CN103479604B

CN103479604B - N-(virtue amino) sulfamide derivative including polymorph and compositions, its using method and preparation method as mek inhibitor

Info

Publication number: CN103479604B
Application number: CN201310317815.8A
Authority: CN
Inventors: J-M·韦尼耶; C·E·罗林斯; J-l·吉拉德特; S·迪莫克; B·夸尔特; J·N.·迈纳
Original assignee: Ardea Biociences Inc
Current assignee: Ardea Biociences Inc
Priority date: 2007-07-30
Filing date: 2008-07-28
Publication date: 2016-08-10
Anticipated expiration: 2028-07-28
Also published as: MA31881B1; EA020624B1; KR20150091434A; HK1147396A1; TN2010000049A1; WO2009018233A1; EP2184984A1; CN103479604A; NZ582929A; CO6470808A2; CN101808516A; ECSP109910A; CA2693390C; AU2008282338B2; JP2015078199A; MX2010001244A; AU2008282338A1; AU2015200390B2; CN101808516B; DOP2010000045A

Abstract

The present invention relates to N-(virtue amino) sulfamide derivative including polymorph as mek inhibitor and compositions, its using method and preparation method.

Description

N-(virtue amino) sulfamide derivative including polymorph as mek inhibitor With compositions, its using method and preparation method

The application be Application No. 200880108829.6, filing date on July 28th, 2008, invention entitled " as N-(virtue amino) sulfamide derivative including polymorph of mek inhibitor and compositions, its using method and preparation method " The divisional application of Chinese patent application.

Cross-Reference to Related Applications

This application claims the U.S. Provisional Application 61/044,886 in submission on April 14th, 2008, March 6 in 2008 Day submit to U.S. Provisional Application 61/034,466 and on March 6th, 2008 submit to U.S. Provisional Application 61/034, The priority of No. 464, it the most intactly quotes addition herein.The application also requires in U.S. that on July 30th, 2007 submits to State applies for the priority of 11/830, No. 733, and this application requires in the U.S. Provisional Application 60/833 that on July 28th, 2006 submits to, The rights and interests of No. 886 and the International Application Serial No. PCT/US2006/028326 submitted on July 21st, 2006 as part continuation application Number rights and interests, its most intactly quote addition herein.International Application Serial No. PCT/No. US2006/028326 was also required in 2005 years The priority of the U.S. Provisional Application 60/701,814 that July 21 submitted to；In submission on August 8th, 2005 60/706,719 Priority, and on October 28th, 2005 submit to 60/731,633 priority, its most intactly quote addition this Wen Zhong.

Technical field

The present invention relates to mek inhibitor N-(2-virtue amino) arylsulfonamide compounds, it includes demonstrating particular powder X X ray diffration pattern x and/or the crystalline polymorph of specific differential scanning amount thermal map.The invention still further relates to comprise chemical combination described herein The pharmaceutical composition of thing and compound as herein described and the using method of compositions, it is included in treatment and/or gives protection against cancer in advance Purposes in disease, excess proliferative disease and the inflammatory patient's condition.The invention still further relates to prepare compound as herein described and compositions Method.

Background technology

The gene that oncogene causes cancer to produce is typically the sudden change of some normal cellular genes (" proto-oncogene ") Form.Oncogene generally encodes signal path component (such as receptor tyrosine kinase, serine-threonine kinase or downstream Signaling molecule) anomaly pattern.Main downstream signaling molecule is Ras albumen, and it is fixed on the inner surface of cytoplasma membrane, and And combining guanosine triphosphate (GTP) (GTP) is hydrolyzed into guanosine diphosphate (GDP).When the grown factor activator of growth factor receptors Time, its initiation causes the guanylic acid reaction chain to the activation of the exchange activity of Ras.(hereafter Ras combines GTP having Be referred to as " Ras.GTP ") the "On" state of activation and have between the inactive "Off" state combining GDP alternately.Activation "On" state, Ras.GTP combine and activate control cell growth and differentiation albumen.

Such as, in " mitogen activity protein kinase (map kinase) cascade ", Ras.GTP causes serine/Soviet Union's ammonia The activation of acid kinase cascade.Known to need Ras.GTP be Raf family to one of some groups of kinases activating their own.Raf Protein activation " MEKl " and " MEK2 ", i.e. mitogen activity ERK activates kinase whose abbreviation, and (wherein ERK represents extracellular signal Regulation protein kinase, it is the another kind of name of MAPK).MEKl and MEK2 is serine/threonine and the cheese ammonia of dual-use function Pka acid, also referred to as map kinase kinases.Therefore, Ras.GTP activates Raf, thus activates MEKl and MEK2, then activates Map kinase (MAPK).Being activated map kinase by mitogen is requisite to propagation, and this kinase whose composition Activation be enough to inducing cell transformation.No matter from cell surface receptor or from carcinogenic Ras mutation induction, block downstream Ras Signal transduction, as by using dominant Raf-1 albumen, can fully suppressed mitosis to occur.

In the control of cell proliferation, the interaction of Raf and Ras is key regulatory steps.So far, except MAPK with Outward, other substrates of not yet identification of M EK；But, report shows that MEK can also be by other stream signal albumen such as MEK recently Kinases or MEKKl and PKC activate.The MAPK activated shifts and is gathered in nucleus, in nucleus it can make to transcribe because of Son such as EIk-1 and Sapla phosphorylation is also activated, and causes the expression of gene such as c-fos gene to strengthen.

Once being activated, Raf and other kinases (are S for MEK1 at two adjacent serine residues²¹⁸And S²²²On) Make MEK phosphorylation.These phosphorylations are for being necessary as the activation of kinase whose MEK.Then, MEK is by single amino acids Separate two residues: tyrosine Y¹⁸⁵With threonine T¹⁸³On make map kinase phosphorylation.Before making map kinase phosphorylation, MEK apparently with map kinase strong bonded, this shows to be made map kinase phosphorylation may need between both albumen in advance by MEK Strong interaction.Specificity that two factors MEK are unique and need before phosphorylation with map kinase between strong phase interaction May be the most different from the mechanism of other protein kinases with the mechanism of action showing MEK, to such an extent as to allow the selectivity of MEK to press down Preparation.Can may not passed through to relate to the more conventional mechanism of blocking-up ATP-binding site by allosterism by such inhibitor Effect.

Therefore, even if when Cancer-causing mutation does not affect the structure of MEK or expresses, MEKl and MEK2 is also verified and is connect The target spot treated for anti proliferative being subject to.See for example U.S. Patent Publication 2003/0149015 He of Barrett et al. The 2004/0029898 of Boyle et al..

The l-that it has been reported MEK replaces some examples of-2 (para-orientation-phenyl amino)-aryl inhibitor.The U.S. is special Profit No. 6,440,966 and No. 6,750,217 and corresponding announcement WO 00/42003 describe and work as mek inhibitor Sulfonamide-replacement-2 (4-idodophenylamino)-benzoate and the carboxylate of N-substituted benzamide and Hydroxamates and N substituted amide derivant.Described sulfonamide can also be that N-is substituted.

United States Patent (USP) 6,545,030 and the corresponding WO 00/42029 that announces describe mek inhibitor l-heterocyclic radical-2 (4- Idodophenylamino)-benzene, wherein said heterocycle is 5 yuan and contains azo-cycle, such as pyrazoles, triazole, azoles, isoxazole and isoxazolines ketone (isoxazolinone).More recently U.S. Patent Publication 2005/004186 describes relevant compound, and wherein ' 030 is special The 4-iodine substituent group of profit is included alkyl, alkoxyl, acyloxy, thiazolinyl, carbamyl, carbamyl alkyl, carboxyl, carboxyl alkane A class group widely of base, N-acyl group sulfonamido and other group substitutes.

United States Patent (USP) 6,469,004 and the corresponding WO 00/42022 that announces describe one group of heterocycle the phenylene condensed The carboxylate of compound (i.e. benzimidazole, benzothiazole, benzothiazole, diazosulfide, quinazoline etc.) and Hydroxamates. Described heterocycle is 7-F-6-(the iodo-phenyl amino of 4-)-5-carboxylate, carboxylic acid amide or Hydroxamates.More recently announcement is beautiful State 2005/0026970 describes similar compound, and wherein 4-iodine substituent group is substituted by a class formation widely.Relevant Compound be described in patent disclosure WO 03/077855, WO 03/77914 and US 2005/0554701.At WO 2005/ In 028426, it appeared that other of the 2-as mek inhibitor being in the news (4-idodophenylamino)-benzohydroxamic acid ester Example.

Patent disclosure WO 02/06213 and corresponding US application serial 10/333,399 (U.S.2004/0054172) Describe the ester of the hydroxyl replacing acid of 1-oxamidic acid .-2 (4-halogenophenyl amino)-3,4-difluorobenzene.United States Patent (USP) 6,891,066 Number and the corresponding WO 03/62191 that announces describe similar compound, wherein 4-halogenic substituent is by a class widely Structure substitutes.Substituent group on 4-position has methyl, ethyl, acetenyl and 2-hydroxyethyl.United States Patent (USP) 6,770,778 In describe concrete related compound.

Be published in JIUYUE, the 2004 patent disclosure WO of 30 days 04/083167 (Japanese) disclose more than 2000 kinds but carry Supply NMR data l-(N-substituted sulphonyl urea)-2 (2, the 4-dihalogenated phenyl amino)-3 of only 400 kinds, 4-difluorobenzene, and And assert that they are used as mek inhibitor.The data showing to suppress MEK are given for a subgroup only 12 kinds of compounds.Remove Outside secondary amine or tertiary amine, this 12 kinds of compounds all comprise one of following group: N, N-bis-substituted sulphonyl urea, N-piperazine sulphonyl Amine, N-piperidine sulfonamide or N-pyrrolidine sulfonamide.

Inflammatory diseases and disease also have been directed to MEK cascade.The U.S.Application Publication of Koch et al. 2006/0030610, The U.S.Application Publication of Furue et al. 2006/0140872.This had both included acute inflammatory disorders, also included chronic inflammatory illnesses Disease.The example of such disease is contact dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel, chronic resistance Disease that plug property lung disorder, psoriasis, multiple sclerosis, asthma, diabetic complication are relevant and disease, and the most acute hat The inflammatory complication of the cardiovascular system of shape superior mesenteric artery syndrome.Inflammatory bowel has Crohn disease and ulcerative colitis.

Even if when Cancer-causing mutation does not affect the structure of MEK or expresses, MEKl and MEK2 is also verified and received Target spot for anti proliferative treatment.See for example the U.S. Patent Publication 2003/0149015 and Boyle etc. of Barrett et al. The 2004/0029898 of people.

Summary of the invention

The compound of Formulas I provided herein or its pharmaceutically acceptable salt, solvate, polymorph, ester, tautomerism Body or prodrug:

Wherein

Z is H or F；

X is F, Cl, CH₃、CH₂OH、CH₂F、CHF₂Or CF₃；

Y is I, Br, Cl, CF₃、C₁-C₃Alkyl, C₂-C₃Thiazolinyl, C₂-C₃Alkynyl, cyclopropyl, OMe, OEt, SMe, phenyl or Het, wherein Het be 5 to the 10 yuan of monocyclic heterocyclic ring radical comprising 1-5 the ring hetero atom independently selected from N, O and S or dicyclo miscellaneous Cyclic group, described heterocyclic group be saturated, olefinic or aromatics；Wherein

Whole described phenyl or Het group are optionally by F, Cl, Br, I, acetyl group, methyl, CN, NO₂、CO₂H、C₁-C₃Alkane Base, C₁-C₃Alkoxyl, C₁-C₃Alkyl-C (=O)-, C₁-C₃Alkyl-C (=S)-, C₁-C₃Alkoxy-C (=S)-, C₁-C₃Alkyl-C (=O)O-、C₁-C₃Alkyl-O-(C=O)-, C₁-C₃Alkyl-C (=O) NH-, C₁-C₃Alkyl-C (=NH) NH-, C₁-C₃Alkyl-NH-(C =O)-, two-C₁-C₃Alkyl-N-(C=O)-, C₁-C₃Alkyl-C (=O) N (C₁-C₃Alkyl)-, C₁-C₃Alkyl-S (=O)₂NH-or three Methyl fluoride replaces；

Whole described methyl, ethyl, C₁-C₃Alkyl and cyclopropyl group are optionally replaced by OH；

Whole described methyl groups are optionally replaced by 1,2 or 3 F atom；

R⁰It is H, F, Cl, Br, I, CH₃NH-、(CH₃)₂N-、C₁-C₆Alkyl, C₁-C₄Alkoxyl, C₃-C₆Cycloalkyl, C₂-C₆Alkene Base, C₂-C₆Alkynyl, phenyl, monosubstituted phenyl, O (C₁-C₄Alkyl), O-C (=O) (C₁-C₄Alkyl) or C (=O) O (C₁-C₄Alkyl)； Wherein

Described alkyl, alkoxyl, cycloalkyl, thiazolinyl, alkynyl and phenyl group be optionally independently selected from F, Cl, Br, 1-3 substituent group of I, OH, CN, cyanogen methyl, nitro, phenyl and trifluoromethyl replaces；

Described C₁-C₆Alkyl and C₁-C₄Alkoxy base is the most optionally by OCH₃Or OCH₂CH₃Replace；G is G₁、G₂、R_1a、 R_1b、R_1c、R_1d、R_1e、Ar₁、Ar₂Or Ar₃；Wherein

G₁It is optionally by amino, a C₁-C₃Alkyl amino or the substituted C of dialkyl amino group₁-C₆Alkyl, described Dialkyl amino group comprise 2 can be identical or different C₁-C₄Alkyl group；Or

G₁It is C₃-C₈Diaminoalkyl group；

G₂It is 5 rings comprising the saturated, undersaturated of 1-3 the ring hetero atom independently selected from N, O and S or aromatics Or 6 rings, it is optionally independently selected from F, Cl, OH, O (C₁-C₃Alkyl), OCH₃、OCH₂CH₃、CH₃C(=O)NH、CH₃C(= O)O、CN、CF₃1-3 the substituent group with the 5 yuan of aromatic heterocyclic groups comprising 1-4 the ring hetero atom independently selected from N, O and S Replace；

R_1aBeing methyl, it is optionally by 1-3 fluorine atom or 1-3 chlorine atom, or OH, ring propoxyl group or C₁-C₃Alkane Epoxide replaces, wherein said ring propoxy group or described C₁-C₃The C of alkoxy base₁-C₃Moieties is optionally by one Hydroxyl or methoxy group replace, and described C₁-C₄All C in alkoxyl₃-alkyl group is the most further by another OH group replaces；

R_1bIt is CH (CH₃)-C_1-3Alkyl or C₃-C₆Cycloalkyl, described alkyl and group of naphthene base are optionally selected independently From F, Cl, Br, I, OH, OCH₃Replace with 1-3 the substituent group of CN；

R_1cIt is (CH₂)_nO_mR′；Wherein

M is 0 or 1；And wherein

When m is 0, n is 1 or 2；

When m is 1, n is 2 or 3；

R ' is C₁-C₆Alkyl, it is optionally independently selected from F, Cl, OH, OCH₃、OCH₂CH₃And C₃-C₆The 1-of cycloalkyl 3 substituent groups replace；

R_1dBe C (A) (A ') (B)-；Wherein

B is H or C_1-4Alkyl, it is optionally replaced by one or two OH group；

A and A ' independently be H or C_1-4Alkyl, it is optionally replaced by one or two OH group；Or

3-6 unit saturated rings is formed with them together with the carbon atom that A and A ' is attached thereto；

R_1eIt is

Wherein

Q is 1 or 2；

R₂And R₃It is each independently H, F, Cl, Br, CH₃、CH₂F、CHF₂、CF₃OCH₃、OCH₂F、OCHF₂、OCF₃, ethyl, N-pro-pyl, isopropyl, cyclopropyl, isobutyl group, sec-butyl, the tert-butyl group or mesyl；

R₄It is H, F, Cl, Br, CH₃、CH₂F、CHF₂、CF₃OCH₃、OCH₂F、OCHF₂、OCF₃, ethyl, n-pro-pyl, isopropyl, Cyclopropyl, isobutyl group, sec-butyl, the tert-butyl group, mesyl, nitro, acetylamino, amidino groups, cyano group, carbamyl, methyl ammonia Formoxyl, dimethylcarbamoyl, l, 3,4-diazole-2-base, 5-methyl-l, 3,4-diazole, 1,3,4-thiadiazoles, 5-first Base-l, 3,4-thiadiazoles, lH-tetrazole radical, N-morpholinyl carbonyl amino, N-morpholinosulfonyl and N-pyrrolidinylcarbonyl ammonia Base；

R₅It is H, F, Cl or methyl；

R₆It is H, F, Cl or methyl；

Ar₁It is

Wherein

U and V independently be N, CR₂Or CR₃；

R₂、R₃And R₄Independently be H, F, Cl, Br, CH₃、CH₂F、CHF₂、CF₃OCH₃、OCH₂F、OCHF₂、OCF₃, ethyl, just Propyl group, isopropyl, cyclopropyl, isobutyl group, sec-butyl, the tert-butyl group, acetylamino, amidino groups, cyano group, carbamyl, methyl ammonia first Acyl group, dimethylcarbamoyl, l, 3,4-diazole-2-base, 5-methyl-l, 3,4-di azoly, 1,3,4-thiadiazolyl group, 5- Methyl-l, 3,4-thiadiazolyl group, lH-tetrazole radical, N-morpholinyl carbonyl amino, N-morpholinosulfonyl, N-pyrrolidinylcarbonyl Amino and mesyl；

R₅And R₆Independently be H, F, Cl or methyl；

Ar₂It is

Wherein

Dotted line represents the optional pro forma position of second ring double bond；

U is-S-,-O-or-N=, and wherein

When U is-O-or-S-, V is-CH=,-CCl=or-N=；

When U is-N=, V is-CH=,-CCl=, or-N=；

R₇It is H or methyl；

R₈It is H, acetylamino, methyl, F or Cl；

Ar₃It is

Wherein

U is-NH-,-NCH₃-or-O-；

R₇And R₈Independently be H, F, Cl or methyl.

In some embodiments, present invention offer is selected from the compound of the Formulas I of following compound:

In some embodiments, the present invention provides the compound of Formulas I, described compound to be selected from:

Wherein 2-OH carbon is in R configuration.

Wherein 2-OH carbon is in S configuration.

In some embodiments, the present invention provides the compositions comprising the compound of formula I selected from compound shown below, Wherein 2-OH carbon is in R configuration, and described compositions is substantially free of S-isomer.

In some embodiments, the present invention provides the compositions comprising the compound of formula I selected from compound shown below, Wherein 2-OH carbon is in S configuration, and described compositions is substantially free of R-isomer.

In some embodiments, the present invention provides the compound of Formulas I, and wherein Y is phenyl, pyridine radicals or pyrazolyl.? In the embodiment of another subgenus, the present invention provides the compound of Formulas I, and wherein Y is substituted phenyl, pyridine radicals or pyrazolyl. In the embodiment of another subgenus, the present invention provides the compound of Formulas I, and wherein Y is Br or I.Embodiment party a subgenus In case, the present invention provides the compound of Formulas I, and wherein G is piperidino, 2-piperidyl, 3-piperidyl or 4-piperidyl.At another In the embodiment of subgenus, the present invention provides the compound of Formulas I, and wherein G is 1-piperazinyl or 2-piperazinyl.In another subgenus In embodiment, the present invention provides the compound of Formulas I, and wherein G is morpholinyl.In the embodiment of another subgenus, the present invention Thering is provided the compound of Formulas I, wherein G is N-methyl-2-amino ethyl.In the embodiment of a subgenus, the present invention provides Formulas I Compound, wherein G is N-methyl-3-amino-n-propyl.In the embodiment of another subgenus, the present invention provides the change of Formulas I Compound, wherein G is (CH₃)₂N-CH₂CH₂-NH-(CH₂)_n-, wherein n is 1,2 or 3.In the embodiment of another subgenus, this The compound of bright offer Formulas I, wherein G is (CH₃CH₂)₂N-CH₂CH₂-NH-(CH₂)_n-, wherein n is 1 or 2.More specifically sub- In the embodiment belonged to, the present invention provides the compound of Formulas I, and wherein G is piperidino, 2-piperidyl, 3-piperidyl or 4-piperazine Piperidinyl；R^oIt is H, halogen or methoxyl group；X is F；And Y is I.In the embodiment of another more specifically subgenus, the present invention provides The compound of Formulas I, wherein G is 1-piperazinyl or 2-piperazinyl；R^oIt is H, halogen or methoxyl group；X is F；And Y is I.At another more In the embodiment of concrete subgenus, the present invention provides the compound of Formulas I, and wherein G is morpholinyl；R^oIt is H, halogen or methoxy Base；X is F；And Y is I.In the embodiment of another more specifically subgenus, the present invention provides the compound of Formulas I, and wherein G is N- Methyl-2-amino ethyl；R^oIt is H, halogen or methoxyl group；X is F；And Y is I.Embodiment in another more specifically subgenus In, the present invention provides the compound of Formulas I, and wherein G is N-methyl-3-amino-n-propyl；R^oIt is H, halogen or methoxyl group；X is F； And Y is I.In the embodiment of another more specifically subgenus, the present invention provides the compound of Formulas I, and wherein G is (CH₃)₂N- CH₂CH₂-NH-(CH₂)_n-, wherein n is 1,2 or 3；R^oIt is H, halogen or methoxyl group；X is F；And Y is I.The most sub-at another In the embodiment belonged to, the present invention provides the compound of Formulas I, and wherein G is (CH₃CH₂)₂N-CH₂CH₂-NH-(CH₂)_n-, wherein n It is 1 or 2；R^oIt is H, halogen or methoxyl group；X is F；And Y is I.

In some embodiments, the present invention provide contained I or its pharmaceutically acceptable salt, solvate, The pharmaceutical composition of polymorph, ester, tautomer or prodrug.In some embodiments, described pharmaceutical composition also wraps Containing at least one pharmaceutically acceptable carrier.

In some embodiments, the present invention provides to comprise and is selected from: 's Compound or its pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or the pharmaceutical composition of prodrug.? In some embodiments, described pharmaceutical composition also comprises at least one pharmaceutically acceptable carrier.In some embodiments, Described compound is in R configuration.In some embodiments, described compound is in R configuration, substantially free of S-isomer.? In some embodiments, described compound is in S configuration.

In some embodiments, described compound is in S configuration, substantially free of R-isomer.In some embodiments In, described compound is:In some embodiments, described compound is:

The invention still further relates to N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-l-(2, 3-dihydroxypropyl) cyclopropane-1-sulfonamide (also referred herein as " compound A " and " N-(-)-((2-is fluoro-for the fluoro-2-of 3,4-bis- 4-idodophenylamino)-6-methoxyphenyl)-l-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide "):Crystalline polymorph A, it demonstrates specific x-ray diffractogram of powder.In some embodiments In, described x-ray diffractogram of powder comprises the peak shown in Fig. 5 of at least 50%.In some embodiments, described powder X-ray is penetrated Ray diffraction diagram comprises the peak shown in Fig. 5 of at least 70%.In some embodiments, described x-ray diffractogram of powder comprise to Peak shown in Fig. 5 of few 90%.In some embodiments, described x-ray diffractogram of powder is penetrated with the powder X-ray shown in Fig. 5 Ray diffraction diagram is essentially identical.By preparing R and the S-MTPA ester on secondary alcohol and contrast chemical shift of proton difference, compound A has been characterized as being " S " isomer.See for example Dale, J.A.；Mosher,H.S.,J.Am.Chem.Soc.,1973,95,512 With Ohtani etc., J.Am.Chem.Soc., 1991,113,4092.

The invention still further relates to N-(R)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-l-(2, 3-dihydroxypropyl) cyclopropane-1-sulfonamide (also referred herein as " compound B " and " N-(+)-((2-is fluoro-for the fluoro-2-of 3,4-bis- 4-idodophenylamino)-6-methoxyphenyl)-l-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide "):By preparing R and the S-MTPA ester on secondary alcohol and contrast chemical shift of proton difference, compound B Have been characterized as being " R " isomer.See for example Dale, J.A.；Mosher,H.S.,J.Am.Chem.Soc.,1973,95,512 With Ohtani etc., J.Am.Chem.Soc., 1991,113,4092.

The invention still further relates to N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-l-(2, 3-dihydroxypropyl) the crystalline polymorph A of cyclopropane-1-sulfonamide:It demonstrates the poorest Show scanning amount thermal map.In some embodiments, described means of differential scanning calorimetry figure and the means of differential scanning calorimetry figure base shown in Fig. 6 This is identical.

The invention still further relates to pharmaceutical composition, it comprises N-(S)-(3,4-bis-fluoro-2-(the 2-fluoro-4-iodophenyl of effective dose Amino)-6-methoxyphenyl) the crystalline polymorph A of-l-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide and pharmacy can The carrier accepted or carrier.

In some embodiments, N-(S)-(3,4-bis-fluoro-2-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)- The crystalline polymorph A of l-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide is used for treatment or prophylaxis of cancer or inflammatory disease Sick.The invention further relates to treatment or prophylaxis of cancer or the method for inflammatory diseases, it include to subject in need to The N-(S) of medicine effective dose-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-l-(2,3-dihydroxy third Base) the crystalline polymorph A of cyclopropane-1-sulfonamide.

In in other respects, the present invention relates to comprise the compound of formula I of effective dose or its pharmaceutically acceptable salt, solvent conjunction The pharmaceutical composition of thing, polymorph, ester, tautomer or prodrug.In some embodiments, described pharmaceutical composition is also Comprise pharmaceutically acceptable carrier.Such compositions can comprise adjuvant, excipient and preservative, for postponing the examination absorbed Agent, filler, binding agent, adsorbent, buffer agent, disintegrating agent, solubilizing agent, other carriers, and other inert fractions.Such The compound method of compositions is well known in the art.

In other respects, the present invention relates to contained I or its pharmaceutically acceptable salt, solvate, polymorphic The pharmaceutical composition of thing, ester, tautomer or prodrug.In some embodiments, described pharmaceutical composition is oral for being suitable for The form being administered.Further or in other embodiment, described pharmaceutical composition be tablet, capsule, pill, powder, Slow releasing preparation, solution, the form of suspensoid, be sterile solution agent, suspensoid or Emulsion for parenteral injection, for local Being administered is ointment or emulsifiable paste, or is suppository for rectally.Further or in other embodiment, described medicine Compositions is to be suitable for the unit dosage forms of correct dose single-dose.Further or other embodiment compounds of formula I Amount in the range of about 0.001 to about 1000mg/kg body weight/day.Further or other embodiment compounds of formula I Amount in the range of about 0.5 to about 50mg/kg/ day.Further or other the amount of embodiment compounds of formula I is about 0.001 to about 7g/ day.Further or other the amount of embodiment compounds of formula I is about 0.002 to about 6g/ day.Entering The amount of one step or other embodiment compounds of formula I is about 0.005 to about 5g/ day.Further or other embodiment party The amount of case compounds of formula I is about 0.01 to about 5g/ day.Further or other the amount of embodiment compounds of formula I is About 0.02 to about 5g/ day.Further or other the amount of embodiment compounds of formula I is about 0.05 to about 2.5g/ day.? Further or other the amount of embodiment compounds of formula I is about 0.1 to about 1g/ day.

Further or in other embodiment, may enough have a surplus less than the dosage level of above-mentioned range lower limit.? Further or in other embodiment, it is likely necessary higher than the dosage level of above-mentioned range limit.Further or its With the compound of single dose Medicine-feeding type I once a day in his embodiment.Further or in other embodiment with many The compound of the dosage every day of Medicine-feeding type I more than once.Further or in other embodiment every day twice Medicine-feeding type I change Compound.At the compound of Medicine-feeding type I three times a day further or in other embodiment.Further or other embodiment party The compound of four times a day Medicine-feeding type I in case.Further or the every day of the change more than four Medicine-feeding type I in other embodiment Compound.

In some embodiments, described pharmaceutical composition is for being administered to mammal.Further or other reality Executing in scheme, described mammal is the mankind.

Further or in other embodiment, described pharmaceutical composition also comprises pharmaceutical carrier, excipient and/or auxiliary Agent.Further or in other embodiment, described pharmaceutical composition also comprises at least one therapeutic agent.Further or its In his embodiment, described therapeutic agent is selected from cytotoxic agent, antiangiogenic agent and antineoplastic agent.Further or other Embodiment in, described antineoplastic agent be selected from alkylating agent, antimetabolite, epidophylltoxin (epidophyllotoxins)；Anti-swollen Tumor enzyme, topoisomerase enzyme inhibitor, procarbazine, mitoxantrone, platinum coordination complex, biological response modifier and growth inhibited Agent, hormone/antihormonal therapy agents and hemopoietic growth factor.Further or in other embodiment, described therapeutic agent is purple China fir alcohol, bortezomib or the two.Further or in other embodiment, it is administered described pharmaceutical composition, treats with other Method is combined.Further or in other embodiment, other therapies described be X-ray therapy, chemotherapy, surgical operation or Their combination in any.Further or in other embodiment, the pharmacy of the contained I of described pharmaceutical composition can The salt accepted.

Provided herein comprising is selected fromCompound compositions and Use comprises and is selected fromThe method of compositions of compound.Implement at some In scheme, the 2-OH carbon on described compound is in R configuration.In some embodiments, at the 2-OH carbon on described compound In S configuration.In some embodiments, described compositions is substantially free of the S-isomer of described compound.Some embodiment party In case, described compositions is substantially free of the R-isomer of described compound.In some embodiments, described compound comprises few S-isomer in the described compound of 10%.In some embodiments, described compound comprises the described chemical combination less than 10% The R-isomer of thing.In some embodiments, described compound comprises the S-isomer of the described compound less than 5%.One In a little embodiments, described compound comprises the R-isomer of the described compound less than 5%.In some embodiments, described Compound comprises the S-isomer of the described compound less than 1%.In some embodiments, described compound comprises less than 1% The R-isomer of described compound.

It is also provided herein and comprises about 1-100mg there is the compound of following structure:Compositions with And with comprising about 1-100mg and have the compound of following structure:Compositions treatment cancer or the side of inflammation Method.In some embodiments, described compositions allows to improve and discharges described compound.In some embodiments, described group Compound allows compound described in sustained release.In some embodiments, described compositions allows to postpone to discharge described compound. In some embodiments, described compound exists with the amount of about 1-50mg.In some embodiments, described compound is with about The amount of 1-10mg exists.In some embodiments, described compound exists with the amount of about 10-20mg.In some embodiments In, described compound exists with the amount of about 20-40mg.In some embodiments, described compound is deposited with the amount of about 40-50mg ?.

It is also provided herein and comprises about 1-50mg there is the compound of following structure:Compositions with And with comprising about 1-50mg and have the compound of following structure:Compositions treatment cancer or the side of inflammation Method, wherein said compositions allows to improve and discharges described medicine.In some embodiments, described compositions also comprises crystallite fibre Dimension element.In some embodiments, described compositions also comprises cross-linked carboxymethyl cellulose sodium.In some embodiments, described Compositions also comprises sodium lauryl sulphate.In some embodiments, described compositions also comprises magnesium stearate.

It is also provided herein and comprises about 1mg there is the compound of following structure:Compositions.One In a little embodiments, described compositions also comprises about 222.2mg microcrystalline Cellulose.In some embodiments, described compositions Also comprise about 12.0mg cross-linked carboxymethyl cellulose sodium.In some embodiments, described compositions also comprises about 2.4mg dodecane Base sodium sulfate.In some embodiments, described compositions also comprises about 2.4mg magnesium stearate.

It is also provided herein and comprises about 10mg there is the compound of following structure:Compositions and Compound with comprising about 10mg and have following structure:Compositions treatment cancer or the method for inflammation. In some embodiments, described compositions also comprises about 213.2mg microcrystalline Cellulose.In some embodiments, described group Compound also comprises about 12.0mg cross-linked carboxymethyl cellulose sodium.In some embodiments, described compositions also comprises about 2.4mg ten Sodium dialkyl sulfate.In some embodiments, described compositions also comprises about 2.4mg magnesium stearate.

It is also provided herein and comprises about 20mg there is the compound of following structure:Compositions and use Comprise about 20mg and there is the compound of following structure:Compositions treatment cancer or the method for inflammation.One In a little embodiments, described compositions also comprises about 203.2mg microcrystalline Cellulose.In some embodiments, described compositions Also comprise about 12.0mg cross-linked carboxymethyl cellulose sodium.In some embodiments, described compositions also comprises about 2.4mg dodecane Base sodium sulfate.In some embodiments, described compositions also comprises about 2.4mg magnesium stearate.

It is also provided herein and comprises about 40mg there is the compound of following structure:Compositions and Compound with comprising about 40mg and have following structure:Compositions treatment cancer or the method for inflammation. In some embodiments, described compositions also comprises about 183.2mg microcrystalline Cellulose.In some embodiments, described group Compound also comprises about 12.0mg cross-linked carboxymethyl cellulose sodium.In some embodiments, described compositions also comprises about 2.4mg ten Sodium dialkyl sulfate.In some embodiments, described compositions also comprises about 2.4mg magnesium stearate.

The compound with following structure that comprise about 0.4 weight % be also provided herein:About 99.6 Weight % pharmaceutically acceptable carrier or the compositions of carrier and with the chemical combination with following structure comprising about 0.4 weight % Thing:The compositions treatment cancer of about 99.6 weight % pharmaceutically acceptable carriers or carrier or inflammation Method.In some embodiments, described pharmaceutically acceptable carrier or carrier include microcrystalline Cellulose.Some embodiment party In case, described microcrystalline Cellulose accounts for described compositions about 92.6 weight %.In some embodiments, described compositions also comprises About 5 weight % cross-linked carboxymethyl cellulose sodium.In some embodiments, described compositions also comprises about 1 weight % dodecyl sulfur Acid sodium.In some embodiments, described compositions also comprises about 1 weight % magnesium stearate.

The compound with following structure that comprise about 4.2 weight % be also provided herein:Peace treaty 95.8 weight % pharmaceutically acceptable carriers or the compositions of carrier and by the following structure that has comprising about 4.2 weight % Compound:The compositions treatment cancer of about 95.8 weight % pharmaceutically acceptable carriers or carrier or inflammation The method of disease.In some embodiments, described pharmaceutically acceptable carrier or carrier include microcrystalline Cellulose.Real at some Executing in scheme, described microcrystalline Cellulose accounts for described compositions about 88.8 weight %.In some embodiments, described compositions is also Comprise about 5 weight % cross-linked carboxymethyl cellulose sodium.In some embodiments, described compositions also comprises about 1 weight % dodecane Base sodium sulfate.In some embodiments, described compositions also comprises about 1 weight % magnesium stearate.

The compound with following structure that comprise about 2 weight % to about 10 weight % be also provided herein:About 98 weight % to about 90 weight % pharmaceutically acceptable carriers or the compositions of carrier and with comprising The compound with following structure of about 2 weight % to about 10 weight %:About 98 weight % are to about 90 weight % The compositions treatment cancer of pharmaceutically acceptable carrier or carrier or the method for inflammation.In some embodiments, described medicine Learn acceptable carrier or carrier also includes microcrystalline Cellulose.In some embodiments, described microcrystalline Cellulose accounts for described About 85 weight % of compositions are to about 95 weight %.In some embodiments, described compositions also comprises about 1 weight % to about 6 weights Amount % cross-linked carboxymethyl cellulose sodium.In some embodiments, described compositions also comprises about 0.1 weight % to about 2 weight % 12 Alkyl sodium sulfate.In some embodiments, described compositions also comprises about 0.25 weight % to about 1.5 weight % magnesium stearate.

It is also provided herein and comprises about 1mg there is the compound of following structure:Compositions and Compound with comprising about 1mg and have following structure:Compositions treatment cancer or the method for inflammation.? In some embodiments, described compositions also comprises about 222.2mg microcrystalline Cellulose.In some embodiments, described combination Thing also comprises about 12.0mg cross-linked carboxymethyl cellulose sodium.In some embodiments, described compositions also comprises about 2.4mg 12 Alkyl sodium sulfate.In some embodiments, described compositions also comprises about 2.4mg magnesium stearate.

It is also provided herein and comprises about 10mg there is the compound of following structure:Compositions and Compound with comprising about 10mg and have following structure:Compositions treatment cancer or the method for inflammation.? In some embodiments, described compositions also comprises about 213.2mg microcrystalline Cellulose.In some embodiments, described combination Thing also comprises about 12.0mg cross-linked carboxymethyl cellulose sodium.In some embodiments, described compositions also comprises about 2.4mg 12 Alkyl sodium sulfate.In some embodiments, described compositions also comprises about 2.4mg magnesium stearate.

It is also provided herein and comprises about 20mg there is the compound of following structure:Compositions with And with comprising about 20mg and have the compound of following structure:Compositions treatment cancer or the side of inflammation Method.In some embodiments, described compositions also comprises about 203.2mg microcrystalline Cellulose.In some embodiments, described Compositions also comprises about 12.0mg cross-linked carboxymethyl cellulose sodium.In some embodiments, described compositions also comprises about 2.4mg Sodium lauryl sulphate.In some embodiments, described compositions also comprises about 2.4mg magnesium stearate.

The compound with following structure that comprise about 0.4 weight % be also provided herein:Peace treaty 99.6 weight % pharmaceutical acceptable carriers or the compositions of carrier and with the change with following structure comprising about 0.4 weight % CompoundThe compositions treatment cancer of about 99.6 weight % pharmaceutical acceptable carriers or carrier or inflammation Method.In some embodiments, described pharmaceutically acceptable carrier or carrier include microcrystalline Cellulose.Some embodiment party In case, described microcrystalline Cellulose accounts for described compositions about 92.6 weight %.In some embodiments, described compositions also comprises About 5 weight % cross-linked carboxymethyl cellulose sodium.In some embodiments, described compositions also comprises about 1 weight % dodecyl sulfur Acid sodium.In some embodiments, described compositions also comprises about 1 weight % magnesium stearate.

The compound with following structure that comprise about 4.2 weight % be also provided herein:Peace treaty 95.8 weight % pharmaceutical acceptable carriers or the compositions of carrier and with the change with following structure comprising about 4.2 weight % Compound:The compositions treatment cancer of about 95.8 weight % pharmaceutical acceptable carriers or carrier or inflammation Method.In some embodiments, described pharmaceutically acceptable carrier or carrier include microcrystalline Cellulose.Implement at some In scheme, described microcrystalline Cellulose accounts for described compositions about 88.8 weight %.In some embodiments, described compositions is also wrapped Containing about 5 weight % cross-linked carboxymethyl cellulose sodium.In some embodiments, described compositions also comprises about 1 weight % dodecyl Sodium sulfate.In some embodiments, described compositions also comprises about 1 weight % magnesium stearate.

The compound with following structure that comprise about 2 weight % to about 10 weight % be also provided herein:About 98 weight % to about 90 weight % pharmaceutical acceptable carriers or the compositions of carrier and with comprising about The compound with following structure of 2 weight % to about 10 weight %:About 98 weight % are to about 90 weight % medicines Learn compositions treatment cancer or the method for inflammation of acceptable carriers or carrier.In some embodiments, described pharmacy can The carrier or the carrier that accept include microcrystalline Cellulose.In some embodiments, described microcrystalline Cellulose accounts for described compositions About 85 weight % are to about 95 weight %.In some embodiments, described compositions also comprises the friendship of about 1 weight % to about 6 weight % Connection carmethose.In some embodiments, described compositions also comprises about 0.1 weight % to about 2 weight % dodecyls Sodium sulfate.In some embodiments, described compositions also comprises about 0.25 weight % to about 1.5 weight % magnesium stearate.

Be also provided herein N-(-)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-l-(2, 3-dihydroxypropyl) the crystalline polymorph A of cyclopropane-1-sulfonamide and comprise the compositions of this compound, described crystallization is many Crystal formation thing A demonstrates the powder X-ray diffraction at the peak identified in x-ray diffractogram of powder shown in the Fig. 5 comprising at least 50% Figure.In some embodiments, described crystalline polymorph A, wherein said x-ray diffractogram of powder comprises Fig. 5 of at least 70% Shown in the peak identified in x-ray diffractogram of powder.In some embodiments, described x-ray diffractogram of powder comprise to The peak identified in x-ray diffractogram of powder shown in Fig. 5 of few 90%.In some embodiments, described X-ray powder spreads out Penetrate figure essentially identical with the x-ray diffractogram of powder shown in Fig. 5.In some embodiments, described crystalline polymorph tool There is the fusing point starting point (melting point onset) being about 143 DEG C measured through differential scanning calorimetry.Implement at some In scheme, described crystalline polymorph is the most anhydrous.In some embodiments, described crystalline polymorph is substantially free of molten Agent.

Be also provided herein N-(-)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-l-(2, 3-dihydroxypropyl) the crystalline polymorph A of cyclopropane-1-sulfonamide and comprise the compositions of this compound, described crystallization is many Crystal formation thing A demonstrates the means of differential scanning calorimetry figure essentially identical with means of differential scanning calorimetry figure shown in Fig. 6.In some embodiments In, described crystalline polymorph has the fusing point starting point being about 143 DEG C measured through differential scanning calorimetry.Implement at some In scheme, the crystalline polymorph of claim 67 or 68, wherein said crystalline polymorph is the most anhydrous.Implement at some In scheme, the crystalline polymorph any one of claim 67-69, wherein said crystalline polymorph is substantially free of solvent.

N-(3,4-bis-fluoro-2-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-l-(2,3-bis-is also provided herein Hydroxypropyl) polymorph of cyclopropane-1-sulfonamide and comprise the compositions of this compound, described polymorph is by including Make unbodied N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-l-(2,3-dihydroxypropyl) Prepared by the method for the step of cyclopropane-1-sulfonamide crystallization.In some embodiments, described crystallisation step includes from acetic acid second The mixture of ester and heptane crystallizes.In some embodiments, the ratio of the mixture of described ethyl acetate and heptane is about 1-4 part ethyl acetate is than about 2-10 part heptane.In some embodiments, the ratio of the mixture of described ethyl acetate and heptane It is that about 2 parts of ethyl acetate are than about 5 parts of heptane.

The method that suppression MEK enzyme is also provided herein, it includes making described MEK enzyme and compound as herein described or combination Thing contacts, and wherein said compound is be enough to there is the amount of described enzyme level at least 25%.In some embodiments, described MEK enzyme is MEK kinases.In some embodiments, described contact occurs intracellular.

The individuality of disease that treatment suffer from MEK mediation described in the method for disease is also provided herein, and it includes to described The compound as herein described of individual effective dosage or compositions.In some embodiments, it is administered described mek inhibitor, It is combined with other therapies.In some embodiments, other therapies described are X-ray therapy, non-MEK kinase inhibitor therapeutics, change Learn therapy, surgical operation, glucocorticoid, methotrexate, biological response modifier or their combination in any.Implement at some In scheme, described MEK mediation disease selected from inflammatory diseases, infection, autoimmune disease, apoplexy, ischemia, cardiac conditions, Neurological disorder, fibrotic conditions, proliferative disorders, hyperproliferative disorders, tumor, leukemia, tumor (neoplasms), cancer Disease, cancer, metabolic disease and malignant diseases.In some embodiments, the disease of described MEK mediation is excess proliferative disease.One In a little embodiments, the disease of described MEK mediation is cancer, tumor, leukemia, tumor or cancer.In some embodiments, described The disease of MEK mediation is inflammatory diseases.In some embodiments, described inflammatory diseases is rheumatoid arthritis or multiple Hardening.

In treatment or the prevention individuality method of proliferative disease is also provided herein, and it includes to described individual administration effectively The compound as herein described of amount or compositions.In some embodiments, described proliferative disease is cancer, psoriasis, again Narrow, disease or atherosclerosis.In some embodiments, described proliferative disease is cancer.In some embodiments In, described cancer is the brain cancer, breast carcinoma, pulmonary carcinoma, ovarian cancer, cancer of pancreas, carcinoma of prostate, renal carcinoma, colorectal cancer, leukemia, marrow Sample leukemia, glioblastoma multiforme, follicular lymphoma (follicular lymphoma), front B acute leukemia, chronic pouring Bar cell B leukemia, gastric cancer, mesothelioma or small cell lung cancer.In some embodiments, described method also includes being administered at least A kind of therapeutic agent.In some embodiments, this step includes using at least one other cancer therapy.In some embodiments In, other therapies described are X-ray therapy, non-MEK kinase inhibitor therapeutics, chemotherapy, surgical operation, glucocorticoid, first Aminopterin, biological response modifier or their combination in any.

In treatment or the prevention individuality method of inflammatory diseases is also provided herein, and it includes to described individual effective dosage The compositions comprising compound described herein.In some embodiments, described inflammatory diseases be rheumatoid arthritis or Multiple sclerosis.

Being also provided herein and make the method that cancerous cell is degenerated, anticancer grows or kills cancerous cell, it includes making institute State cell with effectively make cancerous cell degenerate, anticancer growth or kill cancerous cell amount compound as herein described or Compositions contacts.In some embodiments, described cancerous cell includes brain cancer cell, breast cancer cell, lung carcinoma cell, ovarian cancer Cell, pancreatic cancer cell, prostate gland cancer cell, kidney cancer cell, stomach cancer cell or colorectal cancer cell.

Suppression tumor size is also provided herein in individuality increase, reduce tumor size, reduce tumor proliferation or prevention The method of tumor proliferation, it includes that the compound as herein described to described individual effective dosage or compositions are to suppress tumor Size increases, reduces tumor size, reduces tumor proliferation or prophylaxis of tumours propagation.In some embodiments, described tumor goes out Now in brain, mammary gland, lung, ovary, pancreas, prostate, kidney, stomach, colon or rectum.

Treatment or prevention ankylosing spondylitis, gout, tendinitis, bursitis or the side of sciatica are also provided herein Method, it includes formula (I) compound or pharmaceutically acceptable salt thereof to subject in need's effective dosage:

Wherein:

Z is H or F；

X is F, Cl, CH₃、CH₂OH、CH₂F、CHF₂Or CF₃；

Whole described methyl groups are optionally replaced by 1,2 or 3 F atom；

Described C₁-C₆Alkyl and C₁-C₄Alkoxy base is the most optionally by OCH₃Or OCH₂CH₃Replace；

G is G₁、G₂、R_1a、R_1b、R_1c、R_1d、R_1e、Ar₁、Ar₂Or Ar₃；Wherein

G₁It is C₃-C₈Diaminoalkyl group；

R_1cIt is (CH₂)_nO_mR′；Wherein

M is 0 or 1；And wherein

When m is 0, n is 1 or 2；

When m is 1, n is 2 or 3；

R_1dBe C (A) (A ') (B)-；Wherein

B is H or C_1-4Alkyl, it is optionally replaced by one or two OH group；

R_1eIt is

Wherein

Q is 1 or 2；

R₅It is H, F, Cl or methyl；

R₆It is H, F, Cl or methyl；

Ar₁It is

Wherein

U and V independently be N, CR₂Or CR₃；

R₅And R₆Independently be H, F, Cl or methyl；

Ar₂It is

Wherein

U is-S-,-O-or-N=, and wherein

When U is-O-or-S-, V is-CH=,-CCl=or-N=；

When U is-N=, V is-CH=,-CCl=, or-N=；

R₇It is H or methyl；

R₈It is H, acetylamino, methyl, F or Cl；

Ar₃It is

Wherein

U is-NH-,-NCH₃-or-O-；

R₇And R₈Independently be H, F, Cl or methyl.

In some embodiments, described compound is selected from:

In some embodiments, described compound is selected fromWherein 2-OH carbon is in R configuration.In some embodiments, The compound or pharmaceutically acceptable salt thereof of described formula (I) is selected from Wherein 2-OH carbon is in S configuration.In some embodiments, described compound isSome embodiment party In case, described compound is

As herein described compound by drug treatment effective dose or the side of compositions treatment gastric cancer are also provided herein Method.As herein described compound by drug treatment effective dose or compositions treatment leukemia melanoma are also provided herein (leukemiam melanoma) or the method for hepatoma.

As herein described compound by drug treatment effective dose or compositions treatment non-small cell are also provided herein The method of pulmonary carcinoma.As herein described compound by drug treatment effective dose or compositions treatment colon cancer are also provided herein Method.As herein described compound by drug treatment effective dose is also provided herein or compositions treats CNS cancer Method.As herein described compound by drug treatment effective dose or the side of compositions treatment ovarian cancer are also provided herein Method.As herein described compound by drug treatment effective dose or the method for compositions treatment renal carcinoma are also provided herein.This Literary composition also provides for the compound as herein described by drug treatment effective dose or the method for compositions treatment carcinoma of prostate.Herein In also provide for the compound as herein described by drug treatment effective dose or compositions treatment breast carcinoma method.In various realities Executing in scheme, these methods also include being administered at least one other therapeutic agents.In some embodiments, use at least one its His cancer therapy.In some embodiments, other cancer therapies described be X-ray therapy, chemotherapy, surgical operation or it Combination in any.

It is also provided herein by controlling with the compound as herein described of topical formulations drug treatment effective dose or compositions Treat or prevent psoriatic method.

In various embodiments, compositions described in oral administration.In some embodiments, once a day or every day two The described compositions of secondary administration.In some embodiments, described compositions persistently at least one week it is administered once a day.

In some embodiments, when compositions described in oral administration, it is being administered described compositions to fasted subjects The T of described compound is reached between latter 1 hour to 3 hours_max.In some embodiments, when to snibject, the 1st It described compound reaches C_maxAbout 0.01 μ g/ml to about 1.0 μ g/ml.In some embodiments, when to snibject, C is reached at the 1st day described compound_maxAbout 0.01 μ g/ml to about 0.8 μ g/ml.In some embodiments, when giving to experimenter During medicine, reach C at the 1st day described compound_maxAbout 0.03 μ g/ml to about 0.5 μ g/ml.In some embodiments, 0-12 is little The AUC of compound described in the time is about 0.1 μ g hr/mL to about 5.0 μ g hr/mL.In some embodiments, described compound AUC be about 0.1 μ g hr/mL to about 4.0 μ g hr/mL.In some embodiments, the AUC of described compound is about 0.5 μ g Hr/mL to about 3.0 μ g hr/mL.In some embodiments, the T of described compound_maxBetween 0.5 to 5.0 hour.One In a little embodiments, the T of described compound_maxBetween 1.0 to 3.0 hours.In some embodiments, described compound T_maxBetween 1.0 to 2.5 hours.In some embodiments, the plasma concentration of described compound after single-dose 5 hours Greater than about 0.01mg/mL.In some embodiments, after single-dose 10 hours, the plasma concentration of described compound is greater than about 0.01mg/mL.In some embodiments, after single-dose 15 hours, the plasma concentration of described compound is greater than about 0.01mg/mL。

In some embodiments, when to one group of 10 snibject, reach average at the 1st day described compound C_maxAbout 0.01 μ g/ml to about 1.0 μ g/ml.In some embodiments, when to one group of 10 snibject, at the 1st day Described compound reaches average C_maxAbout 0.01 μ g/ml to about 0.8 μ g/ml.In some embodiments, when being subject to one group 10 When examination person is administered, reach average C at the 1st day described compound_maxAbout 0.03 μ g/ml to about 0.5 μ g/ml.In some embodiments In, the average AUC of described compound is about 0.1 μ g hr/mL to about 5.0 μ g hr/mL.In some embodiments, describedization The average AUC of compound is about 0.1 μ g hr/mL to about 4.0 μ g hr/mL.In some embodiments, described compound is average AUC is about 0.5 μ g hr/mL to about 3.0 μ g hr/mL.In some embodiments, the average T of described compound_max0.5 to Between 5.0 hours.In some embodiments, the average T of described compound_maxBetween 1.0 to 3.0 hours.Implement at some In scheme, the average T of described compound_maxBetween 1.0 to 2.5 hours.

It is also provided herein by being administered compound as herein described and the method for compositions reduction gross tumor volume.At some In embodiment, after being given daily described medicine 5 days, described gross tumor volume is reduced at least about 25%.In some embodiments In, after being given daily described medicine 5 days, described gross tumor volume is reduced at least about 50%.In some embodiments, in every day Being administered described medicine after 5 days, described gross tumor volume is reduced at least about 20-70%.In some embodiments, being given daily After stating medicine 15 days, described gross tumor volume is reduced at least about 25%.In some embodiments, it is being given daily described medicine 15 After it, described gross tumor volume is reduced at least about 50%.In some embodiments, after being given daily described medicine 15 days, described Gross tumor volume is reduced at least about 20-70%.In some embodiments, after being given daily described medicine 30 days, described tumor body Amass and be reduced at least about 25%.In some embodiments, after being given daily described medicine 30 days, described gross tumor volume is decreased to Few about 50%.In some embodiments, after being given daily described medicine 30 days, described gross tumor volume is reduced at least about 20- 70%。

It is also provided herein by being administered compound as herein described and the method for compositions suppression tumor growth.At some In embodiment, after being administered described medicine, described tumor growth is suppressed at least about 20%.In some embodiments, it is administered institute After stating medicine, described tumor growth is suppressed at least about 40%.In some embodiments, after being administered described medicine, described tumor Growth is suppressed at least about 60%.In some embodiments, after being administered described medicine, described tumor growth is suppressed at least about 80%.In some embodiments, after being administered described medicine, described tumor growth is suppressed about 20% to about 100%.Real at some Executing in scheme, after being administered described medicine, described tumor growth is the most suppressed.

In some embodiments, described compositions it is administered for twice every day.In some embodiments, it is administered once a day Described compositions.

In some embodiments, described mek inhibitor does not disturb the administering drug combinations of another kind of tumor inhibitor.

In some embodiments, described compositions be tablet, capsule, soft capsule (gel cap), ingot, bolus or The form of granule.In some embodiments, described compositions is to have capsule or the tablet of about 50mg to about 1000mg gross weight The form of dosage form.In some embodiments, described compositions for have selected from 50mg, 75mg, 100mg, 150mg, 200mg, The capsule of the gross weight of 250mg, 300mg, 350mg, 400mg, 450mg and 500mg or the form of tablet.In some embodiments In, described compositions is capsule or the form of tablet with about 240mg gross weight.

In some embodiments, described compositions also comprises at least one selected from microcrystalline Cellulose, silicified microcrystalline cellulose Element, lactose, sompressible sugar, xylitol, sorbitol, mannitol, pregelatinized Starch, maltodextrin, calcium phosphate, calcium carbonate, shallow lake Powder and the filler of calcium silicates.

In some embodiments, described compositions also comprises at least one selected from cross-linked carboxymethyl cellulose sodium, starch hydroxyl Sodium acetate, crospovidone, methylcellulose, alginic acid, sodium alginate, starch derivatives, bentonite (betonite) and magnesium silicate The disintegrating agent of aluminum.

In some embodiments, described compositions also comprises at least one selected from magnesium stearate, metallic stearate, cunning Stone, sodium stearyl fumarate and stearic lubricant.

In some embodiments, described compositions also comprises at least one selected from sodium lauryl sulphate, glycerol, dehydration Sorbitan oleate, Span60, polyoxyethylated anhydrous sorbitol laurate, cetylate, stearic acid Ester, oleate or six oleates (hexaolate), polyoxyethylene stearyl alcohol and the wetting agent of sorbitan mono-laurate or Surfactant.

Form provided herein is the compositions of capsule or tablet, and uses American Pharmacopeia (USP) apparatus II to exist Under 50rpm, in water, 1% sodium lauryl sulphate is as dissolution medium, and described capsule or tablet discharged at least in 30 minutes The described medicine of 60%.In some embodiments, described compositions is the form of capsule or tablet, and uses U.S.'s medicine Allusion quotation (USP) apparatus II is under 50rpm, and in water, 1% sodium lauryl sulphate is as dissolution medium, and described capsule or tablet exist The described medicine of about 60-100% is discharged in 30 minutes.In some embodiments, described compositions is the shape of capsule or tablet Formula, and use American Pharmacopeia (USP) apparatus II under 50rpm, in water, 1% sodium lauryl sulphate is as dissolution medium, institute State capsule or tablet in 30 minutes, discharge the described medicine of about 60-90%.In some embodiments, described compositions is Capsule or the form of tablet, and use American Pharmacopeia (USP) apparatus II under 50rpm, with 1% lauryl sulphate acid in water Sodium discharged the described medicine of about 60-80% as dissolution medium, described capsule or tablet in 30 minutes.

Batches of capsule or tablet are also provided herein, and it respectively comprises about 1 to about 50mg compound as herein described, and And there is the content uniformity USP admitted value (acceptance value) of below about 15.

Therapeutic Method

The present invention relates to treatment or the method for prophylaxis of cancer, it includes comprising to snibject's effective dose in need The pharmaceutical composition of formula (I) compound as described herein.In various embodiments, the most useful compound With the kind of compositions such as formula (I) or such as run through the application formula (I) in the range of any subgenus as an example or kind Described.

The present invention relates to treatment or the method for prevention inflammatory diseases, it includes to snibject's effective dose in need Comprise the pharmaceutical composition of formula as described herein (I) compound.In various embodiments, the most useful change Compound and the kind of compositions such as formula (I) or any subgenus as an example in the range of such as running through the formula (I) of the application or Described in kind.

In some embodiments, the present invention relates to treatment or prevention ankylosing spondylitis, gout, tendinitis, bursitis Or the method for sciatica, it includes that the formula as described herein (I) that comprises to individuals in need effective dosage is changed The pharmaceutical composition of compound.In various embodiments, the most useful compound and compositions such as formula (I) Kind or as described in any subgenus as an example in the range of the formula (I) running through the application or kind.

In some respects, the invention still further relates to treat the method for disease in the individuality suffering from described disease, it includes to institute State contained I or its pharmaceutically acceptable salt, solvate, polymorph, the ester of individual effective dosage, make a variation mutually Structure body or the compositions of prodrug.

In other respects, the present invention relates to treat the method for disease in mammal, it include to described mammal to The compound of formula I of medicine therapeutically effective amount or its pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or front Medicine.

In other respects, the present invention relates to treat the method for disease in the mankind, it includes being administered to described mammal controlling Treat compound of formula I or its pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or the prodrug of effective dose.

In other respects, the present invention relates to treat the method for hyperproliferative disorders in the mammal including the mankind, its Including to the compound of formula I of described mammal drug treatment effective dose or its pharmaceutically acceptable salt, solvate, polymorphic Thing, ester, tautomer or prodrug.

In other respects, the present invention relates to treat the side of inflammatory diseases, the patient's condition or disease in the mammal including the mankind Method, it includes the compound of formula I to described mammal drug treatment effective dose or its pharmaceutically acceptable salt, ester, prodrug, molten Agent compound, hydrate or derivant.

In other respects, the present invention relates to treat in the mammal including the mankind by disease or the disease of MEK Cascade control The method of condition, it includes being administered to described mammal and effectively regulates the compound of formula I of amount of described cascade or its pharmacy can Salt, ester, prodrug, solvate, hydrate or the derivant accepted.In accordance with known methods, those skilled in the art can be true Determine the suitable dosage of particular patient.

Suppression MEK enzyme

In other respects, the method that the present invention relates to suppress MEK enzyme.In some embodiments, described method includes making Described MEK enzyme be enough to suppress a certain amount of contained I of described enzyme or its pharmaceutically acceptable salt, solvate, The compositions contact of polymorph, ester, tautomer or prodrug, wherein said enzyme is suppressed.Further or other reality Executing in scheme, described enzyme is suppressed at least about 1%.Further or in other embodiment, described enzyme is suppressed at least about 2%.Further or in other embodiment, described enzyme is suppressed at least about 3%.Further or other embodiment In, described enzyme is suppressed at least about 4%.Further or in other embodiment, described enzyme is suppressed at least about 5%.Entering In one step or other embodiment, described enzyme is suppressed at least about 10%.Further or in other embodiment, described Enzyme is suppressed at least about 20%.Further or in other embodiment, described enzyme is suppressed at least about 25%.Further or In other embodiment, described enzyme is suppressed at least about 30%.Further or in other embodiment, described enzyme is pressed down System at least about 40%.Further or in other embodiment, described enzyme is suppressed at least about 50%.Further or other In embodiment, described enzyme is suppressed at least about 60%.Further or in other embodiment, described enzyme is suppressed at least About 70%.Further or in other embodiment, described enzyme is suppressed at least about 75%.Further or other embodiment party In case, described enzyme is suppressed at least about 80%.Further or in other embodiment, described enzyme is suppressed at least about 90%. Further or in other embodiment, described enzyme is substantially completely suppressed.Further or in other embodiment, Described MEK enzyme is MEK kinases.Further or in other embodiment, described MEK enzyme is MEK1.Further or other Embodiment in, described MEK enzyme is MEK2.Further or in other embodiment, described contact occurs intracellular. Further or in other embodiment, described cell is mammalian cell.Further or in other embodiment, Described mammalian cell is human cell.Further or in other embodiment, the pharmacy by contained I can The compositions accepting salt suppresses described MEK enzyme.

The disease of MEK mediation

In other respects, the present invention relates to treat the method for disease described in the individuality suffering from the disease that MEK mediates, its bag Include the contained I to described individual effective dosage or its pharmaceutically acceptable salt, solvate, polymorph, ester, Tautomer or the compositions of prodrug.In some embodiments, oral administration, intraduodenal administration, parenteral (including intravenous administration, subcutaneous administration, intramuscular administration, intravascular administration or administered by infusion), topical or rectally bag Described compositions containing compound of formula I.In some embodiments, described pharmaceutical composition is the shape being suitable for oral administration Formula.Further or in other embodiment, described pharmaceutical composition be tablet, capsule, pill, powder, slow releasing preparation, Solution, the form of suspensoid, be sterile solution agent, suspensoid or Emulsion for parenteral injection, is soft for topical Unguentum or emulsifiable paste, or be suppository for rectally.Further or in other embodiment, described pharmaceutical composition is It is suitable for the unit dosage forms of correct dose single-dose.Further or in other embodiment, described pharmaceutical composition is also Comprise pharmaceutical carriers, excipient and/or adjuvant.

Further or in other embodiment, the amount of compound of formula I is in about 0.001 to about 1000mg/kg body weight/day In the range of.Further or in other embodiment, the amount of compound of formula I about 0.5 to about 50mg/kg/ day scope In.Further or in other embodiment, the amount of compound of formula I is about 0.001 to about 7g/ day.Further or other Embodiment in, the amount of compound of formula I is about 0.01 to about 7g/ day.Further or in other embodiment, Formulas I The amount of compound is about 0.02 to about 5g/ day.Further or in other embodiment, the amount of compound of formula I be about 0.05 to About 2.5g/ day.Further or in other embodiment, the amount of compound of formula I is about 0.1 to about 1g/ day.Further or In other embodiment, may enough have a surplus less than the dosage level of above-mentioned range lower limit.Further or other enforcement In scheme, it is probably necessary higher than the dosage level of above-mentioned range limit.

Further or in other embodiment, with the compound of single dose Medicine-feeding type I once a day.Further or In other embodiment, with the compound of the multiple dose every day of Medicine-feeding type I more than once.Further or other embodiment In, every day twice Medicine-feeding type I compound.Further or in other embodiment, the chemical combination of Medicine-feeding type I three times a day Thing.Further or in other embodiment, the compound of four times a day Medicine-feeding type I.Further or other embodiment party In case, every day is more than the compound of four Medicine-feeding type I.In some embodiments, the individuality of the disease suffering from MEK mediation is to feed Breast animal.Further or in other embodiment, described individuality is the mankind.

In some embodiments, it is administered the described compositions of contained I, is combined with other therapies.Entering one In step or other embodiment, other therapies described are X-ray therapy, chemotherapy, surgical operation or their any group Close.Further or in other embodiment, the described compositions of contained I is given with at least one therapeutic agent Medicine.Further or in other embodiment, described therapeutic agent is selected from cytotoxic agent, antiangiogenic agent and antitumor Medicine.Further or in other embodiment, described antineoplastic agent is selected from alkylating agent, antimetabolite, epidophylltoxin；Antitumor Enzyme, topoisomerase enzyme inhibitor, procarbazine, mitoxantrone, platinum coordination complex, biological response modifier and growth inhibited Agent, hormone/antihormonal therapy agents and hemopoietic growth factor.Further or in other embodiment, described therapeutic agent is selected from Paclitaxel, bortezomib or the two.

In some embodiments, described MEK mediation disease selected from inflammatory diseases, infection, autoimmune disease, in Wind, ischemia, cardiac conditions, neurological disorder, fibrotic conditions, proliferative disorders, hyperproliferative disorders, non-cancer excessively increase Grow sexually transmitted disease (STD) disease, tumor, leukemia, tumor, cancer, cancer, metabolic disease, malignant diseases, vascular restenosis, psoriasis, atherosclerosis, Rheumatoid arthritis, osteoarthritis, heart failure, chronic pain, neuropathic pain, xerophthalmia, angle closure glaucoma and angle of release Type glaucoma.Further or in other embodiment, the disease of described MEK mediation is inflammatory diseases.Further or its In his embodiment, the disease of described MEK mediation is excess proliferative disease.Further or in other embodiment, The disease of described MEK mediation is selected from tumor, leukemia, tumor, cancer, cancer and malignant diseases.Further or other embodiment In, described cancer is the brain cancer, breast carcinoma, pulmonary carcinoma, ovarian cancer, cancer of pancreas, carcinoma of prostate, gastric cancer, renal carcinoma, colorectal cancer or white blood Sick.Further or in other embodiment, described fibrotic conditions is scleroderma, polymyositis, systemic lupus, rheumatoid Property arthritis, liver cirrhosis, keloid formed, interstitial nephritis or pulmonary fibrosis.Further or in other embodiment, The compositions of the pharmaceutically acceptable salt of the contained I of effective dosage.

Obtain effect

In other respects, the method that the present invention relates to obtain effect in patients, it includes to patient's effective dosage Contained I or its pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or the combination of prodrug Thing, wherein said effect is selected from the suppression to various cancers, immune disease and inflammatory diseases.In some embodiments, institute Stating effect is to suppress various cancers.Further or in other embodiment, described effect is suppression immune disease.Entering In one step or other embodiment, described effect is suppression inflammatory diseases.

In some embodiments, it is administered the described compositions of contained I, is combined with other therapies.Entering one In step or other embodiment, other therapies described are X-ray therapy, chemotherapy, surgical operation or their any group Close.Further or in other embodiment, the described compositions of contained I is given with at least one therapeutic agent Medicine.

In some embodiments, oral administration, intraduodenal administration, parenteral (include intravenous administration, skin Lower administration, intramuscular administration, intravascular administration or administered by infusion), compositions described in topical or rectally.Further or In other embodiment, the amount of compound of formula I is in the range of about 0.001 to about 1000mg/kg body weight/day.Further Or in other embodiment, the amount of compound of formula I is in the range of about 0.5 to about 50mg/kg/ day.Further or other Embodiment in, the amount of compound of formula I is about 0.001 to about 7g/ day.Further or in other embodiment, Formulas I The amount of compound is about 0.01 to about 7g/ day.Further or in other embodiment, the amount of compound of formula I be about 0.02 to About 5g/ day.Further or in other embodiment, the amount of compound of formula I is about 0.05 to about 2.5g/ day.Further Or in other embodiment, the amount of compound of formula I is about 0.1 to about 1g/ day.Further or in other embodiment, May enough have a surplus less than the dosage level of above-mentioned range lower limit.Further or in other embodiment, higher than above-mentioned model The dosage level placing limit is probably necessary.

Further or in other embodiment, with the compound of single dose Medicine-feeding type I once a day.Further or In other embodiment, with the compound of the multiple dose every day of Medicine-feeding type I more than once.Further or other embodiment In, every day twice Medicine-feeding type I compound.Further or in other embodiment, the chemical combination of Medicine-feeding type I three times a day Thing.Further or in other embodiment, the compound of four times a day Medicine-feeding type I.Further or other embodiment party In case, every day is more than the compound of four Medicine-feeding type I.In some embodiments, the individuality suffering from cancer is mammal.? Further or in other embodiment, described individuality is the mankind.Further or in other embodiment, effective dosage The compositions of pharmaceutically acceptable salt of contained I.

In other respects, the present invention relates to make the method that cancerous cell is degenerated, anticancer grows or kills cancerous cell, its Including making described cell and effectively making described cell degradation, suppress the growth of described cell or kill the combination of amount of described cell Thing contacts, and the contained I of described compositions or its pharmaceutically acceptable salt, solvate, polymorph, ester, makes a variation mutually Structure body or prodrug.In some embodiments, described cancerous cell includes brain cancer cell, breast cancer cell, lung carcinoma cell, ovarian cancer Cell, pancreatic cancer cell, prostate gland cancer cell, kidney cancer cell or colorectal cancer cell.Further or other embodiment In, described compositions is administered with at least one therapeutic agent.Further or in other embodiment, described therapeutic agent is Paclitaxel, bortezomib or the two.Further or in other embodiment, described therapeutic agent selected from cytotoxic agent, Antiangiogenic agent and antineoplastic agent.Further or in other embodiment, described antineoplastic agent is selected from alkylating agent, anti-generation Thank medicine, epidophylltoxin；Antitumor enzyme, topoisomerase enzyme inhibitor, procarbazine, mitoxantrone, platinum coordination complex, biology are anti- Answer dressing agent and growth inhibitor, hormone/antihormonal therapy agents and hemopoietic growth factor.In some embodiments, described in making Cancerous cell is degenerated.Further or in other embodiment, the described cancerous cell of 1% is made to be degenerated.Further or other In embodiment, the described cancerous cell of 2% is made to degenerate.Further or in other embodiment, the described cancerous cell of 3% is made to move back Change.Further or in other embodiment, the described cancerous cell of 4% is made to degenerate.Further or other embodiment In, make the described cancerous cell of 5% degenerate.Further or in other embodiment, the described cancerous cell of 10% is made to degenerate.Entering In one step or other embodiment, the described cancerous cell of 20% is made to degenerate.Further or in other embodiment, make 25% Described cancerous cell degenerate.Further or in other embodiment, the described cancerous cell of 30% is made to degenerate.Further or In other embodiment, the described cancerous cell of 40% is made to degenerate.Further or in other embodiment, make 50% described Cancerous cell is degenerated.Further or in other embodiment, the described cancerous cell of 60% is made to degenerate.Further or other In embodiment, the described cancerous cell of 70% is made to degenerate.Further or in other embodiment, make the described cancerous cell of 75% Degenerate.Further or in other embodiment, the described cancerous cell of 80% is made to degenerate.Further or other embodiment party In case, the described cancerous cell of 90% is made to degenerate.Further or in other embodiment, the described cancerous cell of 100% is made to degenerate. Further or in other embodiment, substantially all described cancerous cell is made to degenerate.In various embodiments, above-mentioned move back Change and occur in 1 day, 5 days, 10 days, 1 month, 2 months, 6 months or 1 year.

