WO2011112689A2 - Saltz of an indazolylpyrrolotriazine - Google Patents

Saltz of an indazolylpyrrolotriazine Download PDF

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WO2011112689A2
WO2011112689A2 PCT/US2011/027706 US2011027706W WO2011112689A2 WO 2011112689 A2 WO2011112689 A2 WO 2011112689A2 US 2011027706 W US2011027706 W US 2011027706W WO 2011112689 A2 WO2011112689 A2 WO 2011112689A2
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acid salt
sulfonic acid
salt
cancer
triazin
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PCT/US2011/027706
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French (fr)
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WO2011112689A3 (en
WO2011112689A9 (en
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Shripad S. Bhagwat
Timothy David Gross
Patrick B. O'donnel
Traci L. Savall
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Ambit Biosciences Corp.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the sulfonic acid salt is crystalline.
  • methanesulfonic acid salt is used interchangeably with the term “mesylate salt.”
  • the methanesulfonic acid salt of (5)-morpholin-3- ylmethyl 4-( 1 -(3 -fluorobenzyl)- lH-indazol-5 -ylamino)-5 -methylpyrrolo [ 1 ,2-f [ 1 ,2,4]triazin- 6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, is in crystalline Form I-C.
  • the methanesulfonic acid salt in Form I-C has an X-ray powder diffraction pattern substantially as shown in FIG. 1C.
  • the methanesulfonic acid salt in Form I-C has one or more characteristic XRP diffraction peak at two-theta angles selected from approximately 3.3, 6.8, 1 1.2, and 26.2°.
  • the ethanesulfonic acid salt in Form II-C has one or more characteristic XRP diffraction peaks at two-theta angles selected from approximately 4.0, 12.4, 13.8, 16.3, 19.2, 20.3, 21.6, 24.8. 26.0, 26.8, and 29.0°. In certain embodiments, the ethanesulfonic acid salt in Form II-C has characteristic XRP diffraction peaks at two-theta angles of approximately 4.0, 13.8, and 16.3°. In certain embodiments, the ethanesulfonic acid salt in Form II-C has characteristic XRP diffraction peaks at two-theta angles of approximately 4.0, 13.8, 16.3, and 23.2°.
  • the molar ratio of (5)-morpholin-3-ylmethyl 4-(l-(3- fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2 ][l ,2,4]triazin-6-ylcarbamate versus phosphoric acid in the salt provided herein, including hydrates and pharmaceutically acceptable solvates thereof, is ranging from about 0.5 to about 3, from about 0.5 to about 2, or from about 0.8 to about 1.2.
  • the phosphoric acid salt of (5)-morpholin-3-ylmethyl 4- (l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l ,2 ][l,2,4]triazin-6- ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, is in an amorphous form.
  • a pharmaceutical composition comprising (S)-morpholin-3-ylmethyl 4-(l -(3-fluorobenzyl)-lH-indazol-5-ylamino)-5- methylpyrrolo[ l ,2- ] [l ,2,4]triazin-6-ylcarbamate ethanesulfonate, or a pharmaceutically acceptable solvate or hydrate thereof, in combination with hydroxypropyl- -cyclodextrin, mannitol, water, or a mixture thereof.
  • compositions are provided in a dosage form for parenteral administration, which comprise a salt provided herein, and one or more pharmaceutically acceptable vehicles, carriers, diluents, or excipients.
  • the multiple dosage parenteral formulations must contain an antimicrobial agent at bacteriostatic or fungistatic concentrations. All parenteral formulations must be sterile, as known and practiced in the art.
  • starches such as dextrin and maltodextrin; hydrophilic colloids, such as pectin; phosphatides, such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; cellulosics, such as ethyl cellulose (EC), methylethyl 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);
  • EC ethyl cellulose
  • MEC carboxymethyl cellulose
  • CMC carboxy
  • the delivery port(s) on the semipermeable membrane can be formed post- coating by mechanical or laser drilling. Delivery port(s) can also be formed in situ by erosion of a plug of water-soluble material or by rupture of a thinner portion of the membrane over an indentation in the core. In addition, delivery ports can be formed during coating process, as in the case of asymmetric membrane coatings of the type disclosed in U.S. Pat. Nos.
  • the 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 1995, 35, 1-21 ; Verma et ah , Drug Development and Industrial Pharmacy 2000, 26, 695-708; and Verma et al. , J. Controlled Release 2002, 79, 7-27.
  • the salt provided herein is administered to the subject in the amount of about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 134, about 140, about 150, about 160, about 170, about 180, about 190, about 200, about 210, about 220, about 230, about 240, about 250, about 260, about 270, about 280, about 290, or about 300 mg/m 2 /day.
  • the salt provided herein is administered daily in a single dose or divided doses for a total daily dose sufficient to achieve a plasma concentration of the compound at steady state ranging from about 0.5 ⁇ to about 40 ⁇ , from about 1 ⁇ to about 30 ⁇ , from about 5 ⁇ to about 25 ⁇ or from about 10 ⁇ to about 20 ⁇ ; in one embodiment, about 1 ⁇ , about 2 ⁇ , about 5 ⁇ , about 10 ⁇ , about 15 ⁇ , about 30 ⁇ , about 40 ⁇ , or about 50 ⁇ .
  • plasma concentration at steady state is the concentration reached after a period of administration of a compound. Once steady state is reached, there are minor peaks and troughs on the time dependent curve of the plasma concentration of the compound of Formula I.
  • breast cancer including, but not limited to, adenocarcinoma, lobular (small cell) carcinoma, intraductal carcinoma, medullary breast cancer, mucinous breast cancer, tubular breast cancer, papillary breast cancer, primary cancers, Paget's disease, and inflammatory breast cancer;
  • adrenal cancer including, but not limited to, pheochromocytom and adrenocortical carcinoma;
  • thyroid cancer including, but not limited to, papillary or follicular thyroid cancer, medullary thyroid cancer, and anaplastic thyroid cancer;
  • pancreatic cancer including, but not limited to, insulinoma, gastrinoma, glucago
  • the methods provided herein encompass treating a subject regardless of patient's age, although some diseases or disorders are more common in certain age groups. Further provided herein is a method for treating a subject who has undergone surgery in an attempt to treat the disease or condition at issue, as well as the one who have not. Because the subjects with cancer have heterogeneous clinical manifestations and varying clinical outcomes, the treatment given to a particular subject may vary, depending on his/her prognosis.
  • a maleate salt was prepared by dissolving the compound of Formula I in about 35 volume THF at about 35 °C. Ethanesulfonic acid (1.0 M, 1 eq.) in methanol was added slowly. The solution was stirred for 1 hr. MTBE (100 mL) was added and the solids formed within 2 hrs. Additional MTBE (200 mL) was added, and the mixture was stirred for 1 hr. The resulting solid was filtered, washed with MTBE, and dried under vacuum for about 66 hrs at room temperature to yield the desired salt (1 1.4 g) as a white or pale yellow powdery solid in 93% yield.
  • solutions were prepare in various solvents and sonicated between aliquot additions to assist in dissolution. Once a mixture reached complete dissolution, as judged by visual observation, the solution was filtered through a 0.2 ⁇ nylon filter. The filtered solutions were allowed to evaporate at ambient in an uncapped vial.

Abstract

Provided herein are salts of an indazolylpyrrolotriazine, processes of preparation, and pharmaceutical compositions thereof. Also provided are methods of their use for treating, preventing, or ameliorating a proliferative disease.

Description

SALTS OF AN INDAZOLYLPYRROLOTRIAZINE
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Application No.
61/313,038, filed March 11 , 2010, the disclosure of which is incorporated herein by reference in its entirety.
FIELD
[0002] Provided herein are salts of an indazolylpyrrolotriazine, processes of preparation, and pharmaceutical compositions thereof. Also provided are methods of their use for treating, preventing, or ameliorating a proliferative disease.
BACKGROUND
[0003] The Her family of receptor tyrosine kinases is comprised of Her 1 (also known as EGFR or ErbB-1), Her2 (ErbB-2), Her3 (ErbB-3), and Her4 (ErbB-4). The activation or overexpression of its members, such as Herl or Her2, is implicated in human malignancies that include breast cancer, ovarian cancer, endometrial cancer, cervical cancer, esophageal cancer, gastric cancer, colorectal cancer, pancreatic cancer, prostate cancer, non-small cell lung cancer (NSCLC), bladder cancer, head and neck cancer, and glioma including glioblastoma. Her inhibitors have been used clinically for cancer treatment. For example, trastuzumab (HERCEPTIN®), an anti-Her2 antibody, has been approved for the treatment of Her2-positive breast cancer. Lapatinib (TYKERB®), which is a small molecule inhibitor with dual anti-EGFR/Her2 activity, has been approved for the treatment of Her2 -positive breast cancer. Despite these advances in anticancer therapy, there exists a long-felt need for effective therapies for proliferative diseases.
SUMMARY OF THE DISCLOSURE
[0004] Provided herein is a sulfonic acid salt of (5)-morpholin-3-ylmethyl 4-(l-(3- fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2:/][l,2,4]triazin-6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof. In one embodiment, the sulfonic acid salt is crystalline. [0005] Also provided herein is a methanesulfonic acid salt of (5)-morpholin-3- ylmethyl 4-( 1 -(3 -fluorobenzyl)- lH-indazol-5 -ylamino)-5 -methylpyrrolo [ 1 ,2-f [ 1 ,2,4]triazin- 6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof. In one embodiment, the methanesulfonic acid salt is crystalline.
[0006] Additionally provided herein is an ethanesulfonic acid salt of (5)-morpholin-3- ylmethyl 4-( 1 -(3 -fluorobenzyl)- lH-indazol-5 -ylamino)-5 -methylpyrrolo [ 1 ,2-/] [ 1 ,2,4]triazin- 6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof. In one embodiment, the ethanesulfonic acid salt is crystalline.
[0007] Further provided herein is a benzenesulfonic acid salt of (5)-morpholin-3- ylmethyl 4-( 1 -(3 -fluorobenzyl)- lH-indazol-5 -ylamino)-5 -methylpyrrolo [ 1 ,2-/] [ 1 ,2,4]triazin- 6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof. In one embodiment, the benzenesulfonic acid salt is crystalline.
[0008] Provided herein is a 7-toluenesulfonic acid salt of
Figure imgf000003_0001
4-
(l-(3-fluorobenzyl)- lH-indazol-5-ylamino)-5-methylpyrrolo[ l ,2: ][l ,2,4]triazin-6- ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof. In one
embodiment, the -toluenesulfonic acid salt is crystalline.
[0009] Provided herein is an acetic acid salt of (5)-morpholin-3-ylmethyl 4-(l -(3- fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l ,2 ] [l ,2,4]triazin-6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof. In one embodiment, the acetic acid salt is crystalline.
[0010] Provided herein is a maleic acid salt of (5)-morpholin-3 -ylmethyl 4-(l-(3- fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l ,2 ] [l ,2,4]triazin-6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof. In one embodiment, the maleic acid salt is crystalline.
[001 1 ] Provided herein is a nitric acid salt of ( )-morpholin-3 -ylmethyl 4-(l -(3- fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l ,2:/] [l ,2,4]triazin-6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof. In one embodiment, the nitric acid salt is crystalline.
[0012] Provided herein is a phosphoric acid salt of (5)-morpholin-3 -ylmethyl 4-(l -(3- fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2- J[l ,2,4]triazin-6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof. In one embodiment, the phosphoric acid salt is crystalline.
[0013] Provided herein is a pharmaceutical composition, comprising a salt of (S)- morpholin-3-ylmethyl 4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l ,2- /][l ,2,4]triazin-6-ylcarbamate provided herein, including hydrates and pharmaceutically acceptable solvates thereof; in combination with one or more pharmaceutically acceptable excipients.
[0014] Provided herein is a method of treating a proliferative disease in a subject, comprising administering to the subject a salt of (5)-morpholin-3-ylmethyl 4-(l-(3- fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2 /][l ,2,4]triazin-6-ylcarbamate provided herein, including hydrates and pharmaceutically acceptable solvates thereof.
[0015] Provided herein is a method of inhibiting the growth of a cell, comprising contacting the cell with a salt of (£)-morpholin-3-ylmethyl 4-(l-(3-fluorobenzyl)-lH-indazol-
5- ylamino)-5-methylpyrrolo[l ,2- ][l ,2,4]triazin-6-ylcarbamate provided herein, including hydrates and pharmaceutically acceptable solvates thereof.
[0016] Provided herein is a process for the preparing a salt of (5)-morpholin-3- ylmethyl 4-( 1 -(3 -fluorobenzyl)- lH-indazol-5 -ylamino)-5 -methylpyrrolo [ 1 ,2-/] [ 1 ,2,4]triazin-
6- ylcarbamate provided herein, including hydrates and pharmaceutically acceptable solvates thereof, which comprises reacting (5)-morpholin-3-ylmethyl 4-(l-(3-fluorobenzyl)-lH- indazol-5-ylamino)-5 -methylpyrrolo [1 , 2- ] [l,2,4]triazin-6-ylcarbamate with an acid in a solvent at a first predetermined temperature. In one embodiment, the process further comprises precipitating the salt at a second predetermined temperature.
[0017] Provided herein is a method for decreasing the amount of (S)-(4- nitrosomorpholin-3-yl)methyl 4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5- methylpyrrolo[l ,2-y][l ,2,4]triazin-6-ylcarbamate from a salt of (5)-mo^holin-3-ylmethyl 4- (l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l ,2: ][l,2,4]triazin-6- ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof; which comprises contacting the salt with acetone at a first predetermined temperature. In one embodiment, the salt is crystallized in acetone. BRIEF DESCRIPTION OF THE DRAWINGS
[0018] FIGS. 1A to ID depict X-ray powder (XRP) diffractograms of
methanesulfonic acid salts of (5)-morpholin-3-ylmethyl 4-(l-(3-fluorobenzyl)-lH-indazol-5- ylamino)-5-methylpyrrolo[l ,2- |[l ,2,4]triazin-6-ylcarbamate in crystalline Forms I-A, I-B, I- C, and I-D, respectively.
[0019] FIGS. 2A to 2E depict X-ray powder (XRP) diffractograms of ethanesulfonic acid salts of (5)-morpholin-3-ylmethyl 4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5- methylpyrrolo[l ,2-y][l ,2,4]triazin-6-ylcarbamate in crystalline Forms II-A, II-B, II-C, II-D, and II-E, respectively.
[0020] FIGS. 3 A to 3D depict X-ray powder (XRP) diffractograms of maleic acid salts of (5)-morpholin-3-ylmethyl 4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5- methylpyrrolo[l ,2- ][l ,2,4]triazin-6-ylcarbamate in crystalline Forms III-A, III-B, III-C, and III-D, respectively.
DETAILED DESCRIPTION
[0021 ] To facilitate understanding of the disclosure set forth herein, a number of terms are defined below.
[0022] Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, physical chemistry, biochemistry, biology, pharmacology, and others described herein are those well known and commonly employed in the art. Unless defined otherwise, 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 belongs.
[0023] The term "tumor," "neoplasm," and "neoplastic disorder or disease" are used interchangeably herein and are meant to refer to unwanted cell proliferation of one or more subset of cells in a multicellular organism resulting in harm (i.e., discomfort or decreased life expectancy) to the multicellular organisms. In certain embodiments, a tumor can be benign (non- invasive) or malignant (invasive).
[0024] The term "cancer" is meant to refer to a malignant neoplasm, which is characterized by uncontrolled cell proliferation where cells have lost their normal regulatory controls that would otherwise govern the rate of cell growth. These unregulated, dividing cells can spread throughout the body and invade normal tissues in a process referred to as "metastasis."
[0025] The term "naturally occurring" or "native" when used in connection with biological materials such as nucleic acid molecules, polypeptides, host cells, and the like, refers to materials which are found in nature and are not manipulated by man. Similarly, "non-naturally occurring" or "non-native" refers to a material that is not found in nature or that has been structurally modified or synthesized by man.
[0026] The terms "HERl ," "epidermal growth factor receptor," "EGFR," and
"ErbB 1 " are used interchangeably herein and refer to an EGFR receptor protein or variant thereof, as described, for example, in Carpenter et αΙ., Αηη. Rev. Biochem. 1987, 56, 881-914. HER2 variants include proteins substantially homologous to a native EGFR, i.e., proteins having one or more naturally or non-naturally occurring amino acid deletions, insertions or substitutions (e.g., EGFR derivatives, homologs and fragments), as compared to the amino acid sequence of a native EGFR. The amino acid sequence of an HER2 variant is at least about 80% identical, at least about 90% identical, or at least about 95% identical to a native EGFR. An example of naturally occurring mutant forms of a native EGFR, i. e. a deletion mutant EGFR, is described in Humphrey et al , Proc. Natl. Acad. Sci. USA 1990, 87, 4207- 4211.
[0027] The terms "HER2" and "ErbB2" are used interchangeably herein and refer to a
HER2 receptor protein or variant thereof. For example, a human HER2 protein is described in Semba et al., Proc. Natl. Acad. Sci. USA 1985, 82, 6497-6501 and Yamamoto et al. Nature 1986, 319, 230-234 (Genebank accession number X03363). HER2 variants include proteins substantially homologous to a native HER2, i.e., proteins having one or more naturally or non-naturally occurring amino acid deletions, insertions or substitutions (e.g. , HER2 derivatives, homologs and fragments), as compared to the amino acid sequence of a native HER2 . The amino acid sequence of a HER2 variant is at least about 80% identical, at least about 90% identical, or at least about 95% identical to a native HER2.
[0028] The term "overexpress" or "overexpression" is meant that a cell associated with a disease, disorder, or condition comprises a detectably higher level of a protein, such as HERl or HER2, than an otherwise identical cell that is not associated with a disease, disorder or condition.
[0029] 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. The terms "subject" and "patient" are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject, in one embodiment, a human.
[0030] The terms "treat," "treating," and "treatment" are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.
[0031] The terms "prevent," "preventing," and "prevention" are meant to include a method of delaying and/or precluding the onset of a disorder, disease, or condition, and/or its attendant symptoms; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject's risk of acquiring a disorder, disease, or condition.
[0032] The term "contacting" or "contact" is meant to refer to bringing together of a therapeutic agent and cell or tissue such that a physiological and/or chemical effect takes place as a result of such contact. Contacting can take place in vitro, ex vivo, or in vivo. In one embodiment, a therapeutic agent is contacted with a cell in cell culture {in vitro) to determine the effect of the therapeutic agent on the cell. In another embodiment, the contacting of a therapeutic agent with a cell or tissue includes the administration of a therapeutic agent to a subject having the cell or tissue to be contacted.
[0033] The term "therapeutically effective amount" are meant to include the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated. The term "therapeutically effective amount" also refers to the amount of a compound that is sufficient to elicit the biological or medical response of a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.
[0034] The term "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable carrier," or "physiologically acceptable excipient" refers to a pharmaceutically-acceptable material, 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 a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive 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, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et ah, Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.
[0035] The term "about" or "approximately" means an acceptable error for a particular value as determined by one 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.
[0036] The terms "active ingredient" and "active substance" refer to a compound, which is administered, alone or in combination with one or more pharmaceutically acceptable excipients, to a subject for treating, preventing, or ameliorating one or more symptoms of a condition, disorder, or disease. As used herein, "active ingredient" and "active substance" may be an optically active isomer of a compound described herein.
[0037] The terms "drug," "therapeutic agent," and "chemotherapeutic agent" refer to a compound, or a pharmaceutical composition thereof, which is administered to a subject for treating, preventing, or ameliorating one or more symptoms of a condition, disorder, or disease.
[0038] The term "alkyl" refers to a linear or branched saturated monovalent hydrocarbon radical, wherein the alkyl may optionally be substituted with one or more substituents Q as described herein. For example, C1-6 alkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkyl is a linear saturated monovalent hydrocarbon radical that has 1 to 20 (C1-2o), 1 to 15 (C S), 1 to 10 (Ci_ io), or 1 to 6 (C1-6) carbon atoms, or branched saturated monovalent hydrocarbon radical of 3 to 20 (C3-2o), 3 to 15 (C3-15), 3 to 10 (C3-io), or 3 to 6 (C3-6) carbon atoms. As used herein, linear C^g and branched C3-6 alkyl groups are also referred as "lower alkyl." Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms), M-propyl, isopropyl, butyl (including all isomeric forms), «-butyl, isobutyl, sec -butyl, i-butyl, pentyl (including all isomeric forms), and hexyl (including all isomeric forms).
[0039] The term "aryl" refers to a monovalent monocyclic aromatic group and/or monovalent polycyclic aromatic group that contain at least one aromatic carbon ring. In certain embodiments, the aryl has from 6 to 20 (C6-20), from 6 to 15 (Ce-is), or from 6 to 10 (Ce-io) ring atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl. Aryl also refers to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl). In certain embodiments, aryl may be optionally substituted with one or more substituents Q as described herein.
[0040] The term "optionally substituted" is intended to mean that a group or substituent, such as an alkyl or aryl group, may be substituted with one or more substituents Q, each of which is independently selected from, e.g., (a) C\.e alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, Ce-14 aryl, C7-i5 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (b) halo, cyano (-CN), nitro (-N02), -C(0)Ra, -C(0)ORa, -C(0)NRbRc, -C(NRa)NRbR°, -ORa, -OC(0)Ra, -OC(0)ORa, -OC(0)NRbRc,
-OC(=NRa)NRbRc, -OS(0)Ra, -OS(0)2Ra, -OS(0)NRbRc, -OS(0)2NRbRc, -NR Rc, -NRaC(0)Rd, -NRaC(0)ORd, -NRaC(0)NRbRc, -NRaC(=NRd)NRbRc, -NRaS(0)Rd, -NRaS(0)2Rd, -NRaS(0)NRbR°, -NRaS(0)2NRbRc, -SRa, -S(0)Ra, -S(0)2Ra, -S(0)NRbR°, and -S(0)2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen; (ii) Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, Ce-u aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heteroaryl or heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa. As used herein, all groups that can be substituted are "optionally substituted," unless otherwise specified.
[0041] In one embodiment, each Qa is independently selected from the group consisting of (a) cyano, halo, and nitro; and (b) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-i4 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(0) e, -C(0)ORe, -C(0)NRfRg, -C(NRe)NRfRg, -ORe, -OC(0)Re, -OC(0)ORe, -OC(0)NRfRg,
-OC(=NRe)NRfRg, -OS(0)Re, -OS(0)2Re, -OS(0)NRfRg, -OS(0)2NRfRg, -NRfRg,
-NReC(0)Rh, -NReC(0)ORh, -NReC(0)NRfRg, -NReC(=NRh)NRfRg, -NReS(0)Rh, -NReS(0)2Rh, -NReS(0)NRfRg, -NReS(0)2NRfRg, -SRe, -S(0)Re, -S(0)2Re, -S(0)NR Rg, and -S(0)2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-i4 aryl, C7-1s aralkyl, heteroaryl, or heterocyclyl; or (iii) R and Rg together with the N atom to which they are attached form heteroaryl or heterocyclyl.
[0042] The term "solvate" refers to a complex or aggregate formed by one or more molecules of a solute, e.g., a compound provided herein, and one or more molecules of a solvent, which present in stoichiometric or non-stoichiometric amount. Suitable solvents include, but are not limited to, water, methanol, ethanol, «-propanol, isopropanol, and acetic acid. In certain embodiments, the solvent is pharmaceutically acceptable. In one
embodiment, the complex or aggregate is in a crystalline form. In another embodiment, the complex or aggregate is in a noncrystalline form. Where the solvent is water, the solvate is a hydrate. Examples of hydrates include, but are not limited to, a hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate.
Salts of an Indazolylpyrrolotriazine
[0043] (5)-Morpholin-3-ylmethyl 4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5- methylpyrrolo[l,2- ][l,2,4]triazin-6-ylcarbamate, which is also known as AC480 or BMS- 599626, has the structure of Formula I:
Figure imgf000011_0001
(I)
[0044] The compound of Formula I has been identified as a HER kinase inhibitor
(Wong et ah, Clin. Cancer Res. 2006, 12, 6186-6193). The compound of Formula I can be prepared according to U.S. Pat. Nos. 6,916,815; 7,102,001 ; and 7,148,220; and U.S. Pat. Appl. Publ. Nos. 2005/0209454 and 2006/0014741; each of which is incorporated herein by reference in its entirety. An alternative name for the compound of Formula I is [4-[[l-(3- fluorophenyl)methyl]-lH-indazol-5-ylamino]-5-methyl-pyrrolo[2, 1 -f] [ 1 ,2,4]triazin-6-yl]- carbamic acid, (35y3-morpholinylmethyl ester.
