MX2011009413A - Combination of an indazolylaminopyrrolotriazine and taxane for cancer treatment. - Google Patents

Abstract

Provided herein are methods of treating a proliferative disease in a subject, comprising administering to the subject a therapeutically effective amount of an indazolylaminopyrrolotriazine, e.g., a compound of Formula (I), and a taxane. Also provided herein are pharmaceutical compositions which comprise an indazolylaminopyrrolotriazine and taxane, in combination with one or more pharmaceutically acceptable excipients.

Description

! 1 COMBINATION OF AN INDAZOLILAMINOPIRROLOTRIAZINA AND TAXANO FOR TREATMENT AGAINST CANCER CROSS REFERENCE FOR RELATED REQUESTS This request claims priority under 35 U.S.C. §119 (e) for United States Provisional Application No. 61 / 159,404, filed on March 11, 2009, the description of which is incorporated herein by reference in its entirety.

COUNTRYSIDE Methods for treating a proliferative disease in a subject are provided herein, which comprises administering to the subject a therapeutically effective amount of an indazolylaminopyrrolotriazine and a taxane. Also provided herein are pharmaceutical compositions comprising an indazolylaminopyrrolotriazine and taxane, in combination with one or more pharmaceutically acceptable excipients.

BACKGROUND The Her family of the tyrosine kinase receptor is comprised of Heri (also known as EGFR or ErbB-1), Her2 (ErbB-2), Her3 (ErbB-3), and Her4 (ErbB-4). The activation or over-expression of its members, such as Herí or Her2, is implicated in human malignancies including 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 that includes glioblastoma. The currently commercialized anti-EGFR therapies include the small molecules gefitinib (IRESSA®), which was approved for the treatment of NSCLC, and erlotinib (ARCEVA®), which was approved for the treatment of NSCLC and pancreatic cancer. The currently marketed monoclonal antibody therapies include cetuximab (ERBITUX®), an anti-EGFR antibody that was approved for the treatment of colorectal cancer, and trastuzumab (HERCEPTIN®), an anti-Her2 antibody that was approved for the treatment of human cancer. Her2-positive breast. Lapatinib (TY ERB®), which is a small molecule inhibitor with anti-EGFR / Her2 dual activity, was most recently approved for the treatment of Her2-positive breast cancer.

The taxanes are a powerful class of chemotherapeutics that can be isolated from the Taxus genus plants or additionally derivatized as a synthetic analogue. The taxanes that comprise this class share the same chemical scaffolding and similar mechanism of action and have been found to have similar preclinical activity and clinical activity. See, Eisenhauer et al, Drugs 1998, 55, 5-30; Huizing et al, Cancer Investigation 1995, 13, 381-404; and Von Hoff et al, Seminare in Oncology, 1997, 24, S13-3-S13-10. The first taxane, paclitaxel (TAXOL®), which is 4,10-diacetate 2-benzoate 13-ester of 5, 20-epoxy-1, 2a, 4, 7ß, 10ß, 13a-hexahydroxitax-11-ene-9- ona with. { 2R, 3S) -N-benzoyl-3-phenylisoserine, was isolated in 1971 from Pacific yew. { Taxus brevifolia), but can also be prepared using a semi-synthetic process from European yew. { Taxus baccata). Another well-known taxane, docetaxel (TAXOTERE®), which is (2R, 35) -iV-carboxy-3-phenylisoserine, N-tert-butylester, 13-ester with 4-acetate 2-benzoate, 5β-20- trihydrate ????? - 1, 2a, 4, 7β, 10β, 13a-hexahydroxitax-ll-ene-9-one, is also prepared from a semi-synthetic process from Taxus baccata. The taxanes belong to the subclass of antimitotics and exert their effect by promoting the polymerization of tubulin to the extent of interfering with the normal dynamic process of tubulin assembly and disassembly during cell cyclization. This microtubule dysfunction leads to cell death. Despite these advances in anticancer therapy, there is a need that has been perceived for a long time for effective therapies for proliferative diseases, in one modality, for cancers that are refractory to existing therapies.

COMPENDIUM OF THE DESCRIPTION A method for treating a proliferative disease in a subject is provided herein, which comprises administering to the subject a therapeutically effective amount of (i) a taxane; and (ii) an indazolylaminopyrrolotriazine of Formula I: (I) or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; where : R is C6-14 aryl, heteroaryl, or heterocyclyl; R1 is Ci-6 alkyl; R2 is hydrogen, C1-6 alkyl, C3 cycloalkyl. 10, C6-1 aryl, C7-20 heteroaryl aralkyl or heterocyclyl; X is a bond, -0-, -S-, -C (R3R4) -, or -N (R3) -; and each of R3 and R4 is independently hydrogen, Ci-6 alkyl, C5-i4 aryl, C7-2o aralkyl / heteroaryl, or heterocyclyl; wherein each alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl are optionally substituted with one or more substituents Q selected from the group consisting of (a) cyano, halo, and nitro; (b) Ci-6 alkyl, C2-e alkenyl, C2-6 alkynyl C3-10 cycloalkyl, C6-14 aryl, heteroaryl, and heterocyclyl; and (c) -C (0) Ra, -C (0) ORa, -C (0) NRbRc, -C (= NRa) NRbR °, -0Ra, -OC (0) Ra, -OC (0) ORa , -OC (0) NRbRc, -OC (= GRa) NRR °, -0S (0) Ra, -OS (0) 2Ra, -OS (0) NRRc, -OS (O) 2NRbRc, -NRaRcl, -NRaC (O) Rb, -NRaC (0) ORb, -NRaC (0) NRbRc, -NRaC (= NRd) NRRc, -NRaS (0) R, -NRaS (0) 2Rb, -NRaS (0) NRbRc, -NRaS (0) 2NRbRc, -SRa, -S (0) Ra, and -S (0) 2Ra; wherein each of Ra, R, R °, and Rd is independently (i) hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6 - 4 aryl , heteroaryl, or heterocyclyl; or (ii) Rb and Rc together with the N atom to which they are attached form heterocyclyl or heteroaryl.

In one embodiment, the taxane and the indazolylaminopyrrolotriazine described herein, for example, a compound of Formula I or II, which includes a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; are therefore administered in a dosing program provided in this.

Also provided herein is a method of inhibiting the growth of a cell, which comprises contacting the cell with an effective amount of a taxane and an indazolylaminopyrrolotriazine described herein, for example, a compound of Formula I or II, which includes a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

A pharmaceutical composition is further provided herein, comprising (i) a taxane; and (ii) an indazolylaminopyrrolotriazine described herein, for example, a compound of Formula I or II, which includes a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; in combination with one or more pharmaceutically acceptable excipients.

BRIEF DESCRIPTION OF THE DRAWINGS FIGURE 1 shows the synergistic effect of AC480 in combination with paclitaxel in human breast carcinoma MX-1 as determined by tumor size. The animals were treated according to the dosing schedules as shown in Table 1.

FIGURE 2 shows the synergistic effect of AC480 in combination with paclitaxel in human breast carcinoma MX-1 as measured by the percentage of complete regression. The animals were treated according to the dosing schedules as shown in Table 1.

FIGURE 3 shows the synergistic effect of AC480 in combination with paclitaxel in human breast carcinoma MX-1 as measured by the percentage survival after treatment. The animals were treated according to the dosing schedules as shown in Table 1.

FIGURE 4 shows the synergistic effect of AC480 in combination with paclitaxel in human breast carcinoma MX-1 as measured by the percentage of complete regression. The animals were treated according to the dosing schedules as shown in Table 2.

DETAILED DESCRIPTION To facilitate understanding of the description set forth herein, a certain number of terms are defined as follows.

Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, biochemistry, biology, pharmacology, and others described herein are those well known and commonly employed in the art. Unless to the contrary, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art which pertains to the description.

The term "tumor", "neoplasm", and "neoplastic disorder or disease" is used interchangeably herein and is intended to refer to an undesired cell proliferation of one or more subsets of cells in a multicellular organism that results in damage (ie, discomfort or reduced life expectancy) to the multicellular organism. In certain modalities, a tumor may be benign (non-invasive) or malignant (invasive).

The term "cancer" is intended to refer to a malignant neoplasm, which is characterized by uncontrolled cell proliferation wherein the cells have lost their normal regulatory control that could 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".

The term "occurring naturally" or "native" when used in conjunction with biological materials such as nucleic acid molecules, polypeptides, host cells, and the like, refers to materials found in the nature and are not manipulated by man. Similarly, "that does not occur naturally" or "non-native" refers to a material that is not found in nature or that has been modified or synthesized structurally by man.

The terms "HERI", "epidermal growth factor receptor", "EGFR", and "ErbBl" are used interchangeably herein and refer to an EGFR receptor protein or variant thereof, as described, for example. , in Carpenter et al., Ann. Rev. Biochem. 1987, 56, 881-914. Variants of HER2 include proteins substantially homologous to a native EGFR, i.e., proteins having one or more deletions, insertions or amino acid substitutions occurring naturally or not naturally (eg, EGFR derivatives, homologs and fragments), when compared with the amino acid sequence of a native EGFR. 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 EGFR. An example of naturally occurring mutant forms of a native EGFR, i.e., a deleting mutant EGFR, is described in Humphrey et al., Proc. Nati Acad. Sci. USA 1990, 87, 4207-4211.

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. Nati Acad. Sci. USA 1985, 82, 6497-6501 and Yamamoto et al. Nature 1986, 319, 230-234 (access number Genebank X03363). HER2 variants include proteins substantially homologous to a native HER2, i.e., proteins having one or more deletions and insertions or amino acid substitutions occurring naturally or not naturally (eg, derivatives, homologs and fragments of HER2), when compared with 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.

The term "overexpressed" or "overexpression" is intended so that a cell associated with a disease, disorder, or condition comprises a detectably higher level of protein, such as HERI or HER2, than an otherwise identical cell that is not associated with a disease, disorder or condition.

The term "subject" refers to an animal, which includes, but is not limited to, a primate (e.g., a human being), 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 a modality, to a human being.

The terms "treat", "treating", and "treatment" are intended to include the relief or derogation of a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or alleviate or eradicate the cause or causes of the disorder, disease, or condition thereof.

The term "contacting" or "contacting" is intended to refer to bringing together a therapeutic agent and cell or tissue in such a manner that a physiological and / or chemical effect is carried out 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 the cell culture (in vitro) to determine the effect of the therapeutic agent in the cell. In another embodiment, contacting the therapeutic agent with a cell or tissue includes administering a therapeutic agent to a subject having the cell or tissue to contact.

The term "therapeutically effective amount" is intended to include the amount of a compound that, when administered, is sufficient to prevent the development of, or alleviate to some degree, one or more of the symptoms of the disorder, disease, or condition that it is about. He The term "therapeutically effective amount" also refers to the amount of a compound that is sufficient to produce the biological or medical response of a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human being, who is wanted by a researcher, veterinarian, doctor, or clinician.

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 an 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 tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, consistent with a reasonable benefit / risk ratio. See, Remíngton: The Science and Pharmacy of Pharmacy, 2 lava Edition, Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipient, 5th Edition, Rowe et al., Eds. , The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd Edition, Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd Edition, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2009.

The term "about" or "about" means an acceptable error for a particular value as determined by someone of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain modalities, the term "around" or "approximately" means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "around" 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 margin.

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 to treat, prevent, or lessen one or more symptoms of a condition. disorder, or illness. As used herein, "active ingredient" and "active substance" can be an optically active isomer of a compound described herein.

The terms "drug", "therapeutic agent", and "chemotherapeutic agent" refer to a compound, or a pharmaceutical composition thereof, that is administered to a subject to treat, prevent, or lessen one or more symptoms of a condition, disorder, or illness.

The term "alkyl" refers to a linear or branched saturated monovalent hydrocarbon radical, wherein the alkylene may optionally be substituted as described herein. The term "alkyl" also embraces both linear and branched alkyl, unless otherwise specified. In certain embodiments, alkyl is a linear saturated monovalent hydrocarbon radical having from 1 to 20 (Ci-20), 1 to 15 (C1-15), 1 to 10 (Ci-10>, or 1 to 6 (Ci -6) carbon atoms, or branched saturated monovalent hydrocarbon radical of 3 to 20 (C3-2o), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms As used herein, branched and linear C 1-6 alkyl groups are also referred to as "lower alkyl." Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl. (including all isomeric forms), n-propyl, isopropyl, butyl (including all isomeric forms), n-butyl, isobutyl, sec-butyl, t-butyl, pentyl (including all isomeric forms), and hexyl (which includes all isomeric forms.) For example, C 1-6 alkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical. fica of 3 to 6 carbon atoms.

The term "alkenyl" refers to a radical linear or branched monovalent hydrocarbon, containing one or more, in one embodiment, one to five, carbon-carbon double bonds. The alkenyl can be optionally substituted as described herein. The term "alkenyl" also embraces radicals having "cis" and "trans" configurations, or alternatively, "Z" and "E" configurations, as appreciated by those of ordinary skill in the art. As used herein, the term "alkenyl" embraces both linear and branched alkenyl, unless otherwise specified. For example, C2-6 alkenyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, alkenyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2-6) atoms carbon, or a branched monovalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-e) carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, propen-1-yl, propen-2-yl, allyl, butenyl, and 4-methylbutenyl.

The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one, five to three carbon-carbon triple bonds. The alkynyl can optionally be substituted as described herein. The term "alkynyl" also embraces both linear and branched alkynyl, unless otherwise specified. In certain embodiments, alkynyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2-2o), 2 to 15 (C2-i5), 2 to 10 (C2-io), or 2 to 6 (C2-6) atoms carbon, or a branched monovalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C = CH) and propargyl (-CH2C = CH). For example, the C2-6 alkynyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.

The term "cycloalkyl" refers to a bridged and / or unbridged cyclic saturated monovalent hydrocarbon radical, which may optionally be substituted as described herein. In certain embodiments, the cycloalkyl has from 3 to 20 (C3-20), from 3 to 15 (C3-15) / from 3 to 10 (C3-10) or from 3 to 7 (C3-7) carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo [2.1. l] hexyl, bicyclo [2.2.1] heptyl, decalinyl, and adamantyl.

The term "aryl" refers to an aromatic group monocyclic and / or monovalent multicyclic aromatic group containing at least one aromatic hydrocarbon ring. In certain embodiments, the aryl has from 6 to 20 (C6-2o) / from 6 to 15 (C6-15) / or from 6 to 10 (C6-io) atoms in the ring. 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, wherein 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, the aryl may optionally be substituted as described herein.

The term "aralkyl" or "arylalkyl" refers to a monovalent alkyl group substituted with one or more aryl groups. In certain embodiments, aralkyl has from 7 to 30 (C7-30) / from 7 to 20 (C7.2o) or from 7 to 16 (C7-i6) carbon atoms. Examples of aralkyl groups include, but are not limited to, benzyl, 2-phenylethyl, and 3-phenylpropyl. In certain embodiments, the aralkyl may also optionally be substituted as described herein.

The term "heteroaryl" refers to a monocyclic aromatic group and / or multicyclic aromatic group containing at least one aromatic ring, wherein at least one The aromatic ring contains one or more heteroatoms independently selected from 0, S, and N. Each ring of a heteroaryl group may contain one or two atoms of 0, one or two S atoms, and / or one to four N atoms, with the condition that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom. In certain embodiments, the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 atoms in the ring. Examples of monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl. Examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzothiophenyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl. , isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, and thienopyridyl. Examples of tricyclic heteroaryl groups include, but are not are limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl, fenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl. In certain embodiments, the heteroaryl may also optionally be substituted as described herein.

The term "heterocyclyl" or "ethenoyl ether" refers to. a monocyclic non-aromatic ring system and / or multicyclic ring system containing at least one non-aromatic ring, wherein one or more of the atoms in the non-aromatic ring are heteroatoms independently selected from 0, S, or N; and the rest of the atoms in the ring are carbon atoms. In certain embodiments, the heterocyclyl or heterocyclic group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms. In certain embodiments, the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system that may include a fused or bridged ring system in. wherein the nitrogen or sulfur atoms may optionally be oxidized, the nitrogen atoms may, optionally quaternized, and some rings may be partially or fully saturated or aromatic. Heterocyclyl can be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable compound. Examples of such radicals heterocyclics include, but are not limited to, azepinyl, benzodioxani lo, benzodioxolyl, benzofuranonyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, benzothiopyranyl, benzoxazinyl, ß carbolinyl, chromanyl, chromonyl, cinolinyl, coumarinyl, decahydroxyquinolyl, dihydrobenzisothiazolin, dihydrobenzisoxa.zini 1, di, hydrofuran, dihydroisoindole, dihydroxy, dihydropyrimidinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1-dithianyl, furanonyl. , inaidazolidinilo, imidazolinyl, indolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl, isocoumarinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindole yl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4 piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl , tetrahydrofuryl , tetra idroisoguinol inyl, tetrahydropyranyl, tetrah.i drot i.en.i.i, thiamorphoi, ni, ori, ai.azo, i dini, tetrahydroquinol. i nor lo, and 1, 3, 5-t.r.i. Thianyl. In certain embodiments, the heterocyclic may also be optionally substituted as described herein.

The term "halogen", "halide" or "halo" refers to fluorine, chlorine, bromine, and / or iodine.

The term "optionally substituted" is intended to mean that a group, such as an alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, or alkoxy group, may be substituted with one or more substitutes independently selected from, for example, (a) alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl, each optional.men. and substituted with one or more, in one modality, one, two, three, or four, replace tes Q; and (b) halo, cyano (-CN), nitro (-N02), -C (0) R, -C (0) ORa, -C (0) NRbRc, -CNRa) NR Rc, -0Ra, - 0C (0) Ra, -0C (0) 0Ra, -0C (0) NRRc, -0C (= NRa) NRbR °, -0S (0) Ra, -0S (0) 2Ra, -0S (0) NR Rc , -OS (O) 2NRR, -NR Rc, -NRaC (0) Rd, -NRaC (0) 0Rd, -NRaC (0) NRbRc, -NRaC (= NRd) NR Rc, -NRaS (0) Rd, - NRaS (0) 2Rd, -NR '\ S (0) NRbR, -NRaS (0) 2NRbRc, -SRa, -S (0) Ra, - S (0) 2Ra, - S (0) NRbRc, and - S . { 0) 2NRbRc, wherein each of Ra, Rb, Rc, and Ra is independently (i) hydrogen; (ii) Ci-e alkyl, C¾-e alkenyl, alkynyl of, -e, cycloalkyl of C ... 7, aryl of Ce-i, aralkyl of C7 ... 1 & , heteroarylo, or eterocyc ... i1o, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q; or (i i.i.) R ° and R ° together with the N atom to which they are attached form heteroaryl or heterocyclyl, optionally substituted with one or more, in one, two, three, or four embodiment, substituents Q. As used herein, all groups that may be substituted are "optionally substituted" unless otherwise specified.

Another way.

In one embodiment, each Q is independently selected from the group consisting of (a) cyano, halo, and nitro; and (b) C alquilo Í-G alkyl, C2 ... al alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C ^ -u aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C (0) Re, -C (0) ORE, -C (0) NRfRg, -C. { NRe) RfRg, -0Re, -OC (0) Re, -OC (0) 0Re, -OC (O) NRfR9, -OC (= Re) NRfRg, -OS. { 0) Re, -OS (0) 2Re, -OS (0) NRí: R9, -OS (0) 2NRfRy, -NR R9, - REC (0) RH, -NREC (0) 0Rh, -NREC (0) NRERG, -NReC (= NRH) NRfRg, -NRES (0) RB, -NRES (0) ¾Rh, -NRES (0) NRfRg, -NRPS (O) NRfRg, -SRP, S- (O) i, -S (0)? Re, -S (0) NRfR °, and -S (0) 2NRRR9; wherein each of R ", Rr, Rg, and Rh is independently (i) hydrogen, (ii) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C6-i.4 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, or (iii) R1 and R9 together with the N atom to which they are attached form heteroaryl or heterocyclyl.

In certain modalities, "optically active" and "enan iomérically active" refers to a collection, of molecules, which have an enantiomeric excess of not less than about 50%, not less than about 70%, not less than about 80%, not less than about 90%, not less than about 91%, not less than about 92%, not less than about 93%, not less than about 94%, not less around .95%, not less than about 96%, not less than around .97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%. In certain embodiments, the compound comprises about 95% or more of the desired enantiomer and about 5% or less of the less preferred enantiomer based on the total weight of the racemate in question.

When describing an optically active compound, the prefixes R and S are used to indicate the configuration. absolute of the molecule around one or more guiral centers. The (+) and (-) are used to indicate the optical rotation of the compound, that is, the direction in which a plane of polarized light is rotated by the optically active compound. The prefix (-) indicates that the compound is levorotatory, that is, the compound rotates the plane of polarized light to the left or counterclockwise. The prefix (+) indicates that the compound is dextrorotatory, that is, the compound rotates the plane of polarized light to the right or clockwise. Without embarring, the optical rotation signal, (+) and (-), is not related in the. Absolute configuration of the molecule, R and S.

The term "solvate" refers to a compound provided herein or a salt thereof, which also includes a stequiorae rich or non-stoichiometric amount of the solvent bond by the forces intermolecular non-covalent. Where the solvent is water, the solva is a hydrate.

Indazo1i 1aminopyrrolotriazines In one embodiment, the indazolylaminopyrrolotriazine described herein has the structure of. Formula I: (I) and enantiomers, mixtures of enantiomers, and mixtures of two or more diastereomers thereof; and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof; where : R is aryl of Cg-i4, heteroaryl, or heterocyclyl; R1 is Ci-c; I rent; is hydrogen, C 1 -C 6 alkyl, C 1 io cycloalkyl, C 5 alkylaryl, C 7-20 aralkyl, heteroaryl, or heterocyclic 1o; x is a bond, -O-, -S-, -C (RJR4) -, or -N (RJ) -; and each of R * and R4 is independently hydrogen, Ci-6-alkyl # Ce-14 aryl, C7-20 aralkyl, heteroaryl, or heterocyclyl; wherein each alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more substituents Q selected from a group consisting of (a) cyano, halo, and nitro; ib) Ci-6 alkyl, C ^ -s alkenyl, C2-e alkynyl, C3-10 cycloalkyl, C & -U aryl, heteroaryl, and heterocyclyl; and (c) -C (0) Ra, -C (0) ORa, -C. { 0) NRRc, -C (= NRa) NRbRc, -0Ra, -OC (0) Ra, -OC (0) 0R, -OC (0) NRbRc, -OC (= Ra) NRbRc, -OS (O) Ra , -OS (O) 2Ra, -OS (0) NRbRc, -OS (0);;; NRbRc, -NR Rd, -NR C (0) R, -NRaC. { 0) 0Rb, NRaC (0) NRbRc, -NRaC (-NRá) NRbRc, -NRaS (0) Rb, -NRaS (0)? Rh, NR¾S (0) NR R °, -NRaS (0)? NRbRc, -Se ', -S (0) R ", and -S (0)? Ra; where each of Rd, RD, Rc, and Rd is independently (i) hydrogen, alkyl Cx-e, alkenyl of Ca-e »C2-6 alkynyl, Cn-cycloalkyl, aryl of Ce-, heteroaryl, or heterocyclyl, or (ii) Rn and Rc together with the N atom to which they are bound form heterocyclyl or heteroaryl.

