Crystalline salt forms of the tyrosine kinase inhibitor ECF506

Abstract

The present disclosure relates, in part, to crystalline salt forms of tert-butyl 4-(4-amino-1-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d d ]pyrimidin-3-yl)-2-methoxyphenyl)carbamate, pharmaceutical compositions thereof, and methods of use.

Description

[0001] Cross-references to related applications

[0002] This application claims the benefit and priority of U.S. Provisional Patent Application No. 63 / 597,020, filed November 8, 2023, the contents of which are incorporated herein by reference in their entirety. Background Technology

[0003] SRC proteins and their family members are non-receptor tyrosine kinases that play a fundamental role in signal transduction pathways regulated by various cell surface receptors, thereby controlling a wide range of cellular events, including cell growth, survival, cell adhesion, and migration. The carcinogenic role of SRCs in cancer was first proposed in the 1970s. Since then, mounting evidence has shown that SRC kinase activity is disease-associatedly upregulated in many malignancies, including breast and colorectal cancer, and that it is directly involved in mechanisms of cancer metastasis and chemotherapy resistance. Despite the validated etiological role of this target and the development of numerous commercial drug discovery programs over the past three decades, to date, no kinase inhibitor has been approved for cancer treatment solely through its SRC-inhibiting properties. Interestingly, all ATP-competitive SRC kinase inhibitors in clinical use (dasatinib, bosutinib) or in clinical development (cesatinib, AZD0424) are actually dual ABL / SRC inhibitors with additional off-target activity, such as LN; Eadens, M.; Messersmith, W. “Current status of SRC inhibitors in solid tumor malignancies”, Oncologist , 2011, 16 , 566-578; and Roskoski, R. Jr. "Src protein-tyrosine kinase structure, mechanism, and small moleculeinhibitors", Pharmacol. Res. 2015, 94 , 9-25 published.

[0004] While a lack of clinical efficacy, rather than a poor safety profile, is the common attribution for the failure of SRC inhibitors to enter clinical trials, the off-target activity of current inhibitors reduces their therapeutic window. For example, cardiotoxicity is a well-known side effect of ABL inhibitors, as illustrated by Steegmann, JL et al. in "Off-target effects of BCR-ABL1 inhibitors and their potential long-term implications in patients with chronic myeloid leukemia." Leuk. Lymphoma 2012, 53 , 2351-2361 and Nygaard, HB et al. in "A phase Ib multiple ascending dose study of the safety, tolerability, and central nervous system availability of AZD0530(saracatinib) in Alzheimer's disease", Alzheimers Res. Ther. 2015, 7 As shown in , 35.

[0005] Furthermore, several studies have shown that ABL plays an anti-cancer role in some cancers. For example, ABL signaling exerts an anti-cancer effect during breast tumorigenesis by inhibiting oncogenic TGF-β signaling (Allington, TM et al., "Activated Abl kinase inhibits oncogenic transforming growth factor-betasignaling and tumorigenesis in mammary tumors"). FASEB J. 2009, 23 (4231-4243). Following DNA damage, ABL is activated and promotes apoptosis through an adhesion-dependent cell death pathway independent of p53 (Truong, T.; Sun, G. et al., "Modulation of DNA damage-induced apoptosis by cell adhesion is independently mediated by p53 and c-Abl"). Proc. Natl Acad. Sci. USA 2003, 100(10281–10286). These studies strongly caution the use of ABL kinase inhibitors in the treatment of certain breast cancer subtypes and as a combination partner with DNA-damaging chemotherapeutic agents, particularly in metastatic tumors with mutant p53.

[0006] Another example of the off-target activity that reduces drug tolerance to current inhibitors is their effect on the receptor tyrosine kinase KIT. Inhibition of KIT (the protein kinase targeted by dasatinib and bosutinib) activity leads to myelosuppression, which can affect not only a patient's immune defense against infectious diseases but also reduce the immune system's ability to help fight cancer.

[0007] Therefore, in cancer treatment, there is a search for drugs that can selectively inhibit the dysregulated SRC activity by targeting specific kinases, because they do not have the side effects caused by hybrid kinase inhibitors of SRC (dasatinib, bosutinib), such as toxic events, immunosuppression, and pro-carcinogenic effects.

[0008] Polymorphism is the ability of a substance to crystallize in more than one crystal lattice arrangement. Crystallinity or polymorphism can affect many aspects of the solid-state properties of a pharmaceutical substance. Crystalline substances can differ significantly from their amorphous forms, and different crystalline variants of a substance can differ significantly from each other in many ways, including solubility, dissolution rate, and / or bioavailability. Often, it is difficult to predict whether a given compound will form any crystalline solid form. Even more difficult is predicting the physical properties of these crystalline solid forms. Therefore, for certain formulations and / or manufacturing methods, having a crystalline form of the therapeutic agent may be advantageous. Summary of the Invention

[0009] This disclosure relates at least in part to (4-(4-amino-1-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)-1H-pyrazolo[3,4- d The crystalline salt form of tert-butyl pyrimidin-3-yl)-2-methoxyphenyl)carbamate.

[0010] For example, this paper discloses (4-(4-amino-1-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)-1H-pyrazolo[3,4- dThe crystalline form of tert-butyl pyrimidinyl (3-yl)-2-methoxyphenyl)carbamate HCl salt is characterized by a powder X-ray diffraction pattern having a characteristic peak at a 2θ angle of about 5.4, for example, characterized by powder X-ray diffraction patterns having characteristic peaks at 2θ angles of about 5.4, 6.0, and 11.9, for example, characterized by powder X-ray diffraction patterns having characteristic peaks at 2θ angles of about 2.4, 5.4, 6.0, 11.9, 18.4, and 24.8. Powder X-ray diffraction patterns, for example, characterized by having characteristic peaks at 2θ angles of about 2.4, 5.4, 6.0, 7.7, 11.9, 12.2, 15.3, 18.4 and 24.8, and for example, characterized by having characteristic peaks at 2θ angles of about 2.4, 5.4, 6.0, 7.7, 11.9, 12.2, 15.3, 15.9, 17.0, 18.4, 24.8 and 26.2.

[0011] This article also discloses (4-(4-amino-1-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)-1H-pyrazolo[3,4- d The crystalline form of tert-butyl pyrimidinyl (3-yl)-2-methoxyphenyl)carbamate fumarate is characterized by a powder X-ray diffraction pattern having a characteristic peak at a 2θ angle of about 8.9, for example, a powder X-ray diffraction pattern having characteristic peaks at 2θ angles of about 8.9, 17.9, and 19.3, for example, a powder X-ray diffraction pattern having characteristic peaks at 2θ angles of about 4.4, 8.9, 17.9, 19.3, 22.5, and 24.2. Diffraction patterns, for example, are characterized by powder X-ray diffraction patterns having characteristic peaks at 2θ angles of about 4.4, 8.9, 14.3, 17.9, 19.3, 22.5, 23.3, 24.2, and 24.8, and powder X-ray diffraction patterns having characteristic peaks at 2θ angles of about 2.3, 4.4, 8.9, 14.3, 17.9, 19.3, 20.7, 22.5, 23.3, 24.2, 24.8, and 31.0.

