TW200951107A - Derivatives of N-(arylamino) sulfonamides including polymorphs as inhibitors of MEK as well as compositions, methods of use and methods for preparing the same - Google Patents

Abstract

This invention concerns N-(2-arylamino) aryl sulfonamide compounds which are inhibitors of MEK including crystalline polymorphic forms which exhibit a specific powder x-ray diffraction profile and/or a specific differential scanning calorimetry profile. This invention also concerns pharmaceutical compositions comprising A compound disclosed herein and methods of use of the compounds and compositions described herein, including the use in the treatment and/or prevention of cancer, hyperproliferative disorders and inflammatory conditions. The invention also concerns methods of making the compunds and compositions described herein.

Description

200951107 VI. INSTRUCTIONS: This application claims US Patent Provisional Application No. 61/044,886, filed on Apr. 28, 2008, filed on March 6, 2008, U.S. Patent Provisional Application No. 61/034,466 The priority of U.S. Patent Application Serial No. 61/034,464, filed on Jan. 6, 2008, the entire content of which is hereby incorporated by reference. [Prior Art] An oncogene is a mutant form of a specific normal cell gene ("primary oncogene"), in an exceptional case, an abnormal form of an oncogene-coding signal transduction pathway component such as a receptor tyrosine kinase, A serine-threonine kinase or a downstream signal transduction molecule. [Summary of the Invention]

A particular embodiment disclosed herein is a composition comprising a compound selected from the group consisting of: In some embodiments,

The composition further comprises an excipient selected from the group consisting of microcrystalline cellulose, cross-linked sodium methacrylate, sodium lauryl sulfate, magnesium stearate or a combination thereof. In certain embodiments, the composition comprises from about 0.1 wt% to about 15 wt〇/〇

Structured compounds or combinations thereof. In certain embodiments, the composition further comprises about 138999.doc 200951107

HQ OH 85% to about 99.9 wt% of microcrystalline cellulose. In some embodiments, the

The composition contains about 1 mg of HO PH NH MeO.

Η *Γ structural compound

MeO,

A compound of the NH F structure or a combination thereof; about 222.2 mg of microcrystalline cellulose; about 12.0 mg of croscarmellose sodium; about 2.4 mg of sodium lauryl sulfate; and about 2 · 4 mg of stearic acid . In certain embodiments, the set of HO OH compounds comprises: about 10 mg of NH MeO.

Λ, structural compound

HO OH

MeO.

Compounds of NH f structure or combinations thereof; about 21 3 · 2 mg of crystallites

F cellulose; about 12.0 mg of croscarmellose sodium; about 2.4 mg of sodium lauryl sulfate; and about 2.4 mg of magnesium stearate. In some embodiments, the

The HO OH NH f composition comprises: about 20 mg:

MeO,

Structural compound

HO pH

MeO.

Structured compound or combination thereof 'about 203.2 mg of microcrystalline 138999.doc 5- 200951107 cellulose; about 12.0 mg of croscarmellose sodium; about 2.4 mg of sodium lauryl sulfate; and about 2.4 mg of stearin Magnesium acid. In certain embodiments, the composition comprises: about 40 mg:

Structural compound

1 structural compound or combination thereof; about 183.2 mg of microcrystalline cellulose; about 12.0 mg of croscarmellose sodium; about 24 mg of sodium lauryl sulfate; and about 2.4 mg of magnesium stearate. In certain embodiments, the compound achieves a Cmax between about 〇·〇1 μ§/ηι1 to about 1 ·〇 pg/ml on Day 1 when administered to an individual. In certain embodiments, the compound has an AUC between about 0. 1 pg hours/mL to about 5.00 hours/mL from 〇 to 丄 2 hours. In certain embodiments, the compound has a gold syrup concentration of greater than about 0.11 mg/mL after a single dose of about 5 hours. In a particular embodiment, the invention discloses a Ν_(_)·(3,4_difluoro_2_(2_fluoro-4-mothylamino)-6-methoxyphenyl)·ι_(2,3_ Dihydroxypropyl)cyclopropane

The peak of identification. In some embodiments, the powder calender diffraction pattern is substantially the same as the powder X-ray diffraction pattern shown in Figure 5. Ν-(-)-(3,4-Difluoro-2-(2-•(2,3-dihydroxypropyl)cyclopropane) In a particular embodiment, the invention discloses a N 4 dish-based amine group )·6-methoxyphenyl) small (2 138999.doc 200951107 Alkyl polysulfonate A of alkane-1-sulfonamide, which exhibits a differential scanning calorimetric spectrum substantially identical to the differential scan shown in Figure 6. The calorimetric spectrum is the same. In a particular embodiment, the invention discloses an N_(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)_1_( Polymorphic form of 2,3-dihydroxypropyl)cyclopropane _ 1 sulfonamide, which is amorphous N-(3,4-) by a mixture comprising ethyl acetate and heptane. Step of the step of difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-oxime-sulfonamide Prepared by the square φ method. In certain embodiments, the mixture of ethyl acetate and heptane is from about 1 to about 4 parts ethyl acetate to a ratio of from about 2 to about 1 part by weight. In a particular embodiment, The present invention discloses a pharmaceutical composition comprising an effective amount of the crystalline polymorph disclosed herein. In a particular embodiment, the present invention discloses A method of inhibiting MEK enzyme,

In the embodiment, the MEK enzyme is MEK kinase.

In a particular embodiment, the invention features a method of treating a MEK-mediated disorder comprising administering to a subject in need thereof a composition comprising a compound selected from the group consisting of: In certain embodiments, the 'MEK mediated condition is a cytokine-mediated condition. In certain embodiments, the MEK-mediated condition is selected from the group consisting of an immunological disorder, an inflammatory disease, an infectious disorder, a proliferative disorder, or a combination thereof. In certain embodiments, the MEK mediated condition is cancer. In certain embodiments, the MEK-mediated condition is a fibrotic disorder. In certain embodiments, the Tmax of the compound is achieved at 5 hours and 5 hours after the composition is administered to the fasted individual. In certain embodiments, the compound reaches a Cmax between about 〇·〇1 gg/ml to about l.o gg/mi on day i when administered to an individual. In one such embodiment, the compound has an AUC between about 1 hour/mL and about 5.0 pg hours/mL from 〇 to 12 hours. In certain embodiments, the compound has a plasma concentration greater than about & 〇丨m g / m L after a single dose of about 5 hours. Growing

In a particular embodiment, the invention features a method of inhibiting a plurality of target cells which comprises administering to a subject in need thereof a composition comprising a compound selected from the group consisting of <RTIgt; In certain embodiments, the target cells are cancer cells. In certain embodiments, the Tmax of the compound is achieved at 5 hours and 5 hours after the group of cr is administered to the fasted individual. In certain embodiments, the compound achieves a Cmax between about 0.01 pg/m! to about K0 pg/ml on day 2-3 after administration to the individual. In certain embodiments, the compound has an AUC ranging from about 〇 〇 / / mL to about 5 MPa J / mL from 〇 to 12 hours. In certain embodiments, the compound has a plasma concentration greater than about 〇 1 mg/mL after a single sword amount of about 5 hours. [Embodiment] The novel features of the present invention are particularly described in the appended claims. A better understanding of the features and advantages of the present invention can be obtained by the implementation of the exemplary embodiments of the present invention, which can be obtained by using a telecentric accompanying pattern, which utilizes the techniques of the present invention. thought. This section of the headings is for organizational purposes only and is not intended to be construed as limiting the subject matter described herein. All documents or documents referred to in this application, including (but not limited to) patents, patent applications

Projects, papers, books, manuals, and protocol standards are clearly incorporated into this article. I. Specific Terms Unless otherwise specifically stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter of the subject matter of the present invention belongs. It is to be understood that the foregoing description of the invention and the embodiments of the invention are intended to In the present month's petition, the use of singular words includes the plural unless otherwise specified. It must be noted that the singular forms "a", "an", "the" and "the" are used in the singular and It should also be understood that the use of "or" means "and/or" unless otherwise specified. In addition, the use of "including" and other forms such as "inciude", "includes" and "inciuded" is not restricted. The definitions of standard chemical terms can be found in reference books, including "Advanced Organic Chemistry 4th Ed." by Carey and Sundberg, Vols A (2000) and B (2001), Plenum Press, New York. Unless 138999.doc 200951107 provides a special definition', it is familiar with the nomenclature and analytical chemistry, synthetic organic chemistry, and pharmaceutical and medical chemistry experimental procedures and techniques used in analytical chemistry, synthetic organic chemistry, and pharmacy and medicinal chemistry described herein. This technique is well known to those skilled in the art. Unless otherwise specified, the use of a generic chemical term such as, but not limited to, "alkyl", "amine", or "aryl" is equivalent to its superposition. For example, "alkyl" as used herein includes an optionally substituted alkane group. As used herein, "moiety", "chemical group", "group" and "chemical gr〇up" mean a specific fragment or functional group of a molecule. Chemical groups are often recognized as chemical entities embedded in or attached to a molecule. The "sigma bond" or "single bond" means a bond between two atoms or two groups. The atom to which the bond is bonded is regarded as a portion of a larger structure. The terms "optional" or "optionally" are used to mean that subsequent events or circumstances are or may not occur, and that the description includes the event or situation. Examples or examples that do not occur. For example, "optionally substituted alkyl" means "metamorphic" or "substituted base" as defined below. In addition, the undesired group includes unsubstituted (eg, -CH2CH3), fully substituted (eg, '-CFaCF3), monosubstituted (eg, _CH2CH2F) or is completely substituted and single Substitution of any degree between substitutions (eg, -CH2CHF2, _eH2eF3, -CFHCHF2, etc.). Those skilled in the art should have 138999.doc -10- 200951107 to resolve any base containing one or more substituents which are not intended to introduce any substitution or substitution pattern (eg, substituted alkyl) Included are optionally substituted cycloalkyl groups, which are in turn defined to include alkyl groups as the case may be, potentially infinitely large, which are tridimensionally impractical and/or not readily synthesizable. Thus, any of the substituents described should be broadly understood to have a maximum molecular weight of about i,000 otounds, and more typically up to about 500 amps (except where the macromolecular substituents are clearly inclined, such as multiple triumphs) #peptide, polyester, polyethylene glycol, DNA, RNA and their analogues). Unless otherwise noted, general chemical terms, such as although not limited to "unification", "amine" and "aryl" are unsubstituted. As used herein, Cl-Cx includes Cl_C2, Ci_C3_Ci_Cx. By way of example only, a group designated "Cl-C4" indicates that there are from 4 carbon atoms in the group, that is, containing i carbon atoms, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. The group, as well as the Cl_C2 and Ci_C3 ranges. Therefore, just for example. Ci-C4 alkyl" means having 1 to 4 carbon atoms in the alkyl group, that is, selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, and t-butyl groups. A tertiary butyl alkyl group. Whenever a text appears herein, a range of values such as "1 to 10" refers to each integer in a particular range; for example, "1 to 10 carbon atoms" means that the group has one carbon atom, two Carbonogen. Sub, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 1 carbon atom. As used herein, the terms "A and A, together with the carbon atom to which they are attached, form a 3- to 6-membered saturated ring" refer to the following structures used in the compounds disclosed herein: 138999.doc 11 200951107 $ 9 (3⁄4 Cp

_〇·_ I I *,__ ......· o The term "heteroatom or "s" sub-hybrid" as used herein refers to an atom that is not carbon or gas. The heteroatoms are independently selected from the group consisting of oxygen, nitrogen, sulfur, phosphorus, crushed West and tin, but are not limited to such atoms. In the embodiment in which two or two are present: <on the hetero atom, two or more hetero atoms are the same as each other. In embodiments in which two or more heteroatoms are present, two or more heteroatoms are different from each other. The term "alkyl" as used herein, alone or in combination, means a straight or branched saturated hydrocarbon unit having from about 10 carbon atoms or (1) carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-hydrazine-butyl , 3-methyl-butyl butyl, 2-methyl-3-butyl, 2,2-dimethyl 4-propyl, 2-methyl-methyl, methyl-1-pentyl, 4-methyl Pentyl, 2-methyl-2-pentyl, 3-hydrazino-2-pentyl-4-methyl-2-pentyl, 2,2-dimercapto-1-butyl, 3,3-di Butyl butyl, 2-ethyl-i-butyl, n-butyl, isobutyl, t-butyl t-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl and hexyl, With longer alkyl groups such as heptyl, octyl and the like. Whenever present herein, a range of values such as "Cl-C6 alkyl" or "rCM alkyl" means a carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 An alkyl group consisting of a carbon atom or 6 carbon atoms. In one embodiment, "alkyl" is substituted. Unless otherwise specified, 'other bases' are not replaced. The term "alkenyl" as used herein, alone or in combination, means having one or more of 138999.doc • 12·200951107 = carbon double bond 'having from 2 to about 1 carbon atom or from 2 to about 6 carbon atoms: Chain hydrocarbon early group. In certain embodiments, this group is in the vicinity of the double bond = cis configuration. In certain embodiments, this group is in a trans configuration near the double bond. Examples include, but are not limited to, vinyl (_ch=ch2), acrylamide (-CH2CH=CH2), isopropyl sparing [-c(ch3)=ch2], butadiyl I diphosyl and analog. Whenever it appears in this context, a numerical range such as "C2-C6 dilute" or "C2-6 dilute" means that the dilute group can be 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbons. Atom or 6 carbon atoms. In the examples, "dilute base" is substituted. Unless otherwise specified, "alkenyl" is unsubstituted. The term "alkynyl" as used herein, alone or in combination, means having one or more carbon-carbon bonds and having from 2 to about 1 carbon atoms. Or a linear or branched hydrocarbon mono-group of from 2 to about 6 carbon atoms. Examples include, but are not limited to, alkynyl, propyne-2-butane, ortho-triynyl, and the like. Whenever present herein, a range of values such as "c2_C6 alkynyl" $% alkynyl means that the block may be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbons. Atomic composition. In one embodiment, "alkynyl" is substituted. Unless otherwise specified, "alkynyl" is unsubstituted. The terms "heteroalkyl", "heteroalkenyl" and "heteroalkynyl" as used herein, alone or in combination, mean, respectively, an alkyl, a thiol, and a block structure as described above, or a chain carbon atom therein. And any associated hydrogen atom, as appropriate, are each independently a heteroatom (ie, an atom that is not carbon, such as, but not limited to, oxygen, sulfur, sulphur, scale, tin, or combinations thereof), or Atomic radical substitutions such as (but not limited to) _0-0-, -SS-, -OS-, -SO-, =Ν·Ν=, 138999.doc 200951107 -N=N-, -Ν=Ν-ΝΉ·, p/〇\ _ H -p(〇)2-, -〇_P(0)2_, _p(0)2_0_, -S(0)-, -S(〇)2·, _SnH2_ and the like . As used herein, the terms "halogen ship n-generation dilute base" and "dentate alkynyl group", alone or in combination (4), are defined as (4) groups, dilute groups and alkynyl groups as defined above: wherein - or more of the hydrogen atoms are gas, gas, Bromine or iodine atom or a group thereof. In some embodiments, two or more chlorine atoms are substituted with the same (tetra) atom as each other (eg, difluoromethyl); in other embodiments, two or more of the scorpion houses are her style The substituents are substituted with halogen atoms different from each other (for example, 1-chloro-1-fluoro-1-iodoethyl). Non-limiting examples of the chiral alkyl group are fluoromethyl, chloromethyl and hydroxyethyl. A non-limiting example of a toothed dilute base is a vinylidene group. A non-limiting example of an i-alkynyl group is an air acetylene group. The term "carbon chain" as used herein, alone or in combination, means any (tetra), alkenyl, fast-radical, heteroalkyl, heteroalkenyl or heteroalkyl group, etc., which are linear, cyclic, or any combination thereof. If the bond is a moiety of a linking group and the linking group comprises a ring in which m is a partial core skeleton, in order to calculate the length of the bond, the "chain" includes only the bottom or the top of the specific ring and not both. The carbon atoms, and when the top and bottom of the ring are not equal, should be shorter than the length of the poem. If the chain contains a heteroatom as a part of the skeleton, these atoms are not counted as part of the carbon chain length. The term "cycle" as used herein, "cyclic", "ring", "a couple of members", alone or in combination, means any covalently closed structure 'including alicyclic, heterocyclic, (d), as described herein, Heteroaromatic and multi-membered ring fused or _ ring system. The situation was replaced. The ring is part of a slightly closed loop system. The term "member" means the number of atoms representing the bone year 138999.doc 14 200951107. Thus, by way of example only, cyclohexane, pyridine, piperazine and pyrimidine.疋 is a 6-membered ring and cyclopentane, pyrrole, tetrahydrofuran and thiophene are 5-membered rings. The term "fused" as used herein, alone or in combination, means a ring structure in which two or more rings share one or more bonds.

The term "cycloalkyl" as used herein, alone or in combination, means a saturated hydrocarbon monocyclic ring containing from 3 to about 15 ring carbon atoms or from 3 to about 1 ring carbon atoms, although may include additional, non- A ring carbon atom is used as a substituent (for example, methylcyclopropyl). Whenever it appears herein, a numerical range such as "G-C6 cycloalkyl" or "Cw cycloalkyl" means that the cycloalkyl group may be 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbons. The atomic composition, i.e., cyclopropyl, cyclobutyl, cyclodecyl or cycloheptyl, although the definition herein also encompasses the occurrence of the term "cycloalkyl" without the specified numerical range. This term includes fused, non-fused, bridged, and spiro groups. In certain embodiments, a fused cycloalkyl contains two to four fused rings, the attached ring is a cycloalkyl ring, and the other independent rings are alicyclic, heterocyclic, aromatic, Heteroaromatic or any combination thereof. Examples include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, decahydronaphthyl, and bicyclo[2.2.1]heptyl and adamantyl ring systems. Illustrative examples of the description include, but are not limited to, the following groups: ", 〇, 0, 〇, 〇, 〇〇, and their analogs, ,, 、, from, in an embodiment, "cycloalkyl The system was replaced. Unless otherwise specified, this "Environmental Recreation: Base" is not replaced. 138999.doc 15 200951107 The use of mind ". Non-square heterocyclic group" and "heteroalicyclic group" are hum fresh, undesired μ to about 20 ring atoms, non-aromatic 3 κ 哀 早 基 其中 其中 one or more ring atoms are Ζ carbon The atom 'is independently selected from the group consisting of oxygen, nitrogen, sulfur, dish, Shi Xi, Xi and *. ^ a, in a second embodiment, wherein the ring contains two or two with μ pumping ^ 7 . . . 'The two or more heteroatoms of each other= In both embodiments, some or all of the two or more heteroatoms in the presence or absence of two or more heteroatoms are different from each other. This procedure b includes fused, non-fused, bridged and spiro based. In certain embodiments, the 1-membered heterocyclic group contains two to four anthracene rings, wherein attachment 2 is a non-U heterocycle' and the other independent rings are alicyclic, heterocyclic, aromatic, Heteroaromatic or any combination thereof. In some m bridging single or double bond fused carbon:: fused ring system is ^ ^^ is carbon, 妷-hetero atom or hetero atom - ..... bonding. The term also encompasses groups having from 3 to about 12 osteophyte ring =, and groups having from 3 to about 1 skeletal ring atoms = non-aromatic heterocyclic subunits attached via a heteroatom or carbon atom; heteroatoms or carbonogens + The substitution is carried out via a ring via a parental molecule of the original dimorphic example 'Miso, a non-aromatic, (isoxazol-1 -yl or imidazolidin-3-yl) or a carbon atom thereof. 1 sit m taste 4_ base or microphone. Sit-But-5-yl) is attached to or the second-generation I: in the examples, the non-aromatic heterocyclic ring contains - or a plurality of groups; L contains a pendant oxy group and a sulfur-containing group. Examples include, for example, pyrrole hopping A 妓 see a 祜 a 祜 (but not hydroquinanyl, dihydro:: 疒 疒 hydrogen ° fu, tetrahydro (tetra), tetrahydropyranyl, tetrahydrothiopyranyl, Hexahydropyridyl, 138999.doc -16- 200951107 ?, thiophene, thioxanthene, diterpene, azetidinyl, oxetane Oxetanyl, thietanyl, high hexahydropyridyl, oximeyl, thietyl, oxazepinyl, Diazepinyl, thiazepinyl, ,/· tetrahydron ratio bite group, 2-mercaprol group, 3·pyrroline group, porphyrin group, 211_piperone , 4Η·piperidyl, dioxanyl, 1,3-dioxolanyl, pyrazolineyl, dithiaalkyl, dithiolanyl, dihydropyranyl, Dihydrothienyl, dihydrofuranyl, pyrazolyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexane, 3-azabicyclo[4丨〇]heptyl , 3H, fluorenyl = quinazinyl. An illustrative example of a heterocycloalkyl group Referred to as non-aromatic heterocycle package Δ'〇, ό, ό, 0,00, Λ,

Oh · ηΩη °W° . y. φ , , ^ Φ

ό 0 - 0 ό Ό 〇

~ w and its analogues. These terms also include all hydrocarbons limited to monosaccharides, disaccharides, and cockroaches. But not in the case of sugars. In the examples, "non-aromatic heterogeneous groups" or heteroalicyclic groups" Replacement. Unless otherwise specified: "(4) Family Heterocyclyl" or "(4) County" is substituted. The term "aryl" as used herein, alone or in combination, gives 20 ring carbon atoms to the furnace. 3 6 to about Κ 'and includes both fused and non-fused aromatic rings. In some examples 138999.doc • 17- 200951107, fused aromatic ring groups contain two to four: for! rings. In the examples, the other independent ring is a lipid two: including a = heteroaromatic ring or any combination thereof. Further, the term aryl group 3, a fused ring and a face ring of 2 ring carbon atoms, and containing 6 to about 〇 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环 环In one embodiment, the "base" is substituted. Unless otherwise, the aryl group is unsubstituted. The term "hybrid gg ,. y" is used herein. .... The heteroaryl J used alone or in combination means an aromatic mono-group containing about: one ring of a skeleton ring, wherein one or more ring atoms 2 hetero atoms 'the hetero atom is independently selected from oxygen, nitrogen, sulfur , phosphorus, ... and enchantment, but not limited to this weizi, and the condition is that the ring of the county does not contain two strontium or s atoms. In the embodiment where two or more heteroatoms exist in the ring, two or Two or more hetero atoms are identical to each other, or some or all of two or more heteroatoms are different from each other. The term heteroaryl includes fused and non-fused heteroaryl groups having fluorene: a few hetero atoms. Heteroaryl also includes fused and non-fused heteroaryl groups having from 5 to about 12 skeletal ring atoms and those having from 5 to about 1 牟瑗甩 土 土 土 。. In some embodiments , bonded to a heteroaryl group via a ruthenium or a hetero atom. As a non-limiting example, the sulphonate via its carbon atom (sweet base, sulphate or sulphur) The atomic ten sits "· base or 唆 _ _ 3 _ base) bonded to the parent molecule. Also in some embodiments the heteroaryl is further substituted via any or all of its carbon atoms or any or all of its heteroatoms. In certain embodiments, the fused heteroaryl contains two to four fused rings wherein the attached ring is a heteroaryl ring and 138999.doc • 18· 200951107 Ο other independent rings are heterocyclic, aromatic, hetero An aromatic ring or any group thereof. Non-limiting examples of monocyclic heteroaryl groups include (iv) groups; (iv) heteroaryl groups: including benzene: imidazolyl, (tetra)yl, ...; and non-cluorobiheteroaryl including hydrazine.疋基. Other examples of heteroaryl groups include, but are not limited to, furyl, thienyl, w, thiol, cyanozinyl, benzimid. Sit, stupid and fluorenyl, fenyl, benzo(tetra)yl mwa, phenyl phenyl, benzoxazolyl, benzotriazolyl 'imidazolyl' Isoxanyl, isocarbyl, indazine (indGlizinyi), isodecyl, isodecyloxadiazolyl, carbazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyridazyl, sulfhydryl , base, „比. 坐基, 嗓吟基, (四)基, 嗓 base, 嗤琳基, 啥 琳 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基Bases and analogs thereof, and oxides thereof, such as pyridyl-based oxides. Illustrative examples of heteroaryl groups include the following groups: 〇'〇〇0·〇.〇.<ι>·ς〇〇3, Oi, 〇: >, object.

And the like In one embodiment, "Mi Li Gan Mu, Hetero" is substituted. Unless otherwise specified, "heteroaryl" is unsubstituted. As used herein, the term "glycol yw / A heteropoly" is used exclusively or in combination to refer to heteroalicyclic and heteroaryl groups. In the T. <τ text, whenever the number of carbon atoms in the heterocycle is indicated (eg 'c丨-c6 heterocycle), at least one non-carbon atom must be present in the ring 138999.doc -19- 200951107 atom). The reference to the number, rather than the reference, refers to the total number of atoms contained in the ring, which means that the carbon atom in the ring means the ring in the ring, such as the 4-6 member heterocyclic ring. And five, wherein two to four atoms are carbon atoms; therefore, one atom is a hetero atom and its /, a slave atom or a hetero atom or more hetero atom L, /, two Or two or two, 11 or more or two heteroatoms are 5 or different from each other. Non-aromatic heterocycles - including a group of only three atoms in the ring 'and a heterocyclic ring in the ring There are up to 5 atoms. In some practical examples, 'bonding (ie, joining to the mother knife or stepping) to heterogeneous atoms. In some embodiments, bonding The "heterocyclic group" is substituted by a carbon atom in the embodiment - unless otherwise specified, the "heterocyclic group" is unsubstituted. The term "halogen" is used herein. "Halo" or "halide", alone or in combination, means fluoro, chloro, bromo and/or iodine. The term "amine" as used herein, alone or in combination By the meaning of mono-NH2. The term "alkylamino" as used herein, alone or in combination, means mono-NH(alkyl), wherein the alkyl group is as defined herein. The term "dialkylamino" is used herein. Used alone or in combination means mono-N(alkyl)(alkyl), wherein each alkyl is the same or different and is as defined herein. The term "diaminoalkyl" as used herein, alone or in combination, means An alkyl group containing two amine groups, wherein the amine groups are substituents on the alkyl group, which are an amine group, an alkylamino group or a dialkylamino group, or wherein the amine groups are 138999.doc -20- 200951107 One or both may form part of an alkyl chain to form -alkyl-N(H or alkyl)-alkylene-N (H or alkyl or alkylene-) (H or Alkyl or alkylene-). The term "radio" as used herein, alone or in combination, means mono-OH. The term "cyano" as used herein, alone or in combination, means mono-CN. The term "cyanomethyl" used alone or in combination means mono-CH2CN. 〇 The term "nitro" as used herein, alone or in combination, means Base -N〇2. The term "oxy" as used herein, alone or in combination, means a diradical_〇_. The term "sideoxy" as used herein, alone or in combination, means diradical = 术语 terms used herein. "Carbonyl", alone or in combination, means a diradical-c(=o)-, which may also be written as _c(0)_. ❿ The term "carboxy" or "carboxyl" is used herein alone. Or in combination means a group _c(〇)〇H, which may also be written as -COOH 〇' The term "alkoxy" as used herein, alone or in combination, means alkyl ether. Alkyl, ie, Including a group - anthracene-aliphatic group and - anthracene-carbocyclyl, wherein the alkyl, aliphatic and carbocyclic groups are optionally substituted, and wherein the terms alkyl, aliphatic and carbocyclic are used. As defined herein. Non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, second butoxy, third butoxy and analog. 138999.doc •21 · 200951107 The term “sulfinyl” as used herein, alone or in combination, means the bis-s(=o)-. The term "sulfonyl" as used herein, alone or in combination, means double base S (= 0) 2.0. The terms "sulfonamide", "sulfamido" and "amino" (sulfamidyl)" alone or in combination means bibasic-s(=o)2_nh· and -NH,S(=0)2·0 The term "sulfonamide" as used herein, "sulfamid" "" and "continued sulfamidyl", alone or in combination, means a diradical_Nh_S(=0)2-NH-. The term "reactant" as used herein refers to a nucleophile or electrophile for the production of a covalent bond. It will be appreciated that where two or more groups are used continuously to define a substituent attached to a structure, the first named group is considered to be a terminal group and the last named group is considered to be attached to The structure. Thus, for example, a group arylalkyl group is attached to the structure via a pendant. The term "MEK inhibitor" as used herein is intended to mean a compound that exhibits MESK activity as measured by a Mekl kinase assay as generally described herein for an ICSG of no greater than about 1 〇〇 μΜ or no greater than about 50 μΜ. "ICw" is the concentration at which the inhibitor reduces enzyme activity (e.g., MEK) to a half maximum level. The compounds disclosed herein have also been found to exhibit inhibition of MEK. Preferably, the compound of the invention exhibits a MEK of not more than about 10 μΜ, more preferably no more than about 5 μΜ, more preferably no more than about μ μΜ, and most preferably no more than about 200 μη, measured by the Mekl kinase assay described herein. IC50. 138999.doc -22- 200951107

The term "individual" as used herein encompasses both mammals and non-mammals. These terms are not - interpreted as requiring supervision by a medical professional (eg, a physician, nurse, caregiver, shelter worker). Examples of milk animals include, but are not limited to, any member of the mammalian class: humans, non-human primates such as chimpanzees and other baboon and monkey breeds; farm animals such as cattle, horses, sheep, goats, pigs; livestock animals such as Rabbits, dogs, and cats; experimental animals include old-toothed animals such as rat "h and guinea pigs, and their analogs. Examples of non-mammals include, but are not limited to, birds, fish, and the like. In the embodiments of the methods and compositions, the mammal is a human. The terms "treat", "treatment" ((4) (4)" or "treatment" and other grammatical equivalents used herein mean the progression of the condition. Slowing or cessation, causing deterioration of the condition, alleviating the symptoms of the condition, preventing the progression of additional symptoms or presenting additional symptoms, alleviating and/or preventing the underlying cause or combination of symptoms. This term further includes the advantage of achieving prevention. Prophylactic advantages, the compounds or compositions disclosed herein can be administered to an individual at risk of developing a particular condition, apt to develop a particular condition, or to report a disease An individual having one or more physiological symptoms. The term "effective amount", "therapeutically effective amount" or "pharmaceutically effective amount" as used herein means an amount of an agent or compound sufficient to treat a condition. In certain embodiments This result is a slowing and/or alleviation of the symptoms, symptoms or causes of the condition, or any other expected change in the biological system. For example, an "effective amount" for treatment is required for a medically significant alleviation of the condition. The amount of the composition of the compound. The appropriate "effective" amount in any independent case can be determined using techniques such as dose increment studies. 138999.doc -23- 200951107 The terms "substantially anhydrous" and "substantially solvent free" are used herein. Meaning means less than 0.01, (U, 〇2, 0 3〇4, q 5 respectively)

Wt% water or a crystalline polymorph of a solvent. As used herein, the term "substantially the same" means a powder X-ray diffraction spectrum or a differential scanning calorimetry spectrum that is different from the ones described herein, but which may fall within the experimental error range when considered by those skilled in the art. Figure. The term "pharmaceutically acceptable" as used herein means a material, such as a carrier or diluent, which does not destroy the biological activity or properties of the compounds described herein and is relatively non-toxic (ie, the material is cast Interacting with the individual does not result in improper biological utility or in an unfavorable manner with any of the components included in the composition). The term "modulate" as used herein, means altering target activity, whether directly or indirectly interacting with a target, including, by way of example only, promoting target activity, inhibiting target activity, limiting target activity, or extending targets. active.

II. MEK In certain cases, Ras is a signal transduction protein. In certain cases, Ras is activated by the binding of guanosine nucleotides, namely GTP (guanosine triphosphate) or GDP (guanosine dinucleotide). In certain instances, activation of Ras results in activation of the cascade of serine/threonine kinase. In certain instances, activated Ras activates the Raf protein. In certain cases, the activated Raf protein activates "MEK1" and "MEK2". MEK1 and MEK2 are bifunctional serine/threonine and tyrosine protein kinases, which in specific cases activate MAPK. In certain cases, the activation of MAP kinase, activated by mitogen mitogens, appears to induce cell proliferation. In certain cases, the activation of MAPK induces cell transformation. In certain cases, blockade of downstream Ras signaling, such as by blocking with dominant negative Raf-1 protein, inhibits mitosis, whether induced by cell surface receptors or by oncogene Ras mutants Inhibition of the action of cracking substances. III. Compounds Standard techniques are used for chemical synthesis, chemical analysis, pharmaceutical preparation, formulation w, and individual delivery and treatment. The reaction and purification techniques are carried out, for example, using kits of the manufacturer's instructions or generally available in the art or as described herein. Throughout the specification, the groups and substituents may be selected by those skilled in the art to provide stable groups and compounds. The compounds presented herein may have one or more stereocenters and each stereocenter exists in R or S configuration or in a combination thereof. Similarly, the compounds presented herein may have one or more double bonds and each may be in an e (trans) or Z (cis) configuration or in a combination thereof. Presenting a particular stereoisomer, a positional isomer, a non-image isomer, a mirror image isomer or a surface. The presentation of a substance is understood to include all possible stereoisomers, positions. , non-image isomers, mirror image isomers or epimers and their exhibits. Thus, the compounds presented herein include all isolated stereoisomers, regioisomeric, non-image, heterogeneous or epimeric forms 2 and their corresponding mixtures. Presenting a specific chemical structure or chemical name of a compound containing one or more palmar centers, but it does not specify I38999.doc -25- 200951107 special stereochemistry, it should be understood to include all stereoisomers A mixture comprising all possible stereoisomers, pure or substantially pure forms of a particular stereoisomer, and pure or substantially pure form of another stereoisomer. Techniques for inverting or leaving a particular stereocenter that has not changed and techniques for dissolving a mixture of stereoisomers are known in the art, and those skilled in the art are fully capable of selecting an appropriate method depending on the particular situation. See, for example, VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5. sup. TH ED., Longman Scientific and Technical Ltd. j Essex, 1991, 809-816; and Heller, dec. C/zew. Λα. The 1990, 23, 128 ° substituents are designated by their conventional chemical formulas, which are written from left to right, and equally contain substituents of the same chemical nature resulting from right to left writing. As a non-limiting example, -CH20- is equivalent to -OCH2-. A specific embodiment disclosed herein is a compound of formula I:

F

Wherein Z is Η or F; X is F, C1, CH3 'CH2OH, CH2F, CHF2 or CF3; Y is I, Br, Cl, CF3, CVC3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl , cyclopropyl, OMe, OEt, SMe, phenyl or Het, wherein Het is 5-138999.doc •26-200951107 to ίο-membered monocyclic or bicyclic heterocyclic group, the group is saturated, olefin or aromatic a group containing 1-5 ring heteroatoms independently selected from N, 0 and S; wherein all such phenyl or Het groups are optionally F, Cl, Br, I, ethyl thiol, methyl, CN , N02, c〇2H, CVC3, CVC3 alkoxy, cvc3 alkyl _c(=0)·, Ci_C3 alkyl _c(=s)_, Ci_C3 alkoxy-C(=s)-, Cvc3 alkyl-c(=〇)〇_, Ci_c3 alkyl_0 (c=0)_ « , alkyl-C(=〇)NH-, CVC3 alkyl-C(=NH)NH-, CVC3 φ Burning group ·NH_(C=0)·, di-CVC3 alkyl group-N-(C=0)·, Ci-C3 alkyl-alkyl group), Cl_c3 alkyl group 8 (=〇) 2ΝΗ_ or three Fluoromethyl substituted; all such methyl, ethyl, (^-(^alkyl and cyclopropyl) may be optionally substituted by hydrazine; all such thiol groups may be substituted by one, two or three F atoms; R0 is Η, F, C Bu Br, !, CH3NH_ , (CH3)2N_, Ci_C6 alkanoyl, Cl-C4 alkoxy, c3-c6 cycloalkyl, C2-C6 alkenyl, c2-c6 alkynyl, phenyl, monosubstituted phenyl, 0 (Ci_C4 alkyl ), 〇_c(=〇)(Ci_C4 alkyl) or (:(=0)0((^-(:4 alkyl); wherein. such alkyl, alkoxy, cycloalkyl, alkenyl) , alkynyl and phenyl visible • substituted by 1-3 substituents independently selected from the group consisting of F, Cl, Br, I, OH, CN, methyl, nitro, phenyl and trifluoromethyl; 4 C 〗 - C6 alkyl and CVC4 alkoxy can also be substituted by 〇CH3 or 〇CH2CH3; G is G], G2, Rla, Rlb, R1C, Rld, Rie, Ari, Ar2 or 138999.doc -27- 200951107

Ar3; among them

Gi is optionally a Cl_C6 alkyl group substituted with an amine group, a Cl_(:3 alkylamino group or a dialkylamino group, the dialkylamino group comprising two identical or different CrC* alkyl groups; or Gi is C3-C8 diaminoalkyl; G2 is a 5- or 6-membered ring which is a saturated, unsaturated or aromatic ring containing from 1 to 3 ring heteroatoms independently selected from N, fluorene and 8, as appropriate丨3 independently selected from F, C1, OH, 〇 (Cl_C3 alkyl), 〇CH3, OCH2CH3, ch3c(=o)nh, CH3C(=0)0, CN, CF3 and containing 1-4 independent a substituent substituted with a 5-membered aromatic heterocyclic group of a ring hetero atom selected from n, O and S;

Ria is methyl, which may optionally be substituted with 1-3 fluorine atoms or 1-3 gas atoms, or with OH, cyclopropoxy or CkC:3 alkoxy, wherein the cyclopropoxy or such Ci-C3 The alkoxy-substituted Ci-C3 moieties may be optionally substituted with a hydroxy or decyloxy group and wherein all of the C3 alkyl groups in the CrC4 alkoxy group may be further substituted with a second OH group;

Rib is a CHCCHJ-Ci.3 alkyl or CVC6 cycloalkyl group, and the substituents and cycloalkyl groups may optionally be 1-3 substituents independently selected from the group consisting of F, ci, Br, I, 〇H, OCH3 and CN. Replace

Rlc is (CH2)nOmR·; wherein m is 0 or 1; and wherein when m is 0, η is 1 or 2; when m is 1, η is 2 or 3; R· is C丨-C6 alkyl 'It may be substituted by 1 _ 3 substituents independently selected from F, 138999.doc -28· 200951107 α, oh, och3, och2ch3 and c3-c6 cycloalkyl;

Rld is C(A)(A')(B)-; wherein B is hydrazine or Cw alkyl, which may be optionally substituted with one or two OH groups; A and A' are independently hydrazine or C^-4 alkyl , which may be substituted by one or two OH groups; or

A and A' together with the carbon atoms to which they are attached form a 3- to 6-membered saturated ring; 1 e is ^2-6

Rle (CH2)q- wherein q is 1 or 2; R2 and R3 are each independently Η, F, Cl, Br, CH3, CH2F, CHF2, CF3OCH3, OCH2F, OCHF2, OCF3, ethyl, n-propyl, isopropyl Base, cyclopropyl, isobutyl, t-butyl, tert-butyl or methanesulfonyl; R4 is hydrazine, F, Cl, Br, CH3, CH2F, CHF2, CF3OCH3, OCH2F, OCHF2, OCF3, B Base, n-propyl, isopropyl, cyclopropyl, isobutyl, t-butyl, tert-butyl, methanesulfonyl, nitro, acetamido, fluorenyl, cyano, amine hydrazine Methylamine, dimethylamine, dimethylamine, dimethylglyoxime, 1,3,4-oxadiazole-2- 138999.doc • 29· 200951107 base, 5-methyl-1,3,4-oxa Diazole, 1,3,4-thiadiazole, 5-mercapto-1,3,4-thiadiazepine 1H-tetrazolyl, N-morpholinylcarbonylamino, N-morpholinylsulfonyl And a pyridyl carbonylamino group; R^H, F, C1 or methyl; R6 is hydrazine, F, C1 or methyl;

Ar] is ^2-6

An where U and V are independently N, CR2 or CR3; R2, R3 and R4 are independently Η, F, Cl, Br, CH3, CH2F, CHF2, cf3, 〇ch3, OCH2F, OCHF2, OCF3, ethyl, n-propyl Base, isopropyl, cyclopropyl, isobutyl, t-butyl, tert-butyl, acetoguanyl, fluorenyl, cyano, amine carbaryl, methylamine, dimethyl, dimethyl Amine-based, i,3,4-oxadiazol-2-yl' 5-methyl-1,3,4-oxadiazole, iota, 3,4-thiadiazole, 5-methyl-1 , 3,4-thiadiazolyl, 1H-tetrazolyl, N-morpholinylcarbonylamino, N-morpholinylsulfonyl, N-pyrrolidylcarbonylamino and mesylsulfonyl; And 116 are independently Η, F, C1 or methyl;

Ar is 138999.doc

7-8 Ar2 -30· 200951107 wherein the dotted line indicates the selective formal position of the double bond in the second ring; U is -S_, _〇_ or, and wherein when U is -Ο- or -S-, V is -CH=, -cci = or; when U is -Ν=, v is _CH=, -CC1=, or -Ν=; is Η or 曱;

Re is hydrazine, acetamino group, methyl group, f or ci; e

Ar3 is

Αγ3 wherein U is -ΝΗ-, -NCH3- or; R7 and R8 are independently H, F, C1 or methyl.

