Non-hygroscopic crystalline salts of pyrazole compounds, pharmaceutical compositions thereof, and uses thereof

Abstract

The present disclosure provides non-hygroscopic crystalline salts of (1r,4r)-N<supgt;1< / supgt>-(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine and pharmaceutical compositions thereof. Also provided is a method for treating, preventing or ameliorating one or more symptoms of a proliferative disease.

Description

[0001] Cross - reference to related applications

[0002] This application claims the priority benefit of U.S. Provisional Application No. 62 / 856,605, filed on June 3, 2019; the disclosure of the provisional application is hereby incorporated by reference in its entirety. Field of the invention

[0003] Provided herein are non - hygroscopic crystalline salts of (1r,4r)-N 1 -(5 - chloro - 4-(5-(cyclopropylmethyl)-1 - methyl - 1H - pyrazol - 4 - yl)pyrimidin - 2 - yl)cyclohexane - 1,4 - diamine and pharmaceutical compositions thereof. Also provided are methods for treating, preventing, or ameliorating one or more symptoms of proliferative diseases. Background art

[0004] Casein kinases are serine / threonine kinases that phosphorylate proteins to mediate normal biological functions and malignant transformation. Schittek and Sinnberg, Mol. Cancer 2014, 13, 231 - 245. Casein kinase 1α (CK1α) acts as an oncogene through negative regulation of Wnt / β - catenin signaling and p53. Ebert and Kronke, N. Engl. J. Med. 2018, 379, 1873 - 1874. CK1α phosphorylates β - catenin at Ser 45, which leads to ubiquitination and degradation of this signaling protein. Schittek and Sinnberg, Mol. Cancer 2014, 13, 231 - 245; Elyada et al., Nature 2011, 470, 409 - 413. CK1α also phosphorylates murine double minute X (MDMX) at Ser 289, which enhances the binding of MDMX to p53. Wu et al., Mol. Cell. Biol. 2012, 32, 4821 - 4832. In addition, the complex of CK1α with MDM2 also inhibits p53. Elyada et al., Nature 2011, 470, 409 - 413. Thus, inhibition of CK1α and subsequent activation of p53 have the potential to effectively treat a range of cancers.

[0005] N 1-(5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine (“Compound”) is an inhibitor of CK1α and inhibitors of the transcriptional kinases CDK7 and CDK9. Minzel et al., Cell 2018, 175, 171 - 185. The Compound reduces phosphorylation of β-catenin at Ser 45 and increases the expression of p53 and β-catenin. Id. The Compound also significantly reduces the expression of key cancer-initiating genes, which include Myc, MDM2, and MCL1. Id. The Compound, when in the form of its hydrochloride salt, is effective in treating acute myeloid leukemia (AML) in a murine model of AML and in a xenograft mouse model derived from human patients. Id. However, the hydrochloride salt of the Compound is highly hygroscopic and not suitable for pharmaceutical applications. Accordingly, there is a need for N 1 non-hygroscopic salts of -(5-chloro-4-(5-(cyclopropyl-methyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine. SUMMARY OF THE INVENTION

[0006] Provided herein is a non-hygroscopic crystalline salt that is formed from (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine or an isotopic variant thereof with an acid; or a pharmaceutically acceptable solvate thereof. In one embodiment, the acid is acetic acid, adipic acid, benzoic acid, fumaric acid, glycolic acid, hippuric acid, lactic acid, maleic acid, malic acid, methanesulfonic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, or p-toluenesulfonic acid.

[0007] Also provided herein is a crystalline acetate salt of (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine or an isotopic variant thereof; or a pharmaceutically acceptable solvate thereof.

[0008] In addition, provided herein is a crystalline adipate salt of (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine or an isotopic variant thereof; or a pharmaceutically acceptable solvate thereof.

[0009] Also provided herein is a crystalline adipate salt of (1r,4r)-N 1-(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine or a crystalline benzoate of an isotopic variant thereof; or a pharmaceutically acceptable solvate thereof.

[0010] This document provides (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine or a crystalline fumarate of an isotopic variant thereof; or a pharmaceutically acceptable solvate thereof.

[0011] This document provides (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine or a crystalline glycolate of an isotopic variant thereof; or a pharmaceutically acceptable solvate thereof.

[0012] This document provides (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine or a crystalline hippurate of an isotopic variant thereof; or a pharmaceutically acceptable solvate thereof.

[0013] This document provides (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine or a crystalline lactate of an isotopic variant thereof; or a pharmaceutically acceptable solvate thereof.

[0014] This document provides (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine or a crystalline maleate of an isotopic variant thereof; or a pharmaceutically acceptable solvate thereof.

[0015] This document provides (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine or a crystalline malate of an isotopic variant thereof; or a pharmaceutically acceptable solvate thereof.

[0016] This document provides (1r,4r)-N 1-(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine or a crystalline methanesulfonate of an isotopic variant thereof; or a pharmaceutically acceptable solvate thereof.

[0017] This document provides (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine or a crystalline succinate of an isotopic variant thereof; or a pharmaceutically acceptable solvate thereof.

[0018] This document provides (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine or a crystalline sulfate of an isotopic variant thereof; or a pharmaceutically acceptable solvate thereof.

[0019] This document provides (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine or a crystalline tartrate of an isotopic variant thereof; or a pharmaceutically acceptable solvate thereof.

[0020] This document provides (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine or a crystalline thiocyanate of an isotopic variant thereof; or a pharmaceutically acceptable solvate thereof.

[0021] This document provides (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine or a crystalline p-toluenesulfonate of an isotopic variant thereof; or a pharmaceutically acceptable solvate thereof.

[0022] This document provides a pharmaceutical composition comprising (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine or a non-hygroscopic crystalline salt formed with an acid of an isotopic variant thereof; or a pharmaceutically acceptable solvate thereof; and a pharmaceutically acceptable excipient.

[0023] This document provides a method for treating, preventing, or ameliorating one or more symptoms of a proliferative disease in a subject, which comprises administering to the subject (1r,4r)-N 1-(5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine or a non-hygroscopic crystalline salt thereof formed with an acid with an isotopic variant thereof; or a pharmaceutically acceptable solvate thereof.

[0024] Provided herein is a method for treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition mediated by casein kinase 1 (CK1) in a subject, comprising administering to the subject a therapeutically effective amount of (1r,4r)-N 1 -(5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine or a non-hygroscopic crystalline salt thereof formed with an acid with an isotopic variant thereof; or a pharmaceutically acceptable solvate thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 Depicts the X-ray powder diffraction patterns of two crystalline acetates (top and middle diffractograms) and one crystalline adipate (bottom diffractogram) of (1r,4r)-N 1 -(5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine (“Compound”).

[0026] Figure 2 Depicts the differential scanning calorimetry (DSC) / thermogravimetric analysis (TGA) thermograms of the crystalline acetate of the Compound.

[0027] Figure 3 Depicts the DSC / TGA thermograms of the crystalline adipate of the Compound.

[0028] Figure 4 Depicts the X-ray powder diffraction patterns of one crystalline benzoate (top diffractogram) and two crystalline fumarates (middle and bottom diffractograms) of the Compound.

[0029] Figure 5 Depicts the DSC / TGA thermograms of the crystalline benzoate of the Compound.

[0030] Figure 6 Depicts the DSC / TGA thermograms of the crystalline fumarate of the Compound.

[0031] Figure 7 Depicts the X-ray powder diffraction patterns of two crystalline glycolates (top and middle diffractograms) and one crystalline lactate (bottom diffractogram) of the Compound.

[0032] Figure 8 Depicts the DSC / TGA thermograms of the crystalline glycolate of the Compound.

[0033] Figure 9 Depicts the DSC / TGA thermogram of the crystalline lactate salt of the compound.

[0034] Figure 10 Depicts the X-ray powder diffraction patterns of two crystalline hippurate salts (top and middle diffraction patterns) and one crystalline maleate salt (bottom diffraction pattern) of the compound.

[0035] Figure 11 Depicts the DSC / TGA thermogram of the crystalline hippurate salt of the compound.

[0036] Figure 12 Depicts the DSC / TGA thermogram of the crystalline maleate salt of the compound.

[0037] Figure 13 Depicts the X-ray powder diffraction patterns of three crystalline malate salts of the compound.

[0038] Figure 14 Depicts the DSC / TGA thermogram of the crystalline malate salt of the compound.

[0039] Figure 15 Depicts the X-ray powder diffraction patterns of one crystalline mesylate salt (top diffraction pattern) and two crystalline succinate salts (middle and bottom diffraction patterns) of the compound.

[0040] Figure 16 Depicts the DSC / TGA thermogram of the crystalline mesylate salt of the compound.

[0041] Figure 17 Depicts the DSC / TGA thermogram of the crystalline succinate salt of the compound.

[0042] Figure 18 Depicts the X-ray powder diffraction patterns of one crystalline sulfate salt (top diffraction pattern) and one crystalline tartrate salt (bottom diffraction pattern) of the compound.

[0043] Figure 19 Depicts the DSC / TGA thermogram of the crystalline sulfate salt of the compound.

[0044] Figure 20 Depicts the DSC / TGA thermogram of the crystalline tartrate salt of the compound.

[0045] Figure 21 Depicts the X-ray powder diffraction patterns of one crystalline thiocyanate salt (top diffraction pattern) and one crystalline tosylate salt (bottom diffraction pattern) of the compound.

[0046] Figure 22 Depicts the DSC / TGA thermogram of the crystalline thiocyanate salt of the compound.

[0047] Figure 23 Depicts the DSC / TGA thermogram of the crystalline toluenesulfonate salt of the compound.

[0048] Figure 24 Depicts the X-ray powder diffraction pattern of the non-hygroscopic crystalline adipate salt of the compound.

[0049] Figure 25 Depicts the DSC / TGA thermogram of the non-hygroscopic crystalline adipate salt of the compound.

[0050] Figure 26 Depicts the dynamic vapor sorption (DVS) isotherm of the non-hygroscopic crystalline adipate salt of the compound.

[0051] Figure 27 and 28 Depicts the 1 1H NMR spectrum of the non-hygroscopic crystalline adipate salt of the compound.

[0052] Figure 29 Depicts the X-ray powder diffraction pattern of the crystalline benzoate salt of the compound.

[0053] Figure 30 Depicts the DSC / TGA thermogram of the crystalline benzoate salt of the compound.

[0054] Figure 31 Depicts the DVS isotherm of the crystalline benzoate salt of the compound.

[0055] Figure 32 and 33 Depicts the 1 1H NMR spectrum of the crystalline benzoate salt of the compound.

[0056] Figure 34 Depicts the X-ray powder diffraction pattern of the crystalline toluenesulfonate salt of the compound.

[0057] Figure 35 Depicts the DSC thermogram of the crystalline toluenesulfonate salt of the compound.

[0058] Figure 36 Depicts the DVS isotherm of the crystalline toluenesulfonate salt of the compound, where the symbols (◆) and (■) represent adsorption and desorption, respectively.

[0059] Figure 37 Depicts the 1 Magnified region of the 1H NMR spectrum of the crystalline toluenesulfonate salt of the compound.

[0060] Figure 38 Depicts the DVS isotherm of the dihydrochloride salt of the compound.

[0061] Figure 39Depicts the DSC / TGA thermogram of the dihydrochloride salt of the compound. Detailed Description

[0062] To aid in understanding the disclosure set forth herein, a number of terms are defined below.

[0063] In general, the nomenclature used herein and the experimental procedures in organic chemistry, medicinal chemistry, physical chemistry, biochemistry, biology, pharmacology, etc. described herein are those well known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0064] The term "subject" refers to an animal, including but not limited to a primate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. When referring to, for example, a mammalian subject, such as a human subject, the terms "subject" and "patient" may be used interchangeably. In one embodiment, the subject is a human.

[0065] The term "treat / treating / treatment" is intended to include alleviating or eliminating a disorder, disease, or condition, or one or more symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause of the disorder, disease, or condition itself.

[0066] The term "prevent / preventing / prevention" is intended to include a method of achieving: delaying and / or precluding the onset of a disorder, disease, or condition and / or its attendant symptoms; preventing a subject from developing a disorder, disease, or condition; or reducing the risk that a subject will develop a disorder, disease, or condition.

[0067] The term "alleviate / alleviating" refers to moderating or reducing one or more symptoms of a disorder, disease, or condition (e.g., pain). The term may also refer to reducing side effects associated with an active ingredient. Sometimes, the beneficial effects obtained by a subject from a prophylactic or therapeutic agent do not cure the disorder, disease, or condition.

[0068] The term "therapeutically effective amount" or "effective amount" is intended to include an amount of a compound that, upon administration, is sufficient to prevent the development of one or more symptoms of the disorder, disease, or condition being treated or to alleviate one or more symptoms to some extent. The term "therapeutically effective amount" or "effective amount" also refers to an amount of a compound sufficient to cause a biological or medical response in a biomolecule (e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human that is sought by a researcher, veterinarian, medical doctor, or clinician.

[0069] The terms "pharmaceutically acceptable carrier", "pharmaceutically acceptable excipient", "physiologically acceptable carrier" or "physiologically acceptable excipient" refer to a pharmaceutically acceptable substance, composition or vehicle, such as a liquid or solid filler, diluent, solvent or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical formulation and suitable for use in contact with the tissues or organs of a subject (e.g., a human or an animal) without undue toxicity, irritation, allergic response, immunogenicity or other problems or complications, commensurate with a reasonable benefit / risk ratio. See Remington: The Science and Practice of Pharmacy, 22nd Edition; edited by Allen: Philadelphia, PA, 2012; 8th Edition; edited by Sheskey et al.; The Pharmaceutical Press and the American Pharmacists Association: 2017; Handbook of Pharmaceutical Additives, 3rd Edition; edited by Ash and Ash; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd Edition; edited by Gibson; CRC Press: Boca Raton, FL, 2009.

[0070] The term "about" or "approximately" means an acceptable error of a specific value as determined by a person of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" means within 1, 2, 3 or 4 standard deviations. In certain embodiments, the term "about" or "approximately" means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5% or 0.05% of a given value or range.

[0071] The term "isotopically enriched" refers to a compound that contains a non-natural proportion of isotopes at one or more atoms that make up the compound. In certain embodiments, the isotopically enriched compound contains a non-natural proportion of one or more isotopes, including but not limited to hydrogen ( 1 H), deuterium ( 2 H), tritium ( 3 H), carbon-11 ( 11 C), carbon-12 ( 12 C), carbon-13 ( 13 C), carbon-14 ( 14C), nitrogen-13 ( 13 N), nitrogen-14 ( 14 N), nitrogen-15 ( 15 N), oxygen-14 ( 14 O), oxygen-15 ( 15 O), oxygen-16 ( 16 O), oxygen-17 ( 17 O), oxygen-18 ( 18 O), fluorine-17 ( 17 F), fluorine-18 ( 18 F), phosphorus-31 ( 31 P), phosphorus-32 ( 32 P), phosphorus-33 ( 33 P), sulfur-32 ( 32 S), sulfur-33 ( 33 S), sulfur-34 ( 34 S), sulfur-35 ( 35 S), sulfur-36 ( 36 S), chlorine-35 ( 35 Cl), chlorine-36 ( 36 Cl), chlorine-37 ( 37 Cl), bromine-79 ( 79 Br), bromine-81 ( 81 Br), iodine-123 ( 123 I), iodine-125 ( 125 I), iodine-127 ( 127 I), iodine-129 ( 129 I) and iodine-131 ( 131 I). In certain embodiments, the isotope-enriched compound is in a stable form, i.e., non-radioactive. In certain embodiments, the isotope-enriched compound contains non-natural proportions of one or more isotopes, including but not limited to hydrogen ( 1 H), deuterium ( 2 H), carbon-12 ( 12 C), carbon-13 ( 13 C), nitrogen-14 ( 14 N), nitrogen-15 ( 15 N), oxygen-16 ( 16 O), oxygen-17 ( 17 O), oxygen-18 ( 18 O), fluorine-17 ( 17 F), phosphorus-31 ( 31 P), sulfur-32 ( 32 S), sulfur-33 ( 33 S), sulfur-34 ( 34 S), sulfur-36 ( 36 S), chlorine-35 ( 35Cl), chlorine-37( 37 Cl), bromine-79( 79 Br), bromine-81( 81 Br) and iodine-127( 127 I). In certain embodiments, the isotope-enriched compound is in an unstable form, i.e., radioactive. In certain embodiments, the isotope-enriched compound contains a non-natural proportion of one or more isotopes, including but not limited to tritium( 3 H), carbon-11( 11 C), carbon-14( 14 C), nitrogen-13( 13 N), oxygen-14( 14 O), oxygen-15( 15 O), fluorine-18( 18 F), phosphorus-32( 32 P), phosphorus-33( 33 P), sulfur-35( 35 S), chlorine-36( 36 Cl), iodine-123( 123 I), iodine-125( 125 I), iodine-129( 129 I) and iodine-131( 131 I). It should be understood that in the compounds provided herein, where feasible according to the judgment of a person of ordinary skill in the art, for example, any hydrogen can be 2 H, or for example, any carbon can be 13 C, or for example, any nitrogen can be 15 N, or for example, any oxygen can be 18 O.

[0072] The term "isotope enrichment" refers to the percentage of incorporation of a less common isotope of an element (e.g., deuterium D or hydrogen-2) at a given position in a molecule in place of the more common isotope of that element (e.g., protium 1 H or hydrogen-1). As used herein, when an atom at a specific position in a molecule is referred to as a specific less common isotope, it should be understood that the abundance of that isotope at that position substantially exceeds its natural abundance.