[0012] (4-(4-amino-1-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-] d Pyrimidin-3-yl)-2-methoxyphenyl)tert-butyl carbamate is, for example, a tyrosine kinase inhibitor, and is represented by the following formula: .

[0013] This document also envisions a pharmaceutical composition comprising the disclosed (4-(4-amino-1-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-]d The crystalline salt form of tert-butyl pyrimidin-3-yl)-2-methoxyphenyl)carbamate and pharmaceutically acceptable excipients, such as those formulated into compositions for oral administration, are also envisioned herein. A pharmaceutical substance comprising at least a detectable amount of the disclosed (4-(4-amino-1-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-] d The crystalline salt form of tert-butyl pyrimidin-3-yl)-2-methoxyphenyl)carbamate. For example, this article discloses a pharmaceutical substance comprising (4-(4-amino-1-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)-1H-pyrazolo[3,4- d It is the essentially pure crystalline salt form of tert-butyl pyrimidin-3-yl)-2-methoxyphenyl)carbamate.

[0014] This article also provides a method for treating patients in need of cancer, osteoporosis, neurological disorders, angiogenesis-dependent diseases, lung diseases, or metastatic bone diseases, comprising administering to the patient an effective amount of the disclosed (4-(4-amino-1-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)-1H-pyrazolo[3,4- d The crystalline salt form of tert-butyl pyrimidin-3-yl)-2-methoxyphenyl)carbamate.

[0015] For example, this article provides a method for treating cancer in patients in need, such as chronic lymphocytic leukemia, small lymphocytic leukemia, mantle cell lymphoma, non-Hodgkin's lymphoma, marginal zone lymphoma, Waldenström macroglobulinemia, or squamous cell carcinoma (e.g., squamous cell carcinoma of the skin, squamous cell carcinoma of the head and neck, squamous cell carcinoma of the vulva, or squamous cell carcinoma of the lung), the method comprising administering to the patient an effective amount of the disclosed (4-(4-amino-1-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)-1H-pyrazolo[3,4- d The crystalline salt form of tert-butyl pyrimidin-3-yl)-2-methoxyphenyl)carbamate. Attached Figure Description

[0016] Figure 1 The (4-(4-amino-1-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-] d X-ray powder diffraction (XRPD) pattern of tert-butyl pyrimidinyl (3-yl)-2-methoxyphenyl)carbamate HCl salt (form 1).

[0017] Figure 2 Differential scanning calorimetry (DSC) curves of form 1 were plotted.

[0018] Figure 3 The thermogravimetric analysis (TGA) curves for Form 1 were plotted.

[0019] Figure 4 Dynamic vapor adsorption (DVS) curves for Form 1 were plotted.

[0020] Figure 5 The (4-(4-amino-1-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-] d X-ray powder diffraction (XRPD) pattern of tert-butyl pyrimidinyl (3-yl)-2-methoxyphenyl)carbamate fumarate (form 2).

[0021] Figure 6 Differential scanning calorimetry (DSC) curves of form 2 were plotted.

[0022] Figure 7 The thermogravimetric analysis (TGA) curves for Form 2 were plotted.

[0023] Figure 8 Dynamic vapor adsorption (DVS) curves for form 2 were plotted. Detailed Implementation

[0024] The features and other details of this disclosure will now be described in more specific terms. Before further describing this disclosure, certain terms used in the specification, embodiments, and appended claims are collected herein. These definitions should be read in light of the remainder of this disclosure and understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0025] definition The term "crystalline form" refers to a crystalline form or variant that can be characterized by analytical methods such as X-ray powder diffraction (XRPD) and / or differential scanning calorimetry (DSC). The crystalline compounds disclosed herein can exist in both solvated and non-solvated forms with solvents such as water and ethanol. Unless otherwise stated or inferred, the disclosed crystalline compounds are intended to include both solvated and non-solvated forms.

[0026] "Treatment" includes any effect that leads to improvement of a disease, ailment, disorder, etc., such as relief, reduction, regulation, or elimination.

[0027] Unless otherwise stated, the term “symptom” means the term “disease,” “symptom,” or “illness” and is used interchangeably with it.

[0028] "Pharmaceutical or pharmacologically acceptable" includes, as appropriate, molecular entities and compositions that do not produce side effects, allergic reactions, or other adverse reactions when administered to animals or humans. For human use, formulations must meet the FDA's Office of Biologics standards for sterility, pyrogenicity, and general safety and purity.

[0029] As used herein, the terms "pharmaceuticalally acceptable excipient" or "pharmaceuticalally acceptable carrier" refer to any and all solvents, dispersion media, coatings, isotonic and absorption-delaying agents, etc., compatible with drug administration. The use of such media and agents for pharmaceutically active substances is well known in the art. Compositions may also contain other active compounds that provide supplemental, additional, or enhanced therapeutic functions.

[0030] As used herein, the term "pharmaceutical composition" refers to a composition comprising at least one compound as disclosed herein, formulated together with one or more pharmaceutically acceptable excipients.

[0031] The terms “individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, and most preferably humans. The compounds disclosed herein can be applied to mammals, such as humans, but can also be applied to other mammals, such as animals requiring veterinary treatment, such as livestock (e.g., dogs, cats, etc.), farm animals (e.g., cattle, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). Ideally, mammals treated by the methods of this disclosure are those requiring treatment for, for example, cancer or blood disorders. “Regulation” includes antagonism (e.g., inhibition), agonism, partial antagonism, and / or partial agonism.

[0032] In this specification, the terms "effective amount" or "therapeutic effective amount" mean the amount of the subject compound that will elicit a biological or medical response in a tissue, system, or animal (e.g., a mammal or a human) sought by a researcher, veterinarian, physician, or other clinician. The compounds of this disclosure are administered in a therapeutically effective amount to treat a disease. Alternatively, a therapeutically effective amount of a compound is the amount required to achieve the desired therapeutic and / or preventative effect.

[0033] The “SRC family”, “SRC kinase family”, and “family of SRC kinases” refer to the non-receptor tyrosine kinase family, whose members include, but are not limited to, BLK, FGR, FRK, FYN, HCK, LCK, LYN, SRC, and YES.

[0034] Unless otherwise indicated, the term “and / or” is used in this disclosure to mean “and” or “or”.