In addition to the definitions given to groups G, R0, X, γ, and Z herein, it also includes additional substitutions that would be expected by those skilled in the art of chemistry and medical technology. In certain embodiments, the invention provides a compound of Formula 1, wherein hydrazine is (}1 or A. In other embodiments, hydrazine is G. In certain embodiments, hydrazine is G2. In an embodiment, the invention provides a compound of formula I, wherein G is Ria, Rlb, Rlc, Rld, Rle, An, Ar2 or Ar3. In certain embodiments 'G is Rla, Rlb, r1c, Rld or. In certain embodiments, 〇 is. In some embodiments, G is Rlb. In some embodiments, G is 138999.doc • 31 · 200951107

RiC. In certain embodiments, G is Rld. In some embodiments,

Rie. In some embodiments 'G is Ar!, An or An. In some embodiments ' G is Ar!. In certain embodiments, 〇 is Arz. In certain embodiments, G is Ar3. In certain embodiments, the compounds disclosed herein are pharmaceutically acceptable salts, solvates, polymorphs, esters, guanamines, tautomers, prodrugs. Available in combination or in combination. In certain embodiments, Z is Η. In certain embodiments, Z is F. In some embodiments 'X is F. In certain embodiments, X is ci. In certain embodiments, X is CH3. In certain embodiments, X is CH2OH. In some embodiments, X is CH2F. In certain embodiments, X is chf2. In certain embodiments, X is CF3. In certain embodiments, X is F, €1 or CH3. In certain embodiments, G is G > 4G2, X is F, C1 or CH3; Y is I, Br, C, CF3, CVC3 alkyl, phenyl, pyridyl, pyrrolyl, pyridyl. The sitting group, the specific phenyl group, the π ratio bite group, the η ratio 洛基基, and the η 嗤 group may be optionally subjected to F, Cl, Br, I, acetyl group, fluorenyl group, CN, Ν〇2, C〇2H, Ci_C3 alkyl, Ci-C3 alkoxy, Cl_c3 alkyl _(:( = 〇)-, (^-(^alkyl-C(=S)-, CVC3 alkoxy_C(=s)_, CVC3 alkyl-C(=〇)〇·, CrCs alkyl-0-(C=0)·, q-c3 alkyl-C(=0)NH-, CVC3 alkyl-C(=NH)NH- , CVC3 alkyl group -NH-(C=0)-, di-(VC3 alkyl group_N-(00)-, CVC3 alkylalkyl group)-, (:丨-(:3 alkyl-S(=0) 2NH- or trifluoromethyl substituted; and z is deuterium or F. In certain embodiments, G is G or G2, and R0 is F, CH, CVC4 alkyl or C-C4 alkoxy 138999. The doc-32-200951107 group, the CrC4 alkyl group and the heart--alkoxy group may be substituted by f, ci, och3 or och2ch3. In some embodiments, 〇 is or G2, and R0 is Η , F, CM, (VC4 alkyl, decyloxy, ethoxy, or 2-methoxy-ethoxy. In certain embodiments, N-fluorenyl-2-aminoethyl. In some embodiments, G! is (CH3)2N-CH2CH2-NH-(CH2)n-, wherein n is 1, 2 or 3. In some embodiments, 'G1 is CH3) 2N-CH2CH2-NH-(CH2)n-_ wherein η is 1, 2 or 3 and X is F. In certain embodiments, 〇1 is (CH3)2N-CH2CH2-NH-(CH2 N-, wherein η is 1, 2 or 3, X is F and Ζ is F. In certain embodiments, G2 is 1 piperidinyl, 2-piperidinyl, 3-piperidinyl, or 4 -piperidinyl. In certain embodiments, G2 is morpholinyl, hydrazine-piperazinyl or 2-hydrazino. In certain embodiments, G is Rla, Rlb, Rlc, Rld, An, Ar2 or Ar3 and X is F, Cl, or CH3. In certain embodiments, G is 〇Rla, Rlb, Rlc, Rie, An, Ar2, or Αγ3, X is F, Cl, or CH3 and Y is I, Br, Cl, cf3 or (VC3 alkyl. In some embodiments 'G is Rla, Rlb, Rlc, Rld, Rle, Ari, Ar2 or Ar3, X is 'F, €1 or CH3' Y is 1. Br, Cl, CF3, or (: 丨-(: 3 alkyl and Z is Η. or F 〇 In some embodiments, G is Rla, Rlb, Rlc, Rld, Rle, Ari, Ar2 or Ar3 and R0 Is F, Cl, (VC4, or CVC4 alkoxy, the C!-C4 alkyl group and the (:)-(:4 alkoxy group can be optionally subjected to f, Cl, OCH3 or OCHHK3 Replace. In some embodiments, (^Rla, Rlb, 138999.doc -33- 200951107

Ric, Rid, Rie, An, Ar2 or Ar3 and R is Η, F, Cl, ¢^-04 alkyl, decyloxy, ethoxy or 2-decyloxy-ethoxy. In certain embodiments, G is R!a; and Z is F. In certain embodiments, G is Rla, wherein Rla is CH3, R0 is Η; and Y is Br, I, CF3, or CH3. In certain embodiments, G is Rlb and Z is F. In certain embodiments, G is Rlb, Z is F, and R0 is deuterium, F or OCH3. In certain embodiments, 0 is ruler 115, Z is F, R0 is Η, F or OCH3, and X is F or CH3. In certain embodiments, 〇 is R lb, Z is F, R 0 is Η, F or OCH 3 , X is F or CH 3 and Y is Br, I or CH 3 . In certain embodiments, G is Rib ' wherein Rib is C3-C6 cycloalkyl. In certain embodiments, G is Rib ' wherein Rib is substituted C3-C6 cycloalkyl. In certain embodiments, 〇 is 11115 ' wherein R lb is unsubstituted c 3 _ c 6 cycloalkyl. In certain embodiments, 'G is Rlb, wherein Rlb is unsubstituted c3_c6 cycloalkyl and R0 is Η° In certain embodiments, 'G is Rib, wherein Rib is isopropyl or cyclopropyl. In certain embodiments, G is Rlc and Y is I, Br, CH3 or CF3. In certain embodiments, G is Rlc, γ is I, Br, CH3 or CF3, and Z is F. In certain embodiments, g is ru, γ is I, Br, CH3 or CF3, Z is F and m is 0. In certain embodiments, G is Rld and R0 is fluoro, qi, decyl, ethyl, propyl, isopropyl, t-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutane Base, fluoromethyl, methoxy, fluoromethoxy, decylamino or dimethylamino. In certain embodiments, (^ is 尺, R〇 is fluoro, chloro, methyl, ethyl, propyl, isopropyl, t-butyl, isobutyl, tert-butyl, cyclopropyl 138999 .doc 200951107 base, cyclobutyl, fluoromethyl, methyl m ^ w methoxy fluorene, methylamino or dimethylamino and X is F, CI, rtr -v hs ^ u CH3, Or monofluoromethyl, difluoromethyl or tri

Fluorinyl. In some embodiments, 〇 is ~, r. Is fluorine, chlorine, methyl, ethyl, propyl, isopropyl, t-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, aryl, f oxy, fluoromethoxy a group, a methylamino group or a dimethylamino group, X is F, a, CH3, or methyl, dimethyl or trifluoromethyl, and Y is I, Br, c or monofluoro Base, difluoromethyl or trifluoromethyl. In some embodiments, (10) ', R. Is fluorine, chlorine, methyl, ethyl, propyl, isopropyl, t-butyl, isobutyl, tert-butylcyclopropyl, bad butyl, fluoromethyl, methoxy, fluoroantimony a group, a methylamino group or a dimethylamino group, X is F, C, CH3, or a monofluoroindenyl group, a difluoromethyl group or a trifluoromethyl group 'Y is I, Br, C or a monofluoroindolyl group. , difluorodecyl or trifluoromethyl and Z is deuterium or F. In certain embodiments, G is Rid and the size is 1 Å, C1, decyl, ethyl, methoxy, ethoxy or 2-methoxy-ethoxy. In certain embodiments 'G is Rld, R0 is F, C1, methyl, ethyl, methoxy, ethoxy or 2-methoxy-ethoxy and X is f, ci or ch3. In certain embodiments, G is Rld, R0 is F, C1, decyl, ethyl, methoxy, ethoxy, or 2-methoxy-ethoxy, and X is f, C1 or CH3 and Y is I, Br, Cl, or a monofluoroindenyl group, a difluoroindenyl group or a trifluoromethyl group. In certain embodiments, G is Rld, R0 is F, CM, methyl, ethyl, methoxy, ethoxy or 2-methoxyethoxy, and X is f, C1 or CH3, Y Is I, Br, C1, or a monofluoromethyl, difluoromethyl or trifluoromethyl group and z is η or F. In certain embodiments, G is "^ and ruler 0 is Η; X is F, cn, CH3, or a monofluoroindolyl, difluoroindenyl or trifluoroindolyl group. In some embodiments, G is 138999.doc • 35- 200951107

Rld 'RG is Η; X is F, Cl, CH3, or monofluoroindolyl, difluoroindenyl or trifluoroindolyl and Y is I, Br, Cl, or monofluoroindolyl, difluoromethyl or tri Fluoromethyl. In certain embodiments, G is Rld, R0 is Η; X is F, C1, CH3, or monofluoroindenyl, difluoroindenyl or trifluoromethyl, and γ is I, Br, Cl, or monofluoro Methyl, difluoromethyl or trifluoromethyl and z is deuterium or F. In certain embodiments, G is R'd, wherein Rld is c(A)(A,) and C(A)(A') is CVC6 cycloalkyl. In certain embodiments, G is Rld, wherein Rlc^C(A)(A·) and C(A)(A,) are C丨-C6 cycloalkyl and B is deuterium. In certain embodiments, G is R丨d, wherein Rld is C(A)(A,) and ί is alkyl and ethyl, ethyl, 2-hydroxyethyl, n-propyl, 3 - propylidene, 2,3-dihydroxypropyl, 3,4-dihydroxybutyl, isopropyl, 1-methyl-2-hydroxyethyl, n-butyl, t-butyl, isobutyl Or a 2-hydroxyindole-3-ylpropyl group. In certain embodiments 'G is Rld' wherein Rld is C(A)(A') and (:(eight)(eight) is CVC6 cycloalkyl and B is 2,3-dihydroxypropyl or 3, 4-dihydroxybutyl. In certain embodiments 'G is Rld, wherein Rld is C(A)(A,) and C(A)(A') is CVC6 cycloalkyl and B is 2,3- Dihydroxypropyl or 3,4-dihydroxybutyl 'where the palmitic carbon in B is R. In certain embodiments, g is R)d ' where Rld is C(A)(A,) And a cycloalkyl group and B is 2,3-dihydroxypropyl or 3,4-dihydroxybutyl, wherein the palmitic carbon of b is an S configuration. In certain embodiments, G is R'd, wherein Rld is c(A)(A,) and C(A)(A') is a Ci-C6 cycloalkyl group and B is a methyl group, which may optionally be substituted by a hydrazine H group or a CyC: 4 alkyl group. The situation is replaced by one or two hydrazine H groups. In certain embodiments, G is Rld 'where Rld is C(A)(A,) and C(A)(A') 138999.doc -36-200951107 is匕-匸6 ring cyclyl and R0 is fluorine, gas, mercapto, ethyl, propyl, isopropyl, t-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, fluoro Sulfhydryl, decyloxy, fluoromethoxy, methylamino or dimethyl In certain embodiments 'G is Rld, wherein Rld is C(A)(A,) and C(A)(A,) is C6 cycloalkyl and R0 is F, Cl, methyl, ethyl , methoxy, ethoxy, or 2-methoxy-ethoxy. In certain embodiments, g is Rld, wherein Rld is C(A)(A') and C^AKA'^CVC^ Cycloalkyl and R. is η; X is F, CM, CH3, or monofluoroindolyl, difluoroindolyl or trifluoromethyl. In certain embodiments, the invention provides a compound comprising a formula A composition wherein G is Rld, wherein Rld is c(A)(A,) and C(A;KA,) is CV C6 cycloalkyl and B is 2,3-dipropylpropyl or 3,4 - Di-butylidene, wherein the palmitic carbon of b is in the R configuration, which is substantially free of the S isomer. In certain embodiments, the invention provides a composition comprising a compound of formula I, wherein G is 'where Rld is C(A)(A') and (:(eight)(eight,) is (^-(:6-cycloalkyl and B is 2,3-dihydroxypropyl' where B's palm carbon Configuration for R, which is substantially free of 8 φ isomers. In certain embodiments, the present invention provides a composition comprising a compound of Formula I, wherein G is R'd, Is C(A)(A,) and C(A)(A';^C1-C6; and B is 3,4-dihydroxybutyl, wherein b's palm carbon is R configuration, There is substantially no S isomer. In certain embodiments, the invention provides a composition comprising a compound of formula I, wherein Rld >% C(A)(A') and C(A)(A'A CVQ is cycloalkyl and b is 2,3-dihydroxypropyl or 3,4-dihydroxybutyl, wherein the palmitic carbon of b is s configuration, which is substantially free of the R isomer. In certain embodiments, the invention provides a composition comprising a compound of formula I, wherein G is Rld, wherein Rid is 138999.doc -37- 200951107 C(A)(A') and C(A)(A ') is a q-C6 cycloalkyl group and B is a 2 3 dihydroxypropyl group, wherein the palmitic carbon of B is an S configuration, which is substantially free of the R isomer. In certain embodiments, the invention provides a group comprising a compound of formula j, wherein G is Rld, wherein R丨(^C(A)(A,) and C(A)(A,) is c丨_C6 cycloalkyl and B is 3,4-dihydroxybutyl, wherein the palmitic carbon of B is s configuration, which is substantially free of R isomers. ', In some embodiments, G is Rld, wherein is C(A)(A. and C(A)(A') is cyclopropyl. In certain embodiments, 〇 is Rid, where Rid is C(A)(A) and C(A) (A) is a cyclopropyl group and b is η. In certain embodiments: G is R丨d, wherein 1^ is C(A)(A') and C(A)(A,) is cyclopropene And hydrazine is methyl, ethyl, 2-hydroxyethyl, n-propyl, 3-hydroxypropyl, 23-dihydroxypropyl, 3,4-dihydroxybutyl, isopropyl, 丨-methyl _2 hydroxyethyl, n-butyl, t-butyl, isobutyl or 2-hydroxymethyl-3-hydroxypropyl. In certain embodiments, G is Rld, wherein Rld is C(A) ( A,) and C(A)(A,) is cyclopropyl and B is 2,3-dihydroxypropyl or 3,4-dihydroxybutyl. In certain embodiments, G is Rld, wherein Rld Is C(A)(A,) and C(A)(A,) is cyclopropyl and B is 2,3-monopropylidene or 3,4- By a benzyl group, wherein the palmitic carbon in b is R. In some embodiments 'G is Rld, where R is d' <: (eight) (eight') and (: (eight) ( VIII,) is a cyclopropyl group and 8 is a 2,3-dihydroxypropyl group or a 3,4-dihydroxybutyl group, wherein the palmitic carbon in B is an S configuration. In some embodiments, G is Rld, Wherein Rld is c(A)(A,) and C(A)(A,) is a cyclopropyl group and B is a fluorenyl group, which is optionally substituted by an OH group or a c2-C4 yard base, depending on the mud Substituted by one or two OH groups. In certain embodiments, g is Rid, wherein Rld is C(A)(A') and C(A)(A,) is cyclopropyl and R0 is fluorine, 138999 .doc -38- 200951107 Chlorine, methyl, ethyl, propyl, isopropyl, t-butyl, isobutyl, t-butyl, cyclopropyl, cyclobutyl, fluoromethyl, methoxy , fluoromethoxy, methylamino or monomethylamino. In certain embodiments, G is Rld, wherein Rld is C(A)(A') and C(A)(A') is a ring Propyl and R0 are f, c methyl, ethyl, methoxy, ethoxy, or 2-methoxy-ethoxy. In certain embodiments 'G is Rld' where Rld is c(A) (A') and C(A) (A Is a cyclopropyl group and R0 is Η; X is F, Cl, CH3, or monofluoromethyl, difluoromethyl or trifluoromethane Φ ^ °. In certain embodiments, the invention provides a method comprising Formula I A composition of compounds wherein G is Rld, wherein Rid is C(A)(A,) and c(A)(Ai) is cyclopropyl and B is 2,3-dipropylpropyl or 3,4- Dihydroxybutyl, wherein the palmitic carbon in b is an R configuration, which is substantially free of the S isomer. In certain embodiments, the present invention provides a composition comprising a compound of Formula I, wherein G is Rid, wherein Rld is C(A)(A') and C(A)(A,) is cyclopropyl B is 2,3-dihydroxypropyl' wherein the palmitic carbon in B is an R configuration which is substantially free of s isomers. In certain embodiments, the present invention provides a composition comprising a compound of Formula I, wherein G is Rld, wherein Rld is c(A)(A') and C(A)(A,) is cyclopropyl B is 3,4-di-butylbutyl' wherein the palmitic carbon in b is the R group: the state 'which is substantially free of the S isomer. In certain embodiments, the present invention provides a composition comprising a compound of Formula I, wherein G is Rld, wherein Rld is C(A)(A') and C(A)(A') is cyclopropyl and B is 2,3-dihydroxypropyl or 3,4-dihydroxybutyl' wherein the palmitic carbon in B is an S configuration which is substantially free of the R isomer. In certain embodiments, the invention provides a composition comprising a compound of formula I, wherein G is R, wherein Rld is C(A)(A,) and C(A)(A,) 138999.doc • 39· 200951107 is a cyclopropyl group and B is a 2,3-di-dipropyl group, wherein the palmitic carbon of β is “and the state” which is substantially free of the R isomer. In certain embodiments, the invention provides A composition comprising a compound of formula I wherein C(A)(A) and C(A)(A) are cyclopropyl and B is 3 4 dihydroxybutyl which = palm in B Carbon is an S configuration, which is substantially free of isomeric isomers. In some embodiments, G is Rle and 11 is 1. In certain embodiments, g is Rle, R0 is deuterium, and R4_6 is deuterium. R2 and R3 are independently H, F, c, Br, CH3, CH2F, chf2, CF3, 0CH3, 〇ch2f, 0CHF2, OCF3, ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl, second Butyl, tert-butyl, and methanesulfonyl, X is F and γ is I. In certain embodiments, 'G is Ar丨' wherein Arϋ is optionally selected from the group consisting of acetaminophen and fluorenyl , cyano, amine methyl sulfhydryl, methylamine methyl sulfhydryl, dimethyl carbamoyl, 1,3,4- oxa Zyridin-2-yl, 5-methyl-ι, 3,4-oxo. Sodium, 1,3,4-thiadiazolyl, 5-methyl-1,3,4-thiadiazolyl, a phenyl group substituted with a group of 1 Η-tetradecyl, Ν-morphinylamino, Ν-Merlinyl, phenyl, and aryl group, as the case may be. _3 substituents selected from F, C1 and CH3. In some embodiments, 〇

Ar!, wherein Ar! is optionally selected from the group consisting of acetamido, fluorenyl, cyano, amine carbaryl, methylamine thiol, dimethylamine decyl, 1,3,4- Oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 5-mercapto-1,3,4·thiadiazolyl a phenyl group substituted with a group of 1H-tetrazolyl, N-morpholinylcarbonylamino, fluorenyl-morpholinylsulfonyl, fluorenylpyridinylcarbonylamino and sulfonyl, optionally 1 - 3 substituents selected from F, C1 and CH3, R0 is Η, X is F, C1 or methyl and Y is Br, I, CF3, C]-C3 alkane 138999.doc • 40- 200951107 C2-c3 thiol, c2-C3 alkynyl, cyclopropyl, och3, och2ch3 or SCH3. In certain embodiments, G is Ari, wherein ΑιΆ and wherein R2 and R3 are independently Η, F, cn, CH3, CF3, OCH3. In certain embodiments 'G is Ari, wherein Ar^R3_0^ and wherein R2 and R3 are independently Η' F, Cl, CH3, CF3, OCH3, X is F or CH3, Y is I, or Cl; and z Is F. In certain embodiments, G is An, wherein Ar is a stupid or monosubstituted phenyl group. In certain embodiments, G is Ar!, wherein Aq is phenyl or monosubstituted phenyl, X is F or CH3, Υ is I, Br or C is F; and ^ is! ? , methyl, ethyl, methoxy or 2-methoxy-ethoxy. In certain embodiments, G is An, wherein U is N or CR2 and V is N. In certain embodiments 'G' is An, where U is N or CR2 and V is CR. In certain embodiments, G is Αι^ ' wherein U is N or CR2, V is CR, R0 is Η, X is F, C1 or sulfhydryl and Y is Br, I, CF3, CVC3 alkyl, C2- C3 alkenyl, C2-C3 alkynyl, cyclopropyl, hydrazine CH3, OCH2CH3 or SCH3. R7 In certain embodiments, G is Ar2, wherein Ar2 is wherein R7 is deuterium or methyl and & is η, acetamido, fluorenyl, f or Cl. In certain embodiments, G is Ar2, wherein Ar2 is wherein Rule 7 is 11 or methyl, Rs is H, ethenyl, methyl, F or ci'R0 is h, and X is F, C1 or Methyl 'Y is Br, I, CF3, (VC3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, OCH3, OCH2CH3 or SCH3, and Z is F. In certain embodiments, G is Ar2, wherein 八1*2 is 〜1, wherein u is S or Ο, V is CH=, and 118 is Η or CH3, R7 is Η or methyl, and the size 8 is 11, acetamide 138999.doc -41 · 200951107 Group, Methyl, F or Cl, R〇 is H'X is F, ci or methyl, Y is Br, I, CF3, Ci-C^ alkyl, C2-C3 dilute, C2- C3 alkynyl, cyclopropyl, OCH3, OCH2CH3 or SCH3 and Z is F. In certain embodiments, R0 is deuterium. In certain embodiments, R0 is η, X is F or C1 and Y is Br, I, ch2ch3 or sch3 In certain embodiments, G is Ar3, wherein u is -o-. In certain embodiments 'G is Rla, wherein Rla is as defined above. In some embodiments, G is Rla And R0 is η, where Rla is as defined above. In some embodiments 'G is Rla and R0 is as defined above, not η, and Rla is as defined above In certain embodiments, G is Rla, wherein Rla is methyl, mono-methyl, C]-C3 alkoxymethyl, or cyclopropoxymethyl. In certain embodiments, G Is Ru, wherein Ria is a fluorenyl group, a monodentate methyl group, a Ci_ a alkoxymethyl group or a cyclopropoxy fluorenyl group and wherein... is ^, cl, (:1_(:3 alkyl, single gas C)丨-C3 alkyl, c^-Cs alkoxy, trifluoromethoxy, or 2-methoxy•ethoxy. In certain embodiments 'G is Rlb, wherein Rlb is as defined above.

In some embodiments, G is R lb and R 0 is Η, wherein R lb is as defined above. In some embodiments ' <3 is the heart 13, R0 is Η and Z is F, where Rlb is as defined above. In certain embodiments, G is Rlb and R0 is as defined above, not Η, and Rlb is as defined above. In certain embodiments, G is Rlb, wherein R1b is isopropyl, 2-butyl, 2-pentyl, cyclopropyl, J-butyl, cyclopentyl or cyclohexyl, etc. 1 or 2 substituents independently selected from the group consisting of F, C OH and OCH3; in some embodiments 'G is Rib Y is Br, I, decyl or trifluoromethyl. In some, wherein R 1b is isopropyl, 2 · butyl, 2-penta 13 S999.doc 200951107, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, which may be independently selected by 1 or 2 as appropriate. Substituted from substituents of F, Cl, OH and OCH3; γ is

Br, 1 'fluorenyl or trifluoromethyl; and r is F, C1, Cl_C3 alkyl, mono-C1-C3, Ki_C3 alkano, trifluoromethoxy or 2-methoxy- Ethoxy. In certain embodiments, G is Rlb, wherein R1b is isopropyl, 2-butyl, 2-pentyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and the like, One C1 is substituted with 1 or 2 hydrazine H groups; and Y is Br, I, • methyl or dimonyl. In certain embodiments, G is Rlb, wherein R1b is isopropyl, 2-butyl, 2-pentyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl', etc. C1 is substituted with 1 or 2 〇H groups; Y is 仏, 1, methyl or trifluoromethyl; and R0 is F, Cl, C-C3 alkyl, single gas C^C: 3 alkane Base, Cl_C3 alkoxy 'trifluoromethoxy or 2-methoxy-ethoxy. In certain embodiments, G is Rlc, wherein Rle is as defined above. In certain embodiments, G is Rlc and R is H, wherein Ru is as defined above. In some of the only examples of β, G is Rlc and R0 is as defined above, not H, and Ric is as defined. In certain embodiments, G is a ruler. And the ruler is H, where is (CH2)nOmR' ‘where! 11 is 〇 or i, when ^^ is j 2 4 or 3, and when ^ is 〇 η is 1 or 2, and R' is C1-C6 alkyl, which is optionally selected from F Substituted by a substituent of C OH, OCH3, 〇Ch2CH3 and c3_c6 cycloalkyl. In another more specific embodiment, the melon is ruthenium, 11 is 1 or 2, and the Han' is a CrC4 alkyl group, which is optionally substituted as previously defined. In another more specific embodiment, m is 1, n is 2 or 3, and ^ is. /*alkyl, which is replaced as previously defined. In another more specific embodiment, m 138999.doc -43· 200951107 is 〇11 is 1 or 2, and R' is 1 _(:4 alkyl, which is optionally selected from 0 _3 independently from 0H , 〇CH3, C1 and a cyclopropyl group are substituted. In some embodiments 'G is Rld, wherein Rld is as defined above. In some embodiments, G is Rld, and R〇aH, where Rid is In some embodiments, G is Rld and R is as defined above, not H, and is as defined above. In some embodiments, G is Rld and R0 is η, where Rld is C ( A) (A')(B)- 'wherein B, A and A, independently Η or C. 4 alkyl, which is optionally substituted by one or two OH groups or halogen atoms, or A and A1 are attached thereto The carbon atoms together form a 3 to 6 membered saturated ring which optionally contains one or two heteroatoms independently selected from the group consisting of 〇, :^ and S and optionally one or two independently selected from methyl, ethyl, a group of fluorine, gas, bromine and iodine substituted. In certain embodiments, G is Rle, wherein Rle is as defined above. In certain embodiments 'G is Rle, and R0 is Η, wherein Rle is as defined above In some embodiments G is Rle and R0 is as defined above, not Η, and Rle is as defined above. In some embodiments, G is ΑΓι, where Ari is as defined above. In some embodiments, G is Ar!, and R0 For example, where An is as defined above, in some embodiments 'G is in and ^ is 0 as defined above, is not Η, and is as defined above. In some embodiments, G is Ar2, wherein Ar2 is as defined above. In certain embodiments, G is Ar2 and R0 is Η, wherein Ar2 is as defined above. In some embodiments, G is Ar2 and R0 is as defined above, not Η, and Ar2 is In some embodiments, X is F, C1 or CH3; Y is I, Br, C1, 138999.doc 200951107 alkyl, and Z is deuterium or F. In certain embodiments, χ is F ,

Cl or CH3 'Y is I, Br, Cl, CF3 or c--c3 alkyl, Z is Η or F, and R〇 is halogen, Ci-C6 alkyl, monohalo rCi_C6 alkyl, C3_C6 cycloalkyl, (VC6 fluorenyl, CVC: 6 alkynyl, stupid, monosubstituted phenyl, OR3, 0-C(=0)R4 or C(=0)0R5. In certain embodiments, X is F, C1 Or CH3: Y is I, Br, Cl, CF3 or alkyl, Z is Η or F, and RG is a thiol group, a singly phenyl group, a fluorenyl group, an isoindole β sitting group, a β group, a hetero φ Ethyl, pyrrolyl or pyrazolyl. In certain embodiments, X is F, C1 or CH3' Υ is I, Br, cn, CF3 or CVC3 alkyl, Ζ is Η or F, and R0 is F, Cl, Ci-C4 alkyl, CVC3 alkoxy, trifluoromethoxy or 2-decyloxy-ethoxy. In another more specific embodiment, Rld is cycloalkyl or 1_ Alkyl-cycloalkyl wherein 5 Å 1 -alkyl is optionally substituted with two or two OH groups or with one or two halogen atoms. In another more specific embodiment, R0 is halogen, Ci- Q alkyl, φ monodentate Ci-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, (: 2-(:6 alkynyl, phenyl, monosubstituted phenyl, R3, 〇-C(=〇)R4 or c(=o)〇r5; and Rid is a cycloalkyl group or a 1-alkyl-cycloalkyl group, wherein the alkyl group: the group optionally has one or two OH groups Or substituted by one or two mesogenic atoms. • In another more specific example, R0 is a furyl group, a thienyl group, a thiophenyl group, an isoindolyl group, an oxo-based group, an iso-r-tr Base, β ratio σ each group or η ratio. Sitting group; and Rid is cycloalkyl or 丨-alkyl-cycloalkyl, wherein the 丨-alkyl group may be two or two 〇H groups or one or two In another more specific embodiment, Rld is cycloalkyl or 1-alkyl-cyclo 138999.doc -45- 200951107 alkyl" wherein the 1-alkyl group is subjected to one or Two hydrazine H groups are substituted, and wherein Y is Br, I, fluorenyl or trifluoromethyl. In another more specific embodiment, ' Rid is cycloalkyl or 1-alkyl-cycloalkyl, wherein The alkyl group is optionally substituted with one or two fluorine or gas atoms, and wherein γ is Br, I, decyl or trifluoromethyl. In another more specific embodiment, Rid is cycloalkyl or 1_Alkyl)·cycloalkyl, wherein the i-alkyl group is one or two 〇H as the case may be Substituted, and wherein r0· is F, cn, Cl_c3 alkyl, monogas c丨_C3 alkyl, c]_C3 alkoxy, trifluoromethoxy, or 2-methoxy-ethoxy. In another more specific embodiment, Rid is a tetrahydrool group, a tetrahydroindolyl group, a specific base group, a phthyl group, or a morphine group, each of which is regarded as The case is substituted as described above, and wherein YgBr,][, fluorenyl or trifluoromethyl. In another more specific embodiment, Rld is oxazolidinyl, thiazolidinyl, isoxazolidinyl, isothiazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, thiol, brigade The azine group, or morphinyl group, is optionally substituted as described above and wherein m, methyl or trifluoromethyl. In another, more specific, human embodiment, Rld is cyclopropyl or decyl-cyclopropyl, wherein the alkyl group is optionally substituted with one or two OH groups, and wherein r〇^f, C1 A

Rid is 1-(monohydroxyalkyl)alkoxy, benzyl, chloromethyl, Ci_c2 alkoxy, trimethoxy or 2-methoxy-ethoxy. In a more specific embodiment, Rld is 1-(monohydroxyalkyl)ethyl, gas sulfhydryl, CVC2'. In a more specific reality. In another more specific embodiment, wherein R0 is F, C1, trifluoromethoxy or 2-methoxy-ethoxy, Rld is 1-(dihydroxyalkyl)cycloalkyl. In the example, Rld is 1-(dihydroxyalkyl)cycloalkyl, 138999.doc 200951107 fluorenyl, ethyl, chloromethyl, Cl-C2 alkoxy, trifluoromethoxy or 2-methoxy- Ethoxy. In another more specific embodiment, u is CR2 and V is N. In another more specific embodiment, both 〇 and V are N. In another more specific embodiment, U is CR2 and V is CR3. In still another more specific embodiment, the invention provides a compound of formula I wherein G is Ar and ΑΓ is phenyl or monosubstituted phenyl, rg is f, φ methyl, ethyl, C^ C3 alkoxy, trifluoromethoxy or 2-methoxy-ethoxy; X is F, C1 or CH3; Y is I; and Z is F. In another embodiment, the invention provides a compound of formula I, wherein G is ΑΓι, wherein ΑΓι is phenyl or monosubstituted phenyl, RQ is halogen, Cl-C6 alkyl, c3-C6 cycloalkyl, (VC6 alkenyl, Ci-C6 alkynyl, all such alkyl, cycloalkyl, alkenyl and alkynyl groups are optionally selected from 1-3, OH, CN, cyanomethyl, decyl, Substituted by a substituent of a phenyl group and a trifluoromethyl group; or a fluorenyl group is a phenyl group, a fluorene R3 group, a furyl group, a thienyl group, a thiazolyl group, an isothiazolyl group, an oxazolyl group, an iso-pyranyl group, a pyrrolyl group or Pyrazolyl. In a more specific embodiment, the invention provides a compound of formula I wherein A is Ar!, wherein Ar! is phenyl or monosubstituted phenyl, and R0 is F, Cb (VC3) Alkyl, C丨-C3 alkoxy, methoxyethoxy, CVC3 dilute, C; 2-C3 fast radical, trifluoromethyl, phenyl, fluoromethyl or decyl, decyl , isoindole, oxazolyl, oxazolidine, sit-base, ° ratio π base or 0 to ° sit; X is F, C1 or sulfhydryl; γ is I, Br, C1, CFAC^-Cs Base; and Z is F. In another more specific embodiment, the invention A compound of the formula 'wherein G is Ar!, wherein Ar is phenyl or a monosubstituted phenyl group, R〇138999.doc • 47· 200951107 is Η; X is F, Cl or CH3; Y is Br or I And Z is F. In another embodiment, the invention provides a compound of formula I, wherein G is Ah, wherein Ah is 2-thienyl, 2-furyl, 3-thienyl, 3-furanyl, 2-pyrrolyl or 3-pyrrolyl, all optionally substituted by methoxyl, decylaminomethyl hydrazino, etidinyl 'ethinyl, decyl, ethyl, trifluoromethyl or halogen. In another more specific embodiment, the invention provides a compound of formula I, wherein G is Ar2, wherein Ar2 is 2-thienyl, 2-furyl, 3-thienyl, 3-furyl, 2-pyrrole Or a 3-pyrrolyl group, all optionally substituted by methoxycarbonyl, f-aminomethylmercapto, etidinyl, ethyl, methyl, ethyl, trifluoromethyl or halogen; R0 is not hydrazine χ is F, Cl or CH3: Υ is I, Br, Cl, 0? 3 or (: 1-(: 3 alkyl, and Ζ is Η or F. In another embodiment, the invention provides a formula a compound of ι, wherein G is Ah, wherein Ar2 2-thienyl, 2-furyl, 3-thienyl, 3-furyl, 2-pyrrolyl or 3-pyrrolyl, all optionally via oxime oxycarbonyl, methylamine oxime, ethenyl , Ethyl, fluorenyl, ethyl, trifluoromethyl or halogen; R0 is F, C1, alkyl, mono C-C3 alkyl, CrCs alkoxy, trifluoromethoxy, oxime Base-methoxy or 2-methoxy-ethoxy; X is F, C1 or CH3; Y is I, Br, C Bu CF3 or 匸! -^alkyl; and Z is deuterium or F. In another embodiment, the invention provides a compound of formula I, wherein G is Ar2, wherein Ar2 is 2-thienyl, 2-indolyl, 3-nonyl, 3-beta-folyl, 2 -. Bilobyl or 3-° thiol, all optionally substituted with methoxycarbonyl, decylamino, acetamido, ethyl hydrazino, decyl, ethyl, trifluoromethyl or halogen; R0 is Η; Χ is F, C1 or CH3, Υ is I, Br, Cl, alkyl, and Ζ is 138999.doc •48· 200951107 or F. In another embodiment, the present invention provides a compound of formula i, wherein G is Ar2' wherein Αι*2 is an snail group, a singly sigma group, a sylphthyl group, an isoxazolyl group, a pyrrolyl group or a pyridyl group. The oxazolyl 'all are optionally substituted with methoxycarbonyl, decylamine, acetamido, ethyl hydrazino, methyl, ethyl, trifluoromethyl or picon; R0 is hydrazine or decyloxy; X is f, 〇 or (^3, γ is I, Br, Cl, CFdCrC^, and z is ruthenium or F. A specific example disclosed herein is a compound of the compound ruthenium:

F 〇 In certain embodiments, the compound of Compound A is a pharmaceutically acceptable salt, solvate, polymorph, ester, guanamine, tautomer or prodrug. A particular embodiment disclosed herein is a compound of Compound B:

F 〇 In certain embodiments, the compound of Compound B is a pharmaceutically acceptable salt 'solvate, polymorph, s-, guanamine, tautomer or prodrug. A specific example disclosed herein is a compound of Compound A: 138999.doc -49. 200951107

HO

The 2-OH carbon is in the R configuration. In certain embodiments, the compound of Compound a is a pharmaceutically acceptable salt, solvate, polymorph, ester, guanamine, tautomer or prodrug. In certain embodiments, the composition is substantially free of the S-isomer of the compound. In certain embodiments, the compound contains less than 10% of the S-isomer of the compound. In certain embodiments, the compound contains less than 5% of the s-isomer of the compound. In certain embodiments the compound contains less than 1% of the s-isomer of the compound. A particular embodiment disclosed herein is a compound of Compound B:

The 2-OH carbon is in the R configuration. In certain embodiments, the compound of the compound is a pharmaceutically acceptable salt, solvate, polymorph, ester, guanamine, tautomer or prodrug. In certain embodiments, the composition is substantially free of the S-isomer of the compound. In certain embodiments, the compound contains less than 10% of the S-isomer of the compound. In certain embodiments, the compound contains less than 5% of the s-isomer of the compound. In certain embodiments, the compound contains less than 1% of the 8-isomer of the compound.

F. A specific example disclosed herein is a compound of Compound A: 138999.doc 200951107 wherein the 2-OH carbon is in the S configuration. In certain embodiments, the compound of Compound A is a pharmaceutically acceptable salt, solvate, polymorph, scopolamine, tautomer or prodrug. In certain embodiments, esters, armor, the composition is substantially free of the R-isomer of the compound. In certain embodiments, the human has less than 10% of the R-isomer of the compound. In the second embodiment, the compound contains less than 5% of the R_isoindole structure of the compound. In certain embodiments, the compound contains less than 1% of the R isomer of the compound.

A specific example disclosed herein is a compound of Compound B.

The 2-OH carbon is in the S configuration. In certain embodiments, the compound of compound b is a pharmaceutically acceptable salt, solvate, polymorph, ester, guanamine, tautomer or prodrug. In certain embodiments, the composition is substantially free of the R-isomer of the compound. In certain embodiments, the compound contains less than 10% of the R-isomer of the compound. In certain embodiments the compound contains less than 5% of the R-isomer of the compound. In certain embodiments, the compound contains less than 1% of the ruler-isomer of the compound. In certain embodiments, the compounds disclosed herein achieve a cmax between about 0.01/ml and about 1.0 pg/mi on day 1. In certain embodiments, the compounds disclosed herein achieve a Cmax between about 1 g 1 pg /ml to about 0.8 pg /ml on day 1. In certain embodiments, the compounds disclosed herein reach a Cmax of between about 〇3 g3 pg /ml to about 0.5 pg/ml on day 1 138999.doc -51 - 200951107 In certain embodiments, The compounds disclosed herein have an AUC ranging from about 0.1 pg hours/mL to about 5.0 μβ hours/mL from 〇 to i 2 hours. In certain embodiments, the compounds disclosed herein have an AUC of between about 1 hour/mL and about 4.0 hours/mL. In certain embodiments, the compounds disclosed herein have an AUC of between about 0.5 pg hours/mL to about 3.0 pg hours/mL. In certain embodiments, the compounds disclosed herein have an average AUC of between about 1 hour/mL to about 5.0 hours/mL. In certain embodiments, the compounds disclosed herein have an AUC between about 1 hour/mL to about 4.0 pg hours/mL. In certain embodiments, the compounds disclosed herein have an average AUC of between about 0.5 pg hours/mL to about 3.0 pg hours/mL. In certain embodiments, the Tmax of the compounds disclosed herein is achieved from 1 hour to 3 hours after administration of the composition to the fasted individual. In certain embodiments, the compounds disclosed herein have a Tmax of between 0.5 hours and 5 hours. In certain embodiments, the compounds disclosed herein have a Tmax ranging from 1. 5 hours to 3 hours. In certain embodiments, the compounds disclosed herein have a Tmax ranging from 1. hours to 2.5 hours. In certain embodiments, the compounds disclosed herein have an average Tmax of between 〇5 hours and 5 hours. In certain embodiments, the compounds disclosed herein have an average Tmax of between 1.0 hours and 3.0 hours. In certain embodiments, the compounds disclosed herein have an average Tmax of between 1. and 0.5 hours. In certain embodiments, the compounds disclosed herein have a blood population concentration greater than about 0.01 mg/mL after a single dose of 5 hours 138999.doc -52 - 200951107. In certain embodiments, the compounds disclosed herein have a plasma concentration of greater than about 0.01 mg/mL after a single dose of 10 hours. In certain embodiments, the compounds disclosed herein have a plasma concentration of greater than about 0.01 mg/mL after a single dose of 15 hours. Synthetic Procedures The methods of synthesizing the compounds disclosed herein are further disclosed herein. In certain embodiments, the compounds disclosed herein are made by the methods described below. The following procedures and examples are intended to illustrate such methods. Neither a program nor an instance should be construed as limiting the invention in any way. The compounds disclosed herein can also be synthesized using standard synthetic techniques known to those skilled in the art or by methods known in the art. In addition, the solvents, temperatures, and other reaction conditions presented herein may vary depending on the practice and common knowledge of those skilled in the art. In certain embodiments, starting materials for the synthesis of the compounds described herein are available from commercial sources such as Aldrich Chemical Company (Wisconsin, USA), Sigma Chemical Company (St. Louis, Missouri, USA). In certain embodiments, the starting material used to synthesize the compounds described herein is a synthetic material. In certain embodiments, the compounds described herein and other related compounds having different substituents are used as described in Advanced Organic Chemistry 4th Ed. of March, (Wiley 1992); Advanced Organic by Carey and Sundberg

Chemistry 4th Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3rd Ed., (Wileyl 999) (all of which are cited by way of 138999.doc -53 - 200951107 The methods and materials synthesized in the Chinese version). The general methods for preparing the compounds disclosed herein are obtained by reactions known in the art, and in certain embodiments, the reactions are modified by the use of appropriate reagents and conditions to introduce the chemical formulas found herein. Different groups in the middle. Formation of Covalent Bonds by Reaction of Electrophilic Agents with Nucleophiles The compounds disclosed herein are modified with different electrophiles or nucleophiles to form functional groups or substituents. The table below is entitled "Examples of Covalent Bonds and Their Precursors" listing examples of selected covalent bonds and their precursor functional groups. The precursor functional groups are shown as electrophilic and nucleophilic groups. Covalent bond product electrophilic agent nucleophile carboxy guanamine activated acetamide / aniline carboamide hydrazide azide amine / aniline carboamide oxime amide amine / aniline hydrazide hydrazide alcohol / phenolic ester hydrazinocarbonitrile Alcohol / phenol carboxy amide amine amide / aniline aldehyde amine / aniline furfural or ketone furfural or ketone hydroxyl amine alkyl amine alkyl halide amine / aniline alkyl carboxylic acid thioether alkyl Thiol ether base dentate alcohol/phenol thioether alkyl sulfonate thiol ester alkyl sulfonate carboxylate ether alkyl sulfonate alcohol / phenolic ester anhydride alcohol / phenol carboxamide anhydride amine / aniline sulfur Aryl halide thiol arylamine aryl i amide thioether acetophenone thiolate phthalate lysate diol 138999.doc -54- 200951107 Carboxyguanamine carboxylic acid amine / aniline carboxylic acid oxime醯肼carboxylic acid 7V-decyl urea or anhydride carbodiimide carboxylic acid diazo carboxylic acid sulfur mystery epoxide thiol thioether halogen acetamide thiol ammonia triterpenoid halogenated triazine amine / aniline three The azine ether is halogenated three. Qin alcohol / phenolphthalein acetamide / aniline urea isocyanate amine / aniline urethane isocyanate / phenol sulfur gland isothiocyanate amine / aniline thioether maleimide thiol phosphite amine Phosphate oxime alkyl ether oxime alkyl hydride alkylamine amide aniline amine aniline thioether sulfonate thiol ester sulfonate carboxylic acid sulfonate alcohol continuation amine sulfonyl halide amine / aniline sulfonate Acid ester sulfonyl halide phenol/alcohol

Examples of covalent bonds and the use of their precursors

In certain embodiments, it may be necessary to protect the desired reactive functional groups in the final product, such as hydroxyl, amine, imido, thio or carboxy groups to avoid undesired participating reactions. The protecting group is used to block some or all of the reactive groups and prevent such groups from participating in the chemical reaction until the protecting group is removed. In some embodiments, each protecting group can be removed in a different manner. A protecting group that splits under completely different reaction conditions satisfies the need for different removals. In certain embodiments, the protecting group is removed by acid, base, and hydrogenolysis. In certain embodiments, groups such as triphenylsulfonyl, dimethoxytrityl, acetal, and tert-butyldimethylalkyl are acid labile and amine groups protected by a Cbz group. 138999.doc -55- 200951107 'The special group can be hydrogen

The base is blocked by an alkali labile group, which is both acid and base stable but can be removed by hydrolysis. Used to protect carboxyl and hydroxyl reactive groups, decompose and detect unstable Fmoc group removal. In certain embodiments, the carboxylic acid and hydroxyl reactive groups are also blocked by a hydrolyzable removable protecting group such as a phenylhydrazine group, and the amine group bonded to the acid hydrogen bond is unstable with a base such as Fmoc. Base blocking. In certain embodiments, the carboxylic acid reactive group is protected by conversion to a monoester compound as exemplified herein, or it can be blocked by an oxidatively removable protecting group such as 2,4-dimethoxybenzyl. At the same time, the co-existing amine groups are blocked by the fluoride-unsaturated mercaptoalkyl phthalate. In certain embodiments, an allyl blocking group is useful in the presence of an acid protecting group and a base protecting group. For example, the allyl-blocked carboxylic acid is deprotected by a Pd-catalyzed reaction in the presence of an acid labile tert-butyl amide or a base labile acetate amine protecting group. Another form of protecting group is a resin to which a compound or an intermediate can be attached. As long as the residual group is attached to the resin, this functional group is blocked and cannot be reacted. This functional group can be used for the reaction once the resin is released. The protecting group or blocking group is selected from the group consisting of: 138999.doc -56 - 200951107

~Cr". Person, ,°丫^ H3cA Dilyl Bn Cbz aUoc Me , h3c , ,CH3

H3c^V (h3c)3c〆, (h3c)3c,Sl Et tert-butyl TBDMS (ch3)3c/〇'T^? (c6h5)3c~^ ° h3co>^ ?