In some embodiments, described cancerous cell is killed.Further or in other embodiment, 1% described Cancerous cell is killed.Further or in other embodiment, the described cancerous cell of 2% is killed.Further or other In embodiment, the described cancerous cell of 3% is killed.Further or in other embodiment, the described cancerous cell of 4% is killed Extremely.Further or in other embodiment, the described cancerous cell of 5% is killed.Further or other embodiment In, the described cancerous cell of 10% is killed.Further or in other embodiment, the described cancerous cell of 20% is killed.? Further or in other embodiment, the described cancerous cell of 25% is killed.Further or in other embodiment, 30% Described cancerous cell be killed.Further or in other embodiment, the described cancerous cell of 40% is killed.Further Or in other embodiment, the described cancerous cell of 50% is killed.Further or in other embodiment, 60% described Cancerous cell is killed.Further or in other embodiment, the described cancerous cell of 70% is killed.Further or other Embodiment in, the described cancerous cell of 75% is killed.Further or in other embodiment, the described cancerous cell of 80% It is killed.Further or in other embodiment, the described cancerous cell of 90% is killed.Further or other enforcement In scheme, the described cancerous cell of 100% is killed.Further or in other embodiment, substantially all described cancerous cell All it is killed.In various embodiments, the above-mentioned cancerous cell that kills occurs at 1 day, 5 days, 10 days, 1 month, 2 months, 6 months Or in 1 year.

Further or in other embodiment, the growth of described cancerous cell is suppressed.Further or other reality Executing in scheme, the growth of described cancerous cell is suppressed about 1%.Further or in other embodiment, the life of described cancerous cell Long by suppressed about 2%.Further or in other embodiment, the growth of described cancerous cell is suppressed about 3%.Further or In other embodiment, the growth of described cancerous cell is suppressed about 4%.Further or in other embodiment, described cancer The growth of cell is suppressed about 5%.Further or in other embodiment, the growth of described cancerous cell is suppressed about 10%. Further or in other embodiment, the growth of described cancerous cell is suppressed about 20%.Further or other embodiment party In case, the growth of described cancerous cell is suppressed about 25%.Further or in other embodiment, the growth of described cancerous cell It is suppressed about 30%.Further or in other embodiment, the growth of described cancerous cell is suppressed about 40%.Further or In other embodiment, the growth of described cancerous cell is suppressed about 50%.Further or in other embodiment, described The growth of cancerous cell is suppressed about 60%.Further or in other embodiment, the growth of described cancerous cell is suppressed about 70%.Further or in other embodiment, the growth of described cancerous cell is suppressed about 75%.Further or other reality Executing in scheme, the growth of described cancerous cell is suppressed about 80%.Further or in other embodiment, described cancerous cell Growth is suppressed about 90%.Further or in other embodiment, the growth of described cancerous cell is suppressed about 100%.Respectively Planting in embodiment, above-mentioned suppression occurs in 1 day, 5 days, 10 days, 1 month, 2 months, 6 months or 1 year.

In other respects, the present invention relates to reduce tumor size in individuality, suppression tumor size increases, reduce tumor increasing Growing or the method for prophylaxis of tumours propagation, it includes that contained I or its pharmacy to described individual effective dosage can connect The compositions of the salt, solvate, polymorph, ester, tautomer or the prodrug that are subject to.In some embodiments, tumor Size is reduced.Further or in other embodiment, the size of tumor is reduced at least 1%.Further or other In embodiment, the size of tumor is reduced at least 2%.Further or in other embodiment, the size of tumor is reduced At least 3%.Further or in other embodiment, the size of tumor is reduced at least 4%.Further or other enforcement In scheme, the size of tumor is reduced at least 5%.Further or in other embodiment, the size of tumor is reduced at least 10%.Further or in other embodiment, the size of tumor is reduced at least 20%.Further or other embodiment party In case, the size of tumor is reduced at least 25%.Further or in other embodiment, the size of tumor is reduced at least 30%.Further or in other embodiment, the size of tumor is reduced at least 40%.Further or other embodiment party In case, the size of tumor is reduced at least 50%.Further or in other embodiment, the size of tumor is reduced at least 60%.Further or in other embodiment, the size of tumor is reduced at least 70%.Further or other embodiment party In case, the size of tumor is reduced at least 75%.Further or in other embodiment, the size of tumor is reduced at least 80%.Further or in other embodiment, the size of tumor is reduced at least 85%.Further or other embodiment party In case, the size of tumor is reduced at least 90%.Further or in other embodiment, the size of tumor is reduced at least 95%.Further or in other embodiment, described tumor is uprooted.In some embodiments, the size of tumor does not increases Greatly.In various embodiments, the effect above of tumor size is occurred at 1 day, 5 days, 10 days, 1 month, 2 months, 6 months Or in 1 year.

In some embodiments, tumor proliferation is reduced.In some embodiments, tumor proliferation is reduced at least 1%.In some embodiments, tumor proliferation is reduced at least 2%.In some embodiments, tumor proliferation is reduced at least 3%.In some embodiments, tumor proliferation is reduced at least 4%.In some embodiments, tumor proliferation is reduced at least 5%.In some embodiments, tumor proliferation is reduced at least 10%.In some embodiments, tumor proliferation is reduced at least 20%.In some embodiments, tumor proliferation is reduced at least 25%.In some embodiments, tumor proliferation is reduced to Few 30%.In some embodiments, tumor proliferation is reduced at least 40%.In some embodiments, tumor proliferation is reduced At least 50%.In some embodiments, tumor proliferation is reduced at least 60%.In some embodiments, tumor proliferation is subtracted Few at least 70%.In some embodiments, tumor proliferation is reduced at least 75%.In some embodiments, tumor proliferation quilt Reduce at least 75%.In some embodiments, tumor proliferation is reduced at least 80%.In some embodiments, tumor proliferation It is reduced at least 90%.In some embodiments, tumor proliferation is reduced at least 95%.In some embodiments, tumor increases Grow and be prevented from.In various embodiments, cell proliferation the effect above occur 1 day, 5 days, 10 days, 1 month, 2 months, In 6 months or 1 year.

In some embodiments, it is administered the described compositions of contained I, is combined with other therapies.Entering one In step or other embodiment, other therapies described are X-ray therapy, chemotherapy, surgical operation or their any group Close.Further or in other embodiment, the described compositions of contained I is given with at least one therapeutic agent Medicine.Further or in other embodiment, described therapeutic agent is selected from cytotoxic agent, antiangiogenic agent and antitumor Medicine.Further or in other embodiment, described antineoplastic agent is selected from alkylating agent, antimetabolite, epidophylltoxin；Antitumor Enzyme, topoisomerase enzyme inhibitor, procarbazine, mitoxantrone, platinum coordination complex, biological respinse trim and growth inhibited Agent, hormone/antihormonal therapy agents and hemopoietic growth factor.Further or in other embodiment, described therapeutic agent is selected from Paclitaxel, bortezomib or the two.

Further or in other embodiment, with the compound of single dose Medicine-feeding type I once a day.Further or In other embodiment, with the compound of the multiple dose every day of Medicine-feeding type I more than once.Further or other embodiment In, every day twice Medicine-feeding type I compound.Further or in other embodiment, the chemical combination of Medicine-feeding type I three times a day Thing.Further or in other embodiment, the compound of four times a day Medicine-feeding type I.Further or other embodiment party In case, every day is more than the compound of four Medicine-feeding type I.In some embodiments, the individuality suffering from cancer described in is that suckling is moved Thing.Further or in other embodiment, described individuality is the mankind.Further or in other embodiment, it is administered The compositions of the pharmaceutically acceptable salt of the contained I of effective dose.

Proliferative disease

In other respects, the present invention relates to treatment or prevention individuality increaseGrowProperty disease method, it includes to described The contained I of body effective dosage or its pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer Or the compositions of prodrug.In some embodiments, described increasingGrowProperty disease is cancer, psoriasis, restenosis, autoimmunity Disease or atherosclerosis.Further or in other embodiment, described increasingGrowProperty disease is excess proliferative disease. Further or in other embodiment, described increasingGrowProperty disease selected from tumor, leukemia, tumor, cancer, cancer and malignant diseases. Further or in other embodiment, described cancer be the brain cancer, breast carcinoma, pulmonary carcinoma, ovarian cancer, cancer of pancreas, carcinoma of prostate, Renal carcinoma, colorectal cancer, gastric cancer, head and neck cancer or leukemia.Further or in other embodiment, described fibrotic conditions is The formation of scleroderma, polymyositis, systemic lupus, rheumatoid arthritis, liver cirrhosis, keloid, interstitial nephritis or lung are fine Dimensionization.Further or in other embodiment, described cancer be gastric cancer, the brain cancer, breast carcinoma, pulmonary carcinoma, nonsmall-cell lung cancer, Ovarian cancer, cancer of pancreas, hepatocarcinoma, carcinoma of prostate, renal carcinoma, colorectal cancer or leukemia.Further or in other embodiment, Described cancer is the brain cancer or adrenocortical carcinoma.Further or in other embodiment, described cancer is breast carcinoma.Entering In one step or other embodiment, described cancer is ovarian cancer.Further or in other embodiment, described cancer is Cancer of pancreas.Further or in other embodiment, described cancer is carcinoma of prostate.Further or other embodiment In, described cancer is renal carcinoma.Further or in other embodiment, described cancer is colorectal cancer.Further or its In his embodiment, described cancer is myeloid leukemia.Further or in other embodiment, described cancer is colloid Blastoma.Further or in other embodiment, described cancer is follicular lymphoma.Further or other reality Executing in scheme, described cancer is front B acute leukemia.Further or in other embodiment, described cancer is chronic pouring Bar cell B leukemia.Further or in other embodiment, described cancer is mesothelioma.Further or other reality Executing in scheme, described cancer is small cell lung cancer.In other embodiments, described cancer is gastric cancer.

In some embodiments, being administered the described combination of contained I, thing is combined with other therapies.Entering one In step or other embodiment, other therapies described are X-ray therapy, chemotherapy, surgical operation or their any group Close.Further or in other embodiment, the described compositions of contained I is given with at least one therapeutic agent Medicine.Further or in other embodiment, described therapeutic agent is selected from cytotoxic agent, antiangiogenic agent and antitumor Medicine.Further or in other embodiment, described antineoplastic agent is selected from alkylating agent, antimetabolite, epidophylltoxin；Antitumor Enzyme, topoisomerase enzyme inhibitor, procarbazine, mitoxantrone, platinum coordination complex, biological respinse trim and growth inhibited Agent, hormone/antihormonal therapy agents and hemopoietic growth factor.

Further or in other embodiment, described therapeutic agent selected from paclitaxel, bortezomib or the two.At some In embodiment, oral administration, intraduodenal administration, parenteral (include intravenous administration, subcutaneous administration, intramuscular to Medicine, intravascular administration or administered by infusion), compositions described in topical or rectally.

Further or in other embodiment, with the compound of single dose Medicine-feeding type I once a day.Further or In other embodiment, with the compound of the multiple dose every day of Medicine-feeding type I more than once.Further or other embodiment In, every day twice Medicine-feeding type I compound.Further or in other embodiment, the chemical combination of Medicine-feeding type I three times a day Thing.Further or in other embodiment, the compound of four times a day Medicine-feeding type I.Further or other embodiment party In case, every day is more than the compound of four Medicine-feeding type I.In some embodiments, the individuality suffering from proliferative disease described in is Mammal.Further or in other embodiment, described individuality is the mankind.Further or other embodiment In, the compositions of the pharmaceutically acceptable salt of the contained I of effective dosage.

Inflammatory diseases

In other respects, the present invention relates to the method for inflammatory diseases in treatment or prevention individuality, it includes to described individuality The contained I of effective dosage or its pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or The compositions of prodrug.Further or in other embodiment, described inflammatory diseases is selected from chronic inflammatory disease, rheumatoid Arthritis, rheumatoid arthritis, spondyloarthropathy, gouty arthritis, osteoarthritis, juvenile arthritis,juvenile chronic arthritis,juvenile rheumatoid arthritis, acute rheumatic Arthritis, enteropathic arthritis, neuropathic arthritis, psoriatic arthritis, suppurative arthritis, atherosclerosis, it is System property lupus erythematosus, inflammatory bowel, irritable bowel syndrome, ulcerative colitis, reflux esophagitis, Crohn disease, gastritis, Asthma, anaphylaxis, respiratory distress syndrome, pancreatitis, chronic obstructive pulmonary disease, pulmonary fibrosis, psoriasis, eczema or sclerderm Sick.

In some embodiments, it is administered the compositions of contained I, is combined with other therapies.Further or In other embodiment, the described compositions of contained I is administered with at least one therapeutic agent.

Further or in other embodiment, with the compound of single dose Medicine-feeding type I once a day.Further or In other embodiment, with the compound of the multiple dose every day of Medicine-feeding type I more than once.Further or other embodiment In, every day twice Medicine-feeding type I compound.Further or in other embodiment, the chemical combination of Medicine-feeding type I three times a day Thing.Further or in other embodiment, the compound of four times a day Medicine-feeding type I.Further or other embodiment party In case, every day is more than the compound of four Medicine-feeding type I.In some embodiments, the individuality suffering from inflammatory diseases described in is to feed Breast animal.Further or in other embodiment, described individuality is the mankind.Further or in other embodiment, The compositions of the pharmaceutically acceptable salt of the contained I of effective dosage.

Cancer

In other respects, the present invention relates to the method for cancer in treatment or prevention individuality, it includes to described individual administration The contained I of effective dose or its pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug Compositions.Further or in other embodiment, described cancer be the brain cancer, breast carcinoma, gastric cancer, pulmonary carcinoma, ovarian cancer, Cancer of pancreas, carcinoma of prostate, renal carcinoma, colorectal cancer or leukemia.Further or in other embodiment, described fibrotic disease Disease be scleroderma, polymyositis, systemic lupus, rheumatoid arthritis, liver cirrhosis, keloid formed, interstitial nephritis or Pulmonary fibrosis.Further or in other embodiment, described cancer be the brain cancer, breast carcinoma, pulmonary carcinoma, ovarian cancer, cancer of pancreas, Carcinoma of prostate, renal carcinoma, gastric cancer, colorectal cancer or leukemia.Further or in other embodiment, described cancer is the brain cancer Or adrenocortical carcinoma.Further or in other embodiment, described cancer is breast carcinoma.Further or other reality Executing in scheme, described cancer is ovarian cancer.Further or in other embodiment, described cancer is cancer of pancreas.Entering one In step or other embodiment, described cancer is carcinoma of prostate.Further or in other embodiment, described cancer is Renal carcinoma.Further or in other embodiment, described cancer is colorectal cancer.Further or other embodiment In, described cancer is myeloid leukemia.Further or in other embodiment, described cancer is glioblastoma multiforme.? Further or in other embodiment, described cancer is follicular lymphoma.Further or in other embodiment, institute Stating cancer is front B acute leukemia.Further or in other embodiment, described cancer is the white blood of chronic lymphocytic B Sick.Further or in other embodiment, described cancer is mesothelioma.Further or in other embodiment, institute Stating cancer is small cell lung cancer.In some embodiments, described cancer is gastric cancer.

In some embodiments, oral administration, intraduodenal administration, parenteral (include intravenous administration, skin Lower administration, intramuscular administration, intravascular administration or administered by infusion), compositions described in topical or rectally.Further or In other embodiment, the amount of compound of formula I is in the range of about 0.001 to about 1000mg/kg body weight/day.Further Or in other embodiment, the amount of compound of formula I is in the range of about 0.5 to about 50mg/kg/ day.Further or other Embodiment in, the amount of compound of formula I is about 0.001 to about 7g/ day.Further or in other embodiment, Formulas I The amount of compound is about 0.01 to about 7g/ day.Further or in other embodiment, the amount of compound of formula I be about 0.02 to About 5g/ day.Further or in other embodiment, the amount of compound of formula I is about 0.05 to about 2.5g/ day.Further Or in other embodiment, the amount of compound of formula I is about 0.1 to about 1g/ day.Further or in other embodiment, May enough have a surplus less than the dosage level of above-mentioned range lower limit.

Further or in other embodiment, it is probably necessary higher than the dosage level of above-mentioned range limit.? Further or in other embodiment, with the compound of single dose Medicine-feeding type I once a day.Further or other enforcement In scheme, with the compound of the multiple dose every day of Medicine-feeding type I more than once.Further or in other embodiment, every day two The compound of secondary Medicine-feeding type I.Further or in other embodiment, the compound of Medicine-feeding type I three times a day.Further Or in other embodiment, the compound of four times a day Medicine-feeding type I.Further or in other embodiment, every day is many Compound in four Medicine-feeding type I.In some embodiments, the individuality suffering from cancer described in is mammal.Further Or in other embodiment, described individuality is the mankind.Further or in other embodiment, comprising of effective dosage The compositions of the pharmaceutically acceptable salt of compound of formula I.

Quote addition

The whole publications and patent applications mentioned in this manual being quoted addition herein, its degree is equal to respectively Individual publication or patent application specifically and are individually indicated as being and quote addition.

Accompanying drawing is sketched

Detail the novel feature of the present invention in the accompanying claims.With reference to the example illustrating the application principle of the invention Described in detail below and the accompanying drawing of property embodiment, will be better appreciated by inventive feature and advantage.

Fig. 1 represents: be implanted with A375 melanoma, Colo205 colon tumor, A431 epiderm-like tumor or HT-29 knot In the mice of intestinal neoplasms cell, the mean tumour volume chart to time (natural law).To mice oral administration once a day (25mg/kg, 50mg/kg or 100mg/kg), continues 14 days.

Fig. 2 represents: be administered 50mg/kg QD, 25mg/kg BID, 50mg/kg QD and the A375 of 12.5mg/kg BID In xenograft mouse, % Tumor growth inhibition (%TGI) chart.

Fig. 3 represents: in the female nu/nu mice being implanted with Colo205 tumor cell, and plasma concentration (log nM) is right The chart of pERK% suppression.It is administered 2.5,5,10 or the single dose of 25mg/kg to mice.

Fig. 4 represents: after single dose is administered 2mg (2x1mg capsule), 4mg (4x1mg capsule) or 6mg (6x1mg capsule) In the mankind, the plasma concentration (ng/mL) chart to the time (hour).

Fig. 5 is N-(S)-(the fluoro-2-of 3,4-bis-(the 2-fluoro-4-iodophenyl ammonia using Inel XRG-3000 diffractometer to produce Base)-6-methoxyphenyl) powder X-ray diffraction (PXRD) of-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide A type Figure.With the peak intensity defined by counting per second, the angle of diffraction 2 θ (spending) is mapped.

Fig. 6 is N-(S)-(the fluoro-2-of 3,4-bis-(the 2-fluoro-4-iodine using TA instruments differential scanning calorimeter Q1000 to produce Phenyl amino)-6-methoxyphenyl) the modulation differential scanning amount of-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide A type Full-boiled process (DSC) thermal analysis curue.Make in order to normalized heat flow that watt/gram (W/g) the is unit sample temperature DEG C to recording Figure.

Fig. 7 is: use N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-iodophenyl ammonia that Inel XRG-3000 diffractometer produces Base)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide A type PXRD figure (top) and N-(S)- (the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulphonyl PXRD figure (bottom) of amine amorphous substance.With the peak intensity defined by counting per second, the angle of diffraction 2 θ (spending) is mapped.

Fig. 8 represents: use N-(S)-(the fluoro-2-of 3,4-bis-(fluoro-4-of 2-that VTI SGA-100 vapor sorption analyser produces Idodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide A type dynamic vapor sorption/ Desorption (DVS) isothermal line.

Fig. 9 represents: use N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-iodine that TA instrument 2950 thermogravimeter produces Phenyl amino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide (A) type DTG (TG) heat Analysis chart.

Figure 10 (a) and Figure 10 (b) represents: N-(S)-(the fluoro-2-of 3,4-bis-(the 2-fluoro-4-iodophenyl ammonia increased with concentration Base)-6-methoxyphenyl) A375 that dividing of logarithmic (log) phase of-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide contact The growth retardation of cell.Analyze raji cell assay Raji ATP content.Use 1 μM of N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-iodophenyl ammonia Base)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide determines 100% growth retardation.

Figure 11 represents: the 48hr AK in A375 cell measures.Make A375 cell that logarithmic (log) phase dividing and N-(S)- (the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulphonyl Amine contacts 48hr with PD-325901, and analyzes AK release.

Figure 12 A-12C represents: N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide (A) suppression Human Colorectal Cancer Colo205 cell growth (GI₅₀=11nM)； (B) suppression A375 cell growth (GI₅₀=22nM), and (C) suppression MDA-MB231 cell, it is in two dimension anchorage dependence test In do not demonstrate N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxy third Base) growth retardation that causes of cyclopropane-1-sulfonamide.

Figure 13 A represents suppression Human Colorectal Cancer Colo205 cell growth, GI₅₀Value is respectively 6nM and 11nM.

Figure 13 B represents suppression A375 cell growth, GI₅₀Value is 5nM and 22nM.

Figure 14 A and Figure 14 B represents: N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)- The effect of 1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide cell cycle process, this explanation makes A375 cell and N- (S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1- Sulfonamide contact causes stagnates within the G1 phase of cell cycle, and it is all reduced by the cell being in G2 phase and S phase and shows.

Figure 15 A and Figure 15 B represents: N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)- 1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide is to gastric cancer (adenocarcinoma of stomach) cell line AGS (Figure 15 A) after 3 days with after 6 days The effect of (Figure 15 B).Y-axis is the cell number relative to carrier, and x-axis is N-(S)-(3,4-bis-fluoro-2-(2-fluoro-4-iodophenyl ammonia Base)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide concentration uM.

Figure 16 represents: through N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2, 3-dihydroxypropyl) and cyclopropane-1-sulfonamide (2mg/kg, once a day, oral；10mg/kg, once a day, oral；And 50mg/kg, once a day, oral) after treatment, the average liver weight in tumor-bearing mice.

Figure 17 represents: through N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2, 3-dihydroxypropyl) and cyclopropane-1-sulfonamide (2mg/kg, once a day, oral；10mg/kg, once a day, oral；And 50mg/kg, once a day, oral) after treatment, the liver tumor weight in tumor-bearing mice.

Figure 18 represents: through N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2, 3-dihydroxypropyl) cyclopropane-1-sulfonamide (2mg/kg；10mg/kg;And 50mg/kg) treatment after average tumor weight.

Figure 19 represents: cell number (relative to carrier) to N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)- 6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide concentration figure in, pressing down of Hs746t cell proliferation System.

Figure 20 A represents: at the 5th day of process nonsmall-cell lung cancer (NSCLC) MV522 cell, along with N-(S)-(3,4-bis- Fluoro-2-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide concentration Increase, contrast the chart of each level of apoptosis.

Figure 20 B represents: at the 5th day of process nonsmall-cell lung cancer (NSCLC) H358 cell, along with N-(S)-(3,4-bis- Fluoro-2-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide concentration Increase the chart of each level of apoptosis.

Figure 20 C represents: at the 6th day of process nonsmall-cell lung cancer (NSCLC) A549 cell, along with N-(S)-(3,4-bis- Fluoro-2-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide concentration Increase the chart of each level of apoptosis.

Figure 20 D represents: at the 5th day of process nonsmall-cell lung cancer (NSCLC) H727 cell, along with N-(S)-(3,4-bis- Fluoro-2-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide concentration Increase the chart of each level of apoptosis.

Figure 20 E represents: at the 5th day of process colon HT29 cell, along with N-(S)-(3,4-bis-fluoro-2-(2-fluoro-4-iodine Phenyl amino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide concentration each level of apoptosis of increase Chart.

Figure 20 F represents: at the 6th day of process colon HCT116 cell, along with N-(S)-(3,4-bis-fluoro-2-(fluoro-4-of 2- Idodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide concentration each level of apoptosis of increase Chart.

Figure 20 G represents: at the 5th day of process colon HUH7 hepatoma cells, along with N-(S)-(3,4-bis-fluoro-2-(2- Fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-sulfonamide concentration the increase of-1-(2,3-dihydroxypropyl) cyclopropane respectively withers The chart of level of dying.

Figure 20 H represents: at the 5th day of process sarcoma U2-OS cell, along with N-(S)-(3,4-bis-fluoro-2-(2-fluoro-4-iodine Phenyl amino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide concentration each level of apoptosis of increase Chart.

Figure 20 I represents: at the 5th day of process glioma D37 cell, along with N-(S)-(3,4-bis-fluoro-2-(2-fluoro-4-iodine Phenyl amino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide concentration each level of apoptosis of increase Chart.

Figure 21 represents: under 10 μMs, and compound A contrasts the selectivity of one group of 205 enzyme to MEK1 and MEK2.Cell line is Colo205, A375, A431 and HT-29.

Figure 22 represents: in rat carrageenan pawl edema model, is administered 6,20,60 and the N-of 200mg/kg to rat (S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1- After sulfonamide, at the chart that each treatment group median claw volume increases and reduces relative to vehicle Control edema.

Figure 23 A represents: with 2,6 and 20mg/kg N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6- Methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide treatment rat acute stage in, adjuvant causes The suppression of swelling in arthritis model.

Figure 23 B represents: with 2,6 and 20mg/kg N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6- Methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide treatment rat period of delay in, adjuvant causes The suppression of swelling in arthritis model.

Figure 24 represents: with 1,3&10mg/kg QD N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6- Methoxyphenyl) arthritis that causes of glue antigen-antibody of-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide treatment (CAIA) mean arthritic score in mice.

Detailed Description Of The Invention

Chapter title used herein is understood not to limit described theme only for logic purpose.The application The all documents including, but are not limited to patent, patent application, article, books, handbook and paper cited in or part literary composition Offer, the most clearly quote addition with any purpose.

Some technical terms of chemistry

Unless otherwise defined, whole technology used herein and scientific terminology have with the theme of prescription belonging to lead Field technique personnel are generally understood that identical implication.Unless otherwise indicated, run through herein entire disclosure be cited whole specially Profit, patent application, the material of announcement intactly quote addition herein.If term herein has various definitions, with this chapter Definition in joint is main.In the case of to URL or other such identifiers or address reference, understand that such identifier can Energy change and the specifying information on the Internet may be continually changing, but come by search the Internet or other suitable references Source it appeared that equivalent information.Its list of references proves availability and the public propagation of such information.

It should be understood that above-mentioned general introduction and described below be merely exemplary with explanatory, and unrestricted prescription is any Theme.In this application, unless specifically stated otherwise, the use of odd number includes plural number.Must be noted that unless context additionally Clearly state, in this specification and the appended claims use singulative " a ", " an " and " this/this/described (the) referent of plural number " is included.Should also be noted that unless otherwise indicated, use "or" to mean "and/or".And, term " include " and the use of other forms is nonrestrictive.

(include that Carey and Sundberg " ADVANCED ORGANIC CHEMISTRY the 4th edition " rolls up A in reference works (2000) and volume B (2001), Plenum Press, New York) in it appeared that the definition of standard chemistry terms.Unless additionally Illustrate, use mass spectrum, NMR, HPLC, IR and UV/Vis spectrographic method and pharmacological conventional method in art technology.Unless carried For being specifically defined, the name relevant to analytical chemistry as herein described, synthetic organic chemistry and pharmaceutical chemistry of use and this Laboratory method and the technology in a little fields are known in the art.Standard technique can be used for chemosynthesis, chemical analysis, medicine Prepared by thing, preparation and administration, and treatment patient.Such as, use manufacturer's test kit description, or usual according to this area The mode completed, or as described herein, reaction and purification technique can be performed.By conventional method well known in the art, with And the various summaries of running through cited in this specification and discuss and referring more particularly to as described in document, generally can perform State technology and method.In whole this specification, those skilled in the art can select its group and substituent group to provide stable Part and compound.

In the case of their conventional chemical formulas by being write from left to right illustrates substituted radical, they include equally Write the chemically identical substituent group that structure can produce from right to left.With-CH₂O-is equivalent to-OCH₂-as non-limiting reality Example.

Unless otherwise indicated, the general chemical terms of use is equivalent to it such as but not limited to " alkyl ", " amine ", " aryl " The form being optionally substituted.Such as, the alkyl including being optionally substituted used herein to " alkyl ".

Compound as herein described can have one or more stereocenter, and each center can with R or S configuration, Or combinations thereof exists.Similarly, compound as herein described can have one or more double bond, and each double bond is permissible With E (trans) or Z (cis) configuration, or combinations thereof exists.It should be understood that stereoisomer specific to one, regional isomerism The description of body (regioisomer), diastereomer, enantiomer or epimer includes all possible stereoisomer, district Territory isomer, diastereomer, enantiomer or epimer and their mixture.Therefore, compound as herein described includes All single configuration stereoisomeric forms in any ratio, position isomeric form, diastereomer form, enantiomeric form and the epimerism bodily form Formula and their corresponding mixture.It should be understood that to comprising one or more chiral centre but not specified concrete stereochemicalization A kind of specified chemical structure of compound or the description of chemical name include all possible stereoisomer, it include likely The mixture of stereoisomer, the pure form of a kind of particular stereoisomer or the purest form, and available The pure form of stereoisomer or the purest form.Make specific stereocenter upset or keep constant technology and The technology splitting stereoisomer is to it is known in the art that and select suitable method completely in this area for particular case Within the ability of technical staff.See for example, Furniss etc. (eds.), VOGEL ' S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED., Longman Scientific and Technical Ltd., Essex, 1991,809-816；And Heller, Acc.Chem.Res.1990,23,128.

Term used herein " part ", " chemical part ", " group " and " chemical group " means the particular portion of molecule Divide or functional group.Chemical part is typically considered the chemical entities being embedded in intramolecular or being attached on molecule.

Term " key " or " singly-bound " mean the chemical bond between two atoms, or when being recognized by described bonded atom During for being the part of bigger minor structure, it is intended that the chemical bond between two parts.

Term " optional " or " optionally " mean the most described event or situation it may happen that or may not occur, and This description includes the situation that described event or situation occur and do not occur.Such as, " alkyl being optionally substituted " mean as Undefined " alkyl " or " alkyl being replaced ".Further, optionally, the group being replaced can be unsubstituted (as- CH₂CH₃), the most substituted (such as-CF₂CF₃), mono-substituted (such as-CH₂CH₂F), between or completely replacing and be monosubstituted any Replacement (such as-the CH of level₂CHF₂、-CH₂CF₃、-CF₂CH₃、-CFHCHF₂Deng).For comprising one or more substituent group Any group, it will be understood by those skilled in the art that such group is not configured to introduce actual in solid and/or synthesize not Feasible any replacement or substitute mode (alkyl being such as replaced includes the group of naphthene base being optionally substituted, its successively by It is defined as the alkyl group including being optionally substituted, may be unlimited).Therefore, described any substituent group generally it is understood that For having highest weight about 1,000 dalton, more typically, it is up to about 500 dalton (except meaning macromole clearly In the case of substituent group such as polypeptide, polysaccharide, Polyethylene Glycol, DNA, RNA etc.).

Unless otherwise indicated, general chemical terms, such as but not limited to " alkyl ", " amine ", the use of " aryl " be not by Substituted.

C used herein₁-C_xIncluding C₁-C₂、C₁-C₃……C₁-C_x.It is only used as example, is expressed as " C₁-C₄" group Show to there is 1-4 carbon atom in the portion, i.e. comprise 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms, And scope C₁-C₂And C₁-C₃Group.Therefore, it is only used as example, " C₁-C₄Alkyl " show in alkyl group, have 1-4 Carbon atom, the most described alkyl group is selected from methyl, ethyl, propyl group, isopropyl, normal-butyl, isobutyl group, sec-butyl and the tert-butyl group. When such as " 1-10 " occurs numerical range in this article, it is intended that each integer in given range；Such as, " 1-10 carbon Atom " mean described group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 Individual carbon atom, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms.

Term used herein " forms 3-6 unit saturated rings " and means together with the carbon atom that A and A ' is attached thereto with them The having structure of compound of formula I:

The term " hetero atom " being used alone or in combination herein or " miscellaneous " mean the atom in addition to carbon or hydrogen.Miscellaneous former Son independently selected from oxygen, nitrogen, sulfur, phosphorus, silicon, selenium and stannum, but can be not limited to these atoms.There is two or more hetero atom Embodiment in, said two or multiple hetero atom can be mutually the same, or in said two or multiple hetero atom A bit or all can be each different from other hetero atoms.

The term " alkyl " being used alone or in combination herein means containing 1 to about 10 carbon atom or 1-6 carbon The straight or branched saturated hydrocarbons monovalent radical of atom.Example include but not limited to methyl, ethyl, n-pro-pyl, isopropyl, 2-methyl- 1-propyl group, 2-methyl-2-propyl, 2-methyl-1-butene base, 3-methyl isophthalic acid-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1- Propyl group, 2-methyl-1-pentene base, 3-methyl-1-pentene base, 4-methyl-1-pentene base, 2-methyl-2-amyl group, 3-methyl-2-amyl group, 4- Methyl-2-amyl group, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, normal-butyl, isobutyl group, Sec-butyl, the tert-butyl group, n-pentyl, isopentyl, neopentyl, tertiary pentyl and hexyl, and longer alkyl group such as heptyl, pungent Base etc..Whenever numerical range such as " C₁-C₆Alkyl " or " C_1-6Alkyl " when occurring in this article, it is intended that described alkyl group is permissible It is made up of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.An enforcement In scheme, described " alkyl " is replaced.Unless otherwise indicated, described " alkyl " is unsubstituted.

The term " thiazolinyl " being used alone or in combination herein means have one or more carbon-carbon double bond and have 2 extremely About 10 carbon atoms or 2 straight or branched hydrocarbon monovalent radical to about 6 carbon atoms.Group described in double bond be may be at Cis or trans configuration, and it should be understood that described group includes two kinds of isomers.Example includes but not limited to vinyl (-CH= CH₂), 1-acrylic (-CH₂CH=CH₂), isopropenyl [-C (CH₃)=CH₂], cyclobutenyl, 1,3-butadienyl etc..Whenever numerical value Scope such as " C₂-C₆Thiazolinyl " or " C_2-6Thiazolinyl " when occurring in this article, it is intended that described alkenyl group can by 2 carbon atoms, 3 Individual carbon atom, 4 carbon atoms, 5 carbon atoms or 6 carbon atom compositions.In one embodiment, described " thiazolinyl " taken Generation.Unless otherwise indicated, described " thiazolinyl " is unsubstituted.

The term " alkynyl " being used alone or in combination herein means have one or more carbon-carbon triple bond and have 2 To about 10 carbon atoms or 2 to the straight or branched hydrocarbon monovalent radical of about 6 carbon atoms.Example includes but not limited to acetylene Base, 2-propynyl, 2-butyne base, 1,3-diacetylene base etc..Whenever numerical range such as " C₂-C₆Alkynyl " or " C_2-6Alkynyl " at this When literary composition occurs, it is intended that described alkynyl group can be by 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 Carbon atom forms.In one embodiment, described " alkynyl " it is replaced.Unless otherwise indicated, described " alkynyl " is not It is replaced.

The term " miscellaneous alkyl ", " miscellaneous thiazolinyl " and " miscellaneous alkynyl " being used alone or in combination herein is respectively intended to mean as mentioned above Alkyl, thiazolinyl and alkynyl structure, wherein one or more skeletal chain carbon atoms (and any connected suitable hydrogen atom) are each From by hetero atom, (atom the most in addition to carbon, such as but not limited to oxygen, nitrogen, sulfur, silicon, phosphorus, stannum or their group independently Close) or heteroatom group (such as but not limited to-O-O-,-S-S-,-O-S-,-S-O-,=N-N=,-N=N-,-N=N- NH-、-P(O)₂-、-O-P(O)₂-、-P(O)₂-O-、-S(O)-、-S(O)₂-、-SnH₂-etc.) substitute.

The term " haloalkyl " that is used alone or in combination herein, " haloalkenyl group " and " halo alkynyl " be respectively intended to mean as The alkyl of upper definition, thiazolinyl and alkynyl group, wherein one or more hydrogen atoms are former by fluorine atom, chlorine atom, bromine atoms or iodine Son or combinations thereof replace.In some embodiments, two or more hydrogen atoms can be by mutually the same halogen atom Replace (such as difluoromethyl)；In other embodiments, two or more hydrogen atoms can be by the most incomplete same halogen Element atom replaces (the chloro-1-of such as 1-fluoro-1-iodine ethyl).The limiting examples of halogenated alkyl group is methyl fluoride, chloromethyl And bromoethyl.The limiting examples of haloalkenyl radical is bromo vinyl.The limiting examples of halo alkynyl group is chlorine Acetenyl.

The term " carbochain " being used alone or in combination herein means any alkyl, thiazolinyl, alkynyl, miscellaneous alkyl, miscellaneous thiazolinyl Or miscellaneous alkynyl group, they are straight chain, ring-type or their combination in any.If described chain is a part for linker, And this linker comprises the one or more rings as core backbone portion, in order to calculate chain length, described " chain " only includes structure Become those carbon atoms at both the bottom of given ring or top rather than bottom and top, and in the top of ring and bottom length In the case of, shorter distance should be used to determine chain length.If described chain comprises the hetero atom as backbone portion, those atoms Part not as carbon chain length is calculated in interior.

The term " ring (cycle) " that is used alone or in combination herein, " ring-type ", " ring (ring) and " ring " mean Any covalence closed structure, including alicyclic ring as described herein, heterocycle, aromatics, heteroaromatic with multi-ring condense or non-condensed Ring system.Ring can be optionally substituted.Ring can form the part condensing ring system.Term " first " means the looped skeletal atom of structure Number.Therefore, being only used as example, hexamethylene, pyridine, pyrans and pyrimidine are hexatomic rings, and Pentamethylene., pyrroles, oxolane and thiophene Fen is five-membered ring.

The term being used alone or in combination herein " condenses " ring meaning that two or more ring shares one or more key Structure.

The term " cycloalkyl " being used alone or in combination herein means saturated hydrocarbons unit price basic ring, and it comprises 3 to about 15 Individual ring carbon atom or 3 to about 10 ring carbon atoms, but can include that the extra non-ring carbon atom of alternatively base is (such as first Cyclopropyl).Whenever numerical range such as " C₃-C₆Cycloalkyl " or " C_3-6Cycloalkyl " when occurring in this article, it is intended that described ring Alkyl group can be made up of 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, i.e. cyclopropyl, cyclobutyl, ring Amyl group or suberyl (cyclohepty), but this definition is also covered by the appearance of term " cycloalkyl " of not specified numerical range. This term includes condensing, non-condensed, bridge and tap bolt group.Fused cycloalkyl can comprise 2-4 fused rings, and wherein connecting ring is ring Alkyl ring, and other each rings can be ring or their combination in any of alicyclic ring, heterocycle, aromatics or heteroaromatic.Example includes But it is not limited to cyclopropyl, cyclopenta, cyclohexyl, decahydronaphthalene naphthyl and dicyclo [2.2.1] heptyl and adamantyl ring system.Exemplary Example includes but not limited to lower part:

In one embodiment, described " cycloalkyl " it is replaced.Unless otherwise indicated, described " cycloalkyl " is not It is replaced.

The term " non-aromatic heterocycle " being used alone or in combination herein and " heteroalicyclyl " mean to comprise 3 to about 20 Individual annular atoms saturated, part is undersaturated or the monovalent radical of complete undersaturated non-aromatic ring, wherein said annular atoms In one or more be in addition to beyond carbon independently selected from oxygen, nitrogen, sulfur, phosphorus, silicon, selenium and stannum but be not limited to these atoms Atom.Existing in two or more heteroatomic embodiment in ring, said two or multiple hetero atom can be mutually the same, Or some or all in said two or multiple hetero atom can each be different from other hetero atoms.These terms include thick Conjunction, non-condensed, bridge and tap bolt group.The non-aromatic heterocycle group condensed can comprise 2-4 fused rings, wherein connects ring right and wrong Aromatic heterocycle, and other each rings can be ring or their combination in any of alicyclic ring, heterocycle, aromatics or heteroaromatic.Fused rings System can be condensed by singly-bound or double bond, condenses also by carbon-carbon bond, carbon-heteroatom bond or hetero atom-heteroatomic bond.This A little terms also include having 3 to about 12 backbone ring atoms and there are 3 groups to about 10 backbone ring atoms.Non- The heterocyclidene of aromatics and the connection of its parent molecule can pass through hetero atom or carbon atom.Similarly, other replacement is permissible By hetero atom or carbon atom.As limiting examples, imidazolidine non-aromatic heterocyclic can be by its arbitrary atom N (miaow Oxazolidine-1-base or imidazolidine-3-base) or its any carbon atom (imidazolidine-2-base, imidazolidine-4-base or imidazolidine-5- Base) it is connected to parent molecule.In certain embodiments, non-aromatic heterocyclic comprises one or more carbonyl or thiocarbonyl group Such as containing oxo and the group in sulfur-bearing generation.Example includes but not limited to pyrrolidinyl, tetrahydrofuran base, dihydrofuran base, tetrahydrochysene Thienyl, THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiapyran base, piperidino, morpholino, thiomorpholine generation, thiophene alkyl, Piperazinyl, azetidinyl, oxetanyl, Thietane base, homopiperidinyl, oxepane alkyl, thia cycloheptyl Alkyl, oxygen azepineBase, diazaBase, sulfur azepineBase, 1,2,3,6-tetrahydro pyridyl, 2-pyrrolinyl, 3-pyrrolin Base, indoline base, 2H-pyranose, 4H-pyranose, dialkyl group, 1,3-dioxolanyl, pyrazolinyl, dithiane base, two Tiacyclopentane base, dihydro pyranyl, dihydro-thiophene base, dihydrofuran base, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-nitrogen Miscellaneous dicyclo [3.1.0] hexyl, 3-azabicyclo [4.1.0] heptyl, 3H-indyl and quinolizinyl.Heterocycloalkyl is also referred to as The illustrative examples of non-aromatic heterocycle includes:

This term also includes all loop types of carbohydrate, includes but not limited to monosaccharide, disaccharide and oligosaccharide.At one In embodiment, described " non-aromatic heterocycle " or " heteroalicyclyl " are replaced.Unless otherwise indicated, described " non-aromatic Heterocyclic radical " or " heteroalicyclyl " be unsubstituted.

The term " aryl " being used alone or in combination herein means 6 aromatic hydrocarbyls to about 20 ring carbon atoms, and And include that condense and non-condensed aryl rings.The aryl rings group condensed comprises 2-4 fused rings, and wherein connecting ring is aryl Ring, and other each rings can be ring or their combination in any of alicyclic ring, heterocycle, aromatics or heteroaromatic.Additionally, term aryl bag Include comprise 6 to about 12 ring carbon atoms and comprise 6 to about 10 ring carbon atoms condense and the rings of non-condensed.Single The limiting examples of cyclic aryl radicals includes phenyl；The limiting examples of fused rings aromatic yl group includes naphthyl, phenanthryl, anthracene Base, base；The limiting examples of the biaryl group of non-condensed includes xenyl.In one embodiment, described " virtue Base " it is replaced.Unless otherwise indicated, described " aryl " is unsubstituted.

The term " heteroaryl " being used alone or in combination herein means to comprise about 5 virtues to about 20 backbone ring atoms Race's monovalent radical, wherein one or more in annular atoms are independently selected from oxygen, nitrogen, sulfur, phosphorus, silicon, selenium and stannum but are not limited to this The hetero atom of atoms, and condition a bit is that the ring of described group does not comprise two adjacent O or S atom.Two are had in ring Or in multiple heteroatomic embodiment, said two or multiple hetero atom can be mutually the same, or said two or multiple Some or all in hetero atom can each be different from other hetero atoms.Term heteroaryl includes having at least one hetero atom Condense and the heteroaryl groups of non-condensed.Term heteroaryl also include having 5 to about 12 backbone ring atoms and There are 5 heteroaryls with non-condensed condensed to about 10 backbone ring atoms.Carbon atom or hetero atom can be passed through with miscellaneous Aromatic yl group bonding.Accordingly, as limiting examples, imidazole group can by it any carbon atom (imidazoles-2-base, Imidazol-4 yl or imidazoles-5-base), or its any nitrogen-atoms (imidazoles-1-base or imidazo-3-yl) is connected with parent molecule. Similarly, heteroaryl groups can be further by its any or all of carbon atom and/or its any or all of hetero atom It is replaced.The heteroaryl groups condensed can comprise 2-4 fused rings, and wherein connecting ring is heteroaromatic rings, and other each rings are permissible It is alicyclic ring, heterocycle, aromatics, the ring of heteroaromatic or their combination in any.The limiting examples of single ring heteroaryl group includes Pyridine radicals；The limiting examples of fused ring heteroaryl group includes benzimidazolyl, quinolyl, acridinyl；Non-condensed connection is miscellaneous The limiting examples of aromatic yl group includes bipyridyl.Other examples of heteroaryl include furyl, thiophene without limitation Base, oxazolyl, acridinyl, phenazinyl, benzimidazolyl, benzofuranyl, benzoxazolyl group, benzothiazolyl, benzo thiophene two Oxazolyl, benzothienyl, benzodiazole base, benzotriazole base, imidazole radicals, indyl, isoxazolyl, isoquinolyl, indolizine Base, isothiazolyl, isoindolyl di azoly, indazolyl, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl, pyrrole radicals, pyrazine Base, pyrazolyl, purine radicals, phthalazinyl, pteridyl, quinolyl, quinazolyl, quinolyl, triazolyl, tetrazole radical, thiazolyl, Triazine radical, thiadiazolyl group etc., and their oxide, such as pyridinyl-N-oxide.The illustrative examples bag of heteroaryl groups Include with lower part:

In one embodiment, described " heteroaryl " it is replaced.Unless otherwise indicated, described " heteroaryl " is not It is replaced.

The term " heterocyclic radical " being used alone or in combination herein jointly means heteroalicyclyl and heteroaryl groups.Herein In, whenever specifying carbon number (the such as C in heterocycle₁-C₆Heterocycle), at least one non-carbon must be there is in ring (miscellaneous former Son).Title such as " C₁-C₆Heterocycle " only mean the carbon number in ring and the total atom number that is not meant as in ring.Title is such as (i.e. 4 rings, 5 rings or 6 rings, at least one of which atom is that carbon is former to the total atom number that " 4-6 unit heterocycle " comprises in meaning ring Son, at least one atom is hetero atom, and remaining 24 atoms are carbon atom or hetero atom).Two or more miscellaneous for having The heterocycle of atom, those two or more hetero atoms can be same to each other or different to each other.Non-aromatic heterocyclic group only has 3 in including ring The group of individual atom, and aromatic heterocyclic group must have at least 5 atoms in ring.Can by hetero atom or carbon atom with Heterocycle bonding (is i.e. connected to parent molecule or is further substituted with).It is in one embodiment, described that " heterocyclic radical " is to be replaced 's.It is unless otherwise indicated, described that " heterocyclic radical " is unsubstituted.

The term " halogen ", " halo " or " halogenide " being used alone or in combination herein means fluorine, chlorine, bromine and/or iodine.

The term " amino " being used alone or in combination herein means monovalent radical-NH₂。

The term " alkyl amino " being used alone or in combination herein means monovalent radical-NH (alkyl), and wherein alkyl is as originally Literary composition definition.

The term " dialkyl amido " being used alone or in combination herein means monovalent radical-N (alkyl) (alkyl), respectively Alkyl can be identical or different and as defined herein.

The term " Diaminoalkyl " being used alone or in combination herein means to comprise the alkyl group of two amine groups, its Described in amine groups can be the substituent group on alkyl group, it can be amino, alkyl amino or dialkyl amino group, or One or two in the wherein said amine groups of person may be constructed part alkyl chain with formation-alkylidene-N (H or alkyl)-alkylene Base-N (H or alkyl or alkylidene-) (H or alkyl or alkylidene-).

The term " hydroxyl " being used alone or in combination herein means monovalent radical OH.

The term " cyano group " being used alone or in combination herein means monovalent radical CN.

The term " cyanogen methyl " being used alone or in combination herein means monovalent radical-CH₂CN。

The term " nitro " being used alone or in combination herein means monovalent radical-NO₂。

The term " epoxide " being used alone or in combination herein means bilvalent radical-O-.

The term " oxo " being used alone or in combination herein means bilvalent radical=O.

The term " carbonyl " being used alone or in combination herein mean bilvalent radical-C (=O)-, it is also possible to writing-C (O)-.

The term " carboxyl " being used alone or in combination herein means-C (O) OH part, and it can also write-COOH.

The term " alkoxyl " being used alone or in combination herein means alkyl ether groups ,-O-alkyl, it include group- O-aliphatic group and-O-carbocylic radical, wherein said alkyl, aliphatic group and carbocylic radical group can be optionally substituted, and wherein Term alkyl, aliphatic group and carbocylic radical are as defined herein.The limiting examples of alkoxyl includes: methoxyl group, ethyoxyl, positive third Epoxide, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy etc..

The term " sulfinyl " being used alone or in combination herein mean bilvalent radical-S (=O)-.

The term " sulfonyl " being used alone or in combination herein means bilvalent radical-S (=O)₂-。

Term " sulfonamide ", " sulfonamido " and " amino-sulfonyl being used alone or in combination herein (sulfonamidyl) diradical group-S (=O) " is meant₂-NH-and-NH-S (=O)₂-。

The most individually or the term " sulphamide (sulfamide) " that is applied in combination and " aminosulfonyl amino (sulfamido, sulfamidyl) " mean diradical group-NH-S (=O)₂-NH-。

Term used herein " reactant " means the nucleophile for producing covalent bond or electrophile.

It should be understood that in the case of defining, continuously with two or more groups, the substituent group being connected with structure, first The individual group named is considered as end, and the group finally named is considered to be connected to discussed structure.Therefore, example As, group aryl alkyl is connected to discussed structure by alkyl group.

Some technical term of pharmacology

Term used herein " mek inhibitor " means to measure with Mek1 kinase assay outlined herein, for MEK activity demonstrates at most about 100 μMs or the IC of no more than about 50 μMs₅₀Compound.“IC₅₀" it is the activity making enzyme (such as MEK) Reduce the inhibitor concentration to maximum half level.Have been found that compound as herein described demonstrates the inhibitory action to MEK. Measuring with Mek1 kinase assay as herein described, the compound of the present invention demonstrates at most about 10 μMs preferably for MEK IC₅₀, more preferably up to about 5 μMs, even more preferably no more than about 1 μM, and most preferably not more than about 200nM.

The term " experimenter ", " patient " or " individual " etc. individual about ill disease used herein includes mammal And nonmammalian.The example of mammal includes but not limited to any member of Class Mammalia: the mankind's, such as chimpanzee Non-human primate and other ape kinds and monkey kind；The such as domestic animal of cattle, horse, sheep, goat, pig；Such as rabbit, Canis familiaris L. and The domestic animal of cat；Including rodent such as rat, mice and the laboratory animal etc. of Cavia porcellus.The example bag of nonmammalian Include, but be not limited to, bird, fish etc..In one embodiment of the method and composition provided in this article, described mammal is The mankind.

The word that term used herein " is treated " and other are grammatically of equal value, including alleviate, alleviate or improve disease or The symptom of the patient's condition, prevents other symptoms, improves or prevents the potential metabolism cause of symptom, suppression disease or the patient's condition, such as, contain Disease or the development of the patient's condition, palliate a disease or the patient's condition, causes disappearing of disease or the patient's condition, palliates a disease or shape caused by the patient's condition Condition, or terminate disease or the symptom of the patient's condition, and in order to include prevention.This term also includes obtaining treatment benefit and/or pre- Anti-benefit.Treatment benefit means to eradicate or improve just connecing subject potential disease.Additionally, by eradicating or improving and potential disease One or more physiological signs that disease is relevant reach to treat benefit thus observe improvement in patients, but patient may still be subject to Potential disease torments.For prevention benefit, to have occur specified disease risk patient, or to report disease one or more The patient of physiological signs, even if not yet making the diagnosis of this disease, it is also possible to be administered described compositions.

Term used herein " effective dose ", " therapeutically effective amount " or " pharmacy effective dose " means to be enough to treat or prevent At least one reagent of specified disease or the patient's condition or the dosage of compound.Its result can be to reduce and/or alleviate disease Sign, symptom or the cause of disease, or any other desired change of biosystem.Such as, treatment uses " effective dose " is to carry Amount for the required compositions comprising compound disclosed herein that significantly palliates a disease.Use technology such as dosage Incremental research may determine that " effectively " amount suitable in any individual case.

Term used herein " the most anhydrous " and " substantially free of solvent " mean that crystalline polymorph comprises respectively Less than 0.01,0.1,0.2,0.3,0.4,0.5,1 or 2 weight % water or solvent.

Term used herein " essentially identical " means to be not equal to figure specifically described herein, but in this area skill X-ray diffractogram of powder in the experimental error limit that art personnel are considered or means of differential scanning calorimetry figure.

Term used herein " is administered " etc. and to mean may be used to compound or compositions can be delivered to desired The method in biological agent site.These methods include but not limited to oral route, intraduodenal route, parenteral injection (bag Include intravenous administration, subcutaneous administration, Intraperitoneal medication, intramuscular administration, intravascular administration or administered by infusion), topical and straight Enteral administration.The medicine-feeding technology that Compounds and methods for as herein described known to those skilled in the art can use, such as, as Goodman and Gilman, The Pharmacological Basis of Therapeutics, current edition；Pergamon；With Remington ' s, Pharmaceutical Sciences (current edition), Mack Publishing Co., institute in Easton, Pa Discuss.In preferred embodiments, oral administration compound as herein described and compositions.

Term used herein " acceptable ", for preparation, compositions or composition, it is intended that align connect subject The general health of experimenter is without lasting adverse effect.

Term used herein " pharmaceutically acceptable " means not eliminate the biological activity of compound described herein or property The material of the such as carrier or diluent of matter and relative non-toxicity, i.e. can be administered described material to individuality and not cause bad Biological effect, or the most in harmful manner with in the compositions comprising described material any component interact.

Term used herein " pharmaceutical composition " means bioactive compound, its optionally with at least one pharmacy Acceptable chemical composition is (such as, but not limited to carrier, stabilizer, diluent, dispersant, suspending agent, thickening agent and/or tax Shape agent) mixing.

Term used herein " carrier " means the chemistry of the relative non-toxicity promoting that cell or tissue includes compound in Compound or reagent.

Term used herein " agonist " means to strengthen another molecular activity or the such as change of acceptor site activity The molecule of compound, medicine, zymoexciter or hormone regulator.

Term used herein " antagonist " means to weaken or stop another molecular action or acceptor site activity The such as molecule of compound, medicine, enzyme inhibitor or hormone regulator.

Term used herein " regulates " activity to change target spot that means to interact directly or indirectly with target spot, Strengthen the activity of target spot, the activity of suppression target spot including (being only used as example), limit the activity of target spot, or extend the work of target spot Property.

Term used herein " regulator " means the molecule interacted directly or indirectly with target spot.Described mutually Effect includes, but are not limited to the interaction of agonist and antagonist.

Term used herein " pharmaceutically acceptable derivant or prodrug " means that any pharmacy of compound of formula I can connect Salt, ester, the salt of ester or other derivants being subject to, when being administered to receiver, it can provide the present invention's directly or indirectly Compound or its pharmaceutical active metabolite or residue.Derivant first-selected especially or prodrug are when being administered suchization to patient During compound, the derivant of the bioavailability of the compound of the raising present invention or prodrug are (such as by making the chemical combination of oral administration Thing is more easily absorbed in blood), or improve parent compound and deliver to biological compartment (such as brain or lymphsystem) Derivant or prodrug.

" prodrug " used herein is in physiological conditions or can to change into appointed compound by lyolysis Or the compound of the pharmaceutically acceptable salt of such compound.Prodrug includes such compound, wherein amino acid residue or The polypeptide chain of the two or more amino acid residue of person by amido link or ester bond be covalently attached to the free amine group of compound of formula I, Hydroxyl or hydroxy-acid group.The amino acid residue related to includes but not limited to 20 kinds of naturally occurring aminoacid.Other ammonia being suitable for Base acid includes 4-hydroxyproline, oxylysine, desmosine (demosine), isodensmosine (isodemosine), 3-methyl Histidine, norvaline, Beta-alanine, γ-aminobutyric acid, citrulline (cirtulline), homocysteine, homoserine, Ornithine and methionine sulfone.Other kinds of prodrug is well known in the art.

The pharmaceutically acceptable prodrug of compound as herein described includes but not limited to ester, carbonic ester, sulfocarbonate, N- Acyl derivative, N-acyloxyallcyl derivant, the quaternary ammonium derivative of tertiary amine, N-Mannich base, schiff bases, aminoacid are puted together Thing, phosphate ester, slaine and sulphonic acid ester.Various forms of prodrugs are known in the art.See for example, Design of Drugs, Bundgaard, A.Ed., Elseview, 1985 and Method in Enzymology, Widder, K. etc., Ed.；Academic, 1985,vol.42,p.309-396；Bundgaard, H. " Design and Application of Prodrugs " are at A Textbook of Drug Design and Development, Krosgaard-Larsen and H.Bundgaard, Ed., 1991, the 5th chapter, p.113-191；And Bundgaard, H., Advanced Drug Delivery Review, 1992,8,1- 38, it quotes addition herein.Prodrug as herein described includes but not limited to the combination of following group and these groups；Amine derives Prodrug:

Hydroxyl prodrug include but not limited to acyloxyalkyl ether, alkoxycarbonyloxyalkyl esters, Arrcostab, aryl ester and Comprise the disulphide of ester.

Term used herein " pharmaceutically acceptable salt " includes keeping the free acid of appointed compound and free alkali Biological effectiveness and the salt that abiology is the most optimum or other are the most optimum.Described compound can have acidity or basic group Group, and therefore inorganic or organic base and inorganic or organic acid reaction can form pharmaceutically acceptable salt with some.Pharmacy can The example of salt accepted includes being reacted that prepare by compound as herein described and mineral acid or organic acid or inorganic base A little salt, such salt includes acetate, acrylates, adipate, alginate, aspartate, benzoate, benzenesulfonic acid Salt, disulfate, bisulfites, bromide, butyrate, butine-1,4-diacid salt, Camphora hydrochlorate, camsilate, caproic acid Salt, caprylate, chloride, chloro benzoate, chloride, citrate, cyclopentane propionate, caprate, digluconate, phosphorus Acid dihydride salt, dinitro-benzoate, lauryl sulfate, esilate, formates, fumarate, gluceptate (glucoheptanoate), glycerophosphate, glycollate, Hemisulphate, enanthate, caproate, hexin-1,6-diacid salt, Hydroxy benzoate, gamma hydroxybutyrate, hydrochlorate, hydrobromate, hydriodate, 2-isethionate, iodide, different Butyrate, lactate, maleate, malonate, mesylate, mandelate, metaphosphate, mesylate, methoxybenzene Formates, ar-Toluic acid salt, hydrophosphate, 1-naphthalene sulfonic aicd salt, 2-naphthalene sulfonate, nicotinic acid cigarette, nitrate, oxalates, flutter acid Salt (palmoate), pectate (pectinate), persulfate, phenylacetate, phenpropionate, 3-phenpropionate, phosphoric acid Salt, picrate, Pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, propionate, phthalate, benzene Butyrate, propane sulfonic acid ester, pyrophosphate, salicylate, succinate, sulfate, sulphite, succinate, suberate, Sebacate, sulfonate, tartrate, rhodanate, toluene fulfonate, hendecane hydrochlorate (undeconate) and dimethylbenzene sulphur Hydrochlorate.Other acid such as oxalic acid, although themselves be not pharmaceutically acceptable, but can be used for preparation and be used as obtaining this Invention compound and their pharmaceutically acceptable acid-addition salts during intermediate salt (see for example Berge etc., J.Pharm.Sci.1977,66,1-19.).Additionally, those compounds that can comprise free acid group as herein described are permissible React with the suitable hydroxide of the most pharmaceutically acceptable metal cation of alkali, carbonate, bicarbonate, react with ammonia, Or with pharmaceutically acceptable organic primary amine, secondary amine or reactive tertiary amine.Representational alkali metal salt or alkali salt include lithium Salt, sodium salt, potassium salt, calcium salt, magnesium salt and aluminium salt etc..The illustrative example of alkali includes sodium hydroxide, potassium hydroxide, hydroxide gallbladder Alkali, sodium carbonate, N⁺(C_1-4Alkyl)₄Deng.For formed the representative organic amine of base addition salts include ethamine, diethylamine, ethylenediamine, Ethanolamine, diethanolamine, piperazine etc..It should be understood that compound as herein described also includes that any alkalescence that they may comprise is nitrogenous Group quaternized.Produced by such quaternized water solublity or oil-soluble or water dispersible or oil-dispersing property of can obtaining Thing.See for example, Berge etc., see on.Can be prepared these on the spot during the final separation of compound and purification of the present invention Salt, or by making the purified compound of free alkali form and suitable organic or inorganic acid reaction respectively, and separate by These salt prepared by this salt formed.

Term used herein " strengthens " effect or the persistence meaning to improve or extend predictive role.Accordingly, with respect to Strengthening therapeutic agent effect, term " strengthens " and means to improve or extend the other therapeutic agents effect to system in effect or persistence Ability." potentiation amount " used herein means to be enough to the amount of the effect strengthening another therapeutic agent in required system.

Term used herein " drug regimen ", " using other therapies ", " being administered other therapeutic agent " etc., it is intended that by Drug therapy produced by mixing or merging more than one active component, and include fixing and revocable group of active component Close.Term " fixed Combination " means at least one compound as herein described and at least one auxiliary agent with single entities or dosage Form be administered to patient simultaneously.Term " non-fixed combinations " mean by least one compound as herein described and at least one Auxiliary agent to patient with separate entity simultaneously and is deposited ground or is in turn administered with variable limit interval time, the most such It is administered at the effect level providing two or more compound in the patient.These are also applied for conjoint therapy, such as, be administered three Plant or more kinds of active component.

Term used herein " administering drug combinations ", " with ... administering drug combinations " and their grammer equivalence word etc., it is intended that bag Include and be administered selected therapeutic agent to single patient, and be intended to include by identical or different administration routes or identical or Different time is administered the therapeutic scheme of described medicament.In some embodiments, compound as herein described can be with other medicaments It is administered simultaneously.These terms include being administered two or more medicament to animal so that medicament and/or their metabolite are deposited simultaneously In being animal.They include being administered simultaneously with separate compositions, being administered with separate compositions at different time, and/or It is administered with the compositions that two kinds of medicaments are all contained therein.Therefore, in some embodiments, it is administered this with single compositions Bright compound and other medicaments.In some embodiments, compound and other medicaments of the present invention are mixed in described group In compound.

Term used herein " metabolite " means the derivant of the compound formed when compound is metabolized.

Term used herein " active metabolite " means that the biological of the compound formed when compound is metabolized is lived Property derivant.

Term used herein " is metabolized " and means that the summation of the biological process changing predetermined substance (includes but do not limits In hydrolysis and enzymatic reaction).Therefore, enzyme can make compound produce the change of specific structure.Such as, cytochrome P450 is catalyzed various oxidations and reduction reaction, and the glucuronic acid of uridine diphosphate glucuronatetransferase catalytic activation divides Son is to the transfer of aromatic alcohol, fatty alcohol, carboxylic acid, amine and free thiohydroxy group.From The Pharmacological Basis of Therapeutics, the 9th edition, McGraw-Hill (1996) can obtain other about metabolic information.

Compound

There is described herein the compound of Formulas I and pharmaceutically acceptable salt thereof, solvate, polymorph, ester, amide, Tautomer or prodrug:

Wherein

Z is H or F；

X is F, Cl, CH₃、CH₂OH、CH₂F、CHF₂Or CF₃；

Y is I, Br, Cl, CF₃、C₁-C₃Alkyl, C₂-C₃Thiazolinyl, C₂-C₃Alkynyl, cyclopropyl, OMe, OEt, SMe, phenyl or Het, wherein Het be 5 to the 10 yuan of monocyclic heterocyclic ring radical comprising 1-5 the ring hetero atom independently selected from N, O and S or dicyclo miscellaneous Cyclic group, described heterocyclic group is saturated, olefinic or aromatic；Wherein

Whole described methyl groups are optionally replaced by 1,2 or 3 F atom；

R⁰It is: H, F, Cl, Br, I, CH₃NH-、(CH₃)₂N-、C₁-C₆Alkyl, C₁-C₄Alkoxyl, C₃-C₆Cycloalkyl, C₂-C₆ Thiazolinyl, C₂-C₆Alkynyl, phenyl, mono-substituted phenyl, O (C₁-C₄Alkyl), O-C (=O) (C₁-C₄Alkyl) or C (=O) O (C₁-C₄Alkane Base)；Wherein

Described alkyl, alkoxyl, cycloalkyl, thiazolinyl, alkynyl and phenyl group be optionally independently selected from F, Cl, Br, 1-3 substituent group of I, OH, CN, cyano methyl, nitro, phenyl and trifluoromethyl replaces；

G₁It is C₃-C₈Diaminoalkyl group；

G₂It is saturated, the undersaturated or aromatic 5-comprising 1-3 the ring hetero atom independently selected from N, O and S Or 6-ring, it is optionally independently selected from F, Cl, OH, O (C₁-C₃Alkyl), OCH₃、OCH₂CH₃、CH₃C(=O)NH、CH₃C (=O)O、CN、CF₃1-3 the replacement with the 5 membered aromatic heterocycle groups comprising 1-4 the ring hetero atom independently selected from N, O and S Base replaces；

R_1aIt is methyl, optionally by 1-3 fluorine atom or 1-3 chlorine atom, or OH, ring propoxyl group or C₁-C₃Alcoxyl Base replaces, wherein said ring propoxy group or described C₁-C₃The C of alkoxy base₁-C₃Moieties is optionally by a hydroxyl Base or methoxy group replace, and wherein said C₁-C₄Whole C in alkoxyl₃-alkyl group is the most further by separately One OH group replaces；

R_1cIt is (CH₂)_nO_mR′；Wherein

M is 0 or 1；And wherein

When m is 0, n is 1 or 2；

When m is 1, n is 2 or 3；

R_1dBe C (A) (A ') (B)-；Wherein

B is H or C_1-4Alkyl, is optionally replaced by one or two OH group；

A and A ' independently be H or C_1-4Alkyl, is optionally replaced by one or two OH group；Or

3 yuan of-6 yuan of saturated rings are formed with them together with the carbon atom that A and A ' is connected；

R_1eIt is

Wherein

Q is 1 or 2；

R₂And R₃It is each independently: H, F, Cl, Br, CH₃、CH₂F、CHF₂、CF₃OCH₃、OCH₂F、OCHF₂、OCF₃, second Base, n-pro-pyl, isopropyl, cyclopropyl, isobutyl group, sec-butyl, the tert-butyl group or mesyl；

R₄It is: H, F, Cl, Br, CH₃、CH₂F、CHF₂、CF₃OCH₃、OCH₂F、OCHF₂、OCF₃, ethyl, n-pro-pyl, isopropyl Base, cyclopropyl, isobutyl group, sec-butyl, the tert-butyl group, mesyl, nitro, acetylamino, amidino groups, cyano group, carbamoyl, first Base carbamoyl, formyl-dimethylamino, l, 3,4-diazole-2-base, 5-methyl-l, 3,4-diazole, 1,3,4-thiophene Diazole, 5-methyl-l, 3,4-thiadiazoles, lH-tetrazole radical, N-morpholinyl carbonyl amino, N-morpholinosulfonyl and N-pyrrolidine Base carbonylamino；

R₅It is H, F, Cl or methyl；

R₆It is H, F, Cl or methyl；

Ar₁It is

Wherein

U and V independently be N, CR₂Or CR₃；

R₂、R₃And R₄Independently be: H, F, Cl, Br, CH₃、CH₂F、CHF₂、CF₃OCH₃、OCH₂F、OCHF₂、OCF₃, ethyl, N-pro-pyl, isopropyl, cyclopropyl, isobutyl group, sec-butyl, the tert-butyl group, acetylamino, amidino groups, cyano group, carbamoyl, methyl Carbamoyl, formyl-dimethylamino, l, 3,4-diazole-2-base, 5-methyl-l, 3,4-di azoly, 1,3,4-thiophene Di azoly, 5-methyl-l, 3,4-thiadiazolyl group, lH-tetrazole radical, N-morpholinyl carbonyl amino, N-morpholinosulfonyl, N-pyrroles Alkyl-carbonyl-amino, and mesyl；

R₅And R₆Independently be H, F, Cl or methyl；

Ar₂It is

Wherein

U is-S-,-O-or-N=, and wherein

When U is-O-or-S-, V is-CH=,-CCl=or-N=；

When U is-N=, V is-CH=,-CCl=, or-N=；

R₇It is H or methyl；

R₈It is H, acetylamino, methyl, F or Cl；

Ar₃It is

Wherein

U is-NH-,-NCH₃-or-O-；

R₇And R₈Independently be H, F, Cl or methyl.

Except herein to group G, R⁰, outside the definition that is given of X, Y and Z, including chemistry and pharmaceutical field technical staff Can replace by thinkable other.