[0035] As used herein, unless otherwise stated, the words “an” and “a” are intended to include one or more. For example, the term “pharmaceutical” covers a single pharmaceutical agent and a combination of two or more pharmaceutical agents.

[0036] When the term “about” is used before a quantitative value, this disclosure also includes the specific quantitative value itself, unless otherwise expressly stated. As used herein, unless otherwise stated or inferred, the term “about” means a variation of ±10% of the index value. In the context of a peak at an angle of 2θ, the term “about” means an uncertainty of ±0.2 (expressed in 2θ) in a measurement at 2θ. Typically, DSC thermograms can have variations within a range of ±2°C. Therefore, temperature values ​​should be understood to include values ​​within a range of about ±2°C.

[0037] Generally, unless otherwise indicated, this document provides for (4-(4-amino-1-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-] d The crystalline salt form of tert-butyl pyrimidin-3-yl)-2-methoxyphenyl)carbamate is substantially free of any other crystalline forms. As used herein, "substantially free of" or "substantially free of any other crystalline forms" means that the disclosed crystalline form contains about 20% or less, about 10% or less, about 5% or less, about 2% or less, or about 1% or less of (4-(4-amino-1-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-] d Any other crystalline form of tert-butyl pyrimidin-3-yl)-2-methoxyphenyl)carbamate, as measured, for example by XRPD, or less than about 20%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% of (4-(4-amino-1-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-]pyrazolo[3,4-]pyrazolyl] d Any other crystalline form of tert-butyl pyrimidin-3-yl)-2-methoxyphenyl)carbamate, as measured, for example, by XRPD. Therefore, the disclosed (4-(4-amino-1-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-]carbamate, as described herein, is substantially free of any other crystalline form. d The crystalline salt form of tert-butyl pyrimidin-3-yl)-2-methoxyphenyl)carbamate should be understood as containing greater than 80% (w / w), greater than 90% (w / w), greater than 95% (w / w), greater than 98% (w / w), or greater than 99% (w / w) of (4-(4-amino-1-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)-1H-pyrazolo[3,4- dThe crystalline form of tert-butyl pyrimidin-3-yl)-2-methoxyphenyl)carbamate. Therefore, in some embodiments, the disclosed (4-(4-amino-1-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-] d The crystalline salt form of tert-butyl pyrimidin-3-yl)-2-methoxyphenyl)carbamate may contain 1% to 20% (w / w), 5% to 20% (w / w), or 5% to 10% (w / w) of (4-(4-amino-1-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-] d One or more other crystalline forms of tert-butyl pyrimidin-3-yl)-2-methoxyphenyl)carbamate.

[0038] The compounds disclosed herein may contain one or more isotopic substitutions. For example, this disclosure also includes (4-(4-amino-1-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)-1H-pyrazolo[3,4- d The crystalline form of the free base of tert-butyl pyrimidin-3-yl)-2-methoxyphenyl)carbamate is the same as those described herein, except that one or more atoms having atomic masses or mass numbers normally found in nature (e.g., hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine) are different from atoms having atomic masses or mass numbers normally found in nature (e.g., respectively). 2 H, 3 H, 13 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl) substitution. For example, the compound (4-(4-amino-1-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)-1H-pyrazolo[3,4- d The crystalline form of the free base of pyrimidin-3-yl)-2-methoxyphenyl)carbamate tert-butyl ester can have one or more hydrogen atoms replaced by deuterium, for example, hydrogen (H) can be... 2 H (D or deuterium).

[0039] Crystalline form This disclosure relates at least in part to (4-(4-amino-1-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)-1H-pyrazolo[3,4- dCrystalline salt forms of tert-butyl pyrimidin-3-yl)-2-methoxyphenyl)carbamate are also disclosed. Crystalline hydrates, dehydrates, hemihydrates, solvates, tautomers, and cocrystals of any of the crystalline salt forms described herein are also disclosed.

[0040] For example, this paper discloses (4-(4-amino-1-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)-1H-pyrazolo[3,4- d The crystalline form of tert-butyl pyrimidinyl (3-yl)-2-methoxyphenyl)carbamate HCl salt is characterized by a powder X-ray diffraction pattern having a characteristic peak at a 2θ angle of about 5.4 (referred to herein as "Form 1").

[0041] In one embodiment, (4-(4-amino-1-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-] d The crystalline form 1 of pyrimidin-3-yl)-2-methoxyphenyl)carbamate tert-butyl HCl salt is characterized by powder X-ray diffraction patterns having characteristic peaks at 2θ angles of about 2.4, about 5.4, about 6.0, about 7.7, about 11.9, and about 12.2. Powder X-ray diffraction patterns with characteristic peaks, characterized in that a powder X-ray diffraction pattern has a characteristic peak at a 2θ angle of about 15.3, a powder X-ray diffraction pattern has a characteristic peak at a 2θ angle of about 15.9, a powder X-ray diffraction pattern has a characteristic peak at a 2θ angle of about 17.0, a powder X-ray diffraction pattern has a characteristic peak at a 2θ angle of about 18.5, a powder X-ray diffraction pattern has a characteristic peak at a 2θ angle of about 24.8, and / or a powder X-ray diffraction pattern has a characteristic peak at a 2θ angle of about 26.2.

[0042] In another embodiment, crystalline form 1 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at 2θ angles of about 5.4, 6.0, and 11.9. In another embodiment, crystalline form 1 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at 2θ angles of about 2.4, 5.4, 6.0, 11.9, 18.4, and 24.8. In another embodiment, crystalline form 1 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at 2θ angles of about 2.4, 5.4, 6.0, 7.7, 11.9, 12.2, 15.3, 18.4, and 24.8. In another embodiment, crystalline form 1 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at 2θ angles of about 2.4, 5.4, 6.0, 7.7, 11.9, 12.2, 15.3, 15.9, 17.0, 18.4, 24.8, and 26.2. For example, the envisioned crystalline form has Figure 1 The powder X-ray diffraction pattern is shown. In one embodiment, the powder X-ray diffraction pattern of the crystalline form is obtained using Cu Kα radiation.

[0043] The envisioned (4-(4-amino-1-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)-1H-pyrazolo[3,4- d The crystalline form 1 of pyrimidin-3-yl)-2-methoxyphenyl)carbamate tert-butyl HCl salt is characterized by a differential scanning calorimetry (DSC) curve showing a characteristic endothermic (enthalpy 188.3 J / g) curve starting at about 90 °C and peaking at about 97 °C. For example, form 1 is characterized by... Figure 2 The differential scanning calorimetry curve shown is as follows.