[0045] In one embodiment, provided herein is a sulfonic acid salt of (i¾-morpholin-3- ylmethyl 4-( 1 -(3 -fluorobenzyl)- lH-indazol-5 -ylamino)-5 -methylpyrrolo [ 1 ,2-/] [ 1 ,2,4]triazin- 6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof. As used herein, the term "sulfonic acid salt" is used interchangeably with the term "sulfonate salt." In certain embodiments, the sulfonic acid is C1-6 alkyl sulfonic acid, wherein the alkyl is optionally substituted with one or more substituents Q. In certain embodiments, the sulfonic acid is methanesulfonic acid or ethanesulfonic acid. In certain embodiments, the sulfonic acid is C6- 14 aryl sulfonic acid, wherein the aryl is optionally substituted with one or more substituents Q. In certain embodiments, the sulfonic acid is benzenesulfonic acid or 7-toluenesulfonic acid.
[0046] In certain embodiments, the molar ratio of (5)-morpholin-3-ylmethyl 4-(l-(3- fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2 ][l ,2,4]triazin-6-ylcarbamate versus the sulfonic acid in the salt provided herein, including hydrates and pharmaceutically acceptable solvates thereof, is ranging from about 0.5 to about 3, from about 0.5 to about 2, or from about 0.8 to about 1.2. In certain embodiments, the molar ratio of (5)-morpholin-3- ylmethyl 4-( 1 -(3 -fluorobenzyl)- lH-indazol-5 -ylamino)-5 -methylpyrrolo [ 1 ,2-/] [ 1 ,2,4]triazin- 6-ylcarbamate versus the sulfonic acid in the salt provided herein, including hydrates and pharmaceutically acceptable solvates thereof, 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.
[0047] In one embodiment, the sulfonic acid salt of (5 -morpholin-3-ylmethyl 4-(l-
(3-fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2: ][l,2,4]triazin-6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, comprises about one molar equivalent of
Figure imgf000012_0001
4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5- methylpyrrolo[l,2- J[l,2,4]triazin-6-ylcarbamate and about one molar equivalent of a sulfonic acid.
[0048] In certain embodiments, the sulfonic acid salt of
Figure imgf000012_0002
4-
(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2-y][l,2,4]triazin-6- ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, has a purity of at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 98.5%, at least about 99%, at least about 99.2%, at least about 99.4%, at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.8%, or at least about 99.9%. In certain embodiments, the sulfonic acid salt of (5*)-morpholin-3-ylmethyl 4-(l-(3- fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2 ][l,2,4]triazin-6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, contains a nitrosamine, in one embodiment, (5)-(4-nitrosomorpholin-3-yl)methyl 4-(l-(3-fluorobenzyl)-lH-indazol-5- ylamino)-5-methylpyrrolo[l,2- ][l,2,4]triazin-6-ylcarbamate, which has the structure of Formula II, at a level of no greater than about 5 ppm, no greater than about 4 ppm, no greater than about 3 ppm, no greater than about 2 ppm, no greater than about 1.5 ppm, no greater than about 1 ppm, no greater than about 0.8 ppm, no greater than about 0.6 ppm, no greater than about 0.4 ppm, no greater than about 0.2 ppm, or no greater than about 0.1 ppm.
F
Figure imgf000013_0001
(II)
[0049] In one embodiment, the sulfonic acid salt of (5)-morpholin-3-ylmethyl 4-(l-
(3-fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2: ][l,2,4]triazin-6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, is in an amorphous form. In another embodiment, the sulfonic acid salt of (5)-morpholin-3-ylmethyl 4-(l-(3- fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2 ][l,2,4]triazin-6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, is crystalline.
[0050] In one embodiment, provided herein is a methanesulfonic acid salt of (S)- morpholin-3-ylmethyl 4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2- y][l,2,4]triazin-6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof. As used herein, the term "methanesulfonic acid salt" is used interchangeably with the term "mesylate salt."
[0051] In certain embodiments, the molar ratio of (5)-morpholin-3-ylmethyl 4-(l-(3- fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2 ][l,2,4]triazin-6-ylcarbamate versus methanesulfonic acid in the salt provided herein, including hydrates and
pharmaceutically acceptable solvates thereof, is ranging from about 0.5 to about 3, from about 0.5 to about 2, or from about 0.8 to about 1.2. In certain embodiments, the molar ratio of (5 -morpholin-3-ylmethyl 4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5- methylpyrrolo[l,2- ][l,2,4]triazin-6-ylcarbamate versus methanesulfonic acid in the salt provided herein, including hydrates and pharmaceutically acceptable solvates thereof, 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.
[0052] In one embodiment, the methanesulfonic acid salt of (5 -morpholin-3- ylmethyl 4-( 1 -(3 -fluorobenzyl)- lH-indazol-5 -ylamino)-5 -methylpyrrolo [ 1 ,2- J [ 1 ,2,4]triazin- 6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, comprises about one molar equivalent of (^-morpholin-S -ylmethyl 4-(l-(3-fluorobenzyl)-lH-indazol-5- ylamino)-5-methylpyrrolo[l ,2-/][l ,2,4]triazin-6-ylcarbamate and about one molar equivalent of methanesulfonic acid. In certain embodiments, the molar ratio of (5)-morpholin-3- ylmethyl 4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l ,2- J[l ,2,4]triazin- 6-ylcarbamate versus methanesulfonic acid is determined based on its 1H NM spectrum.
[0053] In certain embodiments, the methanesulfonic acid salt of (S)-morpholin-3- ylmethyl 4-( 1 -(3 -fluorobenzyl)- lH-indazol-5 -ylamino)-5 -methylpyrrolo [ 1 ,2- J [ 1 ,2,4]triazin- 6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, has a purity of at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 98.5%, at least about 99%, at least about 99.2%, at least about 99.4%, at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.8%, or at least about 99.9%. In certain embodiments, the methanesulfonic acid salt of (<S)-morpholin-3 -ylmethyl 4-(l-(3- fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2: ][l ,2,4]triazin-6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, contains the nitrosamine at a level of no greater than about 5 ppm, no greater than about 4 ppm, no greater than about 3 ppm, no greater than about 2 ppm, no greater than about 1.5 ppm, no greater than about 1 ppm, no greater than about 0.8 ppm, no greater than about 0.6 ppm, no greater than about 0.4 ppm, no greater than about 0.2 ppm, or no greater than about 0.1 ppm.
[0054] In one embodiment, the methanesulfonic acid salt of (i¾-morpholin-3- ylmethyl 4-( 1 -(3 -fluorobenzyl)- lH-indazol-5 -ylamino)-5 -methylpyrrolo [ 1 ,2-f [ 1 ,2,4]triazin- 6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, is in an amorphous form. In another embodiment, the methanesulfonic acid salt of (5 -morpholin-3- ylmethyl 4-( 1 -(3 -fluorobenzyl)- lH-indazol-5 -ylamino)-5 -methylpyrrolo [ 1 ,2-f [ 1 ,2,4]triazin- 6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, is crystalline. In certain embodiments, the methanesulfonic acid salt has an endotherm with a peak temperature of about 202 °C and an onset temperature of 198 °C in a DSC thermogram. In certain embodiments, the methanesulfonic acid salt has an endotherm with a peak temperature of about 208 °C in a DSC thermogram. In certain embodiments, the
methanesulfonic acid salt shows no greater than about 5%, no greater than about 4%, no greater than about 3%, no greater than about 2%, or no greater than about 1% weight loss between 25 °C to 150 °C in a thermogravimetric thermogram. In certain embodiments, the methanesulfonic acid salt shows about 2% weight loss between 25 °C to 150 °C in a thermogravimetric thermogram.
[0055] In one embodiment, the methanesulfonic acid salt of (i¾-morpholin-3- ylmethyl 4-( 1 -(3 -fluorobenzyl)- lH-indazol-5 -ylamino)-5 -methylpyrrolo [ 1 ,2- | [ 1 ,2,4]triazin- 6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, is in crystalline Form I-A. In certain embodiments, the methanesulfonic acid salt in Form I-A has an X-ray powder diffraction pattern substantially as shown in FIG. 1 A. In certain embodiments, the methanesulfonic acid salt in Form I-A has one or more characteristic XRP diffraction peak at two-theta angles selected from approximately 7.2, 13.0, 28.4, and 29.5°. In certain embodiments, the methanesulfonic acid salt in Form I-A has characteristic XRP diffraction peaks at two-theta angles of approximately 3.5, 8.1, and 17.1°. In certain embodiments, the methanesulfonic acid salt in Form I-A has characteristic XRP diffraction peaks at two-theta angles of approximately 3.5, 8.1, 17.1, and 22.8°. In certain embodiments, the
methanesulfonic acid salt in Form I-A has characteristic XRP diffraction peaks at two-theta angles of approximately 3.5, 7.2, 8.1, 11.5, 14.6, 17.1, 17.7, 19.1, 22.8, 24.0, 25.2, and 26.6°.
[0056] In another embodiment, the methanesulfonic acid salt of (5)-morpholin-3- ylmethyl 4-( 1 -(3 -fluorobenzyl)- lH-indazol-5 -ylamino)-5 -methylpyrrolo [ 1 ,2-/] [ 1 ,2,4]triazin- 6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, is in crystalline Form I-B. In certain embodiments, the methanesulfonic acid salt in Form I-B has an X-ray powder diffraction pattern substantially as shown in FIG. IB. In certain embodiments, the methanesulfonic acid salt in Form I-B has one or more characteristic XRP diffraction peak at two-theta angles selected from approximately 2.6, 12.6, 15.9, and 17.9°. In certain embodiments, the methanesulfonic acid salt in Form I-B has characteristic XRP diffraction peaks at two-theta angles of approximately 2.6, 3.6, and 8.2°. In certain embodiments, the methanesulfonic acid salt in Form I-B has characteristic XRP diffraction peaks at two-theta angles of approximately 2.6, 3.6, 8.2, and 22.9°. In certain embodiments, the
methanesulfonic acid salt in Form I-B has characteristic XRP diffraction peaks at two-theta angles of approximately 2.6, 3.6, 8.2, 12.6, 14.7, 19.3, 21.9, 22.9, and 24.4°.
[0057] In yet another embodiment, the methanesulfonic acid salt of (5)-morpholin-3- ylmethyl 4-( 1 -(3 -fluorobenzyl)- lH-indazol-5 -ylamino)-5 -methylpyrrolo [ 1 ,2-f [ 1 ,2,4]triazin- 6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, is in crystalline Form I-C. In certain embodiments, the methanesulfonic acid salt in Form I-C has an X-ray powder diffraction pattern substantially as shown in FIG. 1C. In certain embodiments, the methanesulfonic acid salt in Form I-C has one or more characteristic XRP diffraction peak at two-theta angles selected from approximately 3.3, 6.8, 1 1.2, and 26.2°. In certain
embodiments, the methanesulfonic acid salt in Form I-C has characteristic XRP diffraction peaks at two-theta angles of approximately 3.5, 8.0, 16.9, and 19.0°. In certain embodiments, the methanesulfonic acid salt in Form I-C has characteristic XRP diffraction peaks at two- theta angles of approximately 3.5, 8.0, 16.9, 19.0, and 22.5°. In certain embodiments, the methanesulfonic acid salt in Form I-C has characteristic XRP diffraction peaks at two-theta angles of approximately 3.3, 8.0, 16.9, 19.0, and 22.5°. In certain embodiments, the methanesulfonic acid salt in Form I-C has characteristic XRP diffraction peaks at two-theta angles of approximately 3.3, 8.0, 14.5, 17.7, 16.9, 19.0, 22.5, 23.6, 24.1, 25.0, and 26.2°.
[0058] In still another embodiment, the methanesulfonic acid salt of (i¾-morpholin-3- ylmethyl 4-( 1 -(3 -fluorobenzyl)- lH-indazol-5 -ylamino)-5 -methylpyrrolo [ 1 ,2- J [ 1 ,2,4]triazin- 6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, is in crystalline Form I-D. In certain embodiments, the methanesulfonic acid salt in Form I-D has an X-ray powder diffraction pattern substantially as shown in FIG. ID. In certain embodiments, the methanesulfonic acid salt in Form I-D has one or more characteristic XRP diffraction peak at two-theta angles selected from approximately 7.4, 8.8, 13.2, 14.9, 27.2, 28.2, and 29.8°. In certain embodiments, the methanesulfonic acid salt in Form I-D has characteristic XRP diffraction peaks at two-theta angles of approximately 7.4. 13.2, and 19.3°. In certain embodiments, the methanesulfonic acid salt in Form I-D has characteristic XRP diffraction peaks at two-theta angles of approximately 7.4, 13.2, 19.3, 22.0, 25.1, and 27.2°.
[0059] In another embodiment, provided herein is an ethanesulfonic acid salt of (S)- morpholin-3-ylmethyl 4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l ,2- ][l ,2,4]triazin-6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof. As used herein, the term "ethanesulfonic acid salt" is used interchangeably with the term "esylate salt."
[0060] In certain embodiments, the molar ratio of (5)-morpholin-3-ylmethyl 4-(l-(3- fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2:/][l ,2,4]triazin-6-ylcarbamate versus ethanesulfonic acid in the salt provided herein, including hydrates and
pharmaceutically acceptable solvates thereof, is ranging from about 0.5 to about 3, from about 0.5 to about 2, or from about 0.8 to about 1.2. In certain embodiments, the molar ratio of ((S)-morpholin-3-ylmethyl 4-(l -(3-fluorobenzyl)-lH-mdazol-5-ylamino)-5- methylpyrrolo[ l ,2- J [l ,2,4]triazin-6-ylcarbamate versus ethanesulfonic acid in the salt provided herein, including hydrates and pharmaceutically acceptable solvates thereof, 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.
[0061 ] In one embodiment, the ethanesulfonic acid salt of (i¾-morpholin-3-ylmethyl
4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[ l ,2: ][l ,2,4]triazin-6- ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, comprises about one molar equivalent of (i¾-morpholin-3-ylmethyl 4-(l-(3-fluorobenzyl)- lH-indazol-5- ylamino)-5-methylpyrrolo[l ,2- | [l ,2,4]triazin-6-ylcarbamate and about one molar equivalent of ethanesulfonic acid. In certain embodiments, the molar ratio of (5)-morpholin-3-ylmethyl 4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[ l ,2-y][l ,2,4]triazin-6- ylcarbamate versus ethanesulfonic acid is determined based on its ¾ NM spectrum.
[0062] In certain embodiments, the ethanesulfonic acid salt of
Figure imgf000017_0001
ylmethyl 4-( 1 -(3 -fiuorobenzyl)- lH-indazol-5 -ylamino)-5 -methylpyrrolo [ 1 ,2-/] [ 1 ,2,4]triazin- 6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, has a purity of at least about 95%, at least about 96%>, at least about 97%, at least about 98%, at least about 98.5%, at least about 99%, at least about 99.2%, at least about 99.4%, at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.8%, or at least about 99.9%. In certain embodiments, the ethanesulfonic acid salt of (5)-morpholin-3-ylmethyl 4-(l -(3- fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l ,2: ] [l ,2,4]triazin-6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, contains the nitrosamine at a level of no greater than about 5 ppm, no greater than about 4 ppm, no greater than about 3 ppm, no greater than about 2 ppm, no greater than about 1.5 ppm, no greater than about 1 ppm, no greater than about 0.8 ppm, no greater than about 0.6 ppm, no greater than about 0.4 ppm, no greater than about 0.2 ppm, or no greater than about 0.1 ppm.
[0063] In one embodiment, the ethanesulfonic acid salt of (5*)-morpholin-3-ylmethyl
4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[ l ,2-y][l ,2,4]triazin-6- ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, is in an amorphous form. In another embodiment, the ethanesulfonic acid salt of (5)-morpholin-3-ylmethyl 4-(l - (3-fluorobenzyl)- lH-indazol-5-ylamino)-5-methylpyrrolo[ l ,2: ][l ,2,4]triazin-6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, is crystalline. In certain embodiments, the ethanesulfonic acid salt has an endotherm with a peak temperature of about 202 °C and an onset temperature of 197 °C in a DSC thermogram. In certain embodiments, the ethanesulfonic acid salt shows no greater than about 1%, no greater than about 0.8%, no greater than about 0.6%, no greater than about 0.4%, no greater than about 0.2%, no greater than about 0.1%, no greater than about 0.09%, no greater than about 0.08%, no greater than about 0.07%, no greater than about 0.06%, or no greater than about 0.05%> weight loss between 25 °C to 150 °C in a thermogravimetric thermogram. In certain embodiments, the ethanesulfonic acid salt shows about 0.1 % weight loss between 25 °C to 150 °C in a thermogravimetric thermogram.
[0064] In one embodiment, the ethanesulfonic acid salt of (6 -morpholin-3-ylmethyl
4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2: ][l,2,4]triazin-6- ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, is in crystalline Form II -A. In certain embodiments, the ethanesulfonic acid salt in Form II-A has an X-ray powder diffraction pattern substantially as shown in FIG. 2A. In certain embodiments, the ethanesulfonic acid salt in Form II-A has one or more characteristic XRP diffraction peaks at two-theta angles selected from approximately 11.9, 24.4, and 28.6°. In certain embodiments, the ethanesulfonic acid salt in Form II-A has characteristic XRP diffraction peaks at two- theta angles of approximately 3.6 and 8.4°. In certain embodiments, the ethanesulfonic acid salt in Form I-A has characteristic XRP diffraction peaks at two-theta angles of
approximately 3.6, 7.4, 8.4, 17.8, and 19.0°. In certain embodiments, the ethanesulfonic acid salt in Form I-A has characteristic XRP diffraction peaks at two-theta angles of
approximately 3.6, 7.4, 8.4, 11.9, 13.4, 15.1, 17.8, 19.0, 24.4, 25.7, 27.2, and 28.6°.
[0065] In another embodiment, the ethanesulfonic acid salt of (5)-morpholin-3- ylmethyl 4-( 1 -(3 -fluorobenzyl)- lH-indazol-5 -ylamino)-5 -methylpyrrolo [ 1 ,2-f [ 1 ,2,4]triazin- 6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, is in crystalline Form II-B. In certain embodiments, the ethanesulfonic acid salt in Form II-B has an X-ray powder diffraction pattern substantially as shown in FIG. 2B. In certain embodiments, the ethanesulfonic acid salt in Form II-B has characteristic XRP diffraction peaks at two-theta angles selected from approximately 24.1 and 25.3°. In certain embodiments, the
ethanesulfonic acid salt in Form II-B has characteristic XRP diffraction peaks at two-theta angles of approximately 3.6 and 8.4°. In certain embodiments, the ethanesulfonic acid salt in Form II-B has characteristic XRP diffraction peaks at two-theta angles of approximately 3.6, 8.4, 25.3, and 28.0°. In certain embodiments, the ethanesulfonic acid salt in Form II-B has characteristic XRP diffraction peaks at two-theta angles of approximately 3.6, 8.4, 15.2, 16.9, 23.2, 25.3, and 28.0°. In certain embodiments, the ethanesulfonic acid salt in Form II-B has an endotherm with a peak temperature of about 202 °C and an onset temperature of 197 °C in a DSC thermogram. In certain embodiments, the ethanesulfonic acid salt in Form II-B shows no greater than about 1%, no greater than about 0.8%, no greater than about 0.6%, no greater than about 0.4%, no greater than about 0.2%, no greater than about 0.1%, no greater than about 0.09%), no greater than about 0.08%, no greater than about 0.07%, no greater than about 0.06%), or no greater than about 0.05% weight loss between 25 °C to 150 °C in a thermogravimetric thermogram. In certain embodiments, the ethanesulfonic acid salt in Form II-B shows about 0.1% weight loss between 25 °C to 150 °C in a thermogravimetric thermogram.
[0066] In yet another embodiment, the ethanesulfonic acid salt of (<S)-morpholin-3- ylmethyl 4-( 1 -(3 -fluorobenzyl)- lH-indazol-5 -ylamino)-5 -methylpyrrolo [ 1 ,2- J [ 1 ,2,4]triazin- 6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, is in crystalline Form II-C. In certain embodiments, the ethanesulfonic acid salt in Form II-C has an X-ray powder diffraction pattern substantially as shown in FIG. 2C. In certain embodiments, the ethanesulfonic acid salt in Form II-C has one or more characteristic XRP diffraction peaks at two-theta angles selected from approximately 4.0, 12.4, 13.8, 16.3, 19.2, 20.3, 21.6, 24.8. 26.0, 26.8, and 29.0°. In certain embodiments, the ethanesulfonic acid salt in Form II-C has characteristic XRP diffraction peaks at two-theta angles of approximately 4.0, 13.8, and 16.3°. In certain embodiments, the ethanesulfonic acid salt in Form II-C has characteristic XRP diffraction peaks at two-theta angles of approximately 4.0, 13.8, 16.3, and 23.2°. In certain embodiments, the ethanesulfonic acid salt in Form II-C has characteristic XRP diffraction peaks at two-theta angles of approximately 4.0, 8.1, 10.6, 12.4, 13.8, 16.3, 21.6, 23.2, and 26.8°.
[0067] In yet another embodiment, the ethanesulfonic acid salt of (5)-morpholin-3- ylmethyl 4-( 1 -(3 -fluorobenzyl)- lH-indazol-5 -ylamino)-5 -methylpyrrolo [ 1 ,2- ] [ 1 ,2,4]triazin- 6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, is in crystalline Form II-D. In certain embodiments, the ethanesulfonic acid salt in Form II -D has an X-ray powder diffraction pattern substantially as shown in FIG. 2D. In certain embodiments, the ethanesulfonic acid salt in Form II-D has one or more characteristic XRP diffraction peaks at two-theta angles selected from approximately 3.2 and 6.7°. In certain embodiments, the ethanesulfonic acid salt in Form II-D has characteristic XRP diffraction peaks at two-theta angles of approximately 3.2 and 8.1°.
[0068] In still another embodiment, the ethanesulfonic acid salt of (5)-morpholin-3- ylmethyl 4-( 1 -(3 -fluorobenzyl)- lH-indazol-5 -ylamino)-5 -methylpyrrolo [ 1 ,2- J [ 1 ,2,4]triazin- 6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, is in crystalline Form II-E. In certain embodiments, the ethanesulfonic acid salt in Form II-E has an X-ray powder diffraction pattern substantially as shown in FIG. 2E. In certain embodiments, the ethanesulfonic acid salt in Form II-E has characteristic XRP diffraction peaks at two-theta angles selected from approximately 4.6, 13.0, 15.4, 23.7, or 25.0°. In certain embodiments, the ethanesulfonic acid salt in Form II-E has characteristic XRP diffraction peaks at two-theta angles of approximately 4.6, 12.2, 14.0, and 15.4°. In certain embodiments, the
ethanesulfonic acid salt in Form II-E has characteristic XRP diffraction peaks at two-theta angles of approximately 4.6, 12.2, 14.0, 15.4, 25.0, 25.8, and 27.9°. In certain embodiments, the ethanesulfonic acid salt in Form II-E has characteristic XRP diffraction peaks at two-theta angles of approximately 4.6, 8.4, 12.2, 14.0, 15.4, 19.5, 25.0, 25.8, and 27.9°.
[0069] In yet another embodiment, provided herein is a benzenesulfonic acid salt of
(5)^ο ηο1ώ-3-ν1ηιείην1 4-(l -(3 -fluorobenzyl)- lH-indazol-5 -ylamino)-5- methylpyrrolo[l,2- ][l,2,4]triazin-6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof. As used herein, the term "benzenesulfonic acid salt" is used interchangeably with the term "benzenesulfonate salt."
[0070] In certain embodiments, the molar ratio of (5)-morpholin-3-ylmethyl 4-(l-(3- fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2:/][l,2,4]triazin-6-ylcarbamate versus benzenesulfonic acid in the salt provided herein, including hydrates and
pharmaceutically acceptable solvates thereof, is ranging from about 0.5 to about 3, from about 0.5 to about 2, or from about 0.8 to about 1.2. In certain embodiments, the molar ratio of ((S)-morpholin-3-ylmethyl 4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5- methylpyrrolo[l,2-y][l,2,4]triazin-6-ylcarbamate versus benzenesulfonic acid in the salt provided herein, including hydrates and pharmaceutically acceptable solvates thereof, 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. [0071] In one embodiment, the benzenesulfonic acid salt of (5)-morpholin-3-ylmethyl
4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2-y][l,2,4]triazin-6- ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, comprises about one molar equivalent of (S)-morpholin-3-ylmethyl 4-(l-(3-fluorobenzyl)-lH-indazol-5- ylamino)-5-methylpyrrolo[l ,2-y][l ,2,4]triazin-6-ylcarbamate and about one molar equivalent of benzenesulfonic acid. In certain embodiments, the molar ratio of ( -morpholin-3- ylmethyl 4-( 1 -(3 -fluorobenzyl)- lH-indazol-5 -ylamino)-5 -methylpyrrolo [ 1 ,2- J [ 1 ,2,4]triazin- 6-ylcarbamate versus benzenesulfonic acid is determined based on its ¾ NM spectrum.