[0073] The term "isotope enrichment factor" refers to the ratio between the isotope abundance in an isotope-enriched compound and the natural abundance of a specific isotope.

[0074] The term "hydrogen" or the symbol "H" refers to the composition of naturally occurring hydrogen isotopes, which includes natural abundances of protium 1 H), deuterium( 2 H or D) and tritium( 3H). Protium is the most common hydrogen isotope, with a natural abundance of over 99.98%. Deuterium is a less common hydrogen isotope, with a natural abundance of approximately 0.0156%.

[0075] The term "deuterium enrichment" refers to the percentage of deuterium incorporated in place of hydrogen at a given position in a molecule. For example, 1% deuterium enrichment at a given position means that 1% of the molecules in a given sample contain deuterium at the specified position. Since the natural distribution of deuterium is on average approximately 0.0156%, the average deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is approximately 0.0156%. As used herein, when an isotopically enriched compound is said to have deuterium at a specific position, it should be understood that the abundance of deuterium at that position in the compound substantially exceeds its natural abundance (0.0156%).

[0076] The term "carbon" or the symbol "C" refers to the composition of the naturally occurring carbon isotopes, which includes carbon-12 ( 12 C) and carbon-13 ( 13 C). Carbon-12 is the most common carbon isotope, with a natural abundance of over 98.89%. Carbon-13 is a less common carbon isotope, with a natural abundance of approximately 1.11%.

[0077] The term "carbon-13 enrichment" or " 13 C enrichment" refers to the percentage of carbon-13 incorporated in place of carbon at a given position in a molecule. For example, 10% carbon-13 enrichment at a given position means that 10% of the molecules in a given sample contain carbon-13 at the specified position. Since the natural distribution of carbon-13 is on average approximately 1.11%, the average carbon-13 enrichment at any position in a compound synthesized using non-enriched starting materials is approximately 1.11%. As used herein, when an isotopically enriched compound is said to have carbon-13 at a specific position, it should be understood that the abundance of carbon-13 at that position in the compound substantially exceeds its natural abundance (1.11%).

[0078] The terms "substantially pure" and "substantially homogeneous" mean sufficiently homogeneous so that, as determined by standard analytical methods used by one of ordinary skill in the art, there appear to be no readily detectable impurities, the standard analytical methods including but not limited to thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography (HPLC), gas chromatography (GC), nuclear magnetic resonance (NMR), and mass spectrometry (MS); or sufficiently pure such that further purification does not result in a detectable change in the physical, chemical, biological, and / or pharmacological properties (e.g., enzyme and biological activity) of the substance. In certain embodiments, "substantially pure" or "substantially homogeneous" refers to a group of molecules in which, as determined by standard analytical methods, at least about 50%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 99.5% by weight of the molecules are a single compound, including a single enantiomer, a racemic mixture, or a mixture of enantiomers. As used herein, when an atom at a specific position in an isotope-enriched molecule is a specific less prevalent isotope, a molecule containing an atom other than the indicated isotope at the designated position is an impurity relative to the isotope-enriched compound. Thus, for a deuterated compound having an atom designated as deuterium at a specific position, a compound containing protium at the same position is an impurity.

[0079] The term "solvate" refers to a complex or aggregate formed by one or more molecules of a solute, such as a compound provided herein, and one or more molecules of a solvent, the molecules being present in stoichiometric or non-stoichiometric amounts. Suitable solvents include but are not limited to water, methanol, ethanol, n-propanol, isopropanol, acetone, acetic acid, and hexane. In certain embodiments, the solvent is pharmaceutically acceptable. In one embodiment, the complex or aggregate is in crystalline form. In another embodiment, the complex or aggregate is in non-crystalline form. Where the solvent is water, the solvate is a hydrate. Examples of hydrates include but are not limited to hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate.

[0080] The phrase "a non-hygroscopic crystalline salt formed by a compound or its isotopic variant with an acid; or a pharmaceutically acceptable solvate thereof" has the same meaning as the phrase "(i) a non-hygroscopic crystalline salt formed by a compound with an acid; (ii) a non-hygroscopic crystalline salt formed by a pharmaceutically acceptable solvate of the compound with an acid; or (iii) a non-hygroscopic crystalline salt formed by an acid with an isotopic variant of the compound; or (iv) a non-hygroscopic crystalline salt formed by a pharmaceutically acceptable solvate of the acid with an isotopic variant of the compound".

[0081] Non-hygroscopic crystalline salts of the compound

[0082] Compound (1r,4r)-N 1-(5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine has the following structure:

[0083]

[0084] This compound is a CK1α, CDK7, and CDK9 inhibitor. Minzel et al., Cell 2018, 175, 1-15. The compound can be prepared according to the procedures described in: Minzel et al., Cell 2018, 175, 1-15; or U.S. Patent Application Publication No. 2018 / 0214447A1; the disclosure of each is incorporated herein by reference in its entirety.

[0085] In one embodiment, provided herein is a non-hygroscopic crystalline salt formed by (1r,4r)-N 1 -(5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine or an isotopic variant thereof with an acid; or a pharmaceutically acceptable solvate thereof.

[0086] In certain embodiments, the molar ratio of the compound to the acid in the crystalline salts provided herein ranges from about 0.5 to about 3 or from about 0.5 to about 2.5. In certain embodiments, the molar ratio of the compound to the acid in the crystalline salts provided herein is about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 1.1, about 1.2, about 1.4, about 1.5, about 1.6, about 1.8, about 2, about 2.2, about 2.4, about 2.6, about 2.8, or about 3. In certain embodiments, the molar ratio of the compound to the acid in the crystalline salts provided herein is about 1. In certain embodiments, the molar ratio of the compound to the acid in the crystalline salts provided herein is about 2.

[0087] In certain embodiments, the acid is acetic acid, adipic acid, benzoic acid, fumaric acid, glycolic acid, hippuric acid, lactic acid, maleic acid, malic acid, methanesulfonic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, or p-toluenesulfonic acid. In certain embodiments, the acid is adipic acid, benzoic acid, or p-toluenesulfonic acid. In certain embodiments, the acid is adipic acid. In certain embodiments, the acid is benzoic acid. In certain embodiments, the acid is p-toluenesulfonic acid.

[0088] In certain embodiments, the non-hygroscopic crystalline salts provided herein have a solubility in water at 25 °C of no more than 10 mg / mL, no more than 5 mg / mL, or no more than 2 mg / mL.

[0089] In certain embodiments, the non-hygroscopic crystalline salts provided herein have a weight gain of no more than 5%, no more than 4%, no more than 3%, no more than 2%, or no more than 1% from 5% to 95% relative humidity (RH) at 25°C. In certain embodiments, the non-hygroscopic crystalline salts provided herein have a weight gain of no more than 5% from 5% to 95% RH at 25°C. In certain embodiments, the non-hygroscopic crystalline salts provided herein have a weight gain of no more than 4% from 5% to 95% RH at 25°C. In certain embodiments, the non-hygroscopic crystalline salts provided herein have a weight gain of no more than 3% from 5% to 95% RH at 25°C. In certain embodiments, the non-hygroscopic crystalline salts provided herein have a weight gain of no more than 2% from 5% to 95% RH at 25°C. In certain embodiments, the non-hygroscopic crystalline salts provided herein have a weight gain of no more than 1% from 5% to 95% RH at 25°C.

[0090] In another embodiment, provided herein is (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine or a crystalline acetate of an isotopic variant thereof; or a pharmaceutically acceptable solvate thereof.

[0091] In certain embodiments, the molar ratio of the compound to acetic acid in the crystalline acetate provided herein ranges from about 0.5 to about 3 or from about 0.5 to about 2.5. In certain embodiments, the molar ratio of the compound to acetic acid in the crystalline acetate provided herein is about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 1.1, about 1.2, about 1.4, about 1.5, about 1.6, about 1.8, about 2, about 2.2, about 2.4, about 2.6, about 2.8, or about 3. In certain embodiments, the molar ratio of the compound to acetic acid in the crystalline acetate provided herein is about 1. In certain embodiments, the molar ratio of the compound to acetic acid in the crystalline acetate provided herein is about 2.

[0092] In one embodiment, the crystalline acetate provided herein comprises about one molar equivalent of the compound and about one molar equivalent of acetic acid. In another embodiment, the crystalline acetate provided herein comprises about one molar equivalent of the compound and about two molar equivalents of acetic acid. In certain embodiments, the molar ratio of the compound to acetic acid in the crystalline acetate provided herein is determined by 1 1H NMR spectroscopy. In certain embodiments, the molar ratio of the compound to acetic acid in the crystalline acetate provided herein is determined by elemental analysis.

[0093] In certain embodiments, the crystalline acetate provided herein has substantially as Figure 1The X-ray powder diffraction pattern (top diffraction pattern) shown in Figure 1 is the X-ray powder diffraction pattern (middle diffraction pattern).

[0094] In certain embodiments, the crystalline acetate provided herein has a DSC thermogram that includes an endothermic peak at about 190 °C. In certain embodiments, the crystalline acetate provided herein has a DSC thermogram that includes an endothermic peak at 190 ± 3 °C. In certain embodiments, the crystalline acetate provided herein has a DSC thermogram that is substantially as shown in Figure 2 . In certain embodiments, the crystalline acetate provided herein has a melting point of about 190 °C.

[0095] In certain embodiments, the crystalline acetate provided herein has a thermogravimetric analysis (TGA) thermogram that shows a weight loss of about 2% from room temperature to 125 °C. In certain embodiments, the crystalline acetate provided herein has a TGA thermogram that shows a weight loss of about 12% from 125 °C to 195 °C. In certain embodiments, the crystalline acetate provided herein has a TGA thermogram that is substantially as shown in Figure 2 .

[0096] In certain embodiments, the crystalline acetate provided herein is solvated. In certain embodiments, the crystalline acetate provided herein is an acetone solvate. In certain embodiments, the crystalline acetate provided herein is a hydrate.

[0097] In yet another embodiment, provided herein is the crystalline adipate of (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine or an isotopic variant thereof; or a pharmaceutically acceptable solvate thereof.

[0098] In certain embodiments, the molar ratio of the compound to adipic acid in the crystalline adipate provided herein ranges from about 0.25 to about 1.5 or from about 0.5 to about 1. In certain embodiments, the molar ratio of the compound to adipic acid in the crystalline adipate provided herein is about 0.25, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 1.1, about 1.2, about 1.3, about 1.4, or about 1.5. In certain embodiments, the molar ratio of the compound to adipic acid in the crystalline adipate provided herein is about 0.5. In certain embodiments, the molar ratio of the compound to adipic acid in the crystalline adipate provided herein is about 1.

[0099] In one embodiment, the crystalline adipate provided herein comprises about two molar equivalents of a compound and about one molar equivalent of adipic acid. In one embodiment, the crystalline adipate provided herein comprises about one molar equivalent of a compound and about one molar equivalent of adipic acid. In certain embodiments, the molar ratio of the compound to adipic acid in the crystalline adipate provided herein is determined by 1 1H NMR spectroscopy. In certain embodiments, the molar ratio of the compound to adipic acid in the crystalline adipate provided herein is determined by elemental analysis.

[0100] In certain embodiments, the crystalline adipate provided herein has an X-ray powder diffraction pattern substantially as shown in Figure 24 .

[0101] In certain embodiments, the crystalline adipate provided herein has a DSC thermogram comprising an endothermic peak at about 164 °C. In certain embodiments, the crystalline adipate provided herein has a DSC thermogram comprising an endothermic peak at 164 ± 3 °C. In certain embodiments, the crystalline adipate provided herein has a DSC thermogram comprising an endothermic peak at about 175 °C. In certain embodiments, the crystalline adipate provided herein has a DSC thermogram comprising an endothermic peak at 175 ± 3 °C. In certain embodiments, the crystalline adipate provided herein has a DSC thermogram substantially as shown in Figure 25 . In certain embodiments, the crystalline adipate provided herein has a melting point of about 164 °C.

[0102] In certain embodiments, the crystalline adipate provided herein has a TGA thermogram showing a weight loss of about 0.3% from room temperature to 150 °C. In certain embodiments, the crystalline adipate provided herein has a TGA thermogram substantially as shown in Figure 25 .

[0103] In certain embodiments, the crystalline adipate provided herein has a dynamic vapor sorption (DVS) isotherm showing a weight loss of about 0.05% after drying at 5% RH. In certain embodiments, the crystalline adipate provided herein has a DVS isotherm showing a weight gain of about 1% from 5% to 95% RH. In certain embodiments, the crystalline adipate provided herein has a DVS isotherm showing a weight loss of about 1% from 95% to 5% RH. In certain embodiments, the crystalline adipate provided herein has a DVS isotherm substantially as shown in Figure 26 .

[0104] In certain embodiments, the crystalline adipate provided herein has a weight gain of no more than 5%, no more than 4%, no more than 3%, no more than 2%, or no more than 1% from 5% to 95% relative humidity (RH) at 25°C. In certain embodiments, the crystalline adipate provided herein has a weight gain of no more than 5% from 5% to 95% RH at 25°C. In certain embodiments, the crystalline adipate provided herein has a weight gain of no more than 4% from 5% to 95% RH at 25°C. In certain embodiments, the crystalline adipate provided herein has a weight gain of no more than 3% from 5% to 95% RH at 25°C. In certain embodiments, the crystalline adipate provided herein has a weight gain of no more than 2% from 5% to 95% RH at 25°C. In certain embodiments, the crystalline adipate provided herein has a weight gain of no more than 1% from 5% to 95% RH at 25°C.

[0105] In certain embodiments, the crystalline adipate provided herein is not solvated. In certain embodiments, the solubility of the crystalline adipate in water at 25°C is about 15 mg / mL.

[0106] In yet another embodiment, provided herein is (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine or a crystalline benzoate of an isotopic variant thereof; or a pharmaceutically acceptable solvate thereof.

[0107] In certain embodiments, the molar ratio of the compound to benzoic acid in the crystalline benzoate provided herein ranges from about 0.5 to about 3 or from about 0.5 to about 2.5. In certain embodiments, the molar ratio of the compound to benzoic acid in the crystalline benzoate provided herein is about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 1.1, about 1.2, about 1.4, about 1.5, about 1.6, about 1.8, about 2, about 2.2, about 2.4, about 2.6, about 2.8, or about 3. In certain embodiments, the molar ratio of the compound to benzoic acid in the crystalline benzoate provided herein is about 1. In certain embodiments, the molar ratio of the compound to benzoic acid in the crystalline benzoate provided herein is about 2.

[0108] In one embodiment, the crystalline benzoate provided herein comprises about one molar equivalent of the compound and about one molar equivalent of benzoic acid. In another embodiment, the crystalline benzoate provided herein comprises about one molar equivalent of the compound and about two molar equivalents of benzoic acid. In certain embodiments, the molar ratio of the compound to benzoic acid in the crystalline benzoate provided herein is determined by 1Determined by \(^1H\) NMR spectroscopy. In certain embodiments, the molar ratio of the compound to benzoic acid in the crystalline benzoate provided herein is determined by elemental analysis.

[0109] In certain embodiments, the crystalline benzoate provided herein has an X-ray powder diffraction pattern substantially as Figure 29 shown therein.

[0110] In certain embodiments, the crystalline benzoate provided herein has a DSC thermogram comprising an endothermic peak at about 229 °C. In certain embodiments, the crystalline benzoate provided herein has a DSC thermogram comprising an endothermic peak at 229 ± 3 °C. In certain embodiments, the crystalline benzoate provided herein has a DSC thermogram substantially as Figure 30 shown therein.

[0111] In certain embodiments, the crystalline benzoate provided herein has a TGA thermogram showing a weight loss of about 1% from room temperature to 175 °C. In certain embodiments, the crystalline benzoate provided herein has a TGA thermogram substantially as Figure 30 shown therein.

[0112] In certain embodiments, the crystalline benzoate provided herein has a DVS isotherm showing a weight loss of about 0.02% after drying at 5% RH. In certain embodiments, the crystalline benzoate provided herein has a DVS isotherm showing a weight gain of about 1.2% from 5% to 95% RH. In certain embodiments, the crystalline benzoate provided herein has a DVS isotherm showing a weight loss of about 1.3% from 95% to 5% RH. In certain embodiments, the crystalline benzoate provided herein has a DVS isotherm substantially as Figure 31 shown therein.

[0113] In certain embodiments, the crystalline benzoate provided herein has a weight gain of no more than 5%, no more than 4%, no more than 3%, no more than 2% or no more than 1% from 5% to 95% relative humidity (RH) at 25 °C. In certain embodiments, the crystalline benzoate provided herein has a weight gain of no more than 5% from 5% to 95% RH at 25 °C. In certain embodiments, the crystalline benzoate provided herein has a weight gain of no more than 4% from 5% to 95% RH at 25 °C. In certain embodiments, the crystalline benzoate provided herein has a weight gain of no more than 3% from 5% to 95% RH at 25 °C. In certain embodiments, the crystalline benzoate provided herein has a weight gain of no more than 2% from 5% to 95% RH at 25 °C. In certain embodiments, the crystalline benzoate provided herein has a weight gain of no more than 1% from 5% to 95% RH at 25 °C.

[0114] In certain embodiments, the crystalline benzoates provided herein are unsolvated. In certain embodiments, the crystalline benzoates have a solubility in water at 25 °C of no more than 1 mg / mL.