Boc pMBn two bases

A detailed description of other protecting groups, as well as techniques that can be used to generate protecting groups and their removal, can be found in Protective Groups in Organic Synthesis by Greene and Wuts, 3rd edition, published by John Wiley & Sons, New York, NY, 1999. , and the Protective Groups of Kocienski, published by Thieme Verlag, New York, NY, in 1994, and their publications are hereby incorporated by reference. Making the Compounds Disclosed herein The compounds disclosed herein can be made by a variety of methods. The following procedures are intended to illustrate such methods, and the examples presented are intended to illustrate the scope of the invention. Such methods or such examples are not to be construed as limiting the invention in any way. I. Preparation of the compound of structure VI is described below. 138999.doc 57- 200951107

The above flow chart i illustrates a method for producing a sulfonamide derivative of the structure ν ι. In certain embodiments '>2_diamine derivatives. The structure ιν) was prepared in two steps from the expected nitro derivative (structure I). In certain embodiments, the compound of Structure IV is reacted with a sulfonium gas derivative (Structure V, see next flow chart) to form the desired sulfonamide. In certain embodiments, the i,2-diamine derivative IV is protected for the production of imidazolidone (structure VII) prior to reaction with the corresponding sulfonium gas. In certain embodiments, under basic conditions Deprotection of hydrazine, 2-diamine VIII provides the desired material vi.一般. General schemes for the synthesis of compounds of the general structure ν are summarized below:

The above Scheme II shows an example of preparing a composite sulfonium gas. In certain embodiments, 'Structure XX is synthesized by IX' and is converted to a salt rejection XH. In certain embodiments, the salt is treated with SOC 12 or POC 13 to provide the desired compound. Further specific procedures for the preparation of unique sulfonium gas derivatives are reported in 138999.doc -58 · 200951107 in the experimental paragraph. III. General Path for the Synthesis of Compounds of General Structure XIII is outlined in Flowchart 3:

The above Scheme III illustrates the preparation of a sulfonamide derivative of the general structure XIII. In certain embodiments, such compounds are obtained by reacting structure VI with an acid acid using a palladium catalyst under Suzuki conditions. IV. General Path for the Synthesis of Compounds of General Structure XIII is outlined in Flowchart 4·

The above Scheme IV illustrates the preparation of a sulfonamide derivative of the general structure XV. In certain embodiments, the vinylsulfonamide (XIV) reacts with an amine to form a derivative of the general structure XV. Other Forms of Compounds Disclosed herein Isoforms of the compounds disclosed herein In certain embodiments, the compounds disclosed herein exist as geometric isomers. In certain embodiments, the compounds disclosed herein have one or more double bonds. The compounds provided herein include all cis, trans, isotropic, reverse, E (entgegena Z (zusammen) isomers and their corresponding mixtures 138999.doc • 59-200951107. In certain embodiments, 'this article The disclosed compounds exist as tautomers. The compounds disclosed herein include all tautomers that are possible in the formulas described herein. In certain embodiments, the compounds disclosed herein have - or more palmitic centers and Each-center can be configured to exist. The compounds disclosed herein include all non-image, isomeric, and epimeric forms and their corresponding mixtures. In the additional examples of the compounds and methods provided herein, Mixtures of mirror-isomers and/or non-an image-isomers of steps, combinations or tautomers may also be used in the applications described herein. In certain embodiments, the compounds disclosed herein may be external to the compound The racemic mixture is reacted with an optically active resolving agent to form a pair of non-image isomers, isolating the non-image isomers, and recovering the optically pure isomers to be prepared as Individual stereoisomers. In certain embodiments, resolution of the mirror image isomers is carried out using covalent non-image-isomerized derivatives of the compounds described herein, or using dissociable complexes (eg, crystalline non- Mirror image isomers.) In certain embodiments, the non-image isomers may be separated by palm chromatography or separation/resolution techniques depending on solubility. In some embodiments, followed by a resolving agent The optical pure image isomers are recovered together by any means that do not actually cause racemization. A more detailed description of the techniques that can be used to separate the stereoisomers of a compound from its racemic mixture can be found in Jean jacques. ,Andre c〇Uet, Samuel H. Wilen, "Enantiomers, Racemates and Res〇luti〇ns", john Wiley

And Sons, Inc,, 1981, the disclosures of which are incorporated herein by reference. The labeled compounds disclosed herein are also described in the context of labeled compounds 138999.doc -60- 200951107. Further, a method of treating a condition by administering a compound disclosed herein has been disclosed. S is in the case of the second embodiment. The compound disclosed herein is an isotope label (also known as 'radioactive isotope). In certain embodiments, the disclosure herein is labeled by the use of a chromophore or fluorophore, a bioluminescent label, or a chemiluminescent label. Isotopically labeled compounds disclosed herein are also equivalent to the φ participants described herein, but wherein one or more of the atoms are replaced by atomic mass or mass number and atoms which are generally identifiable by atomic mass or mass number in nature. The isotopics incorporated in the compounds disclosed herein in certain 3η 36 二广例3 are selected from the group consisting of Po, ^ C, 5 Ν, , 丨 7 〇, 3 丨Ρ, 32 Ρ, 35 s, 18 ρ and . In certain embodiments, the isotopically labeled compounds disclosed herein are used in a musical and/or matrix tissue distribution assay. In certain embodiments, the 'isotopically labeled compounds disclosed herein have greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In certain embodiments, the compounds disclosed herein may be labeled by any convenient means. Pharmaceutically Acceptable Salts of the Compounds Disclosed herein Also described herein are pharmaceutically acceptable salts. Further disclosed herein is the treatment of a disease by administering a pharmaceutically acceptable salt of the compound disclosed herein. In a second embodiment, 'when an acid proton present in a parent compound is replaced by a metal ion, such as a metal ion, a soil metal ion or a metal ion; or a compound disclosed herein, the compound disclosed herein is prepared medically. Salts of 138999.doc • 61 - 200951107 are acceptable. In certain embodiments, a base addition salt is prepared by reacting a free acid form of a compound disclosed herein with a pharmaceutically acceptable inorganic or organic base. The base includes, but is not limited to, an organic base. Such as ethanolamine, diethanolamine, diethanolamine, tromethamine, N-methyl reduced glucosamine and the like and inorganic bases such as aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide and the like Things. In certain embodiments, the compounds disclosed herein are prepared as pharmaceutically acceptable salts by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, Not limited to) inorganic acids such as hydrogen acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid and the like; and organic acids such as acetic acid, propionic acid, caproic acid, cyclopentanepropionic acid, glycolic acid, pyrogluconic acid , lactic acid, malonic acid, succinic acid, hydroxysuccinic acid, maleic acid, fumaric acid, Q-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4 -hydroxyphenylhydrazino)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, hydrazine, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, Benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-mercaptobisbis-[2.2.2]octane-2-ene-1-carboxylic acid, glucoheptanoic acid, 4,4,-indenyl bis-(3_hydroxy- 2-ene-formic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, facial acid, hydroxynaphthoic acid, salicylic acid, stearic acid and Di-dicarboxylic acid. Solvates of the compounds disclosed herein Solvents are also disclosed herein. Further disclosed herein is a method of treating a condition by administering a solvate of a compound disclosed herein. 138999.doc • 62-200951107 The dosage form contains a stoichiometric or non-chemical embodiment. In this example, the article is intended to be _ + & The solvent of 1. The solvate of the compound in a certain way is in the form of a solvent such as water, and (10) in the process of crystallization of medicine and medicinal materials. In certain embodiments, when the solvent is water: a hydrate of the form in the gas path. Alcoholization is formed in the case where the compound 0 mixture of the present invention is an alcohol. The dissolution compound of the compound disclosed herein is formed in the present specification. In certain embodiments, the hydrate of the compound of the road is prepared by recrystallizing from an organic solvent mixture in a mu organic solvent mixture, such as, but not limited to, dioxin, tetrahydrofuran. Or methanol. In some of the above-mentioned targets, the compounds disclosed herein are not solvated. In general, the solvating formula φ is considered equivalent to the unsolvated form for use in the compounds and methods provided herein. Polymorphs of the Compounds Revealed herein Polymorphs are also disclosed herein. Also disclosed herein are methods of treating a condition by administering a polymorph of the compounds disclosed herein. As used herein, "polymorph" includes the arrangement of different crystal layers of the same elemental composition of the compound. In certain cases, each polymorph of a compound has a different X-ray diffraction spectrum 'infrared spectroscopy, melting point, density, hardness, crystal form, optical and electrical properties, stability and solubility. A variety of factors such as the recrystallization solvent's crystallization rate and storage temperature may cause a single crystal shape to dominate. In a particular embodiment, 'N-(S)-(3,4-difluoro-2-(2-ce-4-iodophenylamino)-6-decyloxyphenyl)-1-() is disclosed herein. 2,3-dipropyl propyl) propylene 138999.doc -63· 200951107

Crystalline polymorph A of sulfonamide: In certain embodiments, N-(SH3,4_digas_2_(2_gas+mothylamino)-6-decyloxyphenyl)-HW Di-propyl propyl) propylene-acrylic acid-based crystalline polymorph A exhibits a specific powder calender diffraction spectrum. In certain embodiments, the powder X-ray diffraction spectrum contains at least about 5% of the ridges shown in Figure 5. In some embodiments, the powder x-ray diffraction spectrum contains at least about 70% of the peaks shown in Figure 5. In some implementations, the powder parent light diffraction spectrum contains at least about 90% of the peaks shown in Figure 5. In some embodiments, the powder X-ray diffraction pattern is substantially the same as the powder X-ray diffraction pattern shown in Figure 5. In certain embodiments 'N_(SH3,4-difluoro-2-(2-fluoro-4-isoiodophenylamino)-6-methoxyphenyl H-(2,3-dihydroxypropyl) ring Crystalline polymorph A of propane oxime sulfonamide presents a specific differential scanning calorimetry spectrum. In some embodiments, this particular differential scanning calorimetry spectrum is substantially identical to the differential scanning shown in Figure 6. The calorimetric spectra are the same. In some embodiments, 'crystalline polymorph A has an initial melting point of about 143 ° C as measured by differential scanning calorimetry. In some embodiments 'this N-(SH3, 4-difluoro-2-(2-fluoro-4-isoiodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-oxime-sulfonamide Crystalline polymorph A is obtained by crystallizing amorphous 2N_(s)_(3,4-trifluoro-2-(2-carb-4-ironphenylamino)-6-methoxyphenyl) from a solvent. Made of small (2,3-di-dipropyl)cyclopropane-1-sulfonamide. 138999.doc • 64- 200951107 In certain embodiments, this N-(S)-(3,4- Crystallization of difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-oxime-sulfonamide Polymorph A Prodrugs of alkane and ethyl acetate. Prodrugs of the compounds disclosed herein. Prodrugs are also disclosed herein. Also disclosed herein are methods of treating a condition by administering a prodrug of a compound disclosed herein. As used herein, "prodrug" A form of a compound which, upon administration to a subject and subsequent absorption, is converted to an active or more active substance (i.e., a parent). In certain embodiments, the prodrug is converted to the parent by metabolism. In some embodiments, a prodrug of a compound disclosed herein has a chemical group that renders the compound less active and/or modulates the solubility of the compound. In certain embodiments, cleavage of the chemical group results in a prodrug Converted to the parent. In certain embodiments, the prodrugs of the compounds disclosed herein are easier to administer than the parent. In certain embodiments, prodrugs of the compounds disclosed herein may be bioavailable by oral administration, but The parent may not. In some embodiments, the prodrugs of the compounds disclosed herein are superior in solubility to the parent. Non-limiting examples of rigid drugs may be the combinations described herein. The ester is administered as an ester ("prodrug") to facilitate transport through the cell membrane, where water solubility is unfavorable - but migration is then hydrolyzable to a carboxylic acid, and once the active entity is in the cell, the water solubility is Advantageous. Another example of a prodrug can be bonded to acid

The base of the peptide (the polyamino acid in which the peptide is metabolized to reveal the active group. A 〇 》 刖 刖 刖 》 的 参阅 参阅 参阅 参阅 参阅 参阅 参阅 参阅 参阅 参阅 参阅 参阅 参阅 参阅 参阅 参阅 参阅 参阅 参阅 参阅 参阅 参阅 参阅 参阅 参阅 参阅 参阅 参阅 参阅 参阅 参阅 参阅269 : G210-218 (1995) ; McLoed et al. 138999.doc -65- 200951107

Gastroenterol » 106 · 405-413 (1994); Hochhaus et al., Biomed. C/zrom., 6 · 283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 ( 1987); J. Larsen et al., P/mrwflfcewi/ci, 47, 103 (1988);

Sinkula et al.'s corpse/mrm. «Sci·, 64 : 181-210 (1975); T. Higuchi and V. Stella, Pro-Drwg·? a·? iVove/ De/z'very , ACS Symposium Series Volume 14; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; and Saulnier et al. (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985, The literature is hereby incorporated by reference. In certain embodiments, prodrugs of the compounds disclosed herein are by non-derived compounds disclosed herein and a suitable aminoguanidine agent such as, but not limited to, 1,1-decyloxyalkyl gas. It is prepared by reacting an acid ester, p-nitrophenyl carbonate or the like. In certain embodiments, a prodrug of a compound disclosed herein comprises an amino acid residue covalently linked to a free amine, hydroxy or carboxylic acid group of a compound disclosed herein via a guanamine or ester linkage, or two Or a multi-peptide chain of two or more (ie, two, three or four) amino acid residues. In certain embodiments, the amino acid residue comprises a naturally occurring amino acid, 4-hydroxyproline, hydroxy lysine, demosine, isodemosine, 3-quinone Histamine, n-Glycine, β-alanine, γ-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and 138999.doc -66- 200951107 thiamine Acids In certain embodiments, the compounds disclosed herein having a free amine group, a guanamine group, a hydroxyl group, or a suspending group are converted to prodrugs. In certain embodiments, a compound having a free carboxyl group as disclosed herein is converted to a prodrug by derivatizing a free carboxyl group to a guanamine or alkyl ester. In certain embodiments, the compounds disclosed herein have free radicals by using, but not limited to, hemisuccinates, phosphates, dimethylaminoacetates, and phosphonium methoxycarbonyl groups. The φ group is derived from a free hydroxyl group and converted to a prodrug, as outlined in wzwac/ Dr«, hWew 1996, 115. Also included are hydroxy and amine urethane prodrugs and hydroxy carbonate prodrugs, sulfonates and sulfates. In certain embodiments, prodrugs of the compounds disclosed herein are produced by derivatizing a hydroxy group to a (decyloxy) fluorenyl group and a (decyloxy) ethyl group, wherein the thiol group is a decyl vinegar, as appropriate (but not limited to) the group of ether, amine and diacid functional groups substituted 'or wherein the thiol group is an amino acid ester as described above. The top 10 of this type is described in 丄C/zew. 1996, 39, 10, which is incorporated herein by reference. In certain embodiments, the free amine is derivatized as a guanamine, a sulfonamide or a filled amine. All such prodrug groups can incorporate groups including, but not limited to, ethers, amines, and carboxylic acid functional groups. In certain instances, the sites on the aromatic ring portion of the compounds disclosed herein are susceptible to a variety of metabolic reactions; thus, in certain embodiments, the compounds disclosed herein are included in the aromatic ring structure and incorporated into the appropriate Substituent. IV. Methods of Use In certain embodiments, the compounds or compositions disclosed herein are administered to a subject in need thereof 138999.doc-67-200951107 to inhibit the MEK enzyme. In certain embodiments, a compound or composition disclosed herein is administered to an individual in need thereof to treat a condition. In certain embodiments, a compound or composition disclosed herein is administered to a subject in need thereof to treat a condition mediated by sputum. In certain embodiments, a compound or composition disclosed herein is administered to an individual in need thereof to treat a proliferative disorder. In certain embodiments, the compounds or compositions disclosed herein are administered to an individual in need thereof to treat an inflammatory condition. In certain embodiments, a compound or composition disclosed herein is administered to a subject in need thereof to inhibit chymase. In certain embodiments, the chymase is ΜΕΚ kinase. In certain embodiments, the chymase is ΜΕΚ1. In certain embodiments, the chymase is ΜΕΚ2. In certain embodiments, the chymase is inhibited by at least about 1%. In certain embodiments, the chymase is inhibited by at least about 2%. In certain embodiments, the chymase is inhibited by at least about 3%. In certain embodiments, the chymase is inhibited by at least about 4%. In certain embodiments, the chymase is inhibited by at least about 5%. In certain embodiments, the chymase is inhibited by at least about 10%. In certain embodiments, the chymase is inhibited by at least about 20%. In certain embodiments, the chymase is inhibited by at least about 25%. In certain embodiments, the chymase is inhibited by at least about 30%. In certain embodiments, the chymase is inhibited by at least about 40%. In certain embodiments, the chymase is inhibited by at least about 50%. In certain embodiments, the chymase is inhibited by at least about 60%. In certain embodiments, the chymase is inhibited by at least about 70%. In certain embodiments, the chymase is inhibited by at least about 75%. In certain embodiments, the chymase is inhibited by at least about 80%. In certain embodiments, the chymase is inhibited by at least about 90%. In certain embodiments, 138999.doc -68- 200951107, the MEK enzyme is substantially completely inhibited. In certain embodiments, the compounds or compositions disclosed herein are administered to a subject in need thereof to treat a mediated condition. In certain embodiments, the condition of the viscera is selected from the group consisting of an inflammatory condition, a proliferative condition, an infection, an immune condition (eg, 'autoimmune disease, psoriasis, rheumatoid arthritis, Osteoarthritis, dry eye and glaucoma), cardiac conditions (eg stroke, reperfusion injury, local ash deficiency, atherosclerosis, heart failure), neurological disorders, fibrotic disorders, metabolic diseases, chronic pain and/ Or nerve pain. In certain embodiments, a compound or composition disclosed herein is administered to a subject in need thereof to treat an immunological disorder. In certain embodiments, it is disclosed herein that the S or composition is administered to a subject in need thereof to treat a cytokine mediated disorder (ie, a condition caused by overproduction or unregulated production of a proinflammatory cytokine, pre-inflammatory cells) Hormones include, for example, IL-1, several -6 and IL-8). In certain embodiments, the compounds or compositions disclosed herein are administered to a subject in need thereof to treat an autoimmune disorder, an inflammatory disorder, an infectious disorder, prostaglandin peroxidase synthetase-2 (c〇x_2) Symptoms associated with rheumatoid arthritis, inflammatory bowel disease, inflammatory pain, ulcer steepness, 0 enteritis, Crohn's disorder, periodontal disease, subcondylar joint disease, multiple sclerosis, Diabetes, glomerulonephritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, anemia of gluten, an autoimmune gastritis, autoimmune neutrophils, SL thrombocytopenia , chronic active hepatitis, myasthenia gravis, ectopic dermatitis, graft versus host disease, and psoriasis, asthma, over 138999.doc -69- 200951107 Sensitive, respiratory distress syndrome or acute or chronic pancreatitis and multiple sclerosis . In certain embodiments, a compound or composition disclosed herein is administered to a subject in need thereof to treat an inflammatory condition. In certain embodiments, the inflammatory condition is proliferative glomerulonephritis, chronic inflammatory condition, bursitis, acute rheumatoid arthritis, allergy, bursitis, pulmonary fibrosis, septic arthritis , joint adhesion spondylitis, arthritis, asthma, atherosclerosis, chronic inflammatory disease, chronic obstructive pulmonary disease, diabetes (including diabetic retinopathy), diarrhea, eczema, intestinal arthritis, gastritis, gout , gouty arthritis, inflammatory bowel disease, colonic irritability, ulcerative colitis, juvenile arthritis, neuroarthritis, organ transplant rejection, osteoarthritis, osteoporosis, pancreatitis, proliferative kidney Spherical nephritis, pruritic dermatitis, psoriasis, psoriatic arthritis, pulmonary fibrosis, pulmonary inflammation, septic arthritis, reflux esophagitis, respiratory distress syndrome, acute or chronic pancreatitis, rheumatoid joints Inflammation, scleroderma, cystic fibrosis, systemic lupus erythematosus, tendonitis, ulcerative colitis, valipoli's spondyloarthropathy or Crohn's Disease. In certain embodiments, a compound or composition disclosed herein is administered to a subject in need thereof to treat a proliferative disorder. In certain embodiments, the proliferative disorder is the growth of abnormal cells. In certain embodiments, the proliferative disorder is an aneurysm. In certain embodiments, the proliferative disorder is cancer. In certain embodiments, the cancer is a hematological or non-hematologic blood cancer. In certain embodiments, the cancer is selected from the group consisting of multiple myeloma, leukemia, and lymphoma. In certain embodiments, the cancer is selected from the group consisting of acute and chronic leukemia. In certain embodiments, the cancer is selected from the group consisting of acute lymphocytic leukemia 138999.doc-70.200951107 (ALL) and acute non-lymphocytic leukemia (ANLL). In certain embodiments, the cancer is selected from the group consisting of chronic lymphocytic leukemia (CLL) and chronic myelogenous leukemia (CML). In certain embodiments, the cancer is selected from the group consisting of H〇dgkin, s lymph〇rna, and non-Hodgkin's lymphoma. In certain embodiments, the cancer is multiple bone marrow. In certain embodiments, the cancer is low, medium, and advanced. In certain embodiments, the cancer is selected from the group consisting of brain cancer, head and neck cancer, lung cancer, breast cancer, reproductive system cancer, digestive system cancer, pancreatic cancer, and urinary system cancer. In certain embodiments, the cancer is upper gastrointestinal cancer or colorectal cancer. In certain embodiments, the cancer is bladder cancer or renal cell carcinoma. In certain embodiments, the cancer is prostate cancer. In certain embodiments, the cancer is breast cancer such as breast ductal carcinoma, medullary carcinoma, colloidal carcinoma, tubular cancer, and inflammatory breast cancer in mammary duct tissue; ovarian cancer, including epithelial ovarian tumors such as adenocarcinoma in the ovary And adenocarcinoma that migrates from the ovary into the abdominal cavity; uterine cancer; cervical cancer, such as adenocarcinoma in the cervical epithelium, including squamous cell carcinoma and adenocarcinoma; prostatic adenocarcinoma, such as prostate cancer selected from the group consisting of : adenocarcinoma or adenocarcinoma that migrates to the bone; pancreatic cancer, such as epithelial carcinoma in the pancreatic duct tissue and adenocarcinoma in the pancreatic duct; bladder cancer, such as transitional cell carcinoma in the bladder, urothelial carcinoma: Transitional cell carcinoma] tumors in the urothelial cells of the lining of the bladder: squamous cell carcinoma, adenocarcinoma, and small cell carcinoma; leukemia, such as acute myeloid leukemia (AML), acute lymphocytic leukemia, chronic lymphocytosis Leukemia, chronic myelogenous leukemia, hairy cell leukemia, myelodysplasia, and myeloproliferative disorders; bone cancer; lung cancer, such as non-small cell lung < cancer (NSCLC), which differentiate into squamous cell carcinoma, Cancer and large cell undifferentiated carcinoma 138999.doc -71 - 200951107 and small cell lung cancer; skin cancer 'such as basal cell carcinoma, melanoma, squamous cell carcinoma and actinic keratosis' which sometimes develop into scale Skin symptoms of squamous cell carcinoma, ocular retinoblastoma; skin or intraocular (ocular) melanoma; primary liver cancer (starting cancer in the liver); kidney cancer; squamous adenocarcinoma, such as papillary, Follicular, medulla, and undifferentiated; AIDS-associated lymphomas such as diffuse large B-cell lymphoma, B-cell immunoblastic lymphoma, and small non-cleaved cell lymphoma; Kaposi's Sarcoma; Virus-induced cancer, including hepatitis B virus (HBV), hepatitis C virus (HCv) and liver cancer; type 1 human lymphoblastic virus (HTLVd) and adult tau cell leukemia/lymphoma; and human papillomavirus ( HPV) and cervical cancer; central nervous system cancer (CNS), such as primary brain tumors, including glioma (astrocytoma, degenerative astrocytoma or glioblastoma multiforme), recruitment of dendrites Glioblastoma, ependymoma, brain Medullary, lymphoma, schwannomas, and blastocystoma; peripheral nervous system (PNS) cancer, such as acoustic neuroma and malignant peripheral nerve sheath tumor (MPNST), including neurofibromatosis and schwannomas, malignant fibers Cell tumor, malignant fibrous histiocytoma, malignant cerebral ventricle, malignant mesothelioma and malignant mixed Miillerian tumor; oral and oropharyngeal cancer, such as hypopharyngeal carcinoma, laryngeal cancer, nasopharyngeal Cancer and oropharyngeal cancer; gastric cancer, such as lymphoma, gastric stromal tumor and carcinoid tumor; testicular cancer, such as blastoma tumors (gcTs), including seminoma and non-seminoma and gonadal stromal tumors, Including Leydig cell tumor and Sertoli cell tumor; thymic cancer, such as thymoma, thymic carcinoma, Hodgkin's disease, non-Hodgkin's lymphoid carcinoma or Carcinoid tumors; rectal cancer; knot 138999.doc -72- 200951107 intestinal cancer, kidney cancer, adrenocortical carcinoma, follicular lymphoma, negative pre-B cells (Pre-B) acute leukemia, chronic lymphocytes B_leukemia, gland 'Angiosarcoma, astrocytoma, acoustic neuroma' degenerative astrocytoma, basal cell carcinoma, blastoglioma, chondrosarcoma, choriocarcinoma, 'chordoma, craniopharyngioma, cutaneous melanoma 'Cagular adenocarcinoma, endothelial sarcoma, embryo • Fetal cancer, ependymoma, Ewing's tumor, epithelial cancer, - fibrosarcoma, gastric cancer, genitourinary tract cancer, glioblastoma multiforme, ® Hemangioblastoma, hepatocellular carcinoma, liver cancer, Kaposi's sarcoma, large cell carcinoma, leiomyosarcoma, liposarcoma, lymphangisarcoma, lymphatic endothelial sarcoma, medullary thyroid carcinoma, neural tube blastoma, cerebrospinal Membrane, mesothelioma, bone tumor, mucinous sarcoma, neuroblastoma, neurofibrosarcoma, oligodendroglioma, osteogenic sarcoma, epithelial ovarian cancer, papillary carcinoma, papillary adenocarcinoma , parathyroid tumor, pheochromocytoma, pineal tumor, plasmacytoma, retinoblastoma, rhabdomyosarcoma, sebaceous gland cancer, seminoma, skin cancer, melanoma, small cell lung cancer, squamous • Cell carcinoma, sweat gland cancer, synovial tumor, squamous adenocarcinoma, uveal melanoma and Wilm's tumor, oral and laryngeal cancer, respiratory cancer, bone and joint cancer, soft tissue cancer, skin Cancer, reproductive system cancer, eyes and eyelids: cancer, nervous system cancer, lymphatic system cancer and endocrine system cancer. In a specific embodiment; such a cancer is selected from the group consisting of tongue, mouth, pharynx or other oral cancer; esophageal cancer, gastric cancer or small intestine cancer; colon cancer or rectal, anal or anorectal cancer; liver and liver Endotracheal tube, gallbladder, pancreas or other bile or digestive cancer; throat, bronchial and other respiratory cancer; heart cancer, melanoma, basal cell carcinoma, squamous cell carcinoma, other non-epithelial skin cancer; uterus 138999. Doc -73- 200951107 or cervical cancer; endometrial cancer; nest, vulva, vagina, or other female genital cancer; prostate, testicular, penis or other male genital cancer; bladder cancer; kidney cancer; kidney, pelvis or urethra cancer Or other genitourinary cancer; thyroid cancer or other endocrine cancer; chronic lymphocytic leukemia; and cutaneous T-cell lymphoma 'granular and mononuclear. In certain embodiments, the compounds and/or compositions disclosed herein are administered to an individual in need thereof to treat a proliferative disorder. In certain embodiments, the inflammatory disorder is a fibrotic disorder. In certain embodiments, the proliferative disorder is selected from the group consisting of angiogenesis-related symptoms or symptoms 'Angioplasty, atherosclerosis, cardiac hypertrophy, hyperplasia, immune disorder, inflammation, interstitial nephritis, or pulmonary fibrosis' keloid Formation, cirrhosis, migraine, pain, polymyositis, hyperplasia after medical procedures, restenosis, rheumatoid arthritis, scleroderma, systemic lupus or angiogenesis. In certain two embodiments, the compounds or compositions disclosed herein are administered to a subject in need thereof to treat a proliferative disorder. In certain embodiments, the proliferative disorder is benign skin hyperplasia (e.g., psoriasis) or prostate (e.g., benign prostatic hypertrophy (BPH)). In certain embodiments, a compound or composition disclosed herein is administered to a subject in need thereof to treat a blood disorder. In certain embodiments, the blood disorder is selected from the group consisting of sickle cell anemia, myelodysplastic disorders (MDS), and myeloproliferative disorders. In certain embodiments, the proliferative disorder is selected from the group consisting of polycythemia vera, myelofibrosis, and essential thrombocytosis. In a second embodiment, the compounds or compositions disclosed herein are administered to an individual in need of 138999.doc 200951107 to treat an ophthalmic condition. In certain embodiments, the ophthalmic condition is dry eye (including Sjogren's syndrome (Sjogren.s coffee leg (9), macular degeneration, angle closure and open angle glaucoma, retinal ganglion cell degeneration, ocular ischemia) , retinitis, optic neuropathy (eg, glaucoma, neuropathy, or ocular disease), uveitis, dizziness, eye; inflammatory and pain associated with traumatic trauma (eg, after surgery for eye surgery) Inflammation or pain, such as cataract surgery and refractive surgery. In certain embodiments, the compounds or compositions disclosed herein are administered to a subject in need thereof to treat a skin condition. In certain embodiments, the skin disease is melanin. Tumor, basal cell carcinoma, squamous cell carcinoma, psoriasis, and persistent sowing. In certain embodiments, the compounds or compositions disclosed herein are administered to a subject in need thereof to treat a metabolic disorder. In certain embodiments Among them, metabolic disorders are metabolic syndrome, anti-Tengthin syndrome, and type j and (4) diabetes. In certain embodiments, the compounds or compositions disclosed herein are administered as needed. The body treats conditions associated with tissue damage. In some embodiments, the condition associated with tissue damage is selected from the group consisting of vascular disorders, migraine, nodular arteritis, thyroiditis, aplastic anemia, Hodgkin's Symptoms, sclerodoma, rheumatic fever, type diarrhea, neuromuscular: xiao joint disorders including myasthenia gravis, white matter disorders including multiple sclerosis, · schiacoma, nephritis, renal syndrome, Besett Syndrome (Behcet, s ―), polymyositis, gingivitis, periodontal disease, allergies, post-traumatic swelling, ischemia including myocardial ischemia, partial cardiovascular failure, secondary localization of cardiac arrest Blood, allergic rhinitis, respiratory distress syndrome, endotoxin shock syndrome, and atherosclerosis. 138999.doc • 75· 200951107 In certain embodiments, the compounds or compositions disclosed herein are administered to a subject in need thereof for treatment Cardiovascular disorders. In certain embodiments, the cardiovascular disorder is atherosclerotic, cardiac hypertrophy, spontaneous cardiomyopathy, heart failure, angiogenesis Shape or condition, and hyperplasia induced after medical surgery, including but not limited to restenosis caused by surgery and angioplasty. The compounds or compositions disclosed herein are administered to individuals in need thereof for treatment and treatment. Injury-related neurological disorders. In certain embodiments, the neurological disorder is Parkinson's disease; Alzheimer's disease; Alzheimer's dementia; central nervous system caused by stroke, ischemia, and trauma Injury; epilepsy; neuropathic pain, depression; or bipolar disorder. In certain embodiments, the compounds and/or compositions disclosed herein may be administered to prevent blast cell implantation. In certain embodiments, And a compound and/or composition disclosed herein to degrade cells, inhibit cell growth, or kill cells. In certain embodiments, the cells are cancer cells. In certain embodiments, the cells are brain, breast, lung, Ovarian, pancreas, prostate, kidney or colorectal cancer cells. In certain embodiments, the compounds and/or compositions disclosed herein can be administered to inhibit the growth of a plurality of target cells. In certain embodiments, target cell growth can be inhibited by about 1%. In certain embodiments, target cell growth can be inhibited by about 2/〇. In certain embodiments, cell growth can be inhibited by about 3%. In certain embodiments, target cell growth can be inhibited by about 4%. In some embodiments, stem cell growth can be inhibited by about 5%. In certain embodiments, stem cell growth can be inhibited by about 10%. In certain embodiments, target cell growth can be inhibited by about 2%. In certain embodiments, target cell growth can be inhibited by about 25% by 138999.doc 200951107. In certain embodiments, target cell growth can be inhibited by about 3°. In certain embodiments, target cell growth can be inhibited by about 4%. In certain embodiments, target cell growth can be inhibited by about 5 〇%. In certain embodiments, stem cell growth can be inhibited by about 6%. In certain embodiments, cell growth can be inhibited by about 70%. In certain embodiments, stem cell growth "T is inhibited by about 75 percent. In certain embodiments, stem cell growth can be inhibited by about 80°/°. In certain embodiments, stem cell growth can be inhibited by about 90%. φ In certain embodiments, target cell growth can be inhibited by about 100%. In certain embodiments, the tray cells are cancer cells. In certain embodiments, the compounds and/or compositions disclosed herein can be administered to degrade a plurality of target cells. In certain embodiments, 1% of the target cells are degraded. In certain embodiments, 2% of the target cells are degraded. In some embodiments, < 3% of the cells were degraded. In certain embodiments, 4% of the cells are degraded. In certain embodiments, 5% of the stem cells are degraded. In certain embodiments, 10% of the target cells are degraded. In some implementations, φ of 20% of target cells were degraded. In certain embodiments, 25% of the target cells are degraded. In certain embodiments, 30% of the target cells are degraded. In certain embodiments, 40% of the target cells are degraded. In certain embodiments,: 50% of the target cells are degraded. In certain embodiments, 60% of the target cells are degraded. In certain embodiments, 70% of the target cells are degraded. In some embodiments, 75% of the target cells are degraded. In certain embodiments, 80% of the target cells are degraded. In certain embodiments, 90% of the target cells are degraded. In certain embodiments, 100% of the target cells are degraded. In certain embodiments, substantially all of the stem cells are degraded. In certain embodiments, the stem 138999.doc -77- 200951107 cells are cancer cells. In certain embodiments, the compounds and/or compositions disclosed herein can be administered to kill a plurality of light cells. In certain embodiments, 1% of the cells are killed. In certain embodiments, 2% of the target cells are killed. In some embodiments ' 3% of the cells were killed. In certain embodiments, 4 〇/〇 of target cells are killed. In certain embodiments, 5% of the target cells are killed. In certain embodiments, 10% of the target cells are killed. In certain embodiments, 20% of the target cells are killed. In certain embodiments, 25% of the target cells are killed. In certain embodiments, 30% of the cells are killed. In some embodiments, 40% of the target cells are killed. In certain embodiments, 50% of the target cells are killed. In certain embodiments, 60% of the target cells are killed. In certain embodiments, 70% of the stem cells are killed. In some embodiments, 75% of the target cells are killed. In certain embodiments, 80% of the target cells are killed. In certain embodiments, 90% of the cells are killed. In certain embodiments, 100% of the cells are killed. In certain embodiments, the cells are cancer cells. In certain embodiments, the compounds and/or compositions disclosed herein are administered to an individual in need thereof to reduce tumor size, inhibit tumor growth, reduce metastasis, or prevent metastasis. In certain embodiments, the tumor size is reduced. In certain embodiments, the tumor size is reduced by at least 1%. In certain embodiments, the tumor size is reduced by at least 2%. In certain embodiments, the tumor size is reduced by at least 3%. In certain embodiments, the tumor size is reduced by at least 4%. In certain embodiments, the tumor size is reduced by at least 5%. In certain embodiments, the tumor size is reduced to 138999.doc • 78· 200951107 less than 1%. In certain embodiments, the tumor size is reduced by at least 20°/(^ in certain embodiments, the tumor size is reduced by at least 25%. In certain embodiments, the tumor size is reduced by at least 30%. In certain embodiments, The tumor size is reduced by at least 40%. In certain embodiments, the tumor size is reduced by at least 5%. In certain embodiments, the tumor size is reduced by at least 60%. In certain embodiments, the tumor size is reduced by at least 70%. In certain embodiments, the tumor size is reduced by at least 75%. In certain embodiments, the tumor size is reduced by at least 8%. In certain embodiments, the tumor size is reduced by at least 85%. In some implementations In one embodiment, the tumor size is reduced by at least 90%. In certain embodiments, the tumor size is reduced by at least 95%. In certain embodiments, 'inhibiting tumor growth.' In certain embodiments, tumor growth can be relative to administration of the article. The growth rate prior to the disclosed compound and/or composition is inhibited by at least 1%. In certain embodiments, tumor growth can be inhibited by at least 2% relative to the growth rate prior to the compounds and/or compositions disclosed herein. Some implementations In one embodiment, tumor growth can inhibit at least 3% relative to the growth rate prior to administration of the compounds and/or compositions disclosed herein. In certain embodiments, tumor growth can be relative to administration of the compounds and/or combinations disclosed herein. The growth rate before the growth is inhibited by at least 4%. In some embodiments, the tumor growth can be inhibited by at least 5% relative to the growth rate prior to administration of the compounds and/or compositions disclosed herein. In certain embodiments The growth of the luminal tumor can be inhibited by at least 6% relative to the growth rate of the compounds and/or compositions disclosed herein. In certain embodiments, tumor growth can be relative to administration of the compounds and/or combinations disclosed herein. The growth rate before the growth is inhibited by at least 10%. In certain embodiments, the tumor growth phase 138999.doc-79-200951107 inhibits growth rate by at least 20% prior to administration of the compounds and/or compositions disclosed herein. In certain embodiments, 'tumor growth can be inhibited by at least 30% relative to the growth rate prior to administration of the compounds and/or compositions disclosed herein. ^ In certain embodiments, the growth of the tumor can be phased. The growth rate inhibition prior to administration of the compounds and/or compositions disclosed herein is at least 4%. In certain embodiments, 'tumor growth can be relative to growth rate inhibition prior to administration of the compounds and/or compositions disclosed herein. At least 50%. In certain embodiments, tumor growth can be inhibited by at least 60% relative to the growth rate prior to administration of the compounds and/or compositions disclosed herein. In certain embodiments, tumor growth can be relative to administration The growth rate prior to the compounds and/or compositions disclosed herein is inhibited by at least 70%. In certain embodiments, tumor growth can be inhibited by at least 75 relative to the growth rate prior to administration of the compounds and/or compositions disclosed herein. In certain embodiments, tumor growth can be inhibited by at least 80°/ relative to the growth rate prior to administration of the compounds and/or compositions disclosed herein. . In certain embodiments, tumor growth can be inhibited by at least 9% by weight relative to the growth rate prior to administration of the compounds and/or compositions disclosed herein. In certain embodiments, tumor growth can be inhibited by at least 95% relative to the growth rate prior to administration of the compounds and/or compositions disclosed herein. In certain embodiments, tumor growth can be relative to administration of a compound disclosed herein. And/or the growth rate prior to the composition is inhibited by at least 99 〇/〇. In some embodiments the transfer is inhibited. In certain embodiments, the transfer can inhibit at least one relative to the growth rate prior to administration of the compounds and/or compositions disclosed herein. In certain embodiments, the transfer can inhibit at least 138999.doc • 80 - 200951107 2% relative to the growth rate prior to administration of the compounds and/or compositions disclosed herein. In certain embodiments, the transfer can inhibit at least 3% relative to the growth rate prior to administration of the compounds and/or compositions disclosed herein. In certain embodiments, the transfer can inhibit at least 4% beta relative to the growth rate prior to administration of the compounds and/or compositions disclosed herein. In certain embodiments, the transfer can be relative to administering the compounds disclosed herein and/or Or the growth rate before the composition is inhibited by at least 5%. In certain embodiments, the transfer can be inhibited by at least 6% relative to the growth rate prior to administration of the compounds and/or compositions disclosed herein. In certain embodiments, the transfer can be inhibited by at least 1% relative to the growth rate prior to administration of the compounds and/or compositions disclosed herein. In certain embodiments, the transfer can be inhibited by at least 2% relative to the growth rate prior to administration of the compound and/or compound disclosed herein. In certain embodiments, the transfer can inhibit at least 鄕 relative to the growth rate prior to administration of the compounds and/or compositions disclosed herein. In certain embodiments, the transfer can be inhibited at least relative to the growth rate prior to administration of the compounds and/or compositions disclosed herein. In certain embodiments, the transfer can inhibit at least 50% relative to the growth rate prior to administration of the compounds and/or compositions disclosed herein. In certain embodiments, the transfer can inhibit at least 6% by weight relative to the growth rate prior to administration of the compounds and/or compositions disclosed herein. In some implementations, the transfer can be at least observed relative to the growth prior to administration of the compounds and/or compositions disclosed herein. In certain embodiments, the transfer can inhibit at least 75% relative to the growth rate prior to administration of the compounds and/or compositions disclosed herein. In certain embodiments, the transfer can inhibit at least 8% by weight relative to the growth rate prior to administration of the compounds and/or compositions disclosed herein. In certain embodiments, the transfer can inhibit at least 9% by weight relative to the growth rate prior to administration of the compounds and/or combinations disclosed herein 138999.doc -81 - 200951107. In certain embodiments, the transfer can inhibit at least 95% relative to the growth rate prior to administration of the compounds and/or compositions disclosed herein. In certain embodiments, the transfer can inhibit at least 99% relative to the growth rate prior to administration of the compounds and/or compositions disclosed herein. In certain embodiments, prevention of metastasis. In certain embodiments, the compounds or compositions disclosed herein are for diagnostic purposes and/or used as research reagents. In certain embodiments, the compounds and/or compositions disclosed herein are used in differential and/or combinatorial analysis to account for the pattern of expression of genes expressed in cells and tissues. V. Pharmaceutical Compositions A specific embodiment disclosed herein is a pharmaceutical composition comprising a compound hydrazine or a pharmaceutically acceptable salt, solvate, polymorph, ester, guanamine, tautomer, prodrug thereof , hydrate or derivative. In certain embodiments, the composition comprises Compound A:

The 2-OH carbon is in the R configuration and is substantially free of the S_isomer. In certain embodiments, the 2-OH carbon on the compound is in the R configuration. In certain embodiments, the composition is substantially free of the S-isomer of the compound. In certain embodiments, the compound contains less than 10% of the S-isomer of the compound. In certain embodiments, the compound contains less than 5% of the S-isomer of the compound. In one such embodiment the 'compound contains less than 1% of the s-isomer of the compound. In some embodiments, 138999.doc -82 * 200951107, the compound is in the R configuration. In certain embodiments the composition comprises Compound A:

The 2-OH carbon is in the S configuration and is substantially free of R-isomers. In certain embodiments, the 2-OH carbon on the compound is in the S configuration. In certain embodiments, the reference composition is substantially free of the R-isomer of the compound. In certain embodiments, the compound contains less than 10% of the R-isomer of the compound. In certain embodiments, the compound contains less than 5% of the R-isomer of the compound. In certain embodiments, the compound contains less than 1% of the R-isomer of the compound. In certain embodiments, the compound is in the S configuration. A specific embodiment disclosed herein is a pharmaceutical composition comprising Compound B or a pharmaceutically acceptable salt, solvate, polymorph, S-, guanamine, tautomer, prodrug, hydrate or derivative. ® In certain embodiments, the composition comprises Compound B:

The 2-OH carbon is in the R configuration and is substantially free of S-isomers. In certain embodiments, the 2-OH carbon on the compound is in the R configuration. In certain embodiments, the composition is substantially free of the S-isomer of the compound. In certain embodiments, the compound contains less than 10% of the S-isomer of the compound. In certain embodiments 138999.doc-83-200951107, the compound contains less than 5% of the S-isomer of the compound. In certain embodiments, the compound contains less than 1% of the S-isomer of the compound. In certain embodiments, the compound is in the R configuration. In certain embodiments, the composition comprises Compound B:

The 2-OH carbon is in the S configuration and is substantially free of R-isomers. In certain embodiments, the 2-OH carbon on the compound is in the S configuration. In certain embodiments, the composition is substantially free of the R. isomer of the compound. In certain embodiments, the compound contains less than 10% of the R-isomer of the compound. In certain embodiments, the compound contains less than 5% of the isomer of the compound. In certain embodiments the compound contains less than 1% of the R-isomer of the compound. In certain embodiments, the compound is in the S configuration. A particular embodiment disclosed herein is a pharmaceutical composition comprising a compound disclosed herein. In certain embodiments, the compound is present in an amount of about 50 mg. In certain embodiments, the compound is present in an amount of about 1 _ 1 〇 mg. In certain embodiments, the compound is present in an amount of about 丨〇 2 〇. In certain shell examples, the compound is present in an amount of from about 20 to about 40 mg. In certain embodiments, the compound is present in an amount from about 40 to 50 mg.

