TW201136935A - Salts of an indazolylpyrrolotriazine - Google Patents

Abstract

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

Description

201136935 VI. Description of the Invention: [Technical Field to Which the Invention Is Provided] Provided herein are salts of carbazole pyrrolotriazole, a process for the preparation thereof, and pharmaceutical compositions thereof. Methods of using it to treat, prevent or ameliorate proliferative diseases are also provided. The present application claims priority to U.S. Provisional Application No. 6 1/3, 036, filed on Jan. 31, 2010, the disclosure of which is incorporated herein in its entirety. 〇 [Prior Art] The Her family of receptor tyrosine kinases contains Herl (also known as egfr*)

ErbB-1), Her2 (ErbB-2), Hei:3 (ErbB-3) and Her4 (ErbB-4). Activation or overexpression of members such as Herl or Her2 is implicated in human malignancies, including breast, ovarian, endometrial, cervical, esophageal, gastric, colorectal, pancreatic, prostate, and Cell lung cancer (NSCLC), bladder cancer, head and neck cancer, and nerve (4) tumors, including neuroglia f: cell tumors. Her inhibitors have been used clinically for cancer treatment. For example, the anti-Her2 antibody trastuzumab has been approved as... (10) is called (HERCEPTIN^ for the treatment of Her2 positive breast cancer. Lapat^ (Lapat^ (small molecule inhibitor) with dual anti-EGFR/Her2 activity has been approved. TYKERB, (4) (5) positive breast cancer. Although anti-cancer therapy has made such progress, there is still a long-term need for effective treatment for proliferative diseases. [Summary of the invention] J54673.doc 201136935 is not provided, or its hydration Or a pharmaceutically acceptable solvate. In one embodiment, the sulfonate is in crystalline form. Also provided herein is a 4-(1-(3-fluorobenzyl)-17/-carbazole _5_ Amino group) -5-methyl-pyrano[1,2-/][1,2,4]triazot _6-ylamino decanoic acid (phantom morpho-3-yl-methyl hydrazine) a methanesulfonate, or a hydrate thereof or a pharmaceutically acceptable solvate. In one embodiment, the methanesulfonate is in crystalline form. Further, a 4-(1_(3_fluorobenzoate) is provided herein. Ethyl)-carbazole _5_ylamino)-5-fluorenyl oxazolidine [^"[^^ triazotide--ylaminocarbamic acid bromomorphin-3-ylmethyl ester ethane a sulfonate, or a hydrate thereof or A pharmaceutically acceptable solvate. In one embodiment, the ethanesulfonate is in crystalline form. Further provided herein is a 4-(1-3-fluoro-3-methylcarbazole-5-ylamino)-5 -Methyl"bile-trinitrogenated _6_ylamino decanoic acid (fantasy -3- lin-3-yl vinegar benzene sulfonate, or a hydrate thereof or a pharmaceutically acceptable solvate thereof) In one embodiment, the besylate salt is in crystalline form. Provided herein is 4-(1-(3-fluorobenzylidazole-5-ylamino)-5-methyl-bipiro[1,2 -/][1,2,4]trinitrogen_6_ylaminocarbamic acid (p-tomorphine-3-ylmethyl methyl p-toluate) or its hydrate or pharmaceutically acceptable solvent In one embodiment, the p-toluenesulfonate is in crystalline form. Provided herein is a 4-(1-(3-fluorophenylhydrazinocarbazol-5-ylamino)-5-methyl-bipirin [1,2-/][1,2,4]triazot-6-ylaminophosphonium sulfonate S)-morpholine-3-methylacetate acetate, or a hydrate thereof or pharmaceutically acceptable The solvate. In one embodiment, the acetate is in crystalline form. Provided herein is a 4-(1-(3-fluorophenyl)-lH-indazol-5-ylamino)-5-A 11 piroxime, 2-/1[1,2,4]triazot-6-ylaminocarboxylic acid (phantom-morpholine-3- 154673.doc -4- 201136935 methyl ester of butylene An acid salt, or a hydrate thereof or a pharmaceutically acceptable solvate. In one embodiment, the maleic acid salt is in crystalline form. Provided herein is a 4-(1-(3-fluorobenzyl) group. -17/-carbazol-5-ylamino)_5_ fluorenyl 0-pyrolo[1,2-/][1,2,4]triazinylamino decanoic acid (5> morpholine_3_ group a nitrate of a methyl ester, or a hydrate thereof or a pharmaceutically acceptable solvate. In one embodiment, the epsilon acid salt is in crystalline form. Provided herein is a 4-(1-(3-fluorobenzyl)-1 ugly-indolyl-5-ylamino)-5-indenyl group. Bis-[1,2-/][1,2,4]triazin-6-ylaminocarbamic acid morpholine_3_ methicone discate, or a hydrate thereof or pharmaceutically acceptable Solvate. In one embodiment, the phosphate is in crystalline form. Provided herein is a pharmaceutical composition comprising 4_(ι_(3-气本 methyl)-l/f_π引 „坐_5_ylamino)-5-methylπ ratio π each provided herein [ Ip,2_ /][1,2,4]triazot-6-ylaminocarboxylic acid (5> morpholin-3-ylmethyl ester salt (including hydrates and pharmaceutically acceptable solvates thereof) Combining with one or more pharmaceutically acceptable excipients. Provided herein is a method of treating a proliferative disorder in an individual, the method comprising administering to the individual a derivatized fluorobenzoyl group as provided herein. /_carbazole _ 5-aminoamino)-5-fluorenyl D ratio argon bromide ^24^2,4] triazaindene _6-ylamino decanoic acid (S)-morpholin-3-yl decyl ester The salt 'includes a hydrate thereof and a pharmaceutically acceptable solvate. Provided herein is a method of inhibiting cell growth comprising the step of providing the cell with 4_(1_(3_fluorobenzyl)_ provided herein. 〖Open oxazole _5_ylamino) _5·decylpyrrolo[1,2_/1[1,2,4]triazot-6-ylaminocarboxylic acid (5> The vinegar salt includes contact with its hydrate and pharmaceutically acceptable solution 154673.doc 201136935. Preparation of 4-(1-(3-fluorobenzyl)·17^-oxazol-5-ylamino)·5-methyl-pyridotriazine_6-ylamino hydrazine provided herein A method of the acid (<S)-Mallin-3-glycolide salt, including a hydrate thereof and a pharmaceutically acceptable solvate, the method comprising: 4-(1-) at a first predetermined temperature (3-fluorophenylhydrazinocarbazol-5-ylamino)_5_decylpyrrolo[1,2-/][1,2,4]triazinyl-6-ylaminophosphonic acid (jS) The morpholine _3_ quinone ester is reacted with an acid in a solvent. In one embodiment, the method further comprises thawing the salt at a second predetermined temperature. Provided herein is a reduction of 4-(1-(3- Fluorobenzoyl)-1 dan-carbazole _5_ylamino)-5-fluorenyl " bis-[i,2-/][ι,2,4]triazo-p-6-yl a salt of (S)-morpholin-3-ylmethyl methacrylate or a hydrate thereof or a pharmaceutically acceptable solvate 4-(1-(3-fluorophenylindenyl)]; /_oxazolylamino)_5_mercapto n-r-[1,2-/][1,2,4]triazot-6-ylaminocarboxylic acid (<s)-(4-sub a method of nitromorpholine _3·yl), the method comprising: causing the salt to be C at a first predetermined temperature Ketone contact. In one embodiment, the salt crystallizes in acetone. [Embodiment] To facilitate understanding of the invention described herein, a number of terms are defined below. In general, the nomenclature used herein and described herein Laboratory procedures in organic chemistry, medicinal chemistry, physical chemistry, biochemistry, biology, pharmacology, and other sciences are well known and commonly employed in the art. All technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art, unless otherwise defined. 154673.doc 201136935 The terms "tumor", "tumor" and "neoplastic disease or disease" are used interchangeably herein and are intended to mean a hazard (ie discomfort or reduction) in a multicellular organism to a multicellular organism. Unexpected cell proliferation of one or more subsets of cells of life expectancy. In certain embodiments, the tumor can be benign (non-invasive) or malignant (invasive). The term "cancer" is intended to mean a malignant neoplasm characterized by uncontrolled cell proliferation in which the cell has lost its normal regulatory control of the rate of growth of the tube. These unregulated dividing cells can spread throughout the body and invade normal tissues during what is called "metastasis." The term "naturally occurring" or "native" when used in connection with a biological substance such as a nucleic acid molecule, a polypeptide, a host cell, and the like refers to a substance found in nature and not manipulated by humans. Similarly, "non-naturally occurring" or "non-native" refers to a substance that is not found in nature or has been structurally modified or artificially synthesized. The terms "HER1", "epidermal growth factor receptor", "EGFR" and "ErbB 1" are used interchangeably herein and refer to an eGFr receptor protein or variant thereof as described, for example, in Carpenter et al., hv. , 56, 881-914. The HER2 variant includes a protein that is substantially homologous to native EGFR, ie, a protein having one or more naturally occurring or non-naturally occurring amino acid deletions, insertions or substitutions compared to the amino acid sequence of native EGFR ( For example EGFR derivatives, homologs and fragments). The amino acid sequence of the HER2 variant is at least about 80% identical to native EGFR, at least about 90. /. Consistent or at least about 95% consistent. An example of a naturally occurring mutant form of native egFr, the deletion mutant EgFr, is described in 154673.doc 201136935

Humphrey^ A ? Proc. Natl. 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, human HER2 protein is described in Semba et al., Proc. iVa " Jcad. 5, 1985, <52, 6497-6501 and Yamamoto et al., TVaiwre 1986, 3iP, 230-234 (Genebank Accession No. X03363). The HER2 variant includes a protein substantially homologous to native HER2, ie, a protein having one or more naturally occurring or non-naturally occurring amino acid deletions, insertions or substitutions compared to the amino acid sequence of native HER2 ( For example, HER2 derivatives, homologs and fragments). The amino acid sequence of the HER2 variant is at least about 80% identical to native HER2, or at least about 90% or at least about 95%. The term "overexpression" means that a cell associated with a disease, disorder or condition contains a detectable higher level of protein, such as HER1 or HER2, as compared to a cell that is not related to the disease, disorder or condition but otherwise identical. . The term "individual" refers to an animal, including but not limited to a primate (e.g., a human), a cow, a pig, a sheep, a goat, a horse, a dog, a cat, a rabbit, a rat, or a mouse. The terms "individual" and "patient" are used interchangeably herein and refer to, for example, a mammalian individual, such as a human individual, and in one embodiment, a human. The term "treatment" is intended to include alleviating or eliminating a condition, disease or condition, or one or more symptoms associated with the condition, disease or condition; or reducing or eliminating the cause of the condition, disease or condition itself. The term "prevention" is intended to include delaying and/or preventing a condition, disease or disease. 154673.doc 201136935 hindering an individual from suffering from a disease, disease or

In a poor embodiment, contact of a therapeutic agent with a cell or tissue comprises administering a therapeutic agent to an individual having cells or tissues to be contacted. And/or the accompanying symptoms of the accompanying symptoms; or reducing the individual's condition. The term "therapeutically effective amount" is intended to include, when administered, sufficient to prevent the development or alleviation of one or more symptoms of the condition, disease or condition being treated. The amount of compound. The term therapeutically effective amount also refers to a biological or medical response sought by a researcher, veterinarian, physician or clinician sufficient to cause biomolecules (eg, proteins, enzymes, RNA or DNA), cells, tissues, systems, animals or humans. The amount of the compound. The term "pharmaceutically acceptable carrier", "pharmaceutically acceptable Q-form", "physiologically acceptable carrier" or "physiologically acceptable excipient" means pharmaceutical A pharmaceutically acceptable substance, composition or vehicle, such as a liquid or solid filler, diluent, solvent or encapsulating material. In one embodiment, the components are "pharmaceutically acceptable" which means that they are compatible with the other ingredients of the pharmaceutical formulation and are suitable for use in contact with tissues and organs of humans and animals without undue toxicity, Stimulation, allergic reactions, immunogenicity or other problems or complications are commensurate with the reasonable benefit/risk ratio. See Remington: The Science and Practice of Pharmacy, 21st Edition; Lippincott Williams & Wilkins: Philadelphia, PA, 154673.doc 201136935 2005; Handbook of Pharmaceutical Excipients, 6th Edition, edited by Rowe et al; The Pharmaceutical Press and the American Pharmaceutical Association: 2009 ; Handbook of

Pharmaceutical Additives, 3rd edition, edited by Ash and Ash; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson ed.; CRC Press LLC: Boca Raton, FL, 2009. The term "about" means an acceptable error for a particular value determined by those skilled in the art, in part depending on how the value is measured or determined. In some embodiments, the term "about" means within 1, 2, 3 or 4 standard deviations. In some embodiments, the term "about" means 50% '20% > 15% '10%, 9%, 8%, 7%, 6%, 5%, 4 at a specified value or a specified range. %, 3%, 2%, 1%, 0.5% or 0.05%. The terms "active ingredient" and "active substance" mean a compound that is administered to an individual, alone or in combination with one or more pharmaceutically acceptable excipients, to treat, prevent or ameliorate one or more symptoms of a condition, disorder or disease. . As used herein, "active ingredient" and "active substance" may be optically active isomers of the compounds described herein. The terms "drug", "therapeutic agent" and "chemotherapeutic agent" refer to a compound or a pharmaceutical composition thereof that is administered to an individual to treat, prevent or ameliorate one or more symptoms of the condition, disorder or disease. The term "alkyl" refers to a straight or branched chain saturated monovalent hydrocarbon group wherein the alkyl group is optionally substituted with one or more substituents Q as described herein. For example, c!_6 alkyl refers to a linear saturated monovalent hydrocarbon having 1 to 6 carbon atoms 154673.doc -10·201136935 or a branched chain saturated monovalent hydrocarbon group having 3 to 6 carbon atoms. In certain embodiments, the alkyl group is straight having from 丄 to (9) (Ci 2〇), from 1 to 15, from 1 to 1 ( (C^q) or from 1 to 6 (Cl·6) carbon atoms. The chain is saturated with a monovalent hydrocarbon group, or has 3 to 20 (C3.2.), 3 to 15 (.315), and 3 to (7) (6). Or a branched chain saturated monovalent hydrocarbon group of 3 to 6 (C3_6) carbon atoms. As used herein, linear q-6 alkyl and branched C36 alkyl are also referred to as "lower alkyl." Examples of alkyl groups include, but are not limited to, decyl, ethyl, propyl (including all isomeric forms)

, n-propyl, isopropyl, butyl (including all isomeric forms), n-butyl, isobutyl, t-butyl, tert-butyl, pentyl (including all isomeric forms) and hexyl (including all isomeric forms). The term "square group" refers to a monovalent monocyclic aromatic group and/or a monovalent polycyclic aromatic group containing at least one aromatic carbocyclic ring. In certain implementations, the aryl group has from 1 to 20 (C6-2.), from 6 to 15 (C-... or from 6 to 1 (C6-10) ring atoms. Examples of square groups include, but are not limited to, Phenyl, naphthyl, anthracenyl, decyl, fluorenyl 2 phenanthryl, biphenyl and terphenyl. Aryl also refers to a ring which is (d) and the rest can be saturated 'partially unsaturated or aromatic double ring Or tricyclic: anacyclic ring 'e.g. dihydronaphthyl, (iv), arachidyl and tetrahydronaphthyl (naphthylate). In certain embodiments, the aryl group may be substituted as described by one or more Substituted by Q. + again

The term "optionally substituted" is intended to mean that a group such as an alkyl group or an aryl group may be substituted with or a plurality of substituents Q, each of which is independently C = as (a) Cl_6 alkyl, C2 6 a group, a C2 6 group, a "cycloalkyl group, a ―: a aryl group, an arylalkyl group, a heteroaryl group, and a heterocyclic group, each of which is optionally taken into one or more (in the embodiment, i, 2) , domain 4) substituent V 154673.doc 201136935 substitution; and (b) halo, cyano (-CN), nitro (-N02), -C(0)Ra, -C(0)0Ra, - C(0)NRbRc, -C(NRa)NRbRc, -ORa, -〇C(0)Ra, -0C(0)0Ra, -〇C(0)NRbRe, -OC(=NRa)NRbRc, -〇S (0)Ra, •0S(0)2Ra, -〇S(0)NRbRc, -0S(0)2NRbRc, -NRbRe, -NRaC(0)Rd, -NRaC(0)ORd, -NRaC(0)NRbRc -NRaC(= NRd)NRbRc, -NRaS(0)Rd, -NRaS(0)2Rd, -NRaS(0)NRbRc, -NRaS(0)2NRbRc, -SRa, -S(0)Ra, -S( 0) 2Ra, -S(0)NRbRc&-S(0)2NRbRc, wherein Ra, Rb, Re and Rd are each independently (i) hydrogen; (丨丨) (: 丨-6 alkyl, C2_6 alkenyl , c2_6 block group, C3·7 % alkyl group, C6·! 4 aryl group, C7_15 arylalkyl group, heteroaryl group or heterocyclic group' Substituted (in one embodiment, 1, 2, 3 or 4) substituents Qa substituted; or (iii) Rb and Re together with the N atom to which they are attached form a heteroaryl or heterocyclic group, optionally via one or Multiple (in one embodiment, 1, 2, 3 or 4) substituents Qa substituted. As used herein, unless otherwise stated, all substituted groups are "optionally substituted". In the examples, each Qa is independently selected from the group consisting of: (a) a cyano group, a halogen group, and a nitro group; and (WCw alkyl group, C2-6 alkenyl group, C2-6 alkynyl group, C3·7 ring) Alkyl, C6_M aryl, c7_15 aralkyl, heteroaryl and heterocyclic; and (c)-C(0)Re, -C(0)0Re, -C(0)NRfRg, -C(NRe) NRfRg, -ORe, -0C(0)Re, -〇c(0)〇Re, -OC(0)NRfRg, -OC(=NRe)NRfRg, _〇S(0)Re, -〇S(0) 2Re, _〇S(0)NRfRg, -0S(0)2NRfRg, -NRfRg, -NReC(0)Rh, -NReC(0)〇Rh, -NReC(0)NRfRg, -NReC(=NRh)NRfRg, -NReS(〇)Rh, -NReS(0)2Rh, -NReS(0)NRfRg, -NReS(0)2NRfRg, -SRe, 154673.doc -12- 201136935 -S(0)Re, -S(0) 2Re, -S(0)NRfRg and -S(0)2NRfRg; wherein Re, Rf, R^Rh are independent Is (i) hydrogen; (iQCw alkyl, C2.6 alkenyl, 〇2_6 alkynyl, C3_7 cycloalkyl, C6-M aryl, C?-!5 aryl, heteroaryl or heterocyclic) 'or (丨^)11£ and 1^ together with the N atom to which they are attached form a heteroaryl or heterocyclic group.

The term "solvate" refers to a complex or aggregate formed from one or more solute molecules (eg, a compound provided herein) and one or more solvent molecules' that are present in stoichiometric or non-stoichiometric amounts. . Suitable solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, and acetic acid. In certain embodiments, the solvent is pharmaceutically acceptable. In one embodiment, the complex or aggregate is in crystalline form. In another embodiment, the complex or aggregate is in an amorphous form. The solvate is a hydrate when the solvent is water. Examples of hydrates include, but are not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate. The salt of oxazolidine-triazine P well 4_(1_(3_ 气笨methyloxazol-5-ylamino)-5-fluorenyl" 比比和[,/1[,,]-nitrogen- 6-Aminocarbamic acid (Fantasy-Merazine methyl ester, also known as AC48 (^tBMs_599626, with the structure of the formula:

154673.doc •13· 201136935 The compound of formula I has been identified as a HER kinase inhibitor (Wong et al, c/i «. Cawcer and 2006, 72, 6186-6193). The compounds of formula I can be prepared in accordance with U.S. Patent Nos. 6,916,815, 7,102,001 and 7,148,220, and U.S. Patent Application Publication Nos. 2005/0209454 and 2006/0014741, each of which is incorporated by reference in its entirety. Into this article. An alternative name for the compound of formula I is [4-[[ 1-(3-fluorophenyl)methyl]-1//-oxazol-5-ylamino]-5-fluorenyl]pyrylene [2, 1-/][1,2,4]triazot-6-yl]-carbamic acid (35)-3-methylinylmethyl. In one embodiment, provided herein is 4-(1-(3-fluorobenzylcarbazol-5-ylamino)-5-mercaptodecano[1,2-/][1,2,4] a sulfonate of (S)-morpholin-3-ylmethyl sulfonate, or a hydrate thereof or a pharmaceutically acceptable solvate thereof. As used herein, the term " Sulfonated acid salt can be used interchangeably with the term "sulfonate sah." In certain embodiments, the sulfonic acid is a CN6 alkyl sulfonic acid, wherein the alkyl group is Substituted by one or more substituents q. In certain embodiments, the sulfonic acid is a cerium lanthanum acid or ethane sulfonic acid. In certain embodiments, the sulfonic acid is c6 i4 aryl tartaric acid, wherein aryl is The situation is substituted with one or more substituents Q. In certain embodiments, the sulfonic acid is benzenesulfonic acid or p-toluenesulfonic acid. In certain embodiments, 4-(1-(3-fluorophenylhydrazino) Oxazol-5-ylamino)-5-methylpyrrolo-n jay,2,4]triazolyl amino decanoic acid (5)-morpholin-3-yl decyl ester The salt provided herein The molar ratio of the sulfonic acid in the hydrate and the pharmaceutically acceptable solvate thereof is from about 5 to about 3, about 0.5. In the range of about 2, or about 〇8 to about i 2. In certain embodiments, 4-0-(3-fluorophenylindolyl oxazol-5-ylamino)-5 methyl fluorene [I] — 154673.doc • 14- 201136935 /][1,2,4]trinitrogen _6_ylaminocarbamic acid morpholin-3-yl decyl ester for the salts provided herein (including hydrates thereof The molar ratio of the sulfonic acid in the pharmaceutically acceptable solvate) is about 0.5, about 〇6, about 〇7, about 0.8, about 0.9, about 1, about 1.1, about 1.2, about 1.4, About 1.5, about 1 _6, about 1 _8, about 2, about 2.2, about 2.4, about 2.6, about 2.8, or about 3. In one embodiment, 4-(1-(3-fluorobenzyl)_1 is ugly -oxazol-5-ylamino) _5_methyl-pyrano[1,2-/][1,2,4]triazot-6-ylaminocarboxylic acid (phantom-morpholine-3- The sulfonate of the methyl ester or a hydrate thereof or a pharmaceutically acceptable solvate thereof contains about 1 mole of 4-(1-(3-fluorobenzylcarbazol-5-ylamino)-5- Methyl oxo, 2,4]triazot-6-ylamino decanoic acid 0)-morphin-3-ylmethyl ester and about 1 molar equivalent of tarnish. In some embodiments , 4-(1-(3-fluorophenylindenyl)-1 °. Sodium-5-ylamino) -5-methyl. pyrrolotriazine _6-ylamino decanoic acid (5) _ linal-3-yl methyl ester sulfonate or hydrate thereof or pharmaceutically acceptable solvate The purity is at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 98.5%, at least about 99%, at least about 99.2%, at least about 99.4%, at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.8%, or at least about 99.9%. In certain embodiments, 4-(1-(3-fluorobenzyl)-1//-carbazole-5-ylamino)-5-methylpyrrolo[n/][1,2, 4] Triazolam-6-ylamino decanoic acid ($)-norpoline-3-yl decyl citrate or a hydrate thereof or a pharmaceutically acceptable solvate containing a sub-amine, in a In the examples, 4-(1_(3_fluoro), 丨扒〇 丨 丨 _ _ _ _ _ _ ) -5 _ 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有The content of aminic decanoic acid (<S)-(4-ytazolyl-3-yl) decyl ester is not more than about 5 卯 melon, 154673.doc -15·201136935 not more than about 4 ppm, not more than about 3 ppm, no more than about 2 ppm, no more than about 1.5 ppm, no more than about 1 ppm, no more than about 0.8 ppm, no more than about 0.6 ppm, no more than about 0.4 ppm, no more than about 〇.2 ppm or no more than about 0.1 ppm 〇