[0115] In yet another embodiment, provided herein is the crystalline fumarate of (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine or an isotopic variant thereof; or a pharmaceutically acceptable solvate thereof.

[0116] In certain embodiments, the molar ratio of the compound to fumaric acid in the crystalline fumarates provided herein ranges from about 0.25 to about 1.5 or from about 0.5 to about 1. In certain embodiments, the molar ratio of the compound to fumaric acid in the crystalline fumarates provided herein is about 0.25, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 1.1, about 1.2, about 1.3, about 1.4, or about 1.5. In certain embodiments, the molar ratio of the compound to fumaric acid in the crystalline fumarates provided herein is about 0.5. In certain embodiments, the molar ratio of the compound to fumaric acid in the crystalline fumarates provided herein is about 1.

[0117] In one embodiment, the crystalline fumarates provided herein contain about two molar equivalents of the compound and about one molar equivalent of fumaric acid. In another embodiment, the crystalline fumarates provided herein contain about one molar equivalent of the compound and about one molar equivalent of fumaric acid. In certain embodiments, the molar ratio of the compound to fumaric acid in the crystalline fumarates provided herein is determined by 1 1H NMR spectroscopy. In certain embodiments, the molar ratio of the compound to fumaric acid in the crystalline fumarates provided herein is determined by elemental analysis.

[0118] In certain embodiments, the crystalline fumarates provided herein have an X-ray powder diffraction pattern (middle diffraction pattern) substantially as shown in Figure 4 In certain embodiments, the crystalline fumarates provided herein have an X-ray powder diffraction pattern (bottom diffraction pattern) substantially as shown in Figure 4 In certain embodiments, the crystalline fumarates provided herein have a DSC thermogram containing an endothermic peak at about 147 °C. In certain embodiments, the crystalline fumarates provided herein have a DSC thermogram containing an endothermic peak at 147 ± 3 °C. In certain embodiments, the crystalline fumarates provided herein have a DSC thermogram substantially as shown in

[0119] In certain embodiments, the crystalline fumarates provided herein have a DSC thermogram substantially as shown in Figure 6 In certain embodiments, the crystalline fumarates provided herein have a DSC thermogram substantially as shown in

[0120] In certain embodiments, the crystalline fumarates provided herein have a TGA thermogram showing a 2% weight loss from room temperature to about 160 °C. In certain embodiments, the crystalline fumarates provided herein have a TGA thermogram substantially as Figure 6 shown therein.

[0121] In certain embodiments, the crystalline fumarates provided herein are solvated. In certain embodiments, the crystalline fumarates provided herein are acetone solvates. In certain embodiments, the crystalline fumarates provided herein are hydrates.

[0122] In yet another embodiment, provided herein is a crystalline glycolate of (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine or an isotopic variant thereof; or a pharmaceutically acceptable solvate thereof.

[0123] In certain embodiments, the molar ratio of the compound to glycolic acid in the crystalline glycolates provided herein ranges from about 0.5 to about 3 or from about 0.5 to about 2.5. In certain embodiments, the molar ratio of the compound to glycolic acid in the crystalline glycolates provided herein is about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 1.1, about 1.2, about 1.4, about 1.5, about 1.6, about 1.8, about 2, about 2.2, about 2.4, about 2.6, about 2.8, or about 3. In certain embodiments, the molar ratio of the compound to glycolic acid in the crystalline glycolates provided herein is about 1. In certain embodiments, the molar ratio of the compound to glycolic acid in the crystalline glycolates provided herein is about 2.

[0124] In one embodiment, the crystalline glycolates provided herein comprise about one molar equivalent of the compound and about one molar equivalent of glycolic acid. In another embodiment, the crystalline glycolates provided herein comprise about one molar equivalent of the compound and about two molar equivalents of glycolic acid. In certain embodiments, the molar ratio of the compound to glycolic acid in the crystalline glycolates provided herein is determined by 1 1H NMR spectroscopy. In certain embodiments, the molar ratio of the compound to glycolic acid in the crystalline glycolates provided herein is determined by elemental analysis.

[0125] In certain embodiments, the crystalline glycolates provided herein have an X-ray powder diffraction pattern (top diffraction pattern) substantially as Figure 7 shown therein. In certain embodiments, the crystalline glycolates provided herein have an X-ray powder diffraction pattern (middle diffraction pattern) substantially as Figure 7 shown therein.

[0126] In certain embodiments, the crystalline glycolate provided herein has a DSC thermogram that includes an endothermic peak at about 107 °C. In certain embodiments, the crystalline glycolate provided herein has a DSC thermogram that includes an endothermic peak at 107 ± 3 °C. In certain embodiments, the crystalline glycolate provided herein has a DSC thermogram that includes an endothermic peak at about 168 °C. In certain embodiments, the crystalline glycolate provided herein has a DSC thermogram that includes an endothermic peak at 168 ± 3 °C. In certain embodiments, the crystalline glycolate provided herein has a DSC thermogram that includes an endothermic peak at about 190 °C. In certain embodiments, the crystalline glycolate provided herein has a DSC thermogram that includes an endothermic peak at 190 ± 3 °C. In certain embodiments, the crystalline glycolate provided herein has a DSC thermogram that includes an exothermic peak at about 134 °C. In certain embodiments, the crystalline glycolate provided herein has a DSC thermogram that includes an exothermic peak at 134 ± 3 °C. In certain embodiments, the crystalline glycolate provided herein has a DSC thermogram substantially as Figure 8 shown. In certain embodiments, the crystalline glycolate provided herein has a melting point of about 190 °C.

[0127] In certain embodiments, the crystalline glycolate provided herein has a TGA thermogram showing a weight loss of about 1.5% from room temperature to 150 °C. In certain embodiments, the crystalline glycolate provided herein has a TGA thermogram showing a weight loss of about 9% from 150 °C to 200 °C. In certain embodiments, the crystalline glycolate provided herein has a TGA thermogram substantially as Figure 8 shown.

[0128] In certain embodiments, the crystalline glycolate provided herein is solvated. In certain embodiments, the crystalline glycolate provided herein is an acetone solvate. In certain embodiments, the crystalline glycolate provided herein is a hydrate.

[0129] In yet another embodiment, provided herein is the crystalline lactate of (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine or an isotopic variant thereof; or a pharmaceutically acceptable solvate thereof.

[0130] In certain embodiments, the molar ratio of the compound to lactic acid in the crystalline lactate provided herein ranges from about 0.5 to about 3 or from about 0.5 to about 2.5. In certain embodiments, the molar ratio of the compound to lactic acid in the crystalline lactate provided herein is about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 1.1, about 1.2, about 1.4, about 1.5, about 1.6, about 1.8, about 2, about 2.2, about 2.4, about 2.6, about 2.8, or about 3. In certain embodiments, the molar ratio of the compound to lactic acid in the crystalline lactate provided herein is about 1. In certain embodiments, the molar ratio of the compound to lactic acid in the crystalline lactate provided herein is about 2.

[0131] In one embodiment, the crystalline lactate provided herein comprises about one molar equivalent of the compound and about one molar equivalent of lactic acid. In another embodiment, the crystalline lactate provided herein comprises about one molar equivalent of the compound and about two molar equivalents of lactic acid. In certain embodiments, the molar ratio of the compound to lactic acid in the crystalline lactate provided herein is determined by 1 1H NMR spectroscopy. In certain embodiments, the molar ratio of the compound to lactic acid in the crystalline lactate provided herein is determined by elemental analysis.

[0132] In certain embodiments, the crystalline lactate provided herein has an X-ray powder diffraction pattern (bottom diffraction pattern) substantially as shown in Figure 7 .

[0133] In certain embodiments, the crystalline lactate provided herein has a DSC thermogram comprising an endothermic peak at about 165 °C. In certain embodiments, the crystalline lactate provided herein has a DSC thermogram comprising an endothermic peak at 165 ± 3 °C. In certain embodiments, the crystalline lactate provided herein has a DSC thermogram comprising an endothermic peak at about 179 °C. In certain embodiments, the crystalline lactate provided herein has a DSC thermogram comprising an endothermic peak at 179 ± 3 °C. In certain embodiments, the crystalline lactate provided herein has a DSC thermogram substantially as shown in Figure 9 . In certain embodiments, the crystalline lactate provided herein has a melting point of about 179 °C.

[0134] In certain embodiments, the crystalline lactate provided herein has a TGA thermogram showing a weight loss of about 6% from room temperature to 150 °C. In certain embodiments, the crystalline lactate provided herein has a TGA thermogram showing a weight loss of about 8.5% from 150 °C to 180 °C. In certain embodiments, the crystalline lactate provided herein has a TGA thermogram substantially as shown in Figure 9 .

[0135] In certain embodiments, the crystalline lactates provided herein are solvated. In certain embodiments, the crystalline lactates provided herein are ethanol solvates. In certain embodiments, the crystalline lactates provided herein are hexane solvates. In certain embodiments, the crystalline lactates provided herein are hydrates.

[0136] In yet another embodiment, provided herein is (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine or a crystalline hippurate of an isotopic variant thereof; or a pharmaceutically acceptable solvate thereof.

[0137] In certain embodiments, the molar ratio of the compound to hippuric acid in the crystalline hippurates provided herein ranges from about 0.5 to about 3 or from about 0.5 to about 2.5. In certain embodiments, the molar ratio of the compound to hippuric acid in the crystalline hippurates provided herein is about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 1.1, about 1.2, about 1.4, about 1.5, about 1.6, about 1.8, about 2, about 2.2, about 2.4, about 2.6, about 2.8, or about 3. In certain embodiments, the molar ratio of the compound to hippuric acid in the crystalline hippurates provided herein is about 1. In certain embodiments, the molar ratio of the compound to hippuric acid in the crystalline hippurates provided herein is about 2.

[0138] In one embodiment, the crystalline hippurates provided herein comprise about one molar equivalent of the compound and about one molar equivalent of hippuric acid. In another embodiment, the crystalline hippurates provided herein comprise about one molar equivalent of the compound and about two molar equivalents of hippuric acid. In certain embodiments, the molar ratio of the compound to hippuric acid in the crystalline hippurates provided herein is determined by 1 1H NMR spectroscopy. In certain embodiments, the molar ratio of the compound to hippuric acid in the crystalline hippurates provided herein is determined by elemental analysis.

[0139] In certain embodiments, the crystalline hippurates provided herein have an X-ray powder diffraction pattern (top diffraction pattern) substantially as shown in Figure 10 In certain embodiments, the crystalline hippurates provided herein have an X-ray powder diffraction pattern (middle diffraction pattern) substantially as shown in Figure 10 In certain embodiments, the crystalline hippurates provided herein have an X-ray powder diffraction pattern (bottom diffraction pattern) substantially as shown in

[0140] In certain embodiments, the crystalline hippurate provided herein has a DSC thermogram with an endothermic peak at about 83 °C. In certain embodiments, the crystalline hippurate provided herein has a DSC thermogram with an endothermic peak at 83 ± 3 °C. In certain embodiments, the crystalline hippurate provided herein has a DSC thermogram with an endothermic peak at about 176 °C. In certain embodiments, the crystalline hippurate provided herein has a DSC thermogram with an endothermic peak at 176 ± 3 °C. In certain embodiments, the crystalline hippurate provided herein has a DSC thermogram substantially as Figure 11 shown. In certain embodiments, the crystalline hippurate provided herein has a melting point of about 176 °C.

[0141] In certain embodiments, the crystalline hippurate provided herein has a TGA thermogram showing a weight loss of about 5% from room temperature to 100 °C. In certain embodiments, the crystalline hippurate provided herein has a TGA thermogram showing a weight loss of about 1% from 100 °C to 180 °C. In certain embodiments, the crystalline hippurate provided herein has a TGA thermogram substantially as Figure 11 shown.

[0142] In certain embodiments, the crystalline hippurate provided herein is solvated. In certain embodiments, the crystalline hippurate provided herein is an ethanol solvate. In certain embodiments, the crystalline hippurate provided herein is a hexane solvate. In certain embodiments, the crystalline hippurate provided herein is a hydrate.

[0143] In yet another embodiment, provided herein is the crystalline maleate of (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine or an isotopic variant thereof; or a pharmaceutically acceptable solvate thereof.

[0144] In certain embodiments, the molar ratio of the compound to maleic acid in the crystalline maleate provided herein ranges from about 0.25 to about 1.5 or from about 0.5 to about 1. In certain embodiments, the molar ratio of the compound to maleic acid in the crystalline maleate provided herein is about 0.25, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 1.1, about 1.2, about 1.3, about 1.4, or about 1.5. In certain embodiments, the molar ratio of the compound to maleic acid in the crystalline maleate provided herein is about 0.5. In certain embodiments, the molar ratio of the compound to maleic acid in the crystalline maleate provided herein is about 1.

[0145] In one embodiment, the crystalline maleate provided herein comprises about two molar equivalents of a compound and about one molar equivalent of maleic acid. In another embodiment, the crystalline maleate provided herein comprises about one molar equivalent of a compound and about one molar equivalent of maleic acid. In certain embodiments, the molar ratio of the compound to maleic acid in the crystalline maleate provided herein is determined by 1 1H NMR spectroscopy. In certain embodiments, the molar ratio of the compound to maleic acid in the crystalline maleate provided herein is determined by elemental analysis.

[0146] In certain embodiments, the crystalline maleate provided herein has an X-ray powder diffraction pattern (bottom diffraction pattern) substantially as shown in Figure 10 .

[0147] In certain embodiments, the crystalline maleate provided herein has a DSC thermogram that includes an endothermic peak at about 189 °C. In certain embodiments, the crystalline maleate provided herein has a DSC thermogram that includes an endothermic peak at 189 ± 3 °C. In certain embodiments, the crystalline maleate provided herein has a DSC thermogram substantially as shown in Figure 12 .

[0148] In certain embodiments, the crystalline maleate provided herein has a TGA thermogram showing a weight loss of about 1.5% from room temperature to 150 °C. In certain embodiments, the crystalline maleate provided herein has a TGA thermogram showing a weight loss of about 6% from 150 °C to 200 °C. In certain embodiments, the crystalline maleate provided herein has a TGA thermogram substantially as shown in Figure 12 .

[0149] In certain embodiments, the crystalline maleate provided herein is solvated. In certain embodiments, the crystalline maleate provided herein is an ethanol solvate. In certain embodiments, the crystalline maleate provided herein is a hexane solvate. In certain embodiments, the crystalline maleate provided herein is a hydrate.

[0150] In yet another embodiment, provided herein is the crystalline malate of (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine or an isotopic variant thereof; or a pharmaceutically acceptable solvate thereof.

[0151] In certain embodiments, the molar ratio of the compound to malic acid in the crystalline malate salt provided herein ranges from about 0.25 to about 1.5 or from about 0.5 to about 1. In certain embodiments, the molar ratio of the compound to malic acid in the crystalline malate salt provided herein is about 0.25, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 1.1, about 1.2, about 1.3, about 1.4, or about 1.5. In certain embodiments, the molar ratio of the compound to malic acid in the crystalline malate salt provided herein is about 0.5. In certain embodiments, the molar ratio of the compound to malic acid in the crystalline malate salt provided herein is about 1.

[0152] In one embodiment, the crystalline malate salt provided herein comprises about two molar equivalents of the compound and about one molar equivalent of malic acid. In another embodiment, the crystalline malate salt provided herein comprises about one molar equivalent of the compound and about one molar equivalent of malic acid. In certain embodiments, the molar ratio of the compound to malic acid in the crystalline malate salt provided herein is determined by 1 1H NMR spectroscopy. In certain embodiments, the molar ratio of the compound to malic acid in the crystalline malate salt provided herein is determined by elemental analysis.

[0153] In certain embodiments, the crystalline malate salt provided herein has an X-ray powder diffraction pattern (top diffraction pattern) substantially as shown in Figure 13 . In certain embodiments, the crystalline malate salt provided herein has an X-ray powder diffraction pattern (middle diffraction pattern) substantially as shown in Figure 13 . In certain embodiments, the crystalline malate salt provided herein has an X-ray powder diffraction pattern (bottom diffraction pattern) substantially as shown in Figure 13 .

[0154] In certain embodiments, the crystalline malate salt provided herein has a DSC thermogram comprising an endothermic peak at about 153 °C. In certain embodiments, the crystalline malate salt provided herein has a DSC thermogram comprising an endothermic peak at 153 ± 3 °C. In certain embodiments, the crystalline malate salt provided herein has a DSC thermogram substantially as shown in Figure 14 . In certain embodiments, the crystalline malate salt provided herein has a melting point of about 153 °C.

[0155] In certain embodiments, the crystalline malate salt provided herein has a TGA thermogram showing a weight loss of about 0.3% from room temperature to 160 °C. In certain embodiments, the crystalline malate salt provided herein has a TGA thermogram substantially as shown in Figure 14 .

[0156] In certain embodiments, the crystalline malate salt provided herein is unsolvated.

[0157] In yet another embodiment, provided herein is (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine or a crystalline methanesulfonate of an isotopic variant thereof; or a pharmaceutically acceptable solvate thereof. As used herein, the term "methanesulfonate" is used interchangeably with the term "mesylate".

[0158] In certain embodiments, the molar ratio of the compound to methanesulfonic acid in the crystalline methanesulfonate provided herein ranges from about 0.5 to about 3 or from about 0.5 to about 2.5. In certain embodiments, the molar ratio of the compound to methanesulfonic acid in the crystalline methanesulfonate provided herein is about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 1.1, about 1.2, about 1.4, about 1.5, about 1.6, about 1.8, about 2, about 2.2, about 2.4, about 2.6, about 2.8, or about 3. In certain embodiments, the molar ratio of the compound to methanesulfonic acid in the crystalline methanesulfonate provided herein is about 1. In certain embodiments, the molar ratio of the compound to methanesulfonic acid in the crystalline methanesulfonate provided herein is about 2.