[0044] The envisioned (4-(4-amino-1-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)-1H-pyrazolo[3,4- d The crystalline form 1 of pyrimidin-3-yl)-2-methoxyphenyl)carbamate tert-butyl HCl salt is characterized by thermogravimetric analysis (TGA) curves showing a mass loss of about 12% by weight between about 74°C and about 100°C, and a mass loss of about 16% by weight between about 183°C and about 210°C. For example, form 1 is characterized by... Figure 3 The thermogravimetric analysis curves are shown. In some embodiments, form 1 is a 1:1 molar:molar HCl salt. In other embodiments, crystalline form 1 is a trihydrate form. In still other embodiments, crystalline form 1 exhibits a needle-like morphology as observed by polarized light microscopy.

[0045] In some embodiments, crystalline form 1 may be characterized by a dynamic vapor adsorption (DVS) curve showing a reversible total mass change of about 20% by weight between about 0% and about 90% relative humidity (RH) at 25°C, without any observable change in crystalline form. For example, form 1 may be characterized by... Figure 4 The dynamic vapor adsorption is shown. In other embodiments, crystalline form 1 is chemically and physically stable for at least two weeks at 50°C / 75% RH and 70°C / 0% RH.

[0046] In another embodiment, (4-(4-amino-1-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-] d The crystalline form of tert-butyl pyrimidinyl (3-yl)-2-methoxyphenyl)carbamate fumaric acid is characterized by a powder X-ray diffraction pattern having a characteristic peak at a 2θ angle of about 8.9 (referred to herein as "form 2").

[0047] In one embodiment, (4-(4-amino-1-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-] d The crystalline form 2 of the free base of pyrimidin-3-yl)-2-methoxyphenyl)carbamate is characterized by powder X-ray diffraction patterns having characteristic peaks at 2θ angles of about 2.3, about 4.4, about 8.9, about 14.3, about 17.9, and about 19.3. Powder X-ray diffraction patterns with characteristic peaks, characterized in that a powder X-ray diffraction pattern has a characteristic peak at a 2θ angle of about 20.7°, a powder X-ray diffraction pattern has a characteristic peak at a 2θ angle of about 22.5°, a powder X-ray diffraction pattern has a characteristic peak at a 2θ angle of about 23.3°, a powder X-ray diffraction pattern has a characteristic peak at a 2θ angle of about 24.2°, a powder X-ray diffraction pattern has a characteristic peak at a 2θ angle of about 24.8°, and / or a powder X-ray diffraction pattern has a characteristic peak at a 2θ angle of about 31.0°.

[0048] In one embodiment, crystalline form 2 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at 2θ angles of about 8.9, 17.9, and 19.3. In another embodiment, crystalline form 2 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at 2θ angles of about 4.4, 8.9, 17.9, 19.3, 22.5, and 24.2. In yet another embodiment, crystalline form 2 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at 2θ angles of about 4.4, 8.9, 14.3, 17.9, 19.3, 22.5, 23.3, 24.2, and 24.8. In another embodiment, the crystalline form 2 is characterized by a powder X-ray diffraction pattern having at least one or more characteristic peaks at 2θ angles of about 2.3, 4.4, 8.9, 14.3, 17.9, 19.3, 20.7, 22.5, 23.3, 24.2 and 24.8, 31.0. For example, the envisioned crystalline form has Figure 5 The powder X-ray diffraction pattern is shown. In one embodiment, the powder X-ray diffraction pattern of the crystalline form is obtained using Cu Kα radiation.

[0049] The envisioned (4-(4-amino-1-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)-1H-pyrazolo[3,4- d The crystalline form 2 of pyrimidin-3-yl)-2-methoxyphenyl)carbamate tert-butyl fumarate is characterized by the following: Figure 6 The differential scanning calorimetry curve shown is as follows.

[0050] The envisioned (4-(4-amino-1-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)-1H-pyrazolo[3,4- d The crystalline form 2 of pyrimidin-3-yl)-2-methoxyphenyl)carbamate tert-butyl fumarate is characterized by thermogravimetric analysis (TGA) curves showing a mass loss of about 1.2 wt% between about 48°C and about 72°C and a mass loss of about 25 wt% between about 184°C and about 210°C. For example, form 2 is characterized by... Figure 7 The thermogravimetric analysis curves are shown. In some embodiments, form 2 is a 1:1 salt / eutectic. In other embodiments, crystalline form 2 is anhydrous. In still other embodiments, it exhibits a plate-like morphology as observed by polarized light microscopy.

[0051] In some embodiments, crystalline form 2 may be characterized by a dynamic vapor adsorption (DVS) curve showing a reversible total mass change of about 6.5% by weight between about 0% and about 90% relative humidity (RH) at 25°C, without any observable change in crystalline form. For example, form 2 may be characterized by... Figure 8 The dynamic vapor adsorption is shown. In other embodiments, crystalline form 2 is chemically and physically stable for at least two weeks at 50°C / 75% RH and 70°C / 0% RH.

[0052] In another embodiment, a pharmaceutical composition is disclosed herein comprising the disclosed (4-(4-amino-1-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)-1H-pyrazolo[3,4- d The pharmaceutical composition comprises the crystalline salt form of tert-butyl pyrimidin-3-yl)-2-methoxyphenyl)carbamate and a pharmaceutically acceptable excipient. In another embodiment, the pharmaceutical composition comprises the (4-(4-amino-1-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-] d The disclosed crystalline salt form of pyrimidin-3-yl)-2-methoxyphenyl)carbamate tert-butyl ester is formed. In some embodiments, the disclosed pharmaceutical composition may be a formulation for oral administration.

[0053] In one embodiment, a pharmaceutical substance is disclosed herein comprising at least a detectable amount of the disclosed (4-(4-amino-1-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)-1H-pyrazolo[3,4- d The crystalline salt form of tert-butyl pyrimidin-3-yl)-2-methoxyphenyl)carbamate. In another embodiment, a pharmaceutical substance is disclosed herein comprising (4-(4-amino-1-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)-1H-pyrazolo[3,4- d It is the essentially pure crystalline salt form of tert-butyl pyrimidin-3-yl)-2-methoxyphenyl)carbamate.

[0054] Composition Another aspect of this disclosure provides pharmaceutical compositions comprising a crystalline compound as disclosed herein, formulated with a pharmaceutically acceptable excipient. Specifically, this disclosure provides pharmaceutical compositions comprising a crystalline compound as disclosed herein, formulated with one or more pharmaceutically acceptable excipients. These formulations include those suitable for oral, topical (e.g., transdermal), sublingual, ocular, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), rectal, vaginal, or aerosol administration, but the most suitable form of administration in any given case will depend on the extent and severity of the condition being treated and the nature of the particular compound used. For example, the disclosed compositions may be formulated as unit doses and / or may be formulated for oral, subcutaneous, or intravenous administration.