In some embodiments, the present invention provides the compound of Formulas I, and wherein G is G₁Or G₂.In other embodiments, G is G₁.Further or in other embodiment, G is G₂。

In some embodiments, the present invention provides the compound of Formulas I, and wherein G is R_1a、R_1b、R_1c、R_1d、R_1e、Ar₁、Ar₂ Or Ar₃.Further or in other embodiment, G is R_1a、R_1b、R_1c、R_1dOr R_1e.Further or other embodiment In, G is R_1a.Further or in other embodiment, G is R_1b.Further or in other embodiment, G is R_1c。 Further or in other embodiment, G is R_1d.Further or in other embodiment, G is R_1e.Further or In other embodiment, G is Ar₁、Ar₂Or Ar₃.Further or in other embodiment, G is Ar₁.Further or In other embodiment, G is Ar₂.Further or in other embodiment, G is Ar₃。

Compound or their the pharmaceutically acceptable salt of Formulas I are provided in some embodiments.Further or other Embodiment in, the compound of Formulas I provided herein or their solvate.Further or other embodiment In, the compound of Formulas I provided herein or their polymorphs body.Further or in other embodiment, carry herein Compound or their ester for Formulas I.Further or in other embodiment, the compound of Formulas I provided herein or it Amide.Further or in other embodiment, the compound of Formulas I provided herein or their tautomer. Further or in other embodiment, the compound of Formulas I provided herein or their prodrug.

In some embodiments, Z is H.In some embodiments, Z is F.In some embodiments, X is F.? In some embodiments, X is Cl.In some embodiments, X is CH₃.In some embodiments, X is CH₂OH.At some In embodiment, X is CH₂F.In some embodiments, X is CHF₂.In some embodiments, X is CF₃.Implement at some In scheme, X is F, Cl or CH₃。

In some embodiments, G is G₁Or G₂, X is F, Cl or CH₃；Y is I, Br, Cl, CF₃、C₁-C₃Alkyl, phenyl, Pyridine radicals, pyrrole radicals, pyrazolyl, described phenyl, pyridine radicals, pyrrole radicals and pyrazolyl groups are optionally by F, Cl, Br, I, acetyl Base, methyl, CN, NO₂、CO₂H、C₁-C₃Alkyl, C₁-C₃Alkoxyl, C₁-C₃Alkyl-C (=O)-, C₁-C₃Alkyl-C (=S)-, C₁-C₃ Alkoxy-C (=S)-, C₁-C₃Alkyl-C (=O) O-, C₁-C₃Alkyl-O-(C=O)-, C₁-C₃Alkyl-C (=O) NH-, C₁-C₃Alkyl- C(=NH)NH-、C₁-C₃Alkyl-NH-(C=O)-, two-C₁-C₃Alkyl-N-(C=O)-, C₁-C₃Alkyl-C (=O) N (C₁-C₃Alkane Base)-, C₁-C₃Alkyl-S (=O)₂NH-or trifluoromethyl replace；And Z is H or F.Further or in other embodiment, G It is G₁Or G₂, and R⁰It is F, Cl, C₁-C₄Alkyl or C₁-C₄Alkoxyl, described C₁-C₄Alkyl group and described C₁-C₄Alkoxy base C₁-C₄Moieties is optionally by F, Cl, OCH₃Or OCH₂CH₃Replace.Further or in other embodiment, G is G₁ Or G₂, and R⁰It is H, F, Cl, C₁-C₄Alkyl, methoxyl group, ethyoxyl or 2-Mehtoxy-ethoxy.

In some embodiments, G₁It it is N-methyl-2-amino ethyl.Further or in other embodiment, G₁It is (CH₃)₂N-CH₂CH₂-NH-(CH₂)_n-, wherein n is 1,2 or 3.Further or in other embodiment, G₁It is (CH₃)₂N- CH₂CH₂-NH-(CH₂)_n-, wherein n is 1,2 or 3, and X is F.Further or in other embodiment, G₁It is (CH₃)₂N- CH₂CH₂-NH-(CH₂)_n-, wherein n is 1,2 or 3, and X is F, and Z is F.

In some embodiments, G₂It is piperidino, 2-piperidyl, 3-piperidyl or 4-piperidyl.Further or In other embodiment, G₂It is morpholinyl, 1-piperazinyl or 2-piperazinyl.

In some embodiments, G is R_1a、R_1b、R_1c、R_1d、R_1e、Ar₁、Ar₂Or Ar₃, and X is F, Cl or CH₃.Entering one In step or other embodiment, G is R_1a、R_1b、R_1c、R_1d、R_1e、Ar₁、Ar₂Or Ar₃, X is F, Cl or CH₃, and Y be I, Br, Cl、CF₃Or C₁-C₃Alkyl.Further or in other embodiment, G is R_1a、R_1b、R_1c、R_1d、R_1e、Ar₁、Ar₂Or Ar₃, X It is F, Cl or CH₃, Y is I, Br, Cl, CF₃Or C₁-C₃Alkyl, and Z is H or F.

Further or in other embodiment, G is R_1a、R_1b、R_1c、R_1d、R_1e、Ar₁、Ar₂Or Ar₃, and R⁰Be F, Cl, C₁-C₄Alkyl or C₁-C₄Alkoxyl, described C₁-C₄Alkyl group and described C₁-C₄The C of alkoxy base₁-C₄Moieties is optional Ground is by F, Cl, OCH₃Or OCH₂CH₃Replace.Further or in other embodiment, G is R_1a、R_1b、R_1c、R_1d、R_1e、Ar₁、 Ar₂Or Ar₃, and R⁰It is H, F, Cl, C₁-C₄Alkyl, methoxyl group, ethyoxyl or 2-Mehtoxy-ethoxy.

In some embodiments, G is R_1a；And Z is F.Further or in other embodiment, G is R_1a, wherein R_1aIt is CH₃, R⁰It is H；And Y is Br, I, CF₃Or CH₃.In some embodiments, G is R_1bAnd Z is F.Further or other In embodiment, G is R_1b, Z is F, and R⁰It is H, F or OCH₃.Further or in other embodiment, G is R_1b, Z is F, R⁰It is H, F or OCH₃, and X is F or CH₃.Further or in other embodiment, G is R_1b, Z is F, R⁰It is H, F or OCH₃, X is F or CH₃, and Y is Br, I or CH₃.Further or in other embodiment, G is R_1b, wherein R_1bIt is C₃-C₆Cycloalkyl. Further or in other embodiment, G is R_1b, wherein R_1bIt is the C being replaced₃-C₆Cycloalkyl.Further or other In embodiment, G is R_1b, wherein R_1bIt is unsubstituted C₃-C₆Cycloalkyl.Further or in other embodiment, G is R_1b, wherein R_1bIt is unsubstituted C₃-C₆Cycloalkyl and R⁰It is H.Further or in other embodiment, G is R_1b, wherein R_1bIt is isopropyl or cyclopropyl.

In some embodiments, G is R_1c, and Y is I, Br, CH₃Or CF₃.Further or in other embodiment, G is R_1c, Y is I, Br, CH₃Or CF₃, and Z is F.Further or in other embodiment, G is R_1c, Y is I, Br, CH₃Or CF₃, Z is F and m is 0.

In some embodiments, G is R_1d, and R⁰It is fluorine, chlorine, methyl, ethyl, propyl group, isopropyl, sec-butyl, isobutyl Base, the tert-butyl group, cyclopropyl, cyclobutyl, methyl fluoride, methoxyl group, fluorine methoxyl group, methylamino or dimethylamino.Further Or in other embodiment, G is R_1d, R⁰It is fluorine, chlorine, methyl, ethyl, propyl group, isopropyl, sec-butyl, isobutyl group, tertiary fourth Base, cyclopropyl, cyclobutyl, methyl fluoride, methoxyl group, fluorine methoxyl group, methylamino or dimethylamino, and X is F, Cl, CH₃Or Person's list methyl fluoride, difluoromethyl or trifluoromethyl.Further or in other embodiment, G is R_1d, R⁰It is fluorine, chlorine, first Base, ethyl, propyl group, isopropyl, sec-butyl, isobutyl group, the tert-butyl group, cyclopropyl, cyclobutyl, methyl fluoride, methoxyl group, fluorine methoxy Base, methylamino or dimethylamino, X is F, Cl, CH₃Or single methyl fluoride, difluoromethyl or trifluoromethyl, and Y be I, Br, Cl or single methyl fluoride, difluoromethyl or trifluoromethyl.Further or in other embodiment, G is R_1d, R⁰Be fluorine, chlorine, Methyl, ethyl, propyl group, isopropyl, sec-butyl, isobutyl group, the tert-butyl group, cyclopropyl, cyclobutyl, methyl fluoride, methoxyl group, fluorine methoxy Base, methylamino or dimethylamino, X is F, Cl, CH₃Or single methyl fluoride, difluoromethyl or trifluoromethyl, Y is I, Br, Cl Or single methyl fluoride, difluoromethyl or trifluoromethyl, and Z is H or F.Further or in other embodiment, G is R_1dAnd R⁰It is F, Cl, methyl, ethyl, methoxyl group, ethyoxyl or 2-Mehtoxy-ethoxy.

Further or in other embodiment, G is R_1d, R⁰It is F, Cl, methyl, ethyl, methoxyl group, ethyoxyl or 2- Mehtoxy-ethoxy, and X is F, Cl or CH₃.Further or in other embodiment, G is R_1d, R⁰Be F, Cl, methyl, Ethyl, methoxyl group, ethyoxyl or 2-Mehtoxy-ethoxy, X is F, Cl or CH₃, and Y be I, Br, Cl or single methyl fluoride, two Methyl fluoride or trifluoromethyl.Further or in other embodiment, G is R_1d, R⁰Be F, Cl, methyl, ethyl, methoxyl group, Ethyoxyl or 2-Mehtoxy-ethoxy, X is F, Cl or CH₃, Y is I, Br, Cl or single methyl fluoride, difluoromethyl or fluoroform Base, and Z is H or F.Further or in other embodiment, G is R_1dAnd R⁰It is H；X is F, Cl, CH₃Or single methyl fluoride, Difluoromethyl or trifluoromethyl.Further or in other embodiment, G is R_1d, R⁰It is H；X is F, Cl, CH₃Or single fluorine Methyl, difluoromethyl or trifluoromethyl, and Y is I, Br, Cl or single methyl fluoride, difluoromethyl or trifluoromethyl.Further Or in other embodiment, G is R_1d, R⁰It is H；X is F, Cl, CH₃Or single methyl fluoride, difluoromethyl or trifluoromethyl, Y is I, Br, Cl or single methyl fluoride, difluoromethyl or trifluoromethyl, and Z is H or F.

Further or in other embodiment, G is R_1d, wherein R_1dBe C (A) (A ') be C₁-C₆The group of cycloalkyl. Further or in other embodiment, G is R_1d, wherein R_1dBe C (A) (A ') be C₁-C₆Cycloalkyl and B are the group of H.? Further or in other embodiment, G is R_1d, wherein R_1dBe C (A) (A ') be C₁-C₆Cycloalkyl and B are methyl, ethyl, 2- Hydroxyethyl, n-pro-pyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 3,4-dihydroxy butyl, isopropyl, l-methyl-2-hydroxyl Ethyl, normal-butyl, sec-butyl, isobutyl group or the group of 2-hydroxymethyl-3-hydroxypropyl.

Further or in other embodiment, G is R_1d, wherein R_1dBe C (A) (A ') be C₁-C₆Cycloalkyl and B are 2, 3-dihydroxypropyl or the group of 3,4-dihydroxy butyl.Further or in other embodiment, G is R_1d, wherein R_1dIt is C (A) (A ') is C₁-C₆Cycloalkyl and B are 2,3-dihydroxypropyl or 3, the group of 4-dihydroxy butyl, the wherein chiral carbon in B It is in R configuration.Further or in other embodiment, G is R_1d, wherein R_1dBe C (A) (A ') be C₁-C₆Cycloalkyl and B are 2,3-dihydroxypropyls or 3, the group of 4-dihydroxy butyl, wherein the chiral carbon in B is in S configuration.Further or other Embodiment in, G is R_1d, wherein R_1dBe C (A) (A ') be C₁-C₆Cycloalkyl and B are optionally to be replaced by an OH group Methyl, or the C optionally replaced by one or two OH group₂-C₄The group of alkyl.Further or other embodiment party In case, G is R_1d, wherein R_1dBe C (A) (A ') be C₁-C₆The group of cycloalkyl and R⁰It is fluorine, chlorine, methyl, ethyl, propyl group, isopropyl Base, sec-butyl, isobutyl group, the tert-butyl group, cyclopropyl, cyclobutyl, methyl fluoride, methoxyl group, fluorine methoxyl group, methylamino or dimethyl Amino.Further or in other embodiment, G is R_1d, wherein R_1dBe C (A) (A ') be C₁-C₆The group of cycloalkyl and R⁰ It is F, Cl, methyl, ethyl, methoxyl group, ethyoxyl or 2-Mehtoxy-ethoxy.Further or in other embodiment, G It is R_1d, wherein R_1dBe C (A) (A ') be C₁-C₆The group of cycloalkyl and R⁰It is H；X is F, Cl, CH₃Or single methyl fluoride, difluoro first Base or trifluoromethyl.

Further or in other embodiment, the present invention provides the compositions of contained I, and wherein G is R_1d, Wherein R_1dBe C (A) (A ') be C₁-C₆Cycloalkyl and B are 2,3-dihydroxypropyl or 3, the group of 4-dihydroxy butyl, wherein B In chiral carbon be in R configuration, described compositions is substantially free of S isomer.Further or in other embodiment, this The compositions of the contained I of bright offer, wherein G is R_1d, wherein R_1dBe C (A) (A ') be C₁-C₆Cycloalkyl and B are 2,3- The group of dihydroxypropyl, wherein the chiral carbon in B is in R configuration, and described compositions is substantially free of S isomer.Further Or in other embodiment, the present invention provides the compositions of contained I, and wherein G is R_1d, wherein R_1dIt is C (A) (A ') is C₁-C₆Cycloalkyl and B are 3, the group of 4-dihydroxy butyl, and wherein the chiral carbon in B is in R configuration, described compositions Substantially free of S isomer.Further or in other embodiment, the present invention provides the compositions of contained I, its Middle G is R_1d, wherein R_1dBe C (A) (A ') be C₁-C₆Cycloalkyl and B are 2,3-dihydroxypropyl or the base of 3,4-dihydroxy butyl Group, wherein the chiral carbon in B is in S configuration, and described compositions is substantially free of R isomer.Further or other embodiment party In case, the present invention provides the compositions of contained I, and wherein G is R_1d, wherein R_1dBe C (A) (A ') be C₁-C₆Cycloalkyl And B is 2, the group of 3-dihydroxypropyl, wherein the chiral carbon in B is in S configuration, and described compositions is substantially free of R isomer. Further or in other embodiment, the present invention provides the compositions of contained I, and wherein G is R_1d, wherein R_1d Be C (A) (A ') be C₁-C₆Cycloalkyl and B are 3, the group of 4-dihydroxy butyl, and wherein the chiral carbon in B is in S configuration, described Compositions is substantially free of R isomer.

Further or in other embodiment, G is R_1d, wherein R_1dBe C (A) (A ') be the group of cyclopropyl.Entering In one step or other embodiment, G is R_1d, wherein R_1dIt is that C (A) (A ') is cyclopropyl and B is the group of H.Further or In other embodiment, G is R_1d, wherein R_1dIt is that C (A) (A ') is cyclopropyl and B is methyl, ethyl, 2-hydroxyethyl, just Propyl group, 3-hydroxypropyl, 2,3-dihydroxypropyl, 3,4-dihydroxy butyl, isopropyl, l-methyl-2-hydroxyethyl, positive fourth Base, sec-butyl, isobutyl group or the group of 2-hydroxymethyl-3-hydroxypropyl.Further or in other embodiment, G is R_1d, wherein R_1dIt is that C (A) (A ') is cyclopropyl and B is 2,3-dihydroxypropyl or the group of 3,4-dihydroxy butyl.Entering one In step or other embodiment, G is R_1d, wherein R_1dIt is that C (A) (A ') is cyclopropyl and B is 2,3-dihydroxypropyl or 3,4- The group of dihydroxy butyl, wherein the chiral carbon in B is in R configuration.Further or in other embodiment, G is R_1d, its Middle R_1dIt is that C (A) (A ') is cyclopropyl and B is 2,3-dihydroxypropyl or 3, the group of 4-dihydroxy butyl, the wherein chirality in B Carbon is in S configuration.Further or in other embodiment, G is R_1d, wherein R_1dBe C (A) (A ') be that cyclopropyl and B are for appointing The methyl that selection of land is replaced by an OH group, or the C optionally replaced by one or two OH group₂-C₄The group of alkyl. Further or in other embodiment, G is R_1d, wherein R_1dBe C (A) (A ') be group and the R of cyclopropyl⁰It is fluorine, chlorine, first Base, ethyl, propyl group, isopropyl, sec-butyl, isobutyl group, the tert-butyl group, cyclopropyl, cyclobutyl, methyl fluoride, methoxyl group, fluorine methoxy The group of base, methylamino or dimethylamino.Further or in other embodiment, G is R_1d, wherein R_1dIt is C (A) (A ') is group and the R of cyclopropyl⁰It is F, Cl, methyl, ethyl, methoxyl group, ethyoxyl or 2-Mehtoxy-ethoxy.Entering one In step or other embodiment, G is R_1d, wherein R_1dBe C (A) (A ') be group and the R of cyclopropyl⁰It is H；X is F, Cl, CH₃ Or single methyl fluoride, difluoromethyl or trifluoromethyl.

Further or in other embodiment, the present invention provides the compositions of contained I, and wherein G is R_1d, Wherein R_1dIt is that C (A) (A ') is cyclopropyl and B is 2,3-dihydroxypropyl or 3, the group of 4-dihydroxy butyl, the wherein hands in B Property carbon is in R configuration, and described compositions is substantially free of S isomer.Further or in other embodiment, the present invention provides The compositions of contained I, wherein G is R_1d, wherein R_1dIt is that C (A) (A ') is cyclopropyl and B is 2,3-dihydroxypropyl Group, wherein the chiral carbon in B is in R configuration, and described compositions is substantially free of S isomer.Further or other reality Executing in scheme, the present invention provides the compositions of contained I, and wherein G is R_1d, wherein R_1dBe C (A) (A ') be cyclopropyl And B is 3, the group of 4-dihydroxy butyl, wherein the chiral carbon in B is in R configuration, and described compositions is substantially free of S isomer. Further or in other embodiment, the present invention provides the compositions of contained I, and wherein G is R_1d, wherein R_1d Being that C (A) (A ') is cyclopropyl and B is 2,3-dihydroxypropyl or 3, the group of 4-dihydroxy butyl, wherein at the chiral carbon in B In S configuration, described compositions is substantially free of R isomer.Further or in other embodiment, the present invention provides contained The compositions of I, wherein G is R_1d, wherein R_1dIt is that C (A) (A ') is cyclopropyl and B is 2, the group of 3-dihydroxypropyl, Wherein the chiral carbon in B is in S configuration, and described compositions is substantially free of R isomer.Further or other embodiment In, the present invention provides the compositions of contained I, and wherein G is R_1d, wherein R_1dIt is that C (A) (A ') is cyclopropyl and B is 3, The group of 4-dihydroxy butyl, wherein the chiral carbon in B is in S configuration, and described compositions is substantially free of R isomer.

In some embodiments, G is R_1eAnd n is 1.Further or in other embodiment, G is R_1e, R⁰It is H, R_4-6It is H, R₂And R₃Independently be H, F, Cl, Br, CH₃、CH₂F、CHF₂、CF₃、OCH₃、OCH₂F、OCHF₂、OCF₃, ethyl, positive third Base, isopropyl, cyclopropyl, isobutyl group, sec-butyl, the tert-butyl group and mesyl, X is F and Y is I.

In some embodiments, G is Ar₁, wherein Ar₁Being phenyl, described phenyl is optionally selected from acetylamino, amidine Base, cyano group, carbamyl, methylcarbamoyl, dimethylcarbamoyl, l, 3,4-diazole-2-base, 5-methyl-l, 3,4- Di azoly, 1,3,4-thiadiazolyl group, 5-methyl isophthalic acid, 3,4-thiadiazolyl group, lH-tetrazole radical, N-morpholinyl carbonyl amino, N- One group of quinoline base sulfonyl, N-pyrrolidinylcarbonyl amino and mesyl replaces, and is optionally independently selected from F, Cl And CH₃1-3 substituent group replace.Further or in other embodiment, G is Ar₁, wherein Ar₁It is phenyl, described benzene Base is optionally selected from acetylamino, amidino groups, cyano group, carbamyl, methylcarbamoyl, dimethylcarbamoyl, l, 3,4- Diazole-2-base, 5-methyl-l, 3,4-di azoly, 1,3,4-thiadiazolyl group, 5-methyl isophthalic acid, 3,4-thiadiazolyl group, lH-tetra- One group of oxazolyl, N-morpholinyl carbonyl amino, N-morpholinosulfonyl, N-pyrrolidinylcarbonyl amino and mesyl takes In generation, optionally it is independently selected from F, Cl and CH₃1-3 substituent group replace, R⁰H, X be F, Cl or methyl and Y be Br, I, CF₃、C₁-C₃Alkyl, C₂-C₃Thiazolinyl, C₂-C₃Alkynyl, cyclopropyl, OCH₃、OCH₂CH₃Or SCH₃.In some embodiments, G is Ar₁, wherein Ar₁It isAnd wherein R₂And R₃Independently be H, F, Cl, CH₃、CF₃、OCH₃.Further or other reality Executing in scheme, G is Ar₁, wherein Ar₁It isAnd wherein R₂And R₃Independently be H, F, Cl, CH₃、CF₃、OCH₃, X is F Or CH₃, Y is I, Br or Cl；And Z is F.Further or in other embodiment, G is Ar₁, wherein Ar₁It is phenyl or singly takes For phenyl.Further or in other embodiment, G is Ar₁, wherein Ar₁Being phenyl or monosubstituted phenyl, X is F or CH₃, Y Being I, Br or Cl, Z is F；And R⁰It is F, methyl, ethyl, methoxyl group or 2-Mehtoxy-ethoxy.Further or other reality Executing in scheme, G is Ar₁, wherein U is N or CR₂And V is N.Further or in other embodiment, G is Ar₁, wherein U is N Or CR₂And V is CR.Further or in other embodiment, G is Ar₁, wherein U is N or CR₂, V is CR, R⁰H, X be F, Cl or methyl and Y are Br, I, CF₃、C₁-C₃Alkyl, C₂-C₃Thiazolinyl, C₂-C₃Alkynyl, cyclopropyl, OCH₃、OCH₂CH₃Or SCH₃。

In some embodiments, G is Ar₂, wherein Ar₂It isWherein R₇It is H or methyl and R₈It is H, acetyl Amino, methyl, F or Cl.Further or in other embodiment, G is Ar₂, wherein Ar₂It isWherein R₇It is H Or methyl, R₈It is H, acetylamino, methyl, F or Cl, R⁰Being H, X is F, Cl or methyl, and Y is Br, I, CF₃、C₁-C₃Alkyl, C₂- C₃Thiazolinyl, C₂-C₃Alkynyl, cyclopropyl, OCH₃、OCH₂CH₃Or SCH₃, and Z is F.Further or in other embodiment, G It is Ar₂, wherein Ar₂It isWherein U is S or O, and V is CH=, and R₈It is H or CH₃, R₇It is H or methyl, R₈It is H, acetyl Amino, methyl, F or Cl, R⁰Being H, X is F, Cl or methyl, and Y is Br, I, CF₃、C₁-C₃Alkyl, C₂-C₃Thiazolinyl, C₂-C₃Alkynyl, ring Propyl group, OCH₃、OCH₂CH₃Or SCH₃And Z is F.Further or in other embodiment, R⁰It is H.Further or other In embodiment, R⁰Being H, X is F or Cl and Y is Br, I, CH₂CH₃Or SCH₃。

In some embodiments, G is Ar₃, wherein U is-O-.

Further or in other embodiment, G is R_1a, wherein R_1aAs defined above.Further or other enforcement In scheme, G is R_1a, and R⁰It is H, wherein R_1aAs defined above.Further or in other embodiment, G is R_1aAnd R⁰Except H Outside as defined above, and R_1aAs defined above.Further or in other embodiment, G is R_1a, wherein R_1aIt is methyl, single halogen Acute pyogenic infection of nails base, C₁-C₃Alkoxy methyl or ring propoxy methyl.Further or in other embodiment, G is R_1a, wherein R_1a It is methyl, monohaloalkyl methyl, C₁-C₃Alkoxy methyl or ring propoxy methyl and wherein R⁰It is F, Cl, C₁-C₃Alkyl, monochloro generation C₁-C₃Alkyl, C₁-C₃Alkoxyl, trifluoromethoxy or 2-Mehtoxy-ethoxy.

Further or in other embodiment, G is R_1b, wherein R_1bAs defined above.Further or other enforcement In scheme, G is R_1b, and R⁰It is H, wherein R_1bAs defined above.Further or in other embodiment, G is R_1b, R⁰It is H and Z It is F, wherein R_1bAs defined above.Further or in other embodiment, G is R_1bAnd R⁰In addition to H as defined above, and R_1bAs defined above.Further or in other embodiment, G is R_1b, wherein R_1bIt is isopropyl, 2-butyl, 2-amyl group, ring Propyl group, cyclobutyl, cyclopenta or cyclohexyl, be the most optionally independently selected from F, Cl, OH and OCH₃1 or 2 replacement Base replaces；Y is Br, I, methyl or trifluoromethyl.Further or in other embodiment, G is R_1b, wherein R_1bIt it is isopropyl Base, 2-butyl, 2-amyl group, cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl, be optionally independently selected from F, Cl, OH and OCH₃ 1 or 2 substituent groups replace；Y is Br, I, methyl or trifluoromethyl；And R⁰It is: F, Cl, C₁-C₃Alkyl, monochloro are for C₁-C₃Alkane Base, C₁-C₃Alkoxyl, trifluoromethoxy or 2-Mehtoxy-ethoxy.Further or in other embodiment, G is R_1b, Wherein R_1bIsopropyl, 2-butyl, 2-amyl group, cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl, the most optionally by 1 Cl or Person is replaced by 1 or 2 OH groups；And Y is Br, I, methyl or trifluoromethyl.Further or in other embodiment, G It is R_1b, wherein R_1bIt is isopropyl, 2-butyl, 2-amyl group, cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl, the most optionally by 1 Individual Cl or replaced by 1 or 2 OH groups；Y is Br, I, methyl or trifluoromethyl；And R⁰It is F, Cl, C₁-C₃Alkyl, monochloro For C₁-C₃Alkyl, C₁-C₃Alkoxyl, trifluoromethoxy or 2-Mehtoxy-ethoxy.

Further or in other embodiment, G is R_1c, wherein R_1cAs defined above.Further or other enforcement In scheme, G is R_1c, and R⁰It is H, wherein R_1cAs defined above.Further or in other embodiment, G is R_1cAnd R⁰Except H Outside as defined above, and R_1cAs defined above.Further or in other embodiment, G is R_1c, and R⁰It is H, wherein R_1cIt is (CH₂)_nO_mR ', wherein m is 0 or 1, and when m is 1, n is 2 or 3, and when m is 0, n is 1 or 2, and R ' is C₁-C₆Alkyl, it is optional Be independently selected from F, Cl, OH, OCH₃、OCH₂CH₃And C₃-C₆1-3 substituent group of cycloalkyl replaces.At another more specifically In the embodiment of subgenus, m is 0, and n is 1 or 2, and R ' is C₁-C₄Alkyl, it is optionally substituted as mentioned above.At another more In the embodiment of concrete subgenus, m is 1, and n is 2 or 3, and R ' is C₁-C₄Alkyl, it is optionally substituted as mentioned above.? In the embodiment of one subgenus even more, m is 0, and n is 1 or 2, and R ' is C₁-C₄Alkyl, its be optionally selected from OH, OCH₃, 1-3 group of Cl and cyclopropyl replace.

Further or in other embodiment, G is R_1d, wherein R_1dAs defined above.Further or other enforcement In scheme, G is R_1d, and R⁰It is H, wherein R_1dAs defined above.Further or in other embodiment, G is R_1dAnd R⁰Except H Outside as defined above, and R_1dAs defined above.Further or in other embodiment, G is R_1d, and R⁰It is H, wherein R_1dIt is C (A) (A ') (B)-, wherein B, A and A ' independently be H or the C optionally replaced by one or two OH group or halogen atom_1-4 Alkyl, or form 3-6 unit saturated rings together with the carbon atom that is attached thereto with them of A and A ', described ring optionally comprises independence Ground is selected from one or two hetero atom of O, N and S, and is optionally independently selected from methyl, ethyl, fluorine, chlorine, bromine and iodine One or two group replaces.

Further or in other embodiment, G is R_1e, wherein R_1eAs defined above.Further or other enforcement In scheme, G is R_1e, and R⁰It is H, wherein R_1eAs defined above.Further or in other embodiment, G is R_1eAnd R⁰Except H Outside as defined above, and R_1eAs defined above.

Further or in other embodiment, G is Ar₁, wherein Ar₁As defined above.Further or other enforcement In scheme, G is Ar₁, and R⁰It is H, wherein Ar₁As defined above.Further or in other embodiment, G is Ar₁And R⁰Except Outside H as defined above, and Ar₁As defined above.

Further or in other embodiment, G is Ar₂, wherein Ar₂As defined above.Further or other enforcement In scheme, G is Ar₂, and R⁰It is H, wherein Ar₂As defined above.Further or in other embodiment, G is Ar₂And R⁰Except Outside H as defined above, and Ar₂As defined above.

Further or in other embodiment, X is F, Cl or CH₃；Y is I, Br, Cl, CF₃Or C₁-C₃Alkyl, and Z It is H or F.Further or in other embodiment, X is F, Cl or CH₃；Y is I, Br, Cl, CF₃Or C₁-C₃Alkyl, Z is H Or F, and R⁰It is halogen, C₁-C₆Alkyl, monohaloalkyl C₁-C₆Alkyl, C₃-C₆Cycloalkyl, C₂-C₆Thiazolinyl, C₂-C₆Alkynyl, phenyl, list Substituted-phenyl, OR₃、O-C(=O)R₄Or C (=O) OR₅.Further or in other embodiment, X is F, Cl or CH₃；Y be I, Br、Cl、CF₃Or C₁-C₃Alkyl, Z is H or F, and R⁰It is furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazole Base, pyrrole radicals or pyrazolyl.Further or in other embodiment, X is F, Cl or CH₃；Y is I, Br, Cl, CF₃Or C₁- C₃Alkyl, Z is H or F, and R⁰It is F, Cl, C₁-C₄Alkyl, C₁-C₃Alkoxyl, trifluoromethoxy or 2-Mehtoxy-ethoxy.

In the embodiment of another more specifically subgenus, R_1dIt is cycloalkyl or 1-alkyl-cycloalkyl, wherein said 1-alkane Base group optionally by one or two OH group or is replaced by one or two halogen atom.

In the embodiment of another more specifically subgenus, R⁰It is halogen, C₁-C₆Alkyl, monohaloalkyl C₁-C₆Alkyl, C₃-C₆ Cycloalkyl, C₂-C₆Thiazolinyl, C₂-C₆Alkynyl, phenyl, monosubstituted phenyl, OR₃、O-C(=O)R₄Or C (=O) OR₅；And R_1dIt it is cycloalkyl Or 1-alkyl-cycloalkyl, wherein said 1-alkyl group is optionally by one or two OH group or by one or two halogen Element atom replaces.

In the embodiment of another more specifically subgenus, R⁰It is furyl, thienyl, thiazolyl, isothiazolyl, azoles Base, isoxazolyl, pyrrole radicals or pyrazolyl；And R_1dBeing cycloalkyl or 1-alkyl-cycloalkyl, wherein said 1-alkyl group is optional Ground by one or two OH group or is replaced by one or two halogen atom.

In the embodiment of another more specifically subgenus, R_1dIt is cycloalkyl or 1-alkyl-cycloalkyl, wherein said 1-alkane Base group is optionally replaced by one or two OH group, and wherein Y is Br, I, methyl or trifluoromethyl.At another more specifically Subgenus embodiment in, R_1dCycloalkyl or 1-alkyl-cycloalkyl, wherein said 1-alkyl group optionally by one or Two fluorine atoms or chlorine atom replace, and wherein Y is Br, I, methyl or trifluoromethyl.Enforcement in another more specifically subgenus In scheme, R_1dBeing cycloalkyl or (1-alkyl (alleyl))-cycloalkyl, wherein said 1-alkyl group is optionally by one or two Individual OH group replaces, and wherein R⁰' it is: F, Cl, C₁-C₃Alkyl, monochloro are for C₁-C₃Alkyl, C₁-C₃Alkoxyl, trifluoromethoxy Or 2-Mehtoxy-ethoxy.In the embodiment of another more specifically subgenus, R_1dIt is tetrahydrofuran base, tetrahydro-thienyl, pyrrole Cough up alkyl, piperidyl, piperazinyl or morpholinyl, be optionally substituted each as described above, and wherein Y is Br, I, methyl or three Methyl fluoride.In the embodiment of another more specifically subgenus, R_1dIt is oxazolidinyl, thiazolidinyl, isoxazole alkyl, isothiazole Alkyl, tetrahydrofuran base, tetrahydro-thienyl, pyrrolidinyl, piperidyl, piperazinyl or morpholinyl, the most optionally It is replaced, and wherein Y is Br, I, methyl or trifluoromethyl.In the embodiment of another more specifically subgenus, R_1dIt it is cyclopropyl Or l-alkyl-cyclopropyl, wherein said 1-alkyl group is optionally replaced by one or two OH group, and wherein R⁰' be F, Cl, methyl, ethyl, chloromethyl, C₁-C₂Alkoxyl, trifluoromethoxy or 2-Mehtoxy-ethoxy.At one the most more specifically In embodiment, R_1dIt it is l-(monohydroxy alkyl) cycloalkyl.In another more particular embodiment, R_1dIt is l-(monohydroxy alkane Base) cycloalkyl, wherein R⁰' it is F, Cl, methyl, ethyl, chloromethyl, C₁-C₂Alkoxyl, trifluoromethoxy or 2-methoxyl group-ethoxy Base.In one even more specific embodiment, R_1dIt it is l-(dihydroxyalkyl) cycloalkyl.Another more specifically embodiment party In case, R_1dIt is l-(dihydroxyalkyl) cycloalkyl, wherein R⁰' it is F, Cl, methyl, ethyl, chloromethyl, C₁-C₂Alkoxyl, trifluoro Methoxyl group or 2-Mehtoxy-ethoxy.

In the embodiment of a more specifically subgenus, U is CR₂And V is N.Enforcement in another more specifically subgenus In scheme, U and V is N.In the embodiment of a more specifically subgenus, U is CR₂And V is CR₃。

In the embodiment of a subgenus even more, the present invention provides the compound of Formulas I, and wherein G is Ar₁And Ar₁ It is phenyl or monosubstituted phenyl, R⁰It is F, methyl, ethyl, C₁-C₃Alkoxyl, trifluoromethoxy or 2-Mehtoxy-ethoxy；X is F, Cl or CH₃；Y is I；And Z is F.In the embodiment of another subgenus, the present invention provides the compound of Formulas I, and wherein G is Ar₁, Wherein Ar₁It is phenyl or monosubstituted phenyl, R⁰It is halogen, C₁-C₆Alkyl, C₃-C₆Cycloalkyl, C₂-C₆Thiazolinyl, C₂-C₆Alkynyl, entirely The such alkyl in portion, cycloalkyl, thiazolinyl and alkynyl group are optionally independently selected from halogen, OH, CN, cyanogen methyl, nitro, benzene 1-3 substituent group of base and trifluoromethyl replaces；Or R⁰It is phenyl, OR₃, furyl, thienyl, thiazolyl, isothiazolyl, Oxazolyl, isoxazolyl, pyrrole radicals or pyrazolyl.In the embodiment of a more specifically subgenus, the present invention provides Formulas I Compound, wherein A is Ar₁, wherein Ar₁It is phenyl or monosubstituted phenyl, R⁰It is F, Cl, C₁-C₃Alkyl, C₁-C₃Alkoxyl, 2-first Epoxide ethyoxyl, C₂-C₃Thiazolinyl, C₂-C₃Alkynyl, trifluoromethyl, phenyl, furyl or thienyl, thiazolyl, isothiazolyl, Oxazolyl, isoxazolyl, pyrrole radicals or pyrazolyl；X is F, Cl or methyl；Y is I, Br, Cl, CF₃Or C₁-C₃Alkyl；And Z is F.

In the embodiment of another subgenus even more, the present invention provides the compound of Formulas I, and wherein G is Ar₁, its Middle Ar₁It is phenyl or monosubstituted phenyl, R⁰It is H；X is F, Cl or CH₃；Y is Br or I；And Z is F.

In the embodiment of another subgenus, the present invention provides the compound of Formulas I, and wherein G is Ar₂, wherein Ar₂It it is 2-thiophene Fen base, 2-furyl, 3-thienyl, 3-furyl, 2-pyrrole radicals or 3-pyrrole radicals, the most optionally by methoxycarbonyl, first Base carbamyl, acetylamino, acetyl group, methyl, ethyl, trifluoromethyl or halogen substiuted.A more specifically subgenus In embodiment, the present invention provides the compound of Formulas I, and wherein G is Ar₂, wherein Ar₂It is 2-thienyl, 2-furyl, 3-thiophene Base, 3-furyl, 2-pyrrole radicals or 3-pyrrole radicals, the most optionally by methoxycarbonyl, methylcarbamoyl, acetylamino, Acetyl group, methyl, ethyl, trifluoromethyl or halogen substiuted；R⁰It not H；X is F, Cl or CH₃；Y is I, Br, Cl, CF₃Or C₁-C₃ Alkyl, and Z is H or F.In the embodiment of another subgenus, the present invention provides the compound of Formulas I, and wherein G is Ar₂, wherein Ar₂ It is 2-thienyl, 2-furyl, 3-thienyl, 3-furyl, 2-pyrrole radicals or 3-pyrrole radicals, the most optionally by methoxyl group carbonyl Base, methylcarbamoyl, acetylamino, acetyl group, methyl, ethyl, trifluoromethyl or halogen substiuted；R⁰It is F, Cl, C₁-C₃Alkane Base, monochloro are for C₁-C₃Alkyl, C₁-C₃Alkoxyl, trifluoromethoxy, methoxy-methoxy or 2-Mehtoxy-ethoxy；X be F, Cl or CH₃；Y is I, Br, Cl, CF₃Or C₁-C₃Alkyl, and Z is H or F.In the embodiment of another subgenus, the present invention provides The compound of Formulas I, wherein G is Ar₂, wherein Ar₂Be 2-thienyl, 2-furyl, 3-thienyl, 3-furyl, 2-pyrrole radicals or 3-pyrrole radicals, the most optionally by methoxycarbonyl, methylcarbamoyl, acetylamino, acetyl group, methyl, ethyl, fluoroform Base or halogen substiuted；R⁰It is H；X is F, Cl or CH₃；Y is I, Br, Cl, CF₃Or C₁-C₃Alkyl, and Z is H or F.In another subgenus Embodiment in, the present invention provides the compound of Formulas I, and wherein G is Ar₂, wherein Ar₂Be thiazolyl, isothiazolyl, oxazolyl, Isoxazolyl, pyrrole radicals or pyrazolyl, the most optionally by methoxycarbonyl, methylcarbamoyl, acetylamino, acetyl group, Methyl, ethyl, trifluoromethyl or halogen substiuted；R⁰It is H or methoxyl group；X is F, Cl or CH₃；Y is I, Br, Cl, CF₃Or C₁-C₃Alkane Base, and Z is H or F.

In some embodiments, the compound or pharmaceutically acceptable salt thereof of described formula (I) is selected from

In some embodiments, the present invention provides the compound or pharmaceutically acceptable salt thereof of Formulas I, and it is selected from:Wherein 2-OH carbon is in R configuration.

In some embodiments, the present invention provides the compound or pharmaceutically acceptable salt thereof of Formulas I, and it is selected from:Wherein 2-OH carbon is in S configuration.

Further or in other embodiment, the compound or pharmaceutically acceptable salt thereof of described formula (I) is

In some embodiments, the present invention provides the compound of Formulas I, and wherein Y is phenyl, pyridine radicals or pyrazolyl.? In the embodiment of another subgenus, the present invention provides the compound of Formulas I, and wherein Y is phenyl, pyridine radicals or the pyrazoles being replaced Base.In the embodiment of another subgenus, the present invention provides the compound of Formulas I, and wherein Y is Br or I.Enforcement a subgenus In scheme, the present invention provides the compound of Formulas I, and wherein G is piperidino, 2-piperidyl, 3-piperidyl or 4-piperidyl.Separately In the embodiment of one subgenus, the present invention provides the compound of Formulas I, and wherein G is 1-piperazinyl or 2-piperazinyl.In another subgenus Embodiment in, the present invention provides the compound of Formulas I, and wherein G is morpholinyl.In the embodiment of another subgenus, this The compound of bright offer Formulas I, wherein G is N-methyl-2-amino ethyl.In the embodiment of a subgenus, the present invention provides The compound of Formulas I, wherein G is N-methyl-3-amino-n-propyl.In the embodiment of another subgenus, the present invention provides Formulas I Compound, wherein G is (CH₃)₂N-CH₂CH₂-NH-(CH₂)_n-, wherein n is 1,2 or 3.In the embodiment of another subgenus, The present invention provides the compound of Formulas I, and wherein G is (CH₃CH₂)₂N-CH₂CH₂-NH-(CH₂)_n-, wherein n is 1 or 2.At one more In the embodiment of concrete subgenus, the present invention provides the compound of Formulas I, and wherein G is piperidino, 2-piperidyl, 3-piperidines Base or 4-piperidyl；R⁰It is H, halogen or methoxyl group；X is F；And Y is I.In the embodiment of another more specifically subgenus, this Invention provides the compound of Formulas I, and wherein G is 1-piperazinyl or 2-piperazinyl；R⁰It is H, halogen or methoxyl group；X is F；And Y is I. In the embodiment of another more specifically subgenus, the present invention provides the compound of Formulas I, and wherein G is morpholinyl；R⁰It is H, halogen Or methoxyl group；X is F；And Y is I.In the embodiment of another more specifically subgenus, the present invention provides the compound of Formulas I, its Middle G is N-methyl-2-amino ethyl；R⁰It is H, halogen or methoxyl group；X is F；And Y is I.Reality in another more specifically subgenus Executing in scheme, the present invention provides the compound of Formulas I, and wherein G is N-methyl-3-amino-n-propyl；R⁰It is H, halogen or methoxy Base；X is F；And Y is I.In the embodiment of another more specifically subgenus, the present invention provides the compound of Formulas I, and wherein G is (CH₃)₂N-CH₂CH₂-NH-(CH₂)_n-, wherein n is 1,2 or 3；R⁰It is H, halogen or methoxyl group；X is F；And Y is I.At another more In the embodiment of concrete subgenus, the present invention provides the compound of Formulas I, and wherein G is (CH₃CH₂)₂N-CH₂CH₂-NH- (CH₂)_n-, wherein n is 1 or 2；R⁰It is H, halogen or methoxyl group；X is F；And Y is I.

In some embodiments, the present invention provides pharmaceutical composition, the compound of its contained I or it is pharmaceutically acceptable Salt, solvate, polymorph, ester, amide, tautomer or prodrug.In some embodiments, described drug regimen Thing also comprises at least one pharmaceutically acceptable carrier.

In some embodiments, the present invention provides pharmaceutical composition, and it comprises and is selected from: Compound or its pharmaceutically acceptable salt, solvate, polymorph, ester, amide, mutually Tautomeric or prodrug.In some embodiments, described pharmaceutical composition also comprises at least one pharmaceutically acceptable carrier. In some embodiments, described compound is in R configuration.In some embodiments, described compound is in R configuration, its Substantially free of S-isomer.In some embodiments, described compound is in S configuration.

In some embodiments, described compound is in S configuration, substantially free of R-isomer.In some embodiments In, described compound is:In some embodiments, described compound is:In some embodiments, described compound is:Real at some Executing in scheme, described compound is:

The list of the limiting examples of compound of formula I

Following table show the example of each compound that the present invention provides or relates to.Never should be interpreted as these examples limiting Property example.

Table 1 show the embodiment of the compound of formula I of the present invention, wherein R⁰As defined herein, G is R_1a, wherein R_1aAs Defined in this table, and define X, Y and Z in the table.

Table 1

Table 2 show the embodiment of the compound of formula I of the present invention, wherein R⁰As defined herein, G is R_1b, wherein R_1bAs Defined in this table, and define X, Y and Z in the table.

Table 2

Table 3 show the embodiment of the compound of formula I of the present invention, wherein R⁰As defined herein, G is R_1c, wherein R_1cAs Defined in this table, and define X, Y and Z in the table.

Table 3

Table 4a and 4b show the embodiment of the compound of formula I of the present invention, wherein G=R_1d, Z is F, and X is F, and at this R defined in table_1dAnd R⁰.This table is often gone corresponding to five kinds of only different in Y position materials.

Table 4a

Table 4b

CMPD#	A,A′	B	R⁰
				1(a-d)	H,H	H	2-furyl
2(a-d)	H,H	H	1,2,3-triazole-4-yl
				3(a-d)	H,H	H	4-imidazole radicals
4(a-d)	H,H	H	2-furyl
				5(a-d)	H,H	H	1,2,3-triazole-4-yl
6(a-d)	H,H	H	4-imidazole radicals
				7(a-d)	H,H	-(CH₂)₂CH(OH)CH₂OH	2-furyl
8(a-d)	H,H	-(CH₂)₂CH(OH)CH₂OH	1,2,3-triazole-4-yl
				9(a-d)	H,H	-(CH₂)₂CH(OH)CH₂OH	4-imidazole radicals
10(a-d)	-(CH₂)₂-	-CH₂(C₃H₅)	2-furyl
				11(a-d)	-(CH₂)₂-	-CH₂(C₃H₅)	1,2,3-triazole-4-yl
12(a-d)	-(CH₂)₂-	-CH₂(C₃H₅)	4-imidazole radicals
				13(a-d)	-(CH₂)₂-	CH₃	4-thiazolyl
14(a-d)	-(CH₂)₂-	-CH₂CH₂OH	4-thiazolyl
				15(a-d)	-(CH₂)₂-	-(CH₂)₂CH(OH)CH₂OH	4-thiazolyl
16(a-d)	CH₃,H	-(CH₂)₂CH(OH)CH₂OH	4-thiazolyl
				17(a-d)	-(CH₂)₂-	CH₃	2-oxazolyl
18(a-d)	-(CH₂)₂-	-CH₂CH₂OH	2-oxazolyl
				19(a-d)	-(CH₂)₂-	-(CH₂)₂CH(OH)CH₂OH	2-oxazolyl

CMPD#	A,A′	B	R⁰
				20(a-d)	CH₃,H	-(CH₂)₂CH(OH)CH₂OH	2-oxazolyl
21(a-d)	H,H	H	2-furyl
				22(a-d)	H,H	H	1,2,3-triazole-4-yl
23(a-d)	H,H	H	4-imidazole radicals
				24(a-d)	H,H	H	2-furyl
25(a-d)	H,H	H	1,2,3-triazole-4-yl
				26(a-d)	H,H	H	4-imidazole radicals
27(a-d)	H,H	-CH₂CH(OH)CH₂OH	2-furyl
				28(a-d)	H,H	-CH₂CH(OH)CH₂OH	1,2,3-triazole-4-yl
29(a-d)	H,H	-CH₂CH(OH)CH₂OH	4-imidazole radicals
				30(a-d)	-(CH₂)₂-	-CH₂(C₃H₅)	2-furyl
31(a-d)	-(CH₂)₂-	-CH₂(C₃H₅)	1,2,3-triazole-4-yl
				32(a-d)	-(CH₂)₂-	-CH₂(C₃H₅)	4-imidazole radicals
33(a-d)	-(CH₂)₂-	CH₃	4-thiazolyl
				34(a-d)	-(CH₂)₂-	-CH₂CH₂OH	4-thiazolyl
35(a-d)	-(CH₂)₂-	-(CH₂)₂CH(OH)CH₂OH	4-thiazolyl
				36(a-d)	CH₃,H	-(CH₂)₂CH(OH)CH₂OH	4-thiazolyl
37(a-d)	-(CH₂)₂-	CH₃	2-oxazolyl
				38(a-d)	-(CH₂)₂-	-CH₂CH₂OH	2-oxazolyl
39(a-d)	-(CH₂)₂-	-(CH₂)₂CH(OH)CH₂OH	2-oxazolyl
				40(a-d)	CH₃,H	-(CH₂)₂CH(OH)CH₂OH	2-oxazolyl

Table 5a show the embodiment of the compound of formula I of the present invention, and wherein G is Ar₁、Ar₂Or R_1d, and R⁰Being H, Z is F, And definition G and X in the table.This table is often gone corresponding to five kinds of only different in Y position material (Y_a、Y_b、Y_c、Y_dAnd Y_e), its Middle Y_a=SCH₃；Y_b=Br；Y_c=I；Y_d=Cl；Y_e=CH₃。

Table 5a

Table 5b show the embodiment of the compound of formula I of the present invention, and wherein G is Ar₁、Ar₂Or R_1d, and R⁰Being H, Z is F, And definition G and X in the table.This table is often gone corresponding to five kinds of only different in Y position material (Y_a、Y_b、Y_c、Y_dAnd Y_e), its Middle Y_a=phenyl；Y_b=3-substituted-phenyl；Y_c=3-pyridine radicals；Y_d=4-pyridine radicals；Y_e=3-pyrazolyl.

Table 5b

Synthesis step

On the other hand, it is provided that the method synthesizing compound as herein described.In some embodiments, described herein Compound can be prepared by following method.Following steps and embodiment are intended to those methods are described.Described step and enforcement Example the most should not be interpreted as limiting the present invention by any way.Use Standard synthetic methods well known by persons skilled in the art, or Methods known in the art are used to combine method described herein, it is also possible to synthesize compound as herein described.Additionally, this paper institute Solvent, temperature and other reaction conditions stated can change according to the practice of those skilled in the art and knowledge.

Can obtain from commercial source for synthesizing the raw material of compound described herein, such as Aldrich Chemical Co. (Milwaukee, Wis.), Sigma Chemical Co. (St.Louis, Mo.), or can be with synthesis material.Use this Method known to the skilled person and material, such as at March, A_DVANCED O_RGANIC C_HEMISTRY4th edition, (Wiley 1992)；Carey and Sundberg, A_DVANCED O_RGANIC C_HEMISTRY4th edition, volume A and B (Plenum 2000,2001) and Green and Wuts, P_ROTECTIVE G_ROUPS IN O_RGANIC S_YNTHESIS3rd edition, (Wiley 1999) (it is the most intactly quoted Add) described in, compound as herein described can be synthesized and there are other relevant compounds of different substituents.For The universal method preparing compound disclosed herein may come from reaction known in the art, and, in order to introduce as carried herein Various groups found in the formula of confession, known to technical staff, by using suitable reagent and condition can change institute State reaction.Following synthetic method can be used as guidance.

Formation covalent bond is reacted with nucleophile by electrophile

Use various electrophile or nucleophile, compound as herein described can be modified to form new functional group or replacement Base.The following table of entitled " covalent bond and the example of precursor thereof " lists the selected reality of generated covalent bond and precursor functional groups Example, and can serve as the various available electrophile and guidance of nucleophile combination.Precursor functional groups be expressed as electrophilic group and Nucleophilic group.

Covalent bond and the example of precursor thereof

Covalent bond product	Electrophile	Nucleophile
			Amide-type	Active ester	Amine/phenyl amines
Amide-type	Acyl azide	Amine/phenyl amines
			Amide-type	Carboxylic acid halides	Amine/phenyl amines
Esters	Carboxylic acid halides	Alcohols/phenol
			Esters	Acyl group nitrile	Alcohols/phenol
Amide-type	Acyl group nitrile	Amine/phenyl amines
			Imines	Aldehydes	Amine/phenyl amines
Hydrazone class	Aldehydes or ketone	Hydrazine
			Oximes	Aldehydes or ketone	Azanol class
Alkyl amine	Alkyl halide	Amine/phenyl amines
			Esters	Alkyl halide	Carboxylic acids
Thioether class	Alkyl halide	Thio-alcohol
			Ethers	Alkyl halide	Alcohols/phenol
Thioether class	Alkyl sulfonates	Thio-alcohol
			Esters	Alkyl sulfonates	Carboxylic acids
Ethers	Alkyl sulfonates	Alcohols/phenol
			Esters	Anhydrides	Alcohols/phenol
Amide-type	Anhydrides	Amine/phenyl amines
			Thio phenyl phenols	Aryl halides	Thio-alcohol
Aryl amine	Aryl halides	Amine
			Thioether class	Ethylene imine class	Thio-alcohol

Borate ester	Borate	Glycols
			Amide-type	Carboxylic acid	Amine/phenyl amines
Esters	Carboxylic acid	Alcohols
			Hydrazine	Hydrazides	Carboxylic acid
N-acylureas or anhydride	Carbodiimide	Carboxylic acid
			Esters	Diazoparaffins	Carboxylic acid
Thioether class	Epoxide	Thio-alcohol
			Thioether class	Halogen acid amide	Thio-alcohol
Amino triazine class (ammotriazine)	Halo triazine	Amine/phenyl amines
			Triazine radical ether	Halo triazine	Alcohols/phenol
Amidine class	Imino-ester	Amine/phenyl amines
			Urea	Isocyanates	Amine/phenyl amines
Carbamate	Isocyanates	Alcohols/phenol
			Thiourea	Isothiocyanate	Amine/phenyl amines
Thioether class	Maleimide	Thio-alcohol
			Phosphorous acid esters	Phosphoramidite	Alcohols
Silyl ether	Silicyl halo thing	Alcohols
			Alkyl amine	Sulfonic acid esters	Amine/phenyl amines
Thioether class	Sulfonic acid esters	Thio-alcohol
			Esters	Sulfonic acid esters	Carboxylic acid
Ethers	Sulfonic acid esters	Alcohols
			Sulfonamides	Sulfonic acid halide	Amine/phenyl amines
Sulfonic acid esters	Sulfonic acid halide	Phenol/alcohols

The use of protection group

In described reaction, it may be necessary to protection reactive functional groups (needs the situation of these groups in end product Under), such as hydroxyl, amino, imino group, thio group (thio) or carboxylic group, to avoid them unnecessarily to participate in reaction.Protect Protect base for blocking some or all of reactive group and stoping such group to participate in chemical reaction until described protection group It is removed.In some embodiments, each protection group can be removed by different methods.In diverse reaction condition incision Disconnected protection group meets the needs that diversity removes.Protection group can be removed by acid, alkali and hydrogenolysis.Group such as triphen first Base, dimethoxytrityl, acetal and t-butyldimethylsilyl are unstable to acid, and, using Cbz group In the presence of (it can remove through hydrogenolysis) and the amino group to alkali labile Fmoc radical protection, they can be used for protecting Protect carboxyl and hydroxyl reactive group.With the group such as t-butyl carbamate unstable to acid or with to bronsted lowry acids and bases bronsted lowry all Stable but through hydrolyzing in the presence of the amine that removable carbamate blocks, with to alkali labile group such as but not limited to Methyl, ethyl and acetyl group can block carboxylic acid and hydroxyl reactive group.

Carboxylic acid and hydroxyl reactive group can also block with through hydrolysis removable protection group such as benzyl group, and energy Enough and acid formation hydrogen bond amine groups can block with to alkali labile group such as Fmoc.As exemplified here, by converting Become simple ester compounds, carboxylic acid reaction group can be protected, or they can be by oxidized removable protection group example Such as 2,4-dimethoxy-benzyl blocks, and the amino group coexisted can be with the silicyl carbamic acid unstable to fluoride Ester blocks.

In the presence of allyl-based protection is used for acid and alkaline protection group, because it is stable, and can To remove with metal or π-acid catalyst subsequently.Such as, at the t-butyl carbamate unstable to acid or to alkali labile second In the presence of acid esters amine protecting group, the carboxylic acid that pi-allyl blocks can be with the reaction deprotection of Pd catalysis.The still yet another form of protection group It is compound or resin that intermediate can be attached thereto.As long as residue is connected with resin, this functional group is just blocked and not Can reaction.Once discharging from resin, described functional group may be used to reaction.

Protection group or blocking group can be selected from:

Other protection groups, and be applicable to produce protection group and remove their technology be described in detail in Greene and Wuts, Protective Groups in Organic Synthesis, the 3rd edition, John Wiley & Sons, New York, NY, 1999, and Kocienski, retouched in Protecting Groups, Thieme Verlag, New York, NY, 1994 Stating, it intactly quotes addition herein.

The compound of formula I

The compound of the present invention can be prepared by various methods.Following steps are intended to those methods are described, and are given Embodiment be intended to illustrate the scope of the present invention.These methods and embodiment should not be interpreted as limiting this by any way Bright.

I. the preparation of Formula IV compound is summarized as follows

The method that above route I illustrates to prepare the sulfamide derivative of Formula IV.From desired nitro-derivative (Formulas I) warp Two steps can easily prepare 1,2-diamine derivative (formula IV).The compound of formula IV can be with sulfonyl chloride derivatives (Formula V, ginseng See below a route) the reaction desired sulfonamide of formation.Or, before reacting with corresponding sulfonic acid chloride, can be by 1,2-diamidogen spreads out Biological IV protection is imidazolidinone (Formula VII).Deprotection 1,2-diamidogen VIII obtains desired raw material (formula in the basic conditions VI)。

II. the general routes outlined synthesizing compounds of formula V is summarized as follows

Above route II represents an example of the sulfonic acid chloride of preparation complexity.Can synthesize compounds X X from IX, it is permissible It is partially alkylated or alkylated and is converted to potassium salt XII.Use SOCl₂Or POCl₃Process this salt and obtain desired compound.At experimental section Report other more specifically methods of the unique sulfonyl chloride derivatives of preparation.

III. route 3 outlines the general routes outlined of synthesis general formula X III compound.

Above route III illustrates the preparation of the sulfamide derivative of general formula X III.Such as, under the conditions of Suzuki, make With palladium catalyst, by making compound VI and acid reaction can be readily derived these compounds.

IV. route 4 outlines the general routes outlined of synthesis general formula X III compound.

Above route IV illustrates the preparation of the sulfamide derivative of general formula X V.Vinylic sulfonamides (XIV) reacts with amine Form the derivant of general formula X V.

Other forms of compound of formula I

The isomer of compound of formula I

Compound as herein described can exist with geometric isomer.Compound as herein described is likely to be of one or many Individual double bond.Compound given in this article include all cis, trans, anti-(E) and along (Z) isomer and they mix accordingly Compound.In some cases, compound can exist with tautomer.Compound as herein described includes molecule described herein All possible tautomer in formula.Compound as herein described can have one or more chiral centre, and respectively Center can exist with R or S configuration.Compound as herein described include all diastereomer forms, enantiomeric form and difference to Isomeric forms, and they corresponding mixture.In other embodiments of Compounds and methods for provided herein, by list One preparation process, merging or the mutual enantiomer converting gained and/or the mixture of diastereomer, it is also possible to for herein Described application.It is different that the resolving agent of racemic mixture with optical activity by making described compound reacts a pair diastereomeric of formation Structure body compound, separating obtained diastereomer also reclaims optically pure enantiomer, and compound as herein described can be prepared as it Respective stereoisomer.Use the non-enantiomer derivative of the covalency of compound as herein described, or can use Dissociable complex (such as the diastereoisomeric salt of crystallization), can carry out Chiral Separation.Diastereomer has different physics Character (such as fusing point, boiling point, dissolubility, reactivity etc.), by utilizing these differences easily to be separated.By chirality color Spectrometry or separation based on dissolubility difference/fractionation technology, can separate diastereomer.Then, by outer disappearing will not be caused Any feasible method of rotationization reclaims optically pure enantiomer and resolving agent.At Jean Jacques, Andre Collet, Samuel H.Wilen,“Enantiomers,Racemates and Resolutions,”John Wiley and Sons, Inc., in 1981, it appeared that be applicable to the stereoisomerism body method splitting them from compound racemic mixture more Detailed description, intactly quotes addition herein.

The compound of formula I of labelling

Isotope-labeled compound of formula I and sanatory method are also described herein.Such as, the invention provides logical Cross the method being administered isotope-labeled compound of formula I treatment disease.Described coordination can be administered in the way of pharmaceutical composition The compound of formula I of element labelling.Therefore, the compound of Formulas I also includes isotope-labeled compound, itself and those enumerated herein Compound is identical, but the most one or more atom is had with the atomic mass that is generally found in nature or mass number not Same atomic mass or the atom of mass number substitute.The isotopic example can being contained in the compound of the present invention includes The isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, the most such as²H、³H、¹³C、¹⁴C、^l5N、¹⁸O、¹⁷O、³¹P、³²P、³⁵S、¹⁸F With³⁶C1.Comprise other isotopic compounds as herein described of above-mentioned isotope and/or other atoms or it is pharmaceutically acceptable Salt within the scope of the invention.Some isotope-labeled compound of formula I, such as radiosiotope are such as³H and¹⁴C comprises In those compounds therein, it is useful in medicine and/or substrate tissue measure of spread.Tritium is i.e.³H and carbon-14 are i.e.¹⁴C is same Position element is generally easy to preparation and detection.Additionally, with heavier isotope such as deuterium i.e.²H replacement can generate because of more preferable metabolism Some treatment advantage caused by stability, such as, increases Half-life in vivo or reduces volume requirements, and therefore in some situation Under be probably needs.By using method described herein, replace nonisotopic labels with the isotope labeling reagent being easy to get Reagent, typically can prepare isotope-labeled compound and pharmaceutically acceptable salt thereof.

Compound as herein described can pass through additive method labelling, and described additive method includes but not limited to that use adds lustre to Group or fluorophor, bioluminescence marker or chemiluminescent labeling.

The pharmaceutically acceptable salt of compound of formula I

The pharmaceutically acceptable salt of compound of formula I and sanatory method are described herein.Such as, the present invention carries Method for use by the pharmaceutically acceptable salts for treating disease of Medicine-feeding type I.Can be administered in the way of pharmaceutical composition The pharmaceutically acceptable salt of compound of formula I.

Therefore, compound as herein described can be prepared as pharmaceutically acceptable salt, acid present in the parent compound Character is substituted by metal ion such as alkali metal ion, alkaline-earth metal ions or aluminium ion；Or when being coordinated with organic base, shape Become described pharmaceutically acceptable salt.By make the free acid form of compound as herein described and pharmaceutically acceptable inorganic base or Organic base react, it is also possible to prepare base addition salts, described inorganic base or organic base include but not limited to organic bases such as ethanolamine, Diethanolamine, triethanolamine, trometamol, N-METHYL-ALPHA-L-GLUCOSAMINE etc., and inorganic basis such as aluminium hydroxide, calcium hydroxide, hydrogen-oxygen Change potassium, sodium carbonate, sodium hydroxide etc..Additionally, use raw material or the salt of intermediate, the salt of compound disclosed herein can be prepared Form.

Additionally, compound as herein described can be prepared as pharmaceutically acceptable salt, its dissociating by described compound Alkali form is formed with pharmaceutically acceptable inorganic or organic acid reaction, and described inorganic or organic acid includes but not limited to: mineral acid Such as hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid, Metaphosphoric acid etc.；With organic acids such as acetic acid, propanoic acid, caproic acid, Pentamethylene. third Acid, hydroxyacetic acid, acetone acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, Q-toluenesulfonic acid, tartaric acid, Trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxy benzoyl) benzoic acid, cinnamic acid, mandelic acid, aryl sulfonic acid, first sulphur Acid, ethyl sulfonic acid, 1,2-ethane disulfonic acid, 2-ethylenehydrinsulfonic acid, benzenesulfonic acid, 2-LOMAR PWA EINECS 246-676-2,4-methyl bicycle-[2.2.2] octyl-2- Alkene-1-carboxylic acid, glucoheptonic acid, 4,4 '-di-2-ethylhexylphosphine oxide-(3-hydroxyl-2-alkene-1-carboxylic acid), 3-phenylpropionic acid, trimethylace tonitric, Butylacetic acid, lauryl sulphate acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid.

The solvate of the compound of Formulas I

There is also described herein solvate and the method for the treatment of disease of the compound of Formulas I.Such as, the present invention provides through The solvate of Medicine-feeding type I treats the method for disease.Can in the way of pharmaceutical composition Medicine-feeding type I Solvate.

Solvate comprises stoichiometric or non-stoichiometric quantity of solvent, and can be with pharmaceutically acceptable molten Formed during crystallization such as agent such as water, ethanol etc..When described solvent is water, form hydrate, or when described solvent is During alcohol, form alcohol adduct.In method as described herein, can prepare easily or form the molten of compound as herein described Agent compound.It is only used as example, by from the mixture recrystallization of water/organic solvent, as herein describedization can be prepared easily The hydrate of compound, the organic solvent of use includes but not limited to dioxane, oxolane or methanol.Additionally, it is presented herein Compound can be presented in unsolvated and solvation.It is said that in general, for compound provided in this article Purpose with method, it is believed that described solvation form is equivalent to unsolvated form.

The polymorph of the compound of Formulas I

The polymorph of the compound of Formulas I and sanatory method are also described herein.Such as, the present invention provides through The polymorph of the compound of Medicine-feeding type I treats the method for disease.Can in the way of pharmaceutical composition Medicine-feeding type I Polymorph.

Therefore, compound as herein described includes their crystal types all, referred to as polymorph.Including of polymorph The different crystal packing arrangements of the identical element composition of compound.Polymorph is likely to be of different X-ray diffractogram, infrared Spectrum, fusing point, density, hardness, crystal form, electrical and optical properties, stability and dissolubility.Various factors such as recrystallization is molten It is leading that agent, crystallization rate and reserve temperature may cause single crystal form to account for.

N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-l-(2,3-dihydroxy third Base) crystalline polymorph of cyclopropane-1-sulfonamide

The invention still further relates to demonstrate N-(S)-(the fluoro-2-of 3,4-bis-(the 2-fluoro-4-iodobenzene of particular powder X-ray diffractogram Base amino)-6-methoxyphenyl)-l-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide:Crystallization Polymorph A.In some embodiments, described x-ray diffractogram of powder comprises the peak shown in Fig. 5 of at least about 50%.? In some embodiments, described x-ray diffractogram of powder comprises the peak shown in Fig. 5 of at least about 70%.In some embodiments In, described x-ray diffractogram of powder comprises the peak shown in Fig. 5 of at least about 90%.In some embodiments, described powder X-ray X ray diffration pattern x is essentially identical with the x-ray diffractogram of powder shown in Fig. 5.

The invention still further relates to N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-l-(2, 3-dihydroxypropyl) the crystalline polymorph A of cyclopropane-1-sulfonamide, it demonstrates specific means of differential scanning calorimetry figure.One In a little embodiments, described specific means of differential scanning calorimetry figure is essentially identical with the means of differential scanning calorimetry figure shown in Fig. 6.One In a little embodiments, described crystalline polymorph A has the fusing point starting point measuring about 143 DEG C through differential scanning calorimetry.

The invention still further relates to N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-l-(2, 3-dihydroxypropyl) polymorph of cyclopropane-1-sulfonamide, its by include making from solvent unbodied N-(S)-(3, The fluoro-2-of 4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-l-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide Prepared by the method for the step of crystallization.The invention still further relates to N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxy Base phenyl) polymorph of-l-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide, it is by including from hexane and acetic acid second The mixture of ester make unbodied N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-l-(2, 3-dihydroxypropyl) prepared by the method for step of cyclopropane-1-sulfonamide crystallization.

The invention still further relates to pharmaceutical composition, it comprises N-(S)-(3,4-bis-fluoro-2-(the 2-fluoro-4-iodophenyl of effective dose Amino)-6-methoxyphenyl) the crystalline polymorph A of-l-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide and pharmacy can The carrier accepted or carrier.Other aspects of the present invention relate to pharmaceutical composition, and it comprises described crystalline polymorph A and extremely Few a kind of excipient or carrier.

N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-l-(2,3-dihydroxy third Base) the crystalline polymorph A of cyclopropane-1-sulfonamide is used for treatment or prophylaxis of cancer or inflammatory diseases.The present invention is further Relate to treating or prophylaxis of cancer or the method for inflammatory diseases, it include the N-(S) to subject in need's effective dosage- (the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-l-(2,3-dihydroxypropyl) cyclopropane-1-sulphonyl The crystalline polymorph A of amine.Other other aspects of the present invention relate to the method treating or preventing inflammatory diseases, it include to The crystalline polymorph of subject in need's effective dosage.The further aspect of the present invention relates to treatment or prevention increases The method of growing property disease, it includes the crystalline polymorph to subject in need's effective dosage.

The prodrug of compound of formula I

There is also described herein the prodrug of compound of formula I and sanatory method.Such as, the present invention provides through be administered The prodrug of compound of formula I treats the method for disease.Can in the way of pharmaceutical composition the prodrug of Medicine-feeding type I.

Prodrug is usually the precursor of medicine, and after being administered to patient and absorb subsequently, it is converted into work through some process Property or the higher material of activity, such as by the conversion of metabolic pathway.Some prodrugs have chemical group, institute on prodrug State chemical group make prodrug activity relatively low and/or give described drug solubility or some other character.When described chemical group When being cut off from described prodrug and/or modify, produce active medicine.Because prodrug may than parent drug in some cases Be easier to be administered, all they be typically useful.Such as, prodrug is administered orally and is probably bioavailable, and its Parent is not the most bioavailable.Than parent drug, prodrug is also possible to have more preferable dissolubility in pharmaceutical composition. The limiting examples of prodrug can be compound as described herein, is administered as ester (" prodrug ") and promotes to pass through cell The transport of film, at cell membrane, water solublity is unfavorable to mobility, but, once (water solublity is favourable to its entrance cell wherein ), just it is hydrolyzed into carboxylic acid reactive's entity through metabolism.Other examples of prodrug are probably and the small peptide of acid groups bonding (poly-amino Acid), peptide described at this key discharges active part through metabolism.