In one embodiment, 4-(1-(3-fluorobenzyl)-1//-indazol-5-ylamino)-5-indenyl. a sulfonate of succinyl [1,2-/][1,2,4]triazolam-6-ylaminocarbamate (s)-morpholin-3-ylmethyl ester or a hydrate thereof or medicinal The acceptable solvate is in an amorphous form. In another embodiment, 4-(1-(3-fluorobenzyl)_1 private. 丨0坐-5-ylamino)-5-methyl °biha [1,2-/] [1,2,4]triazopropion_6_ylaminocarbamic acid (*S)-Nalactin-3-yl acetonate or its hydrate or pharmaceutically acceptable solvate is crystallized form. In one embodiment, the present invention provides 4-(1-(3-fluorobenzyl)sa_5-ylamino)-5-methyl-pyrene and [1,2-/][1,2, 4] Tris-n-p--6-ylaminocarbamic acid (S)-Mallin-3-yl-S-pyroxyl sulphate, or a hydrate thereof or a pharmaceutically acceptable solvate thereof. As used herein, the term "methanesulfonic acid salt" is used interchangeably with the term "mesylate salt." 154673.doc -16· 201136935 In certain embodiments, 4-( 1-(3-Fluorobenzylcarbazole-5-ylamino)-5-methyl-la-p-[1,2_/][1,2,4]trinitrogen _6-ylamino decanoic acid The molar ratio of (5) _morpholin-3-ylmethyl ester to methanesulfonic acid in the salts provided herein (including hydrates and pharmaceutically acceptable solvates thereof) is from about 0.5 to about 3. From about 0.5 to about 2, or from about 0.8 to about 12. In certain embodiments, 4-indole-(3-fluorobenzyl)-1-[oxazol-5-ylamino)_5曱 D D 比 [ [1,2-/][1,2,4]triazot _6_ylaminocarboxylic acid ((S)-morpholine-3-ylmethyl ester for the salts provided herein (including its hydrates and pharmaceutically acceptable dissolution The molar ratio of the methanesulfonic acid in the agent||product is about 〇5, about 〇6, about 〇7, about 0-8, about 0.9, force 1, about i", about 丄2. About 4, about 15, about 6, about 1.8, about 2, about 2.2, about 2.4, about 2.6, about 2.8, or about 3. In one embodiment '4-(1-(3-fluorobenzyl) )-1 -carbazole _5_ylamino) -5-methyl " 〇 〇 [1,2_/|[1,2,4] triazobenzene-6-ylamino decanoic acid ( ^_ morpholine-3-yl vinegar oxime sulfonate or a hydrate thereof or a pharmaceutically acceptable solvate thereof containing about 1 mole equivalent of 4_(丨_(3fluorobenzoinyl)_1/ F_carbazole_5_ ◎ arylamino)-5-methyl-pyrano[1,2-/][1,2,4]triazot-6-ylaminophosphonium sulfonate S)-? Lin-3-yl vinegar and about 1 molar equivalent of decane sulfonic acid. In certain embodiments '4-(1-(3-fluorobenzyl)_1/f_carbazole _5-ylamine )5_methylpyrolo[1,2-/][1,2,4]triazot _6_ylaminocarbamate β)-morpholin-3-ylmethyl ester The molar ratio is determined based on its H NMR spectrum. In certain embodiments, 4-(1-(3-fluorobenzyl)-1 ugly-oxazol-5-ylamino)-5-A Base n ratio slightly and three nitrogen tillage _6_ The purity of the amino decanoic acid (M-sulfonyl-3-methyl ketone methanesulfonate or a hydrate thereof or a pharmaceutically acceptable solvate thereof is at least about 95%, at least about 96%, at least about 154673 .doc -17- 201136935 97%, at least about 98%, at least about 98.5%, at least about 99%, at least about 99.2%, at least about 99.4%, at least about 99.5%, at least about 99.6°/. At least about 99.7%, at least about 99.8%, or at least about 99.9°/. . In certain embodiments, 4-(1-(3-fluorobenzyl)-1oxa-oxazol-5-ylamino)-5-methyl-pyrano[1,2-/][ 1,2,4]triazot-6-ylaminocarbamic acid (*S)-morpholin-3-ylmethyl ester of methanesulfonate or a hydrate thereof or a pharmaceutically acceptable solvate thereof Nitramine having a content of no more than about 5 ppm, no more than about 4 ppm, no more than about 3 ppm, no more than about 2 ppm, no more than about 1.5 ppm, no more than about 1 ppm, no more than about 0.8 ppm, no more than about 6.6 ppm, no more than about 0.4 ppm, no more than about 0.2 ppm or no more than about 〇.1 ppm. In one embodiment '4-(1-fluorobenzylidazole-5-ylamino)-5-nonylpyrrolo[1,2-_/][1,2,4] The methanesulfonate of the (S)-morpholin-3-ylmethyl ester of triazobenzene-6-ylaminocarbamate or a hydrate thereof or a pharmaceutically acceptable solvate thereof is in an amorphous form. In another embodiment In the case, 4-(1-(3-fluorobenzyl)-1//-indazol-5-ylamino)-5-mercaptopyrrolidine triazine_6_ylaminocarbamic acid ("S) - 来 基 基 -3- 旨 曱 曱 或其 或其 or its hydrate or pharmaceutically acceptable solvate in crystalline form. In certain embodiments, the methane sulfonate is in the DSC thermogram There is an endotherm with a peak temperature of about 2 〇 2 < t and an onset temperature of 198 ° C. In certain embodiments, the decane read acid salt has a peak temperature of about 2 〇 8 t in the DSC thermogram. Heat absorbing line. In certain embodiments, the methane sulfonate exhibits a weight loss between 25 t and 150 ° C in the thermogravimetric thermogram of no more than about 5%, no more than about 4%, no more than about 3%. No more than about 2. or no more than about 1%. In certain embodiments, the decane sulfonate is shown in the thermogravimetric thermogram. ^The weight loss between 15〇1 I54673.doc -18- 201136935 is about 2%. Ο In the example, 4_(1_(3-fluorobenzyl)-1 oxazole-5-ylamine -5-methyl (tetra) and a sulfonate or a hydrate thereof or a pharmaceutically acceptable compound of (7)-morphin-3-ylmethyl ester The solvate is in crystalline form Ι-A. In certain embodiments, the form of the methyl sulphonate has a diffraction pattern of the ray-ray powder substantially as shown in Figure 1 At. In some embodiments, the form 1_ hexamethyl sulphate has one or more characteristic XRp diffraction peaks at a corner selected from the group consisting of about 7.2, 13.0 28.4, and 29.5. In certain embodiments, the methane sulfonate of Form IA Characteristic XRp diffraction peaks at the 2 Θ corners of about 3 5, 8 1 ° and 17.1. In some embodiments, the methic acid salt of Form IA is at about 35., 81., I? 22.8. There are characteristic XRP diffraction peaks at the 2 corners. In some embodiments, the methanesulfonate in the form of Ι-A is at about 3 5, 7 2, 81 〇 14.60, 17.1, 17.7 °, 19.1〇22.8° ' 24.0° 25.2° and 26.6. 2 corners Characteristic xRP diffraction peaks. Ο In another embodiment, 4-(1-(3-fluorobenzylidene oxazolylamino)-5-mercaptopurine triazolonium-6-ylamine The methane sulfonate of the carbamic acid-morpholin-3-yl decyl ester or a hydrate thereof or a pharmaceutically acceptable bath composition thereof is in the form of a crystalline form Ι-Β. In some embodiments, it is in the form ι β The methanesulfonate has a diffraction pattern of xenon ray powder substantially as shown in Figure 。. In certain embodiments, the decane sulfonate salt in the form of ruthenium is selected from the group consisting of about 2.6°, 12.6. 15.9. And 17.9. There are one or more characteristic diffraction peaks at the 2 corners. In certain embodiments, the decane sulfonate is in the form of about 2-6°, 3.6. And 8.2. At the 20th corner, there is a characteristic 乂1^ diffraction peak. In a certain example, 154 673.doc -19- 201136935, the form of the decane sulfonate of the form I-Β is about 26. , 3 6. 8, 2 2. And 22.9. The 2 corners have a characteristic xRp diffraction peak. In certain embodiments, the oxime-burning acid salt of Form I-B is at about 2.6. 3.6. , 8.20, 12 6. 22.9. And 24.4. The 2 corners have characteristics XRp 14·70, 19.3°, 21.9°, and diffraction peaks. In still another embodiment, 4-(1-(3-fluorophenylhydrazinyloxazolylamino)-5-methyl. More than argon triazine _6-ylaminocarboxylic acid (phantom-morpholine- The 3-methane oxime methanesulfonate or hydrate thereof or pharmaceutically acceptable solvate thereof is in crystalline form ic. In certain embodiments, the shaped methane sulfonate has substantially the same as in Figure (1) The xenon ray powder diffraction pattern is shown. In some embodiments, the form of the decane sulfonate has one or two selected from the group consisting of about 3, 3 6 · 8 , 11 · 2 and 26.2. A plurality of characteristic XRp diffraction peaks. In certain embodiments, the methanesulfonate salt in the form j-C has a characteristic XRp diffraction peak at about 2° angles of about 3.5°, 8.0°, and 16.9H9.0. In certain embodiments, the decane sulfonate salt in the form has a characteristic XRp diffraction peak at about 3, about 8.0, i6.9, 19.0, and 22.5. In some embodiments. The methanesulfonate has a characteristic diffraction peak at about 3 3, 8.0, 16.9, 19.0, and 22.5. In some embodiments, the methane is in the form of ic. The sulfonate is about 33., 8.0., 14.5〇, 17.7 , 16.9, 19_0〇, 22·5〇, 23 6〇, 241〇, 25.0° and 26.2. There are characteristic XRP diffraction peaks at the 2 corners. In another embodiment, 4-(1-(3- Fluorobenzyl)_17^carbazole _5_ylamino)-5-methylindolo[1,2-/][1,2,4]triazogen·6-ylaminocarboxylic acid (5>;) _ morpholin-3-ylmethyl methanesulfonate or hydrate thereof or pharmaceutically acceptable 154673.doc -20- 201136935 The solvate is in crystalline form Ι-D. In certain embodiments The methanesulfonate in the form i_d has an X-ray powder diffraction pattern substantially as shown in Figure 1 D. In certain embodiments, the methanesulfonate in the form of Ι-D is selected from the group consisting of about 7.4 °, 8.8, 13.2, 14.90, 27.2, 28.2, and 29.8. There are one or more characteristic XRP diffraction peaks at the corners. In some embodiments, the methanesulfonate is in the form of Ι-D. 7.4, 13.2, and 19.3. There are characteristic XRP diffraction peaks at the 2 corners. In some embodiments, the methanesulfonate is in the form of about 7.4, 13.2, 19.3, 22.0, 25.1. 27.2. The 2Θ corner has a characteristic XRP diffraction peak. In another embodiment, provided herein is a 4-(1-(3·•fluorobenzyl)-indazol-5-ylamino)-5-fluorenyl group. The ratio is [1,2-/ 3(^2,4) trisynphenyl-6-ylaminocarboxylic acid (<S)-morpholin-3-ylmethyl ester of methane hydride, or a hydrate thereof or a pharmaceutically acceptable solvent Compound. As used herein, the term "ethanesulfonic acid salt" is used interchangeably with the term "ethanesulfonate salt". In certain embodiments, 4-(1-(3-fluorophenylhydrazinocarbazol-5-ylamino)-5-methylpyrrolotriazine _6-ylamino decanoic acid (^_? The molar ratio of oxazino-3-ylmethyl ester to ethanesulfonic acid in the salts provided herein, including hydrates and pharmaceutically acceptable solvates thereof, is from about 至5 to about 3, about 〇· 5 to about 2, or about 〇·8 to about κ 2. In certain embodiments, 4-(1-(3-fluorobenzyl)_1/f_carbazole-5-ylamino) _5 methyl fluoren[1,2-/][1,2,4]triazot _6-ylaminocarboxylic acid (5()-morpholine-3-yl decyl ester for the salts provided herein ( The molar ratio of ethanesulfonic acid in the hydrates and pharmaceutically acceptable solvates thereof is about 、5, about 〇6, about 〇7, about 154673.doc -21 - 201136935 Ο.8, About 0.9, about 1, about 1.1, about 1.2, about 1.4, about 1.5, about 1.6, about 1.8 'about 2, about 2.2, about 2.4, about 2.6, about 2.8, or about 3. In one embodiment, ' 4- U-(3-fluorobenzyl)-1//-carbazol-5-ylamino)-5-methyl. Ratio 0 to each [12-/311,2,4] triazobenzene-6- Amino acid morpholine-3-yl hydrazine acetate or its hydrate or A pharmaceutically acceptable solvate comprises about 1 mole equivalent of 4_(丨_(3_fluorobenzyl)_liy_carbazole-5-amino group)-5-methyl D ratio slightly [1,2_ /][1,2,4]trinitrogen_6_ylaminophosphonium sulfonate S)-Mulline-3-ylmethacrylate and about 1 molar equivalent of ethanesulfonic acid. In some embodiments '4-(1-(3-Fluorobenzylcarbazole-5-ylamino)-5-fluorenyl. Bis-[1,2-/][1,2,4]trinitrogen_6_ The mercaptocarboxylic acid (hydrazine)-morpholine-3-ylmethyl ester is determined based on the spectrum of the oleic acid. In certain embodiments, 4-(1-(3-fluorophenyl) -1//-carbazole _5-ylamino)-5-methylindolo[1,2-/][1,2,4]triazod-6-ylamino decanoic acid a purity of at least about 95%, at least about 96%, at least about 97%, at least about 98, of the methanesulfonate salt of methion-3-ylmethacetate or a hydrate thereof or a pharmaceutically acceptable solvate thereof. %, at least about 98.5 ° /, at least about 99 ° /, at least about 99.2%, at least about 99.4%, at least about 99.53⁄4, at least about 99.6%, at least about 99-7%, at least about 99.8%, or at least about 99.9%. In certain embodiments '4-(1-fluoro-3-methylcarbazole-5-ylamino)_5_ Base η than succinyl[1'2-/] [1,2,4]diazo-p--6-ylaminocarbamic acid (s)-Merlin _3_ ketoacetate a hydrate or pharmaceutically acceptable solvate thereof containing nitrosamine in an amount not exceeding about 5 ppm, not exceeding about 4 ppm, not exceeding about 3 ppm, not exceeding about 2 ppm, not exceeding about 1.5 ppm, Not more than about 1 ppm, no more than about 0.8 ppm, no more than about 〇.6 ppm, no more than about 4 154673.doc •22-201136935 ppm, no more than about 0.2 ppm or no more than about 0.1 ppm. In one embodiment, 4-(1-(3-fluorobenzyl)-1孖-carbazole-5-ylamino)-5-nonylpyrrolo[1,2-/| [1,2 , 4] triazine, 6-ylamino decanoic acid (iS) morpho-3-yl decyl ethanesulfonate or a hydrate thereof or a pharmaceutically acceptable solvate thereof in an amorphous form . In another embodiment, 4-(1-(3-phenethyl)-l/ί-indazol-5-ylamino)-5-fluorenyl. Butyr[1,2-/][1,2,4]triazin-6-ylaminocarbamic acid (S)-morpholin-3-ylmethyl ester of ethanesulfonate or hydrate thereof or The pharmaceutically acceptable solvate is in crystalline form. In some embodiments, the ethanoate has an endotherm with a peak temperature of about 202 and an onset temperature of 197 °C in the DSC thermogram. In certain embodiments, the ethane sulphonate exhibits a weight loss between 2rc and 15 〇<t in the thermogravimetric thermogram of no more than about 1%, no more than about 8%8%, no more than about 〇·6%, no more than about 0.4%, no more than about 0.2%, no more than about %1%, no more than about 0.09%, no more than about 〇.〇8%, no more than about 〇〇7%, no more than about 〇·〇 6% or no more than about 0.05%. In certain embodiments, the ethanesulfonate exhibits at 25 ° C and 150 in a thermogravimetric thermogram. The weight loss between 〇 is about 0.1%. In one embodiment, 4-(1-(3-fluorobenzyl)-; ugly-carbazole-5-ylamino) • -5-methyl tonbolozepine hexamethylene-6-ylamino The ethanesulfonate of (7) morpholine-3--3-indenyl ester or a hydrate thereof or a pharmaceutically acceptable solvate is in the form of a crystal. In certain embodiments, the ethyl sulphonate salt in the form of a human has a ray powder diffraction pattern substantially as shown in Figure 2A. In certain embodiments, the bismuth acetonide salt has one or more characteristic XRp diffractions 154673.doc -23·201136935 peaks at a corner selected from about 4.4 and 28.6. In certain embodiments, the ethanesulfonate salt in the form of Π_Α is at about 3.6. And at the corner of 8.4, there is a characteristic xRp diffraction peak. In certain embodiments, the king form oxime-oxime ethanesulfonate is at about 3.6. 7.4. 8.4. 17.8. And at the corner of 19.0, there is a characteristic xrp diffraction peak. In certain embodiments, the oxime acid salt of the form Π-A is at about 36. , 7 4. 8, 8 4. , U 9. 13.4〇, 15,1. 17.8. , 19.0〇, 24.4. 25.7〇, 27.20 and 28.6. The 2 corners have a characteristic xRp diffraction peak. In another embodiment, 4-(1-(3-fluorophenylhydrazinocarbazol-5-ylsaphthyl)-5-methylindole-pyrrolo[1,24[1,2,4]triazole The ethanesulfonic acid salt of cultivating _6_ylaminocarbamic acid (5>)-morpholin-3-ylmethyl ester or a hydrate thereof or a pharmaceutically acceptable/validated compound is in the form of a crystalline form ΙΙ_Β. In some embodiments, the ethanesulfonate salt in the form of η-β has a diffraction pattern of the ray-ray powder substantially as shown in Figure 2A. In certain embodiments, the ethanesulfonate salt in the form of Π_Β is in It is selected from about 24.1 and 25.3. There are characteristic XRP diffraction peaks at the 2 corners. In some embodiments, the ethanesulfonate of the form Π-Β has characteristics at about 3.6 and 8.4. XRP diffraction peaks. In certain embodiments, the ethanesulfonate salt in the form of Forms 11-] has characteristic XRP diffraction peaks at about 3.6, 8.4, 25.3, and 28.0. In some embodiments, the ethanesulfonate in the form of Π_Β has characteristic XRP diffraction peaks at about 3.6, 8.4, 15.2, 16.9, 23.2, 25.3, and 28.0. In the examples, the oxime sulfonate in the form of Π_Β is in the DSC heat score. The figure has an endotherm with a peak temperature of about 2 〇 2 〇 c and an onset temperature of 1 97 ° C. In certain embodiments, the bis-acid salt in the form h_b is shown in the thermogravimetric thermogram. The weight loss between 25 °c and 150 °C does not exceed about 1%, does not exceed about 〇8%, does not exceed about 154673.doc •24- 201136935 0·6°/., does not exceed about 0.4%, does not exceed About 2%, no more than about 〇1〇/〇, no more than about 0.09%, no more than about 0.08%, no more than about 〇〇7%, no more than about 0.06%, or no more than about 0. 05%. In some embodiments, the ethyl sulphonate in the form of π_ 展示 is shown in the thermogravimetric thermogram. The weight loss between 〇 and 15 〇 is about 1 1 %. In yet another embodiment , 4-(1-(3-fluorobenzyl)-moxi-carbazole-5-ylamino)-5-mercapto-purine-triazine--6-ylaminophosphonic acid ((S)_ The morpholinyl methyl ester of the morpholine methyl ester or a hydrate thereof or a pharmaceutically acceptable solvate thereof is in the crystalline form n-c. In certain embodiments, the ethanesulfonate salt in the form n-c has substantially Figure 2 (: shows the ray-ray powder diffraction pattern. In some In the example, the ethanesulfonate salt of the form sn_c is selected from the group consisting of about 4.0, 12.4, 13.8, 16.3, 19.2, 20.3, 21.6, 24.8, 26.0 26·8, and 29.0. There are one or more characteristic XRp diffraction peaks. In certain embodiments, the ethanesulfonate salt of Form II-C is at about 4.0°, 13.8°, and 16,3. At the 20th corner there is a characteristic XRp diffraction peak. In some cases, the form of Π-C of the ethyl sulphonate is about 4.0. 13.8. 16.3. And 23.2. There are characteristic XRP diffraction peaks at the 2 corners. In certain embodiments, the ethanesulfonate salt in the form of Π-C is at about 4.0. 8.1〇, 1〇.60, • 12·4〇, 13·8°, 16.3. 21.6. , 23.2. And 26.8. The 2Θ corner has a characteristic XRP diffraction peak.

In still another embodiment, 4_(1_(3_fluorobenzoinyl H-vanazole _5•ylamino)_5 · fluorenyl "bibromo, 2-/1 [ 1,2,4] Trinitron-6-ylamino decanoic acid (amorphous morpholin-3-yl decyl ethanesulfonate or a hydrate thereof or a pharmaceutically acceptable solvate thereof in crystalline form Π-D. In certain embodiments, the ethanesulfonate salt in the form „_D 154673.doc -25- 201136935 has an X-ray powder diffraction pattern substantially as shown in Figure 2D. In certain embodiments, Form II The -D ethanesulfonate has one or more characteristic XRP diffraction peaks at two corners selected from about 3_2° and 6.7. In certain embodiments, the ethanesulfonate is Form II-D. Characteristic XRP diffraction peaks at about 2 and about 8.1. In another embodiment, 4-(1-(3-fluorophenylindenyl)-1//-carbazole-5-ylamine B)-5-fluorenylpyrrolo[1,2-/][1,2,4]triazot-6-ylaminocarboxylic acid (<5)-morpholin-3-ylmethyl ester B The alkane sulfonate or hydrate thereof or a pharmaceutically acceptable solvate is in the crystalline form Π-E. In certain embodiments, the ethane sulfonate of the form I]t_E has substantially The X-ray powder diffraction pattern shown in 2E. In certain embodiments, the ethanesulfonate salt in the form of Π_Ε is selected from the group consisting of about 4.6, 13.0, 15.4, 23-7, and 25.0. Having a characteristic XRP diffraction peak. In certain embodiments, the ethanesulfonate in the form of Π_Ε has a characteristic XRP diffraction peak at about 2·6°, 12.2°, 14.0, and 15.4. In certain embodiments, the ethanesulfonate in the form of Π_Ε has a characteristic XRP winding at about 2 4.6, 12.2 〇, 14·0 ο, 15.4, 25. 〇, 25.8, and 27.9. In some embodiments, the ethanesulfonate in the form of Π_Ε is at about 4.6, 8.4, 12.2, 14.0, 15.4, 19.5, 25.0°, 25.8, and 27.9. There is a characteristic XRP diffraction peak. In yet another embodiment, a 4_(1_(3_fluorobenzylthiooxazol-5-ylamino)_5_mercaptopurine triazine is provided herein. a benzenesulfonate of (S)-morpholine-3-ylmethyl, or a hydrate thereof or a pharmaceutically acceptable solvate thereof. As used herein, the term "benzene" Sulfonate Esuifonicacidsalt)" can be used interchangeably with the term "phenyl acid salt" (" 154673.doc -26- 201136935 salt)". In some embodiments '4-(1-(3-fluoro)methyl) ^carbazole _5_ylamino)5-fluorenylpyrrolo-pj-yjnq-diaza__6-ylamino decanoic acid (exomorphol-3-ylmethyl ester for the salts provided herein (including hydrates thereof) The molar ratio of benzenesulfonic acid in the pharmaceutically acceptable solvate is in the range of from about 5 to about 3, from about 0.5 to about 2, or from about 8 to about L2. In certain embodiments, 4-(1-(3-fluorophenylindenyl)-pyroxyl-5-ylamino)_5-methyl^pyrrinopyrene triazine w-6-yl The molar ratio of the amino phthalic acid (Q-morpholin-3-ylmethyl ester) to the benzenesulfonic acid in the salts (including hydrates and pharmaceutically acceptable solvates thereof) provided herein is about 〇· 5, about 0.6, about 〇·7, about 〇8, about 〇.9, (5) 1, about 1.1, about 1.2, about 1.4, about 1.5, about 1-6, about! 8, about 2, about 2_2, about 2.4, about 2.6, about 2.8 or about 3. In one embodiment, 4-(1-(3-fluorophenylindenyl)-Ifcarbazole-5-ylamino)-5-methylpyrrolotriazole A benzenesulfonate or a hydrate thereof or a pharmaceutically acceptable solvent Q of hydroxymethyl morpholine-3 benzyl phthalate containing about 1 mole equivalent of 4-(1-( 3-fluorophenyl fluorenyl is 丨 _ _5_ ylamino)-5• decylpyrrolo[1,2-/][1,2,4]triazin-6-ylaminocarboxylic acid (( 5) morpholine-3-ylmethyl ester and about 丨 丨 molar equivalent of benzenesulfonic acid. In certain embodiments, 4-(1·(3-fluoromethane)-1//-carbazole- 5-aminoamino)-5-methylindolo[1'2-/][1,2,4]trinitrogen_6_ylaminocarbamate 51) The morpholine _3_ dimethyl ester is determined by the 1 h nmr spectrum of the stupid s acid. In certain embodiments, 4_(1_(3_fluorobenzoquinone carbazole·5• Amino group) _5-fluorenyl ratio 咯 Π, 2-/] [1, 2, 4] triazobenzene-6-ylaminocarboxylic acid (<s> morphine 3-methyl acesulfate benzene sulfonate The acid salt or hydrate thereof or a pharmaceutically acceptable solution 154673.doc • 27-201136935 The composition has a purity of at least about 95%, at least about 96%, at least about 97%, at least about 98°/〇, at least About 98.5%, at least about 99°, at least about 99.2%, at least about 99.4%, at least about 99.5%, at least about 99.6%, at least about 99.7°, at least about 99.8%, or at least about 99.9%. In some embodiments, 4-(1-(3-fluorobenzyl)-1//-carbazol-5-ylamino)-5-methyl "bi-[i,2-[][ 1,2,4]triazol-6-ylamino decanoic acid ($)-nor--3-methylmethyl ester benzoate or a hydrate thereof or a pharmaceutically acceptable solvate thereof Nitramine, which contains no more than about 5 ppm, no more than about 4 ppm, no more than about 3 ppm, no more than about 2 ppm, no more than about i_5 ppm, no more than about i ppm, no more than about 0.8 ppm, no More than about 0.6 ppm, no more than about ppm4 ppm, no more than about 0.2 ppm, or no more than about 1.1 ppm. In one embodiment '4-(1-(3-fluorobenzylidazole)-5-yl Amino)-5-methyl-pyrrolo[1,2-/1[1,2,4]triazot-6-ylaminophosphonic acid (lS)-morpholin-3-ylmethyl ester benzene The sulfonate or its hydrate or pharmaceutically acceptable solvate is in an amorphous form. In another embodiment, 4-(1-(3-aminophenyl)-1//-carbazol-5-ylamino)-5-methylpyrrolo[nyjnytrinitrogen_6_ylamine The guanidinoic acid (5> methionine-3-methyl acetal benzoate or a hydrate thereof or a pharmaceutically acceptable solvate thereof is in a crystalline form. In certain embodiments, the besylate is in DSC The thermogram has a peak temperature of about 145. The onset temperature is 13 1. (: The endotherm. In some embodiments, the besylate has a peak temperature of about 23 in the DSC thermogram. And an endothermic temperature of 225. In yet another embodiment, 4-(1-(3-fluorobenzyl)oxazol-5-ylamino)-5-methylpyrazine is provided herein. And [^-力^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ As used herein, the term "p-benzoic acid sulphate 11^1^31!1£〇111 (: deduction 3)" and the term "tosylate salt" Used interchangeably. In certain embodiments, 4-(1-(3-fluorobenzyl)-1//-carbazol-5-ylamino) 5 曱 。. 嘻 fl fl 2 2 2 , , , , , fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl

