the mixture for 8 hours. Cool to 55°C. Maintain stirring at 200 rpm. Remove solids using vacuum filtration. The title compound (1.37 g, 6 8.3%). [Example]

[0068] (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl) (phenyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazo 4-carboxamide, (1R,3S)-1,2,2-trimethylcyclopentane- 1,3-dicarboxylic acid ("camphoric acid") ("BTK-I and mono-camphoric acid co-polymer") (crystal form)

[0069] [ka]

[0070] (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl) (phenyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazo 4-amino-4-carboxamide (466 mg, 0.97 mmol) was saturated with camphoric acid. The mixture was suspended in cyclopentyl methyl ether (20 mL) and stirred at 50°C and 800 rpm. The reaction mixture becomes a slurry of white solids (slightly tan at first). Stir as a slurry for 2 hours. Remove heat and stir the mixture at room temperature overnight. A white solid The solid is isolated by filtration under vacuum to give the title compound (564 mg, 87.4% yield). .

[0071] XRPD of BTK-I and mono-camphoric acid co-crystalline forms The XRPD patterns of the BTK-I and mono-camphoric acid co-crystal solids were measured by CuKα ( It was operated at 40 kV and 40 mA with a 1.5418 Å (1.5418 Å) source and a Linxeye detector. The BTK-I was measured using a Bruker D8 Endeavor X-ray powder diffractometer. and mono-camphoric acid co-crystal morphology samples had a step size of 0.009 2θ° and 0.5 Scanning speed of 1 / sec / step, with a primary slit aperture of 0.3° and a position-sensitive detector of 3.9° The position sensitive detector (PSD) aperture was used to scan the 2θ° range from 4 to 42°. will be examined.

[0072] BTK-I, (1R,3S)-1,2,2-trimethylcyclopentane-1,3-dika XRPD of carboxylic acid BTK-I, (1R,3S)-1,2,2-trimethylcyclopentane-1,3-dika The prepared sample of carboxylic acid has the diffraction peaks (2-theta values) listed in Table 2. In particular, among the peaks selected from the group consisting of 7.2, 14.5, and 16.7 CuKα radiation as having a peak at 17.7 in combination with one or more The XRPD patterns were characterized using a diffraction angle tolerance of ±0.2 degrees.

[0073] [Table 2]

Claims

1. (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl (phenyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazo and a co-polymer selected from the group consisting of adipic acid and camphoric acid. Co-crystalline form with former.

2. (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl (phenyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazo 2. The co-crystalline form of claim 1, comprising methyl-4-carboxamide and adipic acid.

3. (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl (phenyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazo 3. The copolymer of claim 2, wherein the ratio of methyl-4-carboxamide to adipic acid is about 2:

1. Crystal form.

4. 10.4°, 14.2°, 15.1°, 17.0°, and 21.6°. In combination with one or more of the selected peaks, CuKα radiation is used, which has a diffraction peak and a tolerance of the diffraction angle of ±0.2 degrees.

4. The co-crystalline form of claim 3 characterized by its X-ray powder diffraction pattern.

5. One of the peaks selected from the group consisting of 14.2°, 17.0°, and 21.6° and a diffraction peak at a diffraction angle 2-theta of 18.7° in combination with one or more of said diffraction peaks. X-ray powder diffraction patterns were obtained using CuKα radiation with a diffraction tolerance of ±0.2 degrees. The co-crystal form according to any one of claims 1 to 3, characterized in that

6. 17.0° and 21.6°. In addition, it has a diffraction peak at a diffraction angle 2 theta of 18.7°, and the tolerance of the diffraction angle is The claimed invention is characterized by an X-ray powder diffraction pattern using CuKα radiation of ±0.2 degrees. Item 4. The co-crystal form according to any one of Items 1 to 3.

7. 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、１ ２６．６、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． Adamantine at 5, 33.2, 25.1, 24.7, 13.8, and 13.2 ppm Include peaks referenced to the high-field resonance of the ion, with a tolerance of ±0.2 ppm. １３ C solid 4. The co-crystalline form of any one of claims 1 to 3, characterized by its NMR spectrum.

8. Adamantine at 174.6, 91.2, 44.0, 13.8, and 13.2 ppm Include peaks referenced to the high-field resonance of the ion, with a tolerance of ±0.2 ppm. １３ C solid 4. The co-crystalline form of any one of claims 1 to 3, characterized by its NMR spectrum.

9. (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl (phenyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazo 2. The co-crystal form of claim 1, comprising methyl-4-carboxamide and camphoric acid.

10. (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl (phenyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazo 10. The co-polymer of claim 9, wherein the ratio of methyl-4-carboxamide to camphoric acid is about 1:

1. Crystalline form.

11. 7.2°, 8.3°, 12.6°, 14.5°, and 16.7° In combination with one or more of the peaks shown in Fig. 1, a diffraction angle 2-theta of 17.7° is observed. X-rays using CuKα radiation having a peak and a diffraction angle tolerance of ±0.2 degrees.

11. The co-crystalline form of claim 10 characterized by its powder diffraction pattern.

12. One of the peaks selected from the group consisting of 7.2°, 14.5°, and 16.7° In combination with the above, the diffraction peak at a diffraction angle 2-theta of 17.7° is Characterized by X-ray powder diffraction patterns using CuKα radiation with an angular tolerance of ±0.2 degrees.