In one embodiment, in the indazole ilaminopyrrolotriazine of Formula I, R is aryl of CV14, R1 is C1-4 alkyl, each, one optionally substituted with one or more substituents Q, in one embodiment, one, two or three substituents Q .

In another embodiment, in the indazolylaminopyrrolotriazine of Formula I, X is O, and R 'is C, heteroaryl, or heterocyclyl cycloalkyl, each optionally substituted with one or more Q substituents, in one embodiment, one, two or three substituents Q.

In another embodiment, the indazolylaminopyrrolotriazine is selected from the group consisting of: [5-ethyl-4 [[(1-phenylmethyl) -1H-indazol-5-yl] amino] -pyrrolo [2, 1 -f] [1, 2, 4] triazin-6-yl] -carbamic acid, (35) 3 - . 3 -morfo1 i.ni1meti l s er; [5-eti1-4- [[(1-pheni 1 eti1) -1H-indazol-5-yl] amino] pyrrolo [2, .1-f] [1,2,4] triazin-6-yl] - carbamic, (2R) -2-pyrrolidinylmethyl ester, · [5-ethyl-4- [[(1-phenylmethyl) -lH-indazol-5-yl] amino] pyrrolo [2, 1-f] [1,2,4] triazin-6-yl] -carbamic acid, (25) -2-pyrrolidinylmethyl er; [5-ethyl-4- [[(1-phenylmethyl) -1H-indazol-5-yl] amino] pyrrolo [2, 1-f] [1,2,4] triazin-6-yl] -carbamic acid, (3J?) -3-morpholinyl methyl ester; [5-ethyl-4- [[(1-phenylmethyl) -1H-indazol-5-yl] -amino] -pyrrolo [2, 1-f] [1,2,4] triazin-6-yl] -carbamic acid, 3 - [(3 S) -3 -hidrox.i - 1 -pirro1 i dini 1.] propi.1 ester; [5-ethyl-4- [[(1- phenyl.tnet.il) -lH-indazol-5-ylamino] pyrrolo [2, 1-f] [1, 2,4] t.riazin-6 acid -il] -carbamic, 3- [ 35) -3- -hydroxy-l-piperidinyl] propylester; [5-ethyl-4- [[(1-f-enylmethyl) -lH-indazol-5-yl] amino] pyrrolo [2, 1-f] [1, 2, 4] triazin-6-yl] -carbamic acid , (3R) -3-pyrrolidinylmethyl ester; [5-ethyl-4- [[(1-phenylmethyl) -lfi-indazol-5-acid] il] amino] pyrrolo [2, 1-f] [1,2,4] triazin-6-yl] -carbamic acid, 3 - [(3R) -3-hydroxy-1-pyrrolidinyl] propylester; [5-ethyl-4 [[(1-phenylmethyl) -1H-indazole] |||| 5-yl] amino] -irrolo [2, 1 f] [1,2,4] triazin-6-yl] -carbamic acid, [(2S)] 1-methyl-2-pyrrolidinyl] methyl ter; [5-eti1 - 4 - [[(1-phenyl-1-methyl-1) -1H-indazo-5-yl] amino] pyrrolo [2, 1-f] [1, 2, 4] triazin-6- il] -carbamic, (25) -2 -morfol i ni Inteti 'Reader; [5-ethyl-4- [[(1-phenylmethyl) -lJi-indazol-5-yl] amino] acid [2, 1-f J [1, 2, 4] triazin-6-yl] -carbamic acid, (3S) ~ 3 -pyrrolidinylmethyl ester ter; [5-ethyl-4- [[(1-phenylmethyl) -Iff-indazol-5-yl] amino] pyrrolo [2, 1-f] [1,2,] triazin-6-yl] -carbamic acid, ( 2R) -2-morpholinylmethyl ester ter; [5-ethyl-4- [[(1-phenylmethyl) -l-indazol-5-yl] -amino] -pyrrolo [2, 1 f] [1,2,4] triazin-6-yl] -carbamic acid, [(3R) - · 1-methyl-3-pyrrolidinyl] methyl ester; acid [5 -eti .1. - 4- [[(1 - feni1met.i.1) - 1 H- i.nda.zo1 - 5 -i 1] a i., No] pi rrolo [2, 1 - f] [1, 2, 4 ] triaz .in- 6 - i 1] -carbámi co, trans -4. -aminoc ic lohexi. lés ter; [5-ethyl-4- [[(1-phenylmethyl) -lH-indazol-5-yl] amino'lpyrrolo [2, 1-f] [1,2,4] triazin-6-yl] -carbamic acid, . { 3R) -3-piperidinyl ester; [5-ethyl-4- [[(1-phenylmethyl) -lH-indazol-5-yl-1-amino] pyrrolo [2, 1-f] [1,2,4] riazin-6-yl] -carbamic acid, (3S) - 3 - . 3-piperidinyl ester; [5-ethyl-4- [[. { 1-phenylmethyl) -lH-indazol-5-yl] amino] irrolo [2, 1-f] [1,2,4] triazin-6-yl] -carbamic acid, cis-4-aminociclohexyl; [5-ethyl-4 [[(1-phenylmethyl) lH-indazol-5-yl] -amino] -ricarol [2, 1-f] [1, 2,4] -triazin-6-yl] -carbamic acid, (2R, 4.R) -2- (hydroxymethyl) -4-piperid.inlylester; [5-ethyl-4- [[(1-phenylmethyl) -lH-indazol-5-yl] amino] acid [2, 1-f] [1,2,4] triazin-6-yl] -carbamic acid, (25) -2- (hydroxymethyl) -4-piperidinylester; [5-ethyl-4- [[(1-phenylmethyl) -lfl-indazol-5-yl] amino] -ricarol [2, 1-f] [1,2,4] triazin-6-yl] -carbamic acid, cis-4- (aminomethyl) cyclohexyl ester; [5-ethyl-4 ~ [[(1-phenylmethyl) -lfi-indazol-5-yl] amino] pyrrolo [2, 1-f] [1, 2, 4] triazin-6-yl] carbamic acid, cis 4 amino-4-methylcyclohexyl ester; [5-ethyl-4- [[(1-phenylmethyl) -1H-indazole-5] 1] amino] pyrrolo [2, 1-f] [1,2,4] triazi- n-6-ii] -carbamic acid, [(2.R, 4R) -4- (hydroxy-2-piperidinyl] methyl ester; Acid [5-et i1 -4- [[(1-pheni-met i1) -1H-indazo-5-yl]] amino] pyrrolo [2, 1-f] [1,2,4] triazin- 6-yl] -carbamic, trans-4- (aminomethyl) cyclohexyl ester; [5-ethyl-4- [[1- (2-oxazolylmethyl) -lH-indazol-5-yl] amino] acid [2, 1-f] [1,2,4] riazin-6-yl] - carbamic, (35) -3-morpholinyl methyl ester; [5-ethyl-4- [[1- (2-thienylmethyl) -IH-indazol-5-yl] amino] acid [2, 1-f] [1,2,4] triazin-6-yl] - carbamic, (35) -3 morpholinyl methyl ester; [5-ethyl-4 [[1 [(3-fluorophenyl) methyl] 111 indazol-5-yl] amino] acid [2, 1-f] [1,2,4] triazin-6-yl]] carbamic, (3 S) - 3 -morfo1 ini 1met.i 1. és Cer; acid [5-eti 1 -4- [[1- (4-thiazo1. i1me ti 1) -1H- i.nda zol-5-yl] amino] irrolo [2, 1 -f] [1,2, 4] triazin-6-yl] -carbamic acid, (3S) -3-morpholinyl methyl ester; [5-ethyl-4- [[1- (3-thienylmethyl) -lfl-indazol-5-yl] amino] pyrrolo [2, 1-f] [1,2,4 J triazin-6-yl] - acid Carbamic, (35) -3-morpholinyl methyl ester; [5-ethyl-4- [[l- (2-pyridinylmethyl) -1H-indazol-5-yl] amino] pyrrolo [2, 1-f] [1,2,] triazin-6-yl] -carbamic acid , (3) 3 morpholinyl methyl ester; [5-ethyl-4 [[1- (2-thiazolylmethyl) -1 / - / indazol-5-yl] amino] pyrrolo [2, 1 f] [1,2,4] riazin-6-yl] -carbamic acid. { 35 3- orfo1ini 1.raet i.1éster; [5-eti.l-4- [[1- (3-pyridinylmethyl) -1H-indazol-5-y1] amino] pyrrolo [2, 1-f] [1, 2,4] riazin- 6-yl] -carbamic acid, (3) -3-morphyl inylmethyl ester; acid [5-etii-4- [. [1- (pyrazinylmet.il) -lfi-indazol-5-yl] amino] pyrrolo [2, 1-f] [1,2,4] triazin-6-yl] -carbamic acid, (3) -3-morpholinyl methyl ester; [4- [[1- (3-fluorophenyl) methyl] -lH-indazole-5- acid ilamino] -5-methyl-pyrrolo [2, 1-f] [1, 2,] riazin-6-yl] -carbamic, trans-aminocyclicheteroxys ter; [4 - [[1- (3-Fluoro-phenyl) -methyl] -lido indazole |||| 5|||-ylamino] -5-methyl-pyrrolo [2, 1-f] [1,2,4] riazin-6-yl] -carbamic acid, (2i ?, 4JR) 2- (hydroxymethyl) 4-piperidinyl ester; [4- [[1- (3-fluorophenyl) methyl] -Ify-indazol-S-ylamine] -5-m.ethyl-pyrrolo [2, 1-f] [1, 2,4] triazine- acid 6-yl] -carbamic acid, (25-45) -2- (hydroimethylene) -4-piperidylyl ester; [4- [[-1- (3-fluorophenyl) methyl] -1H-indazol-5-ylamino] -5-methyl-pyrrolo [2, 1-f] [1,2, 4] -triazin-6- acid il] -carbamic, cis-4-aminocyclohexyl ester; [4- [[1- (3-Fluorophenyl) methyl] -1H-indazol-5-ylamino] -5-methyl-pyrrolo [2, 1-f] [1,2,4] triazin-6-yl] acid] -carbamic, cis-4-amino-4-methyl-1-cyclohexyl ether; [4 - [[1- (3-fluorophenyl) methyl] -1H-indazol-5-ylamino] -5-methyl-pyrrolo [2, 1-f] [1,2,4] triazin-6-yl] -carbamic acid. { 2R) 2 aminopropyl ester; [4- [[1- (3-Fluorophenyl) methyl] -1H-indazol-5-ylamino] -5-methyl-pyrrolo [2, 1-f] [1,2,4] triazin-6-acid. il] -carbamic acid, (25) -2-aminopropyl ester; [4- [[1- (3-fluorophenyl) methyl] -lfl-indazol-5-ylamino] -5-methyl-pyrrolo [2, 1- f 1 [1, 2, 4] triazin-6-yl] acid] -carbamic, (3R) -3-morpholinylmethersylester; [4- [[1- (3-Fluorophenyl) methyl] -lH-indazol-5-ylamino] -5-methyl-pyrrolo [2, 1-f] [1, 2, 4] triazin-6-yl] acid] - Carbamic, (35) -3-morpholinyl methyl ester; [4- [[1- (3-fluorophenyl) methyl] -lfl-indazol-5-ylamino] 5-methyl pyrrolo [2, 1 f] [1,2,4] triazin-6-yl] acid] carbamic, (3R) -3 piperidin ylester; [4 - [[1- (3-fluorophenyl) methyl] -1H-indazole-5-1-ai-a] -5-met i.1-pyrroium [2, 1-f] [1, 2, 4] t.riazin- 6 - i.1] -carbamic, (35) -3 -piperidini lés ter; 3- [[[[[4- t [1 [(3-fluorophenyl) methy1] -1H-indazol-5-yl.) amino] -5-methylpyrrolo [2, 1- f] [1, 2, 4] -triazin-6-yl] amino] carboni 1] oxy] methyl] -4-morpholinecarboxy 1, (3S) -1, 1-dimethylethyl ester; [4- [[1- (3-fluorophenyl) methyl] -lH-indazol-5-ylamino] -5-me-il-pyrrolo [2, 1-f] [1,2,4] triazin-6-yl acid ] -carbamic, 3-morpholinyl methyl ester; Y [4 - [[1- (3-Fluoro-phenyl) -methyl] -lH-indazol-5-ylamino] -5-yl-pyrrolo [2, 1 f] [1,2,4] triazin-6-yl] carbamic, (3R) 3 morpholinyl methyl ester; and pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof.

In yet another embodiment, the indazolylaminopyrrolotriazine has the structure of Formula II: (II) or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

The compound of Formula II is also known as AC480 or BMS-599 626.

Additional examples of indazolylaminopyrrolotriazines which are suitable for use in the pharmaceutical compositions and methods provided herein are illustrated in US Pat. Nos. 6,916,815; 7,102.001; and 7,148,220; and U.S. Patent Publications Nos. 2005/0209454 and 2006/0014741, each of which is incorporated herein by reference in its entirety.

The compound of Formula I can be prepared according to the methods as described in U.S. Patent Nos. 6,916,815; 7,102.001; and 7, 148,220; and U.S. Patent Publication No. 2005/0209454 and 2006/0014741. The compound can also be synthesized from according to other methods apparent to those with experience in the technique based on the teachings in it.

In one embodiment, the indazolylaminopyrrolotriazine is a compound of Formula I, or a pharmaceutically acceptable solvate or hydrate thereof. In. In a modality, the compound of Formula I is a solid. In another embodiment, the compound of Formula I is a solid in. a form, amorphous. In yet another embodiment, the compound of Formula I is a solid in a crystalline form. In yet another embodiment, the compound of Formula I is a solvate. In yet another embodiment, the compound of. Formula I is a hydrate. In yet another embodiment, the compound of Formula I is a monohydrate. In yet another embodiment, the compound of Formula I is a monohydrate in a crystalline form.

In another embodiment, the indazolylaminopyrrolotriazine used in the methods provided herein is a free base of the compound of the Formula II, or a pharmaceutically acceptable solvate or hydrate thereof. In one embodiment, the free base is a solid. In another, modality, the free base is a solid in an amorphous form. In yet another embodiment, the free base is a solid in a crystalline form, which includes, but is not limited to, the N-2 form. In yet another embodiment, the free base is a solid in the N-2 form. In yet another embodiment, the compound is a solvate. In still another embodiment, the compound is a hydrate. In yet another embodiment, the compound is a monohydrate. In yet another embodiment, the compound is a monohydrate in the H-1 form. The compound of Formula II in solid formsis can be prepared according to the method described in U.S. Patent Publication No. 2006/0014741, which is incorporated in. the present for reference in. its entirety; or using other suitable methods known in the. technique.

The compounds provided herein are intended to encompass all possible stereoisomers, unless a particular stereochemist is specified. Wherein the indazolylaminopyrrolotriazine provided herein contains an alkenyl or alkenylene group, the compound may exist as one or a mixture of geometric cis / trans isomers (or Z / E). Where the structural isomers are interconvertible by a low energy barrier, the indazolylaminopyrrolotriazine can exist as a simple tautomer or a mixture of tautomers. This can take the form of ta.utomeris.mo proton in. the indazolylaminopyrrolotriazine containing, for example, an imino, keto, or oxime group; or the so-called valence tautomerism in the compound that contains an aromatic portion. It follows that a simple indazolylaminopyrrolotriazine may exhibit more than one type of isomerism.

The indizolilaminopirrolotria inas provided herein may be enantiomerically pure, such as a simple enantiomer or a single diastereomer, or be stereoisomeric mixtures, such as a mixture of enantiomers, for example, a racemic mixture of two enantiomers; or a mixture of two or more diastereomers. As such, someone with. experience in the. technique will recognize that the administration of a compound in its form. (R) is equivalent, by compounds undergoing epimerization in vivo, for administration of the compound in its (S) form. Conventional techniques for the preparation / isolation of individual enantiomers include synthesis of a suitable optically pure precursor, asymmetric synthesis of starting material hereral, or resolution of an enantiomeric mixture, eg, chiral chromatography, recrystallization, resolution, diastereomeric salt formation, or derivation in diastereomeric adducts followed by separation.

When the inda.zo1 i..1a..mipopirro1otriaz.inas provided in. present contain a portion, either acidic or basic, can also be provided as a pharmaceutically acceptable salt (see, Berge et al, J. Pharm. Sci. 1977, 66, 1-19; and "Handbook of Pharmaceutical Salts, Pro erLies, and Use, "Stahl and Wermuth, Ed.; Wiley-VCH and VHCA, Zurich, 2002).

Acids suitable for use in the preparation of pharmaceutically acceptable salts include but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulonic acid, acid benzoic acid, 4-acetamidobenzoic acid, boric acid, (+) - camphoric acid, camphor sulphonic acid, (+) - (1S) -camfor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid , cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucohexate acid, D-gluconic acid. , D-glucuronic acid, L-glutamic acid, -oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydrochloric acid, acid (+) Lactic acid, (±) -DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-) -L-malic acid, raonic acid, (±) -DL-mandelic acid, methanesulfonic acid, naph alen-2 acid -phonic serum, naphthalene-1, 5-d.isulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid , L-pyroglutamic acid, sacral acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, acid sulfuric, tannic acid, (+) - L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and valeric acid.

Suitable bases for use in the preparation of pharmaceutically acceptable salts, including, but not limited to, inorganic bases, such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, and sodium hydroxide; and organic bases, such as primary, secondary, tertiary, and quaternary amines, aliphatic, aromatic, heteroaryl, and heterocyclic, including L-arginine, benetamine, benzathine, cloline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2- (diethylamino) -ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl-glucamine, inahydrate, 1H imidazole, L-lysine, morpholine, 4 (2-hydroxyethyl) morpholine, methylamine, piperidine, piperazine, propylamine, pyrroiidine, 1 (2 hi.dro iet i1) -pyrrolidine, pyridine, quinucl idol, quinoxin, isoquinolone, secondary amines, triethanolamine, trimethylamine, triethylamine, -methyl. D-glucamine, 2-ara.i..no-2- (hydroxymethyl) -1, 3-propanediol, and tromethamine.

In one embodiment, the compound suitable for use in the methods provided herein is a pharmaceutically acceptable salt of the compound of Formula II. In one embodiment, the salt is a solid. In another modality, the Salt is a solid in a form, amorphous. In yet another embodiment, the salt is a solid in a crystalline form, which includes, but is not limited to, the N 1 form. In yet another embodiment, the salt is a solid in the N 1 form. In yet another embodiment, Salt is a hydrochloric salt. In yet another embodiment, the hydrochloric sai is, in a crystalline form, which includes, but is not limited to, the N-1 form. In yet another embodiment, the hydrochloric salt is in the N-1 form. The pharmaceutically acceptable salt of the compound of Formula II in solid forms can be prepared according to the method described in U.S. Patent Publication No. 2006/0014741, which is incorporated herein by reference in its entirety; or using other suitable methods known in the art.

In certain embodiments, the salt is a salt of the sulfonic acid. See, for example, the Provisional Application American No., filed on March 11, 2010, the description of which is incorporated herein for reference in its entirety. E certain modalities, sulfonic salt. It is in an amorphous form. In certain embodiments, the sulfonic salt is in one. crystalline form.

In certain embodiments, the compound suitable for use in the methods provided herein is an ethanesulfonic acid salt of 4- (1- (3-fluorobenzyl) -1H-indazol-5-ylamino) -5-methylpyrrolo [1, 2-f] [1,2,4] triazin-6-ylcarbamate of (S) -morpholin-3-methylmethyl, or a hydrate or pharmaceutically acceptable solvate thereof. As used herein, the term "ethanesulfonic acid salt" is used interchangeably with the term "isalt salt".

In certain embodiments, the molar ratio of 4 (1 (3-fluorobe.nc.il) -1H-indazol-5-ylamino) -5-methylpyrrolo [1, 2-f) [1,4] triazin-6-ylcarbamate of (S) -morpholin-3 -.ilmet.i.lo, verses the ethanesulfonic acid in the salt provided herein, which includes pharmaceutically acceptable hydrates and solvates thereof, are found in ranges of about 0.5 to about 3, from about 0.5 to about of 2, or from around 0.8 to around 1.2. In certain embodiments, the molar ratio of 4- (l- (3-fluorobenzyl) -lily-indazol-5-ylamino) -5-methylpyrrolo [1,2-f] [1,2,2] triazin-6-ylcarbamate from ( S) morpholin-3-methylmethyl, versus ethanesulfonic acid in the salt provided herein, includes pharmaceutically acceptable hydrates and solvates thereof, s found around 0.5, about 0.6, about 0.7, around OS, 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 around 3.

In one embodiment, the ethanesulfonic acid salt of 4- (1- (3-ω-luorobenzyl) -lH-indazol-5-ylamino) -5- Methylpyrrolo [1, 2-f] [1, 2, 4] triazin-6-ylcarbamate, of (5) -morpholin-3-ylmethyl, or a pharmaceutically acceptable hydrate or solvate thereof, comprises about one molar equivalent of 4 (1 (3-fluorobenzyl) -1H-indazole-5-lamino) -5-methylpyrrolo [1, 2-f] [1, 2, 4] triazin-6-ylcarbamate of (5) morphoiin-3-yl-methyl-ethyl ester and about one molar equivalent of. Ethanesulfonic acid. In certain embodiments, the molar ratio of 4- (1- (3-fluo.robenzyl) -1H-indazol-5-ylamino) -5-methylpyrrolo [1,2- f] [1,2,4] triazin -6-ylcarbamate of (S) -morpholin-3-ylmethyl versus ethanesulfonic acid is determined based on the trum of LH NMR.

In certain embodiments, the etonic acid salt of 4- (1- (3-fluorobenzyl) -lff-indazol-5-ylamino) -5-methylpyrrolo [1,2-f] [1,2,] triazin-6 - (S) -morpholin-3-ylmethylcarbamate, or a pharmaceutically acceptable hydrate or solvate thereof, has a purity of at least about 95%, at least about 96%, at least about 97%, at least about of 98%, at least to the rededo of 98.5%, at least about 99%, al. less 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 4- (l- (3-fluorobenzyl) indazol-5-ylamino) -5-methylpyrrolo [1,2-f] [1,2,4] triazin-6-ylcarbamate of (S) -raorfolin-3-ylmethyl, or a pharmaceutically acceptable hydrate or sol thereof, contains nitrosamine at a level 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 not greater than about 0.1 ppm.