The molar ratio of the p-toluene acid in the acceptable solvate is in the range of from about 5 to about 3, from about 0.5 to about 2, or from about 0.8 to about 12. In certain embodiments 4_(1_(3·I benzyl)_1 ugly_吲嗤_5_ylamino)_5_mercaptopyrloindole '2·/Ι[1,2,4] Nitrogen 啩6-ylamino decanoic acid (6) morpholine _3 yl methyl ester for the p-toluenesulfonic acid in the salts provided herein (including hydrates or pharmaceutically acceptable solvates thereof) The ear ratio is about 、5, about 〇6, about 〇7, about 8, 〇.9, about 1, about U, about L2, about 1.4, about 1.5, about 1.6, force 18, about 2 About 2.2, about 2.4 'about 2.6, about 2.8 or about 3. In the example, '4-(1-(3_fluorobenzyl)_17^ 嗤_5_ylamino) methyl hydrazino each [1,2- sin, 2,4] triazepine -6-ylamino decanoic acid (7)-morpholine 3 yl methyl ester p-toluene sulfonate or a hydrate thereof or a pharmaceutically acceptable 'combination composition containing about 1 mole equivalent of 4-(1-( 3- gas phenyl hydrazino) -1 ^ 唾 = = · 胺 ) ) _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ The equivalent of terephthalic acid. In certain embodiments, 4_(1-(3-fluorobenzyl)]"♦ sits on the I-amino group)_5_土比咯和[1,2-/][1,2,4]triazole The molar ratio of the _6_ylaminocarbamic acid (5)-morpholinylacetic acid to p-toluene was determined based on its lH NMR* spectrum 154673.doc -29-201136935. In certain embodiments, 4_(1_(3_fluorobenzyl)-1//-oxazol-5-ylamino)-5-methylpyrrolotriazine _6-ylamino decanoic acid (5> morpholin-3-yl decyl ester of p-toluenesulfonate or a hydrate thereof or a pharmaceutically acceptable solvate having a purity of at least about 95%, at least about 96%, at least about 97%, At least about 98%, at least about 98.5%, at least about 99%, at least about 99.2%, at least about 99.4%, at least about 99.5°, at least about 99.6%, at least about 99.7%, at least about 998%, or at least about 99.9%. In certain embodiments '4-(1-fluorobenzylcarbazol-5-ylamino)-5-methylpyrrolo[1,2-/][1,2,4 Trinitrogen _6_ ylaminocarboxylic acid (p- morpholine-3-yl methyl ester of p-toluenesulfonate or its hydrate or pharmaceutically acceptable solvate containing nitrosamines) Not more than about 5 ppm, no more than about 4 ppm, no more than about 3 ppm, no more than about 2 ppm, no more than about 1.5 ppm, no more than about i ppm, no more than about 〇·8 ppm, no more than about 〇·6 Ppin, no more than about 4 ppm, no more than about 0.2 ppm, or no more than about 0.1 ppm. In one embodiment, 4-(1-(3-fluorobenzyl)吲 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ - a methyl or acetal p-toluene acid salt or a hydrate thereof or a pharmaceutically acceptable solvate thereof in an amorphous form. In another embodiment, J〒4-(1-(3-fluorophenyl) -1 ugly-oxazol-5-ylamino)-5-methylindole-l'y"L丄,2,4]triazot-6-ylaminocarbazate-3-morphyl The ester is present in the STT propionate or a hydrate thereof or a pharmaceutically acceptable solvate thereof. In some embodiments, the p-toluenesulfonate is in the DSC. In the thermogram, there is an endothermic line with a peak temperature = about 202 ° C. & '154673.doc -30- 201136935 In yet another embodiment, 4_(1_(3_fluorobenzylmethyloxazolylamino) is provided herein. -5-mercaptopyrazine, 2-/][1,2,4]triazot-6-ylaminocarbamic acid (S)-morpholin-3-ylmethyl ester acetate, or Hydrate or pharmaceutically acceptable solvate. As used herein, the term "acetate" is used interchangeably with the term "acetate salt". In the examples, 4_(1_(3_fluorobenzylmethyl W oxazole 3-5 amino group) _5_methyl ° ratio [1,2-/][1,2,4] triazotide - The molar ratio of 6-ylaminocarbamic acid (5> morpholin-3-ylmethyl ester to acetic acid in the salts (including hydrates and pharmaceutically acceptable solvates thereof) provided herein is from about 0.5 to It is in the range of about 3, about 0.5 to about 2, or about 〇·8 to about 12. In certain embodiments, 4-U_(3-fluorobenzyl) carbazole _5-ylamino) _5_ fluorenyl η is compared to [1]-/][1'2,4] Nitrogen-based 6-ylamino decanoic acid (>s)-morpholine-3-ylmethyl ester to acetic acid in the salts (including hydrates and pharmaceutically acceptable solvates thereof) provided herein The molar ratio is about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 1.1, about 1, 2, about 1.4, about 1. 5, about 1.6, about 1.8, about 2, about 2.2, About 2.4, about 2.6, about 2.8 or about 3. In one embodiment, 4-(1-(3-fluorophenylindenyl)-1//-carbazole-5-ylamino)-5-methyl. Bilo and trisinolate_6-ylaminocarboxylic acid (Acidylmorpholine-3-yl acetonitrile acetate or its hydrate or pharmaceutically acceptable solvate comprises about 1 mole equivalent of 4_(1_ (3_Fluorobenzoyl)_丨 吲 · oxazole _5_ ylamino)-5-methyl hydrazine and trinitrogen _6_ ylaminocarboxylic acid (幻_ _琳-3-基甲Esters and about 1 mole equivalent of acetic acid. In certain embodiments, '4-(1-(3·fluorobenzoinyl)_17/-oxazol-5-ylamino)_5_mercaptopurine// 1[1,2,4]trinitrogen_6·ylaminophosphonic acid•morpholine_3_yl decyl ester to acetic acid 154673.doc -31 · 201136935 The molar ratio is determined based on its 1H NMR spectrum. In certain embodiments, 4-(1-(3-fluorophenylindenyl)-1 danoxazol-5-ylamino)-5-fluorenyl. Biordo[1,2-/][ 1,2,4] Triazol-6-ylaminocarbamic acid ($)-M-line-3-yl decyl acetate or its hydrate or pharmaceutically acceptable solvate has a purity of at least about 95%, at least about 96%, at least about 97%, about 98/0, at least about 98-5%, at least about 99%, at least about 99 2%, at least about 99.4%, at least about 99.5%, at least about 99.6%. At least about 99.7%, at least about 99.8% At least about 99.9 %. In certain embodiments, 4-(1-(3-fluorobenzyl)-1孖-oxazol-5-ylamino)_5-methyl-pyrrolo[12- /][1,2,4] Triazolam-6-ylaminocarboxylic acid (phanyl-morpholin-3-yl decyl acetate or its hydrate or pharmaceutically acceptable solvate containing nitrosyl An amine having a content of no more than about 5 ppm, no more than about 4 ppm, no more than about 3 ppm, no more than about 2 ppm, no more than about 丨5 ppm, no more than about 1 ppm, no more than about 0.8 ppm, no more than Approximately 6 ppm, no more than about 〇.4 ppm, no more than about 0.2 ppm, or no more than about 1. 1 ppm. In one embodiment, 4-(1-(3_fluorobenzoquinone carbazole _5_) -amino-5-methylpyrrolotriazole _6-ylamino decanoic acid ((S)-morpholine 3 -methyl sulfonium acetate or its hydrate or pharmaceutically acceptable solvent The object is in an amorphous form. In another embodiment, 4-(1-(3-fluorophenylindolyl)//-carbazol-5-ylamino)-5-fluorenyl. Plough_6_ylamino decanoic acid (5> morpholin-3-ylmethyl acetate or its hydrate or pharmaceutically acceptable/glutamine compound is in crystalline form. In one embodiment, the acetate has an endothermic line having a peak temperature of about 127 ° C and an onset temperature of i 丨 9. In some embodiments, the acetate has a peak temperature of about 165 ° C and an onset temperature of 154673. .doc -32- 201136935 The heat absorption line of 160 °C. In yet another embodiment, 'in this context, 4-(1-(3-fluorobenzyl)oxazol-5-ylamino)-5-methyl D is more than argonium triazinyl-6-ylaminocarbazide S)-Morphyrin-3-yl decyl ester maleate, or a hydrate thereof or a pharmaceutically acceptable solvate. As used herein, the term "maleic acid salt" is used interchangeably with the term "maleatesalt". In certain embodiments, the 4-(1-(3-fluorobenzyl)- 17/oxazol-5-ylamino group of the salt provided herein (including hydrates or pharmaceutically acceptable solvates thereof) )-5-methyl alpha pyrrolo[1,2_/][1,2,4]triazot _6-ylaminocarboxylic acid (5>morpholin-3-ylmethyl ester to maleic acid The molar ratio is in the range of from about 25 to about 1.5, from about 0.25 to about 1, or from about 4.4 to about 。 6. In certain embodiments, the salts provided herein (including hydrates thereof) a pharmaceutically acceptable solvate) 4-(1_(3_fluorobenzyl)_17/_carbazole_5•ylamino)_5_ = base ratio 咯[1,2-/][ 1,2,4]trinitrogen _6_ylamino phthalic acid morpholine _3_ hydrazine vinegar molar ratio to maleic acid is about 〇2, about 〇25, about Ο], about 〇·35 '约〇·4, 约〇·45, 约〇·5, about 0.55, about 0.6, about 〇.65, about 〇.7, about 〇.75, about 0.8, about 1_〇, about 1.1 , about 1.2, about, about or about 1.5. In one embodiment '((W3-fluorobenzyl)-1 丹 嗤-5-ylamino) 5 曱 比 各 [1, 2 - knife t1, 2, 4] trigasta-6-ylamino decanoic acid (S - 淋 -3- 曱 曱 vinegar cis succinate or its hydrate or pharmaceutically acceptable solvate comprises about ? t # θ η 2 Mo 1 although 4-(1-( 3-fluorophenylhydrazinyl-5-ylamino-review ηαΜ,, !)5 methyl η than hahatriazole _6_ylamino 154673.doc • 33 · 201136935 formic acid (5 > morpholine -3_ylmethyl ester and about! molar equivalent of maleic acid. In certain embodiments '4_(1_(3·fluorobenzylsulfonium-5_ylamino)_5_methylpyrrole [1,2-/][1,2,4]triazo-p-aminocarbamic acid (phantom-morpholine_3_ ketone is determined by the spectrum of maleic acid based on its spectrum. In some embodiments, 4-(1-(3-fluorobenzyl)_li7_carbazole-5-ylamino)-5-methylindoloindole, 2ν][1,2,4]triazole The purity of the _6-ylaminocarboxylic acid (5> morpholin-3-ylmethyl ester maleate or a hydrate thereof or a pharmaceutically acceptable solvate thereof is at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 98.5%, at least about 99%, at least about 99.2%, at least about 99.4%, at least about 99.5%, at least about 99.6%, at least about 99.7% ,to About 99 8% or at least about 99 9%. In certain embodiments 4 Π (3-gasomethyl)_ι//_〇〇丨丨_5_ylamino)_5_methyl 0 to D each And [1,2-/][1,2,4]triazolam _6_ylaminocarbamic acid (fantasy-morpholine_3_yl decyl ester of maleate or its hydrate or medicinal An acceptable solvate containing nitrosamine in an amount not exceeding about 5 ppm, not exceeding about 4 ppm, not exceeding about 3 ppm, not exceeding about 2 ppm, not exceeding about 丨5 ρρηι, not exceeding about 1 ppm No more than about 88 ppm, no more than about 6 ρριη, no more than about ppm4 ppm, no more than about ppm2 ppm or no more than about 〇1 ppm. In one embodiment, 4-(1-(3-fluorophenylindenyl)-1//-carbazol-5-ylamino)-5-methyl-haha, is 24 π, 2, 4] Triazinyl-6-ylamino decanoic acid (fanta-methion-3-yl vinegar maleate or a hydrate thereof or a pharmaceutically acceptable solvate thereof in an amorphous form. In one embodiment, 4-(1 _(3_fluoro 曱 曱 弓 坐 _5-ylamino)-5-mercapto fluoren[1,2-/][1,2,4] Gas 154673.doc -34- 201136935 Ο 耕 -6-6-ylamino decanoic acid (fanta-morpholine-3·yl decyl methoxide or its hydrate or pharmaceutically acceptable solvent The material is in crystalline form. In certain embodiments, the maleate has an endotherm in the DSC thermogram having a peak temperature of about 197 C and an onset temperature of 194 ° C. In certain embodiments, The maleate salt is shown in the thermogravimetric thermogram. The weight loss between hydrazine and hydrazine is about 0.1%. In certain embodiments, the cis-butadiate is shown in the thermogravimetric thermogram. The weight loss between 25t and 15(rc) is no more than about, no more than about 4.5%, no more than about 4%, no more than about 3.5%, no more than about 3%. No more than about 25%, no more than about, no more than about 1.5%, no more than about 1%, no more than about 〇8%, no more than about 〇·6%, * more than about 〇.4%, no more than About 2%, no more than about %1%, no more than about 0_09%, no more than about 〇.〇8%, no more than about 〇〇7%, no more than about 0.06% or no more than about 〇5〇/〇 In the examples, 4_(1_(3_款苯苯克), _5_ylamino) 5-methylindole, 2, 2, 4] triazinyl-6-yl Ammonic acid (7)-Merlin I methic acid maleate or a hydrate thereof or a pharmaceutically acceptable solvate thereof in crystalline form m_Ae, in some embodiments, in the form of this A The enedionate has an X-ray powder diffraction substantially as shown in Figure 3A. In certain embodiments, the maleic acid in the form of ΙΠ-Α is selected from about 10.0., 10.8. U", 17.2., 216., 22 5:, 22.7, 24.6, 26 〇, and 29 6. The (9) corner has one or XRP diffraction peak. In this case, a two-in-one example In the form, the maleic acid salt of ΠΙ-Α is in the range of about 5.1., 12 γΛ. r is defeated. 14·0, 15.2. 5.5. There are characteristic XRP diffraction peaks at the 2 corners. In some solid yoke cases, the maleic 154673.doc -35-201136935 acid salt of the form m_A is about 5.1°, 12.8. , 14. 〇, 15 2, i5 5, π?, 18.0, 20.7, and 22.1. At the 20th corner there is a characteristic XRp diffraction peak. In some embodiments t, the maleic acid salt of the form ΙΠ Α is at about 51. , ' 12.8. , Μ.0. 15.2. , 15.5. 17 7 18 〇. 19 2 . 20.7. , 22.1. And 22.7. The π angle has a characteristic and a meandering peak. In some embodiments, the cis- methenedonate in the crystalline form ΙΠ_Α has an endotherm with a peak temperature of about 2061 in the Dsc thermogram. In certain embodiments, the maleate salt in crystalline form III-A exhibits a weight loss between about 25 ° C and about 150 ° C in a thermogravimetric thermogram. In another embodiment, 4-(1-(3-fluorophenylindenyl)_17/_carbazole-5-ylamino)-5-methylindole [ι,2-/][ι, 2,4] Triazine/6-aminocarbamic acid morpholin-3-ylmethyl ester maleate or a hydrate thereof or a pharmaceutically acceptable solvate thereof in the form of a crystalline form Πϊ-Β. In certain embodiments, the maleic acid salt of Form III-B has a ray diffraction powder diffraction pattern substantially as shown in Figure 3B*. In certain embodiments, the maleic acid salt of the form (1) has a characteristic XRP diffraction peak at 2 corners of 29.8°. In certain embodiments, the maleic acid salt of the form ΙΙΙ-Β is at about u 6 . And 15 6. The 2 corners have characteristic XRP diffraction peaks. In certain embodiments, the cis-indole succinate salt is in the form of about U.6. And 2S". There are characteristic XRp diffraction peaks at the 2 corners. In certain embodiments, the maleic acid salt of the indole-quinone is in the form of about 5.0. , 11.6 〇, 15.6. 251. And 27 4. At the 20th corner, there is a characteristic XRP diffraction peak. In certain embodiments, the maleic acid salt of ruthenium-iridium in crystalline form has a peak temperature of about 198 in the DSC thermogram. (: The endothermic line. In some embodiments, the maleate exhibit in crystalline form III-B 154673.doc -36-201136935 is not between the pyrolysis reset thermograms between 25eC and 122°C The weight loss is about 2.8%. In some embodiments, the maleic acid in the crystalline form ΙΠ-Β is not in the thermogravimetric thermogram. 25. The weight loss between 〇 and 166t is About 3.5%. In another embodiment, 4-(1-(3-fluorobenzyl)-1 dan-oxazol-5-ylamino)-5-mercaptopurine 4]triazole Spraying amine decanoic acid (bumlolin-3-ylmethyl s-methionate or a hydrate thereof or a pharmaceutically acceptable lozenge thereof in crystalline form m_c. In certain embodiments The maleic acid salt of Form III-C has a diffraction pattern of X-ray powder substantially as shown in Figure %. In certain embodiments, the succinic acid sni-c is formed in a shape selected from the group consisting of 8.8., U.〇, n 9, 16 8 , 18 3, Μ".: 〇 and 27.8 of the 2 corners have one or more characteristic XRp diffraction peaks. In some embodiments The maleic acid salt of the form HI-C is at a corner of about 17.4° Characteristic XRp diffraction peaks. In certain embodiments, the maleic acid salt of the form iπ-c has a characteristic XRP diffraction peak at (17) angle Q of about 17 4 〇, 25 3 〇 and 27 〇〇 (9) In certain embodiments, the cis-butanoate salt is present at about 17.4, 22.3, 23.9, 25.3, and 27. 〇. The 20th corner has a characteristic XRP diffraction peak. In one embodiment, '4-(1-(3-fluorobenzyl)-oxazolylamino)-5H is more than hydrazino and (1) is triazalcarbamic acid morpholine-3- The maleic acid salt of the methyl ester or a hydrate thereof or a pharmaceutically acceptable solvate thereof is in the crystalline form m_D. In certain embodiments, the cis-sebacate salt in the form of m-D has substantially Figure 3A shows the diffraction (four) end diffraction pattern. In some embodiments, the maleic acid salt of decene is 154673.doc • 37·201136935 is selected from about 3.6., 4.6. 7·4, 12.4, and 19.5. There are - or a plurality of characteristic XRP diffraction peaks at the 2 corners. In some embodiments, the maleic acid salt in the form is about I3·4, 17_5. And 19.5. At the 20th corner, there is a characteristic XRP winding. In some embodiments, the maleate salt in the form of m_D has an endotherm with a peak temperature of about 82 t in the DSC thermogram. In some embodiments, the form is in-D. The enedionate is shown in the pyrolysis heat profile as 25 (3 and 91 (1; the weight loss is about 14.3%. In yet another embodiment, this article provides 4_(1_(3_Fluorobenzoic) N-"open-carbazol-5-ylamino)-5-methylindolo[^"[^, 叼trinitrogen-p-aminocarbamic acid morpholin-3-ylmethyl ester nitrate, or a hydrate or a pharmaceutically acceptable solvate thereof. As used herein, the term "nitHc acidsalt" is used interchangeably with the term "nitratesalt". In certain embodiments, '4-(1-(3-fluorophenylindenyl)-carbazole-5-ylamino)-5-fluorenyl is compared to [^-/^^, three The molar ratio of nitricin to the amino acid in the salts (including hydrates and pharmaceutically acceptable solvates thereof) provided herein Approximately 5 to about 3, about 5 to about 2, or about 8 to about ι. In certain embodiments, 4-(1-(3-fluorobenzyl)oxazol-5-ylamino)_5_indolyl π is conjugated to /1[1,2,4]triazole Plowing _6_ylaminocarboxylic acid ( <s) _ morpholine _3_ decyl ester The molar ratio of nitric acid in the salt of the salt (including hydrates and pharmaceutically acceptable solvates thereof) to be used herein is about 〇.5, about 〇·6, about 0.7, about 〇.8, about 0.9, about 1, about 1.1, about 1. 2, about 1.4, about 1.5, about 1.6, about 1.8, about 2, about 2_2, about 2.4, about 2.6, about 2.8 or about 3. In one embodiment, 4-(1-(3-fluorophenylhydrazinocarbazol-5-ylamino) 154673.doc -38·201136935 -5_methyl° is more than [12-/^1, 2,4] Triazot-6-ylaminocarboxylic acid (fanta-morpholine-3-ylindole S nitrate or a hydrate thereof or a pharmaceutically acceptable solvate thereof comprising about 1 mole equivalent 4-(1-(3-fluorobenzyl)-1 ugly-oxazol-5-ylamino)_5_methyl" than s-trinitrobenzene _6-ylamino decanoic acid (phantom morpholine) -3-yl decyl ester and about nitric acid equivalent of nitric acid. In certain embodiments, 4-(1-(3-fluorophenylindenyl)-1 dan-oxazol-5-ylamino)_5_曱 ° ° [ [1,2-/1[1,2,4] triazolam-6-ylamino decanoic acid (fanta-lan-3-methyl methyl nitrate or its hydrate or The pharmaceutically acceptable solvate has a purity of at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 98.5%, at least about 99%, at least about 99.2%, at least about 99.4. %, at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.80/〇 or at least about 99.9%. In certain embodiments, 4-(1-(3-fluorobenzyl) -1 ugly oxazol-5-ylamino)-5-decylpyrrolo-][1,2,4] A nitrate of N-morphin-6-ylaminocarbamate (5> morpholin-3-ylmethyl ester or a hydrate thereof or a pharmaceutically acceptable solvate thereof containing nitrosamine in an amount not exceeding about 5 ppm, Not more than about 4 ppm, no more than about 3 ppm, no more than about 2 ppm, no more than about 1.5 ppm, no more than about 1 ppm, no more than about 0.8 ppm, no more than about 〇6 ppm, no more than about 0.4 Ppm, no more than about 0.2 ppm or no more than about 0.1 ppm. In one embodiment, 4-(1-(3-fluorobenzyl)-1-oxazol-5-ylamino)-5-oxime Nitrate [1,2-/][1,2,4]triazot-6-ylaminocarbamate (S)-morpholin-3-ylmethyl ester nitrate or its hydrate or medicine The pharmaceutically acceptable solvate is in an amorphous form. In another embodiment, 4-(1-(3-fluorophenylindenyl)_1openo-oxazol-5-ylamino)-5-fluorenyl吼 并 [1,2-/][1,2,4]triazot-6-ylamine 154673.doc •39- 201136935 carbamic acid (*S)-Mallin-3-yl acetate The acid salt or hydrate thereof or a pharmaceutically acceptable solvate is in crystalline form. In certain embodiments, the citrate salt has a peak temperature of about 21 6 in the DSC thermogram. The starting temperature is an endotherm at 210 ° C. In another embodiment, 4-(1-(3-fluorophenylhydrazinoconazole-5-ylamino)-5-methyl is provided herein. [1,2-/][1,2,4]triazin-6-ylamino decanoic acid (S)-morpholin-3-yl decyl ester or its hydrate or A pharmaceutically acceptable solvate. As used herein, the term "phosphoric acid salt" is used interchangeably with the term "ph〇sphate salt." In certain embodiments, '4-(1-(3-fluoro)methyl)-!"_carbazole-5-ylamino)-5-fluorenyl 0 is more than [1,2-/] [1,2,4]triazot-6-ylamino decanoic acid ($) morpholine-3-yl decyl ester The salts provided herein (including hydrates thereof and pharmaceutically acceptable solvents) The molar ratio of the phosphoric acid in the compound is in the range of from about 5 to about 3, from about 0.5 to about 2, or from about 0.8 to about 1.2. In certain embodiments, 4-(1-(3-fluorobenzyl)-1 · 〇 0 0 sits _5_ ylamino)_5_methyl π than haha [1 /] [1, 2,4] diazepine-6-ylamino decanoic acid (fantasy-morpholine-3-ylmethyl ester) in the salts provided herein (including hydrates and pharmaceutically acceptable solvates thereof) The acid-killing molar ratio is about 〇.5, about 〇·6, about 0.7, about 〇·8, about 〇·9, about 1' about 1.1, about 1.2, about 1. 4, about 1.5, about h6, About 8, 8, about 2.2, about 2.4, about 2.6, about 2_8 or about 3. In one embodiment, 4_(1_(3_fluorobenzylcarbazole-5-ylamino)-5- Methyl hydrazine, 2, 2, 4] trinitrogen P well _6_ylaminocarbamic acid (7) morpholine _3 _ _ _ _ _ salt or its hydrate or pharmaceutically acceptable solvent 154673.doc •40-201136935 contains about 1 molar equivalent of 4-(1-(3-fluorophenylindenyl)-1 ugly-oxazol-5-ylamino)-5-mercapto "咯[12412,4]triazolam _6-ylaminophosphonate morpholin-3-yl decyl ester and about 1 molar equivalent of phosphoric acid. In certain embodiments, 4-(1-(3- Fluorobenzylcarbazol-5-ylamino)-5-methyl"pyrho[i,2-/][i,2,4]trinitrogen- The purity of the 6-aminoamino decanoic acid (*S)-morpholin-3-yl decyl phosphate or a hydrate thereof or a pharmaceutically acceptable solvate thereof is at least about 95%, at least about 96%, At least about 97%, at least about 98%, at least about 98.5%, at least about 99%, at least about 99.2%, at least about 99.4%, at least about 99.5%, at least about 99.6%, at least about 99.7°/〇, at least about 99.8. % or at least about 99.9%. In certain embodiments, 4-(1-(3-fluorobenzyl)-1//-indazol-5-ylamino)-5-methyl [1,2-/][1,2,4]triazot-6-ylaminocarbamic acid (^)-morpholin-3-yl decyl phosphate or a hydrate thereof or pharmaceutically acceptable The solvate contains nitrosamines in an amount not exceeding about 5 ppm, not exceeding about 4 ppm, not exceeding about 3 ppm, not exceeding about 2 ppm, not exceeding about 1.5 ppm, not exceeding about 1 ppm, not exceeding about 0.8. Ppm, no more than about 0.6 ppm, no more than about 0.4 ppm, no more than about 0.2 ppm, or no more than about 0.1 ppm. In one embodiment, '4-(1-(3-fluorobenzyl)-1) _ carbazole _5_ylamino) -5-methylpyrrolo[1,2-/][1,2,4]triazot-6-ylaminocarboxylic acid (S)-morpholine-3 Base oxime The acid salt or a hydrate thereof or a pharmaceutically acceptable solvate is in an amorphous form. In another embodiment, 4-(1-(3-fluorophenylindenyl)-1//-carbazole-5 -aminoamino)-5-fluorenylpyrrolo[1,2·/][1,2,4] triterpenic-6-ylamino decanoic acid ( The salt of <S)-nor--3-methylmethyl ester or a hydrate thereof or a pharmaceutically acceptable solvate is in a crystalline form. In certain embodiments, the citrate 154673.doc -41 - 201136935 has an endotherm with a peak temperature of about 16 passages and a starting temperature of 159 °C in the DSC thermogram. The degree of purity of the salts provided herein can be determined by standard analytical methods such as thin layer chromatography (TLC), gel electrophoresis, gas chromatography, high performance liquid (HPIX) and mass spectrometry. The salts in solid form provided herein can be characterized using a number of methods known to those skilled in the art including, but not limited to, single crystal X-ray diffraction, X-ray powder diffraction (XRPD), microscopy (eg, Scanning electron microscopy (SEM), thermal analysis (eg, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and hot stage microscopy) and spectra (eg, infrared, Raman) And solid state nuclear magnetic resonance). The particle size and size distribution of the salt in solid form provided herein can be determined by conventional methods, such as laser light scattering techniques. It should be understood that the value of the peak of the X-ray powder diffraction pattern of the mouth machine with another machine or of one sample and another sample may be slightly different, and therefore the value should not be regarded as an absolute value, but rather has an allowable The variability is as recommended in the United States Pharmacopeia (pp. 387-389; 2007). . Method of Preparation In one embodiment, provided herein is a 4-(1-(3-fluorobenzyl)oxazol-5-ylamino)-5-mercaptopurine/[1][1] as provided herein. , 2,4] a method for the salt of a ruthenium hexamethylene-6-ylaminocarbazate or a hydrate thereof or a pharmaceutically acceptable solvate thereof; the method comprising the first predetermined temperature 4-(1-(3-fluorobenzyl)_ι/^oxazol-5-ylamino)-5-fluorenylpyrrolo 4]triazh-6-ylaminocarboxylic acid 154673. Doc -42- 201136935 oxa-3-yl decyl ester is reacted with an acid in a solvent. In another embodiment, the method further comprises precipitating the salt at a second predetermined temperature. In certain embodiments, the reaction and/or precipitation steps are carried out under an inert atmosphere. In one such embodiment, the reaction and/or precipitation steps are carried out under a nitrogen or argon atmosphere. Suitable solvents for the preparation of the salts known herein include, but are not limited to, hydrocarbons, including petroleum ether, pentane, hexane, heptane, octane, isooctane, cyclopentane, cyclohexane, methylcyclohexane. Alkanes, benzene, toluene, xylene, tetralin and cumene; halogenated hydrocarbons, including dichloromethane (DCM), 1,2-dichloroethane, i, diethylene, 1,2-dichloride Ethylene, chloroform, trichloroethane, triethylene glycol, tetra-carbonized carbon, perfluoroethylene, benzene and trifluoromethylbenzene; alcohols, including decyl alcohol (MeOH), ethanol (EtOH), trifluoro Ethanol (butyl FE), isopropanol (IPA), 1-propanol, hexafluoroisopropanol (HFTpA), 丨-butanol, 2 butanol, second butanol, 2-mercaptopropanol, 3_ Methyl 4-butanol, 丨-sterol, third pentanol, 2-methoxyethanol, 2-ethoxyethanol and ethylene glycol; ethers, including diethyl ether, diisopropyl ether, methyl tertidine Ether (MTBE), mercapto nonafluorobutyl ether, diphenyl ether 'i,2_dimethoxyethane, bis(2-methoxyethyl) ether, 1,1-dimethoxymethane , 2,2-dimethoxypropane and anisole; ketones, including acetone, methyl ethyl ketone, methyl ethyl Ketone (MEK), mercapto isopropyl ketone, methyl butyl ketone I, methyl isobutyl ketone (MIBK), 3-pentanone and cyclopentanone, esters, including methyl acetate, ethyl citrate, Ethyl acetate (EtoAC), ethyl difluoroacetate, propyl acetate, isopropyl acetate (IPAC), isobutyl acetonate and butyl acetate 'carbonate, including ethylene carbonate and propylene carbonate; , including methotrexate, #,#_二曱基曱醯amine (1) PCT" and #,...二曱154673.doc •43· 201136935 acetamide; nitrile 'including acetonitrile (ACN) and propionitrile; Including dimethyl sulfoxide (DMSO); sulfones, including cyclobutyl hydrazine; nitro compounds, including nitrodecane and nitrobenzene; heterocycles, including decyl pyrrolidone, 2-methyltetrahydrofuran, tetrahydrofuran ( THF), dioxane and pyridine; carboxylic acid, including acetic acid, trichloroacetic acid and trifluoroacetic acid; phosphoniumamine, including hexamethylenephosphonamide; disulfide; water; and mixtures thereof. Medium, the solvent is di-methane, acetone, acetonitrile, ethanol, dicentrone ethanol, isopropanol, hexafluoroisopropanol, ethyl acetate, isopropyl acetate, tetrahydrogen Methane, water, MTBE or mixtures thereof. In certain embodiments, the salt formation step is from about 丨〇 丨〇 to about 15 〇〇 c, from about 10 ° C to about 110. (: or about 20. (: To a temperature of about 10 (TC). In certain embodiments, the salt formation reaction is at about 20 ° C, about 2 yc, about 3 (rc, about 35 C, about 40 C, about 45 ° C, or about 50 The temperature is ° C. In one embodiment, the solvent used in the salt forming step is di-methane, acetone, acetonitrile, ethanol, trifluoroethanol, isopropanol, hexafluoroisopropanol, acetic acid, Isopropyl acetate, tetrahydrofuran, water, or a mixture thereof. In certain embodiments, the salt formation step is carried out in the presence of about an equivalent of acid. In certain embodiments, the salt forming step is carried out in the presence of an excess of acid to maximize the reaction yield. In certain embodiments, the molar ratio of the acidic group on the acid to the compound of formula I is about 丨. , about 丨, 么 (10), about U or about 12. In certain embodiments, the acid group on the acid: the molar ratio of the compound of formula I is in the range of from about 0.5 to about j 〇, about 〇, about 5 or about 0.95 to about 2.5. In certain embodiments, the salt forming step is carried out in solution, i.e., formula 154673.doc -44 - 201136935 i both the compound and the acid are dissolved in a solvent. In certain embodiments, the salt formation step is carried out as a slurry mixture of the compound of formula I and the acid in solvent t. In certain embodiments, the compound of formula I does not completely dissolve and the acid is completely dissolved. In certain embodiments, the salts provided herein are precipitated from a reaction solution or a slurry mixture using conventional methods including, but not limited to, cooling, chilling, solvent evaporation, addition of a counter. Solvent, or add the salt mixture back to the anti-solvent. In certain embodiments, the salts provided herein are precipitated from the reaction solution or slurry mixture upon cooling. In certain embodiments, the salts provided herein are precipitated from the reaction solution or slurry mixture via the addition of an anti-solvent. Suitable anti-solvents include, but are not limited to, hydrocarbons including petroleum ether, pentane sulphide, Gengyuan, octane, isooctane, cyclopentane, cyclohexane, nonylcyclohexane, benzene, toluene, dioxins. Benzene, tetralin and cumene; halogenated hydrocarbons, including 1,2-dichloroethane, di-ethylene, 1,2-dichloroethylene, chloroform, trichloroethane, trichloroethylene, tetra Carbon chloride, perfluoroethylene, benzene and trifluoromethylbenzene; alcohols, including 1-butanol, 2-butanol, tert-butanol, 2-methyl-; μ-propanol, 3-mercapto Butanol, 1-pentanol, second pentanol, 2-methoxyethanol, 2-ethoxyethyl glycol and ethylene glycol; ethers include diethyl ether, diisopropyl ether, decyl tertiary butyl ether ( MTBE), mercapto nonafluorobutyl ether, diphenyl ether, 1}2-dimethoxyethyl, bis(2-methoxyethyl) ether, 1,1-dioxamethane, 2,2 - Dimethoxypropane and phenyl hydrazine; ketone' includes butanone, mercaptoethyl ketone, mercapto isopropyl ketone, decyl butyl ketone, methyl isobutyl ketone (MIBK), 3 - pentanone And cyclopentane 154673.doc •45· 201136935 ketone; ester, including isobutyl acetate and butyl acetate; carbonate, package Ethylene carbonate and propylene carbonate; sulfones, including cyclobutyl hydrazine; nitro compounds, including Shi Xiaoji 曱 • • and basic; heterocycles, including two „ 烧 及 and „ ratio π 定; carbon disulfide; water; mixture. In certain embodiments, the anti-solvent is hydrazine, water, or a mixture thereof. When two solvents are used as the solvent/antisolvent pair, the solubility of the salts provided herein in the solvent is higher than in the antisolvent. In some embodiments, the solvent/antisolvent is at least partially miscible with the solvent and antisolvent of the solvent. In certain embodiments the 'precipitation step is between about -50. (: to about 1 Torr (TC, about -30 C to about 5 (TC or about _10 ° c to about 3 ° ° C. In some embodiments, the 'precipitation step is at about 〇t: , about 5 〇 c, about 1 〇χ:, about 15 C, about 20 C, about 25. (: or about 30. (: at the temperature. In order to accelerate the precipitation (crystallization) step, the method can be further included in The step of seeding the reaction solution or mixture before or during the start of the precipitation step. The amount of the seed crystal added exceeds the saturation amount in the solvent used, so that the undissolved seed crystals are present in the reaction solution. In an embodiment, the method further comprises a separation step wherein the precipitate is separated by conventional methods such as filtration and centrifugation, followed by washing with a solvent, followed by drying.> Other salt formation methods may also be suitable for use in the present invention. The salt of the formula σ can be prepared by converting an salt of the compound (for example, a hydrochloride) to an ethanesulfonate by anion exchange using an anion exchange column. The salt of the compound of the formula j can also be used by In the presence of a solvent, physically 154673.doc -46 - 201136935 Solid 4-(1-(3-fluorophenylhydrazinocarbazole-5-ylamino)_5_indolyl π-pyrolo[1,2_/1[1,2,4]triazotric-6 - Aminocarbamic acid (5 > morpholine _3 quinone ester is produced by grinding together with an acid. In addition to precipitation and crystallization, the solid salt provided herein may also be a conventional method known to those skilled in the art. Preparation, including spray drying, drum drying, lyophilization, and melt crystallization. In another embodiment, provided herein is a reduction of 4_ 〇(1·(3_fluorocrackinyl)·1Η-carbazole as provided herein. I-aminoamino)-5-fluorenyl. Biordinium π, 2_ /] Π, 2, 4] triazolam carbamic acid (iS) _ morpholine _3 yl decyl ester salt or hydrate thereof Or a method of pharmaceutically acceptable in the solvate of the acceptable solvate; the method comprising contacting the salt with propylene at a first predetermined temperature as defined herein. In the embodiment, the salt Dissolved in the propyl group. In another embodiment, the salt is crystallized in acetone. Pharmaceutical Compositions In one embodiment, a pharmaceutical composition is provided herein, which comprises 4_(1_(3·1) Benzoyl)-1 ugly wow w-5-based Amino)-5-methyl D is more than hydrazine, 2-/][1,2,4]triazot _6-ylaminocarboxylic acid (phanyl-morpholine_3_yl decyl ester salt (including a hydrate thereof and a pharmaceutically acceptable solvate thereof in combination with a pharmaceutically acceptable vehicle, carrier, diluent or excipient or mixture thereof. In another embodiment, a pharmaceutical combination is provided herein. , which comprises 4-(1-(3_fluoro alum) & "salt _5_ylamino"_5_methyl hydroxy-[1,2-/][1,2 , 4] triazide _6_ ylamino decanoic acid (5 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ A combination of cyclodextrin, mannitol, water or a mixture thereof. 154673.doc -47- 201136935 In yet another embodiment, provided herein is a pharmaceutical composition comprising 4-(1-(3-fluorobenzylcarbazol-5-ylamino)-5-methylpyrrolo[12- /][1,2,4]diazepine_6_ylaminocarbamic acid (s)_morpholine_3_yl decyl ethanoate or a pharmaceutically acceptable solvate or hydrate thereof In combination with hydroxypropyl cyclodextrin, mannitol, water, or mixtures thereof. In yet another embodiment, provided herein is a pharmaceutical composition comprising about 5% by weight of 4-(1-(3-fluorobenzyl) )-lif•carbazole_5_ylamino)_5_methylindole Π Π '2·/][1,2,4]diazepine-6-ylaminocarboxylic acid (S)-Merlin -3-ylmethyl ester ethalate hydrochloride, about 75% by weight hydroxypropyl-β-cyclodextrin and hydrazine wt% mannitol. In yet another embodiment, a pharmaceutical composition in unit dosage is provided herein. , which comprises about 363 mg of 4-(1-(3-fluorobenzylidene oxalyl-5-ylamino)_5_methylpyrrolotriazole _6•ylaminocarbamic acid (iS)_morpholine_3_ Base oxime ethane sulfonate, about 1,800 mg hydroxypropyl _β_cyclodextrin, and [240 mg (by weight) mannosaccharide. In certain embodiments, The unit dose of the pharmaceutical composition comprises about 363 mg of crystalline form of 4_(ι_(3-fluorobenzyl)_1/7_carbazole-5-ylamino)_5_methylindole trinitron tillage_6_ Amino carboxylic acid (iS) morpholine _3 methyl ethane sulfonate. In certain embodiments, the pharmaceutical composition in unit dose contains about 363 mg in the form of a crystalline form of Π-Β 4-(1 -(3-fluorophenylindenyl)-If-oxazol-5-ylamino)-5-methyl-pyrrolo 2,4]triazotric _6-ylaminocarboxylic acid (5>morpholin-3-yl Methyl Ethyl Sulfonate. Suitable excipients are well known to those skilled in the art, and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for incorporation into a physician 154673.doc • 48 - 201136935 Pharmaceutical composition or agent 胄 胄 ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' 。 。 。 。 。 。 。 。 。 The suitability of a particular excipient may also depend on the particular active ingredient in the dosage form. For example, some of the active ingredients may be decomposed by certain excipients (such as lactose) or when exposed to water. The active ingredient comprising a -amine or a secondary amine is particularly susceptible to such accelerated decomposition. Accordingly, provided herein are pharmaceutical compositions and dosage forms containing minor, if any, lactose or other monosaccharides or disaccharides. The term "lactose-free" means that the amount of lactose present, if any, is insufficient to substantially increase the rate of degradation of the active ingredient. In the examples, the lactose-free composition comprises the active ingredient, binder/filler provided herein. Agents and lubricants. In another embodiment, the lactose-free dosage form comprises the active ingredient, microcrystalline cellulose, pregelatinized powder, and stearic acid lock. The salts provided herein can be administered alone or in combination with one or more other salts provided herein. Pharmaceutical compositions comprising the salts provided herein can be formulated into a variety of dosage forms for oral, parenteral, and topical administration. The pharmaceutical composition may also be formulated into a modified release dosage form, including a delayed release dosage form, an extended release dosage form, a delayed release dosage form, a sustained release dosage form, a pulsatile release dosage form, a controlled release dosage form, an accelerated release dosage form, a rapid release dosage form, a dry release dosage form, and programmed Release dosage form and gastric retention dosage form. Such dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (see