[0072] In certain embodiments, the benzenesulfonic salt of (S)-morpholin-3-ylmethyl
4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2-y][l,2,4]triazin-6- ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, has a purity of at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 98.5%, at least about 99%, at least about 99.2%, at least about 99.4%, at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.8%, or at least about 99.9%. In certain embodiments, the benzenesulfonic acid salt of (S)-morpholin-3-ylmethyl 4-(l-(3- fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2 ][l ,2,4]triazin-6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, contains the nitrosamine at a level of no greater than about 5 ppm, no greater than about 4 ppm, no greater than about 3 ppm, no greater than about 2 ppm, no greater than about 1.5 ppm, no greater than about 1 ppm, no greater than about 0.8 ppm, no greater than about 0.6 ppm, no greater than about 0.4 ppm, no greater than about 0.2 ppm, or no greater than about 0.1 ppm.
[0073] In one embodiment, the benzenesulfonic acid salt of (5)-morpholin-3-ylmethyl
4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2 ][l,2,4]triazin-6- ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, is in an amorphous form. In another embodiment, the benzenesulfonic acid salt of (5)-morpholin-3-ylmethyl 4- (l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l ,2:/][l,2,4]triazin-6- ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, is crystalline. In certain embodiments, the benzenesulfonic acid salt has an endotherm with a peak temperature of about 145 °C and an onset temperature of 131 °C in a DSC thermogram. In certain embodiments, the benzenesulfonic acid salt has an endotherm with a peak temperature of about 230 °C and an onset temperature of 225 °C in a DSC thermogram.
[0074] In yet another embodiment, provided herein is a 7-toluenesulfonic acid salt of
Figure imgf000022_0001
4-(l -(3 -fluorobenzyl)- lH-indazol-5-ylamino)-5- methylpyrrolo[l,2-y][l,2,4]triazin-6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof. As used herein, the term "p-toluenesulfonic acid salt" is used
interchangeably with the term "tosylate salt."
[0075] In certain embodiments, the molar ratio of (5)-morpholin-3-ylmethyl 4-(l-(3- fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2 ][l,2,4]triazin-6-ylcarbamate versus p-toluenesulfonic acid in the salt provided herein, including hydrates and
pharmaceutically acceptable solvates thereof, is ranging from about 0.5 to about 3, from about 0.5 to about 2, or from about 0.8 to about 1.2. In certain embodiments, the molar ratio of ((S)-morpholin-3-ylmethyl 4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5- methylpyrrolo[l,2- J[l,2,4]triazin-6-ylcarbamate versus p-toluenesulfonic acid in the salt provided herein, including hydrates or pharmaceutically acceptable solvates thereof, 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.
[0076] In one embodiment, the p-toluenesulfonic acid salt of (i¾-morpholin-3- ylmethyl 4-( 1 -(3 -fluorobenzyl)- lH-indazol-5 -ylamino)-5 -methylpyrrolo [ 1 ,2-/] [ 1 ,2,4]triazin- 6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, comprises about one molar equivalent of (i¾-morpholin-3-ylmethyl 4-(l-(3-fluorobenzyl)-lH-indazol-5- ylamino)-5-methylpyrrolo[l,2- |[l,2,4]triazin-6-ylcarbamate and about one molar equivalent of p-toluenesulfonic acid. In certain embodiments, the molar ratio of (5)-morpholin-3- ylmethyl 4-( 1 -(3 -fluorobenzyl)- lH-indazol-5 -ylamino)-5 -methylpyrrolo [ 1 ,2-/] [ 1 ,2,4]triazin- 6-ylcarbamate versus p-toluenesulfonic acid is determined based on its ¾ NM spectrum.
[0077] In certain embodiments, the p-toluenesulfonic acid salt of (5)-morpholin-3- ylmethyl 4-( 1 -(3 -fluorobenzyl)- lH-indazol-5 -ylamino)-5 -methylpyrrolo [ 1 ,2-/] [ 1 ,2,4]triazin- 6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, has a purity of at least about 95%, at least about 96%>, at least about 97%, at least about 98%, at least about 98.5%, at least about 99%, at least about 99.2%, at least about 99.4%, at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.8%, or at least about 99.9%. In certain embodiments, the p-toluenesulfonic acid salt of (5)-morpholin-3-ylmethyl 4-(l-(3- fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2:/][l,2,4]triazin-6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, contains the nitrosamine at a level of no greater than about 5 ppm, no greater than about 4 ppm, no greater than about 3 ppm, no greater than about 2 ppm, no greater than about 1.5 ppm, no greater than about 1 ppm, no greater than about 0.8 ppm, no greater than about 0.6 ppm, no greater than about 0.4 ppm, no greater than about 0.2 ppm, or no greater than about 0.1 ppm.
[0078] In one embodiment, the ?-toluenesulfonic acid salt of (i¾-morpholin-3- ylmethyl 4-( 1 -(3 -fluorobenzyl)- lH-indazol-5 -ylamino)-5 -methylpyrrolo [ 1 ,2-f [ 1 ,2,4]triazin- 6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, is in an amorphous form. In another embodiment, the p-toluenesulfonic acid salt of (iS -morpholin-3- ylmethyl 4-( 1 -(3 -fluorobenzyl)- lH-indazol-5 -ylamino)-5 -methylpyrrolo [ 1 ,2- J [ 1 ,2,4]triazin- 6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, is crystalline. In certain embodiments, the -toluenesulfonic acid salt has an endotherm with a peak temperature of about 202 °C in a DSC thermogram.
[0079] In yet another embodiment, provided herein is an acetic acid salt of (5)- morpholin-3-ylmethyl 4-(l-(3-fiuorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l ,2- y][l ,2,4]triazin-6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof. As used herein, the term "acetic acid salt" is used interchangeably with the term "acetate salt."
[0080] In certain embodiments, the molar ratio of (5)-morpholin-3-ylmethyl 4-(l-(3- fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2: ][l ,2,4]triazin-6-ylcarbamate versus acetic acid in the salt provided herein, including hydrates and pharmaceutically acceptable solvates thereof, is ranging from about 0.5 to about 3, from about 0.5 to about 2, or from about 0.8 to about 1.2. In certain embodiments, the molar ratio of (5)-morpholin-3- ylmethyl 4-( 1 -(3 -fluorobenzyl)- lH-indazol-5 -ylamino)-5 -methylpyrrolo [ 1 ,2-f [ 1 ,2,4]triazin- 6-ylcarbamate versus acetic acid in the salt provided herein, including hydrates and pharmaceutically acceptable solvates thereof, 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.
[0081] In one embodiment, the acetic acid salt of (5 -morpholin-3-ylmethyl 4-(l-(3- fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2: ][l ,2,4]triazin-6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, comprises about one molar equivalent of
Figure imgf000023_0001
4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5- methylpyrrolo[l ,2- ][l ,2,4]triazin-6-ylcarbamate and about one molar equivalent of acetic acid. In certain embodiments, the molar ratio of (5)-morpholin-3-ylmethyl 4-(l-(3- fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2 ][l ,2,4]triazin-6-ylcarbamate versus acetic acid is determined based on its XH MR spectrum.
[0082] In certain embodiments, the acetic salt of (S)-morpholin-3-ylmethyl 4-(l-(3- fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2: ][l ,2,4]triazin-6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, has a purity of at least about 95%, at least about 96%, at least about 97%, at least about 98%), at least about 98.5%, at least about 99%, at least about 99.2%, at least about 99.4%, at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.8%o, or at least about 99.9%. In certain embodiments, the acetic acid salt of (5 -morpholin-3-ylmethyl 4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5- methylpyrrolo[l ,2- J[l ,2,4]triazin-6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, contains the nitrosamine at a level of no greater than about 5 ppm, no greater than about 4 ppm, no greater than about 3 ppm, no greater than about 2 ppm, no greater than about 1.5 ppm, no greater than about 1 ppm, no greater than about 0.8 ppm, no greater than about 0.6 ppm, no greater than about 0.4 ppm, no greater than about 0.2 ppm, or no greater than about 0.1 ppm.
[0083] In one embodiment, the acetic acid salt of (5)-morpholin-3-ylmethyl 4-(l-(3- fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2 ][l ,2,4]triazin-6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, is in an amorphous form. In another embodiment, the acetic acid salt of (5)-morpholin-3-ylmethyl 4-(l-(3-fluorobenzyl)- lH-indazol-5-ylamino)-5-methylpyrrolo[l ,2- ][l,2,4]triazin-6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, is crystalline. In certain embodiments, the acetic sale has an endotherm with a peak temperature of about 127 °C and an onset temperature of 119 °C. In certain embodiments, the acetic sale has an endotherm with a peak temperature of about 165 °C and an onset temperature of 160 °C.
[0084] In yet another embodiment, provided herein is a maleic acid salt of (S)- morpholin-3-ylmethyl 4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l ,2- y][l ,2,4]triazin-6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof. As used herein, the term "maleic acid salt" is used interchangeably with the term "maleate salt." [0085] In certain embodiments, the molar ratio of (5)-morpholin-3-ylmethyl 4-(l-(3- fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2 ][l ,2,4]triazin-6-ylcarbamate versus maleic acid in the salt provided herein, including hydrates or pharmaceutically acceptable solvates thereof, is ranging from about 0.25 to about 1.5, from about 0.25 to about 1, or from about 0.4 to about 0.6. In certain embodiments, the molar ratio of (5*)-morpholin- 3-ylmethyl 4-(l -(3-fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[ 1 ,2- y][l ,2,4]triazin-6-ylcarbamate versus maleic acid in the salt provided herein, including hydrates and pharmaceutically acceptable solvates thereof, is about 0.2, about 0.25, about 0.3, about 0.35, about 0.4, about 0.45, about 0.5, about 0.55, about 0.6, about 0.65, about 0.7, about 0.75, about 0.8, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, or about 1.5.
[0086] In one embodiment, the maleic acid salt of (S)-morpholin-3-ylmethyl 4-(l-(3- fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2: ][l ,2,4]triazin-6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, comprises about two molar equivalents of (5 -morpholin-3-ylmethyl 4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5- methylpyrrolo[l ,2- ][l ,2,4]triazin-6-ylcarbamate and about one molar equivalent of maleic acid. In certain embodiments, the molar ratio of (S)-morpholin-3-ylmethyl 4-(l-(3- fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2 ][l ,2,4]triazin-6-ylcarbamate versus maleic acid is determined based on its LH NMR spectrum.
[0087] In certain embodiments, the maleic salt of (5)-morpholin-3-ylmethyl 4-(l-(3- fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2 ][l ,2,4]triazin-6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, has a purity of at least about 95%, at least about 96%, at least about 97%, at least about 98%>, at least about 98.5%, at least about 99%, at least about 99.2%, at least about 99.4%, at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.8%o, or at least about 99.9%. In certain embodiments, the maleic acid salt of (5)-morpholin-3-ylmethyl 4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5- methylpyrrolo[l ,2- ][l ,2,4]triazin-6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, contains the nitrosamine at a level of no greater than about 5 ppm, no greater than about 4 ppm, no greater than about 3 ppm, no greater than about 2 ppm, no greater than about 1.5 ppm, no greater than about 1 ppm, no greater than about 0.8 ppm, no greater than about 0.6 ppm, no greater than about 0.4 ppm, no greater than about 0.2 ppm, or no greater than about 0.1 ppm. [0088] In one embodiment, the maleic acid salt of (S)-morpholin-3-ylmethyl 4-(l-(3- fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2 ][l ,2,4]triazin-6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, is in an amorphous form. In another embodiment, the maleic acid salt of (5)-morpholin-3-ylmethyl 4-(l-(3-fluorobenzyl)- lH-indazol-5-ylamino)-5-methylpyrrolo[l ,2- J[l,2,4]triazin-6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, is crystalline. In certain embodiments, the maleic acid salt has an endotherm with a peak temperature of about 197 °C and an onset temperature of 194 °C in a DSC thermogram. In certain embodiments, the maleic acid salt shows about 0.1% weight loss between 25 °C to 150 °C in a thermogravimetric thermogram. In certain embodiments, the maleic acid salt shows no greater than about 5%, no greater than about 4.5%, no greater than about 4%, no greater than about 3.5%, no greater than about 3%, no greater than about 2.5%, no greater than about 2%, no greater than about 1.5%, no greater than about 1%, no greater than about 0.8%, no greater than about 0.6%, no greater than about 0.4%, no greater than about 0.2%, no greater than about 0.1%, no greater than about 0.09%, no greater than about 0.08%, no greater than about 0.07%, no greater than about 0.06%, or no greater than about 0.05% weight loss between 25 °C to 150 °C in a thermogravimetric thermogram.
[0089] In one embodiment, the maleic acid salt of (S)-morpholin-3-ylmethyl 4-(l-(3- fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2 ][l ,2,4]triazin-6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, is in crystalline Form III-A. In certain embodiments, the maleic acid salt in Form III-A has an X-ray powder diffraction pattern substantially as shown in FIG. 3A. In certain embodiments, the maleic acid salt in Form III-A has one or more characteristic XRP diffraction peaks at two-theta angles selected from approximately 10.0, 10.8, 13.1, 17.2, 21.6, 22.5, 22.7, 24.6, 26.0, and 29.6°. In certain embodiments, the maleic acid salt in Form III-A has characteristic XRP diffraction peaks at two-theta angles of approximately 5.1, 12.8, 14.0, 15.2, and 15.5¾°. In certain embodiments, the maleic acid salt in Form III-A has characteristic XRP diffraction peaks at two-theta angles of approximately 5.1, 12.8, 14.0, 15.2, 15.5, 17.7, 18.0, 20.7, and 22.1 °. In certain embodiments, the maleic acid salt in Form III-A has characteristic XRP diffraction peaks at two-theta angles of approximately 5.1, 12.8, 14.0, 15.2, 15.5, 17.7, 18.0, 19.2, 20.7, 22.1 , and 22.7°. In certain embodiments, the maleic acid salt in crystalline Form III-A has an endotherm with a peak temperature of about 206 °C in a DSC thermogram. In certain embodiments, the maleic acid salt in crystalline Form III-A shows about 0.1% weight loss between 25 °C to 150 °C in a thermogravimetric thermogram.
[0090] In another embodiment, the maleic acid salt of (^)-morpholin-3-ylmethyl 4-(l-
(3-fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2: ][l,2,4]triazin-6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, is in crystalline Form III-B. In certain embodiments, the maleic acid salt in Form III-B has an X-ray powder diffraction pattern substantially as shown in FIG. 3B. In certain embodiments, the maleic acid salt in Form III-B has a characteristic XRP diffraction peak at a two-theta angle of 29.8°. In certain embodiments, the maleic acid salt in Form III-B has characteristic XRP diffraction peaks at two-theta angles of approximately 11.6 and 15.6°. In certain embodiments, the maleic acid salt in Form III-B has characteristic XRP diffraction peaks at two-theta angles of
approximately 11.6, 15.6, and 25.1°. In certain embodiments, the maleic acid salt in Form III-B has characteristic XRP diffraction peaks at two-theta angles of approximately 5.0, 11.6, 15.6, 25.1, and 27.4°. In certain embodiments, the maleic acid salt in crystalline Form III-B has an endotherm with a peak temperature of about 198 °C in a DSC thermogram. In certain embodiments, the maleic acid salt in crystalline Form III-B shows about 2.8% weight loss between 25 °C to 122 °C in a thermogravimetric thermogram. In certain embodiments, the maleic acid salt in crystalline Form III-B shows about 3.5% weight loss between 25 °C to 166 °C in a thermogravimetric thermogram.
[0091] In yet another embodiment, the maleic acid salt of (5)-morpholin-3-ylmethyl
4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2-y][l,2,4]triazin-6- ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, is in crystalline Form III-C. In certain embodiments, the maleic acid salt in Form III-C has an X-ray powder diffraction pattern substantially as shown in FIG. 3C. In certain embodiments, the maleic acid salt in Form III-C has one or more characteristic XRP diffraction peaks at two-theta angles selected from approximately 8.8, 11.0, 11.9, 16.8, 18.3, 22.3, 25.3, 27.0, and 27.8°. In certain embodiments, the maleic acid salt in Form III-C has a characteristic XRP diffraction peak at a two-theta angle of approximately 17.4°. In certain embodiments, the maleic acid salt in Form III-C has characteristic XRP diffraction peaks at two-theta angles of
approximately 17.4, 25.3, and 27.0°. In certain embodiments, the maleic acid salt in Form III-C has characteristic XRP diffraction peaks at two-theta angles of approximately 17.4, 22.3, 23.9, 25.3, and 27.0°. [0092] In still another embodiment, the maleic acid salt of (5)-morpholin-3-ylmethyl
4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2-y][l,2,4]triazin-6- ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, is in crystalline Form III-D. In certain embodiments, the maleic acid salt in Form III-D has an X-ray powder diffraction pattern substantially as shown in FIG. 3D. In certain embodiments, the maleic acid salt in Form III-C has one or more characteristic XRP diffraction peaks at two-theta angles selected from approximately 3.6, 4.6, 7.4, 12.4, and 19.5°. In certain embodiments, the maleic acid salt in Form III-D has characteristic XRP diffraction peaks at two-theta angles of approximately 13.4, 17.5, and 19.5°. In certain embodiments, the maleic acid salt in Form III-D has an endotherm with a peak temperature of about 82 °C in a DSC thermogram. In certain embodiments, the maleic acid salt in Form III-D shows about 14.3% weight loss between 25 °C to 91 °C in a thermogravimetric thermogram.
[0093] In yet another embodiment, provided herein is a nitric acid salt of (S)- morpholin-3-ylmethyl 4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l ,2- y][l ,2,4]triazin-6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof. As used herein, the term "nitric acid salt" is used interchangeably with the term "nitrate salt."
[0094] In certain embodiments, the molar ratio of (5)-morpholin-3-ylmethyl 4-(l-(3- fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2 ][l ,2,4]triazin-6-ylcarbamate versus nitric acid in the salt provided herein, including hydrates and pharmaceutically acceptable solvates thereof, is ranging from about 0.5 to about 3, from about 0.5 to about 2, or from about 0.8 to about 1.2. In certain embodiments, the molar ratio of (S)-morpholin-3- ylmethyl 4-( 1 -(3 -fluorobenzyl)- lH-indazol-5 -ylamino)-5 -methylpyrrolo [ 1 ,2-f [ 1 ,2,4]triazin- 6-ylcarbamate versus nitric acid in the salt provided herein, including hydrates and pharmaceutically acceptable solvates thereof, 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.
[0095] In one embodiment, the nitric acid salt of (5)-morpholin-3-ylmethyl 4-(l-(3- fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2 ][l ,2,4]triazin-6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, comprises about one molar equivalent of (5)-morpholin-3-ylmethyl 4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5- methylpyrrolo[l ,2-y][l ,2,4]triazin-6-ylcarbamate and about one molar equivalent of nitric acid. [0096] In certain embodiments, the nitric salt of (S)-morpholin-3-ylmethyl 4-(l-(3- fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2 ][l ,2,4]triazin-6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, has a purity of at least about 95%, at least about 96%o, at least about 97%, at least about 98%, at least about 98.5%, at least about 99%, at least about 99.2%, at least about 99.4%, at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.8%, or at least about 99.9%. In certain embodiments, the nitric acid salt of (5)-morpholin-3-ylmethyl 4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5- methylpyrrolo[l ,2-y][l ,2,4]triazin-6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, contains the nitrosamine of no greater than about 5 ppm, no greater than about 4 ppm, no greater than about 3 ppm, no greater than about 2 ppm, no greater than about 1.5 ppm, no greater than about 1 ppm, no greater than about 0.8 ppm, no greater than about 0.6 ppm, no greater than about 0.4 ppm, no greater than about 0.2 ppm, or no greater than about 0.1 ppm.
[0097] In one embodiment, the nitric acid salt of (5)-morpholin-3-ylmethyl 4-(l-(3- fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2: ][l ,2,4]triazin-6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, is in an amorphous form. In another embodiment, the nitric acid salt of (5)-mo^holin-3-ylmethyl 4-(l-(3-fluorobenzyl)- lH-indazol-5-ylamino)-5-methylpyrrolo[l ,2- ][l,2,4]triazin-6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, is crystalline. In certain embodiments, the nitric acid salt has an endotherm with a peak temperature of about 216 °C and an onset temperature of 210 °C in a DSC thermogram.
[0098] In still another embodiment, provided herein is a phosphoric acid salt of (S)- morpholin-3-ylmethyl 4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l ,2- y][l ,2,4]triazin-6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof. As used herein, the term "phosphoric acid salt" is used interchangeably with the term
"phosphate salt."
[0099] In certain embodiments, the molar ratio of (5)-morpholin-3-ylmethyl 4-(l-(3- fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2 ][l ,2,4]triazin-6-ylcarbamate versus phosphoric acid in the salt provided herein, including hydrates and pharmaceutically acceptable solvates thereof, is ranging from about 0.5 to about 3, from about 0.5 to about 2, or from about 0.8 to about 1.2. In certain embodiments, the molar ratio of (5)-morpholin-3- ylmethyl 4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l ,2- |[l ,2,4]triazin- 6-ylcarbamate versus phosphoric acid in the salt provided herein, including hydrates and pharmaceutically acceptable solvates thereof, 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.
[00100] In one embodiment, the phosphoric acid salt of (5)-morpholin-3-ylmethyl 4- (l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l ,2 ][l,2,4]triazin-6- ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, comprises about one molar equivalent of (£)-morpholin-3-ylmethyl 4-(l-(3-fluorobenzyl)-lH-indazol-5- ylamino)-5-methylpyrrolo[l ,2- J[l ,2,4]triazin-6-ylcarbamate and about one molar equivalent of phosphoric acid.
[00101] In certain embodiments, the phosphoric acid salt of (5)-morpholin-3-ylmethyl 4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2-y][l,2,4]triazin-6- ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, has a purity of at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 98.5%, at least about 99%, at least about 99.2%, at least about 99.4%, at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.8%, or at least about 99.9%. In certain embodiments, the phosphoric acid salt of (¾-morpholin-3-ylmethyl 4-(l-(3- fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2 ][l ,2,4]triazin-6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, contains the nitrosamine of no greater than about 5 ppm, no greater than about 4 ppm, no greater than about 3 ppm, no greater than about 2 ppm, no greater than about 1.5 ppm, no greater than about 1 ppm, no greater than about 0.8 ppm, no greater than about 0.6 ppm, no greater than about 0.4 ppm, no greater than about 0.2 ppm, or no greater than about 0.1 ppm.
[00102] In one embodiment, the phosphoric acid salt of (5)-morpholin-3-ylmethyl 4- (l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l ,2 ][l,2,4]triazin-6- ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, is in an amorphous form. In another embodiment, the phosphoric acid salt of (S)-morpholin-3-ylmethyl 4-(l-(3- fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2 ][l ,2,4]triazin-6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof, is crystalline. In certain embodiments, the phosphoric acid salt has an endotherm with a peak temperature of about 164 °C and an onset temperature of 159 °C in a DSC thermogram. [00103] The purity of the salts provided herein may be determined by standard analytical methods, such as thin layer chromatography (TLC), gel electrophoresis, gas chromatography, high performance liquid chromatography (HPLC), and mass spectrometry (MS). The salts provided herein in solid forms may be characterized using a number of methods known to a person skilled in the art, including, but not limited to, single crystal X- ray diffraction, X-ray powder diffraction (X PD), microscopy (e.g. , scanning electron microscopy (SEM)), thermal analysis (e.g., differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), and hot-stage microscopy), and spectroscopy (e.g., infrared, Raman, and solid-state nuclear magnetic resonance). The particle size and size distribution of the salts provided herein in solid forms may be determined by conventional methods, such as laser light scattering technique.
[00104] It should be understood that the numerical values of the peaks of the X-ray powder diffraction patterns may vary slightly from one machine to another or from one sample to another, and so the values quoted are not to be construed as absolute, but with an allowable variability, such as 0.1°, which is recommended in the United State Pharmacopeia (pages: 387-389, 2007).
Process of Preparation
[00105] In one embodiment, provided herein is a process for preparing a salt of (S)- morpholin-3-ylmethyl 4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l ,2- y][l ,2,4]triazin-6-ylcarbamate, as provided herein, or a hydrate or pharmaceutically acceptable solvate thereof; which comprises reacting (5)-morpholin-3-ylmethyl 4-(l-(3- fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2 ][l ,2,4]triazin-6-ylcarbamate with an acid in a solvent at a first predetermined temperature. In another embodiment, the process further comprises precipitating the salt at a second predetermined temperature. In certain embodiments, the reaction and/or precipitation steps are performed under an inert atmosphere. In certain embodiments, the reaction and/or precipitation steps are performed under a nitrogen or argon atmosphere.