[0159] In one embodiment, the crystalline methanesulfonate provided herein comprises about one molar equivalent of the compound and about one molar equivalent of methanesulfonic acid. In another embodiment, the crystalline methanesulfonate provided herein comprises about one molar equivalent of the compound and about two molar equivalents of methanesulfonic acid. In certain embodiments, the molar ratio of the compound to methanesulfonic acid in the crystalline methanesulfonate provided herein is determined by 1 1H NMR spectroscopy. In certain embodiments, the molar ratio of the compound to methanesulfonic acid in the crystalline methanesulfonate provided herein is determined by elemental analysis.

[0160] In certain embodiments, the crystalline methanesulfonate provided herein has an X-ray powder diffraction pattern (top diffraction pattern) substantially as shown in Figure 15 the figure.

[0161] In certain embodiments, the crystalline methanesulfonate provided herein has a DSC thermogram that includes an endothermic peak at about 200 °C. In certain embodiments, the crystalline methanesulfonate provided herein has a DSC thermogram that includes an endothermic peak at 200 ± 3 °C. In certain embodiments, the crystalline methanesulfonate provided herein has a DSC thermogram substantially as shown in Figure 16 the figure.

[0162] In certain embodiments, the crystalline mesylate salts provided herein have a TGA thermogram showing a weight loss of about 1.2% from room temperature to 150 °C. In certain embodiments, the crystalline mesylate salts provided herein have a TGA thermogram showing a weight loss of about 5.5% from 150 °C to 210 °C. In certain embodiments, the crystalline mesylate salts provided herein have a TGA thermogram substantially as Figure 16 shown therein.

[0163] In certain embodiments, the crystalline mesylate salts provided herein are not solvated.

[0164] In yet another embodiment, there is provided herein a crystalline succinate salt of (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine or an isotopic variant thereof; or a pharmaceutically acceptable solvate thereof.

[0165] In certain embodiments, the molar ratio of the compound to succinic acid in the crystalline succinate salts provided herein ranges from about 0.25 to about 1.5 or from about 0.5 to about 1. In certain embodiments, the molar ratio of the compound to succinic acid in the crystalline succinate salts provided herein is about 0.25, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 1.1, about 1.2, about 1.3, about 1.4, or about 1.5. In certain embodiments, the molar ratio of the compound to succinic acid in the crystalline succinate salts provided herein is about 0.5. In certain embodiments, the molar ratio of the compound to succinic acid in the crystalline succinate salts provided herein is about 1.

[0166] In one embodiment, the crystalline succinate salts provided herein contain about two molar equivalents of the compound and about one molar equivalent of succinic acid. In another embodiment, the crystalline succinate salts provided herein contain about one molar equivalent of the compound and about one molar equivalent of succinic acid. In certain embodiments, the molar ratio of the compound to succinic acid in the crystalline succinate salts provided herein is determined by 1 1H NMR spectroscopy. In certain embodiments, the molar ratio of the compound to succinic acid in the crystalline succinate salts provided herein is determined by elemental analysis.

[0167] In certain embodiments, the crystalline succinate salts provided herein have an X-ray powder diffraction pattern (middle diffraction pattern) substantially as Figure 15 shown therein. In certain embodiments, the crystalline succinate salts provided herein have an X-ray powder diffraction pattern (bottom diffraction pattern) substantially as Figure 15 shown therein.

[0168] In certain embodiments, the crystalline succinate provided herein has a DSC thermogram that includes an endothermic peak at about 73 °C. In certain embodiments, the crystalline succinate provided herein has a DSC thermogram that includes an endothermic peak at 73 ± 3 °C. In certain embodiments, the crystalline succinate provided herein has a DSC thermogram that includes an endothermic peak at about 125 °C. In certain embodiments, the crystalline succinate provided herein has a DSC thermogram that includes an endothermic peak at 125 ± 3 °C. In certain embodiments, the crystalline succinate provided herein has a DSC thermogram substantially as Figure 17 shown therein.

[0169] In certain embodiments, the crystalline succinate provided herein has a TGA thermogram that shows a weight loss of about 2.5% from room temperature to 125 °C. In certain embodiments, the crystalline succinate provided herein has a TGA thermogram substantially as Figure 17 shown therein.

[0170] In certain embodiments, the crystalline succinate provided herein is solvated. In certain embodiments, the crystalline succinate provided herein is an acetone solvate. In certain embodiments, the crystalline succinate provided herein is a hydrate.

[0171] In yet another embodiment, provided herein is a crystalline sulfate of (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine or an isotopic variant thereof; or a pharmaceutically acceptable solvate thereof.

[0172] In certain embodiments, the molar ratio of the compound to sulfuric acid in the crystalline sulfate provided herein ranges from 0.25 to about 1.5 or from about 0.5 to about 1. In certain embodiments, the molar ratio of the compound to sulfuric acid in the crystalline sulfate provided herein is about 0.25, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 1.1, about 1.2, about 1.3, about 1.4, or about 1.5. In certain embodiments, the molar ratio of the compound to sulfuric acid in the crystalline sulfate provided herein is about 0.5. In certain embodiments, the molar ratio of the compound to sulfuric acid in the crystalline sulfate provided herein is about 1.

[0173] In one embodiment, the crystalline sulfate provided herein contains about two molar equivalents of the compound and about one molar equivalent of sulfuric acid. In another embodiment, the crystalline sulfate provided herein contains about one molar equivalent of the compound and about one molar equivalent of sulfuric acid. In certain embodiments, the molar ratio of the compound to sulfuric acid in the crystalline sulfate provided herein is determined by elemental analysis.

[0174] In certain embodiments, the crystalline sulfate provided herein has an X-ray powder diffraction pattern (top diffraction pattern) substantially as shown in Figure 18 .

[0175] In certain embodiments, the crystalline sulfate provided herein has a DSC thermogram that includes an endothermic peak at about 103 °C. In certain embodiments, the crystalline sulfate provided herein has a DSC thermogram that includes an endothermic peak at 103 ± 3 °C. In certain embodiments, the crystalline sulfate provided herein has a DSC thermogram that includes an endothermic peak at about 152 °C. In certain embodiments, the crystalline sulfate provided herein has a DSC thermogram that includes an endothermic peak at 152 ± 3 °C. In certain embodiments, the crystalline sulfate provided herein has a DSC thermogram that includes an endothermic peak at about 183 °C. In certain embodiments, the crystalline sulfate provided herein has a DSC thermogram that includes an endothermic peak at 183 ± 3 °C. In certain embodiments, the crystalline sulfate provided herein has a DSC thermogram substantially as shown in Figure 19 .

[0176] In certain embodiments, the crystalline sulfate provided herein has a TGA thermogram that shows a weight loss of about 3.5% from room temperature to 200 °C. In certain embodiments, the crystalline sulfate provided herein has a TGA thermogram substantially as shown in Figure 19 .

[0177] In certain embodiments, the crystalline sulfate provided herein is solvated. In certain embodiments, the crystalline sulfate provided herein is an acetone solvate. In certain embodiments, the crystalline sulfate provided herein is a hydrate.

[0178] In yet another embodiment, the present disclosure provides a crystalline tartrate of (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine or an isotopic variant thereof; or a pharmaceutically acceptable solvate thereof.

[0179] In certain embodiments, the molar ratio of the compound to tartaric acid in the crystalline tartrate provided herein ranges from about 0.25 to about 1.5 or from about 0.5 to about 1. In certain embodiments, the molar ratio of the compound to tartaric acid in the crystalline tartrate provided herein is about 0.25, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 1.1, about 1.2, about 1.3, about 1.4, or about 1.5. In certain embodiments, the molar ratio of the compound to tartaric acid in the crystalline tartrate provided herein is about 0.5. In certain embodiments, the molar ratio of the compound to tartaric acid in the crystalline tartrate provided herein is about 1.

[0180] In one embodiment, the crystalline tartrate provided herein comprises about two molar equivalents of a compound and about one molar equivalent of tartaric acid. In another embodiment, the crystalline tartrate provided herein comprises about one molar equivalent of a compound and about one molar equivalent of tartaric acid. In certain embodiments, the molar ratio of the compound to tartaric acid in the crystalline tartrate provided herein is determined by 1 1H NMR spectroscopy. In certain embodiments, the molar ratio of the compound to tartaric acid in the crystalline tartrate provided herein is determined by elemental analysis.

[0181] In certain embodiments, the crystalline tartrate provided herein has an X-ray powder diffraction pattern (bottom diffraction pattern) substantially as shown in Figure 18 .

[0182] In certain embodiments, the crystalline tartrate provided herein has a DSC thermogram that includes an endothermic peak at about 79 °C. In certain embodiments, the crystalline tartrate provided herein has a DSC thermogram that includes an endothermic peak at 79 ± 3 °C. In certain embodiments, the crystalline tartrate provided herein has a DSC thermogram that includes an endothermic peak at about 152 °C. In certain embodiments, the crystalline tartrate provided herein has a DSC thermogram that includes an endothermic peak at 152 ± 3 °C. In certain embodiments, the crystalline tartrate provided herein has a DSC thermogram substantially as shown in Figure 20 . In certain embodiments, the crystalline tartrate provided herein has a melting point of about 152 °C.

[0183] In certain embodiments, the crystalline tartrate provided herein has a TGA thermogram that shows a weight loss of about 0.2% from room temperature to 150 °C. In certain embodiments, the crystalline tartrate provided herein has a TGA thermogram substantially as shown in Figure 20 .

[0184] In certain embodiments, the crystalline tartrate provided herein is solvated. In certain embodiments, the crystalline tartrate provided herein is an acetone solvate. In certain embodiments, the crystalline tartrate provided herein is a hydrate.

[0185] In yet another embodiment, provided herein is a crystalline thiocyanate of (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine or an isotopic variant thereof; or a pharmaceutically acceptable solvate thereof.

[0186] In certain embodiments, the molar ratio of the compound to thiocyanic acid in the crystalline thiocyanate provided herein ranges from about 0.5 to about 3 or from about 0.5 to about 2.5. In certain embodiments, the molar ratio of the compound to thiocyanic acid in the crystalline thiocyanate provided herein is about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 1.1, about 1.2, about 1.4, about 1.5, about 1.6, about 1.8, about 2, about 2.2, about 2.4, about 2.6, about 2.8, or about 3. In certain embodiments, the molar ratio of the compound to thiocyanic acid in the crystalline thiocyanate provided herein is about 1. In certain embodiments, the molar ratio of the compound to thiocyanic acid in the crystalline thiocyanate provided herein is about 2.

[0187] In one embodiment, the crystalline thiocyanate provided herein comprises about one molar equivalent of the compound and about one molar equivalent of thiocyanic acid. In another embodiment, the crystalline thiocyanate provided herein comprises about one molar equivalent of the compound and about two molar equivalents of thiocyanic acid. In certain embodiments, the molar ratio of the compound to thiocyanic acid in the crystalline thiocyanate provided herein is determined by 1 1H NMR spectroscopy. In certain embodiments, the molar ratio of the compound to thiocyanic acid in the crystalline thiocyanate provided herein is determined by elemental analysis.

[0188] In certain embodiments, the crystalline thiocyanate provided herein has an X-ray powder diffraction pattern (top diffraction pattern) substantially as shown in Figure 21 .

[0189] In certain embodiments, the crystalline thiocyanate provided herein has a DSC thermogram that includes an endothermic peak at about 118 °C. In certain embodiments, the crystalline thiocyanate provided herein has a DSC thermogram that includes an endothermic peak at 118 ± 3 °C. In certain embodiments, the crystalline thiocyanate provided herein has a DSC thermogram that includes an endothermic peak at about 225 °C. In certain embodiments, the crystalline thiocyanate provided herein has a DSC thermogram that includes an endothermic peak at 225 ± 3 °C. In certain embodiments, the crystalline thiocyanate provided herein has a DSC thermogram that includes an exothermic peak at about 158 °C. In certain embodiments, the crystalline thiocyanate provided herein has a DSC thermogram that includes an exothermic peak at 158 ± 3 °C. In certain embodiments, the crystalline thiocyanate provided herein has a DSC thermogram substantially as shown in Figure 22 . In certain embodiments, the crystalline thiocyanate provided herein has a melting point of about 224 °C.

[0190] In certain embodiments, the crystalline thiocyanate provided herein has a TGA thermogram showing a weight loss of about 4.5% from room temperature to 190 °C. In certain embodiments, the crystalline thiocyanate provided herein has a TGA thermogram showing a weight loss of about 4.5% from 190 °C to 230 °C. In certain embodiments, the crystalline thiocyanate provided herein has a TGA thermogram substantially as Figure 22 shown in

[0191] In certain embodiments, the crystalline thiocyanate provided herein is solvated. In certain embodiments, the crystalline thiocyanate provided herein is an ethanol solvate. In certain embodiments, the crystalline thiocyanate provided herein is a hexane solvate. In certain embodiments, the crystalline thiocyanate provided herein is a hydrate.

[0192] In yet another embodiment, provided herein is a crystalline p-toluenesulfonate of (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine or an isotopic variant thereof; or a pharmaceutically acceptable solvate thereof. As used herein, the term "p-toluenesulfonate" is used interchangeably with the term "tosylate".

[0193] In one embodiment, the crystalline toluenesulfonate provided herein comprises (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine and p-toluenesulfonic acid.

[0194] In certain embodiments, the molar ratio of the compound to p-toluenesulfonic acid in the crystalline toluenesulfonate provided herein ranges from about 0.5 to about 3 or from about 0.5 to about 2.5. In certain embodiments, the molar ratio of the compound to p-toluenesulfonic acid in the crystalline toluenesulfonate provided herein is about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 1.1, about 1.2, about 1.4, about 1.5, about 1.6, about 1.8, about 2, about 2.2, about 2.4, about 2.6, about 2.8, or about 3. In certain embodiments, the molar ratio of the compound to p-toluenesulfonic acid in the crystalline toluenesulfonate provided herein is about 1. In certain embodiments, the molar ratio of the compound to p-toluenesulfonic acid in the crystalline toluenesulfonate provided herein is about 2.

[0195] In one embodiment, the crystalline tosylate provided herein comprises about one molar equivalent of a compound and about one molar equivalent of p-toluenesulfonic acid. In another embodiment, the crystalline tosylate provided herein comprises about one molar equivalent of a compound and about two molar equivalents of p-toluenesulfonic acid. In certain embodiments, the molar ratio of the compound to p-toluenesulfonic acid in the crystalline tosylate provided herein is determined by 1 1H NMR spectroscopy. In certain embodiments, the molar ratio of the compound to p-toluenesulfonic acid in the crystalline tosylate provided herein is determined by elemental analysis.

[0196] In certain embodiments, the crystalline tosylate provided herein has an X-ray powder diffraction pattern comprising peaks at 2θ angles (°) of approximately 5.5, 7.6, and 21.9. In certain embodiments, the crystalline tosylate provided herein has an X-ray powder diffraction pattern comprising peaks at 2θ angles (°) of approximately 5.5, 7.6, 12.9, 17.3, 21.9, 22.3, 22.5, and 23.8. In certain embodiments, the crystalline tosylate provided herein has an X-ray powder diffraction pattern comprising peaks at 2θ angles (°) of approximately 5.5, 7.6, 12.9, 14.9, 16.2, 17.3, 18.4, 18.6, 21.5, 21.9, 22.3, 22.5, 23.4, 23.8, 24.1, 26.2, 26.9, 27.0, and 28.8. In certain embodiments, the crystalline tosylate provided herein has an X-ray powder diffraction pattern comprising peaks at 2θ angles (°) of approximately 5.5, 6.1, 7.6, 12.9, 14.9, 16.2, 17.3, 18.4, 18.6, 21.5, 21.9, 22.3, 22.5, 23.4, 23.8, 24.1, 26.2, 26.9, 27.0, and 28.8. In certain embodiments, the crystalline tosylate provided herein has an X-ray powder diffraction pattern substantially as Figure 34 shown therein.

[0197] In certain embodiments, the crystalline tosylate provided herein has a DSC thermogram comprising an endothermic peak at about 228 °C. In certain embodiments, the crystalline tosylate provided herein has a DSC thermogram comprising an endothermic peak at 228 ± 3 °C. In certain embodiments, the crystalline tosylate provided herein has a DSC thermogram substantially as Figure 35 shown therein.

[0198] In certain embodiments, the crystalline tosylate has a DVS isotherm substantially as Figure 36 shown therein. In certain embodiments, the crystalline tosylate provided herein is non-hygroscopic.

[0199] In certain embodiments, the crystalline tosylate salts provided herein have a weight gain of no more than 5%, no more than 4%, no more than 3%, no more than 2%, or no more than 1% from 5% to 95% relative humidity (RH) at 25 °C. In certain embodiments, the crystalline tosylate salts provided herein have a weight gain of no more than 5% from 5% to 95% RH at 25 °C. In certain embodiments, the crystalline tosylate salts provided herein have a weight gain of no more than 4% from 5% to 95% RH at 25 °C. In certain embodiments, the crystalline tosylate salts provided herein have a weight gain of no more than 3% from 5% to 95% RH at 25 °C. In certain embodiments, the crystalline tosylate salts provided herein have a weight gain of no more than 2% from 5% to 95% RH at 25 °C. In certain embodiments, the crystalline tosylate salts provided herein have a weight gain of no more than 1% from 5% to 95% RH at 25 °C.