The Science and Practice of Pharmacy, Shang Ai., Modified-h/ and e Dr吆 DWver, 2nd edition; Rathbone et al., ed.; Marcel Dekker, Inc.: New York, NY, 2008). 154673.doc •49· 201136935 In the Examples, the 'pharmaceutical composition is provided for use in the present invention, which comprises the dark, and yyyyyy dosage form of the vehicle, carrier, diluent or H-form provided herein. Agent. Or medicinally acceptable In another embodiment, a pharmaceutical composition comprising a vehicle, carrier, diluent or κ-form of a sputum-parenteral dosage form provided herein. In another embodiment, the doctor is careful, and the sputum is for local administration.

Provided comprising a salt and/or a plurality of: (4) vehicles, carriers, diluents or excipients provided herein. </ RTI> Accepted The pharmaceutical compositions provided herein may be provided in thousands of worms or multiple dosage forms. As used herein, unit dosage form refers to a physically discrete unit that is suitable for the administration and which is known in the art to be individually packaged, individually packaged. The unit dose contains a predetermined amount of the active ingredient to be used in combination with the desired pharmaceutical carrier or excipient. Examples of unit dosage forms include ampoules, ampoules, and individually encapsulated troches and capsules. For example, the _% unit dose can be contained in a packaged lozenge or capsule in an amount of about one or more applications. Multiple dosage forms are a plurality of identical unit dosage forms that are enclosed in a single container for administration in separate unit dosage forms. Examples of multiple dosage forms include vials, lozenges or capsules or pints or gallon bottles. The pharmaceutical compositions provided herein can be administered in a single administration or multiple times over a period of time. It will be appreciated that the precise dose and duration of treatment may vary with the age, weight and condition of the patient being treated and may be determined empirically using empirical testing protocols or based on in vivo or in vitro testing or diagnostic data from outside 154673.doc -50- 201136935 Pushing is correct. It is further understood that for any particular individual, the particular dosage regimen will be adjusted over time according to the individual needs and the professional judgment of the person administering the formulation or supervising the formulation. A. Oral Administration The pharmaceutical compositions for oral administration provided herein can be used in solid, semi-solid or liquid dosage forms for oral administration. As used herein, oral administration also includes buccal, translingual, and sublingual administration. Suitable oral dosage forms include, but are not limited to, lozenges, fast solvents, chewable tablets, capsules, pills, strips, sugar-coated tablets, buccal tablets, tablets, cachets, pellets, medical chewing gum, bulk Powders, effervescent or non-effervescent powders or granules, oral sprays, solutions, emulsions, suspensions, wafers, sprays, elixirs and syrups. In addition to the active ingredient, the pharmaceutical compositions may contain one or more pharmaceutically acceptable carriers or excipients including, but not limited to, binders, fillers, diluents, disintegrating agents, wetting agents, lubricants, aids Flowing agents, colorants, dye migration inhibitors, sweeteners, flavoring agents' emulsifiers, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids and carbon dioxide sources. The binder or granulating agent imparts cohesiveness to the tablet to ensure that the tablet remains intact after compression. Suitable binders or granulating agents include, but are not limited to, starches such as corn starch, mash potato starch and pregelatinized starch (eg starch 1500); gelatin; sugars such as sucrose, dextrose, dextrose, molasses and lactose Natural and synthetic gums, such as acacia, alginic acid, alginates, Irish m〇ss extracts, panwar gum, ghatti gum, cars Pre-shell (isabg〇i 154673.doc -51 · 201136935 husk) glue, carboxymethyl cellulose, sulfhydryl cellulose, polyethylene n-pyrrolidone (PVP), Veegum, larch Arabic galactose, powdered tragacanth and guar gum; cellulose, such as ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl fiber , hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), propyl fluorenyl cellulose (HPMC); microcrystalline cellulose, such as 八¥1 (^1^ PH-101, AVICEL- PH-103, AVICELRC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, PA); and mixtures thereof. Suitable filler package Including but not limited to talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, glucose binder, kaolin, mannitol, citric acid, sorbitol, aged powder, pregelatinized powder and mixtures thereof. The amount of binder or filler in the pharmaceutical compositions provided will vary depending on the type of formulation and can be readily discerned by those skilled in the art. The binder or filler can be from about 50% to about 99% by weight. The hydrazine is present 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 leaven) can be given to some compressed tablets when present in sufficient amounts to allow disintegration in the mouth by chewing. The compressed tablet can be used as a chewable tablet. The amount of diluent in the pharmaceutical compositions provided herein will vary depending on the type of formulation and can be readily discerned by those skilled in the art. solution Including but not limited to agar; bentonite; cellulose, 154673.doc '52· 201136935 such as methyl cellulose and carboxymethyl cellulose; wood products; natural sponge; cation exchange resin; alginic acid; glue, such as guar and Vigor gum HV; orange pulp; cross-linked cellulose, such as croscarmellose; cross-linked polymer, such as crospovidone; cross-linked starch; acid-reducing; microcrystalline cellulose, such as Sodium starch glycolate; polacrilin potassium; starch, such as corn starch, potato starch, tapioca starch, and pregelatinized starch; clay; lignin; and mixtures thereof. The amount of disintegrant in the pharmaceutical compositions provided herein will vary depending on the type of formulation and can be readily discerned by those skilled in the art. The amount of disintegrant in the pharmaceutical compositions provided herein will vary depending on the type of formulation and can be readily discerned by those skilled in the art. The pharmaceutical compositions provided herein may contain from about 5% to about 15% by weight or from about 1% to about 5% by weight of the disintegrant. Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols such as glyceryl behenate and poly Ethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oil, including peanut oil, cottonseed oil, sunflower oil, sesame oil, eucalyptus oil, corn oil and soybean oil; zinc stearate; Vinegar; lauric acid B; agar; temple powder; stone pine nuts; dioxide dioxide or silicone, such as AEROSIL® 200 (WR Grace Co., Baltimore, MD) and CAB-0-SIL® (Cabot Co. of Boston , ΜΑ); and mixtures thereof. The pharmaceutical compositions provided herein may contain from about 5% by weight to about 5% by weight of the lubricant. Suitable glidants include, but are not limited to, colloidal ceria, CAB_〇_154673.doc •53- 201136935 SIL® (B〇ston, MA Cabot c〇.) and non-asbestos talc. Suitable colorants include, but are not limited to, any of the approved qualified water soluble FD&amp;C dyes and water insoluble FD&amp;C dyes and lakes (c〇1〇r lake) and mixtures thereof suspended on hydrated alumina. By. A lake is a combination of a water-soluble dye adsorbed to a heavy metal hydrated oxide to produce an insoluble form of the dye. Suitable flavoring agents include, but are not limited to, natural flavoring agents extracted from plants such as fruits, and synthetic compound blends which produce a taste of the taste, such as peppermint and strontium raspberry. Suitable sweeteners include, but are not limited to, sucrose, lactose, mannitol, syrup, glycerin, and artificial sweeteners such as saccharin and aspartame. Suitable emulsifiers include, but are not limited to, gelatin, gum arabic, tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan mono oil Acid 6a 80 (TWEEN 80) and triethanolamine oleate. Suitable suspending and dispersing agents include, but are not limited to, sodium carboxymethyl cellulose, pectin, tragacanth, weige gum, gum arabic, sodium carboxymethyl cellulose, hydroxypropyl fluorenyl cellulose and polyvinylpyrrole Pyridone. Suitable preservatives include, but are not limited to, glycerin, methyl p-hydroxybenzoate and propyl paraben, benzoic acid, sodium benzoate and ethanol. Suitable humectants include, but are not limited to, propylene glycol monostearate, single Oil &amp;L sorbitan ester, diethylene glycol monolaurate and polyoxyethylene lauryl ether. Suitable solvents include, but are not limited to, glycerin, sorbitol, ethanol, and syrups. Non-aqueous liquids suitable for use in emulsions include, but are not limited to, mineral oil and cottonseed oil. Suitable organic acids include, but are not limited to, citric acid and tartar. Suitable sources of carbon dioxide include, but are not limited to, sodium bicarbonate and sodium carbonate. It will be appreciated that many carriers and excipients can perform a variety of functions even within the same formulation of 154673.doc •54·201136935. The pharmaceutical composition for oral administration provided herein may be a compressed tablet, a tablet wet abrasive, a chewing mouth tablet, a fast-dissolving tablet, a multiple compressed tablet or an enteric tablet, a sugar-coated tablet or a film-coated tablet. Provided by the agent. The enteric coating agent is a compressed tablet coated with a substance which is resistant to gastric acid but which dissolves or disintegrates in the intestine to protect the active ingredient from the acidic environment of the stomach. Casings include, but are not limited to, fatty acids, fats, phenyl sulphate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. A dragee tablet is a compressed tablet that is surrounded by a sugar coating. The sugar coating can be beneficial to mask unpleasant taste or odor and prevent oxidation of the tablet. Film-coated tablets are compressed tablets coated with a thin layer or film of a water-soluble substance. Film coats include, but are not limited to, hydroxyethyl cellulose, slow methyl cellulose sodium, polyethylene glycol 4000, and cellulose acetate phthalic acid vinegar. The film coat imparts the same general characteristics as the sugar coat. The multiple compression tablet is a compressed tablet prepared by one or more compression cycles, including layered tablets and compressed coated tablets or dry coated tablets. The lozenge dosage form can be prepared separately from the active ingredient in powder, crystalline or granular form, or with one or more carriers or excipients (including binders, disintegrating agents, controlled release polymer' lubricants, A diluent and/or a colorant are combined to prepare. Flavoring and sweetening agents are especially useful for forming buccal and buccal bonds. The pharmaceutical compositions for oral administration provided herein may be provided in the form of soft capsules or hard capsules. The capsules may be made of gelatin, methylcellulose, starch or calcium alginate. Hard gelatin capsules (also known as consisting of two parts, part of the sleeve on the other part;; = seal: 154673.doc • 55- 201136935 active ingredient. Soft elastic capsules (SEC) for the addition of glycerol, sorbitol or a soft spherical shell plasticized like a polyol, such as a gelatin shell. The soft gelatin shell may contain a preservative to prevent the growth of microorganisms. Suitable preservatives are preservatives as described herein, including And p-propyl benzoate and sorbic acid. The liquid, semi-solid and solid dosage forms provided herein may be encapsulated in a capsule. Suitable liquid and semi-solid dosage forms include propylene carbonate, vegetable oil or triglyceride g. The solutions and suspensions of the present invention are prepared as described in U.S. Patent Nos. 4,328,245, 4,409,239, and 4,410,545. The capsules are also known to those skilled in the art. Coating to modify or maintain the dissolution of the active ingredient. The pharmaceutical compositions for oral administration provided herein can be provided in liquid and semi-solid dosage forms, including pure solutions, solutions, suspensions, and sugars. An emulsion is a two-phase system in which a liquid is dispersed in the form of small pellets throughout another liquid. The two-phase system may be of the oil-in-water or water-in-oil type. The emulsion may include pharmaceutically acceptable Non-aqueous liquids or solvents, emulsifiers and preservatives. Suspensions may include H-drugs 1 1 i ^ 乐乐学的剂剂剂剂和腐腐剂。 Water-deficient alcohol cold liquid may include pharmaceutically acceptable An acetal, such as a lower (low carbon alkyl) carboxylic acid of a lower alkyl aldehyde, such as diethyl acetal; and a water-miscible solvent having one or more: a base, such as propylene glycol and ethanol. A sweet taste hydroalcohol, gluten. The syrup is a concentrated aqueous solution of sugar (such as sucrose) and may also be: a humic agent. For liquid dosage forms, for example, the solution in polyethylene glycol can be acceptable on the summer medical (four) The liquid carrier (eg, water) is diluted for use in administration. Includes, but is not limited to, other liquid and semi-solid dosage forms suitable for use herein 154673.doc -56 - 201136935 Active ingredient provided and dialkylated monoalkane Alcohol or polyalkylene glycol dosage form, dialkylated monoalkane or polyalkane Including 1,2-dimethoxydecane, diethylene glycol dioxime ether, triethylene glycol dioxime ether, tetraethylene glycol dimethyl ether, polyethylene glycol-350-dimethyl ether, polyethylene Alcohol-550-dimethyl ether, polyethylene glycol-750- Ο

Q Diterpenoids, of which 350, 550 and 750 refer to the approximate average molecular weight of polyethylene glycol. These formulations may further comprise - or a plurality of antioxidants such as butylated hydroxytoluene (BHT), butylated hydroxyphenyl ether (BHA), propyl gallate, vitamin E, hydroquinone , hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its ester, and Thiocarbamate. The pharmaceutical compositions for oral administration provided herein can also be provided in the form of liposomes, micelles, microspheres or nanosystems. The microcyst dosage form can be prepared as described in U.S. Patent No. 6,350,458. The pharmaceutical compositions for oral (iv) provided herein can be provided by non-effervescent or effervescent granules (iv) and powders to be reconstituted into a liquid dosage form. Pharmaceutically acceptable amounts and excipients for use in non-effervescent granules or powders may include diluents, sweeteners and wetters. The medicine used in effervescent granules or powders (4) accepts m-forms including organic acids and carbon dioxide sources. Coloring agents and flavoring agents can be used in all of the above dosage forms. The pharmaceutical preparations for oral administration provided herein can be formulated as immediate release dosage forms or modified release dosage forms, including /, late release forms, sustained release forms, pulse release forms, controlled release. Release form, targeted release form and procedure 154673.doc -57- 201136935 Controlled release form. B. Parenteral Administration For topical or systemic administration, the pharmaceutical compositions provided herein can be administered parenterally by injection, infusion or implantation. Parenteral administration, as used herein, includes intravenous, intra-arterial intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, intralesional, and subcutaneous administration. The pharmaceutical compositions for parenteral administration provided herein can be formulated into any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and A solid form of a solution or suspension formed in a liquid prior to injection. Such dosage forms can be prepared according to conventional methods known to those skilled in the art of medicine (see

Science and Practice 〇f Pharmacy, text, . Pharmaceutical compositions intended for parenteral administration may include one or more pharmaceutical carriers: excipients and excipients including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles. An antimicrobial or preservative, a stabilizer, a dissolution enhancer, an isotonic agent, a buffer, an antioxidant, a local anesthetic, a suspending agent and a dispersing agent, a wetting agent or an emulsifier, a chelating agent for preventing microbial growth ( Sequestering agent/chelating agent), cryoprotectant, lyoprotectant (ly〇pr〇tectant), thickener, pH adjuster and inert gas. Suitable aqueous vehicles include, but are not limited to, water, saline, saline or phosphate buffered saline (PBS), sodium vaporated injection, Ringers injection, isotonic dextrose injection, sterile water injection. , 154673.doc •58· 201136935 Dextrose and lactated Ringer's injection. Suitable non-aqueous vehicles include, but are not limited to, vegetable-derived fixed oils, cannabis oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, chlorinated vegetable oil, hydrogenated large denier Oil and coconut oil chain triglycerides, and palm seed oil. Suitable water miscible vehicles include, but are not limited to, ethanol, hydrazine, 3-butanediol, liquid polyethylene glycol (eg, polyethylene glycol 300 and polyethylene glycol 4 oxime), propylene glycol, glycerin, 7V-A Base-2-pyrrolidone, #,沁 dimethyl acetamide and diterpene. Suitable antimicrobial agents or preservatives include, but are not limited to, phenol, meth, amalgam, benzofuran, chlorobutanol, decyl p-hydroxybenzoate and propyl paraben, thimerosal, gasified alum (e.g., benzethium chloride), p-hydroxybenzoic acid decyl ester and propyl paraben, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium carbonate, glycerin, and dextrose. Suitable buffering agents include, but are not limited to, phosphates and citrates. Suitable antioxidants are the antioxidants as described herein, including bisulfite and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents are suspending and dispersing agents as described herein, including sodium carboxymethylcellulose, propylmethylcellulose and polyvinylpyrrolidone. Suitable emulsifiers are the emulsifiers described herein' including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80 and triethanolamine oleate. Suitable chelating agents include, but are not limited to, EDTA. Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, salt, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl 154673.doc -59-201136935 base + cyclodextrin, contiguous butyl cyclodextrin and contig Butyl ether 7-β-cyclodextrin (CAPTISOL®, CyDex, Lenexa, Ks). When the pharmaceutical compositions provided herein are formulated for multi-dose administration, the multi-dose parenteral formulation must contain an antimicrobial agent that inhibits bacterial concentration or fungal rolling. All parenteral formulations must be sterile as known and practiced in the art. In one embodiment, the pharmaceutical compositions for parenteral and gamma liters are provided in a ready-to-use sterile solution. In another embodiment, the pharmaceutical composition is provided as a sterile dry soluble product to be reconstituted with a vehicle prior to use, including a dry powder and a subcutaneous lozenge. In yet another embodiment, the pharmaceutical composition is provided as a ready-to-use sterile suspension. In still another embodiment, the pharmaceutical composition is provided as a sterile dry insoluble product to be reconstituted with a vehicle prior to use. In another embodiment, the pharmaceutical composition is provided as a ready-to-use sterile emulsion. (4) The parenterally-administered pharmaceutical composition provided herein may be formulated as a release dosage form or a modified release dosage form&apos; including a delayed release form, a sustained release form, a pulsed release form, a controlled release form, a dry release form, and a programmed release form. The pharmaceutical composition for parenteral administration provided herein can be formulated into a suspension 'solid, semi-solid or thixotropic liquid" for administration in an implanted reservoir. In one embodiment, the pharmaceutical composition provided herein is dispersed in a solid inner matrix 'the solid internal matrix is surrounded by the outer polymeric film, although the outer polymeric film is insoluble in the body fluid, but is allowed in the pharmaceutical composition The active ingredient diffuses through. Suitable internal substrates include, but are not limited to, polymethacrylic acid brewing, polymethyl 154673.doc -60-201136935 butyl acrylate, plasticized or unplasticized polyethylene, plasticized nylon, plasticized poly Ethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, polyoxyxene rubber, polydimethyl siloxane, Polyoxycarbonate copolymers, hydrophilic polymers, hydrogels such as acrylic acid and methacrylic acid esters, collagen, crosslinked polyvinyl alcohol and partially hydrolyzed crosslinked polyethylene acetate. Suitable external polymeric films include, but are not limited to, polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, polyoxyxene rubbers, polydimethylsiloxanes, Neoprene rubber, vaporized polyethylene, polyvinyl chloride, vinyl chloride/vinyl acetate copolymer, ethylene dioxide, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber, Gas alcohol rubber, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/ethylene oxyethanol copolymer. C. Topical Administration The pharmaceutical compositions provided herein can be administered topically to the skin, orifice or mucosa. As used herein, topical administration includes dermal (intradermal), transconjunctival, intracavitary, intraocular, transocular, transdermal, transdermal, nasal, transvaginal, transurethral, transrectal, and rectal administration. . The pharmaceutical compositions provided herein can be formulated into any gingival Ayw St 1J dosage form suitable for topical administration to achieve local or systemic effects, including emulsions, solutions, suspensions, creams, gels, hydrogels, preparations. Red, d. flat person T, dusting powder, dressing

Agent, Sfc agent, lotion, sputum, A/hand night, tincture, serum, foam, film, gas 154673.doc -61 - 201136935 Aerosol, irrigant, spray, suppository, bandage and transdermal patch . The topical formulations of the pharmaceutical compositions provided herein may also comprise liposomes, micelles, microspheres, nanosystems, and mixtures thereof. Pharmaceutically acceptable carriers and excipients suitable for use in the topical formulations provided herein include, but are not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous agents, biocides, anti-microbial growth resistance Microbial or preservatives, stabilizers/gluten enhancers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, chelating agents (sequestering agent or chelating agents) Agent), penetration enhancer, cryoprotectant, lyoprotectant, thickener and inert gas. The pharmaceutical composition may also be administered topically by electroporation, iontophoresis, acoustic electroosmosis, ultrasonic electroosmosis or microneedle or needle-free injection, such as