[00106] Suitable solvents for use in preparing the salt provided herein include, but are not limited to, hydrocarbons, including petroleum ether, pentane, hexane(s), heptane(s), octane, isooctane, cyclopentane, cyclohexane, methylcyclohexane, benzene, toluene, xylene, tetralin, and cumene; halogenated hydrocarbons, including dichloromethane (DCM), 1 ,2- dichloroethane, 1,1-dichloroethene, 1 ,2-dichloroethene, chloroform, trichloroethane, trichloroethene, carbon tetrachloride, tetrafluoroethene, chlorobenzene, and
trifluoromethylbenzene; alcohols, including methanol (MeOH), ethanol (EtOH),
trifluoroethanol (TFE), isopropanol (IP A), 1-propanol, hexafluoroisopropanol (HFTPA), 1- butanol, 2-butanol, t-butanol, 2-methyl-l-propanol, 3 -methyl- 1-butanol, 1-pentanol, tert-amyl alcohol, 2-methoxyethanol, 2-ethoxyethanol, and ethyleneglycol; ethers, including diethyl ether, diisopropyl ether, methyl t-butyl ether (MTBE), methyl nonafluorobutyl ether, diphenyl ether, 1 ,2-dimethoxyethane, bi(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-methyl pyrrolindone, 2-methyl tetrahydrofuran, tetrahydrofuran (THF), dioxane, and pyridine; carboxylic acids, including acetic acid, trichloroacetic acid, and trifluoroacetic acid; phosphoramides, including
hexamethylphosphoramide; carbon sulfide; water; and mixtures thereof.
[00107] In certain embodiments, the solvent is dichloromethane, acetone, acetonitrile, ethanol, trifluoroethanol, isopropanol, hexafluoroisopropanol, ethyl acetate, isopropyl acetate, tetrahydrofuran, water, MTBE, or a mixture thereof.
[00108] In certain embodiments, the salt forming step is carried out at a temperature from about -10 to about 150 °C, from about 10 to about 110 °C, or from about 20 to about 100 °C. In certain embodiments, the salt forming reaction is carried out at a temperature of about 20 °C, about 25 °C, about 30 °C, about 35 °C, about 40 °C, about 45 °C, or about 50 °C. In one embodiment, the solvent used in the salt forming step is dichloromethane, acetone, acetonitrile, ethanol, trifluoroethanol, isopropanol, hexafluoroisopropanol, ethyl acetate, isopropyl acetate, tetrahydrofuran, water, or a mixture thereof.
[00109] In certain embodiments, the salt forming step is performed in the presence of about one equivalent of an acid. In certain embodiments, the salt forming step is performed in the presence of an excess amount of an acid to maximize the yield of the reaction. In certain embodiments, the molar ratio of the acidic group on the acid versus the compound of Formula I is about 1, about 1.01, about 1.05, about 1.1, or about 1.2. In certain embodiments, the molar ratio of the acidic group on the acid versus the compound of Formula I is ranging from about 0.5 to about 10, from about 0.9 to about 5, or from about 0.95 to about 2.5.
[00110] In certain embodiments, the salt forming step is performed in a solution, that is, both the compound of Formula I and the acid are dissolved in the solvent. In certain embodiments, the salt forming step is performed as a slurry mixture of the compound of Formula I and the acid in the solvent. In certain embodiments, the compound of Formula I is not fully dissolved, whereas the acid is completely dissolved.
[00111] In certain embodiments, the salt provided herein is precipitated out from the reaction solution or slurry mixture using conventional methods, including, but not limited to, cooling, chilling, solvent evaporation, addition of an anti-solvent, or reverse addition of the mixture of the salt into an anti-solvent. In certain embodiments, the salt provided herein is precipitated out from the reaction solution or slurry mixture upon cooling.
[00112] In certain embodiments, the salt provided herein is precipitated out from the reaction solution or slurry mixture via the addition of an anti-solvent. Suitable anti-solvents include, but are not limited to, hydrocarbons, including petroleum ether, pentane, hexane(s), heptane(s), octane, isooctane, cyclopentane, cyclohexane, methylcyclohexane, benzene, toluene, xylene, tetralin, and cumene; halogenated hydrocarbons, including 1,2- dichloroethane, 1,1-dichloroethene, 1 ,2-dichloroethene, chloroform, trichloroethane, trichloroethene, carbon tetrachloride, tetrafluoroethene, chlorobenzene, and
trifluoromethylbenzene; alcohols, including 1-butanol, 2-butanol, /-butanol, 2-methyl-l- propanol, 3 -methyl- 1-butanol, 1-pentanol, tert-amyl alcohol, 2-methoxyethanol, 2- ethoxyethanol, and ethyleneglycol; ethers, including diethyl ether, diisopropyl ether, methyl t-butyl ether (MTBE), methyl nonafluorobutyl ether, diphenyl ether, 1 ,2-dimethoxyethane, bi(2-methoxyethyl)ether, 1 , 1 -dimethoxymethane, 2,2-dimethoxypropane, and anisole;
ketones, including butanone, methyl ethyl ketone (MEK), 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 sulfide; water; and mixtures thereof. In certain embodiments, the anti-solvent is MTBE, water, or a mixture thereof.
[00113] When two solvents are used as a solvent/anti-solvent pair, the salt provided herein has a higher solubility in the solvent than in the anti-solvent. In certain embodiments, the solvent and the anti-solvent in a solvent/anti-solvent pair are at least partially miscible.
[00114] In certain embodiments, the precipitating step is carried out at a temperature from about -50 to about 100 °C, from about -30 to about 50 °C, or from about -10 to about 30 °C. In certain embodiments, the precipitating step is carried out at a temperature of about 0 °C, about 5 °C, about 10 °C, about 15 °C, about 20 °C, about 25 °C, or about 30 °C.
[00115] To accelerate the precipitation (crystallization) step, the process may further comprise the step of seeding the reaction solution or mixture, prior to or during the initiation of the precipitation step. The amount of seed crystals added exceeds the saturation amount in the solvent being used so that there are undissolved seed crystals present in the reaction solution.
[00116] In certain embodiments, the process further comprises an isolation step, in which the precipitate is isolated by a conventional method, such as filtration and
centrifugation, followed by washing with a solvent and then drying.
[00117] Other salt forming methods may also be applicable in the present invention.
For example, the salt of the compound of Formula I may be prepared by converting a salt of the compound, e.g., an HC1 salt, to an ethanesulfonic acid salt via anion exchange using an anion exchange column. The salt of the compound of Formula I may also be produced by physically grinding solid (5)-morpholin-3-ylmethyl 4-(l-(3-fluorobenzyl)-lH-indazol-5- ylamino)-5-methylpyrrolo[l,2- |[l,2,4]triazin-6-ylcarbamate and an acid together in the absence of a solvent.
[00118] In addition to precipitation and crystallization, the solid salt provided herein may also be prepared using conventional methods known to those skilled in the art, including spray drying, roller drying, lyophilization, and melt crystallization.
[00119] In another embodiment, provided herein is a method for decreasing the amount of the nitrosamine from the salt of (5)-morpholin-3-ylmethyl 4-(l-(3-fluorobenzyl)- lH-indazol-5-ylamino)-5-methylpyrrolo[ l ,2 ][l ,2,4]triazin-6-ylcarbamate, as provided herein, or a hydrate or pharmaceutically acceptable solvate thereof; which comprises contacting the salt with acetone at a first predetermined temperature as defined herein. In one embodiment, the salt is dissolved in acetone. In another embodiment, the salt is crystallized in acetone.
Pharmaceutical Compositions
[00120] In one embodiment, provided herein are pharmaceutical compositions comprising a salt of (5*)-morpholin-3-ylmethyl 4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)- 5-methylpyrrolo[l ,2- J [l ,2,4]triazin-6-ylcarbamate provided herein, including hydrates and pharmaceutically acceptable solvates thereof; in combination with a pharmaceutically acceptable vehicle, carrier, diluent, or excipient, or a mixture thereof.
[00121] In another embodiment, provided herein are pharmaceutical compositions comprising a salt of (i¾-moi holin-3-ylmethyl 4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)- 5-methylpyrrolo[l ,2- ] [l ,2,4]triazin-6-ylcarbamate provided herein, including hydrates and pharmaceutically acceptable solvates thereof; in combination with hydroxypropyl-β- cyclodextrin, mannitol, water, or a mixture thereof.
[00122] In yet another embodiment, provided herein is a pharmaceutical composition comprising (S)-morpholin-3-ylmethyl 4-(l -(3-fluorobenzyl)-lH-indazol-5-ylamino)-5- methylpyrrolo[ l ,2- ] [l ,2,4]triazin-6-ylcarbamate ethanesulfonate, or a pharmaceutically acceptable solvate or hydrate thereof, in combination with hydroxypropyl- -cyclodextrin, mannitol, water, or a mixture thereof.
[00123] In yet another embodiment, provided herein is a pharmaceutical composition comprising about 15% by weight of (5 -morpholin-3-ylmethyl 4-(l -(3-fluorobenzyl)-lH- indazol-5 -ylamino)-5 -methylpyrrolo [ 1 ,2- ] [ 1 ,2,4]triazin-6-ylcarbamate ethanesulfonate, about 75% by weight of hydroxypropyl- -cyclodextrin, and 10% by weight of mannitol.
[00124] In yet another embodiment, provided herein is a pharmaceutical composition in a unit-dosage, comprising about 363 mg of
Figure imgf000035_0001
4-(l-(3- fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l ,2: ] [l ,2,4]triazin-6-ylcarbamate ethanesulfonate, about 1 ,800 mg of hydroxypropyl- -cyclodextrin, and 1 ,240 mg by weight of mannitol. [00125] In certain embodiments, a pharmaceutical composition in a unit-dosage, comprising about 363 mg of (5)-morpholin-3-ylmethyl 4-(l-(3-fluorobenzyl)-lH-indazol-5- ylamino)-5-methylpyrrolo[l,2-y][l,2,4]triazin-6-ylcarbamate ethanesulfonate in a crystalline form. In certain embodiments, a pharmaceutical composition in a unit-dosage, comprising about 363 mg of ((S)-morpholin-3-ylmethyl 4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5- methylpyrrolo[l,2- J[l,2,4]triazin-6-ylcarbamate ethanesulfonate in crystalline Form II-B.
[00126] Suitable excipients are well known to those skilled in the art, and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art, including, but not limited to, the method of administration. For example, oral dosage forms such as tablets may contain excipients not suited for use in parenteral dosage forms. The suitability of a particular excipient may also depend on the specific active ingredients in the dosage form. For example, the
decomposition of some active ingredients may be accelerated by some excipients such as lactose, or when exposed to water. Active ingredients that comprise primary or secondary amines are particularly susceptible to such accelerated decomposition. Consequently, provided herein are pharmaceutical compositions and dosage forms that contain little, if any, lactose, or other mono- or di-saccharides. As used herein, the term "lactose-free" means that the amount of lactose present, if any, is insufficient to substantially increase the degradation rate of an active ingredient. In one embodiment, lactose-free compositions comprise an active ingredient provided herein, a binder/filler, and a lubricant. In another embodiment, lactose-free dosage forms comprise an active ingredient, microcrystalline cellulose, pre- gelatinized starch, and magnesium stearate.
[00127] The salt provided herein may be administered alone, or in combination with one or more other salts provided herein. The pharmaceutical compositions that comprise a salt provided herein can be formulated in various dosage forms for oral, parenteral, and topical administration. The pharmaceutical compositions can also be formulated as modified release dosage forms, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated-, fast-, targeted-, programmed-release, 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 ed.; Rathbone et ah, Eds.; Marcel Dekker, Inc.: New York, NY, 2008).
[00128] In one embodiment, the pharmaceutical compositions are provided in a dosage form for oral administration, which comprise a salt provided herein, and one or more pharmaceutically acceptable vehicles, carriers, diluents, or excipients.
[00129] In another embodiment, the pharmaceutical compositions are provided in a dosage form for parenteral administration, which comprise a salt provided herein, and one or more pharmaceutically acceptable vehicles, carriers, diluents, or excipients.
[00130] In yet another embodiment, the pharmaceutical compositions are provided in a dosage form for topical administration, which comprise a salt provided herein, and one or more pharmaceutically acceptable vehicles, carriers, diluents, or excipients.
[00131] The pharmaceutical compositions provided herein can be provided in a unit- dosage form or multiple-dosage form. A unit-dosage form, as used herein, refers to physically discrete a unit suitable for administration to a human and animal subject, and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of an active ingredient(s) sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carriers or excipients. Examples of a unit- dosage form include an ampoule, syringe, and individually packaged tablet and capsule. For example, a 100 mg unit dose contains about 100 mg of an active ingredient in a packaged tablet or capsule. A unit-dosage form may be administered in fractions or multiples thereof. A multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dosage form. Examples of a multiple-dosage form include a vial, bottle of tablets or capsules, or bottle of pints or gallons.
[00132] The pharmaceutical compositions provided herein can be administered at once, or multiple times at intervals of time. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the patient being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations. A. Oral Administration
[00133] The pharmaceutical compositions provided herein for oral administration can be provided in solid, semisolid, or liquid dosage forms for oral administration. As used herein, oral administration also includes buccal, lingual, and sublingual administration.
Suitable oral dosage forms include, but are not limited to, tablets, fastmelts, chewable tablets, capsules, pills, strips, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, bulk powders, effervescent or non-effervescent powders or granules, oral mists, solutions, emulsions, suspensions, wafers, sprinkles, elixirs, and syrups. In addition to the active ingredient(s), the pharmaceutical compositions can contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, sweetening agents, flavoring agents, emulsifying agents, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and sources of carbon dioxide.
[00134] Binders or granulators impart cohesiveness to a tablet to ensure the tablet remaining intact after compression. Suitable binders or granulators include, but are not limited to, starches, such as corn starch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500); gelatin; sugars, such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums, such as acacia, alginic acid, alginates, extract of Irish moss, panwar gum, ghatti gum, mucilage of isabgol husks, carboxymethylcellulose,
methylcellulose, polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powdered tragacanth, and guar gum; celluloses, such as ethyl cellulose, cellulose acetate,
carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC); microcrystalline celluloses, such as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581 , AVICEL-PH-105 (FMC Corp., Marcus Hook, PA); and mixtures thereof. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre- gelatinized starch, and mixtures thereof. The amount of a binder or filler in the
pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art. The binder or filler may be present from about 50 to about 99% by weight in the pharmaceutical compositions provided herein.
[00135] 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 quantity, can impart properties to some compressed tablets that permit disintegration in the mouth by chewing. Such compressed tablets can be used as chewable tablets. The amount of a diluent in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
[00136] Suitable disintegrants include, but are not limited to, agar; bentonite;
celluloses, such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cation-exchange resins; alginic acid; gums, such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses, such as croscarmellose; cross-linked polymers, such as crospovidone; cross-linked starches; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; polacrilin potassium; starches, such as corn starch, potato starch, tapioca starch, and pre-gelatinized starch; clays; aligns; and mixtures thereof. The amount of a disintegrant in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art. The amount of a disintegrant in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art. The
pharmaceutical compositions provided herein may contain from about 0.5 to about 15% or from about 1 to about 5% by weight of a disintegrant.
[00137] Suitable lubricants include, but are not limited to, calcium stearate;
magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols, such as glycerol behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oil, including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laureate; agar; starch; lycopodium; silica or silica gels, such as AEROSIL® 200 (W.R. Grace Co., Baltimore, MD) and CAB-O-SIL® (Cabot Co. of Boston, MA); and mixtures thereof. The pharmaceutical compositions provided herein may contain about 0.1 to about 5% by weight of a lubricant.
[00138] Suitable glidants include, but are not limited to, colloidal silicon dioxide,
CAB-O-SIL® (Cabot Co. of Boston, MA), and asbestos-free talc. Suitable coloring agents include, but are not limited to, any of the approved, certified, water soluble FD&C dyes, and water insoluble FD&C dyes suspended on alumina hydrate, and color lakes and mixtures thereof. A color lake is the combination by adsorption of a water-soluble dye to a hydrous oxide of a heavy metal, 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 synthetic blends of compounds which produce a pleasant taste sensation, such as peppermint and methyl salicylate. Suitable sweetening agents include, but are not limited to, sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners, such as saccharin and aspartame. Suitable emulsifying agents include, but are not limited to, gelatin, acacia, tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitan monooleate
(TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate. Suitable suspending and dispersing agents include, but are not limited to, sodium carboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable preservatives include, but are not limited to, glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol. 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, ethyl alcohol, and syrup. Suitable non-aqueous liquids utilized in emulsions include, but are not limited to, mineral oil and cottonseed oil. Suitable organic acids include, but are not limited to, citric and tartaric acid. Suitable sources of carbon dioxide include, but are not limited to, sodium bicarbonate and sodium carbonate.
[00139] It should be understood that many carriers and excipients may serve a plurality of functions, even within the same formulation.
[00140] The pharmaceutical compositions provided herein for oral administration can be provided as compressed tablets, tablet triturates, chewable lozenges, rapidly dissolving tablets, multiple compressed tablets, or enteric-coating tablets, sugar-coated, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with substances that resist the action of stomach acid but dissolve or disintegrate in the intestine, thus protecting the active ingredients 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 phthalates. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial in covering up objectionable tastes or odors and in protecting the tablets from oxidation. Film-coated tablets are compressed tablets that are covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coating imparts the same general characteristics as sugar coating. Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets, and press-coated or dry-coated tablets.
[00141] The tablet dosage forms can be prepared from the active ingredient in powdered, crystalline, or granular forms, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled-release polymers, lubricants, diluents, and/or colorants. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges.
[00142] The pharmaceutical compositions provided herein for oral administration can be provided as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate. The hard gelatin capsule, also known as the dry- filled capsule (DFC), consists of two sections, one slipping over the other, thus completely enclosing the active ingredient. The soft elastic capsule (SEC) is a soft, globular shell, such as a gelatin shell, which is plasticized by the addition of glycerin, sorbitol, or a similar polyol. The soft gelatin shells may contain a preservative to prevent the growth of microorganisms. Suitable preservatives are those as described herein, including methyl- and propyl-parabens, and sorbic acid. The liquid, semisolid, and solid dosage forms provided herein may be encapsulated in a capsule. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239; and 4,410,545. The capsules may also be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient.
[00143] The pharmaceutical compositions provided herein for oral administration can be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. An emulsion is a two-phase system, in which one liquid is dispersed in the form of small globules throughout another liquid, which can be oil-in-water or water-in-oil. Emulsions may include a pharmaceutically acceptable non-aqueous liquid or solvent, emulsifying agent, and preservative. Suspensions may include a pharmaceutically acceptable suspending agent and preservative. Aqueous alcoholic solutions may include a pharmaceutically acceptable acetal, such as a di(lower alkyl) acetal of a lower alkyl aldehyde, e.g., acetaldehyde diethyl acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened, and
hydroalcoholic solutions. Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may also contain a preservative. For a liquid dosage form, for example, a solution in a polyethylene glycol may be diluted with a sufficient quantity of a
pharmaceutically acceptable liquid carrier, e.g., water, to be measured conveniently for administration.
[00144] Other useful liquid and semisolid dosage forms include, but are not limited to, those containing the active ingredient(s) provided herein, and a dialkylated mono- or poly- alkylene glycol, including, 1 ,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether,
polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol. These formulations can further comprise one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.
[00145] The pharmaceutical compositions provided herein for oral administration can be also provided in the forms of liposomes, micelles, microspheres, or nanosystems. Micellar dosage forms can be prepared as described in U.S. Pat. No. 6,350,458.
[00146] The pharmaceutical compositions provided herein for oral administration can be provided as non-effervescent or effervescent, granules and powders, to be reconstituted into a liquid dosage form. Pharmaceutically acceptable carriers and excipients used in the non-effervescent granules or powders may include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders may include organic acids and a source of carbon dioxide.
[00147] Coloring and flavoring agents can be used in all of the above dosage forms.
[00148] The pharmaceutical compositions provided herein for oral administration can be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms. B. Parenteral Administration
[00149] The pharmaceutical compositions provided herein can be administered parenterally by injection, infusion, or implantation, for local or systemic administration. Parenteral administration, as used herein, include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, intravesical, and subcutaneous administration.
[00150] The pharmaceutical compositions provided herein for parenteral
administration can be formulated in any dosage forms that are suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes,
microspheres, nanosystems, and solid forms suitable for solutions or suspensions in liquid prior to injection. Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science (see, Remington: The Science and Practice of Pharmacy, supra).
[00151] 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 against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents, and inert gases.
[00152] 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 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 seed oil. Suitable water-miscible vehicles include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycol (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N- methyl-2-pyrrolidone, NN-dimethylacetamide, and dimethyl sulfoxide. [00153] Suitable antimicrobial agents or preservatives include, but are not limited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p- hydroxybenzoates, thimerosal, benzalkonium chloride (e.g. , benzethonium chloride), methyl- and propyl-parabens, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin, and dextrose. Suitable buffering agents include, but are not limited to, phosphate and citrate. Suitable antioxidants are those 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 as described herein, including sodium carboxymethylcelluose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agents are those described herein, including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate. Suitable sequestering or chelating agents include, but are not limited to EDTA. Suitable pH adjusting agents 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 a-cyclodextrin, β-cyclodextrin, hydroxypropyl-β- cyclodextrin, sulfobutylether^-cyclodextrin, and sulfobutylether
7-p-cyclodextrin (CAPTISOL®, CyDex, Lenexa, KS).
[00154] When the pharmaceutical compositions provided herein are formulated for multiple dosage administration, the multiple dosage parenteral formulations must contain an antimicrobial agent at bacteriostatic or fungistatic concentrations. All parenteral formulations must be sterile, as known and practiced in the art.
[00155] In one embodiment, the pharmaceutical compositions for parenteral administration are provided as ready-to-use sterile solutions. In another embodiment, the pharmaceutical compositions are provided as sterile dry soluble products, including lyophilized powders and hypodermic tablets, to be reconstituted with a vehicle prior to use. In yet another embodiment, the pharmaceutical compositions are provided as ready-to-use sterile suspensions. In yet another embodiment, the pharmaceutical compositions are provided as sterile dry insoluble products to be reconstituted with a vehicle prior to use. In still another embodiment, the pharmaceutical compositions are provided as ready-to-use sterile emulsions.
[00156] The pharmaceutical compositions provided herein for parenteral
administration can be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms.
[00157] The pharmaceutical compositions provided herein for parenteral
administration can be formulated as a suspension, solid, semi-solid, or thixotropic liquid, for administration as an implanted depot. In one embodiment, the pharmaceutical compositions provided herein are dispersed in a solid inner matrix, which is surrounded by an outer polymeric membrane that is insoluble in body fluids but allows the active ingredient in the pharmaceutical compositions diffuse through.
[00158] Suitable inner matrixes include, but are not limited to,
polymethylmethacrylate, polybutyl-methacrylate, plasticized or unplasticized
polyvinylchloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers, such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate.
[00159] Suitable outer polymeric membranes include but are not limited to, polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene
terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/vinyloxyethanol copolymer.
C. Topical Administration
[00160] The pharmaceutical compositions provided herein can be administered topically to the skin, orifices, or mucosa. The topical administration, as used herein, includes (intra)dermal, conjunctival, intracorneal, intraocular, ophthalmic, auricular, transdermal, nasal, vaginal, urethral, respiratory, and rectal administration.
[00161] The pharmaceutical compositions provided herein can be formulated in any dosage forms that are suitable for topical administration for local or systemic effect, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusting powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, irrigations, sprays, suppositories, bandages, and dermal patches. The topical formulation of the pharmaceutical compositions provided herein can also comprise liposomes, micelles, microspheres, nanosystems, and mixtures thereof.
[00162] 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 against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers, cryoprotectants, lyoprotectants, thickening agents, and inert gases.
[00163] The pharmaceutical compositions can also be administered topically by electroporation, iontophoresis, phonophoresis, sonophoresis, or microneedle or needle-free injection, such as POWDERJECT™ (Chiron Corp., Emeryville, CA), and BIOJECT™ (Bioject Medical Technologies Inc., Tualatin, OR).
[00164] The pharmaceutical compositions provided herein can be provided in the forms of ointments, creams, and gels. Suitable ointment vehicles include oleaginous or hydrocarbon vehicles, including lard, benzoinated lard, olive oil, cottonseed oil, and other oils, white petrolatum; emulsifiable or absorption 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 varying molecular weight; emulsion vehicles, either water-in-oil (W/O) emulsions 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 emollient but generally require addition of antioxidants and preservatives.