[0200] In certain embodiments, the crystalline tosylate salts provided herein are unsolvated. In certain embodiments, the crystalline tosylate salts have a solubility in water of about 2 mg / mL at 25 °C.

[0201] The purity of the salts provided herein can be determined by standard analytical methods such as elemental analysis, thin layer chromatography (TLC), gel electrophoresis, gas chromatography, high performance liquid chromatography (HPLC), and mass spectrometry (MS). The salts provided herein in solid form can be characterized using a variety of methods known to those skilled in the art, including but not limited to single crystal X-ray diffraction, X-ray powder diffraction (XRPD), microscopy (such as scanning electron microscopy (SEM)), thermal analysis (such as differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and hot stage microscopy), dynamic vapor sorption, and spectroscopy (such as infrared, Raman, and solid state nuclear magnetic resonance). The particle size and particle size distribution of the salts provided herein in solid form can be determined by conventional methods such as laser scattering techniques.

[0202] It should be understood that the numerical values of the peaks in the X-ray powder diffraction pattern may vary slightly between different machines or between different samples, and thus the cited values should not be considered absolute but allow for some variability, such as 0.1° (as recommended by the United States Pharmacopeia (pages 387 - 389, 2007)).

[0203] Preparation method

[0204] In one embodiment, there is provided herein a process for preparing (1r,4r)-N 1-A method for preparing a non-hygroscopic crystalline salt or a pharmaceutically acceptable solvate of (5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine or an isotopic variant thereof, the method comprising reacting a compound in free base form or an isotopic variant thereof with an acid in a solvent at a first predetermined temperature. In another embodiment, the method further comprises precipitating the salt at a second predetermined temperature. In certain embodiments, the reaction and / or precipitation steps are carried out under an inert atmosphere. In certain embodiments, the reaction and / or precipitation steps are carried out under a nitrogen or argon atmosphere.

[0205] Solvents suitable for use in preparing the salts provided herein include, but are not limited to, hydrocarbons including petroleum ether, pentane, hexane, heptane, octane, isooctane, cyclopentane, cyclohexane, methylcyclohexane, benzene, toluene, xylene, indane, and cumene; halogenated hydrocarbons including dichloromethane (DCM), 1,2-dichloroethane, 1,1-dichloroethylene, 1,2-dichloroethylene, chloroform, trichloroethane, trichloroethylene, carbon tetrachloride, perfluoroethylene, chlorobenzene, and benzotrifluoride; alcohols including methanol (MeOH), ethanol (EtOH), trifluoroethanol (TFE), isopropanol (IPA), 1-propanol, hexafluoroisopropanol (HFTPA), 1-butanol, 2-butanol, tert-butanol, 2-methyl-1-propanol, 3-methyl-1-butanol, 1-pentanol, tert-pentanol, 2-methoxyethanol, 2-ethoxyethanol, and ethylene glycol; ethers including diethyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), methyl nonafluorobutyl ether, diphenyl ether, 1,2-dimethoxyethane, bis(2-methoxyethyl) ether, 1,1-dimethoxymethane, 2,2-dimethoxypropane, and anisole; ketones including acetone, butanone, methyl ethyl ketone (MEK), methyl isopropyl ketone, methyl butyl ketone, methyl isobutyl ketone (MIBK), 3-pentanone, and cyclopentanone; esters including methyl acetate, ethyl formate, ethyl acetate (EtOAc), ethyl trifluoroacetate, propyl acetate, isopropyl acetate (IPAC), isobutyl acetate, and butyl acetate; carbonates including ethylene carbonate and propylene carbonate; amides including formamide, N,N-dimethylformamide (DMF), and N,N-dimethylacetamide; nitriles including acetonitrile (ACN) and propionitrile; sulfoxides including dimethyl sulfoxide (DMSO); sulfones including sulfolane; nitro compounds including nitromethane and nitrobenzene; heterocycles including N-methylpyrrolidone, 2-methyltetrahydrofuran, tetrahydrofuran (THF), dioxane, and pyridine; carboxylic acids including acetic acid, trichloroacetic acid, and trifluoroacetic acid; phosphoramides including hexamethylphosphoramide; carbon disulfide; water; and mixtures thereof.

[0206] In certain embodiments, the solvent is acetone, ethanol, methanol, hexane, water, or a mixture thereof. In certain embodiments, the solvent is methanol or acetone.

[0207] In certain embodiments, the step of forming the salt is carried out at a temperature of from about -10 °C to about 150 °C, from about 0 °C to about 100 °C, from about 10 °C to about 100 °C, or from about 25 °C to about 55 °C. In certain embodiments, the step of forming the salt is carried out at a temperature of from about 25 °C to about 55 °C. In one embodiment, the solvent used in the step of forming the salt is acetone, ethanol, methanol, hexane, water, or a mixture thereof. In another embodiment, the solvent used in the step of forming the salt is methanol.

[0208] In certain embodiments, the step of forming the salt is carried out in the presence of about half an equivalent of acid. In certain embodiments, the step of forming the salt is carried out in the presence of about one equivalent of acid. In certain embodiments, the step of forming the salt is carried out in the presence of about two equivalents of acid.

[0209] In certain embodiments, the step of forming the salt is carried out in solution, i.e., both the compound and the acid are dissolved in the solvent. In certain embodiments, the step of forming the salt is carried out with a slurry mixture of the compound and the acid in the solvent.

[0210] In certain embodiments, conventional methods are used, including but not limited to cooling, quenching, solvent evaporation, addition of an antisolvent, or reverse addition of a salt mixture to an antisolvent, to precipitate the salts provided herein from the reaction solution or slurry mixture. In certain embodiments, the salts provided herein are precipitated from the reaction solution or slurry mixture upon cooling.

[0211] In certain embodiments, the salts provided herein are precipitated from the reaction solution or slurry mixture by addition of an antisolvent. Suitable antisolvents include but are not limited to hydrocarbons, including petroleum ether, pentane, hexane, heptane, octane, isooctane, cyclopentane, cyclohexane, methylcyclohexane, benzene, toluene, xylene, tetralin, and cumene; halogenated hydrocarbons, including 1,2-dichloroethane, 1,1-dichloroethylene, 1,2-dichloroethylene, chloroform, trichloroethane, trichloroethylene, carbon tetrachloride, perfluoroethylene, chlorobenzene, and benzotrifluoride; alcohols, including 1-butanol, 2-butanol, tert-butanol, 2-methyl-1-propanol, 3-methyl-1-butanol, 1-pentanol, tert-pentanol, 2-methoxyethanol, 2-ethoxyethanol, and ethylene glycol; ethers, including diethyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), methyl nonafluorobutyl ether, diphenyl ether, 1,2-dimethoxyethane, bis(2-methoxyethyl) ether, 1,1-dimethoxymethane, 2,2-dimethoxypropane, and anisole; ketones, including methyl ethyl ketone, methyl isopropyl ketone, methyl butyl ketone, methyl isobutyl ketone (MIBK), 3-pentanone, and cyclopentanone; esters, including isobutyl acetate and butyl acetate; carbonates, including ethylene carbonate and propylene carbonate; sulfones, including sulfolane; nitro compounds, including nitromethane and nitrobenzene; heterocycles, including dioxane and pyridine; carbon disulfide; water; and mixtures thereof.

[0212] When two solvents are used as a solvent / antisolvent pair, the salts provided herein have a higher solubility in the solvent than in the antisolvent. In certain embodiments, the solvent and antisolvent in the solvent / antisolvent pair are at least partially miscible.

[0213] In certain embodiments, the precipitation step is carried out at a temperature of from about -50 °C to about 100 °C, from about 0 °C to about 100 °C, from about 10 °C to about 50 °C, from about 20 °C to about 40 °C or from about 25 °C to about 35 °C. In certain embodiments, the precipitation step is carried out at a temperature of from about 25 °C to about 35 °C.

[0214] To accelerate the precipitation (crystallization) step, the method may further comprise the step of seeding the reaction solution or mixture before or during the start of the precipitation step. The amount of seed added exceeds the saturation amount in the solvent used so that undissolved seeds are present in the reaction solution.

[0215] In certain embodiments, the method further comprises a separation step, wherein the precipitate is separated by conventional methods such as filtration and centrifugation, then washed with a solvent and then dried.

[0216] Pharmaceutical composition

[0217] In one embodiment, there is provided a pharmaceutical composition comprising a non-hygroscopic crystalline salt provided herein and a pharmaceutically acceptable excipient.

[0218] In one embodiment, the pharmaceutical composition provided herein is formulated into a dosage form for oral administration.

[0219] In another embodiment, the pharmaceutical composition provided herein is formulated into a dosage form for parenteral administration. In one embodiment, the pharmaceutical composition provided herein is formulated into a dosage form for intravenous administration. In another embodiment, the pharmaceutical composition provided herein is formulated into a dosage form for intramuscular administration. In yet another embodiment, the pharmaceutical composition provided herein is formulated into a dosage form for subcutaneous administration.

[0220] In yet another embodiment, the pharmaceutical composition provided herein is formulated into a dosage form for topical administration.

[0221] The pharmaceutical compositions provided herein can be formulated into a variety of dosage forms for oral, parenteral, and topical administration. The pharmaceutical compositions can also be formulated into modified-release dosage forms, including delayed, extended, prolonged, sustained, pulsed, controlled, accelerated, rapid, targeted, programmed release dosage forms, and gastric retention dosage forms. These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (see Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Delivery Technology, 2nd Edition, edited by Rathbone et al., Marcel Dekker, Inc.: New York, NY, 2008).

[0222] The pharmaceutical compositions provided herein can be provided in unit dosage form or multiple-dosage form. As used herein, a unit dosage form refers to a physically discrete unit suitable for administration to human and animal subjects and individually packaged as known in the art. Each unit dose contains a predetermined quantity of the active ingredient sufficient to produce the desired therapeutic effect, as well as the required pharmaceutical carrier or excipient. Examples of unit dosage forms include ampoules, syringes, and individually packaged tablets and capsules. Unit dosage forms can be administered in their fractional or multiple amounts. A multiple-dosage form is a plurality of identical unit dosage forms packaged in a single container and administered in separate unit dosage forms. Examples of multiple-dosage forms include vials, whole bottles of tablets or capsules, or whole bottles of pints or gallons.

[0223] The pharmaceutical compositions provided herein can be administered immediately or in multiple doses at intervals. It will be understood that the precise dosage and duration of treatment will vary with the age, weight, and condition of the patient being treated and can be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro testing or diagnostic data. It is further understood that for any particular individual, the specific dosing regimen should be adjusted over time according to the individual's needs and the professional judgment of the person administering or supervising the administration of the formulation.

[0224] A. Oral administration

[0225] The pharmaceutical compositions provided herein for oral administration can be provided in solid, semi-solid or liquid dosage forms for oral administration. As used herein, oral administration also includes buccal, sublingual and lingual administration. Suitable oral dosage forms include, but are not limited to, tablets, fastmelt tablets, chewable tablets, capsules, pills, strips, lozenges, troches, cachets, pellets, medicated gums, unit-dose powders, effervescent or non-effervescent powders or granules, oral sprays, solutions, emulsions, suspensions, cachets, sprinkles, elixirs and syrups. In addition to the active ingredient, the pharmaceutical composition may also contain one or more pharmaceutically acceptable carriers or excipients, including but not limited to binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, colorants, dye migration inhibitors, sweeteners, flavoring agents, emulsifying agents, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids and carbon dioxide sources.

[0226] Binders or granulators impart cohesiveness to tablets to ensure that the tablets remain intact after compression. Suitable binders or granulating agents include, but are not limited to, starches such as corn starch, potato starch, and pregelatinized starch (e.g., STARCH 1600); gelatin; sugars such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums such as gum arabic, alginic acid, alginates, Irish moss extract, panwar gum, ghatti gum, mucilage of isabgol husk, carboxymethyl cellulose, methyl cellulose, polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, tragacanth powder, and guar gum; celluloses such as ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC); microcrystalline celluloses such as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-681, AVICEL-PH-106 (FMC Corporation, Marcus Hook, PA); and mixtures thereof. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrate, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. The amount of binder or filler in the pharmaceutical compositions provided herein can vary with the type of formulation and is readily discernible to one of ordinary skill in the art. The binder or filler is present in the pharmaceutical compositions provided herein in an amount of about 60% to about 99% by weight.

[0227] Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar. Certain diluents such as mannitol, lactose, sorbitol, sucrose, and inositol, when present in sufficient amounts, can impart certain properties to some compressed tablets to permit disintegration in the mouth by chewing. Such compressed tablets can be used as chewable tablets. The amount of diluent in the pharmaceutical compositions provided herein can vary with the type of formulation and is readily discernible to one of ordinary skill in the art.

[0228] Suitable disintegrants include, but are not limited to, agar; bentonite; cellulose, such as methylcellulose and carboxymethylcellulose; wood products; natural sponges; cation exchange resins; alginic acid; gums, such as guar gum and Veegum HV; citrus pulp; cross-linked cellulose, such as cross-linked carboxymethylcellulose; cross-linked polymers, such as cross-linked povidone; cross-linked starch; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; polacrilin potassium; starch, such as corn starch, potato starch, tapioca starch and pregelatinized starch; clay; alginate; and mixtures thereof. The amount of disintegrant in the pharmaceutical compositions provided herein can vary with the type of formulation and is readily discernible to one of ordinary skill in the art. The amount of disintegrant in the pharmaceutical compositions provided herein can vary with the type of formulation and is readily discernible to one of ordinary skill in the art. The pharmaceutical compositions provided herein can contain from about 0.6 to about 16% or from about 1% to about 6% by weight of disintegrant.

[0229] Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerol; sorbitol; mannitol; glycols, such as glyceryl behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oils, including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; zinc stearate; ethyl oleate; ethyl laurate; agar; starch; lycopodium; silica or silica gel, such as 200 (W.R. Grace & Co., Baltimore, MD) and (Cabot Corp., Boston, MA); and mixtures thereof. The pharmaceutical compositions provided herein can contain from about 0.1 to about 6% by weight of lubricant.

[0230] Suitable glidants include, but are not limited to, colloidal silica, (Cabot Corp., Boston, MA) and asbestos-free talc. Suitable colorants include, but are not limited to, any approved and certified water-soluble FD&C dyes and water-insoluble FD&C dyes suspended on hydrated alumina, and lakes and mixtures thereof. Lakes are formed by adsorption of water-soluble dyes onto hydrated oxides of heavy metals, resulting in an insoluble form of the dye. Suitable flavoring agents include, but are not limited to, natural flavors extracted from plants (such as fruits) and blends of synthetic compounds that produce a pleasant taste, such as peppermint and methyl salicylate. Suitable sweetening agents include, but are not limited to, sucrose, lactose, mannitol, syrup, glycerol and artificial sweeteners, such as saccharin and aspartame. Suitable emulsifying agents include, but are not limited to, gelatin, gum arabic, tragacanth, bentonite and surfactants, such as polyoxyethylene sorbitan monooleate ( 20), polyoxyethylene sorbitan monooleate 80( 80) and triethanolamine oleate. Suitable suspending and dispersing agents include, but are not limited to, sodium carboxymethyl cellulose, pectin, tragacanth, Veegum, gum arabic, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, and polyvinylpyrrolidone. Suitable preservatives include, but are not limited to, glycerin, methylparaben and propylparaben, benzoic acid, sodium benzoate, and alcohols. Suitable wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Suitable solvents include, but are not limited to, glycerin, sorbitol, ethanol, and syrup. Suitable non-aqueous liquids utilized in the emulsion include, but are not limited to, mineral oil and cottonseed oil. Suitable organic acids include, but are not limited to, citric acid and tartaric acid. Suitable sources of carbon dioxide include, but are not limited to, sodium bicarbonate and sodium carbonate.

[0231] It should be understood that many carriers and excipients can have multiple functions, even within the same formulation.

[0232] The pharmaceutical compositions for oral administration provided herein can be provided as compressed tablets, tablet triturates, chewable lozenges, instant tablets, recompressed tablets, or enteric-coated tablets, sugar-coated tablets, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a material that resists the action of gastric acid but dissolves or disintegrates in the intestine, thus protecting the active ingredient from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets coated with a sugar coating that helps to mask unpleasant tastes or odors and protects the tablets from oxidation. Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings impart the same general characteristics as sugar coatings. Recompressed tablets are compressed tablets manufactured by more than one compression cycle, including laminated tablets and extrusion-coated or dry-coated tablets.

[0233] Tablet dosage forms can be prepared from the active ingredient in powder, crystalline, or granular form, alone or in combination with one or more of the carriers or excipients described herein, which carriers or excipients include binders, disintegrants, controlled-release polymers, lubricants, diluents, and / or colorants. Flavoring agents and sweetening agents are particularly useful in formulating chewable tablets and throat lozenges.

[0234] The pharmaceutical compositions for oral administration provided herein can be provided as soft or hard capsules, which can be made of gelatin, methylcellulose, starch, or calcium alginate. Hard gelatin capsules, also known as dry-filled capsules (DFC), consist of two sections that fit one over the other, thus completely encapsulating the active ingredient. Soft elastic capsules (SEC) are soft, spherical shells that are plasticized by the addition of glycerol, sorbitol, or a similar polyol, such as a gelatin shell. The soft gelatin shell can contain preservatives to prevent microbial growth. Suitable preservatives are those described herein, including methylparaben, propylparaben, and sorbic acid. The liquid, semi-solid, and solid dosage forms provided herein can be encapsulated in capsules. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions can be prepared by the methods described in U.S. Patent Nos. 4,328,246, 4,409,239, and 4,410,646. Capsules can also be coated by methods known to those skilled in the art to modify or maintain the dissolution rate of the active ingredient.