POWDERJECTTM (Chiron Corp., Emeryville, CA) and BIOJECTTM (Bioject Medical Technologies Inc. Tualatin, OR). The pharmaceutical compositions provided herein can be provided in the form of ointments, creams and gels. Suitable ointment vehicles include oily Medicament or hydrocarbon vehicle, including lard, benzoic acid lard, eucalyptus oil, cottonseed oil and other oils, white petrolatum, emulsifiable or adsorbent vehicles such as hydrophilic petrolatum, stearic acid sulfate and Anhydrous lanolin; a water-removable vehicle such as a hydrophilic ointment; a water-soluble ointment vehicle comprising polyethylene glycols having different molecular weights; an emulsion vehicle, a water-in-oil (W/O) emulsion or an oil-in-water ( 〇/w) Emulsions, including mannitol, glyceryl monostearate, lanolin, and stearic acid (see and Science). These vehicles are emollients, but It is generally necessary to add antioxidants and preservatives. 154673.doc -62- 201136935 Suitable cream bases can be oil-in-water or water-in-oil. Suitable d can be water washable medium, and contain oil phase, emulsified Agent and water phase. The medium (4) is " Phase, which generally contains petrolatum and a fatty alcohol such as cetyl alcohol or: fat = the volume of the phase usually (but not necessarily) exceeds the oil phase, and generally contains a humectant. The emulsifier in the cream formulation can be Nonionic ionic, cationic or amphoteric surfactants = Ο Gels are semi-solid suspension systems. Single-phase gels contain organic macromolecules that are substantially distributed throughout the liquid carrier. Suitable gelling agents Including but not limited to cross-linked acrylic acid polymers, such as carbomers, slow-base extensions, CARBOPOlV hydrophilic polymers such as polyoxygen: ethylene, polyoxyethylene-polyoxypropylene copolymers and poly Ethyl alcohol; cellulose polymer such as propyl propyl cellulose, ethyl cellulose, propyl cellulose, (tetra) methyl cellulose phthalic acid § and methyl fiber: gel Such as only tannin and dimentia; sodium alginate, and gelatin. In order to prepare a homogenous gel, a dispersing agent such as ethanol or glycerin may be added, or the gel may be dispersed by wet grinding, mechanical mixing and/or stirring. Coagulant. The medical group provided in this article Suppositories, pessaries, probes, lozenges or poultices, pastes, powders, dressings, creams, plasters, contraceptives, ointments, solutions, emulsions, suspensions, tampon, gels 'Blisters, sprays or enemas are in the form of rectal, urethral, vaginal or vaginal forks. These dosage forms can be used as described in the above-mentioned methods. Manufactured. The rectal urethra and vaginal suppository 4 can be inserted into a solid object in the body orifice 'which is solid at room temperature' but melts or softens at body temperature to release the active ingredient within the orifice 154673.doc -63 - 201136935. Pharmaceutically acceptable carriers for use in rectal and vaginal suppositories include a matrix or vehicle which produces a melting point close to body temperature when formulated with the pharmaceutical compositions provided herein, such as a hardening agent; and as described herein Antioxidants, including bisulfite and sodium metabisulfite. Suitable vehicles include, but are not limited to, cocoa butter (cocoa butter), glycerin-gelatin, carbowax (polyoxyethylene glycol), cetyl wax, paraffin wax, white wax and yellow wax, and fatty acid monoglycerin ga, diglyceride and Suitable mixtures of triglycerides, and hydrogels such as polyvinyl alcohol, hydroxyethyl methacrylate and polyacrylic acid. Combinations of various vehicles can also be used. Straight wins and vaginal suppositories can be prepared by compression or molding. Typical weights of rectal and vaginal suppositories are from about 2 g to about 3 g. The pharmaceutical compositions provided herein can be solutions, suspensions, ointments, lotions, gel forming solutions, powders for solutions, gels, ophthalmic inserts and The form of the implant is administered by eye. a Pharmaceutical compositions provided herein can be administered intranasally or by inhaling the respiratory tract. The pharmaceutical composition may be provided separately using a pressurized container, a pump, a nebulizer, atomization: such as an atomizer that utilizes electrohydrodynamics to produce a fine mist, or a shower to be delivered in the form of an aerosol or solution. It is provided in combination with a suitable propellant (such as ^'^四败乙烧5戈^1,1,2,3,3,3-heptafluoropropanone). The medicine can also be supplied as a dry powder (alone or in combination with such as lactose or scales: a sex carrier) and nasal drops. For intranasal use, powder 匕3 bioadhesives, including polyglucosamine or cyclodextrin. = Containers used in sprayers, nebulizers or showers can be formulated to contain ethanol, aqueous ethanol or for use in 154673.doc • 64 - 201136935 An alternative agent for the active ingredient, a propellant (as a solvent); and/or a surfactant such as sorbitan trioleate, oleic acid or polylactic acid. The pharmaceutical compositions provided herein can be micronized to a size suitable for delivery by inhalation, such as about 50 microns or less, or about ίο microns or ίο microns. Particles of such a size can be prepared using a tertiary method known to those skilled in the art, such as spiral jet milling, fluidized bed jet milling/de-cracking to form nanoparticle supercritical fluid processing, high pressure homogenization. Method i or spray drying method. Capsules, foaming agents and cartridges for inhalation into H or in a blower can be formulated 7 a powdered mixture containing the pharmaceutical compositions provided herein, a suitable base matrix (such as lactose or starch) and a potency modulator (such as &quot; leucine, mannitol or magnesium stearate). Lactose can be anhydrous or in the form of a monohydrate. Other suitable excipients or carriers include, but are not limited to, dextran, glucose, wheat sugar, sorbitol, xylitol, fructose, sucrose, and trehalose. The pharmaceutical composition for inhaled/intranasal administration provided herein may further comprise suitable flavoring agents, such as menthol and levomenthol; and/or sweeteners, such as saccharin and sodium saccharin. The pharmaceutical compositions for topical administration provided herein can be formulated as immediate release or modified release, including delayed release, sustained release, pulsed release, controlled release, dry release, and programmed release. D. Modified Release The pharmaceutical compositions provided herein can be formulated into modified release dosage forms. As used herein, the term "modified release" refers to a dosage form of the immediate release dosage form when administered by the same route 154673.doc -65-201136935.

The release rate or location of the active ingredient is different from "modified release dosage forms including, but not limited to, delayed release, extended release dosage forms, sustained release dosage forms, release type 4, accelerated release dosage forms, and rapid release, and sigma can be used in the art. Various modified release devices and methods are known, including but not limited to matrix controlled release devices, osmotic controlled release devices, multiparticulate controlled release devices, ion exchange resins, casings, multilayer coatings, microspheres, liposomes, and combination. The release rate of the active ingredient can also be improved by changing the particle size and polymorphism of the active ingredient. Examples of modified release include, but are not limited to, those described in U.S. Patent Nos. 3,845,770, 3,916,899, 3,536,809, 3,598,123, 4,008,719, 5,674,533, 5,059,595, 5,591, 767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, 5,639,480, 5,733,566, 5,739,108, 5,891,474, 5,922,356, 5,958,458, 5,972,891 , Nos. 5,980,945, 5,993,855, 6,045,830, 6,087,324, 6,113,943, 6,197,350, 6,248,363, 6,264,970, 6,267,981, 6,270,798, 6,375,987, 6,376,461, 6,419,961, 6,589,548, 6,613,358, 6,623,756, 6,699,500, 6,793,936, 6,827,947, 6,902,742, 154,673.doc-66-201136935 6,958,161, 7,255,876, 7,416,738 No. 7, 427, 414, No. 7, 485, 322; Bussemer et al. People, Οίί· and ev. Ther. Drug Carrier Syst. 2001, 18, 433-458 ; Modified-Deh'ver;/ Tec/mo/oa, 2nd edition; edited by Rathbone et al., Marcel Dekker AG: 2005; Maroni Wait,

Drug Deliv. 2005, 2, 855-871; Shi et al, Ο ζ « « « Drug Deliv. 2005, 2, 1039-1058 » Polymers in Drug

De/iver_y; Ijeoma et al., CRC Press LLC: Boca Raton, FL, 2006; Badawy et al., / corpse / zarm. 2007, 9, 948-959;

Modified-Release Drug Delivery Technology, supra; Conway, Recent Pat. Drug Deliv. Formul. 2008, 2, 1-8; Gazzaniga et al., «/. P/mrm. 2008,65, 11- 18 ; Nagarwal et al , Cwrr. Drug Deliv. 2008, 5, 282-289; Gallardo et al., Corp. Ziarm. Dev. Technol. 2008, 13, 413-423; Chrzanowski, AAPS PharmSciTech. 2008, 9, 635-638; Chrzanowski, AAPS PharmSciTech 2008, 9, 639-645 ; Kalantzi et al., 茗De/iv. _For/ww/. 2009,3,49-63 ; Saigal et al., and ece/ίί Ραί. Z)rMg £)e//v Formw/. 2009, 3, 64-70; A Roy# A ? J. Control Release 2009, 134, 74-80 ° 1. Matrix controlled release device The pharmaceutical composition of the modified release dosage form provided herein can be used Matrix controlled release devices known to those skilled in the art are manufactured. See Takada et al., Encyclopedia of Controlled Drug Delivery, yiathio'wi乞z, ed., Wiley: 1999, vol. 154673.doc -67- 201136935 In certain embodiments, the pharmaceutical compositions provided herein in modified release dosage forms are formulated using an erodible matrix device that is water-swellable, invasive or soluble polymer, including However, it is not limited to synthetic polymers and naturally occurring polymers and derivatives such as polysaccharides and proteins. Substances suitable for forming invasive substrates include, but are not limited to, chitin, polyglucamine, dextran, and pullulan; colloidal agar, gum arabic, karaya gum, locust bean gum, gum tragacanth , carrageenan, gum gluten, guar gum, sin gum and scleroglucan; starch, such as dextrin and maltodextrin; hydrocolloid, gelatin; phospholipids, such as lecithin; alginic acid vinegar '·Alginate propionate; gelatin; collagen; cellulose, such as ethyl cellulose (EC), mercaptoethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl Cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl decyl cellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetate trimellitate (hpmcat) and ethyl hydroxyethyl cellulose ( EHEC); polyvinylpyrrolidone; polyvinyl alcohol; polyvinyl acetate; fatty acid glyceride; polypropylene decylamine; polyacrylic acid; Or copolymer of methacrylic acid (EUDRAGIT®, Rohm America, Inc., Piscataway, NJ); poly(2-hydroxyethyl-decyl acrylate); polylactide; L- faceamine and ethyl _ a copolymer of L-glutamate; a degradable lactic acid-glycolic acid copolymer; poly-D-(-)-3-hydroxybutyric acid; and other acrylic acid derivatives such as butyl methacrylate, A Methyl acrylate, ethyl methacrylate, ethyl acrylate, (2-dimethylaminoethyl) methacrylic acid 154673.doc -68- 201136935 vinegar and gasification (tridecylaminoethyl) hydrazine Homopolymers and copolymers of acrylates. In certain embodiments, the pharmaceutical compositions provided herein are formulated with a non-invasive matrix device. The active ingredient is dissolved or dispersed in an inert matrix' and is released primarily by diffusion through an inert matrix after administration. Substances suitable for use as non-erodible matrix devices include, but are not limited to, insoluble plastics such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethyl methacrylate, polymethyl methacrylate Ester, chlorinated polyethylene, polyvinyl chloride, methyl acrylate·methyl methacrylate copolymer, ethylene·vinyl acetate copolymer, ethylene/propylene copolymer, ethylene/ethyl acrylate copolymer, ethylene/vinyl acetate Ester copolymer, diethylene glycol, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber, gas alcohol rubber, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol Polymer, ethylene/ethyleneoxyethanol copolymer, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyoxyethylene rubber, polydimethyl oxalate and polyfluorene Oxycarbonate copolymer; hydrophilic polymers such as ethyl cellulose, cellulose acetate, crospovidone and partially hydrolyzed cross-linked polyvinyl acetate; and aliphatic compounds such as Brazilian palm quinone, micro Crystalline and triacid Glycerin g. In a matrix controlled release system, the desired release kinetics can be controlled, for example, via the type of polymer employed, the viscosity of the polymer, the particle size of the polymer and/or active ingredient, the ratio of active ingredient to polymer, and the composition Other excipients or carriers in the medium. The pharmaceutical composition of the modified release dosage form provided herein can be obtained by the method known to those skilled in the art by 154673.doc-69·201136935. The magnetic_equipment has been directly sized, dry or full granulated. Compressed, and melted after granulation. 2. Osmotic Controlled Release Devices The pharmaceutical compositions of the modified release dosage forms provided herein can be fabricated using osmotic controlled release devices including, but not limited to, single chamber systems, dual chamber systems, asymmetric membrane technology (AMT), and extrusion. Out of the core system (ECS). Generally, such devices have at least two components: (4) a core containing the active ingredient; and 半) a semipermeable membrane having at least one transfer port that encapsulates the core. The semi-permeable membrane controls the influx of water from the aqueous use environment to the core, thereby causing drug release by extrusion through the transfer port. In addition to the active ingredient, the core of the osmotic device optionally includes a penetrant' that produces a driving force to transport water from the environment of use to the core of the device. One type of penetrant is a water-swellable hydrophilic polymer, also known as "permeate polymer" and "hydrogel". Water-swellable hydrophilic polymers suitable as penetrants include, but are not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides (such as calcium alginate), polyethylene oxide (PEO), polyethylene glycol (Peg). ), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic acid), poly(methacrylic acid), polyethylene, butyl ketone (PVP), crosslinked PVP, polyvinyl alcohol (PVA), PVA/PVP copolymer, copolymer of PVA/PVP with hydrophobic monomers such as methyl methacrylate and vinyl acetate, hydrophilic polyamino phthalate containing large PEO block, cross-linking Carboxyvinate sodium 'carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose (CMC) and carboxy Ethyl cellulose (CEC), sodium alginate, polycarbophil (p〇ly Carb〇phil), gelatin, Sanxian 154673.doc • 70· 201136935 Glue and sodium starch glycolate. Another type of penetrant is a zymogen that is capable of absorbing water and affecting the osmotic pressure gradient across the barrier surrounding the coating. Suitable zymogens include, but are not limited to, inorganic salts, such as sulphuric acid, gasification, gasification, gasification, gasification, potassium sulfate, potassium phosphate, sodium carbonate, sodium sulfite, lithium sulfate, potassium carbonate, and sulfuric acid. Sodium; 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; mixture. Penetrants having different dissolution rates can be employed to affect the rapid rate of initial delivery of the active ingredient from the dosage form. For example, amorphous sugars such as mann〇gemtm EZ (SPI Pharma, Lewes, DE) can be used to provide faster delivery during the first few hours to rapidly produce the desired therapeutic effect and gradually and continuously release the remaining amount to lengthen Time to maintain the desired degree of therapeutic or prophylactic effects. In this case, the active ingredient is released at a rate which replaces the amount of the active ingredient which has been metabolized and secreted. The core may also include a variety of other excipients and carriers as described herein to enhance the potency or promote stability or processing of the dosage form. Suitable materials for forming a semipermeable membrane include various grades of acrylic acid, ethylene, ether 'polyamine, polyester and cellulose derivatives, which are water permeable and water insoluble at physiologically relevant pH values, or It is prone to become water insoluble due to chemical changes such as cross-linking. Examples of suitable polymers suitable for use in forming the coating include plasticized, unplasticized and strengthened cellulose acetate 154673.doc-71-201136935 (CA), cellulose diacetate, cellulose triacetate Ester, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), CA amino decanoic acid ethyl ester, CAP, CA methyl carbamate, CA succinate, cellulose B Esters, trimellitate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA oxalate, methyl sulfonate, butyl sulfonate, CA p-toluenesulfonate, agar acetate, amyl triacetate, beta glucan acetate, beta glucan triacetate, diacetate acetate, locust bean gum Acid esters, hydroxylated ethylene-vinyl acetate, EC, PEG, PPG, PEG/PPG copolymer, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly(acrylic) acid and poly(acrylic acid) Ester) and poly(methacrylic acid) and poly(methacrylate) and copolymers thereof, starch, dextran, dextrin, polyglucamine, collagen, gelatin, Olefin, polyether, polysulfone, polyether sulfone, polystyrene, polyethylene, i thereof, polyvinyl esters and ethers, natural waxes and synthetic worthy. The semipermeable membrane may also be a hydrophobic microporous membrane in which the micropores are substantially filled with a gas and are not wetted by the aqueous medium but are permeable to water vapor as disclosed in U.S. Patent No. 5,798,1,9. The hydrophobic but water vapor permeable membranes are typically composed of a hydrophobic polymer such as polyolefin, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, poly Styrene, polyethylene _ compounds, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes and synthetic waxes. The transfer port on the semipermeable membrane can be formed by mechanical or laser drilling after coating. The transfer port can also be thinned by etching the water-soluble substance or embedding the recess in the core 154673.doc -72- 201136935 '. P is formed in situ. In addition, the transfer port may be in the case of an asymmetric film coating of the type disclosed in U.S. Patent No. 5,612, G59 and the number. The total amount of active ingredient released and the rate of release are adjusted by the thickness of the semipermeable membrane and the number, size and position of the pore material, the core d composition and the transfer port. The pharmaceutical compositions of the osmotic controlled release dosage forms may further comprise other conventional excipients or carriers as described herein to facilitate the performance or processing of the formulation. Osmotic controlled release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art. See Remingt〇n: The Science and Secrets, above; Santus and Baker, 乂 1995, 35, 1-21; Verma et al, ~ sigh ~ then price ^ / «i / zmWa / P / zw (four) 叮 2000, 26, 695-708; and Verma et al., j Controlled Release 2QQ2, 79, Ί-2Ί. In certain embodiments, the pharmaceutical compositions provided herein are formulated as an AMT controlled release dosage form comprising an asymmetric osmotic membrane comprising the active ingredient and other pharmaceutically acceptable excipients or carriers. The core of the agent. See U.S. Patent No. 5,612,059 and International Patent Application Publication No. WO 2002/1791. AMT controlled release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation, and dip coating. In certain embodiments, the pharmaceutical compositions provided herein are formulated as ESC controlled release dosage forms comprising a permeable membrane comprising a living ingredient 154673.doc 73· 201136935, hydroxyethyl cellulose, and others The core of a pharmaceutically acceptable excipient or carrier. 3. Multiparticulate Controlled Release Devices The pharmaceutical compositions provided herein in modified release dosage forms can be manufactured as multiparticulate controlled release devices comprising diameters from about 10 μπι to about 3 mm, from about 50 μm to about 2.5 mm or about Multiple particles, granules or pellets ranging from 100 μηη to approximately 1 mm. Such multiparticulates can be made by methods known to those skilled in the art, including wet granulation and dry granulation, extrusion/spheronization, roller compaction, melt solidification, and spray cores. See for example

Oa/ De/zverj, edited by Ghebre-Sellassie;

Marcel Dekker: 1994; less anti-Pharmaceutical Pelletization, edited by Ghebre-Sellassie; Marcel Dekker: 1989. Other excipients or carriers as described herein can be incorporated with the pharmaceutical compositions to aid in processing and forming multiparticulates. The resulting particles may themselves constitute a multi-microparticle device, or may be coated with various film-forming materials, such as enteric polymers, water-swellable, and water-soluble polymers. The multiparticulates can be further processed into capsules or granules. 4. Dry Delivery The pharmaceutical compositions provided herein can also be formulated to target specific tissues, receptors, or other body regions of the subject to be treated, including liposome-based, resealed red blood cells and antibody delivery systems. Examples include, but are not limited to, those disclosed in U.S. Patent Nos. 5,709,874; 5,759,542; 5,840,674; 5,9, 252; 5,972,366; 5,985,307; 6,004,534; 6,039,975 No. 6, 154, 673.doc-74-201136935, 6,048, 736; 6,060,082; 6, 〇71, 495; 6,120,751; 6,131,570; 6,139,865; 6,253,872; , No. 359; No. 6,274,552; No. 6,316,652; and No. 7,169,410. Instructions

In one embodiment, provided herein is a method of treating a proliferative disorder in a subject, the method comprising administering to the individual a therapeutically effective amount of 4_(1(3-fluorophenylindolyl)-1//- 丨 丨 -5-5 -ylamino)_5-methylpyrrolotriazine well-6-ylaminocarboxylic acid (exo-cold sulfonate or its hydrate or pharmaceutically acceptable solvate. In the examples, the amount of the salt provided herein is from about 0.01 to about 1, -mg/kg, about 〇 to about 5 mg/kg, to about 250 mg/kg or about 0.1. To a range of about 100 mg/kg. In certain embodiments, the amount of salt administered herein is from about 0.01 to about 1, 〇〇〇mg/kg/day, from about 〇 to about 500 mg. /kg/day, from about 1 to about 250 mg/kg/day or from about 〇〇 to about 1 mg/kg/day. In certain embodiments, the salt provided herein is administered to an individual The amount is about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 105, about 12, about 180, about 190, about 700, about 750, 1 Oh, about 15, 2〇, about 25, about 30, about 35, about 40, about 5, about 60, about 70, about 75, about 8, about 9, about 1, about 130, about 140, about 15, About 16 〇, about m about 200, about 300, about 400, about 500, about 600, about 8 〇〇, about 900 or about 1, 〇〇〇mg/kg/day. The dosage of the salt provided herein can also be used. Except for the unit of "mg/kg/day 154673.doc -75- 201136935. For example, 'parenteral dosage can be expressed in milligrams per square meter'. Those skilled in the art will be easily informed how to The body weight 6 or body weight or both converts the dose from mg/kg/day to peng/m2/day (see www.fda.g〇v/cder/Cancer/.. coffee (4). For example The dose of 65 kg human i mg / kg / day is approximately equal to 38 mg / m ^ 2 / day. In certain embodiments, the amount of salt administered to the individual is from about 1 to about 1,500 mg / Square meters / day, about 1 to about 1,000 mg / m ^ 2 / day, about 10 to about 500 mg / m ^ 2 / day, about 10 to about 300 mg / m ^ 2 / day or about 20 to In the range of about 2 mg/m 2 /day, in certain embodiments, the amount of salt provided herein is about 1 〇, about 20, about 30, about 40, about 5 〇, about 60, about 70, about 80, about 90, 10 0, about 110, about 12 〇, about 13 〇, about 134, about 14 0, about 1,500, 160, about 170, about 180, about 19 〇 About 200, about 210, about 220, 230, about 240, about 250, about 260, about 270, about 280, about 290 or 300 mg/m2/day. In one embodiment, the salts provided herein are administered in a single dose or in divided doses per dose, wherein the total dose is from about 1 mg to about 2,000 mg, from about 10 mg to about 1,600 mg, about 1 From mg to about i, 2 mg, from about 200 mg to about 1,200 mg, from about 200 mg to about 1,100 mg, from about 300 mg to about 1,100 mg, from about 300 mg to about 1,000 mg, from about 300 mg to From about 800 mg, from about 320 mg to about 800 mg, from about 320 mg to about 700 mg, from about 325 mg to about 650 mg, from about 325 mg to about 600 mg, or from about 350 mg to about 600 mg. 154673.doc 76- 201136935 In another embodiment, the salts provided herein are administered in a single dose or in divided doses per ounce having a total sputum 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 salts provided herein are administered in a single dose or in divided doses (eg, BID) per ounce having a total sputum dose of about 1 mg, about 30 mg, about 65 mg, about 100. Mg, about 200 mg, about 250 mg, about 300 mg, about 320 mg, about 400 mg, about 480 mg, about 500 mg, about 600 mg, about 660 mg, about 700 mg, about 800 mg, about 900 mg, About 1,000 mg, about 1,200 mg, about 1,400 mg, or about 1,600 mg. In certain embodiments, the salts provided herein are administered daily in a single dose or in divided doses, the total daily dose of which is sufficient to achieve a steady state plasma concentration of the compound of from about 0.5 μM to about 40 μM. 1 μΜ to about 30 μΜ, about 5 μΜ to about 25 μΜ or about 10 μΜ to about 20 μΜ; in one embodiment, about 1 μΜ, about 2 μΜ, about 5 μΜ, about 10 μΜ, about 15 μΜ , about 30 μΜ, about 40 μΜ or about 50 μΜ. As used herein, the term "steady state plasma concentration" is the concentration achieved after administration of a compound for a period of time. Upon reaching a steady state, the peaks and valleys on the time-dependent curve of the slurry concentration of the compound of formula I are small. In certain embodiments, the salts provided herein are administered in a single dose or in divided doses, the total amount of which is sufficient to achieve a Cmax of from about 0.1 to about 1 μμ, from about 0.2 to about 50. μΜ, about 4 to about 40 μΜ, about 0.5 to about μΜ, about 5 to about 40 μΜ, about 1 to about 40, about 0.4 to about 4.5 μΜ, or about 3.5 to about 6 μΜ; In the example, 'about 0.1 μΜ, 0.2 154673.doc -77·201136935 μΜ, about 0.3 μΜ, about 0.4 μΜ, about 0.5 μΜ, 〇·6 μΜ, about 0.7 μΜ, 0.8 μίν [, about 0.9 μΜ, about 1 μΜ , about 2 μΜ, about 3 μΜ, about 4 μΜ, about 5 μΜ, about 6 μΜ, 7 μΜ, about 8 μΜ, 9 μΜ, about 10 μΜ, about 15 μΜ, about 20 μΜ, about 30 μΜ, about 40 μΜ , about 50 μΜ. In certain embodiments, the salts provided herein are administered in a single dose or in divided doses, the total dose of which is sufficient to achieve a Cmax of from about 0.1 to about 50 pg/mL, from about 0.2 to about 40 pg/ mL, from about 2 to about 20 pg/mL, from about 1.5 to about 3.2 pg/mL or from about 0.2 to about 2-2 pg/mL. In certain embodiments, the salts provided herein are administered in a single dose or in divided doses, the total dose of which is sufficient to achieve an AUC of from about 60 to about 500, from about 125 to about 500, from about 125 to about 300, or 125 to about 200 pg.hr/mL. In certain embodiments, the salts provided herein are administered in a single dose or in divided doses, the total daily dose of which is sufficient to achieve an AUC of from about 5 to about 1,000, from about 125 to about 1, 〇〇〇, From about 250 to about 500, from about 80 to about 11 or about 5 to about 65 μΜ-hr ° depending on the condition being treated and the condition of the individual, the salts provided herein may be by oral or parenteral (e.g., Intramuscular, intraperitoneal, intravenous, civ, intracisternal injection or infusion, subcutaneous injection or implantation), inhalation, nasal, vaginal, rectal, sublingual or transdermal (eg transdermal or topical) administration versus. The salts provided herein can be formulated, either alone or in combination with pharmaceutically acceptable excipients, adjuvants, and vehicles, in suitable dosage units suitable for the respective routes of administration. The salts provided herein can be delivered in a single dosage form, such as a single bolus 154673.doc 201136935 injection or oral lozenge or pill; or delivered over time, such as continuous infusion over time or fractional administration over time. The salts provided herein can be administered once per dose (QD), or divided into multiple doses such as twice per dose (BID), three times per trip (TID), and four times per minute (QID). In addition, the administration may be continuous (i.e., daily) or intermittent. As used herein, the term "intermittent" or "intermittent" is intended to mean terminating and beginning at regular or irregular intervals. For example, intermittent administration of the salts provided herein is for 1 to 0 days of weekly dosing, with periodic dosing (e.g., daily dosing for 2 to 8 weeks, followed by up to one week of non-dosing) or every other day. In certain embodiments, the frequency of administration of the salts provided herein ranges from about daily administration to about monthly administration. In certain embodiments, the administration of the salt provided herein is once daily, twice daily, three times daily, four times daily, once every other day, twice a week, once a week, once every two weeks, every three times. Once a week or once every four weeks. In one embodiment, the salt system provided herein is administered once a day. In another embodiment, the salts provided herein are administered twice daily. In yet another embodiment, the salts provided herein are administered three times a day. In another embodiment, the salts provided herein are administered four times a day. In certain embodiments, the salts provided herein are administered weekly. In certain embodiments, the salts provided herein are administered on days ith, eighth, and fifteenth of a 28 day period. In certain embodiments, the salts provided herein are administered on days, 8 and 15 of the 21 day cycle. In certain embodiments, the salts provided herein are administered on days 2, 9 and 154673.doc -79 - 201136935 16 days in a 28 day cycle. In certain embodiments, the salts provided herein are administered on days 2, 9, and 16 of the day of the week. In certain embodiments, the salts provided herein are administered on days 3, 1 and 17 of the 2S day cycle. In certain embodiments, the salts provided herein are administered on days 3, 10, and 17 of the 21 day cycle. In certain embodiments, the salts provided herein are administered twice a week. In certain embodiments, the salts provided herein are administered on Day 1, Day 2, Day 8, Day 9, Day is, and Day 6 of the 21 day cycle. In some embodiments, the salts provided herein are administered on days 1, 2, 8, 9, 9, and w of the 28 day cycle. In certain embodiments, the salts provided herein are administered on days 2, 3, 9, 10, 16 and 17 of the 21 day cycle. In certain embodiments, the salts provided herein are administered on days 2, 3, 9, 9, 1 and 16 of the 28 day cycle. In certain embodiments, the salts provided herein are administered on Days 4, 5, Days, 12, 18, and 19 of the 21 day cycle. In certain embodiments, the salts provided herein are administered on days 4, 5, 11, 12, 18, and 19 of the 28 day cycle. In certain embodiments, the salts provided herein are administered for 7 days in a 21 day cycle. In certain embodiments, the salts provided herein are administered for 7 days in a 28 day cycle. In certain embodiments, the salts provided herein are administered daily for a period of three weeks in a 28 day period, followed by a week of rest. In certain embodiments, the salts provided herein are administered daily over a 28 day period and continue for four weeks without interruption. In certain embodiments, the salts provided herein are administered on days 1 and 2 of the 2nd day of the week 154673.doc-80-201136935. In certain embodiments, the salts provided herein are administered for 7 days in a 21 day cycle. In certain embodiments, the salts provided herein are administered for 7 days in a 28 day cycle. In a κ embodiment, the method comprises orally administering the salt provided herein according to a protocol selected from the group consisting of: a. 600 mg/day for 21 days;

b. 600 mg/day for 28 days; C·400 mg for 7 days' for 21 days; and d. 4 to 300 mg/m2/day. In another embodiment, the method comprises administering a salt provided herein according to a protocol selected from the group consisting of: a. sufficient to achieve a Cmax of from about 5 to about 4 μμv]; b. sufficient to achieve a Cmax of a dose of from about 10 to about 4 Torr; c• a dose sufficient to achieve a Cmax of from about 2 to about 2 〇μ§/ηι; • a dose sufficient to achieve a Cmax of from about 3.5 to about 6 μΜ; e. sufficient to achieve a Cmax of about (Μ to a dose of about 4.5 μΜ; • a dose sufficient to achieve a Cmax of from about 1.5 to about 3.2 pg/mL; and g sufficient to achieve a dose having a Cmax of from about 0.2 to about 2.2 pg/mL. In yet another embodiment, The method comprises intravenously administering a salt provided herein according to a regimen selected from the group consisting of a dose sufficient to achieve an AUC of from about 60 to about 500 pg.hr/mL, sufficient to achieve an AUC of from about 125 to about 500 pg.hr/mL. The dose is sufficient to achieve a dose having an AUC of from about 12 5 to about 300 pg.hr/mL, 154673.doc -81·201136935 d. sufficient to achieve an AUC of from about 125 to about 200 pg.hr/mL; e. A dose sufficient to achieve an AUC of from about 125 to about 1,000 pM.hr; f. a dose sufficient to achieve an AUC of from about 250 to about 500 μΜ-hr; g. sufficient to achieve an AUC of from about 4 to about 35 pg.hr/mL Dosage; and h. sufficient to achieve a dose having an AUC of from about 40 to about 55 pg.hr/mL. In yet another embodiment, the method comprises administering a salt provided herein according to a protocol selected from the group consisting of: a. A dose having a Cmax of from about 5 to about 40 μΜ is achieved; b. a dose sufficient to achieve a Cmax of from about 10 to about 40 μΜ; c. a dose sufficient to achieve a Cmax of from about 2 to about 20 pg/mL; d. sufficient to achieve a Cmax of a dose of from about 3.5 to about 6 μΜ; e. a dose sufficient to achieve a Cmax of from about 0.4 to about 4.5 μΜ; f. a dose sufficient to achieve a Cmax of from about 1.5 to about 3.2 gg/mL; and g. sufficient to achieve a Cmax of about 0.2 To a dose of about 2.2 pg/mL. In yet another embodiment, the method comprises intravenously administering a salt of a compound of formula I provided herein according to a protocol selected from the group consisting of: a. sufficient to achieve an AUC of from about 60 to about 500 a dose of pg.hr/mL; b. a dose sufficient to achieve an AUC of from about 125 to about 500 pg.hr/mL; c. a dose sufficient to achieve an AUC of from about 125 to about 300 pg.hr/mL; d. sufficient to achieve AUC is a dose of from about 125 to about 200 pg.hr/mL; e. a dose sufficient to achieve an AUC of from about 125 to about 1,000 μΜ.hr; f. sufficient to achieve an AUC of from about 250 to about 500 a dose of μΜ·1ιι·; g. a dose sufficient to achieve an AUC of from about 4 to about 35 pg.hr/mL; and h. a dose sufficient to achieve an AUC of from about 40 to about 55 pg.hr/mL. 154673.doc -82- 201136935 In certain embodiments, the individual is a mammal. In certain embodiments the mammal is a human. In one embodiment, the proliferative disease is a solid tumor. In the real tumor. In certain embodiments, the disease is a tumor. In another embodiment, in certain embodiments, the solid tumor is late and the solid tumor is a metastatic solid tumor. In yet another embodiment, the proliferative disorder is cancer. In yet another embodiment, the proliferative disorder is advanced cancer. In certain embodiments, the solid tumor is a metastatic cancer.