A particular embodiment disclosed herein is a pharmaceutical, medicinal comprising at least about 5% of a compound. The powder X-ray diffraction spectrum presented contains at least 50% of the display; the peaks identified by the powder diffraction diffraction pattern in the figure. In certain embodiments, the powder X-ray diffraction spectrum comprises at least 7% of the peaks identified by the powder diffraction pattern of powder X 138999.doc 200951107 shown in Figure 5. In some embodiments, the powder parent light diffraction spectrum comprises at least 90% of the peaks identified by the powder X-ray diffraction pattern shown in Figure 5. In some embodiments, the powder X-ray diffraction spectrum is substantially the same as the powder X-ray diffraction pattern shown in Figure 5. In certain embodiments, the composition comprises at least about 75% of the compound, which exhibits a powder X-ray diffraction spectrum comprising at least 50% of the peaks identified by the powder X-ray diffraction pattern shown in Figure 5. In some embodiments, the powder diffraction spectrum

The graph contains at least 7% of the peaks identified by the powder X-ray diffraction pattern shown in Figure 5. In some embodiments, the powder calender diffraction pattern comprises at least 9% of the powder X in Figure 5 The peak identified by the light diffraction spectrum. In some embodiments the &apos;powder X-ray diffraction spectrum is substantially the same as the powder X-ray diffraction spectrum shown in Figure 5. In certain embodiments, the composition comprises at least about 9% by weight of the compound exhibiting a powder calender diffraction pattern comprising at least 5% of the peaks identified by the powder X-ray diffraction pattern shown in Figure 5. In certain embodiments, the powder calender diffraction pattern comprises at least 7% of the peaks identified by the powder X-ray diffraction pattern shown in Figure 5. In certain embodiments, the powder X-ray diffraction spectrum comprises at least 90% of peaks that are not identified by the powder calender diffraction pattern of Figure 5. In some embodiments; the powder X-ray diffraction spectrum is the same as the powder parent diffraction spectrum shown in Figure 5. In some embodiments, substantially all of the compounds present in the composition exhibit a peak of the 1st light diffraction spectrum identified by the powder X-ray pattern shown at least in Figure 5. In some embodiments, the powder calender diffraction pattern package 3 v70% is shown in the peak identified by the powder X-ray diffraction pattern in Figure 5. In some embodiments, 138999.doc -85 - 200951107, the powder X-ray diffraction spectrum comprises at least 9 G% of the peaks identified by the powder X-ray diffraction pattern shown in Figure 5, in some embodiments, powder χ The light diffraction spectrum is substantially the same as the powder diffraction pattern shown in FIG. The crystalline polymorph present in some of the compositions has an initial melting point of about 143 &lt; t as measured by differential scanning calorimetry. In certain embodiments, the crystalline polymorph is substantially anhydrous. In certain embodiments, the crystalline polymorph is substantially solvent free. In certain embodiments, the composition contains at least about 5% by weight of the compound exhibiting a differential scanning calorimetry spectrum substantially identical to the differential scanning calorimetry spectrum® shown in Figure 6. In certain embodiments, the crystalline polymorph has an initial melting point of about 143 &lt; t as measured by differential scanning calorimetry. In certain embodiments, the crystalline polymorph is substantially anhydrous. In certain embodiments, the crystalline polymorph is substantially solvent free. In certain embodiments, the composition comprises at least about 75% of the compound exhibiting a differential scanning calorimetry spectrum substantially in contrast to the differential scanning calorimetry spectrum shown in FIG. The crystalline polymorph has an initial melting point of about 143 t &gt; c as measured by differential scanning calorimetry. In certain embodiments, the crystalline polymorph is substantially anhydrous. In certain embodiments, the crystalline polymorph is substantially solvent free. In certain embodiments, the composition contains at least about 90% of the compound exhibiting a differential scanning calorimetry spectrum substantially identical to the differential scanning calorimetry spectrum shown in Figure 6. In certain embodiments, the crystalline polymorph has an initial melting point of 138,999.doc •86·200951107 as measured by differential scanning calorimetry of about 143 t:. In some embodiments, the crystalline polymorphic sound rent is not dried over the next day. In certain embodiments, the crystalline polymorph is substantially solvent free. In certain embodiments, the differential scanning calorimetry pattern exhibited by all of the compounds in the composition of the composition is the same as the differential scanning calorimetry spectrum shown in Figure 6. In certain embodiments, the crystalline polymorph has about 4 as measured by differential scanning calorimetry. w < an initial value of the melting point of about 143c. In certain embodiments, the crystalline polymorph is in the form of &gt; In certain embodiments, the crystalline polymorph is substantially solvent free. In certain embodiments, the pharmaceutical composition comprises: a polymorphic type of (3,4-difluoro-2-(2-fluoro-4-yl-phenylamino)-6-methoxyphenyl) (5)- Dihydroxypropyl)cyclopropane·ι_sulfonamide, which is composed of a crystalline amorphous form of Ν((3,4-difluoro-2-(2 44·Mothylamino)-6-methoxybenzene) It is prepared by the method of the step of (2,3•dipropylpropyl)cyclopropane-1-sulfonamide. In certain embodiments, the crystallization step comprises crystallizing from a mixture of ethyl acetate and heptane, for example, a mixture of ethyl acetate and heptane is about 4 parts ethyl acetate to about 2 to 1 part.

The ratio of heptane, or more particularly from about 2 parts of ethyl acetate to about 5 parts of heptane. In certain embodiments, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition further comprises an adjuvant, an excipient and a preservative, an agent for delaying absorption, a filler, a binder, an adsorbent, a buffer, a disintegrant, a solubilizer, and the like. Agents, and other inert ingredients. In certain embodiments, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier. The combined pharmaceutical carrier includes an inert diluent or a 138999.doc-87-200951107 filler, water and various organic solvents. In certain embodiments, the composition comprises a filling solution or a diluent. In various embodiments, the 'filler or diluent is selected from the group consisting of micro a &amp; 儆 day cellulose, bismuth microcrystalline cellulose, lactose, mannitol, compressible rotator, calcium phosphate, calcium sulfate, carbonic acid Calcium, calcium citrate and starch. In other solid N T 'fillers or diluents are microcrystalline cellulose. In certain embodiments, in the composition, the disintegrant is selected from the group consisting of cross-linked carboxymethyl povidone, sulfhydryl cellulose, seaweed white stone, and vee gum croscarmellose sodium. Includes disintegrants. In various embodiments, sodium sulphate, sodium sulphate, cross-linking &amp; sodium alginate, starch derivatives, . In certain embodiments, the disintegrant is in various embodiments, the talc, stearin&apos; lubricant is a hard fat. In certain embodiments, the composition includes a lubricant. The medium lubricant is selected from the group consisting of magnesium stearate, metal stearate, sodium fumarate, and stearic acid. In certain embodiments magnesium magnesium. In certain embodiments the composition comprises a humectant or a surfactant. In various embodiments, the humectant or surfactant is selected from the group consisting of sodium lauryl sulfate, glycerin, sorbitan acid vinegar, sorbitan stearate, and polyoxyethylated sorbitan laurate. , palmitate, stearate, oleate or caproate (heXa〇late), polyoxyethylene stearyl alcohol and sorbitan monolaurate. In certain embodiments, the humectant or surfactant is sodium lauryl sulfate. Other excipients such as slip agents, perfumes, and color formers may also be added. Other excipients can be found at The Handbook 〇f Pharmaceutical 138999.doc -88- 200951107

Excipients ^ 5th Edition &gt; 2005 and the FDA Inactive Ingedient Database ° In certain embodiments, the composition comprises microcrystalline cellulose. In certain embodiments, the composition comprises croscarmellose sodium. In certain embodiments, the composition comprises sodium lauryl sulfate. In certain embodiments, the composition comprises magnesium stearate.

某些 In certain embodiments, the composition further comprises at least one member selected from the group consisting of microcrystalline cellulose, shihua microcrystalline cellulose, lactose, compressible sugar, xylitol, sorbitol, mannitol, pregelatinization A filler of starch, maltodextrin, phosphoric acid, calcium carbonate, starch and calcium citrate. In certain embodiments, the composition further comprises at least one member selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, methylcellulose, alginic acid, sodium alginate, starch derivatives, a disintegrating agent of sapphire and magnesium aluminum silicate. In certain embodiments, the composition further comprises at least one lubricant selected from the group consisting of magnesium stearate, stearic acid metal salts, talc, hard fat, sodium butyrate, and stearic acid. In certain embodiments, the composition further comprises at least one selected from the group consisting of sodium lauryl sulfate, glycerin, sorbitan oleate, sorbitan stearate, polyoxyethylated sorbitan lauric acid A humectant or surfactant for the ester 'palmitate, stearate, oleate or hexanoate, polyoxyethylene stearyl alcohol and sorbitan monolaurate. In certain embodiments the 'pharmaceutical composition comprises:

About 1 mg of the following compound: 138999.doc -89- 200951107 about 222.2 mg of microcrystalline cellulose; about 12.0 mg of croscarmellose sodium; about 2.4 mg of sodium lauryl sulfate; and about 2.4 mg Magnesium stearate. In certain embodiments, the pharmaceutical composition comprises:

About 10 mg of the following compound: f about 213.2 mg of microcrystalline cellulose; about 12.0 mg of croscarmellose sodium; about 2.4 mg of sodium lauryl sulfate; and about 2.4 mg of stearic acid. In certain embodiments, the pharmaceutical composition comprises:

About 203.2 mg of microcrystalline cellulose; about 12.0 mg of croscarmellose sodium; about 2.4 mg of sodium lauryl sulfate; and about 2.4 mg of stearic acid. In certain embodiments, the pharmaceutical composition comprises:

138999.doc • 90· 200951107 About 18 3.2 m g of microcrystalline cellulose; about 12.0 mg of croscarmellose sodium; about 2.4 mg of sodium lauryl sulfate; and about 2.4 mg of magnesium stearate. In certain embodiments, a pharmaceutical composition comprises: a compound of:

About 0.4 wt% of the following knots and about 99.6 wt% of pharmaceutically acceptable

Containing: about 5 wt 〇 / 〇 croscarmellose sodium; about i wt 〇 / 〇 lauryl sodium sulphate; and about 1 wt 〇 / 〇 magnesium stearate.

In certain embodiments, the pharmaceutical compositions comprise: about 42% by weight of a compound of the formula: F 1 ; and about 95.8 wt% of a pharmaceutically acceptable carrier or vehicle. In certain embodiments, the pharmaceutically acceptable carrier or vehicle comprises microcrystalline cellulose. In certain embodiments, the microcrystalline cellulose is about 88.8 wt% of the composition. In certain embodiments, the composition further comprises: about 5 wt% croscarmellose sodium; about 1 wt% sodium lauryl sulfate; and about 1 wt% magnesium stearate. In certain embodiments, the pharmaceutical composition comprises: from about 2 wt% to about J 〇 138999.doc -91 - 200951107

A compound of the following structure: wt%; and from about 98% to about 90% by weight of a pharmaceutically acceptable carrier or vehicle. In certain embodiments, a pharmaceutically acceptable carrier or vehicle comprises microcrystalline vitamins. In certain embodiments, the microcrystalline cellulose is from about 85 wt% to about 95 wt/min of the composition. In certain embodiments, the composition further comprises: from about 1% to about 6 wt% per gram of croscarmellose sodium; from about 0.1% to about 2% by weight of sodium lauryl sulfate; and about 0.25 wt% Up to about 1.5% by weight of magnesium stearate. In certain embodiments, a pharmaceutically acceptable carrier or vehicle comprises microcrystalline cellulose. In certain embodiments, the microcrystalline cellulose is from about 85 wt% to about 95 wt% of the composition. In certain embodiments, the composition further comprises: about 1 wt. Up to about 6 wt% of croscarmellose sodium; and about 0.25 wt% to about 1.5 wt% of magnesium stearate. In certain embodiments, the pharmaceutical composition comprises:

About 222.2 mg of microcrystalline cellulose; about 12.0 mg of cross-linked stearyl cellulose; about 2.4 mg of sodium lauryl sulfate; and about 2.4 mg of magnesium stearate. In certain embodiments, the pharmaceutical composition comprises: 138999.doc -92- 200951107 about 10 mg of a compound of the structure

HO OH

NH

Η ί about 213.2 mg of microcrystalline cellulose; about 12.0 mg of cross-linked stearyl cellulose; about 2.4 mg of sodium lauryl sulfate; and about 2.4 mg of magnesium stearate. In certain embodiments, the pharmaceutical composition comprises:

HO 0H

About 20 mg of the following compound: about 203.2 mg of microcrystalline cellulose; about 12.0 mg of croscarmellose sodium; about 2.4 mg of sodium lauryl sulfate; and about 2.4 mg of stearic acid. In certain embodiments, the pharmaceutical composition comprises:

HO OH

About 40 mg of the following compound: about 183.2 mg of microcrystalline cellulose; about 12.0 mg of croscarmellose sodium; about 2.4 mg of sodium lauryl sulfate; and about 2.4 mg of magnesium stearate. In certain embodiments, the pharmaceutical composition comprises: about 0.4 wt% of the following 138999.doc -93- 200951107

HO OH

KIH MeO

:ΛΙ;

Structure of the compound: ; and 99.6 wt% of a pharmaceutically acceptable carrier or vehicle. In certain embodiments, the pharmaceutically acceptable carrier or vehicle comprises microcrystalline cellulose. In certain embodiments, the microcrystalline cellulose is about 92-6 wt% of the composition. In certain embodiments, the composition further comprises: about 5% by weight of croscarmellose sodium; about 1% by weight of sodium lauryl sulfate; and about 1% by weight of stearic acid. In certain embodiments, the 'pharmaceutical composition comprises: about 4.2 wt% of the following Η Ω Ω Η ~ I 7 J 0 々

A compound of the structure I:; and about 95% by weight of a pharmaceutically acceptable carrier or vehicle. In certain embodiments, the pharmaceutically acceptable carrier or vehicle comprises microcrystalline cellulose. In certain embodiments, the microcrystalline cellulose is about 88.8 wt% of the composition. In certain embodiments, the composition further comprises: about 5% by weight of croscarmellose sodium; about 1% by weight of sodium lauryl sulfate; and about 1% by weight of magnesium stearate. In certain embodiments, the medical composition comprises: from about 2% to about 10% by weight of a compound of the structure: and from about 98 Wt% to about 9. Γ1 A pharmaceutically acceptable carrier or vehicle. In certain embodiments, in the embodiment, the microcrystalline cellulose is a composition - to about - 138999.doc -94 - 200951107. In a second embodiment, the composition further comprises: about i wt% to about 6 Wt% carboxymethyl cellulose sodium, about Ga wt% to about 2 « of sodium lauryl sulfate; , · ', 5 wt / 〇 to about 1.5 wt% of stearic acid. In certain embodiments, w a pharmaceutically acceptable carrier or vehicle comprises microcrystalline cellulose. In certain embodiments, the microcrystalline cellulose is from about 85 wt% to about 95 wt% of the composition. In a second embodiment, the composition further comprises: from about 1 to about 6 croscarmellose sodium; and from about 25 wt% to about i 5 stearic acid

town. In certain embodiments, the pharmaceutical composition package comprises:

About 1 mg of the compound of the following structure: about 222.2 mg of microcrystalline cellulose; about 12.0 mg of croscarmellose sodium; about 2.4 mg of sodium lauryl sulfate; and about 2.4 mg of magnesium stearate. The invention also relates to compositions comprising the following:

About 10 mg of the compound of the following structure: about 213.2 mg of microcrystalline cellulose; about 12.0 mg of croscarmellose sodium; about 2.4 mg of sodium lauryl sulfate; and about 2.4 mg of magnesium stearate. 138999.doc • 95· 200951107 In certain embodiments, the pharmaceutical composition comprises:

About 20 mg of a compound of the following structure: about 203.2 mg of microcrystalline cellulose; about 12.0 mg of croscarmellose sodium; about 2.4 mg of sodium lauryl sulfate; and about 2.4 mg of stearic acid. In certain embodiments, the pharmaceutical composition comprises:

About 40 mg of a compound of the following structure: about 1 8 3 · 2 mg of microcrystalline cellulose; about 12.0 mg of croscarmellose sodium; about 2.4 mg of sodium lauryl sulfate; and about 2.4 mg of stearic acid magnesium. Certain embodiments =; the pharmaceutical composition comprises: about 0.4% by weight of a compound of the following structure:

〇^Η u F

Λ; and approximately 99.6 wt% of a pharmaceutically acceptable carrier or vehicle. In certain embodiments, a pharmaceutically acceptable carrier or vehicle comprises microcrystalline cellulose. In certain embodiments, the microcrystalline cellulose is about 92.6 wt% of the composition. In certain embodiments, the composition further comprises: about 5% by weight of croscarmellose sodium; about 1 wt%/0 of lauryl sulfur 138999.doc-96·200951107 sodium; and about 1 wt% Magnesium stearate. In certain embodiments, the pharmaceutical composition comprises: about 4.2% by weight of a compound of the following structure

And approximately 95.8 wt% of pharmaceutically acceptable

Accepted carrier or vehicle. In certain embodiments, the pharmaceutically acceptable carrier or vehicle comprises microcrystalline cellulose. In certain embodiments, the microcrystalline cellulose is about 8 8.8 wt ° / Torr of the composition. In certain embodiments, the composition further comprises: about 5% by weight of croscarmellose sodium; about 1 wt/z of sodium lauryl sulfate; and about 1% by weight of magnesium stearate. In certain embodiments, the pharmaceutical composition comprises from about 2 wt% to about 10

And a compound of the following structure of from about 98% by weight to about wt% per ton of 90% by weight of a pharmaceutically acceptable carrier or vehicle. In certain embodiments, a pharmaceutically acceptable carrier or vehicle comprises microcrystalline cellulose. In certain embodiments, the microcrystalline cellulose is from about 85 wt% to about 95 wt% of the composition. In certain embodiments, the composition further comprises: from about 1 wt% to about 6 wt% of croscarmellose sodium; from about 0.1 wt/〇 to about 2 wt% of sodium lauryl sulfate; and about 0.25 Wt% about 1.5 wt% magnesium stearate. In certain embodiments, a pharmaceutically acceptable carrier or vehicle comprises microcrystalline cellulose. In certain embodiments, the microcrystalline cellulose is from about 85 wt% to about 95 wt% of the composition. In certain embodiments, the composition further comprises: from about 1 wt% to about 6 wt% of croscarmellose sodium; and about 0.25 wt% about 1.5 138999.doc -97 to 200951107 wt% stearic acid magnesium. In certain embodiments, the pharmaceutical composition comprises: N-(S)-(3,4-difluoro-2_(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)di Crystalline polymorph A of hydroxypropyl)cyclopropane-1 -sulfonamide. In certain embodiments, the pharmaceutical composition comprises: N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl) 1-(2,3-dipropylpropyl)cyclopropanone_crystalline crystalline polymorph A' and at least one pharmaceutically acceptable carrier. Dosage Forms In certain embodiments, the compositions disclosed herein are formulated for oral administration. In certain embodiments, the compositions disclosed herein are administered in the form of troches, capsules, pills, powders, solutions, suspensions, caps, troches, pellets or beads. In certain embodiments, the compositions disclosed herein are administered via a lozenge. In certain embodiments, the tablet comprises an inert diluent (eg, calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate); granulation and disintegrant (eg, croscarmellose sodium, cross-linked poly-dimensional) Ketone or sodium starch glycolate); fillers (eg microcrystalline cellulose, deuterated microcrystalline cellulose, pregelatinized starch, lactose, diacid or compressible sugar); binders (eg hypromellose) , povidone, starch, gelatin, polyvinylpyrrolidone or acacia); surfactants (such as sodium lauryl sulfate) and / or lubricants and processing aids (for example, talc, croscarmellose sodium, Corn starch or alginic acid, magnesium stearate, stearic acid, colloidal cerium oxide and sodium lauryl sulfate). In certain embodiments, the lozenge further comprises a sweetener, a flavoring agent, a coloring agent, and a preservative. 138999.d〇c 98· 200951107 In certain embodiments, the tablet comprises citric acid, disintegrant powder, alginic acid, and a specific complex strontium sulphate) and a binder (eg, _, such as starch and gum arabic) . In the case of certain embodiments, the lozenge is uncoated or coated. In this case, the coating will mask the taste of the composition. In certain cases, the disintegration and absorption in the gastrointestinal tract can be improved. Coating ❹ In certain embodiments, the lozenges disclosed herein are prepared in any suitable manner. In certain embodiments, the lozenges disclosed herein are prepared by dry blending::. In certain embodiments, the compounds disclosed herein are prepared in a dosage form by dry blending with an excipient followed by I in a tablet form. In some such "pressed tablets" are prepared by compressing the active ingredient in a free-flowing form such as a powder in any suitable machine, optionally with a viscous agent, inert diluent or lubricant, interfacial activity or dispersion. Mix the agents. 2 In certain embodiments, the tablet disclosed herein is grown in any convenient manner. In certain embodiments, the lozenges disclosed herein are prepared by wet granulation. In certain embodiments, the compounds disclosed herein are added to a dry dose and mixed with a human binder solution, or the drug is dissolved and added as a solution to the granulation. In wet granulation techniques - moxibustion surfactants - the surfactant is added to the dry excipient or to the binder solution and incorporated into the solution. In certain embodiments, the compositions disclosed herein are administered via a capsule. - In the examples, the capsule is a hard capsule. In certain embodiments, the active ingredient is mixed with an inert solid diluent, such as a fatty acid, a dish of acid or kaolin. In certain embodiments, the capsule is a soft capsule. In certain embodiments, 138999.doc -99- 200951107 the active ingredient is mixed with a cut-off money such as polyethylene glycol or oleiferous paraffin or eucalyptus oil. A quality such as a bio-oil, liquid in certain embodiments 'present invention The preparation of the disclosure. The force must be in any suitable method. In a second embodiment, the compound disclosed in the present invention (for example, high molecular weight poly-B-M 糸 cold solution in a material form), filled it Into the hard sac, followed by bonding and sealing. In some: the compound is dissolved in high molecular weight polyethylene glycol. In some embodiments, the mixture is cooled and then filled into gelatin capsules. In some embodiments, the composition is in the form of a sac or lozenge and has a total weight of from about 50 mg to about 1 (). In certain embodiments, the composition is in the form of a capsule or lozenge and has a 5〇mg, 75mg, (10)mg, 15〇mg^ 200mg, 25 The total weight of the group consisting of 3 mg, 350 mg ^ 400 mg . 450 mg and 500 mg. In certain embodiments the composition is in the form of a capsule or lozenge and has a total weight of about 24 mg. In certain embodiments, the composition is in the form of a capsule or lozenge and the dosage form comprises from about 1 to about 50 mg of a compound disclosed herein having a USP acceptable value for content homogeneity of less than about 15. In certain embodiments The compound disclosed herein is administered as an aqueous suspension. In certain embodiments, the aqueous suspension comprises a sweetener or flavoring, coloring matter or dye and, if desired, an emulsifier or suspending agent' with a diluent Such as water, ethanol, propylene glycol, glycerol or a combination thereof. In certain embodiments, the aqueous suspension comprises a suspending agent. In certain embodiments, the 'aqueous suspension comprises sodium carboxymethyl cellulose, thioglycol, Hydroxypropyl methylcellulose, sodium alginate, polyvinyl to ketone, yellow gum and arabic 138999.doc 200951107 Gum In certain embodiments, the aqueous suspension comprises a dispersing or wetting agent. In the embodiment, water The suspension comprises a naturally occurring phospholipid, such as a glycoside or a condensation product of an epoxy burn with a fatty acid, such as polyoxyethylene stearate, or a condensation product of ethylene oxide with a long chain aliphatic alcohol, such as ten七伸. Ethyloxycetyl alcohol, or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and hexitol, such as polyoxyethylene sorbitan monooleate, or ethylene oxide A condensation product of a partial ester derived from a fatty acid and a hexitol anhydride, such as a polyethylene sorbitan monooleate. In certain embodiments, the aqueous suspension comprises a preservative. In certain embodiments, The aqueous suspension comprises ethyl p-hydroxybenzoate or n-propyl p-hydroxybenzoate. In certain embodiments the 'aqueous suspension comprises a sweetener. In certain embodiments, the aqueous suspension comprises sucrose, saccharin or aspartame. In certain embodiments, the compounds disclosed herein are administered in the form of an oily suspension. In certain embodiments, an oily suspension is formulated by suspending the active ingredient in a vegetable oil (e.g., peanut oil, olive oil, sesame oil or coconut oil) or in a mineral φ oil (e.g., liquid paraffin). In certain embodiments, the oily suspension comprises a thickening agent (e.g., beeswax, hard paraffin or hexadecanol). In certain embodiments the 'oily suspension' comprises a sweet: flavoring agent as previously described. In certain embodiments, the oily suspension comprises an antioxidant (e.g., butylated hydroxyanisole or alpha-tocopherol). In certain embodiments, the compositions disclosed herein are formulated for parenteral injection (eg, via injection or perfusion, including intra-arterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, Intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural, and subcutaneous). In certain embodiments 138999.doc - 101 - 200951107, the compositions disclosed herein are administered in the form of a sterile solution, suspension or emulsion. In certain embodiments, the formulation for parenteral administration comprises an aqueous and non-aqueous (oily) sterile injectable solution of the active compound, which may comprise an antioxidant, a buffer, a bacteriostatic agent, and a formulation An isotonic solute of the recipient's blood; and an aqueous and non-aqueous sterile suspension which may include a suspending agent and a thickening agent. In certain embodiments, formulations for parenteral administration include a suitable stabilizer or an agent that increases the solubility of the compound such that a highly concentrated solution can be made. In certain embodiments, the compounds disclosed herein are administered in the form of an aqueous suspension. In certain embodiments, the aqueous suspension comprises water, Ringer's solution or isotonic sodium solution. In certain embodiments, the compounds disclosed herein are administered in the form of an oil-in-water microemulsion wherein the active ingredient is dissolved in the oil phase. In certain embodiments, the compounds disclosed herein are dissolved in a fatty oil such as sesame oil, or a synthetic fatty acid ester such as ethyl oleate or triglyceride, or a liposome. In certain embodiments, the compounds disclosed herein are dissolved in a mixture of soybean oil and lecithin. In certain embodiments, the oil solution is introduced into a mixture of water and glycerin and processed to form a microemulsion. In certain embodiments, the composition formulated for parenteral administration is administered as a single bolus injection. In certain embodiments, the composition formulated for parenteral administration is administered as a continuous intravenous delivery device (e.g., Deltec® 80-卩1^1; 81^5400 intravenous pump). In certain embodiments, the formulation for injection is presented, for example, in an ampule or multi-dose container in unit dosage form with a preservative that is added 138999.doc-102-200951107. In certain embodiments, the formulation for injection is stored in powder form or in a lyophilized (freeze-dried) state which requires only immediate addition of a sterile liquid carrier such as saline or sterile pyrogen-free water prior to use. In certain embodiments, the formulations disclosed herein are administered as a reservoir formulation. In certain embodiments, the reservoir formulation is administered via implantation (eg, subcutaneous or intramuscular) or by intramuscular injection.

In certain *embodiments, the compositions disclosed herein are formulated for topical administration. The administration of the &apos;topical administration&quot; composition described herein allows the compound to not significantly enter the bloodstream. In certain embodiments, the compositions disclosed herein can be applied to the epidermis, buccal cavity, ear, eye, and/or nose. In certain embodiments, the compositions formulated for topical administration are formulated in the form of a gel, lotion, cream, ointment or paste, solution, suspension, emulsion or powder. In certain embodiments, the compositions disclosed herein are administered as a personal cream or a cream. In some embodiments, the group forms disclosed herein are administered. In certain embodiments, the group σ disclosed herein is administered via inhalation. In the case of blowing, some of the ingredients are formulated for delivery via inhalation. Add pressurized packaging or other means suitable for aerosol spray. Burn, three = contain suitable propellant, such as dichloroethylene gas. In the case of Liguang-chlorotetrafluoroethane, carbon dioxide or other suitable to deliver the metered amount: the unit of ΠΠ1 can be taken as a dry powder composition or by a blow-in type by providing a valve-medicine sword. For example, a powder mixture of a compound and a final matrix such as lactose or house powder of 138999.doc 200951107. The powder composition is presented in unit dosage form, e.g., in a capsule, filter cartridge, gelatin or blister pack, for administration of the powder therefrom by means of an inhaler or insufflator. For buccal or sublingual administration, the composition may take the form of a lozenge, buccal, tablet or gel formulated in a conventional manner. The compositions may comprise active ingredients in a flavoring base such as sucrose with gum arabic or tragacanth. In certain embodiments, the compositions disclosed herein are formulated for rectal administration. In certain embodiments, the compositions disclosed herein are administered as a suppository. In certain embodiments, a composition suitable for rectal administration is prepared by mixing a compound disclosed herein with a suitable non-irritating excipient which is solid at ambient temperature but at rectal temperature The lower is a liquid and thus can be dissolved in the rectum to release the drug. In certain embodiments, compositions suitable for rectal administration are prepared by combining the compounds disclosed herein with cocoa butter, glycerinated gelatin, hydrogenated vegetable oil, polyethylene glycol mixtures of different molecular weights or polyethylene glycols. The acid ester is prepared by mixing. For a method of preparing a medical therapeutic composition, see Remingt〇n, s

Pharmaceutical Sciences, Mack Publishing Company,

Ester, Pa., 18th Edition (199〇) e In certain embodiments, 'Using US Pharmacopeia (USP) Apparatus II at 50 rpm, using i〇/〇sodium lauryl sulfate as a dissolution medium' in water Release at least 6% of the drug within 30 minutes. In a second shell application, 'Using US·Pharmacopeia (USP) Apparatus II at 50 rpm' with 1% sodium lauryl sulfate in water as the dissolution medium, the dosage form releases at least 60-100% of the drug in 3 minutes. . In certain embodiments, 138999.doc 200951107 uses US Pharmacopeia (USP) Apparatus II at 50 rpm with 1% sodium lauryl sulfate in water as the dissolution medium, and the dosage form releases at least 60-90% in 3 minutes. Medicine. In certain embodiments, the formulation is at least 6 〇 _ 80 percent in 30 minutes using § § Pharmacopeia (USP) Apparatus II at 50 rpm, 1% in water, sodium lauryl sulfate as the dissolution medium. medicine. Dosage φ The amount of pharmaceutical composition administered will depend first on the mammal being treated. In the case where the pharmaceutical composition is administered to a human individual, the daily dose is usually determined by the prescribing physician, wherein the dosage generally depends on the age, sex, diet, weight, general health and reaction of the individual, the severity of the individual's symptoms, and the clear adaptation of the treatment. The severity of the condition or condition, the indication for treatment or the severity of the condition, the time of administration, the route of administration, the predisposition of the composition, the rate of excretion, the combination of the drug, and the judgment of the prescribing physician. In certain embodiments, the dosage is between about 0.001 and about 丨〇〇〇mg/kg® body weight/day. In certain embodiments, the amount of the compound disclosed herein is in the range of from about 0.5 to about 50 mg/kg/day. In certain embodiments, the amount of the compound disclosed herein is from about 0.001 to about 7 g/day. In certain embodiments, the amount of the compound disclosed herein is from about 0.01 to about 7 g/day. In certain embodiments, the amount of the compound disclosed herein is from about 〇.02 to about 5 g/day. In certain embodiments, the amount of the compound disclosed herein is from about 5 to about 25 g per day. In certain embodiments, the amount of the compound disclosed herein is from about 1 to about 1 g per day. 138999.doc 105· 200951107 In certain embodiments, the amount of the compound disclosed herein is in a single dose per unit. In certain embodiments, the amount of the compound disclosed herein is administered in multiple doses per day or more. In certain embodiments, the amount of the compound disclosed herein is administered twice daily. In certain embodiments, the amount of the compound disclosed herein is administered three times a day. In certain embodiments, the compounds disclosed herein The amount is in the form of a volume; , ^ mother's day, 42. In some embodiments, the amount of the compound disclosed herein is administered more than four times per day. Although in other cases a larger dose is still used without causing Any harmful side effects 'but in some cases doses below the lower limit of the range stated above are more appropriate' by dividing the larger dose into several small doses to make a staple in a day. It may vary depending on the particular heart value of the compound used. In combination applications where the compound is not mono-therapeutic, a lower amount of the compound may be administered while still having a therapeutic or prophylactic effect. IX. Combination Therapy In certain embodiments, 'this article The dew compound is administered in combination with a second therapeutic agent. In certain embodiments, the compounds disclosed herein are administered in combination with surgery and/or radiation therapy. In certain embodiments, the second therapeutic agent is selected from the group consisting of a cytostatic agent. Inhibitors, anti-angiogenic agents, and anti-tumor agents. In certain embodiments, the second therapeutic agent is a white burning agent, an antimetabolite, an epipodoxin 7 (ePid〇Phyll〇toxins); an anti-tumor enzyme, Topoisomerase inhibitor, pr〇carbazines, mit〇xantrones, initial coordination complex, biological response modifier and growth inhibitor, hormone/hormone Therapeutic agent, #士斗 and m xe dish growth factor, 138999.doc • 106· 200951107 Aromatase inhibitor, anti-estrogen, antiandrogen, corticosteroid, gonadotropin agonist, microtubule activator, nitrosamine Base urea, lipid or protein kinase target, IMiDs, protein or lipid phosphatase target, anti-angiogenesis agent, Akt inhibitor, IGF-I inhibitor, FGF3 regulator, mTOR inhibitor, Smac mimetic peptide (Smac Mimetics , HDAC inhibitors, agents that induce cell differentiation, bradykinin 1 receptor antagonists, angiotensin II antagonists, cyclooxygenase inhibitors, heparanase inhibitors, Lymphatic mediators, cytokine inhibitors, IKK inhibitors, P38MAPK inhibitors, HSP90 inhibitors, multi-kinase inhibitors, bisphosphonates, rapamycin derivatives, anti-apoptotic pathway inhibitors, withering Death pathway agonist, PPAR agonist, RAR agonist, Ras isomeric guanidine inhibitor, telomere inhibitor, protease inhibitor, metalloproteinase inhibitor, aminopeptidase inhibitor, SHIP activation Sub-AQX-MN100, Humax-CD20 (ofatumumab), CD20 antagonist, IL2-diphtheria toxin fusion or a combination thereof. In certain embodiments, the second therapeutic agent is selected from the group consisting of ARRY-797, dacarbazine (DTIC), actinomycin, C3, D, guanamine, melphalan, female Estaustine, maytansinol, rifamycin, streptovaricin, doxorubicin, daunorubicin, soft Epirubicin, idarubicin, detorubicin, carminomycin, idarubicin, epirubicin, esorubicin , Mito brewing 138999.doc -107- 200951107 (mitoxantrone), bleomycins A, A2, and B, hi-tree test, Irinotecan, Topotecan, 9 -Amino camptothecin, 10,11-fluorenylene dioxycamptothecin, 9-nitrocamptothecin, bortezomib, temozolomide, TAS103, NPI0052, Kang Combretastatin, Combyl Standin A-2, Combyl Standin A-4, calicheamicins, new Neocarcinostatins, epothilone A, B, C (epothilones A, B, C) and semisynthetic variants, Herceptin, Rituxan, CD40 antibody, aspartate (asparaginase), interleukins, interferon, leuprolide, and pegaspargase, 5-fluorouracil, fluorodeoxyuridine, ptorafur, 5 ·-Deoxy fluorouridine, UFT, MITC, S-1 capecitabine, diethyl hexaploster age, Tamoxifen, toremefine, Domo Tolmudex, thymitaq, flutamide, fluoromethyl hydrazine, bicalutamide, finasteride, estradiol, trovo Trioxifene, dexamethasone, leuproelin acetate, espresso, estramustine, droloxifene, medroxyprogesterone, medigestive Megesterol acetate, aminoglutethimide, testicular S (testo) Lactone), testosterone, diethylstilbestrol, progesterone, mitomycins A, B and C, porfiromycin, cisplatin, Carboplatin, oxaliplatin, 138999.doc -108- 200951107 tetraplatin, start-DACH, ormaplatin, thalidomide, come Lenalidomide, CI-973, telomestatin, CHIR258, RadOOl, SAHA, Tubacin, 17-AAG, sorafenib, JM-216, sneaky Toxin (podophyllotoxin) 'epipodophyllotoxin, etoposide, teniposide, Tarceva, Iressa, Imatinib, rice Miltefosine, Perifosine, aminopterin, methotrexate, methopterin, methotrexate, methotrexate, 6-Wei Wei, thioguanine, azatuoprine, zhetuoprine Alcohol, cladribine, fludarabine, pentostatin, 2-chloroguanamine, deoxycytidine, cytosine arabinoside, arabic cell Cytarabine, azacitidine, 5-aza, azacytosine, gencitabine, 5-gas, azacytosine-arabinoside ), Changchun new test (vincristine), vincentin (vinblastine), vinorelbine, leurosine, leurosidine and vindesine, paclitaxel , taxotere and docetaxel. In certain embodiments, the second therapeutic agent is selected from the group consisting of corticosteroids, non-steroidal anti-inflammatory agents, muscle relaxants, and combinations thereof with other agents, anesthesia 138999.doc 109-200951107 drugs and other agents thereof Combination, expectorant and its combination with other agents, antidepressants, anticonvulsants and combinations thereof; antihypertensive drugs, opioids, topical cannabis, capsaicin, betamethasone dipropionate Betamethasone dipropionate), betamethasone valerate, clobetasol propionate, prednisone, prednisolone, difluoroacetic acid difluoride Diflorasone diacetate, halobetasol propionate, amcinonide, dexamethasone, dexosimethasone, fluocinolone acetononide ), fluocinonide, halocinonide, clocortalone pivalate, dexosimetasone, fluoride Flurandrenalide, salicylic acid, ibuprofen, ketoprofen, etodolac, diclofenac, meclofenamate sodium , naproxen, piroxicam, ceiecoxib, cyclobenzaprine, baclofen, cyclosporine/lidocaine Lidocaine), chloranilide/cyclobenzapine, benzopyrimidine/lidocaine/_giprofen, lidocaine, lidocaine/deoxyglucose, prilocaine, EMLA cream (Local anaesthetic (co-melted mixture of lidocaine 2.5% and prilocaine 2.5%), 0 guafennesin, maifenacin / ketoprofen / benzozapine, Ami Amitryptiline, doxepin, desipramine 138999.doc -110· 200951107 (desipramine), imipramine, amoxapine, clomipraminey , to nortriptyline, protriptyline, duloxetine, mitax Mirtazepine, nisoxetine, maprotiline, reboxetine, reboxetine, fluoxetine, fluvoxamine, carbamazepine , felbamate, lamotrigine, topiramate, tiagabine, oxcarbazepine, carbamezipine, sputum Zonisamide, mexiletine, gabapentin/clonidine, gabapentin/carbamazepine, carbazapine/cyclobenzalpine, antihypertensives including clonidine, Codeine, loperamide, tramadol, phenazine, fentanyl, oxycodone, hydrocodone, left sputum Levophanol, butorphanol, menthol, wintergreen oil, camphor, eucalyptus oil, turpentine; CB1/CB2 ligand, acetaminophen, infliximab, nitric oxide Synthetic enzyme inhibitors, especially one that induces oxygen Inhibitor of nitrogen synthase, PDE4 inhibitor - similar to the mechanism of Ibudilast (AV-411), CDC-801, JNK inhibitor-CC-401, combined TNF/PDE4 inhibitor-CDC-998 , IL1 antagonists, such as Anakinra - Kineret, AMG108, target IL-1 (mAb), SHIP activator-AQX-MN100, C5 antagonist, C5a 138999.doc • 111 - 200951107 Formulation, Pexelizumab, D-Bite Synthetic Inhibitor, Lymph Media Inhibitor, Cytokine Inhibitor, IKK Inhibitor, Ρ38ΜΑΡΚ Inhibitor, ARRY-797, HSP90 Inhibitor, Multi-Kinase Inhibitor, Bisphosphonates, PPAR agonists, Coxl and cox2 inhibitors, anti-CD4 therapy, B-cell inhibitors, COX/LOX dual inhibitors, immunosuppressive agents, iNOS inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), SPLA2 inhibitor, colchicine, allopurinol, oxypurinol, gold, Ridaura-Auranofin, febuxostat, prince Puricase, PEG-uricase formulation, Benzbromarone ), long-acting beta-2 agonists (LABAs), salmeterol (Serevent Diskus) and formoterol (Foradil), white tri-sparing modifiers including montelukast (Singulair) and zafirlukast (Accolate). Inhalation of cromolyn (Intal) or nedocromil (Tilade), tea test. Short-acting beta-2 agonist, Ipratropium (Atrovent), immunotherapy-(allergy-minmentation injection), anti-IgE monoclonal antibody-Xolair, general DMARD including hydroxyquinoquine Plaquenil, gold compound-Auranofin (Reduca), sulphate. Sulfasalazine (Azulfidine), minocycline (Dynacin, Minocin) and sulphate (Rheumatrex), leflunomide (Arava), sulfur. Azathioprine (Imuran), cyclosporine (Neoral, Sandimmune) and Cytoxan, antibiotics, CD80 antagonists, costimulatory factor antagonists, Humax-CD20 (ofatumumab); CD20 antagonists , MEK inhibitor, NFkB inhibition 138999.doc -112- 200951107 agent, anti-B cell antibody, denosumab, specific receptor-derived nuclear factor kappa ligand codon receptor activator (RANKL) mAb. IL17 deactivated antibody, IL-17 receptor antagonist/inhibitor, CTLA inhibitor, CD20 inhibitor, soluble VEGFR-1 receptor, anti-VEGFR-1 receptor antibody, anti-VEGF antibody, integrin receptor antagonist, Selectin inhibitors, P-selectin and E-selectin inhibitors, phospholipase A2 inhibitors, lipoxygenation inhibitors, RANKL and RANK antagonists/antibodies, osteoproteger antagonists, lymphotoxin inhibitors, B - lymphocyte stimulator, MCP-1 inhibitor, MIF inhibitor, inhibitor of CD2, CD3, CD4, CD25, CD40 and CD40 ligand CD152 (CTLA4), macrolide vinegar (Macrolide) immunosuppressant, nucleus Selective inhibitors of nucleotide metabolism, chemotactic inhibitors, CXC receptors and CXC ligand inhibitors, Chemokine antagonists, leukocyte chemotaxis inhibitors, adhesion molecule blockers, selectins Lymphocyte functional antigen-1 (LFA-1, CDlla) antagonist, very late antigen-4 (VLA-4) antagonist, matrix metalloproteinase inhibitor, elastase inhibitor, cathepsin inhibitor. In certain embodiments, the second therapeutic agent is selected from the group consisting of a beta blocker, a carbonic anhydrase inhibitor, an alpha- and beta-adrenergic antagonist, including an alpha-adrenergic antagonist, a cx2 agonist, a miotic drug , prostate analogs, corticosteroids and immunosuppressive agents. In certain embodiments, the second therapeutic agent is selected from the group consisting of timolol, betaxolol (betaxo丨〇1), levobetaxolol, carteolol, and left cloth. Levobunolol, propranolol, brinzolamide, dorzolamide, niprol 138999.doc •113- 200951107 (nipradilol), Aoby bite (iopidine), brimonidine, pilocarpine, adrenaline, latanoprost, travoprost, bimatoprost, uno Ketone (Un〇prostone), dexamethasone, prednisone, methylprednisolone, azathioprine, cyclosporine and immunoglobulin.