In one embodiment, the ethanesulfonic acid salt of 4- (1- (3-fluorobenzyl) -lH-indazol-5-ylamino) -5-methylpyrrolo [1,2-f] [1,2,4] triazine-6 - (S) -morpholin-3-ylmethylcarbamate, or a pharmaceutically acceptable hydrate or solvate thereof, is in an amorphous form. In another embodiment, the salt of ethanesulfonic acid of 4-. { 1- (3-f-luorobenzyl) -1H-indazole-5-ylamino) -5-methylpyrrolo [1, 2-f] [1, 2, 4] triazin-6-ylcarbamate (S) -morpholin-3-ylmethyl ester, or a pharmaceutically acceptable hydrate or solvate of it, it is crystalline. In certain embodiments, the salt of etonic acid has an endotherm with. a peak temperature of about 202 ° C and a start temperature of 197 ° C in a DSC thermogram. In certain embodiments, the salt of ethanesulfonic acid is shown to be 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% , not higher than about 0.1%, not higher than about 0.0.9%, 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 etonic acid salt is shown around 0.1% weight loss between 25 ° C to 150 ° C in a thermogram of t.erm.ogravimet.rico.

In one embodiment, the ethanesulfonic acid salt of 4- (1- (3-fluorobenzyl) -lfi-indazol-5-ylamino) -5-methylpyrrolo [1,2-f] [1,2,2] triazine-6 (S) ~ Morpholin-3-ylmethyl ilcarbamate, or a pharmaceutically acceptable hydrate or solvate thereof, is in a crystalline Form II-A.

In another embodiment, the ethanesulfonic acid salt of 4- (1- (3-fluorourobenzyl) li-indazol-5-ylamino) -5-methylpyrrolo [1,2-f] [1,2,4] triazin-6-ylearbamate of (S) ) ~~ morpholin-3-ylmethyl, or a pharmaceutically acceptable hydrate or solvate thereof, is found in an i -na crystal Form II-B.

In. still another modality, the. Phosonic etansul acid salt of 4- (1- (3-f-luorobenzyl) -lH-indazol-5-ylamino) -5-methylpyrrolo [1, 2-f] [1, 2, 4] triazin- 6- (S) -morpholin-3-ylmethyl ilcarbamate, or a pharmaceutically acceptable hydrate or solvate thereof, is in a crystalline Form II-C.

In yet another embodiment, the ethanesulfonic acid salt of 4- (1-. {3-fluorobenzyl) -1H-indazol-5-ylamino) -5-methylpyrrolo [1, 2-f] [1, 2, 4] triazin-6-ylcarbamate of (S) morpholin-3-ylmethyl, or a pharmaceutically acceptable hydrate or solvate thereof, is in a crystalline Form II D.

In yet another embodiment, the ethanesulfonic acid salt of 4- (1- (3-fluorobenzyl) -lfl-inda.zol-5-lamino) -5-methylpyrrolo [1,2-f] [1,2,2] triazin -6-ylcarbamate from. { S) ~ morpholin-3-ylmethyl, or a pharmaceutically acceptable hydrate or solvate thereof, is in a crystalline Form II-E.

The compound provided herein may also be provided as a prodrug, which is a functional derivative of the compound, for example, of Formula I or II and is readily convertible to the parent compound in vivo. Prodrugs are often useful, in some situations, which may be easier to administer than the main compound. It can, for example, be bioavailable by oral administration while the main compound does not. The prodrug may also have improved solubility in pharmaceutical compositions over the main compound. A prodrug can be converted into the main drug by several mechanisms, including enzymatic processes and metabolic hydrolysis. See Harper, Progress in Drug Research 1962, 4, 221-294; Morozowich et al. in "Design of Biopharmaceutical Properties through Prodrugs and Analogs", Roche Ed., APHA Acad. Pharm. Sei 1977; "Bioreversible Carriers in Drug in Drug Design, Theory and Application", Roche Ed., APHA Acad. Pharm. Sci. 1987; "Design of Prodrugs", Bundgaard, Elsevier, 1985; Wang et al, Curr. Pharm. Design 1999, 5, 265-287; Paule ti et al., Adv. Drug. Delivery Rev. 1997, 27, 235-256; Mizen et al, Pharm. Biotech 1998, 11, 345-365; Gaignault. et al, Pract. Med. Chem. 1996, 671-696; Asgharnejad in "Transport Processes in Pharmaceutical Systems" 1, Amidon et al, Ed., Marcell Dekker, 185-218, 2000; Balant et al, Eur. J. Drug Metah., Pharmacokinet:., 1990, 15, 143-53; R li mane and Sinko, Adv. Drug Delivery Rev. 1999, 39, 183-209; Browne, Clin. Neurophar acol 1997, 20, 1-12; Bundgaard, Arch. Pharm. Chem. 1979, 86, 1 39; Bundgaard , Controlled Drug Delivery 1987, 17, 179 96; Bundgaard, Adv.

Drug Delivery Rev. 1992, 8, 1-38; Fleisher et al, Adv. Drug Delivery Rev. 1996, 19, 115-130; Fleisher et al, Mecroas Enzymol. 1985, 112, 360-381; Farquhar et al, J. Pharm. Sci. 1983, 72, 324-325; Freeman et al, J. Chem. Soc, Chem. Commun. 1991, 875-877; Friis and Bundgaard, Eur. J. Pharm. Sci. 1996, 4, 49-59; Gangwar et al, Des. Biopharm. Prop. Prodrugs Analogs, 1977, 409-421; Nathwani and ood, Drugs 1993, 45, 866-94; Sinhababu and Thakker, Adv. Drug Delivery Rev. 1996, 19, 241-273; Stella et al, Drugs 1985, 29, 455-73; Tan et al, ñdv. Drug Delivery Rev. 1999, 39, 117-151; Taylor, Adv. Drug-Delivery Rev. 1996, 19, 131-148; Valentino and Borchardt, Drug Discovery Today 1997, 2, 148-155; Wiebe and Knaus, Adv. Drug Delivery Rev. 1999, 39, 63 -80; and Waller et al, Br. J. Clin. Pharmac. 1989, 28, 497 507.

Taxans As used herein, the term "taxa.no" includes both naturally derived and chemically synthesized terpenes or derivative thereof, including, but not limited to, paclitaxel (TAXOL®) and docetaxel (TAXOTERE®). Paclitaxel and its derivatives are described in U.S. Patent Nos. 4,942,184; 5,440,056; 5,495,804; 5,641,803; 5,670,537; and 6,380,405; each of which is incorporated herein by reference in its entirety. Docetaxel is described in U.S. Patent Nos. 4,814,470; 5,438,072; 5,698,582; and 5,714,512; each of which is incorporated herein by reference in its entirety.

In certain embodiments, the taxane is paclitaxel. In certain embodiments, the taxane is paclitaxel bound to albumin (ABRAXANEW). In certain embodiments, the taxane is docetaxel.

Pharmaceutical Compositions In one embodiment, there is provided herein pharmaceutical compositions comprising a taxane and an indazolylaminopyrrolotriazine provided herein, for example, a compound of Formula I or II, which includes a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with. the carrier, carrier, diluent, or excipient, or a pharmaceutically acceptable mixture thereof.

In another embodiment, a pharmaceutical composition comprising an indazolylaminopyrrolotriazine provided herein, for example, a compound of Formula I or II, including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers, is provided herein. of the same; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with the carrier, carrier, diluent, or excipient, or a. pharmaceutically acceptable mixture thereof.

In yet another embodiment, there is provided herein pharmaceutical compositions comprising an indazolylaminopyrrolotriazine provided herein, for example, a compound of Formula I or II, which includes a single enantiomer, a mixture of enantiomers, or a mixture of diastere eros of it; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with hydroxypropyl b-cyclodextrin, mannitol, water, or a mixture thereof.

In yet another embodiment, pharmaceutical compositions comprising [4- [[1- (3-fluorophenyl) methyl] -lH-indazol-5-yilamino] -5-methyl-pyrrolo [2] are provided herein. , 1-f] [1, 2, 4] triazin-6-yl] -carbamic acid, (35) -3-morpholinyl methyl ester, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with hydroxypropyl- (3-cyclodextrin, mannitol, water, or a mixture thereof.

In yet another embodiment, a pharmaceutical composition comprising [4- [[1- (3-fluorophenyl) methyl] -1H-indazole-5-ylamino] -5-methyl-pyrrolo [2, 1-f] [1,2, 4] triazin-6-yl] carbamic acid, (3S) 3-morpholinyl methyl ester, ethansulfonate, or a pharmaceutically acceptable solvate or hydrate thereof, in combination with hydroxypropyl-β-c iclodextrin, mannitol, water., Or a mixture thereof.

In yet another embodiment, a pharmaceutical composition comprising about 15% by weight of [4- [[1- (3-fluorofenyl) methyl] -1H-indazol-5-ylamino] -5- acid is provided herein. methyl-pyrrolo [2, 1-f] [1,2,4] triazin-6-yl] -carbamic acid, (3S) -3-morpholinyl methyl ester, ethanesulfonate, about 75% by weight of hydroxypropyl-β-cyclodextrin, and 10% by weight of mannitol.

In yet another embodiment, a pharmaceutical composition is provided in a dosage unit, which comprises about 363 mg of acid [4 [[1 (3 fluorophene) ii) methi 1. J -1 H -indazol-5-yla. mi.no] - 5 -methyl-iron [2, .1 -f] [1, 2,4] tr.i.azi.n-6-.il] -carbamic, (3S) -3-morfol inylmethyl ester , et.ansulfon.ato, about 1,800 mg of hydroxypropyl-cyclodextrin, and 1,240 mg per weight of mannitol.

In certain embodiments, a pharmaceutical composition in a unit dose, comprising about 363 mg of [4- [[1- (3-fluorophenyl) methyl] -lH-indazol-5-ylamino] -5-methyl-pyrrolo acid. [2, 1-f] [1,2,4] triazin-6-yl] -carbamic acid, (3S) 3-morpholinyl methyl ester, ethanesulfonate in a crystalline form. In certain embodiments, a pharmaceutical composition in a dose unit, comprising about 363 mg of [4- [[1- (3-fluorophenyl) methyl] -lH-indazol-5-.1 acid. lamino] -5-meti 1-pyrrolo [2, 1- f] [1,2,4] tr.iazin. ~ 6 ~ i 1] -carbamic, (3S) -3-morfo.li.nilmethyl ester, etansulfonate in. a. Form II-B crystalline.

In yet another embodiment, pharmaceutical compositions comprising a taxane and the carrier, carrier, diluent, or excipient, or a pharmaceutically acceptable mixture thereof are provided herein.

The taxane-containing compositions provided herein may also be formulated as known to those of skill in the art. Some examples of taxane-containing pharmaceutical compositions are described in U.S. Patent Nos. 4,814,470; 4,942,184; 5.4.38.072; 5,440,056; 5,496,804; 5,641,803; 5,670,537; 5,698,582; 5,714,512; and 6,380,405; each of which is incorporated herein by reference in its entirety.

The pharmaceutical compositions provided herein may further comprise an additional active agent provided herein. In one embodiment, the additional active agent is cisplatin, capecitabine, carboplatin, cetuximab, vinorelbine, gefitinib, gemcitabine, etoposide, irinotecan, lapatinib, trastuzumab, vinblastine, mitomycin, ifosfamide, pemetrexed, erlotinib, bevacizumab, or cetuximab.

The pharmaceutical compositions provided in the. present can be formulated in various dosage forms for. oral, parenteral, and topical administration. The pharmaceutical composition can also be formulated as a modified release dosage form, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and rapid-, targeted-, programmed-, and dosage forms of gastric retention. 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 Phar acy, supra; Modified Relay Drug Deliver Technology, Rathbone et al, Eds. , Drugs and the Pharmaceutical Science, Marcel Dekker, Inc .: New York, NY, 2003; Voi 126).

In one embodiment, the pharmaceutical compositions provided herein are formulated in one. dosage form for oral administration. In another embodiment, the pharmaceutical compositions provided herein are formulated in a dosage form for parenteral administration. In yet another embodiment, the pharmaceutical compositions provided herein are formulated in a dosage form for topical administration.

The pharmaceutical compositions provided herein may be provided in a unit dose or multiple dose form. A dosage unit form, as used in the. present, refers to one. a physically discrete unit suitable for administration to a subject, for example, a human and animal subject, and packaged individually as shown in the art. Each dose unit contains a predetermined amount of one or more active ingredients sufficient to produce the desired therapeutic effect, in association with the pharmaceutical carriers or excipients required. Examples of a way of dosage unit include an ampule, j eringa, and individually packed tablets and capsules. A dosage unit form can be administered in fractions or multiples thereof. A multiple dose form is a plurality of identical dosage unit forms packaged in a single container to be administered in the form of a segregated dose unit. Examples of multiple dose forms include a bottle, bottle, tablets or capsules, or bottle of pints or gallons.

The pharmaceutical compositions provided herein may be administered once, or multiple times in time intervals. It will be understood that the precise dose and duration of treatment may vary with the age, weight, and condition of the patient being treated, and can be determined empirically using known test protocols or by extrapolation of tests or diagnostic data in vivo or in vi tro. It will also be understood that for any individual individual, it must be adjusted over time according to the individual need and the professional judgment of the person who administers or supervises the administration of the formulations.

A. Oral administration The pharmaceutical compositions provided herein for oral administration can be provided in solid, semi-solid or liquid dosage forms for oral administration. As used herein, oral administration also includes buccal, lingual, and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, fast-disintegrating tablets, more tablets, capsules, pills, strips, troches, lozenges, pills, sachets, swabs, medicated chewing gum, powders a bulk, effervescent or non-effervescent powders or granulates, oral sprays, solutions, emulsions, suspensions, wafers, sprinklers, elixirs, and syrups. In addition to the active ingredient (s), the pharmaceutical compositions may contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, inhibitors. of dye migration, sweetening agents, flavoring agents, emulsifying agents, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and carbon dioxide sources.

The binders or granulators impart cohesiveness to a tablet to ensure that the tablet remains intact after compression. Suitable binders or granulators include, but are not limited to, starches, such as corn starch, potato starch, and pregelatinized starch (e.g., STARCH 1500); jelly; sugars, such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums, such as acacia, alginic acid, alginates, moss gum extract from Ireland, panwar gum, ghatti gum, mucilage from isabgol shells, carboxymethylcellulose, methylcellulose, polyvini. lpir.rolid.ona (PVP), Veegura, arabogalacta.no larch, powdered tragacanth, and guar gum, celluloses, such as ethylcellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), icrocrystalline 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, ma.ni.tol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures of the same. . The amount of binder or filler in the pharmaceutical compositions provided herein varies depending on the type of formulation, and is easily discernible to those of ordinary skill in the art. Binders or fillers can be presented from around 50 to about 99% by weight in the pharmaceutical compositions provided herein.

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

Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses, such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; ion exchange resin; alginic acid; gums, such as guar gum and Veegum HV; citrus pulp; crosslinked celluloses, such as croscarmellose; crosslinked polymers, such as crospovidone; cross-linked starches; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; potassium polacrilin; starches, such as corn starch, potato starch, tapioca starch, and pregelatinized starch clays; aligners; and mixtures thereof. The amount the amount of a disintegrant in the pharmaceutical compositions provided herein varies with the type of formulation, and is readily perceptible to those of ordinary skill in the art. The amount of a disintegrant in the pharmaceutical compositions provided herein varies with the type of formulation, and is readily perceptible 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.

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; talcum powder; hydrogenated vegetable oil, which includes peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laurate; agar; starch; lycopodium; silica or silica gels, such as AEKOSIL® 200 (.R. Grace Co, Baltimore, MD) and CAB-O-SIL® (Cabot Co., Boston, MA); and mixtures thereof. The pharmaceutical compositions provided herein may contain from about 0.1 to about 5% by weight of a lubricant e.

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 water soluble, certified, approved FD &C dyes and dyes FD &C insolubl. water suspended in alumina hydrate, and color lacquers and mixtures thereof. A color lacquer is the combination by adsorption of a water-soluble dye into a hydrous oxide of a heavy metal, which results 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 that 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 e? Ication agents include, but are not limited to, gelatin, acacia, tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitan monooleate (TWEEN.RTM. 20), polyoxyethylene sorbitan monooleate 80 (TWEEN.RTM. 80) , and trientanolamine oleate. Suitable dispersing and suspending 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 acid, sodium benzoate and alcohol. Suitable humectants include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol raonolaurate, and polyoxyethylene lauryl ether. Suitable solvents include, but are not limited to, glycerin, sorbitol, ethyl alcohol, and syrup. Suitable non-aqueous liquids used 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.

It should be understood that many carriers and excipients can. serve for, various functions, even within the same formulation.

The pharmaceutical compositions provided herein for oral administration can be provided as compressed tablets, crushed tablets, chewable tablets, rapidly dissolving tablets, multiple compressed tablets, or enteric coated tablets, coated with sugar, or film-coated tablets. The 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, shellac with ammonia, and cellulose acetate phthalates. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial in the coating of unpleasant tastes or odors and in the protection of oxidation tablets. The film-coated tablets are compressed tablets that are covered with a thin film or layer of a water-soluble material. Film covers include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and phthalic acid acetate. The film coating imparts the same general characteristics as the sugar coating. Multiple compressed tablets are compressed tablets made by more than one compression cycle, including statified tablets, and pressure-coated or dry-coated tablets.

Dosage forms of tablet can be prepared at starting from the active ingredient in the form of powder, crystalline, or granule, alone or in combination with one or more carriers or excipients described herein, which includes binders, disintegrants, controlled release polymers, lubricants, diluents, and / or dyes Flavoring and sweetening agents are especially useful in the. formation of tablets inasticabl.es and dragees.

The pharmaceutical compositions provided herein for oral administration can be provided as soft or hard capsules, which can be made of gelatin, methylcellulose, starch, or calcium alginate. The hard gelatin capsule, also known as a dry-fill capsule (DFC), consists of two sections, one sliding over the other, thus completely enclosing the active ingredient. The soft elastic capsule (SEO) is a soft globular shell, such as a gelatin shell, which is plasticized by the adhesion of glycerin, sorbitol, or a similar polio.The soft gelatin covers may contain a preservative for. Growth of microorganisms Suitable preservatives are those as described herein, which include methyl- and propyl-parabens, and sorbic acid.The semi-solid and solid liquid dosage forms provided herein may be encapsulated in a capsule. of suitable liquid and semisolid doses include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Patent Nos. 4,328,245; 4,409,239; and 4,410,545. The capsules may also be coated as is known to those skilled in the art to modify: or sustained dissolution of the active ingredient.

The pharmaceutical compositions provided herein for oral administration can be provided in liquid and semisolid dosage forms, which include emulsions, solutions, suspensions, elixirs, and syrups. An emulsion is a two-phase system, in which a liquid is dispersed in the form of small globules through another liquid, which can be oil in water or water in oil. The emulsions may include a non-aqueous solvent or liquid, pharmaceutically acceptable preservative and emulsifying agent. The suspensions may include a pharmaceutically acceptable preservative and suspending agent. Aqueous alcohol solutions can include an aceta! pharmaceutically acceptable, such as di (lower alkyl) acetal of a lower alkylaldehyde, for example, acetaldehyde diethyl acetal, and water miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol. The elixirs are transparent, sweetened, and hydroalcoholic solutions. Syrups are solutions aqueous concentrates 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 can be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, eg, water, to be conveniently measured for administration.

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 polyalkylene glycol, including, 1,2-dimethoxymethane, diglyme, triglyme, tetraglima, 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 polyethylene glycol. These formulations may also comprise one or more antioxidants, such as hydroxy-oluene butadiene (BHT), butylated hydroxyurea, (BHA), propyl gallate, vi amine. E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalignan, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulphite, thiodipropionic acid and its esters, and dithiocarbamates.

The pharmaceutical compositions provided herein for oral administration may also provided in the forms of liposomes, micelles, microspheres, or nanosystems. Ice dosage forms can be prepared as described in U.S. Pat. 6,350,458.

The pharmaceutical compositions provided in the. present for oral administration can be provided as non-effervescent or effervescent granules and powders, which can be reconstituted into a. liquid dosage form. The pharmaceutically acceptable carriers and excipients used in the non-effervescent granules or powders may include diluents, sweeteners, and wetting agents. The pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders may include organic acids and a source of carbon dioxide.

Coloring agents and flavorings can be used in all fornicas of previous doses.

The pharmaceutical compositions provided herein for oral administration can be formulated as immediate or modified release dosage forms, which includes forms of release, -enidas, pulsed, controlled, directed, and programmed.

B. Parenteral Administration The pharmaceutical compositions provided herein may be administered parenterally by injection, infusion, or implantation, for local administration or system. Parenteral administration, as used herein, includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, intravesical administration. , and subcutaneous.

The pharmaceutical compositions provided in. present for parenteral administration can be formulated in any dosage form that is suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosis emas, and solid forms suitable for solutions or suspensions in liquid prior to the 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).

Pharmaceutical compositions intended for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous vehicles, water vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms. , is abilizers, solubility improvers, isotonic agents, buffering agents, antioxidants, local anesthetics, dispersion and suspension agents, wetting or emulsifying agents, complexing agents before, sequestering or chelating agents, cric-protective agents, lyoprotectants, thickeners, pH-adjusting agents, and inert gases.

Suitable aqueous vehicles include, but are not limited to, water, saline, physiological saline or buffered saline, phosphate (PBS), sodium chloride injection, Ringers injection, isotonic dextrose injection, sterile water injection, Lactated and dextrose 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, oil , of sesame, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oils, and medium chain triglycerides of coconut oil, and palm seed oil. Suitable miscible vehicles in water include, but are not limited to, et.an.ol, 1,3-butan.di.ol, liquid polyethylene glycol (for example, polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N- methyl-2-pyrrolidone, N, N-dimethylacetamide, and dimethyl sulfoxide.

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 (for example, 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 treatment. Suitable antioxidants are those as described herein, which include bisulfite and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable dispersing and suspending agents are those as described herein, which includes sodium carboxymethylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agents are those described herein, which include polyoxyethylene sorbitan monoaurate, polyoxyethylene sorbitan monooleate 80, and triethanolanine 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 complexant agents include, but are not limited to, cyclodextrins, which includes a-cyclodextrin, 3-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and sulfobutyl ether-7-α-cyclodextrin.

(CAPTISOL®, CyDex, Lenexa, KS).

When the pharmaceutical compositions provided herein are formulated for multiple dose administration, the multiple dose parenteral formulations should contain an antimicrobial agent of bac eriostatic or fungistatic concentrations. All parenteral formulations should be sterile as is known in the art.