11. The co-crystalline form of claim 1, 9 or 10,

13. 7.2° and 14.5°. The diffraction peak at a diffraction angle 2-theta of 17.7° is obtained, and the tolerance of the diffraction angle is ± Claim characterized by an X-ray powder diffraction pattern using CuKα radiation of 0.2 degrees.

11. The co-crystal form according to claim 1 or 9 or 10.

14. A pharmaceutical composition comprising the co-crystal form of any one of claims 1 to 13, and one or more polymers and a drug and a physiologically acceptable carrier, diluent, or excipient.

15. The one or more polymers are selected from PVP-VA, HPMC, and HPMCAS. The pharmaceutical composition of claim 14.

16. The HPMCAS is HPMCAS-L, HPMCAS-M, or HPMCAS-H. The pharmaceutical composition of claim 15.

17. 17. The pharmaceutical composition of claim 16, wherein the HPMCAS is HPMCAS-M.

18. The pharmaceutical composition comprises about 90 parts by weight of a polymer and about 10 parts by weight of a co-crystalline form, about 80 parts by weight of polymer and about 20 parts by weight of the co-crystalline form, about 70 parts by weight of polymer and about 30 parts by weight of the co-crystalline form parts by weight of the co-crystalline form, or about 50 parts by weight of the co-crystalline form and about 50 parts by weight of the polymer; The pharmaceutical composition according to any one of claims 14 to 17.

19. The co-crystalline form comprises about 20 parts by weight, and the one or more polymers comprise about 80 parts by weight. The pharmaceutical composition according to any one of claims 14 to 17, comprising:

20. The composition comprises less than about 20% by weight of other co-crystal forms of BTK-I with a different coformer. The pharmaceutical composition according to any one of claims 14 to 17, comprising:

21. The composition comprises less than about 10% by weight of other co-crystal forms of BTK-I with a different coformer. The pharmaceutical composition according to any one of claims 14 to 17, comprising:

22. 1. A method of treating a BTK-associated cancer in a patient in need thereof, comprising administering an effective amount of The co-crystal form of any one of claims 1 to 13 or any one of claims 14 to 21. Administering to said patient the pharmaceutical composition of claim 1.

23. The BTK-associated cancer is a B-cell malignancy, a B-cell lymphoma, a marginal zone lymphoma, a diffuse large intestine lymphoma, a leukemia ... Large B-cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, non-Hodgkin's lymphoma Lymphoma, Burkitt's lymphoma, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia , B-cell non-Hodgkin's lymphoma, B-cell prolymphocytic leukemia, Waldenstrom macrophage 23. The method of claim 22, wherein the disease is selected from the group consisting of idiopathic cerebrovascular disease, cerebrovascular accident ... 。

24. The BTK-related cancer is mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic leukemia, Lymphoma, Waldenstrom's macroglobulinemia, follicular lymphoma, and marginal zone lymphoma 24. The method of claim 23, wherein the cancer is selected from the group consisting of lymphomas.

25. A method of treating multiple sclerosis in a patient in need thereof, comprising administering an effective amount of The co-crystal form according to any one of claims 1 to 13 or any one of claims 14 to 21. administering to said patient the pharmaceutical composition described.

26. 10. A method for treating arthritis in a patient in need thereof, comprising administering an effective amount of claim 1 The co-crystal form according to any one of claims 14 to 21 or the co-crystal form according to any one of claims 14 to 21 administering to said patient a pharmaceutical composition.

27. 27. The method of claim 26, wherein the arthritis is rheumatoid arthritis.

28. A co-crystal form or co-crystals according to any one of claims 1 to 13 for use in therapy.

22. The pharmaceutical composition of any one of claims 14 to 21.

29. A method according to any one of claims 1 to 13 for use in the treatment of BTK-associated cancers. A co-crystal form or a pharmaceutical composition according to any one of claims 14 to 21.

30. The BTK-associated cancer is a B-cell malignancy, a B-cell lymphoma, a marginal zone lymphoma, a diffuse large intestine lymphoma, a leukemia ... Large B-cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, non-Hodgkin's lymphoma Lymphoma, Burkitt's lymphoma, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia , B-cell non-Hodgkin's lymphoma, B-cell prolymphocytic leukemia, Waldenstrom macrophage 30. The use according to claim 29, wherein the disease is selected from the group consisting of idiopathic cerebrovascular disease, cerebrovascular accident ... Co-crystal forms or pharmaceutical compositions for

31. The BTK-related cancer is mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic leukemia, Lymphoma, Waldenstrom's macroglobulinemia, follicular lymphoma, and marginal zone lymphoma 31. The co-crystal form or pharmaceutical composition for use according to claim 30, wherein the co-crystal form or pharmaceutical composition for use according to claim 30 is selected from the group consisting of: composition.

32. A composition according to any one of claims 1 to 13 for use in the treatment of multiple sclerosis. A crystalline form or a pharmaceutical composition according to any one of claims 14 to 21.

33. A co-crystal form according to any one of claims 1 to 13 for use in the treatment of arthritis. The pharmaceutical composition according to any one of claims 14 to 21.

34. 34. The co-crystal form for use according to claim 33, wherein the arthritis is rheumatoid arthritis. Or a pharmaceutical composition.

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