[00165] Suitable cream base can be oil-in-water or water-in-oil. Suitable cream vehicles may be water-washable, and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase is also called the "internal" phase, which is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol. The aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation may be a nonionic, anionic, cationic, or amphoteric surfactant. [00166] Gels are semisolid, suspension-type systems. Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the liquid carrier. Suitable gelling agents include, but are not limited to, crosslinked acrylic acid polymers, such as carbomers, carboxypolyalkylenes, and CARBOPOL®; hydrophilic polymers, such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers, and polyvinylalcohol; cellulosic polymers, such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methylcellulose; gums, such as tragacanth and xanthan gum; sodium alginate; and gelatin. In order to prepare a uniform gel, dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by trituration, mechanical mixing, and/or stirring.
[00167] The pharmaceutical compositions provided herein can be administered rectally, urethrally, vaginally, or perivaginally in the forms of suppositories, pessaries, bougies, poultices or cataplasm, pastes, powders, dressings, creams, plasters, contraceptives, ointments, solutions, emulsions, suspensions, tampons, gels, foams, sprays, or enemas. These dosage forms can be manufactured using conventional processes as described in Remington: The Science and Practice of Pharmacy, supra.
[00168] Rectal, urethral, and vaginal suppositories are solid bodies for insertion into body orifices, which are solid at ordinary temperatures but melt or soften at body temperature to release the active ingredient(s) inside the orifices. Pharmaceutically acceptable carriers utilized in rectal and vaginal suppositories include bases or vehicles, such as stiffening agents, which produce a melting point in the proximity of body temperature, when formulated with the pharmaceutical compositions provided herein; and antioxidants as described herein, including bisulfite and sodium metabisulfite. Suitable vehicles include, but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol), spermaceti, paraffin, white and yellow wax, and appropriate mixtures of mono-, di- and triglycerides of fatty acids, and hydrogels, such as polyvinyl alcohol, hydroxyethyl methacrylate, and polyacrylic acid. Combinations of the various vehicles can also be used. Rectal and vaginal suppositories may be prepared by compressing or molding. The typical weight of a rectal and vaginal suppository is about 2 to about 3 g.
[00169] The pharmaceutical compositions provided herein can be administered ophthalmically in the forms of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for solutions, gels, ocular inserts, and implants. [00170] 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 solution for delivery using a pressurized container, pump, spray, atomizer, such as an atomizer using electrohydrodynamics to produce a fine mist, or nebulizer, alone or in combination with a suitable propellant, such as 1,1,1 ,2- tetrafluoroethane or 1,1,1, 2,3, 3,3-heptafluoropropane. 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 nasal drops. For intranasal use, the powder can comprise a bioadhesive agent, including chitosan or cyclodextrin.
[00171] Solutions or suspensions for use in a pressurized container, pump, spray, atomizer, or nebulizer can be formulated to contain ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active ingredient provided herein; a propellant as solvent; and/or a surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
[00172] The pharmaceutical compositions provided herein can be micronized to a size suitable for delivery by inhalation, such as about 50 micrometers or less, or about 10 micrometers or less. Particles of such sizes can be prepared using a comminuting method known to those skilled in the art, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.
[00173] Capsules, blisters, and cartridges for use in an inhaler or insufflator can be formulated to contain a powder mix of the pharmaceutical compositions provided herein; a suitable powder base, such as lactose or starch; and a performance modifier, such as l- leucine, mannitol, or magnesium stearate. The lactose may 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 inhaled/intranasal administration can further comprise a suitable flavor, such as menthol and levomenthol; and/or sweeteners, such as saccharin and saccharin sodium.
[00174] The pharmaceutical compositions provided herein for topical administration can be formulated to be immediate release or modified release, including delayed-, sustained-, pulsed-, controlled-, targeted, and programmed release. D. Modified Release
[00175] The pharmaceutical compositions provided herein can be formulated as a modified release dosage form. As used herein, the term "modified release" refers to a dosage form in which the rate or place of release of the active ingredient(s) is different from that of an immediate dosage form when administered by the same route. Modified release dosage forms include, but are not limited to, delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms. The pharmaceutical compositions in modified release dosage forms can be prepared using a variety of modified release devices and methods known to those skilled in the art, including, but not limited to, matrix controlled release devices, osmotic controlled release devices, multiparticulate controlled release devices, ion-exchange resins, enteric coatings, multilayered coatings, microspheres, liposomes, and combinations thereof. The release rate of the active ingredient(s) can also be modified by varying the particle sizes and polymorphorism of the active ingredient(s).
[00176] Examples of modified release include, but are not limited to, those described in U.S. Pat. Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533;
5,059,595; 5,591,767; 5, 120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474; 5,922,356; 5,958,458; 5,972,891 ; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,1 13,943; 6, 197,350; 6,248,363; 6,264,970; 6,267,981 ; 6,270,798; 6,375,987; 6,376,461; 6,419,961 ; 6,589,548; 6,613,358; 6,623,756; 6,699,500; 6,793,936; 6,827,947; 6,902,742; 6,958, 161 ; 7,255,876; 7,416,738; 7,427,414; 7,485,322; Bussemer et al, Crit. Rev. Ther. Drug Carrier Syst. 2001, 18, 433-458; Modified-Release Drug Delivery
Technology, 2nd ed.; Rathbone et al, Eds.; Marcel Dekker AG: 2005; Maroni et al, Expert. Opin. Drug Deliv. 2005, 2, 855-871; Shi et al, Expert Opin. Drug Deliv. 2005, 2, 1039-1058; Polymers in Drug Delivery; Ijeoma et al, Eds.; CRC Press LLC: Boca Raton, FL, 2006; Badawy et al., J. Pharm. Sci. 2007, 9, 948-959; Modified-Release Drug Delivery Technology, supra; Conway, Recent Pat. Drug Deliv. Formul. 2008, 2, 1-8; Gazzaniga et al, Eur. J.
Pharm. Biopharm. 2008, 68, 1 1-18; Nagarwal et al, Curr. Drug Deliv. 2008, 5, 282-289; Gallardo et al , Pharm. Dev. Technol. 2008, 13, 413-423; Chrzanowski, AAPS
PharmSciTech. 2008, 9, 635-638; Chrzanowski, AAPS PharmSciTech. 2008, 9, 639-645; Kalantzi et al, Recent Pat. Drug Deliv. Formul 2009, 3, 49-63; Saigal et al , Recent Pat. Drug Deliv. Formul. 2009, 3, 64-70; and Roy et al. , J. Control Release 2009, 134, 74-80. 1. Matrix Controlled Release Devices
[00177] The pharmaceutical compositions provided herein in a modified release dosage form can be fabricated using a matrix controlled release device known to those skilled in the art. See, Takada et al. in Encyclopedia of Controlled Drug Delivery; Mathiowitz Ed.; Wiley: 1999; Vol 2.
[00178] In certain embodiments, the pharmaceutical compositions provided herein in a modified release dosage form is formulated using an erodible matrix device, which is water- swellable, erodible, or soluble polymers, including, but not limited to, synthetic polymers, and naturally occurring polymers and derivatives, such as polysaccharides and proteins.
[00179] Materials useful in forming an erodible matrix include, but are not limited to, chitin, chitosan, dextran, and pullulan; gum agar, gum arabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gum ghatti, guar gum, xanthan gum, and scleroglucan;
starches, such as dextrin and maltodextrin; hydrophilic colloids, such as pectin; phosphatides, such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; cellulosics, such as ethyl cellulose (EC), methylethyl 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);
polyvinyl pyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acid esters;
polyacrylamide; polyacrylic acid; copolymers of ethacrylic acid or methacrylic acid
(EUDPvAGIT®, Rohm America, Inc., Piscataway, NJ); poly(2-hydroxyethyl-methacrylate); polylactides; copolymers of L-glutamic acid and ethyl-L-glutamate; degradable lactic acid- glycolic acid copolymers; poly-D-(-)-3-hydroxybutyric acid; and other acrylic acid derivatives, such as homopolymers and copolymers of butylmethacrylate, methyl methacrylate, ethyl methacrylate, ethylacrylate, (2-dimethylaminoethyl)methacrylate, and (trimethylaminoethyl)methacrylate chloride.
[00180] In certain embodiments, the pharmaceutical compositions provided herein are formulated with a non-erodible matrix device. The active ingredient(s) is dissolved or dispersed in an inert matrix and is released primarily by diffusion through the inert matrix once administered. Materials suitable for use as a non-erodible matrix device include, but are not limited to, insoluble plastics, such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethylmethacrylate, polybutylmethacrylate, chlorinated polyethylene, polyvinylchloride, methyl acrylate-methyl methacrylate copolymers, ethylene- vinyl acetate copolymers, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubbers, epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, ethylene/vinyloxyethanol copolymer, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubbers, polydimethylsiloxanes, and silicone carbonate copolymers; hydrophilic polymers, such as ethyl cellulose, cellulose acetate, crospovidone, and cross-linked partially hydrolyzed polyvinyl acetate; and fatty compounds, such as carnauba wax, microcrystalline wax, and triglycerides.
[00181] In a matrix controlled release system, the desired release kinetics can be controlled, for example, via the polymer type employed, the polymer viscosity, the particle sizes of the polymer and/or the active ingredient(s), the ratio of the active ingredient(s) versus the polymer, and other excipients or carriers in the compositions.
[00182] 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.
2. Osmotic Controlled Release Devices
[00183] The pharmaceutical compositions provided herein in a modified release dosage form can be fabricated using an osmotic controlled release device, including, but not limited to, one-chamber system, two-chamber system, asymmetric membrane technology (AMT), and extruding core system (ECS). In general, such devices have at least two components: (a) a core which contains an active ingredient; and (b) a semipermeable membrane with at least one delivery port, which encapsulates the core. The semipermeable membrane controls the influx of water to the core from an aqueous environment of use so as to cause drug release by extrusion through the delivery port(s).
[00184] In addition to the active ingredient(s), the core of the osmotic device optionally includes an osmotic agent, which creates a driving force for transport of water from the environment of use into the core of the device. One class of osmotic agents is water-swellable hydrophilic polymers, which are also referred to as "osmopolymers" and "hydrogels." Suitable water-swellable hydrophilic polymers as osmotic agents include, but are not limited to, hydrophilic vinyl 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, PVA PVP copolymers with hydrophobic monomers such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing large PEO blocks, sodium
croscarmellose, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) and carboxyethyl, cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate.
[00185] The other class of osmotic agents is osmogens, which are capable of imbibing water to affect an osmotic pressure gradient across the barrier of the surrounding coating. 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 phosphates, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate; sugars, such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, 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.
[00186] Osmotic agents of different dissolution rates can be employed to influence how rapidly the active ingredient(s) is initially delivered from the dosage form. For example, amorphous sugars, such as MANNOGEM™ EZ (SPI Pharma, Lewes, DE) can be used to provide faster delivery during the first couple of hours to promptly produce the desired therapeutic effect, and gradually and continually release of the remaining amount to maintain the desired level of therapeutic or prophylactic effect over an extended period of time. In this case, the active ingredient(s) is released at such a rate to replace the amount of the active ingredient metabolized and excreted.
[00187] The core can also include a wide variety of other excipients and carriers as described herein to enhance the performance of the dosage form or to promote stability or processing.
[00188] Materials useful in forming the semipermeable membrane include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulosic derivatives that are water-permeable and water-insoluble at physiologically relevant pHs, or are susceptible to being rendered water-insoluble by chemical alteration, such as crosslinking. Examples of suitable polymers useful in forming the coating, include plasticized, unplasticized, and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methyl carbamate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluene sulfonate, agar acetate, amylose triacetate, beta glucan acetate, beta glucan triacetate, acetaldehyde dimethyl acetate, triacetate of locust bean gum, hydroxylated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPG copolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly(acrylic) acids and esters and poly- (methacrylic) acids and esters and copolymers thereof, starch, dextran, dextrin, chitosan, collagen, gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinyl esters and ethers, natural waxes, and synthetic waxes.
[00189] Semipermeable membrane can also be a hydrophobic microporous membrane, wherein the pores are substantially filled with a gas and are not wetted by the aqueous medium but are permeable to water vapor, as disclosed in U.S. Pat. No. 5,798,119. Such hydrophobic but water-vapor permeable membrane are typically composed of hydrophobic polymers such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes, and synthetic waxes.
[00190] The delivery port(s) on the semipermeable membrane can be formed post- coating by mechanical or laser drilling. Delivery port(s) can also be formed in situ by erosion of a plug of water-soluble material or by rupture of a thinner portion of the membrane over an indentation in the core. In addition, delivery ports can be formed during coating process, as in the case of asymmetric membrane coatings of the type disclosed in U.S. Pat. Nos.
5,612,059 and 5,698,220. [00191] The total amount of the active ingredient(s) released and the release rate can substantially by modulated via the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size, and position of the delivery ports.
[00192] The pharmaceutical compositions in an osmotic controlled-release dosage form can further comprise additional conventional excipients or carriers as described herein to promote performance or processing of the formulation.
[00193] The 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 1995, 35, 1-21 ; Verma et ah , Drug Development and Industrial Pharmacy 2000, 26, 695-708; and Verma et al. , J. Controlled Release 2002, 79, 7-27.
[00194] In certain embodiments, the pharmaceutical compositions provided herein are formulated as AMT controlled-release dosage form, which comprises an asymmetric osmotic membrane that coats a core comprising the active ingredient(s) and other pharmaceutically acceptable excipients or carriers. See, U.S. Pat. No. 5,612,059 and International Pat. Appl. Publ. No. WO 2002/17918. The 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 a dip-coating method.
[00195] In certain embodiments, the pharmaceutical compositions provided herein are formulated as ESC controlled-release dosage form, which comprises an osmotic membrane that coats a core comprising the active ingredient(s), a hydroxylethyl cellulose, and other pharmaceutically acceptable excipients or carriers.
3. Multiparticulate Controlled Release Devices
[00196] The pharmaceutical compositions provided herein in a modified release dosage form can be fabricated as a multiparticulate controlled release device, which comprises a multiplicity of particles, granules, or pellets, ranging from about 10 μιη to about 3 mm, about 50 μηι to about 2.5 mm, or from about 100 μιη to about 1 mm in diameter. Such multiparticulates can be made by the processes known to those skilled in the art, including wet-and dry-granulation, extrusion/spheronization, roller-compaction, melt-congealing, and by spray-coating seed cores. See, for example, Multiparticulate Oral Drug Delivery; Ghebre- Sellassie Ed.; Marcel Dekker: 1994; and Pharmaceutical Pelletization Technology; Ghebre- Sellassie Ed.; Marcel Dekker: 1989.
[00197] Other excipients or carriers as described herein can be blended with the pharmaceutical compositions to aid in processing and forming the multiparticulates. The resulting particles can themselves constitute the multiparticulate device or can be coated by various film-forming materials, such as enteric polymers, water-swellable, and water-soluble polymers. The multiparticulates can be further processed as a capsule or a tablet.
4. Targeted Delivery
[00198] The pharmaceutical compositions provided herein can also be formulated to be targeted to a particular tissue, receptor, or other area of the body of the subject to be treated, including liposome-, resealed erythrocyte-, and antibody-based delivery systems. Examples include, but are not limited to, those disclosed in U.S. Pat. Nos. 5,709,874; 5,759,542;
5,840,674; 5,900,252; 5,972,366; 5,985,307; 6,004,534; 6,039,975; 6,048,736; 6,060,082; 6,071,495; 6,120,751; 6,131,570; 6,139,865; 6,253,872; 6,271,359; 6,274,552; 6,316,652; and 7,169,410.
Methods of Use
[00199] In one embodiment, provided herein is a method of treating a proliferative disease in a subject, comprising administering to the subject a therapeutically effective amount of a salt of
Figure imgf000055_0001
4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)- 5-methylpyrrolo[l,2- ][l,2,4]triazin-6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof.
[00200] In certain embodiments, the salt provided herein is administered to the subject in the amount ranging from about 0.01 to about 1,000 mg/kg, from about 0.1 to about 500 mg/kg, from about 0.1 to about 250 mg/kg, or from about 0.1 to about 100 mg/kg.
[00201] In certain embodiments, the salt provided herein is administered to the subject in the amount ranging from about 0.01 to about 1,000 mg/kg/day, from about 0.1 to about 500 mg/kg/day, from about 0.1 to about 250 mg/kg/day, or from about 0.1 to about 100 mg/kg/day. In certain embodiments, the salt provided herein is administered to the subject in the amount of about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 25, about 30, about 35, about 40 about 50, about 60, about 70, about 75, about 80, about 90, about 100, about 105, about 120, about 130, about 140, about 150, about 160, about 170, about 180, about 190, about 200, about 300, about 400, about 500, about 600, about 700, about 750, about 800, about 900, or about 1,000 mg/kg/day.
[00202] The administered dose of the salt provided herein can also be expressed in units other than the unit "mg/kg/day." For example, doses for parenteral administration can be expressed as mg/m2/day. One of ordinary skill in the art would readily know how to convert doses from mg/kg/day to mg/m2/day to given either the height or weight of a subject or both (See, www.fda.gov/cder/cancer/animalframe.htm). For example, a dose of 1 mg/kg/day for a 65 kg human is approximately equal to 38 mg/m2/day.
[00203] In certain embodiments, the salt provided herein is administered to the subject in the amount ranging from about 1 to about 1,500 mg/m2/day, about 1 to about 1 ,000 mg/m2/day, from about 10 to about 500 mg/m2/day, from about 10 to about 300 mg/m2/day, or from about 20 to about 200 mg/m2/day. In certain embodiments, the salt provided herein is administered to the subject in the amount of about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 134, about 140, about 150, about 160, about 170, about 180, about 190, about 200, about 210, about 220, about 230, about 240, about 250, about 260, about 270, about 280, about 290, or about 300 mg/m2/day.
[00204] In one embodiment, the salt provided herein is administered daily in a single dose or divided doses, where the total daily dose ranges from about 1 mg to about 2,000 mg, from about 10 mg to about 1 ,600 mg, about 100 mg to about 1 ,200 mg, from about 200 mg to about 1 ,200 mg, from about 200 mg to about 1 ,100 mg, from about 300 mg to about 1,100 mg, from about 300 mg to about 1 ,000 mg, from about 300 mg to about 800 mg, from about 320 to about 800 mg, from about 320 to about 700 mg, from about 325 to about 650 mg, from about 325 mg to about 600 mg, or from about 350 mg to about 600 mg.
[00205] In another embodiment, the salt provided herein is administered daily in a single dose or divided doses for a total daily dose of at least 200 mg, at least 250 mg, at least 300 mg, at least 320 mg, at least 325 mg, at least 350 mg, or at least 400 mg.
[00206] In yet another embodiment, the salt provided herein is administered daily in a single dose or divided doses (e.g., BID) for a total daily dose of about 10 mg, about 30 mg, about 65 mg, about 100 mg, about 200 mg, about 250 mg, about 300 mg, about 320 mg, about 400 mg, about 480 mg, about 500 mg, about 600 mg, about 660 mg, about 700 mg, about 800 mg, about 900 mg, about 1,000 mg, about 1,200 mg, about 1,400 mg, or about 1,600 mg.
[00207] In certain embodiments, the salt provided herein is administered daily in a single dose or divided doses for a total daily dose sufficient to achieve a plasma concentration of the compound at steady state ranging from about 0.5 μΜ to about 40 μΜ, from about 1 μΜ to about 30 μΜ, from about 5 μΜ to about 25 μΜ or from about 10 μΜ to about 20 μΜ; in one embodiment, about 1 μΜ, about 2 μΜ, about 5 μΜ, about 10 μΜ, about 15 μΜ, about 30 μΜ, about 40 μΜ, or about 50 μΜ. As used herein, the term "plasma concentration at steady state" is the concentration reached after a period of administration of a compound. Once steady state is reached, there are minor peaks and troughs on the time dependent curve of the plasma concentration of the compound of Formula I.
[00208] In certain embodiments, the salt provided herein is administered in a single dose or divided doses for a total daily dose sufficient to achieve a Cmax from about 0.1 to about 100 μΜ, about 0.2 to about 50 μΜ, about 0.4 to about 40 μΜ, about 0.5 to about 10 μΜ, about 5 to about 40 μΜ, from about 10 to about 40 μΜ, from about 0.4 to about 4.5 μΜ, or from about 3.5 to about 6 μΜ; in one embodiment, about 0.1 μΜ, 0.2 μΜ, about 0.3 μΜ, about 0.4 μΜ, about 0.5 μΜ, 0.6 μΜ, about 0.7 μΜ, 0.8 μΜ, about 0.9 μΜ, about 1 μΜ, about 2 μΜ, about 3 μΜ, about 4 μΜ, about 5 μΜ, about 6 μΜ, 7 μΜ, about 8 μΜ, 9 μΜ, about 10 μΜ, about 15 μΜ, about 20 μΜ, about 30 μΜ, about 40 μΜ, about 50 μΜ..
[00209] In certain embodiments, the salt provided herein is administered in a single dose or divided doses for a total daily dose sufficient to achieve a Cmax of about 0.1 to about 50 μg/mL, about 0.2 to about 40 μg mL, about 2 to about 20 μg/mL, about 1.5 to about 3.2 μg/mL, or about 0.2 to about 2.2 μg mL.
[00210] In certain embodiments, the salt provided herein is administered in a single dose or divided doses for a total daily dose sufficient to achieve an AUC from about 60 to about 500, from about 125 to about 500, from about 125 to about 300, or from 125 to about 200 μg*hr/mL.
[00211] In certain embodiments, the salt provided herein is administered in a single dose or divided doses for a total daily dose sufficient to achieve an AUC from about 5 to about 1 ,000, from about 125 to about 1,000, from about 250 to about 500, from about 80 to about 1 10, or from about 5 to about 65 μΜ*1ΐΓ.
[00212] Depending on the disease to be treated and the subject's condition, the salt provided herein can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracistemal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g. , transdermal or local) routes of administration. The salt provided herein may be formulated, alone or together, in suitable dosage unit with pharmaceutically acceptable excipients, carriers, adjuvants and vehicles, appropriate for each route of administration.
[00213] The salt provided herein can be delivered as a single dose such as, e.g. , a single bolus injection, or oral tablets or pills; or over time such as, e.g., continuous infusion over time or divided bolus doses over time.
[00214] The salt provided herein can be administered once daily (QD), or divided into multiple daily doses such as twice daily (BID), three times daily (TID), and four times daily (QID). In addition, the administration can be continuous, i.e., every day, or intermittently. The term "intermittent" or "intermittently" as used herein is intended to mean stopping and starting at either regular or irregular intervals. For example, intermittent administration of the salt provided herein is administration for one to six days per week, administration in cycles (e.g., daily administration for two to eight consecutive weeks, then a rest period with no administration for up to one week), or administration on alternate days.
[00215] In certain embodiments, the frequency of administration of the salt provided herein is in the range of about a daily dose to about a monthly dose. In certain embodiments, the administration of the salt provided herein is once a day, twice a day, three times a day, four times a day, once every other day, twice a week, once every week, once every two weeks, once every three weeks, or once every four weeks. In one embodiment, the salt provided herein is administered once a day. In another embodiment, the salt provided herein is administered twice a day. In yet another embodiment, the salt provided herein is administered three times a day. In still another embodiment, the salt provided herein is administered four times a day.
[00216] In certain embodiments, the salt provided herein is administered every week. In certain embodiments, the salt provided herein is administered on days 1 , 8, and 15 in a 28 day cycle. In certain embodiments, the salt provided herein is administered on days 1, 8, and 15 in a 21 day cycle. In certain embodiments, the salt provided herein is administered on days 2, 9, and 16 in a 28 day cycle. In certain embodiments, the salt provided herein is administered on days 2, 9, and 16 in a 21 day cycle. In certain embodiments, the salt provided herein is administered on days 3, 10, and 17 in a 28 day cycle. In certain embodiments, the salt provided herein is administered on days 3, 10, and 17 in a 21 day cycle.
[00217] In certain embodiments, the salt provided herein is administered twice a week. In certain embodiments, the salt provided herein is administered on days 1, 2, 8, 9, 15, and 16 in a 21 day cycle. In certain embodiments, the salt provided herein is administered on days 1 , 2, 8, 9, 15, and 16 in a 28 day cycle. In certain embodiments, the salt provided herein is administered on days 2, 3, 9, 10, 16, and 17 in a 21 day cycle. In certain embodiments, the salt provided herein is administered on days 2, 3, 9, 10, 16, and 17 in a 28 day cycle. In certain embodiments, the salt provided herein is administered on days 4, 5, 11, 12, 18, and 19 in a 21 day cycle. In certain embodiments, the salt provided herein is administered on days 4, 5, 11, 12, 18, and 19 in a 28 day cycle.