In one embodiment, pharmaceutical compositions for parenteral administration are provided as sterile ready-to-use solutions. In another embodiment, the pharmaceutical compositions are provided as sterile dry soluble products, including lyophilized powders and hypodermic tablets, for reconstitution with a vehicle before use. In yet another embodiment, the pharmaceutical compositions are provided as sterile suspensions ready for use. In yet another embodiment, the pharmaceutical compositions are provided as sterile dry insoluble products for reconstitution with a vehicle before use. In yet another embodiment, the pharmaceutical compositions are provided as sterile emulsions ready for use.

The pharmaceutical compositions provided herein for parenteral administration can be formulated as immediate or modified release dosage forms, which includes forms of delayed-release, sustained, pulsed-, controlled, directed-, and programmed.

The pharmaceutical compositions provided herein for parenteral administration can be formulated as a suspension, solid, semisolid, or thixotropic liquid, for administration as an implanted reservoir. In a. embodiment, the pharmaceutical compositions provided herein are dispersed in a solid internal matrix, which is surrounded by an outer polymer membrane which is insoluble in body fluids but which allows the active ingredient in the pharmaceutical compositions to spread.

Suitable interior matrices include, but are not limited to, polymethyl methacrylate, 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 acrylic and methacrylic acid ester hydrogels, collagen, crosslinked polyvinyl alcohol, and crosslinked partially hydrolyzed polyvinyl acetate.

Suitable external polymeric membranes include, but are not limited to, polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, copolymers of vinyl chloride with vinyl acetate, vinylidene chloride , ethylene and propylene, ionomer of polyethylene teref a.la.to, butyl rubber epichlorohydrin rubbers, co o! Ethylene / alcoholvinyl iodine, ethylene / vinyl acetate / alcoholvinyl terpolymer, and ethylene / vinyl oxyethanol copolymer.

C. Topical Administration The pharmaceutical compositions provided herein may be topically administered to the skin, orifices, or mucosa. Topical administration, as used herein, includes administration (intra) dermal, conjunctive, intracorneal, infraocular, ophthalmic, auricular, transdermal, nasal, vaginal, urethral, respiratory., And i ec al.

The pharmaceutical compositions provided herein may be formulated in any dosage forms that are suitable for topical administration for the local or systemic effect, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, talcum powder, dressings, elixirs, lotions, suspensions, dyes, pastes, foams, films, sprays, irrigations, sprays, suppositories, bandages, and skin patches. The topical formulation of the pharmaceutical compositions provided herein may also provide liposomes, nuclets, microspheres, nanosystems, and mixtures thereof.

The pharmaceutically acceptable carriers and excipients suitable for use in. The topical formulations provided herein include, but are not limited to, aqueous vehicles, water-iscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants. , local anesthetics, dispersing and suspending agents, wetting or emulsifying agents, complexing agents before, sequestering or chelating agents, penetration enhancers, cryoprotective agents, lyoprotectants, thickeners and inert gases.

The pharmaceutical compositions can also be administered topically by electroporation, iontophoresis, phonophoresis, sonophoresis, or microneedle or needle-free injection, such as PO DERJECT ™ (Chiron Corp, Emeryville, CA), and BIOJECT ™ (Bioject. Medical Technologies Inc., Tualatin, OR).

The pharmaceutical compositions provided herein may be provided in the ointment forms, creams, and gels. Suitable ointment vehicles include oleaginous or hydrocarbon vehicles, including lard, benzoin lard, olive oil, cottonseed oil, and other oils, white petrolatum; emulsifiable or absorption vehicles, such as hydrophilic petrolatum. , hydrox.isteari.na sulfate, and anhydrous lanolin; water extractable vehicles, such as hydrofluoric ointments; water-soluble ointment vehicles, including polyethylene glycols of varying molecular weight; emulsion vehicles, either oil-in-water (W / O) emulsions or water-in-oil (0 / W) emulsions, including cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid. { ease, Remington: The Science and Practice of Pharmacy, supra). These vehicles are emollients but generally require the addition of antioxidants and preservatives.

The right cream base can be oil in water or water in oil. The proper cream vehicles can be washable in water, and they have one. oil phase, an emulsifier, and an aqueous phase. The. oil phase also called the "internal" phase, which is generally comprised of petrolatum and fatty alcohol, such as cetyl or stearyl alcohol. The aqueous phase usually, although not necessarily exceeding the oil phase by volume, and generally contains a humectant. The emulsifier in a The cream formulation may be a non-ionic, anionic, cationic, or amotroteric surfactant.

The; geies are suspension type, semi-solid systems. Single-phase gels contain organic macromolecules distributed substantially and uniformly through the liquid carrier. Suitable gelatinizing 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 polyvinyl alcohol; cellulosic polymers, such as hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, and methylcellulose; gums, such as tragacanth and xanthan gums; sodium alginate; and gelatin. To prepare a uniform gei, dispersing agents such as alcohol or glycerin can be added, or the agent believed they can be dispersed by trituration, mechanical mixing, and / or agitation.

The pharmaceutical compositions provided herein may be administered rectally, urethrally, vaginally, or perivaginally in the forms of suppositories, ovules, catheters, plasters, or cataplasms, pastes, powders, dressings, creams, patches, contraceptives, ointments, solutions, emulsions, suspensions, tampons, gels, foams, sprinklers, or enemas. These dosage forms can be manufactured using conventional processes as described in Remingtoii: The Science and Practice of Phar acy, its a.

Rectal, urethral, and vaginal suppositories are solid bodies for insertion into bodily orifices, which are solid at ordinary temperature but which melt or soften at body temperature to release the active ingredient (s) into the orifices. The pharmaceutically acceptable carriers used in rectal and vaginal suppositories include bases or carriers, such as reinforcing agents, which produce a melting point in the vicinity of body temperature, when formulated with the pharmaceutical compositions provided herein; and antioxidants as described herein, which includes sodium bisulfite and metabisulfite. Suitable carriers include, but are not limited to, cocoa butter (theobroma oil), gelatin-glycerin, carbowax (pol.ioxietil.engl.icol), whale sperm, paraffin, wax, white and yellow, appropriate mixtures of mono-, di- and triglycerides of fatty acids, hydrogels, such as polyvinyl alcohol, hydroxyethyl methacrylate, and polyacrylic acid. Combinations of various vehicles can also be used. Rectal and vaginal suppositories can be prepared by compression or molding. The typical weight of a Rectal and vaginal suppository is around 2 to about 3 g.

The pharmaceutical compositions provided herein may be administered in the form of solutions, suspensions, ointments, emulsions, gel solutions, powders for solutions, gels, eye inserts, and implants.

The pharmaceutical compositions provided herein may be administered intranasally or by inhalation to the respiratory tract. The pharmaceutical compositions may be provided in the form of an aerosol or solution for delivery using a pressurized container, pump, sprinkler, atomizer such as an atomizer that uses 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 may comprise a bioadhesive agent, which includes chitosan or cyclodextrin.

Solutions or suspensions for use in a pressurized container, pump, sprinkler, atomizer, or nebulizer can be formulated to contain ethanol, ethanol aqueous, or a suitable alternative agent to release the dispersion, solubilization, or extension of an active ingredient provided herein; a propellant as a solvent; and / or to surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.

The pharmaceutical compositions provided herein may be micronised to. a suitable size for delivery by inhalation, such as about 50 micrometers or less, or about 10 micrometers or less. Particles of such dimensions can be prepared using a crushing method known to those skilled in the art, such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing to form nanoparticles, high-pressure homogenization, or spray drying.

Capsules, ampoules and cartridges for use in an inhaler or insufflator can be formulated to contain a powder mixture of the pharmaceutical compositions provided therein. I presented; a suitable powder base, such as lactose or starch; and a performance modifier, such as i-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of a 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 may further comprise a suitable flavor, such as menthol and levomenthol; and / or sweeteners, such as saccharin and sodium saccharin.

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

D. Modified Release The pharmaceutical compositions provided herein may 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 one. form of immediate dose when administered by the same route. Modified release dosage forms include, but are not limited to, delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and rapid-, targeted-, programmed-, and dosage forms of gastric retention. The pharmaceutical compositions in the modified release dosage forms can be prepared using a variety of modified release devices and methods known to those of skill in the art, including, but not limited to, matrix controlled release devices, osmotic control release devices, multiparticle controlled release devices, ion exchange resins, enteric coatings, stratified coatings, microspheres, liposomes, and combinations thereof. The release rate of the active ingredient (s) can also be modified by varying the particle sizes and polymorphisms of the active ingredient (s).

Examples of modified release include, but are not limited to, those described in the Patents US 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; r 5, 073, 543; 5, 639, 476, 5,354,556; 5, 639, 480; 5,733,566; 5, 739, 1.08; 5, 891, 474, 5,922,356; 5, 972, 89.1; 5, 980, 945; 5, 993, 855; 6, 045, 830, 687, 329; 6, 113, 943; 6, 197, 350; 6,248,363; 6, 264, 70, 6267, 981; 6, 376, 46.1; 6, 419, 961; 6,589,548; 6, 613,358; and 6, 699, 500.

Matrix controlled release devices The pharmaceutical compositions provided in present in the modified release dosage forms they can be manufactured using a matrix controlled release device known to those skilled in the art (see, Takada et al., "Encyclopedia of Controlled Drug Delivery," Vol. 2, Mathiowitz Ed., Wiley, 1999).

In certain embodiments, the pharmaceutical compositions provided herein in a modified release dosage form are formulated using an erodible matrix device, which is water swellable, erodible, or soluble polymers, including, but not limited to, polymers. synthetics, and naturally occurring polymers and derivatives, such as polysaccharides and pro-eins.

Useful materials in forming erodible matrix include, but are not limited to, chitin, chitosan, dextran, and swarm, gum agar, gum arabic, karaya gum, locust bean gum, gum tragacanth, carrageenan, gum, ghatti, cjuar gum, xanthan gum, and scleroglucan; starches, such as dextrin and maltodextrin; hydrophilic colloids, such as pectin, Eos the idos, such as. lecithin, alginates, propylene glycol alginate, gelatin, collagen, cellulosics, such as ethylcellulose (EC), methyl ethylcellulose (M'EC), carboxymethylcellulose (CMC), CMEC, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), cellulose acetate (CA) ), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate (CAB) butyrate, CAP, CAT, hydroxypropylmethylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropylmethylcellulose acetate trimellitate (HPMCAT), and ethylhydroxyethylcellulose (EHEC); polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, esters of glycerol fatty acids; polyacrylamide, polyacrylic acid, ethacrylic acid or methacrylic acid copolymers (EUDRAGIT®, Rohm America, Inc., Piscataway, NJ); poly (2-hydroxyethyl-methacrylate); polylactides; copolymers of L-glutamic acid and ethyl-L-glutamate; glycolic acid-degradable lactic acid copolymer; poly-D - (-) - 3-hydroxybutyric acid; and other acrylic acid derivatives, such as homopolymers and copolymers of butyl methacrylate, methyl methacrylate, ethyl methacrylate, ethylacrylate, (2-dimethylaminoethyl) methacrylate, and (trimethylaminoethyl) methacrylate.

In certain embodiments, the pharmaceutical compositions provided herein are formulated with a non-erodible matrix device. The active ingredients are dissolved or dispersed in an inert matrix and are released mainly by diffusion through the inert matrix once administered. Suitable materials 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, copolymers of methyl acrylate-methyl methacrylate, ethylene-vinyl acetate copolymers, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers , copolymers of vinyl chloride with vinyl acetate, vinylidene chloride, ethylene and propylene, polyethylene terephthalate ionomer, butyl rubbers, epichlorohydrin rubbers, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer , ethylene / vinyl oxyethanol 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 partially hydrolyzed cross-linked polyvinyl acetate; and fatty compounds, such as carnauba wax, microcrystalline wax, and triglycerides.

In a matrix controlled release system, the desired release kinetics can be controlled, for example, by the type of polymer used, the viscosity of the polymer, the particle sizes of the polymer and / or the active ingredient (s), the proportion of the active ingredients versus the polymer, and other excipients or carriers in the compositions.

The pharmaceutical compositions provided herein in a modified release dosage form can be prepared by methods known to those of skill in the art, including direct compression, dry or wet granulation followed by compression, and melt granulation followed by compression. . 2. Osmotic Controlled Release Devices The pharmaceutical compositions provided herein in a modified release dosage form can be manufactured using an osmotic controlled release device, including, but not limited to, one-chamber system, two-chamber system, asymmetric membrane technology (AMT). ), and extrusion core system (ECS). In general, such devices have at least two components: (a) a core containing an active ingredient; and (b) a semipermeable membrane with at least one supply port, which encapsulates the core. The semipermeable membrane controls the influx of water to the core from an aqueous environment of use in a manner that causes release of the drug by extrusion through the supply port (s).

In addition to the active ingredient (s), the nucleus of the osmotic device optionally includes an osmotic agent, which creates a driving force for transporting water from the environment of use in the core of the device. One class of osmotic agents are hydrophilic water-swellable polymers, which are also referred to as "osmopolymers" and "hydrogels". Water-swellable hydrophilic polymers suitable as osmotic agents include, but are not limited to, hydrophilic and acrylic vinyl polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly (2-hydroxyethyl methacrylate), poly (acrylic acid), poly (metracrylic) 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 blocks of PEO, croscarmellose sodium, carrageenan, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC) and carboxyethylcellulose (CEC), alginate sodium, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate.

The other classes of osmotic agents are osmogens, which are capable of being impregnated with water to affect an osmotic pressure gradient across the surrounding coating barrier. Suitable osmogens include, but are not limited to, inorganic salts, such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphates, sodium carbonate, sulfite sodium, 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.

Osmotic agents of different dissolution index can be used to influence how quickly the active ingredients are initially supplied from the dosage form. For example, amorphous sugars, such as MAN OGEM ™ EZ (SPI Pharma, Lewes, GERMANY) can be used to provide a faster delivery during the first couple of hours to quickly produce the desired therapeutic effect, and gradually and continuously release the remaining amount to maintain the desired level of prophylactic therapeutic effect over an extended period of weather. In this case, the active ingredient (s) are released such as the index to replace the amount of the metabolized and excreted active ingredient.

The core may also include a wide variety of other excipients and carriers as described herein to improve the performance of the dosage form or to promote stability or processing.

The materials useful in the formation of semipermeable membrane include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulose derivatives that are water permeable and insoluble to water at physiologically relevant pHs, or are susceptible to becoming insoluble to water by alteration. chemical, such as crosslinking. Examples of suitable polymers use coating formation, include plasticized, unplasticized, and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), ethyl carbamate of CA, CAP, methyl carbamate of CA, succinate of CA, trimellitate of cellulose acetate (CAT), dimethylaminoacetate of CA, ethyl carbonate of CA, chloroacetate of CA, oxalate of ethyl of CA, sulfonate of methyl of CA, CA butyl sulfonate, CA p-toluene sulfonate, agar acetate, amylose triacetate, beta-glucan acetate, beta-glucan triacetate, acetaldehyde dimethylacetate, apricot gum triacetate, hydroxylated ethylene-vinylacetate, EC copolymers, PEG, PPG, PEG / PPG, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly (acrylic) acids and poly (methacrylic) esters and 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.

The 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 described in U.S. Patent No. 5,798,119. Such hydrophobic but water vapor permeable membranes are typically composed of hydrophobic polymers such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidene fluoride, esters and ethers. of polyvinyl, natural waxes, and synthetic waxes.

The supply port (s) in the semipermeable membrane can be formed after the coating by mechanical perforation or laser. The one or the luminaries of The supply 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 during an indentation in the core. In addition, the supply ports may be formed during the coating process, as in the case of asymmetric membrane coatings of the type described in U.S. Patent Nos. 5,612,059 and 5,698,220.

The total amount of active ingredients released and the rate of release can be modulated substantially by the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size, and position of the delivery ports.

The pharmaceutical compositions in an osmotic controlled release dosage form may further comprise additional conventional excipients or carriers as described herein to promote the operation or processing of the formulation.

Osmotic controlled release dosage forms can be prepared according to conventional methods and techniques known to those of skill in the art (see, Remington: The Science and Practice of Pharmacy, supra; Santus and Baker, J. Controlled Relay 1995, 35). , 1-21; Verma et al., Drug Development and Industrial Pharmacy 2000, 26, 695-708; Verma et al., J. Controlled Release 2002, 79, 7-27).

In certain embodiments, the pharmaceutical compositions provided herein are formulated as controlled release dosage forms of AMT, comprising an asymmetric osmotic membrane that coats a core comprising the active ingredient (s) and other pharmaceutically acceptable carriers or excipients. See, U.S. Patent No. 5,612,059 and WO 2002/17918. The controlled release dosage forms of AMT 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.

In certain embodiments, the pharmaceutical compositions provided herein are formulated as a controlled release dosage form ESC, which comprises an osmotic membrane that coats a core comprising the active ingredients, a hydroxyethyl cellulose, and other pharmaceutically acceptable carriers or excipients. 3. Control Devices Multiparticulate Control The pharmaceutical compositions provided herein in a modified release dosage form can be manufactured as a delivery device. controlled release of multiparticles, comprising a multiplicity of particles, granules, or pellets, ranging from about 10 and m to about 3 mm, from about 50 μp to about 2.5 mm, or from about 100 pm to about of 1 mm in diameter. Such multiparticles can be made by the process known to those skilled in the art, including wet and dry granulation, extrusion / spheronization, roll compaction, melt solidification, and spray coated seed cores. See, for example, Multiparticulate Oral Drug Delivery, Marcel Dekker: 1994; and PharmaceuCical PelletizaCion Technology; Marcel Dekker: 1989.

Other excipients or carriers as described herein may be mixed with the pharmaceutical compositions to aid in the processing and formation of multiparticles. The resulting particles can by themselves constitute the multiparticulate device or can be coated by various materials forming the film, such as enteric polymers, water-swellable polymers, and water-soluble. The multiparticulas can also be processed as a capsule or a tablet. 4. Directed Supply The pharmaceutical compositions provided herein may also be formulated to be directed to a particular tissue, receptor, or other area of the body of the subject to be treated, which includes liposome, re-erythrocyte, and antibody-based delivery systems. Examples include, but are not limited to, those described in U.S. Patent Nos. 6,316,652; 6,274,552; 6,271,359; 6,253,872; 6,139,865; 6,131,570; 6,120,751; 6,071,495; 6,060,082; 6,048,736; 6,039,975; 6,004,534; 5,985,307; 5,972,366; 5,900,252; 5,840,674; 5,759,542; and 5, 709, 874.

Methods of Use In one embodiment, a method of treating a proliferative disease in a subject is provided herein, comprising administering to the subject a therapeutically effective amount of (i) a taxane; and (ii) an indazolylaminopyrrolotriazine provided therein, for example, a compound of Formula I or II, which includes a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In certain embodiments, the combination of the taxane and indazolylaminopyrrolotriazine has a synergistic effect when compared to administration of the taxane or indazolylaminopyrrolotriazine alone.

In another embodiment, the method further comprises administering to the subject a therapeutically effective amount of a platinum-based agent. In certain embodiments, the platinum-based agent is cisplatin, carboplatin, oxaliplatin, satraplatin (JM-216), or CI-973. In certain embodiments, the platinum-based agent is carboplatin. In certain embodiments, the combination of the taxane, the platinum-based agent, and the indazolylaminopyrrolotriazine have a synergistic effect when compared to the administration of the combination of taxane and platinum-based agent, or indazolylaminopyrrolotriazine alone.

In certain embodiments, the indazolylaminopyrrolotriazine provided herein, for example, an indazolylaminopyrrolotriazine of Formula I or II, including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; It is administered once a day. In certain embodiments, the indazolylaminopyrrolotriazine provided herein, for example, an indazolylaminopyrrolotriazine of Formula I or II, including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; It is administered once a day with food. In certain embodiments, the indazolylaminopyrrolotriazine provided herein, for example, an indazolylaminopyrrolotriazine of Formula I or II, which includes a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; It is administered twice a day. In certain embodiments, the indazolylaminopyrrolotriazine provided herein, for example, an indazolylaminopyrrolotriazine of Formula I or II, including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; It is administered twice a day with food.

In certain embodiments, the indazolylaminopyrrolotriazine 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.

In certain embodiments, the indazolylaminopyrrolotriazine 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 indazolylaminopyrrolotriazine provided herein is administered to the subject in the amount of from about 1, from about 2, from about 3, from about 4, from about 5, from about 6, to about 7, from around 8, from around 9, from around 10, from around 15, from around 20, from around 25, from around 30, from around 35, from around 40 to around 50, from around 60, from around 70, from around 75, from around 80, from around 90, from around 100, from around 105, from around 120, from around 130, to around 140, from around 150, from around 160, from around 170, from around 180, from around 190, from around 200, from around 300, from around 400, from around 500, to around 600, of about 700, about 750, about 800, about 900, or about 1,000 mg / kg / day.

The administered dose of the indazolylaminopyrrolotriazine provided herein may also be expressed in units other than the unit "mg / kg / day". For example, the dose for parenteral administration can be expressed as mg / m2 / day. Someone with ordinary skill in the art can easily know how to convert the dose from mg / kg / day to mg / m2 / day to give already be the height or the 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.

In certain embodiments, the indazolylaminopyrrolotriazine provided herein is administered to the subject in the amount ranging from about 1 to about 1,500 mg / m2 / day, from 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 / m / day. In certain embodiments, the indazolylaminopyrrolotriazine provided herein is administered to the subject in the amount of from about 10, from about 20, from about 30, from about 40, from about 50, to about 60, from about 70, from around 80, from around 90, from around 100, from around 110, from around 120, from around 130, from around 134, from around 140, to around 150, from around 160, from around 170, from around 180, from around 190, from around 200, from around 210, from around 220, from around 230, from around 240, from around 250, to around 260, about 270, about 280, about 290, or about 300 mg / m2 / day.

In one embodiment, the indazolylaminopyrrolotriazine provided herein, for example, an indazolylaminopyrrolotriazine of Formula I or II, which includes a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; it is administered daily in a single dose or divided doses, where the total two daily varies from about 1 mg to about 2,000 mg, from about 10 mg to about 1,600 mg, from 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, of 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 around from 350 mg to around 600 mg.

In another embodiment, the indazolylaminopyrrolotriazine provided herein, for example, an indazolylaminopyrrolotriazine of Formula I or II, which includes a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; It is administered daily in a single dose or dose divided 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.