In certain embodiments, the second therapeutic agent is selected from the group consisting of a corticosteroid, an immunosuppressant, a prostate analog, and an antimetabolite. In certain embodiments, the second therapeutic agent is selected from the group consisting of dexamethasone, prednisone, methylprednisolone, azathioprine, cyclosporine, immunoglobulin, latanoprost (latan〇pr〇st) , travoprost (travoprost), bimatoprost, unoprostone, infliximab, rituximab, meth〇trexate, non Steroid anti-inflammatory agents, muscle relaxants and combinations thereof with other agents, anesthetics and combinations thereof with other agents, combination of expectorants and other agents, antidepressants, anticonvulsants and combinations thereof; Blood pressure drugs, opioids, topical cannabinoids, and other drugs such as capsaicin, betamethasone dipropionate (enhanced and unreinforced) 'valeric acid

Betamethasone, propionate gas, betahsine, prednisone, methylprednisolone, diacetate, dipropionate, propionate, dexamethasone, ansinide, dexamethasone, dexan: ketone, c _Fluorine, fluocinolone, flufensulfonate, pivalic acid can be obtained from octmetarone, hydrofluoric acid, salicylic acid, isobuprofen, ah 2, etodoic acid, double Phenoic acid, melofena, naproxen &quot;bibroxicam celecoxib, ring laughter, bucklefin / ring 2,000, bucklefin, benzopyrimidine / lidocaine, Lido: due to bicyclobenzapine/lidocaine/remaining bromocaine/deoxy-D-glucose, prilocaine, 138999.doc -114- 200951107 EMLA cream (local anesthetic (lidocaine 2.5 % and prilocaine (2.5%) of the 'dissolved mixture', η fenfenazin, β fenfenazin / brewed J-buprofen / cyclobenzalpine, amitriptyline, doxepin , desipramine, imipramine, amoxapine, clomipramine, nortriptyline, protriptyline, duloxetine, mitazoplatin, nisoloxine, maprotiline, rapo Westing, fluridine, fluvoxamine, kappazepine, non Urethane, lamotrigine, tolpiride, celecion, oxcarbazepine, carbamazepine, salnifloxacin, mexiletine, gabapentin/clocidine, gabapentin/carbazide, kappazepine/ Cyclobenzate, antihypertensive drugs include clonidine, codeine, tromethamine, tramadol, y #, fentanyl, ketone, hydrocodone, levorno, butorphanol, Menthol, wintergreen oil, camphor, eucalyptus oil, turpentine; CB1/CB2 ligand, acetaminophen, infliximab, monooxygenase inhibitor, in particular, inhibition of nitric oxide synthase And other agents, such as capsaicin. PDE4 inhibitor - similar to the mechanism of Ibudilast (AV-411), CDC-801, JNK inhibitor-CC-401, combined TNF/PDE4 inhibitor-CDC-998, IL1 inhibitor such as An Anakinra-Kineret, AMG108, standard dry IL-1 (mAb), SHIP activator-AQX-MN100, C5 antagonist, C5a inhibitor, Pexelizumab, mouth bite Synthetic inhibitors, lymphotropic agents, cytokine inhibitors, IKK inhibitors, P38MAPK inhibitors, ARRY-797, HSP90 inhibitors, multi-kinase inhibitors, bisphosphonates, PPAR agonists, Coxl and cox2 inhibitors , anti-CD4 therapy, B-cell inhibitor, COX/LOX dual inhibitor, immunosuppressive agent, iNOS inhibitor, NSAID, sPLA2 inhibitor, colchicine, allopurinol, oxime 138999.doc -115- 200951107 Oxypurinol, gold, radura-cinnovin, febuxostat, Puricase, PEG-uricase formulation, benzbromarone Long-acting β-2 agonists (LABAs), Seretert Diskus and Foradil, white tri-saturated modifiers Montelukast (Singulair) and zafirlukast (Accolate). Inhalation of Intal or Tilade, tea test. Short-acting β-2 agonist, Atrovent, Immunotherapy-(Allergy-Desensitization Injection), Anti-IgE monoclonal antibody-Cymol, General DMARD including hydroxyquinoline (Plaquenil), gold Compound - auranofin (Reduca), sulfoximine. Azulfidine, Dynacin, Minocin and Rheumatrex, Arava, Imuran, Cyclosporine (Neoral, Sandimmune) And Cytoxan, antibiotics, CD80 antagonists, co-stimulatory factor antagonists, Humax-CD20 (ofatumumab); CD20 antagonists, MEK inhibitors, NFkB inhibitors, anti-B cell antibodies, mononorm, specific The mAb of the receptor activator (RANKL) of the nuclear factor kappa Β ligand. IL17 deactivated antibody, IL-17 receptor antagonist/inhibitor, CTLA inhibitor, CD20 inhibitor, soluble VEGFR-1 receptor, anti-VEGFR-1 receptor antibody, anti-VEGF antibody, integrin receptor antagonist, Selectin inhibitors, P-selectin and E-selectin inhibitors, lipase A2 inhibitors, lipoxygenation inhibitors, RANKL and RANK antagonists/antibodies, osteoproteger antagonists, lymphotoxin inhibitors, B-lymphocyte stimulator, MCP-1 inhibitor, MIF inhibitor, CD2, CD3, CD4, CD25, CD40 and CD40 ligand CD152 (CTLA4) inhibitor, macrolide (Macrolide) immunosuppressant, Nucleotide metabolism 138999.doc -116- 200951107 Selective inhibitors, chemotactic inhibitors, CXC receptors and cxc ligand inhibitors, chemokine antagonists, leukocyte chemotaxis inhibitors, adhesion molecule resistance Broken agent, selectin lymphocyte functional antigen-l^FAd, CDlla antagonist, very late antigen-4 (VLA-4) antagonist 'matrix metalloproteinase inhibitor, elastase inhibitor, cathepsin inhibitor. In certain embodiments, the second therapeutic agent is selected from the group consisting of insulin, insulin derivatives and peptidomimetics, insulin secretagogues, insulin sensitizers, dual veins, alpha-glucosidase inhibitors, insulinotropic sulfonyl ureas Receptor ligand, protein tyrosine androgenase-ΙΒ (ΡΤΡ-ΙΒ) inhibitor, GSK3 (hepatose synthase kinase-3) inhibitor, GLP-1 (glycoglycin peptide-1), GLP-1 analogue, DPPIV (dipeptidyl peptidase IV) inhibitor, RXR ligand sodium-dependent glucose co-transporter inhibitor, hepatic glucoamylase A inhibitor, AGE fragment, PPAR regulator, LXR And FXR regulator 'non-glitazone type PPARS agonist, selective glucocorticoid antagonist, metformin, Glipizide, glyburide , Amaryl, meglitinides, nateglinide, repaglinide, PT-112, SB-517955, SB4195052, SB-216763, NN-57- 05441, NN-5 7-05445, GW-0791, AGN-.sup.194.sup.204, T-1095, BAY R3401, acarbose Exendin-4, DPP728, LAF 237, vildagliptin, MK-0431, saxagliptin, GSK23A, pioglitazone, rosiglitazone, as described in patent application WO 03/043985 (R)-l-{4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole of the compound of Example 4 - 138999.doc -117- 200951107 4-based oxime a compound, a composition, and a method described herein provide a kit for treating a condition, 'and A condition as described herein. Such kits comprise the compounds, compounds or compositions described herein in a container and optionally include instructions for using the kit in accordance with the various methods and means described herein. The kits may also contain information such as scientific literature references, package page material island bed test results and/or an overview of such information and analogs thereof, which indicate or establish the activity and/or advantages of the composition, and / or describe other information available for its administration, administration, side effects, drug interactions, or health care providers. This information is based on the results of various studies, such as studies using in vivo models of experimental animals and studies based on human clinical trials. The kits described herein are provided, marketed, and/or extended to health care providers&apos; including physicians, nurses, pharmacists, adjusters (-π officiai), and the like. Also, in some embodiments, the kit can be sold directly to the consumer. EXAMPLES General Illustrative Procedure for the Synthesis of Sulfonamide Procedure A: Anhydrous triethylamine (5 eq) was added to a solution of the amine (1 eq) in dry dichloromethane (3 mL/mm 〇i). To this solution was added (iv) gas enthalpy (4) and the solution was stirred under the pulse for 6 hours. The solvent was evaporated and the residue was purified by flash column chromatography on EtOAc. Procedure B Add sulfonium chloride (1.5 eq) to the amine (1 eq) in anhydrous ration (5 ml/mmol). 138999.doc •118- 200951107 solution t. The reaction mixture was stirred at 40 ° for 48 hours. The reaction mixture was partitioned between water and Et. The organic layer was washed with brine &apos; dried (MgSO4) and concentrated. The residue was purified on cerium oxide by flash column chromatography. 'Program C (substitution of iodine atoms): 11 5 in a microwave reactor. (: The next heating contains 1 eq. aryl iodide, 1-5 equivalents of acid or g-pate, 0.25 eq. ♦ PdC12(dPPf)_DCM and 10 eq. anhydrous K2C〇3 powder in dioxane and water. The suspension in the oxygen mixture (31) was allowed to stand for 60 minutes. It was extracted with aqueous nH4C1/thf and the organic portion was dried using Na.sub.2 〇4. Using flash column chromatography (Si, EtOAc/HH or CHCl3/MeOH) The crude reaction product was purified in a yield of 20-40%. Procedure D (N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl); Synthesis of ethanesulfonamide): Add 2_gas_ethanesulfonium (〇丨ml, i mmol) to 5,6-difluoro-Λ^-(2-fluoro-4-benzene The reaction mixture was stirred at room temperature for 16 hours at room temperature with a solution of phenyl-methane, 2-diamine (0.364 g, 1 mmol) and diethylamine (0.28 ml, 2 mmol) in CH2C12 (5 ml). Then, it was treated as an excess of amine (1 〇 eq) in the form of a solution or a neat liquid. The reaction mixture was stirred for 6 hours at room temperature, diluted with Ch 2 C 12 (1 〇 ml) and water (1 〇: This reaction mixture is successively diluted with HCL (2x2〇ml, 2N) and saturated with NaHCO3 (2x10 ml) The organic layer was washed with a liquid. Then, the CHaCl 2 layer was dried (MgS 〇 4) and evaporated to obtain a crude product. The impure product was purified under preparative HpLC conditions to obtain a pure product (yield 5 〇 -6 〇 %). : N-(3,4-Difluoro-2-(2-fluoro-4·iodophenylamino)phenyl) small (2,3-di-dipropyl)cyclopropan-1-one acid 138999.doc -119- 200951107 Step A: butyl cyclopropane sulfonate

Cyclopropanone (5 g, 35 mmol, 1 eq) was dissolved in excess BU〇H (20 ml) at -10. . The reaction mixture was allowed to cool and slowly added dropwise (5.8 mL, 70 mmol, 2 eq). The mixture was slowly warmed at room temperature and stirred overnight. The solvent was removed under reduced pressure and the obtained white solid was dissolved in CH. The organic phase was washed with EtOAc (EtOAc m.) 4 NMR (300 MHz, CDC13) δ 4.25 (t, 2H), 2.46 (m, 1H), 1.74 (m, 2H), 1.45 (m, 2H), 1.25 (dd, 2H), 1.09 (dd, 2H) , 0.93 (t, 3H). Step B: 1-Allylcyclopropane-1-sulfonic acid butyl ester

To a solution of butyl butyl propane sulfonate (4.8 g, 24.9 mmol) in THF was added a solution of butyllithium (15.6 ml, 24.9 mmol, 1 ·6 Μ, THF) at -78 ° C under nitrogen atmosphere. And allyl moth (24.9 mmol). The reaction mixture was stirred at -78 °C for 2 hours and at room temperature for 3 hours. The volatiles were evaporated under reduced pressure and the residue was purified eluting eluting The extract was washed with water, dried (MgSO4) and evaporated. The residue was purified with EtOAc EtOAc (EtOAc:EtOAc: 4 NMR (3 00 MHz ' CDC13) 138999.doc • 120- 200951107 δ 5·6 (m, 1H), 5.13-5.08 (t, 2H), 4.21 (t, 2H), 2.65 (d, 2H), 1.7 (m, 2H), 1.4 (in, 4H), 0.93 (m, 5H). Step C: 1-Allylcyclopropane_丨-sulfonate potassium f Δζ 1-butyl 1-cyclo-cyclopropanesulfonate (3.75 g, 17.2 mmol) and potassium thiocyanate (1.7 g' 17.2 mmol) ) mixed in DME (20 ml) and water (20 ml)

The mixture was refluxed for 16 hours. The volatiles were evaporated to give a crude sulfonic acid salt (3.44 g, quantitative) which was dried under vacuum at 50 ° C for 16 hours. This crude product was used in the next reaction without further purification. 1H NMR (CDC13) δ 5.6 〇, 1 Η), 4.91-4.85 (dd, 2 Η), 2.471-2.397 (d, 2 Η), 0.756 (m, 2H), 0.322 (m, 2H). Step D: N-allyl cyclopropane sulfonate

Λ

A solution of 1-allylcyclopropane&gt;-1--1-acid-removal (3.44 g, 172 mmol), sulfoxide (10 ml) and DMF (5 drops) was refluxed at 60 ° C for 16 hours. The volatiles were evaporated under reduced pressure and the residue was purified eluting with CH. The extract was washed with water, dried (MgSO4) and evaporated eluting eluting ). WNMR (300 MHz, CDC13) δ 5.728 (m, 1H), 5.91 (t, 2H), 2.9 (d, 2H), 0.756 (m, 2H), 0.322 (m, 2H) ° 138999.doc • 121· 200951107 Step E: 1-allyl-N-(3,4-difluoro-2-(2-fluoro-4-isoiodophenylamino)phenyl)cyclopropane-1-sulfonamide

According to the general procedure B, 5,6-difluoroiodophenylindenyl-diamine is reacted with 1-allylcyclopropanesulfonate to obtain the desired product. m/z=507[Ml] 0 Step F: N-(3,4-di 1_2-(2-fluoro-4-isoiodophenylamino)phenyl) small (2,3-diaminopropyl) ring Propylene-1-continuous amine

1-Allyl-N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)cyclopropan-1-propanol (0.77 g, 1.52 mmol) And 4-mercapto-N-oxide (0.18 g, 1.52 mmol) was dissolved in THF (50 mL). Osmium tetroxide (0.152 mmol, 0.965 mL, 4% in H20) was added at room temperature and the reaction mixture was stirred at room temperature for 16 hours. EtOAc was added, the organic layer was washed with water, dried (MgSO. The residue was purified via EtOAc (EtOAc:MeOH) NMR (300 MHz, CDC13+D20) δ 7.38 (dd, J = 1.8 &amp; 10.5 Hz, 1 Η) ' 7.36 (ddd, J=2.4, 5.1 &amp; 9·3 Hz, 1H), 7.25 (d, J= 8.7 Hz, 1H), 7.02 (dd, J=9.0 &amp; 17.7 Hz, 1H), 6.27 (dt ' J=3.0, 8.7 &amp; 17.4 Hz, 1H), 138999.doc 122· 200951107 3.92 (m, 1H) , 3.54 (dd ' J=3.9 &amp; Ui Hz, 1H), 3.39 (dd, J=6.6 &amp; 11.1 Hz, 1H), 2·16 (dd, J=9.6 &amp; 15.9 Hz, 1H), 1.59 ( d, J = 14.1 Hz ' 1H), 1.41 (m, 1H), K26 (m, 1H) ' 0.83 (m, 2H) ; m/z = 542 [Ml] —. Example 2: (s)-N-(3,4-Difluoro-2-(2-I-4-iodophenylamino)phenyl)hepta(2,3-dihydroxypropyl)cyclopropane·丨_sulfonamide

The pure S isomer was obtained by fractional HPLC separation of the racemic mixture (Example 13). 1H NMR (300 MHz, CDC13+D20) δ 738 (dd, J=i.8 &amp; ι〇·5 Hz Η 1Η), 7.36 (ddd, J=2.4, 5.1 &amp; 9.3

Hz, 1H), 7.25 (d, J=8_7 Hz, 1H), 7.02 (dd, J=9.〇&amp; 17.7 Hz, 1H), 6.27 (dt, J=3.0, 8.7 &amp; 17.4 Hz, 1H) , 3.92 (m,1H), 3.54 (dd, J=3.9 &amp; 11.1 Hz, 1H), 3.39 (dd, J=6.6 &amp; 11.1 Hz, 1H) ' 2.16 (dd, J=9.6 &amp; 15.9 Hz, 1H), 1.59 (d ' J = 14.1 Hz, 1H), 1.41 (m, 1H), 1.26 (m, 1H), 0.83 (m, 2H) ; w/z = 542 [Ml] 〇 Example 3: (R -N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl) small (2,3·dimethylpropyl)cyclopropanone-1-continued amine

The pure R isomer was obtained by fractional HPLC separation of the racemic mixture (Example 13) 138999.doc -123 - 200951107. 1H NMR (300 MHz, CDC13+D20): δ 7.38 (dd ' J = 1.8 &amp; 10.5 Hz, 1H), 7.36 (ddd, J = 2.4, 5.1 &amp; 9.3 Hz, 1H), 7.25 (d, J = 8.7 Hz, 1H), 7_02 (dd, J=9.0 &amp; 17.7 Hz, 1H), 6.27 (dt, J=3.0, 8.7 &amp; 17.4 Hz, 1H), 3.92 (m ' 1H) ' 3.54 (dd ' J =3.9 &amp; ll.l Hz, 1H), 3.39 (dd, J=6.6 &amp; ll.i Hz, 1H), 2_16 (dd, J=9.6 &amp; 15.9 Hz, 1H) ' 1.59 (d,&gt; 14.1 Hz, 1H), 1.41 (m, 1H), 126 (m, 1H) ' 0.83 (m, 2H) ; w/z = 542 [Ml]. Example 4. 1-(2,3-Di-propyl-propyl)-cyclopropanone acid [3,4,6·trifluoro-2-(4-fluoro-2-iodo-phenylamino)-phenyl] -acid amine 2-(2-fluoro-4-iodo-phenyl step A 1-allyl-cyclopropanesulfonic acid [3,4,6-trisamino)phenyl]-decylamine

According to the general procedure B, 1-fluoropropyl-cyclo 1 was reacted with fluoro-N-(2-fluoro-4-phenylphenyl)benzene-1,2-diamine, 丨H NMR (CDC13,300 ΜΗζ) δ 7.41 (d( 1Η) ' 7.09 (s,1Η) ' 6.78 (m,1Η),6 (s,1H),5.86 (m,1H), 5.18 (d, 2 only 1·23 (m, 2H) ), 0.872 (m, 2H) 〇Step B l-(2,3-dipropylpropyl)-N-(3,4,6-- •diI-amino)phenyl)cyclopropane-1-sulfonate Indole ring alkane sulfonium with 3,5,6_tri* &amp; 麾 to obtain the title product. 41 (dd, 1 ή,, 7 1 q / heart, 1H), 7.38 (dd, , 6.49 ( m,1H),5.96 2ϊί) ' 2.76 (d,2H), fluoro-2-(2-fluoro-4-iodophenyl 138999.doc •124· 200951107

1-Allyl-cyclopropanesulfonic acid [3,4,6-trifluoro-2-(2-fluoro-4-iodo-phenylamino)-phenyl]-decylamine (110 mg, 0.21 mmol And 4-methylmorpholine N-oxidation (24.6 mg, 0.21 mmol) was dissolved in THF (8 mL). Osmium tetroxide (0.021 mmol, 0·153 mL, 4% in H20) was added at room temperature and the mixture was stirred at room temperature for 16 h. EtOAc was added, the organic phase was washed with water, dried (MgSO.sub.4) and concentrated. The residue was purified with EtOAc EtOAc (EtOAc:EtOAc) 4 NMR (CDC13,300 ΜΗζ) δ 7.39 (dd, J=1.5 &amp; 10.6 Hz, 1Η), 7.29 (d, J=8.8 Hz, ΙΗ), 7.28 (s,1H) ' 6.97 (s,1H) ' 6.76 (m,1H), 6.49 (m, 1H), 4.13 (m,1H), 3.66 (dd,J=3.7 &amp; 11.4 Hz,1H), 3.53 (dd.J=6_7 &amp; 11.2 Hz,1H) , 2.50 (dd, J=10.0 &amp; 16 i

Hz ' 1H),1.6 (m,1H) ' 1.46 (m,1H), 1.28 (m,ih), see 1.20 (m,2H),〇_92 (m,2H) ; w/z=559 [Ml ]—. Example 5: (s)-l-(2,3·Dihydroxypropyl)-N-(3,4,6-trifluoro-2-(2-murine-phenylphenyl)phenyl)cyclopropane- 1-sulfonamide

The pure S isomer was obtained by fractional HPLC separation of the racemic mixture (Example 52). 1H NMR (CDC13,300 ΜΗζ) δ 7.39 (dd 138999.doc -125- 200951107 J=1.5 &amp; 10.6 Hz5 1H), 7.29 (d, J=8.8 Hz, 1H), 7.28 (s, 1H), 6.97 ( s,1H), 6.76 (m,1H), 6.49 (m,1H), 4.13 (m,1H) ' 3.66 (dd,J=3'7 &amp; 11.4 Hz5 1H), 3.53 (dd, J=6.7 &amp;; 11.2 Hz, 1H), 2.50 (dd, J=l〇.〇&amp; 16·1 Hz ' 1H), 1.6 (m, 1H), 1.46 (m, 1H), 1.28 (m, 1H), 1.20 ( m ' 2H), 0.92 (m, 2H) ; m/z = 559 [Ml]_. Example 6: (R)-丨-(2,3-dihydroxypropyl)-N-(3,4,6-trifluoro-2-(2-fluoro-4-iodophenylamino)phenyl) ring Propane-indole sulfonamide

The pure R isomer was obtained by fractional HPLC separation of the racemic mixture (Example 52). 1H NMR (CDC13,300 ΜΗζ) δ 7·39 (dd, J=1.5 &amp; 10.6 Hz, 1Η) ' 7.29 (d, J=8_8 Hz, 1Η), 7.28 (s, 1H), 6.97 (s, 1H) ), 6.76 (m, 1H), 6.49 (m, 1H), 4.13 (m, 1H), 3.66 (dd, J = 3.7 &amp; 11.4 Hz, 1H), 3.53 (dd, J = 6.7 &amp; 11.2) Hz, 1H), 2.50 (dd, J = 10.0 &amp; 16.1 Hz, 1H), 1.6 (m, 1H), 1.46 (m, 1H), 1.28 (m, 1H), 1.20 (m, 2H), 0.92 ( m, 2H) ; m/z = 559 [M-Ι]·. Example 7: N-(3,4-Difluoro-2-(2-fluoro-4-iodophenylamino)phenyl) small (2,3-dihydroxypropyl)cyclopropane-1-sulfonamide Step A 1-allyl-N-3,4-difluoro-2-(2-fluoro-4-iododinylamino)-6-methoxyphenyl)cyclopropane-1-sulfonamide 138999. Doc -126- 200951107

1-Allyl-cyclopropanesulfonium and 5,6-difluoro-Nl-(2-fluoro-4-iodophenyl)-3-methoxybenzene-1,2- according to the general procedure B The diamine reaction is carried out to obtain the title product. NMR (CDC13,300 ΜΗζ) δ 7.417 (dd,1H), 7.309 (s '1Η), 7.25 (m,1Η), 6.89 (m,1Η), 6.52 (m, 1H) ' 6.427 (m,1H), 6.03 (s,1H), 5.668 (m,1H),5.u (t,1H),3.9 (s,3H),2.75 (d,2H),1.21 (m,2H), 0.767 (m,2H) . Step B Ν·(3,4-Difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonate amine

1-Allyl-N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)cyclopropane-1-sulfonamide ( 97 mg, 0.18 mmol) and 4-methylmorphin N-oxide (21 mg, 0.18 mmol) were dissolved in THF (8 mL). Osmium tetroxide (0.018 mmol, 0.13 mL, 4% in H2) was added at room temperature and the mixture was stirred at room temperature for 16 h. EtOAc was added, the organic phase was washed with w~~~~ The residue was purified with EtOAc EtOAc (EtOAc) elute NMR (CDC13,300 ΜΗζ) δ 7.38 (dd, J=1.7 &amp; 10.3 Hz, 1Η), 7·26 (m,1Η), 7.14 (s, 138999.doc -127- 200951107 1H), 6.87 (s, 1H), 6.53 (dd, J=6.8 &amp; 11.4 Hz, 1H), 6.43 (m, 1H), 4.06 (m, 1H), 3.89 (s, 3H), 3.63 (dd, J=3.7 &amp; 11.1 Hz , 1H), 3.49 (dd, J=6.4 &amp; 11.1 Hz, 1H), 2.3 (dd, J=9.7 &amp; 16·1 Hz, 1H), 1.77 (dd, J=1.9 &amp; 16.0 Hz, 1H) ' 1.37 (m, 1H), 1.25 (m, 1H), 1.21 (m, 2H), 0.86 (m, 2H); w/z = 571 [Ml]. Example 8: (S)-N-(3,4-Difluoro-2-(2-fluoro.4-iodophenylamino)-6(methoxyphenyl)-1-(2,3-di Propylamine

The pure S isomer was obtained by fractional HPLC separation of the racemic mixture (Example 55). 1H NMR (CDC13,300 ΜΗζ) δ 7.38 (dd, J=1.7 &amp; 10.3 Hz, 1 Η), 7.26 (m, 1 Η), 7.14 (s, 1 Η), 6.87 (s, 1H), 6.53 (dd, J =6.8 &amp; 11.4 Hz, 1H), 6.43 (m, 1H), 4.06 (m, 1H), 3.89 (s, 3H), 3.63 (dd, J = 3.7 &amp; Ul Hz, 1H), 3.49 (dd, J=6.4 &amp; li.i Hz,1H),2.3 (dd,J=9.7 &amp; 16.1 Hz,1H), 1.77 (dd,J=1.9 &amp; 16.0 Hz, 1H) ' 1.37 (m ' 1H) ' 1.25 (m ' 1H), 1.21 (m, 2H), 0.86 (m, 2H) ; m/z = 571 [Ml]. Example 9: (R)-N-(3,4-Difluoro-2-(2-fluoro-4-mothenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxyl Propyl)cyclopropane-1-sulfonamide 138999.doc •128· 200951107

The pure ruler isomer was obtained by fractional HPLC separation of the racemic mixture (Example 55).咕NMR (CDC13,300 ΜΗζ) δ 7 38 (dd, • 1.7 &amp; 10.3 Hz ' 1H), 7.26 (m, 1H), 714 (s, 1H), 6.87 (s, ih), 6.53 (dd ' J=6.8 &amp; 11.4 Hz,1H),6 43 (m,1H),4.06 (m,1H),3.89 (s,3H),3.63 (dd,J=3.7 φ &amp; η.1 HZ ' 1H) , 3.49 (dd, J=6.4 &amp; 1M Hz, 1H), 2.3 (dd, J=9.7 &amp; 16.1 Hz ' IH) ' 1.77 (dd, J=l.9 &amp; 16.0 Hz, IH), 1.37 ( m,1H) ' 1.25 (m, IH), 1.21 (m, 2H), 0.86 (m, 2H); w々 = 5 7i. Example 10: N-(3,4-Difluoro-2-(2-fluoro-4-phenylamino)-6-methylphenyl)-1-(2,3-dipropylpropyl) ring Propylene Acetone: Step A: (3,4,5-trifluorophenyl)nonanol··

a solution of 3,4,5-trifluorobenzoic acid (7. 〇g, 43.75 mmol) in THF and water (50 m of 9:1) which was cooled (-5 ° C) over 30 min. NaBH4 ( 1.662 g, 43.75 mmol) was slowly added portionwise. The reaction mixture was allowed to reach room temperature over 2 hours and carefully poured into ice-cold diluted HC1 (200 m of 1 N). The oily layer was extracted into CH.sub.2Cl.sub.2 (250 mL) and the organic layer was washed with water (200 ml) dried (MgS04) and evaporated. The crude product obtained (7.08 g, quantitative) was taken to the next step without further purification. 138999.doc -129· 200951107 Step B: S-(bromomethyl)-1,2,3·trifluorobenzene: Ύ To (3,4,5-trifluorophenyl)methanol (40 mmol) in CH2C12 A solution of sulfoxide (6.16 m, 80 mmol) in CH2C12 (50 ml) was slowly added to the solution in (150 ml). The reaction mixture was stirred at room temperature for 6 hours and poured into ice water (200 ml). The organic layer was separated and washed with EtOAc (EtOAc) (EtOAc) This crude product was passed to the next reaction without further purification. Step C: 1,2,3-Trifluoro-5-methylbenzene:

The above-mentioned compound (40 mmol) was mixed with triethyl decane (48 mm 〇1) and the reaction mixture was worked up in small portions of solid PdCh (4 mmol). After a few minutes, a violent exothermic reaction occurred, carefully placing the contents of the flask back by placing a reflux condenser. The reaction mixture was further stirred at room temperature for 6 hours and the contents were allowed to stand for 16 hours. The crude liquid product was then carefully decanted and passed directly to the next-reaction without further purification. It is assumed that the reaction is carried out in quantitative yield. Step D: 1,2,3-trifluoro-5-methyl-4-nitrobenzene: 138999.doc -130- 200951107

1,2,3-Trifluoro-5-methylbenzene (40 mmol) was added to concentrated H.sub.2SO.sub.4 (50 mL). Next, the reaction mixture was slowly treated with concentrated HN03 (3.39 m, 48.44 mmol, 90%) while maintaining the internal temperature below 20 C. The reaction mixture was stirred at room temperature for 16 hr and poured on ice (3 g g). The organic layer was washed with water (2×200 n^), brine (200 ml) and dried (MgSO4) and evaporated to afford crude product. 85%). 1H-NMR (300 MHz, CDC13): δ 6.96 (seven peaks, 1 Η), 2·39 (s, 3 Η). i9FNMR (CDC13): δ -128.18, -141.50, -159.05. Step Ε : 2,3-Difluoro-indole-(2-fluoro-4-iodophenyl)_5-methyl-6-nitroaniline:

2_Fluoro-4-indoline and 1,2,3-difluoro-5-mercapto-4-nitrobenzene were reacted using the conditions described in Example 1 (step Α) to give the title compound. Μ _ Η 10: 407.9. Step F: 5,6-difluoro-Nl-(2-fluoro_4_iodophenyl)_3_methylbenzene

138999.doc • 131 - 200951107 4-Iodophenyl)-5-methyl-6-nitroaniline was reacted to form the title compound. M_H+: 377.4. Step 6: 1-Allyl hydrazine-(3,4-difluoro-2-(2-1-4-iodophenylamino)-6-nonylphenyl)cyclopropane-1·sulfonamide:

1-Allyl-cyclopropanesulfonium (142 mg, 142 mg) and 5,6-difluoro-Nl-(2-fluoro-4-phenylene)-3-indenyl group according to the general procedure B Benzene-1,2-diamine (150 mg '0.4 mmol) was obtained to give the title product (1 mg, 47%); m/z = 521 [M-1]. Step Η : N-(3,4-Difluoro-2-(2-fluoro-4-iodophenylamino)-t-methylphenyl)-1-(2,3-dihydroxypropyl)cyclopropane sulfonate Guanamine:

1-Allyl-N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methylbenyl)cyclopropan-1-one decylamine (150 Mg, 0.29 mmol) and 4-indolyl-N-oxide (33 mg, 0.29 mmol) were dissolved in THF (50 mL). Tetraoxidation (0.029 mmol, 0.18 mL, 4% in H20) was added at room temperature and the mixture was stirred at room temperature for 16 hours. EtOAc was added, the organic phase was washed with water, dried (MgSO.sub.sub.sub.sub.sub.sub. 200951107 The title product (0.110 g, 68%). h-NMR (3 00 MHz, CDC13): δ 7.07 (m, 1H), 6.97 (br m, 2H), 6.84 (m, 2H), 6_60 (br m, 2H), 3_98 (br m, 1H), 3.58 (m,1H), 3.43 (m, 1H), 3_20 (d, J=3.9 Hz, 1H), 2.42 (s, 3H), 2_31 (dd, J=9.9 &amp; 15.6 Hz, 1H), 2.01 ( Br t,1H), 2.31 (dd, J=9.9 &amp; 15.6 Hz, 1H), 1.66 (dd, J=2.1 &amp; 15.9 Hz, 1H), 1.52 (m, 1H), 1.40 (m, 1H), 0.91 (m, 2H). Bioactivity Bioactivity Example 11: IC5. Preparation of data-generating materials and reagents: Human GST-MEK1 and constitutively active dual gene GST-MEK1CA (with mutations Ser218Asp and Ser222Asp) were subcultured from wild-type human MEK1 cDNA to yeast expression vector pGEM4Z (Promega, Madison, WI) )in. GST-MEK1CA was expressed in E. coli (five co/i) and partially purified using a glutathione Sepharose 4B affinity resin (Amersham Pharmacia Biotech, Piscataway, NJ). The ERK2 dual gene was subcloned from the MAPK2/Erk2 cDNA (wild type) (Upstate Biotechnology, Inc., Waltham, MA) in pUSEamp into the vector pET21a (Novagen, Madison, WI) to produce an N-terminal histidine label. Mouse ERK2 dual gene. ERK2 was expressed and purified to homogeneity [Zhang, 1993 #33]. Myelin basic protein (MBP) was purchased from Gibco BRL (Rockville, MD). EasyTides adenosine 5'-triphosphate ([γ-33Ρ]) (ΝΕΝ Perkin Elmer, Wellesley, ΜΑ) is a radiolabeled source for all kinase reactions. Activated Raf-Ι (truncated) and activated MAP kinase 2/ERK2 were purchased from Upstate 138999.doc -133- 200951107 (Lake Placid, NY). 4-20% Criterion Precast gel was purchased from Bio-Rad (Hercules, CA). Determination of enzyme activity: The compound was diluted from dimethyl hydrazine (DMSO) stock to lxHMNDE (20 mM HEPES pH 7, 2, 1 mM MgCl2, 100 mM NaCl, 1 · 25 mM DTT, 0.2 mM EDTA). A typical 25 ml assay contains 0.002 Nemo MEKleA, 0.02 Nemo ERK2, 0.25 Nemo MBP, 0.25 Nemo unlabeled ATP, and 0.1 μ (:ί [γ33Ρ] ATP. The screening assay consists essentially of four Add 5 μM of the diluted compound to a 96-well assay plate, then add 10 μL of 2·5χ enzyme mixture (MEK1GA &amp; ERK2 only) to each well, followed by pre-incubation for 30 minutes at ambient temperature. Then add 10 μΐ of the 2.5x substrate mixture (labeled and unlabeled ΑΤΡ plus ΜΒΡ), then incubate for 60 minutes at ambient temperature. Finally, add 100 μM of 10% trichloroacetic acid (TCA) and in the chamber. Incubate for 30 minutes at ambient temperature to stop the reaction and precipitate the radiolabeled protein product. The reaction product was collected on a glass fiber 96-well filter plate pre-wetted with water and 1% pyrophosphate. The filter plate was then washed 5 times with water. The water was replaced with absolute ethanol and the plate was air dried for 30 minutes at room temperature. A back seal was manually applied and a 40 μL scintillation cocktail was dispensed into each well. A top seal was applied and the plates were counted in a TopCount (2 sec/ Hole). For some experiments A truncated version of MEK requiring activation by Raf kinase was used.Example 12: Production of EC50 data The effect of compounds in cells was determined by Western blotting of phosphorylated ERK. MDA-MB- 23 1 breast cancer fine 138999.doc •134· 200951107

Cells were plated in 48-well plates at 20,000 cells per well and grown in a 37° humidified CO 2 incubator. On the next day, growth medium (DMEM + 10% fetal bovine serum) was removed and replaced with starvation medium (DMEM + 0.1% fetal bovine serum). The cells were cultured for 16 hours in starvation medium and then treated with a series of concentrations of the compound for 30 minutes. After incubation with the compound, the cells were stimulated with 100 ng/ml EGF for 5 minutes. The cells were then lysed and analyzed by Western blotting using monoclonal antibodies raised against phosphorylated ERK. The secondary antibody was combined with a near-infrared dye to amplify the signal and probe on a Licor Odyssey scanner. The signal intensity was quantified and this data was used to generate a dose response curve and an EC50 calculation was performed.

Compound No. Structure Activity μΜ 1018 (racemic) H0 H0-T 6 NH F F A 1020 (racemic) A F A 1023 (R isomer) HO;; m f F B 138999.doc •135- 200951107

Compound number structure activity μΜ 1024 (S isomer) NH F γΛ Β 1029 OH C Legend. A 'EC50=&lt;2.0 η Μ, B ' EC5〇=2.0-15 η Μ, C ' EC5〇=15 ηΜ -100 ηΜ ; D, EC5〇=l〇〇ηΜ-200 ηΜ ; Ε, EC50 &gt; 200 ηΜ ; ND = not measured 活 戌 biological activity Example 13 The compounds and compositions described herein can be used for treatment or prevention One or more conditions including, but not limited to, cancer, inflammatory bowel disorder (IBD), psoriasis and rheumatoid arthritis (RA). The compounds and compositions described herein can also be used once daily or A second oral treatment or prevention of one or more conditions including, but not limited to, cancer, IBD, psoriasis and RA. Compounds of the following structure (Compound A, as described herein) are illustrated in this example

HO OH

Description of the preparation of the live cold test: Μβ0ψ!χ^, 〇

F Human tumors were implanted into nu/nu mice. Once the tumor size was about 1000 mm3, Compound A was administered orally for 14 days. Tumor growth inhibition rate (TGI) was determined after 14 days of treatment, expressed as the rate of decrease in tumor size of the treatment group relative to the vehicle control group. End point time (TTE) is root 138999.doc -136- 200951107 Calculated based on the time at which the tumor reached the specified endpoint volume or the last day of the study, whichever occurs first. Treatment outcomes were determined based on percent tumor growth delay (% TGD), which was defined as the percentage increase in median TTE of treated mice compared to vehicle treated control mice. The animals are also monitored and the reaction is resolved. The pERK content in tumors and brains was determined by Western blotting and was correlated with the plasma content of Compound A for pharmacokinetic/pharmacokinetic studies. Several tumor models were evaluated at different doses and dose schedules. Statistically significant % TGD was shown as treatment at 25 or 50 mg/kg once daily (QD) in A3 75 melanoma tumors, C〇1〇205 colon cancer tumors, and A43 1 epidermoid tumors. Statistically significant TGI was observed for oral administration at 25 mg/kg QD in these tumor models as well as in HT29 colon cancer tumors. The effects of different dosing regimens were evaluated in A3 75 allografts. Although 100 mg/kg of Compound A administered orally once every two days showed a statistically significant % TGD (91%), it was not as good as QD treatment of 25 mg/kg (143% TGD) or 50 mg/kg (233% TGD). As effective. Such as ° /. Ding 01 measured that daily _ secondary (BID) administration was also more effective than QD administration. Administration of 12.5 mg/kg BID produced 79.5% TGI compared to 51.7% of 25 mg/kg QD for Compound A. Administration of 25 mg/kg BID compared to 69.9% of 50 mg/kg QD; yielded 110.1% TGI. A drug in C〇1〇205 allogeneic transplantation. Academic/pharmacokinetic studies showed that pERK formation was inhibited in tumors, while minimal inhibition was observed in the brain, indicating effective antitumor activity, while CNS wear Limited permeability. Compound A is a potent MEK1/2 inhibitor that inhibits tumor cell growth in live and inviting cold. Growth-dependent growth but not fixation independence 138999.doc -137- 200951107 The BRAF status in sexual growth or in allogeneic transplantation determines the sensitivity to growth inhibition by this compound. Maintaining sufficient MEK inhibition during the dosing interval appears to be more important than the peak content because of the greater efficacy under more frequent dosing. Compound A has a favorable pharmacokinetic profile in humans and the estimated therapeutic dose in humans based on xenograft results is 20-40 mg/day. Example 13A: Inhibition of cancer cell growth (GIs〇) Fixation-dependent growth inhibition was measured using CellTiterGlo reagent after treatment of cells grown in 384-well plates with Compound A for 48 hours. Fixation independent growth assay MTS (decane thiosulfonate) reagent was used after 7 days of treatment on cells grown in 0.15% agarose or grown on non-binding plates (A431). Growth inhibition values (GI5G) are shown in the table below. Tumor cell line BRAF status fixation-dependent GI50 (nM soil sd) fixation independence GI50 (nM±sd) A375 melanoma V600E 67±12 68±34 C〇1〇205 Colon V600E 74±45 33±16 HT29 Colon V600E 70±12 No A431 epidermoid normal was detected&gt;10,000 65±19 Example 13B: Anti-tumor allograft activity A375 melanoma, C〇1〇205 colon tumor, A43 1 epidermis were transplanted into female nu/nu mice. Such tumors or HT-29 colon tumor cells allow these cells to grow to 100-200 mm3. Compound A or vehicle (25 mg/kg, 50 mg/kg or 100 mg/kg) was administered orally once a day for 14 days. The mean tumor volume of the vehicle and treatment groups is plotted and shown in Figure 1.