[00218] In certain embodiments, the salt provided herein is administered for 7 days in a 21 day cycle. In certain embodiments, the salt provided herein is administered for 7 days in a 28 day cycle. In certain embodiments, the salt provided herein is administered daily for three weeks, followed by a one-week rest in a 28 day cycle. In certain embodiments, the salt provided herein is administered daily, uninterrupted for 4 weeks in a 28 day cycle. In certain embodiments, the salt provided herein e is administered on days 1 and 2 in a 21 day cycle.
[00219] In certain embodiments, the salt provided herein is administered for 7 days in a 21 day cycle. In certain embodiments, the salt provided herein is administered for 7 days in a 28 day cycle.
[00220] In one embodiment, the method comprises an oral administration of a salt provided herein according to a regimen selected from:
a. 600 mg/day for 21 days;
b. 600 mg/day for 28 days;
c. 400 mg/day for 21 days and
d. 40 to 300 mg/m2/day. [00221] In another embodiment, the method comprises an administration of a provided herein according to a regimen selected from:
a. a dose sufficient to achieve a Cr of about 5 to about 40 μΜ;
a dose sufficient to achieve a Cr of about 10 to about 40 μΜ;
c. a dose sufficient to achieve a C of about 2 to about 20 μg mL;
d. a dose sufficient to achieve a C of about 3.5 to about 6 μΜ;
e. a dose sufficient to achieve a C of about 0.4 to about 4.5 μΜ;
a dose sufficient to achieve a C, of about 1.5 to about 3.2 μg/mL; and
a dose sufficient to achieve a Cmax of about 0.2 to about 2.2 μg/mL.
[00222] In yet another embodiment, the method comprises an intravenous
administration of a salt provided herein according to a regimen selected from:
a. a dose sufficient to achieve an AUC of about 60 to about 500
μg*hr/mL;
b. a dose sufficient to achieve an AUC of about 125 to about 500
μg*hr/mL;
c. a dose sufficient to achieve an AUC of about 125 to about 300
μg*hr/mL;
d. a dose sufficient to achieve an AUC of about 125 to about 200
μg*hr/rnL;
e. a dose sufficient to achieve an AUC of about 125 to about 1,000
nM*hr;
f. a dose sufficient to achieve an AUC of about 250 to about 500 μΜ*1ΐΓ; g. a dose sufficient to achieve an AUC of about 4 to about 35 μg*hr/mL; and
h.. a dose sufficient to achieve an AUC of about 40 to about 55 μg*hr/mL.
[00223] In yet another embodiment, the method comprises an administration of a salt provided herein according to a regimen selected from:
a. a dose sufficient to achieve a Cmax of about 5 to about 40 μΜ;
b. a dose sufficient to achieve a Cmax of about 10 to about 40 μΜ;
c. a dose sufficient to achieve a Cmax of about 2 to about 20 μg/mL;
d. a dose sufficient to achieve a Cmax of about 3.5 to about 6 μΜ; e. a dose sufficient to achieve a Cmax of about 0.4 to about 4.5 μΜ;
f. a dose sufficient to achieve a Cmax of about 1.5 to about 3.2 μ^ηιί; and
g. a dose sufficient to achieve a Cmax of about 0.2 to about 2.2 μg/mL.
[00224] In yet another embodiment, the method comprises an intravenous
administration of a salt of the compound of Formula I provided herein according to a regimen selected from:
a. a dose sufficient to achieve an AUC of about 60 to about 500
μg*hr/rnL;
b. a dose sufficient to achieve an AUC of about 125 to about 500
μg* r/mL;
c. a dose sufficient to achieve an AUC of about 125 to about 300
μg*hr/rnL;
d. a dose sufficient to achieve an AUC of about 125 to about 200
μg*hr/rnL;
e. a dose sufficient to achieve an AUC of about 125 to about 1,000
μΜ+hr;
f. a dose sufficient to achieve an AUC of about 250 to about 500 μΜ*1η·; g.. a dose sufficient to achieve an AUC of about 4 to about 35 μg*hr/mL; and
h.. a dose sufficient to achieve an AUC of about 40 to about 55 μg*hr/mL.
[00225] In certain embodiments, the subject is a mammal. In certain embodiments, the mammal is a human.
[00226] In one embodiment, the proliferative disease is a tumor. In another embodiment, the proliferative disease is a solid tumor. In certain embodiments, the solid tumor is an advanced solid tumor. In certain embodiments, the solid tumor is a metastatic solid tumor. In yet another embodiment, the proliferative disease is cancer. In yet another embodiment, the proliferative disease is advanced cancer. In certain embodiments, the solid tumor is metastatic cancer.
[00227] In certain embodiments, the tumor overexpresses HE l protein. In certain embodiments, the tumor overexpresses HER2 protein. [00228] In certain embodiments, the cancer treatable with the methods provided herein includes, but is not limited to, (1) leukemias, including, but not limited to, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemias such as myeloblastic,
promyelocytic, myelomonocytic, monocytic, erythro leukemia leukemias and myelodysplastic syndrome or a symptom thereof (such as anemia, thrombocytopenia, neutropenia, bicytopenia or pancytopenia), refractory anemia (RA), RA with ringed sideroblasts (RARS), RA with excess blasts (RAEB), RAEB in transformation (RAEB-T), preleukemia, and chronic myelomonocytic leukemia (CMML), (2) chronic leukemias, including, but not limited to, chronic myelocytic (granulocytic) leukemia, chronic lymphocytic leukemia, and hairy cell leukemia; (3) polycythemia vera; (4) lymphomas, including, but not limited to, Hodgkin's disease and non-Hodgkin's disease; (5) multiple myelomas, including, but not limited to, smoldering multiple myeloma, nonsecretory myeloma, osteosclerotic myeloma, plasma cell leukemia, solitary plasmacytoma, and extramedullary plasmacytoma; (6) Waldenstrom's macroglobulinemia; (7) monoclonal gammopathy of undetermined significance; (8) benign monoclonal gammopathy; (9) heavy chain disease; (10) bone and connective tissue sarcomas, including, but not limited to, bone sarcoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma, malignant giant cell tumor, fibrosarcoma of bone, chordoma, periosteal sarcoma, soft-tissue sarcomas, angiosarcoma (hemangiosarcoma), fibrosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, metastatic cancers, neurilemmoma, rhabdomyosarcoma, and synovial sarcoma; (11) brain tumors, including, but not limited to, glioma, glioblastoma, glioblastoma multiforme, astrocytoma, brain stem glioma,
ependymoma, oligodendroglioma, nonglial tumor, acoustic neurinoma, craniopharyngioma, medulloblastoma, meningioma, pineocytoma, pineoblastoma, and primary brain lymphoma; (12) breast cancer, including, but not limited to, adenocarcinoma, lobular (small cell) carcinoma, intraductal carcinoma, medullary breast cancer, mucinous breast cancer, tubular breast cancer, papillary breast cancer, primary cancers, Paget's disease, and inflammatory breast cancer; (13) adrenal cancer, including, but not limited to, pheochromocytom and adrenocortical carcinoma; (14) thyroid cancer, including, but not limited to, papillary or follicular thyroid cancer, medullary thyroid cancer, and anaplastic thyroid cancer; (15) pancreatic cancer, including, but not limited to, insulinoma, gastrinoma, glucagonoma, vipoma, somatostatin-secreting tumor, and carcinoid or islet cell tumor; (16) pituitary cancer, including, but limited to, Cushing's disease, prolactin-secreting tumor, acromegaly, and diabetes insipius; (17) eye cancer, including, but not limited, to ocular melanoma such as iris melanoma, choroidal melanoma, and cilliary body melanoma, and retinoblastoma; (18) vaginal cancer, including, but not limited to, squamous cell carcinoma, adenocarcinoma, and melanoma; (19) vulvar cancer, including, but not limited to, squamous cell carcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma, and Paget's disease; (20) cervical cancers, including, but not limited to, squamous cell carcinoma, and adenocarcinoma; (21) uterine cancer, including, but not limited to, endometrial carcinoma and uterine sarcoma; (22) ovarian cancer, including, but not limited to, ovarian epithelial carcinoma, borderline tumor, germ cell tumor, and stromal tumor; (23) esophageal cancer, including, but not limited to, squamous cancer, adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma, adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma, verrucous carcinoma, and oat cell (small cell) carcinoma; (24) stomach cancer, including, but not limited to, adenocarcinoma, fungating (polypoid), ulcerating, superficial spreading, diffusely spreading, malignant lymphoma, liposarcoma, fibrosarcoma, and carcinosarcoma; (25) colon cancer; (26) rectal cancer; (27) liver cancer, including, but not limited to, hepatocellular carcinoma and hepatoblastoma; (28) gallbladder cancer , including, but not limited to, adenocarcinoma; (29) cholangiocarcinomas, including, but not limited to, pappillary, nodular, and diffuse; (30) lung cancer, including, but not limited to, non-small cell lung cancer, squamous cell carcinoma (epidermoid carcinoma), adenocarcinoma, large-cell carcinoma, and small-cell lung cancer; (31) testicular cancer, including, but not limited to, germinal tumor, seminoma, anaplastic, classic (typical), spermatocyte, nonseminoma, embryonal carcinoma, teratoma carcinoma, and choriocarcinoma (yolk-sac tumor); (32) prostate cancer, including, but not limited to, adenocarcinoma, leiomyosarcoma, and rhabdomyosarcoma; (33) penal cancer; (34) oral cancer, including, but not limited to, squamous cell carcinoma; (35) basal cancer; (36) salivary gland cancer, including, but not limited to, adenocarcinoma, mucoepidermoid carcinoma, and adenoidcystic carcinoma; (37) pharynx cancer, including, but not limited to, squamous cell cancer and verrucous; (38) skin cancer, including, but not limited to, basal cell carcinoma, squamous cell carcinoma and melanoma, superficial spreading melanoma, nodular melanoma, lentigo malignant melanoma, and acral lentiginous melanoma; (39) kidney cancer, including, but not limited to, renal cell cancer, adenocarcinoma,
hypernephroma, fibrosarcoma, and transitional cell cancer (renal pelvis and/or uterer); (40) Wilms' tumor; (41) bladder cancer, including, but not limited to, transitional cell carcinoma, squamous cell cancer, adenocarcinoma, and carcinosarcoma; and other cancer, including, not limited to, myxosarcoma, osteogenic sarcoma, endotheliosarcoma, lymphangio- endothelio sarcoma, mesothelioma, synovioma, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma, bronchogenic carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, and papillary adenocarcinomas (See Fishman et al., 1985, Medicine, 2d Ed., J.B. Lippincott Co., Philadelphia and Murphy et al, 1997, Informed Decisions: The Complete Book of Cancer Diagnosis, Treatment, and Recovery, Viking Penguin, Penguin Books U.S.A., Inc., United States of America).
[00229] In certain embodiments, the cancer that is treatable with the methods provided herein includes, but is not limited to, bladder cancer, breast cancer, cervical cancer, colon cancer (e.g., colorectal cancer), endometrial cancer, esophageal cancer, gastric cancer, glioma (e.g., glioblastoma), head and neck cancer, liver cancer, lung cancer (e.g., small cell and non- small cell lung cancers), melanoma, myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, sarcoma (e.g., osteosarcoma), skin cancer (e.g., squamous cell carcinoma), stomach cancer, testicular cancer, thyroid cancer, and uterine cancer.
[00230] In certain embodiments, the cancer that is treatable with the methods provided herein includes, but is not limited to, bladder cancer, breast cancer, cervical cancer, colon cancer (e.g., colorectal cancer), endometrial cancer, gastric cancer, glioma (e.g.,
glioblastoma), head and neck cancer, liver cancer, non-small cell lung cancer, ovarian cancer, pancreatic cancer, and prostate cancer.
[00231] In certain embodiments, the cancer is non-small cell lung cancer. In certain embodiments, the cancer is non-small cell lung cancer which overexpresses HERl protein. In certain embodiments, the cancer is non-small cell lung cancer which overexpresses HER2 protein. In certain embodiments, the cancer is non-small cell lung cancer which
overexpresses HERl and HER2 proteins. In certain embodiments, the cancer is metastatic non-small cell lung cancer. In certain embodiments, the cancer is metastatic non-small cell lung cancer which overexpresses HERl protein. In certain embodiments, the cancer is metastatic non-small cell lung cancer which overexpresses HER2 protein. In certain embodiments, the cancer is metastatic non-small cell lung cancer which overexpresses HERl and HER2 proteins.
[00232] In certain embodiments, the cancer is breast cancer. In certain embodiments, the cancer is breast cancer which overexpresses HERl protein. In certain embodiments, the cancer is breast cancer which overexpresses HER2 protein. In certain embodiments, the cancer is breast cancer which overexpresses HERl and HER2 proteins. In certain embodiments, the cancer is metastatic breast cancer. In certain embodiments, the cancer is metastatic breast cancer which overexpresses HERl protein. In certain embodiments, the cancer is metastatic breast cancer which overexpresses HER2 protein. In certain
embodiments, the cancer is metastatic breast cancer which overexpresses HERl and HER2 proteins.
[00233] In certain embodiments, the cancer is head and neck cancer. In certain embodiments, the cancer is lung cancer. In certain embodiments, the cancer is lung adenocarcinoma. In certain embodiments, the cancer is esophogeal or upper GI cancer.
[00234] In certain embodiments, the subject to be treated with one of the methods provided herein has not been treated with anticancer therapy. In certain embodiments, the subject to be treated with one of the methods provided herein has been treated with anticancer therapy.
[00235] The methods provided herein encompass treating a subject regardless of patient's age, although some diseases or disorders are more common in certain age groups. Further provided herein is a method for treating a subject who has undergone surgery in an attempt to treat the disease or condition at issue, as well as the one who have not. Because the subjects with cancer have heterogeneous clinical manifestations and varying clinical outcomes, the treatment given to a particular subject may vary, depending on his/her prognosis.
[00236] In each embodiment provided herein, the method may further comprise a diagnostic step for determining the expression level of HERl protein on the cells of the tumor. In one embodiment, the diagnostic step is carried out prior to the administration of a salt of the compound of Formula I provided herein. If the subject has a tumor with overexpressed HERl, the salt provided herein is then administered. In another embodiment, the diagnostic step is carried out during the course of the treatment.
[00237] In certain embodiments, each method provided herein may independently further comprise the step of administering a second therapeutic agent. In one embodiment, the second therapeutic agent is an anticancer agent. In one embodiment, the anticancer agent is an antimetabolite, including, but not limited to, cytarabine (also known as cytosine arabinoside or Ara-C), fludarabine, 5-fluorouracil, gemcitabine, HDAC (high dose cytarabine), 6-mercaptopurine, methotrexate, and pemetrexed. In another embodiment, the anticancer agent is an antimicrotubule agent, including, but not limited to, vinca alkaloids (e.g., vinblastine, vincristine, and vinorelbine) and taxanes (e.g., paclitaxel, albumin-bound paclitaxel (ABRAXANE®), and docetaxel). In yet another embodiment, the anticancer agent is an alkylating agent, including, but not limited to, busulfan, carmustine, chlorambucil, cyclophosphamide, fludarabine, ifosfamide, mechlorethamine, melphalan, and nitrosoureas (e.g., bischloroethylnitrosurea, hydroxyurea, carmustine, and lomustine). In yet another embodiment, the anticancer agent is a platinum agent, including, but not limited to, carboplatin, CI-973, cisplatin, oxaliplatin, and satraplatin (JM-216). In yet another embodiment, the anticancer agent is an anthracycline, including, but not limited to, adriamycin, daunorubicin, and doxrubicin. In yet another embodiment, the anticancer agent is an antitumor antibiotic, including, but not limited to, adriamycin, bleomycin, daunomycin (also known as daunorubicin), doxorubicin, idarubicin, and mitomycin. In yet another embodiment, the anticancer agent is a topoisomerase inhibitor, including, but not limited to, camptothecins, etoposide, irinotecan, and topotecan. In yet another embodiment, the anticancer agent is a kinase inhibitor, including, but not limited to, erlotinib and imatinib. In yet another embodiment, the anticancer agent is a nucleoside, including, but not limited to, gemcitabine. In yet another embodiment, the anticancer agent is selected from the group consisting of enzymes (asparaginase), hormones (tamoxifen, leuprolide, flutamide, and megestrol), hydroxyurea, interferons, and oblimersen. In still another embodiment, the anticancer agent is a monoclonal antibody, including, but not limited to bevacizumab and cetuximab. For a more comprehensive discussion of updated cancer therapies; See, http://www.nci.nih.gov/, a list of the FDA approved oncology drugs at
http://www.fda.gov/cder/cancer/druglistframe.htm, and The Merck Manual, Seventeenth Ed. 1999, the entire contents of which are hereby incorporated by reference.
[00238] The route of administration of the salt provided herein is independent of the route of administration of a second therapy. In one embodiment, the salt provided herein is administered orally. In another embodiment, the salt provided herein is administered intravenously. Thus, in accordance with these embodiments, the salt provided herein is administered orally or intravenously, and the second therapy can be administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery by catheter or stent, subcutaneously, intraadiposally, intraarticularly, intrathecally, or in a slow release dosage form. In one embodiment, the salt provided herein and a second therapy are administered by the same mode of administration, orally or by IV. In another embodiment, the salt provided herein is administered by one mode of administration, e.g., orally, whereas the second agent (an anticancer agent) is administered by another mode of administration, e.g., by IV.
[00239] Other therapies or anticancer agents that may be used in combination with the compound provided herein include surgery, radiotherapy, endocrine therapy, biologic response modifiers (e.g., interferons, interleukins, and tumor necrosis factor (TNF)), hyperthermia and cryotherapy, and agents to attenuate any adverse effects (e.g., antiemetics).
[00240] In yet another embodiment, provided herein is a method of inhibiting the growth of a cell, comprising contacting the cell with an effective amount of a salt provided herein, including a pharmaceutically acceptable salt or solvate thereof.
[00241] In certain embodiments, the cell is a mammalian cell. In certain embodiments, the mammal is a human cell. In certain embodiments, the cell is a tumor cell. In certain embodiments, the cell is mammalian tumor cell. In certain embodiments, the cell is a human tumor cell. In certain embodiments, the cell is a cancerous cell. In certain embodiments, the cell is mammalian cancerous cell. In certain embodiments, the cell is a human cancerous cell.
[00242] In certain embodiments, the tumor cell overexpresses HER1 protein. In certain embodiments, the tumor cell overexpresses HER2 protein.
[00243] In certain embodiments, the cancerous cell that can be treated with the methods provided herein includes, but is not limited to, cells of bladder cancer, breast cancer, cervical cancer, colon cancer (e.g., colorectal cancer), endometrial cancer, esophageal cancer, gastric cancer, glioma (e.g., glioblastoma), head and neck cancer, liver cancer, lung cancer (e.g., small cell and non-small cell lung cancers), melanoma, myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, sarcoma (e.g., osteosarcoma), skin cancer (e.g. , squamous cell carcinoma), stomach cancer, testicular cancer, thyroid cancer, and uterine cancer.
[00244] In certain embodiments, the cell is a cell of bladder cancer, breast cancer, cervical cancer, colon cancer (e.g. , colorectal cancer), endometrial cancer, gastric cancer, glioma (e.g., glioblastoma), head and neck cancer, liver cancer, non-small cell lung cancer, ovarian cancer, pancreatic cancer, or prostate cancer.
[00245] The inhibition of cell growth can be gauged by, e.g., counting the number of cells contacted with a compound of interest, comparing the cell proliferation with otherwise identical cells not contacted with the compound, or determining the size of the tumor that encompasses the cells. The number of cells, as well as the size of the cells, can be readily assessed using any method known in the art (e.g., trypan blue exclusion and cell counting, measuring incorporation of 3H-thymidine into nascent DNA in a cell).
[00246] The salt provided herein can also be provided as an article of manufacture using packaging materials well known to those of skill in the art. See, e.g., U.S. Pat. Nos. 5,323,907; 5,052,558; and 5,033,252. 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 a selected formulation and intended mode of administration and treatment.
[00247] Provided herein also are kits which, when used by the medical practitioner, can simplify the administration of appropriate amounts of active ingredients to a subject. In certain embodiments, the kit provided herein includes containers and dosage forms of the salt provided herein.
[00248] In certain embodiments, the kit includes a container comprising dosage forms of the salt provided herein, in one or more containers.
[00249] Kits provided herein can further include devices that are used to administer the active ingredients. Examples of such devices include, but are not limited to, syringes, needleless injectors drip bags, patches, and inhalers. The kits provided herein can also include condoms for administration of the active ingredients.
[00250] Kits provided herein can further include pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients. For example, if an active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit can comprise a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particulate-free sterile solution that is 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, ethyl alcohol, 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.
[00251] The disclosure will be further understood by the following non- limiting examples.
EXAMPLES
[00252] All ¾ NMR spectra were recorded at 300 MHz on a Bruker NMR
Instruments unless otherwise stated. Coupling constants (J) are in Hertz (Hz) and peaks are listed relative to TMS (δ 0.00 ppm).
[00253] X-ray powder diffraction analyses were performed using an Inel XRG-3000 diffractometer equipped with a CPS (Curved Position Sensitive) detector with a 2Θ range of 120°. Real time data were collected using CuKa radiation. The tube voltage and amperage were set to 40 kV and 30 mA, respectively. The monochromator slit was set at 1-5 mm by Samples were prepared for analysis by packing them into thin-walled glass capillaries. Each capillary was mounted onto a goniometer head that was motorized to permit spinning of the capillary during data acquisition. The samples were analyzed for 300 seconds. Instrument calibration was performed using a silicon reference standard.
[00254] XRPD patterns were collected with a Bruker D-8 Discover diffractometer and Bruker's General Area Diffraction Detection System(GADDS, v. 4.1.20). An incident beam of CuK radiation was produced using a fme-focus tube (40 kV, 40 mA), a Bibbel mirror, and a 0.5 mm double-pinhole collimator. A sample was positioned for analysis by securing a well plate that contained the sample to a translation stage and moving the sample to intersect the incident beam. The sample was analyzed using transmission geometry. The incident beam was scanned and rastered over the sample during the analysis to optimized orientation statistics. A beam-stop was used to minimize air scatter from the incident beam at low angles. A diffraction pattern was collected using a Hi-Star area detector located 1 cm from the sample and processed using GADDS. The intensity in the GADDS image of the diffraction pattern was integrated using a step size of 0.04° 2Θ. Prior to the analysis, a silicon standard was analyzed to verify the Si 1 1 1 peak position. [00255] Differential scanning calorimetry (DSC) was performed using a TA
Instruments differential scanning calorimeter 2920. A sample was placed in an aluminum DSC pan, and the weight was accurately recorded. The pan was covered with a lid and crimped. The sample was equilibrated at 25 °C, heated at 10 °C/min, and analyzed up to a final temperature of either 250 °C or 350 °C. Indium metal was used as the calibration standard. Reported temperatures are at the transition maxima.
[00256] The thermogravimetric analyses (TGA) were performed using a TA
Instruments 2950 termogravimetric analyzer. A sample was placed in an aluminum sample pan and inserted into a TG furnace. The furnace was first equilibrated at 25 °C, heated under nitrogen at 10 °C/min, up to a final temperature of 165 °C or 350 °C. Nickel and ALUMEL™ were used as the calibration standards.
[00257] Infrared spectra were acquired on a MAGNA-IR 860® Fourier transform infrared (FT-IR) spectrophotometer (Thermo Nicolet), equipped with an Ever-Glo mid/far IR source, an extended range potassium bromide (KBr) beamsplitter, and a deuterated triglycine sulfate (STGS) detector. A diffuse reflectance accessory (COLLECTOR™, Thermo Spectra- Tech) was used for sampling. Each spectrum represents 256 co-added scans collected at a spectral resolution of 4.0 cm"1. A sample was analyzed mixed with KBr. A clean crystal background was collected. A log VR (R = reflectance) spectrum was acquired by taking a ratio of these two data sets against each other. Wavelength calibration was performed using polystyrene.
[00258] FT-Raman spectra were acquired on a Raman accessory module interfaced to a MAGNA 860® Fourier transform infrared (FT-IR) spectrophotometer (Thermo Nicolet). This module used an excitation wavelength of 1064 nm and an indium gallium arsenide (InGaAs) detector. Approximately 0.4 - 0.7 W of Nd:YV04 laser power was used to irradiate a sample. The sample was prepared for analysis by placing the sample in a glass tube and positioning the tube in a gold-coated tube holder in the accessory. A total of 256 scans were collected from 3600 - 100 cm"1 at a spectral resolution of 4 cm"1, using Happ- Genzel apodization. Wavelength calibration was performed using sulfur and cyclohexane.