In yet another embodiment, the indazolylaminopyrrolotriazine provided herein, for example, an indazolylaminopyrrolotriazine of the Formula 1 or II, which includes a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; they are administered daily in a single dose or divided doses (eg, BID) for a total daily dose of about 10 mg, of about 30 mg, of about 65 mg, of about 100 mg, of about 200 mg, of about 250 mg, of about 300 mg, of about 320 mg, of about 400 mg, of about 480 mg, of about 500 mg, of about 600 mg, of about 660 mg, of about 700 mg, of about 800 mg, of about 900 mg, of about 1,000 mg, of about 1,200 mg , about 1,400 mg, or about 1,600 mg.

In certain embodiments, the indazolylaminopyrrolotriazine provided herein, for example, an indazolylaminopyrrolotriazine of Formula I or II, including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; is administered daily in a single dose or divided doses for a total daily dose sufficient to achieve a plasma concentration of the compound in a stable state ranging from about 0.5 μ? at around 40 μ ?, of about 1 μ? to about 30 μ ?, of about 5 μ? to around 25 μ? or about 10 μ? at around 20 μ ?; in a mode, from about 1 μ ?, of about 2 μ ?, of about 5 μ ?, of about 10 μ ?, of about 15 μ ?, of about 30 μ ?, of about 40 μ ?, or around 50 μ ?. As used herein, the term "steady state plasma concentration" is the concentration reached after a period of administration of a compound. Once the steady state is reached, there are minor peaks and depressions in the time-dependent curve of the plasma concentration of the compound.

In certain embodiments, the indazolylaminopyrrolotriazine provided herein, for example, an indazolylaminopyrrolotriazine of Formula I or II, including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; administered daily in a single dose or divided doses for a total daily dose calculated to achieve a plasma concentration of the compound in a stable state that varies from about 0.5 μ? to about 40 μ, of about 1 μ? to about 30 μ ?, of about 5 μ? to around 25 μ? or about 10 μ? at around 20 μ ?; in a mode, from about 1 μ ?, of about 2 μ ?, of about 5 μ ?, of about 10 μ ?, of about 15 μ ?, of about 30 μ ?, of about 40 μ ?, or around 50 μ ?.

In certain embodiments, the indazolylaminopyrrolotriazine provided herein, for example, an indazolylaminopyrrolotriazine of Formula I or II, including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; 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 100 μ, from about 0.2 to about 50 μ ?, from about 0.4 to about 40 μ? , from about 0.5 to about 10 μ ?, from about 5 to about 40 μ ?, from about 10 to about 40 μ ?, from about 0.4 to about 4.5 μ ?, or about 3.5 to about 6 μ?, - in a mode, of about 0.1 μ ?, 0.2 μ ?, of about 0.3 μ ?, of about 0.4 μ ?, of about 0.5 μ ?, 0.6 μ ?, of around of 0.7 μ ?, 0.8 μ ?, of about 0.9 μ ?, from about 1 μ ?, of about 2 μ ?, of about 3 μ ?, of about 4 μ ?, of about 5 μ ?, of about 6 μ ?, 7 μ ?, of about 8 μ ?, 9 μ ?, of about 10 μ ?, of about 15 μ ?, of about 20 μ ?, of about 30 μ ?, of about 40 μ ?, of about 50 μ ?.

In certain embodiments, the indazolylaminopyrrolotriazine provided herein, for example, an indazolylaminopyrrolotriazine of Formula I or II, which includes a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, - or a salt, solvate, hydrate, or pharmaceutically acceptable prodrug thereof; is administered in a single dose or divided doses for a total daily dose calculated to achieve a Cmax of about 0.1 to about 100 μ ?, of about 0.2 to about 50 μ ?, of about 0.4 to about 40 μ ?, from about 0.5 to about 10?, from about 5 to about 40?, from about 10 to about 40?, from about 0.4 to about 4.5?, or from about 3.5 to about 6 μ?, - in a mode, of about 0.1 μ ?, 0.2 μ ?, of about 0.3 μ ?, of about 0.4 μ ?, of about 0.5 μ ?, 0.6 μ ?, of about 0.7 μ ?, 0.8 μ ?, of about 0.9 μ ?, of about 1 μ ?, of about 2 μ ?, of about 3 μ ?, of about 4 μ ?, of about 5 μ ?, from around of 6 μ ?, 7 μ, of about 8 μ ?, 9 μ ?, of about 10 μ ?, of about 15 μ ?, of about 20 μ, of about 30 μ ?, of about 40 μ ?, of around 50 μ ?.

In certain embodiments, the indazolylaminopyrrolotriazine provided herein, for example, an indazolylaminopyrrolotriazine of Formula I or II, including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; 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, from about 0.2 to about 40 μg / mL, from about 2 to about 20 μ? / ???, ,, from about 1.5 to about 3.2 μg / mL, or about 0.2 to about 2.2 g / mL.

In certain embodiments, the indazolylaminopyrrolotriazine provided herein, for example, an indazolylaminopyrrolotriazine of Formula I or II, including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; is administered in a single dose or divided doses for a total daily dose calculated to achieve a Cmax of about 0.1 to about 50 μg / mL, about 0.2 to about 40 pg / mL, about 2 to about 20 pg / mL, about 1.5 to about 3.2 pg / mL, or about 0.2 to about 2.2 pg / mL.

In certain embodiments, the indazolylaminopyrrolotriazine provided herein, for example, an indazolylaminopyrrolotriazine of Formula I or II, including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; is administered in a single dose or divided doses for a total daily dose sufficient to achieve an AUC of about 1 to about 500, from about 5 to about 400, from about 60 to about 500, of about 125 to about 500, from about 125 to about 300, from 125 to about 200, from about 4 to about 35, or from about 40 to about 55 pg * hr / mL.

In certain embodiments, the indazolylaminopyrrolotriazine provided herein, for example, an indazolylaminopyrrolotriazine of Formula I or II, including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; is administered in a single dose or divided doses for a total daily dose calculated to achieve an AUC of about 1 to about 500, from about 5 to about 400, from about 60 to about 500, from about 125 to about 500, from about 125 to about 300, from 125 to about 200, from about 4 to about 35, or from about 40 to about 55 pg * hr / mL.

In certain embodiments, the indazolylaminopyrrolotriazine provided herein, for example, an indazolylaminopyrrolotriazine of Formula I or II, including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; is administered in a single dose or divided doses for a total daily dose sufficient to achieve an AUC of about 5 to about 1,000, from about 125 to about 1,000, from about 250 to about 500, of about 80 to around 110, or from around 5 to around 65 pM * hr.

In certain embodiments, the indazolylaminopyrrolotriazine provided herein, for example, an indazolylaminopyrrolotriazine of Formula I or II, including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; it is administered in a single dose or dose divided for a total daily dose calculated to achieve an AUC of about 5 to about 1,000, from about 125 to about 1,000, from about 250 to about 500, from about 80 to about 110, or around from 5 to around 65 pM * hr.

Depending on the disease to be treated and the conditions of the subject, the indazolylaminopyrrolotriazine provided herein, for example, an indazolylaminopyrrolotriazine of Formula I or II, which includes a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers of the same; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; can be administered by oral, parenteral (eg, intramuscular, intraperitoneal, intravenous, CIV, injection or intrasystemic infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical routes (eg, transdermal) or local). The indazolylaminopyrrolotriazine provided herein may be formulated, alone or in combination, in appropriate dosage units with pharmaceutically acceptable carrier excipients, adjuvants and vehicles appropriate for each route of administration.

The indazolylaminopyrrolotriazine provided herein, for example, an indazolylaminopyrrolotriazine of Formula I or II, which includes a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; they may be delivered as a single dose such as, for example, a single bolus injection, or oral tablet or pill; or during the time such as, for example, continuous infusion over time or bolus dose divided over time.

The indazolylaminopyrrolotriazine provided herein, for example, an indazolylaminopyrrolotriazine of Formula I or II, which includes a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; it 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, that is, every day, or intermittently. The term "intermittent" or "intermittently" as used herein is intended to mean the arrest and start at either regular or irregular intervals. For example, intermittent administration of the compound 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 period of Rest without administration for a week, or administration on alternate days.

In certain embodiments, the frequency of administration of the indazolylaminopyrrolotriazine is in the range of about one daily dose to about one dose per month. In certain modalities, the administration of indazolylaminopyrrolotriazine is once a day, twice a day, three times a day, four times a day, once every third day, twice a week, once a week, once every two days. weeks, once every three weeks, or once every four weeks. In one embodiment, the indazolylaminopyrrolotriazine provided herein is administered once a day. In other embodiments, the indazolylaminopyrrolotriazine provided herein is administered twice daily. In yet another embodiment, the indazolylaminopyrrolotriazine provided herein is administered three times a day. In yet another embodiment, the indazolylaminopyrrolotriazine provided herein is administered four times a day.

In certain embodiments, the indazolylaminopyrrolotriazine is administered weekly. In certain embodiments, the indazolylaminopyrrolotriazine is administered on days 1, 8, and 15 in a 28-day cycle. In certain embodiments, the indazolylaminopyrrolotriazine is administered on days 1, 8, and 15 in a 21-day cycle. In In certain embodiments, indazolylaminopyrrolotriazine is administered on days 2, 9, and 16 in a 28-day cycle. In certain embodiments, the indazolylaminopyrrolotriazine is administered on days 2, 9, and 16 in a 21-day cycle. In certain embodiments, the indazolylaminopyrrolotriazine is administered on days 3, 10, and 17 in a 28-day cycle. In certain embodiments, the indazolylaminopyrrolotriazine is administered on days 3, 10, and 17 in a 21-day cycle.

In certain embodiments, the indazolylaminopyrrolotriazine is administered twice a week. In certain embodiments, the indazolylaminopyrrolotriazine is administered on days 1, 2, 8, 9, 15, and 16 in a 21-day cycle. In certain embodiments, the indazolylaminopyrrolotriazine is administered on days 1, 2, 8, 9, 15, and 16 in a 28-day cycle. In certain embodiments, the indazolylaminopyrrolotriazine is administered on days 2, 3, 9, 10, 16, and 17 in a 21-day cycle. In certain embodiments, the indazolylaminopyrrolotriazine is administered on days 2, 3, 9, 10, 16, and 17 in a 28-day cycle. In certain embodiments, the indazolylaminopyrrolotriazine is administered on days 4, 5, 11, 12, 18, and 19 in a 21 day cycle. In certain embodiments, the indazolylaminopyrrolotriazine is administered on days 4, 5, 11, 12, 18, and 19 in a 28-day cycle.

In certain embodiments, the indazolylaminopyrrolotriazine is administered for 7 days in a 21-day cycle. In certain embodiments, the indazolylaminopyrrolotriazine is administered for 7 days in a 28-day cycle. In certain embodiments, the indazolylaminopyrrolotriazine is administered daily for three weeks, followed by a week's rest in a 28-day cycle. In certain embodiments, the indazolylaminopyrrolotriazine is administered daily, uninterruptedly for 4 weeks in a 28-day cycle. In certain embodiments, the indazolylaminopyrrolotriazine is administered on days 1 and 2 in a 21-day cycle.

In certain modalities, the taxane is administered every three weeks. In certain modalities, the taxane is administered every two weeks. In certain modalities, the taxane is administered every week. In certain modalities, the taxane is administered on days 1, 8, and 15 in a 28-day cycle. In certain modalities, the taxane is administered on days 1, 8, and 15 in a 21-day cycle. In certain modalities, the taxane is administered on days 3, 10, and 17 in a 28-day cycle. In certain modalities, the taxane is administered on days 3, 10, and 17 in a 21-day cycle. In certain embodiments, the taxane is administered for 7 days in a 21-day cycle.

In certain modalities, paclitaxel is administered every three weeks. In certain modalities, paclitaxel is administered every two weeks. In certain modalities, paclitaxel is given every week. In certain modalities, paclitaxel is administered on days 1, 8, and 15 in a 28-day cycle. In certain modalities, paclitaxel is administered on days 1, 8, and 15 in a 21-day cycle. In certain modalities, paclitaxel is administered on days 3, 10, and 17 in a 28-day cycle. In certain modalities, paclitaxel is administered on days 3, 10, and 17 in a 21-day cycle. In certain modalities, paclitaxel is administered for 7 days in a 21-day cycle.

In certain embodiments, the taxane is administered intravenously for 1 hour. In certain embodiments, the taxane is administered intravenously for 30 minutes. In certain embodiments, the taxane is administered intravenously for 3 hours. In certain embodiments, the taxane is administered intravenously for 24 hours. In certain embodiments, paclitaxel is administered intravenously for 3 hours. In certain embodiments, paclitaxel is administered intravenously for 24 hours. In certain embodiments, docetaxel is administered intravenously for 1 hour. In certain embodiments, carboplatin is administered intravenously for 30 minutes.

In one embodiment, intravenous administration of the compound of Formula I occurs prior to administration intravenous administration of paclitaxel. In one embodiment, intravenous administration of the compound of Formula I occurs two days before the intravenous administration of paclitaxel. In one embodiment, intravenous administration of the compound of Formula I occurs one day prior to intravenous administration of paclitaxel. In one embodiment, intravenous administration of the compound of Formula I occurs on the same day as intravenous administration of paclitaxel.

In yet another embodiment, intravenous administration of the compound of Formula I occurs after intravenous administration of paclitaxel. In yet another embodiment, intravenous administration of the compound of Formula I occurs one day after intravenous administration of paclitaxel. In yet another embodiment, intravenous administration of the compound of Formula I occurs two days after intravenous administration of paclitaxel.

In certain embodiments, the taxane provided herein is administered to the subject in a single dose or divided dose for a total daily dose ranging from about 10 to about 1,000 mg / m2, from about 20 to about 500 mg / m2, from about 50 to 250 mg / m2, from about 110 to about 200 mg / m2, from about 60 to about 175 mg / m2, from about 60 to about 100 mg / m2, or from around 80 to around 90 mg / m2. In certain embodiments, the taxane provided herein is administered to the subject in a single dose or divided doses for a total daily dose in the amount of about 60, from about 75, from about 80, to about 90, from about 100, about 135, about 150, about 175, about 250 mg / m2, or about 260 mg / m2. In certain embodiments, the taxane provided herein is administered to the subject in a single dose or divided doses for a total daily dose in the amount of about 60, from about 75, from about 80, to about 90, from around 100, from around 135, from around 150, from around 170, from around 175, from around 200, from around 210, from around 225, from around 250, to 255, from around 260 , around 275, around 280 or about 300 mg / m2.

In certain embodiments, paclitaxel is administered intravenously to the subject in the amount of 250 mg / m2 for 3 hours. In certain embodiments, paclitaxel is administered intravenously to the subject in the amount of 250 mg / m2 for 24 hours. In certain embodiments, paclitaxel is administered intravenously to the subject in the amount of 175 mg / m2 for 3 hours. In certain embodiments, paclitaxel is administered intravenously to the subject in the amount of 175 mg / m2 for 24 hours. In certain embodiments, paclitaxel is administered intravenously to the subject in the amount of 150 mg / m2 for 3 hours. In certain embodiments, paclitaxel is administered intravenously to the subject in the amount of 150 mg / m2 for 24 hours. In certain embodiments, paclitaxel is administered intravenously to the subject in the amount of 135 mg / m2 for 3 hours. In certain embodiments, paclitaxel is administered intravenously to the subject in the amount of 135 mg / m2 for 24 hours. In certain embodiments, paclitaxel is administered intravenously to the subject in the amount of 100 mg / m2 for 3 hours. In certain embodiments, paclitaxel is administered intravenously to the subject in the amount of 100 mg / m2 for 24 hours. In certain embodiments, paclitaxel is administered intravenously to the subject in the amount of 80 to 90 mg / m2 for 3 hours. In certain embodiments, paclitaxel is administered intravenously to the subject in the amount of 80 to 90 mg / m2 for 24 hours. In certain embodiments, paclitaxel is administered intravenously to the subject in the amount of 90 mg / m2 for 3 hours. In certain embodiments, paclitaxel is administered intravenously to the subject in the amount of 90 mg / m2 for 24 hours. In certain embodiments, paclitaxel is administered intravenously to the subject in the amount of 80 mg / m2 for 3 hours. In certain embodiments, paclitaxel is administered intravenously to the subject in the amount of 80 mg / m2 for 24 hours.

In certain embodiments, paclitaxel is administered intravenously to the subject in the amount of 175 mg / m2 for 3 hours every three weeks. In certain embodiments, paclitaxel is administered intravenously to the subject in the amount of 100 mg / m2 for 3 hours every two weeks. In certain embodiments, paclitaxel is administered intravenously to the subject in the amount of 135 mg / m2 for 3 hours. In certain embodiments, paclitaxel is administered intravenously to the subject in the amount of 80 to 90 mg / m2 each week. In certain embodiments, paclitaxel is administered intravenously to the subject in the amount of 80 mg / m2 each week. In certain embodiments, paclitaxel is administered intravenously to the subject in the amount of 80 mg / m2 on days 1, 8, and 15 every 28 days.

In certain embodiments, paclitaxel is administered intravenously to the subject in the amount of 30 mg / m2 or 40 mg / m2 in the five consecutive days.

In certain embodiments, albumin bound paclitaxel is administered intravenously to the subject in the amount of 100 mg / m2 every 28 days. In certain embodiments, paclitaxel bound to albumin is intravenously administered to the subject in the amount of 150 mg / m2 on days 1, 8, and 15 every 28 days. In certain modalities, the Albumin-bound paclitaxel is administered intravenously to the subject in the amount of 260 mg / m2 every 21 days. In certain embodiments, paclitaxel bound to albumin is intravenously administered to the subject in the amount of 110-200 mg / m2.

In certain embodiments, paclitaxel is administered intravenously for 1 hour. In certain embodiments, paclitaxel is administered intravenously for 1-2 hours. In certain embodiments, paclitaxel is administered intravenously for 2 hours. In certain embodiments, paclitaxel is administered intravenously for 6 hours. In certain embodiments, paclitaxel is administered intravenously for 24 hours.

In certain embodiments, docetaxel is administered intravenously to the subject for 1 hour. In certain embodiments, docetaxel is administered intravenously to the subject every three weeks. In certain embodiments, docetaxel is administered intravenously to the subject for 1 hour every three weeks. In certain embodiments, docetaxel is administered intravenously to the subject in the amount of 60 to 100 mg / m2. In certain embodiments, docetaxel is administered intravenously to the subject in the amount of 60 to 125 mg / m2. In certain embodiments, docetaxel is administered intravenously to the subject in the amount of 60 mg / m. In certain modalities, docetaxel is administered intravenously to the subject in the amount of 70 mg / m2. In certain embodiments, docetaxel is administered intravenously to the subject in the amount of 75 mg / m2. In certain embodiments, docetaxel is administered intravenously to the subject in the amount of 90 mg / m2. In certain embodiments, docetaxel is administered intravenously to the subject in the amount of 100 mg / m2. In certain embodiments, docetaxel is administered intravenously to the subject in the amount of 115 mg / m2. In certain embodiments, docetaxel is administered intravenously to the subject in the amount of 125 mg / m2.

In certain embodiments, docetaxel is administered intravenously to the subject in the amount of 60, 70 or 75 mg / m2 once every three weeks. In certain embodiments, docetaxel is administered intravenously to the subject in the amount of 60, 70 or 75 mg / m2 once every two weeks. In certain embodiments, docetaxel is administered intravenously to the subject in the amount of 60, 70 or 75 mg / m2 once per week. In certain modalities, docetaxel is administered on day 2 in a 21-day cycle.

In certain embodiments, docetaxel is administered intravenously to the subject in the amount of 50 mg / m2 on days 1 and 8 every 21 days. In certain embodiments, docetaxel is administered intravenously to the subject in the amount of 50 mg / m2 on days 1 and 8 every 30 days. In certain modalities, docetaxel is administered intravenously to the subject in the amount of 50 mg / m2 on days 1 and 8 each month.

In certain embodiments, docetaxel is administered intravenously to the subject in the amount of 14 mg / m2 for 5 consecutive days.

In certain embodiments, the indazolylaminopyrrolotriazine is administered intravenously to the subject on days 1 and 2 every 21 days. In certain embodiments, docetaxel is administered intravenously to the subject once on day 2 every 21 days. In certain embodiments, the indazolylaminopyrrolotriazine is administered intravenously to the subject in the amount of about 20, about 30, about 40, about 80, about 134, about 200, or about 280 mg /. m / day on days 1 and 2 every 21 days. In certain embodiments, docetaxel is administered intravenously to the subject in the amount of about 60 or about 75 mg / m / day on day 2 every 21 days.

In certain embodiments, the indazolylaminopyrrolotriazine is administered intravenously to the subject on days 1 and 2, and docetaxel is administered intravenously to the subject once on day 2, both administered every 21 days. In certain embodiments, the indazolylaminopyrrolotriazine is administered intravenously to the subject in the amount of about 20, about 30, about 40, about 80, about 134, about 200, or about 280 mg / m2 / day on days 1 and 2, and docetaxel is administered intravenously to the subject in the amount of around 60 or about 75 mg / m2 / day on day 2, both administered every 21 days.

In certain embodiments, docetaxel is administered intravenously for 1 hour. In certain embodiments, docetaxel is administered intravenously for 1-2 hours. In certain embodiments, docetaxel is administered intravenously for 2 hours. In certain embodiments, docetaxel is administered intravenously for 6 hours. In certain embodiments, docetaxel is administered intravenously for 24 hours. In certain embodiments, the indazolylaminopyrrolotriazine is administered intravenously for 30 minutes. In certain embodiments, docetaxel is administered immediately after indazolylaminopyrrolotriazine on day 2.

In one embodiment, the method comprises an oral administration of an indazolylaminopyrrolotriazine provided herein in accordance with a regimen selected from: to. 600 mg / day for 21 days; b. 600 mg / day for 28 days; Y c. 400 mg / day for 21 days; and an intravenous administration of a taxane according to a regime selected from: i. 260 mg / m2 for 24 hours ii. 250 mg / m2 for 24 hours iii. 200 mg / m2 for 24 hours iv. 185 mg / m2 for 3 hours; v. 185 mg / m2 for 24 hours; saw. 175 mg / m2 for 3 hours; vii. 175 mg / m2 for 24 hours; viii. 150 mg / m2 for 3 hours; ix. 150 mg / m2 for 24 hours; x. 135 mg / m2 for 3 hours; xi. 135 mg / m2 for 24 hours; xii. 100 mg / m2 for 3 hours; xiii. 80-90 mg / m2; xiv. 80 mg / m2; xv. 30 mg / m2; Y xvi. 20 mg / m2; wherein the indazolylaminopyrrolotriazine and the taxane are administered simultaneously and concurrently, separately, or sequentially.