[0055] The exemplary pharmaceutical compositions of this disclosure can be used in the form of pharmaceutical formulations, such as solid, semi-solid, or liquid forms, containing one or more compounds of this disclosure as active ingredients, mixed with organic or inorganic excipients or excipients suitable for external, enteral, or parenteral application. The active ingredient can be mixed, for example, with generally non-toxic, pharmaceutically acceptable excipients used in tablets, pills, capsules, suppositories, solutions, emulsions, suspensions, and any other suitable form. The active subject compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the symptoms of the method or the disease.

[0056] To prepare solid compositions such as tablets, the main active ingredient can be mixed with a pharmaceutical excipient (e.g., a conventional tableting ingredient, such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gum) and other pharmaceutical diluents (e.g., water) to form a solid preformed composition containing a homogeneous mixture of the compounds disclosed herein. When referring to these homogeneous preformed mixtures, it means that the active ingredient is uniformly dispersed throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0057] In solid dosage forms (capsules, tablets, pills, sugar-coated pills, powders, granules, etc.) for oral administration, the subject composition is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or gum arabic; (3) humectants, etc. Examples of such components include: (4) disintegrants such as agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate; (5) solution blockers such as paraffin; (6) absorption enhancers such as quaternary ammonium compounds; (7) wetting agents such as acetyl alcohol and glyceryl monostearate; (8) absorbents such as kaolin and bentonite; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and (10) colorants. In the case of capsules, tablets, and pills, the composition may also contain a buffer. Similar types of solid compositions may also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or toffee and high molecular weight polyethylene glycol.

[0058] Tablets can be prepared by compression or molding, optionally with one or more excipients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium glycolate starch or croscarmellose sodium), surfactants, or dispersants. Molded tablets can be prepared by molding a mixture of the subject composition moistened with an inert liquid diluent in suitable machinery. Tablets and other solid dosage forms, such as tablets, capsules, pills, and granules, can be optionally prepared using coatings and shells (such as enteric coatings and other coatings well known in the field of pharmaceutical formulation).

[0059] Compositions for inhalation or inhalation comprise solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, nanosuspensions, syrups, and elixirs. In addition to the subject compositions described herein, the liquid dosage forms may comprise inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizers, and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, oils (specifically, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofuranol, polyethylene glycol, and fatty acid esters of sorbitol, cyclodextrins, and mixtures thereof.

[0060] In addition to the main composition, the suspension may contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and tragacanth gum, and mixtures thereof.

[0061] Formulations for rectal or vaginal administration can be presented as suppositories, which can be prepared by mixing a subject composition with one or more suitable non-irritating excipients or excipients containing, for example, cocoa butter, polyethylene glycol, suppository wax, or salicylate, and are solid at room temperature but liquid at body temperature, thus melting in the body cavity and releasing the active agent.

[0062] Dosage forms for transdermal application of the subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalers. The active ingredient can be mixed under aseptic conditions with pharmaceutically acceptable excipients and with any preservatives, buffers, or propellants that may be required.

[0063] In addition to the subject composition, the ointments, pastes, creams and gels may contain excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, astragalus gums, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0064] In addition to the main composition, powders and aerosols may contain excipients such as lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. Aerosols may additionally contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons (such as butane or propane).

[0065] The compositions and compounds disclosed herein can alternatively be administered by aerosol. This is accomplished by preparing aqueous aerosols, liposome formulations, or solid particles containing said compounds. Non-aqueous suspensions (e.g., fluorocarbon propellants) can be used. Sonic sprayers can be used because they minimize the shear exposure of said reagents, which could lead to degradation of the compounds contained in the subject composition. Typically, aqueous aerosols are prepared by formulating an aqueous solution or suspension of the subject composition with conventional pharmaceutically acceptable excipients and stabilizers. Excipients and stabilizers vary depending on the requirements of the particular subject composition but typically include nonionic surfactants (Tween, Pluronic, or polyethylene glycol), harmless proteins such as serum albumin, sorbitol esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars, or sugar alcohols. Aerosols are generally prepared from isotonic solutions.

[0066] The pharmaceutical compositions of this disclosure suitable for parenteral administration comprise a combination of the subject composition with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions just before use, and may contain antioxidants, buffers, antibacterial agents, solutes or suspending agents or thickeners that make the formulation isotonic with the blood of the intended recipient.

[0067] Examples of suitable aqueous and non-aqueous excipients that can be used in the pharmaceutical compositions of this disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate) and cyclodextrins. The desired particle size can be maintained, for example, by using a coating material (such as lecithin), by maintaining the particle size in the case of a dispersion, and by using a surfactant to maintain appropriate flowability. For example, the crystalline forms provided herein can be milled to obtain a specific particle size, and in at least some embodiments, such crystalline forms can remain substantially stable during milling.

[0068] The amount of the crystalline compound described herein in the formulation can vary depending on factors such as an individual's disease state, age, sex, and weight. Dosing regimens can be adjusted to provide an optimal therapeutic response. For example, a single bolus injection can be administered, several separate doses can be administered over time, or the dose can be proportionally reduced or increased depending on the urgency of the treatment situation. For ease of administration and uniformity of dosage, it is particularly advantageous to formulate the parenteral composition in unit dosage form. As used herein, unit dosage form refers to a physically discrete unit suitable as a unit dose for use in a mammalian subject to be treated; each unit contains a predetermined amount of the active crystalline compound calculated to produce the desired therapeutic effect, along with the required drug delivery system.

[0069] The specifications of the dosage unit form of this disclosure are determined by and directly depend on the following factors: (a) the unique properties of the selected crystalline compound and the specific therapeutic effect to be achieved, and (b) the inherent limitations of techniques for mixing such active crystalline compounds to treat individual sensitivities.

[0070] The disclosed compositions can be formulated as solutions, microemulsions, liposomes, or other ordered structures suitable for high drug concentrations. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. Suitable flowability can be achieved, for example, by using a coating such as lecithin, by maintaining the desired particle size in the case of a dispersant, and by using a surfactant. In many cases, it is suitable to include isotonic agents such as sugars, polyols such as mannitol, sorbitol, or sodium chloride in the composition. Extended absorption of the injectable composition can be achieved by including, for example, monostearate and gelatin as agents for extended absorption.

[0071] The disclosed crystalline compounds can be administered in the form of sustained-release formulations, such as compositions comprising sustained-release polymers. The crystalline compounds can be prepared using a carrier that protects the compound from rapid release, such as controlled-release formulations, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyvinyl acetate, polylactic acid, and polylactic acid-polyglycolic acid copolymers (PLGs) can be used. Many methods for preparing such formulations are generally known to those skilled in the art.