Example 13C: Tumor growth inhibition rate (TGI) 25 mg/kg QD The tumor growth inhibition rate of the group treated with 25 mg/kg Compound A at 138999.doc -138- 200951107 was calculated for the indicated tumor xenograft. Tumor growth inhibition rate was measured at the end of one day of dosing at 14 days and was calculated as follows: %TGI = (100) [1-[(measured tumor volume final - tumor volume initially) / (media treated) Tumor Volume Final - Tumor Volume * Initial)]] • The range of A3 75 and C〇1〇205 represents values from 2 independent studies. Tumor allograft % TGI P value A375 melanoma 52-72** &lt; 0.001 C〇1〇205 Colon 70-123** &lt; 0.001 HT29 colon 56 &lt; 0.001 A431 epidermis 67 &lt; 0.001 * During the course of the experiment During the decline, Example 13D was observed: EDS0 in C〇1〇205 allogeneic transplantation C〇1〇205 tumor cells were transplanted into male nu/nu mice. After 10 days, animals were randomized according to tumor size (ranging from 126 to 256 mm3) and treated with Pacific Paclitaxel (IV, QODx5), vehicle or Compound A (PO, QDxl4). The pharmacokinetic parameters were obtained by administering 25 mg/kg of Compound A to Balb/c mice and φ extrapolating the values of the lower dose group and are shown in the table below. Group η treatment protocol initial tumor volume (mm3) tumor volume on day 15 (mm3) TGI% Cmax (pg/mL) Cmin (pg/mL) AUC (με-hour/mL) reagent mg/kg 1 10 vehicle 185 ±11.1 2093±174 - - - - Taiping 2 10 Yang Zi 30 184±9.8 113±9.6 104* - - - Ethyl alcohol 3 10 2.5 184±9.8 1187±127 47* 0.99 0.003 5.5 4 10 Compound 5 183.8±9.8 1175 ±104 48* 1.97 0.006 11.0 5 10 A 10 185.U11.7 1045±160 55* 3.94 0.012 22.0 6 10 25 185.U11.7 762±81 70* 9.85 0.029 55.0 *P&lt;0.001 138999.doc -139 - 200951107 Example 13E: Tumor growth inhibition rate of A375 xenografts Compound A 50 mg/kg QD, 25 mg/kg BID, 50 mg/kg QD and 12.5 mg/kg BID were administered to A375 xenograft mice. The TGI% is calculated and plotted and shown in Figure 2. Example 13F: Plasma concentration in mice Transplanted A3 7 5 tumor cells to nu/nu mice, the cells were grown to 100-200 mm3. Oral administration of Compound A or vehicle (50 mg/kg QD, 25 mg/kg BID, 50 mg/kg QD, and 12.5 mg/kg BID) once daily (QD) or twice daily (BID). The tumor growth inhibition rate was measured at the end of once daily dosing at I4 days and was calculated as follows: o/〇TGI=(100)[l-[(Tumor volume of treated tumor - Tumor volume * Initial V (via vehicle) Tumor volume treated*final-tumor volume*initial)]] AUC (pg·hr/ml) 132.5 117.0 66.5 78.0 23.8 10.2 11.9 7.8 Cmin(ug/ml) 0.06 1.24 0.03 0.49 Cmin free fraction (ng/ml) 0.117 2.48 0.059 0.986 statistical significance = logarithmic scale test example 13G: inhibition of mouse xenograft tumor and brain MEK activity 2.5, 5, 10 or 25 mg was administered to female nu/nu mice transplanted with C〇1〇205 tumor cells /kg single dose of vehicle or compound A. Determine the amount of compound in the plasma sample and determine the pERK content in the tumor and brain samples, which are at 2, 6, 12, and 24 hours after administration. The pERK content obtained by the Western blot method was quantified using LI-COR Odyssey, corrected for total ERK content and compared with the amount of vehicle-treated to determine the % inhibition of MEK. Tumor or brain of each mouse MEK inhibition rate 138999.doc -140· 200951107 Corresponding to compound A in animals Plasma concentration plotted. Nonlinear regression analysis results in MEK inhibition of tumor EC50 of 73 nM. Brain EC50 greater than plasma concentrations of 5000 nM ° (log nM) inhibition of pERK% of the figure shows the preparation. FIG. 3 capsules in

Example 14A ❿ ❿ 备 蓝色 Blue 1 says hard gelatin capsules </ RTI> containing a concentration of 1 mg and 1 〇 mg of the following compound 干 $ dry powder blend composition (see the example 93 above)

Table): Compound A was prepared as described herein, and then a fluid energy grinder (Spiral jet MiU, electro-grinding, having a grinding chamber having a diameter of 5 mm; 5 〇〇·4 χ〇.8 _ nozzle ring; · 8_ injector nozzle diameter and 3 _ injector nozzle distance) micronized. The compound VIII and the partially microcrystalline cellulose were mixed and sieved through a #20 mesh screen and added to a diffusion-rolled blender (ν_ blending benefit). The remaining microcrystalline cellulose was sieved through a #2 〇 mesh screen, added to the contents of the mouth blender and blended. The croscarmellose sodium and the sodium lauryl sulfate are passed through a (iv) mesh sieve (4), added to the material in the blender and blended. The powder blend was passed through a rotary impeller mill (Quadro C〇Mll) and added back to the blender and blending continued. Stearic acid was sieved through a #20 mesh screen and blended with the ground powder blend. = The final blend is filled into the old capsule. The 1 胶囊 capsule is labeled as δ for identification. 138999.doc 200951107 The composition of the capsules is shown in the table below: Component 1 mg capsule 10 mg capsule mg / unit % mg / unit % Compound A 1.0 0.4 10.0 4.2 Microcrystalline cellulose, NF (AvicelPH302) 222.2 92.6 213.2 88.8 Crosslinking Carboxymethylcellulose sodium, NF (Ac-di-Sol) 12.0 5.0 12.0 5.0 sodium lauryl sulfate, NF 2.4 1.0 2.4 1.0 Magnesium stearate, NF 2.4 1.0 2.4 1.0 Total amount a 240.0 100.0 240.0 100.0 Blue No. 1 hard The gelatin capsule shell 1 1 a target fill weight is based on the actual potency adjustment of the blend. Typical batch formulations for 10,000# batches of 1 mg capsules are as follows: Batch formulation components Amount of each batch (g) (10,000 units) Compound A 10.0 Microcrystalline cellulose, NF (AvicelPH302) 2222 Crosslinked carboxyindene fiber Sodium, NF (Ac-di-Sol) 120.0 sodium lauryl sulfate, NF 24.0 magnesium stearate, NF 24.0 total fill weight a 2400 Blue No. 1 hard gelatin capsule shell 10,000 a target fill weight based on blend Actual performance adjustment. Typical batch formulations for 10,000# batches of 10 mg capsules are as follows: Batch formulation components Amount of each batch (g) (10,000 units) Compound A 100.0 Microcrystalline cellulose, NF (Avicel PH302) 2132 Crosslinked carboxymethyl Cellulose Sodium, NF (Ac-Di-Sol) 120.0 Sodium Lauryl Sulfate, NF 24.0 Magnesium Stearate, NF 24.0 Total Filling Weight a 2400 Blue No. 1 Hard Gelatin Capsule Shell 6 10,000 Target Filling Weight Based on Blend Actual performance adjustment. 138999.doc -142- 200951107

Example 14B A blue No. 1 hard gelatin capsule containing a dry powder blend composition of the following compound A at a concentration of 1 mg and 10 mg was prepared (see the example 93 above).

HO pH

NH F • Wide range

F 'Preparation of Compound A as described herein, and using a fluid energy grinder (Spiral Jet Mill, electro-grinding, with a 50 mm diameter grinding chamber; 50ο·4χ0.8 mm nozzle ring; 0.8 mm injector nozzle diameter) And 3 mm injector nozzle distance) micronization. Compound A was mixed with a portion of microcrystalline cellulose and sieved through a #20 mesh screen and added to a diffusion-roll blender (V-blender). The remaining microcrystalline cellulose was sieved through a #20 mesh screen, added to the blender and blended. The croscarmellose sodium and sodium lauryl sulfate were sieved through a #20 mesh screen, added to the blender and blended. The powder blend was passed through a rotary impeller mill (Quadro CoMil) and added back to the blender and blending continued. Magnesium stearate was sieved through a #20 mesh screen and blended with the ground powder blend. © This powder blend is filled into capsule No. 1. Strips of 10 mg capsules were marked for identification. The composition of the capsules is shown in the following table: Component 1 mg capsule 10 mg capsule mg / unit % mg / unit % Compound A 1.0 0.4 10.0 4.2 Microcrystalline cellulose, NF (Avicel PH302) 222.2 92.6 213.2 88.8 Cross-linked carboxymethyl cellulose Sodium, NF (Ac-di-Sol) 12.0 5.0 12.0 5.0 Sodium lauryl sulfate, NF 2.4 1.0 2.4 1.0 Magnesium stearate, NF 2.4 1.0 2.4 1.0 Total amount a 240.0 100.0 240.0 100.0 Blue No. 1 hard gelatin capsule shell 1 1 138999.doc -143- 200951107 Human Activity Cold Activity Example I5: Administration of a Capsule as described in Example 95A to a human cancer individual to a single dose of a human cancer subject. A mg or 10 mg capsule composition. 2x1 mg capsules were administered to the individual for the 2 mg dose; 4x1 mg capsules were administered to the individual for the 4 mg dose; 6xl mg capsules were administered to the individual for the 6 mg dose; 1 X 10 mg capsules were administered to the individual for the 10 mg dose; For the 20 mg dose, 2 mg capsules were administered to the individual. Monitor the concentration-time graph and display it in Figure 4 and the following table: Dose (mg) Day Tmax (hours) Cmax (ng/mL) Ci2-i-»i(ng/niL) AXJC〇-i2 hours (ng· Hour/mL) AUCx ~ (ng·hour/mL) 2 1 2.0 0.111 0.0378 0.700 NA 35 』,0 0.202 0.0756 NA 2.07 ' 4 1 1.5 0.292 0.134 2.26 &quot;na 1〇~~ ~20~^ ---- ---j Sb ~35~ ti; 1.0 ~ττ----- 0.544 0.310 NA 5.12 να 1.57 1.01 NA 14.3 3.28 2.19 NA 29.5 Crystalline polymorphic form Example 16: N_(3,4_Difluoro_2_( Preparation of 2_fluoro·4_iodophenylamino)phenyl)-ίο,, arylpropyl)cyclopropane-1-sulfonamide Ν^3'4-difluoro-2-(2-fluoro 4-Iodophenylamino)phenyl)-1-(2,3-dihydroxypropyl)cycloalkane-l-sulfonamide is prepared according to the foregoing procedure (see published International Patent Application WO 2007) /014011) and is summarized below.

138999.d〇c 200951107 Step d ·· 2-Fluoro-N-(2,3,5-trifluoro-6-nitrophenyl)-4-deoxyaniline 1.0 Μ bis(trimethyldecane)amine A solution of lithium (LiN(SiMe3)2)&quot;LHMDS" (15.37 mL ' 15.37 mmol) was slowly added to the stirred 2_Fluoro-4-iodoaniline (3.64 g, 15.37 mmol) under nitrogen at -78 °C. In a solution of anhydrous, THF (100 mL) and stirring at -78 ° C for an additional hour. • Add 2,3,4,6-tetrafluorodecylbenzene, and allow the reaction mixture to warm to room The mixture was warmed and stirred for a further 6 hours. Ethyl acetate (200 mL) was added and the organic phase was washed with water and dried over sodium sulfate and further purified by column chromatography to afford product as a yellow solid (3.75 g, 59.24 %). M-H+: 410.9. 4 NMR (DMSO, 300 MHz): 6.85 (t, 1H); 7.38 (d, 1H); 7.62 (m, 2H); 8.78 (s, 1H). Fluorine-N-(2,3-fluoro-5-methoxy-6-mercaptophenyl)-4-anisidine (2-fluoro-4-iodo-phenyl)-(2, A solution of 3,5-trifluoro-6-nitro-phenyl)-amine (1.23 g '3 mmol) in dry THF (25 ml) was cooled to -78 °C under nitrogen and slowly added 25% methanol Sodium (0.68 ml, 0.3 mmol) hydrazine solution. The reaction mixture was warmed to room temperature and stirring was continued for a further 16 hours. TLC showed incomplete reaction. Ethyl acetate (丨〇〇mL) was added to the mixture and washed with water. The organic layer was dried over EtOAc EtOAc (EtOAc:EtOAc) : 5,6-Difluorofluoro-4-iodophenyl)-3-methoxybenzene-1,2-diamine will be gasified (1.18 g' 20.16 mmol) and iron powder (1.15 g, 21.44 mmol) Add to the stirred (2 3 difluoro-5-methoxy-6 phenyl)-amine (2H mothyl)-amine (0.57 g, 1.34 mmol) in ethanol (20 mL) 138999.doc - 145-200951107. The mixture was stirred under reflux for 16 hours, cooled to room temperature, filtered over celite and concentrated to dryness. The residue was dissolved in ethyl acetate and washed with water. Drying over sodium sulphate and further purification by crystallization from ethanol to give the product as an off-white solid ( 〇 47 g &gt; 90.30/0) 〇M-H+ : 393.2 NMR (DMSO « 30 0 MHz): 3.76 (s,3H) ; 6.1 (t,1H) ; 6.8-7.0 (m,1H) '· 7·2 (d, 1H) ; 7.35 (s,1H) ; 7.42 (d,1H) . #锞2) : 1_allyl-N-(3,4-difluoro-2_(2-fluoro-4-iodophenylamino)_6_methoxyphenyl)cyclopropanone-1-continuation The amine is mixed with 5,6-difluoro-N1·^-fluoro-4-substituted phenyl)-3-methoxybenzene-1,2-diamine (1 eq) in an anhydrous ratio (5 I-dil-cyclopropanesulfonium (1-5 eq) was added to the solution in ml/mmol). The reaction mixture was stirred at 4 (4 mL EtOAc). EtOAc (EtOAc m. Column chromatography to purify the residue on EtOAc (EtOAc m.). m,1H),6.52 (m,1H) ' 6.427 (m,1H) ' 6.03 (s,1H), 5.668 (m,1H),5.11 (t,1H),3_9 (s,3H),2.75 (d , 2H), 1.21 (m, 2H), 0.767 (m, 2H). #席五: N-(3,4-difluoro-2·(2-fluoro-4-iodophenylamino)-6- Methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1_sulfonamide will be 1-allyl-indole-(3,4-difluoro-2-(2-fluoro) 4-iodophenylamino)-6-methoxyphenyl)cyclopropane-1-sulfonamide (97 mg, 0.18 mmol) and 4-methylmorpholine 138999.doc -146- 200951107 N-oxidation (21 mg, 0.18 mmol) was dissolved in THF (8 mL). Fetanium oxide (0.018 111111 〇1, 0_13 1111^, 4% in 1120) was added at room temperature and the reaction was stirred at room temperature. Mixture 1 6 hours. Tim Ethyl acetate, and the organic phase was washed with water, dried (MgSO.sub.4) and concentrated under reduced pressure. The residue was purified by silica gel chromatography (solvent: EtOAc/MeOH). (0.80 g, 78°/.). 4 NMR (CDC13, 300 MHz): δ ' 7.38 (dd, J = 1.7 &amp; 10.3 Hz, 1 Η), 7.26 (m, 1 Η), 7.14 (s, 1H), 6.87 (s, 1H), 6.53 (dd, J = 6.8 &amp; 11.4 Hz, 1H), 6.43 (m, 1H), 4.06 (m, 1H), 3.89 (s, 3H), 3.63 (dd, J = 3.7 &amp; 11.1 Hz, 1H), 3.49 (dd, J=6.4 &amp; 11.1 Hz, 1H), 2.3 (dd, J=9.7 &amp; 16.1 Hz, 1H), 1.77 (dd, J=1.9 &amp; 16.0 Hz, 1H), 1.37 (m, 1H), 1.25 (m, 1H), 1.21 (m, 2H), 0.86 (m, 2H); m/z = 571 [Ml]. Example 17: N-(S)-(3,4-dioxa-2-(2-fluoro-4-block phenylamino)-6-methoxyphenyl)·丨-(2,3-di Preparation of hydroxypropyl)cyclopropane-1-sulfonamide

纯 . A pure S isomer is obtained by performing a palmitic HPLC separation of the racemic mixture. NMR (CDC13, 300 MHz): δ 7.38 (dd, J = 1.7 &amp; 1 〇 · 3 Hz, 1H), 7.26 (m, 1H), 7.14 (s, 1H), 6.87 (s, 1H), 6.53 ( Dd, J=6.8 &amp; 11.4 Hz, 1H), 6.43 (m, 1H), 4.06 (m, 1H), 3.89 (s, 3H), 3.63 (dd, J=3_7 &amp; 11.1 Hz, 1H), 3.49 (dd, J=6.4 &amp; 11.1 Hz, 1H), 2.3 (dd, 138999.doc -147- 200951107 J=9.7 &amp; 16.1 Hz ' 1H) ' 1.77 (dd, J=1 9 &amp; 16 〇Hz, Out), 1.37 (m ' 1H) ' 1.25 (m ' 1H),! 21 ' 2H), 〇 % (1, 2H) ; m/z = 571 [M-lf. Example 18: N-(R)-(3,4-Difluoro.2_(2_ι_4.iodophenylamino)6-methoxyphenyl)-indole-(2,3-dihydroxypropyl)cyclopropane Preparation of burned guanamine

A pure Chinese isoform is obtained by subjecting the racemic mixture to palmitic HpLC separation. 4 NMR (CDC13, 3〇〇MHz) : δ 7.38 (dd, J=i.7 &amp; 10.3 Hz, 1H) ' 7.26 (m,1H),714 (s,m),6 87 &amp;, 1H) ' 6.53 (dd, J=6.8 &amp; U.4 HZ,iH), 6.43 (m,1H), 4.06 (m,1H),3.89 (s,3H),3 63 (dd,J=3 7 &amp; u"

Hz, 1H), 3.49 (dd, J=6.4 &amp; ll.l Hz, 1H), 2.3 (dd, J=9.7 &amp; 16.1 Hz, 1H) ' 1.77 (dd, J=1 9 &amp; 16 〇Hz ,1H), 1.37 (m,1H) ' 1.25 (m ' 1H), 1.21 (m, 2H), 0.86 (m, 2H) ; w々=571 [Ml] — 〇 Example 19 : N-(S)- (3,4-Difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropanesulfonamide Preparation of crystalline polymorph Form A

Step A: N_(S)-(3,4-Difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxy Propyl)cyclopropanesulfonamide (21 6.1 〇g) was fed into a 4 L Erlenmeyer flask equipped with a large magnetic stir bar and a magnetic stirrer/hot plate. 138999.doc -148· 200951107 Ethyl acetate (approximately 600 mL 'purchased from Fisher) was added. Heating and stirring were initiated to form a brown suspension. The mixture was refluxed at low speed and additional ethyl acetate Sa (about 200 mL) was added to achieve complete dissolution to give a deep smear solution. The heptane (purchased from Acros) was slowly added in portions to the refluxed solution at such a rate that all of the precipitate formed after each addition was 'dissolved quickly and maintained at reflux. After the addition of 2 L of heptane to this solution, the solid formed was very slowly dissolved under reflux. The heating was stopped and the crystallization mixture was allowed to equilibrate to room temperature while being sterilized for 16 days. A thicker layer of crystalline material gradually forms around the surface of the glass during placement. The resulting suspension was equilibrated in an ice/water bath with stirring. The suspension was filtered on a 25 cm Buchner funnel (Buchner Chemical) with a Whatman# filter media. The collected crystals were washed with heptane (1 L) and allowed to air dry under vacuum. The crystals were further dried at 4 ° C / &lt; 1 Torr over 20 hours to give a product as a pink crystalline solid (160.99 g, 77.2%).

Step B φ will be N_(SH3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) ring Propane _ 丨 sulfonamide (13 2 " and ethyl acetate (30 mL) fed into a large magnetic stir bar and a magnetic stirrer / hot plate; in an Erlenmeyer flask. Start stirring and heating to low speed reflux to achieve Completely dissolve: to obtain a dark brown solution. Slowly add heptane to the refluxing solution in portions, so that all the precipitates formed after each addition can be quickly dissolved and maintained under reflux until heptane in the solution. The addition allowed the solid formed to dissolve very slowly under reflux (about 9 mM heptane). The heating was stopped and the crystallization mixture was allowed to equilibrate to room 138999.doc -149 - 200951107 while stirring for 16 hours. A thicker layer of crystalline material gradually formed around the surface of the glass during standing. The resulting suspension was equilibrated in an ice/water bath with stirring. The suspension was filtered on a Buchner funnel with a Whitman #1 filter medium. The collected crystals were washed with heptane and allowed to air dry under vacuum. The crystals were further dried at 40 ° C / &lt; 1 Torr to produce a product which was a pink crystalline solid.

Step C: N-(S)-(3,4-Difluoro-2-(2-fluoro-4-phenylphenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxy Propyl)cyclopropane_丨_sulfonamide (44 8 phantom and ethyl acetate (750 mL) was fed into an Erlenmeyer flask equipped with a large magnetic stir bar and a magnetic stirrer/hot plate. Start mixing and heating to Reflux at low speed to achieve complete dissolution to give a dark brown solution. Slowly add hexane to the refluxed solution in portions, so that all precipitates formed after each addition can be quickly dissolved and maintained in reflux until the solution is in solution. The addition of hexane allowed the solid formed to dissolve very slowly under reflux (about 2 L hexanes). The heating was stopped and the crystallization mixture was allowed to equilibrate to room temperature while stirring for 16 hours. A thicker layer of crystalline material is gradually formed. The resulting suspension is equilibrated in an ice/water bath with stirring. The suspension is filtered on a Büchner funnel equipped with Whitman #1 filter medium. The collected crystals are washed and Allow to air dry under vacuum. Allow these crystals to further at 40 ° C / &lt; 1 over 2 hours Drying down to give the product as a pink crystalline solid. Example 20: N-(R)-(3,4-difluoro-2(2-fluoro- 4-iodophenylamino)-6-methoxybenzene Preparation of crystalline polymorphs of hydrazino-(2,3-dihydroxypropyl)cyclopropane q•sulfonamide 138999.doc -150- 200951107 N-(R)-(3,4-difluoro -2-(2-Fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide (216.10 g) Feed into a 4L Erlenmeyer flask equipped with a large magnetic stir bar and a magnetic stirrer/hot plate. Add ethyl acetate (about 600 mL). Start heating and stirring to form a brown suspension. Allow the mixture to reflow and add at low speed. Additional ethyl acetate (about 200 mL) to achieve complete dissolution to give a dark brown solution. Slowly feed the g-burn to the reflux solution. The rate of addition is such that all precipitates formed after each addition can be Dissolve quickly and maintain reflux. After adding 2 L of heptane to this solution, the solid formed was very slowly dissolved under reflux. The heating was stopped and the crystallization mixture was allowed to equilibrate to room temperature while stirring for 16 hours. A thicker layer of crystalline material gradually formed around the surface of the glass during the period. The resulting suspension was equilibrated with stirring in an ice/water bath. The suspension was filtered on a 25 cm Buchner funnel equipped with Whitman #1 filter media. The collected crystals were washed with heptane (1 L) and allowed to air dry under vacuum. These crystals were further dried at 40 ° C / &lt; 1 Torr over 20 hours. Example 21: ICSG data generation materials and reagents Preparation: Human GST-MEK1 and the constitutively active dual gene GST-MEK1CA (with mutations Ser218Asp and Ser222Asp) were sub-selected from the wild-type human MEK1 cDNA in the yeast expression vector pGEM4Z (Promega, Madison, WI). GST-MEK1CA was expressed in E. coli and partially purified using glutathione Sepharose 4B affinity resin (Amersham Pharmacia Biotech, Piscataway, NJ). The ERK2 dual gene was subcloned from the MAPK2/Erk2 cDNA (wild type) (Upstate Biotechnology, Inc., Waltham, ΜΑ) in pUSEamp in 138999.doc -151 - 200951107 vector pET21a (Novagen, Madison, WI) to generate N-terminal histidine-tagged mouse ERK2 dual gene. ERK2 was expressed and purified to homogeneity [Zhang, 1993 #33]. Myelin basic protein (MBP) was purchased from

Gibco BRL (Rockville, MD). EasyTides adenosine 5'-triphosphate ([γ-33Ρ]) (ΝΕΝ Perkin Elmer, Wellesley, MA) is the radiolabeling source for all kinase reactions. Activated Raf-1 (truncated) and activated MAP kinase 2/ERK2 were purchased from Upstate (Lake Placid, NY). 4-20% Criterion Precast gel was purchased from Bio-Rad (Hercules, CA). Determination of enzyme activity: The compound was diluted from dimethyl sulfoxide (DMSO) stock to lxHMNDE (20 mM HEPES pH 7.2, 1 mM MgCl2, 100 mM NaCl, 1.25 mM DTT, 0.2 mM EDTA). A typical 25 ml assay contains 0.002 Nemo MEK1GA, 0.02 Nemo ERK2, 0.25 Nemo MBP, 0.25 Nemo unlabeled ATP, and 0·1 μ (:ί [γ33Ρ] ATP. The screening assay basically contains Add four times. Dispense 5 μM of the diluted compound into a 96-well assay plate, then add 1 μM of 2·5χ enzyme mixture (MEK1CA and ERK2 only) to each well, followed by pre-incubation at ambient temperature. 30 minutes. Then add 10 μΐ of the 2·5 χ substrate mixture (labeled and unlabeled ΑΤΡ plus ΜΒΡ), then incubate for 60 minutes at ambient temperature. Finally, add 100 μM of 10% tri-glycolic acid (TCA). The mixture was incubated at room temperature for 3 minutes to stop the reaction and precipitate the radiolabeled protein product. The reaction product was collected on a 96-well filter plate of glass fiber pre-wetted with water and 1% pyrophosphate. The filter plate was then washed with water. 5 times. Displace the water with absolute ethanol and allow the plate to air dry for 30 minutes at room temperature. Manually apply a back seal and dispense 40 μM of flash 138999.doc -152- 200951107 to each well. Apply a top seal And count the board in the TopCount (2 /well). For some experiments, a truncated version of MEK that requires activation by Raf kinase was used.Example 22: Generation of EC50 data The effect of compounds in cells was determined by Western blot analysis of phosphorylated ERK. MDA-MB-23 1 breast cancer cells were plated in 48-well plates at 20,000 cells per well and grown in a 37 ° humidified CO 2 incubator. The next day, the growth medium was removed (DMEM + 10% fetal) Bovine serum) was replaced with starvation medium (DMEM + 0.1% fetal bovine serum). Cells were cultured in starvation medium for 16 hours and then treated with a series of concentrations of compound for 30 minutes. After incubation with the compound, at 100 ng /ml EGF stimulates the cells for 5 minutes. The cells are then lysed and analyzed by western blot using monoclonal antibodies raised against phosphorylated ERK. The secondary antibody combined with the near-infrared dye is used to amplify the signal and detect it on the Licor Odyssey scanner. Quantify the signal intensity and use this data to generate a dose response curve and perform an EC50 calculation. Example 23: Activity data of the compounds The compounds described in Examples 1, 2 and 3 were tested in the above assay. Results are summarized in the following table:

Compound number Structure Activity Eg. 97 (racemic) -Ο: λ/ -. ·ψ:χΧ A 138999.doc -153 - 200951107

Compound No. &quot; - Activity Eg. 98 (S isomer) A Eg. 99 (R isomer) B

A » EC5〇=&lt;2.0 nM ; B » EC5〇=2.0-l5 nM

Example 24: XRPD data

The XPRD is equipped with 12 inches. The 29-position curve position is detected on the Inel XRG-3000 diffractometer with a sensitive detector. The real-time data was collected using Cu Κα radiation at a resolution of 0.03. The tube voltage and current are set to 40 kV and 30 mA, respectively. A spectrum of 2.5 to 40. 2 is shown to facilitate direct spectral comparison. By (S)-N-(3,4-difluoro-2-(2-fluoro-4-isoiodophenylamino) 6-methoxyphenyl)_ι_(2,3-dipropylpropyl) Cyclopropanol _ 丨 _ continuation of the amine (synthesized as described herein) was loaded into a thin-walled glass capillary to prepare a sample for analysis. Each capillary is moved to a motorized goniometer head to allow the capillary to rotate during data acquisition. These samples were analyzed for 5 minutes. Instrument calibration is performed daily using the 矽 reference standard. Figure 5gN_(s)_(3,4, difluoro(2-fluoro-4-iodophenylamino)-6-methoxyphenyldihydroxypropyl)cyclopropane-1-sulfonamide Form A powder Twilight diffraction (pXRD) spectrum. Figure 7 is a N(S)-(3,4-difluoro-2-(2-fluoro-4-isoiodophenylamino)-6-methoxyphenyl) (2,3-dihydroxypropyl) ring Powder X-ray diffraction (PXRD) spectra of propane sulfonamide in the form of yttrium (top) and amorphous (bottom). 138999.doc -154- 200951107 Example 25: Differential Scanning Calorimetry (Dsc) was performed on a 示 Instruments Differential Scanning Calorimeter q丨〇〇〇. This instrument was calibrated using indium as a reference material. The sample was placed in a standard Dsc disk with a non-crimped lid construction, 1 and its weight was accurately recorded. · To determine the glass transition temperature (rg) of an amorphous material, cycle the sample tube several times between - (10) and 140 °. The final temperature is raised to 15 (TC. According to the 'inflection point of the final cycle of conversion, record'. The figure is N-(SH3,4-difluoro-φ 2-(2_fluoro_4-iodophenylamino)) Modified Dsc thermogram of -6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide (Form A). This figure is the corrected heat flux. (Watt/g, w/g)) plots the measured sample temperature. Example 26: Dynamic Vapor Sorption/Desorption (DVS) Moisture adsorption/desorption data was collected on a VTI SGA-1 00 vapor adsorption analyzer. The adsorption and desorption data were separated by 5 at 10 Torr/R relative humidity (RH) under a nitrogen nitrogen purge (nitr〇gen purge). /. Collected in the range of 95% RH. φ The sample was not dried before analysis. The balance criterion for analysis is that the weight change is less than 0.0100% in 5 minutes, and if this weight criterion is not met, the maximum equilibrium time is 3 hours. The data for the initial moisture content of the sample was not corrected. Sodium hydride and polyvinylpyrrolidine were used as calibration standards. Figure 8 • shows N-(S)-(3,4 -di|L-2-(2-#l-4 -Ethylamino)_6-decyloxy)-1-(2,3 DVS isotherm of -dihydroxypropyl)cyclopropan-1-one (form A). This material exhibited negligible weight changes during the experiment. Example 27: Thermogravimetric Analysis (TG) Analysis was performed on a TA Instrument 2950 Thermogravimetric Analyzer. Calibration Standard 138999.doc -155- 200951107 The material is nickel and AlumelTM. Each sample was placed in an aluminum sample pan and inserted into a TG furnace. The sample was equilibrated at 25 ° C and then heated at a heating rate of 10 C/min under a stream of nitrogen until the final temperature was 35 ° C. Figure 9 shows N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1_(2,3-dihydroxyl The tg thermogram of propyl)cyclopropane_丨_sulfonamide (form a), which shows a negligible weight loss up to 140 ° C, indicating that the polymorphic form 'form A' is an unsolvate. Example 28: In vitro cancer screening Human tumor cell lines were grown in RPMI 1640 medium containing 5% fetal bovine serum and 2 mM L-glutamic acid. The cells are inoculated in a 96-well microtiter plate with a plating density of 1 to 5 按 depending on the doubling time of the individual cell lines, and the plating density between the cells/wells. . After inoculation of the cells, the microtiter plates were added with N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-nonyloxyphenyl group. _l-(2,3-Dihydroxypropyl)cyclopropane-1-sulfonamide was incubated for 24 hours at 37 ° C, 5% c〇2, 95% air and 100% relative humidity. After 24 hours, the two plates of each cell line were fixed in situ with τ〇α to express the addition of N-(S)-(3,4-difluoro_2·(2_fluoro-4-iodine). Measured value (Tz) of the cell population of each cell strain when phenylamino)6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropanesulfonamide.斗(8)_(3,4_Difluoro_2_(2_fluoro_4_ phenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) ring Propane sulfonamide is dissolved in dimethylene hard at 400 times the maximum test concentration to be final and is cold before use; East preservation ^ when added, cold; aliquot of the eastern concentrate is thawed It was diluted to a concentration twice the maximum test concentration to be finalized with complete medium containing 50 pg/ml gentamicin 138999.doc 200951107 (gentamicin). An additional four 10-fold or % log series dilutions were prepared to provide a total of five concentrations plus control. An aliquot of 100 μΐ of these different dilutions was added to the appropriate microtiter wells already containing 100 μM medium to give the desired final concentration. ·· Add N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-fluorenyloxyphenyl)-1-(2,3) After the -dihydroxypropyl)cyclopropane-1-sulfonamide, the plates were again incubated at 37 ° C, 5% CO 2 , 95% air and 100 ° /. Incubate for 48 hours at relative humidity. For attached cells, this assay is terminated by the addition of cold TCA. The cells were fixed in situ by slowly adding 50 μM cold 50% (w/v) TCA (final concentration, 10% TCA) and incubated at 4 ° C for 60 minutes. The supernatant was discarded, and the plates were washed 5 times with tap water and air dried. A 0.4% (w/v) solution of Sulforhodamine B (SRB) in 100% acetic acid (100 μM) was added to each well, and the plate was incubated at room temperature for 10 minutes. After dyeing, the unbound dye was removed by washing 5 times with 1% acetic acid and the plates were allowed to air dry. The bound dye was then dissolved in a 10 mM Trizma assay and the absorbance was read at a wavelength of 5 15 nm on an automated plate reader. For suspension cells, the method was the same except that the assay was terminated by slowly adding 50 μM of 80% TCA (final concentration, 16% TCA) to fix the settled cells to the bottom of the well. 7 absorbance measurements were used [time 0 (Τζ), control growth (C) and N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodobenzene) at 5 concentrations) Aminoamino)-6-fluorenylphenyl)-1-(2,3-dilightylpropyl)3⁄4propan-1-one-continuous amine in the presence of test growth (Ti)], in each drug The percentage of growth was calculated at the concentration value. The percent growth inhibition is calculated as follows: 138999.doc -157- 200951107 Percent inhibition of growth = (Ti-Tz) xl00 (concentration at Ti&gt;/=Tz) (C-Tz) Percent inhibition of growth = (Ti-Tz) xl 00 (Ti&lt;Tz concentration) Tz calculates three dose response parameters. 50% growth inhibition (GI50) was calculated based on [(Ti-Tz)/(C-Tz)] xl00 = 50, which is an increase in net protein in control cells during drug culture (measured by SRB staining) ) has a reduced concentration of 50%. N-(S)-(3,4-difluoro-2-(2- gas-4-indolylphenyl)-6-indenylphenyl)-1-() leading to total growth inhibition (TGI) The concentration of 2,3 -dipropylpropyl)cyclopropane-1-sulfonamide was calculated from Ti = Tz. The LC50 indicating the net loss of cells after treatment (the concentration of the drug that reduces the measured protein by 50% at the end of the drug treatment compared to the start) is based on [(11-Tz)/Tz] xl 00=-50 Calculation. If the activity value is reached, the value of each of the three parameters is calculated; however, if the effect is not reached or exceeded, the value of the parameter is expressed as greater or less than the maximum or minimum concentration tested. For the indicated cell lines, a discussion group corresponding to white disease, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, and breast cancer was examined, and the results are shown in the following table. Discussion group Cell line ϋΙ50(μΜ) ΙΧ50(μΜ) TGI(pM) Leukemia CCRF-CEM 17.378 100.000 60.256 Leukemia HL-60(TB) 0.010 100.000 100.000 Leukemia K-562 6.607 100.000 100.000 Leukemia MOLT-4 10.965 100.000 69.183 Leukemia RPMI- 8226 26.915 100.000 100.000 Leukemia SR 38.019 100.000 100.000 Non-small cell lung cancer A549/ATCC 0.589 100.000 64.565 Non-small cell lung cancer EKVX 0.214 61.660 13.804 Non-small cell lung cancer HOP-62 0.069 42.658 12.589 Non-small cell lung cancer HOP-92 0.047 58.884 0.324 138999.doc -158- 200951107 Discussion group cell line (50(μΜ) ΙΧ50(μΜ) TGI(pM) Non-small cell lung cancer NCI-H226 3.311 74.131 24.547 Non-small cell lung cancer NCI-H23 0.056 74.131 2.884 Non-small cell lung cancer NCI-H322M 0.162 46.774 15.488 Non-small cell lung cancer NCI-H460 3.631 52.481 19.498 Non-small cell lung cancer NCI-H522 5.248 100.000 29.512 Colon cancer HCC-2998 0.010 0.457 0.035 Colon cancer HCT-116 0.195 67.608 12.589 Colon cancer HCT-15 0.603 60.256 16.982 Colon cancer HT29 0.026 29.512 3.090 Colon cancer KM12 0.229 48.978 13.490 Colon cancer SW-620 0.039 66.069 12.589 CNS cancer SF-268 2.570 100.000 25.704 CNS cancer SF-295 9.333 53.703 23.442 CNS cancer SF-539 1.514 60.256 20.417 CNS cancer SNB-19 0.251 75.858 24.547 CNS cancer SNB-75 0.302 34.674 4.467 CNS cancer U251 0.891 44.668 17.378 Melanoma LOX IMVI 0.195 38.905 10.715 Melanoma MALME-3M 0.010 19.953 0.014 Melanoma M14 0.015 29.512 0.166 Melanoma SK-MEL-28 0.028 22.387 0.214 Melanoma SK-MEL-5 0.062 38.905 13.804 Melanoma UACC-257 0.020 66.069 10.233 Melanoma UACC-62 0.014 20.893 0.170 Ovarian cancer IGROV1 0.018 19.055 0.295 Ovarian cancer OVCAR-3 2.512 48.978 17.783 Ovarian cancer OVCAR-4 0.562 72.444 16.218 Ovarian cancer OVCAR-5 0.017 40.738 12.023 Ovarian cancer SK-OV-3 12.882 100.000 41.687 Kidney cancer 786-0 5.129 63.096 23.442 Kidney cancer A498 0.191 44.668 4.169 Kidney cancer ACHN 0.275 83.176 21.878 Kidney cancer CAKI-1 0.389 100.000 26.915 Kidney cancer SN12C 0.851 47.863 18.621 Kidney cancer TK-10 0.224 100.000 23.442 Renal cancer UO-31 0.158 40.738 11.482 Prostate cancer PC-3 8.128 100.000 37.154 Prostate Cancer DU-145 2.138 95.499 22.387 Breast cancer MCF7 10.965 85.114 30.903 Breast cancer NCI/ADR-RES 3.467 100.000 25.704 Breast cancer MDA-MB-231 0.069 35.481 10.471 Breast cancer HS 578T 0.617 85.114 13.490 138999.doc -159- 200951107 Discussion group cell line GI50 (pM ΙΧ50(μΜ) ΤΘΙ(μΜ) Breast cancer MDA-MB-435 0.035 41.687 12.303 Breast cancer BT-549 5.754 47.863 20.893 Breast cancer T-47D 4.898 100.000 38.019 Breast cancer MDA-MB-468 0.019 54.954 10.233 Example 29: Live life antiproliferative activity In the present example, the test of N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2, The following effects of 3-dihydroxypropyl)cyclopropane-1-sulfonamide: (1) activity against the growth of several tumor cell lines with different mutations (GI5G); (2) targeting several B-Raf mutations The growth activity of the cell line (GI5G); (3) the effect on the growth of fixation-independent cells; (4) the effect on the cell cycle; and (5) the toxic effects on the primary liver and kidney cells. Example 29A: Cell culture/growth inhibition assay Human melanoma A375 cells and human colon cancer C〇1〇205 cell line were obtained from ATCC (Manassas, VA). A375 cells were maintained in DMEM supplemented with 10% fetal bovine serum, glutamic acid (2 mM), penicillin (100 U/ml) and streptomycin (100 pg/ml). The cells were maintained at 37 ° C, 5% CO 2 and 100% humidity. C〇1〇205 cells were maintained in RPMI supplemented with 10% fetal bovine serum, glutamic acid (2 mM), penicillin (100 U/ml), and streptomycin (100 pg/ml). For growth inhibition experiments, cells were plated at 1000 cells/20 μM/well in white 3 84-well microplates. After 24 hours, 5 μL of 5 Χ drug stock solution was added. All drugs were initially prepared as a 20 〇x stock solution in DMSO, so the final DMSO concentration was 0.5%. The cells were incubated at 37 ° C for 48 hours and the ATP content was determined using CellTiterGlo (Promega, Madison, WI). Adenylate kinase (AK) release was determined using Toxilight (Cambrex, Walkersville, MD). Use GraphPad 138999.doc 200951107

Non-linear curve fitting was performed by Prism 4 (GraphPad Software, San Diego, CA). 4-amino-8-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-pyridinium [2,3-d]pyrimidine- 5(8H)-ketone (VRX-14686) is a cytotoxic agent used as a reference compound. Growth inhibition (%) = (media-only control value (RLU) - N-(S)-(3,4-difluoro-2-(2- gas-4-molylamino)-6-oxime Phenyl)-1-(2,3-di-dipropyl)cyclopropane-1-sulfonamide RLU)/(media-only control RLU-1 μΜ N-(S)-(3,4-two Gas - 2-(2- gas-4-Epylamino)-6-methoxyphenyl)-1-(2,3-dipropylpropyl)cyclopropane-1-sulfonamide RLU) ; when measuring ATP content by N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-b (2,3-Dihydroxypropyl)cyclopropane-1-sulfonamide is based on growth arrest. Cell survival (%) = (N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2) , 3-dihydroxypropyl)cyclopropane-1-sulfonamide RLU — 10 μΜ VRX-14686 RLU)/(media-only control RLU-10 μt Tamoxifen RLU); The time is based on cell killing caused by VRX-14686. Cell killing (%) = (N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-( 2,3-Dihydroxypropyl)cyclopropane-1-sulfonamide RLU - vehicle control only RLU) / (10 μM tamoxifen RLU _ vehicle control RLU only); Based on cell killing caused by tamoxifen. RLU = relative luminescence unit Example 29B: Evaluation of cell cycle arrest 138999.doc -161 - 200951107 A375 cells were plated at 10,000 cells/200 μM/well in 96-well microplates. After 24 hours, the cells approached 50% confluence and added 50 μL of the 5 Χ drug stock solution. After another 24 hours, the cells were trypsinized, fixed in 200 μM Prefer (Anatech, Battle Creek, ΜΙ), and stored at 4 ° C overnight. The cells were then washed in PBS, permeabilized and stained in 1. 1% Triton X-100, 200 pg/ml DNase without DNase and 25 pg/ml propylene iodide: (Molecular Probes, Sunnyvale, CA) 'And analysis was performed on Guava PCA-96 (Guava Technologies, Foster City, CA). Data was analyzed using ModFit LT (version 3.0, Verity, Topsham's ME). Evaluation of fixation-independent cell growth inhibition A well of "ultra-low binding" plate (Corning, Acton MA) was filled with 60 μM of a 0.15% agarose solution in complete RPMI. Next, add 6〇01 to 15.15% agarose per well to contain 9〇〇〇(:〇1〇2〇5 cells in complete RPMI. After 24 hours, add 60 μM in complete agarose-free 3 Χ drug solution in RPMI. After 7 days, add 36 μΐ 6 Χ MTS reagent per well (CellTiter 96 Aqueous, Promega, Madison, WI). After 2 hours at 37 ° C, in the M5 plate reader (Molecular Devices) Absorbance at 490 nm was measured on Sunnyvale, CA. Non-linear curve fitting was performed using GraphPad Prism 4. Growth inhibition against MEK-dependent cancer cell growth (Gl50) B-Raf mutant cell A375 (human) Melanoma), A431 (melanoma), C〇1〇205 (colon cancer), HT29 (colorectal adenocarcinoma), MDA-MB231 (breast cancer) and BxPC3 (pancreatic cancer) are exposed to N-(S) -(3,4- 138999.doc • 162· 200951107 two mice - 2- (2-gas-4-molylamino)-6-methyllacyl phenyl)-1-(2,3 - two Propylamine cyclopropane-1-sulfonamide for 48 hours and analysis of ATP content. Using 1 μΜ N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamine) (6-methoxyphenyl)-1-(2,3-dihydroxyl) Propyl)cyclopropane-1-sulfonamide assay for 100% growth arrest

The table below shows the average gi50 value for at least three experiments from each cell line and shows N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)- 6-Methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide in three B-Raf mutant cell lines (A375, C〇1〇205 and HT29) and Growth inhibition was induced in a ras/raf/MEK/MAPK pathway wild-type cell line (A43 1) with an average potency of 79 nM (±9 nM). Cell line average StDev CV A375 71 nM 12.1 nM 17% A431 86 nM 25.4 nM 30% C〇1〇205 89 nM 40.1 nM 45% HT29 70 nM 12.2 nM 18% MDA &gt;1 μΜ BxPC3 &gt;1 μΜ In one In an independent study, B-Raf mutant cells A375 (human melanoma), SK Mel 28 (human melanoma), and C〇1〇205 (human colon cancer) with log-phase division were exposed to N-(S) -(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1 - sulforaphane for 48 hours and analysis of ATP content. The following table shows GI5Q for each cell line indicating N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl) 1-(2,3-Dihydroxypropyl)cyclopropane-1-sulfonamide resulted in growth inhibition near the EC5Q value of its MEK inhibition. 138999.doc -163 - 200951107 Cell line GI5〇(nM) A375 56 SKMel 28 105 C〇1〇205 27 Figure 10A and Figure 10B show exposure to increasing concentrations of N-(S)-(3,4-difluoro Logarithmic phase of -2-(2- gas-4-e-phenylamino)-6-methoxyphenyl)-1-(2,3-dilightylpropyl)cyclopropane-1-sulfonamide The growth of the split A375 cells is stagnant. Analyze the ATP content of the cells. Use 1 μΜ N-(S)-(3,4-difluoro-2-(2-fluoro-4-mothenylamino)-6-methoxyphenyl)-1-(2,3 - two 100% growth arrest was determined by propyl propyl) acetoacetate _ 1 - sulfoximine. Cytotoxic lysis of cell supernatants was analyzed by measuring the release of adenylate kinase (AK). Exposure of log phase split A375 cells to N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1- (2,3-Dihydroxypropyl)cyclopropane-1-sulfonamide and PD-325901 lasted 48 hours. (1 〇〇% cell kill was determined using 20 μM tamoxifen). The results are shown in Figure 11. This data indicates N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl in several sensitive human cancer cell lines. --1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide causes non-toxic growth arrest by (1) growth arrest (ATP quantification); and (ii) lack of cytotoxic cytolysis (AK release) proved. Lack of AK release was confirmed for all cell lines tested. Example 29C: Fixation independent growth inhibition Quantitative assessment of exposure to N-(S)-(3,4-di-2-(2-fluoro-4-iodophenylamino)-6 in a 96-well microplate format -Methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide 7 days of C独立1〇205, A375 and MDA-MB231 cells were independently grown independently. Viability was determined by MTS assay. The GI5 〇 value is shown below: 138999.doc -164- 200951107 Cell line mean StDev CV C〇1〇205 40 nM 8.1 nM 20% A375 84 nM 17.2 nM 21% MDA-MB231 81 nM 55.6 nM 69% Figure 12A-12C Showing N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropane (a) growth inhibition and (A) growth and inhibition of human colorectal cancer C〇1〇205 cells (GI5〇=ll nM), (B) A375 cells (GI5〇=22 nM) C) Inhibition of MDA-MB23 1 cells, which did not show N-(S)-(3,4-difluoro-2-(2-milo-4-mothenylamine) in a two-dimensional fixation-dependent assay ))-6-Methoxyphenyl)-1-(2,3-di-propylpropyl)cyclopropane-1-sulfonamide causes growth arrest. Exposure of log phase split A375 cells to N-(S)-(3,4-difluoro-2-(2-dis-2-ylphenylamino)-6-methoxyphenyl)-1- (2,3-Dipropylpropyl)cyclopropane-1 -sulfonamide (1 μM) was analyzed for growth inhibition (ΑΤΡ content) and cytotoxic dissolution (ΑΚ release) of the cell supernatant over 48 hours. 100% survival was determined in the vehicle-only control wells (ΑΤΡ assay). The results shown in the table below indicate Ν-(S)-(3,4-di--2-(2-up-4-phenylphenylamino)-6-decyloxyphenyl)-1-(2, 3-Dihydroxypropyl)cyclopropane-1-sulfonamide causes non-toxic growth arrest in B-Raf mutant human melanoma A375 cells. Control % ATP, cell viability 27% ΑΚ, cell kill 4% Example 29D: fixation independent growth inhibition Quantitative assessment of sessile independent growth in a 96-well microplate format. Figure 13A shows inhibition of growth of human colorectal cancer C〇1〇205 cells and GI5〇 values at 6 nM and 11 nM, respectively. Figure 13B shows the growth of A375 cells by 138999.doc-165-200951107 and the GI50 values at 5 nM and 22 nM. Example 29E: N-(S)-(3,4-Difluoro-2-(2-l-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropane Cell cycle analysis of growth arrest caused by cyclopropane_methanesulfonamide has been shown to inhibit G1/S phase cell cycle arrest in A3 75 cells. Exposing logarithmic cleavage into 3 75 cells exposed to 1^-(8)-(3,4-difluoro-2-(2-dis-2-ylphenylamino)-6-methoxyphenyl) -1-(2,3-dipropylpropyl)cyclopropan-1 -lanine for 24 hours and using flow cytometry to determine the percentage of stained cells for a phase-dependent amount of intracellular DNA . The following table shows N-(S)-(3,4-difluoro-2-(2-tyano-4-aminophenyl)-6-decyloxyphenyl)-1 -(2,3- Dipropyl propyl) Cyclopropanone-1 _ continued decylamine and control (% of cell distribution in the respective growth phase of vehicle-treated cells. Growth period % G1 S G2 Control 61.8 27.1 11.1 N-(S )-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-oxime 111 nM 84.7 11.8 3.5 oxyphenyl)-1-(2,3-dihydroxypropane Cyclopropanol-1 - sulfonamide 37 nM 74.3 18.7 7.0 Figure 14A and Figure 14B show N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino) Effect of 6-methoxyphenyl)-1-(2,3-di-dipropyl)cyclopropan-1-one on the cell cycle progression, which shows that A375 cells are exposed to N-(S) )-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane- 1-sulfonamide causes a G1 arrest in the cell cycle, as indicated by cell depletion at G2 and S. Example 29F: Assessment of primary hepatocyte and renal cytotoxicity Rat liver cell line obtained from cold CellzDirect (Austin, TX) and according to 138999.doc -166 - 200951107 Manufacturer's Description Apply to collagen coated 96-well plates. Drugs were added 4 hours after plating (final DMSO concentration 0.5%). The coated human hepatic cell line was obtained from CellzDirect and processed according to the manufacturer's instructions. Human renal proximal tubular epithelial cells (RPTEC) were obtained from Cambrex and processed according to the manufacturer's instructions. Cells were expanded for 4 days and then applied to 96-well plates at 50,000 cells/well for drug exposure. After an hour, the supernatant AK content was determined using Toxilight and m was used.