In certain embodiments, the tumor overexpresses the HEiu protein. In certain embodiments, the tumor overexpresses the HER2 protein. In certain embodiments, cancers that can be treated by the methods provided herein include, but are not limited to: (1) leukemia, including but not limited to acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia, such as bone mother cells. Leukemia, pre-Zhao cell leukemia, bone marrow monocytic leukemia, monocytic leukemia, erythrocytic white disease and myelodysplastic syndrome or its symptoms (such as poor, thrombocytopenia, neutropenia) , two kinds of hematocytopenia (bicytopenia) or whole blood cell reduction), refractory anemia (RA), ra (raRS) with ring-shaped iron granulocytes, RA (RAEB) with excess blasts, transformed RAEB (RAEB-T), pre-leukemia and chronic bone marrow leukemia (CMML); (2) chronic white jk disease, including but not limited to chronic bone marrow (granulocyte) leukemia, chronic lymphocytic leukemia and Hairy cell leukemia; (3) polycythemia vera; (4) lymphoma, including but not limited to Hodgkin's disease and non-Hodgkin's disease (non _H〇dgkin, s 154673.doc •83·201136935 disease); (5) multiple myeloma, including but not limited to palliative multiple myeloma, non-secretory myeloma, osteosclerosing myeloma, plasma cell leukemia, Solitary plasmacytoma and extramedullary plasmacytoma; (6) Waldenstr6m's macroglobulinemia; (7) Unspecified monoclonal globulin; (8) Benign individual ball Proteinosis; (9) Heavy chain disease '·(ίο) bone and connective tissue sarcoma, including but not limited to bone sarcoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma, malignant Giant cell tumor, osteofibrosarcoma, chordoma, periosteal sarcoma, soft tissue sarcoma, angiosarcoma (angi〇sarc〇ma/hemangi〇sarcoma), fibrosarcoma, Kapos〇's sarcoma (Kap〇si, s sarcoma), leiomyosarcoma , liposarcoma, lymphangiosarcoma, metastatic carcinoma, schwannomas, rhabdomyosarcoma and synovial sarcoma; (11) brain tumors, including but not limited to glioma, glioblastoma, polymorphic glia Cell tumor, astrocytoma, brain stem glioma, ependymoma, oligodendroglioma, non-glial tumor, acoustic neuroma, pharyngeal tumor, medulloblastoma, meningioma, pineal tumor, Pineal mesoma cell line and primary brain lymphoma; (10) breast cancer, including but not limited to adenocarcinoma, lobular (small cell) cancer, intraductal cancer, medullary breast cancer, mucinous breast cancer, tubular breast cancer, papillary breast cancer, primary Sexual cancer, Paget's disease (paget, s soil (10) (four) and inflammatory breast cancer' (13) adrenal cancer, including but not limited to pheochromocytoma and adrenal cortical adenocarcinoma, (14) thyroid cancer, including but not limited to nipples Buccal thyroid carcinoma, medullary thyroid cancer and pleomorphic squamous adenocarcinoma; 〇5) sputum cancer 'including but not limited to insulinoma, gastrinoma, glucagonoma, gluteal tumor (vip〇ma ), somatostatin secreted tumors and carcinoid tumors or Tengdao cells 154673.doc -84 - 201136935 tumor; (16) pituitary cancer 'including but limited to Cushing, s disease, prolactin secreting tumor, Acromegaly and diabetes insipius; (17) eyes 'including but not limited to ocular melanoma, such as iris melanoma, choroidal melanoma and ciliary body melanoma, and retinoblastoma' (18) vaginal cancer' including but not limited to squamous cell carcinoma, Adenocarcinoma and melanoma; (19) squamous cell carcinoma, including but not limited to squamous cell carcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma, and Paget's disease; (2) cervical cancer, including However, it is not limited to squamous cell carcinoma and adenocarcinoma; (21) uterine cancer, including but not limited to endometrial cancer and uterine sarcoma; (22) ovarian cancer, including but not limited to ovarian epithelial cancer, borderline tumor, germ cell tumor and Matrix tumors; (23) Esophageal cancer, including but not limited to squamous cancer, adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma, adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma, sickle cancer, and oats Cell (small cell) cancer; (24) gastric cancer 'including but not limited to adenocarcinoma, fungal-like growth (polypoid), ulceration, superficial expansion, diffuse spread, malignant lymphoma, liposarcoma, fibrosarcoma, and carcinosarcoma; (25) colon cancer; (26) rectal cancer; (27) liver cancer, But not limited to hepatocellular carcinoma and hepatoblastoma; (28) gallbladder cancer, including but not limited to adenocarcinoma; (29) cholangiocarcinoma, including but not limited to papillary, nodular and diffuse; (3) lung cancer , including but not limited to, non-small cell lung cancer, squamous cell carcinoma (epidermal carcinoma), adenocarcinoma, large cell carcinoma, and small cell lung cancer; (3 1) testicular cancer including but not limited to blastoma, seminoma , polymorphic classic (typical) sperm cell non-seminoma, embryonic carcinoma, teratoma and choriocarcinoma (yolk sac tumor); (32) prostate cancer 'including but not limited to adenocarcinoma, leiomyosarcoma and rhabdomyosarcoma (33) penile cancer; (34) oral cancer 'including but not limited to squamous cell carcinoma; (35) 154673.doc -85-201136935 basal cell carcinoma; (36) salivary adenocarcinoma, including but not limited to adenocarcinoma, Mucinous epidermoid carcinoma and adenoid cystic carcinoma; (37) pharyngeal cancer, including but not limited to squamous cell carcinoma and squamous cell carcinoma; (38) skin cancer, including but not limited to basal cell carcinoma, squamous cell carcinoma and Melanoma, superficial expansion of melanoma, nodular melanoma, freckle malignancy Neoplasia and acral pigmented melanoma; (39) renal cancer, including but not limited to renal cell carcinoma, adenocarcinoma, adrenal adenoma, fibrosarcoma, and metastatic cell carcinoma (pyroid and/or ureter); (40) Wilms' tumor (Wilms, tum〇r); (41) Bladder cancer, including but not limited to metastatic cell carcinoma, squamous cell carcinoma, adenocarcinoma, and carcinosarcoma; and other cancers, including but not limited to mucinous sarcoma, Osteogenic sarcoma, endothelial sarcoma, lymphatic-endothelial sarcoma, mesothelioma, synovial tumor, hemangioblastoma, epithelial cancer, cystadenocarcinoma, bronchial carcinoma, sweat gland cancer, squamous cell carcinoma, papillary carcinoma and nipple Adenocarcinoma (see Fishman et al., 1985, Chronicle 2nd edition, j B Uppinc〇tt c〇,

Phiiadelphia and Murphy et al., 1997, /"

Complete Book of Cancer Diagnosis, Treatment, and

Recovery, Viking Penguin, Penguin Books USA, Inc., United States of America) In certain embodiments, cancers that can be treated by the methods provided herein include, but are not limited to, bladder cancer, breast cancer, cervical cancer, colon cancer ( For example, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, glioma (such as glioblastoma) 'head and neck cancer, liver cancer, lung cancer (such as small cell lung cancer and non-small cell lung cancer), melanoma, Myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, sarcoma (eg osteosarcoma), skin cancer (eg squamous cell carcinoma), gastric cancer, testicular cancer, thyroid itch and 154673.doc -86 * 201136935 Palace cancer. In certain embodiments, cancers treatable by the methods provided herein include, but are not limited to, bladder cancer, breast cancer, cervical cancer, colon cancer (eg, colorectal cancer), endometrial cancer, gastric cancer, glioma (eg, Glial. Breast cell tumor, head and neck cancer, liver cancer, non-small cell lung cancer, Indian cancer, sputum cancer and prostate cancer. In certain embodiments, the cancer is non-small cell lung cancer. In certain embodiments, the cancer is a non-small cell lung cancer that overexpresses the HER1 protein. In certain embodiments, the cancer is a non-small cell lung cancer that overexpresses the HER2 protein. In certain embodiments, the cancer is non-small cell lung cancer that overexpresses HER1 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 HER1 protein. In certain embodiments, the cancer is metastatic non-small cell lung cancer that overexpresses the HER2 protein. In certain embodiments, the cancer is metastatic non-small/cell lung cancer that overexpresses HER1 and HER2 proteins. ❹ In certain embodiments, the cancer is breast cancer. In certain embodiments, the cancer is a breast cancer that overexpresses the HER1 protein. In certain embodiments, the cancer is a breast cancer that overexpresses the HER2 protein. In certain embodiments, the cancer is a breast cancer that overexpresses the HERUHER2 protein. In certain embodiments, the cancer is metastatic breast cancer. In certain embodiments, the cancer is metastatic breast cancer that overexpresses the HER1 protein. In certain embodiments, the cancer is a metastatic breast cancer that exhibits HER2 protein a degree. In certain embodiments, the cancer is metastatic breast cancer that overexpresses HER1 and Ship 2 proteins. 154673.doc -87· 201136935 In certain embodiments, the cancer is head and neck cancer. In certain embodiments, the cancer is lung cancer. In certain embodiments, the cancer is lung adenocarcinoma. In certain embodiments, the cancer is esophageal cancer or upper gastrointestinal cancer. In certain embodiments, the individual to be treated by the methods provided herein has not been treated with an anti-cancer therapy (4). In certain embodiments, an individual treated with one of the methods provided herein has been treated with an anti-cancer therapy. /, Although some diseases or conditions are more common in certain age groups, the methods provided herein encompass treating a subject regardless of the age of the patient. Further provided herein is a method of treating an individual who has undergone surgery to treat a controversial disease or remainder and an individual who has not undergone surgery. Since individuals with cancer have heterogeneous clinical manifestations and different clinical outcomes, treatment given to a particular individual can vary depending on their prognosis. In various embodiments provided herein, the method can further comprise the step of diagnosing the amount of expression of the HER1 protein on the tumor cells. In one embodiment, the diagnostic step is performed prior to administration of a salt of a compound of the formula provided herein. If the individual has an over-expressed tumor, then the intervention provided in this article is performed, and the diagnostic procedure is performed during the treatment period. In certain embodiments, each of the methods provided herein can independently include the step of administering a second therapeutic agent. In the embodiment, the second therapeutic agent is an anticancer agent. In one embodiment, the anticancer agent is an antimetabolite including, but not limited to, cytarabine (also known as cytosine arabinoside or Ara_c), fludarabine, 5-fluorouracil, gemcitabine , HDAC (high dose cytarabine), 6_mercaptopurine, A 154673.doc -88- 201136935 Amine and pemetrexed. In another embodiment, the anti-caries agent is an anti-microtubule agent including, but not limited to, vinca alkaloids (eg, vinblastine, vincristine, and vinorelbine) and yewwood (eg, paclitaxel, albumin combined with paclitaxel (ABRAXANE®) and docetaxel). In yet another embodiment, the anticancer agent is an alkylating agent, including but not limited to busulfan, carmustine, chlorambucil, cyclodamine, fludarabine , isocyclic guanamine, nitrogen boundary, melphalan and quinone nitrosourea (eg, bis-ethyl nitrosourea, hydroxyurea, carmustine, and lomustine) )). In yet another embodiment, the anticancer agent is a retanning agent, including but not limited to carboplatin, CI-973, cisplatin, oxaliplatin, and satraplatin ( JM-216). In yet another embodiment, the anticancer agent is anthracycline, including but not limited to, adriamycin, daunorubicin, and doxrubicin. In yet another embodiment, the anticancer agent is an antitumor antibiotic, including but not limited to doxorubicin, bleomycin, daunomycin (also known as daunorubicin). )), cranberry, idarubicin and mitogen. In yet another embodiment, the anticancer agent is a topoisomerase inhibitor, including but not limited to camptothecins, etoposide, irinotecan, and topotecan . In yet another embodiment, the anticancer agent is a kinase inhibitor, including, but not limited to, erlotinib and imatinib. In yet another embodiment, the anticancer agent is a nucleoside, including but not limited to gemcitabine. In yet another embodiment, the anti-154673.doc •89·201136935 cancer agent is selected from the group consisting of an enzyme (aspartate), a hormone (tamoxifen, leuprolide, flutamide) And a group of megestrol, mesylate, interferon and oblimersen. In another embodiment, the anticancer agent is a monoclonal antibody, including but not limited to bevacizumab and cetuximab. For a more comprehensive discussion of the latest cancer therapies, see http://www.nci.nih.gov/; a list of FDA-approved oncology drugs can be found at http://www.fda.gov/cder/cancer/druglistframe.htm And The Merck Manual, Seventeenth Edition 1999, all of which are incorporated herein by reference. The route of administration of the sputum method is not in another. According to this, the second dermal administration and the passage of the salt provided by the absorbing method are the same. In one embodiment, the salts provided herein are administered orally, and the salts provided herein are administered intravenously. Thus, etc., the salt provided by the present invention can be administered orally, parenterally, intraperitoneally, intravenously, intra-arterially sublingually, intramuscularly, transrectally, buccally, intranasally, It is administered by liposome, transvaginal, intraocular, local delivery via a catheter or stent, subcutaneous, intrauterine, intra-articular, (d) or in a sustained release dosage form. In the embodiment, the salt provided by the 及^ and the second therapy are administered by the same mode of administration (the salt provided by the article is administered by the seeding mode, for example, oral, and the second Another dose of 荦槿彳 d d (anticancer agent) is administered by the Tianli Nuol model, such as intravenous. Other compounds or anticancer agents that can be used with the compounds provided herein include surgery, radiation. Therapy, melon d inner knife 'beneficial therapy, biological response modifier 154673.doc •90* 201136935 (such as interferon, interleukin and tumor necrosis factor (TNF)), high temperature and cold beam therapy, and used to attenuate any bad An effect agent (e.g., an antiemetic agent). In yet another embodiment, provided herein is a method of inhibiting cell growth, the method comprising: culturing a cell with an effective amount of a salt provided herein (including a pharmaceutically acceptable salt thereof) Or a solvate). In certain embodiments, the cell is a mammalian cell. In certain embodiments, the 'mammal is a human cell. In certain embodiments, the cell is a tumor cell. In certain embodiments Medium, the cell is Milk animal tumor cells. In certain embodiments the 'cell is a human tumor cell. In certain embodiments, the cell is a cancer cell. In certain embodiments, the cell is a mammalian cancer cell. In certain embodiments The cells are human cancer cells. In certain embodiments, the tumor cells overexpress the HER1 protein. In certain embodiments, the 'tumor cells overexpress the HER2 protein. In certain embodiments, 'can be treated by the methods provided herein Cancer cells include, but are not limited to, bladder cancer cells, breast cancer cells, cervical cancer cells, colon cancer (eg, colorectal cancer) cells, endometrial cancer cells, esophageal cancer cells, gastric cancer cells, gliomas (eg, glial mother cells) Cells, head and neck cancer cells, liver cancer cells, lung cancer (such as small cell lung cancer and non-small cell lung cancer) cells, melanoma cells, myeloma cells, neuroblastoma cells, ovarian cancer cells, pancreatic cancer cells, prostate Cancer cells, renal cancer cells, sarcoma (eg osteosarcoma) cells, skin cancer (eg squamous cell carcinoma) cells, gastric cancer Cells, testicular cancer cells, squamous cell carcinoma cells, and uterine cancer cells. In certain embodiments, the cells are bladder cancer cells, breast cancer cells, uterus 154673.doc -91 - 201136935 cervical cancer cells, colon cancer (eg, colorectal Cancer cells, endometrial cancer cells, gastric cancer cells, gliomas (eg, glioblastoma cells), head and neck cancer cells, liver cancer cells, non-small cell lung cancer cells, ovarian cancer cells, sputum cancer cells, or prostate cancer Cells can be metered by, for example, counting the number of cells contacted with the relevant compound, comparing cell proliferation to otherwise identical cells that are not in contact with the compound, or determining the size of the tumor that encompasses the cells. Inhibition of growth. Number of cells and cell size 3H-thymidine in nascent DNA in cells can be measured using any method known in the art (eg trypail biUe exciusi〇n and cell count) Incorporation) is easily assessed. The salts provided herein can also be provided in the form of I using encapsulating materials well known to those skilled in the art. See, e.g., U.S. Patent No. 5,323, Pun. No. 5, No. 52,558, and No. 5, No. G33,252. Examples of money encapsulating materials include: but are limited to foam packaging, bottles, tubes, inhalers, pump 'bags, vials, capsules, and any packaging materials suitable for the selected formulation and mode of administration and treatment. This article is also intended to be used as a kit for the administration of appropriate amounts of active ingredients to individuals when they are used by the medical practitioners. In a singular example, the kits provided herein include dosage forms of the granules and the salts provided herein. In certain embodiments, the kits include _ _ _ 15 of the dosage forms provided herein , in — or multiple containers. 1

The kits provided in this article can be further developed. Examples of such devices include, but are included, for the purpose of administering needle-free syringes that are not limited to syringes, active ingredients, I546 73.doc • 92·201136935 drip coatings, patches, and inhalers. This is a condom for active ingredients. The kits may also be included for use. The kits provided herein may further comprise a pharmaceutically acceptable vehicle that can be used to administer the sexually active ingredients. For example, if the second::: is provided in a solid form for parenteral administration, the sealed container of the heart agent, the active ingredient can be dissolved in the medium == non-parenteral sterile solution without parenteral administration . Medically acceptable: injections include, but are not limited to, aqueous vehicles, including but not limited to injection isp, sodium chloride injection, Ringer's injection, right-handed injection, dextrose and chlorination Naphthalate injection and lactated Ringer's injection; water-miscible vehicles, including but not limited to ethanol, polyethylene glycol and polypropylene glycol, and non-aqueous vehicles 'including but not limited to corn oil, cottonseed oil, peanut oil , sesame oil, oleic acid ethyl vinegar, tetradecanoic acid isopropyl vinegar and benzyl benzoate. The present invention will be more readily understood from the following non-limiting examples.实例 Examples All 1H NMR spectra were recorded on a Bruker® instrument at 300 Torr unless otherwise stated. The coupling constant (7) is expressed in Hertz (D) and the peaks are listed relative to TMS (S 0.00 ppm). The use is equipped with a range of 2 inches for 丨20. The inel XRG-3000 diffractometer of the cps (curve position sensitivity) detector performs X-ray powder diffraction analysis. Instant data was collected using CuKa radiation. The tube voltage and current are set to 4 〇 kV and 30 mA, respectively. The monochromator slit is set at 丨_5 melon claws. Samples were prepared for analysis by encapsulating the samples in thin-walled glass capillaries. Capillary Mounting 154673.doc -93- 201136935 On the goniometer head, the goniometer head is motorized to allow the capillary to spin during data capture. The sample was analyzed for 300 seconds. Instrument calibration using the 矽 reference standard. XRPD plots were collected using a Bruker D-8 Discover diffractometer and Bruker's General Area Diffraction Detection .System (GADDS, version 4.1.20). The incident beam of CuK radiation was generated using a fine focusing tube (40 kV, 40 mA), a Bibbel mirror, and a 0.5 mm double pinhole collimator. The sample is placed for analysis by attaching the well plate containing the sample to a translation stage and moving the sample until it intersects the incident beam. Samples were analyzed using transmission geometry. The incident beam is scanned and rasterized over the entire sample during analysis to optimize orientation statistics. A beam-stop is used to minimize the airborne scattering of the incident beam at low angles. The diffraction pattern was collected using a Hi-Star area detector located 15 cm from the sample and processed using GADDS. The intensity of the GADDS image of the diffraction pattern was integrated using 0.04 ° 2 (step of 9 steps. Prior to analysis, the Shi Xi standard was analyzed to verify the position of the Si i 111 peak. Using a differential scanning calorimeter 2920 from TA Instruments Differential Scanning Calorimetry (DSC). Place the sample in a DSC aluminum pan and accurately record its weight. Cover the plate with a cover and crimp it. Allow the sample to equilibrate at 25 ° C to 10 ° C /min was heated and analyzed until the final temperature was 250 ° C or 350 ° C. Metal indium was used as the calibration standard. The temperature at which the transition was greatest was reported. Thermogravimetric analysis (TGA) was performed using a TA Instruments 2950 thermogravimetric analyzer. Place the sample in an aluminum sample pan and insert it into the TG furnace. 154673.doc -94- 201136935 First equilibrate the furnace at 25 ° C and heat at 10 ° C / min under nitrogen until the final temperature is 165°C or 350°C. Nickel and ALUMELTM are used as calibration standards. In the case of Ever-Glo medium/far infrared source, extended range of potassium chloride (KBr) spectroscope and tritiated sulphate (STGS) Detector's MAGNA-IR 860® Fourier Transform Infrared (FT-IR) Spectroscopic Light Infrared spectra were acquired on a Thermo Nicolet. Samples were taken using a diffuse reflectance accessory (COLLECTORTM, Thermo Spectra-Tech). Each spectrum represents 256 overlay scans collected at a spectral resolution of 4.0 cnT1. Samples mixed with KBr were analyzed. A clean crystal background is collected. The log reflectance spectrum is obtained by obtaining the ratio of the two data set values to each other. Wavelength correction was performed using polystyrene. FT-Raman spectra were acquired on a Raman accessory module connected to a MAGNA 860® Fourier Transform Infrared (FT-IR) spectrophotometer (Thermo Nicolet) interface. The module uses an excitation wavelength of 1064 nm and an indium gallium arsenide (InGaAs) detector. The sample was illuminated using a Nd:YV04 laser power of about 0.4-0.7 W. Samples were prepared for analysis by placing the sample in a glass tube and placing the tube in a keyed gold tube holder. A total of 2 5 6 scans of 3600 cnT1 to 100 cnT1 were collected using the Happ-Genzel apodization method with a spectral resolution of 4 cm·1. Wavelength correction was performed using sulfur and cyclohexane. Alternatively, an FT-Raman spectrum was acquired on an FT-Raman 960 spectrometer (Thermo Nicolet) using an excitation wavelength of 1064 nm. The sample was illuminated with a Nd:YV04 laser power of about 0.5 W. The Raman spectrum was measured using an indium gallium arsenide (InGaAs) detector. Samples were prepared for analysis by placing the sample in a glass tube and placing the tube 154673.doc -95- 201136935 in the gold plated clamp of the attachment. A total of 2 5 6 scans of 3700 cnT1 to 100 cnT1 were collected using a Happ-Genzel apodization method with a spectral resolution of 4 cm·1. Wavelength correction was performed using sulfur and cycloheximide. MAGNA-IR 5 60® Fourier Transform Infrared (FT-IR) Spectrophotometer (Thermo Nicolet) equipped with Ever-Glo Medium/Far Infrared Source, Streaming (KBr) Beamsplitter and MCTA Detector Thermogravimetric infrared (TGIR) analysis was performed on a TA Instruments Model 2050 thermogravimetric analyzer interfaced. The sample was placed in a platinum sample pan, inserted into a TG furnace, and accurately weighed by the instrument. The furnace was heated from ambient temperature to 250 ° C at a rate of 20 ° C / min. First, let the TG instrument start working, and then immediately start the FT-IR instrument. Each IR spectrum represents 32 overlay scans collected at a spectral resolution of 4.0 cm_1. The IR spectrum was collected every 32 seconds for about 13 minutes. A background scan was collected before starting the experiment. Wavelength correction was performed using polystyrene. The TG calibration standards are nickel and ALUMELTM. Volatile substances were identified by searching the high-resolution Nicolet TGA gas chromatography library. Coultometric Karl Fischer (KF) analysis was performed using a Mettler Toledo DL39 Karl Fischer titrator to determine water. Approximately 1000 mg of the sample was placed in a KF titration vessel containing approximately 1 mL of Hydranal-Coulomat AD and mixed for 10 seconds to ensure dissolution. The sample is then titrated using a generator electrode that produces iodine by electrochemical oxidation. Implement two iterations to ensure reproducibility. Optical microscopy was performed using a Leica MZ12.5 stereomicroscope. Samples were observed on-site or on a glass slide using a crossed polarizer and a primary red compensator using different objectives ranging from 0.8 to 1 。. 154673.doc •96- 201136935 Hot stage microscopy on a Leica DM LP microscope (Pol· Microscope #1) equipped with a Spot Insight color camera for image acquisition using the Linkam FTIR 600 hot stage with TM593 controller . Obtain images using Spot Advanced software version 4.5.9 unless otherwise indicated. Make the camera white balance. Unless otherwise specified, images are acquired using a 2〇χ〇.4 N.A. working distance objective and a quadrature polarizer and a primary red compensator. This document uses standard abbreviations and abbreviations as defined in 乂 Org. C/zem. 2007 72(1): 23A-24A. Other abbreviations and abbreviations used herein are as follows: ACN Acetonitrile DCM Dichlorodecane EtOAc Ethyl acetate EtOH Ethanol IPA Isopropanol IPAC Isopropyl acetate MeOH Methanol Example 1 4-(1-(3-Phenylphenyl) -1 0 引 0 sit-5-ylamino)-5-fluorenyl α piroxi[1,2-/][1,2,4]triazot-6-ylamino decanoic acid morpholine- 3-Methyl ester salt was charged to each 4〇111 [scint vial charged with 4-(1-(3-fluorobenzyl)-17/-oxazol-5-ylamino)-5-methyloxime [1,2-/][1,2,4] trisynphin-6-ylamino decanoic acid (51)-morphin-3-yl decyl ester. Acetonitrile (20 mL) was added to each vial, and 154673.doc -97-201136935 was heated with a heat gun until a solution was formed. The vial was weighed and slowly opened and the lid was gently released to gently release all of the pressure in the vial. Next, an acid (1. 〇 equivalent) was added in an amount shown in Table 1. Attempts to remove the solvent for the acetate in a vacuum resulted in a boiling. All other salts were concentrated under a stream of air. One part of each salt was analyzed by DSC and the results are summarized in Table 2. The solubility of the salts in various solvents is summarized in Tables 3 and 4. The purity of the salt is summarized in Table 5. 〇 Table 1 Salt compound 1 (g) Acid name amount Acetate 1.08142 Acetic acid 116.7 μί Benzene sulfonate 1.02753 Benzene sulfonic acid 306.4 mg Ethane sulfonate 1.12149 Ethylene sulphonate 172.4 μί Diacid 1.08641 Maleic acid 237.7 mg Oxime sulfonate 1.02542 Methanesulfonic acid 125.4 Nitrate 1.00458 Nitric acid 121.7 μί Phosphate 1.08866 Phosphate 201.11 mg Tosylate 1.01064 p-Toluene acid ή2ο 362.3 mg Table 2. DSC analysis