[0072] According to an alternative aspect of this disclosure, the disclosed crystalline compound can be formulated together with one or more other compounds that enhance the solubility of the compound.

[0073] method The crystalline salt form disclosed herein can be used to inhibit the kinase activity of one or more enzymes. This document provides (4-(4-amino-1-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-] d The crystalline salt form of tert-butyl pyrimidin-3-yl)-2-methoxyphenyl)carbamate is an inhibitor of tyrosine kinases and is therefore used to treat one or more conditions associated with its activity or mutants thereof.

[0074] In one aspect, this disclosure relates to a crystalline salt form as described herein, which is used in medicine. The crystalline salt form as described above can be used to treat mammals with disease states that are alleviated by inhibiting tyrosine kinases or selectively inhibiting SRC family kinases.

[0075] This disclosure also relates to crystalline salt forms as described herein, used for the treatment of cancer; or viral infections; or osteoporosis; or neurological disorders; or angiogenesis-dependent diseases; or lung diseases; or metastatic bone diseases; or atherosclerosis or restenosis (e.g., characterized by migration and excessive proliferation of vascular smooth muscle cells). For example, a neurological disorder could be Alzheimer's disease. In some embodiments, the cancer could be breast cancer, colon cancer, prostate cancer, melanoma, bladder cancer, pancreatic cancer, central nervous system (CNS) cancer, head and neck cancer, and ovarian cancer. CNS cancers could be glioblastoma multiforme or medulloblastoma, such as medulloblastoma group 4. In some embodiments, the cancer is metastatic. In some embodiments, the cancer is not metastatic.

[0076] In some embodiments, the breast cancer is triple-negative breast cancer, HER2-positive breast cancer (e.g., resistant to HER2 therapy), or estrogen-positive (e.g., resistant to hormone therapy and / or estrogen-degrading agents such as tamoxifen or fulvestrant). In some embodiments, the cancer is cancer with YES or SRC gene amplification. In some embodiments, the lung disease is interstitial lung disease, such as idiopathic pulmonary fibrosis (IPF).

[0077] This disclosure also relates to a method for treating mammals suffering from diseases selected from: cancer, osteoporosis, neurological disorders, angiogenesis-dependent diseases, lung disease or metastatic bone disease, atherosclerosis or restenosis (e.g., characterized by migration and excessive proliferation of vascular smooth muscle cells), wherein the method comprises administering to the mammal a therapeutically effective amount of the crystalline salt form described herein. For example, a neurological disorder may be Alzheimer's disease. Cancer may be breast cancer, colon cancer, prostate cancer, melanoma, bladder cancer, pancreatic cancer, central nervous system (CNS) cancer, head and neck cancer, and ovarian cancer. CNS cancer may be glioblastoma multiforme or medulloblastoma, such as medulloblastoma group 4. In some embodiments, the cancer is metastatic. In some embodiments, the cancer is not metastatic.

[0078] In some embodiments, the breast cancer is triple-negative breast cancer, HER2-positive breast cancer (e.g., resistant to HER2 therapy), or estrogen-positive (e.g., resistant to hormone therapy and / or estrogen-degrading agents such as tamoxifen or fulvestrant). In some embodiments, the cancer is cancer with YES or SRC gene amplification. In some embodiments, the lung disease is interstitial lung disease, such as idiopathic pulmonary fibrosis (IPF).

[0079] In one aspect, this disclosure relates to a method of administering the disclosed crystalline form to a mammal having a disease state that is alleviated by selective inhibition of SRC family kinases. In another aspect, this disclosure relates to a method of administering the disclosed crystalline salt form to a mammal having a disease state selected from: cancer, osteoporosis, neurological disorders, angiogenesis-dependent diseases, lung disease or metastatic bone disease, atherosclerosis or restenosis (e.g., characterized by migration and excessive proliferation of vascular smooth muscle cells), wherein the method comprises administering a therapeutically effective amount of the crystalline salt form to the mammal. For example, a neurological disorder may be Alzheimer's disease. Cancer may be breast cancer, colon cancer, prostate cancer, melanoma, bladder cancer, pancreatic cancer, central nervous system (CNS) cancer, head and neck cancer, and ovarian cancer. CNS cancer may be glioblastoma multiforme or medulloblastoma, such as medulloblastoma group 4. In some embodiments, the cancer is metastatic. In some embodiments, the cancer is not metastatic.

[0080] In some embodiments, the breast cancer is triple-negative breast cancer, HER2-positive breast cancer (e.g., resistant to HER2 therapy), or estrogen-positive (e.g., resistant to hormone therapy and / or estrogen-degrading agents such as tamoxifen or fulvestrant). In some embodiments, the cancer is cancer with YES or SRC gene amplification. In some embodiments, the lung disease is interstitial lung disease, such as idiopathic pulmonary fibrosis (IPF).

[0081] In one aspect, this disclosure relates to the use of the disclosed crystalline salt form in the manufacture of a medicament. In one aspect, this disclosure relates to the use of the disclosed crystalline salt form in the manufacture of a medicament for treating mammals with disease states alleviated by selective inhibition of SRC family kinases. In one aspect, this disclosure relates to the use of the disclosed crystalline salt form in the manufacture of a medicament for treating cancer, osteoporosis, neurological disorders, angiogenesis-dependent diseases, lung diseases or metastatic bone diseases, atherosclerosis or restenosis (e.g., characterized by migration and excessive proliferation of vascular smooth muscle cells). For example, a neurological disorder may be Alzheimer's disease. Cancer may be breast cancer, colon cancer, prostate cancer, melanoma, bladder cancer, pancreatic cancer, central nervous system (CNS) cancer, head and neck cancer, and ovarian cancer. CNS cancer may be glioblastoma multiforme or medulloblastoma, such as medulloblastoma group 4. In some embodiments, the cancer is metastatic. In some embodiments, the cancer is not metastatic.

[0082] In some embodiments, the breast cancer is triple-negative breast cancer, HER2-positive breast cancer (e.g., resistant to HER2 therapy), or estrogen-positive (e.g., resistant to hormone therapy and / or estrogen-degrading agents such as tamoxifen or fulvestrant). In some embodiments, the cancer is cancer with YES or SRC gene amplification. In some embodiments, the lung disease is interstitial lung disease, such as idiopathic pulmonary fibrosis (IPF).

[0083] This document also discloses a method for treating patients with cancer carrying a BTK mutation, the method comprising administering to the patient an effective amount of the crystalline salt form described herein. In some embodiments, the cancer is B-cell cancer. In some embodiments, the cancer is selected from the group consisting of chronic lymphocytic leukemia, small lymphocytic leukemia, mantle cell lymphoma, non-Hodgkin lymphoma, marginal zone lymphoma, and Waldenström macroglobulinemia. In some embodiments, the cancer carries a BTK mutation. For example, in some embodiments, the BTK mutation is a C481 mutation, such as a BTK mutation selected from the group consisting of C481F mutation, C481G mutation, C481R mutation, C481S mutation, and C481Y mutation.