CellTiterGlo measures cellular ATP content. The complete lethal value was determined using 15 μΜ VRX-14686. The results are shown below. Very little cell lysis was observed. In a newly implanted primary human hepatocyte at 30 μΜ N-(S)-(3,4-difluoro-2-(2-fluoro-4-cyclopropanyl)-6-methoxy Phenyl)-1-(2,3-dipredylpropyl) was the lowest toxicity (81% survival) observed under 1-sulfonamide. 11? D: (The cells showed dose-dependent sputum consumption and significant cytolysis (30 μΜ). ATP (% cell survival) AK release (% cell survival) Compound A Hepatocyte RPTEC Hepatocyte RPTEC Rat human human rat Human Humans 30.0 57% 81% 34% 91% 109% 41% 10.0 72% 107% 85% 93% 112% 99% 3.3 87% 104% 91% 97% 102% 95% 1.1 114% 108% 94% 96% 92% 96% The above data indicates that (l) N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)- 1-(2,3-Dihydroxypropyl)cyclopropane-1-sulfonamide inhibits cell growth and division of specific human cancer cells in a fixation-dependent proliferation assay (GI50 values in the range of 70-89 nM), However, it did not lead to toxicity as determined by cell lysis assay; (2) N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodobenzene 138999.doc -167- 200951107 Amino)-6-methoxyphenyl) small (2,3-dipropylpropyl)cyclopropanone-inhibition of cell growth in specific human cancer cells in fixation-dependent and independent proliferation assays Splitting, 〇15() values are 51 11 PCT and 22 nM, respectively; (3) n_ (S)-(3'4-difluoro-2-(2-fluoro- 4-iodophenylamino)-6(methoxyphenyl)-b (2,3-dihydroxypropyl)cyclopropanesulfonamide causes arrest in Α375 cells and inhibits detachment-independent growth, providing evidence Indicates anticancer activity in a physiologically relevant live litter model; and (4) N_(S)_(3,4·difluoro_2_(2_fluoro-4-iodophenylamino)-6- Methoxyphenyl)dihydroxypropyl)cyclopropane-1-sulfonamide showed almost no cytotoxicity against primary normal human hepatocytes, human renal proximal small fistula epithelial cells, and rat hepatocytes. Example 30: N-(S)-(3,4-Difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-di Pharmacokinetic profile of propyl propyl sulfonate _1_continued amine in multiple cancers in multiple doses (mg) N Tmax (hours) Cmax (Mg / mL) C^4 hours #g /mL) AUCT (Mg/mL) tl/2 (hours) Rac Cmax Rac AUCT 2 ^ 1.33 0.0504 0.00938 0.517 11.4 1.76 — 1.90 ^ (23.9) (21.7) (49.2) (82.8) (61.2) (38.8) (35.6) 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33.3) (16.6) (12.2) (5.79) (23.8) (38.5) (23.5)

Rac · Cumulative Index * Inaccurate estimates due to limited sampling time are administered N-(S)-(3,4-difluoro-2-(2-) multiple times at 2, 4 or 6 mg per individual N-(S)-(3,4-difluoro-2-(N)(4-(S)-(3,4-difluoro-2-(4-fluorophenyl)dihydroxypropyl)cyclopropane 2-Fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide is easily available in the range 138999.doc -168 - 200951107 "The average u between 1.33 and i.50 hours is absorbed. The average ^: the value increases with the dose in proportion to the dose. The ', 4 曰 range is for cmax. 49 to 丨76 and for a 2 'I at 1.90 to 2, 〇7' this indicates a modest accumulation. Although the half-life cannot be accurately measured due to limited sampling time after multi-human administration, it is expected to be The half-life of the cumulative index can be longer than 22 hours after the administration. These half-life values are significantly longer than those observed in the mouse efficiency model, which is observed in the typical range of 2 to 3 hours. The ideal peak-to-valley ratio can be seen in all doses. Example 31 · N-(S)-(3,4-Difluoro-2-(2-fluoro-4-mothenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxyl) Propyl)cyclopropanesulfonamide is administered in multiple doses in healthy volunteers.

Rac . Cumulative index * Inaccurate estimates due to limited sampling time

N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl) was administered multiple times at 10 or 20 mg per individual. After q _(2,3_dihydroxypropyl)cyclopropane_ 1-sulfonamide, n-(sH3,4_difluoro_2_(2_fluoro_4_iodophenylamino)_6_methoxy Phenylphenyl)-1-(2,3-dihydroxypropyl)cyclopropane_indolesulfonamide is readily absorbed in an average Tmax ranging from 2.00 to 2.25 hours. The mean Cmax, Ct and AUC values increase with dose. Separately, the cumulative index for 138999.doc -169- 200951107

Cmax is between 1.14 and 1.23 and for AUC is between 1.24 and 1.29, which indicates a slight accumulation. For both dose regimes, the half-life is similar and ranges from 13 to 15 hours. These half-life values are shorter than those observed in cancer individuals. Example 32: Invited cold antiproliferative activity In a cell proliferation assay, N_(S)-(3,4-difluoro, 2-(2-fluoro-4-iodophenylamine) was tested in a cell line derived from human gastric cancer. Effect of 6-methoxyphenyl) 4-(2,3-dihydroxypropyl)cyclopropane-indolesulfonamide on inhibition of cell proliferation. Example 32A: Cell Culture/Growth Inhibition Assay: Human gastric cancer Hs746t cell line was obtained from ATCC (Manassas, VA). Hs746t cells were maintained in DMEM supplemented with 10% fetal bovine serum, penicillin (1 〇〇 U/ml) and streptomycin (1 〇〇 pg/mi). The cells were maintained at 37 ° C, 5% CO 2 and 100% humidity. For cell proliferation experiments, cells were plated at 3000 cells/1 μ μΐ/well in white 96-well plates with a transparent substrate. After 24 hours, the cell culture medium was removed and contained N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-fluorenyloxy group at different doses. Substrate replacement of Bu (2,3-dihydroxypropyl)cyclopropane-1-sulfonamide. After incubation for 48 hours at 37 ° C, ATP content was determined using CellTiterGlo (Promega, Madison, WI) and luminescence values were read using LJL Biosystems Analyst HT (Sunnyvale, CA). The ATP content for each dose was determined in triplicate using separate wells. Relative cell number = (average RLU (N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-decyloxyphenyl)-1-( 2,3-Dihydroxypropyl)cyclopropane-1-sulfonate 138999.doc 170· 200951107 Indoleamine treatment))/(average RLU of the vehicle-only control group). Figure 19 shows the number of cells (relative to the vehicle 0iN_(s)_(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)dihydroxypropyl) ring a plot of propane-1 -sulphonamide concentration and showing N_(s)_(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl) Hydroxypropyl)cyclopropane _ 1-bristamine inhibited the proliferation of human gastric cancer Hs746t cells after 48 hours of treatment. Example 33: Live ♦ Anti-proliferative activity In a cell proliferation assay, N_(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamine) was tested in a cell line derived from human gastric cancer. Effect of )6-methoxyphenyl)-1-(2,3-dilightylpropyl)cyclopropanone-indoleamine on inhibition of cell proliferation. Example 33A: Cell Culture/Growth Inhibition Assay The human lunar cancer AGS cell line was obtained from ATCC (Manassas, VA). AGS cells were maintained in DMEM/F12 supplemented with 10% fetal calf serum, penicillin (1 〇〇 U/ml) and streptomycin (100 pg/ml). The cells were maintained at 37. (:, 50/〇C〇2 and 100% humidity. For cell proliferation experiments, cells were plated at 3000 cells/1 μm/well in white 96-well plates with a transparent substrate. After 24 hours , remove the cell culture medium and contain different doses of Ν_(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1 Medium replacement of -(2,3-dihydroxypropyl)cyclopropane-oxime-sulfonamide. After incubation for 3 days at 37 °C, 'ATP content was determined using CellTiterGlo (Promega, Madison, WI) and LJL Biosystems Analyst was used The luminescence value was read by HT (Sunnyvale, CA). The ATp content of each dose was determined in triplicate using 138999.doc -171- 200951107 in separate wells. In another experiment, 1 〇〇〇 cells/1 〇〇μΐ/well plate and cells were treated for 6 days and assayed as described above. Relative cell number = (average RLU (N-(S)-(3,4-difluoro-2-(2-fluoro-4-) Iodophenylamino)-6-methoxyphenyl)-1-(2,3-dipropylpropyl)cyclopropanone _丨_ 醯 醯 治疗 治疗)))) Average RLUp Figure 15A and Figure 15B show exposure to n_(s)-(3,4-difluoro^2-(2-fluoro-4) _ Iodophenylamino)-6-methoxyphenyl)-: 1-(2,3-dihydroxypropyl)cyclopropanesulfonamide (A) 3 days and (B) 6 days later N-( S)-(3,4-Difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane _丨_ sulfonamide concentration versus cell number (relative to vehicle), which shows N_(s)_^, 'difluoro----fluoro-彳-iodophenylamine-based broad-hearted methoxy Benzyl phenyl bromide ^^ dihydroxypropyl)cyclopropane-1-sulfonamide inhibited the growth of human gastric cancer AGS cell line. Example 34: N_(S)-(3,4_difluoro- 2_(2_Fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-Isulfonamide treated nude mice The growth response of in situ human Hep3B tumors was compared with the optimal dose of 5-fluorouracil (75 mg/kg) in BALB/cxian/(10) mice. 'Evaluate N_(8)·(3,4_difluoro·2_(2) _Fluorine_4•iodophenylamino)-6-methyl milk base)-1-(2,3-dipropylpropyl)cyclopropanone-indole_manufactured amine ("Compound Α") is inhibited Dose-response efficacy of in situ Hep3B2.1-7 human hepatocarcinoma development. Animals, in this item Studies using female B ALB / c mice (University of Adelaide, Waite Campus, SA, Australia), 10_14 weeks old, body weight range 138999.doc -172- 200951107 follows: 19.1-29.94 g (mean 22.95 g). The mice were divided into 6 study groups (4 treatment groups and 2 control groups) as follows: Number of mice per group: 1 in Groups 1 to 5; Acceptance rate (Take-Rate) In the control group, j 5 (group 6) maintained the mice in a controlled environment with a 12-hour light/12-hour dark cycle under shielding (isolation) (target range: temperature 21 ± 3 r, humidity) 3〇_ 70°/. 'Air exchange per hour 1 〇 _ 丨 5 times). Continuous monitoring of temperature and relative humidity allowed the animals to consume the commercially available singer diet (Rat and Mouse Cubes &gt; Speciality Feeds Pty Ltd, Glen Forrest, Western Australia) and tap water. All food and water supplies are sterilized using autoclave treatment. Tumor inoculation\ Hep3B human hepatoma cells (from the second passage of working stock VP-Stock 353) were cultured in RPMI 1640 cell culture medium supplemented with 10% FBS and penicillin-streptomycin (50 IU/mL final concentration). The cells collected by trypsinization were washed twice in HBSS and counted. The cells were then resuspended in HBSS · Matrigel (l ·· 1, v/v) and adjusted to a final volume containing lxlO8 cells/mL. Prior to inoculation, the incision site was adequately scrubbed with alcohol and cut through the abdominal wall to expose the liver. 10 pL of cells (1 x 106 cells) were released by introducing the needle through the liver surface. Hold the needle in this position for approximately 30 seconds to allow Matrigel® to polymerize to prevent tumor cells from leaking into the abdominal cavity. Treatment was started 14 days after inoculation. On day 7 of the study (21 days after inoculation), all mice in the 'acceptance rate' control group were sacrificed and visually assessed for the presence of tumors in liver 138999.doc-173-200951107. Materials, the following materials were obtained from their respective suppliers. A sterile saline solution (0.9% NaCl (aq)) was obtained from Baxter Healthcare Australia, Old Toongabbie, NSW, Australia. Cetyl polyoxyethylene ether EL was obtained from Sigma-Aldrich Pty Ltd, Castle Hill, NSW, Australia. 5-Fluorine shouting (clinical formulation, clear, colorless liquid) was obtained from Mayne Pharma Pty Ltd. RPMI 1640 cell culture medium, FBS and HBSS were obtained from Invitrogen Australia Pty Ltd, Mt Waverley, VIC, Australia. Penicillin-streptomycin and trypan blue were obtained from Sigma-Aldrich, Castle Hill, NSW, Australia. Hep3B2.1-7 human hepatoma cell line was derived from American Type Culture Collection 5 ATCC, Rockville, MD, USA. Matrigel® was obtained from BD Biosciences, North Ryde, NSW, Australia o in inoculation suspension The use of Matrigel® in the solution improves tumor acceptance and reduces tumor size variability, and Hep3B2.1-7 human liver cancer grows more stably when inoculated in the presence of this extracellular matrix. Preparation and Administration of Compounds·· Cetyl polyoxyethylene ether EL: brine (1: 9, v/v; vehicle control), N-(S)-(3,4-difluoro-2-(2-fluoro-4-e-benzene) Aminoamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide ("Compound A") or 5-fluorouracil (Compound Control) According to the following schedule: 138999.doc -174- 200951107 Group compound dose (mg/kg) Treatment------------------> Vehicle control 10 mL/kg 35• Continued for 21 days (. Once a day for 19 days (0 to 18 days) Raspberry days last for 19 days (0 to 18 days) Once a day for 19 days (0 to 18 days) 2 Compound A 0.2 mL 10 mL/kg = 2 Mg/kg one per day For 21 days (〇 to 20 days) 3 Compound A 1.0 mL 10 mL/kg = 10 mg/kg Once a day for 21 days (0 to 20 days) 4 Compound A 5.0 mL 10 mL/kg = 50 mg/kg Λς - ---- The mother's family lasts for 21 days (0 to 20 days) once a day for 19 days (〇 to 18 days) 5 5-fluorouracil 7.5 mL 10 mL/kg = 75 mg/kg once a week for 21 days ( Days, 7 and 14 days Ί Mother once a week for three weeks (days 0, 7 and 14) 6 &amp; rate 1 control not treated - - vehicle control hexadecyl ethoxylate EL: saline (1: 9, v/v) was orally administered once a day for a period of 21 days (days to 20 days) at a dose of 10 mL/kg. N-(S)-(3,4-difluoro- 2-(2-Fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane_1_sulfonamide was formulated in cetyl alcohol Polyoxyethylene ether EL: saline (1: 9, v/v). The stock solution was prepared once a week and stored at 4 ° C. The dosing solution was prepared after the respective administration. N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) The cyclopropane-1 -sulfonamide was orally administered once a day for 21 days (days 0 to 20) in a dose of 10 mL/kg. This compound was administered at a dose of 2, 1 Torr and 50 mg/kg. The 5-fluorouracil clinical formulation was diluted in sterile saline and administered intravenously via the tail vein at a concentration of 75 mg/kg in a dose of 10 mL/kg once a week for 3 weeks (at 0, 7 and 14 days). No treatment was applied to the mice in the sixth group ("acceptance rate" control group). On the 7th day of the study (21 days after inoculation), the mice were sacrificed and the liver was exposed to determine the "acceptance rate" and size of the tumor in the liver wall. 138999.doc • 175- 200951107 The body weight of each animal was measured immediately prior to dosing. The volume administered to each mouse was calculated and adjusted based on body weight. Tumor measurement: When the liver and tumor were removed after the death of the mice on the day of the study, the liver and the wet weight of the tumor were measured. At the end of the study, all mice from each study group were sacrificed and weighed. If there is a visible tumor, the number of visible tumors is counted. These tumors were removed from the liver and weighed. Data measurement and sample collection time course 捸 Measure weight ~ Liver weight and swollen sample collected liver and tumor liver and tumor liver ___ Day, then three times a week (Monday, Friday), &lt; The day of the end of the xfe study (for groups 1 to 5 and jyi „ on the day of the bundle, after the death of groups 1 to 5) - and from the fifth group of deaths after the last treatment The liver of the mouse and the wet weight of the tumor. ___ All mice from the 6th group on the 7th day of the study ("Acceptance rate" control group). ________ In the 1st to 5th groups on the day of the end of the study All mice were obtained after death, and from the fifth group that died on the day of the last treatment: snails sold. All mice in groups 1 to 5 were obtained after the end of the study, and from the last treatment. The fifth group of deaths on the day of the death of the water mouse. Data acquisition and calculation: use the barcode reader (LabMax I, DataMars, before getting the data)

Switzerland) Scanning sensors for various animals (Bar Code Data Systems

Pty Ltd, Botany Bay, NSW). All measurements are based on the same hand caliper (Absolute Digimatic Model CD-6" CS, Mitutoyo

Corporation, Japan) obtained. Pendragon Forms 4.0 (Pendragon® Software Corporation, Libertyville, IL, U.S.A.) was used as a transmission software to synchronize the data with the security correlation of vivoPharm 138999.doc •176· 200951107. Use AIDAM v2.4 for data reporting and data calculation. Statistics and calculations: All statistics and calculations were performed using SigmaStat 3.0 (SPSS Australasia Pty Ltd, North Sydney, NSW, Australia). A double sample t test was used to determine the significance of body weight changes from day 0 to day of the study in this treatment group. Perform a Mann-Whitney rating and test when the data fails the normality test or the equivalent difference test. Kruskal-Wallis One-Way Analysis of Variance (Kruskal-Wallis One-Way Analysis of Variance (ANOVA) on The same statistical analysis was performed on the data of mice with tumors in the study. The p value of less than 0.05 was considered significant. The liver weight and tumor weight data of tumor-bearing mice and each mouse with tumors Average weight of liver and tumor in each group in a group Treatment mean liver weight (g) SEM mean tumor weight (g) SEM Number of tumor-bearing mice (number of 10) 1 Vehicle control 4.560 0.673 3.382 0.979 4 2 Compound A (2 mg/kg) 2.775 0.475 1.776 0.576 6 3 Compound A (10 mg/kg) 2.551 0.446 1.407 0.465 7 4 Compound A (50 mg/kg) 1.677 0.161 0.624 0.257 4 5 5FUTM (75 mg/kg) 1.217 0.051 0.143 0.078 4 A sample of mice in Group 5 (75 mg/kg 5-fluorouridine 01 bite) was not collected and this group was killed during the study because in some mice There is a big swelling in the body 138999.doc -177- 200951107 This is indicated by the appearance of the expanded abdomen, which was terminated 18 days after the initial treatment. In N-(SH3,4-difluoro-2-(2-fluoro-4.e-phenylamino)+ A The dose-dependent alleviation trend of hepatic and facial tumors in the oxyphenyl)-=,3·di-propylidene)-cyclopropyl-cansamine treatment group was significant. When considering only tumor-bearing mice When found, the highest dose of N_(s)_(3,4_二气冬(2_气_Μphenylamino)_6_methoxyphenyl) gastric dipropyl propyl) The average liver weight of the group treated with 1-sulfonamide (Group 4, 50 mg/kg) and 5-fluorouracil (Group 5, 5〇mg'kg) was significantly different from that of the vehicle control group (Group 1) ;ρ&lt;0·05). And, it was found to be 8)_(3,4_二说_2_(2_Gas_4_ 峨Phenylamino)-6-methoxyphenyl...2,3-dipropylpropyl) The average tumor weight of the burned + continuation of the amine (group 3 and group 4, respectively, 1 〇 mg / ] ^ 5 〇 _ (8) and ^ fluorouracil (Group 5, 75 mg / kg) was significantly different from the media Control group. These results are presented graphically in Figure 16 (mean liver weight - mice with tumor only) and Figure 17 (liver tumor weight - mice with tumor only). Example 35: in different amounts N_(s)_(3,4_Difluoro_2_(2·fluoro_4_iodophenylamino)-6-methoxyphenyl)dihydroxypropyl)cyclopropane sulfonamide treatment naked Growth response of in situ human HT-29 colon tumors in mice was compared with optimal dose of 5 • fluorouracil (75 mg/kg) in BALB/cxian/„M mice to evaluate N_(s)_ (3,4_Difluoro_2_(2_fluoro_4_iodophenylamino)-6-methoxyphenyl)4-(2,3-dihydroxypropyl)cyclopropane_丨·sulfonate Amine ("Compound A") inhibits in situ ht-29 human colorectal adenocarcinoma development 138999.doc,. 200951107 The dose response effect. Animals: Female BALB/C(10)/(10) mice were used in this study (university of

Adelaide, Waite Campus, SA, Australia) ‘ 7-12 weeks old, weight range is as follows: 16.58-25.39 g (mean 21.52 g). The mice were divided into 6 study groups (4 treatment groups and 2 control groups) as follows: Number of mice per group: 1 in group 1 to group 5; in acceptance rate in control group Nine (Group 6) mice were maintained in a controlled environment with a 12-hour light/12-hour dark cycle under barrier (isolation) conditions (target range: temperature 21 ± 3 〇 c, humidity 70 ° /. Air exchange 104 times per hour). Continuous monitoring of temperature and relative humidity. Animals are given a random diet of commercially available caries (Rat and Mouse Cubes &gt; Speciality Feeds Pty Ltd &gt; Glen Forrest &gt;

Western Australia) and tap water. All food and water supplies are sterilized using autoclave treatment. Tumor inoculation ht-29 human colorectal adenocarcinoma cells cultured in RPMI1640 cell culture medium supplemented with 10% FBS and penicillin-streptomycin (50 IU/mL final concentration) (from the fourth step of the working stock VP-Stock 3 25 generation). Cells were harvested by trypsinization, washed twice in HBSS and counted. The cells were then resuspended in HBSS and adjusted to a final volume containing 2 x 108 cells/mL. Prior to inoculation, the incision site was adequately scrubbed with alcohol and cut through the abdominal wall to expose the cecal wall. The needle was introduced through the surface of the cecum wall to release 5 pL of cells (1 X 1 〇 6 cells). 138999.doc -179- 200951107 Materials · The following materials were obtained from their respective suppliers. A sterile saline solution (0.9% NaCl (aq)) was obtained from Baxter Healthcare Australia, Old Toongabbie, NSW, Australia. Cetyl polyoxyethylene ether EL was obtained from Sigma-Aldrich Pty Ltd, Castle Hill, NSW, Australia. 5 - Say urine, bite (clinical formulation, clear, colorless liquid) was obtained from Mayne Pharma Pty. RPMI 1640 Cell Culture Medium, FBS and HBSS were obtained from Invitrogen Australia Pty Ltd, Mt Waverley, VIC, Australia. Penicillin-Lycomycin and Trypanosoma blue were obtained from Sigma-Aldrich, Castle Hill, NSW, Australia. The HT-29 human colorectal adenocarcinoma cell line is derived from the American Type Culture Collection (ATCC), Rockville, MD, USA. Preparation and administration of compound, cetyl polyoxyethylene ether EL: saline (1: 9, v/v; vehicle control group), N-(S)-(3,4-difluoro-2-(2) -fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide or 5-fluorouracil (compound control) The system was administered according to the following schedule: Group composition dose (mg/kg) Treatment time course treatment 1 Vehicle control 10 mL/kg Once a day for 21 days (days 0 to 20) Once a day for 21 days (Days 0-20) 2 Compound A 0.2 mL 10 mL/kg = 2 mg/kg once daily for 21 days f days 0 to 20) once daily for 10 days (龛〇 to 9 days) 3 Compound A L0 mL 10 mL/kg=10 mg/kg once daily for 21 days (days 0 to 20) once daily for 21 days (days to 20 days) 4 Compound A 5.0 mL 10 mL/kg = 50 mg/kg once daily for 21 Day (Day to 20 days) Once a day for 8 days (Day to 7 days) 5 5-Fluorouracil 7.5 mL 10 mL/kg=75 mg/kg Once a week for three weeks (0, 7 and 14) Once a week for three weeks (0, 7 and 14) 6 "Acceptance rate" control is not treated - - 138999.doc -180- 200951107 Vehicle control cetyl polyoxyethylene ether EL: saline (1: 9, v/v) was orally administered once a day for 2 days at a dose of 10 mL/kg ( Dijon to 20 days). N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropane Base) cyclopropane·〗 _ sulfonamide is formulated in hexadecanol polyoxyethylene shouting EL: brine (1: 9, v/v). Stock solutions were prepared once a week and stored at 4 °C. The dosing solution is prepared by preparing β Ν_〇_(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-l-( 2,3-Di-propylidene)cyclopropanone-1 -ylideamine was administered orally once a day for 21 days at a dose of 2 10mL/kg at doses of 2, 10 and 50 mg/kg ( Dijon to 2 days). The 5-fluorouracil clinical formulation was diluted in sterile saline and administered intravenously via the tail vein at a dose of 75 mg/kg in a dose volume of 1 〇mL/kg once a week for 3 weeks (in Dijon, 7) And Haotian). No treatment was applied to the mice in the sixth group ("acceptance rate" control group). On the 7th day of the study (21 days after inoculation), the mice were sacrificed and the colon was exposed to determine the "acceptance rate" and size of the tumor in the cecum wall. The body weight of each animal was measured immediately before administration. The volume administered to each mouse was calculated and adjusted based on body weight. Tumor measurement: When the cecum and tumor were harvested after the death of the mice on the day of the study, the cecum and tumor wet weight were measured. At the end of the study, the cecum was excised from all mice in each study group and weighed while the tumor remained intact. Tumors were then taken from the intestine and weighed. 138999.doc -181- 200951107 At the end of the study, livers were also removed from all mice in each group and fixed in 10% buffered formalin. Five liver samples from the vehicle control group were embedded in paraffin, sectioned and stained with hematoxylin-eosin stain (H&amp;E) for histological evaluation of morphological changes. Data measurement and sample collection time-course data measurement body weight --- ~ three times a week (on Monday, week, the end of the study (for group 1 to group 5, cecal weight and tumor weight at termination) Blind and pickled samples from the mice in Groups 1 to 5 were collected from the cecum and tumors. All mice in the 6th group on the 7th day of the study ("Acceptance" control group) were obtained after death. The cecum and tumor were obtained from the death of all mice in Groups 1 to 5 on the day of the end of the study, and from the mice that died during the study. All of the groups 1 to 5 on the day of the liver free study. Mice were obtained after death, and from mice that died during the study. Data Acquisition and Calculation: Scanning the sensors of each animal using a barcode reader (LabMax I, DataMars, Switzerland) before acquiring data (Bar Code Data Systems Pty Ltd, Botany Bay, NSW. All measurements were taken with the same hand caliper (Absolute Digimatic Model CD-6" CS, Mitutoyo Corporation, Japan) using Pendragon Forms 4.0 (Pendragon® Softwar) e Corporation, Libertyville, IL, USA) Synchronize data with vivoPharm's security-related database as a transport software. Use AID AM v2.4 for data reporting and data calculation. Statistics and calculations: All statistical calculations use SigmaStat 3.0 (SPSS Australasia 138999.doc -182- 200951107

Pty Ltd’ North Sydney, NSW, Australia). A dual s-pattern t test was used to determine the significance of body weight changes during the day from the end of the study to the end of the study in a treatment group. 2_〇(3,4-fluoro-2-(2-fluoro-4-mothenylamino)-6-methoxyphenyl)-b (2,3) at 2 and 5 mg/kg In the group treated with _dihydroxypropyl)cyclopropane-1·sulphonamide, the treatment was interrupted early due to excessive weight loss. In these groups, a double sample t test was used to determine the significance of body weight changes between day 0 and the end of the study in the treatment group and between the last treatment day and the end day of the study in a treatment group. Perform a Mann_whitney rating and test when the data fails the normality test or the equal difference test. Single factor variability analysis (ANOVA) was performed at the end of the study on cecal weight and tumor weight data (all pairwise multiple comparison procedures and multiple comparisons vs control). When the data fails the normality test, convert the value to a natural logarithm before proceeding with the program. A p value of less than 0.05 was considered significant. Observations: Mean body weight loss was measured in all study groups (including vehicle control). Diarrhea and dehydration symptoms (impaired skin elasticity) were observed in all study groups (including the vehicle control group). Severe weight loss during the study period resulted in the lowest dose (2 mg/kg) and the highest dose (5〇mg/kg) of n_(s)_(3,4_-fluoro-2-(2-fluoro-4-) The treatment of the group of iodophenylamino)-6-methoxyphenyl)-bu (2,3-dihydroxypropyl)cyclopropane-1-sulfonamide was carried out on the 9th and 7th days of the study, respectively. stop. Because it accepts 1〇mg/kg2N_〇(3,4_二氤-2 gas 2_fluoro_ 4-iodophenylamino)-6-methylphenyl)_丨_(2,3_dihydroxy Propyl)cyclopropane_ 138999.doc -183- 200951107 1 - The weight loss of the sulfonamide group is less severe, so all treatments in this group are administered as scheduled. The mean weight loss at the end of the study in this group and the 5-fluorouracil treatment group was significant. Although the acceptance rate of HT-29 tumors in the ^receiving rate' group was 100% 21 days after inoculation, the size of these tumors was far less than expected. This may be due to N-(S)-(3,4-di-2-(2- gas-4-Ethylamino)-6-methoxyphenyl)-1-(2,3) There was no significant difference in mean cecum and tumor weight between the -dihydroxypropyl)cyclopropane-1-sulfonamide treated group and the vehicle control group. 5-fluorouracil also had no effect on the weight of the cecum and HT-29 tumors. Body weight measurement (±SEM) (last day of treatment and study termination) Group compound dose (mg/kg), path, time course host response δ body weight (8) (±SEM) Last day of treatment The last day of %δ body weight treatment δ Body weight (8) (SEM) The last day of treatment with %δ weight treatment (number of survivors/total) 1 Vehicle control - oral daily for 21 days (days 0 to 20) - _ -0· 8±0·4 -3.6 8/10 2 Compound A 2 once a day for 10 days (days 0 to 9) -2_4±1_4 (day 9) -11.1 0.1±0.9 0.4 4/10 3 Compound A 10 Oral once a day for 21 days (days 0 to 20) - -1.5 ± 0.3 -6.9 7/10 4 Compound A 50 once a day for 8 days (days 0 to 7) -3.8 ± 0.5 (day 7) ) -17.8 -1.3±0.9 -5.9 7/10 5 5-Fluorine 75 Intravenous once every week for three weeks (days 0, 7 and 14) - - -3.3±0.4 -15.2 8/10 Not collected Body weight data for Group 6 ("Acceptance" control group). On day 7 of the study (21 days after inoculation), the group was sacrificed to visually assess whether tumor growth was appropriate for the purposes of this study. 138999.doc -184- 200951107 Group 2 (2 mg/kg of N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-anthraquinone The treatment of phenyl)-1-(2,3-dilopropyl)cyclopropan-1-one (continued amine) was discontinued on study day 9 and group 4 (50 mg/kg of N-(S) )-(3,4-digas-2-(2- gas-4-mothylphenylamino)-6-methylphenyl)-1-(2,3-dipropylpropyl)cyclopropane Treatment with -1-sulfonamide was discontinued on study day 7, due to excessive body weight loss in mice. The remaining groups received all scheduled treatments during the study period.