In order to as dressing agent with promote transport of drug to site-specific tissue, prodrug design can be become reversible medicine Thing derivant.So far, the design of prodrug has been to improve effective water solubility of therapeutic compound thus has been the most molten to water The region of agent carries out targeting.See for example Fedorak etc., Am.J.Physiol., 269:G210-218 (1995)； McLoed etc., Gastroenterol, 106:405-413 (1994)；Hochhaus etc., Biomed.Chrom., 6:283-286 (1992)；J.Larsen and H.Bundgaard, Int.J.Pharmaceutics, 37,87 (1987)；J.Larsen etc., Int.J.Pharmaceutics,47,103(1988)；Sinkula etc., J.Pharm.Sci., 64:181-210 (1975)； T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, A.C.S. meeting series volume 14； With Edward B.Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, intactly add herein.

Additionally, by method known to those skilled in the art can prepare compound as described herein prodrug derive (such as, more details see Saulnier etc. to thing, (1994), Bioorganic and Medicinal Chemistry Letters,Vol.4,p.1985).It is only used as example, by making the compound of formula I of non-derivative and suitable carbamoyl Change reagent such as but not limited to 1,1-acyloxyallcyl chloro-formate (1,1-acyloxyalkylcarbanochloridate), P-nitrophenyl carbonate etc. react, and can prepare suitable prodrug.The prodrug forms of compound described herein, wherein said before Produce derivant as described herein through metabolism in medicine body, be included within the scope of the claims.It practice, some this paper institute State compound and be probably the prodrug of another derivant or reactive compound.

In some embodiments, prodrug includes compound, wherein amino acid residue or two or more (as 2,3 Individual or 4) polypeptide chain of amino acid residue is covalently attached to the free ammonia of the compound of the present invention by amido link or ester bond Base, hydroxyl or hydroxy-acid group.Described amino acid residue include but not limited to that usual three letter symbols represents 20 kinds are natural to be deposited Aminoacid, also include 4-hydroxyproline, oxylysine, desmosine, isodensmosine, 3-Methyl histidine, positive figured silk fabrics ammonia Acid, Beta-alanine, γ-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone.Also include Other kinds of prodrug.

The compound of formula I with free amino, hydroxyl or carboxylic group can change into prodrug.Such as, free carboxy Group can be derivatized chemical conversion amide or Arrcostab.As at Advanced Drug Delivery Reviews 1996,19, Outlined in 115, free hydroxyl radicals can be derivatized chemical conversion and include but not limited to hemisuccinic acid ester, phosphate ester, dimethylamino Yl acetate and the group of phosphoryloxymethyl epoxide carbonyl.Hydroxyl and the carbamate prodrugs of amino group, and hydroxyl In the carbonate prodrug of group, sulphonic acid ester and sulfuric ester are also included within.

Also including oh group derivative chemical conversion (acyloxy) methyl ether and (acyloxy) ethylether, wherein said acyl group is permissible Being Arrcostab, it is optionally included but is not limited to the group replacement of ether, amine and carboxylic acid functional, or wherein said acyl group base Group is amino-acid ester as above.This type of prodrug is described in J.Med.Chem.1996,39,10.Unhindered amina can also be spread out Biochemistry is amide, sulfonamide or phosphamide.All these prodrug moieties can introduce and include but not limited to ether, amine or carboxylic-acid functional The group of group.

Site on the aromatic moieties of compound of formula I may be susceptible to occur various metabolic response, therefore at described aromatic ring Introduce suitable substituent group in structure and can reduce, minimize or eliminate this metabolic pathway.

Pharmaceutical composition

Pharmaceutical composition described herein.In some embodiments, described pharmaceutical composition comprises the Formulas I chemical combination of effective dose Thing or its pharmaceutically acceptable salt.In some embodiments, described pharmaceutical composition comprise the compound of formula I of effective dose or its Pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer, prodrug, hydrate or derivant and at least A kind of pharmaceutically acceptable carrier.In some embodiments, described pharmaceutical composition is used for treating disease.Some embodiment party In case, described pharmaceutical composition is for treating the disease in mammal.In some embodiments, described pharmaceutical composition is used Disease in the treatment mankind.

Further, the present invention relates to pharmaceutical composition, its contained I or it is pharmaceutically acceptable Salt, solvate, polymorph, ester, amide, tautomer or prodrug.In some embodiments, described pharmaceutical composition Also comprise pharmaceutically acceptable carrier.Such compositions can comprise adjuvant, excipient and preservative, for postponing absorption Reagent, filler, binding agent, adsorbent, buffer agent, disintegrating agent, solubilizing agent, other carriers, and other inert fractions.So The compound method of compositions be well known in the art.

In some embodiments, described pharmaceutical composition is the form being suitable for oral administration.Further or other Embodiment in, described pharmaceutical composition is the shape of tablet, capsule, pill, powder, slow releasing preparation, solution, suspensoid Formula, is aseptic solution, suspensoid or Emulsion for parenteral injection, is ointment or ointment for topical, or Person is suppository for rectally.

Further or in other embodiment, described pharmaceutical composition uses and is suitable for single-dose correct dose Unit dosage forms.Further or in other embodiment, the amount of compound of formula I about 0.001 to about 1000mg/kg body weight/ In the range of.Further or in other embodiment, the amount of compound of formula I about 0.5 to about 50mg/kg/ day model In enclosing.Further or in other embodiment, the amount of compound of formula I is about 0.001 to about 7g/ day.Further or its In his embodiment, the amount of compound of formula I is about 0.01 to about 7g/ day.Further or in other embodiment, Formulas I The amount of compound is about 0.02 to about 5g/ day.Further or in other embodiment, the amount of compound of formula I is about 0.05 To about 2.5g/ day.Further or in other embodiment, the amount of compound of formula I is about 0.1 to about 1g/ day.Further Or in other embodiment, may enough have a surplus less than the dosage level of above-mentioned range lower limit.Further or other reality Execute in scheme, be probably necessary higher than the dosage level of above-mentioned range limit.

Further or in other embodiment, with the compound of single dose Medicine-feeding type I once a day.Further or In other embodiment, with the compound of the multiple dose every day of Medicine-feeding type I more than once.Further or other embodiment In, every day twice Medicine-feeding type I compound.Further or in other embodiment, the chemical combination of Medicine-feeding type I three times a day Thing.Further or in other embodiment, the compound of four times a day Medicine-feeding type I.Further or other embodiment party In case, every day is more than the compound of four Medicine-feeding type I.In some embodiments, described pharmaceutical composition is for moving to suckling Thing is administered.Further or in other embodiment, described mammal is the mankind.

Further or in other embodiment, described pharmaceutical composition also comprises pharmaceutical carriers, excipient and/or auxiliary Agent.Further or in other embodiment, described pharmaceutical composition also comprises at least one therapeutic agent.Further or its In his embodiment, described therapeutic agent is selected from cytotoxic agent, antiangiogenic agent and antineoplastic agent.Further or other Embodiment in, described antineoplastic agent selects free alkylating agent, antimetabolite, epidophylltoxin, antitumor enzyme, topoisomerase to press down Preparation, procarbazine, mitoxantrone, platinum coordination complex, biological response modifier and growth inhibitor, hormone/hormone antagonist are controlled Treat agent and hemopoietic growth factor.Further or in other embodiment, described therapeutic agent is paclitaxel, bortezomib or two Person.Further or in other embodiment, it is administered described pharmaceutical composition, is combined with other therapies.Further or its In his embodiment, other therapies described are X-ray therapy, chemotherapy, surgical operation or their combination in any.Entering In one step or other embodiment, the pharmaceutically acceptable salt of the contained I of described pharmaceutical composition.

The invention still further relates to compriseCompositions.In some embodiments, on described compound 2-OH carbon be in R configuration.In some embodiments, compositions is substantially free of the S-isomer of described compound.At some In embodiment, described compound comprises the S-isomer of the described compound less than 10%.In some embodiments, described Compound comprises the S-isomer of the described compound less than 5%.In some embodiments, described compound comprises less than 1% The S-isomer of described compound.In some embodiments, described compound is in R configuration.

In some embodiments, the 2-OH carbon on described compound is in S configuration.In some embodiments, combination Thing is substantially free of the R-isomer of described compound.In some embodiments, described compound comprises describedization less than 10% The R-isomer of compound.In some embodiments, described compound comprises the R-isomer of the described compound less than 5%.? In some embodiments, described compound comprises the R-isomer of the described compound less than 1%.In some embodiments, institute Stating compound is S configuration.

In some embodiments, described compositions comprises the compound of at least about 50%, and described compound demonstrates and comprises The x-ray diffractogram of powder at the peak identified in x-ray diffractogram of powder shown in Fig. 5 of at least 50%.In some embodiments In, described x-ray diffractogram of powder comprises the peak identified in x-ray diffractogram of powder shown in Fig. 5 of at least 70%.One In a little embodiments, described x-ray diffractogram of powder comprises to be identified in x-ray diffractogram of powder shown in Fig. 5 of at least 90% Peak.In some embodiments, described x-ray diffractogram of powder phase basic with the x-ray diffractogram of powder shown in Fig. 5 With.

In some embodiments, described compositions comprises the compound of at least about 75%, and described compound demonstrates and comprises The powder x-ray diffraction figure at the peak identified in x-ray diffractogram of powder shown in Fig. 5 of at least 50%.Some embodiment party In case, described x-ray diffractogram of powder comprises the peak identified in x-ray diffractogram of powder shown in Fig. 5 of at least 70%.? In some embodiments, described x-ray diffractogram of powder comprises and is reflected in x-ray diffractogram of powder shown in Fig. 5 of at least 90% Fixed peak.In some embodiments, described x-ray diffractogram of powder phase basic with the x-ray diffractogram of powder shown in Fig. 5 With.

In some embodiments, described compositions comprises the compound of at least about 90%, and described compound demonstrates and comprises The powder x-ray diffraction figure at the peak identified in x-ray diffractogram of powder shown in Fig. 5 of at least 50%.Some embodiment party In case, described x-ray diffractogram of powder comprises the peak identified in x-ray diffractogram of powder shown in Fig. 5 of at least 70%.? In some embodiments, described x-ray diffractogram of powder comprises and is reflected in x-ray diffractogram of powder shown in Fig. 5 of at least 90% Fixed peak.In some embodiments, described x-ray diffractogram of powder phase basic with the x-ray diffractogram of powder shown in Fig. 5 With.

In some embodiments, in described compositions, substantially all described compound all demonstrates and comprises at least 50% Fig. 5 shown in the powder x-ray diffraction figure at peak identified in x-ray diffractogram of powder.In some embodiments, institute State x-ray diffractogram of powder and comprise the peak identified in x-ray diffractogram of powder shown in Fig. 5 of at least 70%.Implement at some In scheme, described x-ray diffractogram of powder comprises the peak identified in x-ray diffractogram of powder shown in Fig. 5 of at least 90%. In some embodiments, described x-ray diffractogram of powder is essentially identical with the x-ray diffractogram of powder shown in Fig. 5.

In some embodiments, the described crystalline polymorph being present in described compositions has through differential scanning amount The fusing point starting point being about 143 DEG C that full-boiled process measures.In some embodiments, described crystalline polymorph is the most anhydrous. In some embodiments, described crystalline polymorph is substantially free of solvent.

In some embodiments, described compositions comprises the compound of at least about 50%, and described compound demonstrates and schemes The means of differential scanning calorimetry figure that means of differential scanning calorimetry figure shown in 6 is essentially identical.In some embodiments, described crystalline polymorphs Thing has the fusing point starting point being about 143 DEG C measured through differential scanning calorimetry.In some embodiments, described crystallization is many Crystal formation thing is the most anhydrous.In some embodiments, described crystalline polymorph is substantially free of solvent.

In some embodiments, described compositions comprises the compound of at least about 75%, and described compound demonstrates and schemes The means of differential scanning calorimetry figure that means of differential scanning calorimetry figure shown in 6 is essentially identical.In some embodiments, described crystalline polymorphs Thing has the fusing point starting point being about 143 DEG C measured through differential scanning calorimetry.In some embodiments, described crystallization is many Crystal formation thing is the most anhydrous.In some embodiments, described crystalline polymorph is substantially free of solvent.

In some embodiments, described compositions comprises the compound of at least about 90%, and described compound demonstrates and schemes The means of differential scanning calorimetry figure that means of differential scanning calorimetry figure shown in 6 is essentially identical.In some embodiments, described crystalline polymorphs Thing has the fusing point starting point being about 143 DEG C measured through differential scanning calorimetry.In some embodiments, described crystallization is many Crystal formation thing is the most anhydrous.In some embodiments, described crystalline polymorph is substantially free of solvent.

In some embodiments, in described compositions substantially all described compound all demonstrate with shown in Fig. 6 The means of differential scanning calorimetry figure that means of differential scanning calorimetry figure is essentially identical.In some embodiments, described crystalline polymorph has Through the fusing point starting point being about 143 DEG C that differential scanning calorimetry measures.In some embodiments, described crystalline polymorph The most anhydrous.In some embodiments, described crystalline polymorph is substantially free of solvent.

In some embodiments, N-(3,4-bis-fluoro-2-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-l- The polymorph of (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide is by including making unbodied N-(3,4-bis-fluoro-2-(2- Fluoro-4-idodophenylamino)-6-methoxyphenyl) step of-l-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide crystallization Prepared by method.In some embodiments, described crystallisation step includes crystallizing from the mixture of ethyl acetate and heptane, example As, the ratio of the mixture of ethyl acetate and heptane be about 1-4 part ethyl acetate than about 2-10 part heptane, or more specifically, ratio Example is that about 2 parts of ethyl acetate are than about 5 parts of heptane.

In some embodiments, described compound is prepared as directly discharging the preparation of described compound.Real at some Execute in scheme, described compound is prepared as the preparation of compound described in sustained release.In other embodiments, by describedization Compound is prepared as the preparation postponing to discharge described compound.

In some embodiments, described compositions is Tabules.In other embodiments, described compositions is glue Cap dosage.Described compositions can be prepared as capsule or Tabules, and can use broad range of optional compositions And preparation method, list of references: (1) Remington, The Science and Practice of Pharmacy, the 20th edition, 2000, (2) Pharmaceutical Dosage Forms Tablets 1-3 volume, 1989, and (3) Modern Pharmaceuticals the 4th edition, 2002.A series of preparation method can be used, it include dry mixed method, wet granulation process, Rolled-on method, squeezing and pressing method, spheronization, coating method and spray drying process.Soft gelatin formulation and preparation method are also applicable.

In some embodiments, described compositions comprises filler or diluent.In various embodiments, fill out described in Fill agent or diluent selected from microcrystalline Cellulose, silicified microcrystalline cellulose, lactose, mannitol, sompressible sugar, calcium phosphate, calcium sulfate, Calcium carbonate, calcium silicates and starch.In other embodiments, described filler or diluent are microcrystalline Cellulose.

In some embodiments, described compositions comprises disintegrating agent.In various embodiments, described disintegrating agent is selected from Cross-linked carboxymethyl cellulose sodium, primojel, crospovidone, methylcellulose, alginic acid, sodium alginate, starch derivatives, swollen Profit soil and aluminium-magnesium silicate.In certain embodiment, described disintegrating agent is cross-linked carboxymethyl cellulose sodium.

In some embodiments, described compositions comprises lubricant.In various embodiments, described lubricant is selected from Magnesium stearate, metallic stearate, Talcum, sodium stearyl fumarate and stearic acid.In some embodiments, described lubricant It it is magnesium stearate.

In some embodiments, described compositions comprises wetting agent or surfactant.In various embodiments, institute State wetting agent or surfactant selected from sodium lauryl sulphate, glycerol, sorbitan monooleate, anhydrous sorbitol stearic acid Ester, polyoxyethylated anhydrous sorbitol laurate, cetylate, stearate, oleate or six oleates, polyoxyethylene are hard Lipidol and sorbitan mono-laurate.In some embodiments, described wetting agent or surfactant are dodecyls Sodium sulfate.

Other excipients such as fluidizer, flavoring agent and coloring agent can also be added.At The Handbook of Pharmaceutical Excipients, the 5th edition, it appeared that other are optional in 2005 and FDA non-active ingredient data bases Excipient.

The invention still further relates to compositions, it comprises:

About 1mg structure isCompound (as defined in any of above embodiment)；

About 222.2mg microcrystalline Cellulose；

About 12.0mg cross-linked carboxymethyl cellulose sodium；

About 2.4mg sodium lauryl sulphate；With

About 2.4mg magnesium stearate.

The invention still further relates to compositions, it comprises:

About 10mg structure isCompound (as defined in any of above embodiment)；

About 213.2mg microcrystalline Cellulose；

About 12.0mg cross-linked carboxymethyl cellulose sodium；

About 2.4mg sodium lauryl sulphate；With

About 2.4mg magnesium stearate.

The invention still further relates to compositions, it comprises:

About 20mg structure isCompound (as defined in any of above embodiment)；

About 203.2mg microcrystalline Cellulose；

About 12.0mg cross-linked carboxymethyl cellulose sodium；

About 2.4mg sodium lauryl sulphate；With

About 2.4mg magnesium stearate.

The invention still further relates to compositions, it comprises:

About 40mg structure isCompound (as defined in any of above embodiment)；

About 183.2mg microcrystalline Cellulose；

About 12.0mg cross-linked carboxymethyl cellulose sodium；

About 2.4mg sodium lauryl sulphate；With

About 2.4mg magnesium stearate.

The invention still further relates to compositions, it comprises: the structure of about 0.4 weight % isCompound (as Defined in any of above embodiment)；The pharmaceutically acceptable carrier of about 99.6 weight % or carrier.Implement at some In scheme, described pharmaceutically acceptable carrier or carrier include microcrystalline Cellulose.Further or in other embodiment, Described microcrystalline Cellulose accounts for about 92.6 weight % of described compositions.Further or in other embodiment, described compositions Also comprise: cross-linked carboxymethyl cellulose sodium of about 5 weight %；The sodium lauryl sulphate of about 1 weight %；The stearic acid of about 1 weight % Magnesium.

The invention still further relates to compositions, it comprises: the structure of about 4.2 weight % isCompound (as Defined in any of above embodiment)；The pharmaceutically acceptable carrier of about 95.8 weight % or carrier.Implement at some In scheme, described pharmaceutically acceptable carrier or carrier include microcrystalline Cellulose.Further or in other embodiment, Described microcrystalline Cellulose accounts for about 88.8 weight % of described compositions.Further or in other embodiment, described compositions Also comprise: cross-linked carboxymethyl cellulose sodium of about 5 weight %；The sodium lauryl sulphate of about 1 weight %；The stearic acid of about 1 weight % Magnesium.

The invention still further relates to compositions, it comprises: about 2 weight % to the structure of about 10 weight % are's Compound (as defined in any of above embodiment)；The pharmaceutically acceptable carrier of about 98 weight % to about 90 weight % or Carrier.In some embodiments, described pharmaceutically acceptable carrier or carrier include microcrystalline Cellulose.Further or In other embodiment, described microcrystalline Cellulose accounts for about 85 weight % of described compositions to about 95 weight %.Further or In other embodiment, described compositions also comprises: cross-linked carboxymethyl cellulose sodium of about 1 weight % to about 6 weight %；About 0.1 Weight % is to the sodium lauryl sulphate of about 2 weight %；The magnesium stearate of about 0.25 weight % to about 1.5 weight %.Real at some Executing in scheme, described pharmaceutically acceptable carrier or carrier include microcrystalline Cellulose.Further or other embodiment In, described microcrystalline Cellulose accounts for about 85 weight % of described compositions to about 95 weight %.Further or other embodiment In, described compositions also comprises: cross-linked carboxymethyl cellulose sodium of about 1 weight % to about 6 weight %；About 0.25 weight % is to about 1.5 The magnesium stearate of weight %.

The invention still further relates to compositions, it comprises:

About 1mg structure isCompound；

About 222.2mg microcrystalline Cellulose；

About 12.0mg cross-linked carboxymethyl cellulose sodium；

About 2.4mg sodium lauryl sulphate；With

About 2.4mg magnesium stearate.

The invention still further relates to compositions, it comprises:

About 10mg structure isCompound；

About 213.2mg microcrystalline Cellulose；

About 12.0mg cross-linked carboxymethyl cellulose sodium；

About 2.4mg sodium lauryl sulphate；With

About 2.4mg magnesium stearate.

The invention still further relates to compositions, it comprises:

About 20mg structure isCompound；

About 203.2mg microcrystalline Cellulose；

About 12.0mg cross-linked carboxymethyl cellulose sodium；

About 2.4mg sodium lauryl sulphate；With

About 2.4mg magnesium stearate.

The invention still further relates to compositions, it comprises:

About 40mg structure isCompound；

About 183.2mg microcrystalline Cellulose；

About 12.0mg cross-linked carboxymethyl cellulose sodium；

About 2.4mg sodium lauryl sulphate；With

About 2.4mg magnesium stearate.

The invention still further relates to compositions, it comprises: the structure of about 0.4 weight % isCompound； The pharmaceutically acceptable carrier of about 99.6 weight % or carrier.In some embodiments, described pharmaceutically acceptable carrier Or carrier includes microcrystalline Cellulose.Further or in other embodiment, described microcrystalline Cellulose accounts for described compositions About 92.6 weight %.Further or in other embodiment, described compositions also comprises: the crosslinking carboxylic first of about 5 weight % Sodium cellulosate；The sodium lauryl sulphate of about 1 weight %；The magnesium stearate of about 1 weight %.

The invention still further relates to compositions, it comprises: the structure of about 4.2 weight % isCompound； The pharmaceutically acceptable carrier of about 95.8 weight % or carrier.In some embodiments, described pharmaceutically acceptable carrier Or carrier includes microcrystalline Cellulose.Further or in other embodiment, described microcrystalline Cellulose accounts for described compositions About 88.8 weight %.Further or in other embodiment, described compositions also comprises: the crosslinking carboxylic first of about 5 weight % Sodium cellulosate；The sodium lauryl sulphate of about 1 weight %；The magnesium stearate of about 1 weight %.

The invention still further relates to compositions, it comprises: about 2 weight % to the structure of about 10 weight % are's Compound；The pharmaceutically acceptable carrier of about 98 weight % to about 90 weight % or carrier.In some embodiments, described Pharmaceutically acceptable carrier or carrier include microcrystalline Cellulose.Further or in other embodiment, described crystallite is fine Dimension element accounts for about 85 weight % of described compositions to about 95 weight %.Further or in other embodiment, described compositions Also comprise: cross-linked carboxymethyl cellulose sodium of about 1 weight % to about 6 weight %；The dodecyl sulfur of about 0.1 weight % to about 2 weight % Acid sodium；The magnesium stearate of about 0.25 weight % to about 1.5 weight %.In some embodiments, described pharmaceutically acceptable load Body or carrier include microcrystalline Cellulose.Further or in other embodiment, described microcrystalline Cellulose accounts for described combination About 85 weight % of thing are to about 95 weight %.Further or in other embodiment, described compositions also comprises: about 1 weight % Cross-linked carboxymethyl cellulose sodium to about 6 weight %；The magnesium stearate of about 0.25 weight % to about 1.5 weight %.

The invention still further relates to compositions, it comprises:

About 1mg structure isCompound；

About 222.2mg microcrystalline Cellulose；

About 12.0mg cross-linked carboxymethyl cellulose sodium；

About 2.4mg sodium lauryl sulphate；With

About 2.4mg magnesium stearate.

The invention still further relates to compositions, it comprises:

About 10mg structure isCompound；

About 213.2mg microcrystalline Cellulose；

About 12.0mg cross-linked carboxymethyl cellulose sodium；

About 2.4mg sodium lauryl sulphate；With

About 2.4mg magnesium stearate.

The invention still further relates to compositions, it comprises:

About 20mg structure isCompound；

About 203.2mg microcrystalline Cellulose；

About 12.0mg cross-linked carboxymethyl cellulose sodium；

About 2.4mg sodium lauryl sulphate；With

About 2.4mg magnesium stearate.

The invention still further relates to compositions, it comprises:

About 40mg structure isCompound；

About 183.2mg microcrystalline Cellulose；

About 12.0mg cross-linked carboxymethyl cellulose sodium；

About 2.4mg sodium lauryl sulphate；With

About 2.4mg magnesium stearate.

The invention still further relates to compositions, it comprises: about 0.4 weight % structure isCompound；With The pharmaceutically acceptable carrier of about 99.6 weight % or carrier.In some embodiments, described pharmaceutically acceptable carrier or Carrier includes microcrystalline Cellulose.Further or in other embodiment, described microcrystalline Cellulose accounts for described compositions About 92.6 weight %.Further or in other embodiment, described compositions also comprises: the crosslinking carboxylic first of about 5 weight % is fine Dimension element sodium；The sodium lauryl sulphate of about 1 weight %；The magnesium stearate of about 1 weight %.

Pharmaceutical composition is also described herein, and it comprises N-(S)-(3,4-bis-fluoro-2-(the 2-fluoro-4-iodophenyl of effective dose Amino)-6-methoxyphenyl) the crystalline polymorph A of-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide.Real at some Executing in scheme, described pharmaceutical composition comprises N-(S)-(3,4-bis-fluoro-2-(2-fluoro-4-the idodophenylamino)-6-first of effective dose Phenyl) the crystalline polymorph A of-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide and at least one pharmacy can connect The carrier being subject to.In some embodiments, described pharmaceutical composition is used for treating disease.In some embodiments, described medicine Compositions is for treating the disease in mammal.In some embodiments, described pharmaceutical composition is used for treating the mankind In disease.In some embodiments, described pharmaceutical composition is used for treating or preventing inflammatory diseases.In some embodiments In, described pharmaceutical composition is used for treating or preventing proliferative disease.

Described compound and the using method of described compositions including polymorph

In other respects, the method that the present invention relates to obtain effect in patient, it includes the Formulas I to patient's effective dosage Compound or its pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer or prodrug, wherein said Effect is selected from the suppression to various cancers, immune disease and inflammatory diseases.In some embodiments, by described compound or Its pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer or prodrug can connect as also comprising pharmacy The carrier being subject to or the ingredient administration of the compositions of carrier.In some embodiments, described effect is to suppress various cancers.? Further or in other embodiment, described effect is suppression immune disease.Further or in other embodiment, Described effect is suppression inflammatory diseases.

Any compositions described herein and prescription may be used in the method that this part provides.

In some embodiments, it is administered the compositions of contained I, is combined with other therapies.Further or In other embodiment, other therapies described are X-ray therapy, chemotherapy or surgical operation or their combination in any.? Further or in other embodiment, the compositions of contained I is administered with at least one therapeutic agent.

In some embodiments of compositions provided herein and method, it is provided that the MEK albumen of the most contained I Inhibitors of kinases, the compound of wherein said Formulas I exists with the amount of about 0.1m to about 200mg.In other embodiments, described The compound of the contained I of MEK kinases inhibitor, and it is with the amount existence of about 0.2mg to about 100mg.Implement at other In scheme, the compound of the described contained I of MEK kinases inhibitor, and it is with the amount existence of about 0.3mg to about 90mg. In other embodiments, the compound of the described contained I of MEK kinases inhibitor, and it is with about 0.4mg to about 80mg Amount exist.In other embodiments, the compound of the described contained I of MEK kinases inhibitor, and it is with about The amount of 0.5mg to about 70mg exists.In other embodiments, the compound of the described contained I of MEK kinases inhibitor, And it exists with the amount of about 0.4mg to about 80mg.In other embodiments, the described contained I of MEK kinases inhibitor Compound, and it exists with the amount of about 0.5mg to about 70mg.In other embodiments, described MEK protein kinase suppression The compound of the contained I of agent, and it is with the amount existence of about 1mg to about 60mg.In other embodiments, described MEK albumen The compound of the contained I of inhibitors of kinases, and it is with the amount existence of about 1.5mg to about 50mg.In other embodiments, institute State the compound of the contained I of MEK kinases inhibitor, and it exists with the amount of about 2mg to about 45mg.Other embodiment party In case, the compound of the described contained I of MEK kinases inhibitor, and it is with the amount existence of about 2.5mg to about 40mg.? In further embodiment, also comprise the MEK kinases inhibitor of the compound of formula I existed with dosage provided herein It is selected from

In some embodiments of compositions provided herein and method, it is provided that the MEK albumen of the most contained I Inhibitors of kinases, the compound of wherein said Formulas I is with about 0.1mg, about 0.2mg, about 0.25mg, about 0.3mg, about 0.4mg, about 0.5mg, about 0.6mg, about 0.7mg, about 0.8mg, about 0.9mg, about 1mg, about 1.5mg, about 2mg, about 2.5mg, about 3mg, about 3.5mg, about 4.0mg, about 4.5mg, about 5mg, about 5.5mg, about 6mg, about 6.5mg, about 7mg, about 7.5mg, about 8mg, about 8.5mg, about 9mg, about 9.5mg, about 10mg, about 10.5mg, about 11mg, about 11.5mg, about 12mg, about 12.5mg, and/or about The amount of 13mg, about 14mg or about 15mg exists.In further embodiment, the Formulas I existed with dosage provided herein Compound is selected from

In some embodiments of compositions provided herein and method, it is provided that the MEK albumen of the most contained I Inhibitors of kinases, the compound of wherein said Formulas I is with about 15mg, about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, About 110mg, about 120mg, about 125mg, about 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 175mg, about The amount of 180mg, about 190mg or about 200mg exists.In further embodiment, the Formulas I existed with dosage provided herein Compound is selected from

In some respects, the present invention relates to treat the method for disease in the individuality suffering from described disease, it includes to described The contained I of individual effective dosage or its pharmaceutically acceptable salt, solvate, polymorph, ester, tautomerism Body or the compositions of prodrug.

The disease of MEK regulation and disease

It is described herein and contacts regulation by a certain amount of compound of formula I making MEK be enough to regulate MEK activity The method of MEK activity.Regulation can be suppression or activate MEK activity.In some embodiments, the present invention provides through make MEK and the method that be enough to suppress a certain amount of compound of formula I contact inhibition MEK activity of MEK activity.In some embodiments In, the present invention provides through make solution and be enough to suppress a certain amount of compound of formula I contact inhibition of MEK activity in described solution The method of MEK activity in described solution.In some embodiments, the present invention provides through make cell be enough to suppress described carefully The method of MEK activity in cell described in the compound contact inhibition a certain amount of as herein described of MEK activity in born of the same parents.Real at some Executing in scheme, it is a certain amount of as herein described be enough to suppress MEK activity in described tissue to the present invention provides through make tissue The method of MEK activity in tissue described in compound contact inhibition.In some embodiments, the present invention provides through to make biological with Be enough to suppress in described biology MEK activity in biology described in the compound contact inhibition a certain amount of described herein of MEK activity Method.In some embodiments, the present invention provides through make animal and be enough to suppress a certain amount of of MEK activity in described animal Compound contact inhibition as herein described described in the method for MEK activity in animal.In some embodiments, the present invention provides By making mammal and be enough to suppress the compound a certain amount of as herein described of MEK activity in described mammal and contact press down Make the method for MEK activity in described mammal.In some embodiments, the present invention provides through make the mankind and be enough to suppress The method of MEK activity in the mankind described in the compound contact inhibition a certain amount of as herein described of MEK activity in the described mankind.

The compound of Formulas I and contained I and its pharmaceutically acceptable salt, solvate, polymorph, ester, The compositions of amide, tautomer or prodrug, can regulate the activity of MEK enzyme；And it is similarly used for treating abnormal MEK Enzymatic activity causes disease or the condition of illness of the patient's condition and/or the disease of symptom or the patient's condition.

In some respects, the present invention relates to treat in the mammal including the mankind by disease or the disease of MEK Cascade control The method of condition, it includes being administered a certain amount of compound of formula I or its medicine effectively regulating described cascade to described mammal Learn acceptable salt, ester, prodrug, solvate, hydrate or derivant.Those skilled in the art according to known methods can be true The fixed suitable dosage for particular patient.

In other respects, the method that the present invention relates to suppress MEK enzyme.In some embodiments, described method includes making Described MEK enzyme contacts with a certain amount of compositions that be enough to suppress described enzyme, the compound of the contained I of described compositions or its medicine Learning acceptable salt, solvate, polymorph, ester, amide, tautomer or prodrug, wherein said enzyme is suppressed.Entering In one step or other embodiment, described enzyme is suppressed at least about 1%.Further or in other embodiment, described enzyme It is suppressed at least about 2%.Further or in other embodiment, described enzyme is suppressed at least about 3%.Further or other Embodiment in, described enzyme be suppressed at least about 4%.Further or in other embodiment, described enzyme is suppressed at least About 5%.Further or in other embodiment, described enzyme is suppressed at least about 10%.Further or other embodiment party In case, described enzyme is suppressed at least about 20%.Further or in other embodiment, described enzyme is suppressed at least about 25%. Further or in other embodiment, described enzyme is suppressed at least about 30%.Further or in other embodiment, Described enzyme is suppressed at least about 40%.Further or in other embodiment, described enzyme is suppressed at least about 50%.Entering one In step or other embodiment, described enzyme is suppressed at least about 60%.Further or in other embodiment, described enzyme It is suppressed at least about 70%.Further or in other embodiment, described enzyme is suppressed at least about 75%.Further or its In his embodiment, described enzyme is suppressed at least about 80%.Further or in other embodiment, described enzyme is suppressed At least about 90%.Further or in other embodiment, described enzyme is substantially completely suppressed.Further or other In embodiment, described MEK enzyme is MEK kinases.Further or in other embodiment, described MEK enzyme is MEK1.Entering In one step or other embodiment, described MEK enzyme is MEK2.Further or in other embodiment, described contact is sent out Raw intracellular.Further or in other embodiment, described cell is the cell of mammal.Further or other Embodiment in, the cell of described mammal is human cell.Further or in other embodiment, described MEK Enzyme is suppressed by the compositions of the pharmaceutically acceptable salt of contained I.

Further or other aspect, the present invention relates to treat disease described in the individuality of the disease suffering from MEK mediation Method, it includes the compositions to described individual effective dosage, and compound or its pharmacy of the contained I of described compositions can Salt, solvate, polymorph, ester, amide, tautomer or the prodrug accepted.In some embodiments, be administered orally to Medicine, intraduodenal administration, parenteral (include intravenous administration, subcutaneous administration, intramuscular administration, intravascular administration or defeated Note is administered), topical or the compositions of the contained I of rectally.In some embodiments, described drug regimen Thing is the form being suitable for oral administration.Further or in other embodiment, described pharmaceutical composition is tablet, capsule Agent, pill, powder, slow releasing preparation, solution, the form of suspensoid, be aseptic solution, suspensoid for parenteral injection Or Emulsion, it is ointment or emulsifiable paste for topical, or is suppository for rectally.Further or other enforcement In scheme, described pharmaceutical composition is the unit dosage forms being suitable for correct dose single-dose.Further or other enforcement In scheme, described pharmaceutical composition also comprises pharmaceutical carriers, excipient and/or adjuvant.

In some embodiments, it is administered the compositions of contained I, is combined with other therapies.Further or In other embodiment, other therapies described are X-ray therapy, chemotherapy, surgical operation or their combination in any.? Further or in other embodiment, the described compositions of contained I is administered with at least one therapeutic agent.? Further or in other embodiment, described therapeutic agent is selected from cytotoxic agent, antiangiogenic agent and antineoplastic agent.Entering In one step or other embodiment, described antineoplastic agent is selected from alkylating agent, antimetabolite, epidophylltoxin, antitumor enzyme, topology Isomerase inhibitors, procarbazine, mitoxantrone, platinum coordination complex, biological response modifier and growth inhibitor, hormone/ Antihormonal therapy agents and hemopoietic growth factor.Further or in other embodiment, described therapeutic agent is selected from paclitaxel, boron Bortezomib or the two.

In some embodiments, described MEK mediation disease selected from inflammatory diseases, infection, autoimmune disease, in Wind, ischemia, cardiac conditions, neurological disorder, fibrotic conditions, proliferative disorders, hyperproliferative disorders, non-cancer excessively increase Grow sexually transmitted disease (STD) disease, tumor, leukemia, tumor, cancer, cancer, metabolic disease, malignant diseases, vascular restenosis, psoriasis, atherosclerosis, Rheumatoid arthritis, osteoarthritis, heart failure, chronic pain, neuropathic pain, xerophthalmia, angle closure glaucoma and angle of release Type glaucoma.Further or in other embodiment, the disease of described MEK mediation is inflammatory diseases.Further or its In his embodiment, the disease of described MEK mediation is excess proliferative disease.Further or in other embodiment, The disease of described MEK mediation is selected from tumor, leukemia, tumor, cancer, cancer and malignant diseases.Further or other embodiment In, described disease is gastric cancer, the brain cancer, breast carcinoma, pulmonary carcinoma, ovarian cancer, cancer of pancreas, carcinoma of prostate, renal carcinoma, colorectal cancer or white blood Sick.Further or in other embodiment, described fibrotic conditions is scleroderma, polymyositis, systemic lupus, rheumatoid Property arthritis, liver cirrhosis, keloid formed, interstitial nephritis or pulmonary fibrosis.Further or in other embodiment, The compositions of the pharmaceutically acceptable salt of the contained I of effective dosage.

The invention still further relates to a certain amount of N-(S)-(the 3,4-bis-fluoro-2-(2-by making MEK be enough to regulate MEK activity Fluoro-4-idodophenylamino)-6-methoxyphenyl) the crystalline polymorph A of-1-(2,3-dihydroxypropyl) ring acrylate-1-sulfonamide The method of contact regulation MEK activity.Regulation can be suppression or activate MEK activity.In some embodiments, the present invention provides By a certain amount of N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-the idodophenylamino)-6-making MEK be enough to suppress MEK activity Methoxyphenyl)-1-(2,3-dihydroxypropyl) ring acrylate-1-sulfonamide crystalline polymorph A contact inhibition MEK activity side Method.In some embodiments, the present invention provides through make solution and be enough to suppress a certain amount of of MEK activity in described solution N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) ring acrylate-1- The method of MEK activity in solution described in the crystalline polymorph A contact inhibition of sulfonamide.In some embodiments, the present invention There is provided by making cell and be enough to suppress a certain amount of N-(S)-(the fluoro-2-of 3,4-bis-(the fluoro-4-of 2-of MEK activity in described cell Idodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) ring acrylate-1-sulfonamide crystalline polymorph A contact press down Make the method for MEK activity in described cell.In some embodiments, the present invention provides through make tissue and be enough to suppress described A certain amount of N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-of MEK activity in tissue The method of MEK activity in tissue described in the crystalline polymorph A contact inhibition of (2,3-dihydroxypropyl) ring acrylate-1-sulfonamide. In some embodiments, the present invention provides through make biological and be enough to suppress a certain amount of N-of MEK activity in described biology (S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) ring acrylate-1-sulphur The method of MEK activity in biology described in the crystalline polymorph A contact inhibition of amide.In some embodiments, the present invention carries For use by making animal and be enough to suppress a certain amount of N-(S)-(the fluoro-2-of 3,4-bis-(the 2-fluoro-4-iodine of MEK activity in described animal Phenyl amino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) ring acrylate-1-sulfonamide crystalline polymorph A contact press down Make the active method of the MEK in described animal.In some embodiments, the present invention provides through make mammal and be enough to press down Make a certain amount of N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-the idodophenylamino)-6-methoxy of MEK activity in described mammal Base phenyl)-1-(2,3-dihydroxypropyl) ring acrylate-1-sulfonamide crystalline polymorph A contact inhibition described in mammal The method of MEK activity.In some embodiments, the present invention provides through make the mankind and be enough to suppress MEK in the described mankind to live A certain amount of N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxy of property Propyl group) ring acrylate-1-sulfonamide crystalline polymorph A contact inhibition described in the method for MEK activity in the mankind.

Cancer

In other respects, the present invention relates to cancer in treatment or prevention (prevention or prophylaxis) individuality Method, it includes the compound of formula I to described individual effective dosage or its pharmaceutically acceptable salt, solvate, polycrystalline Type thing, ester, amide, tautomer or prodrug.In some embodiments, by described compound or it is pharmaceutically acceptable Salt, solvate, polymorph, ester, amide, tautomer or prodrug are as also comprising pharmaceutically acceptable carrier or delivery The ingredient administration of the compositions of body.Further or in other embodiment, described cancer is the brain cancer, breast carcinoma, pulmonary carcinoma, ovum Nest cancer, cancer of pancreas, carcinoma of prostate, renal carcinoma, colorectal cancer, gastric cancer or leukemia.Further or in other embodiment, institute State fibrotic conditions be scleroderma, polymyositis, systemic lupus, rheumatoid arthritis, liver cirrhosis, keloid formed, Matter nephritis or pulmonary fibrosis.Further or in other embodiment, described cancer is the brain cancer, breast carcinoma, pulmonary carcinoma, ovary Cancer, cancer of pancreas, carcinoma of prostate, renal carcinoma, colorectal cancer, leukemia, melanoma, thyroid carcinoma, or basal cell carcinoma.Entering one In step or other embodiment, described cancer is the brain cancer or adrenocortical carcinoma.Further or in other embodiment, Described cancer is breast carcinoma.Further or in other embodiment, described cancer is ovarian cancer.Further or other In embodiment, described cancer is cancer of pancreas.Further or in other embodiment, described cancer is carcinoma of prostate.? Further or in other embodiment, described cancer is renal carcinoma.Further or in other embodiment, described cancer is Colorectal cancer.Further or in other embodiment, described cancer is myeloid leukemia.Further or other enforcement In scheme, described cancer is glioblastoma multiforme.Further or in other embodiment, described cancer is follicular lymph Tumor.Further or in other embodiment, described cancer is front B acute leukemia.Further or other embodiment party In case, described cancer is chronic lymphocytic B leukemia.Further or in other embodiment, described cancer is mesothelium Tumor.Further or in other embodiment, described cancer is small cell lung cancer.In some embodiments, described cancer It is gastric cancer.

In some embodiments, oral administration, intraduodenal administration, parenteral (include intravenous administration, skin Lower administration, intramuscular administration, intravascular administration or administered by infusion), compositions described in topical or rectally.Further or In other embodiment, with the compound of single dose Medicine-feeding type I once a day.Further or in other embodiment, Compound with the multiple dose every day of Medicine-feeding type I more than once.Further or in other embodiment, every day twice Medicine-feeding type The compound of I.Further or in other embodiment, the compound of Medicine-feeding type I three times a day.Further or other In embodiment, the compound of four times a day Medicine-feeding type I.Further or in other embodiment, every day is more than giving for four times The compound of medicine Formulas I.In some embodiments, the individuality suffering from cancer is mammal.Further or other enforcement In scheme, described individuality is the mankind.Further or in other embodiment, the contained I of effective dosage The compositions of pharmaceutically acceptable salt.

Abnormal cell growth

It is also described herein for use of compound, pharmaceutical composition and the method for the abnormal cell growth of suppression.At some In embodiment, described abnormal cell growth occurs in mammal.The method of the cell growth that suppression is abnormal include to The compound of formula I of medicine effective dose or its pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer, front Medicine, hydrate or derivant, wherein abnormal cell growth is suppressed.The method of cell growth abnormal in suppression mammal Including to described mammal be administered a certain amount of compound of formula I or its pharmaceutically acceptable salt, solvate, polymorph, Ester, amide, tautomer, prodrug, hydrate or derivant, the compound of wherein said amount or salt suppress suckling to move effectively Cell growth abnormal in thing.

In some embodiments, described method includes the compound of formula I of effective dose or its pharmaceutically acceptable salt, molten Agent compound, polymorph, ester, amide, tautomer, prodrug, hydrate or derivant, join with a certain amount of chemotherapeutant Close and be administered, wherein said compound or its salt, solvate, polymorph, ester, amide, tautomer, prodrug, hydrate Or the amount of derivant and described chemotherapeutant suppresses abnormal cell to grow the most effectively.Many chemotherapeutants are current It is known in the art, and can be combined with the compound of the present invention.In some embodiments, described chemotherapeutant is selected from Mitotic inhibitor, alkylating agent, antimetabolite, embedding antibiotic, growth factor receptor inhibitors, cell cycle inhibitor, enzyme, open up Flutter isomerase inhibitors, biological response modifier, hormone antagonist, angiogenesis inhibitor and androgen antagonist.

The method also describing cell growth abnormal in suppression mammal, it includes being administered one to described mammal Quantitative compound of formula I or its pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer, prodrug, Hydrate or derivant, with X-ray therapy be combined, wherein said compound or its salt, solvate, polymorph, ester, amide, In the amount of tautomer, prodrug, hydrate or derivant and X-ray therapy combination suppression mammal effectively, exception is thin Excess proliferative disease in intracellular growth or treatment mammal.Use radiotherapeutic technology be it known in the art, and These technology can be combined with therapy as herein described.As described herein may determine that at this conjoint therapy compounds of formula I It is administered.

The invention still further relates to suppress method and pharmaceutical composition, the described medicine group of cell growth abnormal in mammal Compound comprises a certain amount of compound of formula I, or its pharmaceutically acceptable salt, solvate, polymorph, ester, amide, makes a variation mutually Structure body, prodrug, hydrate or derivant, or its isotope-labeled derivant, and a certain amount of selected from antiangiogenic agent, letter Number transduction inhibitor and one or more materials of antiproliferative.

Antiangiogenic agent, such as MMP-2 (MMP2) inhibitor, MMP-9 (GELB) Inhibitor and COX-11 (COX-1 1) inhibitor, can be with the compound of the present invention and drug regimen Internet of Things as herein described With.The example of useful COX-II inhibitor includes: CELEBREX^TM(celecoxib (alecoxib)), valdecoxib and Rofe Former times cloth.The example of useful matrix metallo-proteinase inhibitor be described in WO 96/33172 (being published on October 24th, 1996), WO 96/27583 (being published on March 7th, 1996), european patent application 97304971.1 (being filed on July 8th, 1997), European patent application 99308617.2 (being filed on October 29th, 1999), WO 98/07697 (are published in February 26 in 1998 Day), WO 98/03516 (being published on January 29th, 1998), WO 98/34918 (being published on August 13rd, 1998), WO 98/ 34915 (being published on August 13rd, 1998), WO 98/33768 (being published on August 6th, 1998), WO 98/30566 (are published in On July 16th, 1998), European patent publication 606,046 (being published on July 13rd, 1994), European patent publication 931,788 (being published on July 28th, 1999), WO 90/05719 (being published in May nineteen ninety 31), WO 99/52910 (are published in 1999 On October 21), WO 99/52889 (being published on October 21st, 1999), WO 99/29667 (be published in June 17 in 1999 Day), PCT International Application Serial No. PCT/No. IB98/01113 (being filed on July 21st, 1998), european patent application 99302232.1 (being filed on March 25th, 1999), UK Patent Application 9912961.1 (being filed on June 3rd, 1999), the interim Shen of the U.S. Please No. 60/148,464 (being filed on August 12nd, 1999), United States Patent (USP) 5,863,949 (being issued on January 26th, 1999), U.S. State's patent 5,861,510 (is issued on January 19th, 1999), and European patent publication 780,386 (is published in June, 1997 25 days) in, it is the most intactly quoted and adds as herein.Some MMP-2 and MMP-9 inhibitor are almost without MMP-1 inhibitory activity Or inhibitory activity without MMP-1, and relative to other matrix metalloproteinases (i.e. MAP-1, MMP-3, MMP-4, MMP-5, MMP- 6, MMP-7, MMP-8, MMP-10, MMP-ll, MMP-12 and MMP-13), some MMP-2 and MMP-9 inhibitor optionally press down MMP-2 and/or AMP-9 processed.Some instantiations of MMP inhibitor in the present invention be AG-3340, RO 32-3555 and RS 13-0830。

In other respects, the present invention relates to make the method that cancerous cell is degenerated, anticancer grows or kills cancerous cell, its Including making described cell and effectively making described cell degradation, suppress the growth of described cell or kill the combination of amount of described cell Thing contacts, the contained I of described compositions or its pharmaceutically acceptable salt, solvate, polymorph, ester, amide, mutually Tautomeric or prodrug.In some embodiments, described cancer cell include brain cancer cell, breast cancer cell, lung carcinoma cell, Ovarian cancer cell, pancreatic cancer cell, prostate gland cancer cell, kidney cancer cell or colorectal cancer cell.

Further or in other embodiment, described compositions is administered with at least one therapeutic agent.Entering one In step or other embodiment, described therapeutic agent be paclitaxel, bortezomib or the two.Further or other enforcement In scheme, described therapeutic agent is selected from cytotoxic agent, antiangiogenic agent and antineoplastic agent.Further or other embodiment party In case, described antineoplastic agent is selected from alkylating agent, antimetabolite, epidophylltoxin；Antitumor enzyme, topoisomerase enzyme inhibitor, the third card Bar hydrazine, mitoxantrone, platinum coordination complex, biological response modifier and growth inhibitor, hormone/antihormonal therapy agents and hemopoietic Somatomedin.

In some embodiments, described cancerous cell is made to degenerate.Further or in other embodiment, make the institute of 1% State cancerous cell to degenerate.Further or in other embodiment, the described cancerous cell of 2% is made to degenerate.Further or other In embodiment, the described cancerous cell of 3% is made to degenerate.Further or in other embodiment, the described cancerous cell of 4% is made to move back Change.Further or in other embodiment, the described cancerous cell of 5% is made to degenerate.Further or other embodiment In, make the described cancerous cell of 10% degenerate.Further or in other embodiment, the described cancerous cell of 20% is made to degenerate.? Further or in other embodiment, the described cancerous cell of 25% is made to degenerate.Further or in other embodiment, make The described cancerous cell of 30% is degenerated.Further or in other embodiment, the described cancerous cell of 40% is made to degenerate.Further Or in other embodiment, make the described cancerous cell of 50% degenerate.Further or in other embodiment, make the institute of 60% State cancerous cell to degenerate.Further or in other embodiment, the described cancerous cell of 70% is made to degenerate.Further or other Embodiment in, make the described cancerous cell of 75% degenerate.Further or in other embodiment, make 80% described cancer thin Born of the same parents degenerate.Further or in other embodiment, the described cancerous cell of 90% is made to degenerate.Further or other enforcement In scheme, the described cancerous cell of 100% is made to degenerate.Further or in other embodiment, substantially make whole described cancer thin Born of the same parents degenerate.

In some embodiments, described cancerous cell is killed.Further or in other embodiment, 1% described Cancerous cell is killed.Further or in other embodiment, the described cancerous cell of 2% is killed.Further or other In embodiment, the described cancerous cell of 3% is killed.Further or in other embodiment, the described cancerous cell of 4% is killed Extremely.Further or in other embodiment, the described cancerous cell of 5% is killed.Further or other embodiment In, the described cancerous cell of 10% is killed.Further or in other embodiment, the described cancerous cell of 20% is killed.? Further or in other embodiment, the described cancerous cell of 25% is killed.Further or in other embodiment, 30% Described cancerous cell be killed.Further or in other embodiment, the described cancerous cell of 40% is killed.Further Or in other embodiment, the described cancerous cell of 50% is killed.Further or in other embodiment, 60% described Cancerous cell is killed.Further or in other embodiment, the described cancerous cell of 70% is killed.Further or other Embodiment in, the described cancerous cell of 75% is killed.Further or in other embodiment, the described cancerous cell of 80% It is killed.Further or in other embodiment, the described cancerous cell of 90% is killed.Further or other enforcement In scheme, the described cancerous cell of 100% is killed.Further or in other embodiment, substantially all described cancerous cell All it is killed.

Further or in other embodiment, the growth of described cancerous cell is suppressed.Further or other reality Executing in scheme, the growth of described cancerous cell is suppressed about 1%.Further or in other embodiment, the life of described cancerous cell Long by suppressed about 2%.Further or in other embodiment, the growth of described cancerous cell is suppressed about 3%.Further or In other embodiment, the growth of described cancerous cell is suppressed about 4%.Further or in other embodiment, described cancer The growth of cell is suppressed about 5%.Further or in other embodiment, the growth of described cancerous cell is suppressed about 10%. Further or in other embodiment, the growth of described cancerous cell is suppressed about 20%.Further or other embodiment party In case, the growth of described cancerous cell is suppressed about 25%.Further or in other embodiment, the growth of described cancerous cell It is suppressed about 30%.Further or in other embodiment, the growth of described cancerous cell is suppressed about 40%.Further or In other embodiment, the growth of described cancerous cell is suppressed about 50%.Further or in other embodiment, described The growth of cancerous cell is suppressed about 60%.Further or in other embodiment, the growth of described cancerous cell is suppressed about 70%.Further or in other embodiment, the growth of described cancerous cell is suppressed about 75%.Further or other reality Executing in scheme, the growth of described cancerous cell is suppressed about 80%.Further or in other embodiment, described cancerous cell Growth is suppressed about 90%.Further or in other embodiment, the growth of described cancerous cell is suppressed about 100%.Entering In one step or other embodiment, use the compositions of the pharmaceutically acceptable salt of contained I.

The method that suppression abnormal cell growth is also described herein.In some embodiments, described abnormal cell growth Occur in mammal.The method of suppression abnormal cell growth includes N-(S)-(the 3,4-bis-fluoro-2-(2-of effective dosage Fluoro-4-idodophenylamino)-6-methoxyphenyl) crystalline polymorphs of-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide Thing A, wherein abnormal cell growth is suppressed.In suppression mammal, the method for abnormal cell growth includes to described mammal It is administered a certain amount of N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxy Propyl group) the crystalline polymorph A of cyclopropane-1-sulfonamide, wherein N-(S)-(3,4-bis-fluoro-2-(2-fluoro-4-iodophenyl ammonia Base)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide crystalline polymorph A amount effectively Abnormal cell growth in suppression mammal.

In some embodiments, described method include administering drug combinations effective dose N-(S)-((2-is fluoro-for 3,4-bis-fluoro-2- 4-idodophenylamino)-6-methoxyphenyl) the crystalline polymorph A of-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide With a certain amount of chemotherapeutant, wherein N-(S)-(3,4-bis-fluoro-2-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)- The crystalline polymorph A of 1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide and the amount of described chemotherapeutant are the most effective Ground suppression abnormal cell growth.

At present, many chemotherapeutants are to it known in the art, and can be with the compound of the present invention and combine Internet of Things With.In some embodiments, described chemotherapeutant is selected from mitotic inhibitor, alkylating agent, antimetabolite, embedding antibiosis Element, growth factor receptor inhibitors, cell cycle inhibitor, enzyme, topoisomerase enzyme inhibitor, biological response modifier, hormone antagonist, blood Pipe generation inhibitor and androgen antagonist.

In some embodiments, in suppression mammal the method for abnormal cell growth include to described mammal to A certain amount of N-of medicine (S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxy third Base) the crystalline polymorph A of cyclopropane-1-sulfonamide, it is combined with X-ray therapy, wherein N-(S)-((2-is fluoro-for 3,4-bis-fluoro-2- 4-idodophenylamino)-6-methoxyphenyl) the crystalline polymorph A of-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide The combination of amount and described X-ray therapy effectively suppress abnormal cell growth.It is known in the art for using radiotherapeutic technology , and these technology may be used in conjoint therapy as herein described.

Treatment hyperproliferative disorders

In other respects, the present invention relates to treat mammal and include the method for hyperproliferative disorders in the mankind, its bag Include the compound of formula I to described mammal drug treatment effective dose or its pharmaceutically acceptable salt, solvate, polymorphic Thing, ester, tautomer or prodrug.

In other respects, the present invention relates to the method for proliferative disease in treatment or prevention individuality, it includes to described The compound of formula I of body effective dosage or its pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomerism Body or prodrug.In some embodiments, described compound or its pharmaceutically acceptable salt, solvate, polymorph, ester, Amide, tautomer or prodrug as the ingredient administration of compositions, described compositions also comprise pharmaceutically acceptable carrier or Carrier.In some embodiments, described proliferative disease is cancer, psoriasis, restenosis, autoimmune disease or dynamic Pulse atherosclerosis.Further or in other embodiment, described proliferative disease is excess proliferative disease.Further Or in other embodiment, described proliferative disease is selected from tumor, leukemia, tumor, cancer, cancer and malignant diseases.Further Or in other embodiment, described cancer is the brain cancer, breast carcinoma, pulmonary carcinoma, ovarian cancer, cancer of pancreas, carcinoma of prostate, renal carcinoma, stomach Cancer, colorectal cancer or leukemia.Further or in other embodiment, described fibrotic conditions be scleroderma, polymyositis, The formation of systemic lupus, rheumatoid arthritis, liver cirrhosis, keloid, interstitial nephritis or pulmonary fibrosis.Further or In other embodiment, described cancer be the brain cancer, breast carcinoma, pulmonary carcinoma, ovarian cancer, gastric cancer, cancer of pancreas, carcinoma of prostate, renal carcinoma, Colorectal cancer or leukemia.Further or in other embodiment, described cancer is the brain cancer or adrenocortical carcinoma.Entering In one step or other embodiment, described cancer is breast carcinoma.Further or in other embodiment, described cancer is Ovarian cancer.Further or in other embodiment, described cancer is cancer of pancreas.Further or other embodiment In, described cancer is carcinoma of prostate.Further or in other embodiment, described cancer is renal carcinoma.Further or its In his embodiment, described cancer is colorectal cancer.Further or in other embodiment, described cancer is that marrow sample is white Disorders of blood.Further or in other embodiment, described cancer is glioblastoma multiforme.Further or other embodiment party In case, described cancer is follicular lymphoma.Further or in other embodiment, described cancer is the acute white blood of front B Sick.Further or in other embodiment, described cancer is chronic lymphocytic B leukemia.Further or other In embodiment, described cancer is mesothelioma.Further or in other embodiment, described cancer is small cell lung cancer. In some embodiments, described cancer is gastric cancer.

In some embodiments, it is administered the compositions of contained I, is combined with other therapies.Further or In other embodiment, other therapies described are X-ray therapy, chemotherapy, surgical operation or combinations thereof.Entering one In step or other embodiment, the described compositions of contained I is administered with at least one therapeutic agent.Entering one In step or other embodiment, described therapeutic agent is selected from cytotoxic agent, antiangiogenic agent and antineoplastic agent.Further Or in other embodiment, described antineoplastic agent is selected from alkylating agent, antimetabolite, epidophylltoxin, antitumor enzyme, topoisomerase Enzyme inhibitor, procarbazine, mitoxantrone, platinum coordination complex, biological response modifier and growth inhibitor, hormone/anti-sharp Extract for treating agent and hemopoietic growth factor.Further or in other embodiment, described therapeutic agent selected from paclitaxel, boron for assistant Rice or the two.

Tumor size

In other respects, the present invention relates to reduce tumor size in individuality, suppression tumor size increases, reduce tumor increasing Growing or the method for prophylaxis of tumours propagation, it includes the compound of formula I to described individual effective dosage or it is pharmaceutically acceptable Salt, solvate, polymorph, ester, amide, tautomer or prodrug.In some embodiments, described compound or its Pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer or prodrug are given as the composition of compositions Medicine, described compositions also comprises pharmaceutically acceptable carrier or carrier.In some embodiments, the size of tumor is subtracted Little.Further or in other embodiment, the size of tumor is reduced at least 1%.Further or other embodiment In, the size of tumor is reduced at least 2%.Further or in other embodiment, the size of tumor is reduced at least 3%. Further or in other embodiment, the size of tumor is reduced at least 4%.Further or in other embodiment, The size of tumor is reduced at least 5%.Further or in other embodiment, the size of tumor is reduced at least 10%.? Further or in other embodiment, the size of tumor is reduced at least 20%.Further or in other embodiment, The size of tumor is reduced at least 25%.Further or in other embodiment, the size of tumor is reduced at least 30%.? Further or in other embodiment, the size of tumor is reduced at least 40%.Further or in other embodiment, The size of tumor is reduced at least 50%.Further or in other embodiment, the size of tumor is reduced at least 60%.? Further or in other embodiment, the size of tumor is reduced at least 70%.Further or in other embodiment, The size of tumor is reduced at least 75%.Further or in other embodiment, the size of tumor is reduced at least 80%.? Further or in other embodiment, the size of tumor is reduced at least 85%.Further or in other embodiment, The size of tumor is reduced at least 90%.Further or in other embodiment, the size of tumor is reduced at least 95%.? Further or in other embodiment, described tumor is uprooted.In some embodiments, the size of tumor does not increases.

In some embodiments, tumor proliferation is reduced few.In some embodiments, tumor proliferation is reduced at least 1%.In some embodiments, tumor proliferation is reduced at least 2%.In some embodiments, tumor proliferation is reduced at least 3%.In some embodiments, tumor proliferation is reduced at least 4%.In some embodiments, tumor proliferation is reduced at least 5%.In some embodiments, tumor proliferation is reduced at least 10%.In some embodiments, tumor proliferation is reduced at least 20%.In some embodiments, tumor proliferation is reduced at least 25%.In some embodiments, tumor proliferation is reduced to Few 30%.In some embodiments, tumor proliferation is reduced at least 40%.In some embodiments, tumor proliferation is reduced At least 50%.In some embodiments, tumor proliferation is reduced at least 60%.In some embodiments, tumor proliferation is subtracted Few at least 70%.In some embodiments, tumor proliferation is reduced at least 75%.In some embodiments, tumor proliferation quilt Reduce at least 75%.In some embodiments, tumor proliferation is reduced at least 80%.In some embodiments, tumor proliferation It is reduced at least 90%.In some embodiments, tumor proliferation is reduced at least 95%.In some embodiments, tumor increases Grow and be prevented from.

In some embodiments, it is administered the compositions of contained I, is combined with other therapies.Further or In other embodiment, other therapies described are X-ray therapy, chemotherapy, surgical operation or their any combination.? Further or in other embodiment, the described compositions of contained I is administered with at least one therapeutic agent.? Further or in other embodiment, described therapeutic agent is selected from cytotoxic agent, antiangiogenic agent and antineoplastic agent.Entering In one step or other embodiment, described antineoplastic agent is selected from alkylating agent, antimetabolite, epidophylltoxin, antitumor enzyme, topology Isomerase inhibitors, procarbazine, mitoxantrone, platinum coordination complex, biological response modifier and growth inhibitor, hormone/ Antihormonal therapy agents and hemopoietic growth factor.Further or in other embodiment, described therapeutic agent is selected from paclitaxel, boron Bortezomib or the two.

Inflammatory diseases

In other respects, the present invention relates to the method for inflammatory diseases in treatment or prevention individuality, it includes to described individuality The compound of formula I of effective dosage or its pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer Or prodrug.In some embodiments, described compound or its pharmaceutically acceptable salt, solvate, polymorph, ester, acyl Amine, tautomer or prodrug also comprise pharmaceutically acceptable carrier or fortune as the ingredient administration of compositions, described compositions Carrier.Further or in other embodiment, described inflammatory diseases is selected from chronic inflammatory disease, rheumatoid joint Inflammation, rheumatoid arthritis, spondyloarthropathy, ankylosing spondylitis, gout, tendinitis, bursitis, sciatica, gout Property arthritis, osteoarthritis, juvenile arthritis,juvenile chronic arthritis,juvenile rheumatoid arthritis, acute rheumatic arthritis, enteropathic arthritis, neuropathic arthritis, silver Consider sick arthritis, suppurative arthritis, atherosclerosis, systemic lupus erythematosus (sle), inflammatory bowel, irritable bowel syndrome to be worth doing, burst Ulcer colitis, reflux esophagitis, Crohn disease, gastritis, asthma, anaphylaxis, respiratory distress syndrome, pancreatitis, slow Property obstructive pulmonary disease, pulmonary fibrosis, psoriasis, eczema or scleroderma.

In some embodiments, it is administered the compositions of contained compound, is combined with other therapies.Further or In other embodiment, the described compositions of contained I is administered with at least one therapeutic agent.Implement at some In scheme, oral administration, intraduodenal administration, parenteral (include intravenous administration, subcutaneous administration, intramuscular administration, blood Be administered or administered by infusion in pipe), compositions described in topical or rectally.Further or in other embodiment, The amount of compound of formula I is in the range of about 0.001 to about 1000mg/kg body weight/day.Further or other embodiment In, the amount of compound of formula I is in the range of about 0.5 to about 50mg/kg/ day.Further or in other embodiment, Formulas I The amount of compound is about 0.001 to about 7g/ day.Further or in other embodiment, the amount of compound of formula I is about 0.01 To about 7g/ day.Further or in other embodiment, the amount of compound of formula I is about 0.02 to about 5g/ day.Further Or in other embodiment, the amount of compound of formula I is about 0.05 to about 2.5g/ day.Further or other embodiment In, the amount of compound of formula I is about 0.1 to about 1g/ day.Further or in other embodiment, less than above-mentioned range lower limit Dosage level may enough have a surplus.Further or in other embodiment, higher than the dosage level of above-mentioned range limit It is probably necessary.

Mode of administration

Compound of formula I described herein or its pharmaceutically acceptable salt, solvate, polymorph, ester, amide, make a variation mutually Structure body, prodrug, hydrate or derivant.Also describe contained I or its pharmaceutically acceptable salt, solvate, many The pharmaceutical composition of crystal formation thing, ester, amide, tautomer, prodrug, hydrate or derivant.Compound as herein described and Compositions can be individually dosed, or according to standard pharmaceutical practice, with pharmaceutically acceptable carrier, figuration in pharmaceutical composition Agent or diluent combination medicine-feeding.

Being also described pharmaceutical composition, it comprises N-(S)-(3,4-bis-fluoro-2-(2-fluoro-4-idodophenylamino)-6-first Phenyl) crystalline polymorph (A type) of-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide.Chemical combination as herein described Thing and compositions can be individually dosed, or according to standard pharmaceutical practice, in pharmaceutical composition with pharmaceutically acceptable carrier, Excipient or diluent combination medicine-feeding.Can by any method that described compound can be delivered to action site realize to Medicine.These methods include, but not limited to by enteral route (include being administered orally, stomach or duodenum feeding tube, rectal suppository and straight Intestinal enema), parenteral route (injection or infusion, including in intra-arterial, intracardiac, intradermal, duodenum, in marrow, intramuscular, In bone, in intraperitoneal, sheath, in Ink vessel transfusing, intravenous, vitreous body, epidural and subcutaneous), suction, transdermal, saturating mucosa, Sublingual, Buccal and local (including upper epidermis (epicutaneous), corium, enema, eye drop, ear drop, intranasal, vagina) are administered Deliver, but optimum approach is likely to be dependent on the patient's condition and the disease of such as receiver.Those skilled in the art can know can For the compounds of this invention and the medicine-feeding technology of method.It is only used as example, can be defeated by local during such as surgical operation Note, local application such as ointment or ointment, injection, conduit or implant, partly to the regional administration needing treatment Compound as herein described, described implant (is included such as by such as porous, non-porous or glue material The film of sialastic film or fiber) make.Can also be by being directly injected into row administration at the position of illing tissue or organ.

Can by described compound release to any method of action site can be realized compound described herein and The administration of compositions.These methods include oral route, intraduodenal route, parenteral injection (include intravenous, subcutaneous, Intraperitoneal, intramuscular, Ink vessel transfusing or infusion), topical and rectally.For example, it is possible to give to the local, region needing treatment Medicine compound as herein described.This can be by the most newborn such as but not limited to local infusion during surgical operation, local application Unguentum, ointment, injection, conduit or implant realize, and described implant is by such as porous, the non-porous or material of glue Material (including film or the fiber of such as sialastic film) is made.Can also be by the portion of tissue before tumor or tumor tissue or tumor Position (or former position) direct injection is administered.Those skilled in the art know the system that may be used for the compounds of this invention and method Agent and medicine-feeding technology, such as at Goodman and Gilman, The Pharmacological Basis of Therapeutics, Current edition；Pergamon;And Remington ' s, Pharmaceutical Sciences (current edition), Mack Publishing Co., discussed in Easton, Pa.

Described preparation include being applicable to oral administration, parenteral (include subcutaneous administration, intradermal administration, intramuscular to Be administered in medicine, intravenous administration, intra-articular administration and marrow), Intraperitoneal medication, transmucosal administration, transdermal administration, rectally and Topical (includes transdermal administration, buccal administration, sublingual administration and eye drops), but optimum approach is likely to be dependent on example The patient's condition and disease such as receiver.Described preparation convenient for unit dosage forms, and can be able to pass through known in pharmaceutical field Any method preparation.All methods include compound or its pharmaceutically acceptable salt, solvate, the polymorphic making the present invention Thing, ester, amide, tautomer, prodrug, hydrate or derivant (" active component ") and the load constituting one or more auxiliary agents The step that body combines.It is said that in general, by making active component and liquid-carrier or the solid carrier ground or the two uniform and tight Thickly combine, then, if necessary, make product be configured to required preparation to prepare described preparation.

The preparation being applicable to oral administration can be unit such as capsule, cachet or the tablet separated, and it respectively comprises The active component of scheduled volume；Powder or granule；Solution in waterborne liquid or non-aqueous liquid or suspensoid；Or water bag Oil liquid emulsion or water-in-oil liquid Emulsion.Described active component can also be for injecting agent, electuary or paste.