In another embodiment, the method comprises an oral or intravenous administration of an indazolylaminopyrrolotriazine provided herein in accordance with a regimen selected from: to. 600 mg / day for 21 days; b. 600 mg / day for 28 days; c. 400 mg / day for 21 days; Y d. 40 to 300 mg / m2 / day; and an intravenous administration of a taxane according to a regimen selected from: i. 260 mg / m2 for 24 hours; ii. 250 mg / m2 for 24 hours; iii. 200 mg / m2 for 24 hours; vii. 185 mg / m2 for 3 hours; viii. 185 mg / m2 for 24 hours; xix. 175 mg / m2 for 3 hours; XX. 175 mg / m2 for 24 hours; xxi. 150 mg / m2 for 3 hours; xxii. 150 mg / m2 for 24 hours; xxiii. 135 mg / m2 for 3 hours; xxi. 135 mg / m2 for 24 hours; XXV. 100 mg / m2 for 3 hours; xxvi. 100 mg / m2 for 1 hour; xxvii. 80-90 mg / m2; xxviii. 80 mg / m2; xxi. 30 mg / m2; xxx 20 mg / m2; xxxi. 60 to 125 mg / m2 / day; Y xxxii. 135 to 250 mg / m2 / day; where the indazolylaminopyrrone Taxane is administered simultaneously and concurrently, separately, or sequentially.

In yet another embodiment, the method comprises an intravenous administration of an indazolylaminopyrrolotriazine provided herein in accordance with a regimen selected from: to . 20: mg / m2 on days 1 and 2 b. 30: mg / m2 on days 1 and 2 c. 40 mg / m2 on days 1 and 2 d. 80 mg / m2 on days 1 and 2 e. 100 mg / m2 on days i and f. 134 mg / m2 on days i and g- 135 mg / m2 on days i and h. 150 mg / m2 on days i and i. 200 mg / m2 on days i and j| 250 mg / m2 on days i and k. 275 mg / m2 on days i and 1. 280 mg / m2 on days i and m. 300 mg / m2 on days i and n. 40 to 300 mg / m2 / day; and an intravenous administration of a taxane according to a regimen selected from: i. 260 mg / m2 for 24 hours; ii. 250 mg / m2 for 24 hours; iii. 200 mg / m2 for 24 hours; iv. 185 mg / m2 for 3 hours; V. 185 mg / m2 for 24 hours; saw . 175 mg / m2 for 3 hours, - vii. 175 mg / m2 for 24 hours; viii. 150 mg / m2 for 3 hours; i. 150 mg / m2 for 24 hours; X 135 mg / m2 for 3 hours; xi. 135 mg / m2 for 24 hours; xii. 100 mg / m2 for 3 hours; xiii. 100 mg / m2 for 1 hour; xiv. 80-90 mg / m2; XV 80 mg / m2; xvi. 75 mg / m2; xvii. 70 mg / m2; xviii. 65 mg / m2; xi. 60 mg / m2; XX. 50 mg / m2; xxi. 30 mg / m2; xxii. 20 mg / m2; xxiii. 60 to 125 mg / m2 / day; Y xxiv. 135 to 250 mg / m2 / day; wherein the indazolylaminopyrrolotriazine and the taxane are administered simultaneously and concurrently, separately, or sequentially.

In yet another embodiment, the method comprises a administration of an indazolylaminopyrrolotriazine provided herein according to a regimen selected from: to. a sufficient dose to achieve a Cmax of around 5 to about 40 μ ?; b. a sufficient dose to achieve a Cmax of around 10 to about 40 μ ?; c. a sufficient dose to achieve a Cmax of around 2 to around 20 pg / mL; d. a sufficient dose to achieve a Cmax of around 3.5 to about ß μ; and. a sufficient dose to achieve a Cmax of around 0.4 to about 4.5 μ ?; F. a sufficient dose to achieve a Cmax of around 1.5 to about 3.2 pg / mL; Y g. a sufficient dose to achieve a Cmax of around 0.2 to around 2.2 μg / mL, · and an intravenous administration of a taxane according to a regimen selected from: i. 260 mg / m2 for 24 hours; ii. 250 mg / m2 for 24 hours; iii. 200 mg / m2 for 24 hours; iv. 185 mg / m2 for 3 hours; v. 185 mg / m2 for 24 hours; saw. 175 mg / m2 for 3 hours; vii. 175 mg / m2 for 24 hours; viii. 150 mg / m2 for 3 hours; i. 150 mg / m2 for 24 hours; X 135 mg / m2 for 3 hours; xi. 135 mg / m2 for 24 hours; xii. 100 mg / m2 for 3 hours; xiii. 80-90 mg / m2; xiv. 80 mg / m2; XV 30 mg / m2; xvi. 20 mg / m2; Y xvii. 60 to 100 mg / m2 / day; where the indazolylaminopyrrone Taxanes are administered simultaneously and concurrently, separately, or sequentially.

In yet another embodiment, the method comprises an intravenous administration of an indazolylaminopyrrolotriazine provided herein in accordance with a regimen selected from: to. a sufficient dose to achieve an AUC of around 60 to about 500 and g * hr / mL; b. a sufficient dose to achieve an AUC of around 125 to about 500 pg * hr / mL; c. a sufficient dose to achieve an AUC of around 125 to about 300 pg * hr / mL; d. a sufficient dose to achieve an AUC of around 125 to about 200 and g * hr / mL; and. a sufficient dose to achieve an AUC of about 125 to about 1,000 pM * hr; F. a sufficient dose to achieve an AUC of around 250 to about 500 M * hr; g. a sufficient dose to achieve an AUC of around 4 to about 35 g * hr / mL; Y h. a sufficient dose to achieve an AUC of around 40 to about 55 pg * hr / mL; and an intravenous administration of a taxane according to a regimen selected from: i. 260 mg / m2 for 24 hours; ii. 250 mg / m2 for 24 hours; iii. 200 mg / m for 24 hours; iv. 185 mg / m2 for 3 hours; V. 185 mg / m2 for 24 hours; saw . 175 mg / m2 for 3 hours; vii. 175 mg / m2 for 24 hours; viii. 150 mg / m2 for 3 hours; ix. 150 mg / m2 for 24 hours; X 135 mg / m2 for 3 hours; xi. 135 mg / m2 for 24 hours; ii. 100 mg / m2 for 3 hours; xiii. 80-90 mg / m2; xiv. 80 img / m2; xv. 30 mg / m2; xvi. 20 mg / m2; Y xvii. 60 to 100 mg / m2 / day; wherein the indazolylaminopyrrolotriazine and the taxane are administered simultaneously and concurrently, separately, or sequentially.

In yet another embodiment, the method comprises administering an indazolylaminopyrrolotriazine provided herein in accordance with a regimen selected from: .to. a sufficient dose to achieve a Cmax of around 5 to about 40 μ ?; b. a sufficient dose to achieve a Cmax of around 10 to about 40 μ ?; c. a sufficient dose to achieve a Cmax of around 2 to around 20 pg / mL; d. a sufficient dose to achieve a C max of around 3.5 to about ß pM; and. a sufficient dose to achieve a Cmax of about 0.4 to about 4.5 pM; F. a sufficient dose to achieve a Cmax of around 1.5 to about 3.2 pg / mL; Y g. a sufficient dose to achieve a Cmax of around 0.2 to about 2.2 pg / mL; and an intravenous administration of a taxane according to a regime selected from: i. 20-100 mg / m2; ii. 60 mg / m2; iii. 75 mg / m2; iv. 100 mg / m2; v. 30 mg / m2; saw . 20 mg / m2; Y vii. 60 to 100 mg / m / day; wherein the indazolylaminopyrrolotriazine and the taxane are administered simultaneously and concurrently, separately, or sequentially.

In yet another embodiment, the method comprises an intravenous administration of an indazolylaminopyrrolotriazine provided herein in accordance with a regimen selected from: to. a sufficient dose to achieve an AUC of around 60 to about 500 g * hr / mL; b. a sufficient dose to achieve an AUC of around 125 to about 500 pg * hr / mL; c. a sufficient dose to achieve an AUC of around 125 to about 300 pg * hr / rnL; d. a sufficient dose to achieve an AUC of around 125 to about 200 pg * hr / mL; and. a sufficient dose to achieve an AUC of about 125 to about 1,000 pM * hr; F. a sufficient dose to achieve an AUC of about 250 to about 500 pM * hr; g. a sufficient dose to achieve an AUC of around 4 to about 35 pg * hr / mL; Y h. a sufficient dose to achieve an AUC of around 40 to about 55 pg * hr / mL; and an intravenous administration of a taxane according to a regimen selected from: i. 60-100 mg / m2; ii. 60 mg / m2; iii. 75 mg / m2; Y iv. 100 mg / m2; wherein the indazolylaminopyrrolotriazine and the taxane are administered simultaneously and concurrently, separately, or sequentially.

In yet another embodiment, the method provided herein further comprises an intravenous administration of carboplatin according to a regimen selected from: 1. a sufficient dose to achieve an AUC of around 2 to about 8 mg * min / mL; 2. a sufficient dose to achieve an AUC of around 3 to about 8 mg * min / mL; 3. a sufficient dose to achieve an AUC of around 3 to about 7.5 mg * min / mL; 4. a sufficient dose to achieve an AUC of around 2 mg * min / mL; 5. a sufficient dose to achieve an AUC of around 3 mg * min / mL; 6. a sufficient dose to achieve an AUC of around 5 mg * min / mL; 7. a sufficient dose to achieve an AUC of around 6 mg * min / mL; Y 8. a sufficient dose to achieve an AUC of around 7.5 mg * min / mL; wherein the indazolylaminopyrrolotriazine, taxane, and carboplatin are administered simultaneously and concurrently, separately, or sequentially.

In yet another embodiment, the method provided herein further comprises an intravenous administration of carboplatin according to a regimen selected from: 1. a dose calculated to achieve an AUC of around 2 to about 8 mg * min / mL; 2. a dose calculated to achieve an AUC of around 3 to about 8 mg * min / mL; 3. a dose calculated to achieve an AUC of around 3 to about 7.5 mg * min / mL; 4. a dose calculated to achieve an AUC of around 2 mg * min / mL; 5. a dose calculated to achieve an AUC of around 3 mg * min / mL; 6. a dose calculated to achieve an AUC of around 5 mg * min / mL; 7. a dose calculated to achieve an AUC of around 6 mg * min / mL; Y 8. a dose calculated to achieve an AUC of about 7.5 mg * min / mL; wherein the indazolylaminopyrrolotriazine, taxane, and carboplatin are administered simultaneously and concurrently, separately, or sequentially.

In certain modalities, the subject is a mammal.

In certain modalities, the mammal is a human.

In one embodiment, the proliferative disease is a tumor. In other embodiments, 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 solid metastatic tumor. In yet another modality, the proliferative disease is cancer. In yet another modality, the proliferative disease is advanced cancer. In certain embodiments, the solid tumor is metastatic cancer.

In certain modalities, the tumor overexpresses the HERI protein. In certain modalities, the tumor overexpresses The HER2 protein.

In certain embodiments, cancer treatable with the method provided herein includes, but is not limited to, (1) leukemias, including, but not limited to, acute leukemia, acute myeloid leukemia (AML), acute lymphocytic leukemia, acute myelocytic leukemia such as myeloblastic leukemia, promyelocytic, myelomonocytic, monocytic, erythroleukemia and myelodysplastic syndrome or a symptom thereof (such as anemia, thrombocytopenia, neutropenia, bictopenia or pancytopenia), refractory anemia (RA), RA with ringed sideroblasts (RARS), RA with excess balds (RAEB), RAEB in transformation (RAEB-T), preleukemia, and chronic myelomonocytic leukemia (CMML (2) chronic leukemias, which include, but are not limited to, chronic myelocytic (granulocytic) leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia (CML), and tricyclic leukemia; (3) polycythemia vera; (4) lymphomas, which include, but are not limited to, , Hodgkin's disease and non-Hodgkin's disease; (5) multiple myelomas, which include, but are not limited to, latent multiple myeloma, non-secreting myeloma, osteosclerotic myeloma, leukemia of c plasma cells, solitary plasmacytoma and extramedullary plasmacytoma, (6) aldenstróm macroglobulinemia; (7) monoclonal gammopathy of uncertain 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, bone fibrosarcoma, chordoma, periosteal sarcoma, soft tissue sarcoma , angiosarcoma (hemangiosarcoma), fibrosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, metastatic cancer, neurilemoma, rhabdomyosarcoma, and synovial sarcoma; (11) brain tumors, including, but not limited to, glioma, astrocytoma, brainstem 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 carcinoma (small cell), intraductal carcinoma, medullary breast cancer, mucinous breast cancer, tubular breast cancer, breast papillary cancer, cancers primary, Paget's disease, and inflammatory breast cancer (13); adrenal cancer, including, but not limited to, pheochromocytoma and adrenocortical carcinoma, (14) thyroid cancer, which includes, but is not limited to, papillary or follicular thyroid cancer, medullary thyroid cancer, and anaplastic thyroid cancer; (15) pancreatic cancer, which includes, but is not limited to, insulinoma, gastrinoma, glucagonoma, vipoma, somatostatin-secreting tumor, and carcinoid or islet cell tumor, (16) Pituitary cancer, which includes but is not limited to it is not limited to, Cushing's disease, prolactin-secreting tumor, acromegaly, and diabetes insipidus; (17) Eye cancer, which includes but is not limited to, ocular melanoma such such as iris melanoma, choroidal melanoma, ciliary body melanoma, and retinoblastoma; (18) Vaginal cancer, which includes, but is not limited to, squamous cell carcinoma, adenocarcinoma, and melanoma; (19) vulvar cancer, which includes, but is 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, which includes, but is not limited to, endometrial carcinoma and uterine sarcoma; (22) ovarian cancer, which includes, but is not limited to, ovarian epithelial carcinoma, low malignancy potential tumor, germ cell tumor, and stromal tumor, (23) esophageal cancer, which, includes but not is limited to squamous cell carcinoma, adenocarcinoma, cystic adenoid carcinoma, mucoepidermoid carcinoma, adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma, verrucous carcinoma, and oat cell carcinoma (small cell); (24) stomach cancer, including but not limited to, adenocarcinoma, fungus (polypoid), ulcerated, superficial spread, diffuse diffusion, malignant lymphoma, liposarcoma, fibrosarcoma, and carcinosarcoma; (25) colon cancer; (26) rectal cancer; (27) liver cancer, which includes but is not limited to, hepatocellular carcinoma and hepatoblastoma; (28) gallbladder cancer, which includes but is not limited to, adenocarcinoma; (29) cholangiocarcinomas, including but not limited to, papillary, nodular and diffuse; (30) lung cancer, including but not limited to, non-small cell lung cancer, squamous cell carcinoma (squamous cell carcinoma), adenocarcinoma, large cell carcinoma, and small cell lung cancer, (31) Testicular cancer, which includes, but is not limited to, germinal, seminoma, anaplastic, classic (typical), spermatocytic, nonseminoma, embryonal carcinoma, teratoma carcinoma, and choriocarcinoma (yolk sac tumor); (32) prostate cancer, which includes but is not limited to, adenocarcinoma, leiomyosarcoma, and rhabdomyosarcoma; (33) cancer of the penis, (34) oral cancer, which includes but is not limited to, squamous cell carcinoma; (35) basal cancer; (36) salivary gland cancer, including but not limited to, adenocarcinoma, mucoepidermoid carcinoma, and adenoid cystic carcinoma; (37) Pharyngeal cancer, which includes but is not limited to, squamous and warty cell cancer; (38) skin cancer, including but not limited to, basal cell carcinoma, squamous cell carcinoma and melanoma, superficially extending melanoma, nodular melanoma, lentigo malignant melanoma, and lentiginous acral melanoma, (39) kidney cancer, which includes, but is not limited to, renal cell cancer, adenocarcinoma, hypernephroma, fibrosarcoma, and transitional cell cancer (renal pelvis and / or uterer); (40) Tumor Wilms; (41) bladder cancer including, but not limited to, transitional cell carcinoma, squamous cell cancer, adenocarcinoma, carcinosarcoma, - and other cancers, including, but not limited to, myosarcoma, osteogenic sarcoma, endotheliosarcoma , linfangioendoteliosarcoma, mesothelioma, sinovioma, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma, bronchogenic carcinoma, carcinoma of the sweat gland, sebaceous gland carcinoma, papillary carcinoma and papillary adenocarcinomas (See Fishman et al., 1985, Medicine, 2d Ed., JB Lippincott Co., Philadelphia and Murphy et al, 1997, Informed Decisions: The Complete Book of Cancer Diagnosis, Treatment, and Recovery, Viking Penguin, Penguin Books USA, Inc., United States of America).

In certain embodiments, cancer that is treatable with the methods provided herein includes, but is not limited to, bladder cancer, breast cancer, cervical cancer, colon cancer (eg, colorectal cancer), endometrial cancer, cancer esophageal, gastric cancer, glioma (eg, glioblastoma), head and neck cancer, liver cancer, lung cancer (eg, small cell and non-small cell lung cancers), melanoma, myeloma, neuroblastoma, cancer ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, sarcoma (for example, osteosarcoma), skin cancer (for example, carcinoma of the squamous cells), stomach cancer, testicular cancer, thyroid cancer, and uterine cancer.

In certain embodiments, cancer that is treatable with the methods provided herein includes, but is not limited to, bladder cancer, breast cancer, cervical cancer, colon cancer (eg, colorectal cancer), endometrial cancer, cancer gastric, glioma (eg, glioblastoma), head and neck cancer, liver cancer, non-small cell lung cancer, ovarian cancer, pancreatic cancer, and prostate cancer.

In certain modalities, cancer is non-small cell lung cancer. In certain embodiments, the cancer is non-small cell lung cancer that overexpresses the HERI protein. In certain embodiments, the cancer is non-small cell lung cancer that overexpresses the HER2 protein. In certain embodiments, the cancer is non-small cell lung cancer that overexpresses the HERI 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 that overexpresses the HERI protein. In certain embodiments, the cancer is metastatic non-small cell lung cancer that overexpresses the HER2 protein. In certain modalities, cancer is metastatic non-small cell lung cancer which overexpresses the HERI and HER2 proteins.

In certain modalities, cancer is breast cancer. In certain modalities, cancer is breast cancer that overexpresses the HERI protein. In certain modalities, cancer is breast cancer that overexpresses the HER2 protein. In certain modalities, cancer is breast cancer that overexpresses the HERI and HER2 proteins. In certain modalities, cancer is metastatic breast cancer. In certain modalities, cancer is metastatic breast cancer that overexpresses the HERI protein. In certain modalities, cancer is metastatic breast cancer that overexpresses the HER2 protein. In certain modalities, cancer is metastatic breast cancer that overexpresses the HERI and HER2 proteins.

In certain modalities, cancer is cancer of the head and neck. In certain modalities, cancer is lung cancer. In certain modalities, cancer is adenocarcinoma of the lung. In certain modalities, cancer is esophageal cancer or upper GI.

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.

The methods provided herein encompass the treatment of a subject regardless of the age of the subject. patient, although some diseases or disorders are more common in certain age groups. A method is further provided for treating a subject who has undergone surgery in an attempt to treat the disease or condition in question, as well as the one that has not been submitted. Because subjects with cancer have heterogeneous clinical manifestations and variable clinical outcomes, the treatment given to a particular subject may vary, depending on their prognosis.

The combination regimen can be administered repeatedly if necessary, for example, until the patient experiences stable disease or regression, or until the patient experiences unacceptable disease progression or toxicity. For example, stable disease for solid tumors generally means that the perpendicular diameter of measurable lesions has not increased by 25% or more since the last measurement. The Solid Tumor Response Evaluation Criteria Guide (RECIST), Journal of the National Cancer Institute 2000, 92, 205-216. The stabilization of the disease or lack of it is determined by methods known in the art such as evaluation of patient's symptoms, physical examination, visualization of the tumor that has been formed in images using X-rays, CAT, PET, or the MRI and other evaluation modalities commonly accepted.

In certain embodiments, the combination regimen is administered to the subject for an extended period of time, ranging from 1 day to about 12 months, from 2 days to about 6 months, from 3 days to about 5 months, from 3 days. days to around 4 months, from 3 days to around 12 weeks, from 3 days to around 10 weeks, from 3 days to around 8 weeks, from 3 days to around 6 weeks, from 3 days to around 5 weeks, from 3 days to around 4 weeks, from 3 days to around 3 weeks, from 3 days to around 2 weeks, or from 3 days to around 10 days.

In certain embodiments, the combination regimen is administered in a 21-day cycle. In certain embodiments, the combination regimen is administered in a 28-day cycle. In certain modalities, the combination regimen is administered in a monthly cycle.

In certain embodiments, the combination regimen is administered cyclically to the subject. Cyclic therapy involves administering a combination regimen provided herein for a period of time, followed by a rest for a period of time, and repeating this sequence administration. Cyclic therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, and / or improve the effectiveness of the treatment.

Consequently, in one embodiment, the combination regimen provided herein is administered daily for one week, two weeks, three weeks, four weeks, five weeks, six weeks, eight weeks, ten weeks, fifteen weeks, or twenty weeks, followed for a rest period of about 1 day to about ten weeks. For example, the methods contemplate using cycles of one week, two weeks, three weeks, four weeks, five weeks, six weeks, eight weeks, ten weeks, fifteen weeks, or twenty weeks. In another embodiment, the combination regimen provided herein is administered daily for one week, two weeks, three weeks, four weeks, five weeks, or six weeks with a rest period of 1, 3, 5, 7, 9, 12, 14, 16, 18, 20, 22, 24, 26, 28, 29 or 30 days. In certain modalities, the rest period is 14 days. In certain modalities, the rest period is 28 days. In one modality, the rest period is of a period that is sufficient to recover the bone marrow. The frequency, number and length of the dosing cycles can be increased or decreased.

As used herein, the term "combination regimen" includes the use of more than one therapy (e.g., one or more prophylactic and / or therapeutic agents). However, the use of the term "combination regimen" is not restricted to the order in which the therapies (eg, prophylactic and / or therapeutic agents) are administered to the subject. A first therapy (eg, a prophylactic or therapeutic agent such as an indazolylaminopyrrolotriazine provided herein) can be administered before (eg, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent a (eg, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) of the administration of a second therapy (eg, a prophylactic or therapeutic agent such as taxane described herein) to the subject. Triple therapy is also contemplated herein (for example, a platinum agent is a third therapy).

In certain embodiments, the indazolylaminopyrrolotriazine provided herein, for example, an indazolylaminopyrrolotriazine of Formula I or II, including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; is administered to the subject before the taxane administration. In certain embodiments, the indazolylaminopyrrolotriazine provided herein is administered to the subject about 2 days, about 1 day, about 12 hours, about 6 hours, about 4 hours, about 2 hours, about 60 minutes, about 30 min, around 20 min, about 10 min before administration of the taxane. In certain embodiments, the indazolylaminopyrrolotriazine provided herein is administered to the subject about 2 days prior to administration of the taxane. In certain embodiments, the indazolylaminopyrrolotriazine provided herein is administered to the subject about 1 day prior to administration of the taxane. In certain embodiments, the indazolylaminopyrrolotriazine provided herein is administered to the subject on the same day as the administration of the taxane.