The mean tumor weight for each group is shown in Figure 18. The average tumor weight for each group included only survivors until the last day of the study. The values of mice that died during the study period were not included in the calculated mean. Cecal weight and tumor weight dataset treatment animal ID cecal weight (g) tumor weight (g) mean cecal weight (8) SEM mean tumor weight (S) SEM 173811 0.:% 0.070 170774 0.331 0.160 170729 0.267 0.017 vehicle control group (10173673 0.307 0.005 1 hexaol polyoxyethylene ether 171429 175732 0.311 0.946 0.326 0.627 0.413 0.081 0.149 0.080 bL . Bond water) 171539 0.286 0.038 173576 0.287 0.002 170836 0.397 0.000 172014 0.506 0.176 175867 0.347 0.001 170936 0.170 0.001 172003 0.150 0· (8) 0 2 Compound A (2 176472 0.205 0.005 0.296 0.033 0.033 0.030 mg/kg) 171338 0.377 0.001 170825 0.233 0.122 174466 0.251 0.005 171587 0.322 0.003 3 Compound A (10 173623 0.287 0.000 0.244 0.025 0.078 0.059 mg/kg) 170793 0.198 0.000 172304 0.258 0.257 175676 0.111 0.008 171003 0.263 0.422 138999.doc -185- 200951107 171466 0.237 0.001 176386 0.234 0.014 170858 0.289 0.004 175862 0.320 0.100 171364 0.251 0.000 175697 0.230 0.002 171349 0.254 0.002 174272 0.238 0.000 176335 0.201 0.004 4 Compound A (50 mg/kg) 171041 174536 0.337 0.169 0.166 0.655 0.290 0.038 0.122 0.092 175656 0.328 0.001 173626 0.217 0.001 171437 0.312 0.001 174501 0.463 0.026 171322 0.355 0.245 175559 0.199 0.001 176302 0.360 0.000 176241 0.284 0.000 5 5FUTM (75 mg/kg) 175857 176242 0.421 0.706 0.010 0.329 0.391 0.050 0.069 0.041 174165 0.415 0.130 176417 0.327 0.079 170592 0.237 0.000 171501 0.377 0.003 Shaded box indicated by the study period Samples collected from dead mice. This value is excluded from the calculation of the mean value of cecal weight and tumor weight. The trend is shown at 10 mg/kg of N-(S)-(3,4-difluoro-2_(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-( 2,3 -Di-propyl propyl) 哀 丙 丙 -1 - After sputum treatment, ΗΤ-29 tumor and cecal weight data were reduced. Example 36: Delay in tumor growth in nude mice bearing human Α375 melanoma xenografts Six groups (η=9) of tumorized mice were used. The control group included 10% hexadecanol ethoxylate EL/saline vehicle administered by oral gastric tube (ρ〇), once daily for 14 days (qdxl4), and 30 mg/kg of the tail vein (iv) The second specific paclitaxel was used as a reference agent, administered five times every other day (q〇dx5) 138999.doc -186 - 200951107, and four experimental groups received 25 mg/kg or 50 mg/kg, qdx 14, or 12.5 or 25 mg/kg, bidxl4 orally N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl Dihydroxypropyl)cyclopropane _ 1-stone amide ("Compound A"). Treatment results were assessed as Tgd, which was defined as the difference in tumor volume between the treatment group and the control group at the median endpoint time. Toxicity was assessed by body weight measurement and clinical observation. Animals: Beach-free athymic nude mice, Harlan) were 10 to 11 weeks old and had a body weight (BW) range of 19.3 to 25.5 grams on the first day of the study. Animal Free Access to water (reverse osmosis, 1 ppm C1) and NIH3 1 modification and irradiation of Lab Diet®' consisted of 18.0% crude protein, 5.0% crude fat and 5% crude fiber. The mice were housed in a static micro-separation chamber on an ALPHA-Dri® bed-o'cobs® laboratory animal pad, in a 2-hour photoperiod with 2i_ 22C (70-72°F) and 40-60°/ . Under fullness. Adhere to the recommendations of the Laboratory Animal Feeding Management and Use Regulations for restrictions, grazing, surgical procedures, arrogance and fluid regulations, and veterinary care. Tumor transplant: Allogeneic transplantation was initiated by A375 human melanoma by continuous transplantation in athymic nude mice. A375 tumor fragments (~1 mm3) were subcutaneously transplanted into the right abdomen of each test mouse, and the average size of tumor growth was monitored to be 100-150 mm3. After 13 days, the designated day was the first day of the study, and the animals were divided into 6 Groups and each group consisted of 9 mice (reduced from 10) with individual tumor volumes ranging from 63 to 221 mm3 and the average tumor volume of each group was 125.3 to 125.9 mm3. Tumor volume was calculated using the following equation: tumor volume 138999.doc -187- 200951107 (mn^W^x/)/], where w = width of the A375 tumor (mm) and /= length of the A375 tumor (mm). Material: N-(S)-(3,4-di-2-(2-Ga-4-Ethylamino)-6-methyllacylphenyl)_ 1-(2,3-dihydroxy Propyl)cyclopropane-1-sulfonamide dissolved in 10% hexadecanol Ethyl ether EL salt solution at 5 mg/ml during ultrasonic treatment, vibration and heating to 35 °C to help Dissolved. A 5 mg/mL solution was used as the treatment administration solution for 50 mg/kg, and a treatment administration solution of 25 mg/kg and 12.5 mg/kg was prepared by serial dilution method. The drug solution was stored at room temperature for one week without exposure to light. The paclitaxel (NPI) dosing solution was prepared from a 30 mg/mL stock solution diluted to 3 mg/mL by 5% ethanol in 5% hexadecanol polyoxyethylene ether EL in 5% dextrose in water (D5W). Used for daily use. The paclitaxel dose in the Pacific is 30 mg/kg. The table below shows the treatment plan. Treatment regimen η Agent mg/kg Path time course 1 9 Vehicle - po qd&gt;&lt;14 2 9 Pacific paclitaxel 30 iv qod&gt;&lt;14 3 9 Compound A 50 po qd&gt;&lt;14 4 9 Compound A 25 po Bidxl4 Day 1 Dose 5 9 Compound A 25 po qd&gt;&lt;14 6 9 Compound A 12.5 po bidxl4 Day 1 dose Group 1 mice received a solution of 10% hexadecanol polyoxyethylene ether EL salt solution The vehicle was administered orally by gastric tube (po), administered 14 times a day (qdx 14), and served as a control group for tumor progression. Group 2 animals were administered intravenously 138999.doc -188- 200951107 (iv) with 30 mg/kg of paclitaxel as a reference, administered five times a day (q〇dx5). Mice in groups 3-6 received N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyl orally in the following schedules, respectively. Phenyl)-1-(2,3-dipropylpropyl)cyclopropanol-i_ decylamine: 50 mg/kg, qdxl 4 ; 25 mg/kg 'every day for 14 days, at first And the last day was given in a single dose (bid > <14); 25 mg/kg, qdxl4; and 12.5 mg/kg, bid&gt;&lt;14. All doses were administered in a volume of 0.2 mL per 20 g body weight, which was in accordance with the animal's body weight. End point: Tumors in all groups were measured twice a week using calipers. Each animal was euthanized when the tumor reached a site size of 2000 mm3 or arrived on either of the last day of the study (day 6). The endpoint time (TTE) of each mouse was calculated by the following equation: TTE (days) == (1〇gi〇 (endpoint volume, mm3)-b)/m 'where b is the intercept and m is the log-transformed tumor The slope of the line obtained by linear regression of the growth data set. This data set contains the first observation that exceeds the study endpoint volume and three consecutive observations immediately before the endpoint volume is reached. Animals that did not reach the end point specified a TTE value equal to the last day of the study. Animals classified as having an accidental NTR (non-therapeutic correlation) (NTRa) or died for unknown reasons (NTRu) were excluded from TTE calculations (and all further analyses were classified as tr (treatment-related) death or NTRm (due to metastasis) The non-therapeutic-related animals were assigned a TTE value equal to the day of the study death. The treatment results were determined as tumor growth delay (TGD), which was defined as the increase in the median endpoint (TTE) of the treatment group compared to the control group. :TGD=T_ 138999.doc •189· 200951107 C 'in days, or as a percentage of the TTE median of the control group: %TGD=丁χ100 'where: τ = intermediate value of the treatment group, C = control group The intermediate value of TTE (group 1). Treatment may result in partial regression (pR) or complete regression (CR) of the tumor in the animal. In the PR reaction, during the course of the study, the tumor volume was the first in three consecutive measurements. 50% or less of the volume of 1 day, and equal to or greater than 13.5 mm3 in one or more of the three measurements. In the (:11 reaction, tumor volume was measured in three consecutive measurements during the course of the study Medium less than 丨3 5 mm3 ^ at the end of the study Animals with CR response were additionally classified as tumor-free survivors (TFS). Tumor regression was monitored and recorded. Side effects: Animals were weighed daily for the first five days of the study and then weighed twice a week. Frequent observation of the mice Significant symptoms of any adverse, treatment-related side effects ϋ 5 clinical observations have been observed. Acceptable tolerance is defined as a group of average weight loss of less than 2% during the test period and no more than one treatment in the animal group Τί: The dosing regimen that satisfies these criteria is considered to be greater than the maximum dose (MTD). Death is classified as TR if it is confirmed by medical symptoms and/or anatomy as a side effect of treatment, or if it is administered During the period or during the last day of administration, if it died due to unknown reasons, it is classified as TR. If there is no evidence, the death is classified as MR and the death is classified as MR. System S and graphic analysis: (4) The test was used to analyze the treatment group and the TTE was different. The two-tailed statistical analysis was performed in a significant amount of P=G., and the median value of the tumor growth curve showed that the median tumor volume of each group was 138999.doc Function between 200951107. When the animal withdraws from the study due to tumor size or TR death, the data for the intermediate tumor volume calculated for the subsequent time points includes the final tumor volume recorded for the animal. Since the tumor develops in the group 5〇 The 〇/〇 animal was truncated after exiting the study. The Kapian_Meier graph was constructed to show the percentage of animals remaining in the study as a function of time, and the same data set was used as a logarithmic scale test. Using Windows 3 〇 3 (Wind〇ws3.〇 3) Pnsm (GraphPad) performs all graphical representations and statistical analysis. Therapeutic response profile group intermediate value TTE TC %TGD statistical difference MTV(n) day 60 regression mean BW lowest point PR CR TFS 1 22.8_ - - - _ 0 0 0 λ 28.8 6.0 26 - 0 0 0 -5.3% Day 15 27.5 4.7 21 • 1 0 0 4 59.9 37.1 163 *** 0(4) 4 5 4 -0.6% Day 15 t&gt; 25.6 2.8 12 Ns 0 0 0 6 27.5 4.7 21 氺- 1 0 0 - A375 Growth of tumors in control mice (Group 1): Group 1 animals received 1% hexadecanol polyoxyethylene ether EL/saline vehicle, φ po 'qdx14. Tumors in the control group developed at an intermediate TTE of 22.8 days to a final volume of 2000 mm3. The most likely T-C or 163% TGD was established in the 371-day study. · The effect of paclitaxel treatment (Group 2): : Group 2 animals were administered with paclitaxel as a reference, 30 mg/kg, IV, qodx 5. All 9 animals reached the end of tumor volume. Tumor growth was parallel and slightly shifted to the right compared to the control group. The intermediate TTE value was 28.8 days, corresponding to 26% TGD, with a logarithmic scale analysis as a significant result (Table 2, p = 〇〇 〇〇 88 G1 vs. G2). Tumor regression has nothing to do with the treatment of Pacific yew. 138999.doc -191 · 200951107 N-(S)-(3,4-Difluoro-2-(2-fluoro-4-indolyl)-6-methoxyphenyl) (2,3- Effect of treatment with dihydroxypropyl)cyclopropane-1-sulfonamide (Group 3 6) · Groups 3-6 accept N-(S)-(3,4-difluoro-2-(2-fluoro-) Oral administration of 4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-monopropylidene)cyclopropanol continued as a monotherapy. Group 3 animals were administered 5 〇 mg/kg in qdx 14 time course. Nine tumors in this group reached the end of the volume. The median tumor volume of this group experienced a small net change at the beginning of about 10 days, followed by an increase during the study. A single animal experiences tumor PR. The intermediate TTE value is 27.5 days, or 21% TGD, which is the apparent result ^=0.0054 G1 vs. G). Group 4 animals received 25 mg/kg 2N_(SH3,4_: fluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-^^^ dihydroxypropyl as a bidxl4 time course Base) cyclopropane-1-sulfonamide. Four of the 9 animals in this group remained on day 6 and all were TFS. An additional 2/9 of the animals had tumors reaching the end of the volume one day before the study was terminated. This group has 4/9 pR, 5/9 CR& 4/9 TFS. Median tumor volume decreased for several days from the start of the study and lasted for approximately % days. Tumor regrowth in 5/9 animals indicated that the onset of tumor growth was started on day 32 and continued until the study was terminated. The middle of this group has a value of 59.9 days, and the maximum probability is 163% TGD (p&lt;〇 〇〇〇ι, Table A1). Group 5 mice received 25 mg/kg N-(SH3,4-difluoro_2_(2_fluoro_4_iodophenylamino)-6-methoxyphenyl)_ι_(2,3_2 Hydroxypropyl)cyclopropane sulfonamide, but follows a lower strength qdxl4 time course. Nine animals in Group 5 reached the tumor volume endpoint and no tumor resolved. Tumor growth in this and control groups was closely followed. The intermediate TTE value was 25.6 days, or 12% TGD, which was a significant result other than I38999.doc -192- 200951107 (house = 〇.〇662 G1 vs. G5). The animals in the Dijon group were administered 125 mg/kg n_(SH3,4_difluoro-2-(2-fluoro-4-iodophenylamino)-6(methoxyphenyl)_丨_ (by bidxl4 time course). 2,3_Dihydroxypropyl)cyclopropane-1_sulfonamide. All tumors in this group reached the end of volume. The median tumor volume as in Group 4 'Group 6 decreased early in the study, but 'this decrease lasted only about 9 days with a single PR response. Tumor volume increased from day '10' to study termination. The intermediate TTE value for this group was 27.5 days, corresponding to a significant 21% 100 (/^0.0424 G1 vs. G6). Briefly, N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3- Dihydroxypropyl)cyclopropane_1_sulphonamide exhibits dose-related antitumor activity against human A375 melanoma xenografts once daily and twice daily. Secondary dosing daily is superior to once daily administration in terms of the size of TGD produced and the number of target responses. Therefore, N_(s)_(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1_(2,3-dihydroxypropyl) The antitumor activity of cyclopropane-1-sulfonamide varies according to the dose and time course. Example 37: Active animals for subcutaneous COLO205 human colon cancer xenograft: .. Although athymic nude mice, Harlan) are 12 to 13 weeks old and have a body weight of 18.3 to 27.3 grams on day 1 (BW) )range. Animal Free Access to water (reverse osmosis, 1 ppm C1) and NIH3 1 modification and irradiation [讣 Diet®, which consists of 18.0% crude protein, 5.0% crude fat and 5.0% crude fiber. The mice were housed in a static micro-separation chamber on an ALPHA-Dri® bed-o'cobs® laboratory animal pad, in a 12-hour photoperiod with 21_138999.doc -193- 200951107 22°C (70-72°) F) and 40-60% humidity. Adhere to the guidelines for restrictions, grazing, surgical procedures, feeding and fluid regulations, and veterinary care for laboratory animal feeding management and use practices. Tumor transplantation: Allogeneic transplantation is initiated by COLO205 human colon cancer cells. Tumor cells in 10% heat inactivated fetal bovine serum, 1 〇〇 unit / ml penicillin G sodium, 100 g / mL streptomycin sulfate, 0.25 pg / mL amphotericin B, 25 pg / mL japonicin 2 mM branic acid, 1 mM sodium pyruvate, 10 mM HEPES with 0.075 °/. Cultured in sodium bicarbonate. The cell culture was maintained in a tissue culture flask in a humidified culture tank at 37 ° C, 5% CO 2 and 95% air atmosphere. On the day of tumor cell implantation, C〇1〇205 cells were recovered during logarithmic growth and resuspended in 50% Matrigel matrix (BD Biosciences) in PBS at a concentration of 5χ106 cells/mL. Each test mouse was subcutaneously implanted with 1 x 10 6 C〇1〇205 cells in the right abdomen, and the tumor growth was monitored to an average size of 80-120 mm3. After 14 days, the designated day was the first day of the study, and the animals were divided into Eight groups (n=9) with individual tumor volumes ranging from 63 to 196 mm3 and an average tumor volume of 118-119 mm3 for each group. Tumor volume was calculated using the following equation: tumor volume (mm3) = <w2x/j/2, where w = width of the COLO205 tumor (mm) and / = length of the COLO205 tumor (mm). Tumor weight was estimated by inference of 1 mg equal to 1 mm3 tumor volume. Materials: The administration solution of Compound A was dissolved at 10 0 °/ by the required amount of the compound. The hexadecanol polyoxyethylene ether EL was then freshly prepared daily by diluting it to 10 times with physiological saline. The final dosing solution concentration was 2.5, 5, 10 or 20 mg/mL, 138999.doc -194- 200951107 to provide 25, 50, 100 or 200 mg/kg each dose in a 10 mL/kg dosing volume. Paclitaxel (Natural Pharmaceuticals) was freshly prepared at a daily dose in a vehicle consisting of 5% ethanol and 5% cetyl polyoxyethylene ether EL in 90% D5W (5% EC vehicle). Treatment The table below shows the treatment plan. Treatment regimen η Agent mg/kg Path time course 1 9 Vehicle - po qd&gt;&lt;14 2 9 Pacific paclitaxel 30 iv qod&gt;&lt;14 3 9 Compound A 50 po qd&gt;&lt;14 4 9 Compound A 25 po Bidxl4 Day 1 Dose 5 9 Compound A 25 po qd&gt;&lt;14 6 9 Compound A 12.5 po bidxl4 Day 1 Dose Group 1 received a formulation vehicle (10% cetyl polyoxyethylene ether EL in saline), And as a tumor growth control group. Group 2 received the reference drug paclitaxel (30 mg/kg i.v. qod&gt;&lt;5) administered in the optimal time course of nude mice. Groups 3-6 received Compound A, p.o.qd&gt;&lt;14 doses at doses of 25, 50, 100 and 200 mg/kg, respectively, with Group 6 (200 mg/kg) discontinued due to toxicity after 6 days. All doses were in accordance with animal weight (0.2 mL/20 g body weight). End point: Tumors were measured twice a week using a caliper. Each animal was euthanized when the tumor reached a predetermined endpoint of 2000 mm3 or when either of the last day of the study (day 74) arrived first. However, the control tumor did not exhibit logarithmic growth characteristics after reaching a size of about 800 mm3. Therefore, the 800 mm3 endpoint tumor size was used for the analysis of tumor growth delay (TGD). The endpoint time (TTE) of each mouse is calculated by the following equation: TTE (days) = (logl 〇 (end point 138999.doc • 195 - 200951107 volume, mm) - b) / m, where b is the wear distance and 〇 1 The slope of the line obtained by logarithmically converting the linearity (4) of the tumor growth data set. This data set contains the first three observations that precede the first endpoint of the study endpoint volume and before the endpoint volume was reached. Animals that did not reach the end point specified a TTE value equal to the last day of the study. Animals classified as having an accidental NTR (non-therapeutic or death due to unknown cause (NTRu) are excluded from TTE calculations (and all in-step analysis). Classified as TR (treatment-related) death or NTRm (due to metastases) Animals with non-treatment relevance were assigned a TTE value equal to the day of study death. Treatment results were assessed as tumor growth delay (TGD), defined as the increase in endpoint time (TTE) of the treatment group compared to the control group: C, days, or as a percentage of the TTE median of the control group: -τΧΐ〇〇, where: D = the median value of the treatment group, the middle value of the TTE of the control group (Group 1). The control group was designated as the first Group of mice. Treatment may result in partial regression (pR) or complete regression (CR) of the tumor in the animal. In the PR response, during the course of the study, the tumor volume was 50% of the volume of Day 1 in three consecutive measurements. Or less, and equal to or greater than 13.5 mm3 in one or more of the three measurements. In the CR reaction, the tumor volume was less than 13 5 mm3 in three consecutive measurements during the course of the study. Monitoring the regression response And record. The animals were weighed daily for the first five days of the study and then weighed twice a week. Frequent observations of any adverse, treatment-related side effects of this mouse were observed 138999.doc -196- 200951107 Symptoms: and recorded toxicity during observation. Clinical phenomenon. Acceptable tolerance is defined as the K period - the group average body weight loss is less than 20% and there are not many in the animal group; ° treatment related death, and any dosage regimen that causes greater toxicity

Maximum resistance and dose (MTD). Death is classified as TR if it is confirmed by medical symptoms and/or anatomy as a side effect of treatment, or is evaluated if it is died due to an unknown cause during administration or during the last 1G day of administration. Death is classified as NTR if there is no evidence that death is associated with treatment side effects. Animals are monitored by frequent observations and bribes. The BW was changed to be inconspicuous and all treatments were acceptable tolerated, except for Group 6. Compound a once daily P 〇. 200 mg/kg dose six times resulted in butyl rule death assessment on day 7 and on day 8 another TR died. All rats in Group 6 presented toxic medical conditions including hunchback 'activity reduction and fecal soft strips. Statistical and graphical analysis: Logarithmic scale tests were used to analyze the difference in TTE values between the treated and control groups. Two-tailed statistical analysis was performed on significant quantities 〇=〇·〇5. The median value of the tumor growth curve shows that the median tumor volume of each group is a function of time on a logarithmic scale. When the animal withdrew from the study due to tumor size or TR death, the data for the intermediate tumor volume calculated for the subsequent time points included the final tumor volume recorded for the animals. This curve was truncated after tumor development or after 5 h/0 animals in the group withdrew from the study after the second TR death in the group. Kaplan-Meier plots were constructed to show the percentage of animals remaining in the study as a function of time and the same data set was used as a log rank test. All graph performance and statistical analysis were performed using Prism (GraphPad) of Windows 3.03 (Windows 3.03). 138999.doc •197- 200951107 Therapeutic response overview group median 1-C %TGD SS MTV(8) day 74 average BW PR CR 1FS TR NTR 1 41.0 - - - 322(2) 0 0 0 0 0 1 6U.U 19.0 46% Ns 〇(3) 1 0 0 2 2 i 47.9 6.9 17% ns 〇(3) 1 0 0 2 2 4 59.1 18.1 44% ns 195(1) 4 0 0 0 0 3 74.0 33.0 80% ns 320(5) 4 0 0 1 0 6 57.8 16.8 41% ne 0(3) 1 3 0 2 2 0.1% Day 22 COLO205 tumor growth in control mice (group)) Group 1 tumors showed slow, heterogeneous growth. Tumors of 7/9 vehicle-treated control mice in the i-th group reached the end point of 8〇〇mm3 tumor volume and both mice were maintained until the study was terminated. The median value of Group 1 was 41.0 days, and therefore the maximum TGD possible for this 74-day study was 3 3.0 days (80%). Effect of treatment with paclitaxel (Group 2) Eight of the paclitaxel-treated mice in Group 2 (n==9) were retained in the study on day 74 with a MTV of 143 mm3. This corresponds to the maximum possible TGD (33.0 days or 80%) and statistically significant activity (house = 0.002). Five PR responses were recorded. The mean tumor growth curve showed that when tumor growth resumed, MTV decreased on day 19, followed by a slight change until day 47. Effect of treatment with Compound A (Group 3-6) Groups 3, 4, and 5 produced intermediate TTE values of 47.9, 59_1, and 74.0 days, respectively. Groups 3 and 4 had non-significant log-level results, and the fifth-group log-level test reached boundary significance (P = 0.058). These treatments produced a regression with the amount of dose change. However, this type of regression response (PR vs. CR) and the number of 74 days of survivors in each group were dose-independent. The median value of the tumor growth curve showed similar activity in the three doses at the early stage of the study (until 29 138999.doc -198 - 200951107 days), followed by a dose-dependent delay in tumor regrowth. Group 6 produced 3 TR deaths and the administration stopped after 6 days. Therefore, treatment at 200 mg/kg was considered to be higher than MTD and could not be used for TGD evaluation. Compound A illustrates the dose-dependent activity of COLO205 colon cancer xenografts. Compound A exhibited a TGD of 3% when administered at 25 mg/kg. Compound A produced 46% TGD at .50 mg/kg. Tolerance of treatment at 100 mg/kg was acceptable and, as with paclitaxel treatment, resulted in a maximum TGD possible value in experiments with similar regression numbers. Treatment with 200 mg/kg m produced 3/9 TR death and was higher than MTD. Compound A was observed to have a more pronounced initial decrease in tumor burden compared to paclitaxel; however, this effect lasted for a shorter period of time. Tumor regrowth in the 25 and 50 mg/kg groups began to develop at a faster pace than the control group, and MTV approached the control group before the end of the study. Treatment with 100 mg/kg did not show this rapid regrowth, but showed faster tumor growth than paclitaxel. Example 38: Human Clinical Trial _ Randomized, double-blind, open-label, histologically controlled, one-component, safe/effective humans with Compound A and placebo at the end of the first chemotherapy or metastatic pancreatic cancer Phase I clinical trial. The primary objective of this study was to assess the safety and tolerability of Compound A. Secondary outcomes were to assess response rates, clinical benefit, and tumor shrinkage after treatment with Compound A. Furthermore, this study will be designed to assess the timing and overall survival of disease progression in individuals with pancreatic cancer. In addition, DCE-MRI can be used to assess changes in tumor vascular parameters including, for example, blood flow, blood volume, ♦ value time ROC-recipient operator characteristic curve. 138999.doc -199- 200951107 Furthermore, biomarkers such as MEK1 and MEK2 genetic polymorphisms and serum proteomics were used to correlate results. This also allows for the determination of the rate of resection of the tumor after treatment and the assessment of the MTD of Compound A. During the study, Compound A will be about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 45 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about ι 〇 mg, about 10.5 mg, about 11 mg , about 11.5 mg, about 12 mg, about 12 5 mg, about 13 mg, about 13.5 mg, about 14 mg, about 14.5, or about 15 mg2 are administered at different doses. The selection criteria for this study were based on the following factors: Histology/pathology identified local end-stage unresectable or borderline unresectable pancreatic cancer with no evidence of metastatic disease. The diagnosis of locally unresectable pancreatic cancer is based on the evaluation of biphasic computed tomography and/or endoscopic ultrasonography (EUS) (described in Annex f, eus). The measurable condition according to RECIST was obtained by a two-phase computed tomography scan within 14 days prior to the registration of the treatment proposal. Tumor size is greater than or equal to 2 cm in a biphasic computed tomography scan. Appropriate organ function was recorded within 14 days of registration, and the empirical results were: absolute neutrophil count > 1500/mm3; platelet count; 100 000/mm3; heme 9 gm/dL, no need for blood in the first 4 weeks; Total bilirubin $1,5 times the conventional upper limit (ULN); transaminase (AST and / or ALT) S2.5xULN; PT (or INR) U.5 xULN and aPTT in the normal range (accepted to kill Individuals who received anticoagulant therapy with murine or heparin reagents were allowed to participate; for 138999.doc -200- 200951107 individuals who were killed by warfarin were monitored at least weekly until the INR was measured at pre-dose for stability. , as defined by local care standards; use the Cockcroft-Gault equation to calculate intramuscular guanamine clarity of &gt;6〇. Exclusion criteria included a clinically confirmed tumor invasion of the duodenal mucosa within 6 months prior to enrollment (with endoscopy or endoscopy • Ultrasound S recorded in the study registration for 14 days undergoing minor surgery (eg Fine needle extraction or fine needle biopsy); undergoing 大型 major surgery, significant trauma or severe non-healing wounds, ulcers or monthly fold within 21 days of study registration, experienced the following within 6 months prior to the study of the drug Either: severely unstable 疋 ^ colic (symptoms of angina at rest), newly started angina (starting in the last 3 months) or myocardial infarction, heart-filled heart failure, need anti-arrhythmia treatment Arrhythmia; history of occlusion or embolization events in the past 6 months, such as cerebrovascular accidents or transient cerebral ischemia; history of aneurysms or arteriovenous malformations; known human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C; active clinically severe infection is greater than CTCAE level 2; receive any test drug within 4 weeks of study registration; despite optimal medical control, Blood pressure remains uncontrolled, defined as systolic blood pressure greater than 150 mmHg or diastolic blood pressure greater than 9 〇 mmHg; alveolar hemorrhage/bleeding events greater than CTCAE level 2 within 4 weeks of study enrollment; any within 4 weeks of enrollment Other bleeding/bleeding events greater than CTCAE Level 3; bleeding quality or fact or history of coagulopathy; long-term, daily treatment with aspirin or other non-steroidal anti-inflammatory preparations; use of Hypericum (st. John s Wort), rifampin, rifampicin, ketoconazole, itrac〇naz〇le, Lindonafan I38999.doc -201 - 200951107 (ntonavir) or grapefruit juice Known or suspected condition of a compound that is sensitive to the ability of an individual to swallow a whole pill; any malabsorption problem; other serious, acute or chronic medical or mental condition or possible = accompanying study participation or study drug administration Risk, or may interfere with the interpretation of the study, the investigator judged that the individual was not suitable for the laboratory to check for abnormalities in the study; collagen i tube disease history; any contraindications to the magnetic resonance imaging. Example 39: Human Clinical Trial Randomized, double-blind, open-label, histologically controlled, one-component, Compound A, Compound A, in the first-time chemotherapeutic or metastatic gastric cancer in the manner specified in Example 117 (IV) Safety/Efficacy Phase I clinical trials in humans, except that the individual involved was diagnosed with gastric lymphoma, gastric stromal tumor or gastric carcinoid tumor. Example 40: Rat carrageenan-induced paw edema (CpE) Compound A (6, 20 and 60 mg/) was administered orally 2 hours before the injection of 1 °/. carrageenan suspension to the right hind paw of male Sprague_Dawiey rats (N=6 in the mother treatment group). Kg) or. lead. Indomethacin (3 mg/kg). After 3 hours, the paw volume was assessed by plethysmography to measure hind paw edema. The hind paw edema is reduced by 30 ° /. Or more indicates significant acute anti-inflammatory activity. Indomethacin (Indo) was used as a positive control. Figure 22 shows an increase in paw volume in each treatment group' indicating that oral administration of Compound A caused significant anti-inflammatory activity in the rat carrageenan paw edema model in all dose groups. Example 41: Rat Adjuvant Arthritis Inflammation Assay In the rat adjuvant-induced arthritis model, complete Freund's adjuvant 138999.doc-202·200951107 (Complete Freund's adjuvant, CFA) was injected into the right of the rat. The hind paw is used to induce a lesion similar to rheumatoid arthritis in humans. Compound a was administered orally at 2, 6, and 20 mg/kg for 5 days. Oral administration of dexamethasone at 5 mg/kg for 5 days. On the 1st and 4th days, 1 〇. mg/kg of enalapril (Enbrel) was administered by subcutaneous injection. CFA was injected into the right hind paw 1 hour after the first dose on day 1. For the acute phase, measure the first! The percentage of inhibition of the right hind paw swelling on days and days relative to the vehicle-treated control group, and the left hind paw swelling on the 14th and 18th days of the lag phase versus the vehicle-treated control group. Percentage of inhibition. Multiple arthritis is scored based on the presence of swelling in the front paw, tail, nose or ear. Figures 23A and 23B show the percent inhibition of swelling in the different treatment groups relative to the control group. Compound A at 20 mg/kg showed a significant reduction in swelling during both acute and delayed periods. For the multiple arthritis score, 6 animals in the vehicle treatment group had swelling on the front paw and tail. For the 2 〇 mg/kg Compound A group, 2 out of 6 had no swelling on the forepaw and 4 of the 6 gins had no swelling on the tail. For the etanercept group, none of the animals were free of swelling on the front paws and 3 of the 6 did not have swelling on the tail. Example 42: Collagen-antibody-induced arthritis (caia) in mice. Inhibition of male Balb/c mice (N=8 per treatment group) via intravenous (tail vein) injection on day 2 Mg collagen antibody mixture (Ch〇ndrex). Oral administration of A119 (1, 3 & 1〇qd) or dexamethasone (1 mg/kg QD) from day 4 to day 4, at the same time! On the 3rd day and subcutaneous injection of enamel 138999.doc •203 · 200951107 Xipu. All mice were intraperitoneally injected with LPS (50 μ§) on day 3 except for untested animals. Arthritis scores were determined for all limbs and are shown in Figure 24 (maximum score of 16). Significant anti-inflammatory activity was noted for all test articles and reference drugs. The etanerex universal dexamethasone was used as a positive control. Example 43: In vivo cell proliferation assays Methods for determining cell proliferation counts of cancer cells treated with MEK protein kinase inhibitors are well known in the art and are described in Kenny, L. M. et al. n Emissi〇n T〇m〇gr_y (PET) Imaging of Cell Proliferation in Oncology, Clinical 〇nC〇logy, 16: 176_185 (2〇〇4), which is incorporated herein by reference in its entirety. A MEK protein kinase inhibitor (e.g., Compound A) is tested in vivo to determine its effect on cancer cell proliferation. Five individuals voluntarily participated in the study, all suffering from pancreatic cancer at a stage similar to cancer development. A combination of Compound A was administered to 25 individuals. The last 25 individuals were given a placebo. Each individual is administered a daily dose of radiolabeled tracer (e.g., neolabeled fluoro-2-deoxy-DF-glucose (FDG)) for 14 days. After 12 days of treatment, trained physicians used non-invasive positron emission tomography (PET) imaging devices to detect tumor cell proliferation. Furthermore, the D-training division will measure the cell proliferation count of both the tumor of the individual treated with Compound A and placebo and normal cell tissue. The results indicate a slight decrease in cell proliferation between MEK protein kinase inhibitors (eg, Compound A) and placebo; This assay for determining the cell proliferation count using labeled tracer and ρΕτ imaging is referred to herein as the "in vivo cell proliferation method." 138999.doc 200951107 Other methods of inviting cell proliferation are known in the art. A similar analysis was used to determine the reduction in tumor size. Example 44: In vivo cell apoptosis assay A MEK inhibitor (e.g., Compound A) was tested in vivo to determine its effect on apoptosis of cancer cells. Forty individuals volunteered to participate in the study, all suffering from pancreatic cancer at a stage similar to cancer development. Compound A was administered to 20 individuals and placebo was administered to 20 individuals. A dose of sputum was administered to each individual for 14 days. After 14 days, each individual will consume a detectable lipopolysaccharide binding protein (LBP) reagent coupled to a label. According to WO/2006/054068, which is incorporated herein by reference in its entirety, each individual is in the scan of the scanning device, whereby the scanning device detects the spent reagents associated with dead cells. The number of dead cells is associated with the degree of cellular apoptosis in each individual. The degree of apoptosis in the individual administered to the combination was compared to the degree of apoptosis in the individual administered to the single entity agent and compared to the group administered with placebo. The method for detecting the degree of cell apoptosis using a lipopolysaccharide-binding protein and a scanning device is referred to herein as "in vivo apoptosis". Example 45: Dissolution study A capsule containing Compound A was prepared as in the above examples. The following dissolution data was obtained using the USP &lt;711&gt; dissolution method. 1 mg form 10 mg Form time (minutes) Release % (%1130) Release % (%RSD) 15 78(8.3) 80(7.3) 30 82(7.1) 87(9.2) 45 82(6.7) 92(9.6) 60 88(6.3) 92(7.2) 70 86(5.7) 95(5.4) 138999.doc • 205-

I I200951107 [Simplified Schematic] Figure 1 shows the mean tumor volume and time (days) in mice implanted with A375 melanoma, C〇1〇205 colon tumor, A431 epidermoid tumor or HT-29 colon tumor cell. The schema of the relationship. Mice were orally administered once daily (25 mg/kg, 50 mg/kg or 100 mg/kg) for 14 days; Figure 2 shows administration of 50 mg/kg QD, 25 mg/kg BID, 50 mg/kg QD and Figure of % tumor growth inhibition (%TGI) in A3 75 allograft mice at 12.5 mg/kg BID dose; Figure 3 shows blood concentration in female nu/nu mice transplanted with C〇1〇205 tumor cells (log ιιΜ) A schema for the relationship between pERK inhibition and %. Mice were given a single dose of 2.5, 5, 10 or 25 mg/kg; Figure 4 shows a single dose of 2 mg (2 x 1 mg capsule), 4 mg (4 x 1 mg capsule) or 6 mg (6 x 1 mg capsule) in humans. a plot of post plasma concentration (ng/mL) versus time (hours); Figure 5 is N-(S)-(3,4-difluoro-2-(2-fluoro-4-ephenylamino) )_6_Methoxyphenyl)-1-(2,3-dipropylpropyl)cyclopropane-丨·sulfonamide form a powder χ Light diffraction (PXRD) spectrum diagram Produced using the inei xrg_3〇〇〇 diffractometer. This plot is plotted as the peak intensity defined by the count per second versus the diffraction angle 2 Θ (°); Figure 6 is the N-(S)-(3,4) generated using the TA Instruments differential scanning calorimeter port (7) (8) -difluoro-2-(2-fluoro-4-isoiodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-indole-sulfonamide form a Differential Scanning Calorimetry (DSC) modulated thermograms. This figure is based on the corrected heat flux (in watts/gram, W/g) for the measured sample temperature (I); 138999.doc -206- 200951107 Figure 7 is N-(S)-( 3,4-Difluoro-2-(2-fluoro-4-iodophenylamino)oxanyloxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide Form a (upper) and N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)_1_ (2,3- A plot of the Pxrd spectrum of the amorphous (bottom) amorphous form of dihydroxypropyl)cyclopropanone, which was produced using an Inel XRG-3000 diffractometer. This graph plots the peak intensity defined by the count per second versus the diffraction angle 2 Θ (.); Figure 8 shows the N-(S)-(3,4-two) produced using the VTI SGA-100 vapor sorption analyzer. Fluorin-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dipropylpropyl)cyclopropene-1 - ; Dynamic vapor adsorption/desorption (DVS) isotherm of amine form A; Figure 9 shows N-(S)-(3,4-difluoro-2-(2-fluoro) produced using TA Instrument 2950 thermogravimetric analyzer Thermal analysis (TG) of -4-iodophenylamino)-6-methoxyphenyl)-1_(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide Form A Figure 10(a) and Figure 10(b) show exposure to increasing concentrations of N-(S)-(3,4-dioxa-2-(2-|L-4-molylamino)-6 Growth inhibition of the logarithmic phase splitting of A3 75 cells of -methoxyphenyl)-1-(2,3-dipropylpropyl)cyclopropane-1-sulfonamide. Analyze the ATP content of the cells. Use 1 μΜ N-(S)-(3,4-difluoro-2-(2-fluoro-4-violinylamino)-6-methoxyphenyl)-1-(2,3 - two 100% growth arrest was determined by propylpropyl)cyclopropane-1 -sulfonamide; Figure 11 shows the 48 hour AK assay in A375 cells. Logarithmic phase splitting of A375 cells exposed to N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-( 2,3-dipropylpropyl)cyclopropan-1-rylidene and PD-325901 for 48 hours and analysis of AK release; 138999.doc -207. 200951107 Figure 12A-12C shows N-(S)-( 3,4-Difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonate Inhibition of (A) growth inhibition of human colorectal cancer Coio205 cells (Gl5〇 = 11 nM); (B) growth inhibition of A3 75 cells (GI5G=22 nM) and inhibition of (C) MDA-MB23 1 cells, It does not show N_(S)-(3,4·difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl) in a two-dimensional fixation-dependent assay. -1 -(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide - causes growth arrest; Figure 13A shows inhibition of growth of human colorectal cancer C〇1〇205 cells, and at 6 nM and GI5 〇 value at 11 nM; Figure 13B shows inhibition of growth of A375 cells and GI5 〇 values at 5 nM and 22 nM; Figures 14A and 14B show N-(S)-(3,4-difluoro- 2-(2-Fluoro-4-iodophenylamino)-6-nonyloxy stupyl) Effect of 1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide on cell cycle progression, showing exposure of A375 cells to N-(S)-(3,4-difluoro-2- (2-Fluoro-4·iodophenylamino)-6-methoxyphenyl)-l-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide causes G1 phase of the cell cycle Stagnant, this is indicated by cell depletion at G2 and S phases; Figures 15A and 15B show exposure to N-(S)-(3,4-difluoro-2-(2-fluoro4-iodophenyl) Amino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-l-sulfonamide 3 days (Figure 15A) and 6 days (Figure 15B) after N-( S)-(3,4-Difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane Effect of -1-sulfonamide on AGS of gastric cancer (gastric adenocarcinoma) cell line y axis is the number of cells relative to vehicle and X-axis is N-(S)-(3,4-difluoro-2-(2) -fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dipropylpropyl)cyclopropene-1-continued 138999.doc •208- 200951107 indoleamine μΜ; Figure 16 shows n_(s)-(3,4-difluoro-2-(2-fluoro-4-isoiodophenylamino)-6-methoxybenzene in tumor-bearing mice Base)—^(2,3·dihydroxypropyl Cyclopropane-buprofamide (2 mg/kg once a day, orally (p〇); 1 mg/kg once daily, 5 mg/kg once daily, orally), mean liver weight after treatment; Displayed in tumor-bearing mice as n_(s)_(3,4-difluoro-2-(2-fluoro-4)iodophenylamino)-6-methoxyphenyl)-1- (2,3-dihydroxypropyl)cyclopropane-1 - sulfonamide (2 mg/kg once daily, orally; once daily, 1 mg/kg, orally and once daily 50 mg/kg, orally) after treatment Liver tumor weight; Figure 18 shows N-(S)-(3,4-difluoro-2-(2-fluoro-4-mothenylamino)-6-methoxyphenyl)-1-( 2,3-Dihydroxypropyl)cyclopropane_丨_sulfonamide (2 mg/kg; 10 mg/kg; and 50 mg/kg) mean tumor weight after treatment; Figure 19 shows the number of cells (relative to Vehicle) for N_(s)_(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-fluorenyloxy)_i_(2,3-dihydroxypropyl The inhibition of Hs746t cell proliferation in the graph of the concentration of ciprofloxacin; Figure 20A shows the comparison of N_(s)_(34_difluoro_2_(2_fluoro-4-iodophenyl) at an increased concentration Amino)-6-methoxyphenyl)-i_(2,3-dihydroxyl The degree of apoptosis of propyl)cyclopropane-1-sulfonamide on day 5 of treatment of non-small cell lung cancer (NSCLC) MV522 cells; Figure 20B shows N_(s)_ at increased concentration 4_Difluoro_2_(2_fluoro_4 phenylamino)-6-methoxyphenyl)_ι·(2,3-dihydroxypropyl)cyclopropane flavonoid treatment of non-small cell lung cancer (NSCLC) Degree of individual cell apoptosis on day 5 of H358 cells, 138999.doc •209- 200951107 Figure 20C shows N-(S)-(3,4-difluoro-2-(+) at increasing concentrations 2-Fluoro-4-indolylphenylaminooxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane_丨_ hydrazine in the treatment of non-small cell lung cancer (NSCLC) A549 cells Degree of apoptosis of individual cells on day 6; Figure 20D shows N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodobenyl) methoxyl at increasing concentrations Base group) -i_(2,3-dipropylpropyl)cyclopropane___ continued the degree of apoptosis of individual cells on day 5 of non-small cell lung cancer (NSCLC) H727 cells; Figure 20E It is shown in increasing concentration of N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)_ι_(2,3 -dihydroxypropyl)cyclopropane_丨_ continued The degree of death of individual cells on the 5th day of treatment of colonic HT29 cells by guanamine; Figure 20F shows N_(8)_(3,4·difluoro-2-(2-fluoro-4-decylamine) at increasing concentrations The degree of apoptosis of each cell on day 6 of treatment of colonic HCT116 cells by hexyl-6-methoxyphenyl)_i_(2,3-di-propylidene)cyclopropane 20G is shown at an increasing concentration of N_(S)_(3,4-difluoro-2-(2-fluoro-4-mosynylamino)-6-indoleylphenyl)-1-(2) , 3 - dimercaptopropyl) Cyclopropyl-1-pyrazine in the treatment of colonic HUH7 liver cancer cells on the 5th day of the degree of individual apoptosis; Figure 20H shows the increase in concentration of N_(S) _(3,4-Difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1_(2,3-dihydroxypropyl)cyclopropane-1- The degree of apoptosis of each cell on the 5th day of treatment of sarcoma U2-OS cells by sulfonamide; Figure 201 shows N-(S)-(3,4-difluoro-2-(2-) at increasing concentrations Fluoro-4-iodo 138999.doc -210- 200951107 Phenylamino)-6-decyloxyphenyl)dihydroxypropyl)cyclopropane_丨_sulfonamide for treatment of glioma D3 7 cells 5th The degree of apoptosis of individual cells in the day; Figure 21 shows A compound of MEK1 and MEK2 selectivity with respect to a set of 205 enzyme (10 μΜ) of. The cell lines were c〇i〇2〇5, A375, A431 and HT-29; 圊22 was shown to give rats 6, 20, 60 and 200 mg/kg in the rat carrageenan edema model. ·(8)_(3,4_Difluoro_2_(2_fluoro_4_iodophenylamino)-6-methoxyphenyldihydroxypropyl)cyclopropane_丨_sulfonamide The paw volume in the treatment group was increased and the edema was reduced relative to the vehicle control group; Figure 23A shows N, 2, 6 and 20 mg/kg in the acute phase in the adjuvant-induced arthritis model. (S)-(3,4-Difluoro-2-(2-fluoro-4-iodophenylamino)-6(methoxyphenyl)-1_(2,3-dihydroxypropyl)cyclopropene The swelling of rats in the _1_alkamine treatment was inhibited; Figure 23B shows N-(S)-(3, 2, 6 and 20 mg/kg in the delayed period in the adjuvant-induced arthritis model). 4-Difluoro-2-(2-fluoro-4-iodophenylamino)_6_decyloxy)-1-(2,3-dipropylpropyl)cyclopropyl-1-ethylamine treatment The swelling of the rats was inhibited; and Figure 24 shows N_(s)_(3,'difluoro-2(2·fluoro-4·iodophenylamino)_6 at 1, 3 and 10 mg/kg QD _Methoxyphenyl)dihydroxypropyl)cyclopropanone-1 - Mean arthritis score of collagen-antibody-induced arthritis (CAIA) mice treated with sulfonamide. 138999.doc •211 -

Claims (1)

200951107 VII. Scope of Patent Application·· A composition comprising a selective compound. 2. The composition of claim 1, wherein the ruthenium, *, 旲, 旲, 旲, 、, 父, sodium lauryl sulfate, magnesium stearate or a combination thereof are further selected from the group consisting of microcrystalline cellulose and parent carboxymethyl fiber. The composition of the group of agents. 3. The composition of claim 1 comprising: from about 0.1% to about 15% by weight: Μη 八 u Urt 〜 〇Ά η : ΚΛ, structural compound, The compound of the _F structure or a combination thereof. 4. The composition of claim 1, which comprises from about 85% to about 99.9 Wt% of microcrystalline cellulose. 5. The composition of claim 1, comprising: about 1 mg Structural compound Compound of structure F or a combination thereof; about 222.2 mg of microcrystalline cellulose; about 12.0 mg of croscarmellose sodium about 2.4 mg of sodium lauryl sulfate; and about 2.4 mg of stearic acid. 6. The composition of claim 1 comprising: 138999.doc 200951107 of about 10 mg: A compound of the structure, a compound or a combination thereof; about 213.2 mg of microcrystalline cellulose; about 12.0 mg of croscarmellose sodium; about 2.4 mg of sodium lauryl sulfate; and about 2.4 mg of magnesium stearate. 7. The composition of claim 1 comprising: A compound or combination thereof; about 203.2 mg of microcrystalline cellulose; about 12.0 mg of croscarmellose sodium; about 2.4 mg of sodium lauryl sulfate; and about 2.4 mg of magnesium stearate. 8. The composition of claim 1 comprising: about 40 mg of: a compound of the structure, a compound or a combination thereof; about 183.2 mg of microcrystalline cellulose; about 12.0 mg of croscarmellose sodium; 138999.doc -2- 200951107 about 2.4 mg of sodium lauryl sulfate; and about 2.4 Mg magnesium stearate. 9. The composition of claim 1, wherein when administered to an individual, the Cmax of the compound on day 1 reaches between about 〇.〇1 /mi to about 1.〇 /mi. 1A. The composition of claim 1 wherein the compound is enthalpy to 2 hours of Auc between about 1 pg hour/mL to about 5.0 pg hour/mL. 11. The composition of claim 1, wherein the compound has a blood concentration greater than about 0.01 mg/mL after a single dose of about 5 hours. 12. —N-(-)-(3,4-Difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3 - The crystalline polymorph A' of dihydroxypropyl)cyclopropanesulfonamide exhibits a powder x-ray diffraction spectrum comprising from about 5% to about 9% of the powder X-ray diffraction spectrum shown in Figure 5. The peak identified in the figure. 13. The crystalline polymorph a of claim 12, wherein the powder x-ray diffraction spectrum is substantially identical to the powder X-ray diffraction pattern shown in Figure 5. 14. A pharmaceutical composition comprising an effective amount of a crystalline polymorph as claimed in claim I]. 15. —1—-(-)_(3,4-Difluoro-2-(2-fluoro1-4-phenylamino)-6-methoxyphenyl)-1-(2,3 The crystalline polymorph A' of -dihydroxypropyl)cyclopropane_methanesulfonamide exhibits a differential scanning calorimetry spectrum substantially identical to the differential scanning calorimetry spectrum shown in FIG. 16. A pharmaceutical composition comprising an effective amount of crystalline polymorph as claimed in claim 15. 17. —N-(3'4-dioxa-2-(2-^-4-e-phenylamino)-6-methoxyphenylene)_ 1-(2,3·dihydroxypropyl a polymorph of cyclopropene, which is a crystalline N-(3,4-dioxane (2-I -4- angstrom) crystallized from a mixture of ethyl acetate and heptane by 138999.doc 200951107 Preparation of a phenylamino)-6-methoxyphenyl)_ι_(2,3-dipropylpropyl)cyclopropan-1-one amine step. 1 8. The polymorph of claim 17 wherein the mixture of ethyl acetate and heptane is from about 1 to about 4 parts ethyl acetate to a ratio of from about 2 to about 1 part by weight. 19. A pharmaceutical composition comprising an effective amount of a crystalline polymorph as claimed in claim 18. 20. A method of inhibiting a MEK enzyme, comprising: comprising a MEK enzyme comprising: And a compound composition of the compound of the compound of claim 20, wherein the MEK enzyme is MEK kinase. 22. A method of treating a MEK-mediated disorder comprising administering a compound of the desired HoJ^OH〇JX〇"O, NH HFO^NH p , F 1^Ι, comprising a group selected from the group consisting of ·βοΊφςΝΛ The method of claim 22, wherein the MEK-mediated condition is a cytokine-mediated condition. 24. The method of claim 22, wherein the MEK-mediated condition is selected from the group consisting of: A condition, an inflammatory condition, an infectious condition, a proliferative condition, or a combination thereof. The method of claim 22, wherein the MEK-mediated condition is cancer. 26. The method of claim 22, wherein the MEK is mediated. The condition is a fibrotic disorder. 138999.doc 200951107 27. The method of claim 22, wherein the Tmax of the compound is achieved at 0.5 hours and 5 hours after the composition is administered to the fasted individual. The method wherein, when administered to an individual, the Cmax of the compound on day 达到 is between about o. oi gg/ml and about i 〇 gg/ml. 29. The method of claim 22, wherein the compound is smashed to 12 hours The Auc is between about 0.1 hours/mL to about 5.0 tons/mL. 30. The method of claim 22, wherein the compound has a plasma concentration of greater than about 0 mg/mL after about 5 hours of a single dose. 31. A method for inhibiting growth of a plurality of target fines, comprising administering 有'-Λ-^° Η〇νΧΧχ, 0 ° NH H F 〇4, NH F The group of compounds comprising: a compound according to claim 31, wherein the target cells are cancer cells. 33. The method of claim 31, wherein the compound is reached at 0.5 hours and 5 hours after the composition is administered to the fasted individual. 34. The method of claim 31, wherein when administered to the individual, the Cmax of the compound on day 1 reaches between about 〇1 g1 pg/ml to about 丨〇/out. The method of claim 3, wherein the compound has an AUC of from 0 to 12 hours of from about 0.1 hours/mL to about 5 tons per hour. 36. The method of claim 3, wherein the compound has a plasma concentration of greater than about 0.01 mg/mL after a single dose of about 5 hours. 138999.doc