Pharmaceutical formulation for oral administration includes tablet, is pushed fit capsules agent by what gelatin was made, and by gelatin The sealing soft capsule made with plasticizer such as glycerol or sorbitol.Can be by optionally pressing together with one or more auxiliary agents Contracting or molding prepare tablet.Can by compress in suitable machine optionally with binding agent, inert diluent or lubricant, Surfactant or the active component preparation compacting being in free-flowing form (such as powder or granule) of surface dispersant mixing Tablet.Can be by the mixture molding of the powdered compounds moistening through inert liquid diluent being made in suitable machine Standby molded tablet.Optionally by described tablet coating or indentation, and can prepare described tablet to provide active component Therefrom slow or control discharges.All formulations for oral administration should be the dosage being suitable for so being administered.Described push contract Rubber alloy wafer or tablet can comprise active component；It is mixed with filler such as microcrystalline Cellulose, silicified microcrystalline cellulose, pre-glue Change starch, lactose, calcium hydrogen phosphate or sompressible sugar；Binding agent such as hypromellose, polyvidone or gelatinized corn starch；Disintegrating agent is as handed over Connection carmethose, crospovidone or primojel；Surfactant such as sodium lauryl sulphate and/or lubricant, With processing aid such as Talcum, magnesium stearate, stearic acid or silica sol, and optional stabilizer.In soft capsule, Described reactive compound can be dissolved in or is suspended in suitable liquid such as fatty oil, liquid paraffin or liquid macrogol In.Furthermore, it is possible to interpolation stabilizer.The suitably coating sugar-coat pellet heart.To this end, use concentrated sugar solution, it can be optionally Comprise arabic gum, Talcum, polyvinylpyrrolidone, Carbopol gel, Polyethylene Glycol and/or titanium dioxide, paint solution and Suitable organic solvent or solvent mixture.In order to distinguish or the various combination of characterization active compound doses, can will contaminate Material or pigment add described tablet or dragee coatings.

Pharmaceutical preparation can be prepared as carrying out the system of parenteral by injection such as bolus infusion or continuous infusion Agent.Preparation for injection can be unit dosage form, as in ampoule or in multi-dose container, and is added with preservative.Institute State compositions to use suspensoid, solution or the Emulsion form in such as oiliness or aqueous carrier, and can to comprise and join Prescription (formulatory agents) such as suspending agent, stabilizer and/or dispersant.Described preparation can be that unit dosage holds Device or multi-dose container, the ampoule such as sealed and bottle, and can in powder form or lyophilizing (lyophilization) state protect Deposit, before use, it is only necessary at once add aseptic liquid-carrier, such as saline or aseptic apyrogenic water.From the above-mentioned type Sterile powders, granule and tablet, instant injection solution and suspensoid can be prepared.

Preparation for parenteral includes aqueous and non-aqueous (oiliness) aseptic parenteral solution of reactive compound, and it can To comprise antioxidant, buffer agent, antibacterial, and make the described preparation solute isotonic with the blood of receiver intentionally；And Aqueous and nonaqueous sterile suspensions can comprise suspending agent and thickening agent.The lipophilic solvent or the carrier that are suitable for include fat Fat oil such as Oleum sesami or Acrawax such as ethyl oleate or triglyceride, or liposome.Aqueous inj ection suspensions is permissible Comprise the material improving described suspensoid viscosity, such as sodium carboxymethyl cellulose, sorbitol or glucosan.Optionally, in order to enable The solution of enough compounding high concentrations, described suspensoid can also comprise suitable stabilizer or improve described compound solubility Reagent.

Pharmaceutical preparation can also be prepared as depot formulation.By implanting (be such as subcutaneously implanted or intramuscular is implanted) or passing through Intramuscular injection, can be administered such long-acting type preparation.It is therefoie, for example, described compound can be with suitable polymer or thin Water-based material (such as the Emulsion in acceptable oil) or ion exchange resin are prepared together, or as sl. sol. derivative Thing, the most sl. sol. salt is prepared.

For buccal administration or sublingual administration, described compositions can use the tablet, lozenge, soft prepared in a usual manner Lozenge or gel.Active component can be contained in flavoured base such as sucrose and Radix Acaciae senegalis or Huang by such compositions In Millefolium glue.

Pharmaceutical preparation can also be prepared as rectal compositions such as suppository or enema,retention, such as, comprise the suppository of routine Substrate such as cocoa butter, Polyethylene Glycol or other glyceride.

I.e. can be administered by non-systemic with topical pharmaceutical preparation.This includes by the compound of the present invention externally It is applied to epidermis or oral cavity, and instiled by such compound pleasant, eye and nose, in order to described compound enters the most in large quantities Enter in blood flow.By contrast, systemic applications means oral administration, intravenous administration, Intraperitoneal medication and intramuscular administration.

The pharmaceutical preparation being suitable for topical includes that being adapted to penetrate through skin enters liquid or the semiliquid of inflammation part Preparation, such as gel, liniment, lotion, ointment, ointment or paste, and it is suitable for dripping to eye, ear or nasal administration Agent.For topical, active component can account for 0.001% to the 10%w/w of described preparation, and such as 1 weight % is to 2 weight %.But That active component can account for the up to 10%w/w of described preparation, or can account for described preparation less than 5%w/w, or 0.1% to 1%w/w。

Can be sprayed from insufflator, aerosol apparatus pressurized package or administration aerosol easily by the pharmaceutical preparation of inhalation Other facilitated method dispensers of mist.Pressurized package can comprise suitable propellant such as dichlorodifluoromethane, Arcton 11, Dichlorotetra-fluoroethane, carbon dioxide or other suitable gas.In the case of the aerosol of pressurization, described dosage unit is permissible By the administration that offer valve is quantitative.Or, in order to by sucking or being blown into administration, pharmaceutical preparation can use dry powder composite Form, the most described compound and the mixture of powders of suitable powdered substrate such as lactose or starch.Described powder composition Can be unit dosage form, for example, capsule, cartridge case (cartridge), gelatin or blisterpack, by inhaler or be blown into Device can be administered described powder from which.

Should be understood that in addition to the composition the most specially mentioned, compound as herein described and compositions can comprise pass Other reagent conventional in the field of the preparation type discussed, the composition being for example adapted for oral administration can include seasoning Agent.

Preparation

It should be noted that any compositions as herein described and compound can be used with any preparation that this part is discussed, It is not intended to limit and be understood not to restrictive.

Compound as herein described or compositions can with vesicle such as Liposomal delivery (see for example, Langer, Science 1990,249,1527-1533；Treat etc., Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Bernstein and Fidler, Ed., Liss, N.Y., pp.353-365,1989).This Compound and pharmaceutical composition described in literary composition can also be administered with controlled release system.In one embodiment, it is possible to use pump (ginseng See, Sefton, 1987, CRC Crit.Ref.Biomed.Eng.14:201；Buchwald etc., Surgery, 1,980 88,507； Saudek etc., N.Engl.J.Med.1989,321, (574).Furthermore, it is possible to controlled release system to be placed in (ginseng near therapy target See, Goodson, Medical Applications of Controlled Release, 1984, Vol.2, pp.115-138). Active component can also be included in the form being suitable for orally using by pharmaceutical composition as herein described, such as, uses sheet Agent, dragee, lozenge, aqueous or Oil suspensions, dispersible powder or granule, Emulsion, hard capsule or soft capsule, or sugar Slurry agent or elixir.According to any method preparing pharmaceutical composition known in the art, the group being intended for being administered orally can be prepared Compound, and, in order to provide pharmaceutical elegant and good to eat preparation, such compositions can comprise one or more selected from sweet The reagent of taste agent, flavoring agent, coloring agent and preservative.Tablet comprises described active component and is mixed with being applicable to prepare tablet Avirulent pharmaceutically acceptable excipient.These excipient can be such as, inert diluent such as calcium carbonate, sodium carbonate, breast Sugar, calcium phosphate or sodium phosphate；Granulation agent and disintegrating agent；Filler such as microcrystalline Cellulose, silicified microcrystalline cellulose, pregelatinated form sediment Powder, lactose, calcium hydrogen phosphate or sompressible sugar；Binding agent such as hypromellose, polyvidone or gelatinized corn starch；Disintegrating agent is such as handed over Connection carmethose, crospovidone or primojel；Surfactant such as sodium lauryl sulphate, and/or lubricious Agent, and processing aid such as Talcum, cross-linked carboxymethyl cellulose sodium, corn starch or alginic acid；Bonding agent (binding Agents) such as starch, gelatin, polyvinylpyrrolidone or Radix Acaciae senegalis, and lubricant such as magnesium stearate, stearic acid Or silica sol, and optional Talcum.Taste or delay disintegrate and absorption in gastrointestinal tract for masking agents And the continuous action of longer-term is thus provided, by known method, described tablet can be carried out not coating or coating.Such as, Water soluble taste masking material such as HYDROXY PROPYL METHYLCELLULOSE or hydroxy propyl cellulose, or time delay can be suitably used Material such as ethyl cellulose or acetylbutyrylcellulose.The preparation orally used can also be wherein said for hard gelatin capsule Active component mixes with inert solid diluent such as calcium carbonate, calcium phosphate or Kaolin, or is Perle, Qi Zhongsuo State active component and water-solubility carrier such as Polyethylene Glycol or oil medium such as Oleum Arachidis hypogaeae semen, liquid paraffin or mixed with olive oil.Logical Cross various process technology and include dry mixed and wet granulation technique, described capsule and Tabules can be prepared.Mix in dry method Close in preparation method, by with excipient dry mixed, be then encapsulated in capsule shells or be pressed into tablet form, can be by Described pharmaceutical pack is contained in dosage form.The operation of described dry mixed can be carried out step by step, and is included between blend step Sifting step is so that forming uniform mixture.In wet granulation preparation method, the addition of described medicine can be dried In excipient, mixing, then add binder solution, or can be by described medicine dissolution, and as the solution of granulation sections Add.In wet granulation technique, if using surfactant, then can be added in the excipient being dried, or by it Add in binder solution, and be contained therein in the form of a solution.Glutoid glue can be packed into by being dissolved in by described medicine Softgel shell and can be with in the compatible material of colligation the hard gelatin capsule sealed shell with subsequently, it is also possible to prepare capsule formulation.Logical In the material of the melted form crossing the Polyethylene Glycol that described medicine is dissolved in such as high molecular, it is cooled to solid forms, grinds, And this material is comprised to the course of processing of routine encapsulation and tablet, it is also possible to prepare capsule and Tabules.

Aqueous suspension comprises described active component, and is mixed with the excipient being applicable to prepare aqueous suspension.So Excipient be suspending agent, such as sodium carboxymethyl cellulose, methylcellulose, HYDROXY PROPYL METHYLCELLULOSE, sodium alginate, poly-second Alkene pyrrolidone, gum tragacanth and Radix Acaciae senegalis；The phospholipid that dispersant or wetting agent can be naturally-occurring, such as ovum phosphorus Fat, or the condensation product of alkylene oxide and fatty acid, such as Myrj 45 or oxirane and long-chain fat The condensation product of fat alcohol, such as 17 vinyls-oxygen hexadecanol (heptadecaethylene-oxycetanol) or epoxy second Alkane with derived from the condensation product of partial ester (such as octadecanoic acid ester of polyethylene glycol) of fatty acid and hexitol or epoxy second Alkane and the condensation product of the partial ester (such as polyethylene sorbitan alcohol monoleate) derived from fatty acid and hexitol anhydrides. Described aqueous suspension can also comprise one or more preservative, and (such as ethylparaben or P-hydroxybenzoic acid are just Propyl ester), one or more coloring agent, one or more flavoring agents, and one or more sweeting agents (such as sucrose, saccharin or Ah Si Patan).

By active component being suspended in vegetable oil (such as Oleum Arachidis hypogaeae semen, olive oil, Oleum sesami or Oleum Cocois), or mineral In oil (such as liquid paraffin), Oil suspensions can be prepared.Described Oil suspensions can comprise thickening agent, such as Cera Flava, hard Paraffin or hexadecanol.All sweeting agents as described above and flavoring agent can be added to provide good to eat oral formulations.By adding Add antioxidant, such as butylated hydroxyanisole or alpha-tocopherol, these compositionss can be preserved.

It is mixed with point by water being added to being suitable for preparing in the dispersible powder of aqueous suspension and granule generating Powder or the active component of wetting agent, suspending agent and one or more preservative.Suitably dispersant or wetting agent and suspending agent By the illustration having been mentioned above.Other excipient, such as sweeting agent, flavoring agent and coloring agent can also exist.By adding Add antioxidant such as ascorbic acid, these compositionss can be preserved.

Pharmaceutical composition can also be the form of oil in water emulsion.Oil phase can be vegetable oil (such as olive oil or Semen arachidis hypogaeae Oil), or mineral oil (such as liquid paraffin), or these mixture.The phosphorus that suitably emulsifying agent can be naturally-occurring Fat (such as soybean lecithin), and derived from fatty acid and the ester of hexitol anhydrides or partial ester (such as anhydrous sorbitol list oil Acid esters), and the condensation product (such as polyoxyethylene 20 sorbitan monooleate) of described partial ester and oxireme.Described Emulsion Sweeting agent, flavoring agent, preservative and antioxidant can also be comprised.

Syrup and elixir can be prepared with Sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose.Such preparation is also Demulcent, preservative, flavoring agent and coloring agent and antioxidant can be comprised.

Pharmaceutical composition can be the form of the aqueous solution agent of sterile injectable.At the acceptable carrier that can use With solvent has water, ringer's solution and isotonic sodium chlorrde solution.Described sterile injectable preparation can also is that aseptic injectable Oil-in-water microemulsion, wherein described active component is dissolved in oil phase.Such as, first described active component can be dissolved in greatly In the mixture of Oleum Glycines or soybean lecithin.Then this oily solution is imported in the mixture of water and glycerol, processed formation Microemulsion.Injected by local bolus injection, described injectable solutions or microemulsion can be imported in the blood flow of patient.Or, It is administered solution or microemulsion by this way to keep the constant circulating concentration of instant compound to be probably favourable.In order to Keep such constant density, it is possible to use persistence intravenous administration set.The example of such device is Deltec CADD-PLUS^TMType 5400 intravenous pump.Described pharmaceutical composition can be the sterile injectable water for intramuscular and subcutaneous administration Property or the form of Oil suspensions.According to known technique, use those suitable dispersants of having been mentioned above or wetting agent and Suspending agent can prepare this suspensoid.Described sterile injectable preparation can also is that at the acceptable diluent of avirulence parenteral Or the sterile injectable solution agent in solvent or suspensoid, the such as solution in 1,3 butylene glycol.Non-wave additionally, aseptic Hair oil is used as solvent or suspension medium routinely.To this end it is possible to use, include the monoglyceride of synthesis or any of double glyceride Non-irritating fixed oil.Additionally, fatty acid such as oleic acid is used for preparing injectable agent.

Pharmaceutical composition can also be administered for the suppository form of medicine described in rectally.By by described inhibitor Mixing with suitable non-irritating excipient and can prepare these compositionss, described excipient is solid but at normal temperatures at rectum At a temperature of be liquid, and therefore can melt in the rectum to discharge medicine.Such material includes cocoa butter, glycerin gelatine, hydrogen Change mixture and the fatty acid ester of Polyethylene Glycol of the Polyethylene Glycol of vegetable oil, various molecular weight.

Local is used, comprises compound or the ointment of compositions, ointment, jelly, the solution of the present invention Or suspensoid etc. is for topical.Local application used herein can include collutory and gargarism.

Use suitable nasal carrier and doser by local, or by cutaneous routes, use art technology Those transdermal skin patches forms known to personnel, can be with in intranasal form administration medicine compositions.

Described preparation convenient for unit dosage form, and can be prepared by the method known to pharmaceutical field. All methods include compound or its pharmaceutically acceptable salt, ester, prodrug or solvate (" the activity one-tenth making this subject invention Point ") and the carrier-bound step of one or more auxiliary agents of composition.It is said that in general, by make active component and liquid-carrier or The solid carrier ground or this both uniformly and closely combine, then, if it is desired, product is shaped as required preparation system Standby described preparation.To those skilled in the art, the method preparing various pharmaceutical composition with the reactive compound of specified quantitative It is known, or obviously.In order to be administered with transdermic administration, in whole dosage regimen, dosage form can be even certainly Continue property rather than intermittent.

Dosage

The dosage of pharmaceutical composition is dependent firstly on and connects subject mammal.To human experimenter's administration medicine In the case of compositions, daily dose is generally determined by prescribing physician, and dosage is typically along with age of each patient, sex, diet, body Weight, general health and reaction, the seriousness of patients symptomatic, connect subject indication accurately or the patient's condition, connect subject suitable Should demonstrate,prove or the seriousness of the patient's condition, administration time, route of administration, the disposal of described compositions, drainage rate, drug combination, and The judgment of prescribing physician.And, route of administration can depend on that the patient's condition and seriousness thereof change.Described pharmaceutical composition can Think unit dosage form.With such form, preparation is subdivided into the unit dose comprising appropriate active component, such as, reaches Effective dose to expection purpose.Determine that suitable dosage is in the technology category of this area in light of the circumstances.It is said that in general, use Treatment is started less than the smaller dose of the dose,optimum of described compound.Hereafter, with a small amount of dosage that increases until reaching described In the case of the suitableeest effect.For convenience, if it is desired, by total daily dose portioning and can be administered portionwise by day.Consider Factors described above, according to the dosage judging adjustment compound as herein described and the administration of attending clinicians (doctor) Frequency, and if appropriate, adjust other therapeutic agents and/or the amount of application of therapy and frequency.Therefore, the administration of pharmaceutical composition Dosage may differ by the most remote.Dosage can be about 0.001mg/kg body weight to about 100mg/kg body weight every day (with single dose Or broken dose is administered), or at least about 0.1mg/kg body weight every day.Concrete therapeutic dose can include, such as, about The compound of 0.01mg to about 7000mg, or e.g., from about 0.05mg to about 2500mg.According to concrete purposes, can be about In 0.1mg to 1000mg, about 1mg to 300mg, or 10mg to 200mg, in unit dose formulation activation is altered or modified The content of compound.In some cases, may enough have a surplus less than the dosage level of above-mentioned range lower limit, and in other situations In, it is possible to use the biggest dosage and do not cause any harmful side effect, such as by such larger dose being divided into Some low doses are administered in all day.Dosage can depend on the specific IC of the compound used₅₀Value changes.At described compound It not in the associating dispenser of sole therapy, the compound of relatively low amount may be administered and still there is treatment or preventive effect.

Other dosage are provided in entire disclosure and claim.

Dosage form

Described pharmaceutical composition can be to be for example adapted for the tablet of oral administration, capsule, pill, powder, slow release system Agent, solution, the form of suspensoid, be suitable for the form of sterile solution agent, suspensoid or the Emulsion of parenteral injection, be suitable for The ointment of topical or the form of ointment, or it is suitable for the form of the suppository of rectally.Described pharmaceutical composition It can be the unit dosage form being suitable for single-dose correct dose.Described pharmaceutical composition can include the pharmaceutical carriers of routine Or excipient and the compound of the present invention as active component.Additionally, it can include other medicinal or pharmaceutical agents, loads Body, adjuvant etc..

Exemplary parenteral form of medication include reactive compound aseptic aqueous solution (such as, aqueous propylene glycol or Glucose solution) in solution or suspensoid.It is possible if desired to such dosage form suitably to be carried out buffered.

The pharmaceutical carriers being suitable for includes inert diluent or filler, water and various organic solvent.If it is required, described medicine Compositions can comprise other compositions, such as flavoring agent, binding agent, excipient etc..Therefore, for oral administration, tablet bag Containing various excipient, such as citric acid can with various disintegrating agents (such as starch, alginic acid and the silicate of some complexity) with And binding agent (such as sucrose, gelatin and Radix Acaciae senegalis) is used together.It addition, lubricant such as magnesium stearate, dodecyl sulfur Acid sodium and Talcum are frequently used for film-making purpose.The solid composite of similar type can be used for soft-filled gelatin capsule and firmly fills out Filling gelatine capsule, it comprises the Polyethylene Glycol of lactose and high molecular.When needs aqueous suspension or elixir are for oral administration Time, reactive compound therein can with various sweeting agents or flavoring agent, coloring agent or dyestuff, and, if desired, emulsifying agent or Suspending agent, also diluent (such as water, ethanol, propylene glycol, glycerol or combinations thereof) mixing.

To those skilled in the art, the preparation side of the various pharmaceutical compositions of the reactive compound containing specified quantitative Method is known, or can be apparent from.For example, see Remington ' s Pharmaceutical Sciences, Mack Publishing Company, ester, Pa., the 18 editions (1990).

Conjoint therapy

Compound as herein described or its pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomerism Body, prodrug, hydrate or derivant can be used as monotherapy.Compound as herein described or its pharmacy can also be administered Acceptable salt, solvate, polymorph, ester, amide, tautomer, prodrug, hydrate or derivant, with other one Plant or the combination of multiple therapy.

It is also described N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2,3- Dihydroxypropyl) cyclopropane-1-sulfonamide (A type), it can be used as monotherapy.N-(S)-(3,4-can also be administered Two fluoro-2-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide Crystalline polymorph type A, is combined with other one or more therapies.

Being only used as example, if when accepting compound as herein described for the moment, one of side reaction that patient stands is high Blood pressure, then can suitably administering drug combinations antihypertensive and described compound.Or, it is only used as example, by being administered adjuvant Can improve one of compound as herein described treatment benefit (i.e. adjuvant itself may only have minimum treatment benefit, but The another kind of therapeutic agent of combination, increases total treatment benefit of patient).Or, it is only used as example, described herein by administering drug combinations One of compound and the another kind of therapeutic agent (it also includes therapeutic scheme) also with treatment benefit, patient can be improved and be subject to Benefit.It is only used as example, is relating to being administered in the treating diabetes of one of compound as herein described, it is also possible to by trouble It is real that person provides another kind of Remedies for diabetes to improve treatment benefit.Under any circumstance, do not consider to connect subject disease, disease Disease or the patient's condition, total benefit that patient stands is probably the simple adduction of two kinds of therapeutic agents, or patient can suffer from the benefit worked in coordination with Place.

Other therapies include but not limited to, use other therapeutic agents, X-ray therapy or the two.At chemical combination as herein described In the case of thing and other therapeutic agents administering drug combinations, compound as herein described need not with other therapeutic agents at identical medicine Compositions is administered, and due to different physics and chemical feature, can be by different administration.Such as, described Compound/composition can be taken orally to produce and keep the blood level that it is good, and another kind of therapeutic agent can be with vein Interior administration.In the conceived case, determine the mode of administration in identical pharmaceutical composition and be administered fitness, being professional clinical Known to doctor.Initial stage administration, then, effect according to the observation, professional clinical can be carried out according to the scheme that this area is set up Doctor can adjust dosage, mode of administration and administration time.Compound (and time suitably, other therapeutic agents and/or radiation) Specifically chosen depend on attending doctor diagnosis and they to patient's patient's condition and the judgement of suitable therapeutic scheme.Other therapeutic agents The chemotherapeutant of such as antitumorigenic substance can be included, be selected from mitotic inhibitor (such as vinblastine)；Alkylating agent (such as cisplatin, carboplatin and cyclophosphamide)；Antimetabolite (such as 5-fluorouracil, cytosine arabinoside and hydroxyurea, or such as public Open the antimetabolite such as N-(5-[N-(3,4-dihydro-2-methyl-4-oxo quinoline azoles in european patent application 239362 Quinoline-6-ylmethyl))-N-methylamino]-2-Thenoyl)-Pidolidone)；Growth factor receptor inhibitors；Cyclin-dependent kinase Agent；Embed antibiotic (such as amycin and bleomycin)；Enzyme (such as interferon)；(such as estrogen antagonist is such as with hormone antagonist Nolvadex^TM(tamoxifen) or such as antiandrogen such as Casodex^TM(4 '-cyano group-3-(4-fluorophenylSulphonyl)- 2-hydroxy-2-methyl-3 '-(trifluoromethyl) propionanilide)).By simultaneously, in turn or respectively it is administered each treatment group Point, it is possible to achieve such therapeutic alliance.

Compound as herein described and compositions (with suitable chemotherapeutant and/or X-ray therapy) can be used jointly (the most simultaneously, essentially simultaneously or in same therapeutic scheme), or in turn use, this depends on described patient Disease or the character of disease, and with described compound/composition combination (i.e. in single therapeutic scheme) chemotherapy Agent and/or radiotherapeutic actual selection.

Co-administered with in use, described compound/composition and chemotherapeutant and/or X-ray therapy need not same Time ground or essentially simultaneously use, and described compound/composition and chemotherapeutant and/or radiotherapeutic use at the beginning of Beginning order may be inessential.Therefore, it can first be administered the compound/composition of the present invention, then use chemotherapeutant and/ Or X-ray therapy；Or can first use chemotherapeutant and/or X-ray therapy, then be administered the compound/group of the present invention Compound.During single therapeutic scheme, this optional application process can be repeated.Evaluate patient connect subject disease and After the patient's condition, determine the order of administration during therapeutic scheme and the number of times of each therapy of repetitive administration, at the knowledge model of specialist In enclosing.For example, it is possible to first use chemotherapeutant and/or X-ray therapy, particularly when it is cytotoxic agent, then lead to After being administered the compound/composition continual cure of the present invention subsequently, determining in the case of favourable, then using chemotherapeutant And/or radiation etc., until therapeutic scheme terminates.Therefore, rule of thumb and knowledge, along with treatment is carried out, medical practitioner can root The each dosage regimen needing the adjustment compound/composition for treating according to individual patient.Controlling under judging dosage Whether in treating effectively, attending clinician can consider the general health of patient, and more specific sign, such as disease are correlated with disease The alleviation of shape, the suppression of tumor growth, the actual contraction of tumor or metastasis inhibition.By standard method such as radiologic investigation example Such as CAT or MRI scan, the size of tumor can be measured, and whether follow-up measured value may be used for judging the growth of tumor It is suppressed or has even reversed.The alleviation of disease related symptom such as pain and the improvement of the overall patient's condition can be used for Help to judge the effectiveness for the treatment of.

The concrete limiting examples of possible conjoint therapy includes being combined the compound of the present invention and as described below Medicament in following Drug therapy classification.These lists should not be construed as closing, and should be used as presently relevant treatment field Common illustrative example.And, combination scheme can include various route of administration, and should include being administered orally, intravenous, eye Interior, subcutaneous, local skin and local inhalation.

In order to treat tumor disease, proliferative disorders and cancer, the compound of the present invention can with selected from the medicament of lower group Administering drug combinations, described medicament group includes: aromatase inhibitor, estrogen antagonist, androgen antagonist, corticosteroid, gonadorelin swash Dynamic agent, topoisomerase 1 and inhibitor 2, microtube active, alkylating agent, nitroso ureas, antitumor antimetabolite, platiniferous chemical combination Thing, fat or protein kinase targeting agent, IMiDs, albumen or lipophosphatidic acid enzyme targeting agent, antiangiogenic agent, Akt inhibitor, IGF-I Inhibitor, FGF3 regulator, mTOR inhibitors, Smac analogies, hdac inhibitor, the medicament of Cell differentiation inducing activity, Kallidin I 1 Receptor antagonist, angiotensin-ii antagonist, cyclooxygenase-2 inhibitor, heparitinase (heparanse) inhibitor, lymph Factor inhibitors, cytokine inhibitor, IKK inhibitor, P38MAPK inhibitor, ARRY-797, HSP90 inhibitor, many kinases Inhibitor, diphosphate (bisphosphanate), rapamycin derivative, anti-apoptotic approach restrainer, apoptosis pathway are exciting Agent, PPAR agonist, RAR agonist, Ras isoform inhibitor, telomerase inhibitor, protease inhibitor, metalloproteases Inhibitor, amastatin, SHIP activator-AQX-MN100, Humax-CD20 (ofatumumab), CD20 antagonist, IL2-diphtheria toxin, diphtherotoxin fusions.

In order to treat tumor disease, proliferative disorders and cancer, the compound of the present invention can with selected from the medicament of lower group Administering drug combinations, described group includes: dacarbazine (DTIC), actinomycin C₂, actinomycin C₃, actinomycin D and D actinomycin D F₁, cyclophosphamide, melphalan, estramustine, maytansinol, rifamycin, dalacin, doxorubicin, daunorubicin, table soft Than star, idarubicin, detorubicin, Carubicin, idarubicin, epirubicin, esorubicin, mitoxantrone, win Mycin A, bleomycin A₂With bleomycin B, camptothecine, irinotecan .RTM., hycamtin .RTM., 9-aminocamptothecin, 10,11-methylenedioxycamptothecin, 9-nitrocamptothecin, bortezomib, temozolomide, TAS103, NPI0052, Kang Purui Spit of fland, Combretastatin A-4-2, Combretastatin A-4, calicheamycin, neocarzinostain NCS, Epothilones A, epothilone B, Epothilone C (-)-Deoxyepothilone A With semisynthetic variant, Trastuzumab .RTM., Mabthera .RTM., CD40 antibody, asparaginase, interleukin, interferon, Leuproside and pegaspargase, 5-fluorouracil, fluorodeoxyuridine, ptorafur, 5 '-doxifluridine, UFT, MITC, S-1 Capecitabine, diethylstilbestrol, tamoxifen, toremifene, Tomudex (tolmudex), thymitaq, flutamide, Fluoxymesterone Ketone, bicalutamide, finasteride, estradiol, trioxifene, dexamethasone, leuprorelin acetate, estramustine, droloxifene, Medroxyprogesterone, megestrol acetate, aminoglutethimide, testolactone, testosterone, diethylstilbestrol, hydroxyprogesterone, Mitomycin A, mitomycin B and ametycin, porfiromycin, cisplatin, carboplatin, oxaliplatin, four platinum, platinum-DACH, ormaplatin, Thalidomide, come that degree Amine, CI-973, telomere chalone, CHIR258, Rad 001, SAHA, Tubacin, 17-AAG, Sorafenib, JM-216, podophyllotoxin Element, epipodophyllotoxin, etoposide, teniposide, Erlotinib .RTM., Iressa .RTM., imatinib .RTM., rice replace good fortune It is fast for bird that new .RTM., piperazine found the new .RTM. of good fortune, aminopterin, methotrexate, methopterin, dichioromethotrexate, 6-MP, sulfur Purine, azattuoprine, allopurinol, carat stand shore, fludarabine, pentostatin, 2-chlorine adenosine, deoxycytidine, arabinose born of the same parents Glycosides, cytosine arabinoside, azacitidine, 5-azepine cytosine, gemcitabine, 5-azepine cytosine-galactoside, vincristine, Vinblastine, vinorelbine, leurosine, leurosidine and vindesine, paclitaxel, taxotere and docetaxel.

In order to treat inflammatory diseases or pain, compound of the present invention and the pharmaceutically acceptable salt of described compound Can be administered with the drug combination selected from lower group, described medicament group includes: corticosteroid, non-steroidal anti-inflammatory medicine, muscle pine Relaxation medicine and combination, anesthetis and combination, expectorant and the group with other medicaments thereof with other medicaments with other medicaments Conjunction, antidepressants, anticonvulsant and combinations thereof；Antihypertensive, opiates, locally Cannabinoids, capsaicin, dipropionic acid times he Meter Song (potentiation and non-beneficiated), betamethasone valerate, clobetasol propionate, prednisone, methylprednisolone, oxalic acid difluoro draw Pine, halobetasol propionate, amcinonide, dexamethasone, desoximetasone (dexosimethasone), fluocinolone acetonide, acetic acid fluorine are light Pine, halcinonide (halocinonide), neopentanoic acid clocortolone, desoximetasone (dexosimetasone), acetone contracting fluorine hydrogen Hydroxyl dragon, salicylate (salt), ibuprofen, ketoprofen, etodolac, diclofenac, meclofenamate sodium, naproxen, pyrrole sieve former times Health, celecoxib, cyclobenzaprine, baclofen, cyclobenzaprine/lignocaine, baclofen/cyclobenzaprine, cyclobenzaprine/benefit card Cause/ketoprofen, lignocaine, lignocaine/DDG, prilocaine, EMLA ointment (local anesthetic low Eutectic mixture (lignocaine 2.5% and prilocaine 2.5%), guaifenesin, guaifenesin/ketoprofen/cyclobenzaprine, Amitriptyline (amitryptiline), doxepin, desipramine, imipramine, amoxapine, clomipramine, nortriptyline, general Sieve is for woods, duloxetine, mirtazapine (mirtazepine), nisoxetine, maprotiline, reboxetine, fluoxetine, fluorine volt sand Bright, carbamazepine, felbamate, lamotrigine, topiramate, tiagabine, oxcarbazepine, carbamazepine (carbamezipine), Zonisamide, mexiletine, gabapentin/clonidine, gabapentin/carbamazepine, carbamazepine/cyclobenzaprine, resisting hypertension Medicine includes: clonidine, codeine, loperamide, tramadol, morphine, fentanyl, oxycodone, hydrocodone, levorphanol, cloth support coffee Promise, menthol, wintergreen oil, Camphora, Eucalyptus oil, Oleum Terebinthinae；CB1/CB2 part, acetaminophen, infliximab, an oxygen Change oxide synthase inhibitor, the inhibitor of the most derivable nitricoxide synthase, PDE4 inhibitor mechanism similar in appearance to isobutyl Department special (AV-411), CDC-801, jnk inhibitor CC-401, TNF/PDE4 composite restrainer CDC-998, IL1 antagonist As Antril (Synergen) Kineret, AMG 108, (mAb) of targeting IL-1, SHIP activator-AQX-MN100, C5 antagonist, C5a inhibitor, training gram pearl monoclonal antibody, pyrimidine synthesis inhibitors, lymphokine inhibitor, cytokine inhibitor, IKK inhibitor, P38MAPK inhibitor, ARRY-797, HSP90 inhibitor, multi-kinase inhibitor, bisphosphonates (salt), PPAR agonist, Cox1 With cox2 inhibitor, anti-CD4 therapy, B-cytostatics, COX/LOX double inhibitor, immunosuppressant, iNOS inhibitor, NSAID, sPLA2 inhibitor, Colchicine, allopurinol, oxipurinol, gold, Ruide auranofin, Febustat, Puricase, PEG-uricase preparation, benzbromarone, long-acting type β-2 agonist (LABA), salmaterol (Serevent And formoterol (Foradil), leukotrienes regulator include montelukast (Singulair) and zafirlukast Diskus) (Accolate), induction type cromoglicic acid (Intal) or nedocromil (Tilade), theophylline.Short-acting type β-2 agonist, isopropyl torr Ammonium (Atrovent), immunotherapeutic agent-(allergia gels for desensitization), anti-ig E monoclonal antibody Xolair, common DMARD Including: oxychloroquine (Plaquenil), gold compound auranofin (Ruide), sulfasalazine (Azulfidine), minocycline (Dynacin, Minocin) and methotrexate (Rheumatrex), leflunomide (Arava), azathioprine (according to Drymotaenium miyoshianum (Mak.) Mak.), ring spore Rhzomorph (Neoral, Sandimmune) and cyclophosphamide (Cytoxan), antibiotic, CD80 antagonist, costimulator antagonism Agent, Humax-CD20 (ofatumumab)；CD20 antagonist, mek inhibitor, NF κ-B inhibitor, anti-B-cell antibody, relax The mAb of monoclonal antibody, the specifically receptor activators of targeting Nuclear factor kappa B part (RANKL).IL17 inactivates antibody, IL-17 receptor Antagonist/inhibitor, CTLA inhibitor, CD20 inhibitor, soluble VEGFR-1 receptor, anti-VEGFR-1 receptor antibody, anti- VEGF antibody, integrain receptor antagaonists, selection protein inhibitor, CD62P inhibitor and CD62L suppression Agent, PLA 2 inhibitors, lipoxidase inhibitor, RANKL and RANK antagonist/antibody, OPG antagonist, lymphotoxin Inhibitor, B-lymphocyte stimulatory factors, MCP-1 inhibitor, MIF inhibitor, CD2 inhibitor, CD3 inhibitor, CD4 suppress Agent, CD25 inhibitor, CD40 inhibitor and CD40L CD152 (CTLA4) inhibitor, macrolide immunosuppressant, nucleoside The selective depressant of acid metabolic, the inhibitor of chemotaxis, CXC receptor and CXC ligand inhibitor, chemokine antagonists, Leukocyte chemotaxis inhibitor, adhesion molecule blocker, selection albumen lymphocyte function antigen-1 (LFA-1, CD11a) antagonism Agent, Vla-4-4 (VLA-4) antagonist, matrix metallo-proteinase inhibitor, elastatinal, histone enzyme level Agent.

In order to treat eye disorders and ophthalmic, the compound of the present invention and the pharmaceutically acceptable salt of described compound are permissible With selected from lower group medicament be administered, described group includes: beta-Blocking agent, carbonic anhydrase inhibitors, alpha-adrenergic antagonist and Beta-adrenergic antagonist includes α l-1 adrenergic antagonists, α 2 agonist, miotic, prostaglandin analogue, cortex Steroid and immunosuppressant.

In order to treat eye disorders and ophthalmic, the compound of the present invention and the pharmaceutically acceptable salt of described compound are permissible Being administered with the drug combination selected from lower group, described group includes: timolol, betaxolol, levobetaxolol, carteolol, a left side Bunolol, Propranolol, brinzolamide, dorzolamide, nipradilol, p-aminoclonidine, brimonidine, pilocarpine, epinephrine, Latanoprost, travoprost, bimatoprost, Unoprostone, dexamethasone, prednisone, methylprednisolone, sulfur azoles are fast Purine, cyclosporin and immunoglobulin.

In order to treat autoimmune disease, the compound of the present invention or the pharmaceutically acceptable salt of described compound are permissible Being administered with the drug combination selected from lower group, described group includes: corticosteroid, immunosuppressant, prostaglandin analogue and anti- Metabolism medicine.

In order to treat autoimmune disease, the compound of the present invention can be administered with the drug combination selected from lower group, institute State group to include: dexamethasone, prednisone, methylprednisolone, azathioprine, cyclosporin, immunoglobulin, latanoprost, song Volt prostatitis element, bimatoprost, Unoprostone, infliximab, Rituximab, methotrexate, non-steroidal anti-inflammatory medicine, Muscle relaxant and with the combination of other medicaments, anesthetis and with the combination of other medicaments, expectorant and with other medicines The combination of agent, antidepressants, anticonvulsant and combinations thereof；Antihypertensive, opiates, locally Cannabinoids, and other medicaments, Such as capsaicin, betamethasone dipropionate (potentiation and non-beneficiated), betamethasone valerate, clobetasol propionate, prednisone, Methylprednisolone, oxalic acid diflorasone, halobetasol propionate, amcinonide, dexamethasone, desoximetasone, fluocinolone acetonide, acetic acid Fluocinolone acetonide, halcinonide, neopentanoic acid clocortolone, desoximetasone, flurandrenolide, salicylate (salt), ibuprofen, ketone Ibuprofen, etodolac, diclofenac, meclofenamate sodium, naproxen, piroxicam, celecoxib, cyclobenzaprine, baclofen, Cyclobenzaprine/lignocaine, baclofen/cyclobenzaprine, cyclobenzaprine/lignocaine/ketoprofen, lignocaine, lignocaine/ DDG, prilocaine, EMLA ointment (eutectic mixture (lignocaine 2.5% and the propylamine of local anesthetic Caine 2.5%), guaifenesin, guaifenesin/ketoprofen/cyclobenzaprine, amitriptyline, doxepin, desipramine, third meter Piperazine, amoxapine, clomipramine, nortriptyline, protriptyline, duloxetine, mirtazapine, nisoxetine, maprotiline, auspicious ripple Xi Ting, fluoxetine, fluvoxamine, carbamazepine, felbamate, lamotrigine, topiramate, tiagabine, oxcarbazepine, Karma west Flat, zonisamide, mexiletine, gabapentin/clonidine, gabapentin/carbamazepine, carbamazepine/cyclobenzaprine, anti-high blood Pressing includes: clonidine, codeine, loperamide, tramadol, morphine, fentanyl, oxycodone, hydrocodone, levorphanol, cloth support Coffee promise, menthol, wintergreen oil, Camphora, Eucalyptus oil, Oleum Terebinthinae；CB1/CB2 part, acetaminophen, infliximab；One Inhibitors of nitric oxide synthase, the inhibitor of the most derivable nitricoxide synthase；And other medicaments, such as capsaicin. PDE4 inhibitor mechanism is similar in appearance to ibudilast (AV-411), CDC-801, jnk inhibitor CC-401, TNF/PDE4 combination Inhibitor C DC-998, IL1 antagonist such as (mAb) of Antril (Synergen) Kineret, AMG 108, targeting IL-1, SHIP swash Live agent AQX-MN100, C5 antagonist, C5a inhibitor, training gram pearl monoclonal antibody, pyrimidine synthesis inhibitors, lymphokine inhibitor, Cytokine inhibitor, IKK inhibitor, P38MAPK inhibitor, ARRY-797, HSP90 inhibitor, multi-kinase inhibitor, diphosphine Acid esters (salt), PPAR agonist, Cox1 and cox2 inhibitor, anti-CD4 therapy, B-cytostatics, COX/LOX double inhibition Agent, immunosuppressant, iNOS inhibitor, NSAID, sPLA2 inhibitor, Colchicine, allopurinol, oxipurinol, gold, auspicious Obtain auranofin, Febustat, Puricase, PEG-uricase preparation, benzbromarone, long-acting type β-2 agonist (LABA), sand Mei Teluo (Serevent Diskus) and formoterol (Foradil), leukotrienes regulator include montelukast And zafirlukast (Accolate) (Singulair).Induction type cromoglicic acid (Intal) or nedocromil (Tilade), theophylline.Short Acting type β-2 agonist, ipratropium (Atrovent), immunotherapeutic agent-(allergia gels for desensitization), anti-ig E monoclonal anti Body Xolair, common DMARD include oxychloroquine (Plaquenil), gold compound auranofin (Ruide), sulfasalazine (Azulfidine), minocycline (Dynacin, Minocin) and methotrexate (Rheumatrex), leflunomide (Arava), Azathioprine (according to Drymotaenium miyoshianum (Mak.) Mak.), cyclosporin (Neoral, Sandimmune) and cyclophosphamide (Cytoxan), antibiotic, CD80 are short of money Anti-agent, costimulator antagonist, Humax-CD20 (ofatumumab)；CD20 antagonist, mek inhibitor, NF κ B suppress Agent, anti-B cell antibody, the mAb of Shu Dankang, the specifically receptor activators of targeting Nuclear factor kappa B part (RANKL).IL17 Inactivation antibody, IL-17 receptor antagonist/inhibitor, CTLA inhibitor, CD20 inhibitor, soluble VEGFR-1 receptor, anti- VEGFR-1 receptor antibody, anti-VEGF antibodies, integrain receptor antagaonists, selection protein inhibitor, CD62P suppress Agent and CD62L inhibitor, PLA 2 inhibitors, lipoxidase inhibitor, RANKL and RANK antagonist/antibody, protect Ossein antagonist, lymphotoxin inhibitor, B-lymphocyte stimulatory factors, MCP-1 inhibitor, MIF inhibitor, CD2 inhibitor, In CD3 inhibitor, CD4 inhibitor, CD25 inhibitor, CD40 inhibitor and CD40L CD152 (CTLA4) inhibitor, macro ring Ester immunosuppressant, the selective depressant of nucleotide metabolism, the inhibitor of chemotaxis, CXC receptor and the suppression of CXC part Agent, chemokine antagonists, leukocyte chemotaxis inhibitor, adhesion molecule blocker, selection albumen lymphocyte function antigen-1 (LFA-1, CD11a) antagonist, Vla-4-4 (VLA-4) antagonist, matrix metallo-proteinase inhibitor, Elastase suppress Agent, cathepsin inhibitors.

In order to treat metabolic disorder, the compound of the present invention and the pharmaceutically acceptable salt of described compound can be selected from The drug combination of lower group is administered, and described group includes: insulin, insulin derivates and analogies, insulin secretagogue element, insulin Sensitizer, biguanide agents, alpha-glucosidase inhibitor, pancreotropic hormone sulfonylureas receptors ligand, Protein tyrosine phosphatase-1B (PTP-1B) inhibitor, GSK3 (glycogen synthase kinase-3) inhibitor, GLP-1 (glucagon-like-peptide-1), GLP-1 are similar to Thing, DPPIV (DPP IV) inhibitor, RXR part sodium dependent glucose cotransporter inhibitor, glycogen phosphoric acid Change enzyme A inhibitor, AGE disrupting agent, PPAR regulator, LXR and FXR regulator, Fei Gelie ketone type PPARS agonist, selectivity Glucocorticoid resistance agent, metformin, glipizide, glibenclamide, Ya Moli, meglitinide, nateglinide, Rui Gelie How, PT-112, SB-517955, SB4195052, SB-216763, NN-57-05441, NN-57-05445, GW-0791, AGN- .sup.194.sup.204, T-1095, BAY R3401, acarbose Exendin-4, DPP728, LAF237, vildagliptin, MK-0431, BMS-477118, GSK23A, pioglitazone, rosiglitazone, (R) described in the patent application WO 03/043985- 1-{4-[5-methyl-2-(4-trifluoromethyl-phenyl)-azoles-4-ylmethoxy]-benzenesulfonyl } 2,3-dihydro-1H-indole- 2-carboxylic acid, compound 19 such as embodiment 4, and GI-262570.

Disease

Treatment described herein suffers from the method for disease described in the individuality of disease, and it includes to described individual effective dosage Compound of formula I or its pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer, prodrug, hydration Thing or derivant.

Being also described and treat disease or the method for disease described in the individuality suffering from disease or disease, it includes to described N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2,3-bis-of individual effective dosage Hydroxypropyl) cyclopropane-1-sulfonamide (A type).The present invention relates to N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-iodophenyl ammonia Base)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide (A type) preparation be used for treating disease or Purposes in the medicine of disease.

In some embodiments, the present invention relates to prevention or treat any disease or the disease that MEK kinases plays a role, It includes without limitation: tumor disease, hematologic disease, inflammatory diseases, ocular disease, neuropathy, immune disease, cardiovascular Disease, and dermatosis, and because of exceedingly or do not produce the disease caused by proinflammatory cytokine with regulating and controlling, including such as the mankind Or other mammals exceedingly or with not regulating and controlling produce TNF, IL-1, IL-6 and IL-8.The present invention relates to described compound Such purposes, and described compound in preparation for treating such cytokine mediated disease or the medicine of disease In purposes.Additionally, the present invention relates to the mek inhibitor of effective dose administered to humans to treat any such disease or disease Disease.

MEK kinases directly or plays through proinflammatory cytokine (including cytokine TNF, IL-1, IL-6 and IL-8) to be made Disease or disease include without limitation: xerophthalmia, glaucoma, autoimmune disease, inflammatory diseases, destructive osteopathia, Proliferative disease, neurodegenerative disorders, viral disease, anaphylaxis, infectious disease, heart attack, angiogenesis disorders, apoplexy Time Reperfu-sion/ischemia, the platelet aggregation that causes of blood vessel hyperplasia, organ hypoxia, cardiac hypertrophy, thrombin, and and prostatitis The patient's condition that parathyrine endoperoxidase synthase-2 (COX-2) is relevant.

In certain aspects of the invention, described disease is the excess proliferative patient's condition of the mankind or animal body, it include but not It is limited to cancer, hypertrophy, restenosis, inflammation, immunological diseases, cardiac hypertrophy, atherosclerosis, pain, migraine, blood vessel generation Cause after related conditions or disease, medical conditions (including but not limited to surgical operation, angioplasty or other situations) Propagation.

In further embodiment, the described excess proliferative patient's condition is selected from hematologic disease cancer and non-blood disease cancer Disease.In other other embodiments, described hematologic disease cancer is selected from multiple myeloma, leukemia and lymphoma.? Further in embodiment, described leukemia is selected from acute leukemia and chronic leukemia.Further implementing In scheme, described acute leukemia is selected from acute lymphoblastic leukemia (ALL) and acute nonlymphocytic leukemia (ANLL). In further embodiment, described chronic leukemia is selected from chronic lymphocytic leukemia (CLL) and chronic myelognous Leukemia (CML).In further embodiment, described lymphoma is selected from Hodgkin lymphoma and non-Hodgkin lymphoma. In further embodiment, described hematologic disease cancer is multiple myeloma.In other embodiments, described blood Diseases Cancer is low cancer, moderate cancer or height cancer.In other embodiments, described non-blood diseases Cancer is selected from The brain cancer, head and neck cancer, pulmonary carcinoma, breast carcinoma, the cancer of reproductive system, the cancer of digestive system, cancer of pancreas and urinary system The cancer of system.In further embodiment, the cancer of described digestive system is upper gastrointestinal cancer or colorectal cancer.? In further embodiment, the cancer of described urinary system is bladder cancer or renal cell carcinoma.In further embodiment, The cancer of described reproductive system is carcinoma of prostate.

The treatable other kinds of cancer of Compounds and methods for as herein described is used to include: oral cavity and the cancer of pharynx Disease, the cancer of respiratory system, bone and the cancer in joint, the cancer of soft tissue, skin carcinoma, the cancer of reproductive system, eye and eye socket Cancer, neural cancer, lymphoid cancer, and the cancer of hormonal system.In certain embodiments, these Cancer can select the cancer in free tongue, mouth, pharynx or other oral cavities；The esophageal carcinoma, gastric cancer, or carcinoma of small intestine；Colon cancer or rectal cancer, anus Door cancer or anal orifice and rectal intestine cancer；Hepatocarcinoma, intrahepatic cholangiocarcinoma, carcinoma of gallbladder, cancer of pancreas, or other gallbladders or Alimentary cancer；Larynx The cancer of cancer, bronchogenic carcinoma and other respiratory apparatus；Heart cancer, melanoma, basal cell carcinoma, squamous cell carcinoma, other Non-epithelial cancer；Uterus carcinoma or cervical cancer；Carcinoma of uterine body；Ovarian cancer, carcinoma vulvae, cancer of vagina, or the cancer of other female genital organs Disease；The cancer of carcinoma of prostate, carcinoma of testis, penis or other male genitals；Urinary bladder cancer；The cancer of kidney；Renal carcinoma, pelvis Cancer or urethral cancer, or other cancers of Genito-urinary organ；Thyroid carcinoma or the cancer of other endocrine gland；Chronic lymphatic is thin Born of the same parents' leukemia；And granulocyte and single celled cutaneous T cell lymphoma.

The treatable other other kinds of cancer of Compounds and methods for as herein described is used to include: adenocarcinoma, blood vessel Sarcoma, astrocytoma, acoustic neuroma, glioblastoma multiforme, basal cell carcinoma, glioblastoma multiforme (blastoglioma), chondrosarcoma, choriocarcinoma, chordoma, craniopharyngioma, cutaneous melanoma, cystadenocarcinoma, endotheliosarcoma, Embryonal carcinoma, ependymoma, ewing's tumor, epithelial cancer, fibrosarcoma, gastric cancer, genitourinary tract cancer, pleomorphism glioblast Tumor, hemangioblastoma, hepatocarcinoma, hepatocarcinoma, Kaposi sarcoma, large cell carcinoma, leiomyosarcoma, liposarcoma, lymphatic vessel Sarcoma, lymphangioendothelial sarcoma, medullary thyroid carcinoma, medulloblastoma, meningioma, mesothelioma, myeloma, mucus meat Tumor, neuroblastoma, neurofibrosarcoma, oligodendroglioma, osteogenic sarcoma, epithelial ovarian, papillary carcinoma, nipple Shape adenocarcinoma, parathyroid adenoma, pheochromocytoma, pinealoma, plasmocytoma, retinoblastoma, rhabdomyosarcoma, sebum Adenocarcinoma, spermocytoma, skin carcinoma, melanoma, small cell lung cancer, squamous cell carcinoma, syringocarcinoma, synovioma, thyroid carcinoma, Uveal and wilms' tumor.

Also describing the method for excess proliferative disease in treatment mammal, it includes being administered to described mammal in conjunction The compound of formula I of therapeutically effective amount or its pharmaceutically acceptable salt, solvate, polymorph, ester, amide, tautomer, Prodrug, hydrate or derivant, and antitumor drug.In some embodiments, described antitumor drug is selected from mitosis Inhibitor, alkylating agent, antimetabolite, embedding antibiotic, growth factor receptor inhibitors, cell cycle inhibitor, enzyme inhibitor, topology Isomerase inhibitors, biological response modifier, antihormone, angiogenesis inhibitor, androgen antagonist, SHIP activator AQX- MN100, Humax-CD20 (ofatumumab), CD20 antagonist, IL2-diphtheria toxin, diphtherotoxin fusions.

The disease using compound as herein described, compositions and method treatment can be blood disorder.Implement at some In scheme, described blood disorder is selected from sicklemia, myeloproliferative disorder (MDS) and myeloproliferative diseases.? In further embodiment, described myeloproliferative diseases is selected from polycythemia vera, myelofibrosis and constitutional Thrombocytosis.

Compound as herein described, compositions and method can serve as anti-inflammatory agent and to have harmful side effect significantly the lowest Additional benefits.Compound as herein described, compositions and method are used for treatment of arthritis, include but not limited to rheumatoid joint Inflammation, spondyloarthropathy, ankylosing spondylitis, gout, gouty arthritis, osteoarthritis, systemic lupus erythematosus (sle), juvenile joint Inflammation, acute rheumatic arthritis, enteropathic arthritis, neuropathic arthritis, psoriatic arthritis, and suppurative arthritis. Compound as herein described, compositions and method are additionally operable to treat osteoporosis and other relevant bone disorders.As herein described These compounds, compositions and method are additionally operable to treat the gastrointestinal patient's condition, such as reflux esophagitis, diarrhoea, inflammatory bowel, Crow Engler's disease, gastritis, irritable bowel syndrome and ulcerative colitis.Compound as herein described, compositions and method can also be used In the pneumonia that treatment is such as infected to virus and cystic fibrosis is relevant.Additionally, compound as herein described, compositions and Method the most individually or is combined in Organ Transplantation Patients with conventional immunomodulator.Further, as herein described Compound, compositions and method are used for treating pruritus and vitiligo.Particularly, compound as herein described, compositions and method For treating specific inflammatory diseases rheumatoid arthritis.

Other inflammatory diseasess can prevented or treat include without limitation: asthma, anaphylaxis, respiratory distress are comprehensive Levy, or acute or chronic pancreatitis.Furthermore, it is possible to the respiratory system disease of prevention or treatment includes but not limited to chronic obstruction Property pneumonopathy and pulmonary fibrosis.Additionally, MEK inhibitors of kinases as herein described also with prostaglandin endoperoxidase synthase-2 (COX-2) generation is relevant.Derived from the pro-inflammatory mediator of arachidonic cyclo-oxygenase approach, such as prostaglandin, by can The COX-2 enzyme of induction produces.The regulation of COX-2 can regulate and control these pro-inflammatory mediators, and it has influence on various kinds of cell, and is multiple disease Diseased state and the important and crucial inflammatory mediator of the patient's condition.Particularly, these inflammatory mediators have been directed to pain (such as pain receptor Sensitization) and edema.Therefore, it can prevention or treatment disease kinase mediated for other MEK include edema, analgesia, Fever and pain (such as neuromuscular pain, have a headache, have a toothache, arthritis ache and by the pain caused by cancer).

Additionally, the disease through the treatment of compound as herein described, compositions and method can be eye disease.Ophthalmic diseases The other diseases played a role in pathogenesis with blood vessel generation, can be treated or prevent, and include but not limited to: dry Eye (including Sjogren syndrome), degeneration of macula, angle closure glaucoma and open angle glaucoma, retinal ganglion degeneration, eye Ischemia, retinitis, retinopathy, uveitis, eye photophobia, and the inflammation relevant to ocular tissue acute injury and pain Bitterly.Compound as herein described, compositions and method are used for treating glaucomatous retinopathy and/or diabetic retinal Pathological changes. compound as herein described, compositions and method are additionally operable to the inflammation after iatrotechnics or pain, such as ophthalmic surgery example The inflammation caused such as cataract operation and refractive surgery or pain.In further embodiment, described eye disease is choosing From xerophthalmia, angle closure glaucoma and open angle glaucoma.

Additionally, the disease through the treatment of compound as herein described, compositions and method can be autoimmune disease.Can Include but not limited to the autoimmune disease being prevented or treating: rheumatoid arthritis, inflammatory bowel, inflammatory pain, Ulcerative colitis, Crohn disease, periodontal disease, temporomandibular arthrosis, multiple sclerosis, diabetes, glomerulonephritis, system Property lupus erythematosus, scleroderma, chronic thyroiditis, Graves disease, hemolytic anemia, autoimmune gastritis, autoimmune Property neutrophilic granulocytopenia, thrombocytopenia, chronic active hepatitis, myasthenia gravis, atopic dermatitis, graft resist Host disease and psoriasis.The inflammatory diseases can prevented or treat includes but not limited to: asthma, anaphylaxis, respiratory distress are combined Simulator sickness or acute pancreatitis or chronic pancreatitis.Particularly, compound as herein described, compositions and method are used for treating specific Autoimmune disease rheumatoid arthritis and multiple sclerosis.

Additionally, the disease through the treatment of compound as herein described, compositions and method can be skin disorder.Real at some Executing in scheme, described skin disorder is selected from lower group, and described group includes that melanoma, basal cell carcinoma, squamous are thin without limitation Born of the same parents' cancer, and other non-epithelium skin carcinomas, and psoriasis and persistence pruritus, also have other the most relevant to skin and skin texture Disease, can treat or prevent described skin disorder with the MEK inhibitors of kinases of the present invention.

The metabolic disease can treated or prevent includes metabolism syndrome, insulin resistant without limitation, and I type and II Patients with type Ⅰ DM.Additionally, compositions described herein may be used for treat insulin resistant and typically with excessive inflammatory signal Relevant other metabolic disorder the most atherosclerotic.

Compound as herein described, compositions and method are additionally operable to treat outside such as angiopathy, migraine, periarteritis Film inflammation, thyroiditis, aplastic anemia, Hodgkin, scleroderma (sclerodoma), rheumatic fever, type i diabetes, god Through neuromuscular junction disease (including myasthenia gravis), white matter sick (including multiple sclerosis), sarcoidosis, nephritis, nephrotic syndrome, Swelling after behcet's syndrome, polymyositis, gingivitis, periodontitis (periodontis), allergy, damage, ischemia (bag Include myocardial ischemia, Cardiovascular ischemia and heart stopping collecting secondary ischemic) etc. disease in tissue injury in.As herein describedization Compound, compositions and method can be also used for treating allergic rhinitis, respiratory distress syndrome, endotoxic shock syndrome and moving Pulse atherosclerosis.

Additionally, the disease through the treatment of compound as herein described, compositions and method can be the cardiovascular patient's condition.At some In embodiment, the described cardiovascular patient's condition is selected from atherosclerosis, cardiac hypertrophy, idiopathic cardiomyopathy, heart failure, blood vessel The propagation caused after there is the relevant patient's condition or disease, and medical conditions, described medical conditions includes but not limited to because of surgery Operation and the restenosis caused by angioplasty.

Additionally, the disease through the treatment of compound as herein described, compositions and method can be neurological disorder.At some In embodiment, described neurological disorder selected from parkinson disease, Alzheimer, Alzheimer and because of apoplexy, lack Central nervous system injury caused by blood and wound.In other embodiments, described neurological disorder is selected from epilepsy, nerve Pain, depression and bipolar disorder.

Additionally, the disease through the treatment of compound as herein described, compositions and method can be cancer, the most acute marrow sample Leukemia, thymic carcinoma, the brain cancer, pulmonary carcinoma, squamous cell carcinoma, skin carcinoma, cancer eye, retinoblastoma, ophthalmic melanoma, mouth Chamber and oropharynx cancer, bladder cancer, stomach (gastric) cancer, stomach (stomach) cancer, pancreas, bladder cancer, breast carcinoma, cervical cancer, head Cancer, neck cancer, renal carcinoma, renal carcinoma, hepatocarcinoma, ovarian cancer, carcinoma of prostate, colorectal cancer, the esophageal carcinoma, carcinoma of testis, gynecological cancer, Cancer (such as lymphoma and Kaposi sarcoma) that thyroid carcinoma, CNS cancer, PNS cancer, AIDS are relevant or the cancer that virus causes Disease.In some embodiments, described compound and compositions are used for treating non-cancer hyperproliferative disorders, such as skin (such as psoriasis), restenosis or the hyperplasia of prostate of prostate (such as benign prostatauxe (BPH)).

Additionally, the disease through the treatment of compound as herein described, compositions and method can be the pancreas in mammal Inflammation, kidney disease (including the nephropathy that proliferative glomerulonephritis and diabetes cause), pain and angiogenesis or blood vessel occur Relevant disease, tumor vessel occur, chronic inflammatory disease such as rheumatoid arthritis, inflammatory bowel, atherosclerosis, skin Skin sick (such as psoriasis, eczema and scleroderma), diabetes, diabetic retinopathy, retinopathy of prematurity, age phase Degeneration of macula, hemangioma, tendinitis, bursitis, sciatica, glioma, melanoma, Kaposi sarcoma and the ovary closed Cancer, breast carcinoma, pulmonary carcinoma, cancer of pancreas, carcinoma of prostate, colon cancer and epidermoid carcinoma.

Additionally, the disease through the treatment of compound as herein described, compositions and method can be to stop in mammal Blastocyte is implanted.

According to the method for the present invention, can be with compound as herein described or their pharmaceutically acceptable salt, solvent The patient of compound, polymorph, ester, amide, tautomer, prodrug, hydrate or derivatives for treatment includes, such as, examines The disconnected patient suffering from following disease, described disease includes: psoriasis；Restenosis；Atherosclerosis；BPH；Breast carcinoma, such as The duct carcinoma in tracheal tissue, medullary carcinoma, mucinous carcinoma, tubule cancer and inflammatory breast cancer in mammary gland；Ovarian cancer (includes epithelium ovum The nest tumor such as adenocarcinoma in ovary and have been transferred to the adenocarcinoma abdominal cavity from ovary)；Uterus carcinoma；Cervical cancer, on cervix uteri Adenocarcinoma (including squamous cell carcinoma and adenocarcinoma) in skin；Carcinoma of prostate, as selected from following carcinoma of prostate: have been transferred to the gland of bone Cancer；Cancer of pancreas, such as the Epithelial cancer in pancreatic duct tissue and the adenocarcinoma in pancreatic duct；Bladder cancer, in urinary bladder The tumor in urothelial cell in transitional cell carcinoma, urothelium cancer (transitional cell carcinoma), bladder lining, squamous are thin Born of the same parents' cancer, adenocarcinoma and minicell cancer；Leukemia such as acute myeloid leukemia (AML), acute lymphoblastic leukemia, chronic pouring Bar chronic myeloid leukemia, chronic myeloid leukemia, hairy cell, myelodysplasia and bone marrow proliferative disease；Osteocarcinoma； Pulmonary carcinoma such as nonsmall-cell lung cancer (NSCLC), is divided into squamous cell carcinoma, adenocarcinoma and maxicell undifferentiated carcinoma, and minicell Pulmonary carcinoma；(it is sometimes to develop into squama for skin cancer such as basal cell carcinoma, melanoma, squamous cell carcinoma and actinic keratosis The dermatosis of shape cell carcinoma)；Eyes retina blastoma；Cutaneous melanoma or ophthalmic (eye) melanoma；Primary hepatocarcinoma (originating in the cancer of liver)；Renal carcinoma；Thyroid carcinoma such as papillary thyroid carcinoma, folliculus thyroid carcinoma, medullary thyroid carcinoma and many Shape thyroid carcinoma；AIDS related lymphoma such as diffusivity large B cell lymphoid tumor, B cell immunoblastic lymphoma and little Non-cleaved cell lymphoma；Kaposi sarcoma；The cancer that virus causes (includes hepatitis b virus (HBV), hepatitis C virus (HCV) And hepatocarcinoma)；People's lymphotropic virus 1 type (HTLV-1) and Adult T-cell leukemia/lymphoma；And human papillomavirus And cervical cancer (HPV)；Central nervous system cancer (CNS) such as primary brain tumor, it includes glioma (astrocytoma, multiform Property glioblastoma or glioblastoma multiforme), oligodendroglioma, ependymoma, meningioma, lymphoma, god Through sheath tumor and medulloblastoma；Peripheral nervous system (PNS) cancer such as acoustic neuroma and Malignant Peripheral Nerve Sheath Tumors (MPNST) neurofibroma and schwannoma, malignant fibrous glucagonoma, malignant fibrous histiocytoma, pernicious brain are included Film tumor, malignant mesothe and malignant mixed muller's steatoma；Oral cancer and oropharynx cancer such as swallow cancer, laryngeal carcinoma, nasopharyngeal carcinoma and oropharynx Cancer；Gastric cancer such as lymphoma, stomach stromal tumor and carcinoid tumor；Carcinoma of testis such as germinoma (GCTs), it include spermocytoma and Nonseminoma and gonadal stromal tumor, it includes leydig cell tumor and Sai Ertuoli glucagonoma；Thymic carcinoma such as thymoma, breast Adenocarcinoma, Hodgkin, non-Hodgkin lymphoma carcinoid or carcinoid tumor；Rectal cancer；And colon cancer.

Medicine box

Compound as herein described, compositions and method provide the medicine for treating all diseases as those described herein Box.These medicine boxs comprise one or more compounds as herein described or compositions in a reservoir, and optionally comprise according to Various method and steps as herein described teaching uses the description of described medicine box.Such medicine box can also include such letter Breath, such as scientific references, package insert material, clinical test results and/or these summary etc., its explanation or proof The activity of described compositions and/or advantage, and/or it describes dosage, medication, side effect, drug interaction, or to doctor Treat other information that healthcare provider is useful.Such information can be based on the result of various researchs, such as, uses experimental animal Research, including In vivo model and research based on human clinical trial.Can to medical supplier include doctor, nurse, Pharmacists, prescription official etc. provide, sell and/or promote medicine box as herein described.In some embodiments, it is also possible to directly Medicine box is sold to consumer.

Compound as herein described may be used for diagnostics and is used as research reagent.Such as, compound as herein described, single Solely or with other compounds combining, the instrument in difference and/or combinative analysis that can serve as is to illustrate in cell and tissue The expression pattern of the gene expressed.As a limiting examples, contrast the cell by one or more compound treatment or In-house expression pattern and without the compared with control cells of compound treatment or in-house expression pattern, the pattern analyzing gained is come Measuring the level of difference of gene expression, because they relate to, such as, disease associated, signal path, cell position, detection base The expression of cause, size, structure or function.Through that stimulate or without on the cell stimulated, and affecting expression pattern Under other compound presence or absence, can be carried out these and analyze.

In addition to for human treatment, the compound of the present invention and preparation are additionally operable to house pet (such as Canis familiaris L., cat), rare animal With the veterinary treatment of domestic animal (such as horse), it includes mammal, rodent etc..

Examples provided below and preparation method are further elucidated with and illustrate the compound of the present invention and prepare this The method of the compound of sample.It should be understood that the scope of the present invention is in no way restricted to the scope of following example and preparation method.

Embodiment

The further generalized exemplary step of synthesis sulfonamide

Step A: add anhydrous triethylamine in the amine (1eq) solution (3mL/mmole) in anhydrous methylene chloride (5eq).In this solution, add sulfonic acid chloride (1eq), and be stirred at room temperature this solution 16h.Evaporation solvent, and by quick post Chromatography is through silica gel purification residue.

Step B: add sulfonic acid chloride (1-in the amine (1eq) agitated solution (5ml/mmole) in anhydrous pyridine 5eq).This reactant mixture is stirred 48 hours at 40 DEG C.This reactant mixture is distributed with water and EtOAc.Wash with saline, be dried (MGSO₄), and under reduced pressure concentrate.By flash column chromatography through silica gel purification residue.

Step C: replacement atomic iodine:

In microwave reactor, be included in the 1eq. aryl iodide in the deoxidation mixture of dioxane and water (3:1), 1.5eq. boric acid or borate, 0.25eq.PdCl₂(dppf) x DCM and 10eq. anhydrous K₂CO₃The suspension of powder is at 115 DEG C Heating 60min.Use aq.NH₄Cl/THF extracts, and uses Na₂SO₄It is dried organic moiety.Use flash column chromatography (Si, EtOAc/ Hexane, or CHCl₃/ MeOH) purification of crude product.Yield: 20-40%.

Step D: synthesis N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl)-2-(alkyl amino) second sulphonyl Amine:

Chloro-for 2-ethyl sulfonic chloride (0.1ml, 1mmol) is added the fluoro-N of 5,6-bis-¹-(2-fluoro-4-iodophenyl) benzene-1,2-two Amine (0.364g, 1mmol) and triethylamine (0.28ml, 2mmol) are at CH₂Cl₂(5ml) in the solution in, and it is stirred at room temperature this Reactant mixture 16h.Then with in solution or neat liquid excess amine (10eq) this reactant mixture is processed.? Stirred at rt for another this reactant mixture 6h.Use CH₂Cl₂(10ml) this reactant mixture is diluted with water (10ml).Organic layer is successively With dilute HCl (2x20ml, 2N) and saturated NaHCO₃(2x10ml) solution washing.Then (MgSO it is dried₄)CH₂Cl₂Layer, and evaporate Obtain crude product.The product that purification is impure under the conditions of preparing HPLC obtains the pure products of 50-60% yield.