[0084] In some embodiments, the BTK mutation in the cancer is a result of previous treatment with one or more other cancer therapeutic agents. In some embodiments, treatment with one or more other cancer therapeutic agents is no longer effective in treating the cancer. In other embodiments, one or more other cancer therapeutic agents are selected from, but are not limited to, ibrutinib, acalabrutinib, zanubrutinib, fennabrutinib, tirabrutinib, topbutinib, evobrutinib, pitotubinib, and sipebrutinib.

[0085] This document also discloses a method for treating said cancer in a patient identified as having squamous cell carcinoma and requiring treatment, the method comprising administering to the patient an effective amount of the crystalline salt form described herein. In some embodiments, the squamous cell carcinoma is selected from, for example, the group consisting of squamous cell carcinoma of the skin, squamous cell carcinoma of the head and neck, squamous cell carcinoma of the vulva, and squamous cell carcinoma of the lung.

[0086] Specifically, in some embodiments, this disclosure provides a method of treating the aforementioned medical indication, the method comprising administering to a patient in need an effective amount of the crystalline salt form described herein, or a pharmaceutical composition comprising an effective amount of the disclosed crystalline salt form. In some other embodiments, this disclosure provides a method of treating the aforementioned medical condition in a patient in need, the method comprising administering to the patient orally, subcutaneously, or intravenously a composition comprising the crystalline salt form described herein, or a pharmaceutical composition comprising an effective amount of the disclosed crystalline salt form.

[0087] The crystalline compounds disclosed herein can be used as pharmaceuticals or pharmaceutically acceptable compositions, for example, in the form of pharmaceutical formulations for oral, enteral, parenteral, or topical administration, and the envisioned methods disclosed herein may include oral, enteral, parenteral, or topical administration of the disclosed crystalline compounds, or compositions comprising or formed from such disclosed crystalline compounds. For example, when administered via a route (e.g., oral) or in a formulation, the disclosed crystalline form can control one or more pharmacokinetic properties (e.g., longer or shorter release profiles) compared to different routes (e.g., subcutaneous) or other formulations (e.g., formulations having an amorphous form). In one embodiment, the disclosed crystalline salt form can provide substantial reproducibility from one formulation to another.

[0088] The treatments defined herein can be used as a single therapy, or in addition to the compounds of this invention, may include conventional surgery, radiotherapy, gene therapy, or therapies using chemotherapy agents or molecularly targeted agents. Such combination therapy can be achieved by administering the individual components of the treatment simultaneously, sequentially, or separately. As used herein, the term "combination" means simultaneous, separate, or sequential administration. In some embodiments, "combination" means simultaneous administration. In other embodiments, "combination" means separate administration. In still other embodiments, "combination" means sequential administration. When administration is sequential or separate, a delay in administering the second component should not result in the loss of the beneficial effects of the combination.

[0089] Example The compounds and crystalline forms described herein can be prepared in a variety of ways based on the teachings contained herein and synthetic procedures known in the art. The following non-limiting examples illustrate this disclosure.

[0090] Example 1 The following preparation method is used to prepare (4-(4-amino-1-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-] d The crystalline form of tert-butyl pyrimidin-3-yl)-2-methoxyphenyl)carbamate HCl salt 1. Ethyl acetate was added to (4-(4-amino-1-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)-1H-pyrazolo[3,4- d 500 mg of free base (tert-butyl pyrimidinyl)-2-methoxyphenyl)carbamate was added to obtain a free-flowing but opaque slurry. An aqueous solution of HCl (3 M) was then added, and the slurry was stirred at ambient temperature for seven days. The solid was separated by centrifugation and dried under vacuum at 65 °C for 12 hours. XRPD analysis showed that the dried material was crystalline and its pattern was consistent with Form 1.

[0091] (4-(4-amino-1-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-] d XRPD illustration of the crystalline form 1 of pyrimidin-3-yl)-2-methoxyphenyl)carbamate tert-butyl HCl salt is shown in [image / image / image]. Figure 1 The characteristic peaks include one or more peaks shown in Table 1.

[0092] Table 1

[0093]

[0094] Figure 2 Differential scanning calorimetry (DSC) curves for crystalline form 1 were plotted. For example... Figure 2 As shown, crystalline form 1 exhibits characteristic endothermic behavior with an initial temperature of about 90°C and a peak temperature of about 97°C (enthalpy 188.3 J / g).

[0095] (4-(4-amino-1-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-] d The crystalline form of tert-butyl pyrimidinyl (3-yl)-2-methoxyphenyl)carbamate HCl salt 1 shows thermogravimetric analysis (TGA) curves indicating a mass loss of about 12% by weight between about 74°C and about 100°C and a mass loss of about 16% by weight between about 183°C and about 210°C. Figure 3 ).

[0096] Crystalline form 1 shows a dynamic vapor adsorption (DVS) curve illustrating a reversible total mass change of approximately 20% by weight between approximately 0% and approximately 90% relative humidity (RH) at 25°C. Figure 4 Crystalline form 1 was observed to be a 1:1 molar ratio of HCl: free alkali salt and trihydrate. Crystalline form 1 was observed to be chemically and physically stable for at least two weeks at 50°C / 75% RH and 70°C / 0% RH. Crystalline form 1 was observed to have a needle-like morphology, as observed by polarized light microscopy.

[0097] Example 2 The following preparation method is used to prepare (4-(4-amino-1-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-] d 2. Crystalline form of tert-butyl pyrimidin-3-yl)-2-methoxyphenyl)carbamate fumarate. Fumaric acid was added to (4-(4-amino-1-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-] d500 mg of free base (tert-butyl pyrimidin-3-yl)-2-methoxyphenyl)carbamate was added, followed by the addition of solvent. Ethyl acetate was then added to obtain a free-flowing but opaque slurry. The slurry was stirred at ambient temperature for seven days. The solid was separated by centrifugation and dried under vacuum at 65°C for 12 hours. XRPD analysis showed that the dried material was crystalline and its pattern was consistent with Form 2.

[0098] (4-(4-amino-1-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-] d XRPD illustration of crystalline form 1 of pyrimidin-3-yl)-2-methoxyphenyl)carbamate tert-butyl fumarate is shown in [image / image / etc.]. Figure 5 The characteristic peaks include one or more peaks shown in Table 2.

[0099] Table 2

[0100] Figure 6 Differential scanning calorimetry (DSC) curves for crystal form 2 were plotted.