In certain embodiments, the indazolylaminopyrrolotriazine provided herein, for example, an indazolylaminopyrrolotriazine of Formula I or II, including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; it is administered to the subject after administration of the taxane. In certain embodiments, the indazolylaminopyrrolotriazine provided herein is administer to the subject around 2 days, around 1 day, around 12 hrs, around 6 hrs, around 4 hrs, around 2 hrs, around 60 min, around 30 min, around 20 min, around 10 min after administration of the taxane. In certain embodiments, the indazolylaminopyrrolotriazine provided herein is administered to the subject about 2 days after administration of the taxane. In certain embodiments, the indazolylaminopyrrolotriazine provided herein is administered to the subject about 1 day after administration of the taxane.

In certain embodiments, the indazolylaminopyrrolotriazine provided herein, for example, an indazolylaminopyrrolotriazine of Formula I or II, including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; it is administered to the subject concurrently with the administration of the taxane.

In each embodiment provided herein, the method may further comprise a diagnostic step for determining the level of expression of the HERI protein in the tumor cells. In one embodiment, the diagnostic step is carried out prior to the administration of the combination regimen provided herein. If the subject has a tumor with HERI overexpressed, the combination regimen provided herein is then administered. In another embodiment, the diagnostic step is carried out during the course of the treatment.

In each embodiment provided herein, the method may further comprise a diagnostic step to determine the level of expression of the HER2 protein in the tumor cells. In one embodiment, the diagnostic step is carried out before the administration of the compounds. In another embodiment, the diagnostic step is carried out during the course of the treatment.

The methods provided herein may further comprise administering other therapeutic agents useful in the treatment and / or prevention of a disease described herein.

In certain embodiments, each method provided herein may further independently comprise the step of administering an additional therapeutic agent. Additional therapeutic agents that may be used in combination with the combination regimen herein include, but are not limited to, surgery, endocrine therapy, bgical response modifiers (e.g., interferons, interleukins, and tumor necrosis factors (TNF)). ), hyperthermia and cryotherapy, agents to attenuate any adverse effect (for example, antiemetics), and others approved chemotherapeutic drugs, including, but not limited to, alkylating agents (mechlorethamine, chlorambucil, cyclophosphamide, melphalan, and ifosfamide), antimetabolites (cytarabine (also known as cytosine arabinoside or Ara-C), HDAC (high dose cytarabine) ), and methotrexate), purine antagonists and pyrimidine antagonists (β-mercaptopurine, 5-fluorouracil, citarbina, and gemcitabine), spindle poisons (vinblastine, vincristine, and vinorelbine), podophyllotoxins (etoposide, irinotecan, and topotecan), antibiotics (daunorubicin, doxorubicin, bleomycin, and mitomycin), nitrosoureas (carmustine and lomustine), enzymes (asparaginase), and hormones (tamoxifen, leuprolide, flutamide, and megestrol), imatinib, adriamycin, dexamethasone, and cyclophosphamide. For a more comprehensive discussion of updated cancer therapies; See, http://www.nci.nih.gov/, a list of 'improved oncology drugs' from FDA at http: // www. fda gov / cder / cancer / drugglistframe. htm, and The Merck Manual, Seventeenth Ed. 1999, the complete contents of which is incorporated herein by reference.

In certain embodiments, additional therapeutic agents that can be used in combination with the combination regimen herein include, but are not limited to, vinorelbine, vinblastine, erlotinib, gemcitabine, mitomycin, bevacizumab, etoposide, ifosfamide, cetuximab, irinotecan, and pemetrexed.

In another embodiment, a method for inhibiting the growth of a cell is provided herein, which comprises contacting the cell with an effective amount of a taxane and an indazolylaminopyrrolotriazine described herein, for example, an indazolylaminopyrrolotriazine of Formula I or II, which includes a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

In certain embodiments, the cell is a mammalian cell. In certain embodiments, the mammalian cell is of a human. In certain modalities, the cell is a tumor cell. In certain embodiments, the cell is a mammalian tumor cell. In certain embodiments, the cell is a human tumor cell. In certain modalities, the cell is a cancer cell. In certain embodiments, the cell is a mammalian cancer cell. In certain modalities, the cell is a human cancer cell.

In certain modalities, the tumor cell overexpresses the HERI protein. In certain modalities, the tumor cell overexpresses the HER2 protein.

In certain embodiments, the cancer cell that can be treated with the methods provided herein include, but are not limited to, bladder cancer cells, breast cancer, cervical cancer, colon cancer (e.g., colorectal cancer), endometrial cancer, esophageal cancer, gastric cancer, glioma (e.g., glioblastoma), cancer of head and neck, liver cancer, lung cancer (for example, small cell and non-small cell lung cancers), melanoma, myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, sarcoma ( for example, osteosarcoma), skin cancer (e.g., squamous cell carcinoma), stomach cancer, testicular cancer, thyroid cancer, and uterine cancer.

In certain embodiments, the cell is a bladder cancer cell, breast cancer, cervical cancer, colon cancer (e.g., colorectal cancer), endometrial cancer, gastric cancer, glioma (e.g., glioblastoma), head cancer and neck, liver cancer, non-small cell lung cancer, ovarian cancer, pancreatic cancer, or prostate cancer.

In certain embodiments, the cells are treated by contacting the cells with the indazolylaminopyrrolotriazine provided herein, for example, an indazolylaminopyrrolotriazine of Formula I or II, which includes a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers. Of the same; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; before putting the cell in contact with the taxane. In certain embodiments, the cell is treated with the indazolylaminopyrrolotriazine provided herein, about 2 days, about 1 day, about 12 hours, about 6 hours, about 4 hours, about 2 hours, about 60 minutes. , about 30 min, or about 10 min before contacting the cell with the taxane.

In certain embodiments, cells are treated by contacting the cell with the indazolylaminopyrrolotriazine provided herein, for example, an indazolylaminopyrrolotriazine of Formula I or II, which includes a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers. Of the same; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; concurrently by contacting the cell with the taxane.

In certain embodiments, the cell is treated by contacting the cell with the indazolylaminopyrrolotriazine provided herein, for example, an indazolylaminopyrrolotriazine of Formula I or II, which includes a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers. Of the same; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of the same; after contacting the cell with the taxane. In certain embodiments, the cell is treated with the indazolylaminopyrrolotriazine provided herein, about 2 days, about 1 day, about 12 hours, about 6 hours, about 4 hours, about 2 hours, about 60 minutes. , about 30 min, or about 10 min after contacting the cell with the taxane.

Inhibition of cell growth can be evaluated, for example, by counting the number of cells contacted with the compounds of interest, comparing cell proliferation with other identical cells not contacted with the compounds, or determining the size of the tumor that spans the cells . The number of cells, as well as the size of the cells, can easily be evaluated using any method known in the art (for example, trypan blue exclusion and cell counting, measurement of 3H-thymidine incorporation in the nascent DNA in a cell).

The combination regimes provided herein may also be provided as an article of manufacture using packaging materials well known to those skilled in the art. See, for example, U.S. Patent Nos. 5,323,907; 5,052,558; and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, packages blister, bottles, tubes, inhalers, pumps, bags, jars, containers, syringes, and any suitable packaging material for a selected formulation and the intended mode of administration and treatment.

Also provided herein are equipment which, when used by the medical professional, can simplify the administration of appropriate amounts of active ingredient to a subject. In certain embodiments, the equipment provided herein includes containers and dosage forms of the compound in the combination regimens provided herein.

In certain embodiments, the kit includes a container comprising dosage forms of the compounds in the combination regimens provided herein, in one or more containers.

The kits provided herein may also include devices that are used to administer the active ingredient. Examples of such devices include, but are not limited to, syringes, needleless injectors, drip bags, patches, and inhalers. The kits provided herein may also include condoms for the administration of the active ingredients.

The kits provided herein may further include pharmaceutically acceptable carriers that may be used to administer one or more ingredients assets. For example, if an active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the equipment may comprise a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a sterile, particle-free solution that is suitable. for parenteral administration. Examples of pharmaceutically acceptable carriers include, but are not limited to: aqueous vehicles, including, but not limited to, Water for USP Injection, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Sodium Chloride Injection and Dextrose, and Lactated Ringer's Injection; miscible vehicles in water, 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.

The description will be further understood by the following examples are limiting.

EXAMPLES Example 1 Mouse Xenograft Study with Human Breast Carcinoma MX-I The human breast carcinoma of the MX-I cell line it was from the frozen existence that was passed serially in vivo for no more than 10 continuous passages.

Naked m(Taconic Labs) were inoculated with the MX-1 cell as trocar fragments subcutaneously in the axillary region. The tumors were grown to a size of about 100 mg, which was measured by means of electronic calibration through the skin), and the mwere then randomly selected from the control group and the various treatment groups, with eight mper group in the extensions of effectiveness. During the treatment period, solid tumors were measured three times per week. Body weights were also measured three times per week.

AC480 (Ambit Biosciences, San Diego, CA) was formulated in 50% aqueous propylene glycol at a concentration of 30 mg / ml, and orally administered (PO) once a day (QD). Paclitaxel (Hauser Pharmaceuticals, Denver, CO) was formulated in 10% aqueous ethanol / 10% CREMOFOR® (Sigma, St. Louis, MO) at a concentration of 2 mg / ml, and administered once a day (QD) by intraperitoneal injection (IP). The animals were pooled and dosed as shown in Table 1.

TABLE 1 The results of this study are summarized in FIGURES 1 to 3. The combination of AC480 and paclitaxel appears to be well tolerated.

Example 2 Mouse Xenograft Study with Human Breast Carcinoma MX-1 A second mouse Xenograft study was conducted to study alternative and oral dose combinations. The same protocol as described in Example 1 was followed for body weight and measurements of tumor size. The same compound formulations were also used, but the paclitaxel dose was adjusted to 25 mg / kg and administered intravenously (IV) for this study.

TABLE 2 The results of this study are shown in FIGURE 4.

Example 3 Synthesis of acid [4- [[1- (3-fluorophenyl) methyl] -lH-indazol-5-ylamino] -5-methyl-pyrrolo [2,1-f] [1,2,4] triazin-6 -yl] - carbamic, (3S) -3-morpholinyl methyl ester (AC480) The synthesis of AC480 is shown in Scheme 1. Compound 1 was chlorinated, followed by coupling with compound 2 to form compound 3. Saponification of compound 3 produced acid 4, which was first converted to an azide of acyl and then subjected to the Curtius arrangement in the presence of compound 5 to form compound 6. The removal of the Boc group (N-tert-butoxycarbonyl) with hydrochloric acid, the formation of a hydrochloric salt, and the subsequent neutralization of the compound II of free base, which is then purified by crystallization.

Example 4 Synthesis of acid [4- [[1- (3-fluorophenyl) methyl] -lH-indazol-5-ylamino] -5-methyl-pyrrolo [2, 1-f] [1, 2, 4] triazin-6- il] - carbamic, (3S) -3-morpholinyl methyl ester, ethanesulfonate (esylate AC480) in crystalline Form II-B A mixture of free-base compound II 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 the esylate of AC480 precipitated. After filtration, the filter cake was washed with ethanol cooled to 0 ± 5 ° C. The resulting solid is then dried to the constant weight in a vacuum oven at = 30 ° C to produce the AC480 esylate in crystalline Form II-B, which has a melting point of about 202 ° C.

TABLE 3. Stability of Esilato AC480 at 5 ° C to. AC480 Esilate is a powder white to pale yellow or pale pink, which may contain lumps TABLE 4. Stability of Esilat AC480 at 25 ° C / 60% RH to. AC480 Esilate is a powder white to pale yellow or pale pink, which may contain lumps The stability of the AC480 esilate 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. The results are summarized in Tables 3 to 5.

Example 5 Preparation of the pharmaceutical formulation comprising AC480 esylate A pharmaceutical formulation comprising AC480 esylate was prepared through an aseptic lyophilization process. The composition of the pharmaceutical formulation and the amount of water used in the preparation are summarized in Table 6.

TABLE 5. Stability of AC480 Esilat at 40 ° C / 75% RH to. AC480 Esilate is a powder white to pale yellow or pale pink, which may contain lumps In the preparation of the pharmaceutical formulation, 75% of the required amount of sterile water for injection was added to a clean depyrogenated glass container. The required amount of mannitol powder (2% by weight), hydroxypropyl-β-cyclodextrin (ββ) (15% by weight), and esylate of AC480 was added to the vessel, and mixed until dissolved. The solution was brought to its final lot weight with sterile water for injection, that is, the remaining 25%. The solution was then sterile filtered and filled into amber flasks of 30 cc in 12 mL / flask. The bottles were partially covered, and lyophilized. Once the lyophilization was complete, the bottles were filled with sterile filtered nitrogen, and the plugs were fully inserted. The bottles were then sealed by compression with 20mm White Flip-Off Compression Seals.

TABLE 6 AC480 esilato (363 mg) contained 300 mg of free base AC480 The water was removed during lyophilization.

Before administration to a patient, the vial will be reconstituted with water at 25 mg / mL of free base AC480.

Example 6 Clinical Trial of Phase I of Esilato AC480 in Combination with Docetaxel AC480 esilate will be tested in a Phase I trial in human patients who have a wide range of advanced solid malignancies. This Phase I study is an open-label, increasing dose study of the 2-day pulse IV Administration of the AC480 esilate determined as monotherapy, then in combination with docetaxel once every 3 weeks in patients with advanced solid tumors. In this Phase I study, the safety and PK parameters are determined in a 2-day pulse of AC480 esilate as monotherapy and also in combination with docetaxel once every 3 weeks.

The esilato of AC480 is administered intravenously on days 1 and 2, and docetaxel on day 2 of each treatment cycle of 21 days. Dose escalation is guided by careful monitoring of toxicity with pre-escalation and detention rules. The study population includes adult subjects with metastatic or locally advanced solid cancers, whose diseases have progressed in or following standard therapies currently available or for which there is no standard therapy. Subjects with tumors that are known or likely to express + HER1 and / or HER2, including cancers of the head and neck, lung adenocarcinoma, upper / esophageal GI, and breast, which can respond and derive clinical benefits from treatment with AC480 are included.

Phase I is divided into three parts. Part 1: The safety and tolerability of AC480 esilato as monotherapy is first established, together with the determination of the MTD (MTDl) of a 2-day pulse of IV dose of AC480 esilate. Part 2: PK parameters of docetaxel monotherapy at a reduced dose of 60 mg / m2 (80% of standard dose due to potential overlapping liver toxicity) is determined. Then, the safety and tolerability of the combination of esylate AC480 (administered on days 1 and 2) and docetaxel (administered immediately after esylate AC480 on day 2 in the same reduced dose) is determined, where the Start dose of esylate AC480 is a dose level below MTDl as determined in Part 1. The MTD of the esylate AC480 in combination with reduced dose of docetaxel (MTD2) is also determined. Part 3: The MTD (MTD3) of the combination of esylate AC480 (administered on days 1 and 2) and docetaxel (administered immediately after esylate of AC480 on day 2 in the standard full dose of 75 mg / m2) It is determined.

Part 1: Based on the preclinical monkey data, the IV start dose of esylate AC480 in Part 1 is 40 mg / m2 given over a period of about 30 minutes. During Part 1, the patient receives AC480 esilate as monotherapy on days 1 and 2. The PK blood samples are extracted at the specified time points. Patients then follow weekly for 21 days to assess toxicity. Efficacy is evaluated after Cycle 1 and every two cycles (six months) after this. The DLT evaluation period for AC480 esilato monotherapy is from the first 21 days.

An increase in dose uses an accelerated design for Part 1 and a standard 3 + 3 cohort design for Parts 2 and. In the first two dose cohorts of Part 1, there is only one patient initially and there is an opportunity to increase the dose if the first patient in each cohort completes the first 21-day period without DLT. This applies only to the first two dose escalation cohorts (40 and 80 rag / m). Thus, if the first patient in the first cohort (40 mg / mz) completes the 21-day period without DLT, the next patient begins on. trial in the second cohort (80 mg / m4). Only for these first two patients in their respective cohorts, the DLT is defined as any Degree of toxicity > 2 (based on the Common Toxicity Criteria of the National Institute Against Cancer for Adverse Events Version 4.0 [CTCv4]) at any point during the first 21 days that is to say that they are considered related to study the drug. If the first patient in the second cohort (80 mg / m2) does not experience DLT in the 21-day period either, then the next patient begins the trial in the third cohort (134 mg / m2), and a cohort design of 3 + 3 standard is used after this.

If the first patient in the first or second cohort experiences a DLT, the dose increase is immediately changed to a standard 3 + 3 cohort design. If this occurs in the first or second cohort, and for the third dose cohort and all subsequent dose cohorts in Part 1 and for all cohorts in Parts 2 and 3 of the study, the AC480 esilate dose is increased in the 3 + 3 standard cohorts (explained in the following). The 3 + 3 cohorts, if there is the non-hematological CTCv4 Grade = 3 and / or hematological Grade > 4 (or for Grade 3 neutropenic fever) toxicity at any point during the first 21 days that are considered related to study the drug, this is defined as the DLT for monotherapy, of esylate from AC480. In addition, administration of AC480IV is discontinued permanently and the. Patient leaves the study. Also, if the first cohort becomes a 3 + 3 cohort and more than one of the six patients has a DL, then the dose is reduced to the dose level -1 (Table 7). A similar process is used if a dose reduction at dose level -2 is necessary.

TABLE 7. The Increase Dose Schedule for Part 1, AC480 as Monotherapy The dose increase by the dose cohort is done in a standard modified Fibonacci design for the Phase 1 studies. Each dose level is increased by 100% 33%, using small increments as dose increments. When the dose increase proceeds to the standard 3 + 3 cohort, at least 21 days of treatment and toxicity data should be available for all three patients at. a single cohort before the next cohort can open at the next dose level. If none of the three patients in a cohort experiences DLT, the next cohort is enrolled in the next dose level. If none of the three patients in a cohort experiences DLT, the cohort expands to a total of six patients. If more than one of the six patients has a DLT, then there is no additional dose increase and the current dose is defined as the Maximum Managed Dose (MAD). In this case, the next lower dose level is expanded to a sixth patient or an immediate dose level (between the MAD and the next lower level) is opened for evaluation. The highest dose level in which cua.1. = five of six patients in the r.olera cohort. Dosage is defined as BAT. In Part 1, this is referred to as MTDl. Once the BATM is confirmed in the six total patients, at least three additional patients are enrolled in the BAT for additional PK data. Thus, the MTB of AC480 esilat monotherapy is determined in a total of at least nine patients.

Part 2 : Part 2 begins with the administration of a single dose of docetaxel 60 mg / m2 (80% of the standard dose, reduced in this part of the study due to the potential to overlap the liver toxicity in combination with esylate AC480) on day 1 of a cycle of 21 days. Blood samples for PK studies of docetaxel are extracted at the time points reespecified during this docetaxel monotherapy cycle (Cycle 1 of Part 2). The regimen for all cycles after Cycle 1 consists of diffusion of AC480 esilate on days 1 and 2 in combination with docetaxel a. 60 mg / m / 'on day 2, administered after the esylate of AC480. Each cycle can be repeated every 3 weeks (21 days). The starting dose for the esylate of AC480 in Part 2 is the MTD of Part 1 minus a dose level (MTDl 1). Patients continue in therapy as long as there are no experiences of intolerable toxicity and there is no evidence of progression of the disease. All subsequent cycles in Part 2 are identical to Cycle 2, but without additional PK evaluation. The. Efficacy is evaluated after Cycle 1 immediately before Cycle 2, and every two cycles (six weeks) after this. The DLT although without additional PK evaluation. The DLT evaluation period for Part 2 is the first 21 days of the AC480 esilate combination therapy and docetexel (Cycle 2).

The dose of IV esilato of AC480 can be increased or reduced in Part 2 according to Table 8; however, the maximum dose of esylate of AC480 may not be greater than the MTD found in Part 1 (MTDl). As in Part 1, the dose of IV esilato of AC4.80 in Part 2 is the increased dose in cohorts of 3. If niri.tju.no of the three patients in a cohort experience DLT, then the next cohort Enroll in the next higher dose level. If patients do not tolerate the IV dose of AC480 esylate assigned with the dose of docetaxel 60 mg / m2, the IV dose of AC480 esylate is decreased up to > five of the six patients tolerate the doses. The dose levels for AC480 esilate increase or reduction are those used in Part 1. The highest dose level at which > five of the six patients in the cohort tolerate the dose that is defined as the BAT of the combination therapy. In Part 2, this is referred to as M.T.D2. A 'time that M.TD2 is confirmed in. the six total patients enrolled, three additional patients in the MTD2 for additional PK data.

TABLE 8. The Dose Increase Schedule for Part 2 Part 3 : Once the MTB of AC480 esilate with docetaxel 60 mg / m2 is established (MTD2), the MTD of esylate of AC480 with a full standard dose of docetaxel (75 mg / m3) will be determined (MTD3). The IV dose of AC480 esilate starting in Part 3 is the BAT of Part 2 minus one dose level (MTD2-1). The first dose level of docetaxel is 75 mg / m¿. The esylate of AC480 is administered on days 1 and 2 of each cycle. Docetaxel is administered immediately followed by the 2-day infusion of AC480 esilate. Each cycle lasts for 21 days. If none of the three patients experiences DLT, the next cohort receives the A.C480 esilate in. MTD2, and 1st dose of docetaxel remains at 75 mg / rrf. Patients continue therapy as long as they do not experience intolerable toxicity and there is no evidence of disease progression. All subsequent cycles in Part 3 of the study are for Cycle 2, but without PK evaluations. The effectiveness is evaluated after Cycle 1 immediately before Cycle 2, and every two cycles (six weeks) after this. The DLT evaluation period for Part 3 is in the first 21 days of the combination therapy of esylate of C480 and docetexel (Cycle 2).

The dose increase and dose reduction schedule for Part 3 is similar for the. Part 2 (see, Table 9). The starting dose for the esylate of AC480 is MTD2-1 and the starting dose for docetaxel is 75 mcf / rrr :. The dose of esilato of AC480 increases or decreases with the tolerability of the patient; at the maximum dose of esylate of AC480, however, can not be greater than the MTD found in Part 2 (MTD2). The dose levels for the increase or reduction of AC480IV are those used in Part 1. The dose of docetaxel remains fixed at 75 mg / m2.