Embodiment 1

N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl) Methanesulfomide:

Step A:The fluoro-N-of 2,3-bis-(2-fluoro-4-iodophenyl)-6-nitroaniline:

At 0 DEG C, in the 2-fluoro-4-Iodoaniline (11.40g, 47mmol) solution in the anhydrous THF of 100ml, drip LHMDS 1M solution (47ml) in THF (47mmol).The color of solution becomes mulberry.Solution is transferred to dropping liquid leakage through sleeve pipe Bucket, and at 0 DEG C, this solution (comprising amine free alkali) sub-fraction sub-fraction ground is added 2,3,4-trifluoronitrobenzenes In (8.321g, 47.0mmol) solution in anhydrous THF (50ml).After addition, at room temperature, this is stirred under argon gas Mixture 15 hours.Reduce the volume of solvent, then with ethyl acetate and saline extraction.Organic layer dried over sodium sulfate, removes Solvent, and by flash chromatography (EtOAc/ hexane 1:5, R_f=0.58) purification gained dark oil obtains crude product, and it is through vacuum It is dried and becomes brown solid (yield: 6.23g, 33.6%): m/z=393 [M-1]^-。

Step B:5,The fluoro-N1-of 6-bis-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen:

In the nitro-diaryl amine (6.23g, 15.8mmol) solution in 300ml ethanol add iron powder (13.74g, 246mmol) with ammonium chloride (13.59g, 254mmol) and little with this mixture 14 of agitating heating under 100 DEG C of oil bath temperatures Time.Filter, and with washing with alcohol filtering residue twice.Remove ethanol in a vacuum, and use ethyl acetate/1M NaOH solution extraction Residue.During extracting, filter and discard more precipitations of formation.The organic layer merged saline washs, and through sodium sulfate It is dried.Remove solvent, and from CHCl₃/ hexane (1:50) recrystallization crude product.Obtain brown needles product (2.094g, 66%), R_f=0.44(EtOAc/Hex1:3)。¹H-NMR(500MHz,CDCl₃),δ=7.40-7.38(dd,1H,J=11.3Hz,J= 1.5Hz),7.25-7.23(d,1H,J=8.5Hz),6.97-6.92(q,1H,J=9Hz),6.51-6.48(m,1H),6.24- 6.21(t,1H,J=9Hz),5.3(s,1H,NH,br),3.80(s,2H,NH₂,br),LRMS(ESI):m/z=365[M+H]^-。

Step C:N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl) Methanesulfomide:

According to general step A, 5,6-bis-fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen and mesyl chloride react To desired product.¹HNMR:(500MHz, CDCl₃): δ=7.38-7.37 (d, 1H), 7.35-7.34 (m, 1H), 7.27-7.26 (m,1H),7.20-7.0(q,1H),6.68(s,1H,br),6.15-6.12(q,1H),5.65(s,1H,br),2.95(s,3H)； m/z=441[M-1]^-。

Embodiment 2

2-N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl) cyclopropanesulfonamide:

According to general step A, 5,6-bis-fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen is anti-with cyclopropanesulfonyl chloride Desired product should be obtained.¹HNMR:(500MHz, CDCl₃): δ=7.38-7.37 (d, 1H), 7.35-7.34 (m, 1H), 121- 1Id(m,1H),7.20-7.0(q,1H),6.68(s,1H,br),6.15-6.12(q,1H),5.65(s,1H,br),3.25- 3.20(m,1H),2.4-2.3(m,2H),2.0-1.8(m,2H)；m/z=467[M-1]^-。

Embodiment 3

N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl) propane-2-sulfonamide:

According to general step A, 5,6-bis-fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen is anti-with isopropyl sulphonyl chloride Desired product should be obtained.Yield: 39%.¹H-NMR(500MHz,CDCl₃): δ=7.50-7.43 (m, 1H), 7.35-7.34 (m, 1H),7.27-7.26(m,1H),7.15-7.09(q,1H,J=1.6Hz),6.62(s,1H,br),6.22-6.18(q,1H,J= 1.5Hz),5.65(s,1H,br),3.30-3.28(m,1H),1.38-1.37(d,6H,J=1.2Hz)；m/z=469[M-I]^-。

Embodiment 4

N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl) butane-l-sulfonamide:

According to general step A, 5,6-bis-fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen is anti-with normal-butyl sulfonic acid chloride Desired product should be obtained.Yield: 55%.¹H-NMR(500MHz,CDCl₃): δ=7.50-7.43 (m, 1H), 7.35-7.34 (m, 1H),7.27-7.26(m,1H),7.15-7.09(q,1H,J=1.6Hz),6.62(s,1H,br),6.22-6.18(q,1H,J= 1.5Hz)55.65(s,1H,br),3.06-3.031(t,2H,J=1.4Hz),1.75-1.71(m,2H),1.38-1.36(m, 2H),0.87-0.86(t,3H,J=1.3Hz)；m/z=483[M-1]^-。

Embodiment 5

N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl)-2,2,2-trifluoroethyl sulfonamide:

According to general step A, 5,6-bis-fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen and 1,1,1-trifluoroethyl Sulfonic acid chloride reaction obtains desired product.Yield: 28%.m/z=509[M-1]^-。

Embodiment 6

N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl) butane-2-sulfonanilide:

According to general step A, 5,6-bis-fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen is anti-with sec-butyl sulfonic acid chloride Desired product should be obtained.Yield: 22%.¹H-NMR (500MHz, MeOH [d4]): δ=7.60-7.40 (m, 3H), 7.18-7.00 (q,1H),6.55-6.45(m,1H),3.55-3.50(m,1H),2.20-2.00(m,1H),1.80-1.60(m,1H),1.43- 1.40(d,3H),1.06-1.04(t,3H)；m/z=483[M-1]^-。

Embodiment 7

N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl)-N-methyl cyclopropane sulfonamide:

At-78 DEG C, (see reality to N-(3,4-bis-fluoro-2-(2-fluoro-4-idodophenylamino) phenyl) cyclopropane-sulfonamide Execute 2) (283.9mg, 0.61mmol) solution in the anhydrous THF of 3ml adds the 1M solution (0.6ml, 0.6mol) of LHMDS, And stir this solution 10min at this temperature.Then, add iodomethane (0.8ml, 1.824g, 12.9mmol), and make this mix Thing warms to room temperature and stirs 7h.Remove solvent and with EtOAc and saline extraction leftover.Use Na₂SO₄Dry organic moiety is also Remove solvent.With flash column chromatography (Si, EtOAc/ hexane 1:2, R_f=0.45) purification gained crude product.Yield: (205mg, 70%)。¹H-NMR(500MHz,CDCl₃): δ=7.41-7.39 (d, 1H, J=10Hz), 7.30-7.29 (d, 1H, J=8.0Hz), 7.23-7.20(m,1H),6.98-6.93(q,1H,J=8.5Hz),6.60(s,1H,br),6.51-6.47(m,1H),3.23(s, 3H),2.46-2.42(m,1H),1.19-1.16(m,2H),1.04-1.02(m,2H)；m/z=481[M-1]^-。

Embodiment 8

The chloro-N-of l-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl) Methanesulfomide:

According to general step A, 5,6-bis-fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen reacts with chloromethane sulfonic acid chloride Obtain desired product, m/z=475 [M-1]^-。

Embodiment 9

N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl)-2-methylpropane-2-sulfonamide:

According to general step B, 5,6-bis-fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen and 2-methylpropane-2-sulphur Acyl chlorides (synthesizing according to literature procedure) reaction obtains desired product.¹H NMR(300MHz,CDCl₃): δ 7.50 (m, 1H), 7.43 (dd,J=1.8&10.5Hz,1H),7.28(br s,1H),7.10(dd,J=9.0&17.7Hz,1H),6.48(br s,D₂O can hand over Change, 1H), 6.19 (t, J=7.8&9.6Hz, 1H), 5.58 (br s, D₂O is commutative, 1H), 1.39 (s, 9H)；m/z=383[M- 1]^-。

Embodiment 10

N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl) Pentamethylene. sulfonamide:

According to general step B, 5,6-bis-fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen is anti-with Pentamethylene. sulfonic acid chloride Desired product should be obtained.¹H NMR(300MHz,CDCl₃): δ 7.42 (dd, J=2.1&10.5Hz, 1H), 7.36 (ddd, J= 2.4,4.8,&9.3Hz,1H),7.25(m,2H),7.10(dd,J=9.6&17.7Hz,1H),6.67(br s,D₂O is commutative, 1H),6.20(dt,J=1.5,8.4&17.4Hz,1H),3.53(p,1H),1.80(m,8H)；m/z=495[M-1]^-。

Embodiment 11

N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl) hexamethylene sulfonamide:

According to general step B, 5,6-bis-fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen is anti-with cyclohexanesulfonyl chloride Desired product should be obtained.¹H NMR(300MHz,CDCl₃): δ 7.43 (dd, J=1.5&10.2Hz, 1H), 7.37 (ddd, J= 2.4,4.8&9.6Hz,1H),7.27(m,1H),7.11(dd,J=9.3&18.0Hz,1H),6.64(br s,1H),6.18(dt,J =1.5,9.0&17.4Hz, 1H), 5.63 (br s, 1H), 2.95 (three groups of triplets, 2.10-1.16 (m, 10H)；m/z=509[M- 1]^-。

Embodiment 12

N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl)-l-methyl cyclopropane-l-sulfonamide:

Step A:3-chloro-1-propane sulfonic acid N-butyl:

Will be at CH₂Cl₂(50ml) triethylamine (28ml, 200mmol) in is slowly added into 3-chloro-1-propanesulfonic acid chloride (36.6g, 200mmol) and n-butyl alcohol (18.4g, 240m mol) are at CH₂Cl₂(250ml) in the ice-cold solution in, and continue Stirring 16h.Use CH₂Cl₂(200ml) dilute this mixture, wash (HCl/water solution), be dried (MgSO₄), and evaporate solvent and obtain The micro-butyrous title product 1 (40.85g, 95%) of crude form, without being further purified i.e. for the next step.¹H NMR (CDCl₃₎) δ 0.94 (t, J=7.5Hz, 3H), 1.44 (sextet, 2H), 1.72 (quintet, 2H), 2.31 (quintet, 2H), 3.27(t,J=6.9Hz,2H),3.68(t,J=6.3Hz),4.23(t,J=6.6Hz,2H)。

Step B:Cyclopropane sulfonic acid 1-butyl ester:

At-78 DEG C, under nitrogen atmosphere, by chloro-for 3-l-propane sulfonic acid 1-butyl acetate solution, (4.6g, 21.39mmol are at 25ml In THF) and butyl lithium solution (14.7ml, 23.53mmol, 1.6M, THF) be simultaneously introduced in THF (150ml).Make this solution temperature Heat, to 0 DEG C, then terminates reaction with (2ml).Under reduced pressure evaporation of volatile substances, and use CH₂Cl₂(150ml) extraction residual Thing.Wash extract with water, be dried (MgSO₄), and evaporate the rough desired product of the light yellow oil generating the purest form Thing (3.23g, 78.22%), i.e. uses it for next step without being further purified.¹H NMR(300MHz,CDCl₃)δ0.94(t, J=7.5Hz, 3H), 1.07 (m, 2H), 1.25 (m, 2H), 1.45 (sextet, 2H), 1.74 (quintet, 2H), 2.45 (septuples Peak, 1H), 4.23 (t, J=6.6Hz, 2H).

Step C:L-methyl-cyclopropane sulfonic acid butyl ester:

At-78 DEG C, under nitrogen atmosphere, to cyclopropane sulfonic acid 1-butyl ester (1g, 5.58mmol) solution in THF (15ml) In be slowly added into butyl lithium solution (3.84ml, 6,14mmol, 1.6M, THF).After 15 minutes, addition MeI (0.72ml, 11.16mmol), make solution be warmed to 0 DEG C, and terminate reaction with water (1ml).Under reduced pressure evaporation of volatile substances, and use CH₂Cl₂(100ml) extraction leftover.Wash extract with water, be dried (MgSO₄), and evaporate.Residue is through silica gel chromatography (eluant: hexane/CH₂Cl₂) purification obtains the title product (0.59g, 55.0%) of colorless oil.¹H NMR(300MHz, CDCl₃))δ0.84(m,2H),0.95(t,J=7.2Hz,3H),1.43(m,4H),1.53(s,3H),1.74(m,2H),4.21 ((t,J=6.6Hz,2H)。

Step D:1-methyl-cyclopropane potassium sulfonate:

Make 1-methyl-cyclopropane sulfonic acid 1-butyl ester (0.386g, 2mmol) and potassium thiocyanate (0.194g, 2mmol) at DME (5ml) the mixture backflow 16h and in water (5ml).Evaporation of volatile substances obtains rough sulfonate (0.348g, quantitative), It is dried under vacuum 16h at 50 DEG C.Without be further purified will this crude product for the next step.¹H NMR (300MHz,D₂O)δ0.56(t,J=6.3Hz,2H),0.96(t,J=6.3Hz,2H),1.26(s,3H)。

Step E:L-methyl-cyclopropane sulfonic acid chloride:

At 60 DEG C, make 1-methyl-cyclopropane potassium sulfonate (0.348g, 2mmol), thionyl chloride (5ml) and DMF (5) Solution backflow 16h.Under reduced pressure evaporation of volatile substances, and use CH₂Cl₂(50ml) extracted residues.Wash extract with water, It is dried (MgSO₄), and evaporate obtain yellow colloid oily crude product, i.e. use it for the next step without being further purified.

Step F:N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl)-1-methyl cyclopropane-1-sulfonamide:

According to general step B, 5,6-bis-fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen and 1-methyl-cyclopropane sulphur Acyl chloride reaction obtains desired product.¹H NMR(300MHz,CDCl₃): δ 7.42 (dd, J=1.8&10.5Hz, 1H), 7.36 (ddd,J=2.4,4.5&9.0Hz,1H),7.27(d,J=6.0Hz,1H),7.07(dd,J=9.3&17.7Hz,1H),6.24(dt, J=2.1,8.7&17.4Hz,1H),5.86(br s,1H),1.43(s,3H),1.33(t,J=5.4Hz,2H),0.75(dd,J= 5.1&6.3Hz,2H)；m/z=481[M-1]^-。

Embodiment 13

N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl)-l-(2,3-dihydroxypropyl) cyclopropane-l-sulphur Amide:

Step A:Cyclopropane sulfonic acid butyl ester:

Cyclopropanesulfonyl chloride (5g, 35mmol, 1eq) is dissolved in the BuOH (20ml) of excess, in this reaction of-10 DEG C of coolings Mixture, and drip pyridine (5.8mL, 70mmol, 2eq) lentamente.This mixture is made to warm to room temperature lentamente and stirred Night.Under reduced pressure remove solvent, and gained white solid is dissolved in CHCl₃In.By water, saline washing organic facies, it is dried (MgSO4), generation oil (4.8g, 24.9mmol, 71%) is then concentrated.¹H NMR(300MHz,CDCl₃): 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),.93(t,3H)。

Step B:1-pi-allyl cyclopropane-1-sulfonic acid butyl ester:

At-78 DEG C, under nitrogen atmosphere, in cyclopropane sulfonic acid 1-butyl ester (4.8g, 24.9mmol) solution in THF with Time add butyl lithium solution (15.6ml, 24.9mmol, 1.6M, THF) and allyl iodide (24.9mmol).This is stirred at-78 DEG C Reactant mixture 2 hours, and it is stirred at room temperature 3 hours.Under reduced pressure evaporation of volatile substances, and use CH₂Cl₂(100ml) extraction Take residue.Wash extract with water, be dried (MgSO₄), then evaporate.Residue through silica gel chromatography (eluant: hexane/ CH₂Cl₂) purification obtains the title product (3.75g, 69.0%) of colorless oil.¹H NMR(300MHz,CDCl₃): 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(m,4H),.93(m,5H)。

Step C:L-pi-allyl cyclopropane-l-potassium sulfonate:

L-methyl-cyclopropane sulfonic acid 1-butyl ester (3.75g, 17.2mmol) and potassium thiocyanate (1.7g, 17.2mmol) is made to exist Mixture backflow 16h in DME (20ml) and water (20ml).Evaporation of volatile substances obtains rough sulfonate, and (3.44g determines Amount), it is dried under vacuum 16h at 50 DEG C.Without be further purified will this crude product in the next step.¹H NMR (CDCl₃): δ 5.6 (m, 1H), 4.91-4.85 (dd, 2H), 2.471-2.397 (d, 2H), 0.756 (m, 2H), 0.322 (m, 2H)。

Step D:L-pi-allyl cyclopropane-l-sulfonic acid chloride:

At 60 DEG C, make l-pi-allyl cyclopropane-l-potassium sulfonate (3.44g, 17.2mmol), thionyl chloride (10ml) and DMF The solution backflow 16h of (5).Under reduced pressure evaporation of volatile substances, and use CH₂Cl₂(50ml) extraction leftover.Wash with water Extract, is dried (MgSO₄), and evaporate obtain yellow colloid oily crude product, its through hexane wash, without being further purified i.e. It is used in the next step (2.7g, 15mmol, 87%).¹H NMR(300MHz,CDCl₃): δ 5.728 (m, 1H), 5.191 (t, 2H),2.9(d,2H),0.756(m,2H),0.322(m,2H)。

Step E:L-pi-allyl-N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl) cyclopropane-1-sulfonamide:

According to general step B, 5,6-bis-fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen and 1-pi-allyl cyclopropane- The reaction of l-sulfonic acid chloride obtains desired product.m/z=507[M-1]^-。

Step F:N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl)-1-(2,3-dihydroxypropyl) ring third Alkane-1-sulfonamide:

By 1-pi-allyl-N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl) cyclopropane-1-sulfonamide (0, 77g, 1.52mmol) and 4-methylmorpholine N-oxide (0,18g, 1.52mmol) be dissolved in THF (50mL).At room temperature add (0.152mmol, 0.965mL, 4% are at H for Osmic acid.₂In O), and it is stirred at room temperature this reactant mixture 16 hours.Add EtOAc, washes organic facies with water, is dried (MgSO₄), and concetrated under reduced pressure.Residue through silica gel chromatography (eluant: EtOAc/MeOH) purification obtains title product (0.65g, 79%).¹H NMR(300MHz,CDCl₃+D₂O): δ 7.38 (dd, J= 1.8&10.5Hz,1H),7.36(ddd,J=2.4,5.1&9.3Hz,1H),7.25(d,J=8.7Hz,1H),7.02(dd,J=9.0& 17.7Hz,1H),6.27(dt,J=3.0,8.7&17.4Hz,1H),3.92(m,1H),3.54(dd,J=3.9&11.1Hz,1H), 3.39(dd,J=6.6&11.1Hz,1H),2.16(dd,J=9.6&15.9Hz,1H),1.59(d,J=14.1Hz,1H),1.41(m, 1H),1.26(m,1H),0.83(m,2H)；m/z=542[M-1]^-。

Embodiment 14

(S)-N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl)-l-(2,3-dihydroxypropyl) cyclopropane- L-sulfonamide:

Separate racemic mixture (embodiment 13) by chirality HPLC and obtain pure S isomer.¹H NMR(300MHz, CDCl₃+D₂: δ 7.38 (dd, J=1.8&10.5Hz, 1H), O) 7.36 (ddd, J=2.4,5.1&9.3Hz, 1H), 7.25 (d, J= 8.7Hz,1H),7.02(dd,J=9.0&17.7Hz,1H),6.27(dt,J=3.0,8.7&17.4Hz,1H),3.92(m,1H), 3.54(dd,J=3.9&11.1Hz,1H),3.39(dd,J=6.6&11.1Hz,1H),2.16(dd,J=9.6&15.9Hz,1H), 1.59(d,J=14.1Hz,1H),1.41(m,1H),1.26(m,1H),0.83(m,2H)；m/z=542[M-1]^-。

Embodiment 15

(R)-N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl)-l-(2,3-dihydroxypropyl) cyclopropane- L-sulfonamide:

Separate racemic mixture (embodiment 13) by chirality HPLC and obtain pure R isomer.¹H NMR(300MHz, CDCl₃+D₂: δ 7.38 (dd, J=1.8&10.5Hz, 1H), O) 7.36 (ddd, J=2.4,5.1&9.3Hz, 1H), 7.25 (d, J= 8.7Hz,1H),7.02(dd,J=9.0&17.7Hz,1H),6.27(dt,J=3.0,8.7&17.4Hz,1H),3.92(m,1H), 3.54(dd,J=3.9&11.1Hz,1H),3.39(dd,J=6.6&11.1Hz,1H),2.16(dd,J=9.6&15.9Hz,1H), 1.59(d,J=14.1Hz,1H),1.41(m,1H),1.26(m,1H),0.83(m,2H)；m/z=542[M-1]^-。

Embodiment 16

N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl)-l-(2-hydroxyethyl) cyclopropane-l-sulfonamide:

Step A:2-(1-bromine cyclopropyl) ethanol:

0 DEG C in the pure diethyl zinc (3.3ml, 3.977g, 30mmol) solution in the anhydrous DCM of 100ml the most slow Slowly drip trifluoroacetic acid (2.31ml, 3.4188g, 30mmol).(points for attention: violent gas release, heat release!).TFA adds After entering, stir this suspension 20min at the same temperature, be subsequently adding diiodomethane (2.45ml, 8.134g, 30.4mmol).It is stirred for 20min at 0 DEG C, the most at the same temperature, addition 3-bromine butyl-3-alkene-l-alcohol (1ml, 1.523g, 10.1mmol) the solution in 10ml DCM.After addition, this mixture is made to warm to room temperature and stir 4 hours.With 100ml MeOH and 40ml saline terminate the reaction of this mixture, are then stirred for 30min.Reduce solvent, and use CHCl₃/aq.NH₄Cl extraction leftover.Collected organic layer, washs with saline and water, and removes the 2-of the solvent enough purity of generation (l-bromine cyclopropyl)-ethanol (1.6564g, 100%).¹H-NMR(500MHz,CDCl₃): δ=3.90-3.83 (t, 2H), 1.91- 1.87(t,2H),1.71(s,1H,br),1.14-1.09(m,2H),0.83-0.79(m,2H)。

Step B:2-(the l-bromine cyclopropyl) ethanol of TBS protection:

Anhydrous pyridine is added in the cyclopropyl alcohol (step A) (1.303g, 7.95mmol) solution in the anhydrous DCM of 30ml (1.2ml, 1,1736g, 14.8mmol) and TBSOTf (2.7ml, 3.1077g, 11.76mol), and it is stirred at room temperature this solution 16h.Use CHCl₃/ saline extracts, and uses MgSO₄It is dried organic moiety.Reduce solvent, and with flash column chromatography (Si, CHCl₃/ Hexane 1:10, R_f=0.4) purification of crude product.Yield: 0.796g, 36%.¹H-NMR(500MHz,CDCl₃): δ=3.95-3.75 (t, 2H),1.95-1.85(t,2H),1.15-1.05(m,2H),0.95-0.80(m,HH),0.15-0.05(s,6H)。

Step C:2-(the 1-chlorosulfonyl cyclopropyl) ethanol of TBS protection:

At-78 DEG C, in step B, the Cyclopropyl Bromide (1.1227g, 4.04mmol) of preparation is in 15ml anhydrous diethyl ether Solution adds t-BuLi 1.7M solution (4.8ml, 8.16mmol) in pentane.Stir this solution 30min at this temperature, Then-78 DEG C of sulfonic acid chlorides being transferred to newly to distill by transfer sleeve pipe (transfer canola) (0.65ml, 1.029g, 8.1mmol) in the solution in 8ml diethyl ether.The suspension making yellow warms to room temperature.Remove solvent, and do in a vacuum Dry residue is to remove the sulfonic acid chloride of excess.Then, with hexane extraction leftover twice, after filtration, solvent is evaporated in vacuo Generate the colorless oil sulfonic acid chloride of enough purity.Yield: 870mg (72%).¹H-NMR(300MHz,CDCl₃): δ=3.95-3.85 (t,2H),2.35-2.25(t,2H),1.80-1.70(m,2H),1.45-1.38(m,2H),0.90(s,9H),0.10(s,6H)。

Step D:N-(the fluoro-2-of 3.4-bis-(2-fluoro-4-idodophenylamino) the phenyl)-1-(2-hydroxyethyl) of TBS protection Cyclopropane-1-sulfonamide:

According to general step B, 5,6-bis-fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen and the ring of preparation in step C The reaction of sulfonyl propyl chlorine obtains desired product.¹H-NMR(300MHz,CDCl₃): δ=7.44-7.39 (dd, 1H), 7.32-7.24 (m,2H),7.1-6.98(q,1H),6.34-6.24(m,1H),6.16(s,1H,br),3.85-3.75(t,2H),2.15-2.00 (t,2H),1.35-1.20(m,2H),0.95-0.75(m,11H),0.10(s,6H)；m/z=625[M-1]^-。

Step E:N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl)-l-(2-hydroxyethyl) cyclopropane-l- Sulfonamide:

At 0 DEG C, the sulfonamide (21mg, 0.033mmol) of the TBS protection of preparation in step D solution in 1ml THF Middle addition 0.1ml aq.1.2N HCl solution, and stir this solution 2h.Reduce solvent, and use NaHCO₃Aqueous solution and EtOAc extraction Take residue.Use MgSO₄It is dried organic moiety, and removes volatile material.With flash column chromatography (Si, CHCl₃/MeOH10: 1,R_f=0.45) purification of crude product generates pure product.Yield: 16.9mg (100%).¹H-NMR(300MHz,CDCl₃): δ= 7.44-7.39(dd,1H),7.32-7.24(m,2H),7.1-6.98(q,1H),6.34-6.24(m,1H),6.16(s,1H, br),3.85-3.75(t,2H),2.15-2.00(t,2H),1.35-1.20(m,2H),0.95-0.85(m,2H)；m/z=511 [M-1]^-。

Embodiment 17

N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl)-3-hydroxy propane-l-sulfonamide:

To the chloro-N-of 3-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl)-propane-1-sulfonamide (69.4mg, 0.138mmol) at 8ml1,4-dioxane and 2ml H₂In solution in the mixture of O add KOH powder (0.674g, 12.0mmol), and heat this mixture to reflux temperature continue 3 days.Extract with EtOAc/ saline, use Na₂SO₄It is dried organic portion Point, and remove volatile material.With flash column chromatography (Si, DCM/MeOH5:1, R_f=0.3) purification residues.Yield: 41mg (62%)。¹H-NMR (500MHz, MeOH [d4]): δ=7.38-7.21 (d, 1H), 7.23-7.21 (d, 1H), 7.06-7.00 (q, 1H),6.52-6.50(m,1H),6.17-6.13(t,1H),3.30-3.27(t,2H),2.86-2.83(t,2H),2.05-2.00 (m,2H)；m/z=485[M-1]^-。

Embodiment 18

N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl)-2-methyl-5-(trifluoromethyl) furan-3-sulphonyl Amine:

According to general step B, 5,6-bis-fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen (0.182mmol) and 2-first Base-5-(trifluoromethyl) furan-3-sulfonic acid chloride (0.5mmol) reaction forms N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-iodophenyl ammonia Base) phenyl)-2-methyl-5-(trifluoromethyl) furan-3-sulfonamide.¹H NMR(CDCl₃)δ2.2(s,3H),5.3(s,1H), 6.0(dt,1H),6.8(s,1H),6.95(s,1H),7.0-7.3(m,3H),7.4(dd,1H)。

Embodiment 19

N-(5-(N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl) sulfamoyl)-methylthiazol-2-base) Acetamide:

According to general step B, 5,6-bis-fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen (0.182mmol) and 2-second Acylamino--4-methylthiazol-5-sulfonic acid chloride (0.5mmol) reaction obtains N-(5-(N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-iodophenyl Amino) phenyl) sulfamoyl)-4-methylthiazol-2-base) acetamide.¹H NMR(CDCl₃))δ2.1(s,3H),2.2(s,3H), 5.9(dt,1H),6.05(s,1H),7.0-7.6(m,3H),7.4(dd,1H),8.0(s,1H)。

Embodiment 20

5-(5-chloro-1,2,4-thiadiazoles-3-base)-N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl) thiophene Fen-2-sulfonamide:

According to general step B, 5,6-bis-fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen (0.182mmol) and 5- The reaction of (5-chloro-1,2,4-thiadiazoles-3-base) thiophene-2-sulfonic acid chloride (0.5mmol) obtains 5-(5-chloro-1,2,4-thiadiazoles-3- Base)-N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl) thiophene-2-sulfonamide.¹H NMR(300MHz,CDCl₃))δ 5.8(dt,1H),5.95(s,1H),6.95(d,1H),7.4(m,2H),7.6(d,1H),7.8(s,1H)。

Embodiment 21

N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl)-3,5 dimethyl isoxazole-4-sulfonamide:

According to general step B, 5,6-bis-fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen (0.182mmol) and 3,5- Dimethyl isoxazole-4-sulfonic acid chloride (0.5mmol) reaction obtain N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl)- 3,5-dimethyl isoxazole-4-sulfonamide.¹H NMR(300MHz,CDCl₃))δ2.2(s,3H),2.4(s,3H),5.8(s,1H), 6.0(dt,1H),5.95(s,1H),6.9(s,1H),7.0(q,1H),7.2(m,3H),7.4(dd,1H)。

Embodiment 22

The chloro-N-of 5-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl)-1,3-dimethyl-lH-pyrazoles-4-sulphonyl Amine:

According to general step B, 5,6-bis-fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen (0.182mmol) and 5- The reaction of chloro-1,3-dimethyl-lH-pyrazoles-4-sulfonic acid chloride (0.5mmol) obtains the chloro-N-of 5-(the fluoro-2-of 3,4-bis-(2-fluoro-4-iodine Phenyl amino) phenyl)-1,3-dimethyl-lH-pyrazoles-4-sulfonamide.¹H NMR(300MHz,CDCl₃))δ2.1(s,3H),3.6 (s,3H),5.8(s,1H),5.95(dt,1H),7.0(q,1H),7.2(d,1H),7.3(m,2H),7.4(dd,1H)。

Embodiment 23

N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl)-2,5-dimethyl furan-3-sulfonamide:

According to general step B, 5,6-bis-fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen (0.182mmol) and 2,5- Dimethyl furan-3-sulfonic acid chloride (0.5mmol) reaction obtains N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl)-2, 5-dimethyl furan-3-sulfonamide.¹H NMR(300MHz,CDCl₃))δ2.2(s,3H),2.3(s,3H),5.8(s,1H),6.0 (dt,1H),6.8(s,1H),7.0(q,1H),7.2(d,1H),7.3(m,2H),7.4(dd,1H)。

Embodiment 24

N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl)-l-methyl-3-(trifluoromethyl)-lH-pyrazoles-4- Sulfonamide:

According to general step B, 5,6-bis-fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen (0.182mmol) and l-first Base-3-(trifluoromethyl)-lH-pyrazoles-4-sulfonic acid chloride (0.5mmol) reaction obtains N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-iodophenyl Amino) phenyl)-l-methyl-3-(trifluoromethyl)-lH-pyrazoles-4-sulfonamide.¹H NMR(300MHz,CDCl₃))δ3.8(s, 3H),5.7(s,1H),6.0(dt,1H),7.0(q,1H),7.2(m,2H),7.4(dd,1H),7.8(s,1H)。

Embodiment 25

N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl)-2,4-dimethylthiazole-5-sulfonamide:

According to general step B, 5,6-bis-fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen (0.182mmol) and 2,4- Dimethylthiazole-5-sulfonic acid chloride (0.5mmol) reaction obtains N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl)-2, 4-dimethylthiazole-5-sulfonamide.¹H NMR(300MHz,CDCl₃))δ2.3(s,3H),2.6(s,3H),5.7(s,1H),5.9 (dt,1H),7.1(q,1H),7.2(d,1H),7.3(m,IH),7.4(d,1H),7.4(s,1H)。

Embodiment 26

N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl)-1,2-dimethyl-lH-imidazoles-4-sulfonamide:

According to general step B, 5,6-bis-fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen and 1,2-dimethyl-lH- The reaction of imidazoles-4-sulfonic acid chloride obtains title compound.¹H NMR(300MHz,CDCl₃): δ 7.95 (br s, 1H), 7.37 (dd, J= 1.8&10.8Hz,1H),7.32-7.14(m,3H),6.98(dd,J=9.6&17.7Hz,1H),5.87(dt,J=4.2,9.0& 17.4Hz,1H),5.55(br s,1H),3.49(s,3H),2.31(s,3H)。

Embodiment 27

N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl) thiophene-3-sulfonamide:

According to general step B, 5,6-bis-fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen is anti-with thiophene-3-sulfonic acid chloride Title compound should be obtained.¹H NMR(300MHz,CDCl₃): δ 8.00 (dd, J=1.2&3.3Hz, 1H), 7.45 (dd, J=0.9& 5.1Hz,1H),7.35(m,2H),7.27(m,2H),6.91(dd,J=9.3&17.1Hz,1H),6.64(ddd,J=2.1,4.8& 8.7Hz,1H),6.34(dt,J=5.4,8.7&14.1Hz,1H),5.98(br d,J=2.1Hz,D₂O is commutative, 1H).

Embodiment 28

N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl) furan-2-sulfonamide:

According to general step B, 5,6-bis-fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen is anti-with furan-2-sulfonic acid chloride Title compound should be obtained.¹HNMR(300MHz,CDCl₃): δ 7.53 (br s, D₂O is commutative, 1H), 7.38 (dd, J=1.8& 10.5Hz,1H),7.30(d,J=8.4Hz,1H),7.21(d,J=3.0Hz,1H),6.96(dd,J=8.7&16.5Hz,1H), 6.87(ddd,J=1.8,5.1&9.0Hz,1H),6.53(dd,J=1.8&3.6Hz,1H),6.44(dt,J=5.1,8.7& 13.8Hz,1H),6.22(br s,D₂O is commutative, 1H).

Embodiment 29

N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl)-5-methylthiophene-2-sulfonamide:

According to general step B, 5,6-bis-fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen and 5-methylthiophene-2-sulphur Acyl chloride reaction obtains title compound.¹H NMR(300MHz,CDCl₃): δ 7.34 (dd, J=0.9&10.2Hz, 1H), 7.30 (ddd,J=2.1,4.8&9.0Hz,1H),7.25(d,J=3.9Hz,1H),7.07(m,2H),6.65(dd,J=1.2&3.9Hz, 1H),5.89(dt,J=2.4,8.7&17.4Hz,1H),5.54(br s,D₂O is commutative, 1H), 2.46 (s, 3H).

Embodiment 30

The chloro-N-of 5-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl) thiophene-2-sulfonamide:

According to general step B, 5,6-bis-fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen and 5-chlorothiophene-2-sulphonyl Chlorine reaction obtains title compound.¹H NMR(300MHz,CDCl₃): δ 7.38 (dd, J=1.5&10.2Hz, 1H), 7.32 (ddd, J =2.1,5.1&9.3Hz,1H),7.25(d,J=3.9Hz,1H),7.10(dd,J=9.0&18.6Hz,3H),6.84(d,J= 4.2Hz,1H),5.86(dt,J=1.8,8.7&17.4Hz,1H),5.49(br s,D₂O is commutative, 1H).

Embodiment 31

The bromo-N-of 5-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl) thiophene-2-sulfonamide:

According to general step B, 5,6-bis-fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen and 5-bromothiophene-2-sulphonyl Chlorine reaction obtains title compound.¹H NMR(300MHz,CDCl₃): δ 7.39-7.29 (m, 2H), 7.20-7.05 (m, 3H), 6.96(d,J=3.6Hz,1H),5.85(dt,J=2.1,9.0&17.4Hz,1H),5.54(br s,1H)。

Embodiment 32

The bromo-N-of 4-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl) thiophene-3-sulfonamide:

According to general step B, 5,6-bis-fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen and 4-bromothiophene-3-sulphonyl Chlorine reaction obtains title compound.¹H NMR(300MHz,CDCl₃): δ 7.48 (br m, 2H), 7.39 (dd, J=1.8&10.5Hz, 1H),7.28(ddd,J=2.4,4.8&9.0Hz,1H),7.17(d,J=8.4Hz,1H),7.02(m,1H),6.02(dt,J=2.4, 8.7&17.4Hz,1H),5.68(br s,1H)。

Embodiment 33

The chloro-N-of the bromo-5-of 4-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl) thiophene-2-sulfonamide:

According to general step B, 5,6-bis-fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen and 4-bromo-5-chlorothiophene- The reaction of 2-sulfonic acid chloride obtains title compound.¹H NMR(300MHz,CDCl₃): δ 7.42-7.34 (m, 2H), 7.25 (br m, 3H),7.13(dd,J=9.0&17.1Hz,1H),6.02(dt,J=2.4,6.6&17.4Hz,1H),5.52(br s,1H)。

Embodiment 34

The chloro-N-of the bromo-5-of 3-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl) thiophene-2-sulfonamide:

According to general step B, 5,6-bis-fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen and 3-bromo-5-chlorothiophene- The reaction of 2-sulfonic acid chloride obtains title compound.¹H NMR(300MHz,CDCl₃): δ 7.41 (dd, J=2.1&10.5Hz, 1H), 7.35 (br m,2H),7.31(dd,J=2.1&4.2Hz,1H),7.19(d,J=8.7Hz,1H),7.08(dd,J=9.0&17.4Hz, 1H),6.02(dt,J=2.1,8.4&17.1Hz,1H),5.59(br s,1H)。

Embodiment 35

N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl)-2,5-thioxene-3-sulfonamide:

According to general step B, 5,6-bis-fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen and 2,5-thioxene- The reaction of 3-sulfonic acid chloride obtains title compound.¹H NMR(300MHz,CDCl₃): δ 7.39 (dd, J=1.8&10.2Hz, 1H), 7.24-7.16(br m,2H),7.13(dd,J=9.0&17.4Hz,1H),6.77(d,J=9.6Hz,1H),5.98(dt,J=2.4, 8.7&17.4Hz,1H),5.55(br s,1H),2.33(s,6H)。

Embodiment 36

The chloro-N-of 2,5-bis-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl) thiophene-3-sulfonamide:

According to general step B, 5,6-bis-fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen and 2,5-dichloro-thiophene-3- Sulfonic acid chloride reaction obtains title compound.¹H NMR(300MHz,CDCl₃): δ 7.41 (dd, J=1.5&10.5Hz, 1H), 7.28- 7.20(m,2H),7.08(dd,J=9.0&17.4Hz,2H),6.99(s,1H),6.03(dt,J=2.1,8.7&17.4Hz,1H), 5.56(br s,1H)。

Embodiment 37

3-(N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl) sulfamoyl) thiophene-2-carboxylic acid methyl ester:

According to general step B, 5,6-bis-fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen and 3-(chlorosulfonyl) thiophene The reaction of fen-2-carboxylate methyl ester obtains title compound.¹H NMR(300MHz,CDCl₃): δ 8.58 (s, 1H), 7.43 (dd, J= 5.1&10.8Hz,2H),7.35(dd,J=1.8&10.2Hz,1H),7.31(ddd,J=2.1,4.2&9.3Hz,1H),7.04(m, 2H),5.88(dt,J=2.7,8.7&17.4Hz,1H),5.65(br s,1H),3.85(s,3H)。

Embodiment 38

5-(N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl) sulfamoyl)-l-methyl-lH-pyrroles-2- Carboxylate methyl ester:

According to general step B, 5,6-bis-fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen and 5-(chlorosulfonyl)-l- The reaction of methyl isophthalic acid H-pyrroles's-2-carboxylate methyl ester obtains title compound.¹H NMR(300MHz,CDCl₃): δ 7.37 (dd, J=1.8& 10.5Hz,1H),7.29(m,2H),7.12-6.94(m,4H),5.87(dt,J=1.8,8.4&17.4Hz,1H),5.56(br s, 1H),3.65(s,3H),3.75(s,3H)。

Embodiment 39

N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl)-5-methyl isoxazole-4-sulfonamide:

According to general step A, 5,6-bis-fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen is anti-with corresponding sulfonic acid chloride Title compound should be obtained.Yield: 22%.m/z=508[M-1]^-。

Embodiment 40

The chloro-N-of 3-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl) propane-l-sulfonamide:

According to general step A, 5,6-bis-fluoro-N-1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen and 3-chloropropane-l-sulphur Acyl chloride reaction obtains desired product.¹H NMR(500MHz,CDCl₃): δ=7.39-7.38 (d, 1H), 7.35-7.34 (m, 1H), 7.27-7.26(m,1H),7.10-7.0(q,1H),6.63(s,1H,br),6.15-6.11(q,1H),5.60(s,1H,br), 3.60-3.56(t,2H),3.22-3.20(m,2H),2.22-2.16(m,2H)。

Embodiment 41

N-(2-(4-chloro-2-Fluorophenylamino)-3,4-difluorophenyl) cyclopropanesulfonamide:

See embodiment 1.¹H NMR(300MHz,CDCl₃)δ0.85-0.95(m,2H),1.05-1.15(ra,2H),2.2- 2.4(m,1H),5.8(s,1H),6.3(t,1H),6.6-7.4(m,5H)；m/z=375[M-1]^-。

Embodiment 42

N-(the fluoro-2-of 3,4-bis-(4-iodo-2-MethYlphenylamino) phenyl) cyclopropanesulfonamide:

See embodiment 1.¹H NMR(CDCl₃)δ0.80-1.0(m,2H),1.05-1.20(m,2H),1.55(s,3H), 2.4-2.5(m,1H),5.6(s,1H),6.2(dd,1H),6.4(s,1H),7.1(q,1H),7.3-7.4(m,2H),7.5(s, 1H)；m/z=463[M-1]^-。

Embodiment 43

N-(2-(the 4-tert-butyl group-2-chlorphenylamino)-3,4-difluorophenyl) cyclopropanesulfonamide:

See embodiment 1.¹H NMR(300MHz,CDCl₃)δ0.9-1.0(m,2H),1.05-1.20(m,2H),1.3(s, 9H),2.4-2.5(m,1H),5.8(s,1H),6.3(dd,1H),6.6(s,1H),7.0-7.2(m,2H),7.3-7.4(m,2H)； m/z=413[M-l]^-。

Embodiment 44

N-(2-(2,4 dichloro benzene base amino)-3,4-difluorophenyl) cyclopropanesulfonamide:

See embodiment 1.¹H NMR(300MHz,CDCl₃)δ0.9-1.0(m,2H),1.05-1.20(m,2H),2.4-2.5 (m,1H),6.0(s,1H),6.3(dd,1H),6.6(s,1H),7.0-7.2(m,2H),7.3-7.4(m,2H)；m/z=392[M- 1]^-。

Embodiment 45

The chloro-N-of 3-(the fluoro-2-of 3,4-bis-(2-fluoro-4-trifluoromethyl) phenyl amino) phenyl) propane-1-sulfonamide:

See embodiment 1.¹H NMR(300MHz,CDCl₃): δ 7.39-7.26 (m, 2H), 7.25 (m, 1H), 7.18 (dd, J =9.0&17.7Hz,1H),6.78(br s,D₂O is commutative, 1H), 6.50 (t, J=8.1Hz, 1H), 6.00 (br d, D₂O can hand over Change, J=1.5Hz, 1H), 3.63 (t, J=6.0&6.3Hz, 2H), 3.29 (t, J=7.2&7.8Hz, 2H), 2.26 (quintet, 2H)； m/z=445[M-1]^-。

Embodiment 46

N-(the fluoro-2-of 3,4-bis-(2-chloro-4-trifluoromethyl) phenyl amino) Methanesulfomide:

See embodiment 1.¹H NMR(300MHz,CDCl₃): δ 7.65 (d, J=7.8Hz, 1H), 7.33 (m, 2H), 7.19 (dd,J=9.3&17.4Hz,1H),6.90(br s,D₂O is commutative, 1H), 6.45 (dd, J=1.5&8.4Hz, 1H), 6.39 (br s,D₂O is commutative, 1H), 3.02 (s, 3H)；m/z=399[M-1]^-。

Embodiment 47

The chloro-N-of 3-(the fluoro-2-of 3,4-bis-(2-chloro-4-trifluoromethyl) phenyl amino) phenyl) propane-1-sulfonamide:

See embodiment 1.¹H NMR(300MHz,CDCl₃): δ 7.66 (d, J=1.5Hz, 1H), 7.36 (m, 2H), 7.19 (dd,J=9.0&17.4Hz,1H),6.91(br s,D₂O is commutative, 1H), 6.50 (dd, J=8.4&1.5Hz, 1H), 6.37 (s, D₂O is commutative, 1H), 3.62 (t, J=6.0Hz, 2H), 3.29 (t, J=7.5&7.8Hz, 2H), 2.27 (quintet, 2H)；m/z= 462[M-1]^-。

Embodiment 48

The chloro-N-of 3-(the fluoro-2-of 3,4-bis-(2-bromo-4-trifluoromethyl) phenyl amino) phenyl) propane-l-sulfonamide:

See embodiment 1.¹H NMR(300MHz,CDCl₃): δ 7.82 (s, 1H), 7.38 (m, 2H), 7.20 (dd, J=9.0& 17.7Hz,1H),6.62(br s,D₂O is commutative, 1H), 6.43 (d, J=8.4Hz, 1H), 6.23 (s, D₂O is commutative, 1H), 3.65 (t, J=6.0Hz, 2H), 3.30 (t, J=7.5Hz, 2H), 2.28 (quintet, 2H)；m/z=506[M-1]^-。

Embodiment 49

Cyclopropane sulfonic acid (the fluoro-2-of 3,4,6-tri-(the iodo-phenyl amino of the fluoro-4-of 2-)-phenyl)-amide:

Step A:(the iodo-phenyl of the fluoro-4-of 2-)-(2,3,5-tri-fluoro-6-nitro-phenyl)-amine:

Under a nitrogen, by the stirring in anhydrous THF (100ml) of fluoro-for the 2-4-Iodoaniline (3.64gm, 15.37mmol) Solution is cooled to-78 DEG C, and is slowly added into 1.0M lithium hexamethyldisilazide (LiN (SiMe₃)₂) solution of " LHMDS " (15.37ml,15.37mmol).-78 DEG C of these reactant mixtures the most continuously stirred a hour, it is subsequently adding 2,3,4,6-tetrafluoros Nitrobenzol.Make this reactant mixture warm to room temperature, and be further continued for stirring 16 hours.Ethyl acetate (200ml) is added this anti- Answer in mixture, and wash with water.Organic layer is dried over sodium sulfate, and is further purified generation yellow solid by column chromatography (3.75gm, yield: 59.24%).M-H⁺: 410.9.¹H NMR (DMSO, 300MHz): 6.85 (t, 1H)；7.38(d,1H)；7.62 (m,2H)；8.78(s,1H).

Step B:The fluoro-N of 3,4,6-tri- ² -(the iodo-phenyl of the fluoro-4-of 2-)-benzene-1,2-diamidogen:

Exist to (the iodo-phenyl of the fluoro-4-of 2-)-(2,3,5-tri-fluoro-6-nitro-phenyl)-amine 3 (5.2gm, 12.62mmol) In the solution of the stirring in EtOH (200ml) add ammonium chloride (10.12gm, 189.3mmol) and iron powder (10.57gm, 189.3mmol).This reactant mixture of continuously stirred backflow 16 hours.Reactant mixture is made to cool down, through kieselguhr (celite) mistake Filter and be concentrated to dryness.Gained residue is placed in EtOAc, and washes with water.EtOAc layer is dried over sodium sulfate, and by from EtOH crystallization is purified generation pale solid (3.2gm, yield: 66.39%) further.M-H⁺: 381.1.¹H NMR(DMSO, 300MHz): 5.0 (s, 2H)；6.2(t,1H)；7,2-7.3(m,2H)；7.45(s,1H)；7.5(d,1H).

Step C:The fluoro-l-of 4,6,7-tri-(the iodo-phenyl of the fluoro-4-of ' 2-)-1,3 ,-dihydrobenzo imidazoles-2-ketone:

Exist to the fluoro-N2-of 3,4,6-tri-(the iodo-phenyl of the fluoro-4-of 2-)-benzene-1,2-diamidogen 3 (0.285gm, 0.74mmol) CH₂Cl₂(2ml) solution of the stirring in adds 1,1 '-carbonyl dimidazoles (0.125gm, 0.75mmol).At room temperature continue Stir this reactant mixture 16 hours, period product Precipitation.Filter white solid, its without any purification i.e. by further Use (0.2gm, yield: 65.85%).m/z=407[M-1]^-。

Step D/E:Cyclopropane sulfonic acid (the fluoro-2-of 3,4,6-tri-(the iodo-phenyl amino of the fluoro-4-of 2-)-phenyl)-amide:

Under a nitrogen, by 4,6,7-tri-fluoro-l-(the iodo-phenyl of the fluoro-4-of 2-)-1,3 ,-dihydrobenzo imidazoles-2-ketone The solution of (0.2gm, 0.41mmol) stirring in anhydrous THF (4ml) is cooled to-78 DEG C, and is slowly added into 1.0M LiHMDS solution (0.41ml, 0.41mmol).(2ml) cyclopropanesulfonyl chloride (0.050ml, 0.49mmol) it is subsequently added.In room Under temperature, this reactant mixture continuously stirred 16 hours, are concentrated to dryness, are placed in EtOAc.EtOAc part washes with water, through sulfur Acid sodium is dried, and is concentrated to dryness.By the gained residue fluoro-3-of l-cyclopropanesulfonyl-4,5,7-three (the iodo-phenyl of the fluoro-4-of 2-)- 1,3-dihydro-benzoimidazole-2-ketone 5 is placed in dioxane (2ml), and is added thereto to 1.0N NaOH (0.5ml), and 50 DEG C continuously stirred 16 hours.TLC shows to react the most completely, generates pale solid (4.4mg) by HPLC purified product.M+H⁺: 484.7, M-H⁺: 486.7.¹HNMR(CDCl₃, 300MHZ): 0.9-1.1-(m, 2H)；1.1-1.2(m,2H)；2.45-2.55 (m,1H)；6.05(s,1H)；6.44-6.54(m,1H)；7.1(s,1H)；7.4-7.7(d,1H)；7.38-7.44(dd,1H)；m/ z=485[M-1]^-。

Embodiment 50

N-(the fluoro-2-of 3,4-bis-(4-fluoro-2-idodophenylamino)-6-ethoxyl phenenyl) cyclopropanesulfonamide:

Step A:(2,3-bis-fluoro-5-methoxyl group-6-nitro-phenyl)-(the iodo-phenyl of the fluoro-4-of 2-)-amine:

Under a nitrogen, by (the iodo-phenyl of the fluoro-4-of 2-)-(2,3,5-tri-fluoro-6-nitro-phenyl)-amine (1.23gm, 3mmol) The solution of the stirring in anhydrous THF (25ml) is cooled to-78 DEG C, and be slowly added into 25%NaOMe solution (0.68ml, 0.3mmol).Make reactant mixture warm to room temperature, and be further continued for stirring 16 hours.TLC shows to react the most completely.By acetic acid second Ester (100ml) adds in this reactant mixture, and washes with water.Organic layer is dried over sodium sulfate, and enters one by column chromatography Step purification generates yellow solid (0.6gm, yield: 47.6%).m/z=424[M=H]⁺。

Step B:The fluoro-N1-of 5,6-bis-(4-fluoro-2-iodophenyl)-3-methoxybenzene-1,2-diamidogen:

To (2,3-bis-fluoro-5-methoxyl group-6-nitro-phenyl)-(the iodo-phenyl of the fluoro-4-of 2-)-amine (0.57gm, 1.34mmol) solution of the stirring in EtOH (20ml) adds ammonium chloride (1.18gm, 20.16mmol) and iron powder (1.15gm,21.44mmol).This reactant mixture of continuously stirred backflow 16 hours.Reactant mixture is made to cool down, through kieselguhr mistake Filter, and be concentrated to dryness.Gained residue is placed in EtOAc, and washes with water.EtOAc layer is dried over sodium sulfate, and by from EtOH crystallization is purified generation pale solid (0.47gm, yield: 90.3%) further.M-H⁺: 393.2.¹H NMR(DMSO, 300MHz): 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).

Step C:The fluoro-l-of 6,7-bis-(4-fluoro-2-iodophenyl)-4-methoxyl group-lH-benzo [d] imidazoles-2 (3H)-one:

Exist to the fluoro-N1-of 5,6-bis-(4-fluoro-2-iodophenyl)-3-methoxybenzene-1,2-diamidogen (0.17gm, 0.43mmol) CH₂Cl₂(2ml) solution of the stirring in adds 1,1 '-carbonyl dimidazoles (0.085gm, 0.53mmol).At room temperature continue Stir this reactant mixture 16 hours, period product Precipitation.Filter white solid, its without any purification i.e. by further Use (0.089gm)；m/z=419[M-1]^-。

Step D/F:N-(the fluoro-2-of 3,4-bis-(4-fluoro-2-idodophenylamino)-6-methoxyphenyl) cyclopropanesulfonamide:

Under a nitrogen, by l-(Cyclopropylsulfonyl)-4, the fluoro-3-of 5-bis-(2-fluoro-4-iodophenyl)-7-methoxyl group-lH-benzene And the solution of the stirring that [d] imidazoles-2 (3H)-one (0.89gm, 0.17mmol) is in anhydrous THF (4ml) is cooled to-78 DEG C, and It is slowly added into 1.0M LiHMDS solution (0.17ml, 0.17mmol).(2ml) be subsequently added cyclopropanesulfonyl chloride (0.021ml, 0.21mmol).It is continuously stirred at room temperature this reactant mixture 16 hours, is concentrated to dryness, is placed in EtOAc.EtOAc part Wash through water, dried over sodium sulfate, and be concentrated to dryness.By the fluoro-3-of gained l-(Cyclopropylsulfonyl)-4,5-two (2-fluoro-4-iodine Phenyl)-7-methoxyl group-lH-benzo [d] imidazoles-2 (3H)-one is placed in dioxane (2ml), and is added thereto to 1.0N NaOH , and continuously stirred 16 hours at 50 DEG C (0.5ml).TLC shows to react the most completely, generates canescence by HPLC purified product solid Body (2.5mg).M+H⁺: 484.7, M-H⁺: 497.3.¹H NMR(CDCl₃, 300MHz): 0.85-0.95 (m, 2H)；1.05-1.15 (m,2H)；2.4-2.5(m,1H)；3.9(s,3H)；6.1(s,1H)；6.4-6.6(m,2H)；7.3(m,1H)；7.35-7.4(dd, 1H)；m/z=497[M-1]^-。

Embodiment 51

Methanesulfonic acid (the fluoro-2-of 3,4-bis-(the iodo-phenyl amino of the fluoro-4-of 2-)-6-methoxyl group-phenyl)-amide:

Exist to the fluoro-N1-of 5,6-bis-(4-fluoro-2-iodophenyl)-3-methoxybenzene-1,2-diamidogen (0.150gm, 0.38mmol) Anhydrous CH₂Cl₂(4ml) the agitated solution in is slowly added into TEA (264ml, 1.9mmol) and mesyl chloride.In room temperature Under this reactant mixture continuously stirred 16 hours, TLC shows to react the most completely, it was observed that raw material and two kinds of products.Wash with water Reactant mixture, organic layer is dried over sodium sulfate, and is concentrated to dryness, by column chromatography eluting product.Discovery secondary product is Intended compound (6.4mg).M-H⁺: 471.5.¹H NMR(CDCl₃, 300MHz): 3.9 (s, 3H)；6.05(s,1H)；6.4- 6.5(m,1H)；6.5-6.6(m,1H)；7.2(s,1H)；7.28(d,1H)；7.35-7.4(d,1H)；m/z=471[M-1]^-。

Embodiment 52

L-(2,3-dihydroxy-propyl group)-cyclopropane sulfonic acid [the fluoro-2-of 3,4,6-tri-(the iodo-phenyl amino of the fluoro-2-of 4-)-benzene Base]-amide:

Step A:1-pi-allyl-cyclopropane sulfonic acid [the fluoro-2-of 3,4.6-tri-(the iodo-phenyl amino of the fluoro-4-of 2-) phenyl]-acyl Amine:

According to general step B, 1-pi-allyl-cyclopropanesulfonyl chloride and 3,5,6-tri-fluoro-N¹-(2-fluoro-4-iodophenyl) benzene- 1,2-diamine reactant obtains title product.¹H NMR(CDCl₃, 300MHz): δ 7.41 (dd, 1H), 7.38 (dd, 1H), 7.09 (s, 1H),6.78(m,1H),6.49(m,1H),5.96(s,1H),5.86(m,1H),5.18(d,2H),2.76(d,2H),1.23(m, 2H),0.872(m,2H)。

Step B:L-(2,3-dihydroxypropyl)-N-(the fluoro-2-of 3,4,6-tri-(2-fluoro-4-idodophenylamino) phenyl) ring third Alkane-1-sulfonamide:

By 1-pi-allyl-cyclopropane sulfonic acid [the fluoro-2-of 3,4,6-tri-(the iodo-phenyl amino of the fluoro-4-of 2-)-phenyl]-amide (110mg, 0.21mmol) and 4-methylmorpholine N-oxide (24.6mg, 0.21mmol) are dissolved in THF (8mL).At room temperature (0.021mmol, 0.153mL, 4% are at H to add Osmic acid.₂In O), and it is stirred at room temperature this reactant mixture 16 hours.Add Enter EtOAc, organic phase washed with water, be dried (MgSO₄), and concentrating under reduced pressure.Residue through silica gel chromatography (eluant: EtOAc/MeOH) purification obtains title product (0.89g, 75%).¹H NMR(CDCl₃, 300MHz): δ 7.39 (dd, J=1.5& 10.6Hz,1H),7.29(d,J=8.8Hz,IH),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&11.4Hz,1H),3.53(dd.J=6.7&11.2Hz,1H),2.50(dd,J=10.0& 16.1Hz,1H),1.6(m,lH),1.46(m,1H),1.28(m,1H),1.20(m,2H),0.92(m,2H)；m/z=559[M- 1]^-。

Embodiment 53

(S)-l-(2,3-dihydroxypropyl)-N-(the fluoro-2-of 3,4,6-tri-(2-fluoro-4-idodophenylamino) phenyl) ring third Alkane-l-sulfonamide:

Separate racemic mixture (embodiment 52) by chirality HPLC and obtain pure S isomer.¹H NMR(CDCl₃, 300MHz): δ 7.39 (dd, J=1.5&10.6Hz51H), 7.29 (d, J=8.8Hz, 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&11.4Hz51H),3.53(dd,J=6.7& 11.2Hz,1H),2.50(dd,J=10.0&16.1Hz,1H),1.6(m,lH),1.46(m,1H),1.28(m,1H),1.20(m, 2H),0.92(m,2H)；m/z=559[M-1]^-。

Embodiment 54

(R)-l-(2,3-dihydroxypropyl)-N-(the fluoro-2-of 3,4,6-tri-(2-fluoro-4-idodophenylamino) phenyl) ring third Alkane-l-sulfonamide:

Separate racemic mixture (embodiment 52) by chirality HPLC and obtain pure R isomer.¹H NMR(CDCl₃, 300MHz): δ 7.39 (dd, J=1.5&10.6Hz, 1H), 7.29 (d, J=8.8Hz, 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&11.4Hz,1H),3.53(dd,J=6.7& 11.2Hz,1H),2.50(dd,J=10.0&16.1Hz,1H),1.6(m,lH),1.46(m,1H),1.28(m,1H),1.20(m, 2H),0.92(m,2H)；m/z=559[M-1]^-。

Embodiment 55

Step A:The fluoro-2-of 1-pi-allyl-N-3,4-two (2-fluoro-4-idodophenylamino)-6-methoxyphenyl) cyclopropane- 1-sulfonamide:

According to general step B, 1-pi-allyl-cyclopropanesulfonyl chloride and 5, the fluoro-N1-of 6-bis-(2-fluoro-4-iodophenyl)-3-first Epoxide benzene-1,2-diamine reactant obtains title product.¹H NMR(CDCl₃, 300MHz): δ 7.417 (dd, 1H), 7.309 (s, 1H),7.25(m,1H),6.89(m,1H),6.52(m,1H),6.427(m,1H),6.03(s,lH),5.668(m,1H),5.11 (t,1H),3.9(s,3H),2.75(d,2H),1.21(m,2H),0.767(m,2H)。

Step B:N-(the fluoro-2-of 3.4-bis-(2-fluoro-4-idodophenylamino) phenyl)-1-(2,3-dihydroxypropyl) ring third Alkane-1-sulfonamide:

By l-pi-allyl-N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl) cyclopropane-l-sulphur Amide (97mg, 0.18mmol) and 4-methylmorpholine N-oxide (21mg, 0.18mmol) are dissolved in THF (8mL).At room temperature (0.018mmol, 0.13mL, 4% are at H to add Osmic acid.₂In O), and it is stirred at room temperature this reactant mixture 16 hours.Add Enter EtOAc, organic phase washed with water, be dried (MgSO₄), and concetrated under reduced pressure.Through silica gel chromatography (eluant: EtOAc/ MeOH) purification residues obtains title product (0.80g, 78%).¹H NMR(CDCl₃, 300MHz): δ 7.38 (dd, J=1.7& 10.3Hz,1H),7.26(m,1H),7.14(s,1H),6.87(s,1H),6.53(dd,J=6.8&11.4Hz,1H),6.43(m, 1H),4.06(m,1H),3.89(s,3H),3.63(dd,J=3.7&11.1Hz,1H),3.49(dd,J=6.4&11.1Hz,1H), 2.3(dd,J=9.7&16.1Hz,1H),1.77(dd,J=1.9&16.0Hz,1H),1.37(m,1H),1.25(m,1H),1.21 (m,2H),0.86(m,2H)；m/z=571[M-1]^-。

Embodiment 56

(S)-N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-l-(2,3-dihydroxy third Base) cyclopropane-1-sulfonamide:

Separate racemic mixture (embodiment 55) by chirality HPLC and obtain pure S isomer.¹H NMR(CDCl₃, 300MHz): δ 7.38 (dd, J=1.7&10.3Hz, 1H), 7.26 (m, 1H), 7.14 (s, 1H), 6.87 (s, 1H), 6.53 (dd, J= 6.8&11.4Hz,1H),6.43(m,1H),4.06(m,1H),3.89(s,3H),3.63(dd,J=3.7&11.1Hz,1H),3.49 (dd,J=6.4&11.1Hz,1H),2.3(dd,J=9.7&16.1Hz,1H),1.77(dd,J=1.9&16.0Hz,1H),1.37(m, 1H),1.25(m,1H),1.21(m,2H),0.86(m,2H)；m/z=571[M-1]^-。

Embodiment 57

(R)-N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-l-(2,3-dihydroxy third Base) cyclopropane-l-sulfonamide:

Separate racemic mixture (embodiment 55) by chirality HPLC and obtain pure R isomer.¹H NMR(CDCl₃, 300MHz): δ 7.38 (dd, J=1.7&10.3Hz, 1H), 7.26 (m, 1H), 7.14 (s, 1H), 6.87 (s, 1H), 6.53 (dd, J= 6.8&11.4Hz,1H),6.43(m,1H),4.06(m,1H),3.89(s,3H),3.63(dd,J=3.7&11.1Hz,1H),3.49 (dd,J=6.4&11.1Hz,1H),2.3(dd,J=9.7&16.1Hz,1H),1.77(dd,J=1.9&16.0Hz,1H),1.37(m, 1H),1.25(m,1H),1.21(m,2H),0.86(m,2H)；m/z=571[M-1]^-。

Embodiment 58

1-(2-hydroxyethyl)-N-(the fluoro-2-of 3,4,6-tri-(2-fluoro-4-idodophenylamino) phenyl) cyclopropane-1-sulphonyl Amine:

Step A:1-(2-hydroxyethyl)-N-(the fluoro-2-of 3.4,6-tri-(the 2-fluoro-4-idodophenylamino) benzene of TBS protection Base) cyclopropane-1-sulfonamide:

According to general step B, the sulfonic acid chloride and 5 of preparation, the fluoro-N1-of 6-bis-(2-fluoro-4-iodobenzene in step C of embodiment 16 Base)-3-fluorobenzene-1,2-diamine reactant obtains title product.Yield: 13%.¹H-NMR(300MHz,CDCl₃): δ=7.51 (s, 1H, br),7.37-7.35(d,1H),7.27-7.25(d,1H),6.94(s,1H,br),6.78-6.68(m,1H),6.46-6.44 (m,1H),3.90-3.88(t,2H),2.12-2.10(t,2H),1.31-1.28(m,2H),0.91-0.89(m,2H),0.86 (s,9H),0.05(s,6H)；m/z=643[M-l]^-。

Step B:1-(2-hydroxyethyl)-N-(the fluoro-2-of 3,4,6-tri-(2-fluoro-4-idodophenylamino)-phenyl) cyclopropane- 1-sulfonamide:

With the step in step E of embodiment 16.Yield: 100%.¹H-NMR(300MHz,CDCl₃): δ=7.51 (s, 1H, br),7.37-7.35(d,1H),7.27-7.25(d,1H),6.94(s,1H,br),6.78-6.68(m,1H),6.46-6.44 (m,1H),3.90-3.88(t,2H),2.12-2.10(t,2H),1.31-1.28(m,2H),0.91-0.89(m,2H)；m/z= 529[M-1]^-。

Embodiment 59

N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2-hydroxyethyl) cyclopropane- 1-sulfonamide:

Step A:N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-the idodophenylamino)-6-methoxyphenyl)-1-(2-of TBS protection Hydroxyethyl) cyclopropane-1-sulfonamide:

According to general step B, the sulfonic acid chloride and 5 of preparation, the fluoro-N1-of 6-bis-(2-fluoro-4-iodobenzene in step C of embodiment 16 Base)-3-methoxyl group-benzene-1,2-diamine reactant obtains title product.Yield: 37%.¹H-NMR(300MHz,CDCl₃): δ=7.40- 7.34(dd,1H),7.23-7.21(m,1H),6.61(s,1H,br),6.57-6.49(dd,1H),6.48-6.39(m,1H), 3.9-3.7(m,5H),2.15-2.05(t,2H),1.30-1.20(m,2H),0.95-0.80(m,11H),0.05(s,6H)；m/z =655[M-1]^-。

Step B:N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2-hydroxyethyl) Cyclopropane-1-sulfonamide:

With the step in step E of embodiment 16.Yield: 100%.¹H-NMR(300MHz,CDCl₃): δ=7.40-7.34 (dd,1H),7.23-7.21(m,1H),6.61(s,1H,br),6.57-6.49(dd,1H),6.48-6.39(m,1H),3.9- 3.7(m,5H),2.15-2.05(t,2H),1.30-1.20(m,2H),0.95-0.80(m,2H)；m/z=541[M-1]^-。

Embodiment 60

N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(3-hydroxyl-2-(hydroxyl first Base) propyl group) cyclopropane-1-sulfonamide:

Step A:2-(2-bromine pi-allyl) dimethyl malenate:

At 0 DEG C, under argon gas, to sodium hydride (5.0g, 125mmol) hanging among HMPA (50ml distills from calcium hydride) Supernatant liquid adds the dimethyl malenate (11.7ml, 100mmol) solution in HMPA (5ml).Heat the mixture to 50 DEG C And stir 1 hour.Hereafter, then this solution is cooled to 0 DEG C, and by 2,3-propylene bromide (12.2ml, 100mmol) is at HMPA (5ml) solution in adds in this reactant mixture.Then, this solution is made to be warmed to 40 DEG C and stir 1 hour.This reacts mixing Thing HCl/water solution (10%, 88ml) terminates reaction, and extracts with ether (3x45ml).Collect organic moiety, through MgSO₄It is dried, And remove solvent in a vacuum.Colorless oil title is obtained by silica gel chromatography (eluant: chloroform/hexane) purification of crude liquefaction Product (16.3g, 65%).¹H-NMR(300MHz,CDCl₃)δ5.70(d,J=1.8Hz,1H),5.48(d,J=1.8Hz,1H), 3.63(t,J=7.5Hz,1H),3.76(s,6H),3.04(d,J=7.5Hz,2H)。

Step B:2-(2-bromine pi-allyl) acrylate-1,3-glycol:

Lithium aluminium hydride reduction (1.9g, 7.65mmol) is made to form slurry in anhydrous diethyl ether (50ml), and in dry ice/acetone batch In be cooled to-78 DEG C.Then dropping derives from molten in absolute ether (26ml) of the product (0.639g, 16.84mmol) of step A Liquid.After adding this malonate, make solution warm to room temperature and continue to stir 3 hours.Terminate reaction with saline (50ml), use second Acetoacetic ester (3x25ml) extracts, and through MgSO₄It is dried.Remove solvent in a vacuum and generate desired product (1.3g, 86%), not Next step is i.e. used it for through being further purified.¹H-NMR(300MHz,CDCl₃)δ5.66(d,J=1.2Hz,1H),5.48(d, J=1.5Hz,1H),3.86(m,2H),3.73(m,2H),2.51(d,J=7.5Hz,2H),2.40(br s,2H),2.15(m, 1H)。

Step C:2-(2-bromine pi-allyl) the acrylate-1,3-glycol of di-t-butyl dimetylsilyl protection:

The product (2.8g, 14.20mmol) deriving from step B is dissolved in anhydrous THF (140ml).Add anhydrous pyridine (2.5ml, 31.24mmol), and this is dissolved in is cooled to 0 DEG C.Dropping t-butyldimethylsilyl triflate (7.2ml, 31.24mmol), when adding complete, is heated to 35 DEG C by this reaction solution.After stirring 6 days, with 100ml saline eventually Only reaction, extracts by ethyl acetate (3x50ml), and through MgSO₄It is dried.The organic facies that evaporation merges obtains yellow oily and slightly produces Thing (5.5g, 91%), i.e. uses it in next step without being further purified.¹H-NMR(300MHz,CDCl₃)δ5.54(d,J= 0.9Hz,1H),5.40(d,J=1.2Hz,1H),3.55(d,J=5.4,4H),2.40(d,J=6.9Hz,2H),1.97(m,1H), 0.85(s,18H),0.02(s,9H)。

Step D:2-((1-bromine cyclopropyl) methyl) the acrylate-1,3-glycol of di-t-butyl dimetylsilyl protection:

At 0 DEG C, in reaction flask, add anhydrous CH₂Cl₂(10ml) and diethyl zinc (1.0M in hexane, 4.65ml, 4.65mmol).Dropping trifluoroacetic acid (0.358ml, 4.65mmol), and stir this solution 20 minutes.It is subsequently adding diiodomethane (0.375ml, 4.65mmol), and it is stirred for this solution 20 minutes.Finally, add derive from step C product (0.492g, 1.16mmol), and make this solution be warmed to ambient temperature, stir 16 hours.With saturated NH₄Cl aqueous solution terminates this reaction. Distribute each layer, and by chloroform (3x5ml) aqueous phase extracted.The organic facies merged with saline (10ml) washing, through MgSO₄It is dried, and Remove volatile material in a vacuum.Clarification is generated by silica gel chromatography (eluant: chloroform/hexane) purification gained crude product Oil product (0.280g, 64%).¹H-NMR(300MHz,CDCl₃)δ3.66(d,J=5.4,4H),2.08(m,1H),1.64(d,J =6.9,2H),1.13(m,2H),0.88(s,18H),0.81(m,2H),0.04(s,9H)。

Step E:1-(3-hydroxyl-2-(hydroxymethyl) propyl group) cyclopropane of di-t-butyl dimetylsilyl protection- 1-sulfonic acid chloride:

The product (0.507g, 1.16mmol) deriving from step D is dissolved in absolute ether (6ml), and by this reaction solution It is cooled to-78 DEG C.Hereafter, in 5 minutes, tert-butyl lithium (1.7M in pentane, 1.50ml, 2.55mmol) is dripped.Stirring 0.5 After hour, by sleeve pipe, the product of lithiumation is transferred to sulfonic acid chloride (0.206ml, 2.55mmol) at absolute ether at-78 DEG C (6ml) in the agitated solution in.Once shift complete, just make solution warm to room temperature, evaporate solvent, and by gained white Solid forms slurry in anhydrous hexane.Filter this slurry by kieselguhr immediately, and remove whole volatility thing in a vacuum Matter.Separating obtained crude yellow oil (0.376g, 71%), and i.e. use it in next step without being further purified 。¹H-NMR(300MHz,CDCl₃)δ3.60(m,4H),2.16(m,1H),2.03(d,2H),0.88(s,18H),0.04(s,9H)。

Step F:Di-t-butyl dimetylsilyl protection N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)- 6-methoxyphenyl)-1-(3-hydroxyl-2-(hydroxymethyl) propyl group) cyclopropane-1-sulfonamide:

Under an argon, by 5, the fluoro-N1-of 6-bis-(2-fluoro-4-iodophenyl)-3-methoxybenzene-1,2-diamidogen (8.8mg, 0.022mmol) it is dissolved in anhydrous pyridine (0.5ml).The product deriving from step E in anhydrous pyridine (0.5ml) will be dissolved in (20.5mg, 0.045mmol) adds in reaction flask, and adds this mixture 21 hours at 80 DEG C.Remove solvent in a vacuum, And generate title compound (2.75mg, 15%) by silica gel chromatography (eluant: ethyl acetate/hexane) purification gained crude product. m/z813.5(M-1)。

Step G:N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(3-hydroxyl-2-(hydroxyl Ylmethyl) propyl group) cyclopropane-1-sulfonamide:

The product (27.9mg, 0.0342mmol) deriving from step F is dissolved in THF (1ml), and uses HCl/water solution at 0 DEG C (1.2N, 0.2ml) processes.Stirring gained solution 4 hours.Hereafter, saturated NaHCO is used₃Aqueous solution terminates this reaction, uses acetic acid second Ester extracts, through MgSO₄It is dried, and removes volatile material in a vacuum.By silica gel chromatography (eluant: methanol/chloroform) Then by LC-MS purification, purification gained crude product generates title compound (11.8mg, 59%).¹H-NMR(300MHz,CD₃OD)δ 7.32(dd,1H),7.21(d,1H),6.76(dd,1H),6.33(m,1H),3.82(s,3H),3.52(d,4H),2.01(m, 1H),1.88(d,2H),1.07(m,2H),0.75(m,2H),m/z585.3(M-1)^-。

Embodiment 61

N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl) Tetramethylene. sulfonamide:

Step A:Tetramethylene. sulfonic acid chloride:

Sub-fraction sub-fraction ground in Mg bits (0.790g, 32.5mmol) suspension in 20ml anhydrous diethyl ether Add the cyclobutyl bromine (1.8ml, 2.5722g, 19.1mmol) solution in 20ml diethyl ether, be stirred vigorously simultaneously.Initially Exothermic reaction stop after, reheat this mixture to reflux temperature 30min.This suspension is cooled to room temperature, and by upper Clear liquid sub-fraction sub-fraction ground adds sulfonic acid chloride (4.6ml, 7.728g, 57.2mmol) ice-cold in the anhydrous DCM of 30ml Solution in.After addition, this suspension is warmed to room temperature, and remove volatile material in a vacuum.In vacuum oil pump Middle dried residue 15min, then extracts with hexane (150ml).Filter this hexane suspension, and it is raw to remove hexane in a vacuum Become mulberry oily crude product, i.e. use it for next step without being further purified.Still there are some unreacted cyclopropyl Bromine exists.Crude yield: 1.1g (38%).