Salt Peak #1 Peak #2 Starting Peak Starting Peak Acetate 119.33. . 127.41. . 159.89〇C 165.38〇C Toluenesulfonate 130.73. . 145.00. . 225.20. . 229.85. . Ethyl sulfonate 196.72. . 201.74. . Maleate 194.17〇C 196.85. . Mesylate salt 198.88. . 204.52〇C nitrate 210.21〇C 216.12〇C phosphate 158.70〇C 164.05〇C tosylate 197.85. . 202.3 7°C 154673.doc •98- 201136935

Target 姨宕 姨宕 W荽φ^Ι^.ε^ 154673.doc heptane h-Η tH HH IH K-Η HH HH hexane HH lH l-H HH ΜΤΒΕ 1—Η HH HH lH tH KH HH EtOAc C /3 1—H HH HH HH Hl hH HH THF ΟΟ Η-HH—( HH t—1 HH HH Acetone C/3 HH t—t HH HH HH ACN m HH Kj a cn HH hH HH l·-H HH EtOH Ιη C/3 GO cd Oh C/3 (—( HH hH cd a, GO MeOH m Ol m 00 m σ3 CIh 00 ΙΛ H2〇ce QO t—H in OO CO X/l 00 s tresating acetate benzene sulfonic acid Salt ethanesulfonate maleate methanesulfonate nitrate phosphate benzene sulfonate. 茛¥趣癍 and 婵举铡 invite 蝣石.姨_^绂K-,蘧竣,蝣b长&lt; 菡令二sel , JAt , S d -99· 201136935 Table 4. Solubility of the salt of the compound of formula I Salt 0.1N HC1 pH 2.2 pH 4 pH 5 pH 7 pH 9 pH 12 Water Acetate besylate 1.142 0.419 0.031 0.004 0.000 0.000 0.000 0.014 ethanesulfonate 1.061 1.014 0.051 0.017 0.006 0.002 0.000 0.771 maleate 1.078 1.101 0.052 0.017 0.015 0.003 0.003 0.505 sulfonate 0.914 1.008 0.025 0.016 0.006 0.002 0.004 0.647 Nitrate 1.077 1.060 0.015 0.006 0.001 0.001 0.001 0.391 phosphate 1.711 1.059 0.048 0.017 0.010 0.002 0.003 0.548 benzenesulfonate 0.890 0.006 0.003 0.093 Example 2 4-(1-(3-fluorobenzyl)-1//-carbazole- 5-Aminoamino)-5-methylindolo[1,2-/][1,2,4]triazot-6-ylaminocarbazate morpholin-3-ylmethyl ester salt in amber In a color vial, 4-(1-(3-fluorobenzyl)-177-oxazol-5-ylamino)-5-methyl. Bis-[1,2-/][1,2,4]triazol-6-ylaminocarbazate S)-f--3-yl ester (150 mg or 250 mg) dissolved in 35 volumes In THF. One equivalent of acid was added to the stirred solution. The solution was stirred for 30 minutes, then MTBE was added or the solid was collected by filtration. If MTBE is added, the reaction mixture is stirred for a further 30 to 60 minutes before being filtered. Maleic acid salt was obtained by adding MTBE (8.5 mL) in a yield of 89%. The oxime sulfonate was prepared in quantitative yield without the addition of MTBE. No addition of !^1 butyl 6 to obtain phosphate, the yield was 61%. The ethanesulfonate salt was obtained in quantitative yield by the addition of 丁8 £(4 11^). 154673.doc -100- 201136935

Table 5. HPLC purity of the salt of the compound of formula I salt crystallization solvent HPLC purity (%) nitrite amine content (ppm) acetate MeOH 99.21 1.07 EtOH 99.44 0.45 IPA 98.81 2.42 ACN 99.08 0.48 propyl - 99.29 0.16 THF 99.11 0.54 EtOAc 99.15 0.44 IPAC 98.61 4.41 Benzene sulfonate MeOH 99.36 0.12 EtOH 99.36 0.03 ethanesulfonate EtOH 99.47 0.19 IPA 99.35 0.44 maleate water 98.76 0.31 MeOH 99.03 0.10 EtOH 99.06 0.08 oxime sulfonate MeOH 99.31 0.02 nitrate MeOH 99.39 0.60 Phosphate MeOH 99.25 0.06 Benzene sulfonate MeOH 98.11 1.5 EtOH 98.59 1.03 Example 3 4-(1-(3-Fluorobenzyl)-17/-oxazol-5-ylamino)-5-methyl fluorene And [1,2-/1[1,2,4]triazot-6-ylaminophosphonium sulfonate S&gt; morpholin-3-yl decyl ester salt is generally at about 35° (: , 4-(1-(3-fluorophenylindenyl)-1 ugly-oxazol-5-ylamino)-5-methyl. Bis-[1,2-/][1,2,4 Trinitron-6-ylamino 154673.doc -101 - 201136935 Formic acid morpholin-3-ylmethyl ester is dissolved in 35 or 45 volumes of THF. It is then added at a rate that does not exceed about 35 ° C. 1 equivalent of acid The solution was stirred for 1 hour and cooled to room temperature. MTBE was added (3.5 to 13 volumes, depending on the acid used). The solution was stirred for another 30 minutes. The resulting solid was filtered and washed with 2 to 4 volumes of MTBE and Drying at room temperature under vacuum. The oxime sulfonate was prepared by dissolving the compound of formula I in about 45 volumes of THF at about 35° C. Slowly adding decane-containing sulfonic acid (1.0 Μ, 1 eq. Methanol was stirred for 1 hour. MTBE (50 mL) was added and the solution was stirred for additional 30 min. The obtained solid was filtered, washed with EtOAc and dried over EtOAc The desired salt (21.6 g). HPLC purity: 99.4%; succinamine: 2 ppm; mp: 202.8 〇C to 203.5 〇C. Residual solvent: MTBE: &gt;9675 ppm; THF: 12835 ppm; 736 ppm. XRPD: crystalline solid (possibly mixed crystals and amorphous). Phosphate is prepared by dissolving a compound of formula I in about 35 volumes of THF at 35 ± 5 °C. The sterol containing phosphoric acid (1·〇 Μ, 1 equivalent) was slowly added. The solution was stirred for 1 hour. MTBE (100 mL) was added and the solution was stirred for a further 30 min. The resulting solid was filtered, washed with EtOAc EtOAc (EtOAc) HPLC purity: 99.4%; succinylamine: 2 ppm; mp: 187.1 °C. Residual solvent: MTBE: 5802 ppm; THF: 12467 ppm; MeOH: 296 ppm. XRPD: crystalline solid (possibly mixed crystals and amorphous). The ethanesulfonate salt was prepared by dissolving the compound of formula I (1 〇.〇 g, 18.8 mmol) in 154673.doc -102-201136935 THF (3 50 mL) at 35 °C. Ethanesulfonic acid (156 mL, 19.1 mmol) was dissolved in methanol (19 mL). An acid solution was added to the solution of the compound of formula j within 2 minutes. A solid formed in 5 minutes. Mix the mixture for 1 hour. MTBE (190 mL) was added and the solution was stirred for a further 3 minutes. The resulting solid was filtered, washed with EtOAc (3x30 mL), EtOAc (EtOAc) EtOAc. The yield was 97%. HPLC purity: 99.4 ° / hydrazine; nitrosamine: 2? 1) 111; 11 ^: 198.6. (: to 199.5. (: Residual solvent: MTBE: 432 Ppm; THF: 416 Ppm; MeOH: &lt;108 ppm. XRPD: crystalline solid. The compound of formula I was dissolved at about 3 5 at about 3 5 C The cis-sebacate was prepared in a volume of THF. The methanol containing the acid (1·〇Μ, 1 equivalent) was slowly added. The solution was scrambled for 1 hour. MTBE (l〇〇mL) was added and at 2 A solid formed in the hour. Additional MTBE (200 mL) was added and the mixture was stirred for 1 hour. The solid obtained was filtered, washed with MTBE and dried under vacuum at room temperature for about 66 hours to give a white or pale yellow powder. The desired salt as a solid (11.4 g), yield 93%. HPLC purity: 97.0%; nitrosamine: 3 ppm; mp: 194.0 ° C to 195.3 ° C. Residual solvent: MTBE: 804 ppm; THF: 5838 ppm MeOH: &lt;106 ppm. XRPD: crystalline solid. The solubility of the salt is summarized in Table 6. Example 4 4-(1-(3-Fluorobenzyl)_1 ugly-carbazole-5-ylamino)- 5-methyl. Bilo, 2-, 2-/] Π, 2, 4] 乳乳 p井-6_ylaminocarbamic acid (5*) - morphine-3-yl-methyl gluconate 154673.doc -103- 201136935 Polymorphism of 4-(1-(3-fluorobenzyl) -1 open·carbazole·5-ylamino)_5_methylindole-[1,2-/][1,2,4]triazol-6-ylaminocarboxylic acid (5&gt; morpholine Polymorphic screening of _3_ sulfonate mesylate, ethanesulfonate and maleate. In general, 4-(1-(3-) benzyl methyl azole _5_ Amino group)_5_methyl. A solution of the salt of "_6_ylamino decanoic acid (7) _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ The individual wells of the plates were free of solvent. The solids were slowly evaporated to yield a solid. The results are summarized in Tables 7 to 9. 154673.doc ' 104. 201136935

IPA ea ^ P3 i W t ·〇 ( MeOH 〇aty | 10 mg/mL 12.8 mg/mL ACN/H20 (1:1) 50 mg/mL 250 mg/mL 100 mg/mL 250 mg/mL ACN g? | Eg i ce^ q | Acetone ca ( PS | 03 t 3.6 mg/mL EtOH (95%) ea | eg tb ca ^ HC1 (0.05N) 125 mg/mL 11.9 mg/mL 20 mg/mL 13.2 mg/mL h2o Ea | cS t 〇W l rhyme methanesulfonate phosphate ethanesulfonate maleate. 妷Ki-ls/boUI ς·^ rhyme d.姨^i-luI/sm(N.inch婵馎 馎 ρ 鲶 鲶 哒 i i-ls/&amp;oUI ος-η 面 Γυ Γυ 鲶 鲶 鲶 哒 1 卜 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 salt

Solvent polymorph Form IB C Form IB Propionium/Water Low crystallinity ACN Form IB ACN/Water Form ID 2-butanol Form IA Trioxane Form IA Trichloromethane/Toluene Form IB Cyclohexane Form IA Cyclopentanone Form IC DCM Form IB Ether Form IB 1,4-Dioxo Form IA 1,4-Dioxane/Water Low Crystallinity Ethanol Form IB EtOAc Form IA 2-Ethoxyethanol Low Crystallinity Trifluoroacetic Acid Ethyl ester form IA ethyl trifluoroacetate / TFE low crystallinity fluorobenzene / TFE form IA hexane form IA hexafluoroisopropanol low crystallinity isopropyl ether form IA methyl ethyl ketone form IA methanol form IA methyl nin Fluorobutyl ether form IB 154673.doc -106- 201136935 2-mercapto-1-propanol form Ι-Α 3-pentanone form Ι-Α 1-propanol form Ι-Α 2-propanol form Ι-Α Propionitrile form Ι-Α n-propyl acetate form Ι-Α p-xylene form Ι-Α third pentanol form Ι-Α tert-methyl butyl ether form Ι-Α tetra-ethane ethane low crystallinity THF form Ι -Α THF/water form Ι-Α 曱benzene form Ι-Α α,α,α-trifluorotoluene form Ι-Α Low crystallinity Table 8. ethanesulfonate

Solvent polymorphic form: amorphous form ΙΙ-Β and II-C 嗣/water form ΙΙ-Β ACN form ΙΙ-Β and II-C ACN/water form ΙΙ-Β 2-butanol form II-C chloroform Form II-A Trigasethane/Toluene Form II-B Cyclohexane Amorphous Cyclopentanone Low Crystallinity DCM Form II-B and II-C Ether Form II-B 154673.doc •107- 201136935 1,4- Dioxane form ΙΙ-Α, ΙΙ-Β and II-C 1,4-dioxin/water form ΙΙ-Ε ethanol form ΙΙ-Β EtOAc form ΙΙ-Β and II-C 2-ethoxyethanol amorphous Ethyl trifluoroacetate amorphous ethyl trifluoroacetate/TFE Form II-C Fluorobenzene/TFE Amorphous hexane-fired amorphous hexafluoroisopropanol Amorphous isopropyl ether Amorphous methyl ethyl ketone form ΙΙ-Α 曱Alcohol form ΙΙ-Α decyl nonafluorobutyl ether low crystallinity 2-mercapto-1-propanol form II-C 3-pentanone form ΙΙ-Α 1-propanol form II-C 2-propanol form II -C propionitrile form ΙΙ-Α n-propyl acetate form ΙΙ-Α p-xylene form ΙΙ-Β third pentanol form ΙΙ-Β tert-methyl butyl ether low crystallinity tetra-ethane low crystallinity THF Form II-D THF/water amorphous benzene form ΙΙ-Β α,α,α-three gas benzene forms ΙΙ-Β and II-C water form ΙΙ-Β 154673.doc -108· 201136935 Table 9. Butenoic acid solvent polymorphism amorphous form propylene form III-B propylene _ / water form III-B ACN form III-C ACN / water form III-B 2-butanol form III-C trioxane amorphous Trioxane/toluene form III-A cyclohexane form III-A cyclopentanone amorphous DCM Form III-A diethyl ether amorphous 1,4-dioxin form III-A 1,4-dioxane/water Form III-B Ethanol Form III-A EtOAc Form III-A 2-Ethoxyethanol Amorphous Trifluoroacetate Amorphous Trifluoroacetate/TFE Amorphous Fluorobenzene/TFE Amorphous Burned Amorphous Hexafluoro Isopropanol Form III-D Isopropyl Ether Amorphous Methyl Ethyl Ketone Form III-A Methanol Amorphous Methyl Heptafluorobutyl Ether Unknown 154673.doc -109- 201136935 2-Mercapto-1-propanol Form -Α 3-pentanone form ΙΙΙ-Α 1-propanol form ΙΙΙ-Α 2-propanol form ΙΙΙ-Α propionitrile amorphous n-propyl acetate form ΙΙΙ-Α Benzene form ΙΙΙ-Α Tert-pentanol form ΙΙΙ-Α Tert-butyl butyl ether amorphous tetra-ethane ethane amorphous THF amorphous TIFF/water amorphous benzene amorphous α,α,α-trifluorotoluene Formal water form ΙΙΙ-Β Forms 1-eight to 1-0, 11-person to 11-£ and 111-eight to 111-0 representative 乂110 Figures are shown in Figures 1A to ID, Figures 2A to 2E and 3A to 3E. Some of the 乂110 peaks of Forms 1-8 to 1-0, 11-8 to 11-£ and 111-八 to 111-0 are summarized in Tables 10 to 22, respectively. Table 10. Form X-ray diffraction peak 2Ι angle (°) rf interval (Α) intensity (%) 3.5±0.1 24.948±0.725 52 7.2±0.1 12.3424±0.174 31 8.1±0_1 10.906±0.136 100 11.5± 0.1 70674±0.067 31 13.0±0.1 6.836±0.053 21 14.6±0.1 6.077±0.042 35 154673.doc -110- 201136935

17.1±0.1 5.195 ± 0.030 52 17.7±0.1 5.004±0.028 32 19.1±0.1 4.644±0.024 41 21.7±0.1 4.088±0.019 35 22.1±0.1 4.031±0.018 27 22.5±0.1 3_957±0.017 30 22.8±0.1 3.898±0.017 54 24.0 ±0.1 3.709±0.015 34 24.3±0.1 3.657±0.015 26 25.2±0.1 3.529±0.014 30 26.6±0.1 3.357±0.012 33 27.9±0.1 3.197±0.011 20 28.4±0.1 3.147±0.011 23 29.5±0.1 3.028±0.010 20 Table 11 Form I-Β X-ray diffraction peak 2Θ Angle (°) Interval (A) Strength (%) 2.6±0.1 33.981±1.359 35 3.6 ± 0.1 24.544 ± 0.701 78 8.2±0.1 10.783±0.133 100 11.6±0.1 7.655± 〇.〇67 13 12.6±0.1 7.048±0.056 23 14.7±0.1 6.034±0.041 37 15.9±0.1 5.567±0.035 25 16.8±0.1 5.290±0.032 33 17.2±0.1 5.156±0.030 38 17.9±0.1 4.961±0.028 38 19.3±0.1 4.604±0.024 40 21.9±0.1 4.062±0.018 60 22.9±0.1 3.887±0.017 86 154673.doc -111- 201136935 24.4±0.1 3.654±0.015 61 25.6±0.1 3.480±0.013 40 26.6±0.1 3.35U0.012 39 27.4±0.1 3.260±0.012 33 28.0±0.1 3.187±0.011 26 Table 12. Form X-ray of Ι-C Peak 2 〇 angle interval (A) Intensity (%) 3.3±0.1 26.613±0.826 53 6_8±0.1 12.999±0.194 5 8.0±0.1 11.107±0.141 54 11.2±0.1 7.872±0.070 7 14.1±0.1 6.272±0.045 16 14.5± 0.1 6.117 ± 0.042 21 16.9 ± 0.1 5.253 ± 0.031 68 17.7 ± 0.1 5.005 ± 0.028 43 18.4 ± 0.1 4.822 ± 0.026 39 19.0 ± 0.1 4.681 ± 0.025 70 20.9 ± 0.1 4.254 ± 0.020 27 21.4 ± 0.1 4.145 ± 0.019 39 21.8 ± 0.1 4.077±0.019 40 22.5士 0.1 3.955±0.017 100 23.6±0.1 3.764±0.016 52 24.1±0.1 3.690±0.015 54 25.0±0.1 3.556±0.014 37 26.2±0.1 3.407±0.013 31 27.5±0.1 3.246±0_012 26 28.0±0.1 3.187 ±0.011 26 28.9±0.1 30.92±0.011 21 154673.doc •112- 201136935

Table 13. X-ray diffraction peaks in the form Ι-D 2Θ Angle (°) Interval 〇 4) Intensity (%) 7.4±0.1 12.011±0.165 53 8.8±0.1 10.049±0.115 21 13.2±0.1 6.707±0.051 55 14.2±0.1 6.220±0.044 39 14.9±0.1 5.938±0.040 38 17.6±0.1 5.039±0.029 31 19.3±0.1 4.604±0.024 100 20.5 ±0.1 4.328±0.021 27 21.2±0.1 4.183±0.020 27 22.0±0.1 4.048±0.018 80 23.0±0.1 3.860 ±0.017 40 23.5±0.1 3.783±0.016 46 24.0±0.1 3.708±0.015 35 25.1±0.1 3.551±0.014 87 25.4±0.1 3.507±0.014 78 25_7±0.1 3.469±0.013 68 26.6±0.1 3.356±0.012 48 27.2±0.1 3.279± 0.012 67 28.2±0.1 3.169±0.011 35 28.8±0.1 3.096±0.011 38 29.8±0.1 3.002±0.010 36 Table 14. X-ray diffraction peaks in the form Π-A 2Θ Angle (°) rf interval (4) Intensity (°/«) 3.6±0.1 24.544±0.701 70 7.4±0_1 12.011±0.165 25 8.4±0.1 10.577±0.128 100 11.9±0.1 7.425±0.063 11 154673.doc -113- 201136935 13.4±0.1 6.588±0.049 19 15.U0.1 5.875±0.039 13 17.8±0.1 4.983±0.028 30 19.0±0.1 4.66U0.024 27 22.1±0.1 4.026±0.018 22 23.U0.1 3. 847±0.016 30 24.4士 0.1 3.648±0.015 24 25.7±0.1 3.464±0.013 20 27.2±0.1 3.283±0.012 18 28.6±0.1 3.117±0.011 14 Table 15. X-ray diffraction peak of Form II-B 2Θ Angle (°) Interval (Α) Intensity (%) 3.6±0.1 24.544±0.701 58 7·3±0·1 12.077±0.167 16 8.4±0.1 10.577±0.127 100 10.8±0.1 8.222±0.077 20 12.2±0.1 7.279±0.060 17 13.4±0.1 6.588±0.049 31 14.4±0.1 6.168 ± 0.043 26 15.2±0.1 5.814±0.038 44 15.6±0.1 5.666±0.036 34 16.9±0.1 5.240±0.031 44 17.8±0.1 4.983±0.028 25 18.9±0.1 4.691±0.025 29 19.6±0.1 4.529 ±0.023 33 20.0 ±1 4.444±0.022 25 21.4 ±0.1 4.160±0.019 29 22.2±0.1 4.004±0.018 44 22.6±0.1 3.94U0.017 38 154673.doc -114· 201136935 23.2±0.1 3.828±〇.〇16 44 24.1 ±0.1 3.696±0.015 37 25.3±0.1 3.523±0.014 56 26.4±0.1 3.371±0.013 19 27.2±0.1 3.274±0.012 19 27.4±0.1 3.250±0.012 20 28.0±0.1 3.182±0.011 45 Table 16. Form ΙΙ-C X Ray diffraction peak

2Θ Angle (°) Interval (A) Strength (%) 4.0 ± 0.1 21.872 ± 0.555 60 8. U0.1 10.943 ± 0.137 21 10.6 ± 0.1 8.315 ± 0.079 19 12.4 ± 0.1 7.138 ± 0.058 18 13.8 ± 0.1 6.436 ± 0.047 44 14.4±0.1 6.168±0.043 20 16.3±0.1 5.432±0.033 49 16.8 ± 0.1 5.290±0.032 44 18.7 soil 0.1 4.750±0.025 32 19.2±0.1 4.623±0.024 27 20.3±0.1 4.379±0.021 38 20.8±0_1 4.271±0.020 34 21.6 ±0.1 4.122±0.019 48 22.2±0.1 4.004±0.018 24 23.2±0.1 3.834±0.016 100 24.8±0.1 3.596±0.014 24 26.0±0.1 3.422±0.013 22 26.8±0.1 3.332±0.012 39 27.8±0.1 3.205±0.011 11 29.0± 0.1 3.083±0.010 15 154673.doc -115- 201136935 Table 17. X-ray diffraction peaks in the form ΙΙ-D 2 〇 〇 spacing (A) Strength (%) 3.2±0.1 27.270±0.868 91 6.7±0.1 13.232±0.201 20 8.1±0.1 10.889±0.136 53 14.0±0.1 6.344±0.046 23 17.2±0.1 5.167±0.030 98 18.5±0.1 4.791±0.026 100 21.4±0.1 4.152±0.019 95 21.8±0.1 4.077±0.019 100 22.7±0.1 3.914±0.017 69 23.1 ±0.1 3.854±0.017 65 25.4±0_1 3.507±0.014 54 Table 18. X-ray of the form Π-E Line diffraction peak 2Θ Angle (°) Interval (human) Strength (%) 4.6±0.1 19.379±0.434 47 8.4±0.1 10.477±0.125 33 10.7±0.1 7.284±0.078 28 10.8±0.1 8.162±0.076 20 12.2±0.1 7.255± 0.060 54 13.0±0.1 6.789±0.052 29 14.0±0.1 6.326±0.045 97 15.4±0.1 5.769±0.038 61 17.0±0.1 5.216±0.031 33 18_1±0.1 4.907±0.027 31 18.8±0.1 4.730±0.025 21 19.5±0.1 4.548±0.023 38 21_4±0.1 4.152±0.019 33 154673.doc -116- 201136935 22.4±0.1 3.976±0.018 38 22.5±0.1 3.955±0.017 38 22.8±0.1 3.894±0.017 32 23.7±0.1 3.751±0.016 29 25.0±0.1 3.556±0.014 78 25.8±0.1 3.459±0.013 100 26.2±0.1 3.396±0.013 31 27.3±0.1 3.264±0.012 22 27.9±0.1 3.200±0.011 79

Table 19. X-ray diffraction peaks of Form III-A 2Θ Angle (.) is the interval (Α) intensity (%) 5.U0.1 17·218±0·342 85 9.0±0.1 9.781±0.109 43 10.0±0.1 8.868±0.090 40 10.8±0·1 8.162±0.076 33 12.8±0·1 6.928±0.054 68 13.1±0.1 6.764±0.052 40 14.0±0.1 6·316±0·045 60 14.5±0.1 6·091±0_042 34 15.2 ±0.1 5.843±0.039 89 15·5±0_1 5.700±0.037 70 17.2±0.1 5·154±0·030 44 17_7±0·1 5.023±0.028 60 18·0±0·1 4.918±0.027 68 19·2± 0·1 4.628±0.024 54 20.5±0.1 4.341 ±0.021 53 20.7±0.1 4.290±0.021 81 21·0±0.1 4.228±0·020 39 31·6±0.1 4.107±0.019 39 154673.doc -117- 201136935 22.1± 0.1 4.018士0.018 100 22.5士 0.1 3.957±0.017 88 22.7±0.1 3.909±0.017 93 23.0±0.1 3.869±0.017 89 23.9±0.1 3.720±0.015 47 24.6±0.1 3.617±0.015 39 25.0±0.1 3.562±0.014 44 25.7 ± 0.1 3.468±0.013 32 26.0±0.1 3.427±0.013 54 26.4±0.1 3.374±0.012 53 26.7±0.1 3.335±0.012 30 327.3±0.1 3.269±0.012 35 28_3±0_1 3.159±0.011 34 28.9±0.1 3.088±0.010 25 2 9.3±0.1 3.052±0.010 24 29.6±0_1 3.014±0.010 34 30.0±0.1 2.983±0.010 37 Example 5 4-(1-(3-Fluorobenzyl)-1//-carbazol-5-ylamino) -5-methyl. [1,2-/][1,2,4]triazol-6-ylamino decanoic acid (5&gt;morpholin-3-yl decyl ester of maleic acid butylene The apparent solubility of the acid salt is summarized in Table 23. The weighed sample was treated with an aliquot of the test solvent at room temperature. The mixture was sonicated or agitated between each addition to promote dissolution. The salt is completely dissolved. The solubility is estimated based on the total solvent used for complete dissolution. The actual solubility may be greater than the calculated value due to the solvent aliquot used being too large or due to the slow dissolution rate. If no dissolution occurs during the experiment, 154673 .doc -118- 201136935 The solubility is expressed as less than. If complete dissolution is achieved by adding only one aliquot, the solubility is expressed as greater than. Table 20. X-ray diffraction peaks of Form III-B