[0101] (4-(4-amino-1-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-] d The crystalline form of tert-butyl pyrimidinyl (3-yl)-2-methoxyphenyl)carbamate fumarate 2 shows thermogravimetric analysis (TGA) curves indicating a mass loss of approximately 1.2 wt% between approximately 48 °C and approximately 72 °C and a mass loss of approximately 25 wt% between approximately 184 °C and approximately 210 °C. Figure 7 ).

[0102] Crystalline form 2 shows a dynamic vapor adsorption (DVS) curve illustrating a reversible total mass change of approximately 6.5% by weight between approximately 0% and approximately 90% relative humidity (RH) at 25°C. Figure 4 Crystalline form 1 was observed to be a 1:1 salt / eutectic and anhydrous. Crystalline form 1 was observed to be chemically and physically stable for at least two weeks at 50°C / 75% RH and 70°C / 0% RH. Crystalline form 1 was observed to have a plate-like morphology, as observed by polarized light microscopy.

[0103] By incorporating references All publications and patents mentioned herein (including those listed below) are incorporated herein by reference in their entirety for all purposes, just as each individual publication or patent is specifically and individually incorporated by reference. In the event of any conflict, this specification, including any definitions herein, shall prevail.

[0104] Equivalent Case While specific embodiments of this disclosure have been discussed, the foregoing description is exemplary only and not restrictive. Many variations of this disclosure will become apparent to those skilled in the art upon reading this specification. The full scope of this disclosure should be determined by reference to the full scope of the claims and their equivalents, the description, and such variations.

[0105] Unless otherwise stated, all figures used in the specification and claims to indicate the amount of ingredients, reaction conditions, etc., should be understood to be modified by the term "about" in all cases. Therefore, unless stated to the contrary, the numerical parameters listed in this specification and the appended claims are approximations that may vary depending on the desired characteristics sought to be obtained by this disclosure.

Claims

1. A (4-(4-amino-1-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)-1H-pyrazolo[3,4- d The crystalline form (form 1) of tert-butyl pyrimidin-3-yl)-2-methoxyphenyl)carbamate HCl salt, characterized in that... Powder X-ray diffraction pattern with a characteristic peak at a 2θ angle of approximately 5.

4.

2. The crystalline form as described in claim 1, characterized in that... Powder X-ray diffraction patterns with characteristic peaks at 2θ angles of approximately 5.4, 6.0, and 11.

9.

3. The crystalline form as described in claim 1 or 2, characterized in that... Powder X-ray diffraction patterns with characteristic peaks at 2θ angles of approximately 2.4, 5.4, 6.0, 11.9, 18.4, and 24.

8.

4. The crystalline form as described in any one of claims 1 to 3, characterized in that... Powder X-ray diffraction patterns with characteristic peaks at 2θ angles of approximately 2.4, 5.4, 6.0, 7.7, 11.9, 12.2, 15.3, 18.4, and 24.

8.

5. The crystalline form as described in any one of claims 1 to 4, characterized in that... Powder X-ray diffraction patterns with characteristic peaks at 2θ angles of approximately 2.4, 5.4, 6.0, 7.7, 11.9, 12.2, 15.3, 15.9, 17.0, 18.4, 24.8, and 26.

2.

6. The crystalline form as described in any one of claims 1 to 5, wherein the powder X-ray diffraction pattern is obtained using Cu Kα radiation.

7. The crystalline form as described in any one of claims 1 to 6, characterized in that... It has a characteristic endothermic differential scanning calorimetry (DSC) curve with an initial temperature of about 90°C and a peak temperature of about 97°C.

8. The crystalline form as described in any one of claims 1 to 7, characterized in that... Thermogravimetric analysis (TGA) curves are shown for approximately 12% by weight of mass loss between approximately 74°C and approximately 100°C, and approximately 16% by weight of mass loss between approximately 183°C and approximately 210°C.

9. The crystalline form as described in any one of claims 1 to 8, wherein the crystalline form exhibits a needle-like crystalline morphology as observed by polarized light microscopy.

10. A (4-(4-amino-1-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)-1H-pyrazolo[3,4- d The crystalline form (form 2) of tert-butyl pyrimidinyl (3-yl)-2-methoxyphenyl)carbamate fumarate, characterized by... Powder X-ray diffraction pattern with a characteristic peak at a 2θ angle of approximately 8.

9.

11. The crystalline form as described in claim 10, characterized in that... Powder X-ray diffraction patterns with characteristic peaks at 2θ angles of approximately 8.9, 17.9, and 19.

3.

12. The crystalline form as described in claim 10 or 11, characterized in that... Powder X-ray diffraction patterns with characteristic peaks at 2θ angles of approximately 4.4, 8.9, 17.9, 19.3, 22.5, and 24.

2.

13. The crystalline form as described in any one of claims 10 to 12, characterized in that... Powder X-ray diffraction patterns with characteristic peaks at 2θ angles of approximately 4.4, 8.9, 14.3, 17.9, 19.3, 22.5, 23.3, 24.2, and 24.

8.

14. The crystalline form as described in any one of claims 10 to 13, characterized in that... Powder X-ray diffraction patterns with characteristic peaks at 2θ angles of approximately 2.3, 4.4, 8.9, 14.3, 17.9, 19.3, 20.7, 22.5, 23.3, 24.2 and 24.8, 31.

0.

15. The crystalline form as described in any one of claims 10 to 14, wherein the powder X-ray diffraction pattern is obtained using Cu Kα radiation.

16. The crystalline form as described in any one of claims 10 to 15, characterized in that... Thermogravimetric analysis (TGA) curves are shown for approximately 1.2 wt% mass loss between approximately 48°C and approximately 72°C, and approximately 25 wt% mass loss between approximately 184°C and approximately 210°C.

17. The crystalline form as described in any one of claims 10 to 16, wherein the crystalline form exhibits a plate-like crystalline morphology as observed by polarized light microscopy.

18. A pharmaceutical composition comprising a crystalline form as described in any one of claims 1 to 17 and a pharmaceutically acceptable excipient.

19. A pharmaceutical composition formed in the crystalline form as described in any one of claims 1 to 17.

20. A method of treating a patient in need of breast cancer, colon cancer, prostate cancer, melanoma, bladder cancer, pancreatic cancer, central nervous system (CNS) cancer, head and neck cancer, or ovarian cancer, the method comprising administering to the patient a therapeutically effective amount of the crystalline form as described in any one of claims 1 to 17 or the pharmaceutical composition as described in claim 18 or 19.

21. A method of treating a patient diagnosed with squamous cell carcinoma and requiring treatment, the method comprising administering to the patient a therapeutically effective amount of a crystalline form as described in any one of claims 1 to 17 or a pharmaceutical composition as described in claim 18 or 19.

Images