Step B:N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl) Tetramethylene. sulfonamide:

According to general step B, the cyclobutyl sulfonic acid chloride and 5 of preparation, the fluoro-N1-of 6-bis-(2-fluoro-4-iodobenzene in above step Base)-3-methoxybenzene-1,2-diamine reactant obtains title product.Yield: 75%.¹H-NMR(300MHz,CDCl₃): δ=7.44 (s,1H,br),7.41-7.36(dd,1H),7.24-7.23(m,1H),6.54-6.38(m,2H),5.90(s,1H,br), 3.85-3.75(m,5H),2.60-2.40(m,2H),2.25-2.15(m,1H),2.15-1.95(m,2H)；m/z=511[M- 1]^-。

Embodiment 62

N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-aminomethyl phenyl)-1-(2,3-dihydroxypropyl) ring third Alkane-1-sulfonamide:

Step A:(3,4,5-trifluorophenyl) methanol:

To cooling (-5 DEG C) 3,4,5-trifluro benzaldehyde (7.0g, 43.75mmol) THF and water mixture (50ml, In solution in 9:1), in 30min, it is slowly added to NaBH in batches₄(1.662g,43.75mmol).Make within the time of 2h This reactant mixture reaches room temperature, and is poured into carefully in ice-cold dilute HCl (200ml, 1N).Oil reservoir is extracted into CH₂Cl₂(250ml) in, organic layer washs through water (200ml), is dried (MgSO₄), and evaporate.Gained crude product (7.08g, fixed Amount) it is continuing with without being further purified.

Step B:5-(bromomethyl)-1,2,3-trifluoro-benzene:

To (3,4,5-trifluorophenyl) methanol (40mmol) at CH₂Cl₂(150ml) solution in is slowly added into sulfurous Acylbromide (6.16ml, 80mmol) is at CH₂Cl₂(50ml) solution in.At room temperature, stir this reactant mixture 16h, and by it Pour in frozen water (200ml).Organic layer is separated, with saturated NaHCO₃(2x200ml), water (200ml) washing, be dried (MgSO₄), and evaporate and obtain corresponding pale yellowish oil bromo compound with quantitative yield.Will this without being further purified Crude product continues on for the next step.

Step C:1,2,3-tri-fluoro-5-methylbenzene:

Above bromine compounds (40mmol) mixes with triethyl-silicane (48mmol), and uses solid PdCl₂(4mmol) one Fraction sub-fraction ground processes this reactant mixture.After a few minutes, then there is violent exothermic reaction, note by installing The content of reflux condenser backflow flask.At room temperature, it is stirred for this reactant mixture 6h, and makes this content stand 16h. Topple over crude liquid product the most carefully, it will continue on for the next step without being further purified.Assuming that this reaction with Quantitative yield is carried out.

Step D:1,2,3-tri-fluoro-5-methyl-4-Nitrobenzol:

At 0-5 DEG C, fluoro-for 1,2,3-tri-5-methylbenzene (40mmol) is added dense H₂SO₄(50ml) in.Then dense HNO is used₃ (3.39ml, 48.44mmol, 90%) processes this reactant mixture lentamente, keeps internal temperature less than 20 DEG C simultaneously.In room temperature Lower stirring this reactant mixture 16h, is poured upon on ice (300g), and uses CH₂Cl₂(2x125ml) extraction oil reservoir.Organic layer With water (2x200ml), saline (200ml) washing, it is dried (MgSO₄), and evaporate obtain crude product, this crude product is through Flash silica Chromatography purification obtains title product (6.5g, 85%).¹H-NMR(300MHz,CDCl₃): δ 6.96 (septet, 1H), 2.39 (s, 3H)。¹⁹FNMR(CDCl₃): δ-128.18 ,-141.50 ,-159.05.

Step E:The fluoro-N-of 2,3-bis-(2-fluoro-4-iodophenyl)-5-methyl-6-nitroaniline:

Use the condition described in embodiment 1 (step A), make 2-fluoro-4-Iodoaniline and 1,2,3-tri-fluoro-5-methyl-4- Nitrobenzol reaction forms title compound.M-H⁺: 407.9.

Step F:The fluoro-N1-of 5,6-bis-(2-fluoro-4-iodophenyl)-3-methylbenzene-1,2-diamidogen:

Use condition described in embodiment 1 (step B), reductase 12, the fluoro-N-of 3-bis-(2-fluoro-4-iodophenyl)-5-methyl-6- Nitroaniline forms title compound.M-H⁺: 377.4.

Step G:L-pi-allyl-N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-aminomethyl phenyl) cyclopropane-1- Sulfonamide:

According to general step B, 1-pi-allyl-cyclopropanesulfonyl chloride (142mg, 142mg) and 5, (2-is fluoro-for the fluoro-N1-of 6-bis- 4-iodophenyl)-3-methylbenzene-1,2-diamidogen (150mg, 0.4mmol) reaction obtain title product (100mg, 47%)；m/z=521 [M-1]^-。

Step H:N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-aminomethyl phenyl)-1-(2,3-dihydroxy third Base) cyclopropane-1-sulfonamide:

By 1-pi-allyl-N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-aminomethyl phenyl) cyclopropane-1-sulphonyl Amine (150mg, 0.29mmol) and 4-methylmorpholine N-oxide (33mg, 0.29mmol) are dissolved in THF (5mL).At room temperature (0.029mmol, 0.18mL, 4% are at H to add Osmic acid.₂In O), and it is stirred at room temperature this reactant mixture 16 hours.Add Enter EtOAc, organic phase washed with water, be dried (MgSO₄), and under reduced pressure concentrate.Through silica gel chromatography (eluant: EtOAc/ MeOH) purification residues obtains title product (0.110g, 68%).¹H-NMR(300MHz,CDCl₃): 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=3.9Hz,1H),2.42(s,3H),2.31(dd,J=9.9&15.6Hz,1H),2.01(br t,1H),2.31(dd,J= 9.9&15.6Hz,1H),1.66(dd,J=2.1&15.9Hz,1H),1.52(m,1H),1.40(m,1H),0.91(m,2H)。

Embodiment 63

1-(2,3-dihydroxypropyl)-N-(the fluoro-2-of 6-ethyl-3,4-two (2-fluoro-4-idodophenylamino) phenyl) ring third Alkane-1-sulfonamide:

Step A:1-(3,4,5-trifluorophenyl) ethanol:

It is slowly added into 3,4,5-trifluoro-benzene at-78 DEG C of diethyl ether solutions by MeMgBr (17.41ml, 52.24mmol, 3M) In the formaldehyde (6.96g, 43.53mmol) solution in THF (125ml).It is stirred at room temperature this reactant mixture 16h, cooling (0 DEG C), and terminate reaction with Excess ethyl acetate (10ml) and water (5ml) successively.Add the anhydrous MgSO of excess₄(5g), and It is stirred at room temperature 30 minutes.Filter suspension through kieselguhr, and wash solid by ethyl acetate (2x25ml).Evaporation merges Filtrate obtains product (7.65g) with quantitative yield.

Step B:5-(l-bromoethyl)-1,2,3-trifluoro-benzene:

To 1-(3,4,5-trifluorophenyl) ethanol (7.65g, 43.5mmol) at CH₂Cl₂(250ml) in the solution in slowly Ground adds thionyl bromide (18.1g, 87mmol) at CH₂Cl₂(50ml) solution in.It is stirred at room temperature this reactant mixture 16h, and be poured in frozen water (200ml).Organic layer is separated, and with saturated NaHCO₃(2x200ml), water (200ml) washing, is dried (MgSO₄), and evaporate the corresponding bromine compounds obtaining lark oily with quantitative yield (10.4g).The next step will be continued on for by this crude product without being further purified.

Step C:5-ethyl-1,2,3-trifluoro-benzene:

Above-mentioned bromine compounds (9.65g, 40.4mmol) is mixed with triethyl-silicane (41mmol), and uses solid PdCl₂(177mg, 4mmol) sub-fraction sub-fraction ground processes this reactant mixture.After a few minutes, then occur violent Exothermic reaction, notes the content by installing back flow condenser backflow flask.At room temperature, this reactant mixture it is stirred for 6h, and make this content stand 16h.Topple over crude liquid product the most carefully, will it continue to use without being further purified In the next step.Assuming that this reaction is carried out with quantitative yield.

Step D:The fluoro-2-Nitrobenzol of 1-ethyl-3,4,5-three:

At 0-5 DEG C, fluoro-for 1,2,3-tri-5-methylbenzene (6.46g, 40.4mmol) is added dense H₂SO₄(50ml) in.Then use Dense HNO₃(3.39ml, 48.44mmol, 90%) processes this reactant mixture lentamente, keeps internal temperature less than 20 DEG C simultaneously. It is stirred at room temperature this reactant mixture 16h, is poured upon on ice (300g), and uses CH₂Cl₂(2x125ml) extraction oil reservoir. Organic layer use water (2x200ml), saline (200ml) wash, and are dried (MgSO₄), and evaporate obtain crude product, through Flash silica color This crude product of spectrometry purification obtains title product (6.6g, 79%).¹H NMR(CDCl₃): δ 6.98 (septet, 1H), 2.68 (q, 2H),1.26(t,J=7.8&7.2Hz,3H)。

Step E:The fluoro-N-of 3-ethyl-5,6-two (2-fluoro-4-iodophenyl)-2-nitroaniline:

Use condition described in embodiment 1 (step A), make 2-fluoro-4-Iodoaniline (2.05g, 10mmol) and 1-ethyl-3, 4,5-tri-fluoro-2-Nitrobenzol (2.37g, 10mmol) reaction forms title compound (2.47g, 60%)；m/z=407[M-1]^-。

Step F:The fluoro-N1-of 3-ethyl-5,6-two (2-fluoro-4-iodophenyl) benzene-1,2-diamidogen:

Condition described in use embodiment 1 (step B), reduction 1,2,3-tri-fluoro-5-methyl-4-Nitrobenzol (2.47g, 5.85mmol) form title compound.M-H⁺: 393.

Step G:L-pi-allyl-N-(the fluoro-2-of 6-ethyl-3,4-two (2-fluoro-4-idodophenylamino) phenyl) cyclopropane-l- Sulfonamide:

According to general step B, make l-pi-allyl-cyclopropanesulfonyl chloride (230mg, 1.27mmol) and 5, the fluoro-N1-of 6-bis- (2-fluoro-4-iodophenyl)-3-methylbenzene-1,2-diamidogen (100mg, 0.255mmol) reaction obtains title product (72mg, 53%)； m/z=535[M-1]。

Step H:1-(2,3-dihydroxypropyl)-N-(the fluoro-2-of 6-ethyl-3,4-two (2-fluoro-4-idodophenylamino) benzene Base) cyclopropane-l-sulfonamide:

By l-pi-allyl-N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-aminomethyl phenyl) cyclopropane-1-sulphonyl Amine (70mg, 0.13mmol) and 4-methylmorpholine N-oxide (15mg, 0.13mmol) are dissolved in THF (2mL).At room temperature add (0.013mmol, 0.075mL, 4% are at H to enter Osmic acid.₂In O), and it is stirred at room temperature this reactant mixture 16 hours.Add EtOAc, organic phase washed with water, it is dried (MgSO₄), and under reduced pressure concentrate.Through silica gel chromatography (eluant: EtOAc/ MeOH) purification residues obtains title product.¹H NMR(300MHz,CDC1₃): δ 7.38 (dd, J=2.1&10.8Hz, 1H), 7.27(m,2H),7.12(br s,1H),6.91(dd,J=8.1&10.8Hz,1H),6.69(br s,1H),6.36(dt,J= 4.8,8.7&13.5Hz,1H),4.00(m,1H),3.62(dd,J=3.6&10.5Hz,1H),3.47(br m,2H),2.81(q, 2H),2.40(dd,J=10.2&15.9Hz,1H),1.73(br m,2H),1.58(m,1H),1.43(m,1H),0.94(m,2H)。

Embodiment 64

N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-(2-methoxy ethoxy) phenyl)-l-(2,3-dihydroxy Base propyl group) cyclopropane-1-sulfonamide:

Step A:The fluoro-5-of 1,2,3-tri-(2-methoxy ethoxy)-4-Nitrobenzol:

At 0 DEG C, to 3,4,5-tri-fluoro-2-nitrophenols (1.93,10mmol), Ph₃P (3.93g, 15mmol) and 2-methoxy In the base-ethanol (1.18ml, 15mmol) mixture in anhydrous THF (25ml), add diisopropyl azodiformate (2.91ml, 15mmol) solution in THF (5ml), and it is stirred at room temperature this reactant mixture 16h.Evaporating volatile thing Matter, and dissolve the residue in CH₂Cl₂(100ml) in, organic layer use water (100ml), saline (100ml) wash, and are dried (MgSO₄), and evaporate.The title product (1.70g) that yield is 68% is obtained through flash silica chromatography gained residue.¹H NMR(300MHz,CDCl₃): δ 6.78 (ddd, J=2.4,6.0,11.7Hz, 1H), 4.19 (t, J=4.5Hz, 2H), 3.72 (t, J= 4.5Hz,2H),3.39(s,3H)。

Step B:The fluoro-N-of 2,3-bis-(2-fluoro-4-iodophenyl)-5-(2-methoxy ethoxy)-6-nitroaniline:

Use the condition described in embodiment 1 (step A), make 2-fluoro-4-Iodoaniline (1.6g, 6.8mmol) and 1,2,3- Three fluoro-5-(2-methoxy ethoxy)-4-Nitrobenzol (1.7g, 6.8mmol) reaction forms title compound (1.02g, 32%)； m/z=467[M-1]。

Step C:The fluoro-N1-of 5,6-bis-(2-fluoro-4-iodophenyl)-3-(2-methoxy ethoxy) benzene-1,2-diamidogen:

Use the condition described in embodiment 1 (step B), reductase 12, the fluoro-N-of 3-bis-(2-fluoro-4-iodophenyl)-5-(2-first Epoxide ethyoxyl)-6-nitroaniline (1.017g, 2.17mmol) formation title compound；m/z=337[M-1].

Step D:L-pi-allyl-N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-(2-methoxy ethoxy) benzene Base) cyclopropane-1-sulfonamide:

According to general step B, make l-pi-allyl-cyclopropanesulfonyl chloride (450mg, 2.5mmol) and 5,6-bis-fluoro-N1-(2- Fluoro-4-iodophenyl)-3-(2-methoxy ethoxy) benzene-1,2-diamidogen (219mg, 2.5mmol) reaction obtain title product (230mg,78%)；m/z=581[M-1].

Step E:N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-(2-methoxy ethoxy) phenyl)-l-(2, 3-dihydroxypropyl) cyclopropane-1-sulfonamide:

By l-pi-allyl-N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-(2-methoxy ethoxy) phenyl) Cyclopropane-l-sulfonamide (230mg, 0.395mmol) and 4-methylmorpholine N-oxide (46mg, 0.395mmol) are dissolved in THF (2mL) in.(0.039mmol, 0.25mL, 4% are at H at room temperature to add Osmic acid.₂In O), and it is stirred at room temperature this reaction Mixture 16 hours.Add EtOAc, organic phase washed with water, be dried (MgSO₄), and under reduced pressure concentrate.Through silica gel chromatography (eluant: EtOAc/MeOH) purification residues obtains title product.¹H NMR (300MHz, CDCl3): δ 7.36 (dd, J= 1.8&10.5Hz,1H),7.27(m,2H),6.56(dd,J=6.9&11.4Hz,1H),6.40(dt,J=5.7,7.5&12.9Hz, 1H),4.17(m,2H),4.01(m,1H),3.78(m,2H),3.60(dd,J=3.6&11.1Hz,1H),3.47(m,1H),3.45 (s,3H),2.36(dd,J=9.6&15.9Hz,1H),1.78(dd,J=2.4&15.6Hz,1H),1.45-1.25(m,2H),0.89 (m,2H)。

Embodiment 65

The chloro-N-of 2,4-bis-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl) benzsulfamide:

Suitable sulfonic acid chloride is used to be synthesized by method A, m/z=571 [M-1].

Embodiment 66

The chloro-N-of 2-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl)-4-(trifluoromethyl) benzsulfamide:

Suitable sulfonic acid chloride is used to be synthesized by method A, m/z=605 [M-1].

Embodiment 67

N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl)-2-(trifluoromethoxy) benzsulfamide:

Suitable sulfonic acid chloride is used to be synthesized by method A, m/z=587 [M-1].

Embodiment 68

4-(N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl) sulfamoyl) benzoic acid:

Suitable sulfonic acid chloride is used to be synthesized by method A, m/z=584 [M-1].

Embodiment 69

N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl) benzsulfamide:

Suitable sulfonic acid chloride is used to be synthesized by method A, m/z=503 [M-1].

Embodiment 70

N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl)-2-fluorobenzenesulfonamide:

Suitable sulfonic acid chloride is used to be synthesized by method A, m/z=521 [M-1].

General step D: replacement atomic iodine:

In microwave reactor, by comprise in the deoxidation mixture of dioxane and water (3:1) 1eq. aryl iodide, 1.5eq. boric acid or borate, 0.25eq.PdCl₂(dppf) x DCM and 10eq. anhydrous K₂CO₃The suspension of powder is at 115 DEG C Heating 60min.Use aq.NH₄Cl/THF extracts, and uses Na₂SO₄It is dried organic moiety.Use flash column chromatography (Si, EtOAc/ Hexane or CHCl₃/ MeOH) purification of crude product.Yield: 20-40%.

Embodiment 71

N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-MethYlphenylamino) phenyl) cyclopropanesulfonamide；

General step D:¹H-NMR(500MHz,CDCl₃): δ=7.38-7.36 (m, 1H), 7.06-7.03 (q, 1H), 6.92- 6.90(1H),6.73-6.72(d,1H),6.63(s,1H,br),6.37-6.33(t,1H),5.54(s,1H,br),2.42- 2.39(m,1H),2.25(s,3H),1.14-1.11(m,2H),0.94-0.90(m,2H)；m/z=355[M-1].

In the case of the racemic mixture of chipal compounds has been split into single enantiomer, used herein Phrase " substantially free of " epimer means enantiomeric excess at least 90%.

Embodiment 72

N-(the fluoro-2-of 3,4-bis-(the fluoro-4-of 2-(1H-pyrazoles-4-base) phenyl amino) phenyl) cyclopropanesulfonamide

Step A:The fluoro-N-of 2,3-bis-(2-fluoro-4-iodophenyl)-6-nitroaniline:

At 0 DEG C, in the 2-fluoro-4-Iodoaniline (11.40g, 47mmol) solution in the anhydrous THF of 100ml, drip LHMDS 1M solution (47ml) in THF (47mmol).The color of solution becomes mulberry.Solution is transferred to dropping liquid leakage through sleeve pipe Bucket, and at 0 DEG C, this solution (comprising amine free alkali) sub-fraction sub-fraction ground is added 2,3,4-trifluoronitrobenzenes In (8.321g, 47.0mmol) solution in anhydrous THF (50ml).After addition, at room temperature, this is stirred under argon gas Mixture 15 hours.Reduce the volume of solvent, then with ethyl acetate and saline extraction.Organic layer dried over sodium sulfate, removes Solvent, and by flash chromatography (EtOAc/ hexane 1:5, R_f=0.58) purification gained dark oil obtains crude product, and it is through vacuum It is dried and becomes brown solid (yield: 6.23g, 33.6%).m/z=393[M-1]^-。

Step B:The fluoro-N1-of 5,6-bis-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen

In the nitro-diaryl amine (6.23g, 15.8mmol) solution in 300ml ethanol add iron powder (13.74g, 246mmol) with ammonium chloride (13.59g, 254mmol) and little with this mixture 14 of agitating heating under 100 DEG C of oil bath temperatures Time.Filter, and with washing with alcohol filtering residue twice.Remove ethanol in a vacuum, and use ethyl acetate/1M NaOH solution extraction Residue.During extracting, filter and discard more precipitations of formation.The organic layer merged saline washs, and through sodium sulfate It is dried.Remove solvent, and from CHCl₃/ hexane (1:50) recrystallization crude product.Obtain brown needles product (2.094g, 66%). R_f=0.44(EtOAc/Hex1:3)。¹H-NMR(500MHz,CDCl₃): δ=7.40-7.38 (dd, 1H, J=11.3Hz, J= 1.5Hz).7.25-7.23(d,1H,J=8.5Hz),6.97-6.92(q,1H,J=9Hz),6.51-6.48(m,1H),6.24- 6.21(t,1H,J=9Hz),5.3(s,1H,NH,br),3.80(s,2H,NH₂,br)；LRMS (ESI): m/z=365 [M+H]⁺。

Step C:N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl) cyclopropanesulfonamide:

According to general step A, make 5, the fluoro-N1-of 6-bis-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen and cyclopropanesulfonyl chloride Reaction obtains desired product.(500MHz,CDCl₃): δ=7.38-7.37 (d, 1H), 7.35-7.34 (m, 1H), 7.27-7.26 (m,1H),7.20-7.0(q,1H),6.68(s,1H,br),6.15-6.12(q,1H),5.65(s,1H,br),3.25-3.20 (m,1H),2.4-2.3(m,2H),2.0-1.8(m,2H)；m/z=467[M-1]^-。

Step D:N-(the fluoro-2-of 3,4-bis-(the fluoro-4-of 2-(1H-pyrazoles-4-base) phenyl amino) phenyl) cyclopropanesulfonamide:

General step C:¹H-NMR(500MHz,CDCl₃): δ=8.00-7.90 (m, 2H), 7.30-7.20 (m, 2H), 7.15- 7.10(m,1H),7.05-7.00(m,1H),6.70-6.60(m,1H),2.40-2.35(m,1H),1.05-1.0(m,2H), 0.95-0.85(m,2H)；m/z=407[M-1]^-。

Embodiment 73

N-(the fluoro-2-of 3,4-bis-(the fluoro-4-of 2-(1-methyl isophthalic acid H-pyrazoles-4-base) phenyl amino) phenyl) cyclopropanesulfonamide

General step C:¹H-NMR(500MHz,CDCl₃): δ=7.95 (s, 1H), 7.75 (s, 1H), 7.30-7.20 (m, 2H),7.15-7.10(m,1H),7.05-7.00(m,1H),6.70-6.60(m,1H),3.95(s,3H),2.40-2.35(m, 1H),1.05-1.0(m,2H),0.95-0.85(m,2H)；m/z=421[M-1]^-。

Embodiment 74

N-(the fluoro-2-of 3,4-bis-(the fluoro-4-of 2-(1H-pyrazole-3-yl) phenyl amino) phenyl) cyclopropanesulfonamide

General step C:¹H-NMR(500MHz,CDCl₃): δ=7.90 (s, 1H), 7.80 (s, 1H), 7.30-7.20 (m, 2H),7.15-7.10(m,1H),7.05-7.00(m,1H),6.70-6.60(m,1H),3.95(s,3H),2.40-2.35(m, 1H),1.05-1.0(m,2H),0.95-0.85(m,2H)；m/z=407[M-1]^-。

Embodiment 75

N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-(pyridin-4-yl) phenyl amino) phenyl) cyclopropanesulfonamide

General step C:¹H-NMR(500MHz,CDCl₃): δ=8.62-8.61 (d, 2H), 7.43-7.41 (m, 4H), 7.23- 7.22(m,1H),7.16-7.11(q,1H),6.61-6.58(t,1H),6.11(s,1H,br),2.53-2.50(m,1H), 1.21-1.10(m,2H),1.02-0.99(m,2H)；m/z=418[M-1]^-。

Embodiment 76

N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-(pyridin-3-yl) phenyl amino) phenyl) cyclopropanesulfonamide

General step C:¹H-NMR (500MHz, [D6]-DMSO): δ=9.45 (s, 1H), 8.91 (s, 1H), 8.54 (s, 1H),8.07-8.06(d,1H),7.76-7.70(m,2H),7.46-7.34(m,2H),7.34-7.33(d,2H),6.80-6.78 (m,1H),0.86-0.79(m,4H)；m/z=418[M-1]^-。

Embodiment 77

N-(2-(4-cyano group-2-Fluorophenylamino)-3,4-difluorophenyl) cyclopropanesulfonamide

In microwave reactor, aryl iodide (75.5mg, 0.161mmol), CuCN will be comprised in 1ml dry DMF (46.6mg, 0.520mmol) and Pd (OAc)₂(0.47mg) suspension is heated to 130 DEG C and continues 60min.Use saline/THF Extract this mixture, and use Na₂SO₄It is dried organic moiety.Kermesinus semisolid product is generated through flash column chromatography after with (R_f=0.42 (EtOAc/ hexane 1:1)).Yield: 15%.m/z=366[M-1]^-。

Embodiment 78

N-(the fluoro-2-of 3,4-bis-(3-fluorine biphenyl-4-base amino) phenyl) cyclopropanesulfonamide

General step C:¹H-NMR(500MHz,CDCl₃): δ=7.55-7.53 (m, 2H), 7.45-7.3 (m, 5H), 7.20- 7.15(d,1H),7.13-7.10(q,1H),6.70(s,1H,br),6.60-6.55(t,1H),5.75(s,1H,br),2.53- 2.50(m,1H),1.21-1.10(m,2H),1.02-0.99(m,2H)；m/z=417[M-1]^-。

Embodiment 79

N-(2-(3 '-acetyl group-3-fluorine biphenyl-4-base amino)-3,4-difluorophenyl) cyclopropanesulfonamide

General step C:¹H-NMR(500MHz,CDCl₃): δ=8.6 (s, 1H), 7.86-7.85 (d, 1H), 7.68-7.66 (d,1H),7.49-7.46(t,1H),7.38-7.33(m,2H),7.20-7.18(d,1H),7.09-7.03(q,1H),6.90 (s,1H,br),6.57-6.54(t,1H),5.90(s,1H),br),2.61(s,3H),2.46-2.43(m,1H),1.15-1.13 (m,2H),0.94-0.91(m,2H)；m/z=459[M-1]^-。

Embodiment 80

N-(2-(4 '-cyano group-3-fluorine biphenyl-4-base amino)-3,4-difluorophenyl) cyclopropanesulfonamide

General step C:¹H-NMR(500MHz,CDCl₃): δ=7.68-7.66 (m, 2H), 7.58-7.57 (m, 2H), 7.38- 7.35(m,2H),7.20-7.18(d,1H),7.18-7.02(q,1H),6.67(s,1H,br),6.58-6.54(t,1H),5.99 (s,1H,br),2.47-2.44(m,1H),1.15-1.13(m,2H),0.94-0.91(m,2H)；m/z=442[M-1]^-。

Embodiment 81

N-(2-(3,4 '-DfBP-4-base amino)-3,4-difluorophenyl) cyclopropanesulfonamide

General step C:¹H-NMR(500MHz,CDCl₃): δ=7.44-7.37 (m, 3H), 7.29-7.27 (d, 1H), 7.11- 7.05(m,4H),6.70(s,1H,br),6.53-6.50(t,1H),5.81(s,1H,br),2.47-2.44(m,1H),1.15- 1.13(m,2H),0.94-0.91(m,2H)；m/z=435[M-1]^-。

Embodiment 82

N-(the fluoro-2-of 3,4-bis-(fluoro-4 '-(methanesulfonamido) biphenyl-4-base amino of 3-) phenyl) cyclopropanesulfonamide

General step C:¹H-NMR (500MHz, [D6]-DMSO): δ=9.39 (s, 1H, br), 7.63-7.60 (m, 3H), 7.53-7.50(d,1H),7.30-7.23(m,4H),7.74-7.65(m,1H),2.99(s,3H),0.80-0.73(m,4H)；m/ z=510[M-1]^-。

Embodiment 83

N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-MethYlphenylamino) phenyl) cyclopropanesulfonamide

General step C:¹H-NMR(500MHz,CDCl₃): δ=7.38-7.36 (m, 1H), 7.06-7.03 (q, 1H), 6.92- 6.90(1H),6.73-6.72(d,1H),6.63(s,1H,br),6.37-6.33(t,1H),5.54(s,1H,br),2.42- 2.39(m,1H),2.25(s,3H),1.14-1.11(m,2H),0.94-0.90(m,2H)；m/z=355[M-1]^-。

Embodiment 84

4 '-(6-(cyclopropane sulfonamido)-2,3-Difluorophenylamino)-3 '-fluorine biphenyl-3-carboxylic acid

General step C:¹H-NMR (500MHz, [D4]-MeOH): δ=8.21 (s, 1H), 7.93-7.91 (d, 1H), 7.73- 7.72(d,1H),7.47-7.43(m,2H),7.33-7.31(d,2H),7.15-7.12(q,1H),6.71-6.68(m,1H), 2.51-2.46(m,1H),0.94-0.93(m,2H),0.88-0.87(m,2H)；m/z=499[M-1]^-。

Embodiment 85

N-(the fluoro-2-of 3,4-bis-(fluoro-3 '-(methanesulfonamido) biphenyl-4-base amino of 3-) phenyl) cyclopropanesulfonamide

General step C:¹H-NMR (500MHz, [D4]-MeOH): δ=7.92 (s, 1H), 7.46-7.34 (m, 5H), 7.34- 7.31(d,1H),7.29-7.22(m,1H),7.16-7.15(q,1H),6.74-6.71(m,1H),2.80(s,3H),2.54- 2.51(m,1H),0.94-0.92(m,2H),0.91-0.90(m,2H)；m/z=510[M-1]^-。

Embodiment 86

N-(the fluoro-2-of 3,4-bis-(fluoro-2 '-(methanesulfonamido) biphenyl-4-base amino of 3-) phenyl) cyclopropanesulfonamide

General step C:¹H-NMR (500MHz, [D4]-MeOH): δ=7.50-7.49 (d, 1H), 7.40-7.32 (m, 4H), 7.29-7.28(d,1H),7.26-7.10(m,2H),6.73-6.71(m,1H),2.80(s,3H),2.51-2.49(m,1H), 0.94-0.92(m,2H),0.91-0.90(m,2H)；m/z=510[M-1]^-。

Embodiment 87

N-(the fluoro-2-of 3,4-bis-(fluoro-4 '-(trifluoromethoxy) biphenyl-4-base amino of 3-) phenyl) cyclopropanesulfonamide

General step C:¹H-NMR (500MHz, [D4]-MeOH): δ=7.69-7.67 (d, 2H), 7.46-7.43 (d, 1H), 7.36-7.33(m,4H),7.30-7.29(q,1H),6.73-6.72(m,1H),2.51-2.49(m,1H),0.94-0.92(m, 2H),0.91-0.90(m,2H)；m/z=501[M-1]^-。

Embodiment 88

N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl)-2-(methylamino) ethyl sulfonamide

General step D:¹HNMR(300MHz,CDCl₃): δ 9.01 (br s, D₂O is commutative, 1H), 7.36 (dd, J=2.1& 10.5Hz,1H),7.27(m,1H),7.17(m,1H),7.03(dd,J=9.0&16.8Hz,1H),6.48(s,D₂O is tradable, 1H),6.31(dt,J=3.0,8.7&17.4Hz,1H),3.45(br t.2H).3.31(br s,2H),2.65(s.3H).1.80 (br s,D₂O is commutative, 1H).

Embodiment 89

N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl)-2-(2-(dimethylamino) ethylamino) second sulphur Amide

General step D.¹H NMR(300MHz,CDCl₃): δ 7.35 (m, 1H), 7.25 (m, 1H), 7.18 (d, J=8.7Hz, 1H),7.02(dd,J=8.7&18.0Hz,1H),6.38(m,1H),6.18(dd,J=8.7&17.1Hz,1H),3.62(t,J= 5.7&6.3Hz,2H),3.35(m,2H),3.26(m,2H),3.26(t,J=5.7&6.6Hz,2H),3.11(t,J=5.1& 6.0Hz,2H),2.85(s,6H).

Embodiment 90

N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl)-2-(ethyl (methyl) amino) ethyl sulfonamide

General step D.¹H NMR(300MHz,(CDCl₃+D₂O)): δ 7.39 (dd, J=1.5&10.5Hz, 1H), 7.31 (m, 2H),7.07(dd,J=9.0&17.4Hz,1H),6.30(dt,J=2.4,9.0&17.4Hz,1H),3.55(t,J=6.9&7.8Hz, 2H),3.38(br t,J=6.0&8.7Hz,2H),3.05(q,2H),2.69(s,3H),1.31(t,J=7.2Hz,3H)。

Embodiment 91

N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl)-2-(4-methylpiperazine-1-yl) ethyl sulfonamide

General step D.¹H NMR(300MHz,CD₃OD): δ 7.45 (dd, J=2.1&10.8Hz, 1H), 7.30 (m, 2H), 7.16(dd,J=9.6&17.7Hz,1H),6.39(dt,J=3.3,9.3&17.7Hz,1H),3.26(m,J=7.5Hz,2H),3.10 (br m,6H),2.87(s,3H),2.82(t,J=7.5Hz,2H),2.48(br m,4H)。

Bioactivity

Embodiment 92

The generation of IC50 data

Material and preparation of reagents: mankind GST-MEK1 and composition are activated allele GST-MEK1^CA(with sudden change Ser218Asp and Ser222Asp) from Wild type human's MEK1 cDNA sub-clone to yeast expression vector pGEM4Z In (Promega, Madison, WI).At expression in escherichia coli GST-MEK1^CA, and use the affine tree of glutathione agarose 4B Fat (Amersham Pharmacia Biotech, Piscataway, NJ) carries out partial purification to it.By ERK2 allele from MAPK2/Erk2 cDNA (wild type) Ya Ke in pUSEamp (Upstate Biotechnology, Inc., Waltham, MA) Grand to carrier pET21a (Novagen, Madison, WI), produce the mice ERK2 allele of N-terminal histidine tag. Express ERK2 and be purified to homogeneous [Zhang, 1993#33].Myelin basic protein (MBP) is purchased from Gibco BRL (Rockville,MD).EasyTides adenosine 5'-triphosphate (ATP) ([γ-³³P])(NEN Perkin Elmer, Wellesley, MA) be all kinase reactions radioactive label source.The Raf-1 (truncate) activated and the MAP activated swashs Enzyme 2/ERK2 is purchased from Upstate, Inc. (Lake Placid, NY).4-20%Criterion Precast gel is purchased from Bio- Rad(Hercules,CA)。

Measure enzymatic activity: compound is diluted to 1xHMNDE (20mM HEPES from dimethyl sulfoxide (DMSO) stock solution pH 7.2、1mM MgCl₂, 100mM NaCl, 1.25mM DTT, 0.2mM EDTA) in.Typical 25 microlitres measure and comprise 0.002 nanomole MEK1^CA, 0.02 nanomole ERK2,0.25 nanomole MBP, the 0.25 unlabelled ATP of nanomole and 0.1 μ Ci [γ³³P]ATP.This Screening test consists essentially of 4 interpolations.The compound of 5 μ l dilutions is distributed to 96-hole assay plate.So After, 10 μ l 2.5x enzyme cocktail (only MEK1 are added to each hole^CAAnd ERK2), precincubation 30 minutes the most at ambient temperature.Then Add 10 μ l 2.5x Substrate cocktail (substrate cocktail) (the adding MBP with unlabelled ATP of labelling), exist subsequently Incubation 60 minutes under ambient temperature.Finally, add 100 μ l 10% trichloroacetic acid (TCA), and at room temperature incubation comes eventually for 30 minutes React here and make radiolabeled protein precipitate.Product collection is extremely prewetted with water and 1% pyrophosphate On the screen plate of glass fibre 96 hole.Then this screen plate is washed with water 5 times.Replace water with dehydrated alcohol, and at room temperature make this Plate air-dries 30 minutes.The manual back that seals, and the scintillation solution (scintillation cocktail) of 40 μ l is distributed to each hole. Carrying out top sealing and count this plate in TopCount, speed is 2 seconds/hole.

Some is tested, uses and need by the truncated-type MEK of Raf kinase activator.

Embodiment 93

The generation of EC50 data

The ERK being measured phosphorylation by western blotting detects the effect of compound in cell.With 20,000 cells/ MDA-MB-231 breast cancer cell is plated in 48 orifice plates by hole, and at the CO of 37 ° of humidifications₂Incubator is cultivated.Second day, remove Remove growth medium (DMEM+10% hyclone), and with starvation media (starve media) (DMEM+0.1% tire Sanguis Bovis seu Bubali Substitute clearly).Incubate cells 16 hours in starvation media, then by the compound treatment 30 minutes of a series of concentration.With change After compound incubation, stimulate cell 5 minutes with 100ng/ml EGF.Then dissolve cell, and use anti-phosphorylated CREB monoclonal anti Body passes through western blot analysis.Use the second antibody enhancing signal being combined with nir dye, and at Licor Signal is detected on Odyssey scanner.Measuring the amount of signal intensity, these data are used for generating dose-effect curve and EC50 meter Calculate.

Legend: A, EC₅₀=<2.0nM；B,EC₅₀=2.0-15nM；C,EC₅₀=15nM-100nM；D,EC₅₀>100nM,IC₅₀< 20μM；F,EC₅₀>100nM,IC₅₀>20μM

Legend: A, EC₅₀=<2.0nM；B,EC₅₀=2.0-15nM；C,EC₅₀=15nM-100nM；D,EC₅₀=100nM–200nM； E,EC₅₀>200nM；ND=undetermined

In vivo bioactivity

Embodiment 94

Compound as herein described and compositions be used for treating or prevent one or more diseases, described disease to include but not It is limited to cancer, inflammatory bowel (IBD), psoriasis and rheumatoid arthritis (RA).Compound as herein described and compositions are also For once a day or the oral medication of twice every day or prevention include but not limited to cancer, IBD, psoriasis and RA one or Multiple disease.

In the present embodiment, the internal examination of the compound (the compound A of preparation as described herein) of following structure is described Test:

Human tumor is implanted in nu/nu mice.Once tumor size is about 100mm³, i.e. oral administration of Compound A, holds Continuous 14 days.After treating 14 days, measure Tumor growth inhibition treating in group contrast in the reduction of tumor size and vehicle Control (TGI).With tumor reach time of specific terminal volume or research the most all day in any one Time Calculation first arrived Reach the time (TTE) of terminal.Measure the result for the treatment of from % tumor growth delay (%TGD), it is defined as and vehicle treated Control mice contrasts, and meets the growth % of the TTE intermediate value of subject mice.Also retrograde reaction (the regression to animal Response) monitored.Measure the pERK level in tumor and brain by western blotting, and in order to pharmacodynamics/ Pharmacokinetic studies makes this pERK level be associated with the blood plasma level of compound A.One is evaluated with different dosage and dosage regimen A little tumor models.With 25 or 50mg/kg in A375 melanoma tumor, Colo205 colon carcinoma and A431 epiderm-like tumor The treatment of (QD) once a day demonstrates the %TGD of statistically significant.With 25mg/kg QD oral administration, to these tumor models And in HT29 colon cancer tumours, observe the TGI of statistically significant.Different dosing side is evaluated in A375 xenograft The effect of case.Although every two days one time oral administration 100mg/kg compound A demonstrates the %TGD (91%) of statistically significant, but It is that it is not treated effectively with the QD of 25mg/kg (143% TGD) or 50mg/kg (233% TGD).According to the %TGI measured, often It is administered day twice (BID) and is also administered more effectively than QD.It is administered with 12.5mg/kg BID and causes 79.5% TGI, by contrast, 51.7% TGI is caused to drug compound A with 25mg/kg QD.It is administered with 25mg/kg BID and causes 110.1% TGI, compare it Under, it is administered with 50mg/kg QD and obtains 69.9% TGI.Pharmacodynamics/pharmacokinetic studies in Colo205 xenograft shows to swell In tumor, pERK is formed and is suppressed and observes minimum suppression in brain, this effective antitumor showing to have limited CNS penetrance Activity.

Compound A is effective MEK1/2 inhibitor, and it suppresses in vitro and in vivo growth of tumour cell.BRAF Determines Anchorage Dependent Growth and in the not dependent growth of non-adherent, or compound is caused by xenograft growth inhibiting Sensitivity.The most frequent owing to being administered, effectiveness is the highest, and the MEK suppression therefore remaining enough in whole dosing interval is compared Maintain peak level even more important.According to xenograft result, the mankind use the therapeutic dose 20-40 mg/ day of design, Compound A has favourable pk feature in the mankind.

Embodiment 94A

Anticancer growth (GI₅₀)

After processing, with compound A, cell 48 hr cultivated in 384-orifice plate, use CellTiterGlo reagent measuring patch Wall dependency growth inhibited.It is incubated in the culture medium comprising 0.15% agarose or on non-adhesive plate (A431) processing After cell 7 days, adherent not dependent growth measurement uses MTS (methyl thio sulphonic acid ester) reagent.It show growth in the following table Inhibiting value (GI₅₀)。

Tumor cell line	BRAF state	Anchorage dependence GI₅₀(nM±sd)	Adherent not dependent GI₅₀(nM±sd)
				A375 melanoma	V600E	67±12	68±34
Colo205 colon	V600E	74±45	33±16
				HT29 colon	V600E	70±12	Undetermined
A431 epiderm-like	Normally	>10,000	65±19

Embodiment 94B

Antitumor xenograft activity

A375 melanoma, Colo205 colon tumor, A431 epiderm-like tumor or HT-29 colon tumor cell are implanted Female nu/nu mice, makes these tumor growths to 100-200mm³.Oral administration of Compound A or carrier (25mg/ once a day Kg, 50mg/kg or 100mg/kg), continue 14 days.The mean tumour volume of vehicle group and treatment group is mapped, and table in FIG Show and be given.

Embodiment 94C

Tumor growth inhibition (TGI) 25mg/kg QD

For the tumor xenogeneic graft pointed out, calculating is through the Tumor growth inhibition of the group of 25mg/kg Compound A treatment. At the end of being administered 14 days once a day, measure Tumor growth inhibition, and calculate according to the following formula:

The Range Representation of A375 and Colo205 is from the numerical value of 2 independent studies.

Tumor xenogeneic graft	%TGI	P value
			A375 melanoma	52-72^**	<0.001
Colo205 colon	70-123^**	<0.001
			HT29 colon	56	<0.001
A431 epiderm-like	67	<0.001

^**Degeneration is recorded during testing

Embodiment 94D

ED in Colo205 xenograft₅₀

Colo205 tumor cell is implanted male nu/nu mice.After 10 days, by tumor size (scope 126-256mm³) By animal randomization, and treat with paclitaxel (IV, QODx5), carrier or compound A (PO, QDx14).

Pharmacokinetic parameters is obtained from the extrapolated value of the Balb/c mice and relatively low-dose group that are administered 25mg/kg compound A, and And be given in the table below.

^*P<0.001

Embodiment 94E

Tumor growth inhibition with A375 xenograft

To A375 xenograft mouse be administered compound A-45 0mg/kg QD, 25mg/kg BID, 50mg/kg QD and 12.5mg/kg BID.%TGI is computed and maps, and is presented in Fig. 2.

Embodiment 94F

Plasma concentration in mice

A375 tumor cell is implanted female nu/nu mice, makes tumor growth to 100-200mm³.Once a day (QD) or Every day twice (BID) oral administration of Compound A or carrier (50mg/kg QD, 25mg/kg BID, 50mg/kg QD and 12.5mg/ kg BID).At the end of being administered 14 days once a day, measure Tumor growth inhibition, and calculate according to the following formula:

AUC(μg·hr/ml)	132.5	117.0	66.5	78.0
					C_max(μg/ml)	23.8	10.2	11.9	7.8
C_min(μg/ml)	0.06	1.24	0.03	0.49
					C_minFree fraction (ng/ml)	0.117	2.48	0.059	0.986

Significance,statistical=sequence check

Embodiment 94G

Mouse xenograft tumor and the suppression of brain MEK activity

To be implanted with the female nu/nu mice of Colo205 tumor cell to the carrier of single dose or 2.5,5,10 or The compound A of 25mg/kg.Measure chemical levels in plasma sample, and after measuring administration 2,6,12 and 24hr gather swollen PERK level in tumor and brain sample.Use LI-COR Odyssey, will by the pERK horizontal quantitative from western blotting It is normalized into total ERK level, and measures %MEK suppression with the level contrast through vehicle treated.To each mouse tumor or brain In MEK suppression and animal in the plasma concentration mapping of corresponding compound A.Nonlinear regression draws MEK suppression in tumor EC₅₀For 73nM.Brain EC₅₀>5000nM。

It it is the chart that suppresses relative to pERK% of plasma concentration (log nM) shown in Fig. 3.

The preparation of capsule

Embodiment 95A

Preparation comprises blue size 1 hard gelatin capsule of dry powder blend compositions, and wherein structure is's The concentration of compound A (seeing the table shown in above example 93) is 1mg and 10mg.

The compound A for preparing as described herein, (Spiral Jet Mill, electricity connects by its micronization then to use fluid energy mill Ground, a diameter of 50mm of grinding chamber；50 ° of .4x0.8mm nozzle rings；Injector nozzle diameter 0.8mm, injector nozzle distance 3mm).Generalization Compound A and portions microcrystalline cellulose mixing, sieved by #20 mesh sieve, and add to dispersion roller mixer (diffusion- Tumble blender) in (V-mixer).Sieve remaining microcrystalline Cellulose by #20 mesh sieve, add in mixer In material, mixing.Sieve cross-linked carboxymethyl cellulose sodium and sodium lauryl sulphate by #20 mesh sieve, add in mixer In material, mixing.Make pulverulent mixture by the vane type grinder (Quadro CoMil) in rotating, be added back to mixer In, continue mixing.Sieve magnesium stearate by #20 mesh sieve, and mix with pulverulent mixture.Pulverulent mixture is packed into chi In very little 1 capsule.In order to identify, by 10mg capsule colligation.

It is the composition of capsule shown in following table:

^aThe target filling weight that practical effect according to mixture adjusts.

It is as follows that the typical case of the 1mg capsule of 10,000 batches criticizes formula:

^aThe target filling weight that practical effect according to mixture adjusts.

It is as follows that the typical case of the 10mg capsule of 10,000 batches criticizes formula:

^aThe target filling weight that practical effect according to mixture adjusts.

Embodiment 95B

Preparation comprises blue size 1 hard gelatin capsule of dry powder blend compositions, and wherein structure is's The concentration of compound B (seeing the table shown in above example 93) is 1mg and 10mg.

The compound B for preparing as described herein, and use fluid energy mill by its micronization (Spiral Jet Mill, electrical ground, The a diameter of 50mm of grinding chamber；50 ° of .4x0.8mm nozzle rings；Injector nozzle diameter 0.8mm, injector nozzle distance 3mm).By chemical combination Thing B and portions microcrystalline cellulose mixing, sieved by #20 mesh sieve, and add in dispersion roller mixer (V-mixer).Logical Cross #20 mesh sieve and sieve remaining microcrystalline Cellulose, add in the material in mixer, mixing.Handed over by the screening of #20 mesh sieve Connection carmethose and sodium lauryl sulphate, add in the material in mixer, mixing.Pulverulent mixture is made to pass through to rotate In vane type grinder (Quadro CoMil), be added back in mixer, continue mixing.By #20 mesh sieve screening tristearin Acid magnesium, and mix with ground pulverulent mixture.Pulverulent mixture is packed into size 1 capsule weight.In order to identify, by 10mg Capsule is tied up.

Following table show the composition of capsule:

Activity in vivo in the mankind

Embodiment 96

The capsule described in embodiment 95A it is administered in human patients with cancer

To human patients with cancer to the capsule composition of 1mg or 10mg above-described in embodiment 95A of single dose. For 2mg dosage, it is administered 2x1mg capsule to patient；For 4mg dosage, it is administered 4x1mg capsule to patient；For 6mg dosage, It is administered 6x1mg capsule to patient；For 10mg dosage, it is administered 1x10mg capsule to patient；For 20mg dosage, it is administered to patient 2x10mg capsule.

Monitoring concentration-time profile, and be given in Fig. 4 and following table:

Crystalline polymorph

Embodiment 97: preparation N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino) phenyl)-1-(2,3-dihydroxy third Base) cyclopropane-1-sulfonamide

According to above-mentioned steps (seeing the international patent application WO 2007/014011 of announcement) and preparation N-outlined below (3, The fluoro-2-of 4-bis-(2-fluoro-4-idodophenylamino) phenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide.

The fluoro-N-of step A:2-(2,3,5-tri-fluoro-6-nitrobenzophenone)-4-Iodoaniline

At-78 DEG C, under a nitrogen, by 1.0M lithium hexamethyldisilazide (LiN (SiMe₃)₂) " LHMDS " solution (15.37mL, 15.37mmol) is slowly added into 2-fluoro-4-Iodoaniline (3.64g, 15.37mmol) in anhydrous THF (100mL) Agitated solution in, and be further continued for stirring 1 hour at-78 DEG C.Add 2,3,4,6-tetra-fluoronitrobenzenes, make this reaction mixing Thing warms to room temperature, and is further continued for stirring 16 hours.Add ethyl acetate (200mL), organic phase washed with water, do through sodium sulfate Dry, and it is further purified generation yellow solid product (3.75g, 59.24%) by column chromatography.M-H⁺: 410.9.¹H NMR (DMSO, 300MHz): 6.85 (t, 1H)；7.38(d,1H)；7.62(m,2H)；8.78(s,1H).

The fluoro-N-of step B:2-(2,3-bis-fluoro-5-methoxyl group-6-nitrobenzophenone)-4-Iodoaniline

Under a nitrogen, by (the iodo-phenyl of the fluoro-4-of 2-)-(2,3,5-tri-fluoro-6-nitro-phenyl)-amine (1.23g, 3mmol) Agitated solution in anhydrous THF (25ml) is cooled to-78 DEG C, and be slowly added into 25% sodium methoxide solution (0.68ml, 0.3mmol).Make this reactant mixture warm to room temperature, and be further continued for stirring 16 hours.TLC shows to react the most completely.By acetic acid Ethyl ester (100mL) adds in this reactant mixture, and organic layer washes with water, dried over sodium sulfate, and enters one by column chromatography Step purification generates the expecting compound (0.6g, 47.6%) of yellow solid.m/z=424[M+H]⁺。

The fluoro-N of step C:5,6-bis-¹-(2-fluoro-4-iodophenyl)-3-methoxybenzene-1,2-diamidogen

Ammonium chloride (1.18g, 20.16mmol) and iron powder (1.15g, 21.44mmol) are added (2,3-bis-fluoro-5-methoxy Base-6-nitro-phenyl) agitated molten in ethanol (20mL) of-(the iodo-phenyl of the fluoro-4-of 2-)-amine (0.57g, 1.34mmol) In liquid.Return stirring mixture 16 hours, is cooled to room temperature, filters through kieselguhr, and concentrates the filtrate to do.Residual by gained Stay that thing is molten to be placed in ethyl acetate, wash with water, dried over sodium sulfate and greyish white by being further purified generation from alcohol crystal Color solid (0.47g, 90.3%).M-H⁺: 393.2.¹H NMR (DMSO, 300MHz): 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).

Step D:1-pi-allyl-N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl) cyclopropane- 1-sulfonamide

To the fluoro-N of 5,6-bis-¹-(2-fluoro-4-iodophenyl)-3-methoxybenzene-1,2-diamidogen (1eq) is at anhydrous pyridine (5ml/ Mmole) the agitated solution in adds 1-pi-allyl-cyclopropanesulfonyl chloride (1-5eq).In this reaction mixing of 40 DEG C of stirrings Thing 48 hours.This reactant mixture is distributed by water and ethyl acetate.Organic layer saline washs, and is dried (MgSO₄), and in decompression Lower concentration.Title product is obtained through silica gel purification residue by flash column chromatography.¹H NMR(CDCl₃, 300MHz): δ 7.417(dd,1H),7.309(s,1H),7.25(m,1H),6.89(m,1H),6.52(m,1H),6.427(m,1H),6.03(s, lH),5.668(m,1H),5.11(t,1H),3.9(s,3H),2.75(d,2H),1.21(m,2H),0.767(m,2H)。

Step E:N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-l-(2,3-dihydroxy third Base) cyclopropane-1-sulfonamide

By l-pi-allyl-N-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl) cyclopropane-l-sulphur Amide (97mg, 0.18mmol) and 4-methylmorpholine N-oxide (21mg, 0.18mmol) are dissolved in THF (8mL).At room temperature (0.018mmol, 0.13mL, 4% are at H to add Osmic acid.₂In O), and it is stirred at room temperature this reactant mixture 16 hours.Add Enter ethyl acetate, organic phase washed with water, be dried (MgSO₄), and under reduced pressure concentrate.Through silica gel chromatography (eluant: EtOAc/MeOH) purification residues obtains title product (0.80g, 78%).¹H NMR(CDCl₃, 300MHz): δ 7.38 (dd, J= 1.7&10.3Hz,1H),7.26(m,1H),7.14(s,1H),6.87(s,1H),6.53(dd,J=6.8&11.4Hz,1H),6.43 (m,1H),4.06(m,1H),3.89(s,3H),3.63(dd,J=3.7&11.1Hz,1H),3.49(dd,J=6.4&11.1Hz, 1H),2.3(dd,J=9.7&16.1Hz,1H),1.77(dd,J=1.9&16.0Hz,1H),1.37(m,1H),1.25(m,1H), 1.21(m,2H),0.86(m,2H)；m/z=571[M-1]^-。

Embodiment 98: preparation N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-l- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide

Separate racemic mixture by chirality HPLC, obtain pure S isomer.¹H NMR(CDCl₃, 300MHz): δ 7.38(dd,J=1.7&10.3Hz,1H),7.26(m,1H),7.14(s,1H),6.87(s,1H),6.53(dd,J=6.8& 11.4Hz,1H),6.43(m,1H),4.06(m,1H),3.89(s,3H),3.63(dd,J=3.7&11.1Hz,1H),3.49(dd, J=6.4&11.1Hz,1H),2.3(dd,J=9.7&16.1Hz,1H),1.77(dd,J=1.9&16.0Hz,1H),1.37(m,1H), 1.25(m,1H),1.21(m,2H),0.86(m,2H)；m/z=571[M-1]^-。

Embodiment 99: preparation N-(R)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-l- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide

Separate racemic mixture by chirality HPLC, obtain pure R isomer.¹H NMR(CDCl₃, 300MHz): δ 7.38(dd,J=1.7&10.3Hz,1H),7.26(m,1H),7.14(s,1H),6.87(s,1H),6.53(dd,J=6.8& 11.4Hz,1H),6.43(m,1H),4.06(m,1H),3.89(s,3H),3.63(dd,J=3.7&11.1Hz,1H),3.49(dd, J=6.4&11.1Hz,1H),2.3(dd,J=9.7&16.1Hz,1H),1.77(dd,J=1.9&16.0Hz,1H),1.37(m,1H), 1.25(m,1H),1.21(m,2H),0.86(m,2H)；m/z=571[M-1]^-。

Embodiment 100: preparation N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-l- The crystalline polymorph A of (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide

Preparation is i) by N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-l-(2,3-bis- Hydroxypropyl) cyclopropane-1-sulfonamide (216.10g) adds and is provided with big magnetic stirring bar and magnetic stirring apparatus/heating plate 4L conical flask.Add ethyl acetate (about 600mL, purchased from Fisher).Begin to warm up and stir to form brown suspension.Make this The faint backflow of mixture, more additionally add ethyl acetate (about 200mL) to realize being completely dissolved generation dark brown solution.With every time The whole precipitation rapid solution adding fashionable formation and the speed making backflow keep, slowly add portionwise by heptane (purchased from Acros) Enter in the solution refluxed.When adding 2L heptane to this solution, the solid of formation dissolves slowly under reflux.Stop Heating, and make this crystalline mixture under agitation balance to room temperature through 16h.During seasoning, around glass surface, thickness is formed The crystalline material of layer.Along with stirring, break even income suspension in ice water bath.It is being furnished with Whatman #1 filter medium This suspension is filtered on 25cm buchner funnel.The crystallization collected with heptane (1L) washing, and make it air-dry under vacuo.40 DEG C/<under 1 torr, this crystallization 20h is further dried and generates pink crystalline solid product (160.99g, 77.2%).

Preparation ii) by N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-l-(2,3- Dihydroxypropyl) cyclopropane-1-sulfonamide (13.2g) and ethyl acetate (30mL) add and be provided with big magnetic stirring bar and magnetic force The conical flask of agitator/heating plate.Start to be stirred and heated to faint backflow to realize being completely dissolved generation dark brown solution.With The whole precipitation rapid solution every time adding fashionable formation and the speed making backflow keep, slowly add heptane portionwise and return In the solution of stream, the solid of formation is caused to dissolve slowly (～90mL heptan under reflux until adding heptane in solution Alkane).Stop heating, and make this crystalline mixture under agitation balance to room temperature through 16h.During seasoning, in glass surface week Enclose the crystalline material forming thick-layer.Along with stirring, break even income suspension in ice water bath.It is being furnished with Whatman #1 mistake This suspension is filtered on the buchner funnel of filter medium.The crystallization collected by heptane wash, and make it air-dry under vacuo.40 DEG C/<under 1 torr, this crystallization 20h is further dried and generates pink crystalline solid product.

Preparation iii) by N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-l-(2,3- Dihydroxypropyl) cyclopropane-1-sulfonamide (44.8g) and ethyl acetate (750mL) add and be provided with big magnetic stirring bar and magnetic The conical flask of power agitator/heating plate.Start to be stirred and heated to faint backflow to realize being completely dissolved generation dark brown solution. With the whole precipitation rapid solution adding fashionable formation and the speed making backflow keep every time, hexane is slowly being added portionwise Backflow solution in, until in solution add hexane cause the solid of formation dissolve under reflux slowly (～2L oneself Alkane).Stop heating, and make this crystalline mixture under agitation balance to room temperature through 16h.During seasoning, in glass surface week Enclose the crystalline material forming thick-layer.Along with stirring, break even income suspension in ice water bath.It is being furnished with Whatman #1 mistake This suspension is filtered on the buchner funnel of filter medium.The crystallization that washing is collected, and make it air-dry under vacuo.40 DEG C/< 1 torr Under, this crystallization 20h is further dried and generates pink crystalline solid product.

Embodiment 101: preparation N-(R)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-l- The crystalline polymorph of (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide

By N-(R)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-l-(2,3-dihydroxy third Base) cyclopropane-1-sulfonamide (216.10g) adds and is provided with the 4L taper of big magnetic stirring bar and magnetic stirring apparatus/heating plate Bottle.Add ethyl acetate (about 600mL).Begin to warm up and stir formation brown suspension.Make the faint backflow of this mixture, then volume Outer addition ethyl acetate (about 200mL) is to realize being completely dissolved obtaining dark brown solution.To add the whole heavy of fashionable formation every time Shallow lake rapid solution and make the speed that backflow keeps, slowly adds in the solution refluxed portionwise by heptane.When to this solution When adding 2L heptane, the solid of formation dissolves slowly under reflux.Stop heating, and make this crystalline mixture under agitation Balance to room temperature through 16h.During seasoning, around glass surface, form the crystalline material of thick-layer.Along with stirring, ice/ Break even income suspension in water-bath.The 25cm buchner funnel being furnished with Whatman #1 filter medium filters this suspension.With The crystallization that heptane (1L) washing is collected, and make it air-dry under vacuo.40 DEG C/<under 1 torr, be further dried this crystallization 20h.

Embodiment 102: the generation of IC50 data

Material and preparation of reagents: the allele GST-MEK1 that mankind GST-MEK1 and composition are activated^CA(with sudden change Ser218Asp and Ser222Asp) from Wild type human's MEK1 cDNA sub-clone to yeast expression vector pGEM4Z In (Promega, Madison, WI).At expression in escherichia coli GST-MEK1^CA, and use the affine tree of glutathione agarose 4B Fat (Amersham Pharmacia Biotech, Piscataway, NJ) carries out partial purification to it.By ERK2 allele from MAPK2/Erk2 cDNA (wild type) Ya Ke in pUSEamp (Upstate Biotechnology, Inc., Waltham, MA) Grand to carrier pET21a (Novagen, Madison, WI), produce the mice ERK2 allele of N-terminal histidine tag. Express ERK2 and be purified to homogeneous [Zhang, 1993#33].Myelin basic protein (MBP) is purchased from Gibco BRL (Rockville,MD).EasyTides adenosine 5'-triphosphate (ATP) ([γ-³³P])(NEN Perkin Elmer, Wellesley, MA) be all kinase reactions radioactive label source.The Raf-1 (truncate) activated and the MAP activated swashs Enzyme 2/ERK2 is purchased from Upstate, Inc. (Lake Placid, NY).4-20%Criterion Precast gel is purchased from Bio- Rad(Hercules,CA)。

Measure enzymatic activity: compound is diluted to 1xHMNDE (20mM HEPES from dimethyl sulfoxide (DMSO) stock solution pH 7.2、1mM MgCl₂, 100mM NaCl, 1.25mM DTT, 0.2mM EDTA) in.Typical 25 microlitres measure and comprise 0.002 nanomole MEK1^CA, 0.02 nanomole ERK2,0.25 nanomole MBP, the 0.25 unlabelled ATP of nanomole and 0.1 μ Ci [γ³³P]ATP.This Screening test consists essentially of 4 interpolations.The compound of 5 μ l dilutions is distributed to 96-hole assay plate.So After, 10 μ l 2.5x enzyme cocktail (only MEK1 are added to each hole^CAAnd ERK2), precincubation 30 minutes the most at ambient temperature.Then Add 10 μ l 2.5x Substrate cocktail (the adding MBP with unlabelled ATP of labelling), incubation 60 minutes the most at ambient temperature. Finally, add 100 μ l 10% trichloroacetic acid (TCA), and at room temperature incubation terminates this for 30 minutes and reacts and make radioactivity mark The protein precipitation of note.Product is collected to the glass fibre 96 hole screen plate prewetted with water and 1% pyrophosphate On.Then this screen plate is washed with water 5 times.Replace water with dehydrated alcohol, and at room temperature make this plate air-dry 30 minutes.Manual close Envelope back, and the scintillation solution of 40 μ l is distributed to each hole.Carry out top sealing and in TopCount, this plate counted, speed Degree is 2 seconds/hole.Some is tested, uses and need by the truncated-type MEK of Raf kinase activator.

Embodiment 103: the generation of EC50 data

The ERK being measured phosphorylation by western blotting detects the effect of compound in cell.With 20,000 cells/ MDA-MB-231 breast cancer cell is plated in 48 orifice plates by hole, and at the CO of 37 ° of humidifications₂Incubator is cultivated.Second day, remove Remove growth medium (DMEM+10% hyclone), and substitute with starvation media (DMEM+0.1% hyclone).Train hunger Support Incubate cells 16 hours in base, then by the compound treatment 30 minutes of a series of concentration.After compound incubation, use 100ng/ml EGF stimulates cell 5 minutes.Then dissolve cell, and use anti-phosphorylated CREB monoclonal antibody to pass through protein Northern blot analysis.Use the second antibody enhancing signal being combined with nir dye, and examine on Licor Odyssey scanner Survey signal.Measuring the amount of signal intensity, these data are used for generating dose-effect curve and EC50 calculates.

Embodiment 104: the activity data of compound

The compound described in embodiment 1,2 and 3 is tested in said determination.Result is summarized in (A, EC in following table₅₀=< 2.0nM；B,EC₅₀=2.0-15nM):

Embodiment 105: XRPD data

There is Curved Position Sensitive detector (the curved position-sensitive of 120 ° of 2 θ scope in configuration Detector) XPRD is carried out on Inel XRG-3000 diffractometer.Under the resolution of 0.03 ° of 2 θ, Cu K α radiation is used to adopt Collection real time data.The voltage and current intensity of pipe is respectively set to 40kV and 30mA.From 2.5 to 40 ° of 2 θ display figure so that Directly figure is contrasted.By being filled to thin-walled glass capillaries by sample, preparation is for (the S)-N-(3,4-bis-analyzed Fluoro-2-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-l-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide (as this Literary composition described synthesis) sample.Each capillary tube is moved on vehicularized goniometer head, thus rotates during allowing data acquisition Capillary tube.Analyze sample 5 minutes.Silicon reference standard is used to carry out instrument calibration every day.Fig. 5 is N-(S)-(fluoro-2-of 3,4-bis- (2-fluoro-4-idodophenylamino)-6-methoxyphenyl) powder of-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide A type thing End X-ray diffraction (PXRD) figure.Fig. 7 be N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)- 1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide A type (upper figure) and the powder X-ray diffraction of amorphous substance (figure below) (PXRD) figure.

Embodiment 106: differential scanning calorimetry (DSC)

TA instruments differential scanning calorimeter Q1000 is analyzed.Use indium as reference material calibration instrument.By sample Product are placed in be had in the standard aluminum matter DSC dish that corrugationless lid (non-crimped lid) constructs, and records weight exactly.For Measure the glass transition temperature (T of amorphous substance_g), make sample cell circulate several times between-40 DEG C to 140 DEG C.Make Finishing temperature rises to 150 DEG C.T is reported from the flex point of last conversion and cycle_g.Fig. 6 is that N-(S)-((2-is fluoro-for the fluoro-2-of 3,4-bis- 4-idodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide (A type) modulated DSC heat Analysis chart.In order to normalized heat flow that watt/gram (W/g) is unit to by DEG C in units of the sample temperature recorded make Figure.

Embodiment 107: dynamic vapor sorption/desorption (DVS)

VTI SGA-100 vapor sorption analyser gathers water adsorption/desorption data.It is spaced with 10%RH, at nitrogen Under purging, between 5% to 95% relative humidity (RH) scope, gather absorption/desorption data.Before analysis, sample undried.With It is that weight change is less than 0.0100% in 5 minutes in the tension metrics analyzed, if not met weight standard, then during maximum balance Between be 3 hours.The original water content of sample is not carried out Data correction.Use sodium chloride and polyvinylpyrrolidine (polyvinypyrrolidine) as calibration standard.Fig. 8 show N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-iodophenyl Amino)-6-methoxyphenyl) the DVS isothermal line of-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide (A type).In experiment Period, this material demonstrates that insignificant weight changes.