2Θ Angle (°) Interval (A) Intensity (%) 5.0±0.1 17.534±0.355 29 9.1±0.1 9.697±0.107 12 10.6±0.1 8.315±0.079 26 11.6±0.1 7.655±0.067 44 12.7±0.1 6.959±0.055 19 13.5± 0.1 6.569±0.049 23 13.7±0.1 6.454±0.047 21 13.9±0.1 6_380±0.046 22 15.6±0.1 5.695±0.037 37 16.4±0.1 5.405±0.033 26 17.6±0.1 5.028±0.028 36 18.1±0.1 4.896±0.027 33 20.6±0.1 4.303±0.021 42 22.0 ± 0.1 4.048±0.018 59 23.0 ± 0.1 3.860 ± 0.017 64 23.4 ± 0.1 3.795 ± 0.016 56 23.9 ± 0.1 3.726 ± 0.015 64 25. U0.1 3.55U0.014 100 26.4 ± 0.1 3.376 ± 0.012 40 27.4 ±0.1 3.260±0.012 64 28.3±0.1 3.156±0.011 23 29.8±〇.1 3.002±0.010 22 154673.doc •119- 201136935 Table 2i. X-ray diffraction peak of form mc 2Θ angle (°) 2) Interval (A ) Strength (%) 5.0±0.1 17.674±0.360 3 8.8±0.1 10.049±0.115 12 10.6±0.1 8.346±0.079 5 11.0±0.1 8.014±0.073 15 11.5±0.1 7.708±0.068 11 11.9±0.1 7.425±0.063 9 13.8±0.1 6.436±0.047 10 14.2±0.1 6.237±0.044 6 15.1±0.1 5.860±0.039 11 15.6±0.1 5.666±0.036 4 16.8±0.1 5.290±0.032 13 17.4±0.1 5.097±0.029 39 18.3±0.1 4.853±0.026 14 19.3±0.1 4.604±0.024 3 19.9±0.1 4.466±0.022 4 20.3 Soil 0.1 4.379±0.021 5 21.2±0.1 4.191±0.020 10 21.4±0.1 4.145±0.019 10 22.3±0_1 3.983±0.018 23 23.4±0.1 3.808±0.016 18 23.9±0.1 3.726±0.015 28 25.3±0.1 3.518±0.014 100 27.0±0_1 3.298±0.012 39 27.8 ± 0.1 3.205±0.011 9 28.6 ±0.1 3.125±0.011 4 29.4±0.1 3.034±0.010 11 154673.doc -120- 201136935 Table 22. X-ray diffraction peaks in the form ΙΙΙ-D 2Θ angle (. Z) Interval (A) Intensity (%) 3.6 ± 0_1 24.544 ± 0.701 50 4.6 ± 0.1 19.379 ± 0.434 39 7.4 ± 0_1 12.011i 0.165 33 12.4 ± 0.1 7.115 ± 0.057 31 13.4 ± 0.1 6.588 ± 0.049 69 17.5 ± 0.1 5.062±0.029 100 19.5±0.1 4.548±0.023 100 20.4±0.1 4345±0.021 81 23.5±0.1 3.789±0.016 89

Table 23 Solvent Solubility Acetone &lt;14 ACN &lt;12 Hexafluoroisopropanol (HFTPA) &gt;67 Trifluoroethanol (TFE) &gt; 166 Ο Using different crystallization methods, including slurry formation, slow cooling, slow evaporation, and rapid evaporation Further investigation of 4-(1-(3-fluorobenzyl)-1-oxazol-5-ylamino)-5-fluorenyl in acetone, ACN, HFIPA or THF. The polymorphic form of the maleic acid salt of [1,2-/][1,2,4]triazolam-6-ylaminophosphonate morpholin-3-yl decyl phthalate. The results are summarized in Table 24. For the slurry process, a solvent is added to the weighed solids in the glass vial at a ratio of the presence of undissolved solids. Heat the sample with agitation or stir the sample at ambient temperature. The solid 154673.doc -121 - 201136935 was isolated by vacuum filtration or solvent decantation to air dry the solid under ambient conditions prior to analysis. For the slow cooling method, a saturated solution was prepared in various solvents at a high temperature and warm-filtered through a 0.2 μηη t t-transformer into an open vial. Slowly cool the vial to room temperature. The solid formed was separated by filtration and dried before analysis. For the slow evaporation method, the solution was prepared in various solvents and sonicated between each aliquot of the sample to aid dissolution. According to visual judgment, after the mixture reached complete dissolution, the solution was filtered through a 0.2 μm symmetry or TFE filter. The solution was slowly evaporated under nitrogen or slowly filtered at -50 °C. The solid formed was separated by a transition and dried before analysis. For the rapid evaporation method, solutions were prepared in various solvents and sonicated between aliquots to aid dissolution. According to visual judgment, after the mixture reached complete dissolution, the solution was filtered through a 0.2 μηη nylon filter. The filtered solution was evaporated in an open-cap vial under ambient conditions. The solid formed was isolated by filtration and dried prior to analysis. Table 24 Solvent conditions, polymorphic form C - maintained at room temperature for 8 days after formation of the slurry. Form III-A was maintained at -50 ° C for 7 days after the formation of the slurry. Form III-A slowly evaporated at -50 ° C. Form III-A -50 ° C to -20 ° C, slowly cooling ACN at rC / hr after slurry formation at room temperature for 8 days. Form III-A after slurry formation at -50 ° C for 7 days. Form III-A at -50 Slowly evaporating at a °C, low crystallinity 154673.doc -122- 201136935 1---'^-, slowly cooling the six-gas isopropanol force N by c/hr, Ding Jingping U4 -V 三氟 trifluoroethanol —--------^ΧΛ, 2 r 7}^ Gel, add acetone, then quickly evaporate the form ΙΙΙ-Α and III-B 'disappeared into glass, add acetone, then slowly evaporate and evaporate quickly Gel formation, addition of ACN form ΙΙΙ-Α __ rapid evaporation of form III-B and ΙΙΙ-Α starting from form III-A, forming a poly-liquid at room temperature and maintaining 1 day of form III-B acetic acid ethyl vinegar Using Forms III-A and III-B as starting materials, forming a slurry form ΙΙΙ-Α at 2Ό to 8t, using Forms III-A and III-B as starting materials to form a high-temperature slurry - real 6 Quantify 4-(1-(3-fluorophenylindenyl)-1·ίΓ-. 丨 丨 -5-ylamino)-5-methyl ° than π Π, 2-//[ι, 2,4] Triazolam-6-ylaminocarbamate (5)-(4-nitrosomorpholin-3-yl)methyl ester ("AC480-nitrosamine") in C18 tube (50 mm) On &lt;4.6 mm), AC480-nitrosamine was quantified using HPLC-MS in a triple reaction MS system with multiple reaction monitoring mode. The mobile 〇 phase is A. water containing 〇.1〇/0 formic acid, and B. ACN containing 0.1% formic acid. A stock standard solution (1 〇〇 PPm) was prepared by accurately weighing 10 ± 0.1 mg of the AC480-nitrosamine reference material in a 100 OIL volumetric flask and dissolving and diluting to a specified volume with ACN. The stock standard solution was stabilized to - 9 months at -25 ° C and stored in the dark. Prepare a 0.1 ppm solution by diluting the stock standard solution with ACN/water (9:1, v:v) and transfer 5.0 mL of this 0.1 ppm solution to a 10 〇mL volumetric flask and use ACN/water (9:1, v :v) Prepare a working assay standard solution (5 ppb) in duplicate to the indicated volume. A work certificate 154673.doc •123- 201136935 The standard solution is used as a verification standard. The working test standard solution was allowed to stand at 4 ° C for at least 3 days and stored in the dark. For the analysis of 1 mg of encapsulated tablet, a sample solution was prepared by weighing 3 capsule-free dosage units and transferring the capsules to a 250 mL volumetric flask. Fill the flask with approximately 160 mL ACN/water (9:1, v:v), shake for 10 minutes, then sonicate for 15 minutes, then use ACN/water after equilibration to room temperature (9:1, v:v Dilute to the specified volume. The final concentration of AC480 in the sample solution was 1.2 mg/mL. An aliquot of the sample solution was centrifuged for 10 minutes. Aliquots were transferred to HPLC vials for analysis. The sample solution was allowed to stand at 4 ° C for 3 days and stored in the dark. To analyze the AC480 drug substance, a sample solution was prepared by weighing 12 mg of AC480 drug substance and transferring it to a 10 mL volumetric flask. Fill the flask with approximately 6 mL ACN/water (9:1, v:v), sonicate for 2 minutes, then dilute to AHP/water (9:1, v:v) to equilibrium after equilibration to room temperature volume. The final AC480 concentration of the sample solution was 1.2 mg/mL. Aliquots were transferred to HPLC vials for analysis. The sample solution was allowed to stand at 4 ° C for 3 days and stored in the dark. System suitability was tested by injecting a test standard solution six times and calculating the %RSD of the peak area of the repeated injections. The verification work standard solution was also injected three times. The %RSD of the peak area of the repeated injection work assay standard solution is less than NMT 10%. The weighted corrected area reaction ratio of the working test standard solution and the verification test standard solution is between 0.90 and 1.10. The sample is analyzed by injecting the sample solution in two portions. The mother samples are injected six times, and the working standard solution is used for quality control. Calculate the test sample as follows: 154673.doc • 124- 201136935 The amount of AC480-imide: AC480-subwall amine concentration (ppm) = (average area reaction of two repeated injections of sample solution) X (AC480-nitrogen Amine standard solution (ng/mL)) X (total volume of sample solution (mL)) + [(Average area response of six injections of AC480-nitrosamine standard solution) X (total weight of sample (g))] . Example 7 Synthesis of [4-[[1-(3-fluorophenyl)indolyl]-1//-oxazol-5-ylamino]-5-methyl-pyrrole in crystalline form II-B [2,lf][l,2,4]triazot-6-yl]-carbamic acid (3S)-3-morpholinylmethyl ethanesulfonate (AC480 ethanesulfonate) at 78± The mixture of AC480 free base and ethanesulfonic acid in ethanol was heated at 5 ° C for at least 1 hour. The reaction mixture was then cooled to 20 ± 5 ° C and the AC 480 ethanesulfonate was precipitated. After filtration, the filter cake was washed with ethanol cooled to 0 ± 5 °C. The resulting solid was then dried to constant weight in a vacuum oven at $3 (TC) to afford AC 480 ethanesulfonate as crystalline form II-B with a melting point of about 202 ° C. Crystallization was determined under three different storage conditions Stability of Form AC-ethanesulfonate of Form II-B: i) 5 ° C; ii) 25 ° C and 60% RH; and iii) 40 ° C and 75% RH. The results are summarized in Tables 25 to 27. Table 25. Stability parameters of AC480 ethanesulfonate at 5 °C Initial 1 month 3 months Appearance match a Match a match a AC480 content (HPLC) 100% 102% 99% Total Impurity (HPLC) 0.3% 0.4 % 0.33% Nitrosamine (LC/MS/MS) 0 ppm 0 ppm Oppm Moisture Content (KF) 0.9% 0.9% 0.6% a. AC480 ethanesulfonate is white to light yellow or light pink powder and may contain agglomerates . 154673.doc -125- 201136935 Table 26. Stability parameters of AC480 ethanesulfonate at 25 ° C / 60% RH Initial 1 month 3 months Appearance match a Match 3 match a AC480 content (HPLC) 100% 101 % 100% Total Impurity (HPLC) 0.3% 0.4% 0.33% Nitrosamine (LC/MS/MS) 0 ppm 0 ppm Oppm Moisture Content (KF) 0.9% 0.8% 0.6% a. AC480 ethanesulfonate is white to Light yellow or light pink powder, may contain agglomerates. Table 27. Stability parameters of AC480 ethanesulfonate at 40 ° C / 75% RH Initial 1 month 3 months Appearance match a Match a match a AC480 content (HPLC) 100% 102% 100% total impurities (HPLC 0.3% 0.4% 0.33% Nitrosamine (LC/MS/MS) 0 ppm 0 ppm 0 ppm Moisture Content (KF) 0.9% 0.9% 0.6% a. AC4 80 ethanesulfonate is white to pale yellow or pale pink Powder, which may contain agglomerates. Example 8 Preparation of a pharmaceutical formulation comprising AC480 ethanesulfonate A pharmaceutical formulation comprising AC480 ethanesulfonate was prepared by a sterile lyophilization process. The composition of the pharmaceutical formulation and the amount of water used in the preparation are summarized in Table 28. In preparing the pharmaceutical formulation, 75% of the required amount of sterile water for injection is added to the clean, de-heated glass container. Adding the required amount of powdered mannitol (2% by weight), hydroxypropyl-β-cyclodextrin (HPPCD) (15 154673.doc -126- 201136935 wt%) and AC480 ethanesulfonate to the container, And mix until dissolved. The solution is brought to its final batch weight with sterile water for injection, i.e., the remaining 25%. The solution was then sterile filtered and filled in a 30 cc amber glass vial, 12 ml/vial. Insert the stopper into the vial and freeze to dry. After lyophilization, the vial was backfilled with sterile filtered nitrogen and the stopper was fully inserted. The vial was then crimp sealed using a 20 mm white pull-tab crimp. Each vial was reconstituted at 25 mg/mL AC480 prior to administration to the patient. Component (%) Composition / 300 mg unit dose 12 L (12,000 g) Batch amount AC480 ethanesulfonate 3 3.025% 363 mg 363 g Hydroxypropyl-β-cyclodextrin 15% 1,800 mg 1,800 g Mannose Alcohol 2% 240 mg 240 g Water for injection USPb 79.975% 9,597 mg 9,597 g a. AC480 ethanesulfonate (363 mg) contains 300 mg of AC480 free base. b. Water is removed during lyophilization.

The above examples are provided to provide a complete disclosure and description of the claimed embodiments, and are not intended to limit the scope of the disclosure. Modifications that are apparent to those skilled in the art are readily within the scope of the accompanying claims. All publications, patents, and patent applications cited in this specification are hereby incorporated by reference in their entirety in the extent of The way is incorporated in this document in general. 154673.doc -127- 201136935 [Simplified Schematic] Figures 1A to 1D depict 4-(1-(3-fluorophenyl)-1//- in crystalline form IA, B, JC and I_D, respectively. Oxazol-5-ylamino)-5-methylpyrrolo[1,2-/][1,2,4]triazot-6-ylaminocarbazate morpholin-3-ylmethanone methane X-ray powder (XRP) diffraction pattern of the hydrochloride salt. 2A to 2E depict 4-(1-(3-fluorobenzyl)-1//-carbazole-5-yl as crystalline forms II-A, H_B, Π-C, D and II-E, respectively. Ethyl)-5-methylpyrrolo[1,2-/][1,2,4]triazol-6-ylaminocarbamic acid (51)-morpholin-3-ylmethyl ester ethanesulfonate X-ray powder (XRP) diffraction pattern of the acid salt. Fig. 3 to Fig. 30 respectively depict 4-(1-(3-fluorobenzoinyl)_1 ugly-carbazole in crystalline form 111-in, 111-; 6, 111-(: and III-D_5_ 5-aminopyrroloindole, 2-/1[1,2,4]triazol-6-ylaminocarboxylic acid (*S)-oxalin-3-yl decyl ester X-ray powder (XRP) diffraction pattern of enedionate. 154673.doc 128-

Claims (1)

201136935 VII. Patent application scope: 1. A kind of 4-(1-(3_fluorobenzyl)_1/f_carbazole _5-ylamino)_5-methylpyrrolo[1,2-/][ 1,2,4] Triazolam_6-ylaminocarbamic acid (51)-morpholine-3-methylsulfonate, or a hydrate thereof or a pharmaceutically acceptable solvate thereof. 2. The sulfonate of claim 1, wherein the sulfonic acid is (^-6 alkylsulfonic acid or carylsulfonic acid. 14 3. 4. Ο 5. 6. For the sulfonate of claim 2, Wherein the sulfonic acid is a methanesulfonic acid. The sulfonate of claim 3 is in an amorphous form. The sulfonate of claim 3 is in a crystalline form. The sulfonate of claim 5, Is a sulfonate of the claim 5 or 6 in a crystalline form, having a diffraction pattern of X-ray powder substantially as shown in Figure 1A. 8. The sulfonic acid according to any one of claims 5 to 7. The salt, the diffraction pattern of the ray-ray powder has a peak at about 7.2, 13 〇, 28·4, or 2·5 at 2 。. 9. The sulfonate of claim 5 is crystallized. Form Ι-Β. 10. The sulfonate of claim 5 or 9, which has an X-ray powder diffraction pattern substantially as shown in Figure 11.. 11. As claimed in any of claims 5, 9 and 10. The sulfonate salt, the diffraction pattern of the χ ray powder has a peak of about 2.6, 12.6, 15.9, or 17.9 at 2 ·. The peak of the sulfonate is as follows. Ι-C. 13. Sulfonic acid according to claim 5 or 12. a salt having a diffraction pattern of X-ray powder substantially as shown in Fig. 1C. The sulfonate of any one of items 5, 12 and 13 having a χ ray powder around 154673.doc 201136935 6.8°, The photograph at 11.2° or 26.2° has a peak of about 3.3 at about 3.3. 15. The sulfonate of claim 5 is in crystalline form ι_β. 16. The sulfonate of claim 5 or 15 It has an X-ray powder diffraction pattern substantially as shown in (1). 17. An X-ray powder diffraction pattern having an X-ray powder diffraction pattern as indicated in δ-months 5, 15 and 16 A peak at about 7.4, 8 8 , 13 2, 14 9 , 27.2 °, 28.2 ° or 29.8 ° 18. The sulfonate of claim 2, wherein the sulfonic acid is ethanesulfonic acid. 19. The sulfonate of claim 18 which is in an amorphous form. 2. The sulfonate of claim 18 in crystalline form. 21. The sulfonate of claim 20, The crystalline form is Π_Α. 22. The sulfonate of claim 20 or 21 having a diffraction pattern of X-ray powder substantially as shown in Figure 2α. 23. The continuation of the acid as claimed in any one of claims 20 to 22. salt, The x-ray powder diffraction pattern has a peak at about II.9, 24 4 or 28 6 以 as 2 。 24. The sulfonate salt of claim 20 is in crystalline form Π Β. The sulfonate of the item 20 or 24, which has a diffraction pattern of X-ray powder substantially as shown in Fig. 2β. 26. The sulfonate of any one of claims 20, 24 and 25, the ray-ray powder The diffraction pattern has a mean of 2 在 at about 24.1. Or 25.3. The peak. 27. The sulfonate of claim 20 which is in crystalline form n_c. 28. The sulfonate of claim 20 or 27 which has an X-ray powder diffraction pattern substantially as shown in Figure 2A. 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 12.4. 13.8. , 16 3. 19.2. 20.3. 21.6. 24.8. 26.0. 26.8. Or 29.0. The peak. 30. The sulfonate of claim 20 which is in crystalline form ii-d. 31. The sulfonated salt of claim 20 or 30 which has an X-ray powder diffraction pattern substantially as shown in Figure 21). 32. The competing acid salt of any one of claims 20, 30 and 31, wherein the xenon ray powder diffraction pattern has a mean 在 at about 3.2. Or 6.7. The peak. 33. The sulfonate salt of claim 20 which is in the crystalline form Π-E. 34. The sulfonate of claim 20 or 33 which has an X-ray powder diffraction pattern substantially as shown in Figure 2E. 35. The transverse acid salt of any one of claims 20, 33 and 34, wherein the xenon ray powder diffraction pattern has a Θ of about 4.6. , 13.0. , 15.4. 23.7. Or a peak at 25.0°. 36. The sulfonate of claim 2, wherein the sulfonic acid is benzenesulfonic acid. 3. 7. The sulfonate of claim 36 which is in an amorphous form. 38. The sulfonate of claim 36 which is in crystalline form. 39. The sulfonate of claim 2, wherein the sulfonic acid is p-toluenesulfonic acid. 40. The sulfonate of claim 39 which is in an amorphous form. 41. The sulfonate of claim 39 which is in crystalline form. The sulfonate of any one of claims 1 to 41, which comprises about 1 molar equivalent of 4-(1-(3-phenylenemethyl)-1//·D bow-5-胺 ) -5 -5 -5 4 4 4 ] ] ] ] ] ] ] ] ] ) ) ) ) ) ) ) ) ) ) ) ) 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 154 acid. 43. The sulfonate of any one of claims 1 to 42 which contains no more than 3 ppm of 4-(1-(3-fluorophenylhydrazinocarbazole-5-ylamino)_5_methyl^ More than [1,2-/][1,2,4] diazepine well-6-ylamino decanoic acid (phantom _(4_nitrosoline_3_yl) methyl ester. 44. A 4-(1-(3-fluorophenylhydrazinyl)-5-methylindolodiazepine]-6-ylaminocarbamic acid ($)·吗琳_ 3_Acetylacetate acetate or a hydrate thereof or a pharmaceutically acceptable solvate thereof. 45. The acetate salt of claim 44 which is in an amorphous form. 46. The acetate salt of claim 44 The acetate is in the form of a crystal. The acetate of any one of claims 44 to 46, which comprises about 4-(1-(3-fluorophenylhydrazinyl)-5-yl Amino)-5-mercaptopyrrolo[1,2-/][1'2,4]triazinylamino decanoic acid (5&gt; morpholine-3-yl decyl ester and about 1 molar equivalent of acetic acid. 48. The acetate of any one of claims 44 to 47, which contains no more than 3 ppm of 4-(1-(3-fluorobenzylidenebazole-5-ylamino)-5 Pyryrrolo[1,2-/][1,2,4]trinitrogen _6-ylamino decanoic acid (5 &gt;(4_nitrosomorpholine-3-yl)methyl ester 49. A 4-(1-(3-fluorobenzyl}-1//-carbazole-5-ylamino)_5曱Pyridyl[1,2-/][1,2,4]diazepine_6-ylaminocarbamic acid ($)-morpholine-3-yl decyl ester maleate, or hydrated thereof Or a pharmaceutically acceptable solvate. 50. The maleic acid salt of claim 49, which is in an amorphous form. 51. The maleic acid salt of claim 49, Crystalline form. 154673.doc 201136935 52. The cis-butanyl acid salt of claim 51, which is in crystalline form, such as the maleic acid salt of claim 51 or 52, which has substantially the same An X-ray powder diffraction pattern as shown in any one of claims 51 to 53, wherein the ray-ray powder diffraction pattern has a diffraction pattern of about 2 Å at about 1 Torr, 1〇8, ΐ3 1〇, 26.0. or 29.6. 17.2°, 21.6°, 22.5., 22.7°, 24.6. Peak. 55. According to claim 51, Chuanbei besylate, its In the crystalline form πι_β. 56. The maleic acid salt of claim 51 or 55, which has substantially the same The diffraction pattern of the X-ray powder shown in Figure π. 57. The maleic acid salt of any of claims 51, 55 and 56 having a diffraction pattern of the ray line powder having a mean enthalpy of about 29.8. The peak. 58. The maleic acid salt of claim 51 which is in crystalline form. 59. The maleic acid salt of claim 51 or 58, which has an X-ray powder diffraction pattern substantially as shown in the figure. ??? 60. The maleic acid salt of any one of claims 5, 58 and 59, wherein the ray-ray diffraction pattern has a diffraction pattern of about 8 8 . , ^ 〇. , u, 16.8. , 18·3. 22.3. 25.3. 27 〇. Or 27 8. The peak. 61. The maleic acid salt of claim 51 which is in crystalline form 62. The maleic acid salt of claim 51 or 61 having an X-ray powder substantially as shown in the figure Diffraction pattern. 63. The maleic acid salt of any one of claims 51, 61 and 62, wherein the xenon radiation powder diffraction pattern has a Θ of about 3.6. 4 6 , 7 4. 12 4 Or a peak at 19.5°. The maleic acid salt of any one of claims 49 to 63, which comprises about 2 molar equivalents of 4-(1-(3-fluorobenzylcarbazole-5-yl) Amino)-5-methylpyrrolo[1,2-/][1,2,4]triazin-6-ylaminocarbamic acid morpholin-3-yl decyl ester and about 1 molar equivalent The maleic acid salt of any one of claims 49 to 64, which contains no more than 3 ppm of 4-(1-(3-fluorobenzyl)-1 open-oxime Oxazol-5-ylamino)-5-methyl-pyrano[1,2-/][1,2,4]triazot-6-ylaminophosphonium sulfonate S)-(4-亚Nitroline-3-based) A g. 66. —4-(1-(3-Fluorobenzoyloxazol-5-ylamino)-5-fluorenylpyrrolo[1,2-/1[1,2,4] triazotric tillage a nitrate of -6-ylamino decanoic acid () 5)-morpholin-3-ylmethyl ester, or a hydrate thereof or a pharmaceutically acceptable solvate. 67. The nitrate of claim 66 which is in an amorphous form. 68. The nitrate of claim 66 which is in crystalline form. 69. The nitrate of any one of claims 66 to 68 which comprises about 1 molar equivalent of 4-(1-(3-fluorophenylindenyl)-1 ugly-oxazol-5-ylamino) 5-5-fluorenyl "pyrrolidine, 2-/] [1,2,4] triazolam-6-ylaminocarbamic acid morpholin-3-yl decyl ester and about 1 molar equivalent of nitric acid. 70. The nitrate of any one of claims 66 to 69 which contains no more than 3 ppm of 4-(1-(3-fluorobenzylsulfonylamino)-5-fluorenyl ° And [1,2-/][1,2,4]triazol-6-ylaminocarboxylic acid (phana-(4-nitrosomorpholin-3-yl)). 71 _ —4 -(1,(3-fluorobenzyl)-1open-0-involved 0-spin-5-ylamino)_5·indolyl 0-diloxatriazine--6-ylaminocarbamate (5&gt; a phosphate of -3-methyl ketone, or a hydrate thereof or a pharmaceutically acceptable solvate. 154673.doc -6- 201136935 72. The phosphate of claim 71, which is in an amorphous form. The phosphate of claim 71, which is in the form of a crystal. 74. The phosphate of any one of claims 71 to 73, which comprises about 1 molar equivalent of 4 (1-(3-fluorobenzyl) -1//-carbazol-5-ylamino)-5-methyl"pyrolo[triazot-6-ylaminocarbazate S)-morpholin-3-yl decyl ester and about 1 Mo The phosphoric acid of the ear equivalent. 75. The acid salt of any one of claims 71 to 74 which contains no more than 3 ppm of 4-(1-(3-fluorobenzylcarbazole-5-ylamino) -5-decylpyrrolo-4]triazot-6-ylaminocarboxylic acid (phantom-(4- Nitrosomorpholine-3-yl)methyl ester 76. A pharmaceutical composition comprising a salt according to any one of claims 1 to 75 and a pharmaceutically acceptable excipient. The pharmaceutical composition of 76, wherein the composition is formulated for oral, nasal, transbronchial or topical administration. 78. The pharmaceutical composition of claim 76 or 77, wherein the composition is formulated into a single dosage form. 79. A method of treating a proliferative disorder in an individual, the method comprising administering to the individual a salt of any one of claims 1 to 75 or a pharmaceutical composition according to any one of claims 1 to 78. 80 The method of claim 79, wherein the proliferative disease is a tumor. The method of claim 80, wherein the tumor is a solid tumor. 82. The method of claim 80 or 81 wherein the tumor is malignant Tumor. The method of claim 82, wherein the malignant tumor is bladder cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, gastric cancer, glioma, 154673.doc 201136935 head and neck cancer, liver cancer, non-small cells Lung cancer, ovarian cancer, pancreatic cancer or prostate cancer The method of any one of claims 80 to 83, wherein the tumor overexpresses the HER1 protein. The method of any one of claims 80 to 84, wherein the tumor overexpresses the HER2 protein d 86· A method of inhibiting cell growth, the method comprising contacting the cell with a salt of any one of claims 1 to 75 or a pharmaceutical composition according to any one of claims 76 to 78. 87. The method of claim 86, wherein the cell is a tumor cell. 88. The method of claim 87, wherein the tumor cell is a solid tumor cell. The method of any one of claims 86 to 88, wherein the cell is a cancer cell. The method of claim 89, wherein the cancer cell is a bladder cancer cell, a breast cancer cell, a cervical cancer cell, a colon cancer cell, a endometrial cancer cell, a gastric cancer cell, a glioma cell, a head and neck cancer cell, a liver cancer cell Non-small cell lung cancer cells, ovarian cancer cells, pancreatic cancer cells or prostate cancer cells. The method of any one of clauses 86 to 90, wherein the cell overexpresses the HER1 protein. The method of any one of claims 86 to 91, wherein the cell overexpresses the HER2 protein. A method of preparing a salt according to any one of claims 1 to 76, which comprises subjecting 4-(1-(3-fluorobenzylhydrazine-5-154673.doc 201136935) at a first predetermined temperature. The amino group)-5-methyl material _,2.,24]triazolamide carboxylic acid () oxime ester is reacted with an acid in a solvent. 94. The method of claim 93, further comprising The salt is condensed at a second predetermined temperature. 95. The method of claim 93 or 94, wherein the solvent is dichloromethane, acetone, acetonitrile, ethanol, trifluoroethanol, isopropanol, hexafluoroisopropanol And B&lt;L&gt;L ethyl ester, isopropyl acetate, tetrahydrofuran, water, hydrazine or a mixture thereof. 96_ a reduction of 4_(1_(3_fluorobenzyl) in the salt of any one of claims 1 to 75 )-1//· σ 丨〇 -5 -5 -5 - ylamino)-5 - fluorenyl. The specific ratio of [ι,_2-/][1,2 4]diazepine-6-ylamino A method of the amount of formic acid (*S&gt;(4-nitrosomorpholine-3-yl)methyl ester, the method comprising contacting the salt with acetone. ❹ 154673.doc