TABLE 9. The Dose Increase Schedule for the Part 3 Level of Dosage IV of Esilato Dosage of Docetaxel Dosage AC480 (mg / m2). (mg / m2) -2 MTD2 -3 75 -1 MTD2 -2 75 1 of MTD2 - 1 75 departure) 2 MTD2 75 The examples set forth in the foregoing are described to give those of ordinary skill in the art with a disclosure and complete description of how to make and use the claimed modalities and are not intended to limit the scope of what is described herein. Modifications that are obvious to persons of skill in the art are intended to be within the scope of the following claims. All pubtions, patents, and patent apptions cited in this specification are incorporated by reference as if each of all pubtions, patents, or patent apptions were specifically and individually indicated to be incorporated herein by reference.

Claims (43)

1. A method for treating a prolificrative disease in a subject, comprising administering to the subject a taxane and an indazolylaminopyrrolotriazine of Formula I: or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; where : R is C6-14 aryl, heteroaryl, or heterocyclyl; R1 is Ci-e alkyl; R 2 is hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 6 --4 aryl, C 7-20 aralkyl / heteroaryl or heterocyclyl; X is a bond, -O-, -S-, -C (R3R4) -, or -N (R3) -; and each of R3 and R4 is independently hydrogen, Ci-6 alkyl, C6-i4 aryl, C7-20 aralkyl, heteroaryl, or heterocyclyl; wherein each alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl are optionally substituted with one or more substituents Q selected from the group consisting of (a) cyano, halo, and nitro; (b) Ci-6 alkyl, C2-6 alkenyl / C2-6 alkynyl, C3-10 cycloalkyl, Ce-14 aryl, heteroaryl, and heterocyclyl; and (c) -C (0) Ra, -C (0) ORa, -C (0) NRbRc, -C (= NRa) NRbRc, -0Ra, -OC (0) Ra, -OC (0) ORa, -OC (0) NRbRc, -0C (= GRa) NRbRc, -OS (0) Ra, -OS (0) 2Ra, -OS (0) NRbRc, -OS (0) 2NRbRc, -NRaRd, -NRaC (0) ) Rb, -NRaC (0) 0R, -NRaC (0) NRbRc, -NRaC (= NRd) NRbRc, -NRaS (O) Rb, -NRaS (0) 2Rb, -NRaS (0) NRbRc, -NRaS (O ) 2NRbR °, -SRa, -S (0) Ra, and '-S (0) 2Ra; wherein each of Ra, Rb, Rc, and Rd is independently (i) hydrogen, Ci-6 alkyl, C2-alkenyl, C2 alkynyl. 6, C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl; or (ii) Rb and R ° together with the N atom to which they are attached form heterocyclyl or heteroaryl.

2. The method of claim 1, wherein the ta.xa.no is paclitaxel.

3. The method of claim 2, wherein the. Paclitaxel is paclitaxel albumin.

4. The method of claim 1, wherein the taxane is docetaxel.

5. The method of any of claims 1 to 4, wherein the taxane is administered intravenously.

6. The method of claim 5, wherein the Taxane is administered according to a regimen selected from: i. 260 mg / m2 for 24 hours; ii. 250 g / z for 24 hours; iii. 200 mg / rn2 for 24 hours; iv. 185 mg / m'1 for 3 hours; v. 185 mg / m2 for 24 hours; saw. 175 mg / m2 for 3 hours; vii. 175 mg / m2 for 24 hours; viii. 150 mg / m2 for 3 hours; ix. 150 mg / m for 24 hours; x. 135 mg / m2 for 3 hours; xi. 135 mg / m2 for 24 hours; xii. 100 mg / m2 for 3 hours; xiii. 60-100 mg / m2; xiv. 100 mg / m2; xv. 80-90 mg / m2; xvi. 80 mg / m; xvi i. 75 mg / m2; Y xvi i.i. 60 mg / m2.

7. The method of any of claims 1 to 6, wherein the taxane is administered on days 3, 10, and 17 in a 21 or 28 day cycle.

8. The method of any of claims 1 to 6, wherein the taxane is administered on days 2 into a 21 day cycle.

9. The method of claim 1 to 8, wherein the indazolylaminopyrrolotriazine is administered orally.

10. The method of claim 9, wherein the indazolylaminopyrrolotriazine is administered according to a regimen selected from: to . 600 mg / day; b. 400 mg / day; Y d 40 d 300 mg / m / day.

11. The method of claim 9 or 10, wherein the indazolylaminopyrrolotriazine is administered according to a regimen selected from: to. a dose paira logz ~ ax ~ a Cmax of around 5 to about 40 μ ?; b. a dose to achieve Cmax ele around 10 around 40 μ?, · c. a dose to achieve Cmax of around 2 around 20 jig / mL; d. a dose to achieve Cmax of around 3.5 around 6 μ ?; and. a dose to achieve Cmax of f around 0.4 around .5 μ ?; F. a dose to achieve Cmax of around 1.5 around 3.2 | ag / mL; Y g. a dose to achieve Cmax of around 0.2 around 2.2 | .ig / rr¡L.

12. The method of any of claims 1 to 8, wherein the indazolylaminopyrrolotriazine is administered intravenously.

13. The method of any of the claims 1 to 12, wherein the indazolylaminopyrrolotriazine. is administered in accordance with. A regimen selected from: to. a dose to achieve an AUC of around 60 around 500 pg * hr / mL; b. a dose to achieve an AUC around 125 around 500 g * hr / mL; c. a dose to achieve an AUC of around 125 around 300 pg * hr / mL; d. a dose to achieve an AUC of around 125 around 200 yg * hr / mL; and. a dose to achieve an AUC of around 125 around 1,000 yM * hr; F. a dose to achieve an AUC of around 250 around 500 '· lix.; g. a dose for loe / rare an AUC around 4 around 35 pg * hr / mL; Y h. a dose to achieve an AUC of around 40 around 55 yg * hr / inL.

14. The method of any of claims 1 to 13, wherein the indazolylaminopyrrolotriazine is administered on days 1 and 2 in a 21-day cycle.

15. The method of any of claims 1 to 14, wherein the indazolylaminopyrrolotriazine is administered prior to administration of the taxane.

16. The method of claim 15, wherein the indazolylaminopyrrolotriazine is administered on days 2, 9, and 16 in a cycle of 21 to 28 days.

17. The method of any of claims 1 to 14, wherein the indazolylaminopyrrolotriazine is administered concurrently with the taxane.

18. The method of any of claims 1 to 14, wherein the indazolylaminopyrrolotriazine is administered after administration of the taxane.

The method of any of claims 1 to 18, wherein the indazolylaminopyrrolotriazine is administered on days 3, 10, and 17 in a cycle of 21 to 28 days.

20. The method of any of claims 1 to 19, wherein the. prolific disease is a. tumor.

21. The method of claim 20, wherein the tumor is a solid tumor.

22. The method of claim 20 or 21, wherein the tumor is a malignant tumor.

23. The method of claim 22, wherein the malignant tumor is bladder cancer, breast cancer, 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.

24. The method of any of the claims 20 a. 23, where the tumor overexpresses. the HERI protein.

25. The method of claim 24, in. where the tumor overexpresses the H.ER2 protein.

26. The method of any of claims 1 to 25, further comprising administering to the subject a platinum agent.

27. The method of claim 26, wherein the platinum agent is cisplatin, carboplatin, oxaliplatin, satraplatin (JM-216), or CI-973.

28. The method of claim 26 or 27, wherein the platinum agent is carboplatin.

29. The method of any of claims 26 to 28, wherein the platinum agent is administered in accordance with a. regime, selected from: i. a dose to achieve an AUC of around 2 around 8 mg * min / mL; ii. a dose to achieve an AUC of around 3 around 8 mg * min / mL; iii. a dose to achieve an AUC around 3 about 7.5 mg * min / mL; iv. a dose to achieve an AUC of around 2 v. a dose to achieve an AUC of around 3 mg * min / mL; saw . a dose to achieve an AUC of around 5 mg * min / mL; vi i. a dose to achieve an AUC around viii. a dose to achieve an AUC of around 7.5 mg * min / mL.

30. A method for inhibiting the growth of a cell, comprising contacting the cell with a taxane and an indazolylaminopyrrolotriazine of Formula I: (I) or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; where : R is C6-i4 aryl, heteroaryl, or heterocyclyl; R1 is Ci-6 alkyl; R2 is hydrogen, Ci-6 alkyl, C3-10 cycloalkyl, C6-14 aryl, C7-20 aralkyl / heteroaryl or heterocyclyl; X is a bond, -O-, -S-, -C (R3R4) -, or -N (R3) -; and each of R 3 and R 4 is independently hydrogen, C 1-6 alkyl, C 6 --4 aryl, C 7-2 aralkyl, heteroaryl, or heterocyclyl; wherein each alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl are optionally substituted with one or more substituents Q selected from the group consisting of (a) cyano, halo, and nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, Cs-14 aryl, heteroaryl, and heterocyclyl; and (c) -C (0) Ra, -C (0) ORa, -C (0) NRbRc, -C (= NRa) NRbR °, -ORa, -OC (0) Ra, -OC (0) ORa , -OC (0) NRbRc, -OC (= GRa) NRbRc, -OS (0) Ra, -OS (0) 2Ra, -OS (0) NRbRc, -OS (0) 2NRbRc, -NRaRd, -NRaC ( 0) Rb, - -NRaC (O) OR, -NRaC (0) NRbRc, -NRC (= NRd) NRbRc, -NRaS (0) Rb, -NRaS (0) 2Rb, -NRaS (0) NRbRc, -NRaS (O) 2NRbRc, -SRa, -S (0) Ra, and -S (0) 2Ra; wherein each of Ra, Rb, Rc, and Rd is independently (i) hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C -14 aryl, heteroaryl, or heterocyclyl; or (ii) Rb and Rc together with the N atom to which they are attached form heterocyclyl or heteroaryl.

31. The method of claim 30, wherein the Indazolylaminopyrrolotriazine is contacted with the cell before the taxane.

32. The method of claim 30, wherein the indazolylaminopyrrolotriazine is contacted with the cell concurrently with the taxane.

33. The method of claim 30, wherein the indazolylaminopyrrolotriazine is contacted with the cell after the taxane.

34. The method of any of claims 30 to 33, wherein the cell is a tumor cell.

35. The method of claim 34, wherein the tumor of the cell is a solid tumor cell.

36. The method of any of claims 30 to 35, wherein the cell is a cancer cell.

37. The method of claim 36, wherein the cancer cell is a bladder cancer cell, breast cancer, cervical cancer, colon cancer, endometrial cancer, gastric cancer, gliorna, head and neck cancer, liver cancer, cancer of non-small cell lung, ovarian cancer, pancreatic cancer, or prostate cancer.

38. The method of any of claims 30 'to 37, wherein the cell overexpresses the HERI protein.

39. The method of claim 38, wherein the cell overexpresses the HER2 protein,

40. The method of any of the claims 1 to 39, wherein R is aryl of Ce-i4 # Y rJ is alkyl of d-4 / each optionally substituted with one or more of its elements Q.

41. The method of any one of claims 1 to 40, wherein X is O, and R2 is cycloalkyl or heterocyclyl, each optionally substituted with one or more its Q bonds.

42. The method of any of the claims 1 to 41, wherein the compound is selected from the group consisting of: [5-ethyl-4- [[(1-phenylmethyl) -lH-indazol-5-yl] amino] pyrrolo [2, 1-f] [1,2,4] triazin-6-yl] -carbamic acid, . { 35) -3-morpholinyl methyl ester; [5-ethyl-4- [[(1-phenylmethyl) -lH-inclazol-5-yl] amino] pyrrolo [2, 1-f] [1, 2,4] triazin-6-yl] -carbamic acid. { 2R) 2 pirro1idini 1met i1és ter; [5-ethyl-4 [[(1-phenylmethyl) lH-indazol-5-yl] amino] pyrrolo [2, 1-f] [1, 2,4] triazin-6-yl] -carbamic acid, ( 25) - 2-p.irro1 idini lmetiles ter; acid [5-eti 1-4 - [[(1-fe i Lmeti 1) - 1 H -indazol-5-yl] amino] indole [2, 1- f] [1,2,4] triazin- 6- il ] -carbamic, (3R) -3-morpholinyl methyl ester; [5-ethyl-4- [[(1-f-enylmethyl) -lH-indazol-5-yl] amino] acid] [2, 1-f] [1,2,4] riazin-6-yl] -carbamic acid , 3- [(35) -3-hydroxy-l-pyrrolidinyl] propylester; [5-ethyl-4- [[(1-phenylmethyl) -lIT-indazol-5-yl] amino] acid] [2, 1-f] [1,2,41-triazin-6-yl] -carbamic acid, 3 - [3 S) 3-hydroxy-1-piperidinyl] -propyl ester; [5-ethyl-4- [[(1-phenylmethyl) -1H-indazol-5-yl] aminojpyrrolo [2, 1 f] [1, 2,] triazin-6-yl] -carbamic acid, (3i?) 3 - . 3 - . 3-pyrrole idinylmethyl ester; acid [5-ethyl] -4- [[(.1-feni.1.meti 1.) -.1H-indazo1. - 5-yl] amino] irrolo [2, 1-f] [1,2,4] triazin-6-yl] -carbamic, 3 - [ (3R) -3-Hydroxy-l-pyrrolidinyl] propylester, · [5-ethyl-4- [[(1-phenylmethyl) -lH-indazol-5-yl] amino] pyrrolo [2, 1-f] [1, 2, 4] triazin-6-yl] -carbamic acid, [(25 ') - 1-methi 1 -2-pyrro1idini1] methylester; [5-ethyl-4- [[(1-phenylmethyl) -1H-indazol-5-y1] amino] acid [2, 1-f] [1,2,4] triazin-6-yl] -carbamic acid, (25) -2 morpholinyl methyl ester; [5-Ethyl 4 [[(1-phenylmethyl) -1H-indazol-5-yl] amino] -pyrrolo [2, 1 f] [1,2,4] triazin-6-yl] -carbamic acid, (3S) -3-pyrrolidinylmethyl ester; Acid [5-eti1-4 - [[(1-phen.i1meti1) -1H-inda.zo1-5-yl] amino] pyrrolo [2, 1-f] [1, 2,4] triazin-6 -yl] -carbamic, (2JR) -2-morpholinyl methyl ester; [5-ethyl-4- [[(1-phenylmethyl) -lfl-indazol-5-yl] aminojpyrrolo [2, 1-f] [1,2,4] triazin-6-yl] -carbamic acid, [( 3R) -l- methyl-3-pyrrolid.in.il] ethyl ester ter; [5-ethyl-4- [[(1-phenylmethyl) -lH-indazol-5-acid] il] amino] pyrrolo [2, 1-f] [1,2,4] t: riazin-6-yl] -carbamic acid, trans -4-aminocyclohexyl ester; acid [5 eti1|||| 4|||| [[(1-phenylmet.il) 1H-indazol-5-yl] amino] pyrrolo [2, 1 f] [1,2,4] triazin-6-yl ] -carbamic, (3R) 3 -pipericlinlylester; [5-ethyl-4- [[(1- phenylmet.il) -1..H-indazol-5-yl] amino] acid [2, 1 -f] [1,2,4] triazin-6-acid il] -carbamic acid, (35) -3-piperidinium ester; [5-ethyl-4- [[(1-phenylmethyl) -lH-indazol-5-yl] amino] pyrrolo [2, 1-f] [1, 2, 4] triazin-6-yl] -carbamic acid, Cis-4-aminocyclohexyl; [5-ethyl-4- [[(1-phenylmethyl) -1H-indazol-5-yl] amino] acid [2, 1-f] [1,2,4] triazin-6-yl] -carbamic acid, (2R, .R) -2- (hydroxymethyl) -4-piperidinyl ester; [5-ethyl-4 [[(1-phenylmethyl) -1H-indazol-5-yl] amino] -pyrrolo [2, 1 f] [1,2,4] triazin-6-yl] -carbamic acid, (2S) 2- (hydroxymethyl) 4-piperidinyl ester; [5-ethyl-4- [[(1-phenylmethyl) -lH-indazol-5-yl] amino] pyrrolo [2, 1-f] [1, 2,4] triazi.n-6-.il] acid] -carbamic, cis-4- (ani.inom.ethyl) cyclohexyl ester; [5-ethyl-4- [[(1-phenylmethyl) -1H-indazol-5-yl] amino] pyrrolo [2, 1-f] [1, 2, 4] riazin-6-yl] -carbamic acid, cis-4-amino-4-methylcyclohexyl ester er; [5-ethyl-4- [[(1-phenylmethyl) -lif-indazol-5-yl] amino] acid [2, 1-f] [1, 2,4] triazin-6-yl] -carbamic acid, [(2JR, 41?) -4- (idroxy-2-piperidini1] methyl ester; [5-ethyl-4- [[(1-phenylmethyl) -lfi-indazol-5-yl] amino] pyrrolo [2, 1-f] [1,2,4] triazin-6-yl] carbamic acid, trans 4 (aminomethyl) cyclohexyl ester; [5-ethyl-4 [[1- (2-oxazolyl-methyl-1-yl-indazol-5-yl] -amino] -pyrrolo [2, 1-f] [1, 2,4] -triazin-6-yl] -carbamic acid, (35 ') ) -3-morphyl inylmethyl ester; [5-ethyl-4- [[1- (2-thienylmethyl) -1H-indazol-5-yl] amino] pyrrolo [2, 1-f] [1,2,4] triazin-6-yl] ] -carbamic, (35) -3 -morfo1 iniImeti 1 ester; [5-ethyl-4- [[1- [(3-fluorophenyl) methyl] -1H-indazol-5-yl] amino] pyrrolo [2, 1-f] [1, 2, 4] triazin- 6 - acid il] -carbamic, (35) -3-morpholinylmethyl er; [5-ethyl-4- [[1- (4-thiazolylmethyl) -lfl-indazol-5-yl] amino] pyrrolo [2, 1-f] [1, 2, 4] triazin-6-yl] -carbamic acid, ( 35) 3 -morpholinyl methyl ester; [5-ethyl-4- [[1- (3-thienylmethyl) -1H-indazole-5-yl] -amino] -pyrrolo [2, 1-f] [1, 2,4] tr.iazin-6-yl] -carbamic acid, ( 35) -3-nor.orfo1ini 1.raeti.1éster; [5-ethyl-4- [[1- (2-pi.r.idini "1me il) -1H-indazol-5-yl] aniino] pyrrolo [2, 1-f] [1, 2, 4] ] triazin-6-yl] -carbamic acid, (35) -3-morpholinyl methyl ester; [5-ethyl-4- [[1- (2-thiazolylmethyl) -lH-indazol-5-y1] amino] acid [2, 1-f] [1,2,4] triazin-6-yl] - Carbamic, (35-3-morpholinylmethyl ester; [5-ethyl-4- [[1- (3-pyridinylmethyl) -Ify-indazol-5-yl] amino] pyrrolo [2, 1-f] [1,2,4] riazin-6-yl] - acid Carbamic, (3S) -3 morpholinyl methyl ester, [5-ethyl-4- [[1- (pyrazinylmethyl) -1H-indazol-5-yl] -amino] -pyrrolo [2, 1 f] [1, 2, 4] triazin-6-yl] -carbamic acid, (35) 3 - . 3 -morfo1 irii.1meti 1 ester; [4- [[1- (3-Fluoro-phenyl) -methyl] -β-indazol-5-y1-alkyne] -5-methyl-1-pyridyl [2, 1-f] [1, 2, 4] triazine. 6-1] -carbamic, crans-4-aminocyclohexyl ester; [4- [[1- (3-fluorophenyl) methyl] -lfl-indazol-5-ylamino] -5-methyl-pyrrolo [2, 1-f] [1,2,4] triazin-6-yl] acid] -carbamic, (2R, 41?) -2- (hydroxymethyl) -4-piperidinyl ester; [4- [[1- (3-Fluoro-phenyl) -methyl] -1H-indazol-5-ylamino] -5-yl-pyrrolo [2, 1-f] [1, 2, 4] triazine-6-i acid 1] -Carbamic,. { 2S 45) 2 (hydroxymethyl) 4-piperidinyl ester; [4 - [[1- (3-fluorophenyl) methyl] -1H-indazole-5-ylamino] -5-methyl-pyrrolo [2, 1-f] [1,2,4] -triazin-6-yl] -carbamic acid, ci-4 .-arainocyclohexyl ester 1. ester; [4- [[1- (3-Fluorophenyl) methyl] -lff-indazol-5-ylamino] -5-methyl-1-pyrro! or [2, 1-f] [1,2,4] triazine- acid 6-i 1.] -carbamic, cis-4-amino-4-methyl-cyclohexyl ester; [4- [[1- (3-fluorophenyl) methyl.j -lfl-indazol-5-ylamino] -5-methyl-pyrrolo [2, 1-f] [1,2,4] triazin-6-yl acid ] -carbamic, (2R) -2-aminopropyl ester; [4- [[1- (3-fluorophenyl) methyl] -IH-indazole-5- acid i lamino] -5-methyl-pyrrolo [2, 1-f] [1,2,4] triazin-6-yl] -carbamic acid, (2 S) -2-arninopropy 1-ter, acid [4 [[1. { 3-fluorophenyl) methyl] 1H-indazole |||| 5-ylamino] -5-methyl-pyrrolo [2, 1-f] [1,2,4] triazin-6-yl] -carbamic acid, (3S) 3-morpholinyl methyl ester; [4- [[1- (3-Fluorophenyl) methyl] indazol-5-ylamino] -5-methyl-pyrrolo [2, 1-f] [1,2,4] t iazin-6-yl] acid] -carbamic, (3.R) -3-pipe.ridin.i.l ester; [4- [[1- (3-f luorofenyl) methyl] -lH-indazol-5-ylamino] -5-methyl-pyrrolo [2, 1-f] [1,2,4] triazine- 6 -yl] -carbamic, (3S) -3-piperidinyl ester, -3-t [[[[4- [[1 - [(3-fluorophenyl) methyl] -1H-indazol-5-yl] amino] -5 acid -methylpyrrolo [2, 1-f] [1,2,4] -Riazin-6-yl] amino] carbonyl] oxy] methyl] -4-morpholinecarboxylic, (3S) -1, 1-dimethylethyl ester; [4- [[1- (3-f-luo-phenyl) -methyl] -1H-indazole-5-lamino] -5-yl-pyrrolo [2, 1 f] [1,2,4] triazin-6-yl] carbamic, 3-morpholinyl methyl ester; Y Acid [4 - [[1 - (3-f1uoropheni.1) met.i 1] - 1 H- indazo1 -5-ilamino] -5-methyl-pyrrolo [2, 1-f] [1, 2, 4] triaz ind6 -.yl.] -carbamic acid, (3R) -3-morpholinyl methyl ester; and pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof.

43. The method of any of claims 1 to 42, wherein the indazolylaminopyrrolotriazine is or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.