Embodiment 108: DTG (TG)

TA instrument 2950 DTG analyser is analyzed.Calibration standard is nickel and Alumel^TM.Each sample is put In aluminum quality sample dish, and it is inserted in TG smelting furnace.At 25 DEG C of balance samples, then with the rate of heat addition of 10 DEG C/min at nitrogen Heat under air-flow, until final temperature is 350 DEG C.Fig. 9 show N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-iodophenyl ammonia Base)-6-methoxyphenyl) the TG thermal analysis curue of-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide (A type), until 140 DEG C demonstrate that insignificant weight is lost, show that polymorph A type is non-solvated.

Embodiment 109: external cancer is screened

Human tumor cell is cultivated in RPMI 1640 culture medium comprise 5% hyclone and 2mM L-glutaminate System.With depend on each cell line doubling time in the range of 5,000 to 40, the plating density of 000 cells/well, will be thin with 100 μ L Born of the same parents are inoculated in 96 hole microwell plates.After cell inoculation, at 37 DEG C, 5%CO₂, under 95% air and 100% relative humidity, incubation these Microwell plate 24h, is subsequently adding N-(S)-(3,4-bis-fluoro-2-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2,3- Dihydroxypropyl) cyclopropane-1-sulfonamide.

In order to represent addition N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2, 3-dihydroxypropyl) cyclopropane-1-sulfonamide (Tz) time each cell line the measured value of cell mass, after 24h, with TCA in situ Two plates of fixing each cell line.Final full test concentration needed for 400 times, by N-(S)-((2-is fluoro-for 3,4-bis-fluoro-2- 4-idodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide is dissolved in dimethyl sulfoxide, And freezen protective before use.Fashionable adding, the frozen concentrated liquid of defrosting aliquot, and with comprising 50 μ g/ml gentamycins Complete medium is diluted to double required final full test concentration.In order to provide 5 kinds of concentration altogether to add comparison, additionally 4 times, 10 times or the diluent of 1/2 logarithm series are prepared.The separatory such as 100 μ l of these different diluent are added to comprising In the suitable microtiter well of 100 μ l culture medium, obtain required ultimate density.

Add N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxy Propyl group) after cyclopropane-1-sulfonamide, at 37 DEG C, 5%CO₂, under 95% air and 100% relative humidity, still further these plates of incubation 48h.For adherent cell, terminate measuring by adding cold TCA.By leniently adding 50 cold for μ l 50% (w/v) TCA ( Final concentration, 10%TCA) fixation in situ cell, and 4 DEG C of incubations 60 minutes.Abandoning supernatant, by tap water wash plate 5 times, and Air-dry.By 0.4% (w/v) Sulforhodamine (Sulforhodamine B) (SRB) solution (100 μ l) in 1% acetic acid Add in each hole, and at room temperature these plates of incubation 10 minutes.After dyeing, by removing uncombined 5 times with 1% acetic acid washing Dyestuff, and air-dry these plates.Thereafter the dye combined is dissolved with 10mM tri-(hydroxymethyl) aminomethane (trizma base) Material, and use automatic plate reader, at 515nm wavelength, read absorbance.For suspension cell, except by leniently adding 50 μ l 80%TCA (ultimate density, 16%TCA) be secured in bottom hole the cell of sedimentation to terminate measuring outside, method is identical.Make With 7 absorbance measurement [zero-time (Tz), comparison growth (C) and N-(S)-(the fluoro-2-of 3,4-bis-of 5 kinds of concentration levels (2-fluoro-4-idodophenylamino)-6-methoxyphenyl) survey in the presence of-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide Examination growth (Ti)], calculate the growth % under each drug concentration level.Growth inhibited % is calculated as follows:

Calculate Three doses response parameter.50% growth inhibited is calculated by [(Ti-Tz)/(C-Tz)] x100=50 (GI50), during it is medicine incubation, clean albumen in compared with control cells is caused to increase the dense of (being recorded by SRB dyeing) reduction by 50% Degree.N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-the idodophenylamino)-6-causing complete growth inhibited (TGI) is calculated by Ti=Tz Methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide concentration.Calculated by [(Ti-Tz)/Tz] x100=-50 After expression process, the LC50 of the clean decrement of cell (causes the protein recorded at the end of drug treating reduction compared with time initial The drug level of 50%).If reaching activity level, then calculate each value of these three parameter；But, make if being not up to or exceeding this With, then this parameter is to represent higher or lower than the highest of test or least concentration.

Corresponding to leukemia, nonsmall-cell lung cancer, colon cancer, CN cancer, melanoma, ovarian cancer, renal carcinoma, carcinoma of prostate With the group of breast carcinoma, have detected shown cell line and provide following result.

Embodiment 110: In Vitro Anti proliferation activity

In the present embodiment, have detected N-(S)-(3,4-bis-fluoro-2-(2-fluoro-4-idodophenylamino)-6-methoxybenzene Base) the following effect of-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide: (1) some tumors to suddenling change with difference are thin Born of the same parents are the inhibitory activity (GI of growth₅₀)；(2) inhibitory activity (GI to the growth of some B-Raf mutational cell lines₅₀)；(3) to patch Wall is independent of the effect of cell growth；(4) effect of cell cycle；(5) to primary hepatocyte and the toxic effect of nephrocyte Should.

Cell cultivation/growth inhibited measures

Human melanoma's A375 cell and Human colon cancer Colo205 cell obtain from ATCC (Manassas, VA).? Add in the DMEM of 10% hyclone, glutamine (2mM), penicillin (100U/ml) and streptomycin (100 μ g/ml) and cultivate A375 cell.At 37 DEG C, 5%CO₂With cultivation cell under 100% humidity.Adding 10% hyclone, glutamine (2mM), green grass or young crops The RPMI of mycin (100U/ml) and streptomycin (100 μ g/ml) cultivates Colo205 cell.For growth inhibition test, with 1000 μ l/ hole, cell/20, by plating cells in the microtest plate of white 384-hole.After 24hr, add 5 μ l 5X medicine storages Solution.The 200X stock solution being initially all configured in DMSO by all medicines, making final DMSO concentration is 0.5%.37 DEG C of temperature Hatching cell 48hr, and use CellTiterGlo (Promega, Madison, WI) to measure ATP level.Use Toxilight (Cambrex, Walkersville, MD) measures adenylic acid kinases (AK) release.Use GraphPad Prism 4 (GraphPad Software, San Diego, CA) carry out non-linear curve fitting.4-amino-8-((2R, 3R, 4S, 5R)-3,4-dihydroxy- 5-(hydroxymethyl) oxolane-2-base) pyrido [2,3-d] pyrimidine-5 (8H)-one (VRX-14686) is used as reference chemical combination The cytotoxic agent of thing.

Growth inhibited(%)=(only vehicle Control (RLU)-N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)- 6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide RLU)/(only vehicle Control RLU-1 μM N- (S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1- Sulfonamide RLU)；According to by N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2,3- Dihydroxypropyl) growth retardation that cyclopropane-1-sulfonamide causes, wherein measure ATP level.

Cell viability(%)=(N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1- RLU-10 μM of VRX-14686 RLU of (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide)/(only vehicle Control RLU-10 μM Tamoxifen RLU)；According to the cell killing caused by VRX-14686, wherein measure ATP level.

Cell killing(%)=(N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide RLU-only vehicle Control RLU)/(10 μMs of tamoxifen RLU-only carriers pair According to carrier RLU)；According to the cell killing caused by tamoxifen, wherein measure AK release.

RLU=relative light units

Evaluate cell cycle arrest

With 10,000 μ l/ holes, cell/200 by A375 plating cells in 96 hole microtest plates.After 24hr, cell is about 50% converges, and adds 50 μ l5X drug stock solution.Again after 24hr, cell, through trypsin acting, is fixed on 200 μ l Prefer In (Anatech, Battle Creek, MI), and store overnight at 4 DEG C.Then in PBS, clean cell, carry out permeableization Process, at 0.1%Triton X-100,200 μ g/ml without the ribonuclease of deoxyribonuclease and 25 μ g/ml propidium iodides Dyeing in (Molecular Probes, Sunnyvale, CA), and Guava PCA-96 (Guava Technologies, Foster City, CA) upper analysis.Use ModFit LT (3.0 editions, Verity, Topsham, ME) analytical data.

(1) growth inhibited of adherent not dependent cell is evaluated

The hole making " ultralow adhesiveness " plate (Corning, Acton MA) is full of 0.15% fine jade in complete RPMI of 60 μ l Lipolysaccharide solution.Then, the 60 complete RPMI of μ l of the 9000 Colo205 cells comprised in 0.15% agarose are added each hole. After 24hr, add 60 μ l without the 3X drug solution in the complete RPMI of agarose.After 7 days, by 36 μ l 6X MTS reagent (CellTiter 96 Aqueous, Promega, Madison, WI) adds each hole.At 37 DEG C after 2hr, in M5 plate reader On (Molecular Devices, Sunnyvale, CA), at 490nm, measure absorbance.GraphPad Prism 4 is used to enter Line nonlinearity curve matching.

(2) growth inhibited (GI to MEK dependency growth of cancer cells₅₀)

Make B-Raf mutant cell A375 (human melanoma) that logarithmic (log) phase dividing, A431 (melanoma), Colo205 (colon cancer), HT29 (Colon and rectum adenocarcinoma), MDA-MB231 (adenocarcinoma of breast) and BxPC3 (pancreas adenocarcinoma) and N-(S)- (the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulphonyl Amine contact 48hr, and measure ATP content.Use 1 μM of N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxy Base phenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide measures 100% growth retardation.

Following table show the average GI of each cell line deriving from least three test₅₀Value, and show N-(S)-(3,4-bis- Fluoro-2-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide causes Three kinds of B-Raf mutational cell lines (A375, Colo205 and HT29) and a kind of ras/raf/MEK/MAPK approach wild-type cell Growth inhibited in system (A431), it has Average potency 79nM (± 9nM).

Cell line	Meansigma methods	Standard deviation	C.V.
				A375	71nM	12.1nM	17%
A431	86nM	25.4nM	30%
				Colo205	89nM	40.1nM	45%
HT29	70nM	12.2nM	18%
				MDA	>1uM
BxPC3	>1uM

In independent research, make B-Raf mutant cell A375 (human melanoma) that logarithmic (log) phase dividing, SKMel28 (human melanoma) and Colo205 (Human colon cancer) and N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-iodophenyl Amino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide contact 48hr, and measure ATP content. Following table show the GI of each cell line₅₀, show N-(S)-(3,4-bis-fluoro-2-(2-fluoro-4-idodophenylamino)-6-methoxybenzene Base)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide causes growth inhibited, and it has and is similar to its MEK and suppresses EC₅₀Value Effect.

Cell line	GI₅₀(nM)
		A375	56
SK Mel28	105
		Colo205	27

Figure 10 A and Figure 10 B show with concentration increase N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)- 6-methoxyphenyl) the A375 cell that dividing of logarithmic (log) phase of-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide contact Growth retardation.Analyze raji cell assay Raji ATP content.Use 1 μM of N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)- 6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide measures 100% growth retardation.

Discharge by measuring adenylic acid kinases (AK), analyze cell supernatant and measure cytotoxicity lysis.Make logarithm The A375 cell that phase is dividing and N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide contacts 48hr with PD-325901.(20 μMs of tamoxifens are used to measure 100% Cell killing).Demonstrate result in fig. 11.These data show N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)- 6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide causes in some susceptibility human cancer cell lines Non-toxic growth retardation, this is by i) growth retardation measured value (ATP is quantitative)；And ii) lack cytotoxic cell lysis (AK release) proves.All cells system for test, it was demonstrated that lack AK release.

Adherent not dependent growth inhibited

Evaluate quantitatively and N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-iodophenyl ammonia with 96 hole microtest plate patterns Base)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide contact 7 days Colo205, A375 and The adherent not dependent growth of MDA-MB231 cell.Mensuration vigor is analyzed by MTS.GI₅₀It is worth as follows:

Cell line	Meansigma methods	Standard deviation	C.V.
				Colo205	40nM	8.1nM	20%
A375	84nM	17.2nM	21%
				MDA-MB231	81nM	55.6nM	69%

Figure 12 A-12C show N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1- (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide (A) growth inhibited (GI to Human Colorectal Cancer Colo205 cell₅₀= 11nM)；(B) growth inhibited (GI to A375 cell₅₀=22nM) and (C) suppression to MDA-MB231 cell, it pastes in two dimension Wall dependency does not demonstrates N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-in measuring The growth retardation that (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide causes.

Make A375 cell and N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-that logarithmic (log) phase dividing Methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide (1uM) contacts 48hr, and it is next to analyze cell supernatant Measure growth inhibited (ATP content) and cytotoxicity lysis (AK release).In only Vehicle-control wells, measure 100% vigor (ATP assay).Result shown in following table shows N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyl group Phenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide cause B-Raf sudden change human melanoma's A375 cell in Non-toxic growth retardation.

	% compares
		ATP, cell viability	27%
AK, cell killing	4%

Adherent not dependent growth inhibited

Adherent not dependent growth is evaluated quantitatively with 96 hole microtest plate patterns.Figure 13 A show and ties the mankind directly The growth inhibited of intestinal cancer Colo205 cell, GI₅₀Be worth non-Wei 6nM and 11nM.Figure 13 B show the growth to A375 cell to be pressed down System, GI₅₀Value is 5nM and 22nM.

N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxy third Base) cell cycle analysis of growth retardation that causes of cyclopropane-1-sulfonamide

Have shown that MEK suppression causes G1/S phase cell cycle arrest in A375 cell.

Make A375 cell and N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-that logarithmic (log) phase dividing Methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide contact 24hr, and use flow cytometer measure because of Amount of DNA in stage dependent cell and the percentage ratio of cell that dyes.

Following table show through N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2, 3-dihydroxypropyl) cyclopropane-1-sulfonamide and comparison (only carrier) cell that processes are in each trophophase cell point Cloth percentage ratio.

Figure 14 A and Figure 14 B show N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxybenzene Base) effect of-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide cell cycle process, this explanation make A375 cell with N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane- The contact of 1-sulfonamide causes cell cycle arrest within the G1 phase, and it is all exhausted by the cell being in G2 phase and S phase and shows.

Evaluate primary hepatocyte and nephrocyte toxicity

Cryopreserved rat hepatocytes obtains from CellzDirect (Austin, TX), and book according to the manufacturer's instructions It is plated in 96 orifice plates scribbling collagen.4hr after bed board, adds medicine (final DMSO concentration 0.5%).

The human hepatocytes of bed board obtains from CellzDirect, and book processes according to the manufacturer's instructions.

Cryopreserved mankind's Renal proximal tubular epithelial cell (renal proximal tubule epithelial Cell, RPTEC) obtain from Cambrex, and book processes according to the manufacturer's instructions.Make cell proliferation 4 days, then with 50,000 Cells/well is plated in 96 orifice plates for medicament contact.

After 48hr, use Toxilight to measure supernatant A K level, and use CellTiterGlo to measure cell ATP water Flat.15 μMs of VRX-14686 are used to measure killing value completely.

Result is as follows.Observe few cell lysis.In the Primary human hepatocyte of firm bed board, observe To at 30 μMs of N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxy third Base) minimum toxicity (81% survival rate) under cyclopropane-1-sulfonamide.RPTEC cells show go out dose dependent ATP loss with And under 30 μMs obvious cell lysis.

Data above shows (1) N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1- Cell growth in the human cancer cell that the suppression of (2,3-dihydroxypropyl) cyclopropane-1-sulfonamide is selected and division, adherent In dependency proliferation assay, its GI₅₀Value, in the range of 70-89nM, is not produced poison as measuring in cell lysis analysis Property；(2) N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) Cell growth in the human cancer cell that the suppression of cyclopropane-1-sulfonamide is selected and division, at anchorage dependence be independent of In property proliferation assay, GI₅₀Value is respectively 51nM and 22nM；(3) N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)- 6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide causes G1 to stagnate and suppresses the patch in A375 cell The not dependent growth of wall, it is provided that active anticancer evidence in the external model that physiology is correlated with；(4) N-(S)-(fluoro-2-of 3,4-bis- (2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide to primary normally Human hepatocytes, mankind's Renal proximal tubular epithelial cell and rat hepatocytes show cytotoxicity hardly.

Embodiment 111: N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-iodophenyl ammonia in the cancer patient after multiple dosing Base)-6-methoxyphenyl) pharmacokinetics of-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide

R_ac: index of bunching

^*Owing to limited sample time is evaluated inaccurate

With 2,4 or 6mg/ experimenter multiple dosing N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxy Base phenyl) after-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide, N-(S)-(3,4-bis-fluoro-2-(2-fluoro-4-iodophenyl Amino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide is readily absorbed, its average T_maxModel Enclosing is 1.33 to 1.50hr.Average C_max、C_τWith AUC to increase with dosage in the way of dose proportional.For C_max, accumulation Index range is 1.49 to 1.76, and for AUC, index of bunching scope is 1.90 to 2.07, and this shows accumulation appropriateness.Although due to After multiple dosing, sample time is limited, it is impossible to measure the half-life exactly, but according to index of bunching, it is contemplated that multiple dosing is later half to decline Phase is longer than 22hr.Observed value that these elimination half life values are considerably longer than in mice effectiveness models (the usual scope observed be 2 to 3hr).Additionally, under all dosage, it was observed that challenging peak-to-valley ratio.

Embodiment 112: N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-iodophenyl ammonia in healthy volunteer after multiple dosing Base)-6-methoxyphenyl) pharmacokinetics of-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide

R_a: index of bunching

^*Owing to limited evaluation sample time is inaccurate

With 10 or 20mg/ experimenter multiple dosing N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxy Base phenyl) after-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide, N-(S)-(3,4-bis-fluoro-2-(2-fluoro-4-iodophenyl Amino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide is readily absorbed, its average T_maxModel Enclosing is 2.00 to 2.25hr.Average C_max、C_τIncrease with dosage with AUC.For C_max, index of bunching scope be 1.14 to 1.23, for AUC, index of bunching scope 1.24 to 1.29, this shows to accumulate the most notable.The half-life phase of two kinds of dosage regimens Seemingly, its scope is 13 to 15hr.These elimination half life values are shorter than the observed value in cancer patient.

Embodiment 113: In Vitro Anti proliferation activity

In cell proliferation test, (S)-((2-is fluoro-for 3,4-bis-fluoro-2-to detect N-in the cell line come from Human Gastric carcinoma 4-idodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide is to suppression cell proliferation Effect.

Cell cultivation/growth inhibition test: Human Gastric carcinoma's Hs746t cell obtains from ATCC (Manassas, VA).Mending Add cultivation Hs746t cell in the DMEM of 10% hyclone, penicillin (100U/ml) and streptomycin (100 μ g/ml).37 DEG C, 5%CO₂With cultivation cell under 100% humidity.For cell proliferation test, with 3000 μ l/ holes, cell/100 by plating cells in tool Have in white 96 orifice plate of clear bottom.After 24hr, remove cell culture medium, and with comprising various dosage N-(S)-(3,4-bis- Fluoro-2-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl) training of-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide Support base to substitute.After 37 DEG C of incubation 48hr, CellTiterGlo (Promega, Madison, WI) is used to measure ATP level, and LJL Biosystems Analyst HT (Sunnyvale, CA) is used to read luminous value.Use independent hole in triplicate Measure the ATP level of each dosage.

Relative cell number=(average RLU is (through N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyl group Phenyl) process of-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide))/(average RLU only vehicle Control).

Figure 19 show cell number (relative to carrier) to N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)- 6-methoxyphenyl) chart of-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide concentration, and show to process 48 little Shi Hou, N-(S)-(3,4-bis-fluoro-2-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) ring The propagation of propane-1-sulfonamide suppression Human Gastric carcinoma's Hs746t cell.

Embodiment 114: In Vitro Anti proliferation activity

In cell proliferation test, the cell line coming from mankind's adenocarcinoma of stomach (" gastric cancer ") detects N-(S)-(3,4-bis- Fluoro-2-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide is to pressing down The effect of cell proliferation processed.

Cell cultivation/growth inhibition test

Mankind's adenocarcinoma of stomach ags cell obtains from ATCC (Manassas, VA).Adding 10% hyclone, penicillin (100U/ml) ags cell is cultivated with in the DMEM/F12 of streptomycin (100 μ g/ml).At 37 DEG C, 5%CO₂Train with under 100% humidity Support cell.For cell proliferation test, with 3000 μ l/ holes, cell/100 by plating cells in white 96 hole with clear bottom In plate.After 24hr, remove cell culture medium, and with comprising various dosage N-(S)-(3,4-bis-fluoro-2-(2-fluoro-4-iodophenyl ammonia Base)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide culture medium substitute.37 DEG C of incubations 3 days After, use CellTiterGlo (Promega, Madison, WI) to measure ATP level, and use LJL Biosystems Analyst HT (Sunnyvale, CA) reads luminous value.Independent hole is used to measure the ATP level of each dosage in triplicate. In another is tested, bed board 1000 cells/100ul/ hole, process cell 6 days, and as above measure.

Figure 15 A and Figure 15 B show and N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxybenzene Base)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide contacts after 3 days (A) and after 6 days (B), and N-(S)-(3,4-bis-is fluoro- 2-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide concentration is to carefully The chart of born of the same parents' number (relative to carrier), this shows N-(S)-(3,4-bis-fluoro-2-(2-fluoro-4-idodophenylamino)-6-methoxybenzene Base) propagation of-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide suppression mankind adenocarcinoma of stomach ags cell system.

Embodiment 115: through different amounts of N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxybenzene Base) growth response of nude mice situ mankind's Hep3B tumor of-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide treatment

Contrast with the 5-fluorouracil of dose,optimum (75mg/kg), evaluation N-(S) in BALB/c nu/nu mice-(3, The fluoro-2-of 4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide (" compound A ") dose response usefulness to the suppression that original position Hep3B2.1-7 human liver cancer occurs.

Animal: (University of Adelaide, Waite Campus, SA, Australia is big for female BAl BIc/c nu/nu mice Leah), 10-14 week old, weight range: 19.1-29.94g (average 22.95g) is used for research.Mice is divided into following 6 Seminar's (4 treatment groups and 2 matched groups):

Number of mice/group: include being 10 in 1-5 group

" absorbance " matched group (the 6th group) it is 15

In controlled environment (target zone: temperature 21 ± 3 DEG C, humidity 30-70%, 10-15 time ventilation/hour), screen Under the conditions of barrier (quarantine), with 12 hours illumination/12 hour dark cycles, raise mice.Routinely monitoring temperature is wet with relative Degree.Optionally supply commodity rodent (Rat and Mouse Cubes, Speciality Feeds Pty to animal Ltd, Glen Forrest, Western Australia) and tap water.Food and water are supplied all by autoclaving sterilizing.

Tumor inoculation: cultivate Hep3B human hepatocarcinoma cells in RPMI1640 cell culture medium (from active redundancy VP- Stock's 353 passes on 2), described culture medium adds 10%FBS and Pen .-Strep (50IU/mL ultimate density).Pass through pancreas Cell is collected in protease effect, cleans twice, and count in HBSS.Then, cell is suspended in again HBSS:Matrigel In (1:1, v/v), and it is adjusted to comprise 1x10⁸The final volume of cell/mL.Before inoculation, cut with ethanol wiping fully Port part, and open abdomen exposes liver.Insert a needle into liver surface, inject 10 μ L cell (1x10 herein⁶Cell).For Avoid tumor cell to leak out in abdominal cavity, pin is maintained at this position keep about 30 seconds so thatPolymerization.

Inoculate latter 14 days and start treatment.In the 7th day (after inoculation the 21st day) of research, kill the institute of " absorbance " matched group Mice, visual assessment liver is had to detect the existence of tumor.

Material: following material obtains from each supplier.

Sterile saline solution (0.9%NaCl (aq)) is Australian from Baxter Healthcare, Old Toongabbie, NSW, Australia obtains.Cremophor EL obtains from Sigma-Aldrich Pty Ltd, Castle Hill, NSW, Australia. The 5-fluorouracil clinical preparation of the colourless liquid of clarification obtains from Mayne Pharma Pty Ltd.RPMI1640 cell is cultivated Base, FBS and HBSS obtain from Invitrogen Australia Pty Ltd, Mt Waverley, VIC, Australia.Penicillin- Streptomycin and trypan blue obtain from Sigma-Aldrich, Castle Hill, NSW, Australia.Hep3B2.1-7 human liver cancer Cell derived in American type culture collection (American Type Culture Collection) (ATCC), Rockville,MD,USA。MatrigelFrom BD Biosciences, North Ryde, NSW, Australia obtains.

Inoculation suspension usesImprove the absorbance of tumor and reduce the transmutability of tumor size, and And the growth of Hep3B2.1-7 human hepatocarcinoma cells is more stable when inoculation in the presence of this extracellular matrix.

Compound preparation and administration: according to following timetable administration cremophor EL: saline (1:9, v/v；Vehicle Control), N- (S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1- Sulfonamide (" compound A ") or 5-fluorouracil (compound control):

With the administration volume of 10mL/kg, the most persistently 21 days (the 0th day to the 20th day) oral administration vehicle Control breasts Floating EL: saline (1:9, v/v).

At cremophor EL: preparation N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-in saline (1:9, v/v) Methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide.Prepare weekly stock solution, and preserve at 4 DEG C. It is dispensed to drug solns in the every day being administered.With the administration volume of 10mL/kg, within the most persistently 21 days, (the 0th day to the 20th My god) oral administration N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxy Propyl group) cyclopropane-1-sulfonamide.Compound described in dosed administration with 2,10 and 50mg/kg.

5-fluorouracil clinical preparation is diluted in Sterile Saline, and under concentration 75mg/kg, giving with 10mL/kg Medicine volume, continues 3 weeks (the 0th day, the 7th day and the 14th day) once in a week, carries out intravenous administration via tail vein.

Mice in 6th group (" absorbance " compares) is not applied treatment.The 7th day (inoculating latter 21 days) of research, kill Dead mice, and expose liver to measure the tumor size in " absorbance " and liver wall.

The most at once the body weight of each animal is measured.Calculate according to body weight and adjust the dosage to each mice.

Measurement of tumor: when the expiration date in research is in time after death excising each liver and tumor, measure liver and tumor weight in wet base. At the end of research, hepatectomize from all mices of each seminar and weigh.If visible tumor exists, then count its number Amount.Remove these tumors from liver and weigh.

DATA REASONING and sample collecting timetable

Data acquisition and calculating: gathering before data, at once use bar code reader (LabMax I, DataMars, Switzerland) transponder (Bar Code Data Systems Pty Ltd, Botany Bay, NSW) of each animal is scanned. With identical hand-held caliper (Absolute Digimatic Model CD-6 " CS, Mitutoyo Corporation, Japan) all measured values are obtained.Use Pendragon Forms 4.0 (Software Corporation, Libertyville, IL, U.S.A.) as transmitting software, make data syn-chronization with vivoPharm ' s secure relational database.Will AIDAM v2.4 calculates for data report and data.

Statistics and calculating: use SigmaStat 3.0. (SPSS Australasia Pty Ltd, North Sydney, NSW, Australia) carry out all statistical calculations.

The inspection of double sample t-is used to measure between the 0th day to the expiration date of research the notable of body weight change in treatment group Property.In the case of data are not by test of normality or homogeneity test of variance, carry out Mann-Whitney rank test.

At the end of research, liver weight is carried out one factor analysis of variance (ANOVA) with Tumor weight data and (all becomes To multiple comparison graph (All Pairwise Multiple Comparison Procedure) and with matched group multiple comparisons). In the case of this test fails homogeneity test of variance, carry out Kruskal-Wallis one factor analysis of variance according to grade (ANOVA).The data of tumor-bearing mice in research are carried out identical statistical analysis.

P value is considered to have significance less than 0.05.

The liver often organizing every mice of the liver weight of tumor-bearing mice and Tumor weight data and tumor-bearing mice is with swollen The average weight of tumor

Sample is not gathered from the mice (it is killed during studying) of the 5th group (75mg/kg5-fluorouracil).Due to Some mices exist big tumor (as indicated by abdominal part swollen appearance), within 18 days after initial therapy, terminates this research.

Through N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxy Propyl group) in cyclopropane-1-sulfonamide-treatment group, the dose dependent trend that liver and tumor weight reduce is obvious.When only considering During tumor-bearing mice, find at N-(S)-(3,4-bis-fluoro-2-(the 2-fluoro-4-iodophenyl through maximum dose level (the 4th group with 50mg/kg) Amino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide and 5-fluorouracil (and the 5th group with In group 75mg/kg) treated, the average weight of liver is relative to vehicle Control group (the 1st group；P < 0.05) there is significant difference. And find through N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxy Propyl group) cyclopropane-1-sulfonamide (the 3rd and the 4th group respectively with 10mg/kg and 50mg/kg) and 5-fluorouracil (the 5th group with In group 75mg/kg) treated, the average weight of tumor has significant difference relative to vehicle Control group.

Figure 16 (average liver weight only tumor-bearing mice) and Figure 17 (liver neoplasm weight only tumor-bearing mice) lead to Cross chart and provide these results.

Embodiment 116: through different amounts of N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxybenzene Base) growth of nude mice situ mankind's HT-29 colon tumor of-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide treatment Reaction

Contrast with the 5-fluorouracil (75mg/kg) of dose,optimum, evaluation N-(S) in BALB/c nu/nu mice-(3, The fluoro-2-of 4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide (" compound A ") dose response usefulness to the suppression that original position HT-29 mankind's Colon and rectum adenocarcinoma occurs.

Animal: (University of Adelaide, Waite Campus, SA, Australia is big for female BAl BIc/c nu/nu mice Leah), 7-12 week old, weight range: 16.58-25.39g (average 21.52g) is used for research.Mice is divided into following 6 Seminar's (4 treatment groups and 2 matched groups):

Number of mice/group: include being 10 in 1-5 group

" absorbance " matched group (the 6th group) it is 9

Tumor inoculation: cultivate HT-29 human colorectal adenocarcinoma's cell in RPMI1640 cell culture medium (from from work That makees deposit VP-Stock325 passes on 4), described culture medium adds 10%FBS and Pen .-Strep, and (50IU/mL is the denseest Degree).Collect cell by trypsin acting, clean twice in HBSS, and count.Then, cell is suspended in again In HBSS, and it is adjusted to comprise 2x10⁸The final volume of cell/mL.Before inoculation, with ethanol wiping cutting part fully, and Open abdomen exposes caecum wall.Insert a needle into caecum wall surface, inject 5 μ L cell (1x10 herein⁶Cell).

Material: following material obtains from each supplier.

Sterile saline solution (0.9%NaCl (aq)) is Australian from Baxter Healthcare, Old Toongabbie, NSW, Australia obtains.Cremophor EL obtains from Sigma-Aldrich Pty Ltd, Castle Hill, NSW, Australia. The 5-fluorouracil clinical preparation of the colourless liquid of clarification obtains from Mayne Pharma Pty Ltd.RPMI1640 cell is cultivated Base, FBS and HBSS obtain from Invitrogen Australia Pty Ltd, Mt Waverley, VIC, Australia.Penicillin- Streptomycin and trypan blue obtain from Sigma-Aldrich, Castle Hill, NSW, Australia.HT-29 mankind's Colon and rectum gland Cancer cells is in American type culture collection (ATCC), Rockville, MD, USA.

Compound preparation and administration: according to following timetable administration cremophor EL: saline (1:9, v/v；Vehicle Control), N- (S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1- Sulfonamide or 5-fluorouracil (compound control):

At cremophor EL: preparation N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-in saline (1:9, v/v) Methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide.Prepare weekly stock solution, and preserve at 4 DEG C. It is dispensed to drug solns in the every day being administered.With 2,10 and the dosage of 50mL/kg, with the administration volume of 10mL/kg, once a day Continue 21 days (the 0th day to the 20th day) oral administration N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyl groups Phenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide.

Mice in 6th group (" absorbance " compares) is not applied treatment.The 7th day (inoculating latter 21 days) of research, kill Dead mice, and expose colon to measure the tumor size in " absorbance " and caecum wall.

Measurement of tumor: when the expiration date in research is in time after death excising each caecum and tumor, measure caecum and tumor weight in wet base. At the end of research, from all mice caecectomies of each seminar and intactly weigh together with tumor.Then cut from caecum Except tumor and weigh.

DATA REASONING and sample collecting timetable

Data acquisition and calculating: gathering before data, at once use bar code reader (LabMax I, DataMars, Switzerland) transponder (Bar Code Data Systems Pty Ltd, Botany Bay, NSW) of each animal is scanned. With identical hand-held caliper (Absolute Digimatic Model CD-6 " CS, Mitutoyo Corporation, Japan) all measured values are obtained.Use Pendragon Forms 4.0 (Software Corporation, Libertyville, IL, U.S.A.) as transmitting software, make data syn-chronization with vivoPharm ' s secure relational database.Will AIDAM v2.4 calculates for data report and data

The inspection of double sample t-is used to measure between the 0th day to the expiration date of research the notable of body weight change in treatment group Property.Through 2 and 50mg/kg N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2,3- Dihydroxypropyl) cyclopropane-1-sulfonamide treatment group in, due to excessive body weight loss therapy discontinued.In these groups, make Measure between the 0th day to final treatment day of research and in the last treatment day studied to terminating with the inspection of double sample t- The significance of body weight change in treatment group between.In the case of data are not by test of normality or homogeneity test of variance, Carry out Mann-Whitney rank test.

At the end of research, caecum weight is carried out one factor analysis of variance (ANOVA) with Tumor weight data and (all becomes To multiple comparison graph (All Pairwise Multiple Comparison Procedure) and with matched group multiple comparisons). In the case of data are not by test of normality, before carrying out the method, numerical value is converted into natural logrithm..

P value is considered to have significance less than 0.05.

Observe: in all seminar include vehicle Control group, measure average weight loss.Include carrying in all seminar In body comparison, it was observed that the sign (skin elasticity disappearance) suffered from diarrhoea and be dehydrated.During studying, the severe weight loss of early stage is led Cause within the 9th day and the 7th day, to accept lowest dose level (2mg/kg) and maximum dose level (50mg/kg) N-(S)-(3,4-respectively study Two fluoro-2-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide Treatment in group stops.Because accepting 10mg/kg N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxy Base phenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide group in, body weight loss is less serious, so according to the time This group is implemented all treatments by table.For this group and 5-fluorouracil treatment group, at the end of research, average weight loss has Significance.

Although 21 days after inoculation, in " absorbance " group, the absorbance of HT-29 tumor was 100%, but these tumors is big Little far below desired value.This may cause N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)- Average caecum between 1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide treatment group and vehicle Control group and tumor weight without Significant difference.5-fluorouracil on the weight of caecum and HT-29 tumor also without impact.

Body weight measurements (± SEM) (final treatment day and research Close Date)

Do not collect the weight data of the 6th group (" absorbance " compares).Kill in the 7th day (postvaccinal 21st day) of research It is the most abundant for object of this investigation that this group mice carrys out visual assessment tumor growth.

Due to the body weight that mice loss is excessive, in the interruption in the 9th day the 2nd group studied, (2mg/kg N-(S)-(3,4-bis-is fluoro- 2-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide) in control Treat, in the 4th group of (50mg/kg N-(S)-(3,4-bis-fluoro-2-(2-fluoro-4-the idodophenylamino)-6-first of interruption in the 7th day of research Phenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide) in treatment.During studying, remaining set all accepts institute There is periodic treatments.

It it is the average tumor weight of each group shown in Figure 18.The average tumor weight of each group only includes that survival is final to research The mice of day.The numerical value of mice dead during studying is not included in the meansigma methods calculated.

Caecum weight and Tumor weight data

Shade lattice represent the sample gathered from the mice died from during research.Being computed of caecum weight and tumor weight is put down Average does not include these values.Trend shows, through 10mg/kg N-(S)-(3,4-bis-fluoro-2-(2-fluoro-4-idodophenylamino)-6- Methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide treatment after, HT-29 tumor and the data of caecum weight Reduce.

Embodiment 117: the tumor growth delay in nude mice with mankind's A375 melanoma xenograft

Use 6 groups of (n=9) tumor-bearing mices.Matched group includes being continued once a day 14 days (qd by buccal tubes feeding (po) X14) accept a mice of 10% cremophor EL/saline vehicle, and every other day continue 5 times (qod x5) with 30mg/kg and pass through Tail vein injection (iv) is administered the another mice of the paclitaxel as reference agent.4 test group accept 25mg/kg or 50mg/kg, qd x14, or 12.5 or 25mg/kg, the oral N-(S) of bid x14-(3,4-bis-fluoro-2-(2-fluoro-4-iodobenzene Base amino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide (" compound A ").Commented by TGD Valency therapeutic outcome, it is defined as compared with matched group, reaches the difference of the time intermediate value of terminal gross tumor volume in treatment group.Pass through Toxicity is evaluated in measured body weight and clinical observation.

Animal: at the 1st day of research, female athymic nude mouse (nu/nu, Harlan) be 10 11 weeks greatly, and body weight (BW) scope is 19.3 to 25.5g.With these detoxification water of purpose (reverse osmosis, 1ppm Cl) and NIH 31 Modified and Irradiated LabThis feedstuff is made up of 18.0% thick protein, 5.0% crude fat and 5.0% crude fibre.12 Under hour periodicity of illumination, under 21 22 DEG C (70 72) and 40 60% humidity, raise case in static micro-isolation (microisolator) in, via radiationMice is raised on laboratory animal bedding and padding.Abide by Follow management of laboratory animal and guide for use (Guide for Care and Use of Laboratory Animals) about limit System, animal feeding management, surgical procedure, feedstuff and liquid specifies and the suggestion of veterinary care.

Tumor is implanted: by the serial transplantation in athymic nude mice, start xenogenesis from A375 human melanoma's tumor Transplant.By A375 tumor fragment (～1mm³) be subcutaneously implanted in the right flank abdomen of each test mice, and when mean size is close 100-150mm³Time, monitor tumor growth.After 13 days, it is intended that for the 1st day of research, animal being divided into 6 groups, often group is by each tumor Volume range is 63 to 221mm³And group mean tumour volume is 125.3 to 125.9mm³9 mices (from 10 reduce) composition. Use following formula calculating gross tumor volume:The wherein width (mm) of w=A375 tumor, and l=A375 tumor Length (mm).

Material: with the concentration of 5mg/mL by N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxybenzene Base) in 10% cremophor EL that is dissolved in saline of-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide, along with supersound process, Shake and be heated to 35 DEG C and carry out hydrotropy.5mg/mL solution be used as 50mg/kg treatment to drug solns, and prepared by serial dilution For 25mg/kg and 12.5mg/kg treatment to drug solns.Under room temperature lucifuge, it is administered solution storage up to 1 week.

By at 5% ethanol, 5% cremophor EL in 5% D/W (D5W), 30mg/mL stock solution is diluted to The paclitaxel (NPI) of 3mg/mL preparation use every day gives drug solns.Dose of paclitaxel is 30mg/kg.

Treatment: following table show therapeutic scheme.

The mice of the 1st group, by buccal tubes feeding (po), accepts to every day 14 doses (qd x14) by 10% breast in saline floating The carrier of EL composition, and it is used as the comparison of tumor development.With 30mg/kg, every other day one time 5 doses (qod x5) to the 2nd treated animal Intravenous (iv) is administered the paclitaxel as reference reagent.According to following timetable, the mice of the 3rd 6 group accepts oral N- (S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1- Sulfonamide: 50mg/kg, qd x14；25mg/kg, every day twice, 14 days, gave single dose (bid at the 1st day and last 1 day x14)；25mg/kg,qd x14；And 12.5mg/kg, bid x14.It is administered all doses with 0.2mL volume/20g body weight, and presses The body weight of thing adjusts.

Terminal: use caliper to measure the tumor in all groups semiweekly.When the tumor of each animal, to reach terminal big Little 2000mm³Time, or (the 60th day) the most all day in research, whichever the most extremely, makes each animal euthanasia.From below equation Calculate each mice and reach the time (TTE) of terminal:Wherein b is Linear intercept and m is The slope of straight line, the linear regression of the tumor growth data set that described straight-line pass log converts obtains.

Data set includes that the first time exceeding research terminal volume observes, and is at once reaching before terminal volume three Secondary Continuous Observation.The animal giving not up to terminal specifies the TTE value of the last day equal to research.Due to accident (NTRa) or by In unknown cause (NTRu) be classified as animal dead for NTR (non-treatment dependency) not included in TTE calculate (with all enter one The analysis of step) in.Appointment classifies as TR (treatment dependency) death or NTRm (the non-treatment dependency because of caused by transfer) is dead The TTE value of animal equal to day of death.

Determining therapeutic outcome from tumor growth delay (TGD), it is defined as compared with matched group, reaches terminal in treatment group The increase of time (TTE) intermediate value: TGD=T C, express with natural law, or be expressed as accounting for the percentage ratio of the TTE intermediate value of matched group:Wherein: the TTE intermediate value of T=treatment group, the TTE intermediate value of C=matched group (the 1st group).

Treatment may cause the partial deterioration (PR) of tumours in animals or degenerate (CR) completely.In PR responds, in research During, the gross tumor volume of three continuous measurements is the 50% or less of the 1st day volume, and one or many in these 3 times measurements The gross tumor volume measured is equal to or more than 13.5mm³.In CR responds, in research process, the tumor body of three continuous measurements Long-pending less than 13.5mm³.At the end of research, the animal with CR response is additionally classified as without tumor survival person (TFS).Prison Survey and record tumour regression.

Side effect: weigh animal in first 5 day every day of research, weigh the most twice a week.Observe appointing of mice continually The obvious sign of the side effect the best, treatment is relevant, and clinical sign is recorded when observing.Acceptable toleration Organize the loss of average weight weight during being defined as test and be not more than 1 less than treatment related mortality in 20%, and animal groups Only.Any dosage regimen being unsatisfactory for these standards is deemed out maximum tolerated dose (MTD).If through clinical sign and/ Or postmortem proves to be attributable to treat side effect, then death is classified as TR, if or during being administered or in last administration 10 days in due to unknown cause, then death can be classified as TR.If without the dead evidence relevant with treatment side effect, then Death is classified as NTR.

Statistics and plot analysis: use sequence check to analyze showing of difference between the TTE value for the treatment of group and matched group Work property.At significance level P=0.05, carry out double tail statistical analysis.

Median tumor growth curve shows to organize the function that gross tumor volume intermediate value is the time.When animal is due to tumor size or TR When research is exited in death, final gross tumor volume and data including the animal recorded are for calculating the group tumor of time point subsequently Volume-median.After the animal of 50% exits research due to tumour progression in group, block curve.Make Kaplan-Meier figure to come The research of the function being denoted as the time remains the percentage ratio of animal, and uses the data set identical with sequence check.Will Prism (GraphPad) Windows 3.03 is for all of diagram and statistical analysis.

Treatment response is summed up

The growth of A375 tumor in control mice (the 1st group): the animal of the 1st group accepts 10% cremophor EL/saline vehicle, po, qd x14.The tumor of control mice grows to 2000mm progressively³Terminal volume, TTE intermediate value be 22.8 days (at 37.1 days Research determines the T-C of maximum possible) or TGD be 163%.

The effect treated with paclitaxel (the 2nd group): be administered as the paclitaxel of reference reagent to the 2nd animal, 30mg/kg, iv,qod x5.9 whole animals reach gross tumor volume terminal.Tumor growth is parallel, and contrasts matched group and slightly move right. TTE intermediate value is 28.8 days, corresponding to 26%TGD, has significance through Time-Series analysis (table 2, P=0.0088 G1 vs.G2) result. Relevant with paclitaxel treatment without tumour regression.

Through N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxy third Base) effect treated of cyclopropane-1-sulfonamide (the 3rd 6 group): the 3rd 6 group accepts N-(S)-(3,4-bis-as monotherapy Fluoro-2-(2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide be administered orally It is administered.It is administered 50mg/kg to the 3rd treated animal according to qdx14 timetable.9 tumors in group reach volume terminal.At 1-10 My god, the gross tumor volume intermediate value of group experiences fraction of net change, persistently increases with research afterwards.One animal experience tumor PR.TTE Intermediate value is 27.5 days, or 21%TGD, for notable result (P=0.0054 G1 vs.G).

The animal of the 4th group accepts 25mg/kg N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-iodine according to bid x14 timetable Phenyl amino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide.At the 60th day, in group, 9 were moved 4 residues in thing, all TFS.In the previous day that research terminates, the tumor of 2/9 animal additionally reaches volume terminal.Should Group has 4/9PR, 5/9CR and 4/9TFS.At initial several days of research, gross tumor volume intermediate value started to reduce, and the most about 30 My god.Tumor regrowth in 5/9 animal causes the reproduction originating in the tumor growth intermediate value of the about the 32nd day, and continues to studying knot Bundle.This group TTE intermediate value is 59.9 days, represents the possible 163%TGD (P < 0.0001, Table A 1) of maximum.

5th group of mice also receives 25mg/kg N-(S)-(the fluoro-2-of 3,4-bis-(2-fluoro-4-idodophenylamino)-6-methoxy Base phenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide, but according to more unstrained qd x14 timetable.5th Whole 9 animals of group reach gross tumor volume terminal, without tumour regression.Tumor growth is closely along the tumor growth of matched group Trail change.TTE intermediate value is 25.6 days, or 12%TGD, for non-limiting result (P=0.0662 G1 vs.G5).

According to bid x14 timetable, it is administered 12.5mg/kg N-(S)-(3,4-bis-fluoro-2-(fluoro-4-of 2-to the 6th treated animal Idodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide.All tumors in group are equal Reach volume terminal.Such as the 4th group, research early stage, the gross tumor volume intermediate value of the 6th group reduces, but this reduction is the most lasting About 9 days, and relevant to single PR response.Terminating from the 10th day to research, gross tumor volume increases.The TTE intermediate value of this group is 27.5 days, corresponding to having the 21%TGD (P=0.0424 G1 vs.G6) of significance.

In a word, with once a day with twice oral administration N-(S) every day-(3,4-bis-fluoro-2-(2-fluoro-4-iodophenyl ammonia Base)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide all demonstrates mankind's A375 melanoma The dosage correlation anti-tumor activity of xenograft.In the TGD size produced and the quantitative aspects of target response, every day twice Administration is better than being administered once a day.Therefore, N-(S)-(3,4-bis-fluoro-2-(2-fluoro-4-idodophenylamino)-6-methoxybenzene Base) anti-tumor activity of-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide be dose dependent be also that timetable depends on Rely property.

Embodiment 118: suppress the activity of subcutaneous COLO 205 Human colon cancer xenograft

Animal: at the 1st day of research, female athymic nude mouse (nu/nu, Harlan) be 12 13 weeks greatly, and body weight (BW) scope is 18.3 to 27.3g.With these detoxification water of purpose (reverse osmosis, 1ppm Cl) and NIH 31 Modified and Irradiated LabThis feedstuff is made up of 18.0% thick protein, 5.0% crude fat and 5.0% crude fibre.? Under 12-hour periodicity of illumination, under 21 22 DEG C (70 72) and 40 60% humidity, raise in case in static micro-isolation, Via radiationMice is raised on laboratory animal bedding and padding.Follow management of laboratory animal and use refers to The Southern Pass is in restriction, animal feeding management, surgical procedure, feedstuff and liquid specifies and the suggestion of veterinary care.

Tumor is implanted: start xenotransplantation from COLO 205 human colon cancer cells.At 10% heat-killed tire Sanguis Bovis seu Bubali Clearly, 100 units/mL penicillin G sodium, 100 μ g/mL streptomycin sulfates, 0.25 μ g/mL amphotericin B and 25 μ g/mL celebrating are the most mould Culture of tumor cell in element, 2mM glutamine, 1mM Sodium Pyruvate, 10mM HEPES and 0.075% sodium bicarbonate.At 37 DEG C, 5%CO₂With in the atmosphere of 95% air, humidification incubator in, in tissue culture's culture in glassware cell.Implant at tumor cell Day, during logarithmic growth, collect Colo 205 cell, and with 5x10⁶The concentration of cell/mL is suspended in PBS again In 50%Matrigel substrate (BD Biosciences).Each test mice accepts the 1x10 being implanted subcutaneously at right flank abdomen⁶Individual Colo 205 cell, and when mean size is close to 80 to 120mm³Time, monitor tumor growth.After 14 days, it is intended that for research 1st day, being divided into by animal 8 groups (n=9), each gross tumor volume scope is 63 to 196mm³And group mean tumour volume be 118 to 119mm³.Use following formula calculating gross tumor volume:The wherein width (mm) of w=COLO 205 tumor, and The length (mm) of l=COLO 205 tumor.Assuming that 1mg is equivalent to 1mm³Gross tumor volume, can be evaluated whether tumor weight.

Material: by the compound of requirement is dissolved in 100% cremophor EL, the administration of the compound A that preparation every day is fresh Solution, then with normal saline dilution 10 times.In order to provide 25,50,100 or 200mg/ respectively in being administered volume at 10mL/kg The dosage of kg, the final solution concentration that is administered is 2.5,5,10 or 20mg/mL.In the every day being administered, by 5% ethanol and 90%D5W In the carrier that forms of 5% cremophor EL (5%EC carrier) in, prepare fresh paclitaxel (Natural Pharmaceuticals, Inc.)。

Treatment: following table show therapeutic scheme.

1st group accepts preparations carrier (10% cremophor EL in saline), and is used as tumor growth matched group.2nd group of acceptance is pressed The reference agent paclitaxel of (30mg/kg i.v.qod x5) it is administered according to its optimum time table in nude mouse.3rd 6 group connects respectively By 25,50,100 and the compound A being administered with p.o.qd x14 of 200mg/kg dosage, due to toxicity, interrupt the 6th after 6 days The administration (200mg/kg) of group.Weight according to animal adjusts all of dosage (0.2mL/20g body weight).

Terminal: use caliper to measure tumor semiweekly.When the tumor of each animal reaches predetermined terminal size 2000mm³Time, or (the 74th day) the most all day in research, whichever the most extremely, makes each animal euthanasia.But, reaching big Little about 800mm³Time, control tumor does not demonstrates logarithm growth feature.Therefore, terminal tumor size 800mm³For analyzing tumor Growth delay (TGD).Calculate each mice from below equation and reach time (TTE) of terminal: The slope that wherein b is Linear intercept and m is straight line, the linear of the tumor growth data set that described straight-line pass log converts returns Return and obtain.Data set includes that the first time exceeding research terminal volume observes, and is at once reaching before terminal volume three Secondary Continuous Observation.Specify the TTE value last day equal to research of the not up to animal of terminal.Due to accident (NTRa) or due to Unknown cause (NTRu) be classified as animal dead for NTR (non-treatment dependency) not included in TTE calculate (with all further Analysis) in.It is dead or NTRm (the non-treatment dependency because of caused by transfer) death that appointment classifies as TR (treatment dependency) The TTE value of animal is equal to the day of death.

Being evaluated therapeutic outcome by tumor growth delay (TGD), it is defined as compared with matched group, reaches terminal in treatment group (TTE) increase of time intermediate value: TGD=T C, represents with natural law, or is expressed as accounting for the percentage ratio of the TTE intermediate value of matched group:Wherein: the TTE intermediate value of T=treatment group, the TTE intermediate value of C=matched group.

Matched group is designated as the 1st group of mice.

Treatment may cause the partial deterioration (PR) of tumours in animals or degenerate (CR) completely.In PR responds, in research During, the gross tumor volume of three continuous measurements is the 50% or less of the 1st day volume, and one or many in these 3 times measurements The gross tumor volume measured is equal to or more than 13.5mm³.In CR responds, in research process, the tumor body of three continuous measurements Long-pending less than 13.5mm³.Monitor and record degeneration response.

Side effect: weigh animal in first 5 day every day of research, weigh the most twice a week.Observe appointing of mice continually The obvious sign of the side effect the best, treatment is relevant, and the clinical sign of toxicity is recorded when observing.Acceptable Toxicity is organized average weight loss and is less than 20% during being defined as research, and treats dependency in the animal of 10 treatments (TR) dead not more than 1, any dosage regimen of bigger toxicity is caused to be deemed out maximum tolerated dose (MTD).If Prove to be attributable to treat side effect through clinical sign and/or postmortem, then death is classified as TR, if or during being administered Or due to unknown cause in last 10 days be administered, then death can be evaluated as TR.If without dead and treatment side effect Relevant evidence, then death is classified as NTR.By observing frequently and BW measurement, the side effect of monitoring animal.BW changes not Significantly, and in addition to the 6th group, all treatments are all to tolerate acceptably,.Once a day, the 200mg/kgization of 6 p.o. dosage Compound A, causes 1 TR death on the 7th day evaluate, at the 8th day, causes other 2 TR death.Whole mices of the 6th group show The clinical symptoms of toxicity is shown, including protuberance posture, hypopraxia and loose stool.

Statistics and plot analysis: use sequence check to analyze the notable of difference between the TTE value for the treatment of group and matched group Property.At significance level P=0.05, carry out double tail statistical analysis.

Median tumor growth curve shows that the group gross tumor volume intermediate value of logarithmic scale is the function of time.When animal is due to swollen Research is exited in tumor size or TR death, and final gross tumor volume and data including the animal recorded are for calculating in the time subsequently The group gross tumor volume intermediate value of point.After in group, the animal of 50% exits research due to tumour progression, or in group after the 2nd TR, Block curve.Make Kaplan-Meier figure to represent and research remains the percentage ratio of animal over time, and use The data set identical with sequence check.By Prism (GraphPad) Windows 3.03 for all of diagram and statistics credit Analysis.

Treatment response is summed up

The growth of COLO 205 tumor in control mice (the 1st group)

The tumor of the 1st group demonstrates heterogeneity growth slowly.The tumor of the 1st group of control mice of 7/9 vehicle treated reaches To 800mm³Gross tumor volume terminal, and at the end of research, remain two mices.The TTE intermediate value of the 1st group is 41.0 days, and because of This possible TGD maximum in this research of 74 days is 33.0 days (80%).

By the effect (the 2nd group) of taxol treatment

At the 74th day, being left 8 the 2nd group of mices (n=9) accepting paclitaxel treatment under study for action, it has MTV 143mm³.This is corresponding to maximum possible TGD (33.0 days or 80%) and activity (P=0.002) statistically significantly.Record 5 PR responses.Median tumor growth curve shows until the reduction of the 19th day MTV, slight variations subsequently, until the 47th day works as When tumor growth recovers.

The effect (group 3 6) processed with compound A

3rd, 4,5 groups of TTE intermediate values produced are respectively 47.9,59.1 and 74.0 days.3rd and 4 group has non-limiting Sequence check result, and the 5th group of sequence check inspection reaches edge significance (P=0.058).These treatments produce dosage and depend on Rely the degeneration of property quantity, but, degeneration respond style (PR vs.CR) and the quantity of 74-days survivors often organized are with dosage not Relevant.Median tumor growth curve shows, research early stage (until the 29th day), for 3 kinds of dosage levels, activity is similar, It is followed by the dose-dependent delay of tumor regrowth.6th group produces 3 examples TR death, and stopped being administered after the 6th day.Therefore, recognize Treat more than MTD for 200mg/kg, and TGD can not be evaluated.

Compound A demonstrates the dose dependent activity to COLO 205 colon carcinoma xenograft.When giving at 25mg/kg During medicine, compound A demonstrates the TGD of 3%.The TGD of 46% is produced at 50mg/kg, compound A.Tolerate 100mg/kg acceptably Treatment, and such as paclitaxel treatment, cause maximum possible TGD in test, there is the degeneration response of similar amt. It is dead that 200mg/kg treatment produces 3/9 example TR, and beyond MTD.Contrast paclitaxel, for compound A, it was observed that lotus tumor is more The most initial reduction；But, the duration of effect is shorter.Contrast comparison, in 25 and 50mg/kg groups, initial tumor regrowth Be in progress more quickly, and to research at the end of, MTV close to comparison tumor regrowth.100mg/kg treatment does not demonstrates this Rapid regeneration, but, the tumor regrowth of contrast paclitaxel, really demonstrate faster tumor growth.

Embodiment 119: human clinical trial

Compound A will be used in the patient suffering from (chemo-naive) late period accepting chemotherapy first or transfer cancer of pancreas Comparison placebo enters comparison row stochastic, double blinding, open label, historic, the safety/effectiveness people of single packet Class I clinical trial phase.

The primary and foremost purpose of this research is to evaluate safety and the toleration of compound A.Secondary result is evaluation compound A The speed of response, clinical benefit and tumor regression after treatment.Additionally, this research will be designed to evaluate the time of progression of disease Total survival rate with Pancreas cancer patients.And, by DCE-MRI evaluate the pharmacodynamics in tumor vessel parameter change (include as Blood flow, blood volume, reach time of ROC receiver operator characteristics's peak of curve).

And, use biological marker such as MEK1 and MEK2 hereditism's polymorphism and serum protein group are made result Association.This also will allow measure treatment after tumor resection rate and evaluate compound A MTD.

During studying, with different dosing with compound A, described dosage is: about 1mg, about 1.5mg, about 2mg, about 2.5mg, about 3mg, about 3.5mg, about 4.0mg, about 4.5mg, about 5mg, about 5.5mg, about 6mg, about 6.5mg, about 7mg, about 7.5mg, about 8mg, about 8.5mg, about 9mg, about 9.5mg, about 10mg, about 10.5mg, about 11mg, about 11.5mg, about 12mg, about 12.5mg, about 13mg, about 13.5mg, about 14mg, about 14.5 or about 15mg.

The selection standard of this research will be based on following factor:

● histology is upper/pathology on the Locally Advanced that confirms is unresectable or the unresectable cancer of pancreas in edge, and And the evidence of non-metastatic disease.

● based on by the evaluation (EUS as described in annex F) of two-phase CT scan and/or ultrasonic endoscope (EUS), diagnosis The cancer of pancreas that can not cut for Locally Advanced.

● in first 14 days of agreement treatment registration, according to RECIST with by the two-phase measurable disease of CT scan acquired results Sick.

● through two-phase computerized tomography, tumor size is more than or equal to 2cm.

● in 14 days of registration, the organ dysfunction suitable by the record of following evidence: Absolute neutrophils number > 1500/mm3；Platelet count 100,000/mm3；Hemoglobin³9gm/dL, without blood transfusion in first 4 weeks；Total bilirubin≤normal 1.5 times of higher limit (ULN)；Transaminase (AST and/or ALT)≤2.5x ULN；PT (or INR)≤1.5x ULN and aPTT In normal limits, (patient accepting medicament such as warfarin or heparin anticoagulant therapy will be allowed to participate in；For accepting warfarin Patient, according to the restriction of local nursing standard, evaluation the most weekly is monitored closely, until INR is based at front dose Measured value under Liang is stable；Use the creatinine clearance that Cockcroft-Gault formula calculates > 60ml/min.

Culling level includes: registers in first 6 months, uses Compound A treatment in advance；Duodenal mucosa is invaded by tumor Clinical evidence (as described in by endoscopy or ultrasonic endoscope)；Research registration 14 days in minor surgery operation (as Fine needle aspiration biopsy or needle biopsy)；In 21 days of research registration, big surgical operation, obvious wound Property damage or serious non-healing of wound, ulcer or fracture；In before drugs is administered 6 months, the most any item: tight Weight/unstable angina pectoris (angina pectoris symptom time static), the angina pectoris (originating in nearest 3 months) of new outbreak or the heart Flesh infarction, congestive heart failure, need the cardiac ventricles arrhythmia of antiarrhythmic therapy；In 6 months of past, blood Bolt is formed or the medical history such as cerebrovas-cularaccident or transient ischemic attack of Embolic events；Aneurysm or the disease of arteriovenous malformotion History；Known HIV (human immunodeficiency virus) (HIV) infects or chronic hepatitis B or chronic hepatitis C；Higher than having of CTCAE 2 grades The severe infections clinically of activity；In 4 weeks of research registration, accept any research medicament；Although with through optimal medical science pipe Reason, shrinks and still presses the uncontrolled hypertension defined still greater than 90mmHg more than 150mmHg or diastolic pressure；In research registration 4 weeks in, the lung higher than CTCAE 2 grades is lost blood/bleeding episode；In 4 weeks of research registration, any higher than CTCAE 3 grades Other/bleeding episodes of losing blood；Hemorrhagic diathesis or the proof of coagulopathy or medical history；With aspirin or other Nonsteroidal anti-inflammatory Treatment every day that medicine is long-term；Use Herba Hyperici perforati (St.John ' s Wort), rifampicin, ketoconazole, itraconazole, Li Tuona Wei or grapefruit juice；Known or suspect to compound A allergy；Obstruction patient swallows any patient's condition of the ability of whole pill；Appoint What malabsorption problem；Other serious acute or chronic medical science or psychological conditions, or may make and participate in study thing Matter or drugs are administered the laboratory abnormalities that relevant risk increases, or may interfere with the laboratory of the explanation of result of study Abnormal, and patient can be made to be not suitable for participating in the laboratory abnormalities of this research according to the judgement of researcher；Collagen vascular diseases Medical history；Accept any contraindication of nuclear magnetic resonance.

Embodiment 120: human clinical trial

Suffer from late period or transfer gastric cancer the patient accepting chemotherapy first in, randomly, double-blind method ground, open-label Ground, historical control ground, single packet, use compound A, in the way of identical with described in embodiment 117, carry out safety/usefulness Mankind's I clinical trial phase, except registration patient suffer from lymphoma, stomach stromal tumor or carcinoid of stomach tumor after diagnosing.

Embodiment 121: the pawl edema (CPE) that in rat, carrageenin causes

Oral administration of Compound A (6,20&60mg/kg) or indomethacin (3mg/kg), after 2hr, mix 1% carrageenin Suspension is injected into behind the right side of male Sprague-Dawley rat (N=6/ treatment group) in vola.After 3hr, pass through plethysmography Evaluation corpus unguis amasss measures rear solid end edema.Rear solid end edema reduces by 30% or more and shows significant Acute antiinflammatory activity.Use indole Mei Xin (Indo) is as positive control drug.Being the increase of each treatment group median claw volume shown in Figure 22, this shows, at all dosage In group, oral administration of Compound A causes significant anti-inflammatory activity in rat carrageenan pawl edema model.

Embodiment 122: rat assist agent arthritis inflammation measures

In the arthritis model that rat adjuvant causes, Freund's complete adjuvant (CFA) is injected in the right rear solid end of rat Cause and be similar to the condition of illness of rheumatoid arthritis in the mankind.With 2,6 and 20mg/kg oral administration of Compound A continuous 5 days. Additionally, with 5mg/kg oral administration dexamethasone 5 days.At the 1st day and the 4th day, pass through subcutaneous administrations with 10mg/kg Enbrel.At the 1st day, it is administered latter 1 hour for the first time, CFA is injected in right rear solid end.For acute stage, at the 1st day and Within 5 days, measure relative to the comparison through vehicle treatment, the suppression % to right rear solid end swelling, and for period of delay, at the 14th day and the 18th It measures relative to the comparison through vehicle treatment, the suppression % to left back pawl swelling.When fore paw, afterbody, nose or in ear swelling exist Time, polyarthritis is marked.

It is the different treatment group swelling suppression % relative to comparison shown in Figure 23 A and Figure 23 B.In acute stage and period of delay In, compound A all shows significantly reducing of swelling under 20mg/kg.Polyarthritis is marked, the institute in vehicle treatment group There are fore paw and the equal swelling of afterbody of 6 animals.For 20mg/kg compound A group, the non-swelling of fore paw of 2 in 6 animals, 6 The non-swelling of afterbody of 4 in animal.For enbrel group, all animals all do not avoid fore paw swelling, 3 in 6 animals The non-swelling of afterbody only.

Embodiment 123: the suppression of the arthritis (CAIA) that in mice, collagen antibodies causes

At the 0th day, mix to the collagen antibodies of male Balb/c mice (N=8/ treatment group) intravenous injection (tail vein) 2mg Close liquid (Chondrex).The 0-4 days, oral administration RDEA119 (1,3&10mg/kg QD) or dexamethasone (1mg/kg QD), and at the 1st day and the 3rd day, subcutaneous injection Enbrel.At the 3rd day, to except reception test firstAnimal it Outer all mices give the LPS peritoneal injection of (50 μ g).Determine the arthritis score of all extremity, and as shown in Figure 24 (the highest scoring 16).Record the significant anti-inflammatory activity of all test substances and reference agent.Use Enbrel and dexamethasone As positive control.

Embodiment 124: Cell proliferation in vivo measures

For measuring the method for cell proliferating number in the cancerous cell that MEK kinases inhibitor processes, be this area The method known, and it is described in Kenny, L.M. etc., Positron Emission Tomography (PET) Imaging of Cell Proliferation in Oncology, in Clinical Oncology, 16:176-185 (2004), it is intactly Quote addition herein.Vivo detection MEK kinases inhibitor (such as compound A) measures them to cancer cell multiplication Effect.50 patient's these researchs of voluntary participation, they all suffer from the cancer of pancreas being in similar cancer period of expansion.To 25 patients Combination to drug compound A.It is administered placebo to last 25 patients.It is administered daily dose to each patient, continues 14 days, with radiation Property labelling tracer (fluoro-2-deoxidation-DF-glucose (FDG) of such as labelling) combination.

After processing 14 days, the doctor being trained uses atraumatic positron emission tomography (PET) imager to detect tumor Cell proliferation.And, the doctor being trained can measure through compound A and the tumor of the patient of placebo treatment and normal cell group The cell proliferating number knitted.Result shows, cell proliferation between MEK kinases inhibitor (such as compound A) and placebo The reduction of number.This mensuration using the tracer of labelling and PET imaging to measure cell proliferating number is referred to herein as " internal carefully Born of the same parents' enrichment procedure ".Other Cell proliferation in vivo methods are known in the art.

Similar analysis may be used for measuring the reduction of tumor size.

Embodiment 125: internal apoptosis measures

Vivo detection mek inhibitor (such as compound A) determines its effect to cancer cell-apoptosis.40 patients are voluntary Participating in this research, they all suffer from the cancer of pancreas being in similar cancer period of expansion.To 20 patients to drug compound A and to 20 Position patient is administered placebo.It is administered daily dose to each patient, continues 14 days.

After 14 days, each patient will absorb detectable coupling markd lipopolysaccharide binding protein (LBP) reagent.According to WO/2006/054068 (it intactly quotes addition herein), is then placed in each patient in the region of scanner, scanner The medicament being ingested that detection is combined with dead cell.Dead cell number can associate with the level of apoptosis of each patient.Can be the most right Than being administered the patient of combination medicine and being administered the level of apoptosis of patient of single entities reagent, and be administered the same period of placebo Group compares.This mensuration using lipopolysaccharide binding protein and scanner to detect level of apoptosis is referred to herein as " internal apoptosis Method ".

Embodiment 126: dissolution study

According to the capsule preparing inclusion compound A described in above example.Use for measure dissolution USP < 711 > method obtains following dissolution data.

	1mg form	10mg form
			Time (min)	% discharges (%RSD)	% discharges (%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)

Claims

1. it is selected from:Compound preparation compositions in purposes, Qi Zhongsuo Stating compositions to allow to improve the described compound of release and for treating the disease of MEK mediation, the disease of described MEK mediation is brain Cancer, pulmonary carcinoma, ovarian cancer, cancer of pancreas, carcinoma of prostate, renal carcinoma, colorectal cancer, leukemia, gastric cancer or hepatocarcinoma.

2. the purposes of claim 1, wherein said pulmonary carcinoma is nonsmall-cell lung cancer or small cell lung cancer.

3. the purposes of claim 1, wherein said leukemia is myeloid leukemia, front B acute leukemia or chronic lymphocytic B Leukemia.

4. the purposes of claim 1, wherein said hepatocarcinoma is hepatocarcinoma.

5. the purposes of claim 1, the wherein said brain cancer is glioblastoma multiforme.

6. the purposes of claim 1, the 2-OH carbon on wherein said compound is in R configuration or is in S configuration.

7. the purposes of claim 1 or 6, wherein said compositions is substantially free of the R-isomer or substantially of described compound S-isomer without described compound.

8. the purposes of claim 1 or 6, wherein said compositions is for conjoint therapy and comprises another kind of therapeutic agent further.

9. the purposes of claim 8, wherein said another kind of therapeutic agent is Sorafenib or gemcitabine, and described compositions For treating hepatocarcinoma or cancer of pancreas.

10. the purposes of claim 7, wherein said compound comprises the R-isomer of the described compound less than 5% or few S-isomer in the described compound of 5%.

The purposes of 11. claim 7, wherein said compound comprises the R-isomer of the described compound less than 1% or few S-isomer in the described compound of 1%.

12. compositionss, it comprisesCrystalline polymorph A, described polymorph A demonstrate comprise to The x-ray diffractogram of powder at the peak identified in x-ray diffractogram of powder shown in Fig. 5 of few 50%, and described compositions For treating the disease of MEK mediation, the disease of described MEK mediation is the brain cancer, breast carcinoma, pulmonary carcinoma, ovarian cancer, cancer of pancreas, prostatitis Adenocarcinoma, renal carcinoma, colorectal cancer, leukemia, gastric cancer or hepatocarcinoma.

The compositions of 13. claim 12, wherein said pulmonary carcinoma is nonsmall-cell lung cancer or small cell lung cancer.

The compositions of 14. claim 12, wherein said leukemia is myeloid leukemia, front B acute leukemia or chronic lymphatic Cell B leukemia.

The compositions of 15. claim 12, wherein said hepatocarcinoma is hepatocarcinoma.

The compositions of 16. claim 12, the wherein said brain cancer is glioblastoma multiforme.

The compositions of 17. claim 12, wherein said compositions substantially free of with described R-isomery corresponding for polymorph A Body.

The compositions of 18. claim 12, wherein said polymorph A is by including making unbodied N-(3,4-bis-fluoro-2- (2-fluoro-4-idodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl) cyclopropane-1-sulfonamide crystallization step Method prepare.

The compositions of 19. claim 12, wherein said compositions is for conjoint therapy and comprises another kind of therapeutic agent further.

The compositions of 20. claim 19, wherein said another kind of therapeutic agent is Sorafenib or gemcitabine, and described group Compound is used for treating hepatocarcinoma or cancer of pancreas.