[00259] Alternatively, FT-Raman spectra were acquired on an FT-Raman 960 spectrometer (Thermo Nicolet), which used an excitation wavelength of 1064 nm.
Approximately 0.5 W of Nd:YV04 laser power was used to irradiate a sample. The Raman spectra were measured with an indium gallium arsenide (InGaAs) detector. The sample was prepared for analysis by placing the sample in a glass tube and positioning the tube in a gold- coated tube holder in the accessory. A total of 256 scans were collected from 3700 - 100 cm" 1 at a spectral resolution of 4 cm"1, using Happ-Genzel apodization. Wavelength calibration was performed using sulfur and cyclohexane.
[00260] Thermogravimetric infrared (TGIR) analyses were acquired on a TA
Instruments thermogravimetric analyzer model 2050, interfaced to a MAGNA-IR 560® Fourier transform infrared (FT-IR) spectrophotometer (Thermo Nicolet), equipped with an Ever-Glo mid/far IR source, a potassium bromide (KBr) beamsplitter, and an MCTA detector. A sample was placed in a platinum sample pan, inserted into the TG furnace, and accurately weighed by the instrument. The furnace was heated from ambient to 250 °C at a rate of 20 °C/min. The TG instrument was stared first, immediately followed by the FT-IR instrument. Each IR spectrum represents 32 co-added scans collected at a spectral resolution of 4.0 cm"1. IR spectra were collected every 32 seconds for approximately 13 min. A background scan was collected before the beginning of the experiment. Wavelength calibration was performed using polystyrene. The TG calibration standards were nick and ALUMEL™. Volatiles were identified from a search of the High Resolution Nicolet TGA Vapor Phase spectral library.
[00261] Coulometric Karl Fischer (KF) analysis for water determination was performed using a Mettler Toledo DL39 Karl Fischer titrator. Approximately 1000 mg of a sample was placed in the KF titration vessel containing approximately 1 mL of Hydranal- Coulomat AD and mixed for 10 seconds to ensure dissolution. The sample was then titrated using a generator electrode which produces iodine by electrochemical oxidation. Two replicates were obtained to ensure reproducibility.
[00262] Optical microscopy was performed using a Leica MZ12.5 stereomicroscope.
A sample was viewed in situ or on a glass slide through crossed polarizers and a first order red compensator using various objectives ranging from 0.8 - 10X.
[00263] Hot stage microscopy was performed using a Linkam FTIR 600 hot stage with a TM593 controller on a Leica DM LP microscope (Pol. Microscope #1), equipped with a Spot Insight color camera for acquiring images. Images were acquired using Spot Advanced software version 4.5.9, unless noted. The camera was white balanced. Images were acquired using a 20x 0.4 N.A. long working distance objective with crossed polars and first order red compensator unless noted.
[00264] Standard abbreviations and acronyms as defined in J. Org. Chem. 2007 72(1):
23A-24A are used herein. Other abbreviations and acronyms used herein are as follows:
Figure imgf000072_0001
Example 1
Salts of (5 -morpholin-3-ylmethyl 4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5- methylpyrrolo[ 1 ,2- ] [ 1 ,2,4]triazin-6-ylcarbamate
[00265] (5)-Morpholin-3-ylmethyl 4-(l-(3-fiuorobenzyl)-lH-indazol-5-ylamino)-5- methylpyrrolo[l ,2- ][l ,2,4]triazin-6-ylcarbamate was charged to each 40 mL scintillation vial. Acetonitrile (20 mL) was added to each vial, and the vial was heated with a heat gun until a solution was formed. The vial was allowed to cool slightly and slowly uncapped to gently release any pressure in the vial. An acid (1.0 equivalent) was then added in the amount shown in Table 1. Attempts at removing the solvent in vacuo for the acetate salt resulted in bumping. All other salts were concentrated under a stream of air. A portion of each salt was analyzed by DSC and results are summarized in Table 2. The solubility of the salts in various solvents is summarized in Tables 3 and 4. The purity of the salts is summarized in Table 5. TABLE 1
Figure imgf000073_0001
TABLE 2. DSC Analyses
Figure imgf000073_0002
TABLE 3. Solubility of Salts of the Compound of Formula I
Figure imgf000074_0001
S, M, I, and Spa represent soluble, melt, insoluble, and sparely soluble, respectively. The solubility was measured upon heating.
TABLE 4. Solubility of Salts of the Compound of Formula I
Figure imgf000075_0001
Example 2
Salts of (iS)-morpholin-3-ylmethyl 4-(l -(3-fluorobenzyl)- lH-indazol-5-ylamino)-5- methylpyrrolo[ 1 ,2- ] [ 1 ,2,4]triazin-6-ylcarbamate
[00266] (S)-Morpholin-3-ylmethyl 4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5- methylpyrrolo[ l ,2- J [l ,2,4]triazin-6-ylcarbamate (150 mg or 250 mg) was dissolved in 35 volumes THF in an amber vial. To the stirring solution was added 1 equivalent of an acid. The solutions were stirred for 30 min, and then MTBE was added or solids were collected by fdtration. If MTBE was added, the reaction mixtures were stirred for additional 30 to 60 min before filtration.
[00267] A maleate salt was prepared in 89% yield with the addition of MTBE (8.5 mL). A mesylate salt was prepared in quantitative yield without the addition of MTBE. A phosphate salt was prepared in 61% yield without the addition of MTBE. An esylate salt was prepared in quantitative yield with the addition of MTBE (4 mL). TABLE 5. HPLC Purity of the Salts of the Compound of Formula I
Figure imgf000076_0001
Example 3
Salts of (5)-morpholin-3-ylmethyl 4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5- methylpyrrolo[ 1 ,2- ] [ 1 ,2,4]triazin-6-ylcarbamate [00268] Generally, (S)-morpholm-3-ylmethyl 4-(l-(3-fluorobenzyl)-lH-indazol-5- ylamino)-5-methylpyrrolo[l,2-y][l,2,4]triazin-6-ylcarbamate was dissolved in 35 or 45 volumes THF at about 35 °C. One equivalent of an acid was then added at a rate to keep the temperature of no greater than about 35 °C. The solution was stirred for 1 hr and allowed to cool to room temperature. MTBE (from 3.5 to 13 volumes depending on the acid used) was added. The solution was stirred for additional 30 min. The resulting solids were filtered, washed with 2-4 volumes MTBE and dried under vacuum at room temperature.
[00269] A mesylate salt was prepared by dissolving the compound of Formula I in about 45 volume THF at about 35 °C. Methanesulfonic acid (1.0 M, 1 eq.) in methanol was added slowly. The solution was stirred for 1 hr. MTBE (50 mL) was added and the solution was stirred for additional 30 min. The resulting solid was filtered, washed with MTBE, and dried under vacuum overnight at room temperature to yield the desired salt (21.6 g) as a white solid in a quantitative yield. HPLC purity: 99.4%; Nitrosamine: 2 ppm; mp: 202.8- 203.5 °C. Residual solvents: MTBE: >9675 ppm; THF: 12835 ppm; MeOH: 736 ppm. XRPD: crystalline solid (maybe mixed crystalline and amorphous).
[00270] A phosphate salt was prepared by dissolving the compound of Formula I in about 35 volume THF at 35 ± 5 °C. Phosphoric acid (1.0 M, 1 eq.) in methanol was added slowly. The solution was stirred for 1 hr. MTBE (100 mL) was added and the solution was stirred for additional 30 min. The resulting solid was filtered, washed with MTBE, and dried under vacuum for about 48 hrs at room temperature to yield the desired salt (24.0 g) as a hard, yellow solid in 108% yield. HPLC purity: 99.4%; Nitrosamine: 2 ppm; mp: 187.1 °C. Residual solvents: MTBE: 5802 ppm; THF: 12467 ppm; MeOH: 296 ppm. XRPD:
crystalline solid (maybe mixed crystalline and amorphous).
[00271] An esylate salt was prepared by dissolving the compound of Formula I (10.0 g, 18.8 mmol) in THF (350 mL) at 35 ± 5 °C. Ethanesulfonic acid (1.56 mL, 19.1 mmol) was dissolved in methanol (19 mL). The acid solution was added to the solution of the compound of Formula I within 2 min. Solids formed within 5 min. The mixture was stirred for 1 hr. MTBE (190 mL) was added and the solution was stirred for additional 30 min. The resulting solid was filtered, washed with MTBE (3 x 30 mL), air dried for about 15 min, and dried under vacuum until a constant weight (about 66 hrs) at room temperature to yield the esylate salt (11.7 g) as a white powder in 97% yield. HPLC purity: 99.4%; Nitrosamine: 2 ppm; mp: 198.6-199.5 °C. Residual solvents: MTBE: 432 ppm; THF: 416 ppm; MeOH: < 108 ppm. X PD: crystalline solid.
[00272] A maleate salt was prepared by dissolving the compound of Formula I in about 35 volume THF at about 35 °C. Ethanesulfonic acid (1.0 M, 1 eq.) in methanol was added slowly. The solution was stirred for 1 hr. MTBE (100 mL) was added and the solids formed within 2 hrs. Additional MTBE (200 mL) was added, and the mixture was stirred for 1 hr. The resulting solid was filtered, washed with MTBE, and dried under vacuum for about 66 hrs at room temperature to yield the desired salt (1 1.4 g) as a white or pale yellow powdery solid in 93% yield. HPLC purity: 97.0%; Nitrosamine: 3 ppm; mp: 194.0-195.3 °C. Residual solvents: MTBE: 804 ppm; THF: 5838 ppm; MeOH: < 106 ppm. XRPD:
crystalline solid.
[00273] The solubility of the salts is summarized in Table 6.
Example 4
Polymorphs of salts of (S)-moi holin-3-ylmethyl 4-(l-(3-fluorobenzyl)-lH-indazol-5- ylamino)-5-methylpyrrolo[l,2: ][l ,2,4]triazin-6-ylcarbamate
[00274] Polymorph screenings were conducted for mesylate, esylate, and maleate salts of (5)-morpholin-3-ylmethyl 4-( 1 -(3-fluorobenzyl)- lH-indazol-5-ylamino)-5- methylpyrrolof 1 ,2-f] [ 1 ,2,4]triazin-6-ylcarbamate.
[00275] Generally, a solution (20 mg/mL) of a salt of (5)-morpholin-3-ylmethyl 4-(l-
(3-fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2: ][l,2,4]triazin-6-ylcarbamate in various solvents or solvent mixtures was charged to individual wells of a 96 well plate. A control well for each salt contained no solvent. Solids were generated through slow evaporation of the solvents. Results are summarized in Tables 7 to 9.
TABLE 6. Solubility of Salts of the Compound of Formula I
Figure imgf000079_0001
The salt is insoluble at 5 mg/mL.
The salt forms gel at 25 mg/mL.
The salt forms gel at 50 mg/mL.
d. The salt is sparingly soluble at 4.2 mg/mL.
TABLE 7. Mesylate Salt
Figure imgf000080_0001
Methanol Form I-A
Methyl nonafluorobutyl ether Form I-B
2-M ethyl- 1 -propanol Form I-A
3-pentanone Form I-A
1 -Propanol Form I-A
2-Propanol Form I-A
Propionitrile Form I-A w-Propyl acetate Form I-A 7-xylene Form I-A tert-Amy\ alcohol Form I-A tert-Methyl butyl ether Form I-A
Tetrachloroethane Low crystallinity
THF Form I-A
THF/water Form I-A
Toluene Form I-A α,α,α -Trifluorotoluene Form I-A
Water Low crystallinity
TABLE 8. Esylate Salt
Figure imgf000081_0001
Chloroform/toluene Form II-B
Cyclohexane Amorphous
Cyclopentanone Low crystallinity
DCM Forms II-B and II-C
Diethyl ether Form II-B
1,4-Dioxane Forms II-A, II-B, and II-C
1 ,4-Dioxane/water Form II-E
Ethanol Form II-B
EtOAc Forms II-B and II-C
2-Ethoxyethanol Amorphous
Ethyl trifluoroacetate Amorphous
Ethyl trif uoroacetate/TFE Form II-C
Fluorobenzene/TFE Amorphous
Hexanes Amorphous
Hexafluoroisopropanol Amorphous
Isopropyl ether Amorphous
Methyl ethyl ketone Form II-A
Methanol Form II-A
Methyl nonafluorobutyl ether Low crystallinity
2-Methyl- 1 -propanol Form II-C
3-pentanone Form II-A
1 -Propanol Form II-C
2-Propanol Form II-C
Propionitrile Form II-A
«-Propyl acetate Form II-A
/^-xylene Form II-B Tert-Amyl alcohol Form II-B
Tert-Methyl butyl ether Low crystallinity
Tetrachloroethane Low crystallinity
THF Form II-D
THF/water Amorphous
Toluene Form II-B α,α,α -Trifluorotoluene Forms II-B and II-C
Water Form II-B
TABLE 9. Maleate Salt
Solvent Polymorph
None Amorphous
Acetone Form III-B
Acetone/water Form III-B
ACN Form III-C
ACN/water Form III-B
2-Butanol Form III-C
Chloroform Amorphous
Chloroform/toluene Form III-A
Cyclohexane Form III-A
Cyclopentanone Amorphous
DCM Form III-A
Diethyl ether Amorphous
1,4-Dioxane Form III-A
1 ,4-Dioxane/water Form III-B
Ethanol Form III-A
EtOAc Form III-A 2-Ethoxyethanol Amorphous
Ethyl trifluoroacetate Amorphous
Ethyl trifluoroacetate/TFE Amorphous
Fluorobenzene/TFE Amorphous
Hexanes Amorphous
Hexafluoroisopropanol Form III-D
Isopropyl ether Amorphous
Methyl ethyl ketone Form III-A
Methanol Amorphous
Methyl nonafluorobutyl ether Unknown
2-Methyl- 1 -propanol Form III-A
3-pentanone Form III-A
1 -Propanol Form III-A
2-Propanol Form III-A
Propionitrile Amorphous
«-Propyl acetate Form III-A7-xylene Form III-A
Tert-Amy\ alcohol Form III-A
Teri-Methyl butyl ether Amorphous
Tetrachloroethane Amorphous
THF Amorphous
THF/water Amorphous
Toluene Amorphous
Α,α,α -Trifluorotoluene Amorphous
Water Form III-B [00276] Representative XRD patterns of Forms I-A to I-D, II-A to II-E, and III-A to III-D are shown in FIGS. 1A to ID, 2A to 2E, and 3 A to 3E, respectively. Some XRD peaks of Forms I-A to I-D, II-A to II-E, and III-A to III-D are summarized in Tables 10 to 22, respectively.
TABLE 10. X-Ray Diffraction Peaks for Form I-A
Figure imgf000085_0001
TABLE 11. X-Ray Diffraction Peaks for Form I-B
Figure imgf000086_0001
14.1 ±0.1 6.272 ± 0.045 16
14.5 ±0.1 6.117 ±0.042 21
16.9 ±0.1 5.253 ±0.031 68
17.7 ±0.1 5.005 ±0.028 43
18.4 ±0.1 4.822 ±0.026 39
19.0 ±0.1 4.681 ±0.025 70
20.9 ±0.1 4.254 ±0.020 27
21.4 ± 0.1 4.145 ±0.019 39
21.8 ± 0.1 4.077 ±0.019 40
22.5 ±0.1 3.955 ±0.017 100
23.6 ±0.1 3.764 ±0.016 52
24.1 ±0.1 3.690 ±0.015 54
25.0 ±0.1 3.556 ±0.014 37
26.2 ±0.1 3.407 ±0.013 31
27.5 ±0.1 3.246 ±0.012 26
28.0 ±0.1 3.187 ±0.011 26
28.9 ±0.1 30.92 ±0.011 21
TABLE 13. X-Ray Diffraction Peaks for Form I-D
Two-theta angle (°) d Space (A) Intensity (%)
7.4 ±0.1 12.011 ±0.165 53
8.8 ±0.1 10.049 ±0.115 21
13.2 ±0.1 6.707 ±0.051 55
14.2 ±0.1 6.220 ± 0.044 39
14.9 ±0.1 5.938 ±0.040 38
17.6 ±0.1 5.039 ±0.029 31
19.3 ±0.1 4.604 ± 0.024 100 20.5 ±0.1 4.328 ±0.021 27
21.2 ± 0.1 4.183 ±0.020 27
22.0 ±0.1 4.048 ±0.018 80
23.0 ±0.1 3.860 ±0.017 40
23.5 ±0.1 3.783 ±0.016 46
24.0 ±0.1 3.708 ±0.015 35
25.1 ±0.1 3.551 ±0.014 87
25.4 ±0.1 3.507 ±0.014 78
25.7 ±0.1 3.469 ±0.013 68
26.6 ±0.1 3.356 ±0.012 48
27.2 ±0.1 3.279 ±0.012 67
28.2 ±0.1 3.169 ±0.011 35
28.8 ±0.1 3.096 ±0.011 38
29.8 ±0.1 3.002 ±0.010 36
TABLE 14. X-Ray Diffraction Peaks for Form II-A
Two-theta angle (°) d Space (A) Intensity (%)
3.6 ± 0.1 24.544 ±0.701 70
7.4 ±0.1 12.011 ±0.165 25
8.4 ±0.1 10.577 ±0.128 100
11.9 ± 0.1 7.425 ±0.063 11
13.4 ±0.1 6.588 ±0.049 19
15.1 ±0.1 5.875 ±0.039 13
17.8 ±0.1 4.983 ±0.028 30
19.0 ±0.1 4.661 ±0.024 27
22.1 ±0.1 4.026 ±0.018 22
23.1 ±0.1 3.847 ±0.016 30 24.4 ±0.1 3.648 ±0.015 24
25.7 ±0.1 3.464 ±0.013 20
27.2 ±0.1 3.283 ±0.012 18
28.6 ±0.1 3.117 ± 0.011 14
TABLE 15. X-Ray Diffraction Peaks for Form II-B
Two-theta angle (°) d Space (A) Intensity (%)
3.6 ± 0.1 24.544 ±0.701 58
7.3 ±0.1 12.077 ±0.167 16
8.4 ±0.1 10.577 ±0.127 100
10.8 ±0.1 8.222 ±0.077 20
12.2 ±0.1 7.279 ±0.060 17
13.4 ±0.1 6.588 ±0.049 31
14.4 ±0.1 6.168 ±0.043 26
15.2 ±0.1 5.814 ±0.038 44
15.6 ±0.1 5.666 ±0.036 34
16.9 ±0.1 5.240 ±0.031 44
17.8 ±0.1 4.983 ±0.028 25
18.9 ±0.1 4.691 ±0.025 29
19.6 ±0.1 4.529 ±0.023 33
20.0 ±0.1 4.444 ± 0.022 25
21.4 ± 0.1 4.160 ±0.019 29
22.2 ±0.1 4.004 ±0.018 44
22.6 ±0.1 3.941 ±0.017 38
23.2 ±0.1 3.828 ±0.016 44
24.1 ±0.1 3.696 ±0.015 37
25.3 ±0.1 3.523 ±0.014 56 26.4 ±0.1 3.371 ±0.013 19
27.2 ±0.1 3.274 ±0.012 19
27.4 ±0.1 3.250 ±0.012 20
28.0 ±0.1 3.182 ±0.011 45
TABLE 16. X-Ray Diffraction Peaks for Form II-C
Two-theta angle (°) D Space (A) Intensity (%)
4.0 ±0.1 21.872 ±0.555 60
8.1 ±0.1 10.943 ±0.137 21
10.6 ±0.1 8.315 ±0.079 19
12.4 ±0.1 7.138 ±0.058 18
13.8 ± 0.1 6.436 ±0.047 44
14.4 ±0.1 6.168 ±0.043 20
16.3 ±0.1 5.432 ±0.033 49
16.8 ±0.1 5.290 ±0.032 44
18.7 ±0.1 4.750 ±0.025 32
19.2 ±0.1 4.623 ± 0.024 27
20.3 ±0.1 4.379 ±0.021 38
20.8 ±0.1 4.271 ±0.020 34
21.6 ± 0.1 4.122 ±0.019 48
22.2 ±0.1 4.004 ±0.018 24
23.2 ±0.1 3.834 ±0.016 100
24.8 ±0.1 3.596 ±0.014 24
26.0 ±0.1 3.422 ±0.013 22
26.8 ±0.1 3.332 ±0.012 39
27.8 ±0.1 3.205 ±0.011 11
29.0 ±0.1 3.083 ±0.010 15 TABLE 17. X-Ray Diffraction Peaks for Form II-D
Figure imgf000091_0001
19.5 ±0.1 4.548 ±0.023 38
21.4 ± 0.1 4.152±0.019 33
22.4 ±0.1 3.976 ±0.018 38
22.5±0.1 3.955 ±0.017 38
22.8 ±0.1 3.894 ±0.017 32
23.7 ±0.1 3.751 ±0.016 29
25.0 ±0.1 3.556 ±0.014 78
25.8 ±0.1 3.459 ±0.013 100
26.2 ±0.1 3.396 ±0.013 31
27.3 ±0.1 3.264 ±0.012 22
27.9 ±0.1 3.200 ±0.011 79
TABLE 19. X-Ray Diffraction Peaks for Form III-A
Two-theta angle (°) D Space (A) Intensity (%)
5.1 ±0.1 17.218 ±0.342 85
9.0 ±0.1 9.781 ±0.109 43
10.0 ±0.1 8.868 ±0.090 40
10.8 ±0.1 8.162 ±0.076 33
12.8 ±0.1 6.928 ±0.054 68
13.1 ±0.1 6.764 ±0.052 40
14.0 ±0.1 6.316 ±0.045 60
14.5 ±0.1 6.091 ±0.042 34
15.2 ±0.1 5.843 ±0.039 89
15.5 ±0.1 5.700 ±0.037 70
17.2 ±0.1 5.154 ±0.030 44
17.7 ±0.1 5.023 ±0.028 60
18.0 ±0.1 4.918 ±0.027 68 19.2 ±0.1 4.628 ±0.024 54
20.5 ±0.1 4.341 ±0.021 53
20.7 ±0.1 4.290 ±0.021 81
21.0 ± 0.1 4.228 ±0.020 39
31.6 ± 0.1 4.107 ±0.019 39
22.1 ±0.1 4.018 ±0.018 100
22.5 ±0.1 3.957 ±0.017 88
22.7 ±0.1 3.909 ±0.017 93
23.0 ±0.1 3.869 ±0.017 89
23.9 ±0.1 3.720 ±0.015 47
24.6 ±0.1 3.617 ± 0.015 39
25.0 ±0.1 3.562 ±0.014 44
25.7 ±0.1 3.468 ±0.013 32
26.0 ±0.1 3.427 ±0.013 54
26.4 ±0.1 3.374 ±0.012 53
26.7 ±0.1 3.335 ±0.012 30
327.3 ±0.1 3.269 ±0.012 35
28.3 ±0.1 3.159 ±0.011 34
28.9 ±0.1 3.088 ±0.010 25
29.3 ±0.1 3.052 ±0.010 24
29.6 ±0.1 3.014±0.010 34
30.0 ±0.1 2.983 ±0.010 37
Example 5
Maleate salts of (5)-morpholin-3-ylmethyl 4-(l-(3-fluorobenzyl)-lH-mdazol-5-ylamino)-5- methylpyrrolo[ 1 ,2-] [ 1 ,2,4]triazin-6-ylcarbamate
[00277] Apparent solubility of the maleate salt is summarized in Table 23. A weighed sample was treated with aliquots of a test solvent at room temperature. The mixture was sonicated or agitated between additions to facilitate dissolution. Complete dissolution of the salt was determined by visual inspection. Solubility was estimated based on the total solvent used to provide complete dissolution. The actual solubility may be greater than the value calculated because of the use of solvent aliquots that were too large or due to a slow rate of dissolution. The solubility is expressed as less than if dissolution did not occur during the experiment. If complete dissolution was achieved as a result of only one aliquot addition, the solubility is expressed as greater than.