[0235] The pharmaceutical compositions for oral administration provided herein can be provided in liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. An emulsion is a two-phase system in which one liquid is completely dispersed in the form of small droplets in another liquid, and the emulsion can be water-in-oil or oil-in-water. Emulsions can include pharmaceutically acceptable non-aqueous liquids or solvents, emulsifying agents, and preservatives. Suspensions can include pharmaceutically acceptable suspending agents and preservatives. Aqueous alcoholic solutions can include pharmaceutically acceptable acetals, such as bis(lower alkyl) acetals of lower alkyl aldehydes, such as acetaldehyde diethyl acetal; and water-miscible solvents having one or more hydroxyl groups, such as propylene glycol and ethanol. An elixir is a sweetened, clear aqueous alcoholic solution. A syrup is a concentrated aqueous solution of sugar (e.g., sucrose) and can also contain preservatives. For liquid dosage forms, for example, a solution in polyethylene glycol can be diluted with a sufficient amount of pharmaceutically acceptable liquid carrier (e.g., water) to facilitate quantitative administration.

[0236] Other useful liquid and semi-solid dosage forms include, but are not limited to, dosage forms containing the active ingredients provided herein and dialkylated mono- or polyalkylene glycols, said dialkylated mono- or polyalkylene glycols including 1,2-dimethoxymethane, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, polyethylene glycol-360-dimethyl ether, polyethylene glycol-660-dimethyl ether, polyethylene glycol-760-dimethyl ether, wherein 360, 660 and 760 refer to the approximate average molecular weight of polyethylene glycol. These formulations may also contain one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamate.

[0237] The pharmaceutical compositions for oral administration provided herein may also be provided in the form of liposomes, micelles, microspheres or nanosystems. The micelle dosage form can be prepared according to the method described in U.S. Patent No. 7,360,468.

[0238] The pharmaceutical compositions for oral administration provided herein may be provided as non-effervescent or effervescent granules and powders, which will reconstitute into liquid dosage forms. Pharmaceutically acceptable carriers and excipients used in non-effervescent granules or powders may include diluents, sweeteners and wetting agents. Pharmaceutically acceptable carriers and excipients used in effervescent granules or powders may include organic acids and a source of carbon dioxide.

[0239] Colorants and flavoring agents may be used in all of the above dosage forms.

[0240] The pharmaceutical compositions for oral administration provided herein may be formulated into immediate-release dosage forms or modified-release dosage forms, including delayed, sustained, pulsed, controlled, targeted and programmed release dosage forms.

[0241] B. Parenteral administration

[0242] The pharmaceutical compositions provided herein may be administered parenterally by injection, infusion or implantation for local or systemic use. As used herein, parenteral administration includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, intravesical and subcutaneous administration.

[0243] The pharmaceutical compositions provided herein for parenteral administration can be formulated into any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for reconstitution into a solution or suspension in a liquid prior to injection. Such dosage forms can be prepared by conventional methods known to those skilled in the art of pharmaceutical science (see Remington: The Science and Practice of Pharmacy, supra).

[0244] The pharmaceutical compositions intended for parenteral administration can include one or more pharmaceutically acceptable carriers and excipients, including but not limited to aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives to resist microbial growth, stabilizers, solubilizing agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, masking or chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH regulators, and inert gases.

[0245] Suitable aqueous vehicles include but are not limited to water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringers injection, isotonic dextrose injection, sterile water for injection, dextrose and lactated Ringers injection. Suitable non-aqueous vehicles include but are not limited to fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chain triglycerides of coconut oil, and palm kernel oil. Suitable water-miscible vehicles include but are not limited to ethanol, 1,3-butanediol, liquid polyethylene glycols (such as polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerol, N-methyl-2-pyrrolidone, N,N-dimethylacetamide, and dimethyl sulfoxide.

[0246] Suitable antimicrobial agents or preservatives include, but are not limited to, phenol, cresol, mercury preparations, benzyl alcohol, chlorobutanol, methyl paraben and propyl paraben, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl paraben, propyl paraben, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerol, and dextrose. Suitable buffering agents include, but are not limited to, phosphates and citrates. Suitable antioxidants are those antioxidants as described herein, including bisulfite and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents are those suspending and dispersing agents as described herein, including sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, and polyvinylpyrrolidone. Suitable emulsifying agents are those emulsifying agents as described herein, including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate. Suitable masking or chelating agents include, but are not limited to, EDTA. Suitable pH adjusters include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and sulfobutyl ether 7-β-cyclodextrin( CyDex, Lenexa, KS).

[0247] When the pharmaceutical compositions provided herein are formulated for multi-dose administration, multi-dose parenteral formulations must contain an antimicrobial agent in bacteriostatic or fungistatic concentration. As is known and practiced in the art, all parenteral formulations must be sterile.

[0248] In one embodiment, the pharmaceutical composition for parenteral administration is provided as a ready-to-use sterile solution. In another embodiment, the pharmaceutical composition is provided as a sterile dry soluble product, including freeze-dried powder and subcutaneous injection tablets, which are reconstituted with a vehicle immediately before use. In yet another embodiment, the pharmaceutical composition is provided as a ready-to-use sterile suspension. In yet another embodiment, the pharmaceutical composition is provided as a sterile dry insoluble product, which is reconstituted with a vehicle immediately before use. In still another embodiment, the pharmaceutical composition is provided as a ready-to-use sterile emulsion.

[0249] The pharmaceutical compositions for parenteral administration provided herein can be formulated into immediate-release dosage forms or modified-release dosage forms, including delayed, sustained, pulsed, controlled, targeted, and programmed release dosage forms.

[0250] The pharmaceutical compositions provided herein for parenteral administration can be formulated as suspensions, solids, semi - solids or thixotropic liquids for administration as implant reservoirs. In one embodiment, the pharmaceutical compositions provided herein are dispersed in an inner solid matrix, which is encapsulated by an outer polymeric membrane that is insoluble in body fluids but permits the diffusion of the active ingredient in the pharmaceutical composition.

[0251] Suitable inner matrices include, but are not limited to, polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene - vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, hydrophilic polymers such as acrylates and methacrylates, collagen, cross - linked polyvinyl alcohol and hydrogels of cross - linked partially hydrolyzed polyvinyl acetate.

[0252] Suitable outer polymeric membranes include, but are not limited to, polyethylene, polypropylene, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, ethylene / vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, chloroprene rubber, chlorinated polyethylene, polyvinyl chloride, copolymer of vinyl chloride and vinyl acetate, vinylidene chloride, ethylene and propylene, ethylene terephthalate ionomer, butyl rubber epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer and ethylene / ethyleneoxyethanol copolymer.

[0253] C. Topical administration

[0254] The pharmaceutical compositions provided herein can be administered topically to the skin, orifices or mucous membranes. As used herein, topical administration includes intradermal, conjunctival, intracorneal, intraocular, trans - ocular, trans - otic, transdermal, transnasal, vaginal, urethral, respiratory and rectal administration.

[0255] The pharmaceutical compositions provided herein can be formulated into any dosage form suitable for topical administration to achieve local or systemic effects, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, rinses, sprays, suppositories, bandages and skin patches. The topical formulations of the pharmaceutical compositions provided herein can also contain liposomes, micelles, microspheres, nanosystems and mixtures thereof.

[0256] Pharmaceutically acceptable carriers and excipients suitable for use in the topical formulations provided herein include, but are not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives that resist microbial growth, stabilizers, solubilizing agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending or dispersing agents, wetting or emulsifying agents, complexing agents, masking or chelating agents, penetration enhancers, cryoprotectants, lyoprotectants, thickening agents, and inert gases.

[0257] The pharmaceutical compositions can also be topically administered by electroporation, iontophoresis, phonophoresis, sonophoresis, or micro-needle or needleless injection, such as POWDERJECT TM (Chiron Corporation, Emeryville, CA) and BIOJECT TM (Bioject Medical Technologies, Inc., Tualatin, OR).

[0258] The pharmaceutical compositions provided herein can be provided in the form of ointments, creams, and gels. Suitable ointment vehicles include oily or hydrocarbon vehicles, including lard, benzoinated lard, olive oil, cottonseed oil, and other oils, white petrolatum; emulsifiable or adsorptive vehicles, such as hydrophilic petrolatum, hydroxystearin sulfate, and anhydrous lanolin; water-removable vehicles, such as hydrophilic ointment; water-soluble ointment vehicles, including polyethylene glycols of different molecular weights; emulsion vehicles, water-in-oil (W / O) or oil-in-water (O / W) emulsions, including cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid (see Remington: The Science and Practice of Pharmacy, supra). These vehicles are emollients, but generally require the addition of antioxidants and preservatives.

[0259] Suitable cream bases can be oil-in-water or water-in-oil. Suitable cream vehicles can be washable and contain an oil phase, an emulsifying agent, and an aqueous phase. The oil phase is also referred to as the "internal" phase and generally consists of petrolatum and fatty alcohols such as cetyl alcohol or stearyl alcohol. Although not necessarily, the aqueous phase usually exceeds the oil phase in volume and generally contains a humectant. Emulsifying agents in cream formulations can be nonionic surfactants, anionic surfactants, cationic surfactants, or amphoteric surfactants.

[0260] Gels are semi-solid suspension-type systems. Monophasic gels contain organic macromolecules that are substantially uniformly distributed throughout a liquid carrier. Suitable gelling agents include, but are not limited to, cross-linked acrylic polymers, such as carbomer, carboxy polyolefins, and Hydrophilic polymers such as polyethylene oxide, poly(ethylene oxide - propylene oxide) copolymer, and polyvinyl alcohol; cellulose polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, and methyl cellulose; gums such as tragacanth and xanthan gum; sodium alginate; and gelatin. To prepare a uniform gel, a dispersant such as ethanol or glycerol may be added, or the gelling agent may be dispersed by grinding, mechanical mixing, and / or stirring.

[0261] The pharmaceutical compositions provided herein can be administered rectally, urethrally, vaginally, or perivaginally in the form of suppositories, vaginal suppositories, rods, cataplasms, or patches, pastes, powders, dressings, creams, plasters, contraceptives, ointments, solutions, emulsions, suspensions, tampons, gels, foams, sprays, or enemas. These dosage forms can be manufactured using conventional methods as described in Remington: The Science and Practice of Pharmacy (supra).

[0262] Rectal suppositories, urethral suppositories, and vaginal suppositories are solids for insertion into body orifices that are solid at room temperature but melt or soften at body temperature to release the active ingredient within the orifice. Pharmaceutically acceptable carriers used in rectal and vaginal suppositories include a matrix or vehicle that produces a melting point close to body temperature when formulated with the pharmaceutical compositions provided herein, such as a hardening agent; and antioxidants as described herein, including bisulfites and sodium metabisulfite. Suitable vehicles include, but are not limited to, cocoa butter (theobroma oil), glycerol - gelatin, carbowax (polyethylene glycol), sperm oil, paraffin wax, white wax, and yellow wax, and suitable mixtures of monoglycerides, diglycerides, and triglycerides of fatty acids, and hydrogels such as polyvinyl alcohol, hydroxyethyl methacrylate, and polyacrylic acid;. Combinations of various vehicles can also be used. Rectal and vaginal suppositories can be prepared by compression or molding. The typical weight of rectal and vaginal suppositories is from about 2 g to about 3 g.

[0263] The pharmaceutical compositions provided herein can be administered ophthalmically in the form of solutions, suspensions, ointments, emulsions, gel - forming solutions, powders for solutions, gels, ocular inserts, and implants.

[0264] The pharmaceutical compositions provided herein can be administered intranasally or by inhalation to the respiratory tract. The pharmaceutical compositions can be provided in the form of an aerosol or a solution, alone or in combination with a suitable propellant such as 1,1,1,2 - tetrafluoroethane or 1,1,1,2,3,3,3 - heptafluoropropane, and delivered using a pressurized container, pump, nebulizer, atomizer (e.g., an atomizer that uses electrohydrodynamics to produce fine mists), or a sprayer (nebulizer). The pharmaceutical compositions can also be provided as a dry powder for insufflation, alone or in combination with an inert carrier such as lactose or phospholipids; and as a nasal drop. For intranasal use, the powder can contain bioadhesives, including chitosan or cyclodextrin.

[0265] Solutions or suspensions for use in pressurized containers, pumps, nebulizers, atomizers, or sprayers can be formulated to contain ethanol, aqueous ethanol solutions, or suitable alternatives for dispersing, solubilizing, or slow - releasing the active ingredients provided herein; a propellant as a solvent; and / or a surfactant, such as sorbitan trioleate, oleic acid, or oligolactic acid.

[0266] The pharmaceutical compositions provided herein can be micronized to a size suitable for delivery by inhalation, e.g., about 60 microns or less, or about 10 microns or less. Such sized particles can be prepared using comminution methods known to those skilled in the art, such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing for forming nanoparticles, high - pressure homogenization, or spray drying.

[0267] Capsules, blisters, and cartridges for use in inhalers or insufflators can be formulated to contain a powder mixture of: the pharmaceutical compositions provided herein; a suitable powder matrix, such as lactose or starch; and performance modifiers, such as l - leucine, mannitol, or magnesium stearate. Lactose can be anhydrous or in the form of the monohydrate. Other suitable excipients or carriers include, but are not limited to, dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose. The pharmaceutical compositions provided herein for inhalation / intranasal administration can also contain suitable flavoring agents, such as menthol and levomenthol; and / or sweetening agents, such as saccharin or sodium saccharin.

[0268] The pharmaceutical compositions provided herein for topical administration can be formulated for immediate release or modified release, including delayed, sustained, pulsed, controlled, targeted, and programmed release.

[0269] D. Modified release

[0270] The pharmaceutical compositions provided herein can be formulated into modified release dosage forms. As used herein, the term "modified release" refers to a dosage form in which the rate or location of release of the active ingredient is different from that of an immediate release dosage form when administered by the same route. Modified release dosage forms include delayed, extended, prolonged, sustained, pulsatile, controlled, accelerated, rapid, targeted, programmed release dosage forms, and gastric retention dosage forms. A variety of modified release devices and methods known to those of skill in the art can be used to prepare pharmaceutical compositions in modified release dosage forms, including but not limited to matrix controlled release devices, osmotic controlled release devices, multi-particulate controlled release devices, ion exchange resins, enteric coatings, multi-layer coatings, microspheres, liposomes, and combinations thereof. The release rate of the active ingredient can also be adjusted by changing the particle size and polymorph of the active ingredient.

[0271] Examples of modified release include, but are not limited to, those described in the following: U.S. Patent Nos. 3,846,770; 3,917,899; 3,637,809; 3,698,123; 4,008,719; 6,774,633; 6,069,696; 6,691,777; 6,120,648; 6,073,643; 6,739,477; 6,364,667; 6,739,480; 6,733,677; 6,739,108; 6,891,474; 6,922,367; 6,972,891; 6,980,946; 6,993,866; 7,046,830; 7,087,324; 7,113,943; 7,197,360; 7,248,373; 7,274,970; 7,277,981; 7,377,471; 7,419,971; 7,689,648; 7,713,368; and 7,799,600.

[0272] 1. Matrix-controlled release device

[0273] Matrix controlled release devices known to those of skill in the art can be used to make the pharmaceutical compositions provided herein in modified release dosage forms (see Takada et al., "Encyclopedia of Controlled Drug Delivery," Volume 2, edited by Mathiowitz, Wiley, 1999).

[0274] In certain embodiments, erodible matrix devices are used to formulate the pharmaceutical compositions provided herein in modified release dosage forms, and the erodible matrix devices are water-swellable, erodible, or soluble polymers, including but not limited to synthetic polymers and naturally occurring polymers and derivatives, such as polysaccharides and proteins.

[0275] Materials that can be used to form an erodible matrix include, but are not limited to, chitin, chitosan, dextran, and pullulan; gum agar, gum arabic, karaya gum, locust bean gum, tragacanth gum, carrageenan, ghatti gum, guar gum, xanthan gum, and scleroglucan; starches such as dextrin and maltodextrin; hydrocolloids such as pectin; phospholipids such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; celluloses such as ethyl cellulose (EC), methyl ethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methyl cellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT), and ethyl hydroxyethyl cellulose (EHEC); polyvinylpyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acid esters; polyacrylamide; polyacrylic acid; copolymers of ethyl acrylate or methyl acrylate ( Rohm America, Piscataway, NJ); poly(2-hydroxyethyl methacrylate); poly(lactide); copolymers of L-glutamic acid and ethyl L-glutamate; biodegradable lactic acid-glycolic acid copolymers; poly-D-(-)-3-hydroxybutyric acid; and other acrylic derivatives such as homopolymers and copolymers of butyl methacrylate, methyl methacrylate, ethyl methacrylate, ethyl acrylate, (2-dimethylaminoethyl) methacrylate, and (trimethylaminoethyl) methacrylate chloride.