TABLE 20. X-Ray Diffraction Peaks for Form III-B
Figure imgf000094_0001
25.1 ±0.1 3.551 ±0.014 100
26.4 ±0.1 3.376 ±0.012 40
27.4 ±0.1 3.260 ±0.012 64
28.3 ±0.1 3.156 ±0.011 23
29.8 ±0.1 3.002 ±0.010 22
TABLE 21. X-Ray Diffraction Peaks for Form III-C
Two-theta angle (°) D Space (A) Intensity (%)
5.0 ± 0.1 17.674 ±0.360 3
8.8 ±0.1 10.049 ±0.115 12
10.6 ±0.1 8.346 ±0.079 5
11.0 ± 0.1 8.014 ±0.073 15
11.5 ± 0.1 7.708 ±0.068 11
11.9 ± 0.1 7.425 ±0.063 9
13.8 ± 0.1 6.436 ±0.047 10
14.2 ±0.1 6.237 ±0.044 6
15.1 ±0.1 5.860 ±0.039 11
15.6 ±0.1 5.666 ±0.036 4
16.8 ±0.1 5.290 ±0.032 13
17.4 ±0.1 5.097 ±0.029 39
18.3 ±0.1 4.853 ±0.026 14
19.3 ±0.1 4.604 ± 0.024 3
19.9 ±0.1 4.466 ± 0.022 4
20.3 ±0.1 4.379 ±0.021 5
21.2 ± 0.1 4.191 ±0.020 10
21.4 ± 0.1 4.145 ±0.019 10
22.3 ±0.1 3.983 ±0.018 23 23.4 ±0.1 3.808 ±0.016 18
23.9 ±0.1 3.726 ±0.015 28
25.3 ±0.1 3.518 ±0.014 100
27.0 ±0.1 3.298 ±0.012 39
27.8 ±0.1 3.205 ±0.011 9
28.6 ±0.1 3.125 ±0.011 4
29.4 ±0.1 3.034 ±0.010 11
TABLE 22. X-Ray Diffraction Peaks for Form III-D
Two-theta angle (°) D Space (A) Intensity (%)
3.6 ± 0.1 24.544 ±0.701 50
4.6 ±0.1 19.379 ±0.434 39
7.4 ±0.1 12.011 ±0.165 33
12.4 ±0.1 7.115 ±0.057 31
13.4 ±0.1 6.588 ±0.049 69
17.5 ±0.1 5.062 ±0.029 100
19.5 ±0.1 4.548 ±0.023 100
20.4 ±0.1 4345 ±0.021 81
23.5 ±0.1 3.789 ±0.016 89
TABLE 23
Figure imgf000096_0001
[00278] Polymorphs of a maleate salt of (i¾-morpholin-3-ylmethyl 4-(l-(3- fluorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2 ][l,2,4]triazin-6-ylcarbamate were further explored using different crystallization methods, including slurry, slow cooling, slow evaporation, and fast evaporation, in acetone, ACN, HFIPA, or THF. Results are summarized in Table 24.
[00279] For slurry methods, solvents were added to weighed amounts of the solids in glass vials in a ratio such that undissolved solids were present. Samples were either heated with stirring or agitated at ambient temperature. The solids were isolated by vacuum filtration or by solvent decantation, allowing the solids to air dry at ambient conditions prior to analysis.
[00280] For slow cooling methods, saturated solutions were prepared in various solvents at elevated temperatures and filtered through a 0.2 μιη nylon filter into an open vial while still warm. The vial was allowed to cool slowly to room temperature. Solids that formed were isolated by filtration and allowed to dry prior to analysis.
[00281] For slow evaporation methods, solutions were prepare in various solvents and sonicated between aliquot additions to assist in dissolution. Once a mixture reached complete dissolution, as judged by visual observation, the solution was filtered through a 0.2 μιη nylon or TFE filter. The filtered solutions were slow evaporated under nitrogen or slow evaporated at -50 °C. Solids that formed were isolated by filtration and allowed to dry prior to analysis.
[00282] For fast evaporation methods, solutions were prepare in various solvents and sonicated between aliquot additions to assist in dissolution. Once a mixture reached complete dissolution, as judged by visual observation, the solution was filtered through a 0.2 μιη nylon filter. The filtered solutions were allowed to evaporate at ambient in an uncapped vial.
Solids that formed were isolated by filtration and allowed to dry prior to analysis.
TABLE 24
Figure imgf000097_0001
cooling @ 1 °C/hr
RT slurry for 8 days Form III-A
-50 °C slurry for 7 Form III-A
days
ACN
-50 °C slow Low
evaporation crystallinity
-50 to -20 °C slow - cooling @ 1 °C/hr
Slow evaporation Form III-D
Hexafluoroisopropanol
under N2
Fast evaporation to Forms III-A
gel, acetone added, and III-B
then fast evaporation
Fast evaporation to - glass, acetone added,
Trifluoroethanol then slow evaporation
Fast evaporation to Form III-A
gel, ACN added
Fast evaporation Forms III-B
and III-A
Starting with Form III- Form III-B
Water A, slurry at room
temperature for 1 day
Starting with Forms Form III-A
III-A and III-B, slurry
at 2- 8 °C
Ethyl acetate
Starting with Forms - III-A and III-B,
elevated slurry
Example 6
Quantitation of (5)-(4-nitrosomorpholin-3-yl)methyl 4-(l-(3-fluorobenzyl)-lH-indazol-5- ylamino)-5-methylpyrrolo[l ,2-y][l,2,4]triazin-6-ylcarbamate ("AC480-nitrosamine")
[00283] AC480-nitrosamine was quantitated on a CI 8 colume (50 mm x 4.6 mm) using HPLC-MS with a triple quadruple MS system in multiple reaction monitoring mode. The mobile phases were A. water with 0.1% formic acid, and B. ACN with 0.1% formic acid.
[00284] A stock standard solution (100 ppm) was prepared by accurately weighing 10 ± 0.1 mg of AC480-nitrosamine reference material into a 100-mL volumetric flask, and dissolving and diluting to volume with ACN. The stock standard solution was stable at least for nine months at -25 °C, protected from light. A working assay standard solution (5 ppb) was prepared in duplicate by diluting the stock standard solution with ACN/water (9: 1, v:v) to make a 0.1 ppm solution, and transferring 5.0 mL of this 0.1 ppm solution into 100 mL volumetric flask and diluting to volume with ACN/water (9: 1, v:v). One of the working assay standard solutions was used as a verification standard. The working assay standard solution was stable for at least three days at 4 °C, protected from light.
[00285] For analyzing a 100 mg encapsulated tablet, a sample solution was prepared by weighing three dosage units without capsule shell, and transferring the capsules to a 250 mL volumetric flask. The flask was filled with about 160 mL of ACN/water (9:1, v:v), shaken for 10 min, sonicated for another 1 min, and then diluted to volume with ACN/water (9:1, v:v), after equilibrating to room temperature. The AC480 final concentration of the sample solution was 1.2 mg/mL. An aliquote of the sample solution was centrifuged for 10 min. The aliquate was transferred into a HPLC vial for analysis. The sample solution was stable for 3 days at 4 °C, protected from light.
[00286] For analyzing AC480 drug substance, a sample solution was prepared by weighing and transferring 12 mg AC480 drug substance to a 10 mL volumetric flask. The flask was filled with about 6 mL of ACN/water (9:1, v:v), sonicated for another 2 min, and then diluted to volume with ACN/water (9: 1, v:v), after equilibrating to room temperature. The final AC480 concentration of the sample solution was 1.2 mg/mL. The aliquate was transferred into a HPLC vial for analysis. The sample solution was stable for 3 days at 4 °C, protected from light.
[00287] System suitability was tested by injecting the working assay standard solution six times, and calculating the %RSD of the peak area for the replicate injections. Verification working assay standard solutions were also injected three times. The %RSD for the peak areas of replicate injections of the working assay standard solution was less than NMT 10%. The weight corrected area responses ratio of working and verification assay standard solutions was between 0.90 and 1.10. [00288] Samples were analyzed by injecting the sample solutions in duplicate. Every six samples injections, working standard solution was injected for quality control. The amount of AC480-nitrosamine for a sample tested was calculated as follows: AC480- nitrosamine concentration (ppm) = (Average area responses of two replicate injections of a sample solution) x (AC480-nitrosamine standard solution (ng/mL)) x (Total volume (mL) of the sample solution) ÷ [(Average area responses of six injections of AC480-nitrosamine standard solution) x (Total weight of the sample (g))] .
Example 7
Synthesis of [4-[[ 1 -(3-fluorophenyl)methyl]-lH-indazol-5-ylamino]-5-methyl-pyrrolo[2, 1 - f][l,2,4]triazin-6-yl]-carbamic acid, (3S -3-morpholinylmethyl ester, ethanesulfonate (AC480 esylate) in crystalline Form II-B
[00289] A mixture of AC480 free base and ethanesulfonic acid in ethanol was heated at 78 ± 5 °C for at least one hour. The reaction mixture was then cooled to 20 ± 5 °C and AC480 esylate precipitated. After filtration, the filter cake was washed with ethanol cooled to 0 ± 5 °C. The resulting solid was then dried to constant weight in a vacuum oven at < 30 °C to yield AC480 esylate in crystalline Form II-B, which has a melting point of about 202 °C.
[00290] The stability of AC480 esylate in crystalline Form II-B was determined under three different storage conditions: i) 5 °C; ii) 25 °C and 60% RH; and iii) 40 °C and 75% RH. Results are summarized in Tables 25 to 27.
TABLE 25. Stability of AC480 Esylate at 5 °C
Figure imgf000100_0001
a. AC480 esylate is white to pale-yellow or pale-pink powder, which may contain
lumps. TABLE 26. Stability of AC480 Esylate at 25 °C/60%RH
Figure imgf000101_0001
a. AC480 esylate is white to pale-yellow or pale-pink powder, which may contain
lumps.
TABLE 27. Stability of AC480 Esylate at 40 °C/75%RH
Figure imgf000101_0002
a. AC480 esylate is white to pale-yellow or pale-pink powder, which may contain
lumps.
Example 8
Preparation of a pharmaceutical formulation comprising AC480 esylate
[00291] A pharmaceutical formulation comprising AC480 esylate was prepared through an aseptic lyophilization process. The composition of the pharmaceutical formulation and the amount water used in the preparation are summarized in Table 28.
[00292] In preparation of the pharmaceutical formulation, 75% of the required amount of sterile water for injection was added to a clean depyrogenated glass vessel. The required amounts of powdered mannitol (2% by weight), hydroxypropyl- -cyclodextrin (ΗΡβΟϋ) (15% by weight), and AC480 esylate were added to the vessel, and mixed until dissolved. The solution was brought to its final batch weight with sterile water for injection, that is, the remaining 25%. The solution was then sterile filtered and filled into 30 cc amber glass vials at 12 mL/vial. The vials were partially stoppered, and lyophilized. Once lyophilization was completed, the vials were backfilled with sterile filtered nitrogen, and stoppers were fully inserted. The vials were then crimp sealed using 20 mm White Flip-Off Crimp seals.
[00293] Before administration to a patient, each vial was reconstituted at 25 mg/mL of AC480 free base.
TABLE 28
Figure imgf000102_0001
a. AC480 esylate (363 mg) contained 300 mg of AC480 free base.
b. Water was removed during lyophilization.
[00294] The examples set forth above are provided to give those of ordinary skill in the art with a complete disclosure and description of how to make and use the claimed embodiments, and are not intended to limit the scope of what is disclosed herein.
Modifications that are obvious to persons of 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 incorporated herein by reference as if each such publication, patent or patent application were specifically and individually indicated to be incorporated herein by reference.

Claims

What is claimed is:
1. A sulfonic acid salt of (5)-morpholin-3-ylmethyl 4-(l-(3-fluorobenzyl)-lH- indazol-5-ylamino)-5-methylpyrTolo[l,2- |[l,2,4]triazin-6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof.
2. The sulfonic acid salt of claim 1, wherein the sulfonic acid is a Ci-6 alkyl or C6-14 aryl sulfonic acid.
3. The sulfonic acid salt of claim 2, wherein the sulfonic acid is methanesulfonic acid.
4. The sulfonic acid salt of claim 3 in an amorphous form.
5. The sulfonic acid salt of claim 3 in a crystalline form.
6. The sulfonic acid salt of claim 5 in crystalline Form I-A.
7. The sulfonic acid salt of claim 5 or 6, having an X-ray powder diffraction pattern substantially as shown in FIG. 1A.
8. The sulfonic acid salt of any of claims 5 to 7, having an X-ray powder diffraction pattern with a peak expressed in two-theta at approximately 7.2, 13.0, 28.4, or 29.5°.
9. The sulfonic acid salt of claim 5 in crystalline Form I-B.
10. The sulfonic acid salt of claim 5 or 9, having an X-ray powder diffraction pattern substantially as shown in FIG. IB.
11. The sulfonic acid salt of any of claims 5, 9, and 10, having an X-ray powder diffraction pattern with a peak expressed in two-theta at approximately 2.6, 12.6, 15.9, or 17.9°.
12. The sulfonic acid salt of claim 5 in crystalline Form I-C.
13. The sulfonic acid salt of claim 5 or 12, having an X-ray powder diffraction pattern substantially as shown in FIG. 1C.
14. The sulfonic acid salt of any of claims 5, 12, and 13, having an X-ray powder diffraction pattern with a peak expressed in two-theta at approximately 3.3, 6.8, 11.2, or 26.2 o
15. The sulfonic acid salt of claim 5 in crystalline Form I-D.
16. The sulfonic acid salt of claim 5 or 15, having an X-ray powder diffraction pattern substantially as shown in FIG. ID.
17. The sulfonic acid salt of any of claims 5, 15, and 16, having an X-ray powder diffraction pattern with a peak expressed in two-theta at approximately 7.4, 8.8, 13.2, 14.9, 27.2, 28.2, or 29.8 °.
18. The sulfonic acid salt of claim 2, wherein the sulfonic acid is ethanesulfonic acid.
19. The sulfonic acid salt of claim 18 in an amorphous form.
20. The sulfonic acid salt of claim 18 in a crystalline form.
21. The sulfonic acid salt of claim 20 in crystalline Form II-A.
22. The sulfonic acid salt of claim 20 or 21 , having an X-ray powder diffraction pattern substantially as shown in FIG. 2A.
23. The sulfonic acid salt of any of claims 20 to 22, having an X-ray powder diffraction pattern with a peak expressed in two-theta at approximately 11.9, 24.4, or 28.6°.
24. The sulfonic acid salt of claim 20 in crystalline Form II-B.
25. The sulfonic acid salt of claim 20 or 24, having an X-ray powder diffraction pattern substantially as shown in FIG. 2B.
26. The sulfonic acid salt of any of claims 20, 24, and 25, having an X-ray powder diffraction pattern with a peak expressed in two-theta at approximately 24.1 or 25.3°.
27. The sulfonic acid salt of claim 20 in crystalline Form II-C.
28. The sulfonic acid salt of claim 20 or 27, having an X-ray powder diffraction pattern substantially as shown in FIG. 2C.
29. The sulfonic acid salt of any of claims 20, 27, and 28, having an X-ray powder diffraction pattern with a peak expressed in two-theta at approximately 4.0, 12.4, 13.8, 16.3, 19.2, 20.3, 21.6, 24.8. 26.0, 26.8, or 29.0°.
30. The sulfonic acid salt of claim 20 in crystalline Form II-D.
31. The sulfonic acid salt of claim 20 or 30, having an X-ray powder diffraction pattern substantially as shown in FIG. 2D.
32. The sulfonic acid salt of any of claims 20, 30, and 31, having an X-ray powder diffraction pattern with a peak expressed in two-theta at approximately 3.2 or 6.7°.
33. The sulfonic acid salt of claim 20 in crystalline Form II-E.
34. The sulfonic acid salt of claim 20 or 33, having an X-ray powder diffraction pattern substantially as shown in FIG. 2E.
35. The sulfonic acid salt of any of claims 20, 33, and 34, having an X-ray powder diffraction pattern with a peak expressed in two-theta at approximately 4.6, 13.0, 15.4, 23.7, or 25.0°.
36. The sulfonic acid salt of claim 2, wherein the sulfonic acid is benzenesulfonic acid.
37. The sulfonic acid salt of claim 36 in an amorphous form.
38. The sulfonic acid salt of claim 36 in a crystalline form.
39. The sulfonic acid salt of claim 2, wherein the sulfonic acid is p- toluenesulfonic acid.
40. The sulfonic acid salt of claim 39 in an amorphous form.
41. The sulfonic acid salt of claim 39 in a crystalline form.
42. The sulfonic acid salt of any of claims 1 to 41, comprising of about one molar equivalent of (5)-morpholin-3-ylmethyl 4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5- methylpyrrolo[l ,2- J[l ,2,4]triazin-6-ylcarbamate and about one molar equivalent of the sulfonic acid.
43. The sulfonic acid salt of any of claims 1 to 42, containing no greater than 3 ppm of (5 -(4-nitrosomoφholin-3-yl)methyl 4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5- methylpyrrolo[ 1 ,2-f [ 1 ,2,4]triazin-6-ylcarbamate.
44. An acetic acid salt of ( -morpholin-3-ylmethyl 4-(l-(3-fluorobenzyl)-lH- indazol-5-ylamino)-5-methylpyrrolo[l ,2- ][l,2,4]triazin-6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof.
45. The acetic acid salt of claim 44 in an amorphous form.
46. The acetic acid salt of claim 44 in a crystalline form.
47. The acetic acid salt of any of claims 44 to 46, comprising of about one molar equivalent of
Figure imgf000106_0001
4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5- methylpyrrolo[l ,2- J[l ,2,4]triazin-6-ylcarbamate and about one molar equivalent of acetic acid.
48. The acetic acid salt of any of claims 44 to 47, containing no greater than 3 ppm of (5)-(4-nitrosomorpholin-3-yl)methyl 4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5- methylpyrrolo[ 1 ,2-f] [ 1 ,2,4]triazin-6-ylcarbamate.
49. A maleic acid salt of (S)-morpholin-3-ylmethyl 4-(l-(3-fluorobenzyl)-lH- indazol-5-ylamino)-5-methylpyrrolo[l ,2- ][l,2,4]triazin-6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof.
50. The maleic acid salt of claim 49 in an amorphous form.
51. The maleic acid salt of claim 49 in a crystalline form.
52. The maleic acid salt of claim 51 in crystalline Form III-A.
53. The maleic acid salt of claim 51 or 52, having an X-ray powder diffraction pattern substantially as shown in FIG. 3 A.
54. The maleic acid salt of any of claims 51 to 53, having an X-ray powder diffraction pattern with a peak expressed in two-theta at approximately 10.0, 10.8, 13.1, 17.2,
21.6, 22.5, 22.7, 24.6, 26.0, or 29.6°.
55. The maleic acid salt of claim 51 in crystalline Form III-B.
56. The maleic acid salt of claim 51 or 55, having an X-ray powder diffraction pattern substantially as shown in FIG. 3B.
57. The maleic acid salt of any of claims 51, 55, and 56, having an X-ray powder diffraction pattern with a peak expressed in two-theta at approximately 29.8°.
58. The maleic acid salt of claim 51 in crystalline Form III-C.
59. The maleic acid salt of claim 51 or 58, having an X-ray powder diffraction pattern substantially as shown in FIG. 3C.
60. The maleic acid salt of any of claims 51, 58, and 59, having an X-ray powder diffraction pattern with a peak expressed in two-theta at approximately 8.8, 11.0, 11.9, 16.8, 18.3, 22.3, 25.3, 27.0, or 27.8 °.
61. The maleic acid salt of claim 51 in crystalline Form III-D.
62. The maleic acid salt of claim 51 or 61, having an X-ray powder diffraction pattern substantially as shown in FIG. 3D.
63. The maleic acid salt of any of claims 1, 61, and 62, having an X-ray powder diffraction pattern with a peak expressed in two-theta at approximately 3.6, 4.6, 7.4, 12.4, or 19.5 °.
64. The maleic acid salt of any of claims 49 to 63, comprising of about two molar equivalents of (5)-morpholin-3-ylmethyl 4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5- methylpyrrolo[l,2- J[l,2,4]triazin-6-ylcarbamate and about one molar equivalent of maleic acid.
65. The maleic acid salt of any of claims 49 to 64, containing no greater than 3 ppm of (5)-(4-nitrosomorpholin-3-yl)methyl 4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5- methylpyrrolo[ 1 ,2- J [ 1 ,2,4]triazin-6-ylcarbamate.
66. A nitric acid salt of (5)-morpholin-3-ylmethyl 4-(l-(3-fluorobenzyl)-lH- indazol-5-ylamino)-5-methylpyrrolo[l,2- ][l,2,4]triazin-6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof.
67. The nitric acid salt of claim 66 in an amorphous form.
68. The nitric acid salt of claim 66 in a crystalline form.
69. The nitric acid salt of any of claims 66 to 68, comprising of about one molar equivalent of (5)-morpholin-3-ylmethyl 4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5- methylpyrrolo[l ,2- J[l ,2,4]triazin-6-ylcarbamate and about one molar equivalent of nitric acid.
70. The nitric acid salt of any of claims 66 to 69, containing no greater than 3 ppm of (5 -(4-nitrosomorpholin-3-yl)methyl 4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)-5- methylpyrrolo[ 1 ,2- J [ 1 ,2,4]triazin-6-ylcarbamate.
71. A phosphoric acid salt of (5 -morpholin-3-ylmethyl 4-(l-(3-fluorobenzyl)-lH- indazol-5-ylamino)-5-methylpyrrolo[l ,2- J[l,2,4]triazin-6-ylcarbamate, or a hydrate or pharmaceutically acceptable solvate thereof.
72. The phosphoric acid salt of claim 71 in an amorphous form.
73. The phosphoric acid salt of claim 71 in a crystalline form.
74. The phosphoric acid salt of any of claims 71 to 73, comprising of about one molar equivalent of (i¾-morpholin-3-ylmethyl 4-(l-(3-fiuorobenzyl)-lH-indazol-5-ylamino)- 5-methylpyrrolo[l ,2- J[l ,2,4]triazin-6-ylcarbamate and about one molar equivalent of nitric acid.
75. The phosphoric acid salt of any of claims 71 to 74, containing no greater than 3 ppm of (5)-(4-nitrosomorpholin-3-yl)methyl 4-(l-(3-fluorobenzyl)-lH-indazol-5-ylamino)- 5-methylpyrrolo[l ,2- J[l ,2,4]triazin-6-ylcarbamate.
76. A pharmaceutical composition comprising the salt of any of claims 1 to 75, and a pharmaceutically acceptable excipient.
77. The pharmaceutical composition of claim 76, wherein the composition is formulated for oral, nasal, bronchial, or topical administration.
78. The pharmaceutical composition of claim 76 or 77, wherein the composition is formulated as a single dosage form.
79. A method of treating a proliferative disease in a subject, comprising administering to the subject the salt of any of claims 1 to 75 or the pharmaceutical composition of any of claims 76 to 78.
80. The method of claim 79, wherein the proliferative disease is a tumor.
81. The method of claim 80, wherein the tumor is a solid tumor.
82. The method of claim 80 or 81 , wherein the tumor is a malignant tumor.
83. The method of claim 82, wherein the malignant tumor is bladder cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, gastric cancer, glioma, head and neck cancer, liver cancer, non-small cell lung cancer, ovarian cancer, pancreatic cancer, or prostate cancer.
84. The method of any of claims 80 to 83, wherein the tumor overexpresses HER1 protein.
85. The method of any of claims 80 to 84, wherein the tumor overexpresses HER2 protein.
86. A method of inhibiting the growth of a cell, comprising contacting the cell with the salt of any of claims 1 to 75 or the pharmaceutical composition of any of claims 76 to 78.
87. The method of claim 86, wherein the cell is a tumor cell.
88. The method of claim 87, wherein the tumor cell is a solid tumor cell.
89. The method of any of claims 86 to 88, wherein the cell is a cancerous cell.
90. The method of claim 89, wherein the cancerous cell is a cell of bladder cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, gastric cancer, glioma, head and neck cancer, liver cancer, non-small cell lung cancer, ovarian cancer, pancreatic cancer, or prostate cancer.
91. The method of any of claims 86 to 90, wherein the cell overexpresses HER1 protein.
92. The method of any of claims 86 to 91, wherein the cell overexpresses HER2 protein.
93. A process for the preparation of the salt of any of claims 1 to 76, comprising reacting
Figure imgf000110_0001
4-(l-(3-fluorobenzyl)-lH-mdazol-5-ylamino)-5- methylpyrrolo[l,2- J[l,2,4]triazin-6-ylcarbamate with the acid in a solvent at a first predetermined temperature.
94. The process of claim 93, further comprising precipitating the salt at a second predetermined temperature.
95. The process of claims 93 or 94, wherein the solvent is dichloromethane, acetone, acetonitrile, ethanol, trifluoroethanol, isopropanol, hexafluoroisopropanol, ethyl acetate, isopropyl acetate, tetrahydrofuran, water, MTBE, or a mixture thereof.
96. A method of decreasing the amount of (5')-(4-nitrosomorpholin-3-yl)methyl 4- (l-(3-fiuorobenzyl)-lH-indazol-5-ylamino)-5-methylpyrrolo[l,2: ][l,2,4]triazin-6- ylcarbamate from the salt of any of claims 1 to 75, comprising contacting the salt with acetone.
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