[0276] In certain embodiments, a pharmaceutical composition is formulated with a non-erodible matrix device. The active ingredient is dissolved or dispersed in an inert matrix and released primarily by diffusion in the inert matrix after administration. Materials suitable for use as non-erodible matrix devices include, but are not limited to, insoluble plastics such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethyl methacrylate, polybutyl methacrylate, chlorinated polyethylene, polyvinyl chloride, methyl acrylate-methyl methacrylate copolymer, ethylene-vinyl acetate copolymer, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, vinyl chloride-vinyl acetate copolymer, vinylidene chloride, copolymer of ethylene and propylene, ethylene terephthalate ionomer, butyl rubber, epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, ethylene / ethyleneoxyethanol copolymer, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubber, polydimethylsiloxane, and silicone carbonate copolymer; hydrophilic polymers such as ethyl cellulose, cellulose acetate, crosslinked povidone, and crosslinked partially hydrolyzed polyvinyl acetate; and aliphatic compounds such as carnauba wax, microcrystalline wax, and triglycerides.

[0277] In a matrix controlled release system, the desired release kinetics can be controlled, for example, via the type of polymer employed, the polymer viscosity, the particle size of the polymer and / or the active ingredient, the ratio of the active ingredient to the polymer, and other excipients or carriers in the composition.

[0278] The pharmaceutical compositions provided herein in a modified release dosage form can be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, and melt granulation followed by compression.

[0279] 2. Osmotic-controlled release device

[0280] The pharmaceutical compositions provided herein in a modified release dosage form can be made using an osmotic controlled release device, including but not limited to a single chamber system, a double chamber system, an asymmetric membrane technology (AMT), and an extruding core system (ECS). Generally, such devices have at least two components: (a) a core containing the active ingredient, and (b) a semipermeable membrane encapsulating the core, which has at least one delivery orifice. The semipermeable membrane controls the influx of water from the aqueous environment used into the core so that the drug is released from the delivery orifice by extrusion.

[0281] In addition to the active ingredient, the core of the osmotic device optionally includes an osmotic agent that creates a driving force for transporting water from the environment of use to the core of the device. One class of osmotic agents is water-swellable hydrophilic polymers, which are also referred to as "osmotic polymers" and "hydrogels". Water-swellable hydrophilic polymers suitable as osmotic agents include, but are not limited to, hydrophilic ethylene and acrylic polymers, polysaccharides (such as calcium alginate), polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA), PVA / PVP copolymers, copolymers of PVA / PVP with hydrophobic monomers (such as methyl methacrylate and vinyl acetate), hydrophilic polyurethanes containing large PEO blocks, crosslinked sodium carboxymethylcellulose, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose (CMC) and carboxyethyl cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate.

[0282] Another class of osmotic agents is osmogens, which are capable of absorbing water to achieve an osmotic pressure gradient across the outer coating barrier. Suitable osmogens include, but are not limited to, inorganic salts such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate; sugars such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, melezitose, sorbitol, sucrose, trehalose, and xylitol; organic acids such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamic acid, p-toluenesulfonic acid, succinic acid, and tartaric acid; urea; and mixtures thereof.

[0283] Osmotic agents with different dissolution rates can be employed to affect the rate at which the active ingredient begins to be delivered from the dosage form. For example, amorphous sugars such as MANNOGEM TM EZ (SPI Pharma, Lewes, DE) can be used to provide a faster delivery during the first two hours to rapidly produce the desired therapeutic effect and gradually and continuously release the remaining amount to maintain the desired level of therapeutic or prophylactic effect over a long period of time. In this case, the active ingredient is released at a rate that replaces the amount of active ingredient that is metabolized and excreted.

[0284] The core can also include many other excipients and carriers as described herein to enhance the performance of the dosage form or improve stability or facilitate processing.

[0285] Materials that can be used to form a semipermeable membrane include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulose derivatives that are water-permeable and water-insoluble at physiologically relevant pH values or can be made water-insoluble by chemical changes such as cross-linking. Examples of suitable polymers for forming coatings include plasticized, unplasticized, and reinforced cellulose acetate (CA), diacetate cellulose, triacetate cellulose, propionate CA, cellulose nitrate, cellulose acetate butyrate (CAB), urethane CA, CAP, methylcarbamate CA, succinate CA, cellulose acetate trimellitate (CAT), dimethylaminoacetate CA, ethyl carbonate CA, chloroacetate CA, ethyl oxalate CA, methyl sulfonate CA, butyl sulfonate CA, tosylate CA, acetate agar, triacetate amylose, acetate β-glucan, triacetate β-glucan, dimethyl acetal acetate, triacetate of locust bean gum, hydroxylated ethylene-vinyl acetate, EC, PEG, PPG, PEG / PPG copolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly(acrylic) acid and esters and poly(methacrylic) acid and esters and their copolymers, starch, dextran, dextrin, chitosan, collagen, gelatin, polyolefins, polyethers, polysulfones, polyethersulfones, polystyrene, polyvinyl halides, polyvinyl esters and ethers, natural waxes, and synthetic waxes.

[0286] The semipermeable membrane can also be a hydrophobic microporous membrane in which the pores are substantially filled with gas and not wetted by an aqueous medium but are permeable to water vapor, as disclosed in U.S. Patent No. 6,798,119. Such hydrophobic but water-vapor-permeable membranes are typically composed of hydrophobic polymers such as polyolefins, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylate derivatives, polyethers, polysulfones, polyethersulfones, polystyrene, polyvinyl halides, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes, and synthetic waxes.

[0287] Delivery holes in the semipermeable membrane can be formed after coating by mechanical or laser drilling. Delivery holes can also be formed in situ by eroding a water-soluble material plug or by rupturing a thinner portion of the membrane over a core notch. Additionally, delivery holes can be formed during the coating process, as in the case of asymmetric membrane coatings of the type disclosed in U.S. Patent Nos. 6,712,069 and 6,798,220.

[0288] The total amount and release rate of the released active ingredient can be substantially regulated by the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size, and location of the delivery holes.

[0289] The pharmaceutical composition in an osmotic-controlled release dosage form can also contain additional conventional excipients or carriers as described herein to facilitate the performance or processing of the formulation.

[0290] Osmotic controlled release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (see Remington: The Science and Practice of Pharmacy, supra; Santus and Baker, J. Controlled Release 1996, 36, 1-21; Verma et al., Drug Development and Industrial Pharmacy 2000, 27, 796-708; Verma et al., J. Controlled Release 2002, 79, 7-27).

[0291] In certain embodiments, the pharmaceutical compositions provided herein are formulated as AMT controlled release dosage forms, which comprise an asymmetric osmotic membrane coating a core that contains the active ingredient and other pharmaceutically acceptable excipients or carriers. See U.S. Patent No. 6,712,069 and WO 2002 / 17918. AMT controlled release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation, and dip coating methods.

[0292] In certain embodiments, the pharmaceutical compositions provided herein are formulated as ESC controlled release dosage forms, which comprise an osmotic membrane coating a core that contains the active ingredient, hydroxyethyl cellulose, and other pharmaceutically acceptable excipients or carriers.

[0293] 3. Multiple-unit controlled release device

[0294] The pharmaceutical compositions provided herein in modified release dosage forms can be made into multi-particulate controlled release devices, which comprise a large number of particles, granules, or pellets having a diameter in the range of from about 10 μm to about 3 mm, from about 60 μm to about 2.6 mm, or from about 100 μm to about 1 mm. Such multi-particulates can be prepared by methods known to those skilled in the art, including wet and dry granulation, extrusion / spheronization, roller compaction, melt congealing, and by spraying seeds. See, e.g., Multiparticulate Oral Drug Delivery; Marcel Dekker: 1994; and Pharmaceutical Pelletization Technology; Marcel Dekker: 1989.

[0295] Other excipients or carriers described herein can be admixed with the pharmaceutical composition to aid in processing and forming multi - microparticles. The resulting particles can themselves constitute a multi - microparticle device or can be coated with a variety of film - forming materials such as enteric polymers, swellable and water - soluble polymers. The multi - microparticles can be further processed into capsules or tablets.

[0296] 4. Targeted delivery

[0297] The pharmaceutical compositions provided herein can also be formulated into targeted delivery systems for specific tissues, receptors, or other regions of the body of a subject to be treated, including liposome - based, resealed red blood cell - based, and antibody - based delivery systems. Examples include, but are not limited to, those disclosed in U.S. Patent Nos. 7,317,762; 7,274,662; 7,271,369; 7,263,872; 7,139,876; 7,131,670; 7,120,761; 7,071,496; 7,070,082; 7,048,737; 7,039,976; 7,004,634; 6,986,307; 6,972,377; 6,900,262; 6,840,774; 6,769,642; and 6,709,874.

[0298] Method of use

[0299] In one embodiment, provided herein is a method of treating, ameliorating, or preventing a proliferative disease in a subject, which comprises administering to the subject a non - hygroscopic crystalline salt provided herein.

[0300] In certain embodiments, the proliferative disease is cancer. In certain embodiments, the cancer is bladder cancer, breast cancer, cervical cancer, colon cancer (e.g., colorectal cancer), esophageal cancer, glioma, glioblastoma multiforme, head and neck cancer, leukemia (e.g., acute myeloid leukemia (AML) or chronic myeloid leukemia (CML)), liver cancer, lung cancer (e.g., small cell lung cancer and non - small cell lung cancer), lymphoma, melanoma, myeloma, myelodysplastic syndrome (MDS), neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, salivary gland cancer, sarcoma (e.g., osteosarcoma), skin cancer (e.g., squamous cell carcinoma), stomach cancer, testicular cancer, thyroid cancer, or uterine cancer. In certain embodiments, the cancer is leukemia, melanoma, breast cancer, prostate cancer, or colorectal cancer.

[0301] In certain embodiments, the cancer is metastatic. In certain embodiments, the cancer is refractory. In certain embodiments, the cancer is recurrent. In certain embodiments, the cancer is drug - resistant.

[0302] In certain embodiments, the cancer is AML. In certain embodiments, the cancer is relapsed or refractory AML. In certain embodiments, the cancer is relapsed AML. In certain embodiments, the cancer is refractory AML. In certain embodiments, the cancer is AML with del(5q).

[0303] In certain embodiments, the cancer is MDS. In certain embodiments, the cancer is high-risk MDS. In certain embodiments, the cancer is MDS with del(5q).

[0304] In certain embodiments, a subject to be treated by a method provided herein has not been treated with an anti-cancer therapy for the proliferative disease to be treated prior to administration of the non-hygroscopic crystalline salt provided herein.

[0305] In certain embodiments, a subject to be treated by a method provided herein has been treated with an anti-cancer therapy for the proliferative disease to be treated prior to administration of the non-hygroscopic crystalline salt provided herein.

[0306] In certain embodiments, provided herein is a method for treating a subject who has undergone surgery in an attempt to treat the disease or condition involved and a subject who has not undergone surgery. Because subjects with cancer have heterogeneous clinical presentations and different clinical outcomes, the treatment given to a particular subject can vary depending on their prognosis. A skilled clinician will be able to readily determine, without undue experimentation, the specific second agent, type of surgery, and type of non-drug-based standard therapy that can be effectively used to treat an individual subject with cancer.

[0307] In another embodiment, provided herein is a method of treating one or more symptoms of a CK1-mediated disorder, disease, or condition in a subject, comprising administering to the subject the non-hygroscopic crystalline salt provided herein. In certain embodiments, the CK1-mediated disorder, disease, or condition is a proliferative disease.

[0308] The methods provided herein encompass treating a subject, regardless of the patient's age, although some diseases or conditions are more common in certain age groups.

[0309] Depending on the disease to be treated and the condition of the subject, the non-hygroscopic crystalline salt provided herein can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracisternal injection or infusion, subcutaneous injection or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes of administration. The non-hygroscopic crystalline salt provided herein can be formulated into suitable dosage units alone or in combination with a pharmaceutically acceptable excipient, carrier, adjuvant, or vehicle suitable for each route of administration.

[0310] In one embodiment, the non-hygroscopic crystalline salts provided herein are administered orally. In another embodiment, the non-hygroscopic crystalline salts provided herein are administered parenterally. In yet another embodiment, the non-hygroscopic crystalline salts provided herein are administered intravenously. In yet another embodiment, the non-hygroscopic crystalline salts provided herein are administered intramuscularly. In yet another embodiment, the non-hygroscopic crystalline salts provided herein are administered subcutaneously. In yet another embodiment, the non-hygroscopic crystalline salts provided herein are administered topically.

[0311] The non-hygroscopic crystalline salts provided herein may be delivered as a single dose, such as a single bolus or an oral tablet or pill; or delivered over time, such as by continuous infusion over time or multiple bolus doses over time. The non-hygroscopic crystalline salts provided herein are administered repeatedly as necessary, such as until the patient's disease is stable or regresses, or until the patient's disease progresses or unacceptable toxicity is experienced. Disease stability or its absence is determined by methods known in the art, such as by assessing the patient's symptoms, physical examination, and visually inspecting tumors that have been imaged using X-ray, CAT, PET, or MRI scans and other commonly accepted assessment modalities.

[0312] The non-hygroscopic crystalline salts provided herein may be administered once daily (QD), or divided into multiple daily doses, such as twice daily (BID) and three times daily (TID). Additionally, administration may be continuous, i.e., administered every day, or intermittent. As used herein, the terms "intermittent" or "intermittently" are intended to mean stopping and starting at regular or irregular time intervals. By way of example, intermittent administration of the non-hygroscopic crystalline salts provided herein may be administered one to six days per week, cyclically (e.g., administered continuously for two to eight weeks per day, followed by a rest period of no administration, up to one week), or every other day.

[0313] In certain embodiments, a therapeutically effective amount of the non-hygroscopic crystalline salts provided herein ranges from about 0.001 to about 1 mg per kilogram of subject body weight per day (mg / kg per day), from about 0.01 to about 0.1 mg / kg per day, or from about 0.01 to about 0.05 mg / kg per day, and may be administered as a single or multiple doses. In certain embodiments, a therapeutically effective amount of the non-hygroscopic crystalline salts provided herein ranges from about 0.1 to about 50 mg per day, from about 0.2 to about 20 mg per day, or from about 0.5 to about 10 mg per day. In certain embodiments, a therapeutically effective amount of the non-hygroscopic crystalline salts provided herein is about 0.2 mg per day, about 0.5 mg per day, about 1 mg per day, about 2 mg per day, about 5 mg per day, about 10 mg per day, or about 20 mg per day.

[0314] However, it will be understood that the specific dosage levels and frequency of administration for any particular subject will vary and will depend on multiple factors, including the activity of the specific compound employed, the metabolic stability and duration of action of that compound, age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, severity of the particular disorder, and the host being treated.

[0315] In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human.

[0316] The non-hygroscopic crystalline salts provided herein can also be combined with or co-administered with other therapeutic agents useful for treating and / or preventing the disorders, diseases or conditions described herein.

[0317] As used herein, the term "combination" includes the use of more than one therapy (e.g., one or more prophylactic and / or therapeutic agents). However, the use of the term "combination" does not limit the order in which the therapies (e.g., prophylactic and / or therapeutic agents) are administered to a subject having a disease or condition. The first therapy (e.g., a prophylactic or therapeutic agent, such as a compound provided herein) can be administered to the subject before (e.g., 6 minutes, 16 minutes, 30 minutes, 46 minutes, 1 hour, 2 hours, 4 hours, 7 hours, 12 hours, 24 hours, 48 hours, 72 hours, 97 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 7 weeks, 8 weeks or 12 weeks before), concurrently with or after (e.g., 6 minutes, 16 minutes, 30 minutes, 46 minutes, 1 hour, 2 hours, 4 hours, 7 hours, 12 hours, 24 hours, 48 hours, 72 hours, 97 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 7 weeks, 8 weeks or 12 weeks after) the administration of the second therapy (e.g., a prophylactic or therapeutic agent). Triple therapy is also contemplated herein.

[0318] The route of administration of the non-hygroscopic crystalline salts provided herein is independent of the route of administration of the second therapy. In one embodiment, the non-hygroscopic crystalline salts provided herein are administered orally. In another embodiment, the non-hygroscopic crystalline salts provided herein are administered intravenously. Thus, according to these embodiments, the non-hygroscopic crystalline salts provided herein are administered orally or intravenously, and the second therapy can be administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, buccally, intranasally, liposomally, via inhalation, vaginally, intravitreally, locally via catheter or stent, subcutaneously, intralipally, intraarticularly, intrathecally or in a slow release formulation. In one embodiment, the non-hygroscopic crystalline salts provided herein and the second therapy are administered by the same mode of administration, orally or by IV. In another embodiment, the non-hygroscopic crystalline salts provided herein are administered by one mode of administration, e.g., orally, while the second agent (anticancer agent) is administered by another mode of administration, e.g., IV.

[0319] In certain embodiments, each method provided herein further independently includes the step of administering a second therapeutic agent.

[0320] The non-hygroscopic crystalline salts provided herein may also be provided in articles using packaging materials well understood by those skilled in the art. See, for example, U.S. Patent Nos. 6,323,907; 6,062,668; and 6,033,262. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, and any packaging material suitable for the selected formulation and the intended mode of administration and treatment.

[0321] In certain embodiments, kits are also provided herein which, when used by a practicing physician, can simplify the administration of an appropriate amount of the active ingredient to a subject. In certain embodiments, the kits provided herein include a container and a dosage form of the non-hygroscopic crystalline salts provided herein.

[0322] In certain embodiments, the kit includes a container that contains a dosage form of the non-hygroscopic crystalline salts provided herein in a container that contains one or more other therapeutic agents.

[0323] The kits provided herein may also include a device for administering the active ingredient. Examples of such devices include, but are not limited to, syringes, needleless syringes, infusion bags, patches, and inhalers. The kits provided herein may also include a condom for administering the active ingredient.

[0324] The kits provided herein may also include a pharmaceutically acceptable vehicle that can be used to administer one or more active ingredients. By way of example, if the active ingredient is provided in solid form that must be reconstituted for parenteral administration, the kit may contain a sealed container of a suitable vehicle in which the active ingredient can be dissolved in the vehicle to form a particulate-free sterile solution suitable for parenteral administration. Examples of pharmaceutically acceptable vehicles include, but are not limited to: aqueous vehicles, including but not limited to Water for Injection USP, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles, including but not limited to ethanol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles, including but not limited to corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[0325] The following non-limiting examples will further illustrate the present disclosure.

[0326] Examples

[0327] Example 1

[0328] Screening (1r,4r)-N 1-Crystalline salt of (5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine

[0329] By partitioning between aqueous sodium hydroxide and dichloromethane, the free base (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine dihydrochloride was prepared to obtain the free base (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine.

[0330] For the case of forming a crystalline salt with the free base (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine, twenty acids were screened. The conditions examined are outlined in Table 1.

[0331] Table 1. Screening conditions for crystalline salts

[0332]

[0333]

[0334]

[0335] The salt formation reaction was carried out by reacting one molar equivalent of the free base (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine with one molar equivalent of each acid.

[0336] The crystallinity of each solid salt formed was determined by X-ray powder diffraction (XRPD). XRPD analysis was performed on a Rigaku Smart-Lab X-ray diffraction system configured to use the reflection Bragg-Brentano geometry with a line source X-ray beam. The X-ray source was a Cu long-fine focus tube operating at 40 kV and 44 mA, which provided an incident beam profile on the sample that varied from a narrow line at large angles to a wide rectangle at small angles. Beam conditioning slits were used on the in-line X-ray source to ensure that the maximum beam size along and perpendicular to the line was less than 10 mm. The Bragg-Brentano geometry is a parafocusing geometry controlled by passive divergence and receiving slits, where the sample itself acts as the focusing component of the optical device. The inherent resolution of the Bragg-Brentano geometry is determined to some extent by the diffractometer radius and the width of the receiving slit used. The Rigaku Smart-Lab was operated to obtain a peak width of 0.1° 2θ or less. The axial divergence of the X-ray beam in both the incident and diffracted optical paths was controlled by 5.0° Soller slits.

[0337] More specifically, powder salt samples were prepared in a low-background Si holder using light manual pressure to keep the sample surface flat and flush with the reference surface of the sample holder. Each salt sample was analyzed from 2 to 40° 2θ using a continuous scan of 6° 2θ per minute with an effective step size of 0.02° 2θ.

[0338] If the solid was determined to be crystalline, further analysis was performed. Differential scanning calorimetry (DSC) analysis was carried out using a TA Instruments Q2000 instrument. The instrument temperature was calibrated using indium. The DSC cell was maintained under a nitrogen purge of approximately 50 mL per minute during each analysis. The solid salt sample was placed in a standard crimped aluminum pan and heated from 25 °C to 350 °C at a rate of 10 °C per minute.

[0339] Thermogravimetric analysis was performed using a TA Instruments Q50 instrument. The instrument balance was calibrated using class M weights and the temperature was calibrated using alumel. The nitrogen purge was approximately 40 mL per minute on the balance and approximately 60 mL per minute on the furnace. The solid salt sample was placed in a pre-tared platinum pan and heated from 20 °C to 350 °C at a rate of 10 °C per minute.

[0340] Figures 1 to 23 The analysis results of the crystalline salts identified in Table 1 are shown.

[0341] Example 2

[0342] (1r,4r)-N 1Preparation and Characterization of Crystalline Adipate, Benzoate, and Tosylate Salts of (5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine

[0343] (1r,4r)-N was prepared under the conditions shown in Table 2 1 Crystalline adipate, benzoate, and tosylate salts of (5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine

[0344] Table 2. Conditions for Crystalline Salt Formation

[0345]

[0346]

[0347] The crystalline adipate, benzoate, and tosylate salts were characterized by XRPD, DSC, TGA, and DVS. DVS analysis was performed using a TA Instruments Q5000 Dynamic Vapor Sorption analyzer. The instrument was calibrated with standard weights and a sodium bromide standard for humidity. The adipate salt was analyzed at 25 °C from 5% to 95% RH (adsorption cycle) and 95% to 5% RH (desorption cycle) in 10% relative humidity (RH) steps with a maximum equilibration time of 60 minutes Figures 24 to 33 The analysis results are shown in

[0348] Figure 24 The X-ray powder diffraction pattern in shows that the adipate salt is crystalline Figure 25 The TGA thermogram in shows that the adipate salt has a 0.29% loss up to 150 °C, indicating that the crystalline adipate salt is not solvated

[0349] Figure 26 The DVS isotherm plot in shows that the adipate salt (i) has a 0.05% loss after drying at 5% RH; (ii) has a 1.05% increase from 5% to 95% RH; and (iii) has a 1.11% loss from 95% to 5% RH; indicating that the crystalline adipate salt is non-hygroscopic

[0350] Figure 27 and 28 in 1 The 1H NMR spectrum shows that the adipate salt contains one molar equivalent of (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine and one molar equivalent of adipic acid

[0351] Figure 29 The X-ray powder diffraction pattern in Figure 30 shows that the benzoate is crystalline. The TGA thermogram in

[0352] Figure 31 shows that the benzoate has a 1.01% loss up to 175 °C; this indicates that the crystalline benzoate is not solvated. The DVS isotherm in

[0353] Figure 32 and 33 shows that the benzoate (i) has a 0.02% loss after drying at 5% RH, (ii) has a 1.20% increase from 5% to 95% RH, and (iii) has a 1.30% loss from 95% to 5% RH; this indicates that the crystalline benzoate is non-hygroscopic. 1 The HNMR spectrum in 1 shows that the benzoate contains one molar equivalent of (1r,4r)-N

[0354] For comparison, Figure 38 the DVS isotherm in

[0355] shows that the dihydrochloride (i) has a 1.2% loss after drying at 5% RH, (ii) has a 17% increase from 5% to 95% RH, and (iii) has a 16% loss from 95% to 5% RH; this indicates that the dihydrochloride adipate is highly hygroscopic. The solubility of the crystalline adipates, benzoates, and tosylates of the compounds, as well as the dihydrochloride, was determined by adding an aliquot of the test solvent (e.g., water) to a weighed portion of each crystalline solid salt and judging by visual inspection whether dissolution occurred after each addition of the solvent aliquot. The results are shown in Table 3.

[0356] Table 3. Solubility of Certain Salts of the Compounds

[0357]

[0358]

[0359] Example 3

[0360] (1r,4r)-N 1 Preparation and Characterization of the Crystalline Xylenesulfonate of

[0361] To a stirred, clear solution of (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine dihydrochloride (20.0 g, 1.0 eq) in water (10 volumes) was slowly added 10% aqueous Na2CO3 solution (5 volumes) at 25 - 35 °C. The reaction mixture was stirred for 10 h, and the resulting solid was filtered and washed with water (5.0 volumes) to form a slurry of the solid. The wet material was blotted dry and dried in an oven at 50 - 55 °C for 24 h to give (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine in free base form.

[0362] To a stirred, turbid solution of the above free base compound (1.0 eq) in methanol (10 volumes) at 25 - 35 °C was added p-toluenesulfonic acid·H2O (2.2 eq) (immediately forming a clear solution which soon became a solid suspension again). The solid suspension was stirred at 50 - 55 °C for 4 h, then methanol was distilled off under vacuum at < 50 °C, the suspension was co-distilled with acetone (3.0 volumes), and the residue was slurried in acetone (10.0 volumes) at 25 - 35 °C for 1 - 2 h. The solid suspension was then filtered and the wet compound was dried in vacuo at 50 - 60 °C. 1 1H NMR (400 MHz, CD3OD) δ 8.45 (br, 1H), 8.37 (s, 1H), 7.71 (m, 4H), 7.22 (m, 4H0, 3.92 (m, 1H), 3.91 (s, 3H), 3.17 (m, 2H), 3.14 (m, 1H), 2.33 (s, 6H), 2.13 (m, 4H), 1.58 (m, 4H), 1.04 (m, 1H), 0.50 (m, 2H), 0.24 (m, 2H). 13 13C NMR (100 MHz, CD3OD) δ 165.72, 152.87, 149.11 (2), 147.32, 143.34, 142.39, 141.87 (2), 129.88 (4), 126.89 (4), 115.57, 115.46, 51.03, 50.32, 37.61, 30.87 (2), 30.31 (2), 29.90, 21.31 (2), 11.07, 5.04 (2).

[0363] The toluenesulfonate was also characterized by XRPD, DSC and DVS. Figure 34The X-ray powder diffraction pattern in [[]] indicates that the toluenesulfonate is crystalline. Certain XRDR peaks of the toluenesulfonate are outlined in Table 4.

[0364] Table 4. Certain XRPD Peaks of the Xylenesulfonate

[0365]

[0366]

[0367] Figure 35 The DSC thermogram in [[]] shows that the crystalline toluenesulfonate has an onset value of 224 °C and an endothermic peak at 228 °C. Figure 36 The DVS isotherm in [[]] indicates that the crystalline toluenesulfonate is non-hygroscopic.

[0368] Figure 37 in [[]] 1 The HNMR spectrum indicates that the crystalline toluenesulfonate contains one molar equivalent of (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine and two molar equivalents of p-toluenesulfonic acid. The measured bulk density of the xylenesulfonate is 0.377 g / mL.

[0369] Example 4

[0370] (1r,4r)-N 1 Stability of the non-hygroscopic crystalline xylenesulfonate of (1r,4r)-N

[0371] The stability of the non-hygroscopic crystalline xylenesulfonate was determined under storage conditions of 25 ± 2 °C / 60 ± 5% RH and 40 ± 2 °C / 75 ± 5% RH. For the stability study, the xylenesulfonate was packaged in a black transparent polyethylene bag. As shown in Table 5 below, the xylenesulfonate is stable under both storage conditions of 25 °C / 60% RH and 40 °C / 75% RH, and no significant changes were observed in any of the measured parameters.

[0372] Table 5. Stability of the Xylenesulfonate

[0373]

[0374] *****

[0375] The examples set forth above are provided to give those of ordinary skill in the art a complete disclosure and description of how to make and use the claimed embodiments, and are not intended to limit the scope of the disclosure herein. Modifications that are obvious to those of ordinary skill in the art are intended to be within the scope of the following claims. All publications, patents, and patent applications cited in this specification are hereby incorporated by reference in their entirety to the same extent as if each such publication, patent, and patent application was specifically and individually indicated to be incorporated by reference.

Claims

1. A non-hygroscopic crystalline salt, the non-hygroscopic crystalline salt being (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine or an isotopic variant thereof formed with an acid; or a pharmaceutically acceptable solvate thereof; wherein the acid is adipic acid or benzoic acid, and when the acid is adipic acid, the non-hygroscopic crystalline salt has an X-ray powder diffraction pattern as shown in Figure 24, and when the acid is benzoic acid, the non-hygroscopic crystalline salt has an X-ray powder diffraction pattern as shown in Figure 29.

2. The non-hygroscopic crystalline salt according to claim 1, wherein the acid is adipic acid.

3. The non-hygroscopic crystalline salt according to claim 2, wherein the salt comprises one molar equivalent of (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine or an isotopic variant thereof and one molar equivalent of adipic acid.

4. The non-hygroscopic crystalline salt according to claim 2, which has a DSC thermogram containing an endothermic peak at 164 °C.

5. The non-hygroscopic crystalline salt according to claim 2, which has a DSC thermogram containing an endothermic peak at 175 °C.

6. The non-hygroscopic crystalline salt according to claim 2, which has a DSC thermogram as shown in Figure 25.

7. The non-hygroscopic crystalline salt according to claim 2, which has a TGA thermogram showing a 0.3% weight loss from room temperature to 150 °C.

8. The non-hygroscopic crystalline salt according to claim 2, which has a TGA thermogram as shown in Figure 25.

9. The non-hygroscopic crystalline salt according to claim 2, which has a DVS isotherm as shown in Figure 26.

10. The non-hygroscopic crystalline salt according to claim 2, wherein the salt is not solvated.

11. The non-hygroscopic crystalline salt according to claim 2, wherein the salt has a solubility in water of 14 mg / mL at 25 °C.

12. The non-hygroscopic crystalline salt according to claim 1, wherein the acid is benzoic acid.

13. The non-hygroscopic crystalline salt according to claim 12, wherein the salt comprises one molar equivalent of (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine or an isotopic variant thereof and two molar equivalents of benzoic acid.

14. The non-hygroscopic crystalline salt according to claim 12, which has a DSC thermogram containing an endothermic peak at 229 °C.

15. The non-hygroscopic crystalline salt according to claim 12, which has a DSC thermogram as shown in Figure 30.

16. The non-hygroscopic crystalline salt according to claim 12, which has a TGA thermogram showing a 1% weight loss from room temperature to 175 °C.

17. The non-hygroscopic crystalline salt according to claim 12, which has a TGA thermogram as shown in Figure 30.

18. The non-hygroscopic crystalline salt according to claim 12, which has a DVS isotherm as shown in Figure 31.

19. The non-hygroscopic crystalline salt according to claim 12, wherein the salt is not solvated.

20. The non-hygroscopic crystalline salt according to claim 12, wherein the salt has a solubility in water of not more than 1 mg / mL at 25 °C.

21. A non-hygroscopic crystalline salt, the non-hygroscopic crystalline salt being (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine or an isotopic variant thereof formed with an acid; or a pharmaceutically acceptable solvate thereof; wherein the acid is p-toluenesulfonic acid, and the non-hygroscopic crystalline salt has an X-ray powder diffraction pattern having peaks at 5.5°, 7.6° and 21.9° expressed as 2θ.

22. The non-hygroscopic crystalline salt according to claim 21, wherein the salt comprises one molar equivalent of (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine or an isotopic variant thereof and two molar equivalents of p-toluenesulfonic acid.

23. The non-hygroscopic crystalline salt according to claim 21, wherein the salt comprises one molar equivalent of (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine and two molar equivalents of p-toluenesulfonic acid.

24. The non-hygroscopic crystalline salt according to claim 21, which has an X-ray powder diffraction pattern having peaks represented by 2θ at 5.5°, 7.6°, 12.9°, 17.3°, 21.9°, 22.3°, 22.5° and 23.8°.

25. The non-hygroscopic crystalline salt according to claim 21, which has an X-ray powder diffraction pattern having peaks represented by 2θ at 5.5°, 7.6°, 12.9°, 14.9°, 16.2°, 17.3°, 18.4°, 18.6°, 21.5°, 21.9°, 22.3°, 22.5°, 23.4°, 23.8°, 24.1°, 26.2°, 26.9° and 27.0°, 28.8°.

26. The non-hygroscopic crystalline salt according to claim 21, which has a DSC thermogram containing an endothermic peak at 228 °C.

27. The non-hygroscopic crystalline salt according to claim 21, which has a DSC thermogram as shown in Figure 35.

28. The non-hygroscopic crystalline salt according to claim 21, which has a DVS isotherm diagram as shown in FIG.

36.

29. The non-hygroscopic crystalline salt according to claim 21, wherein the salt is not solvated.

30. The non-hygroscopic crystalline salt according to claim 21, wherein the solubility of the salt in water at 25 °C is 2 mg / mL.

31. A non-hygroscopic crystalline salt, the non-hygroscopic crystalline salt being (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine or an isotopic variant thereof formed with an acid; or a pharmaceutically acceptable solvate thereof; wherein the acid is p-toluenesulfonic acid and the non-hygroscopic crystalline salt has an X-ray powder diffraction pattern as shown in Figure 34.

32. The non-hygroscopic crystalline salt according to claim 31, which has a DSC thermogram containing an endothermic peak at 228 °C.

33. The non-hygroscopic crystalline salt according to claim 31, which has a DSC thermogram as shown in FIG.

35.

34. The non-hygroscopic crystalline salt according to claim 31, which has a DVS isotherm diagram as shown in FIG.

36.

35. The non-hygroscopic crystalline salt according to claim 31, wherein the salt is not solvated.

36. The non-hygroscopic crystalline salt according to claim 31, wherein the solubility of the salt in water at 25 °C is 2 mg / mL.

37. A pharmaceutical composition comprising the non-hygroscopic crystalline salt according to any one of claims 1 to 36 and a pharmaceutically acceptable excipient.

38. The pharmaceutical composition according to claim 37, wherein the composition is in a single dosage form.

39. The pharmaceutical composition according to claim 37, wherein the composition is in an oral, parenteral or intravenous dosage form.

40. The pharmaceutical composition according to claim 39, wherein the composition is formulated for oral administration.

41. The pharmaceutical composition according to claim 40, wherein the oral dosage form is a tablet or a capsule.

42. Use of the non-hygroscopic crystalline salt according to any one of claims 1 to 36 in the preparation of a medicament for the treatment of cancer, wherein the cancer is acute myeloid leukemia or myelodysplastic syndrome.

43. The use according to claim 42, wherein the acute myeloid leukemia is relapsed or refractory.

44. The use according to claim 42, wherein the acute myeloid leukemia is acute myeloid leukemia with deletion of 5q.

45. The use according to claim 42, wherein the cancer is high-risk myelodysplastic syndrome.

46. The use according to claim 42, wherein the myelodysplastic syndrome is myelodysplastic syndrome with deletion of 5q.

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